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Pesticide-Induced Diseases: Cancer
Bladder Cancer ● Bone Cancer ● Brain Cancer ● Breast Cancer ● Cervical Cancer ● Colorectal Cancer ● Eye Cancer ● Gallbladder Cancer ● Kidney/Renal Cancer ● Larynx Cancer ● Leukemia ● Lip Cancer ● Liver/Hepatic Cancer ● Lung Cancer ● Lymphoma ● Melanoma ● Mouth Cancer ● Multiple Myeloma ● Neuroblastoma ● Oesophageal Cancer ● Ovarian Cancer ● Pancreatic Cancer ● Prostate Cancer ● Sinonasal Cancer ● Soft Tissue Sarcoma ● Stomach Cancer ● Testicular Cancer ● Thyroid Cancer ● Uterine Cancer
The link between pesticides and cancer has long been a concern. While agriculture has traditionally been tied to pesticide-related illnesses, 26 of 40 commonly used lawn pesticides and 28 of 40 commonly used school pesticides are linked to cancer. Even with the growing body of evidence linking environmental exposures to cancer in recent years, a report released May 6, 2010 by the President’s Cancer Panel finds that the true burden of environmentally-induced cancer is greatly underestimated. The Panel’s report, Reducing Environmental Cancer Risk: What We Can Do Now, concludes that while environmental exposure is not a new front on the war on cancer, the grievous harm from carcinogenic chemical use has not been addressed adequately by the nation’s cancer program.
Bladder Cancer
- Comprehensive assessment of pesticide use patterns and increased cancer risk
Pesticides are an essential feature of modern-day agriculture that adds to the list of factors that increase cancer risk. Our study aims to comprehensively evaluate this relationship through a population-based approach that considers confounding variables such as county-specific rates of smoking, socioeconomic vulnerability, and agricultural land. We achieved our goal with the implementation of latent-class pesticide use patterns, which were further modeled among covariates to evaluate their associations with cancer risk. Our findings demonstrated an association between pesticide use and increased incidence of leukemia; non-Hodgkin's lymphoma; bladder, colon, lung, and pancreatic cancer; and all cancers combined that are comparable to smoking for some cancer types. Through our comprehensive analysis and unique approach, our study emphasizes the importance of a holistic assessment of the risks of pesticide use for communities, which may be used to impact future policies regarding pesticides.
[Gerken, J. et al. (2024) Comprehensive assessment of pesticide use patterns and increased cancer risk, Frontiers. Available at: https://www.frontiersin.org/journals/cancer-control-and-society/articles/10.3389/fcacs.2024.1368086/full. ] - Pesticides and Bladder Cancer: Mechanisms Leading to Anti-Cancer Drug Chemoresistance and New Chemosensitization Strategies
Multiple risk factors have been associated with bladder cancer. This review focuses on pesticide exposure, as it is not currently known whether agricultural products have a direct or indirect effect on bladder cancer, despite recent reports demonstrating a strong correlation. While it is known that pesticide exposure is associated with an increased risk of bladder cancer in humans and dogs, the mechanism(s) by which specific pesticides cause bladder cancer initiation or progression is unknown. In this narrative review, we discuss what is currently known about pesticide exposure and the link to bladder cancer. This review highlights multiple pathways modulated by pesticide exposure with direct links to bladder cancer oncogenesis/metastasis (MMP-2, TGF-β, STAT3) and chemoresistance (drug efflux, DNA repair, and apoptosis resistance) and potential therapeutic tactics to counter these pesticide-induced affects.
[Lucchesi, C.A., Vasilatis, D.M., Mantrala, S., Chandrasekar, T., Mudryj, M. and Ghosh, P.M., 2023. International journal of molecular sciences, 24(14), p.11395.] - Agricultural exposure and risk of bladder cancer in the AGRIculture and CANcer cohort.
This study aimed at assessing the role of a large range of agricultural activities and tasks on bladder cancer risk. The study population was the AGRIculture and CANcer cohort, a large prospective cohort of individuals affiliated to the agricultural health insurance scheme (MSA) in France. Incident bladder cancers were identified by cancer registries from enrolment (2005-2007) to 2009. Data on agricultural exposure during professional lifetime (5 animals, 13 crops, specific tasks) were obtained from the enrolment questionnaire. Associations between bladder cancer and agricultural exposure were analyzed using a Cox model, adjusted for gender and smoking history. Among the 148,051 farm owners and workers included in this analysis, 179 incident bladder cancers were identified. We observed an elevated risk among field-grown vegetable workers [HR 1.89, 95% CI (1.20-2.99)], with an exposure-response relationship with duration of work [≥30 years: HR 2.54, 95% CI (1.11-5.83), p-trend = 0.02], and higher risk among women [HR 3.82, 95% CI (1.58-9.25), p-interaction = 0.05]. Non-significantly increased risks were also observed in greenhouse farmers (HR = 1.95), pea sowing (HR = 1.84), rape sowing (HR = 1.64); several tasks involving pesticide use, especially seed treatment (HR = 1.24); and in activities and tasks potentially exposing to arsenic compounds via pesticide use (HR = 1.49) or re-entry tasks (HR = 1.63). Our analyses raise the question of a possible link between agricultural activity, especially field-grown vegetables, and greenhouse cultivation and bladder cancer.
[Boulanger M, Tual S, Lemarchand C, Guizard AV, et al. 2017. Int Arch Occup Environ Health. 90(2):169-178.] - Occupational exposure to pesticides and bladder cancer risk.
Study used data from the Agricultural Health Study, a prospective cohort study which includes 57 310 pesticide applicators with detailed information on pesticide use, to evaluate the association between pesticides and bladder cancer. Results found associations with bladder cancer risk for two imidazolinone herbicides, imazethapyr and imazaquin, which are aromatic amines. Ever use of imazaquin was associated with increased risk whereas the excess risk among users of imazethapyr was evident among never smokers. Study also observed increased risks overall and among never smokers for use of several chlorinated pesticides including chlorophenoxy herbicides and organochlorine insecticides. Several associations between specific pesticides and bladder cancer risk were observed, many of which were stronger among never smokers, suggesting that possible risk factors for bladder cancer may be more readily detectable in those unexposed to potent risk factors like tobacco smoke.
[Koutros S, Silverman DT, Alavanja MC, Andreotti G, et al. 2015. Int J Epidemiol. pii: dyv195.] - Pesticides, gene polymorphisms, and bladder cancer among Egyptian agricultural workers.
This study examined the associations between pesticide exposure, genetic polymorphisms for NAD(P)H:
quinone oxidoreductase I (NQO1) and superoxide dismutase 2 (SOD2), and urinary bladder cancer risk among male agricultural workers in Egypt. Exposure to pesticides was associated with increased bladder cancer risk: 1.68 (1.23-2.29)) in a dose-dependent manner. The association was slightly stronger for urothelial (1.79 (1.25-2.56)) than for squamous cell (1.55 (1.03-2.31)), and among participants with combined genotypes for low NQO1 and high SOD2 (2.14 (1.19-3.85)) activities as compared with those with high NQO1 and low SOD2 genotypes (1.53 (0.73-3.25)). In conclusion, among male agricultural workers in Egypt, pesticide exposure is associated with bladder cancer risk and possibly modulated by genetic polymorphism.
[Amr S, Dawson R, Saleh DA, Magder LS, et al. 2015. Arch Environ Occup Health. 70(1):19-26.] - Diuron-induced rat urinary bladder carcinogenesis: mode of action and human relevance evaluations using the International Programme on Chemical Safety framework.
Diuron, a high volume substituted urea herbicide, induced high incidences of urinary bladder carcinomas and low incidences of kidney pelvis papillomas and carcinomas in rats exposed to high doses (2500 ppm) in a 2-year bioassay. Diuron is registered for both occupational and residential uses and is used worldwide for more than 30 different crops. The proposed rat urothelial mode of action (MOA) for this herbicide consists of metabolic activation to metabolites that are excreted and concentrated in the urine, leading to cytotoxicity, urothelial cell necrosis and exfoliation, regenerative hyperplasia, and eventually tumors. Authors show evidence for this MOA for diuron using the International Programme on Chemical Safety (IPCS) conceptual framework for evaluating an MOA for chemical carcinogens, and the United States Environmental Protection Agency (USEPA) and IPCS framework for assessing human relevance.
[Da Rocha MS, Arnold LL, De Oliveira ML, Catalano SM, et al. 2014. Crit Rev Toxicol. 44(5):393-406.] - Does occupational exposure to solvents and pesticides in association with glutathione S-transferase A1, M1, P1, and T1 polymorphisms increase the risk of bladder cancer? The Belgrade case-control study.
Study investigated the role of the glutathione S-transferase A1, M1, P1 and T1 gene polymorphisms and potential effect modification by occupational exposure to different chemicals in Serbian bladder cancer male patients. A hospital-based case-control study of bladder cancer in men comprised 143 histologically confirmed cases and 114 age-matched male controls.The glutathione S-transferase A1, T1 and P1 genotypes did not contribute independently toward the risk of bladder cancer, while the glutathione S-transferase M1-null genotype was overrepresented among cases. The most pronounced effect regarding occupational exposure to solvents and glutathione S-transferase genotype on bladder cancer risk was observed for the low activity glutathione S-transferase A1 genotype. The glutathione S-transferase M1-null genotype also enhanced the risk of bladder cancer among subjects exposed to solvents. The risk of bladder cancer development was 5.3-fold elevated among glutathione S-transferase T1-active patients exposed to solvents in comparison with glutathione S-transferase T1-active unexposed patients. Moreover, men with glutathione S-transferase T1-active genotype exposed to pesticides exhibited 4.5 times higher risk in comparison with unexposed glutathione S-transferase T1-active subjects.
[Matic MG, Coric VM, Savic-Radojevic AR, et al. 2014. PLoS One. 9(6):e99448.] - Gene environment interaction in urinary bladder cancer with special reference to organochlorine pesticide: a case control study.
Urinary bladder cancer (UBC) is a common disease worldwide with a higher incidence rate in developed countries. Organochlorine pesticides (OCPs), potent endocrine disrupters, are found to be associated with several cancers such as prostate, breast, bladder, etc. The present study was carried out in UBC subjects and healthy control subjects with an aim to determine the role of Glutathione S-transferase (GST) and GSTT1 polymorphism and its implication on the OCP detoxification or bioaccumulation which may increase the risk of UBC in humans. This study was also designed to identify the "gene-environment interaction" specifically between gene polymorphism in xenobiotic metabolizing genetic enzyme(s) and blood OCP levels. The results demonstrated a significant increase in frequency of GSTM1/GSTT1(null) genotype in UBC cases without interfering the distribution of other GSTT1/GSTM1 genotypes. Findings indicate that "gene-environment interaction" may play a key role in increasing the risk for UBC in individuals who are genetically more susceptible due to presence of GSTM1/GSTT1 null deletion during their routine encounter with or exposure to OCPs.
[Sharma T, Jain S, Verma A et al. 2013. Cancer Biomark.13(4):243-51] - Heterocyclic aromatic amine pesticide use and human cancer risk: results form the U.S. Agricultural Health Study
Imazethapyr, a heterocyclic aromatic amine, is a widely used crop herbicide first registered for use in the United States in 1989. We evaluated cancer incidence among imazethapyr-exposed pesticide applicators enrolled in the Agricultural Health Study. The Agricultural Health Study is a prospective cohort of 57,311 licensed pesticide applicators in the U.S., enrolled from 1993-1997. Among the 49,398 licensed pesticide applicators eligible for analysis, 20,646 applicators reported use of imazethapyr and 2,907 incident cancers developed through 2004. Imazethapyr exposure was classified by intensity-weighted lifetime exposure days calculated as [years of use × days per year × intensity level]. Poisson regression analysis was used to evaluate the relationship between imazethapyr exposure and cancer incidence. We found significant trends in risk with increasing lifetime exposure for bladder cancer (p for trend 0.01) and colon cancer (p for trend 0.02). Rate ratios were increased by 137% for bladder cancer and 78% for colon cancer when the highest exposed were compared with the nonexposed. The excess risk for colon cancer was limited to proximal cancers, (Rate Ratio =2.73, 95% confidence intervals 1.42, 5.25, p for trend 0.001). No association was observed for prostate, lung, rectum, kidney, oral, pancreas, lymphohematopoietic cancers or melanoma. These findings provide new evidence that exposure to aromatic amine pesticides may be an overlooked exposure in the etiology of bladder and colon cancer. The use of imazethapyr and other imidazolinone compounds should continue to be evaluated for potential risk to humans.
[Koutros, S., et al. 2009. Int J Cancer 124(5):1206-1212.] - Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
This study describes geographical differences in cancer incidence in Costa Rica, and investigates if some of these differences may be related to pesticides. Data were combined from the cancer registry (1981-1993), the 1984 population census, the 1984 agricultural census, and a national pesticide data set. The 81 counties of Costa Rica were the units for the ecological analyses. Adjacent counties were grouped into 14 regions (3 urban and 11 rural) with relatively similar socioeconomic characteristics. County indices for population density and agricultural variables were constructed and categorized. Differences across regions and categories were assessed by comparing observed numbers of incident cases to expected values derived from national rates. Within the tertile of most rural counties, rate ratios between categories of high and low pesticide use were calculated. In urban regions, excesses were observed for lung, colorectal, breast, uterus, ovary, prostate, testis, kidney, and bladder cancers; and in rural regions for gastric, cervical, penile, and skin cancers. Skin cancers (lip, melanoma, non-melanocytic skin and penile cancer) occurred in excess in coffee growing areas with extensive use of paraquat and lead arsenate. In the most rural subset, heavy pesticide use was associated with an increase of cancer incidence overall and at a considerable number of specific sites, including lung cancer (relative risk [RR] 2.0 for men and 2.6 for women) and all female hormone-related cancers (RR between 1.3 and 1.8). Regions and populations at high risk for specific cancers were identified. Several hypotheses for associations between pesticides and cancer emerged. The findings call for studies at the individual level.
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.] - Cancer among farmers in central Italy
This case-referent study evaluated cancer risks among farmers in central Italy. Cancer cases (N = 1674, 17 sites) were selected from all deceased men aged 35-80 years; a random sample of 480 decedents formed the reference series. Farmers had a decreased risk of lung and bladder cancer and melanoma and nonsignificant excess risks for stomach, rectal, kidney, and nonmelanoma skin cancer. Stomach and kidney cancer were significantly increased among the farmers with > 10 years' experience, and stomach, rectal, and pancreatic cancer were increased among licensed pesticide users with > 10 years' experience. Possible relationships emerged between specific crops and cancer: fruit and colon and bladder cancer, wheat and prostate cancer, olives and kidney cancer, and potato and kidney cancer. The results regarding stomach, pancreatic, lung, bladder, and prostate cancer and melanoma congrue with earlier results. The kidney cancer excess, the association of colon and bladder cancer with orchard farming, and the excess of rectal cancer among licensed farmers are new and unexpected findings.
[Forastiere, F, et al. 1993. Scand J Work Environ Health 19(6):382-389.]
Bone Cancer
- Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with agricultural activity finds an elevated risk for malignant bone tumors (OR 2.3) and for subtype osteosarcoma (OR 2.7) at high agricultural activity (greater than 60% of county acreage devoted to farming). Also linked to Ewing’s sarcoma (OR 4.3) and HL (OR 2.1) at high agricultural activity (greater than 60% of county acreage devoted to farming), and for oat crop acreage and Ewing’s (OR 2.3).
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - Occupational factors and risk of adult bone sarcomas: a multicentric case-control study in Europe
A nuliticentric case-control study in 7 European countries finds that individuals that have ever used pesticides have over a two-fold increase risk of bone sarcoma (OR 2.33), yet the study finds that duration of use of pesticides showend no increase trend in the risk.
[Merietti, F., et al. 2006. Int J Cancer 118(3):721-727.] - Parental occupational exposures and Ewing’s sarcoma
A NIH case-control study finds that although exposure to pesticides is not significantly associated with Ewing’s sarcoma, a higtory of household pesticide extermination is associated with ES among boy aged 15 years or younger (OR 3.0).
[Moore, L.E., et al. 2005. Int J Cancer 114(3):472-478.] - Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
A study in Costa Rica finds heavy pesticide use in rural counties is associated with an increase risk for bone cancer in males (OR 1.81).
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.] - Ewing’s bone sarcoma, paternal occupational exposure, and other factors
To determine risk factors for Ewing's bone sarcoma, the authors interviewed mothers of 43 patients diagnosed between January 1978 and August 1986 and 193 controls in the San Francisco Bay Area, California, regarding medical and occupational history of parents and other factors related to the subjects and their immediate families. Controls were selected by using random digit dial telephone methods. Adjusted relative risk estimates suggest that risks were elevated for children whose fathers were engaged in agricultural occupations during the period from 6 months prior to conception of the subject up to the time of diagnosis for the patients or interview for the controls (relative risk (RR) = 8.8, 95% confidence interval (CI) 1.8-42.7) and for children whose fathers had occupational exposure to herbicides, pesticides, or fertilizers (RR = 6.1, 95% CI 1.7-21.9, p = 0.002). Prior ingestion of poison or an overdose of medication was more common in patients than in controls (RR = 4.4, 95% CI 1.4-13.5). These and other findings should be investigated in larger population-based studies to determine specific factors that may account for the associations.
[Holly, E.A., at al. 1992. Am J Epidemiol 135(2):122-129.]
Brain Cancer
Childhood Brain Cancer
- Exposure to pyrethroid pesticides and the risk of childhood brain tumors in East China
Pesticide exposure is hypothesized as one of the risk factors for the development of childhood brain tumors (CBT). This hospital-based case-control study evaluated the association of pyrethroid pesticide exposure with the risk for CBT in a children population in East China. In total, 161 CBT cases and 170 controls were recruited from 2 children's medical centers in Shanghai (Xinhua Hospital and Shanghai Children's Medical Center) between September 2012 and June 2015. The cases and controls were matched for age, sex, and province of residence. Pyrethroid pesticide exposure was evaluated by urinalysis of 3 nonspecific metabolites of pyrethroids (cis-DCCA, trans-DCCA, and 3-PBA) using gas chromatography-mass spectrometry (GC-MS) detection and by administering a questionnaire. Unconditional logistic regression showed that trans-DCCA, 3-PBA, and total metabolites (sum of the 3 metabolites) were positively associated with the increased risk of CBT. Children in the highest quartile had a nearly 3-fold increased risk of CBT compared with those in the lowest quartile after adjusting for confounding factors (trans-DCCA, odds ratio (OR) = 2.58, 95% confidence interval (CI), 1.38-4.80, p = 0.003; 3-PBA, OR = 3.26, 95% CI, 1.73-6.14, p < 0.0001; total metabolites, OR = 3.60, 95% CI, 1.87-6.93, p < 0.0001). We also found that exposure to both mosquitocide and cockroach killer was related to the increased risk of CBT (mosquitocide, OR = 1.68, 95% CI, 1.06-2.67, p = 0.027; cockroach killer, OR = 1.83, 95% CI, 1.13-2.95, p = 0.013). These findings indicate that exposure to pyrethroid pesticides might be associated with increased risk of CBT. Prospective cohort studies with larger sample sizes are required to confirm this conclusion
[Chen S, Gu S, Wang Y, Yao Y, et al. 2016. Environ Pollut. 218:1128-1134.] - Increased risk of childhood brain tumors among children whose parents had farm-related pesticide exposures during pregnancy.
Malignant brain tumors rank second in both incidence and mortality by cancer in children, and they are the leading cause of cancer death in children. While there are several studies which link pesticide exposure to increased risk of CBT, findings have been inconsistent. Authors performed a meta-analysis on 15 published epidemiological studies to test that in utero exposure to pesticides may be involved in the development of brain cancer in children. Findings of meta-analyses revealed a significantly increased risk of CBT among children whose mothers had farm-related exposures during pregnancy (RR=1.48, 95% CI=1.18-1.84). A dose response was recognized when this risk estimate was compared to those for risk of CBT from maternal exposure to non-agricultural pesticides (e.g., home extermination, pest strips) during pregnancy (RR=1.36, 1.10-1.68), and risk of CBT among children exposed to agricultural activities (RR=1.32, 1.04-1.67). Three studies combined for the paternal exposure to pesticides during preconception produced a calculated summary risk estimate of odds ratio (OR) = 2.29 (95% CI: 1.39-3.78). Meta-analysis of five studies of paternal exposure to pesticides during pregnancy produced a final calculated summary risk estimate of OR = 1.63 (95% CI: 1.16-2.31). The search of the CTD databases revealed association between herbicide and astrocytoma and more than 300 genes are altered by exposure to herbicide, fungicide, insecticide or pesticides. Based on the collective results of these meta-analyses, it appears that pesticide exposure may increase risk of CBT, with preconception and prenatal exposures being especially important factors in increasing risk of its development.
[Kunkle B, Bae S, Singh KP, Roy D. 2014. JP J Biostat. 11(2):89-101] - Exposure to pesticides and the risk of childhood brain tumors.
Previous research has suggested positive associations between parental or childhood exposure to pesticides and risk of childhood brain tumors (CBT). This Australian case-control study of CBT investigated whether exposures to pesticides before pregnancy, during pregnancy and during childhood, were associated with an increased risk. Cases were recruited from 10 pediatric oncology centers, and controls by random-digit dialing, frequency matched on age, sex, and State of residence. The odds ratios (ORs) for professional pest control treatments in the home in the year before the index pregnancy, during the pregnancy, and after the child's birth were 1.54 (95% confidence interval (CI): 1.07, 2.22), 1.52 (95% CI: 0.99, 2.34) and 1.04 (95% CI: 0.75, 1.43), respectively. ORs for treatments exclusively before pregnancy and during pregnancy were 1.90 (95% CI: 1.08, 3.36) and 1.02 (95% CI: 0.35, 3.00), respectively. The OR for the father being home during the treatment was 1.79 (95% CI: 0.85, 3.80). The OR for paternal occupational exposure in the year before the child's conception was 1.36 (95% CI: 0.66, 2.80). ORs for prenatal home pesticide exposure were elevated for low- and high-grade gliomas; effect estimates for other CBT subtypes varied and lacked precision. These results suggest that preconception pesticide exposure, and possibly exposure during pregnancy, is associated with an increased CBT risk. It may be advisable for both parents to avoid pesticide exposure during this time.
[Greenop KR, Peters S, Bailey HD, et al. 2013. Cancer Causes Control. 24(7):1269-78] - Childhood brain tumors, residential insecticide exposure, and pesticide metabolism genes
Insecticides that target the nervous system may play a role in the development of childhood brain tumors (CBTs). Constitutive genetic variation affects metabolism of these chemicals. We analyzed population-based case-control data to examine whether CBT is associated with the functional genetic polymorphisms PON1C-108T, PON1Q192R, PON1L55M, BCHEA539T, FMO1C-9536A, FMO3E158K, ALDH3A1S134A, and GSTT1 (null). DNA was obtained from newborn screening archives for 201 cases and 285 controls, <or= 10 years of age, and born in California or Washington State between 1978 and 1990. Conception-to-diagnosis home insecticide treatment history was ascertained by interview. We observed no biologically plausible main effects for any of the metabolic polymorphisms with CBT risk. However, we observed strong interactions between genotype and insecticide exposure during childhood. Among exposed children, CBT risk increased per PON1-108T allele [odds ratio (OR) = 1.8; 95% confidence interval (CI), 1.1-3.0] and FMO1-9536A (*6) allele (OR = 2.7; 95% CI, 1.2-5.9), whereas among children never exposed, CBT risk was not increased (PON1: OR = 0.7; 95% CI, 0.5-1.0, interaction p = 0.005; FMO1: OR = 1.0; 95% CI, 0.6-1.6, interaction p = 0.009). We observed a similar but statistically nonsignificant interaction between childhood exposure and BCHEA539T (interaction p = 0.08). These interactions were present among both Hispanic and non-Hispanic white children. Based on known effects of these variants, these results suggest that exposure in childhood to organophosphorus and perhaps to carbamate insecticides in combination with a reduced ability to detoxify them may be associated with CBT. Confirmation in other studies is required.
[Nielsen, S.S., et al. 2010. Childhood brain tumors, residential insecticide exposure, and pesticide metabolism genes. Environmental Health Perspectives 118(1):144-149] - Critical Confluence: Gene Variants, Insecticide Exposure May Increase Childhood Brain Tumor Risk
Epidemiologic data have suggested a link between pesticide exposures and childhood brain tumors. The link may be specific to insecticides such as organophosphorus and carbamate compounds, which are known to target the nervous system. Previously published work investigated the role of individual genetic variation with a focus on paraoxonase (PON1), a key enzyme in the metabolism of organophosphorus insecticides commonly used in homes at the time but now banned for residential use. This work showed that children with brain tumors were more likely to carry a common single-nucelotide polymorphism (SNP) gene variant in the promoter region of the PON1 gene (PON1C-108T) than other children, and that the association between this SNP and brain tumors was stronger in children with a history of home insecticide exposure. Research in an expanded study population now provides additional evidence that exposure to insecticides, paired with specific metabolism gene variants, may increase the risk of childhood brain tumors.
[Barrett, J. 2010. Environ Health Perspect. 118(1): A35] - Parental exposure to pesticides and childhood brain cancer: U.S. Atlantic coast childhood brain cancer study.
The etiology of childhood brain cancer remains largely unknown. However, previous studies have yielded suggestive associations with parental pesticide use. Study aimed to evaluate parental exposure to pesticides at home and on the job in relation to the occurrence of brain cancer in children. Authors included 526 one-to-one-matched case-control pairs. Brain cancer cases were diagnosed at < 10 years of age, and were identified from statewide cancer registries of four U.S. Atlantic Coast states. Using information on residential pesticide use and jobs held by fathers during the 2-year period before the child's birth, authors assessed potential exposure to insecticides, herbicides, and fungicides. A significant risk of astrocytoma was associated with exposures to herbicides from residential use. Combining parental exposures to herbicides from both residential and occupational sources, the elevated risk remained significant. However, these findings should be viewed in light of limitations in exposure assessment and effective sample size.
[Shim YK, Mlynarek SP, van Wijngaarden E. 2009.Environ Health Perspect. 117(6):1002-6.] - A case-control study of childhood brain tumors and fathers' hobbies: a Children's Oncology Group study
A case-control study evaluating parental risk factors for childhood brain tumors finds a significant association for home lawn care pesticide applications during pregnancy (OR 1.6) and after birth (OR 1.8) and thus pesticides may increase the risk of medulloblastoma and primitive neuroectodermal tumors in children.
[Rosso, A.L., et al. 2008. Cancer Causes Control 19(10)1201-1207] - The Upper Midwest Health Study: a case-control study of primary intracranial gliomas in farm and rural residents.
A NIOSH population based case control study finds moving to a farm as an adolescent (between the ages of 11 and 20), rather than moving to a farm as an adult, is associated with a greater risk for gliomas.
[Ruder, A.M., et al. 2006. J Agric Saf Health 12(4):255-274] - Risk of brain tumors in children and susceptibility to organophosphorus insecticides: the potential role of paraoxonase (PON1).
Prior research suggests that childhood brain tumors (CBTs) may be associated with exposure to pesticides. Organophosphorus insecticides (OPs) target the developing nervous system, and until recently, the most common residential insecticides were chlorpyrifos and diazinon, two OPs metabolized in the body through the cytochrome P450/paraoxonase 1 (PON1) pathway. To investigate whether two common PON1 polymorphisms, C-108T and Q192R, are associated with CBT occurrence, authors conducted a population-based study of 66 cases and 236 controls using DNA from neonatal screening archive specimens in Washington State, linked to interview data. The risk of CBT was nonsignificantly increased in relation to the inefficient PON1 promoter allele [per PON1(-108T) allele, relative to PON1(-108CC): odds ratio (OR) = 1.4; 95% confidence interval (CI), 1.0-2.2; p-value for trend = 0.07]. Notably, this association was strongest and statistically significant among children whose mothers reported chemical treatment of the home for pests during pregnancy or childhood (per PON1(-108T) allele: among exposed, OR = 2.6; 95% CI, 1.2-5.5; among unexposed, OR = 0.9; 95% CI, 0.5-1.6) and for primitive neuroectodermal tumors (per PON1(-108T) allele: OR = 2.4; 95% CI, 1.1-5.4). Larger studies that measure plasma PON1 levels and incorporate more accurate estimates of pesticide exposure will be required to confirm these observations.
[Searles Nielsen S, Mueller BA, De Roos AJ, et al. 2005. Environ Health Perspect.113(7):909-13.] - Farm-related exposures and childhood brain tumours in seven countries: results from the SEARCH International Brain Tumour Study.
A total of 1218 cases of childhood brain tumours (CBT) and 2223 control subjects from the general population were included in a population-based case-control study conducted in nine centres in seven countries. Mothers were asked about farm- or agriculture-related exposures. Significantly elevated odds ratios (OR) for CBT were associated with children's personal and maternal prenatal exposure while living on a farm with pigs (child OR = 1.7, mother OR = 2.3), horses (child OR = 1.6, mother OR = 1.8), dogs (child OR = 1.5, mother OR = 1.5) and cats (child OR = 1.5, mother OR = 1.7). Children who were exposed to pigs, horses and cats combined, while living on a farm, had a threefold elevated OR for CBT. Increased ORs for primitive neuroectodermal tumours (PNET) were associated with children's farm exposure to dogs (OR = 1.9) and cats (OR = 2.2), and maternal farm exposure to pigs (OR = 4.2). The OR for CBT was elevated (OR = 2.3) for children of mothers who had preconception/prenatal farm- or agriculture-related employment involving potential contact with animals, relative to no farm- or agriculture-related employment. In particular, increased ORs for CBT were observed for children of mothers who were employed as general farmers (OR = 4.1) or general farm workers (OR = 3.8). During the 5 years preceding the index child's birth, maternal exposures were related to CBT, relative to no maternal exposure to agricultural chemicals or animal products: fertilisers (OR = 1.8), pesticides (OR = 2.0), animal manure (OR = 2.0) and unprocessed wool (OR = 3.0). Our findings suggest that various farm-related exposures are positively associated with CBT and warrant further investigation into the public health importance of these associations.
[Efird, J.T., et al. 2003. Paediatr Perinat Epidemiol 17(2):201-211] - Parental occupational exposure to pesticides and childhood brain cancer.
A community-based case-control study of parental occupational pesticide exposure and childhood brain cancer finds a slightly elevated risk of astrocytoma for paternal exposure to insecticides, herbicides, and fungicides; a slightly elevated risk of primitive neuroectodermal tumors (PNET) for paternatal exposure to herbicides. The study also finds a small elevated risk for astrocytoma for maternal exposure to insecticides and non-agricultural fungicides.
[Van Wijngaarden, E., et al. 2003. American Journal of Epidemiology 157(11):989-997] - Farm and animal exposures and pediatric brain tumors: results from the United States West Coast Childhood Brain Tumor Study.
Nineteen counties from San Francisco and Los Angeles, California and Seattle, Washington were the United States sites for a large population-based case-control study of childhood brain tumors (CBTs), sponsored by the National Cancer Institute. CBT patients who were < 20 years of age and were diagnosed between 1984 and 1991 were reported to each region's cancer registry. The 801 control subjects were obtained by random digit dial and were frequency-matched to the 540 CBT patients in San Francisco and Seattle (one patient to two controls) and in Los Angeles (one patient to one control). Data collected by in-person interview with subjects' mothers were analyzed to investigate an association between risk for CBTs and life on a farm, exposure to farm animals (dairy cattle, beef cattle, pigs, sheep/goats, poultry, and horses), and some cat and non-farm horse exposures. Elevated risks for CBTs were observed in association with mothers' exposure to pigs [odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.2-12] and horses (OR = 2.2, 95% CI = 1.0-4.8) on a farm during the index pregnancy. Children diagnosed with primitive neuroectodermal tumors showed elevated risks for CBTs with personal and maternal prenatal exposure to pigs (child, OR = 4.0, 95% CI = 1.2-13; mother, OR = 11.9, 95% CI = 2.8-51) and poultry (child, OR = 3.0, 95% CI = 1.1-8.0; mother, OR = 4.0, 95% CI = 1.2-14). No other animal exposures of children or mothers were found to be consistently related to CBTs. Children diagnosed with primitive neuroectodermal tumors who were on a farm for > 1 year and were first on a farm when they were < 6 months of age also had increased risk for CBTs (OR = 3.9, 95% CI = 1.2-13). A somewhat increased risk for CBTs was found for children of mothers who ever had worked on livestock farms compared with mothers who never had worked on a farm (OR = 7.4, 95% CI = 0.86-64, based on five case mothers and one control mother who worked on livestock farms during the 5 years preceding the birth of the index child). The associations are consistent with those of two previous studies in Norway (P. Kristensen et al., Int. J. Cancer, 65: 39-50, 1996) and the United States and Canada (G. R. Bunin et al., Cancer Epidemiol. Biomark. Prev., 3: 197-204, 1994) that investigated the role of farm-related exposures in the etiology of CBTs.
[Holly, E.A., et al. 1998. Cancer Epidemiol Biomarkers Prev 7(9):797-802] - Household pesticides and risk of pediatric brain tumors.
A follow-up to a population-based case-control study of pediatric brain tumors in Los Angeles County, California, involving mothers of 224 cases and 218 controls, investigated the risk of household pesticide use from pregnancy to diagnosis. Risk was significantly elevated for prenatal exposure to flea/tick pesticides -odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.1-2.6-, particularly among subjects less than 5 years old at diagnosis (OR = 2.5; CI, 1. 2-5.5). Prenatal risk was highest for mothers who prepared, applied, or cleaned up flea/tick products themselves (OR = 2.2; CI, 1.1-4.2; for subjects less than 5 years of age, OR = 5.4; CI, 1.3-22.3). A significant trend of increased risk with increased exposure was observed for number of pets treated (p = 0.04). Multivariate analysis of types of flea/tick products indicated that sprays/foggers were the only products significantly related to risk (OR =10.8; CI, 1.3-89.1). Elevated risks were not observed for termite or lice treatments, pesticides for nuisance pests, or yard and garden insecticides, herbicides, fungicides, or snail killer. Certain precautions,if ignored, were associated with significant increased risk: evacuating the house after spraying or dusting for pests (OR = 1.6; CI, 1.0-2.6), delaying the harvest of food after pesticide treatment (OR = 3.6; CI, 1.0-13.7), and following instructions on pesticide labels (OR = 3. 7;CI, 1.5-9.6). These findings indicate that chemicals used in flea/tick products may increase risk of pediatric brain tumors and suggest that further research be done to pinpoint specific chemicals involved.
[Pogoda, J.M. and Preston-Martin, S. 1997. Environmental Health Perspectives 105:1214-1220] - Cancer in offspring of parents engaged in agricultural activities in Norway: incidence and risk factors in the farm environment.
In this study of cancer in offspring we demonstrate that factors linked to horticulture and use of pesticides are associated with cancer at an early age, whereas factors in animal husbandry, in particular poultry farming, are associated with cancers in later childhood and young adulthood. Incident cancer was investigated in offspring born in 1952-1991 to parents identified as farm holders in agricultural censuses in Norway in 1969-1989. In the follow-up of 323,292 offspring for 5.7 million person-years, 1,275 incident cancers were identified in the Cancer Registry for 1965-1991. The standardized incidence for all cancers was equal to the total rural population of Norway, but cohort subjects had an excess incidence of nervous-system tumours and testicular cancers in certain regions and strata of time that could imply that specific risk factors were of importance. Classification of exposure indicators was based on information given at the agricultural censuses. Risk factors were found for brain tumours, in particular non-astrocytic neuroepithelial tumours: for all ages, pig farming tripled the risk [rate ratio (RR), 3.11; 95% confidence interval (CI), 1.89-5.13]; indicators of pesticide use had an independent effect of the same magnitude in a dose-response fashion, strongest in children aged 0 to 14 years (RR, 3.37; 95% CI, 1.63-6.94). Horticulture and pesticide indicators were associated with all cancers at ages 0 to 4 years, Wilms' tumour, non-Hodgkin's lymphoma, eye cancer and neuroblastoma. Chicken farming was associated with some common cancers of adolescence, and was strongest for osteosarcoma and mixed cellular type of Hodgkin's disease. The main problem in this large cohort study is the crude exposure indicators available; the resulting misclassification is likely to bias any true association towards unity.
[Kristensen, P., et al. 1996. Int J Cancer 65(1):39-50] - Incidence and risk factors for childhood brain tumors in the Ile de France.
A case-control study investigating risk factors for childhood brain tumors was conducted in the Ile de France (Paris region). During a 2-year period (1985-1987) 109 newly diagnosed cases were identified and, of these, 75 could be interviewed. In the same region, 113 population controls, frequency-matched for year of birth, were interviewed. Odds ratios adjusted for child's age and sex and for maternal age were estimated for each risk factor present in utero or during childhood by conditional logistic regression. Statistically significant associations were found for the following risk factors: farm residence, cat scratches, home treated with pesticides, passive smoking, family history of cancer, antihistamine intake. Intake of vitamin supplements during childhood was associated with a decrease in risk. This study is part of a multicentric case-control study coordinated by the International Agency for Research on Cancer and its results will be compared for consistency, and pooled with those of other centers using the same protocol.
[Cordier, S., et al. 1994. Int J Cancer 59(6):776-782] - Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the Children's Cancer Group
A case-control study focusing on gestational exposures find elevated risks for primitive neuroectodermal tumor (PNET), one the of the most common subtypes of brain tumors in children, for mother’s residence on a farm during pregnancy and for the child’s residence on a farm for at least one year. Mothers of astrocytoma brain cancer cases were more likely than their controls to report weekly use of insect sprays and pesticides.
[Bunin, G.R., et al. 1994. Cancer Epidemiology, Biomarkers and Prevention 3:197-204] - Family pesticide use and childhood brain cancer.
The relationship between family pesticide use and childhood brain cancer was examined in a case-control study. Telephone interviews were conducted from June 1989 through March 1990 with the natural mothers of 45 childhood brain cancer cases, 85 friend controls, and 108 cancer controls. In comparisons to friend controls, significant positive associations were observed for use of pesticides to control nuisance pests in the home, no-pest-strips in the home, pesticides to control termites, Kwell shampoo, flea collars on pets, diazinon in the garden or orchard, and herbicides to control weeds in the yard. In comparisons to cancer controls, significant positive associations were observed for use of pesticide bombs in the home, pesticides to control termites, flea collars on pets, insecticides in the garden or orchard, carbaryl in the garden or orchard, and herbicides to control weeds in the yard. In general, positive associations in comparisons to one control group were supported by elevated odds ratios in comparisons to the other control group. Several potentially important associations were identified in this study. However, small sample sizes, potential recall bias, multiple comparisons, and lack of detailed exposure verification require further research to confirm these findings.
[Davis, J., et al. 1993. Family pesticide use and childhood brain cancer. Archives of Environmental Contamination and Toxicology 24:87-92] - Parental occupation and intracranial neoplasms of childhood: results of a case-control interview study.
A case-control study of childhood brain tumors finds paternal employment in agriculture is associated with excess risk.
[Wilkins, J.R. and T. Sinks. 1990. Am J Epidemiol 132(2):275-292] - Paternal occupation and brain cancer in offspring: a mortality-based case-control study
A mortality-based case-control study of Ohio-born children who died from brain cancer looking at paternal occupation finds that case fathers are more likely than control fathers to have been employed, at the time of the child’s birth, in agriculture.
[Wilkins, J.R. and Koutras, R.A. 1988. Am J Ind Med 14(3):299-318] - Risk factors for brain tumors in children
An exploratory case-control study in Baltimore, Maryland finds that more children with brain tumors and children with other cancers are found to have been exposed to insecticides than other children.
[Gold, E., et al. 1979. American Journal of Epidemiology 109(3):309-319]
Adult Brain Cancer
- Farming, Pesticides, and Brain Cancer: A 20-Year Updated Systematic Literature Review and Meta-Analysis
Twenty additional years of epidemiologic literature have become available since the publication of two meta-analyses on farming and brain cancer in 1998. The current systematic literature review and meta-analysis extends previous research and harmonizes findings. A random effects model was used to calculate meta-effect estimates from 52 studies (51 articles or reports), including 11 additional studies since 1998. Forty of the 52 studies reported positive associations between farming and brain cancer with effect estimates ranging from 1.03 to 6.53. The overall meta-risk estimate was 1.13 (95% CI = 1.06, 1.21), suggesting that farming is associated with a 13% increase in risk of brain cancer morbidity or mortality. Farming among white populations was associated with a higher risk of brain cancer than among non-white populations. Livestock farming (meta-RR = 1.34; 95% CI = 1.18, 1.53) was associated with a greater risk compared with crop farming (meta-RR = 1.13; 95% CI = 0.97, 1.30). Farmers with documented exposure to pesticides had greater than a 20% elevated risk of brain cancer. Despite heterogeneity among studies, we conclude that the synthesis of evidence from 40 years of epidemiologic literature supports an association between brain cancer and farming with its potential for exposure to chemical pesticides.
[Gatto, N.M., Ogata, P. and Lytle, B. Cancers, 13(17), p.4477.] - Occupational exposure to pesticides and risk of adult brain tumors.
A hospital-based case-control study finds that woman with occupational herbicide exposure show an increased risk meningioma compared to woman who never used herbicides (OR 2.4), a significant trend for increasing risk with increasing years of herbicide exposure and increasing cumulative exposure.
[Samanic, C.M., et al. 2008. American Journal of Epidemiology 167(8):976-985] - Brain tumours and exposure to pesticides: a case-control study in southwestern France.
Brain tumours are often disabling and rapidly lethal; their aetiology is largely unknown. Among potential risk factors, pesticides are suspected. To examine the relationship between exposure to pesticides and brain tumours in adults in a population-based case-control study in southwestern France. Between May 1999 and April 2001, 221 incident cases of brain tumours and 442 individually matched controls selected from the general population were enrolled. Histories of occupational and environmental exposures, medical and lifestyle information were collected. A cumulative index of occupational exposure to pesticides was created, based on expert review of lifelong jobs and tasks. Separate analyses were performed for gliomas and meningiomas. A non-statistically significant increase in risk was found for brain tumours when all types of occupational exposure to pesticides were considered (OR = 1.29, 95% CI 0.87 to 1.91) and slightly higher but still non-statistically significant when gliomas were considered separately (OR = 1.47, 95% CI 0.81 to 2.66). In the highest quartile of the cumulative index, a significant association was found for brain tumours (OR = 2.16, 95% CI 1.10 to 4.23) and for gliomas (OR = 3.21, 95% CI 1.13 to 9.11), but not for meningiomas. A significant increase in risk was also seen for the treatment of home plants (OR = 2.24, 95% CI 1.16 to 4.30) owing to environmental exposure to pesticides. These data suggest that a high level of occupational exposure to pesticides might be associated with an excess risk of brain tumours, and especially of gliomas.
[Provost, D., et al. 2007. Brain tumours and exposure to pesticides: a case-control study in southwestern France. Occupational and Environmental Medicine 64:509-514] - Agricultural pesticide use and risk of glioma in Nebraska, United States
In a population-based case-control study in eastern Nebraska, men living or working on a farm for at least 55 years is associated with an almost 4-fold increased risk of glioma. Among male farmers, the study finds an increase risk for glioma for those exposed to herbicides metribuzin and paraquat, insecticides bufencarb and chlorpyrifos and coumaphos.
[Lee, W., et al. 2005. Occupational and Environmental Medicine 62(11):786-792] - Occupational risk factors for brain cancer: a population-based case-control study in Iowa
A population case-control study in Iowa finds a significant increased risk to a type of brain cancer called glioma for women employed in agriculture services or farming.
[Zheng, T., et al. 2001.Journal of Occupational and Environmental Medicine 43(4): 333-340] - Occupational Exposure to Carbofuran and the Incidence of Cancer in the Agricultural Health Study
A geographical study looking at pesticide use and cancer incidence in Costa Rica finds that in areas of mainly coffee production there are elevated number of brain cancers, particularly for men; it also found that for rural counties with heavy pesticide use there is an association with an increase risk for brain cancer in females.
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28: 365-374] - Brain cancer mortality among French farmers: the vineyard pesticide hypothesis.
In this study, the authors assessed the contribution of vineyard pesticides to brain cancer mortality among agricultural workers. A pesticide exposure index (PEI) in vineyards was calculated for 89 French geographical units (départements). The authors estimated standardized mortality ratios among male farmers and farm laborers aged 35-74 y for the years 1984-1986. Poisson regression models, which were fitted to the ecological data, included random effects. Mortality from brain cancer among farmers was significantly higher than mortality for the overall population (standardized mortality ratio = 1.25, p < .001). Univariate analysis revealed a significant link with pesticide exposure in vineyards (relative risk = 1.10; 95% confidence interval = 1.03, 1.18), as did multivariate analysis (relative risk = 1.11; 95% confidence interval = 1.03, 1.19). These results corroborate the evidence that pesticides in vineyards contribute to mortality from brain cancer among farmers.
[Viel, J.F., et al. 1998. Brain cancer mortality among French farmers: the vineyard pesticide hypothesis. Arch Environ Health 53(1):65-70] - Correlation analysis of pesticide use data and cancer incidence rates in California counties.
An ecological study in California analyzing a cancer registry and statewide pesticide use reporting system finds a correlation between Hispanic males diagnosed with brain cancer and atrazine.
[Mills, P.K. 1998. Arch Environ Health 53(6):410-413] - Glioma and occupational exposure in Sweden, a case-control study.
The aim of the study was to analyse whether any job titles, industrial codes, and certain occupational exposures were associated with an increased risk of glioma. A population based case-control study of incident primary brain tumours in adults was carried out in Uppsala, Sweden in the period 1987-90. The study included 192 cases of glioma and 192 matched controls. It also included cases with other tumours of the central nervous system with matched controls. Information from all 343 controls was used in this study. Information was collected by means of a questionnaire that was sent to all subjects. An occupational hygienist reviewed the questionnaires for self reported exposures to substances and assessed whether these reported exposures were plausible or not in the corresponding occupation. The kappa coefficient for those classified by the two methods ranged between 0.46 and 0.88, and they were almost the same for cases and controls. For men exposed to solvents a relative risk (RR) of 2.6 (95% CI 1.3 to 5.2) was found. For men exposed to pesticides the RR was 1.8 (95% CI 0.6 to 5.1), and for plastic materials the RR was 3.6 (95% CI 1.0 to 12.4). For men employed in forestry and logging the RR was 2.2 (95% CI 0.9 to 5.3) and in basic metal industries 2.0 (95% CI 1.0 to 4.0). An increased risk of glioma was associated with use of solvents, pesticides, and plastic materials but this should be interpreted with some caution.
[Rodvall, Y., et al. 1996. Occupational and Environmental Medicine 53:526-532] - Proportionate mortality study of golf course superintendents.
A proportionate mortality study of a cohort of 686 golf course superintendents finds an elevated number deaths from brain cancer (PMR 234), large intestine cancer (PMR 175), NHL (PMR 237), and prostate cancer (PMR 293).
[Kross, B.C., et al. 1996. Am J Ind Med 29(5):501-506] - Cancer mortality in a cohort of rural licensed pesticide users in the province of Rome.
The mortality of a cohort of 2310 male workers who obtained a licence to handle pesticides in the period 1973-1979 in the province of Rome was investigated. The cohort contributed 26,846 person-years of exposure. The vital status of the cohort was determined up to the end of 1988. The causes of death of the 207 who had died were ascertained from death certificates. Standardized mortality ratios (SMR) were computed using both the provincial and the national mortality rates. The two methods yielded very similar results. Using the national rates, the SMR for all causes was 56 (95% confidence interval (CI) : 45.3-59.8), for cardiovascular diseases 47 (95% CI : 37.1-59.1), and for all cancers 72 (95% CI : 57.8-89.3). A statistically significant excess was noted for brain cancer (SMR = 270, 95% CI : 108.6-556.9). In addition, the cohort experienced statistically significant lower lung cancer mortality (SMR = 57, 95% CI : 35.6-80.0).
[Figa-Talamanca, I. et al. 1993. Int J Epidemiol 22(4):579-583] - Prevalence of glioblastoma multiforme subjects with prior herbicide exposure.
A descriptive study of glioblastoma multiforme in Arkansas diagnosed patients finds a link to their occupational exposure to herbicides.
[Smith-Rooker, J.L., et al. 1992. J neurosci Nurs 24(5):260-264] - A case-control study of brain gliomas and occupational exposure to chemical carcinogens: the risk to farmers.
A case control study shows an increased risk for brain gliomas for farmers who reported the use of pesticides and fertilizers (RR 1.6) with a significant increased risk for those that used insecticides and fungicides (RR 2.0).
[Musicco, M., et al. 1988. American Journal of Epidemiology 128(4):778-785] - Mortality among white and nonwhite farmers in North Carolina, 1976-1978.
A mortality study of North Carolinian farmers finds that although there was no increased mortality for whites, nonwhite farmers have an increased frequency of leukemia (proportional mortality ratios (PMR) 1.9)
[Delzell, E., and Grufferman, S. 1985. Am J Epidemiol 121(3):391-402] - Lung cancer and other causes of death among licensed pesticide applicators.
A cohort study of 3,827 white male licensed structural pest control workers in Florida finds excess of deaths for cancers of the brain.
[Blair, A., et al. 1983. J Natl Cancer Inst 71(1):31-37]
Breast Cancer
- Pesticide exposure and increased breast cancer risk in women population studies
Pesticide exposure is emerging as a risk factor for various human diseases. Breast cancer (BC) is a multifactorial disease with known genetic and non-genetic risk factors. Most BC cases are attibutable to non-genetic risk factors, with a history of adverse environmental exposures playing a significant role. Pesticide exposure can occur at higher levels in female populations participating in rural activities such as spraying of pesticides in the field, unprotected handling of pesticides at home, and washing of contaminated clothes. Exposure can also be significant in the drinking water of certain populations. Here, we reviewed the literature on women's exposure to pesticides and the risk of BC. We summarize the main links between pesticide exposure and BC and discuss the role of dose and exposure context, as well as potential mechanisms of toxicity. Overall, reports reviewed here have documented stronger associations between higher levels of exposure and BC risk, including documenting direct and acute pesticide exposure in certain female populations. However, discrepancies among studies regarding dose and mode of exposure may result in misunderstandings about the risks posed by pesticide exposure. Plausible mechanisms linking pesticides to breast cancer risk include their impacts as endocrine disruptors, as well as their roles as genotoxic agents, and modulators of the epigenome. Besides establishing links between pesticide exposure and breast cancer, the literature also highlights the critical need to understand the routes and doses of women's exposure to pesticides and the specific associations and mechanisms that are determinants of disease etiology and prognosis.
[Panis, C. and Lemos, B. (2024) Pesticide exposure and increased breast cancer risk in women population studies, Science of The Total Environment. Available at: https://www.sciencedirect.com/science/article/pii/S0048969724031358?via%3Dihub. ] - Atrazine promotes breast cancer development by suppressing immune function and upregulating MMP expression
There is evidence that the triazine herbicide atrazine, which is used extensively, is present in both surface water and groundwater, and its interfering effect on immune systems, endocrine systems, and tumours has been reported by laboratory and epidemiological studies. This study explored how atrazine affected 4T1 breast cancer cell development in vitro and in vivo. The obtained results showed that after exposure to atrazine, the cell proliferation and tumour volume were significantly increased and the expression of MMP2, MMP7, and MMP9 was upregulated. The thymus and spleen indices, the CD4 + and CD3 + lymphocyte percentages which from the spleen and inguinal lymph nodes, and the CD4 + /CD8 + ratio were noticeably lower than they were in the control group. Importantly, tumour-infiltrating lymphocytes such as CD4 + , CD8 + , and NK cells were decreased while Treg cells were increased. Moreover, IL-4 was increased and IFN-γ and TNF-α were decreased in the serum and tumour microenvironment. These results suggested that atrazine can suppress systemic as well as local tumour immune function and upregulate MMPs to promote breast tumour development.
[Wang, M., Chen, J., Zhao, S., Zheng, J., He, K., Liu, W., Zhao, W., Li, J., Wang, K., Wang, Y. and Liu, J., 2023. Ecotoxicology and Environmental Safety, 253, p.114691.] - Endocrine-disrupting chemicals (EDCs) and cancer: new perspectives on an old relationship
Environmental endocrine-disrupting chemicals (EDCs) are a mixture of chemical compounds capable to interfere with endocrine axis at different levels and to which population is daily exposed. This paper aims to review the relationship between EDCs and breast, prostate, testicle, ovary, and thyroid cancer, discussing carcinogenic activity of known EDCs, while evaluating the impact on public health. A literature review regarding EDCs and cancer was carried out with particular interest on meta-analysis and human studies. The definition of EDCs has been changed through years, and currently there are no common criteria to test new chemicals to clarify their possible carcinogenic activity. Moreover, it is difficult to assess the full impact of human exposure to EDCs because adverse effects develop latently and manifest at different ages, even if preclinical and clinical evidence suggest that developing fetus and neonates are most vulnerable to endocrine disruption. EDCs represent a major environmental and health issue that has a role in cancer development. There are currently some EDCs that can be considered as carcinogenic, like dioxin and cadmium for breast and thyroid cancer; arsenic, asbestos, and dioxin for prostate cancer; and organochlorines/organohalogens for testicular cancer. New evidence supports the role of other EDCs as possible carcinogenic and pregnant women should avoid risk area and exposure. The relationship between EDCs and cancer supports the need for effective prevention policies increasing public awareness.
[Modica, R., Benevento, E. and Colao, A., 2023. Journal of Endocrinological Investigation, 46(4), pp.667-677.] - Exposome epidemiology for suspect environmental chemical exposures during pregnancy linked to subsequent breast cancer diagnosis.
Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry of pregnancy cohort biospecimens in the Child Health and Development Studies to test for associations with breast cancer identified via the California Cancer Registry. Second and third trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both second and third trimesters to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol, linked to variations in amino acid and nucleotide pathways in second trimester and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in third trimester. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer.
[Go, Y.M., Weinberg, J., Teeny, S., Cirillo, P.M., Krigbaum, N.Y., Singer, G., Tran, V., Cohn, B.A. and Jones, D.P., 2023. Environment International, 178, p.108112.] - Risk of breast cancer in daughters of agricultural workers in Denmark.
Agricultural workers face unique occupational hazards such as pesticide exposure, which has been associated with breast cancer. However, research considering the association between parental agricultural work and breast cancer in female offspring is lacking. Therefore, the aim of the present nested case-control study was to explore this association. The Danish Cancer Registry was utilized to identify women diagnosed with primary breast cancer. A total of 5587 cases were included in the study, and for each case, 20 cancer-free female controls were selected, matched on year of birth. It was a requisition that both cases and controls were born in Denmark and that either maternal or paternal employment history was available. Adverse associations were consistently noted for different time windows of maternal employment in "Horticulture" and breast cancer. Inverse associations were observed for paternal employment in most of the examined agricultural industries, although a small increased risk was indicated for perinatal employment in "Horticulture". Furthermore, maternal preconceptional employment in "Horticulture" was observed to increase the risk of ER + tumors (odds ratio [OR] = 1.79, 95% confidence interval [CI]: 1.13-2.85, whereas parental perinatal employment was linked to an elevated risk of ER-tumors (maternal employment: OR = 2.48, 95% CI: 1.18-5.21; paternal employment: OR = 1.62, 95% CI: 0.70-3.77). The present study indicates that maternal horticultural employment in different potential susceptible time windows may elevate the risk of breast cancer subtypes. These findings need to be reproduced in future prospective cohort studies, including information on e.g., pesticide exposure withing job categories and lifestyle factors.
[Pedersen, J.E. and Hansen, J., 2023. Environmental Research, p.117374.] - Breast carcinogenesis induced by organophosphorous pesticides
Breast cancer is a major health threat to women worldwide and the leading cause of cancer-related death. The use of organophosphorous pesticides has increased in agricultural environments and urban settings, and there is evidence that estrogen may increase breast cancer risk in women. The mammary gland is an excellent model for examining its susceptibility to different carcinogenic agents due to its high cell proliferation capabilities associated with the topography of the mammary parenchyma and specific stages of gland development. Several experimental cellular models are presented here, in which the animals were exposed to chemical compounds such as pesticides, and endogenous substances such as estrogens that exert a significant effect on normal breast cell processes at different levels. Such models were developed by the effect of malathion, parathion, and eserine, influenced by estrogen demonstrating features of cancer initiation in vivo as tumor formation in rodents; and in vitro in the immortalized normal breast cell line MCF-10F, that when transformed showed signs of carcinogenesis such as increased cell proliferation, anchorage independence, invasive capabilities, modulation of receptors and genomic instability. The role of acetylcholine was also demonstrated in the MCF-10F, suggesting a role not only as a neurotransmitter but also with other functions, such as induction of cell proliferation, playing an important role in cancer. Of note, this is a unique experimental approach that identifies mechanistic signs that link organophosphorous pesticides with breast carcinogenesis.
[Calaf, G.M., 2022. Advances in Pharmacology (San Diego, Calif.), 96, pp.71-117.] - Neonicotinoid insecticides promote breast cancer progression via G protein-coupled estrogen receptor: In vivo, in vitro and in silico studies
Neonicotinoid insecticides (NIs) have been widely detected in environmental media and human body with concentrations reaching hundreds of nanomolar to micromolar levels. However, the information about their human health toxicology and mechanism is deficient. Previous studies have implied that NIs might exert estrogenic disruption and promote breast cancer progression, but the molecular mechanism is unclear, especially the molecular initiating event. G protein-coupled estrogen receptor (GPER), as a candidate therapeutic target, plays vital roles in the development of breast cancer. This work aimed to reveal the potential mechanism through GPER pathway. Firstly, we screened the activities of seven most common NIs on GPER signal pathway by calcium mobilization assay. Clothianidin, acetamiprid (ACE), and dinotefuran activated GPER most potently and ACE displayed the highest agonistic activity with the lowest observed effective concentration (LOEC) of 1 μM. The molecular docking and dynamics simulation showed favored interaction trend between the NIs and GPER. The three NIs with GPER activity induced 4T1 breast cancer cells migration and ACE showed the highest potency with LOEC of 100 nM. ACE also induced 4T1 cells proliferation at high concentration of 50 μM and up-regulated GPER expression in a dose-dependent manner. We speculated that both the induction effects of ACE on 4T1 cells proliferation and migration might be owing to the activation and up-regulation of GPER. By using 4T1-Luc cells injected orthotopic tumor model, we found that ACE also promoted in-situ breast cancer growth and lung metastasis in normal mouse dependent on GPER. However, ACE only promoted in-situ breast cancer growth through GPER but not lung metastasis in ovariectomized mice, implying that the ACE-induced lung metastasis should be related to endogenous estrogen from ovary. Overall, we demonstrated that NIs promoted breast cancer progression via GPER pathway at human related exposure levels and their female health risks need urgent concerns.
[Li, X., He, S., Xiao, H., He, T.T., Zhang, J.D., Luo, Z.R., Ma, J.Z., Yin, Y.L., Luo, L. and Cao, L.Y., 2022. Environment International, 170, p.107568.] - Cancer and occupational exposure to pesticides: an umbrella review
Purpose
The aim was to identify the scope of the epidemiology literature reviewed regarding the risk of cancer as related to occupational exposure to pesticides and to compare regulatory toxicity results where feasible.Methods
Review studies of breast, lung, prostate, non-Hodgkin lymphoma, and colorectal cancer were identified from the published literature from 2010 to 2020 using a priori inclusion and exclusion criteria. Epidemiology observations were first assessed and then compared against carcinogenicity profiles derived from regulatory toxicology studies.Results
Several active ingredients were associated with specific cancer but overall, there was neither strong nor consistent epidemiologic data supportive of a positive association between pesticide exposure in occupational settings and cancer. Authors noted common themes related to the heterogeneity of exposure, study design, control for confounders, and the challenge to collect these data reliably and validly with an adequate sample size. Toxicology studies in laboratory animals that assessed carcinogenic potential did not reveal cancer outcomes that were concordant with reported epidemiologic findings.Conclusions
Farming and pesticides represent diverse exposures that are difficult to quantify in epidemiologic studies. Going forward, investigators will need creative and novel approaches for exposure assessment. Integration of epidemiologic and toxicological studies with attention to biological plausibility, mode of toxicological action and relevance to humans will increase the ability to better assess associations between pesticides and cancer.
[Burns, C.J. and Juberg, D.R. (2021) Cancer and occupational exposure to pesticides: An Umbrella Review, International Archives of Occupational and Environmental Health. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238729/. ] - Endocrine disrupting chemicals and breast cancer: a systematic review of epidemiological studies
Abstract
Background: Endocrine-disrupting compounds (EDCs) are ubiquitous substances that are found in our everyday lives, including pesticides, plasticizers, pharmaceutical agents, personal care products, and also in food products and food packaging. Increasing epidemiological evidence suggest that EDCs may affect the development or progression of breast cancer and consequently lead to lifelong harmful health consequences, especially when exposure occurs during early life in humans. Yet so far no appraisal of the available evidence has been conducted on this topic.
Objective: To systematically review all the available epidemiological studies about the association of the levels of environmental exposures of EDCs with breast cancer risk.
Methods: The search was performed in accordance with the PRISMA guidelines. We retrieved articles from PubMed (MEDLINE) until 10 March 2021. The key words used in this research were: "Endocrine disruptor(s)" OR "Endocrine disrupting chemical(s)" OR any of the EDCs mentioned below AND "Breast cancer" to locate all relevant articles published. We included only cohort studies and case-control studies. All relevant articles were accessed in full text and were evaluated and summarized in tables.
Results: We identified 131 studies that met the search criteria and were included in this systematic review. EDCs reviewed herein included pesticides (e.g. p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), atrazine, 2,3,7,8-tetrachloridibenzo-p-dioxin (TCDD or dioxin)), synthetic chemicals (e.g. bisphenol A (BPA), phthalates, per- and polyfluoroalkyl substances (PFAS), parabens, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), contraceptive pills), phytoestrogens (e.g. genistein, resveratrol), and certain mycotoxins (e.g. zearalenone). Most studies assessed environmental EDCs exposure via biomarker measurements.
Conclusion: We identified certain EDC exposures could potentially elevate the risk of breast cancer. As majority of EDCs are highly persistent in the environment and bio-accumulative, it is essential to assess the long-term impacts of EDC exposures, especially multi-generational and transgenerational. Also, since food is often a major route of exposure to EDCs, well-designed exposure assessments of potential EDCs in food and food packing are necessary and their potential link to breast cancer development need to be carefully evaluated for subsequent EDC policy making and regulations.
Keywords: Breast cancer; dietary; endocrine-disrupting chemicals; environmental; epidemiological studies; systematic review.
[Wan, M.L., Co, V.A. and El-Nezami, H. (2021) ‘Endocrine disrupting chemicals and breast cancer: A systematic review of Epidemiological Studies’, Critical Reviews in Food Science and Nutrition, 62(24), pp. 6549–6576. doi:10.1080/10408398.2021.1903382. ] - Grandmaternal Perinatal Serum DDT in Relation to Granddaughter Early Menarche and Adult Obesity: Three Generations in the Child Health and Development Studies Cohort
Serum DDTs during or just after pregnancy were associated with breast cancer in mothers (F0), and with breast cancer, mammographic density, and obesity in adult daughters (F1) in the Child Health and Development Studies multi-generational cohort in prior publications. Here, we investigate F0 perinatal serum DDT associations with granddaughters'(F2) measured obesity at a median age of 26 and self-reported age at menarche. F2 weight, height and waist circumference were measured by trained examiners. o,p'-DDT, p,p'-DDT and p,p'-DDE were measured in archived F0 perinatal serum. F0 DDT associations with F2 outcomes, accounting for F1 characteristics, were estimated in log-linear models adjusted for F0 and F1 body mass index (BMI), race, and menarche timing (N = 258 triads for obesity; N = 235 triads for early menarche). Interactions between F0 BMI and DDTs were estimated. F0 o,p'-DDT was associated with F2 obesity [Odds ratio (OR), 2.6; 95% confidence interval (CI), 1.3–6.7; tertile 3 vs. 1), among normal weight F0 (70%), but not among overweight and obese F0 (Pinteraction = 0.03), independent of other DDTs. F0 o,p'-DDT was also associated with F2 early menarche (OR, 2.1; 95% CI, 1.1–3.9, tertile 3 vs. 1) and this association was not modified by F0 BMI. Ancestral exposure to environmental chemicals, banned decades ago, may influence the development of earlier menarche and obesity, which are established risk factors for breast cancer and cardiometabolic diseases. Discovery of actionable biomarkers of response to ancestral environmental exposures in young women may provide opportunities for breast cancer prevention.
[Cirillo, P.M., La Merrill, M.A., Krigbaum, N.Y. and Cohn, B.A. Cancer Epidemiology and Prevention Biomarkers.] - Exposure to organophosphorus insecticides and increased risks of health and cancer in US women
Results of this paper provide evidence that chronic long-term exposure to organophosphorus insecticides poses a significantly higher health risk for US women than for men, based on dialkylphosphate biomarker data from NHANES cycles 2003-2012. The risk of cardiovascular disease for female non-smokers aged 60-85 years in the highest dimethylthiophosphate (DMTP) urinary concentration quartile is 3.0 (odds ratio, OD = 3.0, 95%CI 1.4-6.4) times higher than that in the lowest quartile. Women with higher urinary DMTP concentrations also have significantly higher risk of asthma at the ages 6-39 years and an apparently higher risk of chronic bronchitis at the ages 60-85. Overall cancer risk is significantly higher for female non-smokers aged 60-85 years in the higher urinary DMTP quartiles (OD = 2.7, 95% CI 1.3-5.9). Increasing risks of breast cancer for female smokers and prostate cancer for male smokers aged 60-85 years with higher exposure to organophosphorus insecticides in the US are also significant.
[Sun, H., Sun, M.L. and Barr, D.B., 2020. Environmental Toxicology and Pharmacology, 80, p.103474.] - Incidence of male breast cancer in Scotland over a twenty-five-year period (1992–2017)
Male breast cancer (MBC) accounts for around 1% of all breast cancers diagnosed. There are inconsistent reports on the incidence of MBC which some propose may be rising. Here, for the first time, the incidence of MBC in Scotland over 25 years from 1992 to 2017 was examined through interrogating the Information Services Division Scotland database. Results showed MBC incidence rose with age, peaking in the 65–70 and 75–79 age groups. Both the total number and the age-adjusted incidence of MBC increased in Scotland since 1992. This rising trend was most clear in the North of Scotland. Interestingly a higher MBC incidence in some rural areas was also observed. Our findings emphasise the need for a better understanding of MBC risk factors so that improved prevention policies can be applied for patient benefit.
[Reddington, R., Galer, M., Hagedorn, A., Liu, P., Barrack, S., Husain, E., Sharma, R., Speirs, V. and Masannat, Y., 2020. European Journal of Surgical Oncology.] - US EPA's regulatory pesticide evaluations need clearer guidelines for considering mammary gland tumors and other mammary gland effects
Breast cancer risk from pesticides may be missed if effects on mammary gland are not assessed in toxicology studies required for registration. Using US EPA's registration documents, we identified pesticides that cause mammary tumors or alter development, and evaluated how those findings were considered in risk assessment. Of 28 pesticides that produced mammary tumors, EPA's risk assessment acknowledges those tumors for nine and dismisses the remaining cases. For five pesticides that alter mammary gland development, the implications for lactation and cancer risk are not assessed. Many of the mammary-active pesticides activate pathways related to endocrine disruption: altering steroid synthesis in H295R cells, activating nuclear receptors, or affecting xenobiotic metabolizing enzymes. Clearer guidelines based on breast cancer biology would strengthen assessment of mammary gland effects, including sensitive histology and hormone measures. Potential cancer risks from several common pesticides should be re-evaluated, including: malathion, triclopyr, atrazine, propylene oxide, and 3-iodo-2-propynyl butylcarbamate (IPBC).
[Cardona, B. and Rudel, R.A., 2020. Molecular and Cellular Endocrinology, p.110927.] - DDT and Breast Cancer: Prospective Study of Induction Time and Susceptibility Windows
In a previous Child Health and Development Studies report, p, p’-DDT was associated with a fivefold increased risk of premenopausal (before age 50 years) breast cancer for women first exposed before puberty. Here we extend our observation to breast cancer diagnosed during early postmenopause (ages 50–54 years) to determine whether age at diagnosis modifies the interaction of DDT with age at exposure. We conducted a second prospective, nested case-control study in the Child Health and Development Studies (153 incident breast cancer cases diagnosed at ages 50–54 years and 432 controls matched to cases on birth year). These were analyzed separately and pooled with our previous study (129 breast cancer cases diagnosed at ages 31–49 years and 129 controls matched on birth year). Blood samples were obtained during pregnancy (median age, 26 years), 1–3 days after delivery from 1959 to 1967 in Oakland, California. Serum was assayed for p, p’-DDT, o, p’-DDT, and p, p’-DDE. Odds ratios (ORs) below are given for doubling of serum p, p’-DDT. All statistical tests were two-sided. For early postmenopausal breast cancer, p, p’-DDT was associated with risk for all women (ORDDT 50–54 = 1.99, 95% CI = 1.48 to 2.67). This association was accounted for by women first exposed to DDT after infancy (ORDDT 50–54 for first exposure after infancy = 2.83, 95% CI = 1.96 to 4.10 vs ORDDT 50–54 for first exposure during infancy = 0.56, 95% CI = 0.26 to 1.19; Pinteraction DDT x age at first exposure = .01). In contrast, for premenopausal breast cancer, p, p’-DDT was associated with risk among women first exposed during infancy through puberty, but not after (ORDDT = 3.70, 95% CI = 1.22 to 11.26, Pinteraction DDT x age at first exposure x age at diagnosis = .03). p, p’-DDT was associated with breast cancer through age 54 years. Risk depended on timing of first exposure and diagnosis age, suggesting susceptibility windows and an induction period beginning in early life. DDT appears to be an endocrine disruptor with responsive breast targets from in utero to menopause.
[Cohn, B.A., Cirillo, P.M. and Terry, M.B., 2019. 111(8), pp.803-810.] - Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway
Aromatase (CYP19) is a key enzyme in estrogens biosynthesis. In the mammary gland, CYP19 gene is expressed at low levels under the regulation of its I.4 promoter. In hormone-dependent breast cancer, fibroblast cells surrounding the tumor express increased levels of CYP19 mRNA due to a decrease of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter activity. Little is known about the effects of environmental chemicals on the promoter-specific CYP19 expression.We aimed to determine the effects of two neonicotinoids (thiacloprid and imidacloprid) on promoter-specific CYP19 expression in Hs578t breast cancer cells and understand the signaling pathways involved.Hs578t cells were exposed to various signaling pathway stimulants or neonicotinoids for 24 h. Promoter-specific expression of CYP19 was determined by real-time quantitative polymerase chain reaction and catalytic activity of aromatase by tritiated water release assay. To our knowledge, we are the first to demonstrate that the normal I.4 promoter and the breast cancer-relevant PII, I.3, and I.7 promoters of CYP19 are active in these cells. We found that the expression of CYP19 via promoters PII, I.3, and I.7 in Hs578t cells was, in part, dependent on the activation of two VEGF signaling pathways: mitogen-activated protein kinase (MAPK) 1/3 and phospholipase C (PLC). Exposure of Hs578t cells to environmental concentrations of imidacloprid and thiacloprid resulted in a switch in CYP19 promoter usage, involving inhibition of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter-mediated CYP19 expression and aromatase catalytic activity. Greater effects were seen at lower concentrations. Our results suggest that thiacloprid and imidacloprid exert their effects at least partially by inducing the MAPK 1/3 and/or PLC pathways. We demonstrated in vitro that neonicotinoids may stimulate a change in CYP19 promoter usage similar to that observed in patients with hormone-dependent breast cancer.
[Caron-Beaudoin, É., Viau, R. and Sanderson, J.T., 2018. Environmental health perspectives, 126(4), p.047014.] - Organochlorine pesticide residues in human breast tissue and their relationships with clinical and pathological characteristics of breast cancer.
Agricultural pesticides are abundant environmental contaminants worldwide, prompting interest in studying their possible detrimental health effects. We examined organochlorine residues by quadrant (n = 245) in breast adipose tissues from 51 women with various stages of breast health to determine patterns of bioaccumulation within the breast and to assess relationships with patient clinical characteristics. Three organochlorine residues-2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), and mirex-assayed by high resolution gas chromatography were abundant in breast tissue. p,p'-DDE (745 ± 1054 ng/g lipid) was the most prevalent residue, comprising 97.5% of the total chemical burden. Mean levels of p,p'-DDE and HCB were significantly correlated (P < .001) with patient age at mastectomy, and levels of p,p'-DDE were correlated (P < .05) with BMI. Pesticide concentrations did not differ significantly by breast quadrant and were not different in the quadrant(s) where the primary tumor was located compared to other cancer-free quadrants. In invasive cancer patients, organochlorine levels differed significantly based on clinical characteristics of the primary carcinoma, including stage, grade, ER status, and HER2 status, indicating that body burden of organochlorines may influence the development of specific subtypes of breast cancer. Potentially carcinogenic organochlorines were present at high levels within the human breast warranting further research to determine the impact of organochlorines in the etiology of breast cancer.
[Ellsworth RE1, Kostyniak PJ2, Chi LH, et al. 2018. Environ Toxicol. doi: 10.1002/tox.22573.] - Comparison of Weibull and Lognormal Cure Models with Cox in the Survival Analysis Of Breast Cancer Patients in Rafsanjan.
The current study retrospective cohort study was conducted on 140 patients referred to Ali Ibn Abitaleb Hospital, Rafsanjan southeastern Iran from 2001 to 2015 suffering from breast cancer. According to AIC, log-normal model was more consistent than Weibull. In the multivariable Lognormal model, the effective factors like smoking, second -hand smoking, drinking herbal tea and the last breast-feeding period were included. In addition, using Cox regression factors of significant were the disease grade, size of tumor and its metastasis (p-value<0.05). As Rafsanjan is surrounded by pistachio orchards and pesticides applied by farmers, people of this city are exposed to agricultural pesticides and its harmful consequences. The effect of the pesticide on breast cancer was studied and the results showed that the effect of pesticides on breast cancer was not in agreement with the models used in this study. Based on different methods for survival analysis, researchers can decide how they can reach a better conclusion. This comparison indicates the result of semi-parametric Cox method is closer to clinical experiences evidences.
[Hoseini M, Bahrampour A, Mirzaee M. 2017. J Res Health Sci. 17(1):E1-6.] - Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents.
The safety, including the endocrine disruptive capability, of glyphosate-based herbicides (GBHs) is a matter of intense debate. Authors evaluated the estrogenic potential of glyphosate, commercial GBHs and polyethoxylated tallowamine adjuvants present as co-formulants in GBHs. Glyphosate (≥10,000 μg/L or 59 μM) promoted proliferation of estrogen-dependent MCF-7 human breast cancer cells. Glyphosate also increased the expression of an estrogen response element-luciferase reporter gene (ERE-luc) in T47D-KBluc cells, which was blocked by the estrogen antagonist ICI 182,780. Commercial GBH formulations or their adjuvants alone did not exhibit estrogenic effects in either assay. Transcriptomics analysis of MCF-7 cells treated with glyphosate revealed changes in gene expression reflective of hormone-induced cell proliferation but did not overlap with an ERα gene expression biomarker. Calculation of glyphosate binding energy to ERα predicts a weak and unstable interaction (-4.10 kcal mol-1) compared to estradiol (-25.79 kcal mol-1), which suggests that activation of this receptor by glyphosate is via a ligand-independent mechanism. Induction of ERE-luc expression by the PKA signalling activator IBMX shows that ERE-luc is responsive to ligand-independent activation, suggesting a possible mechanism of glyphosate-mediated activation. Study reveals that glyphosate, but not other components present in GBHs, can activate ERα in vitro, albeit at relatively high concentrations.
[Mesnage R, Phedonos A, Biserni M, et al. 2017. Food Chem Toxicol. 108(Pt A):30-42.] - Levels of persistent organic pollutants in breast milk of Maya women in Yucatan, Mexico.
In this study, 24 breast milk samples, obtained from rural Maya women, from municipalities of Yucatan, Mexico, were analyzed for organochlorine pesticide (OCP) residues by gas chromatography. Recent studies have shown that Maya communities have a poor perception about the proper usage and handling of OCP. The karstic soil in this area has a high vulnerability to groundwater pollution by the use of OCP in agriculture and livestock activities. The impact of the ecosystem on human health is much more critical due to the prevailing poverty and a very low educational level of these communities. About 30% of the Maya population consumes water directly from contaminated wells and sinkholes, resulting in a chronic exposure to OCP. The samples served to identify and quantify high levels of OCP residues (18.43 mg/kg of heptachlor epoxide and 1.92 mg/kg of endrin in the metropolitan zone; 2.10 mg/kg of dieldrin, 0.117 mg/kg of endosulfan II, 0.103 mg/kg of heptachlor, 0.178 mg/kg of endrin, and 0.127 mg/kg of endrin aldehyde in the main agricultural zone and on the west coast). The detected levels of OCP residues are a major concern and represent a potential risk to women and children in the region. This could be associated with the high rates of cervical uterine and breast cancer mortality in Yucatan. Thus, regulations on the usage of OCP and their enforcement are necessary, and it is important to establish a yearly monitoring program for OCP residues in breast milk and groundwater, as well as to implement health promotion programs for women in particular and the general population in general.
[Polanco Rodríguez ÁG, Inmaculada Riba López M, Angel DelValls Casillas T, et al. 2017. Environ Monit Assess. 189(2):59] - Occupational exposures and genetic susceptibility to urinary tract cancers: a systematic review and meta-analysis.
This study aims to summarize the current knowledge on the relationship between genetic polymorphisms, occupational exposures, and urinary tract cancers. Authors searched MEDLINE, ISI Web of science, and SCOPUS online databases for all articles published in English language up to September 2016. A meta-analysis was performed to provide summary estimates for the association between a certain genetic polymorphism, occupational exposure and bladder cancer (BC) or kidney cancer (KC), when appropriate. Fifteen studies on BC and six on KC were deemed eligible for the review. With regard to BC, an overall odds ratio (OR) of 2.07 [95% confidence interval (CI): 1.38-3.09] for those with GSTM1 and an OR of 2.07 (95% CI: 1.38-3.09) for those with GSTT1 null genotype were reported when exposed to polycyclic aromatic hydrocarbons (PAHs). NAT2 slow genotype carriers had an OR of 3.59 (95% CI: 2.62-4.93) for BC when exposed to aromatic amines and an OR of 2.07 (95% CI: 1.36-3.15) when exposed to PAHs. With regard to KC and pesticide exposure, the meta-analysis reported an OR of 4.38 (95% CI: 2.28-8.41) for GSTM1 present genotype, an OR of 2.59 (95% CI: 1.62-4.15) for GSTT1-present genotype and an OR of 6.51 (95% CI: 2.85-14.89) for combined effects of GSTM1 and GSTT1 active genotypes. This meta-analysis indicates a possible association between the variant genotypes of GSTM1, GSTT1, NAT2 and SULT1A1, occupational exposure to aromatic amines or PAHs, and development of BC. Our results suggest that polymorphisms in GSTM1 and GSTT1 genes could influence the risk for developing KC in individuals occupationally exposed to pesticides.
[Stojanovic J, Milovanovic S, Pastorino R, et al. 2017. Eur J Cancer Prev. doi: 10.1097/CEJ.0000000000000364] - Organochlorine pesticides accumulation and breast cancer: A hospital-based case-control study.
The aim of this study is to detect the accumulation status of organochlorine pesticides in breast cancer patients and to explore the relationship between organochlorine pesticides contamination and breast cancer development. A hospital-based case-control study in 56 patients with breast cancer and 46 patients with benign breast disease was conducted. The accumulation level of several organochlorine pesticides products (β-hexachlorocyclohexane, γ-hexachlorocyclohexane, polychlorinated biphenyls-28, polychlorinated biphenyls-52, pentachlorothioanisole, and pp'-dichlorodiphenyldichloroethane) in breast adipose tissues of all 102 patients was detected. Thereafter, authors examined the expression status of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 (HER2), and Ki-67 in 56 breast cancer cases by immunohistochemistry. In addition, they analyzed the risk of breast cancer in those patients with organochlorine pesticides contamination using a logistic regression model. Data showed that breast cancer patients suffered high accumulation levels of pp'-dichlorodiphenyldichloroethane and polychlorinated biphenyls-52. However, the concentrations of pp'-dichlorodiphenyldichloroethane and polychlorinated biphenyls-52 were not related to clinicopathologic parameters of breast cancer. Further logistic regression analysis showed polychlorinated biphenyls-52 and pp'-dichlorodiphenyldichloroethane were risk factors for breast cancer. Results provide new evidence on etiology of breast cancer.
[He TT, Zuo AJ, Wang JG, Zhao P. 2017. Tumour Biol. 39(5):1010428317699114] - Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer
Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.
[Di Donato M, Cernera G, Giovannelli P, et al. 2017. Mol Cell Endocrinol. pii: S0303-7207(17)30158-2. ] - Serum levels of environmental pollutants is a risk factor for breast cancer in Inuit: a case control study.
The association between POPs and breast cancer has been widely studied but the conclusions are inconsistent. The present study examined the associations between serum levels of Persistent Organic Pollutants (POPs) and breast cancer with focus on the highly exposed Greenlandic Inuit population.The study design was a case-control study of Inuit women from Greenland. The participants were asked to complete a questionnaire with information on reproductive history and lifestyle and to provide a blood sample. The sampling was carried out in two time periods (2000-2003 and 2011-2014). The serum levels were determined of 14 polychlorinated biphenyls (PCBs), 11 organochlorine pesticides (OCPs), 16 perfluoroalkyl acids (PFAAs), 1 polybrominated biphenyl (PBB), and 9 polybrominated diphenyl ethers (PBDEs).The study population included 77 breast cancer cases and 84 controls. The majority of the measured compounds declined significantly from 2000 - 2003 to 2011-2014. However, for the perfluorinated carboxylic acids (PFCAs) an increase was observed. The serum levels were significantly higher in cases compared to controls for the majority of the compounds, and after adjusting for age the difference. For the lipophilic POPs, high serum levels (middel/highest vs. lowest tertile) were associated with breast cancer risk; for the amphiphilic PFAAs, high serum levels of ∑PFAA, ∑PFCA, ∑PFSA, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), PFHxS, and PFOS were associated with breast cancer risk. Significant, positive associations between breast cancer risk and PCBs and PFAAs were observed. The associations indicate that environmental exposure to POPs can be a factor increasing the risk for breast cancer in Inuit women.
[Wielsøe M, Kern P, Bonefeld-Jørgensen EC. 2017. Environ Health. 16(1):56. ] - Childhood and Adolescent Pesticide Exposure and Breast Cancer Risk.
To date, epidemiologic studies have not strongly supported an association between pesticide exposure and breast cancer. However, few previous studies had the ability to assess specific time periods of exposure. Studies that relied on adult serum levels of metabolites of organochlorine pesticides may not accurately reflect exposure during developmental periods. Furthermore, exposure assessment often occurred after diagnosis and key tumor characteristics, such as hormone receptor status, have rarely been available to evaluate tumor subtype-specific associations. We examined the association between pesticide exposure during childhood and adolescence and breast cancer risk in the prospective Sister Study cohort (N = 50,884 women) to assess this relation by tumor subtype. During an average 5-year follow-up, 2,134 incident invasive and in situ breast cancer diagnoses were identified. Residential and farm exposure to pesticides were self-reported at study enrollment during standardized interviews. Multivariable hazard ratios and 95% confidence intervals for breast cancer risk were calculated with Cox proportional hazards regression. HRs were near null for the association between childhood/adolescent pesticide exposure and breast cancer risk overall or among ER+/PR+ invasive tumors. However, among women who were ages 0-18 before the ban of dichlordiphenyltrichloroethane in the US, exposure to fogger trucks or planes was associated with a hazard ratio = 1.3 for premenopausal breast cancer (95% confidence interval: 0.92, 1.7). These findings do not support an overall association between childhood and adolescent pesticide exposure and breast cancer risk. However, modest increases in breast cancer risk were associated with acute events in a subgroup of young women.
[Niehoff NM, Nichols HB, White AJ, 2016. Epidemiology. 27(3):326-33. ] - Correlation between toxic organochlorine pesticides and breast cancer.
Organochlorines (OCs) are common environmental pollutants that have been linked to cancer. This work aims to assess the role of OCs as a risk factor for breast cancer and to evaluate the cellular changes induced by exposure to such environmental contaminants. The study included 70 cancer patients subjected to thorough history taking and routine investigations. Samples from tumor and normal adjacent tissue were taken to measure OCs' levels and to perform molecular analysis (some oncogenic and apoptotic markers) by flow cytometry. There were significantly higher concentrations of methoxychlor, dichloro-diphenyl-trichloroethane (DDT), hexa-chlorobenzene (HCB), and chlordane in tumor tissue samples compared to the surrounding normal tissue. There was a positive statistically significant correlation between G2m and dichloro-diphenyl-dichloroethane, DDT, and methoxychlor. There was also a negative correlation between propidium iodide (PI) and heptachlor as well as between PI, B-cell lymphoma 2, and methoxychlor. Annexin showed a negative correlation with HCB and methoxychlor. In conclusion, the higher level of organochlorine pesticides in the tissue specimens of breast cancer and the resultant molecular dysfunction highlight a possible association. Further research is warranted to elucidate the other possible mechanisms involved in the process of carcinogenesis.
[Eldakroory SA, Morsi DE, Abdel-Rahman RH, et al. 2016. Hum Exp Toxicol.:960327116685887] - Differences in GPR30 Regulation by Chlorotriazine Herbicides in Human Breast Cells
Over 200,000 cases of invasive breast cancer are diagnosed annually; herbicide contaminants in local water sources may contribute to the growth of these cancers. GPR30, a G protein coupled receptor, was identified as a potential orphan receptor that may interact with triazine herbicides such as atrazine, one of the most commonly utilized chlorotriazines in agricultural practices in the United States. Our goal was to identify whether chlorotriazines affected the expression of GPR30. Two breast cancer cell lines, MDA-MB-231 and MCF-7, as well as one normal breast cell line, MCF-10A, were treated with a 100-fold range of atrazine, cyanazine, or simazine, with levels flanking the EPA safe level for each compound. Using real-time PCR, we assessed changes in GPR30 mRNA compared to a GAPDH control. Our results indicate that GPR30 expression increased in breast cancer cells at levels lower than the US EPA drinking water contamination limit. During this treatment, the viability of cells was unaltered. In contrast, treatment with chlorotriazines reduced the expression of GPR30 in noncancerous MCF-10A cells. Thus, our results indicate that cell milieu and potential to metastasize may play a role in the extent of GPR30 response to pesticide exposure.
[Florian CP, Mansfield SR, Schroeder JR. Biochem Res Int. 2016:2984081] - Differential gene expression pattern in human mammary epithelial cells induced by realistic organochlorine mixtures described in healthy women and in women diagnosed with breast cancer.
Organochlorine pesticides (OCs) have been associated with breast cancer development and progression, but the mechanisms underlying this phenomenon are not well known. In this work, we evaluated the effects exerted on normal human mammary epithelial cells (HMEC) by the OC mixtures most frequently detected in healthy women (H-mixture) and in women diagnosed with breast cancer (BC-mixture), as identified in a previous case-control study developed in Spain. Cytotoxicity and gene expression profile of human kinases (n=68) and non-kinases (n=26) were tested at concentrations similar to those described in the serum of those cases and controls. Although both mixtures caused a down-regulation of genes involved in the ATP binding process, our results clearly indicate that both mixtures may exert a very different effect on the gene expression profile of HMEC. Thus, while BC-mixture up-regulated the expression of oncogenes associated to breast cancer (GFRA1 and BHLHB8), the H-mixture down-regulated the expression of tumor suppressor genes (EPHA4 and EPHB2). Our results indicate that the composition of the OC mixture could play a role in the initiation processes of breast cancer. In addition, the present results suggest that subtle changes in the composition and levels of pollutants involved in environmentally relevant mixtures might induce very different biological effects, which explain, at least partially, why some mixtures seem to be more carcinogenic than others. Nonetheless, our findings confirm that environmentally relevant pollutants may modulate the expression of genes closely related to carcinogenic processes in the breast, reinforcing the role exerted by environment in the regulation of genes involved in breast carcinogenesis.
[Rivero J, Henríquez-Hernández LA, Luzardo OP, et al. Toxicol Lett. 246:42-8. ] - Epidemiological trends of hormone-related cancers in Slovenia.
The incidence of hormone-related cancers tends to be higher in the developed world than in other countries. In Slovenia, six hormone-related cancers (breast, ovarian, endometrial, prostate, testicular, and thyroid) account for a quarter of all cancers. Their incidence goes up each year, breast and prostate cancer in particular. The age at diagnosis is not decreasing for any of the analysed cancer types. The risk of breast cancer is higher in the western part of the country, but no differences in geographical distribution have been observed for other hormone-related cancers. Furthermore, areas polluted with endocrine-disrupting chemicals that affect hormone balance such as PCBs, dioxins, heavy metals, and pesticides, do not seem to involve a greater cancer risk. We know little about how many cancers can be associated with endocrine disruptors, as there are too few reliable exposure studies to support an association.
[Zadnik V, Krajc M. 2016. Arh Hig Rada Toksikol. 67(2):83-92. ] - Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review
Endocrine disrupting chemicals (EDCs) are released into the environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDCs have major risks for humans by targeting different organs and systems in the body (e.g. reproductive system, breast tissue, adipose tissue, pancreas, etc.). Due to the ubiquity of human exposure to these compounds the aim of this review is to describe the most recent data on the effects induced by phthalates, bisphenol A and parabens in a critical window of exposure: in utero, during pregnancy, infants, and children. The interactions and mechanisms of toxicity of EDCs in relation to human general health problems, especially those broadening the term of endocrine disruption to 'metabolic disruption', should be deeply investigated. These include endocrine disturbances, with particular reference to reproductive problems and breast, testicular and ovarian cancers, and metabolic diseases such as obesity or diabetes.
[Giulivo M, Lopez de Alda M, Capri E, Barceló D. 2016. Environ Res. 151:251-264.] - Occupational exposure and risk of breast cancer
Breast cancer is a multifactorial disease and the most commonly diagnosed cancer in women. Traditional risk factors for breast cancer include reproductive status, genetic mutations, family history and lifestyle. However, increasing evidence has identified an association between breast cancer and occupational factors, including environmental stimuli. Epidemiological and experimental studies demonstrated that ionizing and non-ionizing radiation exposure, night-shift work, pesticides, polycyclic aromatic hydrocarbons and metals are defined environmental factors for breast cancer, particularly at young ages. However, the mechanisms by which occupational factors can promote breast cancer initiation and progression remains to be elucidated. Furthermore, the evaluation of occupational factors for breast cancer, particularly in the workplace, also remains to be explained. The present review summarizes the occupational risk factors and the associated mechanisms involved in breast cancer development, in order to highlight new environmental exposures that could be correlated to breast cancer and to provide new insights for breast cancer prevention in the occupational settings. Furthermore, this review suggests that there is a requirement to include, through multidisciplinary approaches, different occupational exposure risks among those associated with breast cancer development. Finally, the design of new epigenetic biomarkers may be useful to identify the workers that are more susceptible to develop breast cancer.
[Fenga C. Biomed Rep. 4(3):282-292.] - Chlorpyrifos inhibits cell proliferation through ERK1/2 phosphorylation in breast cancer cell lines.
It has been reported that oxidative stress may be induced by pesticides and it could be the cause of health alteration mediated by pollutants exposure. The present investigation was designed to identify the pathway involved in chlorpyrifos (CPF)-inhibited cell proliferation in MCF-7 and MDA-MB-231 breast cancer cell lines. In addition, authors determined if CPF-induced oxidative stress is related to alterations in antioxidant defense system. The molecular mechanisms underlying in the cell proliferation inhibition produced by the pesticide were also looked at. Study demonstrates that CPF (50 μM) induces redox imbalance altering the antioxidant defense system in breast cancer cells. The main mechanism involved in the inhibition of cell proliferation induced by CPF is an increment of p-ERK1/2 levels mediated by H2O2 in breast cancer cells. Study concluded that ERK1/2 phosphorylation is subsequent to ROS production induced by CPF but not the inverse.
[Ventura C, Venturino A, Miret N, et al. 2015. Chemosphere. 120:343-50.] - DDT Exposure in Utero and Breast Cancer
Context: Currently no direct evidence links in utero dichlorodiphenyltrichloroethane (DDT) exposure to human breast cancer. However, in utero exposure to another xenoestrogen, diethylstilbestrol, predicts an increased breast cancer risk. If this finding extends to DDT, it could have far-reaching consequences. Many women were heavily exposed in utero during widespread DDT use in the 1960s. They are now reaching the age of heightened breast cancer risk. DDT exposure persists and use continues in Africa and Asia without clear knowledge of the consequences for the next generation.Hypothesis: In utero exposure to DDT is associated with an increased risk of breast cancer.
Design: This was a case-control study nested in a prospective 54-year follow-up of 9300 daughters in the Child Health and Development Studies pregnancy cohort (n = 118 breast cancer cases, diagnosed by age 52 y and 354 controls matched on birth year).
Setting and participants: Kaiser Foundation Health Plan members who received obstetric care in Alameda County, California, from 1959 to 1967, and their adult daughters participated in the study.
Main outcome measure: Daughters' breast cancer diagnosed by age 52 years as of 2012 was measured.
Results: Maternal o,p'-DDT predicted daughters' breast cancer (odds ratio fourth quartile vs first = 3.7, 95% confidence interval 1.5-9.0). Mothers' lipids, weight, race, age, and breast cancer history did not explain the findings.
Conclusions: This prospective human study links measured DDT exposure in utero to risk of breast cancer. Experimental studies are essential to confirm results and discover causal mechanisms. Findings support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk.
[Cohn, B. et al. (2015) DDT exposure in utero and breast cancer, The Journal of Clinical Endocrinology and Metabolism. Available at: https://pubmed.ncbi.nlm.nih.gov/26079774/. ] - Effects of environmental organochlorine pesticides on human breast cancer: putative involvement on invasive cell ability
POPs are known to be particularly toxic and have been associated with endocrine-disrupting effects in several mammals, including humans even at very low doses. As environmental estrogens, they could play a critical role in carcinogenesis, such as in breast cancer. With the purpose of evaluating their effect on breast cancer biology, o,p'-DDT, p,p'-DDE, and p,p'-DDD (50-1000 nM) were tested on two human breast adenocarcinoma cell lines: MCF-7 expressing estrogen receptor (ER) α and MDA-MB-231 negative for ERα, regarding cell proliferation and viability in addition to their invasive potential. Cell proliferation and viability were not equally affected by these compounds. In MCF-7 cells, the compounds were able to decrease cell proliferation and viability. On the other hand, no evident response was observed in treated MDA-MB-231 cells. Concerning the invasive potential, the less invasive cell line, MCF-7, had its invasion potential significantly induced, while the more invasive cell line MDA-MB-231, had its invasion potential dramatically reduced in the presence of the tested compounds. Altogether, the results showed that these compounds were able to modulate several cancer-related processes, namely in breast cancer cell lines, and underline the relevance of POP exposure to the risk of cancer development and progression, unraveling distinct pathways of action of these compounds on tumor cell biology.
[Pestana D, Teixeira D, Faria A, Domingues V, et al. 2015. Environ Toxicol. 30(2):168-76.] - In vitro evaluation of oestrogenic/androgenic activity of the serum organochlorine pesticide mixtures previously described in a breast cancer case-control study.
Some organochlorine pesticides (OCs) have been individually linked to breast cancer (BC) because they exert oestrogenic effects on mammary cells. In this work authors evaluated the in vitro effects exerted on human BC cells by the OC mixtures that were most frequently detected in two groups of women who participated in a BC case-control study developed in Spain: healthy women and women diagnosed with BC. The cytotoxicity, oestrogenicity, and androgenicity of the most prevalent OC mixtures found in healthy women (H-mixture) and in BC patients (BC-mixture) were tested at concentrations that resembled those found in the serum of the evaluated women. Our results showed that both OC mixtures presented a similar oestrogenic activity and effect on cell viability, but BC-mixture showed an additional anti-androgenic effect. These results indicate that although the proliferative effect exerted by these mixtures on human breast cells seems to depend mainly on their oestrogenic action, the BC-mixture might additionally induce cell proliferation due to its anti-androgenic activity, therefore increasing the carcinogenic potential of this mixture. The findings of this study demonstrate that subtle variations in the composition of a mixture may induce relevant changes in its biological action.
[Rivero J, Luzardo OP, Henríquez-Hernández LA, Machín RP, et al. 2015. Sci Total Environ. 537:197-202] - Organochlorine insecticides DDT and chlordane in relation to survival following breast cancer.
Study examined associations between organochlorine insecticides p,p'-DDT , its primary metabolite, p,p'-DDE, and chlordane assessed shortly after diagnosis and survival among women with breast cancer. A population-based sample of women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997 and with available organochlorine blood measures (n = 633) were followed for vital status through 2011. After follow-up of 5 and 15 years, authors identified 55 and 189 deaths, of which 36 and 74, respectively, were breast cancer-related. At 5 years after diagnosis, the highest tertile of DDT concentration was associated with all-cause (HR = 2.19; 95% CI: 1.02, 4.67) and breast cancer-specific (HR = 2.72; 95% CI: 1.04, 7.13) mortality. At 15 years, middle tertile concentrations of DDT (HR = 1.42; 95% CI 0.99, 2.06) and chlordane (HR = 1.42; 95% CI: 0.94, 2.12) were modestly associated with all-cause and breast cancer-specific mortality. Third tertile DDE concentrations were inversely associated with 15-year all-cause mortality (HR = 0.66; 95% CI: 0.44, 0.99). This is the first population-based study in the United States to show that DDT may adversely impact survival following breast cancer diagnosis. Further studies are warranted given the high breast cancer burden and the ubiquity of these chemicals.
[Parada H Jr, Wolff MS, Engel LS, White AJ, et al. 2015. Int J Cancer. doi: 10.1002/ijc.29806] - Organophosphate insecticide use and cancer incidence among spouses of pesticide applicators in the Agricultural Health Study
Organophosphates (OPs) are among the most commonly used insecticides. OPs have been linked to cancer risk in some epidemiological studies, which have been largely conducted in predominantly male populations. This study evaluated personal use of specific OPs and cancer incidence among female spouses of pesticide applicators in the prospective Agricultural Health Study cohort. Among 30 003 women, 25.9% reported OP use, and 718 OP-exposed women were diagnosed with cancer during the follow-up period. Any OP use was associated with an elevated risk of breast cancer (RR=1.20, 95% CI 1.01 to 1.43). Malathion, the most commonly reported OP, was associated with increased risk of thyroid cancer (RR=2.04, 95% CI 1.14 to 3.63) and decreased risk of non-Hodgkin lymphoma (RR=0.64, 95% CI 0.41 to 0.99). Diazinon use was associated with ovarian cancer (RR=1.87, 95% CI 1.02 to 3.43).Authors observed increased risk with OP use for several hormonally-related cancers, including breast, thyroid and ovary, suggesting potential for hormonally-mediated effects. This study represents the first comprehensive analysis of OP use and cancer risk among women, and thus demonstrates a need for further evaluation.
[Lerro CC, Koutros S, Andreotti G, Friesen MC, et al. 2015. Occup Environ Med. 72(10):736-44] - Risk of female breast cancer and serum concentrations of organochlorine pesticides and polychlorinated biphenyls: a case-control study in Tunisia
The aim of this study was to investigate the association between serum concentrations of a group of organochlorine pesticides/polychlorinated biphenyls with xenoestrogenic potential and the risk of breast cancer in a female population from Tunisia. β-hexachlorocyclohexane (β-HCH), hexachlorobenzene, heptachlor, polychlorinated biphenyl congeners 138, 153, and 180, and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were positively associated with breast cancer risk. However, when the models were further adjusted for the selected covariates, only β-HCH and p,p'-DDE remained statistically significant, and heptachlor was borderline significant. In addition, analyses using POP concentration tertiles corroborated a positive dose-response relationship that was significant for p,p'-DDE. A similar trend was also confirmed for β-HCH, in which concentrations≥limit of detection were positively associated with breast cancer risk (vs. concentrations<limit of detection, OR=3.44, p<0.05). Finally, the relative influence of each chemical in the presence of the others was assessed by entering the three chemicals in a single model with all covariates, and only β-HCH remained positively associated with the risk of cancer. Findings suggest a potential association between exposure to at least one organochlorine pesticide and breast cancer risk. However, our results should be interpreted with caution, and further research is warranted to confirm these findings.
[Arrebola JP, Belhassen H, Artacho-Cordón F, Ghali R, Ghorbel H, et al. 2015. Sci Total Environ. 520:106-13] - The organochlorine pesticides residues in the invasive ductal breast cancer patients.
75 invasive ductal carcinoma (IDC) patients were enrolled with control of 79 benign breast diseases patients and control of 80 healthy women. Morning fasting blood specimens and adipose tissue specimens beside the primary lesion were detected with gas chromatograph. In blood specimens, both levels of β-HCH and PCTA were higher in IDC than those in both controls, and increasingly higher among the three IDC degrees. In adipose tissue specimens, all levels of β-HCH, PCTA and pp'-DDE were higher in IDC than those in control (all p<0.05) and increasingly higher among three IDC degrees. The levels of β-HCH, PCTA in both blood specimens and adipose tissue specimens were higher in estrogen receptor (ER) positive IDC than those in ER negative IDC. The higher level of organochlorine pesticides residues in blood and adipose tissue specimens of IDC infers its association with IDC, but the details remains to reveal, and this study may helpful in this field.
[Yang JZ, Wang ZX, Ma LH, Shen XB, et al. 2015. Environ Toxicol Pharmacol. 40(3):698-703] - Timing of Environmental Exposures as a Critical Element in Breast Cancer Risk
Literature was reviewed and evidence gathered on the effects of the environment on risk of breast cancer or mammary tumor development in animal research models as it pertained to the influence of timing of exposure on later-life outcomes.Evidence has accumulated for several chemicals that environmental factors have a stronger effect on breast cancer risk when exposure occurred early in life. The insecticide, dichlorodiphenyltrichloroethane, is an excellent example and is just one of several chemicals for which there seems to be both animal and human evidence for the developmental basis of adult disease. The developing breast undergoes many changes in early life, leaving it vulnerable to the effects of epigenetic marks, endocrine disruption, and carcinogens. More research is needed in the area of early beginnings of breast cancer, with prevention of the disease as the ultimate goal.
[Fenton S and Birnbaum, L. 2015. Endocrine Soc. http://dx.doi.org/10.1210/jc.2015-2848] - Assessing the underlying breast cancer risk of Chinese females contributed by dietary intake of residual DDT from agricultural soils.
The greatest concern over DDT exposure in China arose since the early 1990s for the rising breast cancer incidence, and the cause still remains to be elucidated. An extensive survey of DDT background in agricultural soils, covered the entire region of China, was conducted. Considering the geographical differences with diverse DDT contributions and different diet products and habits, the average daily dietary intake was modeled and estimated to be 0.34 μg/kg p,p'-DDE (the main bioactive constituent in DDT). Population attributable fraction derived from a case-control study from 78 women with breast cancer and 72 controls was used to assess the DDT exposure risk to breast cancer. Based on the estimated population attributable fraction with a median value of 0.6% (IQR 0.23-2.11%), the excess annual breast cancer incidence rate attributable to p,p'-DDE exposure averaged 0.06×10(-5) with significant spatial variations varying from 0.00021×10(-5) to 11.05×10(-5) in Chinese females. Exposure to DDT is a contributor to breast cancer, but the overall limited relative risk and population attributable fraction imply confounding factors for breast cancer in Chinese females.
[Tang M, Zhao M, Zhou S, et al. 2014. Environ Int. 73:208-15] - Case-control study of breast cancer and exposure to synthetic environmental chemicals among Alaska Native women.
Exposure to environmental chemicals may impair endocrine system function. Alaska Native (AN) women may be at higher risk of exposure to these endocrine disrupting chemicals, which may contribute to breast cancer in this population. To measure the association between exposure to select environmental chemicals and breast cancer among AN women. A case-control study of 170 women (75 cases, 95 controls) recruited from the AN Medical Center from 1999 to 2002. Participants provided urine and serum samples. Serum was analyzed for 9 persistent pesticides, 34 polychlorinated biphenyl (PCB) congeners, and 8 polybrominated diethyl ether (PBDE) congeners. Urine was analyzed for 10 phthalate metabolites. We calculated geometric means (GM) and compared cases and controls using logistic regression. Serum concentrations of most pesticides and 3 indicator PCB congeners (PCB-138/158; PCB-153, PCB-180) were lower in case women than controls. BDE-47 was significantly higher in case women (GM=38.8 ng/g lipid) than controls (GM=25.1 ng/g lipid) (p=0.04). Persistent pesticides, PCBs, and most phthalate metabolites were not associated with case status in univariate logistic regression. The odds of being a case were higher for those with urinary mono-(2-ethylhexyl) phthalate (MEHP) concentrations that were above the median; this relationship was seen in both univariate (OR 2.16, 95% CI 1.16-4.05, p=0.02) and multivariable (OR 2.43, 95% CI 1.13-5.25, p=0.02) logistic regression. Women with oestrogen receptor (ER)-/progesterone receptor (PR)-tumour types tended to have higher concentrations of persistent pesticides than did ER+/PR+ women, although these differences were not statistically significant. Exposure to the parent compound of the phthalate metabolite MEHP may be associated with breast cancer. However, our study is limited by small sample size and an inability to control for the confounding effects of body mass index. The association between BDE-47 and breast cancer warrants further investigation.
[Holmes AK, Koller KR, Kieszak SM, Sjodin A, et al. 2014. Int J Circumpolar Health. 73:25760.] - Effect of nonpersistent pesticides on estrogen receptor, androgen receptor, and aryl hydrocarbon receptor.
Nonpersistent pesticides are considered less harmful for the environment, but their impact as endocrine disruptors has not been fully explored. The pesticide Switch was applied to grape vines, and the maximum residue concentration of its active ingredients was quantified. The transactivation potential of the pesticides Acorit, Frupica, Steward, Reldan, Switch, Cantus, Teldor, and Scala and their active compounds (hexythiazox, mepanipyrim, indoxacarb, chlorpyrifos-methyl, cyprodinil, fludioxonil, boscalid, fenhexamid, and pyrimethanil) were tested on human estrogen receptor α (ERα), androgen receptor (AR) and arylhydrocarbon receptor (AhR) in vitro. Relative binding affinities of the pure pesticide constituents for AR and their effect on human breast cancer and prostate cancer cell lines were evaluated. Residue concentrations of Switch's ingredients were below maximum residue limits. Fludioxonil and fenhexamid were ERα agonists (EC50 -values of 3.7 and 9.0 μM, respectively) and had time-dependent effects on endogenous ERα-target gene expression (cyclin D1, progesterone receptor, and nuclear respiratory factor 1) in MCF-7 human breast cancer cells. Fludioxonil, mepanipyrim, cyprodinil, pyrimethanil, and chlorpyrifos-methyl were AhR-agonists (EC50 s of 0.42, 0.77, 1.4, 4.6, and 5.1 μM, respectively). Weak AR binding was shown for chlorpyrifos-methyl, cyprodinil, fenhexamid, and fludioxonil. Assuming a total uptake which does not take metabolism and clearance rates into account, in vitro evidence suggests that pesticides could activate pathways affecting hormonal balance, even within permitted limits, thus potentially acting as endocrine disruptors.
[Medjakovic S, Zoechling A, Gerster P, et al. 2014. Environ Toxicol. 29(10):1201-16] - Exogenous hormonal regulation in breast cancer cells by phytoestrogens and endocrine disruptors.
Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor
[Albini A, Rosano C, Angelini G, Amaro A, et al.2014. Curr Med Chem. 21(9):1129-45.] - Household and occupational exposure to pesticides and risk of breast cancer.
The association between breast cancer in women and the use of household or occupational pesticides was examined in a population-based case-control study. This study was conducted in Western Australia in 2009-2011 and included 1,789 controls and 1,205 cases. Information on household pesticide exposure was collected from questionnaires. For occupational pesticide exposure, job-specific modules (JSMs) were used. Women's exposures to pesticides in households and workplaces were not related to increased risk of breast cancer. The prevalence of occupational exposure to pesticides among women in our study was low. In the stratified analyses, the odd ratios associated with household pesticide use were similar among participants who believed pesticides increased breast cancer risk and those who did not. The results of our study did not show associations between breast cancer and household or occupational exposure to pesticides.
[El-Zaemey S, Heyworth J, Glass DC, 2014. Int J Environ Health Res. 24(2):91-102] - Progression of Breast Cancer Cells Was Enhanced by Endocrine-Disrupting Chemicals, Triclosan and Octylphenol, via an Estrogen Receptor-Dependent Signaling Pathway in Cellular and Mouse Xenograft Models
In the present study, we determined whether two endocrine-disrupting chemicals (EDCs), triclosan (TCS) and octylphenol (OP), are able to alter the expression of two cell cycle regulators, cyclin D1 and p21, in both in vitro and mouse breast cancer models. In addition, we determined whether the stimulatory effects of OP or TCS on breast cancer progression may be associated with an estrogen receptor (ER)-mediated signaling pathway. Altered expressions of cyclin D1 and p21 were observed in MCF-7 human breast cancer cells treated with TCS and OP, which is linked to the G1/S transition of cell cycle, leading to cell proliferation. In a xenograft mouse model, breast tumor masses were established following exposure to TCS and OP for 8 weeks. In these animals, the tumor cells with BrdU-positive nuclei were increased by treatment with 17β-estradiol (E2), OP, and TCS compared to that of a control (corn oil), suggesting that TCS and OP increase DNA synthesis during the S phase in tumor cells. Increased level of cyclin D1 protein by TCS and OP was also observed in vivo, implying that the effects of these EDCs possessing estrogenic activity alter the expression of genes related to cancer progression. It was of interest that the effects of TCS and OP were reversed by ICI 182,780, an ER antagonist, indicating that EDC-induced activities are mediated by an ER-dependent signaling pathway. Taken together, these results suggest that TCS and OP may promote breast cancer progression, via an ER-mediated signaling cascade.
[Lee, HR et al. 2014. Chemical Research in Toxicology doi: 10.1021/tx5000156. ] - DDT/DDE and breast cancer: a meta-analysis.
The biological basis for investigating dichlorodiphenyltrichloroethane (DDT) exposure and breast cancer risk stems from in vitro and animal studies indicating that DDT has estrogenic properties. The objective of this study was to update a meta-analysis from 2004 which found no association between dichlorodiphenyldichloroethylene (DDE) and breast cancer. Summary Odds Ratios (ORs) with 95% confidence intervals (CIs) were calculated for the prevalence of breast cancer in the highest versus the lowest exposed groups for DDT and DDE. Difference of means of exposure for cases versus controls was analyzed for DDT and DDE. From the 500 studies screened, 46 were included in the meta-analysis. Slightly elevated, but not statistically significant summary ORs were found for DDE. Lipid adjusted difference of means analysis found a significantly higher DDE concentration in cases versus controls. No other difference of means analysis found significant relationships. The existing information does not support the hypothesis that exposure to DDT/DDE increases the risk of breast cancer in humans.
[Ingber SZ, Buser MC, Pohl HR, et al. 2013. Regul Toxicol Pharmacol. 67(3):421-33] - Glyphosate induces human breast cancer cells growth via estrogen receptors.
This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10⁻¹² to 10⁻⁶M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study.
[Thongprakaisang S, Thiantanawat A, Rangkadilok N, et al. 2013. Food Chem Toxicol.59:129-36] - Noticing pesticide spray drift from agricultural pesticide application areas and breast cancer: a case-control study.
Study examined the relationship between self-reported noticing of pesticide spray drift from agricultural areas and breast cancer. A case-control study of breast cancer was conducted in Western Australia from 2009 to 2011. Awareness of pesticide spray drift from agricultural areas was assessed by a self-report of whether the participant had noticed spray drift. This analysis included 1,743 controls and 1,169 cases. Among women who reported 'ever noticed' pesticide spray drift from agricultural areas, an increased risk of breast cancer was also observed. A dose response relationship between lifetime exposure to noticing pesticide spray drift and risk of breast cancer was observed. An increased risk of breast cancer was observed among women who noticed pesticide spray drift: initially at the age of 20 or younger; at least 20 years before diagnosis; and for 10 years or more. These findings support the hypothesis that women who ever noticed spray drift or who first noticed spray drift at a younger age had increased risk of breast cancer.
[El-Zaemey S, Heyworth J, Fritschi L. 2013. Aust N Z J Public Health.37(6):547-55.] - Complex organochlorine pesticide mixtures as determinant factor for breast cancer risk: a population-based case-control study in the Canary Islands (Spain)
This population-based study was designed to evaluate the profile of mixtures of organochlorines detected in 103 healthy women and 121 women diagnosed with breast cancer from Gran Canaria Island, and the relation between the exposure to these compounds and breast cancer risk.The most prevalent mixture of organochlorines among healthy women was the combination of lindane and endrin, and this mixture was not detected in any affected women. Breast cancer patients presented more frequently a combination of aldrin, dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), and this mixture was not found in any healthy woman. After adjusting for covariables, the risk of breast cancer was moderately associated with DDD (OR = 1.008, confidence interval 95% 1.001-1.015, p = 0.024).This study indicates that healthy women show a very different profile of organochlorine pesticide mixtures than breast cancer patients, suggesting that organochlorine pesticide mixtures could play a relevant role in breast cancer risk.
[Boada LD, Zumbado M, Henríquez-Hernández LA, et al. 2012. Environ Health. 11:28] - In vitro effects of herbicides and insecticides on human breast cells.
Authors examined the cytotoxicity of more environmentally relevant concentrations of four herbicides, acetochlor, atrazine, cyanazine, and simazine, and two insecticides, chlorpyrifos and resmethrin, in three human breast cell lines. Interestingly, cytotoxicity was not observed in the estrogen-dependent MCF-7 mammary epithelial carcinoma cells; rather increases in cell viability were seen for some of the compounds at select concentrations. These results vary greatly from what was observed in the estrogen independent MDA-MB-231 breast cancer cells and the non-cancerous MCF-10A breast cells. This gives insight into how different tumors may respond to pesticide exposure and allows us to make more accurate conclusions about the potential cytotoxicity or, at times, stimulatory actions of these pesticides.
[Rich JD, Gabriel SM, Schultz-Norton JR. 2012. ISRN Toxicol. 2012:232461] - Synergistic effect of malathion and estrogen on mammary gland carcinogenesis.
Breast cancer is the most frequent malignancy diagnosed in women and is a classical model of hormone-dependent malignancy. Over the past 15-20 years, epidemiological studies have pointed to an increased breast cancer risk associated with prolonged exposure to female hormones. On the other hand, environmental chemicals such as malathion, an organophosphorous pesticide used to control a wide range of sucking and chewing pests of field crops, may be involved in the etiology of breast cancers. Results indicated that estrogen alone increased average number of lobules per mm2 of rat mammary glands in comparison to control and malathion alone at 30, 124, 240 and 400 days after 5-day treatments. On the other hand, malathion alone significantly increased the number of ducts in stage of proliferation at 10-240 days after 5-day treatments. Furthermore, markers for cancer detection such as mutant p53, c-myc, c-fos and CYPs proteins were overexpressed after treatments. Atropine, an anticholinergic drug, counteracted these effects when it was combined with malathion under similar conditions. The combination of malathion and estrogen synergistically increased number of lobules and ducts per mm2 of rat mammary glands after treatments and inducing mammary cancer. It can be concluded that combination of an environmental substance such as the pesticide malathion and an endogenous substance such as estrogen can enhance the deleterious effects in human mammary glands inducing cancer and atropine is able to diminish these effects.
[Calaf GM and Echiburú-Chau C. 2012. Oncol Rep. 28(2):640-6.] - Environmental exposure and breast cancer among young women in Rio de Janeiro, Brazil
Increasing breast cancer rates among young women (less than 40 years old) have been reported by the population-based cancer registries in Brazil. A case series study was carried out in Rio de Janeiro aiming to obtain epidemiological information allowing the generation of hypotheses to be further evaluated in analytical studies. One hundred and ten women 20-35 years old diagnosed with breast cancer were interviewed to determine the role environment plays in patients cased upon residential location. A comprehensive questionnaire including personal information (medical and lifestyle antecedents, reproductive history, family history of cancer, chemical and radiation exposure) was employed, and the obtained data were further compared with data provided by controls (women without cancer). An unconditional logistic regression was further employed to ascertain the respective odds ratios (OR) and their 95% confidence intervals (CI). Seventy-one percent of cancer cases were sporadic breast cancer, and familial aggregation (first degree relatives) was observed in just 3.5% (5.5% including second-degree relatives). Forty (51.3%) of the cancer cases were reported to have resided at a distance of less than 20 m from an electrical power transformer. Bivariate analysis revealed OR = 5.62 (95% CI 2.63-12) for residential use of pesticides during adulthood, OR = 2.15 (95% CI 1.22-3.77) for dental diagnostic x-rays, and OR= 1.53 (95% 0.77-3.04) for living nearby an electrical power transformer. Further multivariate analysis showed an adjusted OR = 3.5 (95% CI 1.11-11.0) for residential use of pesticides, and an adjusted OR = 2 (95% CI 1.24-3.23) for dental diagnostic x-rays during adulthood. The observed results highlight the importance of exploring the contribution of selected environmental agents possibly involved in breast carcinogenesis among young women.
[Ortega Jacome, G.P., et al. 2010. J Toxicol Environ Health A. 73(13-14):858-65.] - Environmental Oestrogens and Breast Cancer: Evidence for Combined Involvement of Dietary, Household and Cosmetic Xenoestrogens
Many environmental compounds with oestrogenic activity are measurable in the human breast and oestrogen is a known factor in breast cancer development. Exposure to environmental oestrogens occurs through diet, household products and cosmetics, but concentrations of single compounds in breast tissue are generally lower than needed for assayable oestrogenic responses. Results presented here and elsewhere demonstrate that in combination, chemicals can give oestrogenic responses at lower concentrations, which suggests that in the breast, low doses of many compounds could sum to give a significant oestrogenic stimulus. Updated incidence figures show a continued disproportionate incidence of breast cancer in Britain in the upper outer quadrant of the breast which is also the region to which multiple cosmetic chemicals are applied. If exposure to complex mixtures of oestrogenic chemicals in consumer products is a factor in breast cancer development, then a strategy for breast cancer prevention could become possible.
[Darbre, P and Charles, A. 2010. Anticancer Research. 30(3): 815-827] - Pesticides and breast cancer risk: a comparison between developed and developing countries
Literature review links DDT to breat cancer in the developing world. According to the authors, there is a dearth of studies in developing countries, which cannot be made up for generalizing the results from developed countries to the developing and third world.
[Shakeel MK, George PS, Jose J, Jose J, Mathew A. 2010. Asian Pac J Cancer Prev. 2010;11(1):173-80.] - Mammary Gland Development as a Sensitive End Point after Acute Prenatal Exposure to an Atrazine Metabolite Mixture in Female Long-Evans Rats
Atrazine (ATR), a widely used chlorotriazine herbicide, inhibits a number of endocrine-dependent processes, including gonadotrophin surges and mammary gland development in rats. Chlorotriazine herbicides are rapidly metabolized in plants and animals to form a group of metabolites that are detected both in the environment and in exposed animals. The extent to which these metabolites are responsible directly for the observed health effects is not understood. Our goal was to determine if a mixture of ATR metabolites, in proportions found in the environment, might produce developmental effects in Long-Evans rats following exposure late in pregnancy. We administered an ATR metabolite mixture (AMM) containing ATR, hydroxyatrazine, diaminochlorotriazine, deethylatrazine, and deisopropylatrazine orally to pregnant Long-Evans rats at 0.09, 0.87, or 8.73 mg/kg body weight (bw)/day, on gestation days 15–19, using 0 and 100 mg ATR/kg bw/day as negative and positive controls, respectively. We observed no significant effect of acute AMM exposure on body weight gain in dams during the dosing period, weight loss in pups on postnatal day (PND)4, or pubertal timing, as is seen with ATR alone. However, as with ATR, we detected delayed mammary gland development, evaluated by whole mount analysis, as early as PND4 in all treatment groups. Our data suggest that acute exposure to AMM at levels as low as 0.09 mg/kg bw during late pregnancy causes persistent alterations in mammary gland development of female offspring, and that these effects do not appear to be related to bw or associated with pubertal timing.
[Enoch R.R., et al. 2007. Environmental Health Perspectives, 115(4).] - Reported residential pesticide use and breast cancer risk on Long Island, New York
A population based, case control study of Long Island, New York breast cancer cases finds an increased risk associated with: (a) lifetime residential pesticide use (OR 1.39); (b) application of lawn insecticides themselves (OR 1.56) and is higher if it is in liquid form (OR 1.77) or a combination of product type for outdoor plants (OR 1.83); (c) professional application of pesticides in a vegetable and fruit garden more than doubled (OR 2.29); and, (d) application of pesticides for insects or diseases on outdoor plants by self (OR 1.58) or by professional (OR 1.79).
[Teitelbaum, S.L., et al. 2007. American Journal of Epidemiology 165(6):643-651.] - Breast cancer risk in Hispanic agricultural workers in California
In a registry-based case-control study of breast cancer in farm labor union members in California, 128 breast cancer (BC) cases newly diagnosed in 1988--2001 and 640 cancer-free controls were investigated. Stage and grade of disease at diagnosis were about the same as in the California Hispanic population. Risk of breast cancer was not associated with work with any specific crops or commodities except mushrooms, where the adjusted odds ratio (OR) was 6.00 (95% CI 2.01-18.0). Controlling for covariates, adjusted ORs (and 95% CIs) for breast cancer in quartiles of pesticide use were 1.00, 1.30 (0.73-2.30), 1.23 (0.67-2.27), and 1.41 (0.66-3.02). Chlordane, malathion, and 2,4-D were associated with increased risk. Risk associated with chemical use was stronger in younger women, those with early-onset breast cancer, and those diagnosed earlier (1988--1994).
[Mills, P.K. and Yang, R., 2005. Breast cancer risk in Hispanic agricultural workers in California. International journal of occupational and environmental health, 11(2), pp.123-131.] - Pesticide Use and Breast Cancer Risk among Farmers’ Wives in the Agricultural Health Study
The authors examined the association between pesticide use and breast cancer incidence among farmers’ wives in a large prospective cohort study in Iowa and North Carolina. Participants were 30,454 women with no history of breast cancer prior to cohort enrollment in 1993–1997. Through 2000, 309 incident breast cancer cases were identified via population-based cancer registries. Rate ratios were calculated for individual pesticides using Poisson regression, controlling for confounding factors. Breast cancer standardized incidence ratios were 0.87 (95% confidence interval: 0.74, 1.02) for women who reported ever applying pesticides and 1.05 (95% confidence interval: 0.89, 1.24) for women who reported never applying pesticides. There was some evidence of increased risk associated with use of 2,4,5-trichloro-phenoxypropionic acid (2,4,5-TP) and possibly use of dieldrin, captan, and 2,4,5-trichlorophenoxyacetic acid (2,4,5-TP), but small numbers of cases among those who had personally used the pesticides precluded firm conclusions. The authors found no clear association of breast cancer risk with farm size or washing of clothes worn during pesticide application, but risk was modestly elevated among women whose homes were closest to areas of pesticide application. Further follow-up of this cohort should help clarify the relation between pesticide exposure and breast cancer risk.
[Engel, L, Hill, D, Hoppin, J, et al. 2005. Am. J. Epidemiol. 161 (2): 121-135.] - Breast cancer and serum organochlorine residues.
The aim of this study was to compare the blood levels of total dichlorodiphenyltrichloroethane (DDT) and hexachlorobenzene (HCB) in samples collected at the time of breast cancer discovery, in order to avoid the potential consequences of body weight change (after chemotherapy or radiotherapy) on the pesticide residue levels. Blood levels of HCB and total DDT were compared in 159 women with breast cancer and 250 presumably healthy controls. Risk of breast cancer associated with organochlorine concentration was evaluated. Mean levels of total DDT and HCB were significantly higher for breast cancer patients than for controls. No differences in serum levels of total DDT or HCB were found between oestrogen receptor positive and oestrogen receptor negative patients with breast cancer. These results add to the growing evidence that certain persistent pollutants may occur in higher concentrations in blood samples from breast cancer patients than controls.
[Charlier C, Albert A, Herman P, et al.2003. Occup Environ Med. 60(5):348-51.] - Occupational histories of cancer patients in a Canadian cancer treatment center and the generated hypothesis regarding breast cancer and farming
Occupational exposures increase cancer risks. The Windsor Regional Cancer Centre in Windsor, Ontario, was the first Canadian cancer treatment center to collect the work histories of its patients, which were recorded using a computer-based questionnaire. Breast cancer cases represented the largest respondent group. The lifetime occupational histories of 299 women with newly diagnosed breast cancers were compared with those of 237 women with other cancers. Odds ratios (ORs) were calculated using logistic regression, adjusting for age, social class, and education. The OR for women < or = 55 years of age with breast cancer who had ever farmed, compared with women of the same age with other cancers, was 9.05 (95% CI 1.06, 77.43). Patients' occupational histories can help to inform understanding of cancer etiology and prevention. This effort points to a need for investigation of the possible association between breast cancer and agricultural hazards such as pesticides.
[Brophy, J.T., Keith, M.M., Gorey, K.M., Laukkanen, E., Hellyer, D., Watterson, A., Reinhartz, A. and Gilberston, M., 2002. International journal of occupational and environmental health, 8(4), pp.346-353.] - Mammographic findings and occupational exposure to pesticides currently in use on Crete
Women occupationally exposed to pesticides in Crete greenhouses have higher risks of incidence for number of breast tissue legions, which are risk markers for subsequent invasive breast cancer.
[Dolapsakis, G., et al. 2001. Eur J Cancer 37(12):1531-1536.] - A population-based case-control study of farming and breast cancer in North Carolina
A population based, case control study of North Carolina female farmers finds that while farmers in general tend to have lower breast cancer risk, for those women who reported being present in fields during or shortly after a pesticide application (OR 1.8) and for those who reported not using protective clothing while applying pesticides (OR 2.0) are at increased risk for breast cancer.
[Duell, E.J., et al. 2000. Epidemiology 11(5):523-531.] - Identification of occupational cancer risks in British Columbia
Lifetime occupational histories as well as information on known and suspected breast cancer risk factors were collected by means of a self-administered questionnaire from 1018 women with incident breast cancer ascertained from the British Columbia Cancer Registry, and from 1020 population controls. A matched case-control study design was used. Conditional logistic regression for matched sets data and the likelihood ratio were used in a two-step procedure and were performed separately for pre-menopausal women, post-menopausal women, and for all cases combined. Excess risk was noted for several white-collar occupations. Significantly increased risk was observed: (1) among pre-menopausal women: in electronic data-processing operators; barbers and hairdressers; in sales and material processing occupations; and in the food, clothing, chemical and transportation industries; (2) among post-menopausal women: in schoolteaching; in medicine, health, and nursing occupations; in laundry and dry-cleaning occupations; and in the aircraft and automotive, including gasoline service station, industries. Several significant associations were also seen in the combined group of pre- and post-menopausal women, particularly in crop farmers and in the fruit and vegetable, publishing and printing, and motor vehicle repair industries. The results of this study suggest excess breast cancer risk in a number of occupations and industries, notably those that entail exposure to solvents and pesticides.
[Band, P.R., et al. 2000. J Occup Environ Med 42(3):284-310.]
Cervical Cancer
- Cancer incidence in a cohort of licensed pesticide applicators in Florida
This study is a standardized incidence ratio (SIR) analysis of cancer incidence of licensed pesticide applicators in Florida, compared with that of Florida's general population. Through extensive data linkages, 33,658 applicators were assembled who had 1266 incident cancers and 279,397 person-years from January 1, 1975, to December 31, 1993. Disease risk from ethanol and tobacco use were significantly decreased. Among males, prostate cancer (SIR = 1.91; 95% confidence interval [CI], 1.72-2.13) and testicular cancer (SIR = 2.48; 95% CI, 1.57-3.72) were significantly elevated. No confirmed cases of soft tissue sarcoma (STS) were found, and the incidence of non-Hodgkin's lymphoma was not increased. There were few female applicators; nevertheless, cervical cancer incidence (SIR = 3.69; 95% CI, 1.84-6.61) was significantly increased, while the incidence of breast cancer was significantly decreased. Cancers that have been associated with estrogen disrupters were found in male, but not female, pesticide applicators. The lack of soft tissue sarcoma is at odds with prior literature associated with the use of phenoxy herbicides.
[Fleming, L., et al. 1999. Journal of Occupational and Environmental Medicine 41(4):279-288.]
Colorectal Cancer
- Comprehensive assessment of pesticide use patterns and increased cancer risk
Pesticides are an essential feature of modern-day agriculture that adds to the list of factors that increase cancer risk. Our study aims to comprehensively evaluate this relationship through a population-based approach that considers confounding variables such as county-specific rates of smoking, socioeconomic vulnerability, and agricultural land. We achieved our goal with the implementation of latent-class pesticide use patterns, which were further modeled among covariates to evaluate their associations with cancer risk. Our findings demonstrated an association between pesticide use and increased incidence of leukemia; non-Hodgkin's lymphoma; bladder, colon, lung, and pancreatic cancer; and all cancers combined that are comparable to smoking for some cancer types. Through our comprehensive analysis and unique approach, our study emphasizes the importance of a holistic assessment of the risks of pesticide use for communities, which may be used to impact future policies regarding pesticides.
[Gerken, J. et al. (2024) Comprehensive assessment of pesticide use patterns and increased cancer risk, Frontiers. Available at: https://www.frontiersin.org/journals/cancer-control-and-society/articles/10.3389/fcacs.2024.1368086/full. ] - The role of perfluorooctane sulfonic acid (PFOS) exposure in inflammation of intestinal tissues and intestinal carcinogenesis
PFAS (per- and polyfluoroalkyl substances) are organofluorine substances that are used commercially in products like non-stick cookware, food packaging, personal care products, fire-fighting foam, etc. These chemicals have several different subtypes made of varying numbers of carbon and fluorine atoms. PFAS substances that have longer carbon chains, such as PFOS (perfluorooctane sulfonic acid), can potentially pose a significant public health risk due to their ability to bioaccumulate and persist for long periods of time in the body and the environment. The National Academies Report suggests there is some evidence of PFOS exposure and gastrointestinal (GI) inflammation contributing to ulcerative colitis. Inflammatory bowel diseases such as ulcerative colitis are precursors to colorectal cancer. However, evidence about the association between PFOS and colorectal cancer is limited and has shown contradictory findings. This review provides an overview of population and preclinical studies on PFOS exposure and GI inflammation, metabolism, immune responses, and carcinogenesis. It also highlights some mitigation approaches to reduce the harmful effects of PFOS on GI tract and discusses the dietary strategies, such as an increase in soluble fiber intake, to reduce PFOS-induced alterations in cellular lipid metabolism. More importantly, this review demonstrates the urgent need to better understand the relationship between PFOS and GI pathology and carcinogenesis, which will enable development of better approaches for interventions in populations exposed to high levels of PFAS, and in particular to PFOS.
[Durham, J. et al. (2023) The role of perfluorooctane sulfonic acid (PFOS) exposure in inflammation of intestinal tissues and intestinal carcinogenesis, Frontiers in Toxicology. Available at: https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2023.1244457/full. ] - Exposures to pesticides and risk of cancer: Evaluation of recent epidemiological evidence in humans and paths forward
Knowledge of the role in cancer etiology of environmental exposures as pesticides is a prerequisite for primary prevention. We review 63 epidemiological studies on exposure to pesticides and cancer risk in humans published from 2017 to 2021, with emphasis on new findings, methodological approaches, and gaps in the existing literature. While much of the recent evidence suggests causal relationships between pesticide exposure and cancer, the strongest evidence exists for acute myeloid leukemia (AML) and colorectal cancer (CRC), diseases in which the observed associations were consistent across several studies, including high-quality prospective studies and those using biomarkers for exposure assessment, with some observing dose-response relationships. Though high-quality studies have been published since the IARC monograph on organophosphate insecticides in 2017, there are still gaps in the literature on carcinogenic evidence in humans for a large number of pesticides. To further knowledge, we suggest leveraging new techniques and methods to increase sensitivity and precision of exposure assessment, incorporate multi-omics data, and investigate more thoroughly exposure to chemical mixtures. There is also a strong need for better and larger population-based cohort studies that include younger and nonoccupationally exposed individuals, particularly during developmental periods of susceptibility. Though the existing evidence has limitations, as always in science, there is sufficient evidence to implement policies and regulatory action that limit pesticide exposure in humans and, hence, further prevent a significant burden of cancers.
[Cavalier, H., Trasande, L. and Porta, M. (2022) Exposures to pesticides and risk of cancer: Evaluation of recent epidemiological evidence in humans and paths forward, International Journal of Cancer. Available at: https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.34300. ] - Cancer and occupational exposure to pesticides: an umbrella review
Purpose
The aim was to identify the scope of the epidemiology literature reviewed regarding the risk of cancer as related to occupational exposure to pesticides and to compare regulatory toxicity results where feasible.Methods
Review studies of breast, lung, prostate, non-Hodgkin lymphoma, and colorectal cancer were identified from the published literature from 2010 to 2020 using a priori inclusion and exclusion criteria. Epidemiology observations were first assessed and then compared against carcinogenicity profiles derived from regulatory toxicology studies.Results
Several active ingredients were associated with specific cancer but overall, there was neither strong nor consistent epidemiologic data supportive of a positive association between pesticide exposure in occupational settings and cancer. Authors noted common themes related to the heterogeneity of exposure, study design, control for confounders, and the challenge to collect these data reliably and validly with an adequate sample size. Toxicology studies in laboratory animals that assessed carcinogenic potential did not reveal cancer outcomes that were concordant with reported epidemiologic findings.Conclusions
Farming and pesticides represent diverse exposures that are difficult to quantify in epidemiologic studies. Going forward, investigators will need creative and novel approaches for exposure assessment. Integration of epidemiologic and toxicological studies with attention to biological plausibility, mode of toxicological action and relevance to humans will increase the ability to better assess associations between pesticides and cancer.
[Burns, C.J. and Juberg, D.R. (2021) Cancer and occupational exposure to pesticides: An Umbrella Review, International Archives of Occupational and Environmental Health. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238729/. ] - Use of acetochlor and cancer incidence in the Agricultural Health Study
Study evaluated the use of acetochlor and cancer incidence among licensed pesticide applicators in the Agricultural Health Study. Among 33,484 men, there were 4,026 applicators who used acetochlor and 3,234 incident cancers, with 304 acetochlor-exposed cases. Increased risk of lung cancer was observed among acetochlor users compared to nonusers, and among individuals who reported using acetochlor/atrazine product mixtures, compared to nonusers of acetochlor. Colorectal cancer risk was significantly elevated among the highest category of acetochlor users compared to never users. However the lack of exposure-response trends, small number of exposed cases and relatively short time between acetochlor use and cancer development prohibit definitive conclusions.
[Lerro CC, Koutros S, Andreotti G, Hines CJ, et al. 2015. Int J Cancer.doi: 10.1002/ijc.29416.] - Cancer risk among farmers in the Province of Vercelli (Italy) from 2002 to 2005: an ecological study
Farmers living in the Province of Vercelli (Italy) were observed to verify if they have a higher cancer risk than the rest of the local employed population. The present ecological study considered all cancer new cases recorded among the mean employed population with a range of age from 25 to 84 years and resident in the Province of Vercelli during the four-year period 2002-2005. Farmers showed a higher risk for the following tumors: colorectal (OR 2.38, IC95%: 1,76-2,87), leaukaemia (OR 2.65, IC95%:2,12-2,89), digestive system (OR 2.16, IC95% 1,92-2,33), and others. Farmers showed a higher risk for several cancers. Further studies are needed, in order to examine in detail the issue, to encourage the use of personal protective equipment and to promote a more responsible pesticides use.
[Salerno C, Sacco S, Panella M, et al.2014. Ann Ig. 26(3):255-63.] - A weight-of-evidence review of colorectal cancer in pesticide applicators: the agricultural health study and other epidemiologic studies.
The study aimed to systematically evaluate epidemiologic studies on pesticides and colon cancer and rectal cancer in agricultural pesticide applicator populations using a transparent "weight-of-evidence" (WOE) methodological approach. Twenty-nine (29) publications from the Agricultural Health Study (AHS) and 13 additional epidemiologic studies were identified that reported data for pesticide applicators and/or specific pesticide compounds and colorectal, colon, or rectal cancer. Occupation as a pesticide applicator or pesticide application as a farming-related function was not associated with increasing the risk of colon or rectal cancer. Only aldicarb and colon cancer and imazethapyr and proximal colon cancer-appears warrant further discussion regarding a possible causal relationship, although the epidemiologic data are limited. For the remainder, a lack of a clear dose-response trend, inconsistencies in associations between exposure metrics and comparison groups, imprecise associations, variable participation rates for analyses of specific compounds, and the reliance upon data from one study (the AHS) limit interpretation regarding risk.
[Alexander DD, Weed DL, Mink PJ, Mitchell ME. 2012. Int Arch Occup Environ Health. 85(7):715-45.] - Lifestyle, occupational, and reproductive factors and risk of colorectal cancer
Lifestyle factors and environmental exposures might help explain the risk of colorectal carcinoma in countries where the incidence is low, but unique patterns of young onset and a high proportion of rectal cancer exist. Authors obtained detailed lifestyle information from 421 patients with colorectal cancer and 439 hospital-controls in Egypt. A history of pesticide exposure and more frequently eating food directly from farms were significantly associated with a higher risk of colorectal carcinoma (odds ratio = 2.6 and odds ratio = 4.6 respectively). Parous women who reported 7 or more live births or breastfed for 19 months or longer per live birth had a significantly lower risk for colorectal carcinoma. Compared with patients aged 40 years or older, industrial exposures were more common in younger patients. Agricultural and industrial exposures were associated with increased risk of colorectal carcinoma, whereas prolonged lactation and increased parity were inversely associated with colorectal carcinoma in women. Further research to elucidate the biological role of intense environmental and industrial exposures and reproductive factors including lactation may further clarify the etiology of colorectal cancer.
[Lo AC, Soliman AS, Khaled HM, et al. 2010. Dis Colon Rectum. 53(5):830-7.] - Heterocyclic aromatic amine pesticide use and human cancer risk: results form the U.S. Agricultural Health Study
A prospective cohort study of the Agricultural Health Study evaluated imazethapyr, a heterocyclic aromatic amine herbicide, finding significant trend in risk with increasing lifetime exposure for colon cancer, limited to proximal cancers.
[Koutros, S., et al. 2009. Int J Cancer 124(5):1206-1212.] - Cancer incidence among pesticide applicators exposed to trifluralin in the Agricultural Health Study.
Trifluralin, 2,6-dinitro-N,N-dipropyl-4-trifluoromethylaniline, is a 2,6-dinitro herbicide widely used to control annual grasses and broadleaf weeds in agricultural settings. The association between trifluralin use and common cancer incidence was evaluated among 50,127 private and commercial pesticide applicators in the Agricultural Health Study (AHS), a prospective cohort study of licensed pesticide applicators and their spouses in Iowa and North Carolina. Poisson regression was used to examine internal dose–response relationships, while controlling for important lifestyle factors and other agricultural exposures. Two metrics of exposure (lifetime days and intensity-weighted lifetime days) were used in exposure–response analyses with non-exposed applicators, as well as applicators in the lowest tertile of exposure, as reference groups. Incident cancers were identified through state tumor registries from enrollment in 1993 through 2002. Trifluralin exposure was not associated with cancer incidence overall among 51% of private and commercial applicators (n=25,712) who had used trifluralin. However, there was an excess of colon cancer in the exposure category of higher half of highest tertile (rate ratios (RR) of 1.76 (95% CI=1.05–2.95) using the non-exposed as a referent and 1.93 (95% CI=1.08–3.45) using those with the lowest tertile of exposure as the referent). There was also a non-significantly elevated risk for kidney cancer and bladder cancer in the highest exposure group, although only the kidney cancer finding was consistent across exposure metrics. Although there was a possible link between trifluralin exposure and colon cancer, small numbers and inconsistencies in dose–response and subgroup analyses indicate that this may be a chance finding.
[Kang, D. et al., 2008. Environmental research, 107(2), pp.271-276.] - S-Ethyl-N,N-dipropylthiocarbamate exposure and cancer incidence among male pesticide applicators in the Agricultural health Study: A perspective cohort
An association between the highest category of lifetime the thiocarbamate herbicide EPTC (S-Ethyl-N,N-dipropylthiocarbamate )exposure days and colon cancer is found in participants in the Agricultural Health Study.
[van Bemmel, D.M., et al. 2008. Environmental Health Perspectives 116(11):1541-1546.] - Pesticide use and colorectal cancer risk in the Agricultural Health Study
A study of agricultural pesticides and colorectal cancer incidence in the Agricultural Health Study, chlorpyrifos shows significant exposure response trend for rectal cancer.
[Lee, W.J., et al. 2007. Int J Cancer 121(2):339-346.] - Cancer incidence among pesticide applicators exposed to dicamba in the Agricultural Health Study
Dicamba is an herbicide commonly applied to crops in the United States and abroad. We evaluated cancer incidence among pesticide applicators exposed to dicamba in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in North Carolina and Iowa. Detailed pesticide exposure information was obtained through a self-administered questionnaire completed from 1993 to 1997. Cancer incidence was followed through 31 December 2002 by linkage to state cancer registries. We used Poisson regression to estimate rate ratios and 95% confidence intervals for cancer subtypes by tertiles of dicamba exposure. Two dicamba exposure metrics were used: lifetime exposure days and intensity-weighted lifetime exposure days (lifetime days × intensity score). A total of 41,969 applicators were included in the analysis, and 22,036 (52.5%) reported ever using dicamba. Exposure was not associated with overall cancer incidence nor were there strong associations with any specific type of cancer. When the reference group comprised low-exposed applicators, we observed a positive trend in risk between lifetime exposure days and lung cancer (p = 0.02), but none of the individual point estimates was significantly elevated. We also observed significant trends of increasing risk for colon cancer for both lifetime exposure days and intensity-weighted lifetime days, although these results are largely due to elevated risk at the highest exposure level. There was no apparent risk for non-Hodgkin lymphoma. Although associations between exposure and lung and colon cancer were observed, we did not find clear evidence for an association between dicamba exposure and cancer risk.
[Samanic, C., et al. 2006. Environ Health Perspect 114(10):1521-1526.] - Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
A study in Costa Rica finds heavy pesticide use in rural counties is associated with an increase risk in females for rectum cancer (OR 1.86) and colon cancer (OR 1.65).
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.] - Cancer mortality among Iowa farmers: recent results, time trends, and lifestyle factors (United States)
To update the cancer mortality patterns among Iowa (United States) farmers for the years 1987-93 and compare these results with those previously reported for 1971-86 as well as relate the PMR patterns to risk-factor survey data. We extracted usual occupation and cause of death from 88,090 Iowa death certificates for White males aged 20 and older for the years 1987-93. Proportional mortality ratios (PMR), adjusted for age, and 95 percent confidence intervals (CI) were calculated using deaths among nonfarmers to generate expected numbers. We compared lifestyle profiles for farmers and nonfarmers using male controls (n = 1,596) from a population-based case-control study conducted in Iowa from 1986-89. Iowa farmers had deficit PMRs for all-cause cancer mortality (PMR = 0.92, CI = 0.90-0.94) and for lung (PMR = 0.70, CI = 0.66-0.73), liver (PMR = 0.65, CI = 0.50-0.86), and other cancer sites strongly related to smoking and alcohol use. Farmers at all ages had excess deaths for cancers of the prostate (PMR = 1.26, CI = 1.19-1.33), rectum (PMR = 1.29, CI = 1.07-1.56), brain (PMR = 1.10, CI = 0.92-1.32), multiple myeloma (PMR = 1.17, CI = 0.98-1.40), non-Hodgkin's lymphoma (PMR = 1.09, CI = 0.96-1.23), and Hodgkin's disease (PMR = 1.62, CI = 1.04-2.54). Younger farmers (aged 20 to 64 years) had excess deaths for colon cancer (PMR = 1.52, CI =1.26-1.85) and skin melanoma (PMR = 1.60, CI = 1.07-2.38), while older farmers (aged 65+ years) had excess deaths for cancers of the pancreas (PMR = 1.18, CI = 1.04-1.34), lip (PMR = 1.58, CI = 0.59-4.21), and leukemia (PMR = 1.26, CI = 1.09-1.46). Since the 1970s, the PMR for stomach cancer has declined to expected values, while the PMRs for prostate, large intestine, pancreas, and Hodgkin's disease have increased; PMRs for other sites are consistent with earlier data. A survey from 1986-89 showed that farmers, compared with nonfarmers, smoked less, used less alcohol, had less formal education, and consumed more total calories, and calories from protein, fat, and meat while consuming fewer calories from fruits and vegetables. Iowa farmers continue to be at elevated risk of mortality due to certain cancers, and, of particular interest, the risk for prostate and colon cancer appears to be increasing since 1970.
[Cerhan, J.R., et al. 1998. Cancer Causes Control 9(3):311-319.] - Cancer incidence among Icelandic pesticide users
This study was done to examine the cancer risk among pesticide users in Iceland. We have followed a cohort of 2449 licensed pesticide users, students from a horticultural college, members of a pension fund for market gardeners, horticulturists and vegetable farmers up until the end of 1993 In the Icelandic Cancer Registry of cancer incidence. The observed number of cancers was compared with expected values calcualted on the basis of cancer incidence for males and females in Iceland. The standardized incidence ratio (SIR) for all cancer sites was 0.80. Among females the increased incidence for cancer of lymphatic and haematopoietic tissue was significant (SIR = 5.56, 95% confidence interval (CI) 1.12–16.23). The incidence of rectal cancer was three times that expected (SIR = 4.63, 95% CI: 1.49–10.80). All cancers of the rectum were adenocarcinoma, however, one was adenocarcinorna in villous adenoma and one adenocarcinoma in tubulo-villous adenorna. The results provide some support for the suggestion that pesticide exposure may lead to cancer of the lymphatic and haematopoietic tissue in females. We suggest that some of the pesticides to which the licensed pesticide users were exposed may lead to rectal cancer.
[Zhong, Y. and Rafnsson, V. 1996. International Journal of Epidemiology 25(6):1117-1124.] - Proportionate mortality study of golf course superintendents.
A proportionate mortality study of a cohort of 686 golf course superintendents finds an elevated number deaths from brain cancer (PMR 234), large intestine cancer (PMR 175), NHL (PMR 237), and prostate cancer (PMR 293).
[Kross, B.C., et al. 1996. Am J Ind Med 29(5):501-506] - Cancer among farmers in central Italy
This case-referent study evaluated cancer risks among farmers in central Italy. Cancer cases (N = 1674, 17 sites) were selected from all deceased men aged 35-80 years; a random sample of 480 decedents formed the reference series. Farmers had a decreased risk of lung and bladder cancer and melanoma and nonsignificant excess risks for stomach, rectal, kidney, and nonmelanoma skin cancer. Stomach and kidney cancer were significantly increased among the farmers with > 10 years' experience, and stomach, rectal, and pancreatic cancer were increased among licensed pesticide users with > 10 years' experience. Possible relationships emerged between specific crops and cancer: fruit and colon and bladder cancer, wheat and prostate cancer, olives and kidney cancer, and potato and kidney cancer. The results regarding stomach, pancreatic, lung, bladder, and prostate cancer and melanoma congrue with earlier results. The kidney cancer excess, the association of colon and bladder cancer with orchard farming, and the excess of rectal cancer among licensed farmers are new and unexpected findings.The study also finds a significantly increased risk of rectal cancer among licensed pesticides users with greater than 10 years’ experience.
[Forastiere, F, et al. 1993. Scand J Work Environ Health 19(6):382-389.]
Eye Cancer
- Prenatal ambient pesticide exposure and childhood retinoblastoma
Retinoblastoma is a rare tumor of the retina, most commonly found in young children. Due to the rarity of this childhood cancer, few studies have been able to examine prenatal pesticide exposure as a risk factor. To examine the relationship between childhood retinoblastoma and prenatal exposure to pesticides through residential proximity to agricultural pesticide applications. We conducted a population-based case-control study using cases aged 5 and younger identified from the California Cancer Registry, and controls randomly selected from California birth certificates. Frequency matching cases to controls by age resulted in 221 cases of unilateral retinoblastoma and 114 cases of bilateral retinoblastoma, totaling 335 cases and 123,166 controls. Based on addresses from birth certificates we employed Pesticide Use Reports and land use information within a geographic information system approach to individually assess exposures to specific pesticides within 4000 m of the residence reported on birth certificates. The associations between retinoblastoma (all types combined and stratified by laterality) and individual pesticides were expressed as odds ratios estimates obtained from unconditional logistic regression models including a single pesticide, and from a hierarchical logistic regression model including all pesticides. We found that exposures to acephate (OR: 1.70, 95% CI: 1.20, 2.41) and bromacil (OR: 1.87, 95% CI: 1.07, 3.26) were associated with increased risk for unilateral retinoblastoma. In addition to acephate, we found that pymetrozine (OR: 1.45, 95% CI: 1.00, 2.08) and kresoxim-methyl (OR: 1.60, 95% CI: 1.00, 2.56) were associated with retinoblastoma (all types combined). Our findings suggest that certain types of prenatal ambient pesticide exposure from residing near agricultural fields may play a role in the development of childhood retinoblastoma.
[Thompson, S., Ritz, B., Cockburn, M. and Heck, J.E., 2022. International Journal of Hygiene and Environmental Health, 245, p.114025.] - A case-control study of paternal occupational exposures and the risk of childhood sporadic bilateral retinoblastoma.
The risk factors for sporadic (ie, non-familial) retinoblastoma remain largely unknown. Authors examined the relationship between paternal occupational exposures from jobs held 10 years and 1 year prior to conception and the risk of sporadic bilateral retinoblastoma in children.Paternal occupational data were obtained for 198 incident cases diagnosed with sporadic bilateral retinoblastoma from January 1998 to May 2006 and 245 referral-based controls from the case child's relatives and friends who were matched to 135 of the cases on birth year. There was some indication of an elevated risk associated with paternal pesticide exposure in the 10 years prior to conception as well as in the year before conception. However, results for pesticide exposure were inconsistent and varied by analysis approach. Exposure-response trends were observed for pesticides and non-welding metal exposures. Findings suggest a potential role of paternal occupational exposures to non-welding metals and perhaps pesticides in the aetiology of childhood retinoblastoma.
[Abdolahi A, van Wijngaarden E, McClean MD, et al. 2013. Occup Environ Med. 70(6):372-9] - Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
Retinoblastoma associated with increased risk estimates for children less than one year of year and up through nine years of age is found in a study looking at children with cancer residence at diagnosis relative to the percent of land used for agriculture in the county.
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - Cancer in offspring of parents engaged in agricultural activities in Norway: incidence and risk factors in the farm environment.
Parental agricultural exposure to pesticides is associated with eye cancer.
[Kristensen, P., et al. 1996. Int J Cancer 65(1):39-50]
Gallbladder Cancer
- The association of cancer risks with pentachlorophenol exposure: Focusing on community population in the areas along certain section of Yangtze River in China.
Pentachlorophenol (PCP) was used in large quantities, and mainly for killing the intermediate host snails of schistosome in China, thereby resulting in ubiquitous PCP residue in the environment. However, studies considering the carcinogenicity of PCP for humans mainly focused on occupational workers, and the actual carcinogenicity of PCP for general population is uncertain. To investigate the association between cancer risks and PCP exposure in a community population, an ecological study was conducted in three contaminated areas along the Yangtze River. Standardized rate ratio (SRR) was calculated to represent the risk of cancer incidence, by using incidence in the low PCP exposure category as the reference group. A total of 15,962 cancer records were collected, and 76 water samples and 213 urine samples in three areas were examined. Findings suggested that compared with the low PCP group, the high PCP group had significantly excessive incidences of various cancers related to different organs including lymph (SRR = 19.44, 95% CI = 15.00-25.19), blood (SRR = 17.24, 95% CI = 12.92-23.01), nasopharynx (SRR = 3.97, 95% CI = 3.75-4.21), gallbladder (SRR = 3.46, 95% CI = 3.09-3.87), pancreas (SRR = 3.41, 95% CI = 3.07-3.79), respiratory system (SRR = 3.41, 95% CI = 3.27-3.57) and liver (SRR = 3.31, 95% CI = 3.09-3.56). Taken together, the present study provides evidence that general community population exposed to high level of PCP exhibits a broader spectrum of increased cancer risks as compared to occupational groups.
[Cui Y, Liang L, Zhong Q, He Q, et al. 2017. Environ Pollut. 224:729-738.] - Mortality in a cohort of pesticide applicators in an urban setting: sixty years of follow-up
A cohort study in Rome of urban pesticide applicators finds an increased risk for cancer of the gallbladder, liver, and nervous system.
[Giordano, F., et al. 2006. Int J Immunopathol Pharmacol 19(Suppl 4):61-65.] - Organochlorine pesticides in carcinoma of the gallbladder: a case-control study.
Carcinoma of the gallbladder is the third most common malignancy of the gastrointestinal tract in the Eastern Uttar Pradesh and Western Bihar regions of India. The main source of drinking water in this region is the river Ganges, which is heavily polluted with agricultural pesticides. Organochlorine pesticides were estimated in bile by gas liquid chromatography in 60 patients (30 carcinoma of the gallbladder and 30 cholelithiasis) to observe its association with aetiopathogenesis of carcinoma of the gallbladder. The mean biliary concentration of benzene hexachloride (BHC) was found to be significantly higher in carcinoma of the gallbladder (0.0471 ppm) than in cholelithiasis (0.0352 ppm) (P < 0.04). The mean biliary concentration of dichlorodiphenyltrichloroethane (DDT) was also significantly higher in carcinoma of the gallbladder (0.418 ppm) than in cholelithiasis (0.0103 ppm) (P < 0.03). Biliary aldrin and endosulfan concentrations were higher in carcinoma of the gallbladder (0.0008 and 0.00132 ppm) than in cholelithiasis (0.0005 and 0.0126 ppm) but the difference was statistically not significant (P < 0.06 and P < 0.9). The levels of pesticides in blood did not show significant differences in either carcinoma of the gallbladder or cholelithiasis. Significantly high biliary BHC and DDT concentrations suggest that these pesticides might be associated with gallbladder carcinogenesi.
[Shukla VK, Rastogi AN, Adukia TK, et al. 2001. Eur J Cancer Prev. 10(2):153-6.] - Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
A study in Costa Rica finds heavy pesticide use in rural counties is associated with an increase risk for gallbladder cancer in males (OR 1.49) and in females (OR 1.73).
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.]
Kidney/Renal Cancer
- Environmental Exposures Related to Parental Habits in the Perinatal Period and the Risk of Wilms' Tumor in Children
Wilms' tumor is the most frequently diagnosed renal tumor in children. Little is known about its etiology. The aim of this study was to investigate the potential role of specific exposures related to parental habits such as parental smoking, maternal alcohol consumption and the use of household pesticides during pregnancy. The ESTELLE study was a nationwide case-control study that included 117 Wilms' tumor cases and 1100 control children from the general French population, frequency-matched by age and gender. Unconditional logistic regression was used to estimate odds ratios and 95 % confidence intervals. After controlling for matching variables and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with the risk of Wilms' tumor in children (OR 1.6 [95 % CI 1.1-2.3]). Insecticides were the most commonly reported type of pesticide and there was a positive association with their use (OR 1.7 [95 % CI 1.1-2.6]. The association was stronger when they were used more often than once a month (OR 1.9 [95 % CI 1.2-3.0]. Neither maternal smoking during pregnancy nor paternal smoking during preconception/pregnancy was associated with a risk of Wilms' tumor (ORs 1.1[95 % CI 0.7-1.8] and 1.1 [95 % CI 0.7-1.7], respectively). No association was observed with maternal alcohol intake during pregnancy (OR 1.2 [95 % CI 0.8-2.0]). Our findings suggest an association between the maternal use of household pesticides during pregnancy and the risk of Wilms' tumor.
[Rios, P., Bauer, H., Schleiermacher, G., Pasqualini, C., Boulanger, C., Thebaud, E., Gandemer, V., Pellier, I., Verschuur, A., Sudour-Bonnange, H. and Coulomb-l'Hermine, A., 2020. Cancer Epidemiology, 66, p.101706.] - Evidence of risks of renal function reduction due to occupational exposure to agrochemicals: A systematic review.
Agriculture accounts for an important economic activity worldwide and the search for the increased productivity incorporated the use of pesticides in this practice. Such compounds have significant environmental and human health effects, especially for workers exposed to them. Among the main health problems caused by pesticides are the renal alterations, which in more advanced stages comprise an important public health problem. For this reason, this systematic review aimed at gathering evidence of the risk of renal changes induced by occupational exposure to pesticides. The search was made in PubMed, Scopus, Lilacs and Scielo in December 2017, using keywords as pesticides, poisoning, kidney, renal insufficiency. After the application of inclusion criteria, 11 studies were selected. It was possible to gather evidence on the prevalence and risk (3.12-6.71) of renal injury from the occupational exposure of agricultural workers and its association with the exposure to agrichemicals, as organophosphates and herbicides.
[Prudente IRG, Cruz CL, Nascimento LC, Kaiser CC, Guimarães AG. 2018. Environ Toxicol Pharmacol. 63:21-28] - Occupational exposures and genetic susceptibility to urinary tract cancers: a systematic review and meta-analysis.
This study aims to summarize the current knowledge on the relationship between genetic polymorphisms, occupational exposures, and urinary tract cancers. Authors searched MEDLINE, ISI Web of science, and SCOPUS online databases for all articles published in English language up to September 2016. A meta-analysis was performed to provide summary estimates for the association between a certain genetic polymorphism, occupational exposure and bladder cancer (BC) or kidney cancer (KC), when appropriate. Fifteen studies on BC and six on KC were deemed eligible for the review. With regard to BC, an overall odds ratio (OR) of 2.07 [95% confidence interval (CI): 1.38-3.09] for those with GSTM1 and an OR of 2.07 (95% CI: 1.38-3.09) for those with GSTT1 null genotype were reported when exposed to polycyclic aromatic hydrocarbons (PAHs). NAT2 slow genotype carriers had an OR of 3.59 (95% CI: 2.62-4.93) for BC when exposed to aromatic amines and an OR of 2.07 (95% CI: 1.36-3.15) when exposed to PAHs. With regard to KC and pesticide exposure, the meta-analysis reported an OR of 4.38 (95% CI: 2.28-8.41) for GSTM1 present genotype, an OR of 2.59 (95% CI: 1.62-4.15) for GSTT1-present genotype and an OR of 6.51 (95% CI: 2.85-14.89) for combined effects of GSTM1 and GSTT1 active genotypes. This meta-analysis indicates a possible association between the variant genotypes of GSTM1, GSTT1, NAT2 and SULT1A1, occupational exposure to aromatic amines or PAHs, and development of BC. Our results suggest that polymorphisms in GSTM1 and GSTT1 genes could influence the risk for developing KC in individuals occupationally exposed to pesticides.
[Stojanovic J, Milovanovic S, Pastorino R, et al. 2017. Eur J Cancer Prev. doi: 10.1097/CEJ.0000000000000364] - Renal cell carcinoma, occupational pesticide exposure and modification by glutathione S-transferase polymorphisms.
This study investigated associations between occupational pesticide exposure and renal cell carcinoma (RCC) risk. Study also considered whether this association could be modified by glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) genotypes. About 1097 RCC cases and 1476 controls from Central and Eastern Europe were interviewed to collect data on lifetime occupational histories. Occupational information for jobs held for at least 12 months duration was coded for pesticide exposures and assessed for frequency and intensity of exposure. GSTM1 and GSTT1 gene deletions were analyzed using TaqMan assays. A significant increase in RCC risk was observed among subjects ever exposed to pesticides. After stratification by genotypes, increased risk was observed among exposed subjects with at least one GSTM1 active allele but not among exposed subjects with two GSTM1 inactive alleles compared with unexposed subjects with two inactive alleles. Risk was highest among exposed subjects with both GSTM1 and GSTT1 active genotypes compared with unexposed subjects with at least one GSTM1 or T1 inactive genotype. In the largest RCC case-control study with genotype information conducted to date, it was observed that risk associated with pesticide exposure was exclusive to individuals with active GSTM1/T1 genotypes. These findings further support the hypothesis that glutathione S-transferase polymorphisms can modify RCC risk associated with occupational pesticide exposure.
[Karami S, Boffetta P, Rothman N, Hung RJ, Stewart T, et al. 2008. Carcinogenesis. 29(8):1567-71] - Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with moderate to high agriculture activity finds statistically significantly elevated risk for renal carcinoma at moderate agriculture activity (OR 2.3) and at high agriculture activity (OR 3.3). In regards to specific crops grown, the study finds a link between cotton crops and renal carcinomas (OR 6.9).
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - Wilm’s tumor and exposure to residential and occupational hazardous chemicals
A case-control study by the CDC finds elevated risk for pesticides during pregnancy and during the 2-year period prior to birth.
[Tsai, J., et al. 2006. Int J Hyg Environ Health 209(1):57-64.] - Glutathione S-transferases M1-1 and T1-1 as risk modifiers for renal cell cancer associated with occupational exposure to chemicals.
Study aimed to investigate the possible interaction between occupational risk factors and genotype for glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) in renal cell cancer (RCC).One hundred patients with RCC and 200 outpatient controls were enrolled at Parma University Hospital. The polymorphisms of glutathione S-transferase M1-1 (GSTM1) and T1-1 (GSTT1) were investigated by PCR; occupational history was collected by a structured questionnaire. Subjects with GSTM1 present genotype showed higher risks for RCC, compared to GSTM1 null subjects, if exposed to metals or pesticides. The GSTT1 present genotype also enhanced the risk (about twofold) of RCC among subjects exposed to solvents and pesticides, compared with those GSTT1 null.Results support the hypothesis that GSTM1 and GSTT1 polymorphisms can interact with several occupational exposures to significantly modify the risk of RCC among exposed subjects.
[Buzio L, De Palma G, Mozzoni P, et al. 2003. Occup Environ Med. 60(10):789-93] - Occupational risk factors for renal cell cancer. An Italian case-control study.
“Prolonged” occupational exposures to pesticides is associated with an increased risk for renal cell cancer (OR 2.0).
[Buzio, L., et al. 2002. Med Lav 93(4):303-309.] - Renal cell carcinoma and occupational exposure to chemicals in Canada
An increased risk of renal cell carcinoma in males is associated with exposure to herbicides (1.6 OR) and pesticides (1.8 OR) and in particular a dose-response relationship for herbicides.
[Hu, J., et al. 2002. Occup Med 52(3):157-164.] - Childhood cancer and paternal employment in agriculture: the role of pesticides
Previous studies have suggested that the offspring of men potentially exposed to pesticides at work may be at increased risk of kidney cancer (Wilms' tumour), brain tumours, Ewing's bone sarcoma and acute leukaemia. This paper examines the association between potential occupational exposure of fathers to pesticides and offspring's death from cancer in a large national database. Records for 167703 childhood deaths occurring during 1959-63, 1970-78 and 1979-90 in England and Wales have been analysed. Among the offspring of men with potential occupational exposure to pesticides there were 5270 deaths, of which 449 were due to cancer. Associations were assessed using proportional mortality ratios (PMRs), with adjustment for age, year of death and paternal social class. Of the childhood cancers previously linked with potential paternal occupational exposure to pesticides, the only statistically significant excess was for kidney cancer (PMR=1.59, 95% CI=1.18-2.15, based on 42 deaths). Although these results offer some support for the suggestion that paternal occupational exposure to pesticides may be related to the subsequent development of kidney cancer in offspring, other explanations cannot be excluded. In the light of the findings presented here and elsewhere, further, more detailed, research into the nature of this relationship is warranted.
[Fear, N.T., et al. 1998. Br J Cancer 77(5):825-829.] - Cancer in offspring of parents engaged in agricultural activities in Norway: incidence and risk factors in the farm environment.
Parental agricultural exposure to pesticides is associated with Wilms’ tumor, as well as other forms of cancer.
[Kristensen, P., et al. 1996. Int J Cancer 65(1):39-50] - Parental exposures to pesticides and risk of Wilms’ tumor in Brazil
Elevated risk is found for farm work involving paternal (3.24 OR) and maternal (128.6 OR) frequent use of pesticides.
[Sharpe, C.R., et al. 1995. Am J Epidemiol 141(3):210-217.] - Occupational risk factors for renal-cell carcinoma in Denmark
Risk of renal-cell carcinoma was found to be associated with employment as a truck driver, exposure to gasoline, other hydrocarbons, and insecticides and herbicides. The risk of renal-cell carcinoma was higher in the lower socioeconomic strata for both the men and the women.
[Mellemgaard, A., et al. 1994. Scand J Work Environ Health 20(3):160-165.] - Cancer among farmers in central Italy
A case-referent study of Italian farmers finds a significantly increased risk of kidney cancer among farmers with greater than 10 years experience and a possible relationship between olives and potato growing and kidney cancer.
[Forastiere, F, et al. 1993. Scand J Work Environ Health 19(6):382-389.] - Risk factors for Wilms tumor
A study examining nonoccupational risk factors for Wilms tumor finds an association with a history of household insect extermination.
[Olshan, A.F., et al. 1993. Cancer 72(3):938-944.]
Laryngeal Cancer
- Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
A study in Costa Rica finds heavy pesticide use in rural counties is associated with an increase risk for larynx cancer in males (OR 1.88).
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.] - Occupational risk factors for cancer of the larynx in Spain.
Spain is one of the countries with the highest incidence of laryngeal cancer and, together with France, is the country with the lowest percentage of women with this disease. In order to identify the occupational risk factors associated with laryngeal cancer in this country a case-control study was performed. Cases included 85 patients with epidermoid carcinoma of the larynx diagnosed in "La Paz" Hospital, Madrid, between 1985 and 1987. A sample of 170 patients from the same hospital was used as control. The results of the study revealed that 56.5% of larynx cancer patients had a sedentary occupation working in the service sector. Exposure to insecticides or silica were strongest risk factors for laryngeal cancer.
[Bravo MP, Espinosa J, Calero JR. 1990. Neoplasma. 37(4):477-81.]
Leukemia
Childhood Leukemia
- Environmental Pollution and Risk of Childhood Cancer: A Scoping Review of Evidence from the Last Decade
The long-term effects of environmental pollution have been of concern as several pollutants are carcinogenic, potentially inducing a variety of cancers, including childhood cancer, which is a leading cause of death around the world and, thus, is a public health issue. The present scoping review aimed to update and summarize the available literature to detect specific environmental pollutants and their association with certain types of childhood cancer. Studies published from 2013 to 2023 regarding environmental pollution and childhood cancer were retrieved from the PubMed database. A total of 174 studies were eligible for this review and were analyzed. Our search strategy brought up most of the articles that evaluated air pollution (29%) and pesticides (28%). Indoor exposure to chemicals (11%), alcohol and tobacco use during pregnancy (16%), electromagnetic fields (12%), and radon (4%) were the subjects of less research. We found a particularly high percentage of positive associations between prenatal and postnatal exposure to indoor (84%) and outdoor (79%) air pollution, as well as to pesticides (82%), and childhood cancer. Positive associations were found between leukemia and pesticides and air pollution (33% and 27%); CNS tumors and neuroblastoma and pesticides (53% and 43%); and Wilms tumor and other rare cancers were found in association with air pollution (50%). Indoor air pollution was mostly reported in studies assessing several types of cancer (26%). Further studies are needed to investigate the mechanisms underlying the potential associations between indoor/outdoor air pollution and pesticide exposure with childhood cancer risk as more preventable measures could be taken.
[Navarrete-Meneses, M.D.P. et al. (2024) Environmental pollution and risk of childhood cancer: A scoping review of evidence from the last decade, International journal of molecular sciences. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10970446/. ] - Association between Residential Proximity to Viticultural Areas and Childhood Acute Leukemia Risk in Mainland France: GEOCAP Case-Control Study, 2006-2013
Pesticide exposures are suspected of being a risk factor for several childhood cancers, particularly acute leukemia (AL). Most of the evidence is based on self-reported parental domestic use of pesticides, but some studies have also addressed associations with agricultural use of pesticides near the place of residence. The objective of the study was to evaluate the risk of AL in children living close to vines, a crop subject to intensive pesticide use. Data were drawn from the national registry-based GEOCAP study. We included all of the AL cases under the age of 15 years diagnosed in 2006-2013 (n = 3,711) and 40,196 contemporary controls representative of the childhood population in France. The proximity of the vines (probability of presence within 200, 500, and 1,000m) and the viticulture density (area devoted to vines within 1,000 m) were evaluated around the geocoded addresses in a geographic information system combining three national land use maps. Logistic regression models were used to estimate odds ratios (ORs) for all AL and for the lymphoblastic (ALL) and myeloid (AML) subtypes. Heterogeneity between regions was studied by stratified analyses. Sensitivity analyses were carried out to take into account, in particular, geocoding uncertainty, density of other crops and potential demographic and environmental confounders. In all, about 10% of the controls lived within 1 km of vines. While no evidence of association between proximity to vines and AL was found, viticulture density was positively associated with ALL [OR=1.05 (1.00-1.09) for a 10% increase in density], with a statistically significant heterogeneity across regions. No association with AML was observed. The results remained stable in all the sensitivity analyses. We evidenced a slight increase in the risk of ALL in children living in areas with high viticulture density. This finding supports the hypothesis that environmental exposure to pesticides may be associated with childhood ALL.
[Mancini, M., Hémon, D., de Crouy-Chanel, P., Guldner, L., Faure, L., Clavel, J. and Goujon, S., 2023. Environmental Health Perspectives, 131(10), p.107008.] - Occupational exposure to pesticides in mothers and fathers and risk of cancer in the offspring: A register-based case-control study from Sweden (1960–2015)
Maternal and paternal occupational exposure to pesticides was linked to leukemia in the offspring in some previous studies. Risks for other cancers, particularly from maternal exposure, are largely unknown. We examined the association between maternal and paternal exposure to pesticides and childhood cancer in a Swedish register-based case-control study (1960–2015). Cancer cases
[Rossides, M. et al. (2022) Occupational exposure to pesticides in mothers and fathers and risk of cancer in The offspring: A register-based case-control study from Sweden (1960–2015), Environmental Research. Available at: https://www.sciencedirect.com/science/article/pii/S0013935122011471?via%3Dihub. ] - Residential proximity to croplands at birth and childhood leukemia
Domestic and parental occupational pesticide exposures are suspected of involvement in the occurrence of childhood acute leukaemia (AL), but the role of exposure to agricultural activities is little known. In a previous ecological study conducted in France, we observed an increase in acute lymphoblastic leukaemia (ALL) incidence rate with increasing viticulture density in the municipalities of residence at diagnosis. This study aimed to test the hypothesis that residential proximity to croplands at birth increases the risk of childhood AL, with a particular focus on vineyards. We identified all the primary AL cases diagnosed before the age of 15 years in the cohorts of children born in the French municipalities between 1990 and 2015. We estimated crop densities in each municipality of residence at birth using agricultural census data, for ten crop types. Variations in standardized incidence ratios (SIR) were evaluated with Poisson regression models, for all AL, ALL and acute myeloid leukaemia (AML), separately. Among the 19,809,700 children born and residing in mainland France at birth in 1990–2015, 8,747 AL cases (7,236 ALL and 1,335 AML) were diagnosed over the period. We did not evidence any statistically significant positive association between total crop density or any specific crop density in the municipality of residence at birth and all AL, ALL or AML. Interestingly, we observed a higher ALL incidence rate in the municipalities with the highest viticulture densities (SIR = 1.25 95%CI [1.01–1.54]). Adjusting for the main potential confounders did not change the results. Our study does not support the hypothesis that residential proximity to croplands, particularly vineyards, around birth plays a role in childhood leukaemia. The slightly higher ALL incidence rate in children born in the municipalities with the highest viticulture densities may reflect the previously-observed association at diagnosis.
[Bamouni, S., Hémon, D., Faure, L., Clavel, J. and Goujon, S., 2022. Environ Health 21, 103 (2022). ] - Exposure to pesticides and childhood leukemia risk: A systematic review and meta-analysis
Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15–3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39–4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00–1.99) and insecticide (OR: 1.60, 95%CI: 1.11–2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12–0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44–3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98–5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (ORparental: 1.75, 95%CI: 1.08–2.85; ORpaternal: 1.20, 95%CI: 1.07–1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure.Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15–3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39–4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00–1.99) and insecticide (OR: 1.60, 95%CI: 1.11–2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12–0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44–3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98–5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (ORparental: 1.75, 95%CI: 1.08–2.85; ORpaternal: 1.20, 95%CI: 1.07–1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure.
[Karalexi, M.A., Tagkas, C.F., Markozannes, G., Tseretopoulou, X., Hernández, A.F., Schüz, J., Halldorsson, T.I., Psaltopoulou, T., Petridou, E.T., Tzoulaki, I. and Ntzani, E.E. Environmental Pollution, p.117376.] - Agricultural crop density in the municipalities of France and incidence of childhood leukemia: An ecological study
Pesticide exposure is suspected to play a role in the etiology of childhood leukemia (AL). Various sources of exposure have been explored, but few studies have investigated the risk of childhood AL in relation to residential exposure to agricultural pesticides. Since around 50% of France is agricultural land, with marked pesticide use, France is a suitable location to investigate for an association. We aimed to analyze the association between the agricultural crop density in the municipalities of France and the incidence of childhood AL between 1990 and 2014. 11,487 cases of AL diagnosed in children aged 0–14 years were registered by the French National Registry of Childhood Hematological Malignancies over 1990–2014. National agricultural census data for 1990, 2000 and 2010 were used to estimate the densities of the most common crops in France. The incidence of AL was estimated in the 35,512 municipalities, by age and gender, and 3 observation periods, and expressed as the standardized incidence ratio (SIR). We observed a moderate log-linear association between viticulture density and the incidence of AL, with a 3% increase in SIR for a 10% increase in viticulture density (SIRR = 1.03; 95%CI [1.00–1.06]). The association remained for lymphoblastic AL but not for myeloid AL. The association was stable after stratification by geographic area, age and period, and after adjustment on UV radiation and a French deprivation index. No consistent association was observed for other crop types. This nationwide study shows a moderate increase in incidence of childhood AL in municipalities where viticulture is common. Future individual studies are needed to know whether this observation is confirmed and related to particular use of pesticides.
[Coste, A., Goujon, S., Faure, L., Hémon, D. and Clavel, J., 2020. Environmental Research, p.109517.] - Prenatal pesticide exposure and childhood leukemia - A California statewide case-control study
A number of epidemiologic studies with a variety of exposure assessment approaches have implicated pesticides as risk factors for childhood cancers. Here we explore the association of pesticide exposure in pregnancy and early childhood with childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) utilizing land use and pesticide use data in a sophisticated GIS tool. We identified cancer cases less than 6 years of age from the California Cancer Registry and cancer-free controls from birth certificates. Analyses were restricted to those living in rural areas and born 1998-2011, resulting in 162 cases of childhood leukemia and 9,805 controls. Possible carcinogens were selected from the Environmental Protection Agency's classifications and pesticide use was collected from the California Department of Pesticide Regulation's (CDPR) Pesticide Use Reporting (PUR) system and linked to land-use surveys. Exposures for subjects were assessed using a 4000m buffer around the geocoded residential addresses at birth. Unconditional logistic and hierarchical regression models were used to assess individual pesticide and pesticide class associations. We observed elevated risks for ALL with exposure to any carcinogenic pesticide (adjusted Odds Ratio (aOR): 2.83, 95% CI: 1.67-4.82), diuron (Single-pesticide model, adjusted (OR): 2.38, 95% CI: 1.57-3.60), phosmet (OR: 2.10, 95% CI: 1.46-3.02), kresoxim-methyl (OR: 1.77, 95% CI: 1.14-2.75), and propanil (OR: 2.58, 95% CI: 1.44-4.63). Analyses based on chemical classes showed elevated risks for the group of 2,6-dinitroanilines (OR: 2.50, 95% CI: 1.56-3.99), anilides (OR: 2.16, 95% CI: 1.38-3.36), and ureas (OR: 2.18, 95% CI: 1.42-3.34). Our findings suggest that in rural areas of California exposure to certain pesticides or pesticide classes during pregnancy due to residential proximity to agricultural applications may increase the risk of childhood ALL and AML. Future studies into the mechanisms of carcinogenicity of these pesticides may be beneficial.
[Park, A.S., Ritz, B., Yu, F., Cockburn, M. and Heck, J.E., 2020. International journal of hygiene and environmental health, 226, p.113486.] - Prenatal pesticide exposure and childhood leukemia – A California statewide case-control study
A number of epidemiologic studies with a variety of exposure assessment approaches have implicated pesticides as risk factors for childhood cancers. Here we explore the association of pesticide exposure in pregnancy and early childhood with childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) utilizing land use and pesticide use data in a sophisticated GIS tool. We identified cancer cases less than 6 years of age from the California Cancer Registry and cancer-free controls from birth certificates. Analyses were restricted to those living in rural areas and born 1998–2011, resulting in 162 cases of childhood leukemia and 9,805 controls. Possible carcinogens were selected from the Environmental Protection Agency's classifications and pesticide use was collected from the California Department of Pesticide Regulation's (CDPR) Pesticide Use Reporting (PUR) system and linked to land-use surveys. Exposures for subjects were assessed using a 4000m buffer around the geocoded residential addresses at birth. Unconditional logistic and hierarchical regression models were used to assess individual pesticide and pesticide class associations. We observed elevated risks for ALL with exposure to any carcinogenic pesticide (adjusted Odds Ratio (aOR): 2.83, 95% CI: 1.67–4.82), diuron (Single-pesticide model, adjusted (OR): 2.38, 95% CI: 1.57–3.60), phosmet (OR: 2.10, 95% CI: 1.46–3.02), kresoxim-methyl (OR: 1.77, 95% CI: 1.14–2.75), and propanil (OR: 2.58, 95% CI: 1.44–4.63). Analyses based on chemical classes showed elevated risks for the group of 2,6-dinitroanilines (OR: 2.50, 95% CI: 1.56–3.99), anilides (OR: 2.16, 95% CI: 1.38–3.36), and ureas (OR: 2.18, 95% CI: 1.42–3.34). Our findings suggest that in rural areas of California exposure to certain pesticides or pesticide classes during pregnancy due to residential proximity to agricultural applications may increase the risk of childhood ALL and AML. Future studies into the mechanisms of carcinogenicity of these pesticides may be beneficial.
[Park, A.S., Ritz, B., Yu, F., Cockburn, M. and Heck, J.E., 2020. International journal of hygiene and environmental health, 226, p.113486.] - A task-based assessment of parental occupational exposure to pesticides and childhood acute lymphoblastic leukemia.
Associations between parental occupational pesticide exposure and childhood acute lymphoblastic leukemia (ALL) vary across studies, likely due to different exposure assessment methodologies. This study assessed parental occupational pesticide exposure from the year before pregnancy to the child's third year of life for 669 children diagnosed with ALL and 1021 controls. Authors conducted expert rating using task-based job modules (JM) to estimate exposure to pesticides among farmer workers, gardeners, agricultural packers, and pesticide applicators. Compared to complete JMs, partial JMs and JEM led to 3.1% and 9.4% of parents with pesticide exposure misclassified, respectively. Misclassification was similar in cases and controls. Using complete JMs, we observed an increased risk of ALL for paternal occupational exposure to any pesticides (OR=1.7; 95% CI=1.2, 2.5), with higher risks reported for pesticides to treat nut crops (OR=4.5; 95% CI=0.9, 23.0), and for children diagnosed before five years of age (OR=2.3; 95% CI: 1.3, 4.1). Exposure misclassification from JEM attenuated these associations by about 57%. Maternal occupational pesticide exposure before and after birth was not associated with ALL. The risk of ALL was elevated in young children with paternal occupational pesticide exposure during the perinatal period, using more detailed occupational information for exposure classification.
[Gunier RB, Kang A, Hammond SK, Reinier K, et al. 2017. Environ Res. 156:57-62.] - Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research.
Infant leukaemia (less 1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease-secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide-and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future.
[Pelkonen O, Terron A, Hernandez AF, et al. 2017. Arch Toxicol. 91(8):2763-2780.] - Spatial clustering of childhood leukaemia with the integration of the Paediatric Environmental History.
Leukaemia remains the most common type of paediatric cancer and its aetiology remains unknown, but considered to be multifactorial. It is suggested that the initiation in utero by relevant exposures and/or inherited genetic variants and, other promotional postnatal exposures are probably required to develop leukaemia. This study aimed to map the incidence and analyse possible clusters in the geographical distribution of childhood acute leukaemia during the critical periods and to evaluate the factors that may be involved in the aetiology by conducting community and individual risk assessments. Researchers analysed all incident cases of acute childhood leukaemia diagnosed in a Spanish region during the period 1998-2013. At diagnosis, the addresses during pregnancy, early childhood and diagnosis were collected and codified to analyse the spatial distribution of acute leukaemia. A total of 158 cases of acute leukaemia were analysed. The crude rate for the period was 42.7 cases per million children. Among subtypes, acute lymphoblastic leukaemia had the highest incidence (31.9 per million children). A spatial cluster of acute lymphoblastic leukaemia was detected using the pregnancy address (p<0.05). The most common environmental risk factors related with the aetiology of acute lymphoblastic leukaemia, identified by the Paediatric Environmental History were: prenatal exposure to tobacco (75%) and alcohol (50%); residential and community exposure to pesticides (62.5%); prenatal or neonatal ionizing radiation (42.8%); and parental workplace exposure (37.5%). Study suggests that environmental exposures in utero may be important in the development of childhood leukaemia. Due to the presence of high-incidence clusters using pregnancy address, it is necessary to introduce this address into the childhood cancer registers. The Paediatric Environmental History which includes pregnancy address and a careful and comprehensive evaluation of the environmental exposures will allow us to build the knowledge of the causes of childhood leukaemia.
[Cárceles-Álvarez A, Ortega-García JA, López-Hernández FA, et al. 2017. Environ Res. 156:605-612] - A review of risk factors for childhood leukemia.
Leukemia is the most common cancer of childhood, with AML, CML, ALL and CLL being the most common. Environmental and genetic factors have been studied extensively in children with childhood leukemia. Other factors, such as the prenatal parental use of controlled substances, have not been investigated to the same degree. We review what is currently known about environmental and parental factors and the occurrence of leukemia in children.Electronic databases were searched for studies correlated pediatric leukemia with (1) ionizing radiation; (2) benzene; (3) parental drug use (4) parental alcohol use; (5) genetic factors.The two known significant environment risk factors for the occurrence leukemia are ionizing radiation and benzene. However, at least 4 studies have been published over the last century have looked at other environmental factors such as pesticides and drug and alcohol use as well as genetic factors such as gene fusions and translocations. We determined the risk of environmental and genetic factors that could be the cause of childhood leukemia in an effort to reduce the incidence of this disease.
[Jin MW, Xu SM, An Q, Wang P. 2016. Eur Rev Med Pharmacol Sci. 20(18):3760-3764.] - Childhood Leukemia and Primary Prevention.
Leukemia is the most common pediatric cancer, affecting 3800 children per year in the United States. Its annual incidence has increased over the last decades, especially among Latinos. Although most children diagnosed with leukemia are now cured, many suffer long-term complications, and primary prevention efforts are urgently needed. The early onset of leukemia-usually before 5 years of age-and the presence at birth of "pre-leukemic" genetic signatures indicate that pre- and postnatal events are critical to the development of the disease. In contrast to most pediatric cancers, there is a growing body of literature-in the United States and internationally-that has implicated several environmental, infectious, and dietary risk factors in the etiology of childhood leukemia, mainly for acute lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In contrast, intake of vitamins and folate supplementation during the preconception period or pregnancy, breastfeeding, and exposure to routine childhood infections have been shown to reduce the risk of childhood leukemia. Some children may be especially vulnerable to these risk factors, as demonstrated by a disproportionate burden of childhood leukemia in the Latino population of California. The evidence supporting the associations between childhood leukemia and its risk factors-including pooled analyses from around the world and systematic reviews-is strong; however, the dissemination of this knowledge to clinicians has been limited. To protect children's health, it is prudent to initiate programs designed to alter exposure to well-established leukemia risk factors rather than to suspend judgment until no uncertainty remains. Primary prevention programs for childhood leukemia would also result in the significant co-benefits of reductions in other adverse health outcomes that are common in children, such as detriments to neurocognitive development.
[Whitehead TP, Metayer C, Wiemels JL, et al. 2016. Curr Probl Pediatr Adolesc Health Care. 46(10):317-352.] - Childhood Leukemia: A Preventable Disease.
In contrast to most pediatric cancers, there is a growing body of literature, nationally and internationally, that has implicated the role of several environmental indoor and outdoor hazards in the etiology of childhood leukemia. For example, exposures to solvents, traffic, pesticides, and tobacco smoke have consistently demonstrated positive associations with the risk of developing childhood leukemia. Intake of vitamins and folate supplementation during the preconception period or pregnancy has been demonstrated to have a protective effect. Despite the strength of these findings, the dissemination of this knowledge to clinicians has been limited. Some children may be more vulnerable than others as documented by the high and increasing incidence of childhood leukemia in Hispanics. To protect children's health, it is prudent to establish programs to alter exposure to those factors with well-established associations with leukemia risk rather than to suspend judgment until no uncertainty remains. This is particularly true because other serious health outcomes (both negative and positive) have been associated with the same exposures. Study draws from historical examples to put in perspective the arguments of association versus causation, as well as to discuss benefits versus risks of immediate and long-term preventive actions.
[Metayer C, Dahl G, Wiemels J, Miller M. 2016. Pediatrics. 138(Suppl 1):S45-S55.] - Linking Pesticide Exposure with Pediatric Leukemia: Potential Underlying Mechanisms.
Leukemia is the most common cancer in children, representing 30% of all childhood cancers. The disease arises from recurrent genetic insults that block differentiation of hematopoietic stem and/or progenitor cells (HSPCs) and drives uncontrolled proliferation and survival of the differentiation-blocked clone. Pediatric leukemia is phenotypically and genetically heterogeneous with an obscure etiology. The interaction between genetic factors and environmental agents represents a potential etiological driver. Although information is limited, the principal toxic mechanisms of potential leukemogenic agents (e.g., etoposide, benzene metabolites, bioflavonoids and some pesticides) include topoisomerase II inhibition and/or excessive generation of free radicals, which may induce DNA single- and double-strand breaks (DNA-DSBs) in early HSPCs. Chromosomal rearrangements (duplications, deletions and translocations) may occur if these lesions are not properly repaired. The initiating hit usually occurs in utero and commonly leads to the expression of oncogenic fusion proteins. Subsequent cooperating hits define the disease latency and occur after birth and may be of a genetic, epigenetic or immune nature (i.e., delayed infection-mediated immune deregulation). Here, we review the available experimental and epidemiological evidence linking pesticide exposure to infant and childhood leukemia and provide a mechanistic basis to support the association, focusing on early initiating molecular events.
[Hernández AF, Menéndez P. 2016. Int J Mol Sci. 17(4):461.] - Passive exposure to agricultural pesticides and risk of childhood leukemia in an Italian community.
Exposure to pesticides has been suggested as a risk factor for childhood leukemia, but definitive evidence on this relation and the specific pesticides involved is still not clear.We carried out a population-based case-control study in a Northern Italy community to assess the possible relation between passive exposure to agricultural pesticides and risk of acute childhood leukemia.We assessed passive pesticide exposure of 111 childhood leukemia cases and 444 matched controls by determining density and type of agricultural land use within a 100-m radius buffer around children's homes. We focused on four common crop types, arable, orchard, vineyard and vegetable, characterized by the use of specific pesticides that are potentially involved in childhood induced leukemia. The use of these pesticides was validated within the present study. We computed the odds ratios (OR) of the disease and their 95% confidence intervals (CI) according to type and density of crops around the children's homes, also taking into account traffic pollution and high-voltage power line magnetic field exposure. Childhood leukemia risk did not increase in relation with any of the crop types with the exception of arable crops, characterized by the use of 2.4-D, MCPA, glyphosate, dicamba, triazine and cypermethrin. The very few children (n=11) residing close to arable crops had an OR for childhood leukemia of 2.04 (95% CI 0.50-8.35), and such excess risk was further enhanced among children aged
[Malagoli C, Costanzini S, Heck JE, Malavolti M, et al. 2016. Int J Hyg Environ Health. 219(8):742-748.] - Agricultural crop density and risk of childhood cancer in the midwestern United States: an ecologic study.
This study examined the association of county level agricultural land use and the incidence of specific childhood cancers.Authors linked county-level agricultural census data (2002 and 2007) and cancer incidence data for children ages 0-4 diagnosed between 2004 and 2008 from cancer registries in six Midwestern states. Crop density (percent of county area that was harvested) was estimated for total agricultural land, barley, dry beans, corn, hay, oats, sorghum, soybeans, sugar beets, and wheat. Results found statistically significant exposure-response relationships for dry beans and total leukemias and acute lymphoid leukemias (ALL); oats and acute myeloid leukemias (AML); and sugar beets and total leukemias and ALL. State-level analyses revealed some additional positive associations for total leukemia and CNS tumors and differences among states for several crop density-cancer associations. However, some of these analyses were limited by low crop prevalence and low cancer incidence.The associations observed in this study need to be confirmed by analytic epidemiologic studies using individual level exposure data and accounting for potential confounders that could not be taken into account in this ecologic study.
[Booth BJ, Ward MH, Turyk ME, Stayner LT. 2015. Environ Health. 14(1):82] - Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium.
Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, authors pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39, 1.43 and 1.36, respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49, 1.55 and 1.08, respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants' exposure to multiple pesticides, or recall bias.
[Bailey HD, Infante-Rivard C, Metayer C, Clavel J, Lightfoot T, et al. 2015. Int J Cancer. 137(11):2644-63.] - Household pesticide exposure and the risk of childhood acute leukemia in Shanghai, China.
Childhood acute leukemia (AL) is the most common malignant tumor in children, but its etiology remains largely unknown. Study investigated the relationship between household exposure to pesticides and childhood AL. Between 2009 and 2010 in Shanghai, a total of 248 newly diagnosed cases of AL and 111 gender-, age-, and hospital-matched controls were included. Five nonspecific dialkyl phosphate (DAP) metabolites of organophosphate pesticides (OPPs) [including dimethyl phosphate (DMP), diethyl phosphate (DEP), dimethyl thiophosphate (DMTP), diethyl thiophosphate (DETP), and diethyl dithiophosphate (DEDTP)] in the urine were analyzed by gas chromatography. The results showed that the median DMP, DEP, DMTP, DETP, and DEDEP levels adjusted for creatinine (Cr) in cases were all significantly elevated compared with those in controls. The household use of mosquito repellent was significantly associated with an increased risk of childhood AL. Moreover, higher exposures were significantly associated with an elevated risk of childhood AL for DMs, DEs, and DAPs. Findings support the notion that the household use of pesticides may play a role in the etiology of childhood AL and provide some evidence to warrant further investigation of the link between household pesticide exposures and childhood AL in Shanghai.
[Zhang Y, Gao Y, Shi R, Chen D, Wang X, et al. 2015. Environ Sci Pollut Res Int. 22(15):11755-63.] - Relationship between exposure to pesticides and occurrence of acute leukemia in Iran.
One of the causes of acute leukemia can be exposure to certain chemicals such as pesticides. This study determined the relationship between exposure to pesticides and the occurrence of acute leukemia in Fars province, south of Iran. Between April 2011 and April 2013 in a case-control study conducted in Nemazee Hospital in Shiraz, Southern Iran; 314 subjects diagnosed with acute leukemia (94 pediatric cases and 220 adults) were enrolled to determine any correlation between exposure to pesticides and the occurrence.There was a history of exposure to pesticides among 85% of pediatric cases an d 69% of their controls and 83% of adult cases and 75% of their controls while 87.5% of pediatric cases and 90% of adult cases reported exposure to intermediate and high doses of pesticides and among the controls, the exposure to low doses of pesticides was 70.5% and 65%, respectively. Exposure to indoor pesticides was seen among most of cases and controls. Being a farmer was at a significantly more increased risk of developing acute leukemia in comparison to other jobs, especially for their children. Exposure to pesticides was shown to be one of the most important causes of acute leukemia.
[Maryam Z, Sajad A, Maral N, Zahra L, et al. 2015. Asian Pac J Cancer Prev. 16(1):239-44.] - Residential Exposure to Pesticide During Childhood and Childhood Cancers: A Meta-Analysis.
In this meta-analysis, authors aimed to examine associations between residential childhood pesticide exposures and childhood cancers.The literature search yielded 277 studies that met inclusion criteria.Sixteen studies were included in the meta-analysis, and authors found that childhood exposure to indoor but not outdoor residential insecticides was associated with a significant increase in risk of childhood leukemia (odds ratio [OR] = 1.47; 95% CI, 1.26-1.72; I(2) = 30%) and childhood lymphomas (OR = 1.43; 95% CI, 1.15-1.78; I(2) = 0%). A significant increase in risk of leukemia was also associated with herbicide exposure (OR = 1.26; 95% CI, 1.10-1.44; I(2) = 0%). Results from this meta-analysis indicated that children exposed to indoor insecticides would have a higher risk of childhood hematopoietic cancers. Additional research is needed to confirm the association between residential indoor pesticide exposures and childhood cancers. Meanwhile, preventive measures should be considered to reduce children's exposure to pesticides at home.
[Chen M, Chang CH, Tao L, Lu C. 2015. Pediatrics. 136(4):719-29.] - Maternal factors and risk of childhood leukemia.
The aim of this study was to examine association of childhood leukemia with maternal factors especially during pregnancy, to help in avoiding risk factors.This case-control study included children younger than 18 years diagnosed with leukemia from 2008 to 2012. Statistically significant associations between risk of childhood leukemia with mother's education , occupation and pesticides exposure during pregnancy were found. However, there were no significant links with maternal age, history of fetal loss, history of radiography during pregnancy, history of drug intake and infection during pregnancy.The results showed increased risk of leukemia in children whose mothers were working in agriculture and were exposed to pesticides during pregnancy. The further study needs to be investigated to know association of various maternal risk factors with leukemia which remained unknown in this study.
[Kumar A, Vashist M, Rathee R. 2014. Asian Pac J Cancer Prev. 15(2):781-4.] - Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: findings from the childhood leukemia international consortium.
Maternal occupational pesticide exposure during pregnancy and/or paternal occupational pesticide exposure around conception have been suggested to increase risk of leukemia in the offspring. Authors pooled individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium (CLIC). Using exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls the odds ratio (OR) for maternal exposure during pregnancy and the risk of acute lymphoblastic leukemia (ALL) was 1.01 and for paternal exposure around conception 1.20. For acute myeloid leukemia (AML), the OR for maternal exposure during pregnancy was 1.94 and for paternal exposure around conception 0.91. Finding of a significantly increased risk of AML in the offspring with maternal exposure to pesticides during pregnancy is consistent with previous reports. Study also found a slight increase in risk of ALL with paternal exposure around conception which appeared to be more evident in children diagnosed at the age of 5 years or more and those with T cell ALL which raises interesting questions on possible mechanisms.
[Bailey HD, Fritschi L, Infante-Rivard C, Glass DC, et al. 2014. Int J Cancer. 135(9):2157-72.] - Exposure to herbicides in house dust and risk of childhood acute lymphoblastic leukemia.
Study examines the association between exposure to herbicides and childhood acute lymphoblastic leukemia (ALL). Dust samples were collected from homes of 269 ALL cases and 333 healthy controls (<8 years of age at diagnosis/reference date and residing in same home since diagnosis/reference date) in California, using a high-volume surface sampler or household vacuum bags. Amounts of agricultural or professional herbicides (alachlor, metolachlor, bromoxynil, bromoxynil octanoate, pebulate, butylate, prometryn, simazine, ethalfluralin, and pendimethalin) and residential herbicides (cyanazine, trifluralin, 2-methyl-4-chlorophenoxyacetic acid (MCPA), mecoprop, 2,4-dichlorophenoxyacetic acid (2,4-D), chlorthal, and dicamba) were measured. The risk of childhood ALL was associated with dust levels of chlorthal; compared to homes with no detections, ORs for the first, second, and third tertiles were 1.49, 1.49, and 1.57, respectively. The magnitude of this association appeared to be higher in the presence of alachlor. No other herbicides were identified as risk factors of childhood ALL. The data suggest that home dust levels of chlorthal, and possibly alachlor, are associated with increased risks of childhood ALL.
[Metayer C, Colt JS, Buffler PA, Reed HD, et al. 2013. J Expo Sci Environ Epidemiol. 23(4):363-70.] - Pyrethroid pesticide exposure and risk of childhood acute lymphocytic leukemia in Shanghai.
Significant amounts of pyrethroid pesticides are used throughout China. Previous studies have suggested that exposure to pesticides may increase the risk of childhood cancer; however, few studies have focused on pyrethroid metabolites. This study investigated five nonspecific metabolites of pyrethroid pesticides found in children's urine and examined the correlation with childhood leukemia. A hospital-based case-control study of childhood acute lymphocytic leukemia (ALL) in Shanghai between 2010 and 2011 was carried out and included 176 children aged 0-14 years and 180 controls matched for age and sex. Compared with those in the lowest quartiles of total and individual metabolites, the highest quartiles were associated with an approximate 2-fold increased risk of ALL [total metabolites: odds ratio (OR) = 2.75, 1.43-5.29; cis-DCCA: OR = 2.21; trans-DCCA: OR = 2.33; and 3-PBA: OR = 1.84], and most of the positive trends were significant. Findings suggest that urinary levels of pyrethroid metabolites may be associated with an elevated risk of childhood ALL and represent a previously unreported quantitative exposure assessment for childhood leukemia.
[Ding G, Shi R, Gao Y, Zhang Y, Kamijima M, et al. 2012. Environ Sci Technol. 46(24):13480-7] - Risk of childhood acute lymphoblastic leukaemia following parental occupational exposure to pesticides
Study was performed to ascertain whether there was an association between parental occupational exposure to pesticides and increased risk of acute lymphoblastic leukaemia (ALL) in the offspring. A population-based case-control study of childhood ALL was conducted in Australia. Information about the occupational pesticide exposure of mothers and fathers was collected using job-specific modules. Information on the types and extent of pesticide exposure was collected for mothers and fathers before and around the time of conception, and also for mothers during pregnancy for the index case or control and for 1 year after birth. Paternal occupational exposure to pesticides before or around conception was not related to increased risk of childhood ALL. There was a low prevalence of occupational exposure to pesticides among women that reduced after birth. Paternal occupational exposure to pesticides was not found to be associated with an increased risk of acute lymphoblastic leukaemia in the offspring. The study was underpowered with respect to maternal exposure to pesticides.
[Glass DC, Reid A, Bailey HD, et al. 2012. Occup Environ Med. 69(11):846-9.] - Exposure to pesticides and risk of childhood cancer: a meta-analysis of recent epidemiological studies.
The authors performed a meta-analysis of case-control and cohort studies to clarify the possible relationship between exposure to pesticides and childhood cancers. Two cohort and 38 case-control studies were selected for the first meta-analysis. Meta-analysis of the three cohort studies did not show any positive links between parental pesticide exposure and childhood cancer incidence. However, the meta-analysis of the 40 studies with OR values showed that the risk of lymphoma and leukemia increased significantly in exposed children when their mother was exposed during the prenatal period (OR=1.53; 95% CI 1.22 to 1.91 and OR=1.48; 95% CI 1.26 to 1.75). The risk of brain cancer was correlated with paternal exposure either before or after birth (OR=1.49; 95% CI 1.23 to 1.79 and OR=1.66; 95% CI 1.11 to 2.49). The OR of leukemia and lymphoma was higher when the mother was exposed to pesticides. Despite some limitations in this study, the incidence of childhood cancer does appear to be associated with parental exposure during the prenatal period.
[Vinson F, Merhi M, Baldi I, Raynal H, Gamet-Payrastre L. 2011. Occup Environ Med. 68(9):694-702.] - Exposure to professional pest control treatments and the risk of childhood acute lymphoblastic leukemia.
Previous studies suggest that exposure to pesticides increases the risk of childhood acute lymphoblastic leukemia (ALL). The aim of this analysis was to investigate whether professional pest treatments in or around the home before birth or during childhood increased the risk of childhood ALL. Data from 388 cases and 870 frequency-matched controls were analyzed using unconditional logistic regression, adjusting for study matching variables and potential confounders, to calculate odds ratios (ORs). The ORs for any professional pest control treatments were 1.19 in the year before pregnancy, 1.30 during pregnancy and 1.24 for those done after the child's birth. The ORs for exposure after birth were highest when it occurred between the ages of two and three years. ORs were elevated for termite treatments before birth. ORs were higher for pre-B than T cell ALL and for t(12;21) (ETV6-Runx-1) than other cytogenetic sub-types. Results provide some evidence of a modestly increased risk of ALL for professional pest control treatments done during the index pregnancy and possibly in the child's early years.
[Bailey HD, Armstrong BK, de Klerk NH, et al. 2011. Int J Cancer. 129(7):1678-88] - Residential exposures to pesticides and childhood leukemia
The aim of this study was to conduct a systematic review of published studies on the association between residential/household/domestic exposure to pesticides and childhood leukaemia, and to provide a quantitative estimate of the risk. Publications in English were searched in MEDLINE (1966-31 December 2009) and from the reference list of identified publications. Separate analyses were conducted after stratification for exposure time windows, residential exposure location, biocide category and type of leukaemia. Statistically significant associations with childhood leukaemia were observed when combining all studies. Exposure during and after pregnancy was positively associated with childhood leukaemia, with the strongest risk for exposure during pregnancy. Other stratifications showed the greatest risk estimates for indoor exposure, for exposure to insecticides as well as for acute non-lymphocytic leukaemia (ANLL). Outdoor exposure and exposure of children to herbicides (after pregnancy) were not significantly associated with childhood leukaemia. Findings support the assumption that residential pesticide exposure may be a contributing risk factor for childhood leukaemia but available data were too scarce for causality ascertainment. It may be opportune to consider preventive actions, including educational measures, to decrease the use of pesticides for residential purposes and particularly the use of indoor insecticides during pregnancy.
[Van Maele-Fabry G, Lantin AC, Hoet P, Lison D. 2011. Environ Int. 37(1):280-91.] - Residential pesticides and childhood leukemia: a systematic review and meta-analysis.
Study is a systematic review and meta-analysis of previous observational epidemiologic studies examining the relationship between residential pesticide exposures during critical exposure time windows (preconception, pregnancy, and childhood) and childhood leukemia. Exposures during pregnancy to unspecified residential pesticides insecticides, and herbicides were positively associated with childhood leukemia. Exposures during childhood to unspecified residential pesticides and insecticides were also positively associated with childhood leukemia, but there was no association with herbicides. Positive associations were observed between childhood leukemia and residential pesticide exposures. Further work is needed to confirm previous findings based on self-report, to examine potential exposure-response relationships, and to assess specific pesticides and toxicologically related subgroups of pesticides in more detail.
[Turner MC, Wigle DT, Krewski D. 2011. Cien Saude Colet. 16(3):1915-31.] - A systematic review and meta-analysis of childhood leukemia and parental occupational pesticide exposure.
Authors conducted a systematic review and meta-analysis of childhood leukemia and parental occupational pesticide exposure.They found no overall association between childhood leukemia and any paternal occupational pesticide exposure; there were slightly elevated risks in subgroups of studies with low total-quality scores, ill-defined exposure time windows, and exposure information collected after offspring leukemia diagnosis. Childhood leukemia was associated with prenatal maternal occupational pesticide exposure (OR = 2.09; 95% CI, 1.51-2.88); this association was slightly stronger for studies with high exposure-measurement-quality scores (OR = 2.45; 95% CI, 1.68-3.58), higher confounder control scores (OR = 2.38; 95% CI, 1.56-3.62), and farm-related exposures (OR = 2.44; 95% CI, 1.53-3.89). Childhood leukemia risk was also elevated for prenatal maternal occupational exposure to insecticides (OR = 2.72; 95% CI, 1.47-5.04) and herbicides (OR = 3.62; 95% CI, 1.28-10.3). Childhood leukemia was associated with prenatal maternal occupational pesticide exposure in analyses of all studies combined and in several subgroups.
[Wigle DT, Turner MC, Krewski D. 2009. Environ Health Perspect. 117(10):1505-13] - Pediatric acute lymphoblastic leukemia and exposure to pesticides.
A case-control study of children diagnosed with ALL and their mothers in the Washington DC area finds an association between the development of childhood ALL and common household pesticides, as ALL child-mother pairs have elevated levels for the organophosphate metabolites diethylthiophosphate and diethyldithiophosphate and more case mothers (33%) than controls (14%) reported using insecticides in the home.
[Soldin, O.P., et al. 2009. Therapeutic Drug Monitoring 31(4):495-501] - Residential proximity to agricultural pesticide applications and childhood acute lymphoblastic leukemia
A population based, case control study in California using residential histories and proximity to agricultural pesticide use shows an elevated risk of childhood ALL associated with moderate exposure, but not high exposure, to pesticides classified as organophosphates, chlorophenoxy herbicides, and triazines, and with agricultural pesticides used as insecticides or fumigants.
[Rull, R.P., et al. 2009. Environ Res 109(7):891-9] - Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with agricultural activity finds an elevated risk for AML at high agricultural activity (greater than 60% of county acreage devoted to farming).
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - Association between prenatal pesticide exposures and the generation of leukemia-associated T(8;21)
A study analyzing umbilical cord blood samples of infants whose meconium sample detected the pesticide propoxur, finds a two-fold increase incidence of t(8;21)(a22;a22), one of the most common cytogenetic abnormalities in childhood acute myeloid leukemia, suggesting that prenatal pesticide exposure is a factor in the generation of leukemia-associated chromosomal translocations.
[Lafiura, K.M., et al. 2007. Pediatr Blood Cancer 48(5):624-628] - Household exposure to pesticides and risk of childhood hematopoietic malignancies: The ESCALE study (SFCE)
We investigated the role of household exposure to pesticides in the etiology of childhood hematopoietic malignancies. The national registry-based case-control study ESCALE (Etude sur les cancers de l'enfant) was carried out in France over the period 2003-2004. Population controls were frequency matched with the cases on age and sex. Maternal household use of pesticides during pregnancy and paternal use during pregnancy or childhood were reported by the mothers in a structured telephone questionnaire. Insecticides (used at home, on pets, or for garden crops), herbicides, and fungicides were distinguished. We estimated odds ratios (ORs) using unconditional regression models closely adjusting for age, sex, degree of urbanization, and type of housing (flat or house). We included a total of 764 cases of acute leukemia (AL), 130 of Hodgkin lymphoma (HL), 166 of non-Hodgkin lymphoma (NHL), and 1,681 controls. Insecticide use during pregnancy was significantly associated with childhood AL [OR = 2.1; 95% confidence interval (CI), 1.7-2.5], both lymphoblastic and myeloblastic, NHL (OR = 1.8; 95% CI, 1.3-2.6), mainly for Burkitt lymphoma (OR = 2.7; 95% CI, 1.6-4.5), and mixed-cell HL (OR = 4.1; 95% CI, 1.4-11.8), but not nodular sclerosis HL (OR = 1.1; 95% CI, 0.6-1.9). Paternal household use of pesticides was also related to AL (OR = 1.5; 95% CI, 1.2-1.8) and NHL (OR = 1.7; 95% CI, 1.2-2.6); but for AL the relationships did not remain after adjustment for maternal pesticide use during pregnancy. The study findings strengthen the hypothesis that domestic use of pesticides may play a role in the etiology of childhood hematopoietic malignancies. The consistency of the findings with those of previous studies on AL raises the question of the advisability of preventing pesticide use by pregnant women.
[Rudant, J., et al. 2007. Environmental Health Perspectives 115(12):1787-1793] - Parental occupational exposure to pesticides and the risk of childhood leukemia in Costa Rica.
In a Costa Rica population-based, case-control study, researchers find parental occupational exposure to pesticides increases the risk of childhood leukemia. Maternal pesticide exposure doubles offspring leukemia risk, whether before conception (OR 2.4), or during the first (OR 22) or second trimesters (OR 4.5) the risk is significant. Paternal pesticide exposure during the second trimester also increases risk (1.5 OR) in offspring. In regards to organophosphates, maternal exposure during the first trimester is three and a half times higher (OR 3.5). Exposure to benzimidazole pesticides during pregnancy also has twice the risk for childhood leukemia (OR 2.2)
[Monge, P., et al. 2007. Scandinavian Journal of Work, Environment and Health 33(4):293-303] - Child and maternal household chemical exposure and the risk of acute leukemia in children with Down's syndrome: a report from the Children's Oncology Group
Compared with the general pediatric population, children with Down's syndrome have a much higher risk of acute leukemia. This case-control study was designed to explore potential risk factors for acute lymphoblastic leukemia and acute myeloid leukemia in children with Down's syndrome living in the United States or Canada. Mothers of 158 children with Down's syndrome and acute leukemia (97 acute lymphoblastic leukemia, 61 acute myeloid leukemia) diagnosed between January 1997 and October 2002 and mothers of 173 children with Down's syndrome but without leukemia were interviewed by telephone. Positive associations were found between acute lymphoblastic leukemia and maternal exposure to professional pest exterminations (odds ratio = 2.25, 95% confidence interval: 1.13, 4.49), to any pesticide (odds ratio = 2.18, 95% confidence interval: 1.08, 4.39), and to any chemical (odds ratio = 2.72, 95% confidence interval: 1.17, 6.35). Most of the associations with acute myeloid leukemia were nonsignificant, and odds ratios were generally near or below 1.0. This exploratory study suggests that household chemical exposure may play a role in the development of acute lymphoblastic leukemia in children with Down's syndrome.
[Alderton, L.E., et al. 2006. American Journal of Epidemiology 164(3):212-221] - Household exposure to pesticides and risk of childhood acute leukaemia
The study included 280 incident cases of acute leukemia and 288 controls frequency-matched on gender, age, hospital, and ethnic origin. The data were obtained from standardized face-to-face interviews of the mothers with detailed questions on parental occupational history, home and garden insecticide use, and insecticidal treatment of pediculosis. Odds ratios were estimated using unconditional regression models including the stratification variables parental socioeconomic status and housing characteristics. Acute leukemia was observed to be significantly associated with maternal home insecticide use during pregnancy (OR = 1.8, 95% CI 1.2 to 2.8) and during childhood (OR = 1.7, 95% CI 1.1 to 2.4), with garden insecticide use (OR = 2.4, 95% CI 1.3 to 4.3), and fungicide use (OR = 2.5, 95% CI 1.0 to 6.2) during childhood. Insecticidal shampoo treatment of pediculosis was also associated with childhood acute leukemia (OR = 1.9, 95% CI 1.2 to 3.3). The results reported herein support the hypothesis that various types of insecticide exposure may be a risk factor for childhood acute leukemia. The observed association with insecticidal shampoo treatment of pediculosis, which has never been investigated before, requires further study.
[Menegaux, F., et al. 2006. Occup Environ Med 63(2):131-134] - Agricultural pesticide use and childhood cancer in California.
Looking at residential proximity to agricultural pesticides, a population-based case-control study of early childhood cancer, ages 0-4 years, in California finds an elevated risk for leukemia associated with probable and possible carcinogen use and with nearby agricultural applications of organochlorines and organophosphates during pregnancy (metam sodium OR 2.05 and dicofol OR 1.83)
[Reynolds, P, et al. 2005. Epidemiology 16(1):93-100] - Childhood cancer and agricultural pesticide use: an ecologic study in California.
We analyzed population-based childhood cancer incidence rates throughout California in relation to agricultural pesticide use. During 1988-1994, a total of 7,143 cases of invasive cancer were diagnosed among children under 15 years of age in California. Building on the availability of high-quality population-based cancer incidence information from the California Cancer Registry, population data from the U.S. Census, and uniquely comprehensive agricultural pesticide use information from California's Department of Pesticide Regulation, we used a geographic information system to assign summary population, exposure, and outcome attributes at the block group level. We used Poisson regression to estimate rate ratios (RRs) by pesticide use density adjusted for race/ethnicity, age, and sex for all types of childhood cancer combined and separately for the leukemias and central nervous system cancers. We generally found no association between pesticide use density and childhood cancer incidence rates. The RR for all cancers was 0.95 [95% confidence interval (CI), 0.80-1.13] for block groups in the 90th percentile and above for use of pesticides classified as probable carcinogens, compared to the block groups with use of < 1 lb/mi(2). The RRs were similar for leukemia and central nervous system cancers. Childhood leukemia rates were significantly elevated (RR = 1.48; 95% CI, 1.03-2.13) in block groups with the highest use of propargite, although we saw no dose-response trend with increasing exposure categories. Results were unchanged by further adjustment for socioeconomic status and urbanization.
[Reynolds, P., et al. 2002. Environmental Health Perspectives 110(3):319-324] - Critical windows of exposure to household pesticides and risk of childhood leukemia.
The potential etiologic role of household pesticide exposures was examined in the Northern California Childhood Leukemia Study. A total of 162 patients (0-14 years old) with newly diagnosed leukemia were rapidly ascertained during 1995-1999, and 162 matched control subjects were randomly selected from the birth registry. The use of professional pest control services at any time from 1 year before birth to 3 years after was associated with a significantly increased risk of childhood leukemia [odds ratio (OR) = 2.8; 95% confidence interval (CI), 1.4-5.7], and the exposure during year 2 was associated with the highest risk (OR = 3.6; 95% CI, 1.6-8.3). The ORs for exposure to insecticides during the 3 months before pregnancy, pregnancy, and years 1, 2, and 3 were 1.8 (95% CI, 1.1-3.1), 2.1 (95% CI, 1.3-3.5), 1.7 (95% CI, 1.0-2.9), 1.6 (95% CI, 1.0-2.7), and 1.2 (95% CI, 0.7-2.1), respectively. Insecticide exposures early in life appear to be more significant than later exposures, and the highest risk was observed for exposure during pregnancy. Additionally, more frequent exposure to insecticides was associated with a higher risk. In contrast to insecticides, the association between herbicides and leukemia was weak and nonsignificant. Pesticides were also grouped based on where they were applied. Exposure to indoor pesticides was associated with an increased risk, whereas no significant association was observed for exposure to outdoor pesticides. The findings suggest that exposure to household pesticides is associated with an elevated risk of childhood leukemia and further indicate the importance of the timing and location of exposure.
[Ma, X., et al. 2002. Critical windows of exposure to household pesticides and risk of childhood leukemia. Environmental Health Perspectives 110:955-960] - Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion
A small case-control, population-based study finds a significant increase risk for infant acute leukemia for maternal exposure to insecticides (OR 9.68) during pregnancy, including the carbamate propoxur.
[Alexander, F.E., et al. 2001. Cancer Res 61(6):2542-2546] - Risk of childhood leukemia associated with exposure to pesticides and with gene polymorphisms.
A population-based case-control study of childhood ALL finds an increased risk for homeowner use of indoor insecticides and garden and interior plant pesticides, in particular with use during pregnancy and among carriers of the CYP1A1m1 and CYP1a1m2 gene mutations.
[Infante-Rivard, C., et al. 1999. Epidemiology 10(5):481-487] - Childhood leukaemia and exposure to pesticides: results of a case-control study in northern Germany
The association between childhood leukaemia and exposure to pesticides was examined in a population-based case-control study conducted in Lower Saxony, Northern Germany. Between July 1988 and June 1992, 219 newly diagnosed cases were identified, of whom 173 participated in the study. Two sex- and age-matched control groups were recruited: local controls from the same communities as the newly diagnosed cases of leukaemia and state controls from other randomly selected communities in Lower Saxony. An additional study group consisted of 175 cases of solid tumours. When the leukaemia cases were compared with the local controls, positive associations with parental occupational exposure, particularly agriculture-related exposure, were observed, which were statistically non-significant. A significant association was found for pesticide use in gardens (odds ratio = 2.52, 95% confidence interval: 1.0-6.1). No positive associations were seen when the leukaemia cases were compared to the state controls, but this finding could be explained by a higher proportion of state controls living in rural areas. In communities with a significantly elevated standardised incidence ratio of childhood leukaemia over the last decade (1984-1993), the prevalence of pesticide use in the garden was 21%, compared with the 10% in other communities. None of the examined risk factors were more common among cases of solid tumours. Our findings add some evidence to the hypothesis that pesticides are a risk factor for childhood leukaemia, and there are good reasons to consider abundant pesticide use in rural areas as a possible cause for clustering of childhood leukaemia.
[Meinert, E., et al. 1996. Eur J Cancer32A(11):1943-1948] - Home pesticide use and childhood cancer: A case-control study
The association between childhood cancer and home pesticide use was examined in a case-control study of children under 15 years of age. Parents of 252 children diagnosed with cancer in the Denver area between 1976 and 1983 and of 222 control subjects were interviewed regarding use of home pest extermination, yard treatment, and pest strips. The strongest associations were found for yard treatments and soft tissue sarcomas (odds ratios [ORs] around 4.0) and for use of pest strips and leukemias (ORs between 1.7 and 3.0). These results suggest that use of home pesticides may be associated with some types of childhood cancer.
[Leiss, J., et al. 1995. American Journal of Public Health 85:249-252] - Case-control study on the association between a cluster of childhood haematopoietic malignancies and local environmental factors in Aalsmeer, The Netherlands.
In Aalsmeer, a horticultural community near the main international airport in The Netherlands, a more than fourfold increase in the incidence of haematopoietic malignancies in young people was observed between 1980 and 1985. In a population based case-control study, the association with local environmental factors was investigated. For each patient younger than 40 years of age (n = 14) diagnosed between 1975 and 1989, four age and sex-matched controls were selected via local general practitioners. All parents of patients and controls completed a questionnaire on their lifestyle, living conditions, and health, for several years preceding each individual diagnosis. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated, matched, and, if necessary, stratified for neighbourhood. Increased ORs were recorded for intensive use of petroleum products and pesticides by the patients themselves and their fathers: OR petroleum products: 8.0 (95% CI 2.2, 129.9) and 9.0 (1.0, 66.1) respectively; OR pesticides: 6.0 (0.6, 49.3) and 3.2 (1.0, 10.1) respectively. Swimming in a local pond was also significantly associated with the disease: OR = 5.3 (1.3, 17.4). In the 1970s this pond had been polluted by petroleum products and pesticides. The increased incidence of childhood haematopoietic malignancies in Aalsmeer may have been associated with several specific local environmental factors. Interpretation of the results, however, should take into account the fact that confidence intervals were wide because of the limited number of case
[Mulder, Y.M., et al. 1994. Journal of Epidemiology and Community Health 48:161-165] - Epidemiological characteristics of childhood acute lymphocytic leukemia. Analysis by immunophenotype. The Childrens Cancer Group.
While a number of epidemiological studies of childhood acute lymphocytic leukemia (ALL) have been conducted, separate analysis of risk factors for ALL subtypes has generally not been possible. We report the results of an analysis of data obtained from parents of children with ALL (and a control group of children without cancer), linked to a clinical database. Cases were classified into four ALL subtypes, and odds ratios (OR) were determined for each subtype for a broad range of factors. Numerous significant associations were found, some across all subtypes and others that were subtype-specific. Factors with elevated and/or significant ORs included: (i) for common ALL (n = 286): Down syndrome; family history (FH) of bone/joint diseases; postnatal jaundice; birthweight; MMR vaccination; exposure to gases and insecticides; and parental occupational exposure to insecticides. (ii) for pre-B ALL (n = 38): FH of gastrointestinal, hematological or bone/joint diseases, or allergy; cat ownership; exposure to solvents, fumes, petroleum products, cleaning agents and farm animals; and parental exposure to farm animals, fumes and solvents; (iii) for T-cell ALL (n = 158): FH of gastrointestinal disorders, maternal age, male gender, and parental occupational exposure to metals; (iv) for null-cell ALL (n = 65): FH of congenital heart disorders; measles; and parental occupational exposure to fumes, metals or solvents. This analysis should be considered as a hypothesis-generating process for future case-control interview studies.
[Buckley, J.D., et al. 1994. Leukemia 8(5):856-864] - Parental occupation and other environmental factors in the etiology of leukemias and non-Hodgkin's lymphomas in childhood: a case-control study
A hospital-based case-control study in Italy finds a positive association with paternal work as a farmer and childhood ALL
[Magnani, C., et al. 1990. Tumori 76(5):413-419] - Occupational Exposures of Parents of Children with Acute Nonlymphocytic Leukemia: A Report from the Childrens Cancer Study Group
A case-control study finds a consistent pattern of association of AML, also known as acute nonlymphoblastic leukemia (ANLL), risk with paternal exposure to pesticides for jobs held longer than three years, which is substantially increased for children under age 6 at diagnosis. An elevated risk is also found for a child’s direct exposure to pesticides in the home and for maternal exposure to home pesticides at the time of pregnancy.
[Buckley, J.D., et al. 1989. Cancer Research 49:4030-4037] - A population-based case-control study of childhood leukemia in Shanghai
A population based case-control study in China of childhood leukemia cases finds an association between ALL with maternal occupational exposure to pesticides.
[Shu, X.O., et al. 1988. Cancer 62(3):635-644] - Environmental factors in childhood leukaemia.
Various factors have been suspected of influencing childhood leukaemia; this in itself indicates how limited and uncertain is our understanding to date of the epidemiology of the disease. In this case-control study an attempt was made to examine the various hypotheses that have been proposed... The small French case-control study finds paternal occupational exposures to pesticides as a risk factor for leukemia (12 cases versus 3 controls)
[Laval, G. and Tuyns, A.J. 1988. British Journal of Industrial Medicine 45:843-844] - Childhood leukemia and parents' occupational and home exposures.
A case-control study in California finds household pesticide use can more than triple the risk of childhood leukemia and that garden pesticides increase the risk to over six-fold.
[Lowengart, R., et al. 1987. Journal of the National Cancer Institute 79(1):39-46]
Adult Leukemia
- Comprehensive assessment of pesticide use patterns and increased cancer risk
Pesticides are an essential feature of modern-day agriculture that adds to the list of factors that increase cancer risk. Our study aims to comprehensively evaluate this relationship through a population-based approach that considers confounding variables such as county-specific rates of smoking, socioeconomic vulnerability, and agricultural land. We achieved our goal with the implementation of latent-class pesticide use patterns, which were further modeled among covariates to evaluate their associations with cancer risk. Our findings demonstrated an association between pesticide use and increased incidence of leukemia; non-Hodgkin's lymphoma; bladder, colon, lung, and pancreatic cancer; and all cancers combined that are comparable to smoking for some cancer types. Through our comprehensive analysis and unique approach, our study emphasizes the importance of a holistic assessment of the risks of pesticide use for communities, which may be used to impact future policies regarding pesticides.
[Gerken, J. et al. (2024) Comprehensive assessment of pesticide use patterns and increased cancer risk, Frontiers. Available at: https://www.frontiersin.org/journals/cancer-control-and-society/articles/10.3389/fcacs.2024.1368086/full. ] - Organochlorine pesticides, oxidative stress biomarkers, and leukemia: a case-control study
Exposure to pesticides has been linked to an elevated risk of leukemia. The present research aimed to evaluate the relationship between organochlorine (OC) pesticides and biomarkers of oxidative stress in leukemia patients. This work was conducted on 109 patients with leukemia and 109 healthy controls. The serum concentrations of seven derivatives of OCs including alpha-HCH, beta-HCH, gamma-HCH, 2,4-DDT, 4,4-DDT, 2,4-DDE, and 4,4-DDE along with acetylcholinesterase (AChE), glutathione peroxidase (GPx), superoxide dismutase (SOD), paraoxonase-1 (PON1), and catalase (CAT) activities as well as total antioxidant capacity (TAC), nitric oxide (NO), protein carbonyl (PC), and malondialdehyde (MDA) levels were measured in all the subjects. Levels of OCs were remarkably higher in leukemia patients compared to the controls (p < 0.05). In addition, levels of SOD, AChE, GPx, PON-1, and TAC were remarkably lower in leukemia patients compared to controls (p < 0.05). In contrast, MDA, NO, and PC concentrations were higher in leukemia patients than in the controls (p < 0.05). Moreover, the serum level of 4,4-DDE was negatively associated with GPx activity (p = 0.038). Our findings suggest that OCs may play a role in the development of leukemia by disrupting the oxidant/antioxidant balance.
[Rafeeinia, A., Asadikaram, G., Karimi Darabi, M., Abolhassani, M., Moazed, V. and Abbasi-Jorjandi, M., 2023. Journal of Investigative Medicine, 71(3), pp.295-306.] - Exposures to pesticides and risk of cancer: Evaluation of recent epidemiological evidence in humans and paths forward
Knowledge of the role in cancer etiology of environmental exposures as pesticides is a prerequisite for primary prevention. We review 63 epidemiological studies on exposure to pesticides and cancer risk in humans published from 2017 to 2021, with emphasis on new findings, methodological approaches, and gaps in the existing literature. While much of the recent evidence suggests causal relationships between pesticide exposure and cancer, the strongest evidence exists for acute myeloid leukemia (AML) and colorectal cancer (CRC), diseases in which the observed associations were consistent across several studies, including high-quality prospective studies and those using biomarkers for exposure assessment, with some observing dose-response relationships. Though high-quality studies have been published since the IARC monograph on organophosphate insecticides in 2017, there are still gaps in the literature on carcinogenic evidence in humans for a large number of pesticides. To further knowledge, we suggest leveraging new techniques and methods to increase sensitivity and precision of exposure assessment, incorporate multi-omics data, and investigate more thoroughly exposure to chemical mixtures. There is also a strong need for better and larger population-based cohort studies that include younger and nonoccupationally exposed individuals, particularly during developmental periods of susceptibility. Though the existing evidence has limitations, as always in science, there is sufficient evidence to implement policies and regulatory action that limit pesticide exposure in humans and, hence, further prevent a significant burden of cancers.
[Cavalier, H., Trasande, L. and Porta, M. (2022) Exposures to pesticides and risk of cancer: Evaluation of recent epidemiological evidence in humans and paths forward, International Journal of Cancer. Available at: https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.34300. ] - Dicamba use and cancer incidence in the agricultural health study: an updated analysis
The herbicide dicamba has been commonly used agriculturally and residentially. Recent approval of genetically engineered dicamba-resistant crops is expected to lead to increased dicamba use, and there has been growing interest in potential human health effects. A prior analysis in the Agricultural Health Study (AHS) suggested associations between dicamba and colon and lung cancer. We re-evaluated dicamba use in the AHS, including an additional 12 years and 2702 exposed cancers. The AHS is a prospective cohort of pesticide applicators in Iowa and North Carolina. At enrollment (1993–1997) and follow-up (1999–2005), participants reported dicamba use. Exposure was characterized by cumulative intensity-weighted lifetime days, including exposure lags of up to 20 years. We estimated relative risks (RR) and 95% confidence intervals (CI) using multivariable Poisson regression for incident cancers diagnosed from enrollment through 2014/2015. Among 49 922 applicators, 26 412 (52.9%) used dicamba. Compared with applicators reporting no dicamba use, those in the highest quartile of exposure had elevated risk of liver and intrahepatic bile duct cancer (nexposed = 28, RRQ4 = 1.80, CI: 1.26–2.56, Ptrend < 0.001) and chronic lymphocytic leukaemia (CLL, nexposed = 93, RRQ4 = 1.20, CI: 0.96–1.50, Ptrend = 0.01) and decreased risk of myeloid leukaemia (nexposed = 55, RRQ4 = 0.73, CI: 0.51–1.03, Ptrend = 0.01). The associations for liver cancer and myeloid leukaemia remained after lagging exposure of up to 20 years. With additional follow-up and exposure information, associations with lung and colon cancer were no longer apparent. In this first evaluation of liver and intrahepatic bile duct cancer, there was an association with increasing use of dicamba that persisted across lags of up to 20 years.
[Lerro, C.C., Hofmann, J.N., Andreotti, G., Koutros, S., Parks, C.G., Blair, A., Albert, P.S., Lubin, J.H., Sandler, D.P. and Beane Freeman, L.E., 2020. International Journal of Epidemiology.] - Cancer risk among farmers in the Province of Vercelli (Italy) from 2002 to 2005: an ecological study
Farmers living in the Province of Vercelli (Italy) were observed to verify if they have a higher cancer risk than the rest of the local employed population. The present ecological study considered all cancer new cases recorded among the mean employed population with a range of age from 25 to 84 years and resident in the Province of Vercelli during the four-year period 2002-2005. Farmers showed a higher risk for the following tumors: colorectal (OR 2.38, IC95%: 1,76-2,87), leaukaemia (OR 2.65, IC95%:2,12-2,89), digestive system (OR 2.16, IC95% 1,92-2,33), and others. Farmers showed a higher risk for several cancers. Further studies are needed, in order to examine in detail the issue, to encourage the use of personal protective equipment and to promote a more responsible pesticides use.
[Salerno C, Sacco S, Panella M, et al.2014. Ann Ig. 26(3):255-63.] - The impact of Agent Orange exposure on presentation and prognosis of patients with chronic lymphocytic leukemia.
Exposure to Agent Orange (AO) and the contaminating chemical 2,3,7,8-tetrachlorodibenzodioxin (TCDD) has been associated with the development of chronic lymphocytic leukemia (CLL). Of the 195 veterans diagnosed with CLL from 2001 to 2010 in a retrospective cohort from the Minneapolis Veterans Affairs Medical Center, 33 (17%) were exposed to AO. Prognostic factors including Rai stage, lymphocyte doubling time and cytogenetics did not differ between exposed and unexposed patients. Exposed patients were younger at diagnosis (61 vs. 72 years, p < 0.0001) and time to CLL treatment was shorter (9.6 vs. 30.2 months, p = 0.02). Overall survival did not differ between exposed and unexposed patients on Kaplan-Meier analysis, but when adjusted for age, AO exposure had a hazard ratio of death of 1.8 compared to non-exposure. The high estimate of the mortality hazard combined with the relatively low numbers in the exposure group suggests that further examination in a larger patient population is warranted.
[Baumann Kreuziger LM, Tarchand G, Morrison VA. 2014. Leuk Lymphoma. 55(1):63-6.] - Epidemiology of leukemia and multiple myeloma in Golestan, Iran.
The aim of this paper was to present the incidence rates of leukemia and multiple myeloma (MM) in Golestan province located in northeastern Iran during 2004-2009. This was a descriptive cross-sectional study. Data on newly diagnosed (incident) leukemia and MM cases were obtained from collected from Golestan population-based cancer registry. Totally, 11036 new cancer cases were registered in GPRC from 2004-2009. Leukemia and MM accounted for 693 and 124 of cases, respectively. The mean age in patients with leukemia and MM was 43.8 and 62.4 years, respectively. The ASRs for leukemia among men and women were 10.4 and 7.8, respectively. The ASRs for MM were 2.1 and 2 in men and women, respectively. The rate of leukemia was significantly higher in rural areas whereas the incidence of MM was higher in urban areas. High exposure to pesticides and other agricultural-related products may be a possible explanation for epidemiological pattern of leukemia in this area. Determining and controlling important risk factors, especially environmental factors, of leukemia may lead to decrease in its burden in Golestan province of Iran.
[Rajabli N, Naeimi-Tabeie M, Jahangirrad A, et al. 2013.Asian Pac J Cancer Prev. 14(4):2333-6.] - Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study
Study investigated associations between use of terbufos and the incidence of cancer. The Agricultural Health Study is a prospective cohort study of 57,310 licensed pesticide applicators from Iowa and North Carolina. Detailed information about 50 pesticides, including terbufos, and potential confounders was obtained from self-administered questionnaires. Overall cancer risk was slightly increased among terbufos users. Suggestive associations were observed between terbufos use and cancers of the prostate and lung, leukemia, and non-Hodgkin's lymphoma, although the exposure-response gradients were non-monotonic and p for trends were not significant. However, cautious interpretation of these results is warranted by the lack of existing experimental and epidemiologic evidence to support carcinogenic effects of terbufos.
[Bonner, M.R., et al. 2010. Cancer Causes Control 21(6):871-7] - Pesticide sales and adult male cancer mortality in Brazil.
A study of pesticides sales in different parts of Brazil and cancer mortality rates a decade later finds a statistically significant correlation between pesticide sales with the mortality rates for leukemia and cancer of the lip, esophagus, pancreas, and prostate.
[Chrisman, J.D., et al. 2009. Int J Hyg Environ Health ;212(3):310-21] - Risk of leukaemia among pesticide manufacturing workers: a review and meta-analysis of cohort studies
A meta-analysis of 14 cohort studies published between 1984 and 2004 on occupational exposure in pesticide manufacturing plants and leukemia finds a significant risk specifically for developing myeloid leukemia.
[Van Maele-Fabry, G., et al. 2008. Environ Res 106(1):121-137] - A systematic review of myeloid leukemias and occupational pesticide exposure
A meta-analysis of 17 cohort and 16 case-control studies between 1979 and 2005 finds strong evidence of an increased risk of myeloid leukemia and occupation exposure of pesticide applicators.
[Van Maele-Fabry, G., et al. 2007. Cancer Causes Control 18(5):457-478] - Occupational exposure to pesticides and risk of hematopoietic cancers: meta-analysis of case-control studies
A meta-analysis of 13 case-control studies on hematopoietic cancers published between 1990 and 2005 finds a significant positive association for occupational pesticide exposure of more than 10 years and all hematopoietic cancers.
[Merhi, M, et al. 2007. Cancer Causes Control 18(10):1209-1226] - Cancer and pesticides: an overview and some results of the Italian multicenter case-control study on hematolymphopoietic malignancies
Exposure to pesticides is recognized as an important environmental risk factor associated with development of cancer. Epidemiological studies, although sometimes contradictory, have linked phenoxy acid herbicides with non-Hodgkin's lymphoma (NHL) and Soft Tissue Sarcoma (STS); organochlorine insecticides with STS, NHL, and leukemia; organophosphorous compounds with NHL and leukemia; and triazine herbicides with ovarian cancer. Exposure assessment is a crucial point in studying the association between cancer and pesticides. In order to investigate the association between hematolymphopoietic malignancies and occupational exposures, including pesticides, a population-based case-control study was carried out in Italy in 11 areas, 9 of which are agricultural or mixed areas. All newly diagnosed cases of hematolymphopoietic malignancies were collected in a 3-year period (1991-1993). The control group consisted of a random sample of the population residing in each area. The approach to infer exposures in agriculture was based on: the use of an agricultural questionnaire with 24 crop-specific questionnaires; expert agronomists who reviewed the collected information for each subject and translated it into pesticides histories. In total, 1925 cases and 1232 controls were interviewed in the nine agricultural areas. Increased risk was observed for some specific classes of pesticides. Furthermore, a nonstatistically significant increased risk of NHL was observed for subjects who were exposed to phenoxy herbicides not using protective equipment and a significant increased risk for exposure to 2, 4-dichlorophenoxy acetic acid (2,4-D).
[Miligi, L., et al. 2006. Ann N Y Acad Sci 1076:366-377] - Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon
Little is known about the potential carcinogenicity associated with routine application of diazinon, a common organophosphate insecticide. The authors explored a possible association of diazinon exposure with cancer risk in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in Iowa and North Carolina enrolled in 1993-1997. A total of 23,106 male applicators provided information in a self-administered questionnaire. Among 4,961 applicators who reported using diazinon, 301 incident cancer cases were diagnosed during the follow-up period ending December 2002 compared with 968 cases among 18,145 participants who reported no use. Poisson regression was used to calculate rate ratios and 95% confidence intervals. Two quantitative exposure metrics were used: lifetime exposure days and intensity-weighted lifetime exposure days, a measure that incorporates probability of pesticide exposure with lifetime pesticide application frequency. When lifetime exposure days were used, increased risks for the highest tertile of exposure and significant tests for trend for lung cancer and leukemia were observed. No other cancer site showed an association with diazinon for the highest tertile of exposure. Because these results were based on small numbers, additional analyses are necessary as more cases accrue to clarify whether diazinon is associated with cancer risk in humans.
[Beane Freeman, L.E., et al. 2005. American Journal of Epidemiology 162(11):1070-1079] - Health impacts of pesticide exposure in a cohort of outdoor workers.
A historical cohort study of agricultural workers exposed to pesticides finds an increase in leukemia mortality for the lowest exposure group (standardized mortality ratio [SMR] 6.41).
[Beard, J., et al. 2003. Environmental Health Perspectives 111(5):724-730] - Mortality among aerial pesticide applicators and flight instructors: follow-up from 1965-1988
A retrospective cohort mortality study of aerial pesticide applicator pilots finds a significantly elevated risk for leukemia
[Cantor, K.P. and Silberman, W. 1999. Am J Ind Medicine 36(2):239-47] - Correlation analysis of pesticide use data and cancer incidence rates in California counties.
An ecological study in California analyzing data on pesticide use and cancer incidence finds a correlation between Hispanic males diagnosed with leukemia and use of the pesticides atrazine, 2.4-D, and captan.
[Mills, P.K. 1998. Arch Environ Health 53(6):410-413] - Case-control study on the association between a cluster of childhood haematopoietic malignancies and local environmental factors in Aalsmeer, The Netherlands.
In Aalsmeer, a horticultural community near the main international airport in The Netherlands, a more than fourfold increase in the incidence of haematopoietic malignancies in young people was observed between 1980 and 1985. In a population based case-control study, the association with local environmental factors was investigated. For each patient younger than 40 years of age (n = 14) diagnosed between 1975 and 1989, four age and sex-matched controls were selected via local general practitioners. All parents of patients and controls completed a questionnaire on their lifestyle, living conditions, and health, for several years preceding each individual diagnosis. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated, matched, and, if necessary, stratified for neighbourhood. Increased ORs were recorded for intensive use of petroleum products and pesticides by the patients themselves and their fathers: OR petroleum products: 8.0 (95% CI 2.2, 129.9) and 9.0 (1.0, 66.1) respectively; OR pesticides: 6.0 (0.6, 49.3) and 3.2 (1.0, 10.1) respectively. Swimming in a local pond was also significantly associated with the disease: OR = 5.3 (1.3, 17.4). In the 1970s this pond had been polluted by petroleum products and pesticides. The increased incidence of childhood haematopoietic malignancies in Aalsmeer may have been associated with several specific local environmental factors. Interpretation of the results, however, should take into account the fact that confidence intervals were wide because of the limited number of case
[Mulder, Y.M., et al. 1994. Journal of Epidemiology and Community Health 48:161-165] - Myeloid leukemias and myelodysplastic syndromes: chemical exposure, histological subtype and cytogenetics in a case-control study
An Italian case-control study finds a statistically significant association for woman exposed to pesticides (4.4 OR) for AML.
[Ciccone, G., et al. 1993. Cancer Genet Cytogenet 68(2):135-139] - Morphologic, immunologic and cytogenetic studies in acute myeloid leukemia following occupational exposure to pesticides and organic solvents.
An Italian study looking at chromosome changes of AML diagnosed patients finds a link to occupational exposure to pesticides.
[Cuneo, A. et al. 1992. Leuk Res 16(8):789-796.] - Cancer mortality in the U.S. flour industry
The mortality experience among 22,938 white males who were enrolled in the life insurance program of the American Federation of Grain Millers was assessed for the period 1955 through 1985 in a cohort mortality analysis and in a nested case-control analysis. Significantly fewer deaths were observed among this group than expected for all causes of death combined [standardized mortality ratio (SMR) = 89] compared with the number of deaths observed among the general population of U.S. white males of the same age. Excess risks for developing non-Hodgkin's lymphoma (NHL) (SMR = 149), leukemia (SMR = 136), and pancreatic cancer (SMR = 133) were restricted to workers employed in flour mills, where pesticides are used more frequently than in other segments of the industry. In the nested case-control analysis, excess risks for developing these cancers were also observed in these workers, but the relative risk for developing NHL [odds ratio (OR) = 4.2] was approximately twice that for developing pancreatic cancer (OR = 2.2) and that for developing leukemia (OR = 1.8). Within the flour mills, the workers who had ever worked in the maintenance department (OR = 8.1) or in the elevator department (OR = 2.8) were at particularly elevated risk of developing NHL, suggesting that exposures in these departments should receive further attention.
[Alavanja, M.C., et al. 1990. J Natl Cancer Inst 82(10):840-848] - Pesticide exposures and other agricultural risk factors for leukemia among men in Iowa and Minnesota.
A population-based case-control interview study of white males with luekemia in Iowa and Minnesota finds a slight, yet significant, elevated risk of farmers for all leukemia and specifically for CLL.
[Brown, L.M., et al. 1990. Cancer Research 50:6585-6591] - Mortality among white and nonwhite farmers in North Carolina, 1976-1978.
A mortality study of North Carolinian farmers finds that although there was no increased mortality for whites, nonwhite farmers have an increased frequency of leukemia (proportional mortality ratios [PMR] 1.9).
[Delzell, E., and Grufferman, S. 1985. Am J Epidemiol 121(3):391-402] - Lung cancer and other causes of death among licensed pesticide applicators.
A cohort study of causes of death among licensed pesticide applicators in Florida finds excess deaths due to leukemia, particularly myeloid leukemia.
[Blair, A., et al. 1983. J Natl Cancer Inst 71(1):31-37]
Lip Cancer
- Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC).
Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. Study present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers. Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.
[Kachuri L, Harris MA, MacLeod JS, et al. 2017. BMC Cancer. 17(1):343] - Pesticide sales and adult male cancer mortality in Brazil.
A study of pesticides sales in different parts of Brazil and cancer mortality rates a decade later finds a statistically significant correlation between pesticide sales with the mortality rates for leukemia and cancer of the lip, esophagus, pancreas, and prostate.
[Chrisman, J.D., et al. 2009. Int J Hyg Environ Health ;212(3):310-21] - Cancer incidence among farmers exposed to lindane while sheep dipping
The objective of this study was to determine whether site-specific cancer incidence among farmers exposed to the insecticide lindane (g-hexachlorocyclohexane) while dipping sheep differs from that of the general population in Iceland.Cohorts of 7882 men and 429 women, who, according to records on sheep dipping, were sheep owners, were followed from 1962 to 2003 in the Cancer Registry for cancer incidence.For men the standardized incidence ratio (SIR) for all cancer sites was 0.79, with a 95% confidence interval (95% CI) of 0.76-0.83. For both the men and the women a significantly increased risk for lip cancer was found, with SIR of 1.50 (95% CI 1.08-2.04) and 9.09 (95% CI 1.02-32.82), respectively. Cancer of the lip was the only cancer type in significant excess among both genders, and the stomach cancer rates were near unity, but, in previous studies on Icelandic farmers, an increase had been found for stomach cancer. The site-specific cancer incidence for sheep-dipping farmers did not differ substantially from that of the general population.
[Rafnsson V. 2006. Scand J Work Environ Health. 32(3):185-9.] - Incidence of lip cancer in the male Norwegian agricultural population
Study explored lip cancer (LC) associations with work environmental exposures in a record-linkage study of Norwegian farmers. A cohort of 131,243 male Norwegian farmers born 1925-1971 was established by cross-linkage of national registers and followed up through 1999 for incident LC, (ICD-7 site 140) in the Cancer Registry of Norway. Study identified 108 LC cases (rate 4.4 per 100,000 person-years) and found LC to be moderately associated with horses on the farm (RR = 1.6, CI = 1.0-2.4), construction work employment (RR = 1.7, CI = 1.1-2.6), pesticide use (RR = 0.7, CI = 0.4-1.0), grain production (RR = 1.3, CI = 0.9-2.1) and increasing levels of fungal forecasts (RR = 1.6, CI = 0.9-2.8 in the highest two quartiles).Moderate associations of LC with grain production and fungal forecasts and the negative association with pesticide could possibly be explained by exposure to immunosuppressive mycotoxins. Some of the associations observed could be explained by solar exposure.
[Nordby KC, Andersen A, Kristensen P. 2004. Cancer Causes Control. 15(6):619-26.] - Cancer mortality among Iowa farmers: recent results, time trends, and lifestyle factors (United States)
To update the cancer mortality patterns among Iowa (United States) farmers for the years 1987-93 and compare these results with those previously reported for 1971-86 as well as relate the PMR patterns to risk-factor survey data. We extracted usual occupation and cause of death from 88,090 Iowa death certificates for White males aged 20 and older for the years 1987-93. Proportional mortality ratios (PMR), adjusted for age, and 95 percent confidence intervals (CI) were calculated using deaths among nonfarmers to generate expected numbers. We compared lifestyle profiles for farmers and nonfarmers using male controls (n = 1,596) from a population-based case-control study conducted in Iowa from 1986-89. Iowa farmers had deficit PMRs for all-cause cancer mortality (PMR = 0.92, CI = 0.90-0.94) and for lung (PMR = 0.70, CI = 0.66-0.73), liver (PMR = 0.65, CI = 0.50-0.86), and other cancer sites strongly related to smoking and alcohol use. Farmers at all ages had excess deaths for cancers of the prostate (PMR = 1.26, CI = 1.19-1.33), rectum (PMR = 1.29, CI = 1.07-1.56), brain (PMR = 1.10, CI = 0.92-1.32), multiple myeloma (PMR = 1.17, CI = 0.98-1.40), non-Hodgkin's lymphoma (PMR = 1.09, CI = 0.96-1.23), and Hodgkin's disease (PMR = 1.62, CI = 1.04-2.54). Younger farmers (aged 20 to 64 years) had excess deaths for colon cancer (PMR = 1.52, CI =1.26-1.85) and skin melanoma (PMR = 1.60, CI = 1.07-2.38), while older farmers (aged 65+ years) had excess deaths for cancers of the pancreas (PMR = 1.18, CI = 1.04-1.34), lip (PMR = 1.58, CI = 0.59-4.21), and leukemia (PMR = 1.26, CI = 1.09-1.46). Since the 1970s, the PMR for stomach cancer has declined to expected values, while the PMRs for prostate, large intestine, pancreas, and Hodgkin's disease have increased; PMRs for other sites are consistent with earlier data. A survey from 1986-89 showed that farmers, compared with nonfarmers, smoked less, used less alcohol, had less formal education, and consumed more total calories, and calories from protein, fat, and meat while consuming fewer calories from fruits and vegetables. Iowa farmers continue to be at elevated risk of mortality due to certain cancers, and, of particular interest, the risk for prostate and colon cancer appears to be increasing since 1970.
[Cerhan, J.R., et al. 1998. Cancer Causes Control 9(3):311-319.] - Swedish agricultural workers: A group with a decreased risk of cancer
A Swedish study based on a cancer registry of agricultural workers finds an increased risk of cancer of the lip by a factor of greater than 2.
[Wiklund, K. 1983. Cancer 51(3):566-568.]
Liver/Hepatic Tumors
- 2,4-D Herbicide-Induced Hepatotoxicity: Unveiling Disrupted Liver Functions and Associated Biomarkers
Abstract
2,4-dichlorophenoxyacetic acid (2,4-D) is a widely used herbicide worldwide and is frequently found in water samples. This knowledge has prompted studies on its effects on non-target organisms, revealing significant alterations to liver structure and function. In this review, we evaluated the literature on the hepatotoxicity of 2,4-D, focusing on morphological damages, toxicity biomarkers and affected liver functions. Searches were conducted on PubMed, Web of Science and Scopus and 83 articles were selected after curation. Among these studies, 72% used in vivo models and 30% used in vitro models. Additionally, 48% used the active ingredient, and 35% used commercial formulations in exposure experiments. The most affected biomarkers were related to a decrease in antioxidant capacity through alterations in the activities of catalase, superoxide dismutase and the levels of malondialdehyde. Changes in energy metabolism, lipids, liver function, and xenobiotic metabolism were also identified. Furthermore, studies about the effects of 2,4-D in mixtures with other pesticides were found, as well as hepatoprotection trials. The reviewed data indicate the essential role of reduction in antioxidant capacity and oxidative stress in 2,4-D-induced hepatotoxicity. However, the mechanism of action of the herbicide is still not fully understood and further research in this area is necessary.
[Martins, R.X. et al. (2024) ‘2,4-D herbicide-induced hepatotoxicity: Unveiling disrupted liver functions and associated biomarkers’, Toxics, 12(1), p. 35. doi:10.3390/toxics12010035. ] - Dicamba use and cancer incidence in the agricultural health study: an updated analysis
The herbicide dicamba has been commonly used agriculturally and residentially. Recent approval of genetically engineered dicamba-resistant crops is expected to lead to increased dicamba use, and there has been growing interest in potential human health effects. A prior analysis in the Agricultural Health Study (AHS) suggested associations between dicamba and colon and lung cancer. We re-evaluated dicamba use in the AHS, including an additional 12 years and 2702 exposed cancers. The AHS is a prospective cohort of pesticide applicators in Iowa and North Carolina. At enrollment (1993–1997) and follow-up (1999–2005), participants reported dicamba use. Exposure was characterized by cumulative intensity-weighted lifetime days, including exposure lags of up to 20 years. We estimated relative risks (RR) and 95% confidence intervals (CI) using multivariable Poisson regression for incident cancers diagnosed from enrollment through 2014/2015. Among 49 922 applicators, 26 412 (52.9%) used dicamba. Compared with applicators reporting no dicamba use, those in the highest quartile of exposure had elevated risk of liver and intrahepatic bile duct cancer (nexposed = 28, RRQ4 = 1.80, CI: 1.26–2.56, Ptrend < 0.001) and chronic lymphocytic leukaemia (CLL, nexposed = 93, RRQ4 = 1.20, CI: 0.96–1.50, Ptrend = 0.01) and decreased risk of myeloid leukaemia (nexposed = 55, RRQ4 = 0.73, CI: 0.51–1.03, Ptrend = 0.01). The associations for liver cancer and myeloid leukaemia remained after lagging exposure of up to 20 years. With additional follow-up and exposure information, associations with lung and colon cancer were no longer apparent. In this first evaluation of liver and intrahepatic bile duct cancer, there was an association with increasing use of dicamba that persisted across lags of up to 20 years.
[Lerro, C.C., Hofmann, J.N., Andreotti, G., Koutros, S., Parks, C.G., Blair, A., Albert, P.S., Lubin, J.H., Sandler, D.P. and Beane Freeman, L.E., 2020. International Journal of Epidemiology.] - Non‑infective occupational risk factors for hepatocellular carcinoma: A review (Review)
Liver cancer is the second leading worldwide cause of cancer‑associated mortalities. Hepatocellular carcinoma, which accounts for the majority of liver tumors, ranks fifth among types of human cancer. Well‑established risk factors for liver cancer include the hepatitis B and C viruses, aflatoxins, alcohol consumption, and oral contraceptives. Tobacco smoking, androgenic steroids, and diabetes mellitus are suspected risk factors. Current knowledge regarding non‑infective occupational risk factors for liver cancer is inconclusive. The relevance of liver disorders to occupational medicine lies in the fact that the majority of chemicals are metabolized in the liver, and toxic metabolites generated via metabolism are the predominant cause of liver damage. However, their non‑specific clinical manifestations that are similar in a number of liver diseases make diagnosis difficult. Furthermore, concomitant conditions, such as viral hepatitis and alcohol or drug abuse, may mask liver disorders that result from occupational hepatotoxic agents and block the demonstration of an occupational cause. The identification of environmental agents that result in human cancer is a long and often difficult process. The purpose of the present review is to summarize current knowledge regarding the association of non‑infective occupational risk exposure and HCC, to encourage further research and draw attention to this global occupational public health problem.
[Ledda C, Loreto C, Zammit C, Marconi A, et al. 2017. Mol Med Rep. 15(2):511-533.] - Pesticide exposure and liver cancer: a review
Study reviewed the epidemiologic literature examining pesticide exposure and liver cancer incidence (examining hepatocellular carcinoma (HCC) or primary liver cancer). A search of the MEDLINE and Embase databases was conducted in October 2015. Forty-eight papers were assessed for eligibility and 15 studies were included in the review. The majority of studies were conducted in China and Egypt (n = 8), used a case-control design (n = 14), and examined HCC (n = 14). Most studies showed no association between self-reported and/or occupational exposure to pesticides and liver cancer risk. Six studies demonstrated statistically significant positive associations, including three biomarker-based studies (two using pre-diagnostic sera) that reported higher serum levels of dichlorodiphenyltrichloroethane (DDT) were associated with increased HCC risk. Studies indirectly measuring pesticide exposure using self-reported exposure, occupation, job-exposure matrices, or geographic residence demonstrated inconsistent results. These studies were limited by exposure assessment methods, lack of confounder information, minimal case confirmation, selection bias, and/or over-adjustment. There is mixed evidence suggesting a possible association between specific pesticides and HCC risk, with the strongest evidence observed in biomarker-based studies. In particular, organochlorine pesticides, including DDT, may increase HCC risk. Future research should focus on improved pesticide exposure assessment methods, potentially incorporating multiple approaches including biomonitoring while considering the chemicals of interest, historical exposure to address latency periods, and examining specific chemicals and exposure pathways.
[VoPham T1,2, Bertrand KA3, Hart JE, et al. 2017. Cancer Causes Control. 28(3):177-190.] - The association of cancer risks with pentachlorophenol exposure: Focusing on community population in the areas along certain section of Yangtze River in China.
Pentachlorophenol (PCP) was used in large quantities, and mainly for killing the intermediate host snails of schistosome in China, thereby resulting in ubiquitous PCP residue in the environment. However, studies considering the carcinogenicity of PCP for humans mainly focused on occupational workers, and the actual carcinogenicity of PCP for general population is uncertain. To investigate the association between cancer risks and PCP exposure in a community population, an ecological study was conducted in three contaminated areas along the Yangtze River. Standardized rate ratio (SRR) was calculated to represent the risk of cancer incidence, by using incidence in the low PCP exposure category as the reference group. A total of 15,962 cancer records were collected, and 76 water samples and 213 urine samples in three areas were examined. Findings suggested that compared with the low PCP group, the high PCP group had significantly excessive incidences of various cancers related to different organs including lymph (SRR = 19.44, 95% CI = 15.00-25.19), blood (SRR = 17.24, 95% CI = 12.92-23.01), nasopharynx (SRR = 3.97, 95% CI = 3.75-4.21), gallbladder (SRR = 3.46, 95% CI = 3.09-3.87), pancreas (SRR = 3.41, 95% CI = 3.07-3.79), respiratory system (SRR = 3.41, 95% CI = 3.27-3.57) and liver (SRR = 3.31, 95% CI = 3.09-3.56). Taken together, the present study provides evidence that general community population exposed to high level of PCP exhibits a broader spectrum of increased cancer risks as compared to occupational groups.
[Cui Y, Liang L, Zhong Q, He Q, et al. 2017. Environ Pollut. 224:729-738.] - Myclobutanil worsens nonalcoholic fatty liver disease: An in vitro study of toxicity and apoptosis on HepG2 cells.
Myclobutanil is a conazole class fungicide widely used as an agrichemical. Its widespread use has raised the issue of possible health risks for agrarian communities and the general population, which can be exposed to residues present in food and drinking water. The toxicities identified include adverse effects on liver and kidney and on the development of male reproductive organs. Since the liver is the first-line organ in the defense against xenobiotics, toxic effects on hepatic metabolism cause degeneration, necrosis, and tissue hypertrophy. Therefore, we investigated myclobutanil's effects on the human liver cell line HepG2. We found that myclobutanil increases the amount of fatty acids in these hepatic cells, as evaluated with Oil Red O staining, and progressively reduces cell viability from 1ppm to 500ppm. Analysis of biomarkers such as Bcl-xL/Bak and Mcl-1/Bak confirmed activation of cell death pathways at low doses. Therefore, myclobutanil may play an important role in the pathogenesis and progression of chronic hepatocellular diseases in humans.
[Stellavato A, Lamberti M, Pirozzi AV, et al. 2016. Toxicol Lett. 262:100-104] - Mode of action analysis for pesticide-induced rodent liver tumours involving activation of the constitutive androstane receptor: relevance to human cancer risk.
A number of non-genotoxic chemicals, including some pesticides, have been shown to increase the incidence of liver tumours in rats and/or mice. Frameworks for analysing the modes of action (MOAs) by which chemicals produce liver tumours in rodents and the relevance of such tumour data for human risk assessment have now been established. One common MOA for rodent liver tumour formation by non-genotoxic chemicals involves activation of the constitutive androstane receptor (CAR). Key and associative events for a CAR-activation MOA include receptor activation, liver hypertrophy, induction of cytochrome P450 enzyme activities, increased replicative DNA synthesis, altered hepatic foci and liver tumours. While some effects of rodent CAR activators can be observed in human liver, a major species difference is that, unlike rodents, CAR activators do not increase replicative DNA synthesis in human hepatocytes. The CAR-activation MOA for rodent liver tumour formation is thus not plausible for humans, and hence such compounds do not pose a hepatocarcinogenic hazard for humans.
[Lake BG, Price RJ, Osimitz TG. 2015.Pest Manag Sci.71(6):829-34] - Pesticide exposure and hepatocellular carcinoma risk: A case-control study using a geographic information system (GIS) to link SEER-Medicare and California pesticide data.
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is associated with low survival. Study aimed to clarify the association between pesticide exposure and HCC by implementing a novel data linkage between Surveillance, Epidemiology, and End Results (SEER)-Medicare and California Pesticide Use Report (PUR) data using a geographic information system (GIS).Controls were frequency-matched to HCC cases diagnosed between 2000 and 2009 in California by year, age, race, sex, and duration of residence in California. ZIP Code exposure estimates were linked to subjects using Medicare-provided ZIP Codes to calculate pesticide exposure. Among California residents of agriculturally intensive areas, previous annual ZIP Code-level exposure to over 14.53kg/km2 of organochlorine pesticides (75th percentile among controls) was associated with an increased risk of HCC after adjusting for liver disease and diabetes (adjusted odds ratio [OR] 1.87). ZIP Code-level organochlorines were significantly associated with an increased risk of HCC among males (adjusted OR 2.76), but not associated with HCC among females (adjusted OR 0.83).This is the first epidemiologic study to use GIS-based exposure estimates to study pesticide exposure and HCC. Our results suggest that organochlorine pesticides are associated with an increase in HCC risk among males but not females.
[VoPham T, Brooks MM, Yuan JM, Talbott EO, et al. 2015. Environ Res.143(Pt A):68-82.] - Evaluation of hepatotoxicity and clastogenicity of carbofuran in male Wistar rats.
The present study examined the hepatotoxicity and clastogenic effects of carbofuran in rats. Male Wistar rats were exposed to carbofuran (p.o) at 0-5mg/kg bw for 5weeks. Carbofuran induced significant increase in the serum activity of gamma-glutamyltransferase when compared with the negative control, but not activity of serum alanine and aspartate aminotransferases. It also significantly induced micronucleated polychromatic erythrocytes formation in the bone marrow as compared with the control. The level of induction is dose dependent in both cases. In addition, there was significant higher number of hepatic cells in the cell/mm(2) assay for the group treated with carbofuran. Findings from this study suggest that carbofuran has clastogenic and hepatotoxic effects in rats. It therefore may constitute an environmental health risks in individuals so exposed.
[Gbadegesin MA, Owumi SE, Akinseye V, Odunola OA. 2014. Food Chem Toxicol. 65:115-9.] - Impact of isomalathion on malathion cytotoxicity and genotoxicity in human HepaRG cells.
In the present study, cytotoxicity and genotoxicity of malathion and isomalathion either individually or in combination, were assessed using the metabolically competent human liver HepaRG cell line. Isomalathion reduced cell viability starting at a 100 μM concentration after a 24h exposure. It also significantly induced caspase-3 activity in a dose-dependent manner starting at 5 μM. Co-exposure of both compounds resulted in decreased toxicity of isomalathion. By contrast, malathion and isomalathion either separately or in combination, slightly induced micronuclei formation at low concentrations and had additive genotoxic effects when combined at 25 μM. Individually or combined isomalathion directly inhibited activity of carboxyesterases which are involved in detoxication of malathion. Results showed that isomalathion was much more cytotoxic than malathion while both compounds had comparable genotoxic effects in HepaRG hepatocytes at low concentrations and brought further support to the importance of considering impurities and interactions during evaluation of health risks of pesticides.
[Josse R, Sharanek A, Savary CC, Guillouzo A. 2014. Chem Biol Interact. 209:68-76] - Potential involvement of chemicals in liver cancer progression: an alternative toxicological approach combining biomarkers and innovative technologies.
In order to evaluate the in vitro effects of chemicals present in the diet, study began by combining viability, real-time cellular impedance and high throughput screening data to identify a concentration "zone of interest" for the six xenobiotics selected: endosulfan, dioxin, carbaryl, carbendazim, p'p'DDE and hydroquinone. Study identified a single concentration of each pollutant allowing a modulation of the impedance in the absence of vital changes (nuclear integrity, mitochondrial membrane potential, cell death). Based on the number of observed modulations known to be involved in hepatic homeostasis dysfunction that may lead to cancer progression such as cell cycle and apoptosis regulators, EMT biomarkers and signal transduction pathways, authors then ranked the pollutants in terms of their toxicity. Endosulfan, was able to strongly modulate all the studied cellular processes in HepG2 cells, followed by dioxin, then carbendazim. Results of in vitro data indicate that these xenobiotics may contribute to the evolution and worsening of hepatocarcinoma.
[Peyre L, Zucchini-Pascal N, de Sousa G, et al. 2014. Toxicol In Vitro. 28(8):1507-20.] - The commonly used antimicrobial additive triclosan is a liver tumor promoter
Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated.
[Yueh, M.F., Taniguchi, K., Chen, S., Evans, R.M., Hammock, B.D., Karin, M. and Tukey, R.H., 2014. Proceedings of the National Academy of Sciences, 111(48), pp.17200-17205.] - Global DNA methylation screening of liver in piperonyl butoxide-treated mice in a two-stage hepatocarcinogenesis model.
To identify key molecules in piperonyl butoxide (PBO)-induced hepatocarcinogenesis, study searched hypermethylated genes using CpG island (CGI) microarrays in non-neoplastic liver cells as a source of proliferative lesions at 25 weeks after tumor promotion with PBO using mice. The study further performed methylation-specific polymerase chain reaction (PCR), real-time reverse transcription PCR, and immunohistochemical analysis in PBO-promoted liver tissues. Ebp4.1, Wdr6 and Cmtm6 increased methylation levels in the promoter region by PBO promotion, although Cmtm6 levels were statistically non-significant.Results suggest that PBO promotion may cause altered epigenetic gene regulation in non-neoplastic liver cells surrounding proliferative lesions to allow the facilitation of hepatocarcinogenesis. Both Wdr6 and Cmtm6 showed decreased expression in non-neoplastic liver cells in contrast to positive immunoreactivity in the majority of proliferative lesions produced by PBO promotion. These results suggest that both Wdr6 and Cmtm6 were spared from epigenetic gene modification in proliferative lesions by PBO promotion in contrast to the hypermethylation-mediated downregulation in surrounding liver cells. Considering the effective detection of proliferative lesions, these molecules could be used as detection markers of hepatocellular proliferative lesions and played an important role in hepatocarcinogenesis.
[Yafune A, Kawai M, Itahashi M, et al. 2013. Toxicol Lett. 222(3):295-302] - Risk of hepatocellular carcinoma in workers exposed to chemicals
In this study, a review of the literature found that while laboratory data clearly indicate that the liver is an important target of chemical carcinogenesis, epidemiological studies provide very limited evidence on occupational risk factors for HCC. Nevertheless, study found some case reports and epidemiological data showing a moderately increased risk of HCC development in people exposed to vinyl chloride, organic solvents, pesticides, polychlorinated biphenyls, and arsenic. Occupational exposure to chemicals may be another risk factor for HCC development, but the interpretation of currently available findings is limited by the small number of studies, questionable accuracy of the diagnosis of liver cancer, and potential confounding or modifying factors such as chronic hepatitis virus infection and alcohol consumption. Further relevant investigations are required for clarifying the actual contribution of occupational exposure to chemicals in HCC development.
[Uccello M, Malaguarnera G, Corriere T, et al. 2012. Hepat Mon. 12(10 HCC):e5943.] - Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with agricultural activity finds an elevated risk for hepatic tumors (OR 3.3) and for subtype hepatoblastoma (OR 4.0) at high agricultural activity (greater than 60% of county acreage devoted to farming).
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - Mortality in a cohort of pesticide applicators in an urban setting: sixty years of follow-up
A cohort study in Rome of urban pesticide applicators finds an increased risk for cancer of the gallbladder, liver, and nervous system.
[Giordano, F., et al. 2006. Int J Immunopathol Pharmacol 19(Suppl 4):61-65.] - Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
A study in Costa Rica finds heavy pesticide use in rural counties is associated with a two-fold increase risk for liver cancer in females (OR 2.20).
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.]
Lung Cancer
- Comprehensive assessment of pesticide use patterns and increased cancer risk
Pesticides are an essential feature of modern-day agriculture that adds to the list of factors that increase cancer risk. Our study aims to comprehensively evaluate this relationship through a population-based approach that considers confounding variables such as county-specific rates of smoking, socioeconomic vulnerability, and agricultural land. We achieved our goal with the implementation of latent-class pesticide use patterns, which were further modeled among covariates to evaluate their associations with cancer risk. Our findings demonstrated an association between pesticide use and increased incidence of leukemia; non-Hodgkin's lymphoma; bladder, colon, lung, and pancreatic cancer; and all cancers combined that are comparable to smoking for some cancer types. Through our comprehensive analysis and unique approach, our study emphasizes the importance of a holistic assessment of the risks of pesticide use for communities, which may be used to impact future policies regarding pesticides.
[Gerken, J. et al. (2024) Comprehensive assessment of pesticide use patterns and increased cancer risk, Frontiers. Available at: https://www.frontiersin.org/journals/cancer-control-and-society/articles/10.3389/fcacs.2024.1368086/full. ] - Comprehensive assessment of pesticide use patterns and increased cancer risk
Pesticides are an essential feature of modern-day agriculture that adds to the list of factors that increase cancer risk. Our study aims to comprehensively evaluate this relationship through a population-based approach that considers confounding variables such as county-specific rates of smoking, socioeconomic vulnerability, and agricultural land. We achieved our goal with the implementation of latent-class pesticide use patterns, which were further modeled among covariates to evaluate their associations with cancer risk. Our findings demonstrated an association between pesticide use and increased incidence of leukemia; non-Hodgkin's lymphoma; bladder, colon, lung, and pancreatic cancer; and all cancers combined that are comparable to smoking for some cancer types. Through our comprehensive analysis and unique approach, our study emphasizes the importance of a holistic assessment of the risks of pesticide use for communities, which may be used to impact future policies regarding pesticides.
[Gerken, J. et al. (2024) Comprehensive assessment of pesticide use patterns and increased cancer risk, Frontiers. Available at: https://www.frontiersin.org/journals/cancer-control-and-society/articles/10.3389/fcacs.2024.1368086/full. ] - Identification of volatile biomarkers for lung cancer from different histological sources: A comprehensive study
The identification of noninvasive volatile biomarkers for lung cancer is a significant clinical challenge. Through in vitro studies, the recognition of altered metabolism in cell volatile organic compound (VOC) emitting profile, along with the occurrence of oncogenesis, provides insight into the biochemical pathways involved in the production and metabolism of lung cancer volatile biomarkers. In this research, for the first time, a comprehensive comparative analysis of the volatile metabolites in NSCLS cells (A549), SCLC cells (H446), lung normal cells (BEAS-2B), as well as metabolites in both the oxidative stress (OS) group and control group. Specifically, the combination of eleven VOCs, including n-dodecane, acetaldehyde, isopropylbenzene, p-ethyltoluene and cis-1,3-dichloropropene, exhibited potential as volatile biomarkers for lung cancer originating from two different histological sources. Furthermore, the screening process in A549 cell lines resulted in the identification of three exclusive biomarkers, isopropylbenzene, formaldehyde and bromoform. Similarly, the exclusive biomarkers 1,2,4-trimethylbenzene, p-ethyltoluene, and cis-1,3-dichloropropene were present in the H446 cell line. Additionally, significant changes in trans-2-pentene, acetaldehyde, 1,2,4-trimethylbenzene, and bromoform were observed, indicating a strong association with OS. These findings highlight the potential of volatile biomarkers profiling as a means of noninvasive identification for lung cancer diagnosis.
[Lv, W. et al. (2024) Identification of volatile biomarkers for lung cancer from different histological sources: A comprehensive study, Analytical Biochemistry. Available at: https://www.sciencedirect.com/science/article/abs/pii/S000326972400071X. ] - Cancer and occupational exposure to pesticides: an umbrella review
Purpose
The aim was to identify the scope of the epidemiology literature reviewed regarding the risk of cancer as related to occupational exposure to pesticides and to compare regulatory toxicity results where feasible.Methods
Review studies of breast, lung, prostate, non-Hodgkin lymphoma, and colorectal cancer were identified from the published literature from 2010 to 2020 using a priori inclusion and exclusion criteria. Epidemiology observations were first assessed and then compared against carcinogenicity profiles derived from regulatory toxicology studies.Results
Several active ingredients were associated with specific cancer but overall, there was neither strong nor consistent epidemiologic data supportive of a positive association between pesticide exposure in occupational settings and cancer. Authors noted common themes related to the heterogeneity of exposure, study design, control for confounders, and the challenge to collect these data reliably and validly with an adequate sample size. Toxicology studies in laboratory animals that assessed carcinogenic potential did not reveal cancer outcomes that were concordant with reported epidemiologic findings.Conclusions
Farming and pesticides represent diverse exposures that are difficult to quantify in epidemiologic studies. Going forward, investigators will need creative and novel approaches for exposure assessment. Integration of epidemiologic and toxicological studies with attention to biological plausibility, mode of toxicological action and relevance to humans will increase the ability to better assess associations between pesticides and cancer.
[Burns, C.J. and Juberg, D.R. (2021) Cancer and occupational exposure to pesticides: An Umbrella Review, International Archives of Occupational and Environmental Health. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238729/. ] - Influence of pesticides on respiratory pathology – a literature review
Pesticides are widely employed in agriculture, and the food industry is forced to combat the pests and diseases they cause. Respiratory pathology is related to occupational exposure to pesticides. Impairment of pulmonary function was observed among people professionally exposed to pesticides. Because of the marked use of pesticides in agriculture during the last 20 years, there has been a significant increase in respiratory problems within the population, not only among people who come in direct contact with them, but even in the case of manipulators. The aim is a review of the literature of the past 10 years on the correlation between occupational exposure to pesticides and respiratory pathology. Electronic search in ‘Pub Med’ and ‘Web of Science’ was performed in September 2019 to find papers regarding the above-investigated aspects. Abstracts and full-text articles containing the targeted subject were included. Reviews and studies about the influence of pesticides on other pathologies than respiratory were excluded. After applying the inclusion and exclusion criteria, eligible full-text articles were identified. Exposure to pesticides is highly correlated with respiratory pathologies (asthma, COPD, lung cancer). Contact with these substances can occur at any time in the production, transport, preparation or application of the treatments. Numerous studies documented the association between exposure to pesticides, and therefore the increased incidence of respiratory, cardiovascular and renal diseases, as well as the aging phenomenon.
[Tarmure, S., Alexescu, T.G., Orasan, O., Negrean, V., Sitar-Taut, A.V., Coste, S.C. and Todea, D.A., 2020. Annals of Agricultural and Environmental Medicine: AAEM, 27(2), pp.194-200.] - Pesticide exposure and lung cancer risk: A case-control study in Nakhon Sawan, Thailand
Pesticide exposure might increase risk of lung cancer. The purpose of this study was to investigate the association between the historical use of pesticides commonly found in Thailand, and lung cancer. This case-control study compared a lifetime pesticide exposure of 233 lung cancer cases, and 447 healthy neighbours matched for gender, and age (±5 years). Data on demographic, pesticide exposure and other related factors were collected using a face-to-face interview questionnaire. Associations between lung cancer and types of pesticides as well as individual pesticides were analyzed using logistic regression adjusted for gender (male, female), age (≤54, 55-64, 65-74, ≥75), cigarette smoking ( never smoked, smoked < 109,500, smoked ≥ 109,500), occupation (farmer, non-farmer), cooking fumes exposure (yes, no), and exposure to air pollution (yes, no). It was found that lung cancer was positively associated with lifetime use of herbicides, insecticides, and fungicides. Compared to people in the lowest quartile of number of days using the herbicides and insecticides, those in a higher quartile had an elevated risk of lung cancer, with odds ratio (OR) between 3.31 (95% confidence interval (CI) 1.49–7.34), and 12.58 (95% CI 5.70-27.75) (p < 0.001). For fungicides, only the most exposed group had a significant risk (OR = 4.25; 95% CI 1.23-14.72). For individual pesticides, those presenting a significant association with lung cancer were dieldrin (OR = 2.56; 95% CI 1.36-4.81), chlorpyrifos (OR = 3.29; 95 % CI 1.93-5.61), and carbofuran (OR = 2.10; 95% CI 1.28-3.42). The results showed that lung cancer among Thai people in Nakhon Sawan province is associated with previous pesticide use. This finding was consistent with previous studies in other parts of the world. Further study should focus on identifying more individual compounds that may cause lung cancer, as well as other types of cancer.
[Kangkhetkron, T. and Juntarawijit, C., 2020. F1000Research, 9(492), p.492.] - Occupational Exposure to Pesticides and the Incidence of Lung Cancer in the Agricultural Health Study.
Occupational pesticide use is associated with lung cancer in some, but not all, epidemiologic studies. In the Agricultural Health Study (AHS), we previously reported positive associations between several pesticides and lung cancer incidence.We evaluated use of 43 pesticides and 654 lung cancer cases after 10 years of additional follow-up in the AHS, a prospective cohort study comprising 57,310 pesticide applicators from Iowa and North Carolina.Information about lifetime pesticide use and other factors was ascertained at enrollment (1993-1997) and updated with a follow-up questionnaire (1999-2005). Hazard ratios were elevated in the highest exposure category of lifetime days of use for pendimethalin (1.50; 95% CI: 0.98, 2.31), dieldrin (1.93; 95% CI: 0.70, 5.30), and chlorimuron ethyl (1.74; 95% CI: 1.02, 2.96), although monotonic exposure-response gradients were not evident. The HRs for intensity-weighted lifetime days of use of these pesticides were similar. For parathion, the trend was statistically significant for intensity-weighted lifetime days (p = 0.049) and borderline for lifetime days (p = 0.073). None of the remaining pesticides evaluated was associated with lung cancer incidence.These analyses provide additional evidence for an association between pendimethalin, dieldrin, and parathion use and lung cancer risk. We found an association between chlorimuron ethyl, a herbicide introduced in 1986, and lung cancer that has not been previously reported. Continued follow-up is warranted.
[Bonner MR1, Freeman LE, Hoppin JA, Koutros S, Sandler DP, et al. 2017. Environ Health Perspect. 125(4):544-551.] - Chronic exposure to chlorophenol related compounds in the pesticide production workplace and lung cancer: a meta-analysis.
Chlorophenols (CPs) and related phenoxyacetic acids (PAs) are pesticide groups contaminated with highly toxic 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) during production. PAs and CPs exposure is associated with risk of cancer, but the situation regarding lung cancer has not been clearly defined. Study is a meta-analysis of published researches to evaluate relationship between chronic exposure to PAs and CPs in pesticide production workplaces and the risk of lung cancer.Five papers with six reports were included in the final analysis. The standardized mortality rate for lung cancer from the random model was 1.18 with moderate heterogeneity. Publication bias was not found for included studies in meta-analysis (p=0.9).Our findings has strengthen the evidence of lung cancer from chronic exposure to chlorophenol related compounds (PAs, CPs).
[Zendehdel R, Tayefeh-Rahimian R, Kabir A. 2014. Asian Pac J Cancer Prev. 15(13):5149-53.] - Risk factors for lung cancer in the Pakistani population.
In this retrospective case-control study, 400 cases and 800 controls were enrolled from different hospitals of all provinces of Pakistan. Information about socio-demographic, occupational, lifestyle and dietary variables was extracted by questionnaire from all subjects. Strong associations were observed for smoking (OR=9.4), pesticide exposure (OR=5.1), exposure to diesel exhaust (OR=3.1). Other associated factors observed were family history (OR=2.0) wood dust (OR=1.9), asbestos exposure(OR=1.5). Strongest dose-response relationships were observed for smoking , pesticide exposure and exposure to diesel exhaust.
[Luqman M, Javed MM, Daud S, Raheem N, et al. 2014. Asian Pac J Cancer Prev. 15(7):3035-9.] - TP53 gene mutations of lung cancer patients inupper northern Thailand and environmental risk factors
A study that evaluated the risk factors that influence TP53 gene mutation (which is observed in about 40-70% of lung cancer tissues) in lung cancer patients finds that these mutations are induced by exposure to substances other than tocacoo smoke, possibly pesticide exposure.
[Bumroongkit, K., et al. 2008. Cancer Genet Cytogenet 185(1):20-27.] - Cancer incidence among pesticide applicators exposed to dicamba in the Agricultural Health Study
Dicamba is an herbicide commonly applied to crops in the United States and abroad. We evaluated cancer incidence among pesticide applicators exposed to dicamba in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in North Carolina and Iowa. Detailed pesticide exposure information was obtained through a self-administered questionnaire completed from 1993 to 1997. Cancer incidence was followed through 31 December 2002 by linkage to state cancer registries. We used Poisson regression to estimate rate ratios and 95% confidence intervals for cancer subtypes by tertiles of dicamba exposure. Two dicamba exposure metrics were used: lifetime exposure days and intensity-weighted lifetime exposure days (lifetime days × intensity score). A total of 41,969 applicators were included in the analysis, and 22,036 (52.5%) reported ever using dicamba. Exposure was not associated with overall cancer incidence nor were there strong associations with any specific type of cancer. When the reference group comprised low-exposed applicators, we observed a positive trend in risk between lifetime exposure days and lung cancer (p = 0.02), but none of the individual point estimates was significantly elevated. We also observed significant trends of increasing risk for colon cancer for both lifetime exposure days and intensity-weighted lifetime days, although these results are largely due to elevated risk at the highest exposure level. There was no apparent risk for non-Hodgkin lymphoma. Although associations between exposure and lung and colon cancer were observed, we did not find clear evidence for an association between dicamba exposure and cancer risk.
[Samanic, C., et al. 2006. Environ Health Perspect 114(10):1521-1526.] - Cancer incidence among pesticide applicators exposed to metolachlor in the Agricultural Health Study
Metolachlor is one of the most widely used herbicides in the United States. We evaluated the incidence of cancer among pesticide applicators exposed to metolachlor in the Agricultural Health Study, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina. A total of 50,193 pesticide applicators were included. Detailed information on pesticide exposure and lifestyle factors was obtained from self-administered enrollment questionnaires completed between 1993 and 1997; average length of follow-up was 7.33 years. Two metolachlor exposure metrics were used : (i) lifetime days personally mixed or applied metolachlor and (ii) intensity-weighted lifetime days (lifetime days x an intensity level). Poisson regression analysis was used to estimate relative risks (RR) and 95% confidence intervals (95%CI) for cancer subtypes by tertiles of metolachlor exposure. No clear risk for any cancer subtype was found for exposure to metolachlor. A significantly decreased RR was found for prostate cancer in the highest category of lifetime days exposure (RR = 0.59; 95%CI, 0.39-0.89) and in the second highest category of intensity-weighted lifetime days exposure (RR = 0.66; 95%CI, 0.45-0.97); however, the test for trend was not significant for either exposure metric. A nonsignificantly increased risk was found for lung cancer with lifetime days exposure in the highest category (RR = 2.37; 95%CI, 0.97-5.82, p-trend = 0.03) but not with intensity-weighted lifetime days. Given the widespread use of metolachlor and the frequent detection of metolachlor in both surface and ground water, future analyses of the AHS will allow further examination of long-term health effects, including lung cancer and the less common cancers.
[Rusiecki, J.A., et al. 2006. Int J Cancer 118(12):3118-3123.] - Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon
Little is known about the potential carcinogenicity associated with routine application of diazinon, a common organophosphate insecticide. The authors explored a possible association of diazinon exposure with cancer risk in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in Iowa and North Carolina enrolled in 1993-1997. A total of 23,106 male applicators provided information in a self-administered questionnaire. Among 4,961 applicators who reported using diazinon, 301 incident cancer cases were diagnosed during the follow-up period ending December 2002 compared with 968 cases among 18,145 participants who reported no use. Poisson regression was used to calculate rate ratios and 95% confidence intervals. Two quantitative exposure metrics were used: lifetime exposure days and intensity-weighted lifetime exposure days, a measure that incorporates probability of pesticide exposure with lifetime pesticide application frequency. When lifetime exposure days were used, increased risks for the highest tertile of exposure and significant tests for trend for lung cancer and leukemia were observed. No other cancer site showed an association with diazinon for the highest tertile of exposure. Because these results were based on small numbers, additional analyses are necessary as more cases accrue to clarify whether diazinon is associated with cancer risk in humans.
[Beane Freeman, L.E., et al. 2005. American Journal of Epidemiology 162(11):1070-1079] - Parental occupational exposures and Ewing’s sarcoma
A study in Costa Rica finds heavy pesticide use in rural counties is associated with a twofold increase risk for lung cancer for both males and females (OR 2.01 males; 2.63 females).
[Moore, L.E., et al. 2005. Int J Cancer 114(3):472-478.] - Cancer Incidence Among Pesticide Applicators Exposed to Chlorpyrifos in the Agricultural Health Study
Chlorpyrifos is one of the most widely used insecticides in the United States. We evaluated the incidence of cancer among pesticide applicators exposed to chlorpyrifos in the Agricultural Health Study, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina. A total of 54 383 pesticide applicators were included in this analysis. Detailed information on pesticide exposure and lifestyle factors was obtained from self-administered questionnaires completed at the time of enrollment (December 1993–December 1997). Poisson regression analysis was used to evaluate the association between chlorpyrifos exposure and cancer incidence after adjustment for potential confounders. All statistical tests were two-sided. A total of 2070 incident malignant neoplasms were diagnosed through 2001. The rate ratio for all cancers combined among chlorpyrifos-exposed applicators compared with nonexposed applicators was 0.97 (95% confidence interval = 0.87 to 1.08). For most cancers analyzed, there was no evidence of an exposure–response relationship. However, the incidence of lung cancer was statistically significantly associated with both chlorpyrifos lifetime exposure-days ( Ptrend = .002) and chlorpyrifos intensity-weighted exposure-days ( Ptrend = .036). After adjustment for other pesticide exposures and demographic factors, individuals in the highest quartile of chlorpyrifos lifetime exposure-days (>56 days) had a relative risk of lung cancer 2.18 (95% confidence interval = 1.31 to 3.64) times that of those with no chlorpyrifos exposure. Our findings suggest an association between chlorpyrifos use and incidence of lung cancer that deserves further evaluation.
[Lee WJ, et al. 2004. J Natl Cancer Inst. 96(23):1781-9.] - Pesticides and lung cancer risk in the Agricultural Health Study Cohort
Four agricultural pesticides are associated with a significant excess lung cancer risk in the Agricultural Health Study cohort.
[Alavanja, M.C.R., et al. 2004. American Journal of Epidemiology 160(9):876-885.] - Cohort mortality and nested case-control study of lung cancer among structural pest control workers in Florida (United States)
A previous report on the mortality of this cohort of Florida (United States) pest control workers found the risk of lung cancer was positively associated with the number of years licensed. An additional follow-up (1977–82) of this male cohort confirmed the excess (SMR=1.4) and the rising risk with increasing number of years licensed (SMR=2.2 among workers employed more than 20 years). A nested case-control study was undertaken to determine the effects of smoking and the type of pesticide exposure on lung cancer risk. Occupational histories and other data were obtained on 65 deceased lung cancer cases, 122 deceased controls, and 172 living controls. Interviews were conducted with next-of-kin regardless of the vital status of the subject. Odds ratios (OR) were adjusted by age and smoking. Adjustments for diet and other occupations had no effect on risk estimates and were not included in the final model. Using information from licensing records, ORs for lung cancer were greater for workers first licensed before age 40 (OR=2.4, 95 percent confidence interval [CI]=1.0–5.9 with deceased controls) and increased from 1.4 (CI=0.7–3.0) for subjects licensed 10–19 years to 2.1 (CI=0.8–5.5) for subjects licensed 20 or more years. Using living controls, an association with duration of employment was observed when years of licensure were lagged five years, but was not observed in unlagged analyses. Using information from the questionnaire, the risk of lung cancer was greater among those who worked as pest control operators than non-pest control workers. Although numbers were typically small, lung cancer risk among pest control operators was associated with reported exposure to carbamates, organophosphates, and phenoxyacetic acids and more specifically with diazinon, DDT, carbaryl, and propoxur. These results further suggest that pesticides may play a role in lung cancer risk and underscore the need for research that focuses on specific chemicals.
[Pesatori, A.C., et al. 1994. Cancer Causes and Control 5:310-318.] - Occupational risk factors for lung cancer among nonsmoking women: a case-control study in Missouri (United States)
A population-based, case-control study of nonsmokers finds elevated risk among women exposed to pesticides (OR 2.4) for lung cancer.
[Brownson, R.C., et al. 1993. Cancer Causes Control 4(5):449-454.] - Lung cancer and other causes of death among licensed pesticide applicators.
A cohort study of causes of death among licensed pesticide applicators in Florida finds excess deaths due to lung cancer. Although individuals’ tobacco use was not available, a 1983 study of causes of death among licensed pesticide applicators in Florida finds excess deaths due to cancer of the lungs and that the risk increased with the number of years licensed. Mortality is shown to be greatest for those first licensed before age 40 than among those individuals licensed after age 40.
[Blair, A., et al. 1983. J Natl Cancer Inst 71(1):31-37] - Increased risk of lung cancer in pesticide-exposed male agricultural workers
The cancer morbidity in a large group of male German agricultural workers exposed to pesticides was investigated through a retrospective cohort study. A total of 169 malignant tumors were diagnosed in 1658 men who began to work with pesticides between 1948 and 1972, and who continued this type of activity for at least 5 yr. The SMR (standardized mortality ratio) of 2.0 for lung cancer morbidity (mortality) in these pesticide-exposed subjects was significantly higher than that for the general male population of the German Democratic Republic. A positive correlation between the duration of employment and the mortality due to lung cancer (mainly undifferentiated and small-cell carcinomas) suggested a dose-effect relation. The smoking habits of the exposed men did not differ from those of the general male population of the German Democratic Republic. Because the subjects had been exposed to many different substances, the study does not permit any conclusions to be drawn in respect to the carcinogenicity of individual pesticides. The increased mortality due to lung cancer is presumably the result of an additive effect of different pesticide ingredients or of by-products whose carcinogenic effect has been definitely or tentatively established through experimental or epidemiologic studies (e.g. arsenic, asbestos, chlorinated dibenzodioxins, DDT). The results of the present investigation emphasize the need for effective measures to protect workers during occupational contact with pesticides.
[Barthel, E. 1981. J Toxicol Environ Health 8(5-6):1027-1040.]
Lymphoma
Hodgkin's Lymphoma
- Exposure to pesticides and risk of Hodgkin lymphoma in an international consortium of agricultural cohorts (AGRICOH)
Some pesticides may increase the risk of certain lymphoid malignancies, but few studies have examined Hodgkin lymphoma (HL). In this exploratory study, we examined associations between agricultural use of 22 individual active ingredients and 13 chemical groups and HL incidence. We used data from three agricultural cohorts participating in the AGRICOH consortium: the French Agriculture and Cancer Cohort (2005-2009), Cancer in the Norwegian Agricultural Population (1993-2011), and the US Agricultural Health Study (1993-2011). Lifetime pesticide use was estimated from crop-exposure matrices or self-report. Cohort-specific covariate-adjusted overall and age-specific (< 40 or ≥ 40 years) hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression and combined using random effects meta-analysis. Among 316 270 farmers (75% male) accumulating 3 574 815 person-years at risk, 91 incident cases of HL occurred. We did not observe statistically significant associations for any of the active ingredients or chemical groups studied. The highest risks of HL overall were observed for the pyrethroids deltamethrin (meta-HR = 1.86, 95% CI 0.76-4.52) and esfenvalerate (1.86, 0.78-4.43), and inverse associations of similar magnitude were observed for parathion and glyphosate. Risk of HL at ≥ 40 years of age was highest for ever-use of dicamba (2.04, 0.93-4.50) and lowest for glyphosate (0.46, 0.20-1.07). We report the largest prospective investigation of these associations. Nonetheless, low statistical power, a mixture of histological subtypes and a lack of information on tumour EBV status complicate the interpretability of the results. Most HL cases occurred at older ages, thus we could not explore associations with adolescent or young adult HL. Furthermore, estimates may be attenuated due to non-differential exposure misclassification. Future work should aim to extend follow-up and refine both exposure and outcome classification.
[Kim, J., Leon, M.E., Schinasi, L.H., Baldi, I., Lebailly, P., Freeman, L.E.B., Nordby, K.C., Ferro, G., Monnereau, A., Brouwer, M. and Kjaerheim, K., 2023. Cancer Causes & Control, pp.1-9.] - Exposures to multiple pesticides and the risk of Hodgkin lymphoma in Canadian men.
Study's aim was to determine the risk of Hodgkin lymphoma (HL) associated with exposures to multiple pesticides grouped by various classes, including carcinogenic classifications. Data collected in the Cross-Canada Study of Pesticides and Health, a population-based incident case-control study in six provinces conducted between 1991 and 1994, were analyzed using unconditional logistic regression. Overall, there was an increase in the risk of HL among all subjects who reported use of five or more insecticides (OR 1.88) and among subjects younger than 40 who reported use of two acetylcholinesterase inhibitors (OR 3.16). There was an elevated odds ratio associated with reported use of three or more probably carcinogenic pesticides (OR 2.47), but no increase in risk for use of possibly carcinogenic pesticides. The risk of HL from reported use of fungicides or any pesticides was greater for cases diagnosed before age 40 than for cases diagnosed at or after age 40. This study found associations between HL and fungicides, insecticides, specifically acetylcholinesterase inhibitors, and pesticides previously identified as probable human carcinogens.
[Navaranjan G, Hohenadel K, Blair A, Demers PA, et al. 2013. Cancer Causes Control. 24(9):1661-73] - Hodgkin lymphoma and pesticides exposure in men: a Canadian case-control study.
The objective of this study was to investigate the putative associations of specific pesticides with Hodgkin lymphoma. A population-based, case-control study of Hodgkin lymphoma was conducted among males in six regions of Canada. Comparisons of 316 Hodgkin lymphoma cases and 1506 controls identified several factors as predictors for increased Hodgkin lymphoma risk: family history of cancer, exposure to the insecticide chlorpyrifos [OR (95% CI) = 1.19 (1.03, 1.37)], and previous diagnosis of acne or shingles. The increased risk of developing Hodgkin lymphoma detected among Canadian men who used chlorpyrifos must be interpreted cautiously; however the strength of its association indicates that it requires investigation in other populations.
[Karunanayake CP, Spinelli JJ, McLaughlin JR, et al. 2012. J Agromedicine. 17(1):30-9.] - Ethnicity and incidence of Hodgkin lymphoma in Canadian population
Research has shown that ethnicity is a significant predictor of Hodgkin lymphoma (HL). Other risk factors important in the etiology of HL are medical history and exposure to pesticides. In this report authors investigated the association between ethnicity and HL in the presence of medical history, and exposure to pesticides.In the study population, the distribution of ethnic groups was: 38.5% North American, 15% British, 8.4% Western European, 8.2% Eastern European, 1.7% Asian, 1.4% Scandinavian and 27% of other ethnic origin. Compared to North Americans (i) the risk of HL was greater among the Eastern European descendents (Odds Ratio (ORadj): 1.82) and Western European (ORadj: 1.62) descent population; and (ii) the risk of HL was lower in Asian descents. Exposure to individual herbicide dichlorprop showed an increased risk of HL (ORadj: 6.35).
[Pahwa P, Karunanayake CP, Spinelli JJ, et al. 2009. BMC Cancer. 9:141] - Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with agricultural activity finds an elevated risk for malignant bone tumors (OR 2.3) and for subtype osteosarcoma (OR 2.7) at high agricultural activity (greater than 60% of county acreage devoted to farming). Also linked to Ewing’s sarcoma (OR 4.3) and HL (OR 2.1) at high agricultural activity (greater than 60% of county acreage devoted to farming), and for oat crop acreage and Ewing’s (OR 2.3).
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - Household exposure to pesticides and risk of childhood hematopoietic malignancies: The ESCALE study (SFCE)
A 2007 case-control study in France finds that the mothers use of any household pesticide use is associated with mixed-cell Hodgkin lymphoma (HL).
[Rudant, J., et al. 2007. Environmental Health Perspectives 115(12):1787-1793] - Occupation and lymphoid malignancies: results from a French case-control study
A multicentered hospital based case-control study in France finds that self-declared occupational pesticide exposure is significantly associated with HL
[Orsi, L, et al. 2007. J Occup Environ Med 49(12):1339-1350] - Exposure to non-arsenic pesticides is associated with lymphoma among farmers in Spain
To estimate the risk of lymphoma among farmers in Spain. This is a multicentre case control study conducted in Spain. Cases were subjects diagnosed with lymphoma according to the World Health Organization (WHO) classification in four hospitals between 1998- 2002. Hospital controls were frequency matched to the cases by sex, age, and centre. All subjects were interviewed about jobs ever held in lifetime for at least one year and the exposures in those jobs were recorded. The risk of lymphomas among subjects ever having had a job as a farmer was compared with all other occupations. Farmers were analysed according to the type of farming job performed: crop farming, animal farming, and general farming. Occupational exposure was summarised into 15 main categories: organic dust, radiation, contact with animals, PAH, non‐arsenic pesticides (carbamates, organophosphates, chlorinated hydrocarbons, triazines and triazoles, phenoxy herbicides, chlorophenols, dibenzodioxin, and dibenzofuran), arsenic pesticides, contact with meat, contact with children, solvents, asbestos, soldering fumes, organic colorants, polychlorinated biphenyls, ethylene oxide, and hair dyes. Although farmers were not at an increased risk of lymphoma as compared with all other occupations, farmers exposed to non‐arsenic pesticides were found to be at increased risk of lymphoma (OR = 1.8, 95% CI 1.1 to 2). This increased risk was observed among farmers working exclusively either as crop farmers or as animal farmers (OR = 2.8, 95% CI 1.3 to 5.8). Risk was highest for exposure to non‐arsenic pesticides for over nine years (OR = 2.4, 95% CI 1.2 to 2.8). Long term exposure to non‐arsenic pesticides may induce lymphomagenesis among farmers.
[van Balen, E., et al. 2006. Occupational and Environmental Medicine 63:663-668] - Cancer risk and parental pesticide application in children of Agricultural Health Study participants.
Parental exposure to pesticides may contribute to childhood cancer risk. Through the Agricultural Health Study, a prospective study of pesticide applicators in Iowa and North Carolina, we examined childhood cancer risk and associations with parental pesticide application. Identifying information for 17,357 children of Iowa pesticide applicators was provided by parents via questionnaires (1993-1997) and matched against the Iowa Cancer Registry. Fifty incident childhood cancers were identified (1975-1998). Risk of all childhood cancers combined was increased [standardized incidence ratio (SIR) = 1.36; 95% confidence interval (CI), 1.03-1.79]. Risk of all lymphomas combined was also increased (SIR = 2.18; 95% CI, 1.13-4.19), as was risk of Hodgkin's lymphoma (SIR = 2.56; 95% CI, 1.06-6.14). We used logistic regression to explore associations between self-reported parental pesticide application practices and childhood cancer risk. No association was detected between frequency of parental pesticide application and childhood cancer risk. An increased risk of cancer was detected among children whose fathers did not use chemically resistant gloves [odds ratio (OR) = 1.98; 95% CI, 1.05-3.76] compared with children whose fathers used gloves. Of 16 specific pesticides used by fathers prenatally, ORs were increased for aldrin (OR = 2.66), dichlorvos (OR = 2.06), and ethyl dipropylthiocarbamate (OR = 1.91). However, these results were based on small numbers and not supported by prior biologic evidence. Identification of excess lymphoma risk suggests that farm exposures including pesticides may play a role in the etiology of childhood lymphoma.
[Flower, K., et al. 2004. Environmental Health Perspectives 112:631-635] - Cancer mortality among Iowa farmers: recent results, time trends, and lifestyle factors (United States)
A cancer mortality study of Iowa farmers shows an excess of deaths for Hodgkin's disease.
[Cerhan, J.R., et al. 1998. Cancer Causes Control 9(3):311-319.] - Some occupational exposures as risk factors for malignant lymphomas.
A Swedish case-referent occupational exposure study finds a significant risk for Hodgkin lymphoma (OR 7.4) for workers exposed to phenoxy herbicides
[Persson, B., et al. 1993. Cancer 72(5):1773-1778]
Non-Hodgkin's Lymphoma
- Occupational exposures, animal exposure and smoking as risk factors for hairy cell leukaemia evaluated in a case-control study.
A population based case-control occupational study of Swedish males with hairy cell leukemia find that exposure to herbicides (OR 2.9), insecticides (OR 2.0), fungicides (OR 3.8) and impregnating agents (OR 2.4) shows increased risk.
[Nordstrom, M., et al. 1998. Br J Cancer 77(11):2048-2052.] - Comprehensive assessment of pesticide use patterns and increased cancer risk
Pesticides are an essential feature of modern-day agriculture that adds to the list of factors that increase cancer risk. Our study aims to comprehensively evaluate this relationship through a population-based approach that considers confounding variables such as county-specific rates of smoking, socioeconomic vulnerability, and agricultural land. We achieved our goal with the implementation of latent-class pesticide use patterns, which were further modeled among covariates to evaluate their associations with cancer risk. Our findings demonstrated an association between pesticide use and increased incidence of leukemia; non-Hodgkin's lymphoma; bladder, colon, lung, and pancreatic cancer; and all cancers combined that are comparable to smoking for some cancer types. Through our comprehensive analysis and unique approach, our study emphasizes the importance of a holistic assessment of the risks of pesticide use for communities, which may be used to impact future policies regarding pesticides.
[Gerken, J. et al. (2024) Comprehensive assessment of pesticide use patterns and increased cancer risk, Frontiers. Available at: https://www.frontiersin.org/journals/cancer-control-and-society/articles/10.3389/fcacs.2024.1368086/full. ] - Occupational Exposures and Risks of Non-Hodgkin Lymphoma: A Meta-Analysis
Non-Hodgkin lymphoma (NHL) is a heterogeneous group with different types of diseases. It remains unclear as to what has led to an increase in incidences of NHL, however, chemical substance exposure is known to be one of the risk factors for the disease. Therefore, we performed a systematic review and meta-analysis including case-control, cohort, and cross-sectional observational epidemiological studies to verify the association between occupational exposure to carcinogens and NHL risk. Articles between the years 2000 and 2020 were collected. Two different reviewers performed a blind selection of the studies using the Rayyan QCRI web app. Post-completion, the selected articles were extracted and analyzed via the RedCap platform. Our review resulted in 2719 articles, of which 51 were included in the meta-analysis, resulting in an overall OR of 1.27 (95% CI 1.04-1.55). Furthermore, it was observed that the main occupation associated with the increased risk of NHL was that in which workers are exposed to pesticides. We therefore conclude that the evidence synthesis of the epidemiological literature supports an increased risk for NHL, regardless of subtype, considering occupational exposure to certain chemical compounds, mainly pesticides, benzene, and trichlorethylene, and certain classes of work, primarily in the field of agriculture.
[Francisco, L.F.V., da Silva, R.N., Oliveira, M.A., dos Santos Neto, M.F., Gonçalves, I.Z., Marques, M.M. and Silveira, H.C., 2023. Cancers, 15(9), p.2600.] - Cancer and occupational exposure to pesticides: a bibliometric study of the past 10 years
Occupational exposure to pesticides has been identified as a major trigger of the development of cancer. Pesticides can cause intoxication in the individuals who manipulate them through either inhalation, ingestion, or dermal contact. Given this, we investigated the association between the incidence of cancer and occupational exposure to pesticides through a bibliometric analysis of the studies published between 2011 and 2020, based on 62 papers selected from the Scopus database. The results indicated an exponential increase in the number of studies published over the past decade, with most of the research being conducted in the USA, France, India, and Brazil, although a further 17 nations were also involved in the research on the association between cancer and pesticides. The principal classes of pesticides investigated in relation to their role in intoxication and cancer were insecticides, herbicides, and fungicides. The types of cancer reported most frequently were multiple myeloma, bladder cancer, non-Hodgkin’s lymphoma, prostate cancer, leukemia, and breast cancer. Despite the known association between pesticides and cancer, studies are still relatively scarce in comparison with the global scale of the use of these xenobiotic substances, which is related to the increasing demand for agricultural products throughout the world
[Pedroso, T.M.A., Benvindo-Souza, M., de Araújo Nascimento, F., Woch, J., Dos Reis, F.G. and de Melo e Silva, D. Environmental Science and Pollution Research, pp.1-12.] - Cancer and occupational exposure to pesticides: an umbrella review
Purpose
The aim was to identify the scope of the epidemiology literature reviewed regarding the risk of cancer as related to occupational exposure to pesticides and to compare regulatory toxicity results where feasible.Methods
Review studies of breast, lung, prostate, non-Hodgkin lymphoma, and colorectal cancer were identified from the published literature from 2010 to 2020 using a priori inclusion and exclusion criteria. Epidemiology observations were first assessed and then compared against carcinogenicity profiles derived from regulatory toxicology studies.Results
Several active ingredients were associated with specific cancer but overall, there was neither strong nor consistent epidemiologic data supportive of a positive association between pesticide exposure in occupational settings and cancer. Authors noted common themes related to the heterogeneity of exposure, study design, control for confounders, and the challenge to collect these data reliably and validly with an adequate sample size. Toxicology studies in laboratory animals that assessed carcinogenic potential did not reveal cancer outcomes that were concordant with reported epidemiologic findings.Conclusions
Farming and pesticides represent diverse exposures that are difficult to quantify in epidemiologic studies. Going forward, investigators will need creative and novel approaches for exposure assessment. Integration of epidemiologic and toxicological studies with attention to biological plausibility, mode of toxicological action and relevance to humans will increase the ability to better assess associations between pesticides and cancer.
[Burns, C.J. and Juberg, D.R. (2021) Cancer and occupational exposure to pesticides: An Umbrella Review, International Archives of Occupational and Environmental Health. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238729/. ] - Exposure to Glyphosate-Based Herbicides and Risk for Non-Hodgkin Lymphoma: A Meta-Analysis and Supporting Evidence.
Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13–1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11–1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.
[Zhang, L., Rana, I., Taioli, E., Shaffer, R.M. and Sheppard, L., 2019. Mutation Research/Reviews in Mutation Research.] - Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC).
Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. Study present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers. Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.
[Kachuri L, Harris MA, MacLeod JS, et al. 2017. BMC Cancer. 17(1):343] - Glyphosate Use and Cancer Incidence in the Agricultural Health Study.
Glyphosate is the most commonly used herbicide worldwide, with both residential and agricultural uses. In 2015, the International Agency for Research on Cancer classified glyphosate as "probably carcinogenic to humans," noting strong mechanistic evidence and positive associations for non-Hodgkin lymphoma (NHL) in some epidemiologic studies. A previous evaluation in the Agricultural Health Study (AHS) with follow-up through 2001 found no statistically significant associations with glyphosate use and cancer at any site.The AHS is a prospective cohort of licensed pesticide applicators from North Carolina and Iowa. Here, we updated the previous evaluation of glyphosate with cancer incidence from registry linkages through 2012 (North Carolina)/2013 (Iowa). Lifetime days and intensity-weighted lifetime days of glyphosate use were based on self-reported information from enrollment (1993-1997) and follow-up questionnaires (1999-2005). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounders, including use of other pesticides. All statistical tests were two-sided.Among 54 251 applicators, 44 932 (82.8%) used glyphosate, including 5779 incident cancer cases (79.3% of all cases). In unlagged analyses, glyphosate was not statistically significantly associated with cancer at any site. However, among applicators in the highest exposure quartile, there was an increased risk of acute myeloid leukemia (AML) compared with never users (RR = 2.44, 95% CI = 0.94 to 6.32, Ptrend = .11), though this association was not statistically significant. Results for AML were similar with a five-year (RRQuartile 4 = 2.32, 95% CI = 0.98 to 5.51, Ptrend = .07) and 20-year exposure lag (RRTertile 3 = 2.04, 95% CI = 1.05 to 3.97, Ptrend = .04). In this large, prospective cohort study, no association was apparent between glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes. There was some evidence of increased risk of AML among the highest exposed group that requires confirmation.
[Andreotti G, Koutros S, Hofmann JN, Sandler DP, Lubin JH, et al. 2017. J Natl Cancer Inst. doi: 10.1093/jnci/djx233.] - Non-Hodgkin lymphoma among Brazilian agricultural workers: A death certificate case-control study.
To estimate the non-Hodgkin lymphoma (NHL) mortality risk among agricultural workers in Brazil's southern states, we used death certificates to identify cases of NHL between the ages of 20 and 69 years from residents of nonurban municipalities between 1996 and 2005 (n = 1,317). Controls were randomly selected from those whose underlying cause of death did not include neoplasm or hematological diseases and paired with cases by sex, age, year of death, and state of residence (n = 2,634). Odds of being an agricultural worker among cases and controls were estimated by conditional logistic regression, stratified and adjusted by sex, state, education, and race. An increased risk of death by NHL was observed among agricultural workers 20-39 years old (ORadj = 2.06; 95% CI 95%, 1.20-3.14). Our results suggest that the young agricultural workers from southern Brazil were more likely to die of NHL compared to nonagricultural workers.
[Boccolini PM, Boccolini CS, Chrisman JR, et al. 2017. Arch Environ Occup Health. 72(3):139-144] - Glyphosate pathways to modern diseases V: Amino acid analogue of glycine in diverse proteins
Glyphosate, a synthetic amino acid and analogue of glycine, is the most widely used biocide on the planet. Its presence in food for human consumption and animal feed is ubiquitous. Epidemiological studies have revealed a strong correlation between the increasing incidence in the United States of a large number of chronic diseases and the increased use of glyphosate herbicide on corn, soy and wheat crops. Glyphosate, acting as a glycine analogue, may be mistakenly incorporated into peptides during protein synthesis. A deep search of the research literature has revealed a number of protein classes that depend on conserved glycine residues for proper function. Glycine, the smallest amino acid, has unique properties that support flexibility and the ability to anchor to the plasma membrane or the cytoskeleton. Glyphosate substitution for conserved glycines can easily explain a link with diabetes, obesity, asthma, chronic obstructive pulmonary disease (COPD), pulmonary edema, adrenal insufficiency, hypothyroidism, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, prion diseases, lupus, mitochondrial disease, nonHodgkin’s lymphoma, neural tube defects, infertility, hypertension, glaucoma, osteoporosis, fatty liver disease and kidney failure. The correlation data together with the direct biological evidence make a compelling case for glyphosate action as a glycine analogue to account for much of glyphosate’s toxicity. Glufosinate, an analogue of glutamate, likely exhibits an analogous toxicity mechanism. There is an urgent need to find an effective and economical way to grow crops without the use of glyphosate and glufosinate as herbicides.
[Samsel, A. and Seneff, S., 2016. J Biol Phys Chem, 16(6), pp.9-46.] - Analysis of Environmental Chemical Mixtures and Non-Hodgkin Lymphoma Risk in the NCI-SEER NHL Study.
There are several suspected environmental risk factors for non-Hodgkin lymphoma (NHL). The associations between NHL and environmental chemical exposures have typically been evaluated for individual chemicals. Study determined the association between a mixture of 27 correlated chemicals measured in house dust and NHL risk.A population-based case-control study of NHL in four National Cancer Institute-Surveillance, Epidemiology, and End Results centers-Detroit, Michigan; Iowa; Los Angeles County, California; and Seattle, Washington-from 1998 to 2000 was conducted. The WQS index was statistically significantly associated with NHL overall and in the study sites of Detroit, Los Angeles, and Iowa. The most highly weighted chemicals for predicting risk overall were PCB congener 180 and propoxur. Highly weighted chemicals varied by study site; PCBs were more highly weighted in Detroit, and pesticides were more highly weighted in Iowa. An index of chemical mixtures was significantly associated with NHL. Results show the importance of evaluating chemical mixtures when studying cancer risk.
[Czarnota J, Gennings C, Colt JS, De Roos AJ, et al. 2015. Environ Health Perspect. 123(10):965-70] - Insecticide exposure and farm history in relation to risk of lymphomas and leukemias in the Women's Health Initiative observational study cohort.
In questionnaires, women self-reported history living or working on a farm, personally mixing or applying insecticides, insecticide application in the home or workplace by a commercial service, and treating pets with insecticides. Relationships with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, plasma cell neoplasms, and myeloid leukemia were investigated. The analysis included 76,493 women and 822 NHL cases. Women who ever lived or worked on a farm had 1.12 times the risk of NHL compared to those who did not. Women who reported that a commercial service ever applied insecticides in their immediate surroundings had 65% higher risk of CLL/SLL. Women aged less than 65 years who ever applied insecticides had 87% higher risk of DLBCL. Insecticide exposures may contribute to risk of CLL/SLL and DLBCL.
[Schinasi LH, De Roos AJ, Ray RM, Edlefsen KL, et al. 2015. Ann Epidemiol. 25(11):803-810.e4] - Soft tissue sarcoma, non-Hodgkin's lymphoma and chronic lymphocytic leukaemia in workers exposed to phenoxy herbicides: extended follow-up of a UK cohort.
Study aimed to provide further information on the possible carcinogenicity of phenoxy herbicides, and in particular their relationship to soft tissue sarcoma (STS), non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). Authors extended follow-up to December 2012 for 8036 men employed at five factories in the UK which had manufactured phenoxy herbicides, or in a contract spraying business. Mortality from all causes and all cancers was close to expectation, but an excess of deaths from NHL was observed among men who had worked for ≥1 year in jobs with more than background exposure to phenoxy herbicides (19 deaths, SMR 1.85, 95% CI 1.12 to 2.89). Four deaths from STS occurred among men potentially exposed above background (3.3 expected). Findings are consistent with the current balance of epidemiological evidence. If phenoxy herbicides pose a hazard of either STS or NHL, then any absolute increase in risk is likely to be small.
[Coggon D, Ntani G, Harris EC, et al. 2015. Occup Environ Med.72(6):435-41.] - Non-Hodgkin lymphoma and occupational exposure to agricultural pesticide chemical groups and active ingredients: a systematic review and meta-analysis.
This paper describes results from a systematic review and a series of meta-analyses of nearly three decades worth of epidemiologic research on the relationship between non-Hodgkin lymphoma (NHL) and occupational exposure to agricultural pesticide active ingredients and chemical groups. Estimates of associations of NHL with 21 pesticide chemical groups and 80 active ingredients were extracted from 44 papers, all of which reported results from analyses of studies conducted in high-income countries. Random effects meta-analyses showed that phenoxy herbicides, carbamate insecticides, organophosphorus insecticides and the active ingredient lindane, an organochlorine insecticide, were positively associated with NHL. In a handful of papers, associations between pesticides and NHL subtypes were reported; B cell lymphoma was positively associated with phenoxy herbicides and the organophosphorus herbicide glyphosate. Diffuse large B-cell lymphoma was positively associated with phenoxy herbicide exposure. Despite compelling evidence that NHL is associated with certain chemicals, this review indicates the need for investigations of a larger variety of pesticides in more geographic areas, especially in low- and middle-income countries, which, despite producing a large portion of the world's agriculture, were missing in the literature that were reviewed.
[Schinasi L, Leon ME. 2014. Int J Environ Res Public Health. 11(4):4449-527.] - Non-hodgkin lymphoma risk and insecticide, fungicide and fumigant use in the agricultural health study.
Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Study evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.
[Alavanja MC, Hofmann JN, Lynch CF, Hines CJ, et al. 2014. PLoS One. 9(10):e109332] - Case-control study of risk factors for Non-Hodgkin lymphoma in Mumbai, India.
In the year 2010, it is estimated that nearly 0.36 million new cases and 0.19 million deaths with Non-Hodgkin lymphoma occurred. In India, among males, NHL incidence rates vary across the country which has encouraged us to conduct a case-control study to study risk factors. The present unmatched hospital-based case-control study conducted at Tata Memorial Hospital included subjects registered between the years 1997-99. There were 390 'lymphoma cases' and 1,383 'normal controls. Data on age, tobacco habits, occupational history, dietary factors, tea, coffee were collected by the social investigators. Univariate and multivariate methods were applied for obtaining the odds ratios for risk factors. In the study, cigarette smoking (OR=2.0) and bidi smoking (OR=2.8), were associated with excess risk of lymphoma. Among the dietary items, only consumption of mutton showed 7.3-fold significant excess risk for lymphoma. Consumption of milk showed a 6-fold excess risk (OR=1.5); while coffee showed a 50% reduction in risk for lymphoma. Among occupational exposure, exposure to use of pesticides showed 3-fold excess risk for lymphoma.
[Balasubramaniam G, Saoba S, Sarade M, Pinjare S. 2013. Asian Pac J Cancer Prev. 14(2):775-80.] - Exposures to multiple pesticides and the risk of Hodgkin lymphoma in Canadian men.
Study's aim was to determine the risk of Hodgkin lymphoma (HL) associated with exposures to multiple pesticides grouped by various classes, including carcinogenic classifications. Data collected in the Cross-Canada Study of Pesticides and Health, a population-based incident case-control study in six provinces conducted between 1991 and 1994, were analyzed using unconditional logistic regression. Overall, there was an increase in the risk of HL among all subjects who reported use of five or more insecticides (OR 1.88) and among subjects younger than 40 who reported use of two acetylcholinesterase inhibitors (OR 3.16). There was an elevated odds ratio associated with reported use of three or more probably carcinogenic pesticides (OR 2.47), but no increase in risk for use of possibly carcinogenic pesticides. The risk of HL from reported use of fungicides or any pesticides was greater for cases diagnosed before age 40 than for cases diagnosed at or after age 40. This study found associations between HL and fungicides, insecticides, specifically acetylcholinesterase inhibitors, and pesticides previously identified as probable human carcinogens.
[Navaranjan G, Hohenadel K, Blair A, Demers PA, et al. 2013. Cancer Causes Control. 24(9):1661-73] - Hypospadias and residential proximity to pesticide applications.
Examine the association of hypospadias with residential proximity to commercial agricultural pesticide applications. The study population included male infants born from 1991 to 2004 to mothers residing in 8 California counties. Cases (n = 690) were ascertained by the California Birth Defects Monitoring Program; controls were selected randomly from the birth population (n = 2195). Authors determined early pregnancy exposure to pesticide applications within a 500-m radius of mother's residential address, using detailed data on applications and land use. Forty-one percent of cases and controls were classified as exposed to 57 chemical groups and 292 chemicals. Despite >500 statistical comparisons, there were few elevated odds ratios with confidence intervals that excluded 1 for chemical groups or specific chemicals. Those that did were for monochlorophenoxy acid or ester herbicides; the insecticides aldicarb, dimethoate, phorate, and petroleum oils; and adjuvant polyoxyethylene sorbitol among all cases; 2,6-dinitroaniline herbicides, the herbicide oxyfluorfen, and the fungicide copper sulfate among mild cases; and chloroacetanilide herbicides, polyalkyloxy compounds used as adjuvants, the insecticides aldicarb and acephate, and the adjuvant nonyl-phenoxy-poly(ethylene oxy)ethanol among moderate and severe cases. Odds ratios ranged from 1.9 to 2.9.Most pesticides were not associated with elevated hypospadias risk. For the few that were associated, results should be interpreted with caution until replicated in other study populations.
[Carmichael SL, Yang W, Roberts EM, et al. 2013. Pediatrics. 132(5):e1216-26] - Non-Hodgkin lymphoma and pesticide exposure in Turkey.
The study used data from 1995 to 2010 on the patients who were histopathologically diagnosed with NHL during these years. An increase in the NHL incidence over the years was identified, with a 2.42-fold increment found from 1995 to 2005 and a 2.77 fold elevation from 1995 to 2010. The use of pesticides increased 1.89 fold over the same period.Study investigated the relationship of the pesticides used with NHL patients diagnosed during the same year. Since the time elapsing after exposure to pesticides until the development of cancer is not clear, no comparison can be made at present. We believe that the increase in use of pesticides since 1995 may be associated with the increase in the incidence of NHL and therefore that further studies on the issue including measurements of serum pesticide levels, are required.
[Yildirim M, Karakilinc H, Yildiz M, Kurtoglu E, et al. 2013. Asian Pac J Cancer Prev. 14(6):3461-3.] - Non-hodgkin's lymphoma and work in agriculture: Results of a two case-control studies in Saskatchewan, Canada.
The objective was to examine the association between non-Hodgkin's lymphoma (NHL) and farming-related activities, gender, pesticides exposure, and exposure to chemicals other than pesticides in Saskatchewan. Male and female study participants were taken from two separate case-control studies conducted in Saskatchewan province, Canada. A case was defined as any man or woman aged 19 years and older with a first diagnosis of NHL registered by the Saskatchewan Cancer Agency during the study period. Farming exposure and exposure to pesticides-contaminated cloths were related to an increased risk of NHL. Exposure to pesticides was strongly associated with an increased risk of NHL, especially for men.
[Karunanayake CP, Dosman JA, Pahwa P. 2013. Indian J Occup Environ Med.17(3):114-21] - Pesticide use and non-Hodgkin's lymphoma mortality in Brazil.
Brazil is one of the major pesticide consumers in the world. The continuous exposure to these substances may be etiologically associated with the development of Non-Hodgkin's Lymphoma (NHL). Study's goal was to Estimate the correlation between the per capita sales of pesticides in 1985 (exposure) and NHL mortality rates between 1996 and 2005 (outcome), by Brazilian micro-regions. A moderate correlation between per capita pesticides consumption and standardized mortality rate for NHL was observed (r=0.597). In addition, using the lowest quartile of pesticide consumption as a reference, the higher the quartile of pesticide consumption, the higher was NHL mortality risk: men - (second quartile - MRR=1.69, CI 95% 1.68-1.84; third quartile - MRR=2.41, CI 95% 2.27-2.57; fourth quartile - MRR=2.92, CI 95% 2.74-3.11) and females (second quartile - MRR=1.87, CI 95% 1.69-2.06; third quartile - MRR=2.28, IC 95% 2.10-2.47; fourth quartile - MRR=3.20; CI 95% 2.98-3.43).Results suggest that pesticide exposure may play a role in the etiology of NHL.
[Boccolini Pde M, Boccolini CS, Chrisman Jde R, et al. 2013. Int J Hyg Environ Health. 216(4):461-6.] - A prospective study of organochlorines in adipose tissue and risk of non‑Hodgkin lymphoma.
Purpose here was to examine associations between organochlorine concentrations in prediagnostic adipose tissue samples and the risk of NHL.Authors conducted a case–cohort study using a prospective Danish cohort of 57,053 persons enrolled between 1993 and 1997 and measured concentrations of 8 pesticides and 10 polychlorinated biphenyl (PCB) congeners in adipose tissue collected upon enrollment. Results found a higher risk of NHL in association with higher adipose tissue levels of DDT, cis-nonachlor, and oxychlordane, but no association with PCBs. This is the first study of organochlorines and NHL using prediagnostic adipose tissue samples in the exposure assessment and provides new environmental health evidence that these organochlorines contribute to NHL risk.
[Bräuner EV, Sørensen M, Gaudreau E, LeBlanc A, et al. 2012. Environ Health Perspect.120(1):105-11.] - Pesticide use, immunologic conditions, and risk of non-Hodgkin lymphoma in Canadian men in six provinces.
Pesticide exposures and immune suppression have been independently associated with the risk of non-Hodgkin lymphoma (NHL), but their joint effect has not been well explored. Data from a case-control study of men from six Canadian provinces were used to evaluate the potential effect modification of asthma, allergies, or asthma and allergies and hay fever combined on NHL risk. Incident NHL cases (n = 513) diagnosed between 1991 and 1994 were recruited from provincial cancer registries and hospitalization records and compared to 1,506 controls. Subjects with asthma, allergies, or hay fever had non-significantly elevated risks of NHL associated with use of MCPA (OR = 2.67) compared to subjects without any of these conditions (OR = 0.81). Conversely, those with asthma, allergies, or hay fever who reported use of malathion had lower risks of NHL (OR = 1.25) versus subjects with none of these conditions (OR = 2.44). Similar effects were observed for asthma and allergies evaluated individually. Although there were some leads regarding effect modification by these immunologic conditions on the association between pesticide use and NHL, small numbers, measurement error and possible recall bias limit interpretation of these results.
[Pahwa M, Harris SA, Hohenadel K, McLaughlin JR, et al.2012.Int J Cancer. 131(11):2650-9.] - Increased risk of non-Hodgkin lymphoma and serum organochlorine concentrations among neighbors of a municipal solid waste incinerator.
Study investigated organochlorines and the risk of NHL among neighbors of a French MSWI with high levels of dioxin emissions (Besançon, France), using serum concentrations to assess exposure. Risks of NHL associated with each lipid-corrected serum concentration were estimated using exact logistic regression. The pesticides β-hexachlorocyclohexane (odds ratio [OR]=1.05, 95% confidence interval [CI]=1.00-1.12, per 10 ng/g lipid) and p,p' dichloro-diphenyl-trichloroethane (DDT) (OR=1.20, 95% CI=1.01-1.45, per 10 ng/g lipid) were associated with NHL risk. Evidence indicated an increased NHL risk associated with cumulative WHO(1998)-toxic equivalency factor (TEQ) concentrations (dioxins, OR=1.12, 95% CI=1.03-1.26; furans, OR=1.16, 95% CI=1.03-1.35; dioxin-like PCBs, OR=1.04, 95% CI=1.00-1.07; and total TEQ, OR=1.04, 95% CI=1.01-1.05), as well as with non dioxin-like PCBs (OR=1.02, 95% CI=1.01-1.05, per 10 ng/g lipid). Most congener-specific associations were statistically significant. This study provides strong and consistent support for an association between serum cumulative WHO(1998)-TEQ concentrations, at levels experienced by people residing in the vicinity of a polluting MSWI, and risk of NHL.
[Viel JF, Floret N, Deconinck E, Focant JF, et al. 2011. Environ Int. 37(2):449-53.] - Mortality of US pentachlorophenol production workers through 2005.
A cohort of 2122 US pentachlorophenol (PCP) production workers from four plants in the National Institute for Occupational Safety and Health Dioxin Registry was exposed to PCP and to polychlorinated dibenzo-p-dioxin and dibenzofuran contaminants of PCP production. A subcohort of 720 was also exposed to 2,3,7,8-tetrachlorodibenzodioxin, a contaminant of trichlorophenol (TCP) while using TCP or a TCP derivative. PCP and several production contaminants have been implicated as animal carcinogens. A priori hypotheses were that the cohort would have elevated standardized mortality ratios (SMRs) for aplastic anemia, soft-tissue sarcoma, and non-Hodgkin lymphoma, as suggested by human studies, and for leukemia and liver, adrenal, thyroid, and parathyroid cancer, as suggested by animal studies. From 1940 to 2005 1165 deaths occurred with an overall SMR of 1.01 [95% confidence limits (CI), 0.95-1.07]. Overall cancer mortality (326 deaths, SMR 1.17, CI 1.05-1.31) was in statistically significant excess. There were excess deaths for trachea, bronchus and lung cancers (126 deaths, SMR 1.36, CI 1.13-1.62), non-Hodgkin lymphoma (17 deaths, SMR 1.77, CI 1.03-2.84), chronic obstructive pulmonary disease (63 deaths, SMR 1.38, CI 1.06-1.77), and medical complications (5 deaths, SMR 3.52, CI 1.14-8.22).The excess of cancers of a priori interest, non-Hodgkin lymphoma and leukemia, provide some support for the carcinogenicity of PCP, however, further studies with more detailed exposure assessment are needed.
[Ruder AM, Yiin JH. 2011.Chemosphere. 83(6):851-61.] - Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study
Study investigated associations between use of terbufos and the incidence of cancer. The Agricultural Health Study is a prospective cohort study of 57,310 licensed pesticide applicators from Iowa and North Carolina. Detailed information about 50 pesticides, including terbufos, and potential confounders was obtained from self-administered questionnaires. Overall cancer risk was slightly increased among terbufos users. Suggestive associations were observed between terbufos use and cancers of the prostate and lung, leukemia, and non-Hodgkin's lymphoma, although the exposure-response gradients were non-monotonic and p for trends were not significant. However, cautious interpretation of these results is warranted by the lack of existing experimental and epidemiologic evidence to support carcinogenic effects of terbufos.
[Bonner, M.R., et al. 2010. Cancer Causes Control 21(6):871-7] - High risk occupations for non-Hodgkin's lymphoma in New Zealand: case-control study.
Previous studies into occupational risk factors for non-Hodgkin's lymphoma (NHL) in New Zealand have indicated that farmers and meat workers are at increased risk for these neoplasms. A new nationwide case-control study was conducted to assess whether previously observed associations persist and to identify other occupations that may contribute to the risk of NHL in the New Zealand population. A total of 291 incident cases of NHL (age 25-70 years) notified to the New Zealand Cancer Registry during 2003 and 2004, and 471 population controls, were interviewed face-to-face. The questionnaire collected demographic information and a full occupational history. The relative risk for NHL associated with ever being employed in particular occupations and industries was calculated by unconditional logistic regression adjusting for age, sex, smoking, ethnicity and socioeconomic status. Estimates were subsequently semi-Bayes adjusted to account for the large number of occupations and industries being considered. An elevated NHL risk was observed for field crop and vegetable growers (OR 2.74, 95% CI 1.04 to 7.25) and horticulture and fruit growing (OR 2.28, 95% CI 1.37 to 3.79), particularly for women (OR 3.44, 95% CI 0.62 to 18.9; OR 3.15, 95% CI 1.50 to 6.61). Sheep and dairy farming was not associated with an increased risk of NHL. Meat processors had an elevated risk (OR 1.97, 95% CI 0.97 to 3.97), as did heavy truck drivers (OR 1.98, 95% CI 0.92 to 4.24), workers employed in metal product manufacturing (OR 1.92, 95% CI 1.12 to 3.28) and cleaners (OR 2.11, 95% CI 1.21 to 3.65). After semi-Bayes adjustment the elevated risks for horticulture and fruit growing, metal product manufacturing and cleaners remained statistically significant, representing the most robust findings of this study. This study has confirmed that crop farmers and meat workers remain high risk occupations for NHL in New Zealand, and has identified several other occupations and industries of high NHL risk that merit further study.
[Mannetje, A., et al. 2008. Occupational and Environmental Medicine 65:354-363] - Pesticide exposure as risk factor for non-Hodgkin lymphoma including histopathological subgroup analysis.
A Swedish population based case-control study of male and female NHL patients finds the highest risk is for exposure to: herbicides; MCPA with a latency period greater than ten years; glyphosate ; and, glyphosate exposure with a latency period of greater than ten years . When different NHL subtypes are analyzed: (a) diffuse large B-cell lymphoma is significantly associate with exposure to phenoxyacetic acids and especially for MCPA; (b) small lymphocytic lymphoma/chronic lymphocytic leukemia is associated with exposure to phenoxy herbicides, MCPA , and glyphosate ; (c) the category “other specific B-cell lymphoma (mantle cell lymphoma, marginal zone lymphoma)” an association is found for exposure to phenoxyacetic acids, MCPA and glphyosate; and (d) the category “unspecific NHL” subtypes are associated with herbicides, phenoxyacetic acids, MCPA and glyphosate.
[Eriksson, M., et al. 2008. Int J Cancer 123(7):1657-1663] - Atopy, exposure to pesticides and risk of non-Hodgkin lymphoma
Although the Australian population based case control study did not find a clear connection with asthma and pesticide exposure and NHL, it did find an increased risk of NHL with occupational pesticide exposure and a history of asthma as well as with occupational pesticide exposure an no history of asthma.
[Vajdic, C.M., et al. 2007. Int J Cancer 120(10):2271-2274] - Household exposure to pesticides and risk of childhood hematopoietic malignancies: The ESCALE study (SFCE)
A case-control study in France finds prenatal insecticide use is significantly associated with childhood lymphoblastic and myelobastic NHL, mainly for Burkitt lymphoma, and finds paternal household use of pesticides is associated with NHL. Household use of any pesticide during pregnancy is significantly more frequent in NHL cases.
[Rudant, J., et al. 2007. Environmental Health Perspectives 115(12):1787-1793] - Occupational exposure to organochlorine insecticides and cancer incidence in the Agricultural Health Study
A NIH prospective cohort study of licensed pesticide applicators in Iowa and North Carolina finds a significant increase in risk for NHL and lindane.
[Purdue, M.P., et al. 2007. Int J Cancer 120(3):642-649] - Occupational exposure to pesticides and risk of hematopoietic cancers: meta-analysis of case-control studies
A meta-analysis of 13 case-control studies on hematopoeietic cancers finds that occupational pesticide exposure greater than ten years significantly increases risk of NHL (OR 1.65).
[Merhi, M, et al. 2007. Cancer Causes Control 18(10):1209-1226] - Agricultural pesticide use and risk of t(14;18)-defined subtypes of non-Hodgkin lymphoma.
A population-based, case-control study in Nebraska looking at different molecular subtypes of NHL discovered that the risk of t(14;18)-positive NHL subtype is significantly elevated among farmers who used animal insecticides (OR 2.6), crop insecticides (OR 3.0), herbicides (OR 2.9) and fumigants (5.0 OR) and that there was no increased risk of t(14;18)-negative NHL subtype for these pesticides, which may explain some of the inconsistencies in epidemiological study of NHL and pesticide exposure. They also find that the risk increases with a longer duration of use.
[Chiu, B., et al. 2006. Blood 108(4):1363-1369] - Cancer and pesticides: an overview and some results of the Italian multicenter case-control study on hematolymphopoietic malignancies
A population based case-control study in Italy finds a significant increase in risk of NHL for occupational exposure to 2,4D.
[Miligi, L., et al. 2006. Ann N Y Acad Sci 1076:366-377] - Integrative assessment of multiple pesticides as risk factors for non-Hodgkin's lymphoma among men
A study using three National Cancer Institute case-controls of NHL in Iowa, Minnesota, Kansas, and Nebraska farmers finds coumaphos (OR 1.7), diazinon (OR 1.7), and glyphosate (OR 1.6) are associated with an increase in NHL incidence.
[De Roos, A.J., et al. 2003. Occupational and Environmental Medicine 60(9):e11] - Exposure to pesticides as risk factor for non-Hodgkin's lymphoma and hairy cell leukemia: pooled analysis of two Swedish case-control studies.
previously been reported. To further elucidate the importance of phenoxyacetic acids and other pesticides in the etiology of NHL a pooled analysis was performed on two case-control studies, one on NHL and another on hairy cell leukemia (HCL), a rare subtype of NHL. The studies were population based with cases identified from cancer registry and controls from population registry. Data assessment was ascertained by questionnaires supplemented over the telephone by specially trained interviewers. The pooled analysis of NHL and HCL was based on 515 cases and 1141 controls. Increased risks in univariate analysis were found for subjects exposed to herbicides (OR 1.75, CI 95% 1.26-2.42), insecticides (OR 1.43, CI 95% 1.08-1.87), fungicides (OR 3.11, CI 95% 1.56-6.27) and impregnating agents (OR 1.48, CI 95% 1.11-1.96). Among herbicides, significant associations were found for glyphosate (OR 3.04, CI 95% 1.08-8.52) and 4-chloro-2-methyl phenoxyacetic acid (MCPA) (OR 2.62, CI 95% 1.40-4.88). For several categories of pesticides the highest risk was found for exposure during the latest decades before diagnosis. However, in multivariate analyses the only significantly increased risk was for a heterogeneous category of other herbicides than above.
[Hardell, L., et al. 2002. Leuk Lymphoma 43(5):1043-1049] - Agricultural risk factors for t(14;18) subtypes of non-Hodgkin's lymphoma.
A study using a case-control study of male farmers in Iowa and Minnesota finds that the t(14;18)-positive subtypes of NHL is associated with farming (OR 1.4), lindane (OR 2.3), atrazine (OR 1.7) and fungicides (OR 1.8) and no association with t(14;18)-negative NHL
[Schroeder, J., et al. 2001. Epidemiology 12(6):701-709] - Non-Hodgkin's lymphoma and specific pesticide exposures in men: cross-Canada study of pesticides and health.
A Canadian multi-center population based incident case control study among men finds an increase risk of NHL for exposure to dicamba, carbamates, OPs, amide fungicides and fumigant carbon tetrachloride, mecoprop, malathion and carbaryl.
[McDuffie, H., et al. 2001.Cancer Epidemiology, Biomarkers & Prevention 10:1155-1163] - Leukemia and Non-Hodgkin's Lymphoma in Childhood and Exposure to Pesticides: Results of a Register-based Case-Control Study in Germany
Previous studies have suggested an association between exposure to pesticides and different types of childhood cancer. This paper presents results from a population-based case-control interview study of parents of children less than 15 years of age, which was conducted in the states of West Germany from 1993 to 1997. Cases were 1,184 children with leukemia, 234 with non-Hodgkin's lymphoma, and 940 with a solid tumor; 2,588 controls were also included. Parental occupational exposures were found to be related to childhood cancer regardless of the time period of exposures and the type of cancer. This finding might partially be explained by different recall of past exposures by the parents of cases and controls. Residential use of insecticides was assodated with childhood lymphoma: both extermination of insects by professional pest controllers (odds ratio (OR) = 2.6, 95% confidence interval (CI): 1.2, 5.7) and frequency of parental use of household insecticides (pfor trend = 0.02) were significant risk factors for this diagnosis. The use of pesticides on farms was weakly related to childhood leukemia (OR = 1.5, 95% CI: 1.0, 2.2), while their use in gardens was not assodated with childhood leukemia (OR = 1.0, 95% CI: 0.8, 1.2). The major strengths of this study were the population base and the large number of cases and controls included; a drawback was assessment of expasure on the basis of parental interviews. The data provide some evidence for an increased leukemia risk for children living on farms and for an association between use of household pesticides and risk of childhood leukemia or lymphoma.
[Meinert, R., et al. 2000. American Journal of Epidemiology 151(7):639-646] - Pesticide exposures in children with non-Hodgkin lymphoma.
A case-control study in the U.S. finds a significant association between risk of childhood NHL and frequency of reported prenatal home pesticide use, and professional treatments in the home. Postnatal home pesticide exposure also shows a significant association . In children, elevated risk for T-cell, B-cell lymphomas, lymphoblastic, large cell, and Burkitt morphologies are found.
[Buckley, J.D., et al. 2000. Cancer 89(11):2315-2321] - A case-control study of non-Hodgkin lymphoma and exposure to pesticides
A population based case-control study in Sweden finds an increased risk for NHL for people exposed to herbicides, specifically significant is exposure to MCPA, and fungicides.
[Hardell, L., et al. 1999. Cancer 85(6):1353-1360] - Meta-analyses of non-Hodgkin's lymphoma and farming.
A meta-analyses of 36 studies on NHL and farming suggests that male U.S. farmers have a slightly elevated risk of NHL.
[Khuder, S.A., et al 1998. Scand J Work Environ Health 24(4):255-261] - Cancer in offspring of parents engaged in agricultural activities in Norway: incidence and risk factors in the farm environment.
A cohort study of cancer in offspring of parents working in Norway horticulture finds parental pesticide purchase associated with childhood NHL.
[Kristensen, P., et al. 1996. Int J Cancer 65(1):39-50] - Cancer incidence among Icelandic pesticide users
A small cohort study in Iceland shows that female licensed pesticide applicators for agricultural purposes have a significant increased incidence for cancers of the lymphatic and hematopoietic tissue in women.
[Zhong, Y. and Rafnsson, V. 1996. International Journal of Epidemiology 25(6):1117-1124.] - Farming, pesticide use and hairy-cell leukemia.
This paper analyzes the role of farming and pesticide exposures in the occurrence of hairy-cell leukemia (HCL). The study included 226 men with HCL and 425 matched hospital referents. Pesticide exposure was assessed by expert review of detailed interview data on occupational histories and agricultural activities and exposures. Altogether, 77 cases and 116 referents had farmed for at least six months, giving an odds ratio (OR) of 1.5 [95% confidence interval (95% CI) 1.0-2.2]. Forage growing was reported by 20.8% of the cases and 11.1% of the referents and was associated with HCL (OR 2.8, 95% CI 1.6-4.9), even among farmers who had never handled pesticides (OR 3.4, 95% CI 1.0-11.0). A significant association was found between HCL and pesticide use, the overall odds ratios for insecticide, fungicide, and herbicide use ranging from 1.5 to 2.4. Organophosphorus insecticides were the only agrochemicals with a positive association with HCL after other pesticide exposures, smoking, and forage growing were accounted for. A clear-cut negative interaction was found between smoking and exposure to organophosphorus insecticides. A multivariate analysis yielded odds ratio estimates of 2.8 (95% CI 1.4-5.6) for exposure to forage and 7.5 (95% CI 0.9-61.5) for nonsmokers exposed to organophosphorus insecticides. The present study argues for a role of organophosphorus insecticides in HCL among nonsmoking farmers and shows an unexpected association with forage growing. No evidence of an association with phenoxyacetic acids, triazines, or organochlorine insecticides was found.
[Clavel, J., et al. 1996. Scand J Work Environ Health 22(4):285-293] - Proportionate mortality study of golf course superintendents.
A proportionate mortality study of a cohort of 686 golf course superintendents finds an elevated number deaths from brain cancer (PMR 234), large intestine cancer (PMR 175), NHL (PMR 237), and prostate cancer (PMR 293).
[Kross, B.C., et al. 1996. Am J Ind Med 29(5):501-506] - Soft tissue sarcoma and non-Hodgkin's lymphoma in workers exposed to phenoxy herbicides, chlorophenols, and dioxins: two nested case-control studies
Abstract
We examined the effect of exposure to chemicals present in the production and spraying of phenoxy herbicides or chlorophenols in two nested case-control studies of soft tissue sarcoma and non-Hodgkin's lymphoma. Eleven sarcoma and 32 lymphoma cases occurring within an international cohort were matched for age, sex, and country of residence with 55 and 158 controls, respectively. Exposures to 21 chemicals or mixtures were estimated by three industrial hygienists who were blind to the subject's case-control status. Excess risk of soft tissue sarcoma was associated with exposure to any phenoxy herbicide [odds ratio (OR) = 10.3; 95% confidence interval (CI) = 1.2-91] and to each of the three major classes of phenoxy herbicides (2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, and 4-chloro-2-methylphenoxyacetic acid), to any polychlorinated dibenzodioxin or furan (OR = 5.6; 95% CI = 1.1-28), and to 2,3,7,8-tetrachlorodibenzo-p-dioxin (OR = 5.2; 95% CI = 0.85-32). Sarcoma risk was not associated with exposure to raw materials or other process chemicals. In the non-Hodgkin's lymphoma study, associations were generally weaker than those found in the study on sarcoma. These findings indicate that workers exposed to phenoxy herbicides and their contaminants are at a higher risk of soft tissue sarcoma.
[Kogevinas, M. et al. (1995) ‘Soft tissue sarcoma and Non-Hodgkinʼs lymphoma in workers exposed to phenoxy herbicides, chlorophenols, and dioxins’, Epidemiology, 6(4), pp. 396–402. doi:10.1097/00001648-199507000-00012. ] - Non-Hodgkin's lymphoma and agricultural practices in the prairie provinces of Canada.
A follow-up to a previous cohort study in Canada finds a significant increase risk for fatal NHL for male farmers according to acres sprayed herbicides
[Morrison, H.I., et al. 1994. Scand J Work Environ Health 10(1):42-47] - The role of agricultural pesticide use in the development of non-Hodgkin's lymphoma in women
A population-based case control study in Nebraska finds that NHL risk is significantly increased for woman who handle OP insecticides, for use of chlorinated hydrocarbon insecticides, and for chlorinated hydrocarbon insecticide use on cattle. The study finds that pesticide related risk are grater for woman with a family history of cancer.
[Zahm, S., et al. 1993. Archives of Environmental Health 48(5):353-358] - Herbicides and Cancer
Herbicides are a heterogeneous class of chemicals used in agriculture, forestry, and urban settings to kill weeds, shrubs, and broad-leaved trees. The role of herbicides in the etiology of cancer is controversial. Potential studies for review were identified through a MEDLINE 1 search and from a check of references in related review articles. This review of the literature shows reasonable evidence suggesting that occupational exposure to phenoxy herbicides results in increased risk of developing non-Hodgkin's Iymphoma. Several studies have noted large increases in risk of soft-tissue sarcomas with phenoxy herbicide exposure. In contrast, others have failed to observe increased risks, and evidence of an exposure—risk relationship is lacking. Although there have been too few appropriate studies for adequate assessment of risk of cancer at other sites, some findings have linked herbicide exposure with cancers of the colon, lung, nose, prostate, and ovary as well as to leukemia and multiple myeloma. Future studies must better identify and quantify the nature of herbicide exposures. In the interim, it seems only prudent to monitor and promote safety practices among persons occupationally exposed to phenoxy herbicides, particularly farmers and professional sprayers.
[Morrison, H.I., et al. 1992. J Natl Cancer Inst 84(24):1866-1874] - Pesticides and Other Agricultural Risk Factors for Non-Hodgkin's Lymphoma among Men in Iowa and Minnesota
A population based study of white male farmers finds a significant increase in risk for (a) diffuse NHL and organophosphates (OP) on crops, non-halogenated aliphatic OP on crops, cyclodiene chlorinated hydrocarbons used on livestock, and triazine herbicides; (b) small lymphocytic NHL with “natural product insecticides used on livestock” (although nowhere in the study does it define “natural”), and halongenated aromatic OP for livestock); and, (c) other and unclassified forms of NHL and chlorinated hydrobarbon insecticides for crops, cyclodienes for crops, and halogenated aliphatic OPs used on livestock
[Cantor, K., et al. 1992. Cancer Research 52:2447-2455] - A case-control study of non-Hodgkin's lymphoma and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska.
A population based case-control study in Nebraska finds a slight increase NHL risk for men who mix or apply 2,4-D. A significant risk is found for: men who mix or apply 2,4-D for 20 days or more a year; men who mix or apply 2,4-D and fungicides; men who mix or apply 2,4-D and OPs; and, men who mix or apply 2,4-D, fungicides and OPs.
[Zahm, S., et al. 1990. Epidemiology 1(5):349-356] - Cancer mortality in the U.S. flour industry
A nested case control mortality study of workers employed in U.S. flour mills, where according to the study author’s, “pesticides are used more frequently than in other segments of the industry,” an increased risk for NHL (OR 4.2) is found.
[Alavanja, M.C., et al. 1990. J Natl Cancer Inst 82(10):840-848] - Mortality study of Canadian male farm operators: cancer mortality and agricultural practices in Saskatchewan.
A cohort mortality study of male Saskatchewan farmer finds a significant dose-response relationship is found between risk of NHL and acres sprayed with herbicides
[Wigle, D., et al. 1990. Journal of the National Cancer Institute 82(7):575-582] - Soft tissue sarcoma and non-Hodgkin's lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington.
A population-based case-control study in Washington state finds an elevated risk of NHL among male forestry herbicide applicators and for men that are potential exposed to phenoxy herbicides in any occupation for 15 or more years prior to their cancer diagnosis.
[Woods, J.S., et al. 1987. J Natl Cancer Inst 78(5):899-910] - Agricultural herbicide use and a risk of lymphoma and soft-tissue sarcoma.
A population based case control study in Kansas finds farm herbicide use increases risk associated with NHL; risk increased significantly for those men exposed to herbicides more than 20 days a year; and, those men that frequently mixed or applied herbicides themselves also have a significant increased risk to phenoxyacetic acid herbicides, specifically 2,4D.
[Hoar, S., et al. 1986. Journal of the American Medical Association 259(9): 1141-1147] - Malignant lymphoma and multiple myeloma linked with agricultural occupations in a New Zealand Cancer Registry-based study.
A case-control study of New Zealand agriculture and forestry workers finds a significant excess of patients with nodular lymphoma, mycosis fungoldes, and NHL.
[Pearce, N.E., et al. 1985. Am J Epidemiol 121(2):225-237] - Farming and mortality from non-Hodgkin's lymphoma: A case-control study
A case‐control study of non‐Hodgkin's lymphoma (NHL) and its subtypes among males was conducted using computerized mortality listings from the State of Wisconsin for the years 1968‐1976. Age, year of death, race, county of usual residence, marital status, and usual occupation were abstracted for the 774 records of male deaths due to NHL and a matched series of deaths due to other causes. The frequency of farming occupation among NHL cases was compared to the frequency among controls, and odds ratios (OR) were calculated. Farming was more common among cases than among controls (OR=1.22). The association of NHL with farming occupation was greater among decedents under 65 years of age (ORequlas;1.7) than among those who were older. The younger decedents were at higher risk of reticulum‐cell sarcoma (ORequlas;2.7) than of other cell types. The strength of the association increased over the 9‐year study period. County levels of selected agricultural characteristics were used as surrogate measures of farming exposures in residence counties of farmers and were summarized by factor analysis. Major findings were of elevated risk among younger farmers for reticulum‐cell sarcoma in counties high in summary measures of general agricultural activity (ORequlas;3.2), of small grain acreage and acres treated with insecticides (ORequlas;6.6), and of wheat acreage (ORequlas;4.4). Given the limitations of the data, further investigation of non‐Hodgkin's lymphoma in farmers is warranted.
[Cantor, KP. 1982. Int J Cancer 29(3):239-247]
Melanoma
- Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC).
Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. Study present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers. Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.
[Kachuri L, Harris MA, MacLeod JS, et al. 2017. BMC Cancer. 17(1):343] - A Review of the Association Between Parkinson Disease and Malignant Melanoma
An association between melanoma and Parkinson disease (PD) has been hinted at in the neurology and oncology literature since the 1970s after the initiation of levodopa (L-DOPA) therapy for PD. Given that L-DOPA is a substrate in melanin synthesis, there existed a concern that this therapy might cause melanoma.The objective was to research possible etiological links to explain the connection between PD and melanoma. Patients with PD have an overall decreased risk of cancer diagnoses. However, breast cancer and melanoma have an uncharacteristically high rate of co-occurrence with PD. Family history of melanoma and lighter hair and skin color confer a higher risk of developing PD, and having a first-degree relative with either disease conveys a significantly increased risk of developing the other. Other possible connections that have been explored include pigmentation genes in neural-derived cells, pesticides, MC1R polymorphisms, and abnormal cellular autophagy. Although a link between PD and melanoma exists, the etiology of this link continues to be elusive. Both PD and melanoma are likely multifactorial diseases involving genetic and environmental risk factors.
[Disse M, Reich H, Lee PK, Schram SS. 2016. Dermatol Surg. 42(2):141-6.] - Occupational Exposure to Pesticides With Occupational Sun Exposure Increases the Risk for Cutaneous Melanoma.
The objective of the study was to examine the association between occupational exposure to pesticides and cutaneous melanoma, controlling for all possible confounders.A pooled analysis of two case-control studies was conducted in two different geographic areas (Italy and Brazil). Detailed pesticides exposure histories were obtained. Ever use of any pesticide was associated with a high risk of cutaneous melanoma (odds ratio 2.58; 95% confidence interval 1.18-5.65) in particular exposure to herbicides (glyphosate) and fungicides (mancozeb, maneb), after controlling for confounding factors. When subjects were exposed to both pesticides and occupational sun exposure, the risk increased even more (odds ratio 4.68; 95% confidence interval 1.29-17.0). The study suggests an augmented risk of cutaneous melanoma among subjects with exposure to pesticides, in particular among those exposed to occupational sun exposure.
[Fortes C, Mastroeni S, Segatto M M, Hohmann C, et al. 2016. J Occup Environ Med. 58(4):370-5. ] - Residential and occupational exposure to pesticides may increase risk for cutaneous melanoma: a case-control study conducted in the south of Brazil.
Incidences of primary cutaneous melanoma (CM) have risen over the last few decades, mainly among populations of White European extraction. Some risk factors for melanoma have been clearly established, but other potential risk factors, such as exposure to pesticides, are currently under study.A case-control study on melanoma was conducted during 2012 and 2013 at three dermatological reference centers in Porto Alegre, Brazil. A total of 191 CM patients and sex- and age-matched control subjects were enrolled in the study. Subjects exposed to pesticides had twice the level of risk for melanoma (odds ratio [OR] 2.03). When pesticides were used indoors for >10 years, the risk for CM increased further (OR 2.84). A high frequency of indoor use of pesticides (four or more times per year) was associated with a 44% increase in the risk for melanoma (OR 1.44). The domestic use of pesticides outdoors was not associated with increased risk. Subjects exposed to pesticides at an occupational level were at four times greater risk than subjects who were not occupationally exposed (OR 4.23).These findings indicate that the general use of pesticides, particularly indoor domestic use, frequently and over a long period, may be an independent environmental risk factor for CM.
[Segatto MM, Bonamigo RR, Hohmann CB, Müller KR, et al. 2015. Int J Dermatol. doi: 10.1111/ijd.12826] - Specific pesticide-dependent increases in α-synuclein levels in human neuroblastoma (SH-SY5Y) and melanoma (SK-MEL-2) cell lines.
Epidemiological studies indicate a role of genetic and environmental factors in Parkinson's disease involving alterations of the neuronal α-synuclein (α-syn) protein. Objective was to precisely assess changes in α-syn levels in human neuroblastoma (SH-SY5Y) and melanoma (SK-MEL-2) cell lines following acute exposure to pesticides (rotenone, paraquat, maneb, and glyphosate). These human cell lines express α-syn endogenously, and overexpression of α-syn (wild type or mutated A53T) can be obtained following recombinant adenoviral transduction. Study found that endogenous α-syn levels in the SH-SY5Y neuroblastoma cell line were markedly increased by paraquat, and to a lesser extent by rotenone and maneb, but not by glyphosate. Rotenone also clearly increased endogenous α-syn levels in the SK-MEL-2 melanoma cell line. In the SH-SY5Y cell line, similar differences were observed in the α-syn adenovirus-transduced cells, with a higher increase of the A53T mutated protein. Paraquat markedly increased α-syn in the SK-MEL-2 adenovirus-transduced cell line, similarly for the wild-type or A53T proteins. Data support the hypothesis that pesticides can trigger some molecular events involve malignant melanoma that consistently shows a significant but still unexplained association with Parkinson's disease.
[Chorfa A, Bétemps D, Morignat E, Lazizzera C, et al. 2013. Toxicol Sci. 133(2):289-97.] - Plasma levels of polychlorinated biphenyls and risk of cutaneous malignant melanoma: a preliminary study.
This preliminary study examined the relationship between organochlorine compounds(OCC) residues in plasma and risk of cutaneous malignant melanoma (CMM) adjusting for sun sensitivity and sun exposure. A case-control study of 80 CMM patients and 310 control subjects was conducted. Lifetime sun exposure information, along with data on pigmentation variables and sun sensitivity data was collected, along with a blood sample. Strong associations were seen between risk of CMM and plasma levels of non-dioxin-like PCBs (Adjusted OR = 7.02) and several PCB congeners, organochlorine pesticides or metabolites. These associations persisted after control for sun sensitivity and sun exposure. Results from this investigation require independent confirmation in larger studies. However, they suggest that environmental factors other than UV radiation may play a role in genesis of CMM, and indicate that it may be productive to search for further agents which might increase risk.
[Gallagher RP, Macarthur AC, Lee TK, Weber JP, et al. 2011. Int J Cancer. 128(8):1872-80] - Pesticide Use and Cutaneous Melanoma in Pesticide Applicators in the Agricultural Heath Study
Research finds found significant associations between cutaneous melanoma and maneb/mancozeb (>or= 63 exposure days: OR = 2.4), parathion (>or= 56 exposure days: OR = 2.4), and carbaryl (>or= 56 exposure days: OR = 1.7). Other associations with benomyl and ever use of arsenical pesticides are also suggested.
[Dennis LK, et al. 2010. Environ Health Perspect. 118(6):812-7. Epub 2010 Feb 17.] - Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with agricultural activity finds an elevated risk for malignant bone tumors (OR 2.3) and for subtype osteosarcoma (OR 2.7) at high agricultural activity (greater than 60% of county acreage devoted to farming). Also linked to Ewing’s sarcoma (OR 4.3) and HL (OR 2.1) at high agricultural activity (greater than 60% of county acreage devoted to farming), and for oat crop acreage and Ewing’s (OR 2.3).
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - Carbaryl exposure and incident cancer in the Agricultural Health Study
Carbaryl is a carbamate insecticide with a broad spectrum of uses in agricultural, commercial and household settings. It has previously been linked with non-Hodgkin lymphoma (NHL) but studies of cancer risk in humans are limited. We examined occupational carbaryl use and risk of all cancers in the Agricultural Health Study, a prospective study of a cohort of pesticide applicators in North Carolina and Iowa. This analysis included 21,416 subjects (1,291 cases) enrolled from 1993-1997 and followed for cancer incidence through 2003. Pesticide exposure and other data were collected using self-administered questionnaires. Poisson regression was used to calculate rate ratios (RRs) and 95% confidence intervals (CIs) while controlling for potential confounders. Carbaryl was not associated with cancer risk overall. Relative to subjects who never used carbaryl, melanoma risk was elevated with >175 lifetime exposure-days (RR = 4.11; 95%CI, 1.33-12.75; p-trend = 0.07), >10 years of use (RR = 3.19; 95%CI, 1.28-7.92; p-trend = 0.04), or >or=10 days of use per year (RR = 5.50; 95%CI, 2.19-13.84; p-trend < 0.001). Risk remained after adjusting for sunlight exposure. Although not significant, there appeared to be a trend of decreasing prostate cancer risk with increasing level of exposure. A small increase in NHL risk was observed using some, but not all, exposure measures. No associations were observed with other examined cancer sites. Because the observed results were not hypothesized a priori and because of limited study of their biological plausibility, they should be interpreted with caution.
[Mahajan, R., et al. 2007. Int J Cancer 121(8):1799-1805.] - The association between residential pesticide use and cutaneous melanoma
A case-control study of cutaneous melanoma finds an increased risk for indoor pesticide use four times a year (OR 2.18) compared to one time a year and for those exposed for 10 years or more an almost two and half times the risk as those exposed for less than 10 years indicating residential pesticide exposure may be a factor for cutaneous melanoma.
[Fortes, C., et al. 2007. Eur J Cancer 43(6):1066-1075.] - Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
A study in Costa Rica finds heavy pesticide use in rural counties is associated with an increase risk for skin melanoma cancer in males (OR 1.77).
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.]
Mouth Cancer
- Cancer of the mouth and pharynx, occupation and exposure to chemical agents in Finland (1971-95)
The objective of this article was to find associations between cancer of the mouth and pharynx, occupation and chemical exposure. A cohort of Finns born between 1906 and 1945 was followed-up for 46.8 (21.5 in males and 25.3 in females) million person-years during 1971-95. Incident cases of cancer of the mouth and pharynx (n = 2,708) were identified in a record linkage with the Finnish Cancer Registry. The Census occupations in 1970 were converted to chemical exposures with a job-exposure matrix (FINJEM). Cumulative exposure (CE) was calculated as the product of prevalence, level and duration of the exposure. Standardized incidence ratio (SIR) was calculated for each of the 393 occupations, and for CE categories of the 43 chemical agents, using total Finnish population as reference. Relative risks (RR) comparing various CE-categories with unexposed ones were defined for selected agents by Poisson regression analysis. Elevated SIRs were observed among lawyers, authors, journalists, performing artists, musicians, electronics and telefitters, painters (building), building hands, dockers, unskilled labourers and hotel porters in males and private secretaries, dressmakers, shoemakers and cobblers, waiters, pursers and stewardesses in females. The multivariate analyses showed high RRs for high exposure to aliphatic and alicyclic hydrocarbons, pesticides and alcohol. In conclusion, occupations with high SIRs were mostly the ones with high consumption of alcohol. Exposure to solvents and possibly to pesticides, engine exhaust, textile dust and leather dust may increase the risk of cancer of mouth and pharynx.
[Tarvainen, L., et al. 2008. Int J Cancer 123(3):653-659.]
Multiple Myeloma
- Cancer and occupational exposure to pesticides: a bibliometric study of the past 10 years
Occupational exposure to pesticides has been identified as a major trigger of the development of cancer. Pesticides can cause intoxication in the individuals who manipulate them through either inhalation, ingestion, or dermal contact. Given this, we investigated the association between the incidence of cancer and occupational exposure to pesticides through a bibliometric analysis of the studies published between 2011 and 2020, based on 62 papers selected from the Scopus database. The results indicated an exponential increase in the number of studies published over the past decade, with most of the research being conducted in the USA, France, India, and Brazil, although a further 17 nations were also involved in the research on the association between cancer and pesticides. The principal classes of pesticides investigated in relation to their role in intoxication and cancer were insecticides, herbicides, and fungicides. The types of cancer reported most frequently were multiple myeloma, bladder cancer, non-Hodgkin’s lymphoma, prostate cancer, leukemia, and breast cancer. Despite the known association between pesticides and cancer, studies are still relatively scarce in comparison with the global scale of the use of these xenobiotic substances, which is related to the increasing demand for agricultural products throughout the world
[Pedroso, T.M.A., Benvindo-Souza, M., de Araújo Nascimento, F., Woch, J., Dos Reis, F.G. and de Melo e Silva, D. Environmental Science and Pollution Research, pp.1-12.] - Lifetime Pesticide Use and Monoclonal Gammopathy of Undetermined Significance in a Prospective Cohort of Male Farmers
Farmers have a higher incidence of multiple myeloma, and there is suggestive evidence of an elevated prevalence of its precursor, monoclonal gammopathy of undetermined significance (MGUS), relative to the general population. Pesticide exposures are suspected to play a role; however, the biologic plausibility for associations with multiple myeloma remains unclear. Our objectives were to examine the prevalence of MGUS and evaluate associations with a wide range of pesticides in a large sample of farmers. We obtained sera and assessed MGUS among 1,638 male farmers ≥50years">≥50years≥50years of age in the Agricultural Health Study (AHS), a prospective cohort in Iowa and North Carolina. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate associations with MGUS for recent use (within the 12 months before phlebotomy) and cumulative intensity-weighted lifetime days of use of specific pesticides. The age-standardized MGUS prevalence was significantly elevated among AHS farmers (7.7%) compared with demographically similar men in the National Health and Nutrition Examination Survey (2.8%) or Olmsted County, Minnesota (3.8%; p<0.001">p<0.001p<0.001). Recent use of permethrin was associated with MGUS [recent use vs. no recent use, OR=1.82">OR=1.82OR=1.82 (95% CI: 1.06, 3.13)], especially among those who had also used it in the past [recent and past use vs. never use, OR=2.49">OR=2.49OR=2.49 (95% CI: 1.32, 4.69)]. High intensity-weighted lifetime use of the organochlorine insecticides aldrin and dieldrin was associated with MGUS relative to those who never used either of these pesticides [OR=2.42">OR=2.42OR=2.42 (95% CI: 1.29, 4.54); ptrend=0.006">ptrend=0.006ptrend=0.006]. We also observed a positive association with high lifetime use of petroleum oil/distillates as an herbicide, as well as an inverse association with fonofos use. This is the largest investigation of MGUS in farmers and the first to identify an association with MGUS for permethrin, a pyrethroid insecticide previously associated with multiple myeloma. Given the continued widespread use of permethrin in various residential and commercial settings, our findings may have important implications for exposed individuals in the general population. https://doi.org/10.1289/EHP6960.
[Hofmann, J.N., Beane Freeman, L.E., Murata, K., Andreotti, G., Shearer, J.J., Thoren, K., Ramanathan, L., Parks, C.G., Koutros, S., Lerro, C.C. and Liu, D., 2021. Environmental Health Perspectives, 129(1), p.017003.] - Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC).
Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. Study present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers. Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.
[Kachuri L, Harris MA, MacLeod JS, et al. 2017. BMC Cancer. 17(1):343] - Pesticide exposures and the risk of multiple myeloma in men: An analysis of the North American Pooled Project
Multiple myeloma (MM) has been consistently linked with agricultural activities, including farming and pesticide exposures. Three case-control studies in the United States and Canada were pooled to create the North American Pooled Project (NAPP) to investigate associations between pesticide use and haematological cancer risk. This analysis used data from 547 MM cases and 2700 controls. Pesticide use was evaluated as follows: ever/never use; duration of use (years); and cumulative lifetime-days (LD) (days/year handled × years of use). Increased MM risk was observed for ever use of carbaryl (OR = 2.02, 95% CI = 1.28-3.21), captan (OR = 1.98, 95% CI = 1.04-3.77) and DDT (OR = 1.44, 95% CI = 1.05-1.97). Using the Canadian subset of NAPP data, we observed a more than threefold increase in MM risk (OR = 3.18, 95% CI = 1.40-7.23) for ≤10 cumulative LD of carbaryl use. The association was attenuated but remained significant for >10 LD of carbaryl use (OR = 2.44; 95% CI = 1.05-5.64; ptrend = 0.01). For captan, ≤17.5 LD of exposure was also associated with a more than threefold increase in risk (OR = 3.52, 95% CI = 1.32-9.34), but this association was attenuated in the highest exposure category of >17.5 LD (OR = 2.29, 95% CI = 0.81-6.43; ptrend = 0.01). An increasing trend (ptrend = 0.04) was observed for LD of DDT use (LD > 22; OR = 1.92, 95% CI = 0.95-3.88). In this large North American study of MM and pesticide use, we observed significant increases in MM risk for use of carbaryl, captan and DDT.
[Presutti R, Harris SA, Kachuri L, Spinelli JJ, et al. 2016. Int J Cancer. 139(8):1703-14.] - Multiple myeloma and glyphosate use: a re-analysis of US Agricultural Health Study (AHS) data.
A previous publication of 57,311 pesticide applicators enrolled in the US Agricultural Health Study (AHS) produced disparate findings in relation to multiple myeloma risks in the period 1993-2001 and ever-use of glyphosate (32 cases of multiple myeloma in the full dataset of 54,315 applicators without adjustment for other variables: rate ratio (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.4; 22 cases of multiple myeloma in restricted dataset of 40,719 applicators with adjustment for other variables: RR 2.6, 95% CI 0.7 to 9.4). It seemed important to determine which result should be preferred. RRs for exposed and non-exposed subjects were calculated using Poisson regression; subjects with missing data were not excluded from the main analyses. Using the full dataset adjusted for age and gender the analysis produced a RR of 1.12 (95% CI 0.50 to 2.49) for ever-use of glyphosate. Additional adjustment for lifestyle factors and use of ten other pesticides had little effect (RR 1.24, 95% CI 0.52 to 2.94). There were no statistically significant trends for multiple myeloma risks in relation to reported cumulative days (or intensity weighted days) of glyphosate use. The doubling of risk reported previously arose from the use of an unrepresentative restricted dataset and analyses of the full dataset provides no convincing evidence in the AHS for a link between multiple myeloma risk and glyphosate use.
[Sorahan T .2015. Int J Environ Res Public Health. 12(2):1548-59.] - Risk Factors for Multiple Myeloma: A Systematic Review of Meta-Analyses
This systematic review aims to synthesize meta-analyses examining risk factors for MM so as to provide a comprehensive, parsimonious summary of the current evidence. Eligible meta-analyses were sought in PubMed adopting a predefined. Among the 22 ultimately included meta-analyses, 9 examined occupational factors, 4 assessed aspects of lifestyle (smoking, alcohol, body mass index), 5 evaluated the presence of other diseases, and 4 addressed genetic factors as potential risk factors of MM. A vast compendium of significant associations arose, including farming, exposures to chemicals or pesticides, overweight and obesity, pernicious anemia, gene promoter methylation, and polymorphisms. In conclusion, MM is a multifactorial disease, encompassing a wide variety of risk factors that span numerous life aspects. Further accumulation of evidence through meta-analyses is anticipated in this rapidly growing field.
[Sergentanis TN, Zagouri F, Tsilimidos G, et al. 2015. Clin Lymphoma Myeloma Leuk. 15(10):563-577.e3] - Multiple myeloma and occupation: a pooled analysis by the International Multiple Myeloma Consortium.
Authors investigated occupational risk of multiple myeloma (MM) in a pooled analysis of five international case-control studies. Gardeners and nursery workers combined, most likely exposed to pesticides, showed a 50% increase in risk (OR = 1.50), while other farming jobs did not. Metal processors, female cleaners, and high level exposure to organic solvents also showed moderately increased risks. Additional case-control studies of MM aetiology are warranted to further investigate the nature of the repeatedly reported increase in MM risk in several occupational groups.
[Perrotta C, Kleefeld S, Staines A, Tewari P, De Roos AJ, et al 2013. Cancer Epidemiol.37(3):300-5.] - Multiple pesticide exposures and the risk of multiple myeloma in Canadian men
Multiple myeloma (MM) has been linked to certain agricultural exposures, including pesticides. This analysis aimed to investigate the association between lifetime use of multiple pesticides and MM risk using two exposure metrics: number of pesticides used and days per year of pesticide use. A frequency-matched, population-based case-control study was conducted among men in six Canadian provinces between 1991 and 1994. Positive trends in risk were observed for fungicides (ptrend=0.04) and pesticides classified as probably carcinogenic or higher (ptrend=0.03). Excess risks of MM were observed among men who reported using at least one carbamate pesticide (OR=1.94), one phenoxy herbicide (OR=1.56) and ≥3 organochlorines (OR=2.21, 1.05-4.66). Significantly higher odds of MM were seen for exposure to carbaryl (OR=2.71) and captan (OR=2.96). Use of mecoprop for >2 days per year was also significantly associated with MM (OR=2.15). Focusing on multiple pesticide exposures is important because this more accurately reflects how exposures occur in occupational settings. Significant associations observed for certain chemical classes and individual pesticides suggest that these may be MM risk factors.
[Kachuri L, Demers PA, Blair A, Spinelli JJ, et al. 2013. Int J Cancer. 133(8):1846-58.] - Multiple myeloma and exposure to pesticides: a Canadian case-control study.
The objective of this study was to investigate the putative associations of specific pesticides with multiple myeloma. A matched, population-based, case-control study was conducted among men residing in six Canadian provinces (Quebec, Ontario, Manitoba, Saskatchewan, Alberta, and British Columbia). Exposure to pesticides grouped into major chemical classes resulted in increased risk being detected only for carbamate insecticides. An exposure to fungicide captan was positively associated with the incidence of multiple myeloma. While an exposure to carbaryl was associated with the incidence of multiple myelome with borderline significance. The authors further suggest that certain pesticide exposures may have a role in multiple myeloma etiology, and identify specific factors warranting investigation in other populations.
[Pahwa P, Karunanayake CP, Dosman JA, et al. 2012. J Agromedicine. 17(1):40-50.] - Multiple Myeloma and lifetime occupation: results from the EPILYMPH study.
The EPILYMPH study applied a detailed occupational exposure assessment approach to a large multi-centre case-control study conducted in six European countries. This paper analysed multiple myeloma (MM) risk associated with level of education, and lifetime occupational history and occupational exposures, based on the EPILYMPH data set.A low level of education was associated with MM. An increased risk was observed for general farmers and cleaning workers adjusting for level of education. Risk was also elevated, although not significant, for printers. Pesticide exposure over a period of ten years or more increased MM risk. These results confirm an association of MM with farm work, and indicate its association with printing and cleaning. While prolonged exposure to pesticides seems to be a risk factor for MM, an excess risk associated with exposure to organic solvents could not be confirmed.
[Perrotta C, Staines A, Codd M, Kleefeld S, Crowley D, et al. 2012. J Occup Med Toxicol. 7(1):25.] - Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study
Exposure to certain pesticides doubles one’s risk of developing an abnormal blood condition called MGUS (monoclonal gammopathy of undetermined significance) compared with individuals in the general population.
[Landgren, O, et al. 2009. Blood, Vol. 113, No. 25, pp. 6386-6391] - Occupation, exposure to chemicals, sensitizing agents, and risk of multiple myeloma in Sweden
A historical cohort study of occupation exposure in Sweden finds an excess risk among agricultural, horticultural and forestry workers in men and “occasional, although intense, exposure to pesticides is also associated with riks of myeloma.”
[Lope, V., et al. 2008. Cancer Epidemiol Biomarkers Prev 17(11):3123-3127.] - Occupational exposure to pesticides and risk of hematopoietic cancers: meta-analysis of case-control studies
A meta-analysis of 13 case-control studies on hematopoeietic cancers (leukemia, NHL, and multiple myeloma) published between 1990 and 2005 finds a significant positive association for occupational pesticide exposure of more than 10 years and all hematopoietic cancers (OR 2.18).
[Merhi, M, et al. 2007. Cancer Causes Control 18(10):1209-1226] - Cancer mortality among Iowa farmers: recent results, time trends, and lifestyle factors (United States)
Cancer mortality among Iowa farmers shows an excess of deaths for multiple myeloma (1.17 PMR).
[Cerhan, J.R., et al. 1998. Cancer Causes Control 9(3):311-319.] - Incidence and risk factors of cancer among men and women in Norwegian agriculture
The objective of the study was to examine cancer incidence and identify risk factors among subjects born in 1925-1971 and engaged in agricultural activities in Norway. A cohort was established through linkage between agricultural censuses in 1969-1989 and the Central Population Register, which identifies farm holders and their spouses. Available census information on the activity of the farm provided the exposure indicators. Incident cancer in 1969-1991 was identified in the Cancer Register. In an analysis for standardized incidence ratios (SIR), the cohort was compared with the total rural population of Norway. Associations with exposure indicators were investigated in a Poisson regression analysis. In the follow-up of 136,463 men for 1.5 million person-years and 109,641 women for 0.6 million person-years, 3333 and 2145 cancer cases were identified, respectively. The subset defined as farmers had an SIR of 77 [95% confidence interval (95% CI) 73-81] for the men and 92 (95% CI 85-99) for the women, with particularly low SIR values for lung cancer and other sites linked to life-style. The several positive associations found confirmed the a priori hypothesis of an association between dairy farming and acute leukemia among men [rate ratio 1.76, 95% CI 1.02-3.05]. Multiple myeloma was associated with pesticide indicators for both genders, mainly for subjects cultivating potatoes. The results support the hypothesis of a relationship between acute leukemia and animal contact and between multiple myeloma and pesticides in potato cultivation. Other exposure associations, especially for cancer among women, warrant further investigation.
[Kristensen, P., et al. 1996. Dcand J Work Environ Health 22(1):14-26.] - Malignant lymphoma and multiple myeloma linked with agricultural occupations in a New Zealand Cancer Registry-based study.
A case-control study of New Zealand agriculture and forestry workers finds a significant excess of patients with multiple myeloma (OR 2.22).
[Pearce, N.E., et al. 1985. Am J Epidemiol 121(2):225-237] - Selected cancer mortality and farm practices in Iowa
A mortality study of Iowan farmers who died between 1964 and 1978 finds an elevated mortality from multiple myeloma in association with herbicide and insecticide use.
[Burmeister, L.F., et al. 1983.Am J Epidemiol 118(1):72-77.]
Neuroblastoma
- Agricultural exposures and risk of childhood neuroblastoma: a systematic review and meta-analysis.
While neuroblastoma accounts for an estimated 8% of childhood cancers, it causes about 15% of childhood cancer deaths in the United States. The role of agricultural exposures in the development of neuroblastoma is unclear. We conducted a systematic review and meta-analysis of studies examining the relationship between agricultural exposures and neuroblastoma. MEDLINE, EMBASE, Scopus, and Google Scholar were searched in February 2022, identifying 742 publications. Seventeen articles met the inclusion criteria; all were published between 1985 and 2020 and included 14 case-control, one cross-sectional, and two cohort studies. Random and fixed effects models were used to calculate summary odds ratios (sORs) and 95% confidence intervals (CIs). An increased odds of developing neuroblastoma with parental exposure to any pesticides (sOR = 1.25, 95% CI: 1.03-1.48; 4 studies), insecticides (sOR = 1.55, 95% CI: 1.19-1.91; 3 studies), and residential exposure to crops/vegetables (sOR = 1.04, 95% CI: 1.01-1.06; 2 studies) was seen. Heterogeneity was low in all analyses, and no publication bias was evident. No significant associations were found with agricultural occupations, herbicides, and agricultural dusts. The studies were limited by exposure measurements and small sample sizes. Further studies are needed to explore mechanisms in the development of neuroblastoma in children with parental agricultural exposures, especially pesticides, and to improve methods of measuring agricultural-related exposures.
[Hymel, E., Degarege, A., Fritch, J., Farazi, E., Napit, K., Coulter, D., Schmidt, C. and Watanabe-Galloway, S., 2023. Environmental Science and Pollution Research, pp.1-12.] - Cytotoxicity induced by cypermethrin in Human Neuroblastoma Cell Line SH-SY5Y.
The purpose of this study was to evaluate the cytotoxic potential of Cypermethrin (CM) on cultured human Neuroblastoma SH-SY5Y cells. SH-SY5Y cells were treated with CM at 0-200µM for 24, 48, and 72 h, in vitro. It was found that CM induced the cell death of Neuroblastoma cells in a dose- and time-dependent manner, as shown by LDH assays. Next, some aspects of the process of cell death triggered by CM in the human SH-SY5Y cell line were investigated. It was revealed that the pan-caspase inhibitor Q-VD-OPh, sensitizes SH-SY5Y cells to necroptosis caused by CM. Furthermore, signal transduction inhibitors PD98059, SL-327, SB202190, SP600125 failed to attenuate the effect of the pesticide. Finally, it was shown that inhibition of TNF-a by Pomalidomide (PLD) caused statistically significant reduction in CM-induced cytotoxicity. Overall, the data obtained suggest that CM induces neurotoxicity in SH-SY5Y cells by necroptosis.
[Raszewski G, Lemieszek MK, Łukawski K. 2016. Ann Agric Environ Med. 23(1):106-10.] - Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with agricultural activity finds an elevated risk (OR 1.9) for primitive neuroectodermal tumors (central nervous system) at high agricultural activity (greater than 60% of county acreage devoted to farming). Also sympathetic nervous system tumors at high agricultural activity, with subtypes neuroblastomas (OR 1.8) and retinoblastomas (OR 2.6) showing an increased risk.
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - Childhood cancer in Texas counties with moderate to intense agricultural activity
With few established risk factors, cancer remains the second leading cause of death for children in the U.S. Agricultural pesticide use is one of many suspected factors that may contribute to the etiology of childhood cancer. This study tests the hypothesis that birth in Texas counties with moderate to intense agricultural activity increases childhood cancer risk. This case-control study analyzed 6974 cases and controls ages 0 to 14, identified through the Texas Cancer Registry and Texas birth records, respectively. Exposure data were obtained from the Census of Agriculture. Percent cropland in the county of birth and total county-specific pesticide exposure incorporating the EPA's carcinogenicity classification served as surrogates for pesticide exposure. Cancer sites examined include: all cancers, leukemia, lymphoma, CNS tumors, and several specific subsites. Elevated, although not statistically significant, ORs for the association between birth in counties with > or =50% cropland were produced for all CNS tumors (OR = 1.3, 95% CI = 0.9-1.8), astrocytoma (OR = 1.4, 95% CI = 0.8-2.2), and PNET (OR = 1.3, 95% CI = 0.7-2.5). A similar pattern was not observed using the index of total county-specific pesticide exposure. Although imprecise, these exposure assessment methods represent novel applications of agricultural census data. Although a pattern of increased risk was observed between percent cropland and CNS tumors, this study's results do not support an association between birth in Texas counties with moderate to intense agricultural activity and childhood cancer. Due to study limitations, such an association should not be ruled out. Future research should incorporate individual-level data from various sources to increase precision and decrease misclassification in the exposure assessment.
[Walker, K.M., et al. 2007. J Agric Saf Health 13(1):9-24.] - Mortality in a cohort of pesticide applicators in an urban setting: sixty years of follow-up
A cohort study in Rome of urban pesticide applicators finds an increased risk for cancer of the gallbladder, liver, and nervous system.
[Giordano, F., et al. 2006. Int J Immunopathol Pharmacol 19(Suppl 4):61-65.] - Paternal occupational exposures and childhood cancer
Paternal occupational pesticide exposure is associated with an increased risk of nervous system tumors (relative risk 2.36).
[Feychting, M., e tal. 2001. Environ health Perspect 109(2):193-196.] - Residential pesticide exposure and neuroblastoma
Home (OR 1.6) and garden (OR 1.7) pesticide use are associated with neuroblastoma, with a more than double the risk for infants when exposed to garden pesticides.
[Daniels, J.L., et al. 2001. Epidemiology 12(1):20-27.] - Cancer in offspring of parents engaged in agricultural activities in Norway: incidence and risk factors in the farm environment.
Parental agricultural exposure to pesticides is associated with neuroblastoma.
[Kristensen, P., et al. 1996. Int J Cancer 65(1):39-50] - Mortality and tumour morbidity among Swedish market gardeners and orchardists
Swedish horticulturists’ trade association members below the age of 60 have an elevated number of tumors of the nervous system.
[Littorin, M., et al. 1993. Int Arch Occup Environ Health 65(3):163-169.]
Oesophageal Cancer
- Esophageal cancer among Brazilian agricultural workers: case-control study based on death certificates.
In the present study, the magnitude of the association between agricultural working and esophageal cancer mortality was evaluated in a high pesticide use area in Brazil, through a death certificate-based case-control study. Results showed that, in general, agricultural workers were at significantly higher risk to die by esophageal cancer, when compared to non-agricultural workers. Stratified analysis also revealed that the magnitude of such risk was slightly higher among illiterate agricultural workers, and simultaneous adjustment for several covariates showed that the risk was quantitatively higher among younger southern agricultural workers. These results suggest the esophageal cancer may be included among those types of cancer etiologically associated to agricultural working.
[Meyer A, Alexandre PC, Chrisman Jde R, et al. 2011. Int J Hyg Environ Health. 214(2):151-5.] - Pesticide sales and adult male cancer mortality in Brazil.
A study of pesticides sales in different parts of Brazil and cancer mortality rates a decade later finds a statistically significant correlation between pesticide sales with the mortality rates for leukemia and cancer of the lip, esophagus, pancreas, and prostate.
[Chrisman, J.D., et al. 2009. Int J Hyg Environ Health ;212(3):310-21] - Airborne occupational exposures and risk of oesophageal and cardia adenocarcinoma
A Swedish population-based case-control study assessing cumulative airborne occupational exposure finds a positive association between high exposure to pesticides and risk of oesophageal (OR 2.3) and cardia adenocarcinoma (OR 2.1).
[Jansson, C., et al. 2006. Occup Environ Med 63(2):107-112.] - Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
A study in Costa Rica finds heavy pesticide use in rural counties is associated with an increase risk for oesophagus cancer in males (OR 1.69).
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.]
Ovarian Cancer
- Agricultural exposure and risk of ovarian cancer in the AGRIculture and CANcer (AGRICAN) cohort
Abstract
Background
Ovarian cancer is rare with a poor prognosis and few established risk factors. Hormones and reproductive factors significantly impact its development, suggesting a potential link with endocrine disrupters.Methods
In the AGRICAN cohort, 59 391 female farmers completed data on lifelong agricultural exposures and reproductive life. Cox models with attained age as timescale (HR and 95% CI) were used. The role of hormonal factors as potential confounders was considered along with specific time windows for exposure (childhood, puberty and menopause). Female farmers were the reference group (for the principal analyses).
Results
Between enrolment (2005–2007) and the end of follow-up (31 December 2017), 262 incident ovarian cancers were identified. An increased risk was observed for females involved in pigs (HR=2.12 (95% CI 1.27 to 3.52)) including during puberty (HR=1.83 (95% CI 1.13 to 2.94)), fruit-growing (HR=2.17 (95% CI 1.09 to 4.30)) and potato seed treatment (HR=2.81 (95% CI 1.29 to 6.09)). Conversely, females born on farms growing grain cereals (HR=0.64 (95% CI 0.46 to 0.90)) or pig-breeding (HR=0.78 (95% CI 0.55 to 1.12)) presented a reduced risk of ovarian cancer. Triazine herbicide exposure was not associated with ovarian cancer. The effect of agricultural exposures remained unchanged in multivariate models considering contraception, parity, puberty age, menopause age and body mass index.
Conclusion
This study is the first to assess the association between specific agricultural exposures and ovarian cancer comprehensively. Some of the positive associations observed suggest that some pesticide exposure (especially during puberty) could play a role in the development of ovarian cancer. On the other hand, agricultural exposure during early life could have a protective effect, as observed for lung cancer among farmers. Finally, we did not confirm the previous putative effect of exposure to triazine herbicides.
[Renier, M. et al. (2024) ‘Agricultural Exposure and risk of ovarian cancer in the Agriculture and Cancer (Agrican) cohort’, Occupational and Environmental Medicine, 81(2), pp. 75–83. doi:10.1136/oemed-2023-109089. ] - Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology
Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations.
[Kubsad, D., Nilsson, E.E., King, S.E., Sadler-Riggleman, I., Beck, D. and Skinner, M.K., 2019. Scientific reports, 9(1), pp.1-17.] - Simazine, a triazine herbicide, disrupts swine granulosa cell functions
Abstract
The triazine herbicide simazine is a pesticide commonly detected in surface and ground waters, although banned in most European countries since 2004. Concerns for humans and animal health result from its potential endocrine disrupting action, that can lead to reproductive disorders. The present in vitro study was undertaken to study simazine effects on swine granulosa cell function, namely cell viability, proliferation, steroidogenesis and NO production. Moreover, the ability of this substance to interfere with the angiogenetic process, a crucial event in reproductive function, was taken into account. Our data document that simazine treatment, at 0.1 or 10 μM concentration levels, stimulates granulosa cell proliferation and viability and impairs steroidogenesis, increasing in particular progesterone production. In addition, the in vitro angiogenesis bioassay revealed a significant simazine stimulatory effect on immortalized porcine Aortic Endothelial Cell proliferation. Collectively, these results show that simazine can display disruptive effects on ovarian cell functional parameters, possibly resulting in reproductive dysfunction. This hypothesis is also supported by the observed pro-angiogenetic properties of this herbicide, as already suggested for different endocrine disruptors.
[Grasselli, F. et al. (2018) ‘Simazine, a triazine herbicide, disrupts swine granulosa cell functions’, Animal Reproduction, 15(1), pp. 3–11. doi:10.21451/1984-3143-2017-ar960. ] - Effects of Endocrine-Disrupting Chemicals and Epigenetic Modifications in Ovarian Cancer: A Review.
Ovarian cancer (OC) is a relatively fatal female reproductive malignancy. Since the underlying causes are uncertain, it brings us to believe that both genetic and external factors contribute toward development of this lethal disorder. Exposure to endocrine-disrupting chemicals (EDCs) in the form of occupational usage of pesticides, fungicides, herbicides, plasticizers, cosmetics, and so on is potentially carcinogenic and their ability to cause epigenetic modifications has led us to hypothesize that they may play a catalytic role in OC progression. In response to synthetic chemicals, animal models have demonstrated disturbances in the development of ovaries and steroid hormonal levels but in humans, more research is required. The present review is an attempt to address the impact of EDCs on the hormonal system and gene methylation levels that may lead to malfunctioning of the ovaries which may consequently develop in the form of cancer. It can be concluded that endocrine disruptors do have a potential carcinogenicity and their high proportions in human body may cause epigenetic modifications, prompting ovarian surface epithelium to grow in an abnormal manner.
[Samtani R, Sharma N, Garg D. 2017. Reprod Sci. 1933719117711261.] - Atrazine in public water supplies and risk of ovarian cancer among postmenopausal women in the Iowa Women's Health Study.
Few studies have evaluated environmental chemical exposures in relation to ovarian cancer. We previously found an increased risk of ovarian cancer among postmenopausal women in Iowa associated with higher nitrate levels in public water supplies (PWS). However, elevated nitrate levels may reflect the presence of other agricultural chemicals, such as atrazine, one of the most commonly detected pesticides in Iowa PWS. We evaluated the association between atrazine in drinking water and incident ovarian cancer (N=145, 1986-2010) among 13 041 postmenopausal women in the Iowa Women's Health Study who used their PWS for ≥11 years as reported in 1989. Average levels of atrazine (1986-1987), nitrate-nitrogen (NO3-N, 1955-1988) and estimated levels of total trihalomethanes (TTHM, 1955-1988) from PWS monitoring data were linked to the participants' cities of residence. Atrazine was detected in water samples from 69 cities where 4155 women (32%) lived and levels were moderately correlated with NO3-N (ρ=0.35) and TTHM (ρ=0.24). Atrazine levels were not associated with ovarian cancer risk with or without adjusting for NO3-N and TTHM levels (p-trend=0.50 and 0.81, respectively). Further, there was no evidence for effect modification of the atrazine association by NO3-N or TTHM levels.In our study with low atrazine detection rates, we found no association between atrazine in PWS and postmenopausal ovarian cancer risk.
[Inoue-Choi M, Weyer PJ, Jones RR, Booth BJ, et al. 2016. Occup Environ Med. 73(9):582-7] - Organophosphate insecticide use and cancer incidence among spouses of pesticide applicators in the Agricultural Health Study
Organophosphates (OPs) are among the most commonly used insecticides. OPs have been linked to cancer risk in some epidemiological studies, which have been largely conducted in predominantly male populations. This study evaluated personal use of specific OPs and cancer incidence among female spouses of pesticide applicators in the prospective Agricultural Health Study cohort. Among 30 003 women, 25.9% reported OP use, and 718 OP-exposed women were diagnosed with cancer during the follow-up period. Any OP use was associated with an elevated risk of breast cancer (RR=1.20, 95% CI 1.01 to 1.43). Malathion, the most commonly reported OP, was associated with increased risk of thyroid cancer (RR=2.04, 95% CI 1.14 to 3.63) and decreased risk of non-Hodgkin lymphoma (RR=0.64, 95% CI 0.41 to 0.99). Diazinon use was associated with ovarian cancer (RR=1.87, 95% CI 1.02 to 3.43).Authors observed increased risk with OP use for several hormonally-related cancers, including breast, thyroid and ovary, suggesting potential for hormonally-mediated effects. This study represents the first comprehensive analysis of OP use and cancer risk among women, and thus demonstrates a need for further evaluation.
[Lerro CC, Koutros S, Andreotti G, Friesen MC, et al. 2015. Occup Environ Med. 72(10):736-44] - Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
A study in Costa Rica finds heavy pesticide use in rural counties is associated with an increase risk for oesophagus cancer in males (OR 1.69).
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.] - Triazine herbicides and ovarian epithelial neoplasms
A population-based case referent study finds a significant increased risk for ovarian neoplasm (relative risk 2.7).
[Donna, A., et al. 1990. Scand J Work Environ Health 15(1):47-53.]
Pancreatic Cancer
- Comprehensive assessment of pesticide use patterns and increased cancer risk
Pesticides are an essential feature of modern-day agriculture that adds to the list of factors that increase cancer risk. Our study aims to comprehensively evaluate this relationship through a population-based approach that considers confounding variables such as county-specific rates of smoking, socioeconomic vulnerability, and agricultural land. We achieved our goal with the implementation of latent-class pesticide use patterns, which were further modeled among covariates to evaluate their associations with cancer risk. Our findings demonstrated an association between pesticide use and increased incidence of leukemia; non-Hodgkin's lymphoma; bladder, colon, lung, and pancreatic cancer; and all cancers combined that are comparable to smoking for some cancer types. Through our comprehensive analysis and unique approach, our study emphasizes the importance of a holistic assessment of the risks of pesticide use for communities, which may be used to impact future policies regarding pesticides.
[Gerken, J. et al. (2024) Comprehensive assessment of pesticide use patterns and increased cancer risk, Frontiers. Available at: https://www.frontiersin.org/journals/cancer-control-and-society/articles/10.3389/fcacs.2024.1368086/full. ] - Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC).
Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. Study present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers. Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.
[Kachuri L, Harris MA, MacLeod JS, et al. 2017. BMC Cancer. 17(1):343] - Exposure to environmental chemicals and heavy metals, and risk of pancreatic cancer.
Exposure to various chemicals and heavy metals has been associated with risk of different cancers; however, data on whether such exposures may increase the risk of pancreatic cancer (PC) are very limited and inconclusive. We examined PC risk with self-reported exposures to chemicals and heavy metals. The design was a clinic-based, case-control study of data collected from 2000 to 2014 at Mayo Clinic in Rochester, Minnesota, USA. Cases were rapidly ascertained patients diagnosed with pancreatic ductal adenocarcinoma (n = 2,092). Controls were cancer-free patients in primary care clinics (n = 2,353), frequency-matched to cases on age, race, sex, and state/region of residence. Cases and controls completed identical risk factor questionnaires, which included yes/no questions about regular exposure to pesticides, asbestos, benzene, chlorinated hydrocarbons, chromium, and nickel. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) comparing those who affirmed exposure to each of the chemicals/heavy metals to those who reported no regular exposure, adjusting for potential confounders. Self-reported regular exposure to pesticides was associated with increased odds of PC (OR 1.21, 95% CI 1.02-1.44). Regular exposure to asbestos (OR 1.54, 95% CI 1.23-1.92), benzene (OR 1.70, 95% CI 1.23-2.35), and chlorinated hydrocarbons (OR 1.63, 95% CI 1.32-2.02) also was associated with higher odds of PC. Chromium and nickel exposures were not significantly associated with PC. These findings add to the limited data suggesting that exposure to pesticides, asbestos, benzene, and chlorinated hydrocarbons may increase PC risk. They further support the importance of implementing strategies that reduce exposure to these substances.
[Antwi SO, Eckert EC, Sabaque CV, Leof ER, et al. 2015. Cancer Causes Control. 26(11):1583-91.] - Agricultural pesticide use and pancreatic cancer risk in the Agricultural Health Study Cohort.
Pancreatic cancer is a rapidly fatal disease that has been linked with pesticide use. To further examine the potential associations between the use of a number of pesticides and pancreatic cancer, authors conducted a case-control analysis in the Agricultural Health Study, one of the largest prospective cohorts with over 89,000 participants including pesticide applicators and their spouses in Iowa and North Carolina. Among pesticide applicators, 2 herbicides (EPTC and pendimethalin) of the 13 pesticides examined for intensity-weighted lifetime use showed a statistically significant exposure-response association with pancreatic cancer. Applicators in the top half of lifetime pendimethalin use had a 3.0-fold risk compared with never users, and those in the top half of lifetime EPTC use had a 2.56-fold risk compared with never users. Organochlorines were not associated with an excess risk of pancreatic cancer in this study. These findings suggest that herbicides, particularly pendimethalin and EPTC, may be associated with pancreatic cancer.
[Andreotti G, Freeman LE, Hou L, Coble J, Rusiecki J, et al. 2009. Int J Cancer. 124(10):2495-500.] - Pesticide sales and adult male cancer mortality in Brazil.
A study of pesticides sales in different parts of Brazil and cancer mortality rates a decade later finds a statistically significant correlation between pesticide sales with the mortality rates for leukemia and cancer of the lip, esophagus, pancreas, and prostate.
[Chrisman, J.D., et al. 2009. Int J Hyg Environ Health ;212(3):310-21] - Lifestyle, occupational, and reproductive factors in relation to pancreatic cancer risk
This study examined the epidemiology of pancreatic cancer in Egypt. We obtained detailed information on smoking, occupational, medical, and reproductive histories from 194 pancreatic cancer cases and 194 controls. Compared with not smoking, smoking cigarettes alone or in conjunction with other smoking methods (eg, water pipe, cigar) was associated with an increased risk (odds ratio [OR], 4.5 and 7.8; 95% confidence interval [95% CI], 1.9-10.7 and 3.0-20.6, respectively). Passive smoking was also a significant risk factor (OR, 6.0; 95% CI, 2.4-14.8). The risk of pancreatic cancer was elevated among subjects exposed to pesticides (OR, 2.6; 95% CI, 0.97-7.2). A prior diagnosis of diabetes mellitus for a period of 10 years was associated with higher risk (OR, 5.4; 95% CI, 1.5-19.9). For women, having 7 or more live births and lactating for 144 months or longer were associated with a reduced risk (OR, 0.5 and 0.2; 95% CI, 0.2-1.3 and 0.1-0.9, respectively). No association was found between family history, allergy, or obesity and pancreatic cancer in Egypt. Multiple tobacco consumption methods, passive smoking, pesticide exposures, and diabetes are associated with an increased risk for pancreatic cancer. Prolonged lactation and increased parity are associated with a reduced risk for pancreatic cancer.
[Lo, A.C., et al. 2007. Pancreas 35(2):120-129.] - Occupational exposure to pesticides and pancreatic cancer
Excess risk is found for occupational exposure to fungicides (OR 1.5) and herbicides (OR 1.6).
[Ji, B.T., et al. 2001. Am J Ind Med 39(1):92-99.] - Risk of pancreatic cancer and occupational exposures in Spain
In a small study, occupational exposures to pesticides cause a three-fold increased risk for pancreatic cancer. For each type of pesticide group, moderately increased odds ratios were apparent in the high-intensity category, highest for arsenical pesticides (OR 3.4), and ‘other pesticides’ (OR 3.17).
[Alguacil, J., et al. 2000. Ann Occup Hyg 44(5):391-403.] - Mortality among aerial pesticide applicators and flight instructors: follow-up from 1965-1988
A retrospective cohort mortality study of aerial pesticide applicator pilots finds a significantly elevated risk for pancreatic cancer (risk ratio 2.71).
[Cantor, K.P. and Silberman, W. 1999. Am J Ind Medicine 36(2):239-47] - Pancreatic cancer in industrial branches and occupations in Finland
Finnish study finds a more than six-fold increased risk for male gardeners to pancreatic cancer.
[Partanen, T., et al 1994. Am J Ind Med 25(6):851-866.] - Cancer among farmers in central Italy
A case-referent study of Italian farmers finds a significantly increased risk of pancreatic cancer, as well as other cancers, among licensed pesticides users with greater than 10 years’ experience.
[Forastiere, F, et al. 1993. Scand J Work Environ Health 19(6):382-389.] - Cancer mortality in the U.S. flour industry
A study of U.S. flour mill workers finds an two-fold increased risk for pancreatic cancer (OR 2.2.) believed to be related to pesticide exposure.
[Alavanja, M.C., et al. 1990. J Natl Cancer Inst 82(10):840-848]
Prostate Cancer
- Endocrine-disrupting chemicals (EDCs) and cancer: new perspectives on an old relationship
Environmental endocrine-disrupting chemicals (EDCs) are a mixture of chemical compounds capable to interfere with endocrine axis at different levels and to which population is daily exposed. This paper aims to review the relationship between EDCs and breast, prostate, testicle, ovary, and thyroid cancer, discussing carcinogenic activity of known EDCs, while evaluating the impact on public health. A literature review regarding EDCs and cancer was carried out with particular interest on meta-analysis and human studies. The definition of EDCs has been changed through years, and currently there are no common criteria to test new chemicals to clarify their possible carcinogenic activity. Moreover, it is difficult to assess the full impact of human exposure to EDCs because adverse effects develop latently and manifest at different ages, even if preclinical and clinical evidence suggest that developing fetus and neonates are most vulnerable to endocrine disruption. EDCs represent a major environmental and health issue that has a role in cancer development. There are currently some EDCs that can be considered as carcinogenic, like dioxin and cadmium for breast and thyroid cancer; arsenic, asbestos, and dioxin for prostate cancer; and organochlorines/organohalogens for testicular cancer. New evidence supports the role of other EDCs as possible carcinogenic and pregnant women should avoid risk area and exposure. The relationship between EDCs and cancer supports the need for effective prevention policies increasing public awareness.
[Modica, R., Benevento, E. and Colao, A., 2023. Journal of Endocrinological Investigation, 46(4), pp.667-677.] - Cancer and occupational exposure to pesticides: an umbrella review
Purpose
The aim was to identify the scope of the epidemiology literature reviewed regarding the risk of cancer as related to occupational exposure to pesticides and to compare regulatory toxicity results where feasible.Methods
Review studies of breast, lung, prostate, non-Hodgkin lymphoma, and colorectal cancer were identified from the published literature from 2010 to 2020 using a priori inclusion and exclusion criteria. Epidemiology observations were first assessed and then compared against carcinogenicity profiles derived from regulatory toxicology studies.Results
Several active ingredients were associated with specific cancer but overall, there was neither strong nor consistent epidemiologic data supportive of a positive association between pesticide exposure in occupational settings and cancer. Authors noted common themes related to the heterogeneity of exposure, study design, control for confounders, and the challenge to collect these data reliably and validly with an adequate sample size. Toxicology studies in laboratory animals that assessed carcinogenic potential did not reveal cancer outcomes that were concordant with reported epidemiologic findings.Conclusions
Farming and pesticides represent diverse exposures that are difficult to quantify in epidemiologic studies. Going forward, investigators will need creative and novel approaches for exposure assessment. Integration of epidemiologic and toxicological studies with attention to biological plausibility, mode of toxicological action and relevance to humans will increase the ability to better assess associations between pesticides and cancer.
[Burns, C.J. and Juberg, D.R. (2021) Cancer and occupational exposure to pesticides: An Umbrella Review, International Archives of Occupational and Environmental Health. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238729/. ] - Exposure to organophosphorus insecticides and increased risks of health and cancer in US women
Results of this paper provide evidence that chronic long-term exposure to organophosphorus insecticides poses a significantly higher health risk for US women than for men, based on dialkylphosphate biomarker data from NHANES cycles 2003-2012. The risk of cardiovascular disease for female non-smokers aged 60-85 years in the highest dimethylthiophosphate (DMTP) urinary concentration quartile is 3.0 (odds ratio, OD = 3.0, 95%CI 1.4-6.4) times higher than that in the lowest quartile. Women with higher urinary DMTP concentrations also have significantly higher risk of asthma at the ages 6-39 years and an apparently higher risk of chronic bronchitis at the ages 60-85. Overall cancer risk is significantly higher for female non-smokers aged 60-85 years in the higher urinary DMTP quartiles (OD = 2.7, 95% CI 1.3-5.9). Increasing risks of breast cancer for female smokers and prostate cancer for male smokers aged 60-85 years with higher exposure to organophosphorus insecticides in the US are also significant.
[Sun, H., Sun, M.L. and Barr, D.B., 2020. Environmental Toxicology and Pharmacology, 80, p.103474.] - Exposure to organophosphorus insecticides and increased risks of health and cancer in US women
Results of this paper provide evidence that chronic long-term exposure to organophosphorus insecticides poses a significantly higher health risk for US women than for men, based on dialkylphosphate biomarker data from NHANES cycles 2003-2012. The risk of cardiovascular disease for female non-smokers aged 60-85 years in the highest dimethylthiophosphate (DMTP) urinary concentration quartile is 3.0 (odds ratio, OD = 3.0, 95%CI 1.4-6.4) times higher than that in the lowest quartile. Women with higher urinary DMTP concentrations also have significantly higher risk of asthma at the ages 6-39 years and an apparently higher risk of chronic bronchitis at the ages 60-85. Overall cancer risk is significantly higher for female non-smokers aged 60-85 years in the higher urinary DMTP quartiles (OD = 2.7, 95% CI 1.3-5.9). Increasing risks of breast cancer for female smokers and prostate cancer for male smokers aged 60-85 years with higher exposure to organophosphorus insecticides in the US are also significant.
[Sun, H., Sun, M.L. and Barr, D.B., 2020. Environmental Toxicology and Pharmacology, 80, p.103474.] - Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology
Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations.
[Kubsad, D., Nilsson, E.E., King, S.E., Sadler-Riggleman, I., Beck, D. and Skinner, M.K., 2019. Scientific reports, 9(1), pp.1-17.] - Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC).
Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. Study present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers. Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.
[Kachuri L, Harris MA, MacLeod JS, et al. 2017. BMC Cancer. 17(1):343] - Computational study involving identification of endocrine disrupting potential of herbicides: Its implication in TDS and cancer progression in CRPC patients.
Several environmental pollutants, including herbicides, act as endocrine disrupting chemicals (EDCs). They can cause cancer, diabetes, obesity, metabolic diseases and developmental problems. Present study was conducted to screen 608 herbicides for evaluating their endocrine disrupting potential. The screening was carried out with the help of endocrine disruptome docking program, http://endocrinedisruptome.ki.si (Kolsek et al., 2013). This program screens the binding affinity of test ligands to 12 major nuclear receptors. As high as 252 compounds were capable of binding to at least three receptors wherein 10 of them showed affinity with at-least six receptors based on this approach. The latter were ranked as potent EDCs. Majority of the screened herbicides were acting as antagonists of human androgen receptor (hAR). A homology modeling approach was used to construct the three dimensional structure of hAR to understand their binding mechanism. Docking results reveal that the most potent antiandrogenic herbicides would bind to hydrophobic cavity of modeled hAR and may lead to testicular dysgenesis syndrome (TDS) on fetal exposure. However, on binding to T877 mutant AR they seem to act as agonists in castration-resistant prostate cancer (CRPC) patients.
[Ahmad MI, Usman A, Ahmad M. 2017. Chemosphere. 173:395-403.] - Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review.
Human health is beset with a legion of ailments, which is exacerbated by lifestyle errors. Out of the numerous enzymes in human body, aromatase, a cytochrome P450 enzyme is particularly very critical. Occurring at the crossroads of multiple signalling pathways, its homeostasis is vital for optimal health. Unfortunately, medications, hormone therapy, chemical additives in food, and endocrine-disrupting personal care products are oscillating the aromatase concentration beyond the permissible level. As this enzyme converts androgens (C19) into estrogens (C18), its agitation has different outcomes in different genders and age groups. Some common pathologies associated with aromatase disruption include breast cancer, prostate cancer, polycystic ovary syndrome (PCOS), endometriosis, osteoporosis, ovarian cancer, gastric cancer, pituitary cancer, Alzheimer's disease, schizophrenia, male hypogonadism, and transgender issues. Several drugs, cosmetics and pesticides act as the activators and suppressors of this enzyme. This carefully-compiled critical review is expected to increase public awareness regarding the threats resultant of the perturbations of this enzyme and to motivate researchers for further investigation of this field.
[Patel S. 2017. J Steroid Biochem Mol Biol.168:19-25] - High pesticide exposure events and DNA methylation among pesticide applicators in the agricultural health study.
Pesticide exposure has been associated with acute and chronic adverse health effects. DNA methylation (DNAm) may mediate these effects. Study evaluated the association between experiencing unusually high pesticide exposure events (HPEEs) and DNAm among pesticide applicators in the Agricultural Health Study (AHS), a prospective study of applicators from Iowa and North Carolina. DNA was extracted from whole blood from male AHS pesticide applicators (n = 695). Questionnaire data were used to ascertain the occurrence of HPEEs over the participant's lifetime. Pyrosequencing was used to quantify DNAm in CDH1, GSTp1, and MGMT promoters, and in the repetitive element, LINE-1. Linear and robust regression analyses evaluated adjusted associations between HPEE and DNAm. Ever having an HPEE (n = 142; 24%) was associated with elevated DNAm in the GSTp1 promoter at CpG7 (chr11:67,351,134; P < 0.01) and for the mean across the CpGs measured in the GSTp1 promoter (P < 0.01). In stratified analyses, elevated GSTP1 promoter DNAm associated with HPEE was more pronounced among applicators >59 years and those with plasma folate levels ≤16.56 ng/mL (p-interaction <0.01); HPEE was associated with reduced MGMT promoter DNAm at CpG2 (chr10:131,265,803; P = 0.03), CpG3 (chr10:131,265,810; P = 0.05), and the mean across CpGs measured in the MGMT promoter (P = 0.03) among applicators >59 years and reduced LINE-1 DNAm (P = 0.05) among applicators with ≤16.56 ng/mL plasma folate. Non-specific HPEEs may contribute to increased DNAm in GSTp1, and in some groups, reduced DNAm in MGMT and LINE-1. The impacts of these alterations on disease development are unclear, but elevated GSTp1 promoter DNAm and subsequent gene inactivation has been consistently associated with prostate cancer.
[Rusiecki JA, Beane Freeman LE, Bonner MR, Alexander M, et al. 2017. Environ Mol Mutagen. 58(1):19-29] - Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer
Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.
[Di Donato M, Cernera G, Giovannelli P, et al. 2017. Mol Cell Endocrinol. pii: S0303-7207(17)30158-2. ] - Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer.
Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.
[Di Donato M, Cernera G, Giovannelli P, et al. Mol Cell Endocrinol. pii: S0303-7207(17)30158-2. ] - Serum persistent organic pollutants (POPs) and prostate cancer risk: A case-cohort study.
This prospective cohort study evaluated the associations between serum POPs concentrations and prostate cancer risk. Within a case-cohort study, authors identified 110 people diagnosed with prostate cancer and randomly selected 256 sub-cohort participants without prostate cancer. Serum concentrations of 32 polychlorinated biphenyl (PCB) congeners and 19 organochlorine pesticides (OCPs) were measured. Compared to the lowest tertile, increased risks of prostate cancer incidence were observed in the upper tertile of following PCBs: the moderately chlorinated (HR: 4.19; 95% CI: 1.30-13.54), the highly chlorinated (HR: 4.14; 95% CI: 1.75-9.79), biologically persistent as CYP1A and CYP2B inducers (HR: 4.44; 95% CI: 1.33-14.83), the sum of non- dioxin-like (HR: 3.47; 95% CI: 1.21-9.98), and ∑PCBs (HR: 4.29; 95% CI: 1.52-12.08). In dose-response curves, ∑PCBs was associated with the increased risk of prostate cancer. Findings suggested a possible role of POPs in the etiology of prostate cancer.
[Lim JE, Nam C, Yang J, Rha KH, et al. 2017. Int J Hyg Environ Health. 220(5):849-856] - Atrazine promotes RM1 prostate cancer cell proliferation by activating STAT3 signaling.
Atrazine, a widely used pesticide, is frequently detected in soil and surface water, which alarms epidemiologists and medical professionals because of its potential deleterious effects on health. Indeed, atrazine is a potent endocrine disruptor that increases aromatase expression in some human cancer cell lines. Both animal and human studies have suggested that atrazine is possibly carcinogenic, although discrepant results have been reported. In this study, RM1 cells were used to explore the atrazine effects on prostate cancer. Proliferation, migration and invasion of RM1 cells were assessed by colony formation, wound-healing and invasion assays, respectively, after in vitro exposure to atrazine. In addition, an RM1 cell xenograft model was generated to evaluate the effects of atrazine in vivo. To explore the molecular mechanisms, qRT‑PCR, immunohistochemistry, and western blot analyses were employed to detect mRNA and protein levels of STAT3 signaling and cell cycle related proteins, including p53, p21, cyclin B1 and cyclin D1. Interestingly, RM1 cell proliferation was increased after treatment with atrazine, concomitantly with STAT3 signaling activation. These results suggest that atrazine promotes RM1 cell growth in vitro and in vivo by activating STAT3 signaling.
[Hu K, Tian Y, Du Y, Huang L, Chen J, et al. 2016. Int J Oncol. 48(5):2166-74] - Ca²⁺ Movement Induced by Deltamethrin in PC3 Human Prostate Cancer Cells.
This study explored the effect of deltamethrin, a pesticide, on intracellular free Ca²⁺ concentration ([Ca²⁺]i) in PC3 human prostate cancer cells. Deltamethrin at concentrations between 5 μM and 20 μM evoked [Ca²⁺]i rises in a concentration-dependent manner. This Ca²⁺ signal was inhibited by 22% by removal of extracellular Ca²⁺. Nifedipine, econazole, and SKF96365 also inhibited the Ca²⁺ signal. Treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) in Ca²⁺-free medium nearly abolished deltamethrin-induced [Ca²⁺]i rises. Treatment with deltamethrin also inhibited most of BHQ-induced [Ca²⁺]i rises. Inhibition of phospholipase C (PLC) with U73122 failed to alter deltamethrin-evoked [Ca²⁺]i rises. Deltamethrin killed cells at concentrations of 20-100 μM in a concentration-dependent fashion. Chelation of cytosolic Ca²⁺ with 1,2-bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid/acetoxymethyl ester (BAPTA/AM) did not prevent deltamethrin's cytotoxicity. Together, in PC3 human prostate cancer cells, deltamethrin induced [Ca²⁺]i rises that involved Ca²⁺ entry through store-operated Ca²⁺ channels and PLC-independent Ca²⁺ release from the endoplasmic reticulum. Deltamethrin induced cytotoxicity in a Ca²⁺-independent manner.
[Lee HH, Chou CT, Liang WZ, Chen WC, et al. 2016. Chin J Physiol. 59(3):148-55.] - Epidemiological trends of hormone-related cancers in Slovenia.
The incidence of hormone-related cancers tends to be higher in the developed world than in other countries. In Slovenia, six hormone-related cancers (breast, ovarian, endometrial, prostate, testicular, and thyroid) account for a quarter of all cancers. Their incidence goes up each year, breast and prostate cancer in particular. The age at diagnosis is not decreasing for any of the analysed cancer types. The risk of breast cancer is higher in the western part of the country, but no differences in geographical distribution have been observed for other hormone-related cancers. Furthermore, areas polluted with endocrine-disrupting chemicals that affect hormone balance such as PCBs, dioxins, heavy metals, and pesticides, do not seem to involve a greater cancer risk. We know little about how many cancers can be associated with endocrine disruptors, as there are too few reliable exposure studies to support an association.
[Zadnik V, Krajc M. 2016. Arh Hig Rada Toksikol. 67(2):83-92. ] - Exposure to pesticides and prostate cancer: systematic review of the literature
Investigations about the association between prostate cancer and environmental and/or occupational pesticide exposure have evidenced a possible role of these chemical substances on tumor etiology, related to their action as endocrine disruptors.To assess the association between pesticide exposure and prostate cancer by conducting a systematic review of the scientific literature.The review included 49 studies published between 1993 and 2015. All studies were in English and analyzed exposure to pesticides and/or agricultural activities. Most studies (32 articles) found a positive association between prostate cancer and pesticides or agricultural occupations, with estimates ranging from 1.01 to 14.10.The evidence provided by the reviewed studies indicates a possible association between the development of prostate cancer and pesticide exposure and/or agricultural occupations.
[Silva JF, Mattos IE, Luz LL, Carmo CN, Aydos RD. Rev Environ Health. 31(3):311-27. ] - Prostate cancer risk among French farmers in the AGRICAN cohort.
Prostate cancer is one of the most frequent cancers among men worldwide. Its etiology is largely unknown, but an increased risk has been repeatedly observed among farmers. Our aim was to identify occupational risk factors for prostate cancer among farmers in the prospective cohort study AGRICAN.Data on lifetime agricultural exposures (type of crops, livestock and tasks including pesticide use, re-entry and harvesting) were collected from the enrolment questionnaire. During the period from enrolment (2005-2007) to 31 December 2009, 1672 incident prostate cancers were identified. We found an increased risk for cattle breeders using insecticides [HR 1.20, 95% confidence interval (95% CI) 1.01-1.42] with a significant dose-response relationship with number of cattle treated (P for trend 0.01). A dose-response relationship was also observed with the number of hogs (P for trend 0.06). We found an excess of prostate cancer risk among people involved in grassland activities, mainly in haymaking (HR 1.18, 95% CI 1.02-1.36). Pesticide use and harvesting among fruit growers were associated with an elevated prostate cancer risk, with a two-fold increased risk for the largest area. For potato and tobacco producers, an elevated prostate cancer risk was observed for almost all tasks, suggesting a link with pesticide exposure since all of them potentially involved pesticide exposure.Our analysis suggests that the risk of prostate cancer is increased in several farming activities (cattle and hog breeding, grassland and fruit-growing) and for some tasks including pesticide use.
[Lemarchand C, Tual S, Boulanger M, Levêque-Morlais N, et al. 2016. Scand J Work Environ Health. 42(2):144-52.] - Sex Steroid Hormone Single-Nucleotide Polymorphisms, Pesticide Use, and the Risk of Prostate Cancer: A Nested Case-Control Study within the Agricultural Health Study.
Study evaluated whether single-nucleotide polymorphisms (SNPs) involved in hormone homeostasis alter the effect of pesticide exposure on prostate cancer risk. Authors evaluated pesticide-SNP interactions between 39 pesticides and SNPs with respect to prostate cancer among 776 cases and 1,444 controls nested in the Agricultural Health Study cohort. In these interactions included candidate SNPs involved in hormone synthesis, metabolism or regulation (N = 1,100), as well as SNPs associated with circulating sex steroid concentrations, as identified by genome-wide association studies (N = 17). Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. A significant interaction was observed, which was robust to multiple comparison testing, between the herbicide dicamba and rs8192166 in the testosterone metabolizing gene SRD5A1 (p-interaction = 4.0 × 10-5; q-value = 0.03), such that men with two copies of the wild-type genotype CC had a reduced risk of prostate cancer associated with low use of dicamba (OR = 0.62 95% CI: 0.41, 0.93) and high use of dicamba (OR = 0.44, 95% CI: 0.29, 0.68), compared to those who reported no use of dicamba; in contrast, there was no significant association between dicamba and prostate cancer among those carrying one or two copies of the variant T allele at rs8192166. In addition, interactions between two organophosphate insecticides and SNPs related to estradiol metabolism were observed to result in an increased risk of prostate cancer. While replication is needed, these data suggest both agonistic and antagonistic effects on circulating hormones, due to the combination of exposure to pesticides and genetic susceptibility, may impact prostate cancer risk.
[Christensen CH1, Barry KH2, Andreotti G3, Alavanja MC, et al. 2016. Front Oncol. 6:237. eCollection 2016.] - Warfarin use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer.
Anticoagulants, especially vitamin K antagonists (VKAs) such as warfarin, have been hypothesized to have antitumor properties, and use of VKAs has been associated with a lower prostate cancer (PCa) risk. This study estimated PCa risk among users of warfarin and other anticoagulants. All anticoagulant use among 78,615 men during 1995-2009 was analyzed. In total, 6537 men were diagnosed with PCa during 1995-2009 (1210 among warfarin users). Compared to non-users, warfarin use was associated with an increased risk of PCa [multivariable-adjusted hazard ratio (HR) = 1.11, 95% confidence interval (CI) 1.01-1.22]. This was limited to short-term, low-dose use, and was not observed in long-term use. A similar overall risk increase was observed for Gleason grade 7-10 PCa. Low-dose, short-term use of warfarin was associated with an increased risk of metastatic PCa. However, the increase in risk vanished with continued use. Compared to other anticoagulants, low-dose use of warfarin was associated with a slightly elevated overall PCa risk (HR = 1.19, 95% CI 1.00-1.43). The increase in risk disappeared in long-term, high-dose use. This study, which included a larger number of PCa cases with warfarin exposure than previous studies, does not support previous notions of decreased risk of PCa among warfarin users. A similar risk of PCa was found among warfarin users and the general population, and no difference in risk was found between warfarin and other anticoagulants.
[Kinnunen PT, Murtola TJ, Talala K, Taari K, et al. 2016. Scand J Urol. 50(6):413-419] - Chronic chlorpyrifos exposure does not promote prostate cancer in prostate specific PTEN mutant mice.
Environmental factors are likely to interact with genetic determinants to influence prostate cancer progression. The Agricultural Health Study has identified an association between exposure to organophosphorous pesticides including chlorpyrifos, and increased prostate cancer risk in pesticide applicators with a first-degree family history of this disease. Authors used bioluminescence imaging and histopathological analyses to test whether chronic exposure to chlorpyrifos in a grain-based diet for 32 weeks was able to promote prostate cancer development. Chronic exposure to chlorpyrifos in the diet did not promote prostate cancer development in mice despite achieving sufficient levels to inhibit acetylcholinesterase activity in plasma. The mechanistic basis of pesticide-induced prostate cancer may be complex and may involve other genetic variants, multiple genes, or nongenetic factors that might alter prostate cancer risk during pesticide exposure in agricultural workers.
[Svensson RU, Bannick NL, Marin MJ, et al. 2013. J Environ Pathol Toxicol Oncol.32(1):29-39] - Farming, reported pesticide use, and prostate cancer.
Prostate cancer is the leading cancer type diagnosed in American men and is the second leading cancer diagnosed in men worldwide. Although studies have been conducted to investigate the association between prostate cancer and exposure to pesticides and/or farming, the results have been inconsistent. This study performed a meta-analysis to summarize the association of farming and prostate cancer. Prostate cancer cases were almost four times more likely to be farmers compared with controls with benign prostate hyperplasia. Reported pesticide exposure was inversely associated with prostate cancer, whereas no association with exposure to fertilizers was observed. Our findings confirm that farming is a risk factor for prostate cancer, but this increased risk may not be due to exposure to pesticides.
[Ragin C, Davis-Reyes B, Tadesse H, et al. 2013. Am J Mens Health.7(2):102-9] - Genetic susceptibility loci, pesticide exposure and prostate cancer risk.
Uncovering SNP (single nucleotide polymorphisms)-environment interactions can generate new hypotheses about the function of poorly characterized genetic variants and environmental factors, like pesticides. Authots evaluated SNP-environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in 776 cases and 1,444 controls in the Agricultural Health Study. Among men carrying two T alleles in EH domain binding protein 1 (EHBP1) SNP, the risk of prostate cancer in those with high malathion use was 3.43 times those with no use. Among men carrying two A alleles in TET2, the risk of prostate cancer associated with high aldrin use was 3.67 times those with no use. In contrast, associations were null for other genotypes. Although additional studies are needed and the exact mechanisms are unknown, this study suggests known genetic susceptibility loci may modify the risk between pesticide use and prostate cancer.
[Koutros S, Berndt SI, Hughes Barry K et al. 2013. PLoS One. 8(4):e58195] - Pesticide exposure and inherited variants in vitamin d pathway genes in relation to prostate cancer.
Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin D's anticarcinogenic properties.Study hypothesizes that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants. Study evaluated interactions between 41 pesticides and 152 single-nucleotide polymorphisms (SNP) in nine vitamin D pathway genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of Caucasian pesticide applicators within the Agricultural Health Study.Five significant interactions displayed a monotonic increase in prostate cancer risk with individual pesticide use in one genotype and no association in the other. These interactions involved parathion and terbufos use and three vitamin D genes (VDR, RXRB, and GC). In this study, genetic variations in vitamin D pathway genes, particularly GC rs7041, an SNP previously linked to lower circulating vitamin D levels, modified pesticide associations with prostate cancer risk. Because this study is the first to examine this relationship, additional studies are needed to rule out chance findings.
[Karami S, Andreotti G, Koutros S, Barry KH, et al. 2013.Cancer Epidemiol Biomarkers Prev. 22(9):1557-66] - Risk of total and aggressive prostate cancer and pesticide use in the Agricultural Health Study.
Because pesticides may operate through different mechanisms, the authors studied the risk of prostate cancer associated with specific pesticides in the Agricultural Health Study (1993-2007). With 1,962 incident cases, including 919 aggressive prostate cancers among 54,412 applicators, this is the largest study to date. Three organophosphate insecticides were significantly associated with aggressive prostate cancer: fonofos, malathion and terbufos. The organochlorine insecticide aldrin was also associated with increased risk of aggressive prostate cancer. This analysis has overcome several limitations of previous studies with the inclusion of a large number of cases with relevant exposure and detailed information on use of specific pesticides at 2 points in time. Furthermore, this is the first time specific pesticides are implicated as risk factors for aggressive prostate cancer.
[Koutros S, Beane Freeman LE, Lubin JH, et al. 2013. Am J Epidemiol. 177(1):59-74] - Environmental exposures and prostate cancer.
Many malignancies have been linked to specific environmental exposures. Several environmental and occupational factors have been studied for an association to prostate cancer (CaP) risk. These include Agent Orange exposure, farming and pesticides, sunlight/ultraviolet radiation, as well as trace minerals used in tire and battery manufacturing. This manuscript reviews the literature on these environmental exposures and CaP.
[Mullins JK, Loeb S. 2012. Urol Oncol. 30(2):216-9] - Prostate cancer and toxicity from critical use exemptions of methyl bromide: environmental protection helps protect against human health risks.
Authors performed a systematic review of the literature, including in vitro toxicological and epidemiological studies of occupational and community exposure to the halogenated hydrocarbon pesticide methyl bromide. Study focused on toxic (especially chronic) or carcinogenic effects from the use of methyl bromide, on biomonitoring data and reference values. Out of the 542 peer reviewed publications between 1990-2011, 91 referring to toxicity of methyl bromide and 29 using the term "carcinogenic", "neoplastic" or "mutagenic". Overall, exposure to methyl bromide is associated with an increased risk of prostate cancer. Two epidemiological studies have analyzed environmental, non-occupational exposure to methyl bromide providing evidence for its health risk to the general public. Both the epidemiological evidence and toxicological data suggest a possible link between methyl bromide exposure and serious health problems, including prostate cancer risk from occupational and community exposure. The environmental risks of methyl bromide are not in doubt, but also its health risks, especially for genetically predisposed subjects, should not be underestimated.
[Budnik LT, Kloth S, Velasco-Garrido M, Baur X. 2012. Environ Health.11:5] - Genetic variation in base excision repair pathway genes, pesticide exposure, and prostate cancer risk.
Authors evaluated interactions between 39 pesticides and 394 tag single-nucleotide polymorphisms (SNPs) for 31 BER genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of white Agricultural Health Study (AHS) pesticide applicators. The interaction between fonofos and rs1983132 in NEIL3 [nei endonuclease VIII-like 3 (Escherichia coli)], which encodes a glycosylase that can initiate BER, was the most significant overall. Fonofos exposure was associated with a monotonic increase in prostate cancer risk among men with CT/TT genotypes for low and high use compared with no use, whereas fonofos was not associated with prostate cancer risk among men with the CC genotype. These findings regarding fonofos is consistent with previous AHS findings of increased prostate cancer risk with fonofos exposure among those with a family history of prostate cancer. Although requiring replication, our findings suggest a role of BER genetic variation in pesticide-associated prostate cancer risk.
[Barry KH, Koutros S, Berndt SI, Andreotti G, et al. 2011. Environ Health Perspect. 119(12):1726-32] - Prostate cancer and ambient pesticide exposure in agriculturally intensive areas in California.
In a population-based case-control study in California's intensely agricultural Central Valley (2005-2006), the authors investigated relations between environmental pesticide/fungicide exposure and prostate cancer. In comparison with unexposed persons, increased risks of prostate cancer were observed among persons exposed to compounds which may have prostate-specific biologic effects (methyl bromide and a group of organochlorines) but not among those exposed to other compounds that were included as controls (simazine, maneb, and paraquat dichloride).
This study provides evidence of an association between prostate cancer and ambient pesticide exposures in and around homes in intensely agricultural areas. The associations appear specific to compounds with a plausible biologic role in prostate carcinogenesis.
[Cockburn M, Mills P, Zhang X, et al. 2011. Am J Epidemiol. 173(11):1280-8] - Prostate cancer risk and exposure to pesticides in British Columbia farmers.
Several epidemiologic studies have reported an increased risk of prostate cancer among farmers. The aim of this study was to assess the risk of developing prostate cancer in relation to exposure to specific active compounds in pesticides. A case-control approach was used with 1,516 prostate cancer patients and 4,994 age-matched internal controls consisting of all other cancer sites excluding lung cancer and cancers of unknown primary site. Lifetime occupational history was obtained through a self-administered questionnaire and used in conjunction with a job exposure matrix to estimate the participants' lifetime cumulative exposure to approximately 180 active compounds in pesticides. The significant association between prostate cancer risk and exposure to DDT, simazine, and lindane is in keeping with those previously reported in the literature. Authors also observed a significant excess risk for several active ingredients that have not been previously reported in the literature such as dichlone, dinoseb amine, malathion, endosulfan, 2,4-D, 2,4-DB, and carbaryl. Some findings in this study were not consistent with those reported in the literature, including captan, dicamba, and diazinon. It is possible that these findings showed a real association and the inconsistencies reflected differences of characteristics between study populations.
[Band PR, Abanto Z, Bert J, et al.2011. Prostate. 71(2):168-83] - Xenobiotic-metabolizing gene variants, pesticide use, and the risk of prostate cancer.
Researchers evaluated pesticide-SNP interactions between 45 pesticides and 1913 XME SNPs with respect to prostrate cancer among 776 cases and 1444 controls in the Agricultural Health Study. A positive monotonic interaction was observed between petroleum oil/petroleum distillate use and rs1883633 in the oxidative stress gene glutamate cysteine ligase; men carrying at least one variant allele (minor allele) experienced an increased prostate cancer risk. Among men carrying the variant allele for thioredoxin reductase 2 (TXNRD2) rs4485648, microsomal epoxide hydrolase 1 (EPHX1) rs17309872, or myeloperoxidase (MPO) rs11079344, an increased prostate cancer risk was observed with high, compared with no, petroleum oil/petroleum distillate, or terbufos use. Researchers observed several pesticide-SNP interactions in oxidative stress and phase I/II enzyme genes and risk of prostate cancer. Additional work is needed to explain the joint contribution of genetic variation in XMEs, pesticide use, and prostate cancer risk.
[Koutros S, Andreotti G, Berndt SI, et al. 2011. Pharmacogenet Genomics. 21(10):615-23] - An update of cancer incidence in the Agricultural Health Study.
The objective was to reevaluate cancer incidence among Agricultural Health Study participants. A significant excess of prostate cancer was seen for private and commercial applicators. Excesses were observed for lip cancer and multiple myeloma among private applicators from North Carolina and for marginal zone lymphoma among Iowa spouses. Although lower rates of smoking and increased physical activity probably contribute to the lower overall cancer incidence, agricultural exposures including pesticides, viruses, bacteria, sunlight, and other chemicals may increase risks for specific cancer sites.
[Koutros S, Alavanja MC, Lubin JH, et al. 2010. J Occup Environ Med. 52(11):1098-105] - Chlordecone exposure and risk of prostate cancer.
Determining whether environmental estrogens are associated with the risk of prostate cancer may have important implications for our general understanding of this disease. The estrogenic insecticide chlordecone was used extensively in the French West Indies, contaminating the population for more than 30 years. We analyzed the relationship between exposure to chlordecone and the risk of prostate cancer. We investigated 623 men with prostate cancer and 671 controls. Exposure was analyzed according to case-control status, using either current plasma concentration or a cumulative exposure index based on years of exposure. We genotyped two single-nucleotide polymorphisms (rs3829125 and rs17134592) in the gene encoding chlordecone reductase. We found a significant increase in the risk of prostate cancer with increasing plasma chlordecone concentration (odds ratio [OR], 1.77; 95% CI, 1.21 to 2.58 for the highest tertile of values above the limit of detection [LD]; P trend = .002) and for cumulative exposure index (OR, 1.73; 95% CI, 1.04 to 2.88 for the highest quartile; P trend = .004). Stronger associations were observed among those with a positive family history of prostate cancer and among those who had lived in a Western country. The rs3829125 and rs17134592 allele variants were in complete linkage disequilibrium and were found at low frequency (0.04). Among subjects with plasma chlordecone concentrations above the LD, carriers of the allele variants had a higher risk of prostate cancer (OR, 5.23; 95% CI, 0.82 to 33.32). These findings support the hypothesis that exposure to environmental estrogens increases the risk of prostate cancer.
[Multigner L, Ndong JR, Giusti A, et al. 2010. J Clin Oncol. 28(21):3457-62] - Coumaphos exposure and incident cancer among male participants in the Agricultural Health Study (AHS).
Previous research in the Agricultural Health Study (AHS) cohort observed a positive association between coumaphos and prostate cancer in men with a family history of prostate cancer. This study was performed to determine the association between coumaphos and other major cancer sites and to explore the consistency of the association with prostate cancer early (1993-1999) and later (2000-2005) in AHS follow-up. This study included 47,822 male licensed pesticide applicators.
Approximately 8% of applicators reported use of coumaphos; 8.5% reported a family history of prostate cancer. Cumulative exposure to coumaphos was not associated with cancer risk overall or with any major cancer site including prostate. In men with a family history of prostate cancer, we observed a positive association between ever use of coumaphos and prostate cancer in both early periods of follow-up. Across all years, this association was statistically significant. Coumaphos was not associated with any cancer evaluated here. In men with a family history of disease, there was evidence of an association between coumaphos and prostate cancer, possibly due to genetic susceptibility.
[Christensen CH, Platz EA, Andreotti G, et al. 2010. Environ Health Perspect. 118(1):92-6] - Pesticide use modifies the association between genetic variants on chromosome 8q24 and prostate cancer.
In the Agricultural Health Study, a prospective study of licensed pesticide applicators,authors observed increased prostate cancer risk with specific pesticide use among those with a family history of prostate cancer. Thus, study evaluated the interaction among pesticide use, 8q24 variants, and prostate cancer risk. The authors estimated odds ratios (OR) and 95% confidence intervals (95% CI) for interactions among 211 8q24 variants, 49 pesticides, and prostate cancer risk in 776 cases and 1,444 controls. Authors observed a significant interaction among variants on chromosome 8q24, pesticide use, and risk of prostate cancer. Insecticides, particularly organophosphates, were the strongest modifiers of risk, although the biological mechanism is unclear. This is the first report of effect modification between 8q24 and an environmental exposure on prostate cancer risk.
[Koutros S, Beane Freeman LE, Berndt SI, et al. 2010. Cancer Res. 70(22):9224-33] - Does exposure to agricultural chemicals increase the risk of prostate cancer among farmers?
Several studies suggest that farmers may be at increased risk of prostate cancer. The present analysis, based on a large population-based case-control study conducted among men in the Montreal area in the early 1980's, aim at identifying occupational chemicals which may be responsible for such increases. The original study enrolled 449 prostate cancer cases, nearly 4,000 patients with other cancers, as well as 533 population controls. The present analysis was restricted to a study base of men who had worked as farmers earlier in their lives. There were a total of 49 men with prostate cancers, 127 with other cancers and 56 population controls. There was evidence of a two-fold excess risk of prostate cancer among farmers with substantial exposure to pesticides, as compared to unexposed farmers. There was some suggestion, based on few subjects, of increased risks among farmers ever exposed to diesel engine emissions. The results for pesticides are particularly noteworthy in the light of findings from previous studies. Suggestions of trends for elevated risks were noted with other agricultural chemicals, but these are largely novel and need further confirmation in larger samples.
[Parent ME, Désy M, Siemiatycki J. 2009. Mcgill J Med. 12(1):70-7] - Pesticide sales and adult male cancer mortality in Brazil.
A study of pesticides sales in different parts of Brazil and cancer mortality rates a decade later finds a statistically significant correlation between pesticide sales with the mortality rates for leukemia and cancer of the lip, esophagus, pancreas, and prostate.
[Chrisman, J.D., et al. 2009. Int J Hyg Environ Health ;212(3):310-21] - Agent Orange exposure, Vietnam War veterans, and the risk of prostate cancer
Twice as many Vietnam veterans exposed to Agent Oragne were identified with prostate cancer (239 vs 124 unexposed men, respectively; (OR 2.19). Individuals who were exposed to Agent Orange had an increased incidence of prostate cancer; developed the disease at a younger age, and had a more aggressive variant than their unexposed counterparts.
[Chamie, K., deVere White, R. W., Lee, D., Ok, J. and Ellison, L. M. 2008. Cancer, 113: 2464–2470.] - A case-control study of farming and prostate cancer in African-American and Caucasian men
A population-based case-control study in South Carolina finds farming is associated with increase risk of prostate cancer in Caucasians (OR 1.8) but not African-Americans. The study also finds that farmers who mixed or applied pesticides have a greater risk (OR 1.6); and, the increased risk is found only for those farming less than 5 years. The authors conclude that the racial difference in the association between farming and prostate cancer may be explained by different farming activities or different gene–environment interactions by race.
[Meyer, T.E., et al. 2007. Occup Environ Med 64(3):155-160.] - Prostate cancer and exposure to pesticides in agricultural settings
Individuals that have worked in agriculture is associated with a 40% increased risk of prostate cancer (OR 1.4)
[Settimi, L., et al. 2003. Int J Cancer 104(4):458-461.] - Prostate cancer risk in California farm workers
Hispanic farmworkers are found to be at an increased risk for prostate cancer when exposed to relatively high levels of certain organochlorines, organophosphates, fumigants and triazine herbicides.
[Mills, P.K. and Yang, R. 2003. J Occup Environ Med 45(3):249-258.] - Use of agricultural pesticides and prostate cancer risk in the Agricultural Health Study cohort
A prospective cohort study of Iowa and North Carolina male pesticide applicators finds that the two highest exposure scenarios (OR 2.73 and 3.47) significantly increase risk for prostate cancer. Significant interaction odds ratios occurred among persons who used butylate (OR 1.93); four organophosphorothioate insecticides including coumaphos (OR 2.58), fonofos (OR 2.04), chlorpyrifos (OR 1.65), and phorate (OR 1.64); and a pyrethroid, permethrin (for animal use) (OR 2.31).
[Alavanja, M., et al. 2003. American Journal of Epidemiology 157:800-814.] - Cancer incidence among triazine herbicide manufacturing workers
This study evaluated cancer incidence and prostate specific antigen (PSA) testing among workers at a plant in Louisiana (LA) that made atrazine and other triazine herbicides. The study covered the time period 1985 through 1997 and included 2045 subjects, of whom 757 worked for the company that owned the plant and 1288 were contract employees. Linkage with a population-based cancer registry and review of death certificates and plant medical records identified cancer cases. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) compared subjects' cancer incidence rates with those of a regional general population. Plant medical records provided data on the proportion receiving PSA tests among male company employees. Subjects had 46 observed and 40 expected cases of all cancers combined (SIR = 114, CI = 83-152) and had 11/6.3 prostate cancers (SIR = 175, CI = 87-312). The prostate cancer excess was greater in actively working company employees (5/1.3, SIR = 394, CI = 128-920) than in contract employees or inactive company employees (6/5.0, SIR = 119, CI = 44-260) and was limited to men under 60 years of age. Of the 11 prostate cancer cases, nine were diagnosed at an early clinical stage. From 1993 to 1999, the proportion of male company employees who had at least one PSA test was 86% for those who reached 40 years of age while actively working and was 98% for those who reached 45 years of age. The observed prostate cancer increase may have been due to the frequent PSA testing of actively working company employees. There is no epidemiologic or other information that clearly supports a causal relation between atrazine and prostate cancer.
[MacLennan, P.A., et al. 2002. J Occup Environ Med 44(11):1048-1058.] - Occupation and prostate cancer
Occupational exposures to pesticides including farmers, forestry workers or horticulturists finds a slight increased risk among farmers, speculating that certain pesticides act as hormone modifiers and influence the prostate cancer risk.
[Parent, M. and Siemiatycki, J. 2001. Epidemiologic Reviews 23(1):138-143.] - Occupation and prostate cancer risk in Sweden
Swedish stuy shows significantly elevated standardized incidence ratio are found in farmers and ceratin occupations and industries with exposures to herbicides and fertilizers. Results suggest that farmers; certain occupations and industries with exposures to cadmium, herbicides, and fertilizers; and men with low occupational physical activity levels have elevated prostate cancer risks.
[Sharma-Wagner, S., et al. 2000. J Occup Environ Med 42(5):517-525.] - Cancer incidence in a cohort of licensed pesticide applicators in Florida
A standardized incidence ratio anaylsis (SIR) of licensed pesticide applicators in Florida, compared with Florida’s general population, finds an increased incidence rate for prostate cancer (SIR 1.91).
[Fleming, L., et al. 1999. Journal of Occupational and Environmental Medicine 41(4):279-288.] - Cancer mortality among Iowa farmers: recent results, time trends, and lifestyle factors (United States)
A cancer mortality study of Iowa farmers shows an excess of deaths for cancers of the prostate (1.26 PMR).
[Cerhan, J.R., et al. 1998. Cancer Causes Control 9(3):311-319.] - Correlation analysis of pesticide use data and cancer incidence rates in California counties.
An ecological study in California analyzing data on pesticide use and cancer incidence finds a correlation between black males diagnosed with prostate cancer and atrazine and captan.
[Mills, P.K. 1998. Arch Environ Health 53(6):410-413] - Prostate cancer in pesticide applicators in Swedish agriculture
A cohort of over 20,000 licensed agriculture pesticide applicators in Sweden finds a statistically significant increased risk of prostate cancer.
[Dich, J., and Wiklund, K. 1998. Prostate 34(2):100-112.] - Meta-analyses of prostate cancer and farming
A meta-analyses of prostate cancer and farming studies between 1983 and 1994 finds a positive association between prostate cancer and farming, which the study authors attribute to exposure to hormonally active agricultural chemicals.
[Keller-Byrne, J.E., et al. 1997. Am J Ind Med 31(5):580-586.] - Proportionate mortality study of golf course superintendents.
A mortality study of a cohort of 686 deceased U.S. male golf course superintendents from the finds elevated levels for prostate cancer (PMR 293).
[Kross, B.C., et al. 1996. Am J Ind Med 29(5):501-506] - Farming and prostate cancer among African-Americans in the Southeastern Untied States
A study looking at African-American farmers shows further support that prostate cancer risk is associated with farming occupations.
[Dosemeci, M., et al. 1994. Journal of the National Cancer Institute 86(22):1718-1719.] - Cancer among farmers in central Italy
A case-referent study of Italian farmers finds a possible relationship between wheat crops and prostate cancer.
[Forastiere, F, et al. 1993. Scand J Work Environ Health 19(6):382-389.] - Farming and prostate cancer mortality
Although farmers appear to be at an increased risk of prostate cancer, the specific exposures which produce the excess risk remain unexplained. This study was based on a retrospectively assembled cohort of male Manitoba, Saskatchewan, and Alberta, Canada, farmers age 45 years or older identified in the 1971 Canadian censuses of population and agriculture. The cohort was linked to the Canadian National Mortality Database using an iterative computer record linkage system for the period June 1971 to the end of 1987. A total of 1,148 prostate cancer deaths and 2,213,478 person-years were observed. Using Poisson regression, the study examined the relation between the risk of dying from prostate cancer and various farm practices as identified on the 1971 Census of Agriculture, including exposure to chickens, cattle, pesticides, and fuels. A weak, but statistically significant, association was found between number of acres sprayed with herbicides in 1970 and risk of prostate cancer mortality. When the analysis was restricted to farmers believed to be subject to the least amount of misclassification, the risk associated with acres sprayed with herbicides increased (rate ratio (RR) = 2.23 for 250 or more acres sprayed; 95% confidence interval (CI) 1.30-3.84; test for trend, p < 0.01). No other farm exposure examined was associated with any detectable pattern of increased or decreased risk. These findings encourage further research to examine the effects of herbicides on prostate cancer.
[Morrison, H., et al. 1993. American Journal of Epidemiology 137(3):270-280.] - Mortality among white and nonwhite farmers in North Carolina, 1976-1978.
A mortality study of farmers in North Carolina finds an increased frequency of prostate cancer among white decedents under 65 years of age (PMR 1.6).
[Delzell, E., and Grufferman, S. 1985. Am J Epidemiol 121(3):391-402]
Sinonasal cancer
- Genotoxicity studies on permethrin, DEET and diazinon in primary human nasal mucosal cells
Possible genotoxic effects exerted by three widely used pesticides, permethrin, N,N-diethyl-m-toluamide (DEET) and diazinon, in primary human nasal mucosal cells were investigated. Primary nasal mucosa cells were prepared from tissue biopsies taken from 21 patients who underwent nasal surgery. Cells were exposed to 0.5-1.0 mM concentrations of permethrin, DEET and diazinon for 60 min. Genotoxic effects were detected by the alkaline microgel electrophoresis assay ("comet assay"). Within the concentration range, no significant cytotoxic effects were observed, but all three tested pesticides showed a significant genotoxic response that was concentration dependent. More pronounced genotoxic effects were observed in mucosal cells from the middle turbinate than in the inferior turbinate. The results provide some evidence for the potential carcinogenicity of these agents to human nasal mucosal cells. This should be further investigated.
[Tisch, M., et al. 2002. Eur Arch Otorhinolaryngol 259:150-153.]
Soft Tissue Sarcoma
- Comparison of questionnaire data and analyzed dioxin concentrations as a measure of exposure in soft-tissue sarcoma studies.
Soft-tissue sarcoma is one of the few specific tumors thought to be caused by polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and specifically TCDD. Evidence is, however, based on questionnaire-based case-control studies, and on very few cancer cases in cohort studies at high occupational exposures to chlorophenols or chlorophenoxy acid herbicides with dioxin impurities. Recall bias has been suspected to influence the reporting of exposure, but this possibility has never been adequately put to test. In the present study 87 cancer patients and 308 controls answered a questionnaire asking their exposure to wood preservatives, fungicides and herbicides, and insecticides, and their PCDD/F concentrations were also measured. After matching for age and area 67-69 sarcoma patients and 153-156 controls were available for the study depending on the chemical group, 1-3 controls for each sarcoma patient. Sarcoma patients reported exposure to these chemicals significantly more often than controls did, odds ratios were 6.7 for wood preservatives (p=0.02), 16 for fungicides and herbicides (p=0.01), and 4.9 for insecticides (p=0.06). There was no association, when the analysis was based on measured PCDD/F concentrations (odds ratios close to 1). Although it is not possible to exclude the role of the main chemical as the cause with certainty, the results indicate that recall bias is very likely in previous studies. Thus the causality between contaminant PCDD/Fs and soft tissue sarcoma cannot be considered proven.
[Tuomisto J, Airaksinen R, Pekkanen J, et al. 2017. Toxicol Lett. 270:8-11.] - Wartime toxin exposure: recognising the silent killer
Wartime toxin exposures have been implicated in the genesis of malignancy in war veterans. Agent Orange, one toxin among many, has been linked to malignancy and the subcomponent phenoxyacetic acid has been associated with soft tissue sarcomas (STSs). This case demonstrates the association between a wartime toxin exposure (Agent Orange) and subsequent cancer development. Ultimately, we aim to highlight the importance of simple, specific questions in the patient history to account for previous wartime toxin exposures.
[Khan K, Wozniak SE, Coleman J, Didolkar MS. 2016. BMJ Case Rep. pii: bcr2016217438.] - Pesticide sales and adult male cancer mortality in Brazil.
A study of pesticides sales in different parts of Brazil and cancer mortality rates a decade later finds a statistically significant correlation between pesticide sales with the mortality rates for leukemia and cancer of the lip, esophagus, pancreas, and prostate.
[Chrisman, J.D., et al. 2009. Int J Hyg Environ Health ;212(3):310-21] - Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with agricultural activity finds an elevated risk for soft tissue sarcomas at high agricultural activity (greater than 60% of county acreage devoted to farming). When looking at sub-types, risk increased for rhabdomyosarcomas and category including germ cell, trophoblastic, and gonadal neoplasms. When looking at crop acreage, an increased risk if found for germ cell carcinomas and oat crops.
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - Home pesticide use and childhood cancer: A case-control study
A 1995 case-control study of Denver children finds that yard pesticide applications are linked to a four-fold increase in risk to soft tissue sarcomas.
[Leiss, J., et al. 1995. American Journal of Public Health 85:249-252] - Soft tissue sarcoma and non-Hodgkin's lymphoma in workers exposed to phenoxy herbicides, chlorophenols, and dioxins: two nested case-control studies.
A nested international occupational case-control study finds excess risk of soft tissue sarcoma with exposure to chlorophenoxy herbicides (OR 10.3) including 2,4-D.
[Kogevinas, M, et al. 1995. Epidemiology 6(4):396-402] - Risk factors for soft tissue sarcomas in childhood: a case-control study.
A hospital-based case-control study on childhood soft tissue sarcomas in Italy finds a positive association with maternal employment as a farmer,=.
[Magnani, C., et al. 1989. Tumori 75(4):396-400]
Stomach Cancer
- Cancer risk among farmers in the Province of Vercelli (Italy) from 2002 to 2005: an ecological study
Farmers living in the Province of Vercelli (Italy) were observed to verify if they have a higher cancer risk than the rest of the local employed population. The present ecological study considered all cancer new cases recorded among the mean employed population with a range of age from 25 to 84 years and resident in the Province of Vercelli during the four-year period 2002-2005. Farmers showed a higher risk for the following tumors: colorectal (OR 2.38, IC95%: 1,76-2,87), leaukaemia (OR 2.65, IC95%:2,12-2,89), digestive system (OR 2.16, IC95% 1,92-2,33), and others. Farmers showed a higher risk for several cancers. Further studies are needed, in order to examine in detail the issue, to encourage the use of personal protective equipment and to promote a more responsible pesticides use.
[Salerno C, Sacco S, Panella M, et al.2014. Ann Ig. 26(3):255-63.] - Methyl bromide exposure and cancer risk in the Agricultural Health Study.
Study used Poisson regression to calculate rate ratios (RR) and 95 % confidence intervals (CI) for associations between methyl bromide use and all cancers combined, as well as 12 specific sites, among 53,588 Agricultural Health Study pesticide applicators with follow-up from 1993 to 2007. A total of 7,814 applicators (14.6 %) used methyl bromide, predominantly before enrollment. Based on 15 exposed cases, stomach cancer risk increased monotonically with increasing methyl bromide use for low and high use compared with no use. No other sites displayed a significant monotonic pattern. Results provide little evidence of methyl bromide associations with cancer risk for most sites examined; however, study observed a significant exposure-dependent increase in stomach cancer risk. Small numbers of exposed cases and declining methyl bromide use might have influenced our findings. Further study is needed in more recently exposed populations to expand on these results.
[Barry KH, Koutros S, Lubin JH, et al. 2012. Cancer Causes Control. 23(6):807-18] - Agricultural exposures and gastric cancer risk in Hispanic farm workers in California
Occupation in the citrus industry (OR 2.88) and in areas with high 2,4-D use (OR 1.85) and use of acaricide propargite (OR 2.86) or trifluralin (OR 1.69) are associated with gastric cancer.
[Mills, P.K., and Yang, R.C. 2007. Environ Res 104(2):282-289.] - Associations between stomach cancer incidence and drinking water contamination with atrazine and nitrate in Ontario (Canada) agroecosystems, 1987-1991
Nitrate and atrazine are two chemicals that are heavily used in certain sectors of agriculture. They are suspected to be associated with the development of certain types of tumours. Existing data were obtained on the incidence of specific types of cancers, contamination of drinking water with atrazine and nitrate, and related agricultural practices for the 40 ecodistricts in the province of Ontario. The data were merged into a georelational database for geographical and statistical analyses. Weighted (by population size) least squares regression analyses were conducted while controlling for confounding socioeconomic and lifestyle factors. Maximum likelihood spatial error models were estimated when least square regression error terms were found to be spatially autocorrelated using the Moran's I statistic. Atrazine contamination levels (range 50-649 ng/l, maximum acceptable concentration [MAC] = 60000 ng/l) were positively associated (P < 0.05) with stomach cancer incidence and negatively associated with colon cancer incidence. Nitrate levels, (range 0-91 mg/l, MAC = 10 mg/l) were negatively associated with stomach cancer incidence. The associations found at the ecodistrict level, both positive and negative, if confirmed by other studies, raise serious questions about maximum allowable limits for atrazine, as well as possibilities of complex trade-offs among disease outcomes, and interactions of biophysical and social mechanisms which might explain them. Although the negative associations appear to have no direct biological explanations, such counter-intuitive outcomes may occur in complex systems where social and biological variables interact.
[Van Leeuwen, J.A., et al. 1999. International Journal of Epidemiology 28:836-840.] - Cancer among farmers in central Italy
A case-referent study of Italian farmers finds a significantly increased risk of stomach cancer among farmers with greater than 10 years experience and among licensed pesticides users with greater than 10 years’ experience.
[Forastiere, F, et al. 1993. Scand J Work Environ Health 19(6):382-389.]
Testicular Cancer
- Prenatal proximity to agricultural use of endocrine-disrupting pesticides and risk of testicular germ cell tumor (TGCT) among Latino and non-Latino adolescents in California
The incidence of testicular germ cell tumors (TGCTs) has increased steadily in the United States in recent years, especially among Latinos. This study assessed the association between TCGT diagnosis and agricultural application of 22 endocrine-disrupting pesticides using California’s Pesticide Use Reporting database within a 3km-radius of participants’ birth address in the year prior to birth. Acephate, an organophosphate insecticide, was associated with an increased risk for TGCT, possibly contributing 5-10 percent to the prevalence of TGCT among Latinos in California.
[Swartz, S.J., Morimoto, L., Whitehead, T., Gunier, R., Wiemels, J., Ma, X. and Metayer, C., 2020. Conference: Abstracts: AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved. ] - Occupational and environmental exposures associated with testicular germ cell tumours: systematic review of prenatal and life-long exposures.
Testicular germ cell tumours (TGCT) are the most common cancers in men aged between 15 and 44 years and the incidence has increased steeply over the past 30 years. The rapid increase in the incidence, the spatial variation and the evolution of incidence in migrants suggest that environmental risk factors play a role in TGCT aetiology. The purpose of this review was to summarise the current state of knowledge on occupational and environmental factors thought to be associated with TGCT. After exclusion of duplicate reports, 72 relevant articles were selected; 65 assessed exposure in adulthood, 7 assessed parental exposures and 2 assessed both. Associations with occupation was reported for agricultural workers, construction workers, firemen, policemen, military personnel, as well as workers in paper, plastic or metal industries. Electromagnetic fields, PCBs and pesticides were also suggested. However, results were inconsistent and studies showing positive associations tended to had lower quality ranking using the assessment scale. Current evidence does not allow concluding on existence of any clear association between TGCT and adulthood occupational or environmental exposure. The limitations of the studies may partly explain the inconsistencies observed. The lack of association with adulthood exposure is in line with current hypotheses supporting the prenatal origin of TGCT. Future research should focus on prenatal or early life exposure, as well as combined effect of prenatal and later life exposure. National and international collaborative studies should allow for more adequately powered epidemiological studies. More sophisticated methods for assessing exposure as well as evaluating gene-environment interactions will be necessary to establish clear conclusion.
[Béranger R, Le Cornet C, Schüz J, Fervers B. 2013. PLoS One. 8(10):e77130] - Pesticide exposure and serum organochlorine residuals among testicular cancer patients and healthy controls.
The incidence of testicular cancer (TC) has been increasing worldwide during the last decades. The reasons of the increase remains unknown, but recent findings suggest that organochlorine pesticides (OPs) could influence the development of TC. A hospital-based case-control study of 50 cases and 48 controls was conducted to determine whether environmental exposure to OPs is associated with the risk of TC, and by measuring serum concentrations of OPs, including p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) isomer and hexachlorobenzene (HCB) in participants. A significant association was observed between TC and household insecticide use. Crude and adjusted ORs for TC were also significantly associated with higher serum concentrations of total OPs in cases compared with controls. These findings give additional support to the results of previous research that suggest that some environmental exposures to OPs may be implicated in the pathogenesis of TC.
[Giannandrea F, Gandini L, Paoli D, et al. 2011. J Environ Sci Health B. 46(8):780-7] - Cancer incidence in a cohort of licensed pesticide applicators in Florida
This study is a standardized incidence ratio (SIR) analysis of cancer incidence of licensed pesticide applicators in Florida, compared with that of Florida's general population. Through extensive data linkages, 33,658 applicators were assembled who had 1266 incident cancers and 279,397 person-years from January 1, 1975, to December 31, 1993. Disease risk from ethanol and tobacco use were significantly decreased. Among males, prostate cancer (SIR = 1.91; 95% confidence interval [CI], 1.72-2.13) and testicular cancer (SIR = 2.48; 95% CI, 1.57-3.72) were significantly elevated. No confirmed cases of soft tissue sarcoma (STS) were found, and the incidence of non-Hodgkin's lymphoma was not increased. There were few female applicators; nevertheless, cervical cancer incidence (SIR = 3.69; 95% CI, 1.84-6.61) was significantly increased, while the incidence of breast cancer was significantly decreased. Cancers that have been associated with estrogen disrupters were found in male, but not female, pesticide applicators. The lack of soft tissue sarcoma is at odds with prior literature associated with the use of phenoxy herbicides.
[Fleming, L., et al. 1999. Journal of Occupational and Environmental Medicine 41(4):279-288.] - Correlation analysis of pesticide use data and cancer incidence rates in California counties.
An ecological study in California analyzing data on pesticide use and cancer incidence finds a correlation between Hispanic males diagnosed with testicular cancer and atrazine.
[Mills, P.K. 1998. Arch Environ Health 53(6):410-413] - Testicular cancer associated with employment in agriculture and oil and natural gas extraction
A hospital-based case-control study find an increased risk for testicular cancer in men who work in the agricultural industry.
[Mills, P.K., et al. 1984. Lancet 1(8370):207-210.]
Thyroid Cancer
- Endosulfan use and the risk of thyroid cancer: an ecological study
Endosulfan, an organochlorine pesticide, has been understudied in the literature on thyroid cancer. The aim of this ecological study was to assess the correlation between endosulfan exposure and thyroid cancer incidence rates (IRs) in the United States (US). Age-adjusted thyroid cancer IRs per 100,000 people per state for the years 1999 to 2019 were obtained from the Center for Disease Control and Prevention (CDC). To assess the state-level use of endosulfan, data were obtained from the US Geological Survey (USGS). Endosulfan usage estimates (kilograms/acres cropland; quintiles) and thyroid cancer IRs were mapped together. The correlation between age-adjusted thyroid cancer IRs and statewide endosulfan use was calculated using the Spearman correlation. Overall endosulfan usage in the US trended downwards between 1992 and 2007 (T = −0.77; P < 0.001), while thyroid cancer IR trended upwards between 1999 and 2019 (T = 0.69; P < 0.001). There was a statistically significant correlation between 1992 endosulfan use and 2012 (r = 0.32; P = 0.03) and 2014 (r = 0.32; P = 0.03) thyroid cancer IRs. Although restrictions on endosulfan use seem effective, the potential impact of endosulfan exposure remains due to the persistent, semi-volatile, bioaccumulative, and biomagnifying properties of endosulfan metabolites in particular, indicating the need for future thyroid research of highly exposed populations.
[Vasan, V., Alsen, M., Vujovic, D., Genden, E., Sinclair, C. and van Gerwen, M., 2023. Journal of Environmental Science and Health, Part B, 58(1), pp.51-57.] - Organochlorine pesticides and epigenetic alterations in thyroid tumors.
Cancer incidence depends on various factors e.g., pesticide exposures which cause epigenetic alterations. The present research aimed to investigate the organochlorine pesticides (OCPs) impacts on promoter methylation of three tumor-suppressor genes and four histone modifications in thyroid nodules in 61 Papillary thyroid carcinoma (PTC) and 70 benign thyroid nodules (BTN) patients. OCPs were measured by Gas chromatography. To identify promoter methylation of TSHR, ATM, and P16 genes, the nested-methylation-specific PCR (MSP) was utilized, and histone lysine acetylation (H3K9, H4K16, and H3K18) and lysine methylation (H4K20) were detected by performing western blot analysis. Further TSHR methylation and less P16 methylation were observed in PTC than in BTN. No substantial difference was detected for ATM methylation between PTC and BTN groups. Also, OCP dramatically increased the odds ratio of TSHR (OR=3.98, P=0.001) and P16 (OR=5.65, P<0.001) methylation while confounding variables reduced the chances of ATM methylation arising from 2,4-DDE and 4,4-DDT influence. Hypomethylation of H4K20 and hypo-acetylation of H3K9, H4K16, and H3K18 (P<0.001) were observed in PTC samples than BTN. Furthermore, OCPs substantially decreased the odds ratio of H3K9 (OR=3.68, P<0.001) and H4K16 (OR=6.03, P<0.001) acetylation. The current research indicated that OCPs could contribute to PTC progression by TSHR promoter hypermethylation and decreased acetylation of H3K9 and H4K16. In addition, in PTC patients, assessing TSHR promoter methylation and acetylation of H3K9 and H4K16 could have predictive values.
[Salimi, F., Asadikaram, G., Ashrafi, M.R., Nejad, H.Z., Abolhassani, M., Abbasi-Jorjandi, M. and Sanjari, M., 2023. Frontiers in Endocrinology, 14.] - Occupational exposure to pesticides and other biocides and risk of thyroid cancer.
The study assessed the associations between occupational exposure to biocides and pesticides and risk of thyroid cancer. Using data from a population-based case-control study involving 462 incident thyroid cancer cases and 498 controls in Connecticut collected in 2010-2011, authors examined the association with occupational exposure to biocides and pesticides through a job-exposure matrix. Individuals who were occupationally ever exposed to biocides had an increased risk of thyroid cancer (OR=1.65, 95% CI 1.16 to 2.35), and the highest risk was observed for the high cumulative probability of exposure (OR=2.18, 95% CI 1.28 to 3.73). The observed associations were similar when restricted to papillary thyroid cancer and well-differentiated thyroid cancer. Stronger associations were observed for thyroid microcarcinomas (tumour size ≤1 cm). No significant association was observed for occupational exposure to pesticides. Study provides the first evidence linking occupational exposure to biocides and risk of thyroid cancer. The results warrant further investigation.
[Zeng F, Lerro C, Lavoué J, Huang H, et al. 2017. Occup Environ Med. 74(7):502-510.] - Occupation and thyroid cancer.
Here authors review the epidemiology studies of occupations and occupational exposures and thyroid cancer incidence to provide insight into preventable risk factors for thyroid cancer. They summarised the findings of 30 articles that examined thyroid cancer incidence in relation to occupations or occupational exposure. The most studied (19 of 30 studies) and the most consistent associations were observed for radiation-exposed workers and healthcare occupations. Suggestive, but inconsistent, associations were observed in studies of pesticide-exposed workers and agricultural occupations.
[Aschebrook-Kilfoy B, Ward MH, Della Valle CT, Friesen MC. 2014. Occup Environ Med. 71(5):366-80] - Nitrate intake and the risk of thyroid cancer and thyroid disease
Study finds an increased risk of thyroid cancer with higher average nitrate levels in public water supplies (nitrate is a contaminant of drinking water in agricultural areas) and with longer consumption of water exceeding 5 mg/L nitrate-N (for >or=5 years at >5 mg/L, relative risk = 2.6).
[Ward MH, et al. 2010. Epidemiology. 21(3):389-95] - Risk factors of thyroid tumors: role of environmental and occupational exposures to chemical pollutants.
The rising incidence of thyroid cancer observed during the last few decades in most western countries is explained in large part by increasing numbers of diagnoses due to changes in medical screening practices. However, beside radiation exposure, exposure to environmental chemicals may also play a role in thyroid cancer etiology and in the increased incidence. This paper presents the main chemicals suspected to induce thyroid tumorigenesis, and epidemiological results on the association between chemical exposure and thyroid tumors.This review found that environmentally abundant chemicals may disrupt thyroid function and/or play a role in tumorigenesis through a variety of mechanisms. Epidemiological results provide insufficient evidence of a causal link between exposure to environmental chemicals and thyroid tumors, but raise the hypothesis of an increased risk of thyroid neoplasm for workers in the leather, wood, and paper industries, and those exposed to certain solvents and pesticides.
[Leux C, Guénel P. 2010. Rev Epidemiol Sante Publique.58(5):359-67] - Thyroid disruption: mechanism and clinical implications in human health.
Exposure to specific environmental toxins, including polychlorinated biphenyls, dioxins, phthalates, polybrominated diphenyl ethers (PBDEs), and other halogenated organochlorines, has been shown to interfere with the production, transportation, and metabolism of thyroid hormones by a variety of mechanisms. A broad range of chemicals, with structural similarity to thyroid hormone, have been shown to bind to thyroid receptors with both agonist and antagonist effects on thyroid hormone signaling. The incidence of thyroid disease in the United States, particularly for thyroid cancer and thyroid autoimmune disease, is increasing substantially. The evidence for the significant effects of background levels of thyroid-disrupting chemicals, the known pathways for thyroid disruptors, and the evidence and implications for neurodevelopmental damage due to thyroid-disrupting chemicals is reviewed.
[Patrick L. 2009. Altern Med Rev. 14(4):326-46] - Mechanism of trifluralin-induced thyroid tumors in rats.
Trifluralin has been reported to cause a significant increase in thyroid follicular cell tumors in male Fischer 344 rats. This study was designed to determine the mechanism of thyroid hyperactivity after trifluralin exposure. A group of 15 male Fischer 344 rats were exposed to trifluralin-fortified (6500 ppm) diet for 2 weeks. In the trifluralin treated rats, the serum T3 and T4 levels decreased by 17% and 90%, respectively and TSH increased by 37% more than the control rats. The decrease in total serum T3 and T4 levels in the trifluralin treated rats was due to enhanced peripheral metabolism and an increase in bile flow that results in a compensatory increase in TSH synthesis and secretion. The increased levels of TSH with chronic exposure to trifluralin would exert a continuous stimulation of the thyroid gland leading to cellular hypertrophy and proliferation predisposing to the development of follicular cell tumors in rats.
[Saghir SA, Charles GD, Bartels MJ, et al. 2008. Toxicol Lett.180(1):38-45] - Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with moderate to high agricultural activity finds statistically significantly elevated risk for thyroid carcinomas (OR 3.0) at high agricultural activity (greater than 60 percent of the total county acreage is devoted to farming). An increased risk is also found for thyroid carcinomas and oat crop acreage (OR 2.0).
[Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.] - A mode of action for induction of thyroid gland tumors by Pyrethrins in the rat.
Prolonged treatment with high doses of pyrethrins results in thyroid gland tumors in the rat. To elucidate the mode of action for tumor formation, the effect of pyrethrins on rat thyroid gland, thyroid hormone levels and hepatic thyroxine UDPglucuronosyltransferase activity was investigated. Treatment with pyrethrins and NaPB increased hepatic microsomal thyroxine UDPglucuronosyltransferase activity and serum thyroid stimulating hormone levels (TSH), but reduced serum levels of either thyroxine (T4) and/or triiodothyronine (T3). The effects of pyrethrins in female rats were dose-dependent, with 100 ppm being a no-effect level, and on cessation of treatment were essentially reversible in both sexes. The concordance between the effects of pyrethrins and NaPB suggests that the mode of action for Pyrethrins-induced rat thyroid gland tumors is similar to that of some other non-genotoxic inducers of hepatic xenobiotic metabolism.
[Finch JM, Osimitz TG, Gabriel KL, et al. 2006. Toxicol Appl Pharmacol.214(3):253-62]
Uterine Cancer
- Levels of persistent organic pollutants in breast milk of Maya women in Yucatan, Mexico.
In this study, 24 breast milk samples, obtained from rural Maya women, from municipalities of Yucatan, Mexico, were analyzed for organochlorine pesticide (OCP) residues by gas chromatography. Recent studies have shown that Maya communities have a poor perception about the proper usage and handling of OCP. The karstic soil in this area has a high vulnerability to groundwater pollution by the use of OCP in agriculture and livestock activities. The impact of the ecosystem on human health is much more critical due to the prevailing poverty and a very low educational level of these communities. About 30% of the Maya population consumes water directly from contaminated wells and sinkholes, resulting in a chronic exposure to OCP. The samples served to identify and quantify high levels of OCP residues (18.43 mg/kg of heptachlor epoxide and 1.92 mg/kg of endrin in the metropolitan zone; 2.10 mg/kg of dieldrin, 0.117 mg/kg of endosulfan II, 0.103 mg/kg of heptachlor, 0.178 mg/kg of endrin, and 0.127 mg/kg of endrin aldehyde in the main agricultural zone and on the west coast). The detected levels of OCP residues are a major concern and represent a potential risk to women and children in the region. This could be associated with the high rates of cervical uterine and breast cancer mortality in Yucatan. Thus, regulations on the usage of OCP and their enforcement are necessary, and it is important to establish a yearly monitoring program for OCP residues in breast milk and groundwater, as well as to implement health promotion programs for women in particular and the general population in general.
[Polanco Rodríguez ÁG, Inmaculada Riba López M, Angel DelValls Casillas T, et al. 2017. Environ Monit Assess. 189(2):59] - Monitoring of organochlorine pesticides in blood of women with uterine cervix cancer
In Yucatan, Mexico, chronic exposure of Mayan population to pesticides is expected as about 30 per cent are drinking polluted water. Residues of organochlorine pesticides (OCP) were monitored in 18 municipalities of Yucatan with high mortality rates due to uterine cervix cancer. 70 blood samples collected from Mayan women living in livestock, agricultural and metropolitan area were analyzed for OCP. Solid Phase Extraction was performed on C18 cartridges and analyzed by Gas Chromatography with Electron Capture Detector. The results showed that the highest OCP levels were detected in blood of women living in the livestock area. OCP detected were endosulfan I (7.35 μg/mL), aldrin (3.69 μg/mL), 4,4' DDD (2.33 μg/mL), 1.39 and 1.46 μg/mL of δ-HCH. Women from the agricultural area had high concentrations of OCP in their blood, particularly dieldrin (1.19 μg/mL), and 1.26 μg/mL of 4,4' DDE. In the metropolitan area, 0.080 μg/mL of γ-HCH and 0.064 μg/mL of heptachlore were detected. This monitoring study was also based on epidemiological data of uterine cervical cancer. It was found that environmental factors may have facilitated the infiltration of OCP to the aquifer used for potable water supply. These factors in addition to poverty can have impacts on public health. This first exploratory study suggests that monitoring of OCP in human is important for the establishment of health promotion programs. The integrative analysis of both, environmental and social factors would be helpful to characterize the bioaccumulation of pesticides in humans.
[Polanco Rodríguez ÁG, Riba López MI, DelValls Casillas TÁ, et al. 2017. Environ Pollut. 220(Pt B):853-862.] - An endocrine-disrupting chemical, fenvalerate, induces cell cycle progression and collagen type I expression in human uterine leiomyoma and myometrial cells.
Fenvalerate (Fen), widely used for its high insecticidal potency and low mammalian toxicity, is classified as an endocrine-disrupting chemical. Recently, Fen has received great attention for its adverse effects on human reproductive health. In this study, we found that Fen (10 microM) had a stimulatory effect on the growth of both cell lines at 24 h compared with controls by MTS (p < 0.01) and BrdU (p < 0.01) assays in hormonally responsive uterine leiomyoma (UtLM) cells and normal uterine smooth muscle cells (UtSMC). Data shows that Fen can stimulate the growth of both UtLM cells and UtSMC, which involves a combination of enhanced cell cycle progression and inhibition of apoptosis. Also this compound can increase collagen I expression, at both mRNA and protein levels. Results also indicate that Fen exposure could be considered a novel risk factor for uterine fibroids through molecular mechanisms that do not directly involve the ERs.
[Gao X, Yu L, Castro L, Moore AB, et al. 2010. Toxicol Lett. 196(3):133-41] - Geographical differences of cancer incidence in Costa Rica in relation to environmental and occupational pesticide exposure
A study in Costa Rica finds heavy pesticide use in rural counties is associated with an increase risk for cancer of the corpus uteri (OR 1.78).
[Wesseling, C., et al. 1999. International Journal of Epidemiology 28:365-374.]