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In 2005, the births of three babies born in Florida with severe birth defects to mothers who all worked for Ag-Mart Produce, a company that produces chemically-treated tomatoes and other agricultural products, brought the connection between birth defects and pesticide exposure into the public consciousness. Birth defects are structural or functional abnormalities present at birth that cause physical or mental disabilities, ranging from mild to fatal. Researchers have identified thousands of different types of birth defects. Currently, birth defects are the leading cause of death for infants during the first year of life.

• Pesticide exposure and spontaneous abortion risk: A comprehensive systematic review and meta-analysis
  Backgrounds and aim
  Exposure to pesticides has been proposed as a potential contributor to adverse pregnancy outcomes, possibly through the induction of inflammation, oxidative stress, and disruption of endocrine functions. Nevertheless, the definitive link between prenatal pesticide exposure and the risk of Spontaneous Abortion (SAB) remains uncertain. The objective of this systematic review is to explore and analyze the existing evidence regarding the link between pesticide exposure and the risk of SAB.
  Methods
  A comprehensive systematic literature search was carried out on PubMed, Web of Science, and Scopus from their inception until February 2024 to identify relevant studies exploring the potential link between pesticide exposure and SAB. The frequency of SAB events and the total number of patients in each group were used to calculate the Relative Risk (RR) using the Mantel-Haenszel random-effects model. Heterogeneity among the studies was evaluated by visually inspecting the forest plot and performing the Chi-square test and I2 tests. We also used RevMan version 5.4 for Windows for the analysis. We also used the NIH tool to assess the quality of the included studies.
  Results
  The initial database search yielded 2121 results, with 1525 articles remaining after removing duplicates. After screening, 29 articles were eligible for full-text review, and 18 studies (Four case-control, eleven cohorts, three cross-sectional) were included in the meta-analysis, comprising 439,097 participants. All included studies evaluated the primary outcome, SAB. Most of the included studies were cross-sectional in design, and pesticide exposure was primarily assessed through questionnaires administered to patients. We found that most of our observational studies, precisely 12 out of the total, were deemed fair quality. Four studies were rated poor quality, while only two received a good quality rating. The analysis demonstrated a significant 41 % increase in SAB risk among pregnant women exposed to pesticides compared to pregnant women without exposure to pesticides (RR= 1.41, 95 % CI; [1.10, 1.80], P= 0.006).
  Conclusion
  Our systematic review and meta-analysis revealed a significant 41 % increase in the risk of SAB among pregnant women exposed to pesticides. However, it is essential to acknowledge the limitations of the current evidence: potential publication bias and the inability to establish causality. Moving forward, future research should focus on longitudinal studies, mechanistic insights, and risk reduction strategies. In summary, our findings underscore the urgency of public health measures to protect maternal and fetal health in pesticide-exposed areas. Rigorous research and preventive strategies are crucial to mitigate adverse outcomes.
  [Albadrani, M.S., Aljassim, M.T. and El-Tokhy, A.I. (2024) Pesticide exposure and spontaneous abortion risk: A comprehensive systematic review and meta-analysis, Ecotoxicology and Environmental Safety. Available at: https://www.sciencedirect.com/science/article/pii/S0147651324010765.]
• Exploring associations between residential exposure to pesticides and birth outcomes using the Dutch birth registry
  Maternal occupational exposure to pesticides has been linked to adverse birth outcomes but associations with residential pesticide exposures are inconclusive. To explore associations between residential exposure to specific pesticides and birth outcomes using individual level exposure and pregnancy/birth data. From all 2009-2013 singleton births in the Dutch birth registry, we selected mothers > 16 years old living in non-urban areas, who had complete address history and changed addresses at most once during pregnancy (N = 339,947). We estimated amount (kg) of 139 active ingredients (AI) used within buffers of 50, 100, 250 and 500 m around each mother's home during pregnancy. We used generalized linear models to investigate associations between 12 AIs with evidence of reproductive toxicity and gestational age (GA), birth weight (BW), perinatal mortality, child́s sex, prematurity, low birth weight (LBW), small for gestational age (SGA) and large for gestational age (LGA), adjusting for individual and area-level confounders. For the remainder 127 AIs, we used minimax concave penalty with a stability selection step to identify those that could be related to birth outcomes. Regression analyses showed that maternal residential exposure to fluroxypyr-meptyl was associated with longer GA, glufosinate-ammonium with higher risk of LBW, linuron with higher BW and higher odds of LGA, thiacloprid with lower odds of perinatal mortality and vinclozolin with longer GA. Variable selection analysis revealed that picoxystrobin was associated with higher odds of LGA. We found no evidence of associations with other AIs. Sensitivity and additional analysis supported these results except for thiacloprid. In this exploratory study, pregnant women residing near crops where fluroxypyr-meptyl, glufosinate-ammonium, linuron, vinclozolin and picoxystrobin were applied had higher risk for certain potentially adverse birth outcomes. Our findings provide leads for confirmatory investigations on these compounds and/or compounds with similar modes of action.
  [Simões, M., Vermeulen, R., Portengen, L., Janssen, N. and Huss, A., 2023. Environment International, p.108085.]
• Exposure to pesticide components causes recurrent pregnancy loss by increasing placental oxidative stress and apoptosis: a case–control study
  We investigated the plasma levels of pesticides components namely polychlorinated biphenyls (PCBs), dieldrin, dichlorodiphenyldichloroethylene (DDE), ethion, malathion, and chlorpyrifos in recurrent pregnancy loss (RPL) cases, and tested their associations with placental oxidative stress (OS) biomarkers [nitric oxide (NO.), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), and superoxide dismutase (SOD)] and with placental apoptotic/antiapoptotic indices (Bcl-2 and caspase-3), and evaluated their possible cut-off points to distinguish RPL cases. The study recruited 101 pregnant women divided into; G1 [n = 49, control, normal 1st-trimester pregnancy, normal obstetric history with at least one previous normal live birth], G2 [n = 26, cases with missed abortion (< 3 abortions) before 24 weeks of gestation], and G3 [n = 26, cases with missed abortion (≥ 3 abortions) before 24 weeks of gestation]. The plasma pesticide levels were analyzed by gas chromatography-mass spectrometry. Plasma human chorionic gonadotrophin (HCG), placental OS, Bcl-2, and caspase-3, were analyzed by their corresponding methods and kits. Plasma PCBs, DDE, dieldrin, and ethion levels were significantly higher in RPL cases than in normal pregnancies (p ≤ 0.001). These levels correlated positively with placental OS and apoptosis and negatively with plasma HCG levels. Also, these levels were reliable markers of risk to RPL. Malathion and chlorpyrifos were not detected in any of the study’s participants. Pesticides may be risk factors in cases of spontaneous RPL cases. They are associated with an increasing placental OS and placental apoptosis. Specific measures should be taken to decrease maternal exposure to these pollutants’ sources, especially in underdeveloped and developing countries.
  [El-Baz, M.A., Amin, A.F. and Mohany, K.M., 2023.Scientific Reports, 13(1), p.9147.]
• Mammary Gland Development in Male Rats Perinatally Exposed to Propiconazole, Glyphosate, or their Mixture.
  This study aimed to assess whether perinatal exposure to propiconazole (PRO), glyphosate (GLY) or their mixture (PROGLY) alters key endocrine pathways and the development of the male rat mammary gland. To this end, pregnant rats were orally exposed to vehicle, PRO, GLY, or a mixture of PRO and GLY from gestation day 9 until weaning. Male offspring were euthanized on postnatal day (PND) 21 and PND60. On PND21, GLY-exposed rats showed reduced mammary epithelial cell proliferation, whereas PRO-exposed ones showed increased ductal p-Erk1/2 expression without histomorphological alterations. On PND60, GLY-exposed rats showed reduced mammary gland area and estrogen receptor alpha expression and increased aromatase expression, whereas PRO-exposed ones showed enhanced lobuloalveolar development and increased lobular hyperplasia. However, PROGLY did not modify any of the endpoints evaluated. In summary, PRO and GLY modified the expression of key molecules and the development of the male mammary gland individually but not together.
  [Gomez, A.L., Altamirano, G.A., Alcaraz, M.R., Montemurro, M., Schierano-Marotti, G., Oddi, S.L., Culzoni, M.J., Muñoz-de-Toro, M., Bosquiazzo, V.L. and Kass, L., 2023. Environmental Toxicology and Pharmacology, p.104184.]
• Prenatal and Childhood Exposure to Organophosphate Pesticides and Behavior Problems in Adolescents and Young Adults in the CHAMACOS Study
  We previously reported associations of prenatal exposure to organophosphate (OP) pesticides with poorer neurodevelopment in early childhood and at school age, including poorer cognitive function and more behavioral problems, in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a birth cohort study in an agriculture community. We investigated the extent to which early-life exposure to OP pesticides is associated with behavioral problems, including mental health, in youth during adolescence and early adulthood. We measured urinary dialkylphosphates (DAPs), nonspecific OP metabolites, in urine samples collected from mothers twice during pregnancy (13 and 26 wk) and at five different times in their children (ages 6 months to 5 y). We assessed maternal report and youth report of externalizing and internalizing behavior problems using the Behavior Assessment System for Children, 2nd edition (BASC-2), when the youth were ages 14, 16, and 18 y. Because there was evidence of nonlinearity, we estimated associations across quartiles of DAPs and modeled repeated outcome measures using generalized estimating equations. There were 335 youths with prenatal maternal DAP measures and 14-. 16-, or 18-y BASC-2 scores. Prenatal maternal DAP concentrations (specific gravity–adjusted median, quartile 1 to quartile 3 equals 159.4Q1–Q3=159.4, 79.7 to 350.4 nanomoles per liter78.7–350.4 nmol/L) were associated with higher T-scores (more behavior problems) from maternal report, including more hyperactivity [fourth vs. first quartile of exposure lowercase beta equals 2.32β=2.32; 95% confidence interval (CI): 0.18, 4.45], aggression (lowercase beta equals 1.90β=1.90; 95% CI: 0.15, 3.66), attention problems (lowercase beta equals 2.78β=2.78; 95% CI: 0.26, 5.30), and depression (lowercase beta equals 2.66β=2.66; 95% CI: 0.08, 5.24). Associations with youth report of externalizing problems were null, and associations with depression were suggestive (fourth vs. first quartile of exposure lowercase beta equals 2.15β=2.15; 95% CI: negative 0.36−0.36, 4.67). Childhood DAP metabolites were not associated with behavioral problems. We found associations of prenatal, but not childhood, urinary DAP concentrations with adolescent/young adult externalizing and internalizing behavior problems. These findings are consistent with prior associations we have reported with neurodevelopmental outcomes measured earlier in childhood in CHAMACOS participants and suggests that prenatal exposure to OP pesticides may have lasting effects on the behavioral health of youth as they mature into adulthood, including their mental health.
  [Sagiv, S.K., Mora, A.M., Rauch, S., Kogut, K.R., Hyland, C., Gunier, R.B., Bradman, A., Deardorff, J. and Eskenazi, B., 2023. Environmental health perspectives, 131(6), p.067008.]
• Assessment of genotoxicity and oxidative stress in pregnant women contaminated to organochlorine pesticides and its correlation with pregnancy outcome
  The present study was aimed to assess the correlation between transplacental transfer of xenobiotics and resulting biochemical alterations (including genotoxicity and oxidative stress) in non-occupational pregnant women of North India along with the effect on pregnancy outcomes. Maternal and cord blood samples were collected from 221 healthy mother-infant couples and divided according to their gestational age and birth weight. Genotoxic effects in mother and cord blood were examined using comet assay. The quantitative determination of Organo-chlorine pesticides in blood serum of study population was carried out using gas chromatography-mass spectrometry (GC-MS). Notably higher Organo-chlorine pesticides levels were observed in maternal blood of preterm than term subjects for almost all of the compounds detected, with the maximum concentration found for aldrin (3.26 mg/l) in maternal blood and dieldrin (2.69 mg/l) in cord blood. The results showed a significant increment in olive tail moment, tail full length, catalase, super-oxide dismutase, and malondialdehyde levels whereas lower glutathione reductase and peroxidase were found in preterm babies when compared with term group and it varied in the order: maternal blood > cord blood. A clear trend was observed for preterm babies with their lower birth weight and cesarean mode of delivery. Therefore, reduction in birth weight in newborns may be the consequence of increased oxidative damage and genotoxicity brought about by pesticides and these markers could be employed for early detection of pesticides related ailments and toxicities. To the best of our knowledge, this was a pioneering study and it may help to increase our knowledge with regard to xenobiotic exposure in biological system and the need for stringent guidelines for agricultural use of pesticides.
  [Dwivedi, N., Mahdi, A.A., Deo, S., Ahmad, M.K. and Kumar, D. Environmental Research, 204, p.112010.]
• Glyphosate exposure in early pregnancy and reduced fetal growth: a prospective observational study of high-risk pregnancies
  Prenatal glyphosate (GLY) exposure is associated with adverse reproductive outcomes in animal studies. Little is known about the effects of GLY exposure during pregnancy in the human population. This study aims to establish baseline urine GLY levels in a high-risk and racially diverse pregnancy cohort and to assess the relationship between prenatal GLY exposure and fetal development and birth outcomes. Random first trimester urine specimens were collected from high risk pregnant women between 2013 and 2016 as part of the Indiana Pregnancy Environmental Exposures Study (PEES). Demographic and clinical data were abstracted from mother and infant medical records. Urine glyphosate levels were measured as a proxy for GLY exposure and quantified using liquid chromatography-tandem mass spectrometry. Primary outcome variables included gestation-adjusted birth weight percentile (BWT%ile) and neonatal intensive care unit (NICU) admission. Relationships between primary outcome variables and GLY exposure were assessed using univariate and multivariate linear and logistic regression models. Urine GLY levels above the limit of detection (0.1 ng/mL) were found in 186 of 187 (99%) pregnant women. Further analyses were limited to 155 pregnant women with singleton live births. The mean age of participants was 29 years, and the majority were non-Hispanic white (70%) or non-Hispanic Black (21%). The mean (± SD) urine GLY level was 3.33 ± 1.67 ng/mL. Newborn BWT%iles were negatively related to GLY (adjusted slope ± SE = -0.032 + 0.014, p = 0.023). Infants born to women living outside of Indiana’s large central metropolitan area were more likely to have a lower BWT%ile associated with mother’s first trimester GLY levels (slope ± SE = -0.064 ± 0.024, p = 0.007). The adjusted odds ratio for NICU admission and maternal GLY levels was 1.16 (95% CI: 0.90, 1.67, p = 0.233). GLY was found in 99% of pregnant women in this Midwestern cohort. Higher maternal GLY levels in the first trimester were associated with lower BWT%iles and higher NICU admission risk. The results warrant further investigation on the effects of GLY exposure in human pregnancies in larger population studies.
  [Gerona, R.R., Reiter, J.L., Zakharevich, I., Proctor, C., Ying, J., Mesnage, R., Antoniou, M. and Winchester, P.D., 2022. Environmental Health, 21(1), pp.1-12.]
• Perinatal exposure to a glyphosate pesticide formulation induces offspring liver damage
  The present study investigated the effects of perinatal exposure to glyphosate-based herbicide (GBH) in offspring's liver. Pregnant Wistar rats were exposed to GBH (70 mg glyphosate/Kg body weight/day) in drinking water from gestation day 5 to postnatal day 15. The perinatal exposure to GBH increased 45Ca2+ influx in offspring's liver. Pharmacological tools indicated a role played by oxidative stress, phospholipase C (PLC) and Akt pathways, as well as voltage-dependent Ca2+ channel modulation on GBH-induced Ca2+ influx in offspring's liver. In addition, changes in the enzymatic antioxidant defense system, decreased GSH content, lipid peroxidation and protein carbonylation suggest a connection between GBH-induced hepatotoxic mechanism and redox imbalance. The perinatal exposure to GBH also increased the enzymatic activities of transaminases and gamma-glutamyl transferase in offspring's liver and blood, suggesting a pesticide-induced liver injury. Moreover, we detected increased iron levels in liver, blood and bone marrow of GBH-exposed rats, which were accompanied by increased transferrin saturation and decreased transferrin levels in blood. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were increased in the liver of rats perinatally exposed to GBH, which were associated with. Increased phospho-p65NFκB immunocontent. Therefore, we propose that excessive amounts of iron in offspring's liver, blood and bone marrow induced by perinatal exposure to GBH may account for iron-driven hepatotoxicity, which was associated with Ca2+ influx, oxidative damage and inflammation. Further studies will clarify whether these events can ultimately impact on liver function.
  [Rieg, C.E.H., Cattani, D., Naspolini, N.F., Cenci, V.H., Cavalli, V.L.D.L.O., Jacques, A.V., Nascimento, M.V.P.D.S., Dalmarco, E.M., De Moraes, A.C.R., Santos-Silva, M.C. and Silva, F.R.M.B., 2022. Toxicology and Applied Pharmacology, 454, p.116245.]
• 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.]

• Mixtures of persistent organic pollutants are found in vital organs of late gestation human fetuses
  Persistent organic pollutants (POPs) are industrial chemicals with long half-lives. Early life exposure to POPs has been associated with adverse effects. Fetal exposure is typically estimated based on concentrations in maternal serum or placenta and little is known on the actual fetal exposure. We measured the concentrations of nine organochlorine pesticides (OCPs), ten polychlorinated biphenyl (PCB) congeners, and polybrominated diphenyl ether (PBDE) congeners by gas chromatography – tandem mass spectrometry in maternal serum, placenta, and fetal tissues (adipose tissue, liver, heart, lung and brain) in 20 pregnancies that ended in stillbirth (gestational weeks 36–41). The data were combined with our earlier data on perfluoroalkyl substances (PFASs) in the same cohort (Mamsen et al. 2019). HCB, p,p’-DDE, PCB 138 and PCB 153 were quantified in all samples of maternal serum, placenta and fetal tissues. All 22 POPs were detected in all fetal adipose tissue samples, even in cases where they could not be detected in maternal serum or placenta. Tissue:serum ratios were significantly higher in later gestations, male fetuses, and pregnancies with normal placental function. OCPs showed the highest tissue:serum ratios and PFAS the lowest. The highest chemical burden was found in adipose tissue and lowest in the brain. Overall, all studied human fetuses were intrinsically exposed to mixtures of POPs. Tissue:serum ratios were significantly modified by gestational age, fetal sex and placental function. Importantly, more chemicals were detected in fetal tissues compared to maternal serum and placenta, implying that these proxy samples may provide a misleading picture of actual fetal exposures.
  [Björvang, R.D., Vinnars, M.T., Papadogiannakis, N., Gidlöf, S., Mamsen, L.S., Mucs, D., Kiviranta, H., Rantakokko, P., Ruokojärvi, P., Lindh, C.H. and Andersen, C.Y. Chemosphere, p.131125.]
• Prenatal exposure to pesticides and risk for holoprosencephaly: a case-control study
  Pesticide exposure during susceptible windows and at certain doses are linked to numerous birth defects. Early experimental evidence suggests an association between active ingredients in pesticides and holoprosencephaly (HPE), the most common malformation of the forebrain in humans (1 in 250 embryos). No human studies to date have examined the association. This study investigated pesticides during multiple windows of exposure and fetal risk for HPE. It is hypothesized that pre-conception and early pregnancy, the time of brain development in utero, are the most critical windows of exposure. A questionnaire was developed for this retrospective case-control study to estimate household, occupational, and environmental pesticide exposures. Four windows of exposure were considered: preconception, early, mid and late pregnancy. Cases were identified through the National Human Genome Research Institute’s ongoing clinical studies of HPE. Similarly, controls were identified as children with Williams-Beuren syndrome, a genetic syndrome also characterized by congenital malformations, but etiologically unrelated to HPE. We assessed for differences in odds of exposures to pesticides between cases and controls. Findings from 91 cases and 56 controls showed an increased risk for HPE with reports of maternal exposure during pregnancy to select pesticides including personal insect repellants (adjusted odds ratio (aOR) 2.89, confidence interval (CI): 0.96–9.50) and insecticides and acaricides for pets (aOR 3.84, CI:1.04–16.32). Exposure to household pest control products during the preconception period or during pregnancy was associated with increased risk for HPE (aOR 2.60, OR: 0.84–8.68). No associations were found for occupational exposures to pesticides during pregnancy (aOR: 1.15, CI: 0.11–11.42), although exposure rates were low. Higher likelihood for HPE was also observed with residency next to an agricultural field (aOR 3.24, CI: 0.94–12.31). Observational findings are consistent with experimental evidence and suggest that exposure to personal, household, and agricultural pesticides during pregnancy may increase risk for HPE. Further investigations of gene by environment interactions are warranted.
  [Addissie, Y.A., Kruszka, P., Troia, A., Wong, Z.C., Everson, J.L., Kozel, B.A., Lipinski, R.J., Malecki, K.M. and Muenke, M., 2020. Environmental Health, 19(1), pp.1-13.]
• 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.]
• Association of Maternal Insecticide Levels With Autism in Offspring From a National Birth Cohort
  Autism is a complex neurodevelopmental disorder with a largely unknown etiology. To date, few studies have investigated prenatal exposure to toxins and risk of autism by using maternal biomarkers of exposure. Persistent organic pollutants are lipophilic halogenated organic compounds and include the insecticide dichlorodiphenyltrichloroethane (DDT), as well as its metabolite p,p′-dichlorodiphenyl dichloroethylene (p,p′-DDE), and polychlorinated biphenyls (PCBs). The objective of this study was to test whether elevated maternal levels of persistent organic pollutants are associated with autism among offspring. The investigation was derived from the Finnish Prenatal Study of Autism, a national birth cohort study based on a nested case-control design. Cases of autism among children born between 1987 and 2005 were ascertained by national registry linkages. In cases of childhood autism and matched control subjects (778 matched case-control pairs), maternal serum specimens from early pregnancy were assayed for levels of p,p′-DDE and total levels of PCBs. The odds of autism among offspring were significantly increased with maternal p,p′-DDE levels that were in the highest 75th percentile, with adjustment for maternal age, parity, and history of psychiatric disorders (odds ratio=1.32, 95% CI=1.02, 1.71). The odds of autism with intellectual disability were increased by greater than twofold with maternal p,p′-DDE levels above this threshold (odds ratio=2.21, 95% CI=1.32, 3.69). There was no association between total levels of maternal PCBs and autism. These findings provide the first biomarker-based evidence that maternal exposure to insecticides is associated with autism among offspring. Although further research is necessary to replicate this finding, this study has implications for the prevention of autism and may provide a better understanding of its pathogenesis.
  [Brown, A.S., Cheslack-Postava, K., Rantakokko, P., Kiviranta, H., Hinkka-Yli-Salomäki, S., McKeague, I.W., Surcel, H.M. and Sourander, A., 2018. American Journal of Psychiatry, 175(11), pp.1094-1101.]
• Mixed "Antiandrogenic" Chemicals at Low Individual Doses Produce Reproductive Tract Malformations in the Male Rat.
  Biomonitoring efforts have clearly shown that all humans are exposed to chemical mixtures. Of concern is whether or not exposure to mixtures during pregnancy contributes to congenital abnormalities in children even when each chemical is at an individual dose that does not affect the fetus. Here, we hypothesized that in utero exposure to a mixture of chemicals covering multiple "antiandrogenic" mechanisms of action at doses that individually have no adverse effect would result in permanent reproductive tract alterations in the male rat after birth. Pregnant dams were exposed to a range of dilutions (100%, 50%, 25%, 12.5%, 6.25%, or vehicle control) of a mixture containing pesticides, phthalates, and drugs (p, p'-DDE, linuron, prochloraz, procymidone, pyrifluquinazon, vinclozolin, finasteride, flutamide, simvastatin, and 9 phthalates [dipentyl, dicyclohexyl, di-2-ethylhexyl, dibutyl, benzyl butyl, diisobutyl, diisoheptyl, dihexyl, and diheptyl]). The top dose contained each chemical at 20% of its lowest observed adverse effect level (LOAEL) for the most sensitive male reproductive alteration following in utero exposure. We found that male rat offspring displayed a variety of neonatal, pubertal, and permanent adult effects across all dose levels. Even at the lowest dose (each chemical approximately 80-fold below lowest observed adverse effect level) there were permanent reductions in several reproductive tract tissue weights. In the top dose group, 100% of male offspring displayed permanent severe birth defects including genital malformations. Despite acting via 5 different molecular initiating events, a mixture of 18 chemicals can combine to produce additive effects even when each compound is at a relatively low dose.
  [Conley JM, Lambright CS, Evans N, Cardon M, et al. Toxicol Sci. 164(1):166-178]
• Prenatal Exposure to Ambient Pesticides and Preterm Birth and Term Low Birthweight in Agricultural Regions of California.
  Findings from studies of prenatal exposure to pesticides and adverse birth outcomes have been equivocal so far. We examined prenatal exposure to agricultural pesticides in relation to preterm birth and term low birthweight, respectively, in children born between 1998 and 2010, randomly selected from California birth records. We estimated residential exposure to agriculturally applied pesticides within 2 km of residential addresses at birth by pregnancy trimester for 17 individual pesticides and three chemical classes (organophosphates, pyrethroids, and carbamates). Among maternal addresses located within 2 km of any agricultural pesticide application, we identified 24,693 preterm and 220,297 term births, and 4412 term low birthweight and 194,732 term normal birthweight infants. First or second trimester exposure to individual pesticides (e.g., glyphosates, paraquat, imidacloprid) or exposure to 2 or more pesticides in the three chemical classes were associated with a small increase (3⁻7%) in risk for preterm birth; associations were stronger for female offspring. We did not find associations between term low birthweight and exposure to pesticides other than myclobutanil (OR: 1.11; 95% CI: 1.04⁻1.20) and possibly the pyrethroids class. Our improved exposure assessment revealed that first and second trimester exposure to pesticides is associated with preterm delivery but is rarely linked with term low birthweight.
  [Ling C, Liew Z, von Ehrenstein OS, Heck JE, et al. 2018. Toxics. 6(3). pii: E41]
• Agricultural pesticide use and adverse birth outcomes in the San Joaquin Valley of California
  Virtually all agricultural communities worldwide are exposed to agricultural pesticides. Yet, the health consequences of such exposure are poorly understood, and the scientific literature remains ambiguous. Using individual birth and demographic characteristics for over 500 000 birth observations between 1997–2011 in the agriculturally dominated San Joaquin Valley, California, we statistically investigate if residential agricultural pesticide exposure during gestation, by trimester, and by toxicity influences birth weight, gestational length, or birth abnormalities. Overall, our analysis indicates that agricultural pesticide exposure increases adverse birth outcomes by 5–9%, but only among the population exposed to very high quantities of pesticides (e.g., top 5th percentile, i.e., ~4200 kg applied over gestation). Thus, policies and interventions targeting the extreme right tail of the pesticide distribution near human habitation could largely eliminate the adverse birth outcomes associated with agricultural pesticide exposure documented in this study.
  [Larsen, A.E., Gaines, S.D. and Deschênes, O., 2017. 8(1), pp.1-9.]
• Association of reproductive disorders and male congenital anomalies with environmental exposure to endocrine active pesticides.
  There is growing evidence that environmental exposure to pesticides may increase the risk of developing reproductive and developmental disorders. This study determined the prevalence and risk of developing gestational disorders and male congenital genitourinary malformations in areas with distinct exposure to pesticides, many of them with potential endocrine disrupting properties. A population-based case-control study was carried out on pregnant women and male children living in ten health districts of Andalusia classified as areas of high and low environmental exposure to pesticides according to agronomic criteria. The study population included 45,050 cases and 950,620 controls matched for age and health district. Data were collected from computerized hospital records between 1998 and 2005. Prevalence rates and risk of miscarriage, low birth weight, hypospadias, cryptorchidism and micropenis were significantly greater in areas with higher use of pesticides in relation to those with lower use, thus supporting and extending previous information.
  [García J, Ventura MI, Requena M, Hernández AF, et al. 2017. Reprod Toxicol. 71:95-100.]
• Combined exposure to low doses of pesticides causes decreased birth weights in rats
  Decreased birth weight is a common effect of many pesticides in reproductive toxicity studies, but there are no empirical data on how pesticides act in combination on this endpoint. We hypothesized that a mixture of six pesticides (cyromazine, MCPB, pirimicarb, quinoclamine, thiram, and ziram) would decrease birth weight, and that these mixture effects could be predicted by the Dose Addition model. Data for the predictions were obtained from the Draft Assessment Reports of the individual pesticides. A mixture of equi-effective doses of these pesticides was tested in two studies in Wistar rats, showing mixture effects in good agreement with the additivity predictions. Significantly lower birth weights were observed when compounds were present at individual doses below their no-observed adverse effect levels (NOAELs). These results emphasize the need for cumulative risk assessment of pesticides to avoid potentially serious impact of mixed exposure on prenatal development and pregnancy in humans.
  [Hass U, Christiansen S, Axelstad M, Scholze M, Boberg J. 2017. Reprod Toxicol. 72:97-105]
• Exposure to PFOA and PFOS and fetal growth: a critical merging of toxicological and epidemiological data.
  Toxicological and epidemiological evidence on the association between perfluorooctanoic acid (PFOA) or perfluorooctane sulfonic acid (PFOS) and birth/fetal weight was assessed. An extensive search for toxicological information in rats and mice, and a systematic search for epidemiological evidence were conducted. The linear regression coefficient (LRC) of birth weight (BrthW) on PFOA/PFOS was considered, and separate random effects meta-analyses for untransformed (i.e. not mathematically transformed) and log-transformed values were performed. Toxicological evidence: PFOA: 12 studies (21 datasets) in mice showed statistically significant lower birth/fetal weights from 5 mg/kg body weight per day. PFOS: most of the 13 studies (19 datasets) showed lower birth/fetal weights following in utero exposure. Epidemiological evidence: Sixteen articles were considered. The pooled LRC for a 1 ng/mL increase in untransformed PFOA (12 studies) in maternal plasma/serum was -12.8 g (95% CI -23.2; 2.4), and -27.1 g (95% CI -50.6; -3.6) for an increase of 1 loge ng/mL PFOA (nine studies). The pooled LRC for untransformed PFOS (eight studies) was -0.92 g (95%CI -3.4; 1.6), and for an increase of 1 loge ng/mL was -46.1(95% CI -80.3; -11.9). No consistent pattern emerged for study location or timing of blood sampling. Epidemiological and toxicological evidence suggests that PFOA and PFOS elicit a decrease in BrthW both in humans and rodents. However, the effective animal extrapolated serum concentrations are 102-103 times higher than those in humans. Thus, there is no quantitative toxicological evidence to support the epidemiological association, thus reducing the biological plausibility of a causal relationship.
  [Negri E, Metruccio F, Guercio V, Tosti L, et al. 2017. Crit Rev Toxicol. 47(6):482-508]
• Glyphosate and Paraquat in Maternal and Fetal Serums in Thai Women
  This longitudinal study measured the glyphosate and paraquat concentrations found in maternal and umbilical cord serum in 82 pregnant women who gave birth in three provinces of Thailand.Through questionnaires and biological samples collected at childbirth, factors such as personal characteristics, family members occupation, agricultural activities, and herbicide use in agricultural work were evaluated as predictors of glyphosate and paraquat levels in the pregnant women. Statistical analysis used univariate and binary multiple logistic regression, where the outcome was the probability of exposure to paraquat or glyphosate above the limit of detection associated with occupation and household factors.The glyphosate concentrations in the pregnant women's serum at childbirth (median: 17.5, range: 0.2-189.1 ng/mL) were significantly higher (P < .007) than those in the umbilical cord serum (median: 0.2, range: 0.2-94.9 ng/mL). However, the paraquat concentrations in the serum of the pregnant women at childbirth (83% ≤limit of detection [LOD], with maximum of 58.3 ng/mL) were similar to those in the umbilical cord serum (80% <LOD, with maximum of 47.6 ng/mL). Women with glyphosate levels >LOD in serum at childbirth were 11.9 times more likely to report work as an agriculturist (P < .001), 3.7 times more likely to live near agricultural areas (P = .006), and 5.9 times more likely to have a family member who worked in agriculture (P < .001). The only factors affecting paraquat exposures in pregnant women at childbirth were reporting the agricultural activity of digging in farm soil and working in the agricultural fields in the third trimester of pregnancy.These results show that pregnant women who work in agriculture or live in families that work in agriculture have higher exposures to the herbicides glyphosate and paraquat. The potential for long-term health impacts of these prenatal exposures to children should be evaluated, and greater regulation of the sale and use of herbicides should be considered in Thailand.
  [Kongtip P, Nankongnab N, Phupancharoensuk R, et al. 2017. J Agromedicine. 22(3):282-289. ]
• Neurodevelopmental disorders and pesticide exposure: the northeastern Italian experience.
  Endocrine disruptors are chemical substances that can interfere with the endocrine system. They include pesticides, metals, additives or contaminants in food, and personal care products. Pesticides are the only substances intentionally released into our environment to kill living things (herbicides, insecticides, fungicides, rodenticides). There is scientific evidence that exposure to pesticides produces a growing number of human pathological conditions; among these, stillbirth is an emerging issue.
  [Roncati L, Pusiol T, Piscioli F, Lavezzi AM. Arch Toxicol. 91(2):603-604.]
• Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in human breast milk and associated health risks to nursing infants in Northern Tanzania
  This is the first study to report organochlorines (OCs), including chlorinated pesticides (OCPs) and polychlorinated biphenyls (PCBs) in human milk from Tanzania. The main aims of this study were to assess the level of contamination and the possible health risks related to OC exposure in nursing infants from the Northern parts of Tanzania. Ninety-five healthy mother-infant couples attending Mount Meru Regional Referral Hospital (MMRRH), Arusha, Tanzania, were assessed for associations between maternal/infant characteristics, i.e. mother's age, BMI, gestational weight gain, occupation, residence and fetal growth parameters and breast milk levels of OCPs, such as dichlorodiphenyltrichloroethane (DDT) and its metabolites, dieldrin and PCBs. p,p'-DDE and p,p'-DDT were detected in 100% and 75% of the breast milk samples, respectively, and ranged between 24 and 2400ng/g lipid weight (lw) and
  [Müller MH, Polder A, Brynildsrud OB, Karimi M, et al. 2017. Environ Res. 154:425-434]
• Potential short-term neurobehavioral alterations in children associated with a peak pesticide spray season: The Mother’s Day flower harvest in Ecuador
  

  Exposures to cholinesterase inhibitor pesticides (e.g. organophosphates) have been associated with children’s neurobehavioral alterations, including attention deficit and impulsivity. Animal studies have observed transient alterations in neurobehavioral performance in relation to cholinesterase inhibitor pesticide exposures; however, limited evidence exists regarding transient effects in humans. We estimated the associations between neurobehavioral performance and time after Mother’s Day flower harvest (the end of a heightened pesticide usage period) among 308 4-to 9-year-old children living in floricultural communities in Ecuador in 2008 who participated in the ESPINA study. Children’s neurobehavior was examined once (NEPSY-II: 11 subtests covering 5 domains), between 63 and 100 days (SD: 10.8 days) after Mother’s Day harvest (blood acetylcholinesterase activity levels can take 82 days to normalize after irreversible inhibition with organophosphates). The mean (SD) neurobehavioral scaled scores across domains ranged from 6.6 (2.4) to 9.9 (3.3); higher values reflect greater performance. Children examined sooner after Mother’s Day had lower neurobehavioral scores than children examined later, in the domains of (score difference per 10.8 days, 95%CI): Attention/Inhibitory Control (0.38, 0.10–0.65), Visuospatial Processing (0.60, 0.25–0.95) and Sensorimotor (0.43, 0.10–0.77). Scores were higher with longer time post-harvest among girls (vs. boys) in Attention/Inhibitory Control. Our findings, although cross-sectional, are among the first in non-worker children to suggest that a peak pesticide use period may transiently affect neurobehavioral performance, as children examined sooner after the flower harvest had lower neurobehavioral performance than children examined later. Studies assessing pre- and post-exposure measures are needed.

  
  [Suarez-Lopez, J.R., Checkoway, H., Jacobs Jr, D.R., Al-Delaimy, W.K. and Gahagan, S., 2017. Neurotoxicology, 60, pp.125-133.]
• Relationship between pesticide exposure and adverse pregnancy outcomes among reproductive couples in rural areas of China
  To analyze the association between pesticide exposure and adverse pregnancy outcomes in women from the rural areas of China. Data of "National Free Preconception Health Examination Project (NFPHEP)" from January 2010 to December 2012 was used for analysis. A total of 248 501 families that were planning to deliver a baby in the next 6 months were enrolled. Data on paternal exposure to pesticides before or during pregnancy was collected through questionnaires, with related outcomes on pregnancy recorded by doctors. Among all the 248 501 participants, 1 806 (0.74%) women and 2 653 (1.09%) men reported to have been exposed to pesticide before pregnancy, with 505 (0.21%) reported of having been exposed to pesticide during the period of pregnancy. Maternal exposure to pesticide was found a risk factor related to stillbirth (OR=3.37, 95%CI: 2.05-5.55), peculiar smell pregnancy (OR=3.17, 95%CI:1.18-8.55) and low birth weight (OR=7.56, 95% CI: 5.36-10.66). Paternal exposure to pesticide was also found related to miscarriage (OR=1.37, 95% CI: 1.03-1.80), low birth weight (OR=3.65, 95% CI:1.51-8.84), or giant infant (OR=0.64, 95%CI: 0.44-0.93). Maternal exposure to pesticide during pregnancy appeared a risk factor on miscarriage (OR=4.65, 95% CI: 3.47-6.24). Other adverse outcomes on pregnancy would include premature birth and high birth weight.Parental pesticide exposure appeared a risk factor on stillbirth, peculiar smell pregnancy, low birth weight and miscarriage.
  [Qu YM, Chen S, Li JJ, Jin RR, et al. 2017. Zhonghua Liu Xing Bing Xue Za Zhi. 38(6):732-736]
• Association between Exposure to Endocrine Disruptors in Drinking Water and Preterm Birth, Taking Neighborhood Deprivation into Account: A Historic Cohort Study.
  The relationship between preterm birth (PTB) and endocrine disruptor exposure in drinking-water has only occasionally been studied. The objective of this work was to investigate the relation between exposure to atrazine metabolites, or atrazine/nitrate mixtures, in drinking-water during pregnancy and prevalence of PTB neonates, while taking neighborhood deprivation into account. A historic cohort study in Deux-Sèvres, France, between 2005 and 2010 with a multiple imputation model for data of exposure to atrazine metabolites and a logistic regression were carried out. The study included 13,654 mother/neonate pairs living in 279 different census districts. The prevalence of PTB was 4%. The average atrazine metabolite concentration was 0.019 ± 0.009 (0.014-0.080) µg/L and 39% of mothers lived in less deprived areas. The individual data were associated with risk of PTB. The risk of PTB when exposed to highest concentration of atrazine metabolite adjusted for confounders, was ORa 1.625 95% CI [0.975; 2.710]. Taking, or not, neighborhood deprivation into account did not change the result. Exposure to atrazine/nitrate mixtures remained non-significant. Even if we took neighborhood deprivation into account, we could not show a significant relationship between exposure to atrazine metabolites, or mixtures, in drinking-water during the second trimester of pregnancy and PTB.
  [Albouy-Llaty M, Limousi F, Carles C, Dupuis A, et al. 2016. Int J Environ Res Public Health.13(8).]
• Environmental Chemicals in an Urban Population of Pregnant Women and Their Newborns from San Francisco
  Exposures to environmental pollutants in utero may increase the risk of adverse health effects. We measured the concentrations of 59 potentially harmful chemicals in 77 maternal and 65 paired umbilical cord blood samples collected in San Francisco during 2010-2011, including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), hydroxylated PBDEs (OH-PBDEs), and perfluorinated compounds (PFCs) in serum and metals in whole blood. Consistent with previous studies, we found evidence that concentrations of mercury (Hg) and lower-brominated PBDEs were often higher in umbilical cord blood or serum than in maternal samples (median cord:maternal ratio > 1), while for most PFCs and lead (Pb), concentrations in cord blood or serum were generally equal to or lower than their maternal pair (median cord:maternal ratio ≤ 1). In contrast to the conclusions of a recent review, we found evidence that several PCBs and OCPs were also often higher in cord than maternal serum (median cord:maternal ratio > 1) when concentrations are assessed on a lipid-adjusted basis. Our findings suggest that for many chemicals, fetuses may experience higher exposures than their mothers and highlight the need to characterize potential health risks and inform policies aimed at reducing sources of exposure.
  [Morello-Frosch R, Cushing LJ, Jesdale BM, Schwartz JM, et al. 2016. Environ Sci Technol. 50(22):12464-12472]
• Glyphosate and adverse pregnancy outcomes, a systematic review of observational studies
  A study in frog and chicken embryos, and reports of a high incidence of birth defects in regions of intensive GM-soy planting have raised concerns on the teratogenic potential of glyphosate-based herbicides. These public concerns prompted us to conduct a systematic review of the epidemiological studies testing hypotheses of associations between glyphosate exposure and adverse pregnancy outcomes including birth defects.A case-control study on the association between pesticides and congenital malformations in areas of extensive GM soy crops in South America, and reports on the occurrence of birth defects in these regions were reviewed. The search found ten studies testing associations between glyphosate and birth defects, abortions, pre-term deliveries, small for gestational date births, childhood diseases or altered sex ratios. Two additional studies examined changes of time-to-pregnancy in glyphosate-exposed populations. Except for an excess of Attention Deficit Hyperactivity Disorder - ADHD (OR = 3.6, 1.3-9.6) among children born to glyphosate appliers, no significant associations between this herbicide and adverse pregnancy outcomes were described. Evidence that in South American regions of intensive GM-soy planting incidence of birth defects is high remains elusive.Current epidemiological evidence, albeit limited to a few studies using non-quantitative and indirect estimates and dichotomous analysis of exposures, does not lend support to public concerns that glyphosate-based pesticides might pose developmental risks to the unborn child. Nonetheless, owing to methodological limitations of existing analytical observational studies, and particularly to a lack of a direct measurement (urine and/or blood levels), or an indirect estimation of exposure that has proven valid, these negative findings cannot be taken as definitive evidence that GLY, at current levels of occupational and environmental exposures, brings no risk for human development and reproduction.
  [de Araujo JS, Delgado IF, Paumgartten FJ. 2016. BMC Public Health. 16:472]
• Associations of maternal organophosphate pesticide exposure and PON1 activity with birth outcomes in SAWASDEE birth cohort, Thailand.
  Prenatal organophosphate (OP) pesticide exposure has been reported to be associated with adverse birth outcomes and neurodevelopment. However, the mechanisms of toxicity of OP pesticides on human fetal development have not yet been elucidated. Our pilot study birth cohort, the Study of Asian Women and Offspring's Development and Environmental Exposures (SAWASDEE cohort) aimed to evaluate environmental chemical exposures and their relation to birth outcomes and infant neurodevelopment in 52 pregnant farmworkers in Fang district, Chiang Mai province, Thailand. A large array of data was collected multiple times during pregnancy including approximately monthly urine samples for evaluation of pesticide exposure, three blood samples for pesticide-related enzyme measurements and questionnaire data. This study investigated the changes in maternal acetylcholinesterase (AChE) and paraoxonase 1 (PON1) activities and their relation to urinary diakylphosphates (DAPs), class-related metabolites of OP pesticides, during pregnancy. Maternal AChE, butyrylcholinesterase (BChE) and PON1 activities were measured three times during pregnancy and urinary DAP concentrations were measured, on average, 8 times from enrollment during pregnancy until delivery. Among the individuals in the group with low maternal PON1 activity (n=23), newborn head circumference was negatively correlated with log10 maternal ∑DEAP and ∑DAP at enrollment (gestational age=12±3 weeks; β=-1.0 cm, p=0.03 and β=-1.8 cm, p<0.01, respectively) and at 32 weeks pregnancy (β=-1.1cm, p=0.04 and β=-2.6 cm, p=0.01, respectively). Furthermore, among these mothers, newborn birthweight was also negatively associated with log10 maternal ∑DEAP and ∑DAP at enrollment (β=-219.7 g, p=0.05 and β=-371.3g, p=0.02, respectively). Associations between maternal DAP levels and newborn outcomes were not observed in the group of participants with high maternal PON1 activity. Our results support previous findings from US birth cohort studies. This is the first study to report the associations between prenatal OP pesticide exposure and birth outcomes in Thailand.
  [Naksen W, Prapamontol T, Mangklabruks A, Chantara S, et al. 2015. Environ Res. 142:288-96.]
• Is Hypospadias Associated with Prenatal Exposure to Endocrine Disruptors? A French Collaborative Controlled Study of a Cohort of 300 Consecutive Children Without Genetic Defect.
  This study's aim was to identify the role of occupational and environmental exposures to EDCs in nongenetic isolated hypospadias. A total of 408 consecutive children with isolated hypospadias and 302 normal boys were prospectively included (2009-2014) in a multi-institutional study in the south of France, the area of the country with the highest prevalence of hypospadias surgery. In patients without AR, SRD5A2, and MAMLD1 mutations, parental occupational and professional exposures to EDCs were evaluated based on European questionnaire QLK4-1999-01422 and a validated job-exposure matrix for EDCs.Fetal exposure to EDCs around the window of genital differentiation was more frequent in the case of hypospadias. The substances were paints/solvents/adhesives (16.0%), detergents (11.0%), pesticides (9.0%), cosmetics (5.6%), and industrial chemicals (4.0%). Jobs with exposure were more frequent in mothers of hypospadiac boys, especially cleaners, hairdressers, beauticians, and laboratory workers. Paternal job exposure was more frequent in the cases of hypospadias. Industrial areas, incinerators, and waste areas were more frequent within a 3-km radius for mothers of hypospadiac boys . Association of occupational and environmental exposures increases this risk.This multicenter prospective controlled study with a homogeneous cohort of hypospadiac boys without genetic defects strongly suggests that EDCs are a risk factor for hypospadias through occupational and environmental exposure during fetal life. The association of various types of exposures may increase this risk.
  [Kalfa N, Paris F, Philibert P, Orsini M, et al.2015. Eur Urol.pii: S0302-2838(15)00409-1]
• Maternal occupational pesticide exposure and risk of congenital heart defects in the national birth defects prevention study.
  Congenital heart defects (CHDs) are common birth defects, affecting approximately 1% of live births. Pesticide exposure has been suggested as an etiologic factor for CHDs, but previous results were inconsistent.Study examined maternal occupational exposure to fungicides, insecticides, and herbicides for 3328 infants with CHDs and 2988 unaffected control infants of employed mothers using data for 1997 through 2002 births from the National Birth Defects Prevention Study, a population-based multisite case-control study. Maternal occupational exposure to pesticides was not associated with CHDs overall. In examining specific CHD subtypes compared with controls, some novel associations were observed with higher estimated pesticide exposure: insecticides only and secundum atrial septal defect; both insecticides and herbicides and hypoplastic left heart syndrome, as well as pulmonary valve stenosis; and insecticides, herbicides, and fungicides and tetralogy of Fallot (TOF). Broad pesticide exposure categories were not associated with CHDs overall, but examining specific CHD subtypes revealed some increased odds ratios. These results highlight the importance of examining specific CHDs separately. Because of multiple comparisons, additional work is needed to verify these associations.
  [Rocheleau CM, Bertke SJ, Lawson CC, et al. 2015. Birth Defects Res A Clin Mol Teratol.103(10):823-33.]
• Early pregnancy agricultural pesticide exposures and risk of gastroschisis among offspring in the San Joaquin Valley of California.
  Prevalence of gastroschisis has inexplicably been increasing over the past few decades. The intent of this study was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis. Authors used population-based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California. Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects. Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1-5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking.
  [Shaw GM, Yang W, Roberts E, et al. 2014. Birth Defects Res A Clin Mol Teratol.100(9):686-94]
• Hypospadias in offspring is associated with chronic exposure of parents to organophosphate and organochlorine pesticides.
  Authors have currently evaluated the possible association between hypospadias and exposure to organophosphorus (OP) and organochlorine (OC) pesticides. here, they measured the dialkyl phosphate metabolites of organophosphate pesticides (DAPs) in the hair and blood, as well as OC pesticides (DDTs, HCHs) in the hair collected from children with hypospadias and their parents. The concentration of HCHs in the hair samples obtained from mothers was higher than that previously reported for people working in open cultivations, while the concentration of DDTs in the hair samples obtained from mothers, fathers and their children with hypospadias was much higher than that previously reported for occupationally exposed individuals. The DMP concentration in hair samples obtained from mothers was much higher not only from that reported for the general population, but even higher than that reported for occupationally exposed individuals. Furthermore, SUMDEPs and SUMDAPs in the hair samples obtained both from the hypospadiac boys, as well as from their parents were higher than the corresponding values previously reported for the general population. Our study supports the hypothesis that organophosphate and organochlorine pesticide exposure may be a potential risk factor for hypospadias.
  [Michalakis M, Tzatzarakis MN, et al. 2014. Toxicol Lett. 230(2):139-45.]
• Maternal periconceptional occupational exposure to pesticides and selected musculoskeletal birth defects.
  This population-based U.S. study investigated the association between major musculoskeletal malformations and periconceptional maternal occupational pesticide exposure for a wide range of occupations. We conducted a multi-site case-control analysis using data from the National Birth Defects Prevention Study among employed women with due dates from October 1, 1997 through December 31, 2002. Cases included 871 live-born, stillborn, or electively terminated fetuses with isolated craniosynostosis, gastroschisis, diaphragmatic hernia, or transverse limb deficiencies. Controls included 2857 live-born infants without major malformations. Using self-reported maternal occupational information, an industrial hygienist used a job-exposure matrix and expert opinion to evaluate the potential for exposure to insecticides, herbicides or fungicides for each job held during one month pre-conception through three months post-conception. Exposures analyzed included any exposure (yes/no) to pesticides, to insecticides only, to both insecticides and herbicides (I+H) and to insecticides, herbicides and fungicides (I+H+F). Occupational exposure to I+H+F was associated with gastroschisis among infants of women aged 20 years or older, but not for women under age 20. No significant associations for the other defects were found. Additional research is needed to validate these findings in a separate population.
  [Kielb C, Lin S, Herdt-Losavio M, Bell E, et al. 2014. Int J Hyg Environ Health. 217(2-3):248-54.]
• Maternal periconceptional occupational pesticide exposure and neural tube defects.
  Adverse associations between maternal pesticide exposure and neural tube defects (NTDs) have been suggested but not consistently observed. This study used data from the multisite National Birth Defects Prevention Study to examine associations between maternal periconceptional (1 month preconception through 2 months postconception) occupational pesticide exposure and NTDs. Mothers of 502 NTD cases and 2950 unaffected live-born control infants with estimated delivery dates from 1997 through 2002 were included. Duration, categorical intensity scores, and categorical frequency scores for pesticide classes (e.g., insecticides) were assigned using a modified, literature-based job-exposure matrix and maternal-reported occupational histories. Positive, but marginally significant or nonsignificant, aORs were observed for exposure to insecticides + herbicides for all NTD cases combined and for spina bifida alone. Similarly, positive aORs were observed for any exposure and cumulative exposure to insecticides + herbicides + fungicides and anencephaly alone and encephalocele alone. All other aORs were near unity. Pesticide exposure associations varied by NTD subtype and pesticide class. Several aORs were increased, but not significantly. Future work should continue to examine associations between pesticide classes and NTD subtypes using a detailed occupational pesticide exposure assessment and examine pesticide exposures outside the workplace.
  [Makelarski JA, Romitti PA, Rocheleau CM, et al.2014. Birth Defects Res A Clin Mol Teratol.100(11):877-86.]
• Maternal Residential Atrazine Exposure and Risk for Choanal Atresia and Stenosis in Offspring
  Objective
  To assess the relationship between estimated residential maternal exposure to atrazine during pregnancy and risk for choanal atresia or stenosis in offspring.

  Study Design
  Data for 280 nonsyndromic cases and randomly selected, population-based controls delivered during 1999 to 2008 were obtained from the Texas Birth Defects Registry. County-level estimates of atrazine levels obtained from the United States Geological Survey were assigned to cases and controls based on maternal county of residence at delivery. Unconditional logistic regression was used to assess the relationship between maternal residential atrazine exposure and risk for choanal atresia or stenosis in offspring.

  Results
  Compared to offspring of mothers with low levels of estimated residential atrazine exposure, those with high levels had nearly a two-fold increase in risk for choanal atresia or stenosis (adjusted odds ratio: 1.79, 95% confidence interval: 1.17–2.74). A significant linear trend was also observed with increasing levels of atrazine exposure (adjusted P = 0.002).

  Conclusions
  A link between maternal exposure to endocrine disruptors, such as atrazine, and choanal atresia risk is plausible based on previous findings. Our results further support this hypothesis.
  [Agopian, A.J. et al. (2014) Maternal residential atrazine exposure and risk for choanal atresia and stenosis in offspring, The Journal of Pediatrics. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105141/. ]

• Residential agricultural pesticide exposures and risk of selected congenital heart defects among offspring in the San Joaquin Valley of California.
  Study examined the potential association of congenital heart defects with residential proximity to commercial agricultural pesticide applications in the San Joaquin Valley, California. Study subjects included 569 heart defect cases and 785 non-malformed controls born from 1997 to 2006 whose mothers participated in a population-based case-control study. Associations with any versus no exposure to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for relevant covariates, for 8 heart defect phenotypes that included ≥ 50 cases and pesticide exposures with ≥ 5 exposed cases and controls, which resulted in 235 comparisons. 38% of cases and controls were classified as exposed to pesticides within a 500 m radius of mother's address during a 3-month periconceptional window. Adjusted odds ratios (AORs) with 95% CIs excluding 1.0 were observed for 18 comparisons; all were >1 and ranged from 1.9 to 7.1. They included tetralogy of Fallot and neonicotinoids; hypoplastic left heart syndrome and strobins; coarctation of the aorta and pyridazinones; pulmonary valve stenosis and bipyridyliums and organophosphates; ventricular septal defects and avermectins and pyrethroids; and atrial septal defects and dichlorphenoxy acid or esters, organophosphates, organotins, and pyrethroids. No AORs met both of these criteria for d-transposition of the great arteries or heterotaxia.Most pesticides were not associated with increased risk of specific heart defect phenotypes. For the few that were associated, results should be interpreted with caution until replicated in other study populations.
  [Carmichael SL, Yang W, Roberts E, et al. 2014. Environ Res. 135:133-8.]
• Risk of cryptorchidism among sons of horticultural workers and farmers in Denmark
  Previous studies indicate an increased risk of cryptorchidism, incomplete testicular descent, among sons of women working with pesticides. This study assessed the risk of cryptorchidism among boys of parents employed as horticultural workers and farmers using nationwide registers on occupation and cryptorchidism.The cohort consisted of >600 000 boys born in Denmark from 1980-2007 with a parent in employment during pregnancy. These boys were followed for cryptorchidism from 1980-2009 comparing risks among sons of horticultural workers and farmers with sons of parents in other occupations. Sons of maternal farmers were at increased risk of cryptorchidism compared to boys of mothers in other occupations. Paternal occupation as farmer was unrelated to the risk among sons. Maternal occupation as a horticultural worker was associated with a non-significantly increased risk. A similar association was found for paternal horticultural workers. Sons of maternal farmers or horticultural workers who likely worked in the first trimester were not at increased risk of cryptorchidism. This nationwide cohort study found a slightly increased risk of cryptorchidism in sons of maternal horticultural workers and farmers. However, subgroup analyses indicated similar findings for paternal horticultural workers, and no association for women likely working in the first trimester. The main findings should therefore be interpreted with caution.
  [Jørgensen KT, Jensen MS, Toft GV,et al. 2014. Scand J Work Environ Health. 40(3):323-30]
• 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]
• Association of selected persistent organic pollutants in the placenta with the risk of neural tube defects
  Placental concentrations of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers were analyzed in 80 fetuses or newborns with neural tube defects (NTDs). A dose–response relationship was observed between PAH levels and the risk of NTDs.
  [Ren, A. et al. 2011. PNAS. 108 (31) 12770-12775]
• Urinary Biomarkers of Prenatal Atrazine Exposure and Adverse Birth Outcomes in the PELAGIE Birth Cohort
  This study, a case-cohort design nested in a prospective birth cohort conducted in the Brittany region from 2002 through 2006, collected maternal urine samples to examine pesticide exposure biomarkers before the 19th week of gestation. Quantifiable levels of atrazine were found in urine samples from 5.5% of 579 pregnant women, and various metabolites were identified in 20-40% of samples. The presence versus absence of quantifiable levels of atrazine or a specific atrazine metabolite was associated with fetal growth restriction and small head circumference. Head circumference was also inversely associated with the presence of the herbicide metolachlor. Daily News
  [Chevrier C, Limon G, Monfort C, Rouget F, Garlantézec R, Petit C, et al. 2011. Environ Health Perspect. doi:10.1289/ehp.1002775]
• Agricultural-related chemical exposures, season of conception, and risk of gastroschisis in Washington State
  Reserchers conducted a retrospective, case-controlled study using Washington State Birth Certificate and US Geological Survey databases. Cases included all live-born singleton infants with gastroschisis. Distance between a woman's residence and site of elevated exposure to agrichemicals was calculated. Gastroschisis occurred more frequently among those who resided <25 km from a site of high atrazine concentration (odds ratio, 1.6). Risk was related inversely to the distance between the maternal residence and the closest toxic atrazine site.
  [Waller, S.A., Paul, K., Peterson, S.E. andHitti, J.E. . 2010. Am J Obst Gyn. 202(3): 241.e1–241.e6.]
• Chlorpyrifos Exposure and Urban Residential Environment Characteristics as Determinants of Early Childhood Neurodevelopment
  

  We evaluated whether neighborhood characteristics correlated with early neurodevelopment and whether these characteristics confounded the previously reported association between exposure to chlorpyrifos (an organophosphate insecticide) and neurodevelopment. We obtained prenatal addresses, chlorpyrifos exposure data, and 36-month Psychomotor Development Index (PDI) and Mental Development Index (MDI) scores for a birth cohort in New York City (born 1998–2002). We used data from the 2000 US Census to estimate measures of physical infrastructure, socioeconomic status, crowding, demographic composition, and linguistic isolation for 1-kilometer network areas around each child's prenatal address. Generalized estimating equations were adjusted for demographics, maternal education and IQ, prenatal exposure to tobacco smoke, caretaking environment quality, and building dilapidation. Of 266 children included as participants, 47% were male, 59% were Dominican, and 41% were African American. For each standard deviation higher in neighborhood percent poverty, the PDI score was 2.6 points lower (95% confidence interval [CI] = −3.7, −1.5), and the MDI score was 1.7 points lower (95% CI = −2.6, −0.8). Neighborhood-level confounding of the chlorpyrifos-neurodevelopment association was not apparent. Neighborhood context and chlorpyrifos exposure were independently associated with neurodevelopment, thus providing distinct opportunities for health promotion.
  [Lovasi , G. et al. 2010. Am J Public Health. AJPH.2009.168419v1]

• Correlation Between Pesticide Use in Agriculture and Adverse Birth Outcomes in Brazil: An Ecological Study
  This ecological study analyzed the association between pesticide use and prematurity, low weight and congenital abnormality at birth, infant death by congenital abnormality, and fetal death in Brazil in 2001. Simple linear regression analysis has determined a positive association between pesticide use and prematurity, low birth weight, and congenital abnormality. The association between pesticide use and low birth weight (p = 0.045) and, congenital abnormality (p = 0.004) and infant death rate by congenital abnormality (p = 0.039) remained after the adjustment made by the proportion of pregnant women with a low number of prenatal care visits. Brazil accounts for approximately 50% of the agricultural pesticides consumed in Latin America (Agencia Nacional de Vigilancia Sanitaria 2005). Its use increased after the implementation of agriculture financing in the 70’s (Waissmann 2007) and, recently, with the implementation of the National Family Farm Program – PRONAF (Kageyama 2003). From 1995 to 2005, herbicides, insecticides, fungicides, and acaricides were, in decreasing order, the most consumed types of pesticides in the country especially in soy, sugarcane, cotton, corn, and citrus crops (Ministerio da Agricultura, Pecuaria e Abastecimento 2005). Exposure to agricultural pesticides in the Brazilian population has been monitored through the National Program for Food Residues Analysis – PARA, which was implemented in 2001. This program was able to identify nonauthorized agricultural pesticides or pesticide levels above the maximum limit permitted in food samples. Some pesticides detected by the PARA, such as endosulfan, acephate, chlorpyrifos, dichlorvos, and methamidophos (Agencia Nacional de Vigilancia Sanitaria 2009), are the active ingredients for the development of endocrine disruption and reproductive toxicity, therefore increasing risks of adverse events on the human fetus (Peiris-John and Wickremasinghe 2008). Experimental studies have shown that many agricultural pesticides have an impact on production, release, transport, metabolism, and elimination of hormones that regulate homeostasis and other developmental processes (Woodruff et al. 2008). In the human species, the exposure of one or both parents to agricultural pesticides have been related to prematurity risk increase (Fenster et al. 2006), low birth weight (Whyatt et al. 2004), congenital abnormality (Bell et al. 2001), and fetal death (Longnecker et al. 2005), among other reproductive health problems. This ecological study performed an exploratory analysis on the correlation between pesticide use and prematurity, low birth weight and congenital abnormality at birth, infant death caused by congenital abnormality, and fetal death in Brazil using the national information systems.
  [de Siqueira, MT et al. 2010. Bull Environ Contam Toxicol. 84(6):647-51]
• Impact on fetal growth of prenatal exposure to pesticides due to agricultural activities: a prospective cohort study in Brittany, France
  Pesticide use is widespread in agriculture. Several studies have shown that pesticides used in agricultural fields can contaminate the domestic environment and thus be an important source of pesticide exposure of populations residing nearby. Epidemiological studies that have examined the health effects of in utero pesticide exposure from residence near agricultural activities suggest adverse effects, but the results are inconsistent. Our purpose was to investigate the effect on intrauterine growth of such exposure due to agricultural activities in the residential municipality. A prospective birth cohort recruited 3421 pregnant women in a French agricultural region (Brittany, 2002-2006) through gynecologists, ultrasonographers, and maternity hospitals during routine prenatal care visits before 19 weeks of gestation. The national agricultural census in 2000 provided the percentages of the municipality area devoted to cultivation of corn, wheat, colza, peas, potatoes, and fresh vegetables. Birth weight and the risk of fetal growth restriction were not associated with agricultural activities in the municipality of residence in early pregnancy. Children whose mother lived in a municipality where peas were grown had a smaller head circumference at birth than those in municipalities not growing peas (-0.2 cm, p = 0.0002). Head circumference also tended to be lower when wheat was grown, but not to a statistically significant degree (p-trend = 0.10). Risk of an infant with a small head circumference was higher for mothers living in a municipality where peas (OR = 2.2; 95% CI = 1.2-3.6) or potatoes (OR = 1.5; 95% CI = 0.9-2.4) were grown. Agricultural activities in the municipality of residence may have negative effects on cranial growth. Cultivation of pea crops and, to a lesser degree, potato and wheat crops, may negatively affect head circumference. Insecticides, including organophosphate insecticides, were applied to most of the area devoted to pea and potato crops; this was less true for corn and wheat crops. These results must be interpreted in light of the study's limitations, in particular, the scale at which we could assess pesticide exposure.
  [Petit, C., et al. 2010. Environmental Health, 9(71).]
• Maternal Pesticide Exposure and Neural Tube Defects in Mexican Americans
  The relation between maternal pesticide exposures and neural tube defects (NTDs) in offspring was evaluated in 184 Mexican American case-women and 225 comparison women. women who reported using pesticides in their homes or yards were two times more likely to have NTD-affected pregnancies than women without these reported exposures. Case-women were also more likely to report living within 0.25 mile of cultivated fields than control-women. As sources of pesticide exposure opportunities increased, risk of NTDs also increased.
  [Brender, JD., et al. 2010. Ann Epidemiol. 20(1):16-22]
• Parental occupational exposure to potential endocrine disrupting chemicals and risk of hypospadias in infants
  The aim of this study was to investigate the association between both maternal and paternal occupational exposures to endocrine disrupting chemcials (EDCs) and hypospadias. Analysis showed a strong association with potential maternal occupational exposure to heavy metals with an over twofold increased risk of hypospadias and women exposed to phthalates were more likely to have an affected son. The risks of moderate–severe hypospadias or multiple defects were increased up to two- and fivefold, respectively, with maternal exposure to most types of EDCs. Paternal occupational exposures to polychlorinated organic and bi-phenolic compounds were also possible risk factors.
  [Nassar, N. et al. 2010. Occup Environ Med. 67:585-589]
• PESTICIDES: Examining DDT’s Urogenital Effects
  Review of reserach documenting a variety of urogenital malformations in male babies born to women living in an area of South Africa where the potentially endocrine-disrupting pesticide DDT is still used.
  [Lubick, N. 2010. Environ Health Perspect. 118(1): A18]
• Agrichemicals in surface water and birth defects in the United States
  Researchers compiled data for monthly concentrations of pesticides/nitrates and birth defect rates between 1996 and 2002, and found that the months (April-July) with the highest rates of pesticides conincided with the months with the highest rates of birth defects.
  [Winchester, P., et al. 2009. Acta Paediatrica, 98(4).]
• Glyphosate Formulations Induce Apoptosis and Necrosis in Human Umbilical, Embryonic, and Placental Cells
  We have evaluated the toxicity of four glyphosate (G)-based herbicides in Roundup (R) formulations, from 105 times dilutions, on three different human cell types. This dilution level is far below agricultural recommendations and corresponds to low levels of residues in food or feed. The formulations have been compared to G alone and with its main metabolite AMPA or with one known adjuvant of R formulations, POEA. HUVEC primary neonate umbilical cord vein cells have been tested with 293 embryonic kidney and JEG3 placental cell lines. All R formulations cause total cell death within 24 h, through an inhibition of the mitochondrial succinate dehydrogenase activity, and necrosis, by release of cytosolic adenylate kinase measuring membrane damage. They also induce apoptosis via activation of enzymatic caspases 3/7 activity. This is confirmed by characteristic DNA fragmentation, nuclear shrinkage (pyknosis), and nuclear fragmentation (karyorrhexis), which is demonstrated by DAPI in apoptotic round cells. G provokes only apoptosis, and HUVEC are 100 times more sensitive overall at this level. The deleterious effects are not proportional to G concentrations but rather depend on the nature of the adjuvants. AMPA and POEA separately and synergistically damage cell membranes like R but at different concentrations. Their mixtures are generally even more harmful with G. In conclusion, the R adjuvants like POEA change human cell permeability and amplify toxicity induced already by G, through apoptosis and necrosis. The real threshold of G toxicity must take into account the presence of adjuvants but also G metabolism and time-amplified effects or bioaccumulation. This should be discussed when analyzing the in vivo toxic actions of R. This work clearly confirms that the adjuvants in Roundup formulations are not inert. Moreover, the proprietary mixtures available on the market could cause cell damage and even death around residual levels to be expected, especially in food and feed derived from R formulation-treated crops.
  [Benachour, N., et al. 2009. Chemical Research in Toxicology, 22(1)]
• Pesticides and hypospadias: A meta-analysis
  Study used meta-analytic techniques to synthesize the findings of the current body of published literature regarding the risk of hypospadias resulting from parental exposure to pesticides. Elevated but marginally significant risks of hypospadias were associated with maternal occupational exposure and paternal occupational exposure. Exposure assessment using a job-exposure matrix resulted in slightly higher estimated risk than agricultural occupation in fathers; but this effect was reversed in mothers, suggesting the importance of indirect and residential pesticide exposures in this group.
  [Rocheleau CM, Romitti PA, Dennis LK. 2009. J Pediatr Urol. 5(1):17-24]
• Risk of limb birth defects and mother's home proximity to cornfields
  Authors studied birth defects in relation to the area of corn or soybeans within 500 m of the mother's residence. Results found that limb birth defects increased in relation to cornfields. None of the birth defect types studied was associated with soybeans.
  [Ochoa-Acuña, H. and Carbajo. C. 2009. Sci Total Environ. 407(15):4447-51]
• Use of biocides and insect repellents and risk of hypospadias
  Study found an association between the use of insect repellent and total biocide score and risk of hypospadias. The use of insect repellent during the first trimester of pregnancy was associated with an 81% increased risk of hypospadias.
  [Dugas J., et al. 2009. Occupational and Environmental Medicine, doi:10.1136/oem.2009.047373]
• Cryptorchidism at birth in Nice area (France) is associated with higher prenatal exposure to PCBs and DDE, as assessed by colostrum concentrations
  A 2008 study finds a link between total chemical contamination in the bodies of pregnant women and the risk of cryptorchidism in their male babies. Mothers whose babies were born with the defect had the highest concentrations of persistent organic pollutants (POPs), mostly organochlorines like PCB and DDE, in their breast milk. The study compares prebirth exposure to chemicals, as measured through their mother’s milk, and the risk of undescended testicles or cryptorchidism, during a three-year period. While all subjects in the study had detectable levels of these chemicals in either their blood or breast milk, the researchers found that mothers in the highest exposure group for PCBs and DDE in breast milk had two-fold greater odds of giving birth to a boy baby with cryptorchidism, as compared to moms with low to medium exposure. The occurrence of cryptorchidism indicates that testosterone production and/or hormone signaling conditions in the womb have gone awry. Both of these conditions are related to sperm production and the risk of testicular cancer later in life. Cryptorchidism is seen in about 3% of male full-term births, 30% of premature births and is one cause of male infertility.
  [Brucker-Davis F., et al. 2008. Human Reproduction, 23(8).]
• Neonatal exposure to chlorpyrifos affects maternal responses and maternal aggression of female mice in adulthood
  CD-1 mice were exposed to the organophosphate pesticide chlorpyrifos (CPF) throughout postnatal days (PND) 11–14 at the subtoxic dose of 3 mg/kg. At adolescent age, females and males underwent a sociability test in which level of sociability and social preference were measured. At adulthood only females' behavior was analyzed. Maternal behavior of CPF-exposed females was assessed on postpartum day 1 after removal of the pups for 1 h, while anxiety levels were measured in a 5 min dark–light test on postpartum day 2. Nest defense response to an unfamiliar male intruder was assessed on postpartum day 7. In addition, from birth to postpartum day 7 a detailed analysis of nest building activity was carried out. Neonatal CPF exposure does not interfere with social behavior and social preferences at adolescence, whereas at adulthood it induces significant behavioral alterations in lactating females. Motivation to build and defend the nest was decreased in CPF females that were also less anxious than controls in the dark–light paradigm. These results confirm that developmental exposure to CPF induces long-lasting alterations in selected sexual-dimorphic responses of the adult social repertoire, and suggest that early exposure to CPF might interfere with hypothalamic neuroendocrine mechanisms regulating social responses.
  [Venerosi, A., Cutuli, D., Colonnello, V., Cardona, D., Ricceri, L. and Calamandrei, G., 2008. Neurotoxicology and teratology, 30(6), pp.468-474.]
• 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).]
• 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]
• Differential Effects of Glyphosate and Roundup on Human Placental Cells and Aromatase
  Roundup is a glyphosate-based herbicide used worldwide, including on most genetically modified plants that have been designed to tolerate it. Its residues may thus enter the food chain, and glyphosate is found as a contaminant in rivers. Some agricultural workers using glyphosate have pregnancy problems, but its mechanism of action in mammals is questioned. Here we show that glyphosate is toxic to human placental JEG3 cells within 18 hr with concentrations lower than those found with agricultural use, and this effect increases with concentration and time or in the presence of Roundup adjuvants. Surprisingly, Roundup is always more toxic than its active ingredient. We tested the effects of glyphosate and Roundup at lower nontoxic concentrations on aromatase, the enzyme responsible for estrogen synthesis. The glyphosate-based herbicide disrupts aromatase activity and mRNA levels and interacts with the active site of the purified enzyme, but the effects of glyphosate are facilitated by the Roundup formulation in microsomes or in cell culture. We conclude that endocrine and toxic effects of Roundup, not just glyphosate, can be observed in mammals. We suggest that the presence of Roundup adjuvants enhances glyphosate bioavailability and/or bioaccumulation.
  [Richard S., et al. 2005. Environmental Health Perspectives, 113(6).]
• Low-Dose Agrochemicals and Lawn-Care Pesticides Induce Developmental Toxicity in Murine Preimplantation Embryos
  Lawn pesticide products containing herbicides and fertilizers (such as “weed and feed” products) tested on mice show increased risk of infertility, miscarriage and birth defects at very low dosages.
  [Greenlee, A., et al. 2004. Environmental Health Perspectives, 112(6): 703-709.]
• Pesticides and children
  This study examines how children are at risk for other effects of organophosphates and synthetic pyrethroids, including physical and mental retardation, alterations of the cardiovascular system and musculoskeletal defects, alterations of the menstrual cycle, obesity, and failure to develop secondary sex characteristics.
  [Garry, V.F., 2004. Toxicology and Applied Pharmacology, 198(2): p. 152-163.]
• Prenatal Insecticide Exposures and Birth Weight and Length Among an Urban Minority Cohort
  Insecticide exposures are widespread among minority women in New York City during pregnancy and that levels of the organophosphate chlorpyrifos in umbilical cord plasma were inversely associated with birth weight and length. Here authors analyse insecticides (the organophosphate diazinon and the carbamate propoxur), a sample size (n = 314 mother-newborn pairs), and insecticide measurements in maternal personal air during pregnancy as well as in umbilical cord plasma at delivery. Authors found no association between maternal personal air insecticide levels and birth weight, length, or head circumference. For each log unit increase in cord plasma chlorpyrifos levels, birth weight decreased by 42.6 g and birth length decreased by 0.24 cm. Combined measures of (ln)cord plasma chlorpyrifos and diazinon were also inversely associated with birth weight and length. Birth weight averaged 186.3 g less among newborns with the highest compared with lowest 26% of exposure levels. Further, the associations between birth weight and length and cord plasma chlorpyrifos and diazinon were highly significant among newborns born before the 2000-2001 U.S. Environmental Protection Agency's regulatory actions to phase out residential use of these insecticides. Among newborns born after January 2001, exposure levels were substantially lower, and no association with fetal growth was apparent. The propoxur metabolite 2-isopropoxyphenol in cord plasma was inversely associated with birth length, a finding of borderline significance after controlling for chlorpyrifos and diazinon. Results indicate that prenatal chlorpyrifos exposures have impaired fetal growth among this minority cohort and that diazinon exposures may have contributed to the effects. Findings support recent regulatory action to phase out residential uses of the insecticides.
  [Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, et al. 2004. Environ Health Perspect.112(10):1125-32.]
• Birth Malformations and Other Adverse Perinatal Outcomes in Four U.S. Wheat-Producing States.
  Earlier studies by our group suggested the possibility that offspring of pesticide appliers might have increased risks of birth anomalies. To evaluate this hypothesis, 935 births to 34,772 state-licensed, private pesticide appliers in Minnesota occurring between 1989 and 1992 were linked to the Minnesota state birth registry containing 210,723 live births in this timeframe. The birth defect rate for all birth anomalies was significantly increased in children born to private appliers. Specific birth defect categories, circulatory/respiratory, urogenital, and musculoskeletal/integumental, showed significant increases. For the general population and for appliers, the birth anomaly rate differed by corp-growing region. Western Minnesota, a major wheat, sugar beet, and potato growing region, showed the highest rate of birth anomalies per/1000 live births: 30.0 for private appliers versus 26.9 for the general population of the same region. The lowest rates, 23.7/1000 for private appliers versus 18.3/1000 for the general population, occurred in noncorp regions. The highest frequency of use of chlorophenoxy herbicides and fungicides also occurred in western Minnesota. Births in the general population of western Minnesota showed a significant increase in birth anomalies in the same three birth anomaly categories as appliers and for central nervous system anomalies. This increase was most pronounced for infants conceived in the spring. The seasonal effect did not occur in other regions. The male/female sex ratio for the four birth anomaly categories of interest in areas of high phenoxy herbicide/fungicide use is 2.8 for appliers versus 1.5 for the general population of the same region (p = 0.05). In minimal use regions, this ratio is 2.1 for appliers versus 1.7 for the general population. The pattern of excess frequency of birth anomalies by pesticide use, season, and alteration of sex ratio suggests exposure-related effects in appliers and the general population of the crop-growing region of western Minnesota.
  [Schreinemachers, D. 2003. Environmental Health Perspectives, 111(9).]
• Effects of Transplacental Exposure to Environmental Pollutants on Birth Outcomes in a Multiethnic Population.
  Inner-city, minority populations are high-risk groups for adverse birth outcomes and also are more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), polycyclic aromatic hydrocarbons (PAHs), and pesticides. In a sample of 263 nonsmoking African-American and Dominican women, we evaluated the effects on birth outcomes of prenatal exposure to airborne PAHs monitored during pregnancy by personal air sampling, along with ETS estimated by plasma cotinine, and an organophosphate pesticide (OP) estimated by plasma chlorpyrifos (CPF). Plasma CPF was used as a covariate because it was the most often detected in plasma and was highly correlated with other pesticides frequently detected in plasma. Among African Americans, high prenatal exposure to PAHs was associated with lower birth weight (p = 0.003) and smaller head circumference (p = 0.01) after adjusting for potential confounders. CPF was associated with decreased birth weight and birth length overall (p = 0.01 and p = 0.003, respectively) and with lower birth weight among African Americans (p = 0.04) and reduced birth length in Dominicans (p < 0.001), and was therefore included as a covariate in the model with PAH. After controlling for CPF, relationships between PAHs and birth outcomes were essentially unchanged. In this analysis, PAHs and CPF appear to be significant independent determinants of birth outcomes. Further analyses of pesticides will be carried out. Possible explanations of the failure to find a significant effect of PAHs in the Hispanic subsample are discussed. This study provides evidence that environmental pollutants at levels currently encountered in New York City adversely affect fetal development.
  [Perera, F. et al. Feb. 2003. Environmental Health Perspectives, 111(2).]
• Developmental neurotoxicity of chlorpyrifos modeled in vitro: Comparative effects of metabolites and other cholinesterase inhibitors on DNA synthesis in PC12 and C6 cells.
  Extensive and unusual patterns of birth defects noted in four children included defects of the brain, eyes, ears, palate, teeth, heart, feet, nipples, and genitalia. Brain defects were present in the ventricles, corpus callosum, choroid plexus, and septum pellucidum, and genital defects included the testes (undescended), microphallus, and labia (fused). All children had growth retardation, and three had hypotonia and profound mental retardation. The children were exposed in utero to chlorpyrifos (Dursban). Published literature and unpublished documents by the U.S. Environmental Protection Agency contain reports that identify similarities in defects found in test animals and in children exposed to Dursban. A pattern of defects found in the four children in this study may represent a heretofore unrecognized syndrome that should be considered when Dursban-exposed women have children with birth defects.
  [Qiao, D. et al. 2001. Environmental Health Perspectives, 109(9):909-913.]
• Chlorpyrifos (Dursban)-associated birth defects: report of four cases.
  

  The relationship between the use of biocides and insect repellents and the risk of hypospadias was examined in a large case–control study in the South East of England. A case–control study was carried out among 471 cases of hypospadias referred to surgeons, and 490 randomly selected population-based controls, born between 1 January 1997 and 30 September 1998. Telephone interviews were conducted between September 2000 and March 2003. The questionnaire included information on demographic, lifestyle and environmental factors, including the use of biocides and insect repellents, during pregnancy. A total biocide score was created from summing positive responses to an eight-item biocide exposure questionnaire. The use of insect repellent (adjusted OR 1.81, 95% CI 1.06 to 3.11) during the first trimester of pregnancy was associated with risk of hypospadias, but none of the biocides, or indicators for them, except for the total biocide score for the highest two exposure categories (score 3: adjusted OR 1.73, 95% CI 1.02 to 2.94; and scores 4 and 5 combined: adjusted OR 2.98, 95% CI 1.01 to 8.78) showed statistically significant associations. The authors found an association between the use of insect repellent and total biocide score and risk of hypospadias. In particular, the use of insect repellent warrants further investigation, specifically in relation to type, content and frequency of use since this information was missing in the current study.
  [Sherman, J.D. 1996. Environmental Health Perspectives, 51(1).]

• Pesticide appliers, biocides, and birth defects in rural Minnesota.
  A study of live births in Minnesota farming communities links the use of 2,4-D and other penoxy-acetic acid-derived herbicides to significantly higher rates of central nervous system, urogenital, circulatory/respiratory, or musculoskeletal anomalies in the children of pesticide applicators versus the average population.
  [Garry, V., et al. 1996. Environmental Health Perspectives 104(4):394-399.]