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Pesticide-Induced Diseases: Learning / Developmental Disorders
Attention Deficit Hyperactivity Disorder ● Autism ● Developmental Delays
Roughly one in six children in the U.S. has one or more developmental disabilities, ranging from a learning disability to a serious behavioral or emotional disorder. Scientists believe that the amount of toxic chemicals in the environment that cause developmental and neurological damage are contributing to the rise of physical and mental effects being found in children. Studies show children’s developing organs create “early windows of great vulnerability” during which exposure to pesticides can cause great damage. In the U.S., requirements for testing pesticides and other chemicals for potential developmental and learning disorders are minimal.
A developing brain is much more susceptible to the toxic effects of chemicals than an adult brain. During development, the brain undergoes a highly complex series of processes at different stages. Interference from toxic substances that disrupt these processes can have permanent consequences. That vulnerability extends from fetal development through infancy and childhood to adolescence. Research has shown that environmental toxicants, such as pesticides, at low levels of exposure can have subclinical effects—not clinically visible, but still important adverse effects, such as decreases in intelligence or changes in behavior.
Attention Deficit Hyperactivity Disorder (ADHD)
- Assessing Chemical Intolerance in Parents Predicts the Risk of Autism and ADHD in Their Children
Background: We sought to replicate our 2015 findings linking chemical intolerance in parents with the risk of their children developing autism and/or ADHD. Drawing upon our 2021 discovery of a strong association between chemical intolerance and mast cells, we propose an explanation for this link. Methods: In a population-based survey of U.S. adults, we used the internationally validated Quick Environmental Exposure and Sensitivity Inventory (QEESI) to assess symptom severity and chemical intolerance. Parents were asked how many of their biological children had been diagnosed with autism and/or ADHD. Results: Parents with chemical intolerance scores in the top versus bottom tenth percentile had 5.7 times the risk of reporting a child with autism and 2.1 times for ADHD. Conclusions: High chemical intolerance scores among parents of children with autism, coupled with our 2021 discovery of mast cell activation as a plausible biomechanism for chemical intolerance, suggest that (1) the QEESI can identify individuals at increased risk, (2) environmental counseling may reduce personal exposures and risk, and (3) the global rise in autism and ADHD may be due to fossil-fuel-derived and biogenic toxicants epigenetically “turning on” or “turning off” critical mast cell genes that can be transmitted transgenerationally. It is important to note that this study was observational in nature; as such, further research is needed using controlled trials to confirm causality and explore the proposed mechanism.
[Palmer, R.F. et al. (2024) Assessing chemical intolerance in parents predicts the risk of autism and ADHD in their children, J. Xenobiot. Available at: https://www.mdpi.com/2039-4713/14/1/22. ] - Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults
Background
Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years.Methods
We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language.Results
There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (β per ten-fold increase in DAPs = 3.37; 95% CI: −0.02, 6.77 and β = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (β = −3.10; 95% CI: −6.43, 0.22 and β = −3.67; 95% CI: −7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task.Discussion
We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts.
[Sagiv, S. et al. (2024) Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults, Environmental Research. Available at: https://www.sciencedirect.com/science/article/pii/S0013935123025604?via%3Dihub. ] - Neonatal rotenone lesions cause onset of hyperactivity during juvenile and adulthood in the rat.
Attention deficit hyperactivity disorder (ADHD) is characterized by behavioral and cognitive symptoms. Longitudinal studies demonstrated that the symptoms remains clinically significant for the majority of ADHD children into adulthood. Furthermore, a population-based birth cohort provided the initial evidence of adult ADHD that lacks a history of childhood ADHD. We previously demonstrated that neonatal exposure to bisphenol A, an environmental chemical caused hyperactivity in the juvenile. Here, we extend to examine other chemical such as rotenone, a dopaminergic toxins. Oral administration of rotenone (3mg/kg) into 5-day-old male Wistar rats significantly caused hyperactivity at adulthood (8∼11 weeks old; p<0.05). It was about 1.3∼1.4-fold more active in the nocturnal phase after administration of rotenone than control rats. Higher dose (16mg/kg) or repeated lower dose of rotenone (1mg/kg/day for 4days) caused hyperactivity in the juvenile. Furthermore, DNA array analyses showed that neonatal exposure to rotenone altered the levels of gene expression of several molecules related to apoptosis/cell cycle, ATPase, skeletal molecule, and glioma. Bivariate normal distribution analysis indicates no correlation in gene expression between a hyperactivity disorder model and a Parkinson's disease model by rotenone. Thus, we demonstrate a rotenone models of ADHD whose onset varies during juvenile and adulthood.
[Ishido M, Suzuki J, Masuo Y. 2017. Toxicol Lett. 266:42-48] - Neurodevelopmental Delay Diagnosis Rates Are Increased in a Region with Aerial Pesticide Application
A number of studies have implicated pesticides in childhood developmental delay (DD) and autism spectrum disorder (ASD). The influence of the route of pesticide exposure on neurodevelopmental delay is not well defined. To study this factor, we examined ASD/DD diagnoses rates in an area near our regional medical center that employs yearly aerial pyrethroid pesticide applications to combat mosquito-borne encephalitis. The aim of this study was to determine if areas with aerial pesticide exposure had higher rates of ASD/DD diagnoses. This regional study identified higher rates of ASD/DD diagnoses in an area with aerial pesticides application. Zip codes with aerial pyrethroid exposure were 37% more likely to have higher rates of ASD/DD (adjusted RR = 1.37, 95% CI = 1.06-1.78, p = 0.02). A Poisson regression model controlling for regional characteristics (poverty, pesticide use, population density, and distance to medical center), subject characteristics (race and sex), and local birth characteristics (prematurity, low birthweight, and birth rates) identified a significant relationship between aerial pesticide use and ASD/DD rates. The relationship between pesticide application and human neurodevelopment deserves additional study to develop safe and effective methods of mosquito prevention, particularly as communities develop plans for Zika virus control.
[Hicks SD, Wang M, Fry K, Doraiswamy V, Wohlford EM. 2017. Front Pediatr. 5:116.] - 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] - Increased risk of attention-deficit/hyperactivity disorder associated with exposure to organophosphate pesticide in Taiwanese children.
Attention-deficit/hyperactivity disorder (ADHD) is male predominated, and the etiology of this disorder remains unclear. Past studies have assessed the association of low-level organophosphate pesticide exposure with childhood ADHD cross-sectionally and prospectively. However, the results have been inconsistent. A first case-control study was performed to investigate the relationship between organophosphate pesticide exposure and ADHD with adjusted covariates. We recruited 97 doctor-diagnosed ADHD cases and 110 non-ADHD controls who were 4-15 years of age. Exposure was assessed using urinary levels of dialkylphosphate metabolites, which are biomarkers of OP pesticide exposure. Blood lead levels and polymorphisms of two commonly verified dopaminergic-related genes (the D4 dopamine receptor gene DRD4 and the dopamine transporter gene DAT1) were also analyzed. The sociodemographics and lifestyles of the children and of the mothers during pregnancy were collected using a questionnaire. The blood lead levels of both groups were similar (1.57 ± 0.73 vs. 1.73 ± 0.77 μg/dL, p = 0.15). Significant urinary concentration differences in one of the six dialkylphosphate metabolites, dimethylphosphate (DMP), were found between ADHD and control subjects (322.92 ± 315.68 vs. 224.37 ± 156.58 nmol/g cr., p < 0.01). A dose-response relationship was found between urinary concentrations of DMP and ADHD in both crude and adjusted analyses (p for trend<0.05). Children with higher urinary DMP concentrations may have a twofold to threefold increased risk of being diagnosed with ADHD. We report a dose-response relationship between child DMP levels and ADHD. Organophosphate pesticide exposure may have deleterious effects on children's neurodevelopment, particularly the development of ADHD.
[Yu CJ, Du JC, Chiou HC, Chung MY, et al. 2016. Andrology. 4(4):695-705.] - ADHD-like behaviour in the offspring of female rats exposed to low chlorpyrifos doses before pregnancy
The aim of this study was to investigate how chronic low-dose chlorpyrifos exposure of female Wistar rats before and during pregnancy affects behavioural parameters in their offspring. Four months before pregnancy, we exposed three groups of rats to chlorpyrifos doses of 5, 10, and 15 mg kg-1 body weight every day for 30 days, whereas one group received a single 30 mg kg-1 dose on gestational day 6. When the offspring of the exposed rats grew up, we studied their anxiety rate, motor activity, and cognitive abilities using the respective behavioural tests: open field test, dark/light box, and the extrapolation escape test. The offspring of rats exposed before pregnancy had significantly higher activity rate than controls, and even showed motor agitation and hyperactivity signs. The offspring of rats exposed to the single dose had difficulties solving the extrapolation escape test and showed poorer short- and long-term memory performance. This confirmed that even pre-pregnancy chlorpyrifos exposure can cause neurobehavioral consequences in offspring. Even though the mechanisms of the observed changes remain unclear and need further investigation, these data seem alarming and may serve as an important argument for revising the terms of safe pesticide use.
[Grabovska S, Salyha Y. 2015. Arh Hig Rada Toksikol. 66(2):121-7] - Association of pyrethroid pesticide exposure with attention-deficit/hyperactivity disorder in a nationally representative sample of U.S. children.
Study examined the association between pyrethroid pesticide exposure and ADHD in a nationally representative sample of US children, and tested whether this association differs by sex. Data are from 8-15 year old participants (N = 687) in the 2001-2002 National Health and Nutrition Examination Survey. Children with urinary 3-PBA above the limit of detection (LOD) were twice as likely to have ADHD compared with those below the LOD. Hyperactive-impulsive symptoms increased by 50 % for every 10-fold increase in 3-PBA levels; effects on inattention were not significant. Authors observed possible sex-specific effects: pyrethroid biomarkers were associated with increased odds of an ADHD diagnosis and number of ADHD symptoms for boys but not girls. Results found an association between increasing pyrethroid pesticide exposure and ADHD which may be stronger for hyperactive-impulsive symptoms compared to inattention and in boys compared to girls.
[Wagner-Schuman M, Richardson JR, Auinger P, et al. 2015. Environ Health.14:44.] - Developmental neurotoxic effects of two pesticides: Behavior and neuroprotein studies on endosulfan and cypermethrin.
Developmental neurotoxicity of industrial chemicals and pharmaceuticals have been of growing interest in recent years due to the increasing reports of neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and autism. The present study investigated the potential developmental neurotoxic effects of two different types of pesticides, endosulfan and cypermethrin, after a single neonatal exposure during a critical period of brain development. Ten-day-old male NMRI mice were administrated an oral dose of endosulfan or cypermethrin (0.1 or 0.5mg/kg body weight, respectively). Levels of proteins were measured in the neonatal and adult brain, and adult behavioral testing was performed. The results indicate that both pesticides may induce altered levels of neuroproteins, important for normal brain development, and neurobehavioral abnormalities manifested as altered adult spontaneous behavior and ability to habituate to a novel home environment. The neurotoxic behavioral effects were also presentseveral months after the initial testing, indicating long-lasting or even persistent irreversible effects. Also, the present study suggests a possible link between the altered levels of neuroprotein and changes in behavior when exposed during a critical period of brain development.
[Lee I, Eriksson P, et al. 2015. Toxicology. 335:1-10.] - Developmental neurotoxicity of persistent organic pollutants: an update on childhood outcome.
Organohalogens are persistent organic pollutants that have a wide range of chemical application. There is growing evidence that several of these chemical compounds interfere with human development in various ways. The aim of this review is to provide an update on the relationship between various persistent organic pollutants and childhood neurodevelopmental outcome from studies from the past 10 years. This review focuses on exposure to polychlorinated biphenyls (PCBs), hydroxylated PCBs (OH-PCBs), polybrominated diphenyl ethers (PBDEs) and dichlorodiphenyldichloroethylene (DDE), and in addition on exposure to phthalates, bisphenol A, and perfluorinated compounds and their associations with neurodevelopmental outcome in childhood, up to 18 years of age. This review shows that exposure to environmental chemicals affects neurodevelopmental outcome in children. Regarding exposure to PCBs and OH-PCBs, most studies report no or inverse associations with neurodevelopmental outcomes. Regarding exposure to PBDEs, lower mental development, psychomotor development and IQ were found at preschool age, and poorer attention at school age. Regarding exposure to DDE, most studies reported inverse associations with outcome, while others found no associations. Significant relations were particularly found at early infancy on psychomotor development, on attention and ADHD, whereas at school age, no adverse relationships were described. Additionally, several studies report gender-related vulnerability. Future research should focus on the long-term effects of prenatal and childhood exposure to these environmental chemicals, on sex-specific and combined exposure effects of environmental chemicals, and on possible mechanisms by which these chemicals have their effects on neurodevelopmental and behavioral outcomes.
[Berghuis SA, Bos AF, Sauer PJ, Roze E. 2015. Arch Toxicol. 89(5):687-709] - Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder.
Study used behavioral, molecular, and neurochemical techniques to characterize the effects of developmental exposure to the pyrethroid pesticide deltamethrin. Authors also used epidemiologic methods to determine whether there is an association between pyrethroid exposure and diagnosis of ADHD. Mice exposed to the pyrethroid pesticide deltamethrin during development exhibit several features reminiscent of ADHD, including elevated dopamine transporter (DAT) levels, hyperactivity, working memory and attention deficits, and impulsive-like behavior. Increased DAT and D1 dopamine receptor levels appear to be responsible for the behavioral deficits. Epidemiologic data reveal that children aged 6-15 with detectable levels of pyrethroid metabolites in their urine were more than twice as likely to be diagnosed with ADHD. Our epidemiologic finding, combined with the recapitulation of ADHD behavior in pesticide-treated mice, provides a mechanistic basis to suggest that developmental pyrethroid exposure is a risk factor for ADHD.
[Richardson JR, Taylor MM, Shalat SL, Guillot TS, et al. 2015. FASEB J. 29(5):1960-72] - Elucidating the Links Between Endocrine Disruptors and Neurodevelopment
Recent data indicate that approximately 12% of children in the United States are affected by neurodevelopmental disorders, including attention deficit hyperactivity disorder, learning disorders, intellectual disabilities, and autism spectrum disorders. Accumulating evidence indicates a multifactorial etiology for these disorders, with social, physical, genetic susceptibility, nutritional factors, and chemical toxicants acting together to influence risk. Exposure to endocrine-disrupting chemicals during the early stages of life can disrupt normal patterns of development and thus alter brain function and disease susceptibility later in life. This article highlights research efforts and pinpoints approaches that could shed light on the possible associations between environmental chemicals that act on the endocrine system and compromised neurodevelopmental outcomes.
[Schug TT, Blawas AM, Gray K, et al. 2015. Endocrinology. 156(6):1941-51.] - Maternal Chemical and Drug Intolerances: Potential Risk Factors for Autism and Attention Deficit Hyperactivity Disorder (ADHD)
Purpose: The aim of this study was to assess whether chemically intolerant women are at greater risk for having a child with autism spectrum disorders (ASD) or attention deficit hyperactivity disorder (ADHD).Methods: We conducted a case–control study of chemical intolerance among mothers of children with ASD (n = 282) or ADHD (n = 258) and children without these disorders (n = 154). Mothers participated in an online survey consisting of a validated chemical intolerance screening instrument, the Quick Environmental Exposure and Sensitivity Inventory (QEESI). Cases and controls were characterized by parental report of a professional diagnosis. We used a one-way, unbalanced analysis of variance to compare means across the 3 groups.
Results: Both mothers of children with ASD or ADHD had significantly higher mean chemical intolerance scores than did mothers of controls, and they were more likely to report adverse reactions to drugs. Chemically intolerant mothers were 3 times more likely (odds ratio, 3.01; 95% confidence interval, 1.50–6.02) to report having a child with autism or 2.3 times more likely (odds ratio, 2.3; 95% confidence interval, 1.12–5.04) to report a child with ADHD. Relative to controls, these mothers report their children are more prone to allergies (P < .02), have strong food preferences or cravings (P < .003), and have greater sensitivity to noxious odors (P < .04).
Conclusion: These findings suggest a potential association between maternal chemical intolerance and a diagnosis of ADHD or ASD in their offspring.
[Heilbrun, L.P. et al. (2015) Maternal chemical and drug intolerances: Potential risk factors for autism and attention deficit hyperactivity disorder (ADHD), The Journal of the American Board of Family Medicine. Available at: https://www.jabfm.org/content/28/4/461. ] - Exposure to neurotoxicants and the development of attention deficit hyperactivity disorder and its related behaviors in childhood.
A review of published research literature was conducted on associations between exposures to prenatal and postnatal environmental agents including cigarette smoke, childhood exposure to lead, and prenatal exposure to organophosphate pesticides and outcomes of ADHD or behaviors related to ADHD. Review of the literature in these areas provides some evidence of associations between each of the exposures and ADHD-related behaviors, with the strongest evidence from prenatal cigarette and alcohol exposure and postnatal lead exposure. However, research on each exposure also produced evidence of weaknesses in these hypothesized links due to imprecise research methodologies and issues of confounding and inaccurate covariate adjustment. More rigorous studies are needed to provide definitive evidence of associations between each of these prenatal or postnatal exposures and the development of ADHD or symptoms of ADHD. Future studies need to clarify the underlying mechanisms between these exposures and the increased risk for ADHD and associated behaviors. More research is also needed utilizing study designs that include genetic information, as ADHD is highly heritable and there appear to be some protective mechanisms offered by certain genetic characteristics as evidenced in gene by environmental studies. Finally, while studies focusing on individual drugs and chemicals are an important first step, we cannot ignore the fact that children are exposed to combinations of drugs and chemicals, which can interact in complex ways with each other, as well as with the child's genetic makeup and psychosocial environment to influence ADHD risk.
[Yolton K, Cornelius M, Ornoy A, et al. 2014. Neurotoxicol Teratol. 44:30-45.] - Prenatal exposure to organophosphate pesticides and reciprocal social behavior in childhood.
Prenatal exposure to organophosphate pesticides (OPs) has been associated with adverse neurodevelopmental outcomes in childhood, including low IQ, pervasive developmental disorder (PDD), attention problems and ADHD. Many of these disorders involve impairments in social functioning. Authors investigated the relationship between biomarkers of prenatal OP exposure and impaired reciprocal social behavior in childhood, as measured by the Social Responsiveness Scale (SRS). Using a multi-ethnic urban prospective cohort of mother-infant pairs in New York City recruited between 1998 and 2002 (n=404) study examined the relation between third trimester maternal urinary levels of dialkylphosphate (ΣDAP) OP metabolites and SRS scores among 136 children who returned for the 7-9year visit. Overall, there was no association between OPs and SRS scores, although in multivariate adjusted models, associations were heterogeneous by race and by sex. Among blacks, each 10-fold increase in total diethylphosphates (ΣDEP) was associated with poorer social responsiveness. There was no association among whites or Hispanics, or for total ΣDAP or total dimethylphosphate (ΣDMP) biomarker levels. Additionally, stratum-specific models supported a stronger negative association among boys for ΣDEPs, with no notable association among girls. Results support an association of prenatal OP exposure with deficits in social functioning among blacks and among boys, although this may be in part reflective of differences in exposure patterns.
[Furlong MA, Engel SM, et al. 2014. Environ Int. 70:125-31.] - Pyrethroid pesticide exposure and parental report of learning disability and attention deficit/hyperactivity disorder in U.S. children: NHANES 1999-2002.
Authors examined the cross-sectional association between postnatal pyrethroid exposure and parental report of learning disability (LD) and attention deficit/hyperactivity disorder (ADHD) in 1,659-1,680 children 6-15 years of age participating in the National Health and Nutrition Examination Survey (1999-2002). The prevalence rates of parent-reported LD, ADHD, and both LD and ADHD were 12.7%, 10.0%, and 5.4%, respectively. Metabolite detection frequencies for pyrethroid metabolites 3-PBA [3-phenoxybenzoic acid], cis-DCCA [cis-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid], and trans-DCCA [trans-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid] were 77.1%, 35.6%, and 33.9%, respectively. The geometric mean 3-PBA concentration was 0.32 μg/L, cis- and trans-DCCA 75th-percentile concentrations were 0.21 μg/L and 0.68 μg/L, respectively. Log10-transformed 3-PBA concentrations were associated with adjusted odds ratios (ORs) of 1.18 for parent-reported LD, 1.16 for ADHD, and 1.45 for both LD and ADHD. Adjusted ORs remained nonsignificant and decreased after controlling for creatinine and other environmental chemicals previously linked to altered neurodevelopment. Postnatal pyrethroid exposure was not associated with parental report of LD and/or ADHD. Given the widespread and increasing use of pyrethroids, future research should evaluate exposures at current levels, particularly during critical windows of brain development.
[Quirós-Alcalá L, Mehta S, Eskenazi B. 2014. Environ Health Perspect. 122(12):1336-42] - Acetylcholinesterase activity and neurodevelopment in boys and girls.
Organophosphate exposures can affect children's neurodevelopment, possibly due to neurotoxicity induced by acetylcholinesterase (AChE) inhibition, and may affect boys more than girls. Authors tested the hypothesis that lower AChE activity is associated with lower neurobehavioral development among children living in Ecuadorian floricultural communities. In 2008, authors examined 307 children (age: 4-9 years; 52% male) and quantified AChE activity and neurodevelopment in 5 domains: attention/executive functioning, language, memory/learning, visuospatial processing, and sensorimotor (NEPSY-II test). Mean ± standard deviation AChE activity was 3.14 ± 0.49 U/mL (similar for both genders). The range of scores among neurodevelopment subtests was 5.9 to 10.7 U. Girls had a greater mean attention/executive functioning domain score than boys. In boys only, there were increased odds ratios of low neurodevelopment among those in the lowest tertile versus the highest tertile of AChE activity after adjustment for socioeconomic and demographic factors, height-for-age, and hemoglobin. Within these domains, attention, inhibition and long-term memory subtests were most affected.Overall, low AChE activity was associated with deficits in neurodevelopment, particularly in attention, inhibition, and memory in boys but not in girls. These critical cognitive skills affect learning and academic performance. Added precautions regarding secondary occupational pesticide exposure would be prudent.
[Suarez-Lopez JR1, Himes JH, et al. 2013. Pediatrics.132(6):e1649-58.] - Chemical exposure early in life and the neurodevelopment of children--an overview of current epidemiological evidence
A number of chemicals have been shown to demonstrate neurotoxic effects either in human or laboratory animal studies. This article aims at evaluating the impact of exposure to several chemicals including: organophosphate, organochlorine pesticides, polychlorinated biphenyls (PCBs), mercury and lead on the neurodevelopment of children by reviewing the most recent published literature, and answer the question whether any progress has been made in the epidemiology of the neurodevelopment of children induced by exposure to those chemicals. The result of the presented studies show that exposure to the above-mentioned chemicals may impair the neurodevelopment of children. Neonates exposed to organophosphate pesticides demonstrated a higher proportion of abnormal reflexes, and young children had more attention problems. Exposure to organochlorine pesticides in children was associated with alertness, quality of alert responsiveness, cost of attention and other potential attention associated measures. Because the neurotoxicants may cross the placenta and the fetal brain, exposure consideration regarding the reduction of exposure to those chemicals should be implemented.
[Jurewicz J, Polańska K, Hanke W. 2013. Ann Agric Environ Med. 20(3):465-86] - Environmental toxic and its effect on neurodevelopment
Neurodevelopmental disorders are the result of a disturbance of brain function. They are frequent, with varied symptomatology, manifest themselves at different times of life and tend to be persistent with impact at the individual, family and social level. The association of these disorders with genetic entities is low. Although the research supports a mode of genetic inheritance, epigenetic factors and environmental factors can play an important role. In recent years there was a striking increase of these disorders especially attention deficit hyperactivity disorders and pervasive development disorder. Environmental factors such as the intoxication of the fetus by especially heavy metals lead and mercury are to blame in some children, of these disorders. Other substances of wide use, little degradation and maintenance in the food chain as pesticides, polychlorinated biphenyls and now the recycling of electronic waste put especially infants and children at risk, and even more so in the developing countries.
[Arroyo HA, Fernández MC. 2013. Medicina (B Aires). 73 Suppl 1:93-102.] - Prenatal exposure to environmental contaminants and behavioural problems at age 7-8 years.
Animal studies showed that the developing brain is particularly sensitive to chemical exposure. Human studies carried out in areas with high exposures have proven neurodevelopmental disorders in relation to e.g. lead and PCBs. Authors assessed the association between prenatal exposure to lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE and behavioural problems in 7-8year old children. Prenatal exposure data were obtained from the Flemish mother-new-born cohort. Lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE were analysed in cord blood. Results found that doubling the prenatal lead exposure (cord blood lead levels) was associated with a 3.43 times higher risk for hyperactivity in both boys and girls. In addition, total difficulties were 5.08 times more likely in the highest tertile for prenatal lead exposure compared to the lowest tertile. In girls, total difficulties were 4.92 more likely when doubling cord blood p,p'-DDE, whereas no significant association was found in boys. Further, we noted in boys a 1.53 times higher risk for emotional problems when doubling cord blood cadmium, whereas no significant association was found in girls. These results indicate that the presence of environmental contaminants influences the mental health of the next generation.
[Sioen I, Den Hond E, Nelen V, et al. 2013. Environ Int. 59:225-31.] - Prenatal exposure to environmental contaminants and behavioural problems at age 7-8years
Animal studies showed that the developing brain is particularly sensitive to chemical exposure. Human studies carried out in areas with high exposures have proven neurodevelopmental disorders in relation to e.g. lead and PCBs. Whether these chemicals are associated with behavioural problems in childhood at current environmental levels is not well known. Therefore, we assessed the association between prenatal exposure to lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE and behavioural problems in 7-8year old children. Prenatal exposure data were obtained from the Flemish mother-new-born cohort. Lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE were analysed in cord blood. When the child reached 7-8years, 270 mothers completed the Strengths and Difficulties Questionnaire assessing their children's behavioural health. We found that doubling the prenatal lead exposure (cord blood lead levels) was associated with a 3.43 times higher risk for hyperactivity in both boys and girls. In addition, total difficulties were 5.08 times more likely in the highest tertile for prenatal lead exposure compared to the lowest tertile. In girls, total difficulties were 4.92 more likely when doubling cord blood p,p'-DDE, whereas no significant association was found in boys. Further, we noted in boys a 1.53 times higher risk for emotional problems when doubling cord blood cadmium, whereas no significant association was found in girls. These results indicate that the presence of environmental contaminants influences the mental health of the next generation.
[Sioen I, Den Hond E, Nelen V, Van de Mieroop E, et al. 2013. Environ Int. 59:225-31.] - Review of current evidence on the impact of pesticides, polychlorinated biphenyls and selected metals on attention deficit / hyperactivity disorder in children.
The aim of this review was to investigate the association between attention deficit / hyperactivity disorder (ADHD) or ADHD-related symptoms and industrial chemicals, such as organophosphates and organochlorine pesticides, polychlorinated biphenyls (PCBs), lead, mercury and manganese. The review is restricted to human studies published in English in peer-reviewed journals since 2000. Most of the presented studies focused on pesticides, PCB and lead. The impact of mercury and manganese was investigated less frequently. The findings indicate that children's exposure to organophosphate pesticides may cause symptoms consistent with pervasive developmental disorder, ADHD or attention problems. Exposures to organochlorine pesticides and PCBs were associated with ADHD-like behaviors such as alertness, quality of alert response, and cost of attention. The studies provided evidence that blood lead level below 10 μg/dl was associated with ADHD or ADHD-related symptoms. Two studies indicated that exposure to manganese is related to ADHD; such exposure and its impact on children neurodevelopment need to be further investigated. Future studies should use a prospective design with multiple biological samples collected over time for better assessment of exposure and its critical windows. Additionally, inclusion of potential confounding factors and co-exposures is crucial.
[Polańska K, Jurewicz J, Hanke W. 2013. Int J Occup Med Environ Health. 26(1):16-38] - Urinary 3,5,6-trichloro-2-pyridinol (TCPY) in pregnant women from Mexico City: Distribution, temporal variability, and relationship with child attention and hyperactivity.
The etiology of ADHD and ADHD-related behavior is unclear, but genetic and environmental factors, such as pesticides, have been hypothesized. The objective of this study was to investigate the relationship between in utero exposure to chlorpyrifos, chlorpyrifos-methyl, and/or 3,5,6-trichloro-2-pyridinol (TCPY) and ADHD in school-age Mexican children using TCPY as a biomarker of exposure. Third trimester urinary TCPY concentrations were measured in 187 mother-child pairs from a prospective birth cohort. Child neurodevelopment in children 6-11 years of age was assessed using Conners' Parental Rating Scales-Revised (CRS-R), Conners' Continuous Performance Test (CPT), and Behavior Assessment System for Children-2 (BASC-2). Authors did not observe any statistically significant associations between tertiles of maternal TCPY concentrations and ADHD-related outcomes in children. However, compared to the lowest tertile we found suggestive evidence for increased ADHD index in the highest TCPY tertile in boys and increased attention problems for the middle tertile in girls. Considering the continued widespread agricultural and possible residential use of chlorpyrifos and chlorpyrifos-methyl in Mexico and the educational implications of cognitive and behavior deficits, these relationships deserve further study.
[Fortenberry GZ, Meeker JD, Sánchez BN, Barr DB, et al. 2013. Int J Hyg Environ Health. pii: S1438-4639(13)00112-0] - Longitudinal association between early life socio-environmental factors and attention function at the age 11 years
Prenatal and early-life exposures can affect the course of children's neuropsychological development well into pre-adolescence, given the vulnerability of the developing brain. However, it is unknown which socio-environmental factors at early childhood can influence specific cognitive processes like attention at a later age. This study aimed to determine social and environmental exposures in early childhood that may be associated with attention function of 11-year-olds. Attention function using the continuous performance test-II (CPT-II) on 393 11-year old children from the Menorca's birth-cohort within the INMA-project (Spain), and pre-selected a list of socio-environmental observations taken when they were up to 4 years of age was measured. Earlier socio-environmental characteristics, such as parental social class, educational level and maternal mental health were found to be associated with later inattentive and impulsive symptomatology through a higher rate of omission and commission errors. Breastfeeding played a protective role against commission errors, while higher DDE and PCBs levels at age 4 were associated with slow speed response. Our findings suggest that a number of life socio-environmental factors during prenatal life and early childhood, such as socio-demographic characteristics, breastfeeding, maternal nutritional supplementation with folic acid and vitamins and exposure to some organochlorine compounds may influence inattentive and hyperactive/impulsive symptomatology during pre-adolescence.
[Forns J, Torrent M, Garcia-Esteban R, et al. 2012. Environ Res. 117:54-9] - Neuropsychological measures of attention and impulse control among 8-year-old children exposed prenatally to organochlorines
The goal of this study was to corroborate these findings using neuropsychological measures of inattentive and impulsive behaviors. Authors investigated the association between cord serum polychlorinated biphenyls (PCBs) and p,p'-dichlorodiphenyl dichloroethylene (p,p'-DDE) and attention and impulse control using a Continuous Performance Test (CPT) and components of the Wechsler Intelligence Scale for Children. Participants came from a prospective cohort of children born during 1993-1998 to mothers residing near a PCB-contaminated harbor in New Bedford. Study detected associations between PCBs and neuropsychological deficits for 578 and 584 children with CPT and WISC-III measures, respectively, but only among boys. For example, boys with higher exposure to ΣPCB4 had a higher rate of CPT errors of omission and slower WISC-III Processing Speed. Weaker associations were found for p,p'-DDE. For girls, associations were in the opposite direction for the CPT and null for the WISC-III. These results support an association between organochlorines (mainly PCBs) and neuropsychological measures of attention among boys only.
[Sagiv SK, Thurston SW, Bellinger DC, et al. 2012. Environ Health Perspect. 120(6):904-9] - Pesticide exposure and child neurodevelopment: summary and implications.
Widely used around the world, pesticides play an important role in protecting health, crops, and property. However, pesticides may also have detrimental effects on human health, with young children among the particularly vulnerable. Recent research suggests that even low levels of pesticide exposure can affect young children's neurological and behavioral development. Evidence shows a link between pesticides and neonatal reflexes, psychomotor and mental development, and attention-deficit hyperactivity disorder. Implications include a need for improved risk assessment and health histories by clinicians, greater education at all levels, more common use of integrated pest management, and continued policy and regulatory strategies to mitigate the effects of and the need for pesticides.
[Liu J, Schelar E. 2012. Workplace Health Saf. 60(5):235-42] - Pesticide exposure in children.
Pesticides are a collective term for a wide array of chemicals intended to kill unwanted insects, plants, molds, and rodents. Food, water, and treatment in the home, yard, and school are all potential sources of children's exposure. Exposures to pesticides may be overt or subacute, and effects range from acute to chronic toxicity. In 2008, pesticides were the ninth most common substance reported to poison control centers, and approximately 45% of all reports of pesticide poisoning were for children. Organophosphate and carbamate poisoning are perhaps the most widely known acute poisoning syndromes, can be diagnosed by depressed red blood cell cholinesterase levels, and have available antidotal therapy. However, numerous other pesticides that may cause acute toxicity, such as pyrethroid and neonicotinoid insecticides, herbicides, fungicides, and rodenticides, also have specific toxic effects; recognition of these effects may help identify acute exposures. Evidence is increasingly emerging about chronic health implications from both acute and chronic exposure. A growing body of epidemiological evidence demonstrates associations between parental use of pesticides, particularly insecticides, with acute lymphocytic leukemia and brain tumors. Prenatal, household, and occupational exposures (maternal and paternal) appear to be the largest risks. Prospective cohort studies link early-life exposure to organophosphates and organochlorine pesticides (primarily DDT) with adverse effects on neurodevelopment and behavior. Among the findings associated with increased pesticide levels are poorer mental development by using the Bayley index and increased scores on measures assessing pervasive developmental disorder, inattention, and attention-deficit/hyperactivity disorder. Related animal toxicology studies provide supportive biological plausibility for these findings. Additional data suggest that there may also be an association between parental pesticide use and adverse birth outcomes including physical birth defects, low birth weight, and fetal death, although the data are less robust than for cancer and neurodevelopmental effects. Children's exposures to pesticides should be limited as much as possible.
[Roberts JR, Karr CJ. 2012. Pediatrics. 130(6):e1765-88.] - Urinary trichlorophenol levels and increased risk of attention deficit hyperactivity disorder among US school-aged children.
Trichlorophenols (TCPs) are organochlorine compounds which are ubiquitous in the environment and well known for their carcinogenic effects. However, little is known about their neurotoxicity in humans. The goal was to examine the association between body burden of TCPs (ie, 2,4,5-TCP and 2,4,6-TCP) and attention deficit hyperactivity disorder (ADHD). Study reports children with low levels (<3.58 μg/g) and high levels (≥3.58 μg/g) of urinary 2,4,6-TCP had a higher risk of parent-reported ADHD compared to children with levels below the limit of detection after adjusting for covariates. No association was found between urinary 2,4,5-TCP and parent-reported ADHD. Exposure to TCP may increase the risk of behavioural impairment in children. The potential neurotoxicity of these chemicals should be considered in public health efforts to reduce environmental exposures/contamination, especially in countries where organochlorine pesticides are still commonly used.
[Xu X, Nembhard WN, Kan H, et al. 2011. Occup Environ Med. 68(8):557-61] - Attention-Deficit/Hyperactivity Disorder and Urinary Metabolites of Organophosphate Pesticides
The goal was to examine the association between urinary concentrations of dialkyl phosphate metabolites of organophosphates and attention-deficit/hyperactivity disorder (ADHD) in children 8 to 15 years of age. Cross-sectional data from the National Health and Nutrition Examination Survey (2000–2004) were available for 1139 children, who were representative of the general US population. A structured interview with a parent was used to ascertain ADHD diagnostic status, on the basis of slightly modified criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. One hundred nineteen children met the diagnostic criteria for ADHD. Children with higher urinary dialkyl phosphate concentrations, especially dimethyl alkylphosphate (DMAP) concentrations, were more likely to be diagnosed as having ADHD. A 10-fold increase in DMAP concentration was associated with an odds ratio of 1.55 (95% confidence interval: 1.14–2.10), with adjustment for gender, age, race/ethnicity, poverty/income ratio, fasting duration, and urinary creatinine concentration. For the most-commonly detected DMAP metabolite, dimethyl thiophosphate, children with levels higher than the median of detectable concentrations had twice the odds of ADHD (adjusted odds ratio: 1.93 [95% confidence interval: 1.23–3.02]), compared with children with undetectable levels. These findings support the hypothesis that organophosphate exposure, at levels common among US children, may contribute to ADHD prevalence. Prospective studies are needed to establish whether this association is causal.
[Bouchard, M. et al. 2010. Pediatrics (doi:10.1542/peds.2009-3058)] - Organophosphate Pesticide Exposure and Attention in Young Mexican-American Children
OP exposure, as measured by maternal urinary dialkyl phosphate (DAP) metabolites during pregnancy, was non-significantly associated with maternal report of attention problems and ADHD at age 3½, but were significantly related at age 5. Some outcomes exhibited interaction by sex with associations found only among boys.
[Marks AR, Harley K, Bradman A, Kogut K, Barr DB, et al. 2010. Environ Health Perspect. doi:10.1289/ehp.1002056] - Prenatal organochlorine exposure and behaviors associated with attention deficit hyperactivity disorder in school-aged children.
Organochlorines are environmentally persistent contaminants that readily cross the placenta, posing a potential risk to the developing fetus. Evidence for neurodevelopmental effects at low levels of these compounds is growing, though few studies have focused on behavioral outcomes. The authors investigated the association between prenatal polychlorinated biphenyl (PCB) and p,p'-dichlorodiphenyl dichloroethylene (p,p'-DDE) levels and behaviors associated with attention deficit hyperactivity disorder (ADHD), measured with the Conners' Rating Scale for Teachers (CRS-T), in a cohort of 607 children aged 7-11 years (median age, 8.2 years) born in 1993-1998 to mothers residing near a PCB-contaminated harbor in New Bedford, Massachusetts. The authors found higher risk for ADHD-like behaviors assessed with the CRS-T at higher levels of PCBs and p,p'-DDE. These results support an association between low-level prenatal organochlorine exposure and ADHD-like behaviors in childhood.
[Sagiv SK, Thurston SW, Bellinger DC, et al. 2010. Am J Epidemiol. 171(5):593-601] - Long-term sex selective hormonal and behavior alterations in mice exposed to low doses of chlorpyrifos in utero
Exposure to low levels of the organophosphate insecticide chorpyrifos during pregnancy can impair learning, change brain function and alter thyroid levels of offspring into adulthood for tested mice, especially females.
[Haviland, Butz, Porter. 2009. Reprod Toxicol, doi:10.1016/j.reprotox.2009.10.008] - Impact of environmental chemicals on the thyroid hormone function in pituitary rat GH3 cells
Endocrine disrupting chemicals (EDCs) are widespread in the environment and suspected to interfere with the function of thyroid hormones (THs). We investigated the TH disrupting activity of different classes of EDCs including plasticizers (bisphenol A, bisphenol A dimethacrylate), alkylphenols (4-n-nonylphenol, 4-octylphenol), pesticides (prochloraz, iprodion, chlorpyrifos), PCB metabolites (OH-PCB 106, OH-PCB 121, OH-PCB 69) and brominated flame-retardants (tetrabromobisphenol A). The ED potential of a chemical was determined by its effect on the cell proliferation of TH-dependent rat pituitary GH3 cell line. All tested chemicals significantly interfered with the cell proliferation alone or upon co-treatment with T3. The growth of GH3 cells was stimulated by all tested chemicals, but 4-n-nonylphenol, 4-octylphenol, prochloraz and iprodion elicited an inhibitory effect on cell growth. In conclusion, these EDCs have the potential to exert TH disruption increasing the risk or a negative impact on fetal brain development, resulting in cognitive dysfunctions.
[Ghisari M, Bonefeld-Jorgensen EC. 2005. Mol Cell Endocrinol;244(1-2):31-41] - Summary health statistics for U.S. children: National Health Interview Survey, 2003.
This report presents both age-adjusted and unadjusted statistics from the 2003 National Health Interview Survey (NHIS) on selected health measures for children under 18 years of age, classified by sex, age, race, Hispanic origin, family structure, parent's education, family income, poverty status, health insurance coverage, place of residence, region, and current health status. The topics covered are asthma, allergies, learning disability, Attention Deficit Hyperactivity Disorder (ADHD), use of prescription medication, respondent-assessed health status, school-loss days, usual place of health care, time since last contact with a health care professional, unmet dental needs, time since last dental contact, and selected measures of health care access. In 2003, most U.S. children under 18 years of age had excellent or very good health (83%). However, 10% of children had no health insurance coverage, and 5% of children had no usual place of health care. Thirteen percent of children had ever been diagnosed with asthma. An estimated 8% of children 3-17 years of age had a learning disability, and an estimated 6% of children had ADHD.
[Centers for Disease Control and Prevention. 2005. Vital and Health Statistics 10 (223)] - Neurodevelopment and endocrine disruption.
Article explores the possibility that contaminants contribute to the increasing prevalence of attention deficit hyperactivity disorder, autism, and associated neurodevelopmental and behavioral problems in developed countries. It discusses the exquisite sensitivity of the embryo and fetus to thyroid disturbance and provide evidence of human in utero exposure to contaminants that can interfere with the thyroid.
[Colborn T. 2004. Environ Health Perspect;112(9):944-9] - Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA.
We previously demonstrated that the frequency of birth defects among children of residents of the Red River Valley (RRV), Minnesota, USA, was significantly higher than in other major agricultural regions of the state during the years 1989-1991, with children born to male pesticide applicators having the highest risk. The present, smaller cross-sectional study of 695 families and 1,532 children, conducted during 1997-1998, provides a more detailed examination of reproductive health outcomes in farm families ascertained from parent-reported birth defects. In the present study, in the first year of life, the birth defect rate was 31.3 births per 1,000, with 83% of the total reported birth defects confirmed by medical records. Inclusion of children identified with birth or developmental disorders within the first 3 years of life and later led to a rate of 47.0 per 1,000 (72 children from 1,532 live births). Conceptions in spring resulted in significantly more children with birth defects than found in any other season (7.6 vs. 3.7%). Twelve families had more than one child with a birth defect (n = 28 children). Forty-two percent of the children from families with recurrent birth defects were conceived in spring, a significantly higher rate than that for any other season. Three families in the kinships defined contributed a first-degree relative other than a sibling with the same or similar birth defect, consistent with a Mendelian inheritance pattern. The remaining nine families did not follow a Mendelian inheritance pattern. The sex ratio of children with birth defects born to applicator families shows a male predominance (1.75 to 1) across specific pesticide class use and exposure categories exclusive of fungicides. In the fungicide exposure category, normal female births significantly exceed male births (1.25 to 1). Similarly, the proportion of male to female children with birth defects is significantly lower (0.57 to 1; p = 0.02). Adverse neurologic and neurobehavioral developmental effects clustered among the children born to applicators of the fumigant phosphine (odds ratio [OR] = 2.48; confidence interval [CI], 1.2-5.1). Use of the herbicide glyphosate yielded an OR of 3.6 (CI, 1.3-9.6) in the neurobehavioral category. Finally, these studies point out that (a) herbicides applied in the spring may be a factor in the birth defects observed and (b) fungicides can be a significant factor in the determination of sex of the children of the families of the RRV. Thus, two distinct classes of pesticides seem to have adverse effects on different reproductive outcomes. Biologically based confirmatory studies are needed.
[Garry, V.F. et al. 2002. Environ. Health Persp. 110 (Suppl. 3):441-449]
Autism
- Assessing Chemical Intolerance in Parents Predicts the Risk of Autism and ADHD in Their Children
Background: We sought to replicate our 2015 findings linking chemical intolerance in parents with the risk of their children developing autism and/or ADHD. Drawing upon our 2021 discovery of a strong association between chemical intolerance and mast cells, we propose an explanation for this link. Methods: In a population-based survey of U.S. adults, we used the internationally validated Quick Environmental Exposure and Sensitivity Inventory (QEESI) to assess symptom severity and chemical intolerance. Parents were asked how many of their biological children had been diagnosed with autism and/or ADHD. Results: Parents with chemical intolerance scores in the top versus bottom tenth percentile had 5.7 times the risk of reporting a child with autism and 2.1 times for ADHD. Conclusions: High chemical intolerance scores among parents of children with autism, coupled with our 2021 discovery of mast cell activation as a plausible biomechanism for chemical intolerance, suggest that (1) the QEESI can identify individuals at increased risk, (2) environmental counseling may reduce personal exposures and risk, and (3) the global rise in autism and ADHD may be due to fossil-fuel-derived and biogenic toxicants epigenetically “turning on” or “turning off” critical mast cell genes that can be transmitted transgenerationally. It is important to note that this study was observational in nature; as such, further research is needed using controlled trials to confirm causality and explore the proposed mechanism.
[Palmer, R.F. et al. (2024) Assessing chemical intolerance in parents predicts the risk of autism and ADHD in their children, J. Xenobiot. Available at: https://www.mdpi.com/2039-4713/14/1/22. ] - Exposure of pregnant women and their children to pyrethroid insecticides in Rio de Janeiro, Brazil
Background: Pyrethroids are commonly used insecticides in Brazil. Gestational and early childhood exposure to pyrethroids has been linked to adverse health effects, including neurodevelopmental delays, behavioral issues, and endocrine disruption. This study evaluated the exposure of pregnant women and their children to pyrethroid insecticides in Rio de Janeiro, Brazil.
Methods: Creatinine-adjusted levels of the pyrethroid metabolites 3-phenoxy benzoic acid (3-PBA) and 4-fluoro-3-phenoxybenzyl acid (4-FPBA) were measured in the urine of 142 pregnant women and their children at birth and in the first, third, and 6th months of life.
Results: The geometric mean (GM) and 95% confidence interval (95% CI) of 3-PBA and 4-FPBA urinary concentrations in pregnant women were 0.50 (0.37–0.67) and 0.37 (0.05–2.90) ng/mg, detected in 47.2 and 10.6%, respectively. Urinary concentrations of 3-PBA in the children were 0.18 (0.15–0.23) ng/mg at birth, 0.36 (0.08–1.56) ng/mg at 1-month-old, 0.68 (0.36–1.27) ng/mg at 3-month-old, and 1.36 (0.77–2.42) ng/mg at 6-month-old, and the detection rates were respectively 10.8, 9.4, 20.9, and 20.7%.
Discussion: This study is one of the few that has evaluated the urinary concentrations of pyrethroids in newborns and children in their 1st year of life. The results of this study show that children's exposure to pyrethroids significantly increases after birth.
[Martins, A.F. et al. (2023) ‘Exposure of pregnant women and their children to pyrethroid insecticides in Rio de Janeiro, Brazil’, Frontiers in Public Health, 11. doi:10.3389/fpubh.2023.1274724. ] - Prenatal and infant exposure to ambient pesticides and autism spectrum disorder in children: population based case-control study
Data from California state mandated Pesticide Use Reporting were integrated into a geographic information system tool to estimate prenatal and infant exposures to pesticides (measured as pounds of pesticides applied per acre/month within 2000 m from the maternal residence). 11 high use pesticides were selected for examination a priori according to previous evidence of neurodevelopmental toxicity in vivo or in vitro (exposure defined as ever v never for each pesticide during specific developmental periods). Risk of autism spectrum disorder was associated with prenatal exposure to glyphosate (odds ratio 1.16, 95% confidence interval 1.06 to 1.27), chlorpyrifos (1.13, 1.05 to 1.23), diazinon (1.11, 1.01 to 1.21), malathion (1.11, 1.01 to 1.22), avermectin (1.12, 1.04 to 1.22), and permethrin (1.10, 1.01 to 1.20). For autism spectrum disorder with intellectual disability, estimated odds ratios were higher (by about 30%) for prenatal exposure to glyphosate (1.33, 1.05 to 1.69), chlorpyrifos (1.27, 1.04 to 1.56), diazinon (1.41, 1.15 to 1.73), permethrin (1.46, 1.20 to 1.78), methyl bromide (1.33, 1.07 to 1.64), and myclobutanil (1.32, 1.09 to 1.60); exposure in the first year of life increased the odds for the disorder with comorbid intellectual disability by up to 50% for some pesticide substances.
[von Ehrenstein, et al. 2019. BMJ 2019;364:l962 ] - 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.] - Autism in 2016: the need for answers
Autism spectrum disorders are lifelong and often devastating conditions that severely affect social functioning and self-sufficiency. The etiopathogenesis is presumably multifactorial, resulting from a very complex interaction between genetic and environmental factors. The dramatic increase in autism spectrum disorder prevalence observed during the last decades has led to placing more emphasis on the role of environmental factors in the etiopathogenesis. The objective of this narrative biomedical review was to summarize and discuss the results of the most recent and relevant studies about the environmental factors hypothetically involved in autism spectrum disorder etiopathogenesis. While the association between air pollutants, pesticides and other endocrine-disrupting chemicals, and risk for autism spectrum disorder is receiving increasing confirmation, the hypothesis of a real causal relation between them needs further data. The possible pathogenic mechanisms by which environmental factors can lead to autism spectrum disorder in genetically predisposed individuals were summarized, giving particular emphasis to the increasingly important role of epigenetics. Future research should investigate whether there is a significant difference in the prevalence of autism spectrum disorder among nations with high and low levels of the various types of pollution. A very important goal of the research concerning the interactions between genetic and environmental factors in autism spectrum disorder etiopathogenesis is the identification of vulnerable populations, also in view of proper prevention.
[Posar A, Visconti P. 2017. J Pediatr (Rio J). 93(2):111-119.] - Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder.
Maternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals. We examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD). Participants were California children born from 2000-2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case-control study at age 2-5 y, were clinically confirmed to have ASD (n=296) or typical development (n=220), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003-2011. High vs. low daily FA intake was dichotomized at 800μg (median). Mothers' addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure. High FA intake (≥800μg) during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with <800μg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models. In this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed.
[Schmidt RJ, Kogan V, Shelton JF, Delwiche L, Hansen RL, et al. 2017. Environ Health Perspect. 125(9):097007.] - Current nutritional approaches in managing autism spectrum disorder: A review
The link between nutrition and autism spectrum disorder (ASD), which is a complex developmental disorder manifesting itself in significant delays or deviation in interaction and communication, has provided a fresh point of view and signals that nutrition may have a role in the aetiology of ASD, as well as play an active role in treatment by alleviating symptoms.In this review study aimed at evaluating, with scientific and concrete proof, the current medical nutrition implementations on ASD, existing medical nutrition therapies have been addressed and their effects on ASD symptoms have been discussed in light of current research. The research put forward that in individuals with ASD, while gluten-free/casein-free and ketogenic diets, camel milk, curcumin, probiotics, and fermentable foods can play a role in alleviating ASD symptoms, consumption of sugar, additives, pesticides, genetically modified organisms, inorganic processed foods, and hard-to-digest starches may aggravate symptoms. Further prospective controlled trials with large sample sizes are needed before recommendations can be made regarding the ideal ASD diet. This review emphasizes the value of identifying current nutritional approaches specific to individuals with ASD and integrating their effects on symptoms to the conversation and presents suggestions for future research designed to identify medical nutrition therapies targeting this population to better understand the link between ASD and nutrition.
[Cekici H, Sanlier N. 2017. Nutr Neurosci. 1-11.] - Effects of Neonicotinoid Pesticide Exposure on Human Health: A Systematic Review.
Numerous studies have identified detectable levels of neonicotinoids (neonics) in the environment, adverse effects of neonics in many species, including mammals, and pathways through which human exposure to neonics could occur, yet little is known about the human health effects of neonic exposure.In this systematic review, we sought to identify human population studies on the health effects of neonics. Eight studies investigating the human health effects of exposure to neonics were identified. Four examined acute exposure: Three neonic poisoning studies reported two fatalities (n = 1,280 cases) and an occupational exposure study of 19 forestry workers reported no adverse effects. Four general population studies reported associations between chronic neonic exposure and adverse developmental or neurological outcomes, including tetralogy of Fallot (AOR 2.4, 95% CI: 1.1, 5.4), anencephaly (AOR 2.9, 95% CI: 1.0, 8.2), autism spectrum disorder [AOR 1.3, 95% credible interval (CrI): 0.78, 2.2], and a symptom cluster including memory loss and finger tremor (OR 14, 95% CI: 3.5, 57). Reported odds ratios were based on exposed compared to unexposed groups.The studies conducted to date were limited in number with suggestive but methodologically weak findings related to chronic exposure. Given the wide-scale use of neonics, more studies are needed to fully understand their effects on human health.
[Cimino AM, Boyles AL, Thayer KA, Perry MJ. 2017. Environ Health Perspect. 125(2):155-162] - Neurodevelopmental Delay Diagnosis Rates Are Increased in a Region with Aerial Pesticide Application
A number of studies have implicated pesticides in childhood developmental delay (DD) and autism spectrum disorder (ASD). The influence of the route of pesticide exposure on neurodevelopmental delay is not well defined. To study this factor, we examined ASD/DD diagnoses rates in an area near our regional medical center that employs yearly aerial pyrethroid pesticide applications to combat mosquito-borne encephalitis. The aim of this study was to determine if areas with aerial pesticide exposure had higher rates of ASD/DD diagnoses. This regional study identified higher rates of ASD/DD diagnoses in an area with aerial pesticides application. Zip codes with aerial pyrethroid exposure were 37% more likely to have higher rates of ASD/DD (adjusted RR = 1.37, 95% CI = 1.06-1.78, p = 0.02). A Poisson regression model controlling for regional characteristics (poverty, pesticide use, population density, and distance to medical center), subject characteristics (race and sex), and local birth characteristics (prematurity, low birthweight, and birth rates) identified a significant relationship between aerial pesticide use and ASD/DD rates. The relationship between pesticide application and human neurodevelopment deserves additional study to develop safe and effective methods of mosquito prevention, particularly as communities develop plans for Zika virus control.
[Hicks SD, Wang M, Fry K, Doraiswamy V, Wohlford EM. 2017. Front Pediatr. 5:116.] - Polychlorinated Biphenyl and Organochlorine Pesticide Concentrations in Maternal Mid-Pregnancy Serum Samples: Association with Autism Spectrum Disorder and Intellectual Disability
Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are neurodevelopmental toxicants, but few studies have examined associations with autism spectrum disorder (ASD).We aimed to determine whether prenatal exposure to PCBs and OCPs influences offspring risk of ASD and intellectual disability without autism (ID).We conducted a population-based case-control study among Southern California births, including children with ASD (n = 545) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV-TR) criteria and ID (n = 181), as well as general population (GP) controls (n = 418). Concentrations of 11 PCB congeners and 2 OCPs measured in banked second-trimester serum samples were compared between the diagnostic groups. Logistic regression was used to calculate crude and adjusted odds ratios (AOR) for associations with ASD, and separately for ID, compared with GP controls, by quartiles of analyte concentrations in primary analyses.Geometric mean levels of several PCB congeners were higher in the ASD group than in the ID and GP groups. ASD risk was elevated for a number of PCB congeners, particularly for the highest vs. lowest quartile of PCB138/158 (AOR = 1.79; 95% CI: 1.10, 2.71) and PCB153 (AOR = 1.82; 95% CI: 1.10, 3.02), and for highest deciles of other congeners in secondary analyses. PCB138/158 was also associated with increased ID (AOR = 2.41; 95% CI: 1.18, 4.91), though no trend was suggested. OCPs were not associated with increased risk of ASD in primary analyses, whereas nonmonotonic increases in risk of ID were found with p,p´-DDE. Our results suggest higher levels of some organochlorine compounds during pregnancy are associated with ASD and ID.
[Lyall K, Croen LA, Sjödin A, Yoshida CK, et al. 2017. Environ Health Perspect. 125(3):474-480] - Prenatal exposure to pyrethroid pesticides and childhood behavior and executive functioning.
Several previous studies of pyrethroid biomarkers and behavior have reported associations between concurrent pyrethroid levels and adverse behavioral problems in children. One geospatial study reported associations between prenatal exposure to pyrethroids and autism. However, the association between prenatal pyrethroid biomarkers and childhood behavior is unknown. The Mount Sinai Children's Environmental Health Center is a prospective birth cohort with urinary pyrethroid biomarkers during pregnancy and behavioral measurements at 4, 6, and 7-9 years of age. Primiparous women were enrolled between 1998 and 2002. 162 mother/child pairs with complete exposure and behavioral outcomes data were used to investigate associations between detectable levels of prenatal pyrethroid metabolites and scores on the Behavioral Assessment System for Children and the Behavior Rating Inventory of Executive Function. Overall, detection frequencies of pyrethroid metabolites were low (<30%). In longitudinal mixed models, detectable levels of 3-PBA during pregnancy were associated with worse Internalizing (β -4.50, 95% CI -8.05, -0.95), Depression (β -3.21, 95% CI -6.38, -0.05), Somatization (β -3.22, 95% CI -6.38, -0.06), Behavioral Regulation (β -3.59, 95% CI -6.97, -0.21), Emotional Control (β -3.35, 95% CI -6.58, -0.12), Shifting (β -3.42, 95% CI -6.73, -0.11), and Monitoring (β -4.08, 95% CI -7.07, -1.08) scales. Detectable levels of cis-DCCA were associated with worse Externalizing (β -4.74, 95% CI -9.37, -0.10), Conduct Problems (β -5.35, 95% CI -9.90, -0.81), Behavioral Regulation (β -6.42, 95% CI -11.39, -1.45), and Inhibitory Control (β -7.20, 95% CI -12.00, -2.39). Although detection frequencies of pyrethroid metabolites were low, we found suggestive evidence that prenatal exposure to 3-PBA and cis-DCCA may be associated with a variety of behavioral and executive functioning deficits.
[Furlong MA, Barr DB, Wolff MS, Engel SM. 2017. Neurotoxicology. 62:231-238.] - Prenatal Residential Proximity to Agricultural Pesticide Use and IQ in 7-Year-Old Children.
Residential proximity to agricultural pesticide use has been associated with neural tube defects and autism, but more subtle outcomes such as cognition have not been studied.We evaluated the relationship between prenatal residential proximity to agricultural use of potentially neurotoxic pesticides and neurodevelopment in 7-year-old children.Participants included mothers and children (n=283) living in the agricultural Salinas Valley of California enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. We estimated agricultural pesticide use within 1 km of maternal residences during pregnancy using a geographic information system, residential location, and California’s comprehensive agricultural Pesticide Use Report data. We used regression models to evaluate prenatal residential proximity to agricultural use of five potentially neurotoxic pesticide groups (organophosphates, carbamates, pyrethroids, neonicotinoids, and manganese fungicides) and five individual organophosphates (acephate, chlorpyrifos, diazinon, malathion, and oxydemeton-methyl) and cognition in 7-year-old children. All models included prenatal urinary dialkyl phosphate metabolite concentrations.We observed a decrease of 2.2 points [95% confidence interval (CI): −3.9, −0.5] in Full-Scale IQ and 2.9 points (95% CI: −4.4, −1.3) in Verbal Comprehension for each standard deviation increase in toxicity-weighted use of organophosphate pesticides. In separate models, we observed similar decrements in Full-Scale IQ with each standard deviation increase of use for two organophosphates (acephate and oxydemeton-methyl) and three neurotoxic pesticide groups (pyrethroids, neonicotinoids, and manganese fungicides).This study identified potential relationships between maternal residential proximity to agricultural use of neurotoxic pesticides and poorer neurodevelopment in children.
[Gunier RB, Bradman A, Harley KG, Kogut K, Eskenazi B. 2017. Environ Health Perspect. 125(5):057002] - Urinary organophosphate insecticide metabolite concentrations during pregnancy and children's interpersonal, communication, repetitive, and stereotypic behaviors at 8 years of age: The home study.
Prenatal exposure to organophosphate insecticides may be associated with autism spectrum disorders and related behaviors. This association may be modified by single nucleotide polymorphisms in the paraoxonase (PON1) enzyme.
We examined the relationship of prenatal organophosphate insecticide biomarkers with reciprocal social, repetitive, and stereotypic behaviors in 8-year old children, and modification of this relationship by child PON1 polymorphisms.Among 224 pregnant women, we quantified concentrations of six nonspecific dialkyl phosphate (DAP) metabolites of organophosphate insecticides in two urine samples collected at ~16 and ~26 weeks gestation. When children were eight years old, we administered the Social Responsiveness Scale (SRS), a continuous measure of various dimensions of interpersonal behavior, communication, and repetitive/stereotypic behaviors. We estimated the association between a 10-fold increase in the sum of six DAP concentrations (ΣDAP) and SRS scores. We examined whether child PON1192 and PON1-108 genotypes modified this association.After covariate adjustment, ΣDAP concentrations were not associated with SRS scores [β=-1.2; 95% confidence interval (CI): -4.0, 1.6]. Among children with the PON1-108TT genotype, ΣDAP concentrations were associated with 2.5-point higher (95% CI: -4.9, 9.8) SRS scores; however, the association was not different from the 1.8-point decrease (95% CI: -5.8, 2.2) among children with PON1-108CT/CC genotypes (ΣDAP × PON1-108 p-value =0.54). The association between ΣDAP concentrations and SRS scores was not modified by PON1192 (ΣDAP × PON1192 p-value =0.89).In this cohort, prenatal urinary DAP concentrations were not associated with children's social behaviors; these associations were not modified by child PON1 genotype.
[Millenson ME, Braun JM, Calafat AM, Barr DB, et al. 2017. Environ Res. 157:9-16.] - A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder
Exposure to ambient air pollution is widespread and may be detrimental to human brain development and a potential risk factor for Autism Spectrum Disorder (ASD). We conducted a systematic review of the human evidence on the relationship between ASD and exposure to all airborne pollutants, including particulate matter air pollutants and others (e.g. pesticides and metals).We conducted a comprehensive search of the literature, identified relevant studies using inclusion/exclusion criteria pre-specified in our protocol (registered in PROSPERO, CRD # 42015017890), evaluated the potential risk of bias for each included study and identified an appropriate subset of studies to combine in a meta-analysis.Of 1,158 total references identified, 23 human studies met our inclusion criteria (17 case-control, 4 ecological, 2 cohort). Risk of bias was generally low across studies for most domains; study limitations were related to potential confounding and accuracy of exposure assessment methods. We rated the quality of the body of evidence across all air pollutants as "moderate." From our meta-analysis, we found statistically significant summary odds ratios (ORs) of 1.07 (95% CI: 1.06, 1.08) per 10-μg/m3 increase in PM10 exposure (n = 6 studies) and 2.32 (95% CI: 2.15, 2.51) per 10-μg/m3 increase in PM2.5 exposure (n = 3 studies). For pollutants not included in a meta-analysis, we collectively evaluated evidence from each study in rating the strength and quality of overall evidence considering factors such as inconsistency, imprecision, and evidence of dose-response. All included studies generally showed increased risk of ASD with increasing exposure to air pollution, although not consistently across all chemical components.After considering strengths and limitations of the body of research, we concluded that there is "limited evidence of toxicity" for the association between early life exposure to air pollution as a whole and diagnosis of ASD. The strongest evidence was between prenatal exposure to particulate matter and ASD. However, the small number of studies in the meta-analysis and unexplained statistical heterogeneity across the individual study estimates means that the effect could be larger or smaller (including not significant) than these studies estimate. Our research supports the need for health protective public policy to reduce exposures to harmful airborne contaminants among pregnant women and children and suggests opportunities for optimizing future research.
[Lam J, Sutton P, Kalkbrenner A, et al. 2016. PLoS One. 11(9):e0161851.] - Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products.
The increasing incidence of autism suggests a major environmental influence. Epidemiology has implicated many candidates and genetics many susceptibility genes. Gene/environment interactions in autism were analysed using 206 autism susceptibility genes (ASG's) from the Autworks database to interrogate ∼1 million chemical/gene interactions in the comparative toxicogenomics database. Any bias towards ASG's was statistically determined for each chemical. Many suspect compounds identified in epidemiology, including tetrachlorodibenzodioxin, pesticides, particulate matter, benzo(a)pyrene, heavy metals, valproate, acetaminophen, SSRI's, cocaine, bisphenol A, phthalates, polyhalogenated biphenyls, flame retardants, diesel constituents, terbutaline and oxytocin, inter alia showed a significant degree of bias towards ASG's, as did relevant endogenous agents (retinoids, sex steroids, thyroxine, melatonin, folate, dopamine, serotonin). Numerous other suspected endocrine disruptors (over 100) selectively targeted ASG's including paraquat, atrazine and other pesticides not yet studied in autism and many compounds used in food, cosmetics or household products, including tretinoin, soy phytoestrogens, aspartame, titanium dioxide and sodium fluoride. Autism polymorphisms influence the sensitivity to some of these chemicals and these same genes play an important role in barrier function and control of respiratory cilia sweeping particulate matter from the airways. Pesticides, heavy metals and pollutants also disrupt barrier and/or ciliary function, which is regulated by sex steroids and by bitter/sweet taste receptors. Further epidemiological studies and neurodevelopmental and behavioural research is warranted to determine the relevance of large number of suspect candidates whose addition to the environment, household, food and cosmetics might be fuelling the autism epidemic in a gene-dependent manner.
[Carter CJ, Blizard RA. Neurochem Int. pii: S0197-0186(16)30197-8.] - Chemicals, Nutrition, and Autism Spectrum Disorder: A Mini-Review
The rapid increase of the prevalence of autism spectrum disorder (ASD) suggests that exposure to chemicals may impact the development of ASD. Therefore, we reviewed literature on the following chemicals, nutrient to investigate their association with ASD: (1) smoke/tobacco, (2) alcohol, (3) air pollution, (4) pesticides, (5) endocrine-disrupting chemicals, (6) heavy metals, (7) micronutrients, (8) fatty acid, and (9) parental obesity as a proxy of accumulation of specific chemicals or nutritional status. Several chemical exposures such as air pollution (e.g., particular matter 2.5), pesticides, bisphenol A, phthalates, mercury, and nutrition deficiency such as folic acid, vitamin D, or fatty acid may possibly be associated with an increased risk of ASD, whereas other traditional risk factors such as smoking/tobacco, alcohol, or polychlorinated biphenyls are less likely to be associated with ASD. Further research is needed to accumulate evidence on the association between chemical exposure and nutrient deficiencies and ASD in various doses and populations.
[Fujiwara T, Morisaki N, Honda Y, et al. 2016. Front Neurosci. 10:174.] - Environmental factors in the development of autism spectrum disorders
Autism spectrum disorders (ASD) are highly heterogeneous developmental conditions characterized by deficits in social interaction, verbal and nonverbal communication, and obsessive/stereotyped patterns of behavior and repetitive movements. Social interaction impairments are the most characteristic deficits in ASD. There is also evidence of impoverished language and empathy, a profound inability to use standard nonverbal behaviors (eye contact, affective expression) to regulate social interactions with others, difficulties in showing empathy, failure to share enjoyment, interests and achievements with others, and a lack of social and emotional reciprocity. In developed countries, it is now reported that 1%-1.5% of children have ASD, and in the US 2015 CDC reports that approximately one in 45 children suffer from ASD. Despite the intense research focus on ASD in the last decade, the underlying etiology remains unknown. Genetic research involving twins and family studies strongly supports a significant contribution of environmental factors in addition to genetic factors in ASD etiology. A comprehensive literature search has implicated several environmental factors associated with the development of ASD. These include pesticides, phthalates, polychlorinated biphenyls, solvents, air pollutants, fragrances, glyphosate and heavy metals, especially aluminum used in vaccines as adjuvant. Importantly, the majority of these toxicants are some of the most common ingredients in cosmetics and herbicides to which almost all of us are regularly exposed to in the form of fragrances, face makeup, cologne, air fresheners, food flavors, detergents, insecticides and herbicides. In this review we describe various scientific data to show the role of environmental factors in ASD.
[Sealey LA, Hughes BW, Sriskanda AN, et al. 2016. Environ Int. 88:288-298. ] - Environmental pollutants and child health-A review of recent concerns
In recent years, many new studies have evaluated associations between environmental pollutants and child health. This review aims to provide a broad summary of this literature, comparing the state of epidemiological evidence for the effects of a wide range of environmental contaminants (air pollutants, heavy metals, organochlorine compounds, perfluoroalkyl substances, polybrominated diphenyl ethers, pesticides, phthalates and bisphenol A) on child health outcomes. The review addresses effects on foetal growth and prematurity, neurodevelopment, respiratory and immune health, and childhood growth and obesity. Findings of recent prospective studies and meta-analyses have corroborated previous good evidence, often at lower exposure levels, for effects on foetal growth of air pollution and polychlorinated biphenyls (PCBs), for neurotoxic effects of lead, methylmercury, PCBs and organophosphate pesticides, and for respiratory health effects of air pollution. Moderate evidence has emerged for a potential role of environmental pollutants in attention deficit hyperactivity disorder and autism (lead, PCBs, air pollution), respiratory and immune health (dichlorodiphenyldichloroethylene - DDE - and PCBs), and obesity (DDE). In addition, there is now moderate evidence that certain chemicals of relatively recent concern may be associated with adverse child health outcomes, specifically perfluorooctanoate and foetal growth, and polybrominated diphenyl ethers and neurodevelopment. For other chemicals of recent concern, such as phthalates and bisphenol A, the literature is characterised by large inconsistencies preventing strong conclusions. In conclusion, since most of the recent literature evaluates common exposures in the general population, and not particularly high exposure situations, this accumulating body of evidence suggests that the unborn and young child require more protection than is currently provided. Large, coordinated research efforts are needed to improve understanding of long-term effects of complex chemical mixtures.
[Vrijheid M, Casas M, Gascon M, Valvi D, Nieuwenhuijsen M. 2016. Int J Hyg Environ Health. 219(4-5):331-42] - Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD).
Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan-McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-β2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. β2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter < 2.5 and 10 μm in diameter (PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are only partially proven, and not all are "clean" of different confounding factors. The associations described in this review emphasize again how little we know about the etiology and pathogenesis of ASD. It is obvious that we need more epidemiologic data to establish many of these associations, but if proven, they might be promising avenues for prevention.
[Ornoy A, Weinstein-Fudim L, Ergaz Z. 2016. Front Neurosci.10:316.] - Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration
Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders, by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson’s disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer’s disease and Huntington’s disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders.
[Pearson, B.L., Simon, J.M., McCoy, E.S., Salazar, G., Fragola, G. and Zylka, M.J., 2016. Nature communications, 7(1), pp.1-12.] - Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: A review.
Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism.
[Saeedi Saravi SS, Dehpour AR. 2016. Life Sci.145:255-64] - Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism.
Autism spectrum disorders (ASD) are emerging as polygenic and multifactorial disorders in which complex interactions between defective genes and early exposure to environmental stressors impact on the correct neurodevelopment and brain processes. Organophosphate insecticides, among which chlorpyrifos (CPF), are widely diffused environmental toxicants associated with neurobehavioral deficits and increased risk of ASD occurrence in children. In the present study, we aimed at investigating whether the behavioral effects of gestational CPF administration are associated with brain increased oxidative stress and altered lipid mediator profile.Brain levels of F2-isoprostanes (15-F2t-IsoP), as index of in vivo oxidative stress, and prostaglandin E2 (PGE2), a major arachidonic acid metabolite released by immune cells and by specific glutamatergic neuron populations mainly in cortex and hippocampus, were assessed by specific enzyme-immuno assays in brain homogenates from BTBR T+tf/J and C57Bl6/J mice, exposed during gestation to either vehicle or CPF. Measures were performed in mice of both sexes, at different postnatal stages (PNDs 1, 21, and 70).At birth, BTBR T+tf/J mice exhibited higher baseline 15-F2t-IsoP levels as compared to C57Bl6/J mice, suggestive of greater oxidative stress processes. Gestational treatment with CPF-enhanced 15-F2t-IsoP and PGE2 levels in strain- and age-dependent manner, with 15-F2t-IsoP increased in BTBR T+tf/J mice at PNDs 1 and 21, and PGE2 elevated in BTBR T+tf/J mice at PNDs 21 and 70. At PND 21, CPF effects were sex-dependent being the increase of the two metabolites mainly associated with male mice. CPF treatment also induced a reduction of somatic growth, which reached statistical significance at PND 21.These findings indicate that the autistic-like BTBR T+tf/J strain is highly vulnerable to environmental stressors during gestational period. The results further support the hypothesis that oxidative stress might be the link between environmental neurotoxicants such as CPF and ASD. The increased levels of oxidative stress during early postnatal life could result in delayed and long-lasting alterations in specific pathways relevant to ASD, of which PGE2 signaling represents an important one.
[De Felice A, Greco A, Calamandrei G, Minghetti L. 2016. J Neuroinflammation. 13(1):149] - Prenatal Residential Proximity to Agricultural Pesticide Use and IQ in 7-Year-Old Children.
Residential proximity to agricultural pesticide use has been associated with neural tube defects and autism but more subtle outcomes like cognition have not been studied.This study aimed to evaluate the relationship between prenatal residential proximity to agricultural use of potentially neurotoxic pesticides and neurodevelopment in 7-year old children.Participants included mothers and children (n=283) living in the agricultural Salinas Valley of California enrolled in the Center for the Health Assessment of Mothers and Children Of Salinas (CHAMACOS) study. We estimated agricultural pesticide use within one km of maternal residences during pregnancy using a geographic information system, residential location, and California's comprehensive agricultural Pesticide Use Report data. We used regression models to evaluate prenatal residential proximity to agricultural use of five potentially neurotoxic pesticide groups (organophosphates, carbamates, pyrethroids, neonicotinoids, and manganese fungicides) and five individual organophosphates (acephate, chlorpyrifos, diazinon, malathion and oxydemeton-methyl) and cognition in 7-year old children. All models included prenatal urinary dialkyl phosphate metabolite concentrations.We observed a decrease of 2.2 points (95% Confidence Interval (CI): -3.9, -0.5) in Full-Scale intelligence quotient (IQ) and 2.9 points (95% CI: -4.4, -1.3) in verbal comprehension for each standard deviation increase in toxicity-weighted use of organophosphate pesticides. In separate models, we observed similar decrements in Full-Scale IQ with each standard deviation increase of use for two organophosphates (acephate and oxydemeton-methyl) and three neurotoxic pesticide groups (pyrethroids, neonicotinoids, and manganese fungicides).This study identified potential relationships between maternal residential proximity to agricultural use of neurotoxic pesticides and poorer neurodevelopment in children.
[Gunier RB, Bradman A, Harley KG, et al. 2016. Environ Health Perspect. DOI: 10.1289/EHP504] - Pyrethroid Pesticide Metabolite in Urine and Microelements in Hair of Children Affected by Autism Spectrum Disorders: A Preliminary Investigation.
The number of children affected by Autism Spectrum Disorders (ASD) is dramatically increasing as well as the studies aimed at understanding the risk factors associated with the development of ASD. Since the etiology of ASD is partly genetic and partly environmental, factors (i.e., heavy metals, pesticides) as well as lifestyle seem to have a key role in the development of the disease. ASD and Control (CTR) children, aged 5-12 years, were compared. Gas chromatography coupled with trap mass detector was used to measure the level of 3-PBA, the main pyrethroid metabolite in urine in a group of ASD patients, while optical emission spectrometry analysis was employed to estimate the level of metals and microelements in hair in a different group of ASD children. The presence of 3-PBA in urine seems to be independent of age in ASD children, while a positive correlation between 3-PBA and age was observed in the control group of the same age range. Urine concentration of 3-BPA in ASD children had higher values than in the control group, which were marginally significant (p = 0.054). Mg results were significantly decreased in ASD with respect to controls, while V, S, Zn, and Ca/Mg were marginally increased, without reaching statistical significance. Results of Principal Component (PC) analysis of metals and microelements in hair were not associated with either age or health status. In conclusion, 3-PBA in urine and Mg in hair were changed in ASD children relative to control ones.
[Domingues VF, Nasuti C, Piangerelli M, et al. 2016. Int J Environ Res Public Health.13(4):388.] - Self-reported pregnancy exposures and placental DNA methylation in the MARBLES prospective autism sibling study.
Human placenta is a fetal-derived tissue that offers a unique sample of epigenetic and environmental exposures present in utero. In the MARBLES prospective pregnancy study of high-risk younger siblings of children with autism spectrum disorder (ASD), pregnancy and environmental factors collected by maternal interviews were examined as predictors of placental DNA methylation, including partially methylated domains (PMDs), an embryonic feature of the placental methylome. DNA methylation data from MethylC-seq analysis of 47 placentas of children clinically diagnosed at 3 years with ASD or typical development using standardized assessments were examined in relation to: child's gestational age, birth-weight, and diagnosis; maternal pre-pregnancy body mass index, smoking, education, parity, height, prenatal vitamin and folate intake; home ownership; pesticides professionally applied to lawns or gardens or inside homes, pet flea/tick pouches, collars, or soaps/shampoos used in the 3 months prior to or during pregnancy. Sequencing run, order, and coverage, and child race and sex were considered as potential confounders. Akaike information criterion was used to select the most parsimonious among candidate models. Final prediction models used sandwich estimators to produce homoscadisticity-robust estimates of the 95% confidence interval (CI) and P-values controlled the false discovery rate at 5%. The strongest, most robust associations were between pesticides professionally applied outside the home and higher average methylation over PMDs [0.45 (95% CI 0.17, 0.72), P = 0.03] and a reduced proportion of the genome in PMDs [-0.42 (95% CI - 0.67 to -0.17), P = 0.03]. Pesticide exposures could alter placental DNA methylation more than other factors.
[Schmidt RJ, Schroeder DI, Crary-Dooley FK, Barkoski JM, et al. 2016. Environ Epigenet. 2(4). pii: dvw024.] - The barrier, airway particle clearance, placental and detoxification functions of autism susceptibility genes.
Even taking problems of diagnosis into account, a five-fold increase in the incidence of autism in recent decades, in the absence of any known changes in the human gene pool suggests a strong environmental influence. Numerous pollutants have been implicated in epidemiological studies, including pesticides, heavy metals, industrial solvents, air pollutants, particulate matter, bisphenol A, phthalates and flame retardants. Many genes have been implicated in autism, some of which are directly related to detoxification processes. Many are also expressed prenatally in the frontal cortex when the effects of such toxins on neurodevelopment are most relevant. To gain access to the foetal brain, toxins must pass placental and blood/brain barriers and access to maternal or children's blood necessitates passage across skin, airway and intestinal barriers. Literature survey of a subset of 206 genes, defined as prime autism susceptibility candidates from an Autworks/Genotator analysis, revealed that most could be related to barrier function at blood/brain, skin, intestinal, placental or other interfaces. These genes were highly enriched in proteome datasets from blood/brain and placental trophoblast barriers and many localised to skin, intestinal, lung, umbilical and placental compartments. Many were also components of the exosomal/transcytosis pathway that is involved in the transfer of compounds across cells themselves, rather than between them. Several are involved in the control of respiratory cilia that sweep mucus and noxious particles from the airways. A key role of autism susceptibility genes may thus relate to their ability to modulate the access of numerous toxins to children, and adults and, during gestation, to the developing foetal brain.
[Carter CJ. 2016. Neurochem Int. 99:42-51] - Elucidating the Links Between Endocrine Disruptors and Neurodevelopment
Recent data indicate that approximately 12% of children in the United States are affected by neurodevelopmental disorders, including attention deficit hyperactivity disorder, learning disorders, intellectual disabilities, and autism spectrum disorders. Accumulating evidence indicates a multifactorial etiology for these disorders, with social, physical, genetic susceptibility, nutritional factors, and chemical toxicants acting together to influence risk. Exposure to endocrine-disrupting chemicals during the early stages of life can disrupt normal patterns of development and thus alter brain function and disease susceptibility later in life. This article highlights research efforts and pinpoints approaches that could shed light on the possible associations between environmental chemicals that act on the endocrine system and compromised neurodevelopmental outcomes.
[Schug TT, Blawas AM, Gray K, et al. 2015. Endocrinology. 156(6):1941-51.] - Maternal Chemical and Drug Intolerances: Potential Risk Factors for Autism and Attention Deficit Hyperactivity Disorder (ADHD)
Purpose: The aim of this study was to assess whether chemically intolerant women are at greater risk for having a child with autism spectrum disorders (ASD) or attention deficit hyperactivity disorder (ADHD).Methods: We conducted a case–control study of chemical intolerance among mothers of children with ASD (n = 282) or ADHD (n = 258) and children without these disorders (n = 154). Mothers participated in an online survey consisting of a validated chemical intolerance screening instrument, the Quick Environmental Exposure and Sensitivity Inventory (QEESI). Cases and controls were characterized by parental report of a professional diagnosis. We used a one-way, unbalanced analysis of variance to compare means across the 3 groups.
Results: Both mothers of children with ASD or ADHD had significantly higher mean chemical intolerance scores than did mothers of controls, and they were more likely to report adverse reactions to drugs. Chemically intolerant mothers were 3 times more likely (odds ratio, 3.01; 95% confidence interval, 1.50–6.02) to report having a child with autism or 2.3 times more likely (odds ratio, 2.3; 95% confidence interval, 1.12–5.04) to report a child with ADHD. Relative to controls, these mothers report their children are more prone to allergies (P < .02), have strong food preferences or cravings (P < .003), and have greater sensitivity to noxious odors (P < .04).
Conclusion: These findings suggest a potential association between maternal chemical intolerance and a diagnosis of ADHD or ASD in their offspring.
[Heilbrun, L.P. et al. (2015) Maternal chemical and drug intolerances: Potential risk factors for autism and attention deficit hyperactivity disorder (ADHD), The Journal of the American Board of Family Medicine. Available at: https://www.jabfm.org/content/28/4/461. ] - Organic Compounds Detected in Deciduous Teeth: A Replication Study from Children with Autism in Two Samples
Biological samples are an important part of investigating toxic exposures and disease outcomes. However, blood, urine, saliva, or hair can only reflect relatively recent exposures. Alternatively, deciduous teeth have served as a biomarker of early developmental exposure to heavy metals, but little has been done to assess organic toxic exposures such as pesticides, plastics, or medications. The purpose of our study was to determine if organic chemicals previously detected in a sample of typically developing children could be detected in teeth from a sample of children with autism. Eighty-three deciduous teeth from children with autism spectrum disorders (ASD) were chosen from our tooth repository. Organic compounds were assessed using liquid chromatography tandem mass spectrometry and gas chromatography methods. Consistent with a prior report from Camann et al., (2013), we have demonstrated that specific semivolatile organic chemicals relevant to autism etiology can be detected in deciduous teeth. This report provides evidence that teeth can be useful biomarkers of early life exposure for use in epidemiologic case-control studies seeking to identify differential unbiased exposures during development between those with and without specific disorders such as autism.
[Palmer RF, Heilbrun L, Camann D, Yau A, et al. 2015. J Environ Public Health. 2015:862414.] - Prenatal exposure to a common organophosphate insecticide delays motor development in a mouse model of idiopathic autism
Autism spectrum disorders are characterized by impaired social and communicative skills and repetitive behaviors. Emerging evidence supported the hypothesis that these neurodevelopmental disorders may result from a combination of genetic susceptibility and exposure to environmental toxins in early developmental phases. This study assessed the effects of prenatal exposure to chlorpyrifos (CPF), a widely diffused organophosphate insecticide endowed with developmental neurotoxicity at sub-toxic doses, in the BTBR T+tf/J mouse strain, a validated model of idiopathic autism that displays several behavioral traits relevant to the autism spectrum. To this aim, pregnant BTBR mice were administered from gestational day 14 to 17 with either vehicle or CPF at a dose of 6 mg/kg/bw by oral gavages. Offspring of both sexes underwent assessment of early developmental milestones, including somatic growth, motor behavior and ultrasound vocalization. To evaluate the potential long-term effects of CPF, two different social behavior patterns typically altered in the BTBR strain (free social interaction with a same-sex companion in females, or interaction with a sexually receptive female in males) were also examined in the two sexes at adulthood. Our findings indicate significant effects of CPF on somatic growth and neonatal motor patterns. CPF treated pups showed reduced weight gain, delayed motor maturation (i.e., persistency of immature patterns such as pivoting at the expenses of coordinated locomotion) and a trend to enhanced ultrasound vocalization. At adulthood, CPF associated alterations were found in males only: the altered pattern of investigation of a sexual partner, previously described in BTBR mice, was enhanced in CPF males, and associated to increased ultrasonic vocalization rate. These findings strengthen the need of future studies to evaluate the role of environmental chemicals in the etiology of neurodevelopment disorders.
[De Felice A, Scattoni ML, Ricceri L, Calamandrei G. 2015. PLoS One. 10(3):e0121663] - Prenatal exposure to common environmental factors affects brain lipids and increases risk of developing autism spectrum disorders.
The prevalence of autism spectrum disorders (ASDs) has been on the rise over recent years. The presence of diverse subsets of candidate genes in each individual with an ASD and the vast variability of phenotypical differences suggest that the interference of an exogenous environmental component may greatly contribute to the development of ASDs. The lipid mediator prostaglandin E2 (PGE2 ) is released from phospholipids of cell membranes, and is important in brain development and function; PGE2 is involved in differentiation, synaptic plasticity and calcium regulation. A previous review already described extrinsic factors, including deficient dietary supplementation, and exposure to oxidative stress, infections and inflammation that can disrupt signaling of the PGE2 pathway and contribute to ASDs. In this review, the structure and establishment of two key protective barriers for the brain during early development are described: the blood-brain barrier; and the placental barrier. Then, the first comprehensive summary of other environmental factors, such as exposure to chemicals in air pollution, pesticides and consumer products, which can also disturb PGE2 signaling and increase the risk for developing ASDs is provided. Also, how these exogenous agents are capable of crossing the protective barriers of the brain during critical developmental periods when barrier components are still being formed is described. This review underlines the importance of avoiding or limiting exposure to these factors during vulnerable periods in development.
[Wong CT, Wais J, Crawford DA. 2015. Eur J Neurosci. doi: 10.1111/ejn.13028.] - Prenatal factors associated with autism spectrum disorder (ASD)
Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal and postnatal etiologies. We discuss the known associated prenatal factors affecting the fetus throughout pregnancy; whenever relevant, also summarize some animal data. Among the maternal diseases in pregnancy associated with ASD are pregestational and/or gestational diabetes mellitus (PGDM, GDM), maternal infections (i.e. rubella, cytomegalovirus (CMV)), prolonged fever and maternal inflammation, which cause changes in a variety of inflammatory cytokines. Among the drugs are valproic acid, thalidomide, and possibly misoprostol and serotonin reuptake inhibitors (SSRIs). Associations were described with ethanol, and possibly cocaine, heavy metals heavy smoking and Folic acid deficiency. Heavy exposure to pesticides and air pollution during pregnancy was recently associated with ASD. We need more epidemiologic data to establish many of these associations; if proven, they might be promising avenues for prevention.
[Ornoy A, Weinstein-Fudim L, Ergaz Z. 2015. Reprod Toxicol. 56:155-69] - A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors.
The prevalence of diagnosed autism has increased rapidly over the last several decades among U.S. children. Environmental factors are thought to be driving this increase and a list of the top ten suspected environmental toxins was published recently.Temporal trends in autism for birth years 1970-2005 were derived from a combination of data from the California Department of Developmental Services (CDDS) and the United States Individuals with Disabilities Education Act (IDEA). Temporal trends in suspected toxins were derived from data compiled during an extensive literature survey. The CDDS and IDEA data sets are qualitatively consistent in suggesting a strong increase in autism prevalence over recent decades. The quantitative comparison of IDEA snapshot and constant-age tracking trend slopes suggests that ~75-80% of the tracked increase in autism since 1988 is due to an actual increase in the disorder rather than to changing diagnostic criteria. Most of the suspected environmental toxins examined have flat or decreasing temporal trends that correlate poorly to the rise in autism. Some, including lead, organochlorine pesticides and vehicular emissions, have strongly decreasing trends. Among the suspected toxins surveyed, polybrominated diphenyl ethers, aluminum adjuvants, and the herbicide glyphosate have increasing trends that correlate positively to the rise in autism. Environmental factors with increasing temporal trends can help suggest hypotheses for drivers of autism that merit further investigation.
[Nevison, CD. 2014. Environ Health.13:73.] - Autism spectrum disorder, flea and tick medication, and adjustments for exposure misclassification: the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.
The environmental contribution to autism spectrum disorders (ASD) is largely unknown, but household pesticides are receiving increased attention. This study examined associations between ASD and maternally-reported use of imidacloprid, a common flea and tick treatment for pets. The analytic dataset included complete information for 262 typically developing controls and 407 children with ASD. Compared with exposure among controls, the odds of prenatal imidacloprid exposure among children with ASD were slightly higher, with an odds ratio (OR) of 1.3. A susceptibility window analysis yielded higher ORs for exposures during pregnancy than for early life exposures, whereas limiting to frequent users of imidacloprid, the OR increased to 2.0. Within plausible estimates of sensitivity and specificity, the association could result from exposure misclassification alone. The association between imidacloprid exposure and ASD warrants further investigation, and this work highlights the need for validation studies regarding prenatal exposures in ASD.
[Keil AP, Daniels JL, Hertz-Picciotto I. 2014. Environ Health. 13(1):3.] - Environment and Autism: Current State of the Science
Research into environmental risk factors for autism has grown dramatically over the past 10 years, providing evidence that non-genetic factors acting during the prenatal period may influence the underlying neurodevelopmental processes. This paper reviews the evidence on modifiable preconception and/or prenatal factors that have been associated with autism spectrum disorder (ASD), including only human studies with at least 50 cases of ASD, having a valid comparison group, conducted within the past decade, and focusing on maternal lifestyle or environmental chemicals. Consistent results have been reported for an association of higher maternal intake of certain nutrients and supplements with reduction in ASD risk, with the strongest evidence for folic acid supplements. A number of studies have demonstrated significant increases in ASD risk with estimated exposure to air pollution during the prenatal period, particularly for heavy metals and particulate matter. A few studies suggest a link with organophosphate pesticides. More rigorous ascertainment of exposure is needed for studies of substance use; most investigations adjusting for potential confounders, but relying on self-reported use, have shown no links between maternal smoking or alcohol consumption and ASD. Little research has assessed other persistent and non-persistent organic chemical pollutants, such as are found in common household or personal care products, in association with ASD specifically. More work is needed to examine fats, vitamins, and other maternal nutrients, as well as endocrine-disrupting chemicals and pesticides, in association with ASD, given sound biological plausibility and evidence regarding other neurodevelopmental outcomes. In addition, the field could be advanced by the use of large-scale epidemiologic studies, attention to critical etiologic windows and how these vary by exposure, interactions with genetic susceptibility, and a focus on underlying mechanisms.
[Schmidt RJ, Lyall K, Hertz-Picciotto I. 2014. Cut Edge Psychiatry Pract. 1(4):21-38.] - Environmental chemical exposures and autism spectrum disorders: a review of the epidemiological evidence.
In this review, authors covered studies of autism and estimates of exposure to tobacco, air pollutants, volatile organic compounds and solvents, metals (from air, occupation, diet, dental amalgams, and thimerosal-containing vaccines), pesticides, and organic endocrine-disrupting compounds such as flame retardants, non-stick chemicals, phthalates, and bisphenol A. Studies include those that had individual-level data on autism, exposure measures pertaining to pregnancy or the 1st year of life, valid comparison groups, control for confounders, and adequate sample sizes. Despite the inherent error in the measurement of many of these environmental exposures, which is likely to attenuate observed associations, some environmental exposures showed associations with autism, especially traffic-related air pollutants, some metals, and several pesticides, with suggestive trends for some volatile organic compounds (e.g., methylene chloride, trichloroethylene, and styrene) and phthalates. Whether any of these play a causal role requires further study. Given the limited scope of these publications, other environmental chemicals cannot be ruled out, but have not yet been adequately studied. Future research that addresses these and additional environmental chemicals, including their most common routes of exposures, with accurate exposure measurement pertaining to several developmental windows, is essential to guide efforts for the prevention of the neurodevelopmental damage that manifests in autism symptoms.
[Kalkbrenner AE, Schmidt RJ, Penlesky AC. 2014. Curr Probl Pediatr Adolesc Health Care. 44(10):277-318.] - Environmental toxicants and autism spectrum disorders: a systematic review.
Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. Authors compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case-control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls.Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.
[Rossignol DA, Genuis SJ, Frye RE. 2014. Transl Psychiatry. 4:e360.] - Gestational exposure to endocrine-disrupting chemicals and reciprocal social, repetitive, and stereotypic behaviors in 4- and 5-year-old children: the HOME study.
Endocrine-disrupting chemicals (EDCs) may be involved in the etiology of autism spectrum disorders, but identifying relevant chemicals within mixtures of EDCs is difficult. Our goal was to identify gestational EDC exposures associated with autistic behaviors. We measured the concentrations of 8 phthalate metabolites, bisphenol A, 25 polychlorinated biphenyls (PCBs), 6 organochlorine pesticides, 8 brominated flame retardants, and 4 perfluoroalkyl substances in blood or urine samples from 175 pregnant women in the HOME (Health Outcomes and Measures of the Environment) Study (Cincinnati, OH). When children were 4 and 5 years old, mothers completed the Social Responsiveness Scale (SRS), a measure of autistic behaviors. We examined confounder-adjusted associations between 52 EDCs and SRS scores using a two-stage hierarchical analysis to account for repeated measures and confounding by correlated EDCs.Most of the EDCs were associated with negligible absolute differences in SRS scores (≤ 1.5). Each 2-SD increase in serum concentrations of polybrominated diphenyl ether-28 (PBDE-28) (β = 2.5; 95% CI: -0.6, 5.6) or trans-nonachlor (β = 4.1; 95% CI: 0.8-7.3) was associated with more autistic behaviors. In contrast, fewer autistic behaviors were observed among children born to women with detectable versus nondetectable concentrations of PCB-178 (β = -3.0; 95% CI: -6.3, 0.2), β-hexachlorocyclohexane (β = -3.3; 95% CI: -6.1, -0.5), or PBDE-85 (β = -3.2; 95% CI: -5.9, -0.5). Increasing perfluorooctanoate (PFOA) concentrations were also associated with fewer autistic behaviors (β = -2.0; 95% CI: -4.4, 0.4).Some EDCs were associated with autistic behaviors in this cohort, but our modest sample size precludes us from dismissing chemicals with null associations. PFOA, β-hexachlorocyclohexane, PCB-178, PBDE-28, PBDE-85, and trans-nonachlor deserve additional scrutiny as factors that may be associated with childhood autistic behaviors.
[Braun JM, Kalkbrenner AE, Just AC, Yolton K, et al. 2014. Environ Health Perspect. 122(5):513-20.] - Gestational/perinatal chlorpyrifos exposure is not associated with autistic-like behaviors in rodents
Although animal models cannot exactly replicate human psychiatric disorders, they may be useful to investigate whether the behaviors associated with certain exposures in animals parallel those observed in people. According to the most current version of the Diagnostic and Statistical Manual of Mental Disorders, autism is diagnosed based on (1) persistent deficits in social communication and social interaction; and (2) the presence of restricted, repetitive patterns of behavior, interests and activities. To address whether developmental chlorpyrifos (CPF) exposure was associated with the development of autistic behaviors, a literature search was conducted to identify studies in rats and mice involving gestational or early postnatal exposure to CPF or CPF oxon (CPO, the active metabolite of CPF) and subsequent behavioral testing to assess behaviors related to autism. A total of 13 studies conducted in six different laboratories were identified. Analysis of these studies found that perinatal CPF exposure was generally associated with (1) no effect or increased social communications; (2) no effect or increased social encounters; (3) no effect, reduced stereotypies, or conflicting findings on stereotypic behaviors; and (4) no effect or increased preference for novelty and reduced anxiety in novel environments. These behavioral findings are generally inconsistent with the types of behaviors that would be expected in children with clinical autism. Based on the results of this analysis of rodent model studies involving CPF/CPO exposure, it cannot be concluded that gestational and/or perinatal CPF exposure is likely to be associated with the development of autism-like behaviors in humans.
[Williams AL, DeSesso JM. 2014. Crit Rev Toxicol. 44(6):523-34] - Maternal lifestyle and environmental risk factors for autism spectrum disorders.
Over the past 10 years, research into environmental risk factors for autism has grown dramatically, bringing evidence that an array of non-genetic factors acting during the prenatal period may influence neurodevelopment.
This paper reviews the evidence on modifiable preconception and/or prenatal factors that have been associated, in some studies, with autism spectrum disorder (ASD), including nutrition, substance use and exposure to environmental agents. This review is restricted to human studies with at least 50 cases of ASD, having a valid comparison group, conducted within the past decade and focusing on maternal lifestyle or environmental chemicals. Higher maternal intake of certain nutrients and supplements has been associated with reduction in ASD risk, with the strongest evidence for periconceptional folic acid supplements. Although many investigations have suggested no impact of maternal smoking and alcohol use on ASD, more rigorous exposure assessment is needed. A number of studies have demonstrated significant increases in ASD risk with estimated exposure to air pollution during the prenatal period, particularly for heavy metals and particulate matter. Little research has assessed other persistent and non-persistent organic pollutants in association with ASD specifically. More work is needed to examine fats, vitamins and other maternal nutrients, as well as endocrine-disrupting chemicals and pesticides, in association with ASD, given sound biological plausibility and evidence regarding other neurodevelopmental deficits. The field can be advanced by large-scale epidemiological studies, attention to critical aetiological windows and how these vary by exposure, and use of biomarkers and other means to understand underlying mechanisms.
[Lyall K, Schmidt RJ, Hertz-Picciotto I. 2014. Int J Epidemiol. 43(2):443-64.] - Neurodevelopmental Disorders and Prenatal Residential Proximity to Agricultural Pesticides: The CHARGE Study.
To evaluate whether residential proximity to agricultural pesticides during pregnancy is associated with autism spectrum disorders (ASD) or developmental delay (DD) in the Childhood Autism Risks from Genetics and Environment (CHARGE) Study.The CHARGE study is a population-based case-control study of ASD, developmental delay (DD), and typical development. For 970 participants, commercial pesticide application data from the California Pesticide Use Report (1997-2008) were linked to the addresses during pregnancy. Pounds of active ingredient applied for organophophates, organochlorines, pyrethroids, and carbamates were aggregated within 1.25km, 1.5km, and 1.75km buffer distances from the home. Approximately one-third of CHARGE Study mothers lived, during pregnancy, within 1.5 km (just under one mile) of an agricultural pesticide application. Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for ASD, higher for 3rd trimester exposures, and 2nd trimester chlorpyrifos applications: OR = 3.3. Children of mothers residing near pyrethroid insecticide applications just prior to conception or during 3rd trimester were at greater risk for both ASD and DD, with OR's ranging from 1.7 to 2.3. Risk for DD was increased in those near carbamate applications, but no specific vulnerable period was identified.This study of ASD strengthens the evidence linking neurodevelopmental disorders with gestational pesticide exposures, and particularly, organophosphates and provides novel results of ASD and DD associations with, respectively, pyrethroids and carbamates.
[Shelton JF, Geraghty EM, Tancredi DJ, et al. 2014. Environ Health Perspect. DOI:10.1289/ehp.1307044] - Pre- and postnatal exposure to low dose glufosinate ammonium induces autism-like phenotypes in mice.
Glufosinate ammonium (GLA) is one of the most widely used herbicides in agriculture. As is the case for most pesticides, potential adverse effects of GLA have not been studied from the perspective of developmental neurotoxicity. Early pesticides exposure may weaken the basic structure of the developing brain and cause permanent changes leading to a wide range of lifelong effects on health and/or behavior. Authors addressed the developmental impact of GLA by exposing female mice to low dose GLA during both pre- and postnatal periods and analyzed potential developmental and behavioral changes of the offspring during infancy and adulthood. A neurobehavioral test battery revealed significant effects of GLA maternal exposure on early reflex development, pup communication, affiliative behaviors, and preference for social olfactory cues, but emotional reactivity and emotional memory remained unaltered. These behavioral alterations showed a striking resemblance to changes seen in animal models of Autistic Spectrum Disorders. At the brain level, GLA maternal exposure caused some increase in relative brain weight of the offspring. In addition, reduced expression of Pten and Peg3 - two genes implicated in autism-like deficits - was observed in the brain of GLA-exposed pups at postnatal day 15. Results thus provide new data on the link between pre- and postnatal exposure to the herbicide GLA and the onset of autism-like symptoms later in life. It also raises fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during critical developmental periods.
[Laugeray A, Herzine A, Perche O, et al. 2014. Front Behav Neurosci. 8:390.] - A macroepigenetic approach to identify factors responsible for the autism epidemic in the United States
The demand for special education services continues to rise in disability categories associated with pervasive developmental disorders. Neurodevelopment can be adversely impacted when gene expression is altered by dietary transcription factors, such as zinc insufficiency or deficiency, or by exposure to toxic substances found in our environment, such as mercury or organophosphate pesticides. Gene expression patterns differ geographically between populations and within populations. Gene variants of paraoxonase-1 are associated with autism in North America, but not in Italy, indicating regional specificity in gene-environment interactions. In the current review, authors utilize a novel macroepigenetic approach to compare variations in diet and toxic substance exposure between these two geographical populations to determine the likely factors responsible for the autism epidemic in the United States.
[Dufault, R., W.J. Lukiw, R. Crider, R. Schnoll, D. Wallinga and R. Deth. 2012. Clinical Epigenetics. 4(1):6] - A Research Strategy to Discover the Environmental Causes of Autism and Neurodevelopmental Disabilities
This editorial explores the ongoing research, both genetic and environmental studies,to identify the potentially preventable causes of neuro-develop-mental disorders (NDDs). Genetic research has demonstrated that austism spectrum disorder (ASD) and certain other NDDs have a strong hereditary component. Exploration of the environmental causes of autism and other NDDs has been catalyzed by growing recognition of the exquisite sensitivity of the developing human brain to toxic chemicals. This susceptibility is greatest during unique “windows of vulnerability” that open only in embryonic and fetal life and have no later counter-part. Additional prospective studies have linked loss of cognition (IQ), dyslexia, and ADHD to lead, methyl-mercury, organophosphate insecticides, organo-chlorine insecticides, polychlorinated biphenyls, arsenic and others.A major unanswered question is whether there are still undiscovered environ-mental causes of autism or other NDDs among the thousands of chemicals currently in wide use in the United States. The significance of early chemical exposures for children’s health is not yet fully understood. A great concern is that a large number of the chemicals in widest use have not undergone even minimal assessment of potential toxicity, and only about 20% have been screened for potential toxicity during early development. Unless studies specifically examine develop-mental consequences of early exposures to untested chemicals, sub-clinical dysfunction caused by these exposures can go unrecognized for years.
[Landrigan P.J., Lambertini,L and Birnbaum, L.S. 2012. Environ Health Perspect. 120(7): a258-a260] - Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review.
This study provides an overview of studies on perinatal exposure in humans to endocrine disrupting chemicals (EDCs) in relation to autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. Positive associations were found for ASD in relation to exposure to all chemicals investigated, which included hazardous air pollutants, pesticides and bisphenol A (BPA). Increased risks of ADHD or positive associations were found for exposure to polychlorinated biphenyls (PCBs), dialkyl phosphate (DAP) and chlorpyrifos. BPA, polybrominated diphenylethers (PBDEs) and low molecular weight (LMW) phthalates were positively associated with externalizing behaviour. Five of 17 studies did not find any association between exposure and ADHD. Perinatal exposure to EDCs appears to be associated with the occurrence of ASD as well as ADHD. Disruption of thyroid hormone function and gamma-aminobutyric acid (GABA)ergic mechanisms may offer an explanation for the observed relations; though, conclusive evidence in humans is limited.
[de Cock M, Maas YG, van de Bor M. 2012. Acta Paediatr. 101(8):811-8] - Tipping the Balance of Autism Risk: Potential Mechanisms Linking Pesticides and Autism
Autism spectrum disorders (ASDs) have been increasing in many parts of the world and a portion of cases are attributable to environmental exposures. Conclusive replicated findings have yet to appear on any specific exposure; however, mounting evidence suggests gestational pesticides exposures are strong candidates.Authors review and discuss previous research related to autism risk, developmental effects of early pesticide exposure, and basic biological mechanisms by which pesticides may induce or exacerbate pathophysiological features of autism. In experimental and observational research, certain pesticides may be capable of inducing core features of autism, but little is known about the timing or dose, or which of various mechanisms is sufficient to induce this condition. In animal studies, authors encourage more research on gene × environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene × environment are needed to determine if there are susceptible subpopulations at greater risk from pesticide exposures.
[Shelton, J.F., Hertz-Picciotto, I. and Pessah, I.H. 2012. Environ Health Persp. 120 (7): 944-951.] - The Rise in Autism and the Role of Age at Diagnosis
Study found that a seven- to eight-fold increase in the number children born in California with autism since 1990. These results suggest that research should shift from genetics to the host of chemicals and infectious microbes in the environment that are likely at the root of changes in the neurodevelopment of California’s children, including pesticides and household chemicals.
[Hertz-Picciotto, I. and Delwiche, L. 2009. Epidemiology:20(1) - pp 84-90 doi: 10.1097/EDE.0b013e3181902d15] - Household Pesticide Use in Relation to Autism
A population-based study looking at how genes and environmental factors interact shows that pet shampoos containing insecticides may trigger autism spectrum disorders (ASD). The study findings, presented at the International Meeting for Autism Research, show that mothers of children with an ASD are twice as likely to have used an insecticidal pet shampoo during the prenatal and/or postnatal period when compared to mothers of healthy children. The strongest association was during the second trimester of pregnancy.
[Hertz-Picciotto, et al. Oral Presentation at the International Meeting for Autism Research (ORAL 2899). London, England, May 15, 2008)] - Autism: Transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents
The incidence and prevalence of autism have increased during the past two decades. Despite comprehensive genetic studies the cause of autism remains unknown. This review emphasizes the potential importance of environmental factors in its causation. Alterations of cortical neuronal migration and cerebellar Purkinje cells have been observed in autism. Neuronal migration, via reelin regulation, requires triiodothyronine (T3) produced by deiodination of thyroxine (T4) by fetal brain deiodinases. Experimental animal models have shown that transient intrauterine deficits of thyroid hormones (as brief as 3 days) result in permanent alterations of cerebral cortical architecture reminiscent of those observed in brains of patients with autism. I postulate that early maternal hypothyroxinemia resulting in low T3 in the fetal brain during the period of neuronal cell migration (weeks 8–12 of pregnancy) may produce morphological brain changes leading to autism. Insufficient dietary iodine intake and a number of environmental antithyroid and goitrogenic agents can affect maternal thyroid function during pregnancy. The most common causes could include inhibition of deiodinases D2 or D3 from maternal ingestion of dietary flavonoids or from antithyroid environmental contaminants. Some plant isoflavonoids have profound effects on thyroid hormones and on the hypothalamus–pituitary axis. Genistein and daidzein from soy (Glycine max) inhibit thyroperoxidase that catalyzes iodination and thyroid hormone biosynthesis. Other plants with hypothyroid effects include pearl millet (Pennisetum glaucum) and fonio millet (Digitaria exilis); thiocyanate is found in Brassicae plants including cabbage, cauliflower, kale, rutabaga, and kohlrabi, as well as in tropical plants such as cassava, lima beans, linseed, bamboo shoots, and sweet potatoes. Tobacco smoke is also a source of thiocyanate. Environmental contaminants interfere with thyroid function including 60% of all herbicides, in particular 2,4-dichlorophenoxyacetic acid (2,4-D), acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, mancozeb, and thioureas. Other antithyroid agents include polychlorinated biphenyls (PCBs), perchlorates, mercury, and coal derivatives such as resorcinol, phthalates, and anthracenes. A leading ecological study in Texas has correlated higher rates of autism in school districts affected by large environmental releases of mercury from industrial sources. Mercury is a well known antithyroid substance causing inhibition of deiodinases and thyroid peroxidase. The current surge of autism could be related to transient maternal hypothyroxinemia resulting from dietary and/or environmental exposure to antithyroid agents. Additional multidisciplinary epidemiological studies will be required to confirm this environmental hypothesis of autism.
[Román, G, C. 2007. Journal of the Neurological Sciences; 262(1-2), pp 15-26] - Maternal Residence Near Agricultural Pesticide Applications and Autism Spectrum Disorders Among Children in the California Central Valley.
Study shows that children born to mothers living near agricultural fields where organochlorine pesticides, specifically endosulfan and dicofol, were applied during their first trimester of pregnancy were six times more likely to have children that develop autism spectrum disorders (ASDs). compared to mothers who did not live near the fields.
[Roberts, E, M. et al. 2007. Environ Health Perspect 115:1482-1489. doi:10.1289/ehp.10168]
Developmental Delays
- A pilot study of chlormequat in food and urine from adults in the United States from 2017 to 2023
Abstract
Chlormequat chloride is a plant growth regulator whose use on grain crops is on the rise in North America. Toxicological studies suggest that exposure to chlormequat can reduce fertility and harm the developing fetus at doses lower than those used by regulatory agencies to set allowable daily intake levels. Here we report, the presence of chlormequat in urine samples collected from people in the U.S., with detection frequencies of 69%, 74%, and 90% for samples collected in 2017, 2018–2022, and 2023, respectively. Chlormequat was detected at low concentrations in samples from 2017 through 2022, with a significant increase in concentrations for samples from 2023. We also observed high detection frequencies of chlormequat in oat-based foods. These findings and chlormequat toxicity data raise concerns about current exposure levels, and warrant more expansive toxicity testing, food monitoring, and epidemiological studies to assess health effects of chlormequat exposures in humans.
Impact
This study reports the detection of chlormequat, an agricultural chemical with developmental and reproductive toxicity, in the U.S. population and U.S. food supplies for the first time. While similar levels of the chemical were found in urine sampled from 2017 to 2022, markedly increased levels were found in samples from 2023. This work highlights the need for more expansive monitoring of chlormequat in U.S. foods and in human specimens, as well as toxicological and epidemiological study on chlormequat, as this chemical is an emerging contaminant with documented evidence of low-dose adverse health effects in animal studies.
[Temkin, A.M. et al. (2024) ‘A pilot study of chlormequat in food and urine from adults in the United States from 2017 to 2023’, Journal of Exposure Science & Environmental Epidemiology [Preprint]. doi:10.1038/s41370-024-00643-4. ] - Embryotoxicity Induced by Triclopyr in Zebrafish (Danio rerio) Early Life Stage
Triclopyr, an auxin-like herbicide that is widely employed for managing weeds in food crops and pastures, has been identified in various environmental settings, particularly aquatic ecosystems. Limited understanding of the environmental fate of this herbicide, its potential repercussions for both the environment and human health, and its insufficient monitoring in diverse environmental compartments has caused it to be recognized as an emerging contaminant of concern. In this study, we have investigated how triclopyr affects zebrafish, considering a new alternative methodology. We focused on the endpoints of developmental toxicity, neurotoxicity, and behavior of zebrafish embryos and larvae. We determined that triclopyr has a 96 h median lethal concentration of 87.46 mg/L (341.01 µM). When we exposed zebrafish embryos to sublethal triclopyr concentrations (0.5, 1, 5, 10, and 50 μM) for up to 144 h, we found that 50 µM triclopyr delayed zebrafish egg hatchability. Yolk sac malabsorption was significant at 0.5, 1, 5, and 10 µM triclopyr. In zebrafish larvae, uninflated swim bladder was significant only at 50 µM triclopyr. Furthermore, zebrafish larvae had altered swimming activity after exposure to 10 µM triclopyr for 144 h. In summary, these comprehensive results indicate that even low triclopyr concentrations can elicit adverse effects during early zebrafish development.
[Bertoni, Í. et al. (2024) Embryotoxicity Induced by Triclopyr in Zebrafish (Danio rerio) Early Life Stage, Toxics. Available at: https://www.mdpi.com/2305-6304/12/4/255. ] - Gestational glyphosate exposure and early childhood neurodevelopment in a Puerto Rico birth cohort
Abstract
Introduction
N-(phosphonomethyl)glycine, or glyphosate, is a non-selective systemic herbicide widely used in agricultural, industrial, and residential settings since 1974. Glyphosate exposure has been inconsistently linked to neurotoxicity in animals, and studies of effects of gestational exposure among humans are scarce. In this study we investigated relationships between prenatal urinary glyphosate analytes and early childhood neurodevelopment.
Methods
Mother-child pairs from the PROTECT-CRECE birth cohort in Puerto Rico with measures for both maternal urinary glyphosate analytes and child neurodevelopment were included for analysis (n = 143). Spot urine samples were collected 1–3 times throughout pregnancy and analyzed for glyphosate and aminomethylphosphonic acid (AMPA), an environmental degradant of glyphosate. Child neurodevelopment was assessed at 6, 12, and 24 months using the Battelle Developmental Inventory, 2nd edition Spanish (BDI-2), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. We used multivariable linear regression to examine associations between the geometric mean of maternal urinary glyphosate analytes across pregnancy and BDI-2 scores at each follow-up. Results were expressed as percent change in BDI-2 score per interquartile range increase in exposure.
Results
Prenatal AMPA concentrations were negatively associated with communication domain at 12 months (%change = −5.32; 95%CI: 9.04, −1.61; p = 0.007), and communication subdomain scores at 12 and 24 months. At 24 months, four BDI-2 domains were associated with AMPA: adaptive (%change = −3.15; 95%CI: 6.05, −0.25; p = 0.038), personal-social (%change = −4.37; 95%CI: 7.48, −1.26; p = 0.008), communication (%change = −7.00; 95%CI: 11.75, −2.26; p = 0.005), and cognitive (%change = −4.02; 95%CI: 6.72, −1.32; p = 0.005). Similar trends were observed with GLY concentrations, but most confidence intervals include zero. We found no significant associations at 6 months.
Conclusions
Our results suggest that gestational exposure to glyphosate is associated with adverse early neurodevelopment, with more pronounced delays at 24 months. Given glyphosate's wide usage, further investigation into the impact of gestational glyphosate exposure on neurodevelopment is warranted.
[Jenkins, H.M. et al. (2024) ‘Gestational glyphosate exposure and early childhood neurodevelopment in a Puerto Rico birth cohort’, Environmental Research, 246, p. 118114. doi:10.1016/j.envres.2024.118114. ] - Glyphosate formulations cause mortality and diverse sublethal defects during embryonic development of the amphibian Xenopus laevis
The human impact on environmental landscapes, such as land use, climate change or pollution, is threatening global biodiversity and ecosystems maintenance. Pesticides like the herbicide glyphosate have garnered considerable attention due to their well-documented harmful effects on non-target species. During application, the active ingredient glyphosate is utilized in various formulations, each containing different additive adjuvants. However, the possible effects of these formulations on amphibians - the group with the highest decline rates among vertebrates - remain largely unknown.
Therefore, the present study investigated the effects of four glyphosate formulations (Glyphosat TF, Durano TF, Helosate 450 TF, Kyleo) on the embryonic development of the model organism Xenopus laevis (South African clawed frog). Embryos at the 2-cell stage were exposed to various concentrations of glyphosate formulations (glyphosate: 0.01–100 mg/L), and mortality as well as sublethal effects on different organs and tissues were analyzed. The results indicated that the formulations had different effects, particularly on the mortality of Xenopus laevis embryos. At sublethal concentrations, the formulations altered the embryos' external appearance, leading to malformations such as reduced eye and head size. In addition, exposure to formulations impaired heart morphology and function, and the expression of heart-specific genes was altered at a molecular level.
Our results confirmed that glyphosate formulations had a stronger effect on Xenopus laevis embryogenesis than pure glyphosate. Therefore, it is crucial to evaluate the active ingredient and the co-formulations independently, as well as the combined, commercially available products, during pesticide risk assessments and renewal procedures of agrochemicals. The severe global decline of amphibians, partly due to herbicide use, highlights the need for strict and efficient monitoring of environmental pesticide loads and application areas.
[Flach, H. et al. (2024) Glyphosate formulations cause mortality and diverse sublethal defects during embryonic development of the amphibian Xenopus laevis, Chemosphere. Available at: https://www.sciencedirect.com/science/article/pii/S0045653524025244.] - Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults
Background
Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years.Methods
We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language.Results
There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (β per ten-fold increase in DAPs = 3.37; 95% CI: −0.02, 6.77 and β = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (β = −3.10; 95% CI: −6.43, 0.22 and β = −3.67; 95% CI: −7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task.Discussion
We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts.
[Sagiv, S. et al. (2024) Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults, Environmental Research. Available at: https://www.sciencedirect.com/science/article/pii/S0013935123025604?via%3Dihub. ] - Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid function, and intelligence quotient at 7 years of age: Findings from the Sheyang Mini Birth Cohort Study
Background
Prenatal exposure to per- and polyfluoroalkyl substances (PFASs) influences neurodevelopment. Thyroid homeostasis disruption is thought to be a possible underlying mechanism. However, current epidemiological evidence remains inconclusive.
Objectives
This study aimed to explore the effects of prenatal PFAS exposure on the intelligence quotient (IQ) of school-aged children and assess the potential mediating role of fetal thyroid function.
Methods
The study included 327 7-year-old children from the Sheyang Mini Birth Cohort Study (SMBCS). Cord serum samples were analyzed for 12 PFAS concentrations and 5 thyroid hormone (TH) levels. IQ was assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models (GLM) and Bayesian Kernel Machine Regression (BKMR) were used to evaluate the individual and combined effects of prenatal PFAS exposure on IQ. Additionally, the impact on fetal thyroid function was examined using a GLM, and a mediation analysis was conducted to explore the potential mediating roles of this function.
Results
The molar sum concentration of perfluorinated carboxylic acids (ΣPFCA) in cord serum was significantly negatively associated with the performance IQ (PIQ) of 7-year-old children (β = -6.21, 95 % confidence interval [CI]: −12.21, −0.21), with more pronounced associations observed among girls (β = -9.57, 95 % CI: −18.33, −0.81) than in boys. Negative, albeit non-significant, cumulative effects were noted when considering PFAS mixture exposure. Prenatal exposure to perfluorooctanoic acid, perfluorononanoic acid, and perfluorooctanesulfonic acid was positively associated with the total thyroxine/triiodothyronine ratio. However, no evidence supported the mediating role of thyroid function in the link between PFAS exposure and IQ.
Conclusions
Increased prenatal exposure to PFASs negatively affected the IQ of school-aged children, whereas fetal thyroid function did not serve as a mediator in this relationship.
[Zhang, B. et al. (2024) Prenatal exposure to per- and polyfluoroalkyl substances, fetal thyroid function, and intelligence quotient at 7 years of age: Findings from the Sheyang Mini Birth Cohort Study, Environment International. Available at: https://www.sciencedirect.com/science/article/pii/S0160412024003064. ] - Update of the risk assessment of polybrominated diphenyl ethers (PBDEs) in food
The European Commission asked EFSA to update its 2011 risk assessment on polybrominated diphenyl ethers (PBDEs) in food, focusing on 10 congeners: BDE-28, -47, -49, -99, -100, -138, -153, -154, -183 and ‑209. The CONTAM Panel concluded that the neurodevelopmental effects on behaviour and reproductive/developmental effects are the critical effects in rodent studies. For four congeners (BDE-47, -99, -153, -209) the Panel derived Reference Points, i.e. benchmark doses and corresponding lower 95% confidence limits (BMDLs), for endpoint-specific benchmark responses. Since repeated exposure to PBDEs results in accumulation of these chemicals in the body, the Panel estimated the body burden at the BMDL in rodents, and the chronic intake that would lead to the same body burden in humans. For the remaining six congeners no studies were available to identify Reference Points. The Panel concluded that there is scientific basis for inclusion of all 10 congeners in a common assessment group and performed a combined risk assessment. The Panel concluded that the combined margin of exposure (MOET) approach was the most appropriate risk metric and applied a tiered approach to the risk characterisation. Over 84,000 analytical results for the 10 congeners in food were used to estimate the exposure across dietary surveys and age groups of the European population. The most important contributors to the chronic dietary Lower Bound exposure to PBDEs were meat and meat products and fish and seafood. Taking into account the uncertainties affecting the assessment, the Panel concluded that it is likely that current dietary exposure to PBDEs in the European population raises a health concern.
[Schrenk, D. et al. (2024) Update of the risk assessment of polybrominated diphenyl ..., EFSA Journal. Available at: https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2024.8497. ] - Developmental Exposure to DDT Disrupts Transcriptional Regulation of Postnatal Growth and Cell Renewal of Adrenal Medulla
Dichlorodiphenyltrichloroethane (DDT) is the most widespread persistent pollutant with endocrine-disrupting properties. DDT has been shown to disrupt secretory and morphogenetic processes in the adrenal cortex. The present investigation aimed to evaluate transcriptional regulation of postnatal growth of the adrenal medulla and formation of the pools necessary for self-renewal of medullary cells in rats that developed under low-dose exposure to DDT. The study was performed using male Wistar rats exposed to low doses of o,p'-DDT during prenatal and postnatal development. Light microscopy and histomorphometry revealed diminished medulla growth in the DDT-exposed rats. Evaluation of Ki-67 expression in chromaffin cells found later activation of proliferation indicative of retarded growth of the adrenal medulla. All DDT-exposed rats exhibited a gradual decrease in tyrosine hydroxylase production by adrenal chromaffin cells. Immunohistochemical evaluation of nuclear β-catenin, transcription factor Oct4, and ligand of sonic hedgehog revealed increased expression of all factors after termination of growth in the control rats. The DDT-exposed rats demonstrated diminished increases in Oct4 and sonic hedgehog expression and lower levels of canonical Wnt signaling activation. Thus, developmental exposure to the endocrine disruptor o,p'-DDT alters the transcriptional regulation of morphogenetic processes in the adrenal medulla and evokes a slowdown in its growth and in the formation of a reserve pool of cells capable of dedifferentiation and proliferation that maintain cellular homeostasis in adult adrenals.
[Yaglova, N.V., Nazimova, S.V., Obernikhin, S.S., Tsomartova, D.A., Yaglov, V.V., Timokhina, E.P., Tsomartova, E.S., Chereshneva, E.V., Ivanova, M.Y. and Lomanovskaya, T.A., 2023. International Journal of Molecular Sciences, 24(3), p.2774.] - Maternal exposure to a glyphosate-based herbicide impairs placental development through endoplasmic reticulum stress in mice
Glyphosate-based herbicides (GBHs) are the most widely used agrochemicals worldwide, increasing the risk of their occurrence in the environment. This study aimed to explore effects and mechanisms of GBH exposure on placental development in vivo during pregnancy in mice. Pregnant mice received GBH by gavage at 0, 5, and 50 mg⋅kg-1⋅day-1 doses from gestational day (GD) 1 to GD 13 and were sacrificed on GD 13 or GD19. Our data indicated that GBH administration significantly increased the number of resorbed fetuses, reduced the weight of fetuses and placentas, and inhibited placental growth, as evident from decreased placental total area and spongiotrophoblast area on GD 19. GBH treatment also inhibited proliferation and induced apoptosis of placenta via upregulation of Bax, cleaved caspase-3 and -12 expression, and downregulation of B cell lymphoma (Bcl)-2 expression. Further study showed that GBH exposure significantly increased expression levels of glucose-regulated protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and C/EBP homologous protein (CHOP) mRNAs and proteins and triggered oxidative stress in placenta on GD 13 and GD 19. In conclusion, our findings suggest that maternal exposure to GBH can impair placental development through the endoplasmic reticulum stress-mediated activation of GRP78/PERK/CHOP signaling pathway in mice.
[Liu, M., Lu, S., Yang, C., Zhang, D., Zhu, J., Yin, J., Zhao, H., Yang, B. and Kuang, H., 2023. Food and Chemical Toxicology, 173, p.113640.] - Neurodevelopmental Disorders (NDDs): Beyond the Clinical Definition and Translational Approach
Neurodevelopmental disorders (NDDs) are complex and heterogeneous disorders that affect the growth and development of the brain and are often associated with impairments in cognitive and motor functions, communication, and adaptive behavior. Although the diagnostic manuals define NDDs as separate entities, they co-occur with high frequency, determining a more complex clinical presentation, and therefore a more challenging evaluation and treatment. Moreover, they are frequently associated with other health conditions, causing increased negative individual and family burden and very high costs. Thus, the aim of this Special Issue of Children was to shed light on recent data in the field of NDDs, with regard to the etiopathogenesis of these disorders, as well as common and specific underpinnings, in order to raise awareness about the need for a deeper awareness of the specificities within these disorders and their common transdiagnostic mechanisms, with the goal of identifying new therapeutic targets and options.
[Pallanti, S. and Salerno, L. (2023) ‘Neurodevelopmental Disorders (ndds): Beyond the clinical definition and translational approach’, Children, 10(1), p. 99. doi:10.3390/children10010099. ] - Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse
Piperonyl butoxide (PBO) is a popular insecticide synergist present in thousands of commercial, agricultural, and household products. PBO inhibits cytochrome P450 activity, impairing the ability of insects to detoxify insecticides. PBO was recently discovered to also inhibit Sonic hedgehog signaling, a pathway required for embryonic development, and rodent studies have demonstrated the potential for in utero PBO exposure to cause structural malformations of the brain, face, and limbs, or more subtle neurodevelopmental abnormalities. The current understanding of the pharmacokinetics of PBO in mice is limited, particularly with respect to dosing paradigms associated with developmental toxicity. To establish a pharmacokinetic (PK) model for oral exposure, PBO was administered to female C57BL/6J mice acutely by oral gavage (22–1800 mg/kg) or via diet (0.09 % PBO in chow). Serum and adipose samples were collected, and PBO concentrations were determined by HPLC-MS/MS. The serum concentrations of PBO were best fit by a linear one-compartment model. PBO concentrations in visceral adipose tissue greatly exceeded those in serum. PBO concentrations in both serum and adipose tissue decreased quickly after cessation of dietary exposure. The elimination half-life of PBO in the mouse after gavage dosing was 6.5 h (90 % CI 4.7–9.5 h), and systemic oral clearance was 83.3 ± 20.5 mL/h. The bioavailability of PBO in chow was 41 % that of PBO delivered in olive oil by gavage. Establishment of this PK model provides a foundation for relating PBO concentrations that cause developmental toxicity in the rodent models to Sonic hedgehog signaling pathway inhibition.
[Jenkins, A. et al. (2023) Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse, Toxicology Reports. Available at: https://www.sciencedirect.com/science/article/pii/S2214750023001099. ] - 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.] - The association of prenatal phthalates, organophosphorous pesticides, and organophosphate esters with early child language ability in Norway
Prenatal exposure to phthalates, organophosphate esters, and organophosphorous pesticides have been associated with neurodevelopmental deficits including language ability, however, few studies consider the effect of exposure mixtures and the potential longitudinal detriments over time. This study examines the influence of prenatal exposure to phthalates, organophosphate esters, and organophosphorous pesticides, on children's language ability from toddlerhood to the preschool period. This study includes 299 mother-child dyads from Norway in the Norwegian Mother, Father and Child Cohort Study (MoBa). Prenatal exposure to chemicals were assessed at 17 weeks’ gestation, and child language skills were assessed at 18 months using the Ages and Stages Questionnaire communication subscale and at preschool age using the Child Development Inventory. We ran two structural equation models to examine the simultaneous influences of chemical exposures on parent-reported and teacher-reported child language ability. Prenatal organophosphorous pesticides were negatively associated with preschool language ability through language ability at 18 months. Additionally, there was a negative association between low molecular weight phthalates and teacher-reported preschool language ability. There was no effect of prenatal organophosphate esters on child language ability at either 18 months or preschool age. This study adds to the literature on prenatal exposure to chemicals and neurodevelopment and highlights the importance of developmental pathways in early childhood.
[Ramos, A.M., Herring, A.H., Villanger, G.D., Thomsen, C., Sakhi, A.K., Cequier, E., Aase, H. and Engel, S.M., 2023. Environmental Research, 225, p.115508.] - Effects of prenatal and infant daily exposure to pyrethroid pesticides on the language development of 2-year-old toddlers: A prospective cohort study in rural Yunnan, China
Prenatal and infant daily exposures to pyrethroid pesticides (PYRs), used in the elimination of harmful organisms in the family environment and agricultural activities, may have an impact on children's language development. To determine the impacts of prenatal and infant PYRs exposure on 2-year-old toddlers' language development. From January 2016 to December 2018, women in the third trimester of pregnancy, in Yunnan rural area, China, were recruited, and the development of their newborns was observed from birth till the age of two. We examined three PYRs metabolites: 3-phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F3PBA), and cis-2,2dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA) in urine samples collected from women in the third trimester of pregnancy and their infants of 6-8 months after birth, and assessed language development of 2-year-old toddlers by the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Generalized linear models were used to analyze the impacts of exposure to PYRs on 2-year-old toddlers' language development. The median concentrations of 3PBA, 4F3PBA and DBCA creatinine-adjusted were 0.21, 0.19, and 0.15 μg/g in pregnancy, and 0.25, 0.72, and
[Chen, S., Xiao, X., Qi, Z., Chen, L., Chen, Y., Xu, L., Zhang, L., Song, X. and Li, Y. NeuroToxicology.] - Exposure impacts of Imazapyr formulation on larval development and thyroid histology of Xenopus laevis
There are increased concerns about the thyroidal effects of many anthropogenic substances in the environment. These substances include agricultural pesticides and industrial and pharmaceutical chemicals among others. Their potential thyroidal effects are of serious health and ecological concerns, as thyroid hormones mediate numerous physiological processes, including growth regulation, general metabolism and metamorphosis in metamorphic animals. This study assessed thyroidal activities of Arsenal formulation (Imazapyr) at environmentally relevant concentrations of 0.5, 2.0 and 3.5 mg/L following a Xenopus metamorphosis assay (XEMA). The result shows that the Arsenal formulation significantly delayed the tadpole development, reduced the hind-limb length (HLL) and increased the whole-body mass (WBM) at a concentration of 3.5 mg/L relative to the control exposure. In histopathology, the formulation increased the epithelium height, at all exposure concentrations, but reduced the colloidal area at 0.5 and 2 mg/L, respectively, and the gland area at 2 mg/L relative to the control. Consequently, the Arsenal formulation is thyroid-active at environmentally relevant concentrations and poses a threat to both human and wildlife, especially metamorphic organisms. With this exposure impact, more studies are imperative to further characterise other endocrine-disrupting potential of this formulation.
[Babalola, O.O. and van Wyk, J.H. (2021) Exposure impacts of Imazapyr formulation on larval development and thyroid histology of Xenopus laevis, Environmental Science and Pollution Research. Available at: https://link.springer.com/article/10.1007/s11356-021-14227-4. ] - Agrochemicals disrupt multiple endocrine axes in amphibians
Concern over global amphibian declines and possible links to agrochemical use has led to research on the endocrine disrupting actions of agrochemicals, such as fertilizers, fungicides, insecticides, acaricides, herbicides, metals, and mixtures. Amphibians, like other species, have to partition resources for body maintenance, growth, and reproduction. Recent studies suggest that metabolic impairments induced by endocrine disrupting chemicals, and more particularly agrichemicals, may disrupt physiological constraints associated with these limited resources and could cause deleterious effects on growth and reproduction. Metabolic disruption has hardly been considered for amphibian species following agrichemical exposure. As for metamorphosis, the key thyroid hormone-dependent developmental phase for amphibians, it can either be advanced or delayed by agrichemicals with consequences for juvenile and adult health and survival. While numerous agrichemicals affect anuran sexual development, including sex reversal and intersex in several species, little is known about the mechanisms involved in dysregulation of the sex differentiation processes. Adult anurans display stereotypical male mating calls and female phonotaxis responses leading to successful amplexus and spawning. These are hormone-dependent behaviours at the foundation of reproductive success. Therefore, male vocalizations are highly ecologically-relevant and may be a non-invasive low-cost method for the assessment of endocrine disruption at the population level. While it is clear that agrochemicals disrupt multiple endocrine systems in frogs, very little has been uncovered regarding the molecular and cellular mechanisms at the basis of these actions. This is surprising, given the importance of the frog models to our deep understanding of developmental biology and thyroid hormone action to understand human health. Several agrochemicals were found to have multiple endocrine effects at once (e.g., targeting both the thyroid and gonadal axes); therefore, the assessment of agrochemicals that alter cross-talk between hormonal systems must be further addressed. Given the diversity of life-history traits in Anura, Caudata, and the Gymnophiona, it is essential that studies on endocrine disruption expand to include the lesser known taxa. Research under ecologically-relevant conditions will also be paramount. Closer collaboration between molecular and cellular endocrinologists and ecotoxicologists and ecologists is thus recommended.
[Trudeau, V. et al. (2020) Agrochemicals disrupt multiple endocrine axes in amphibians, Molecular and Cellular Endocrinology. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0303720720301611. ] - How do pesticides affect bats? – A brief review of recent publications
Increased agricultural production has been increased use of pesticides worldwide, which poses a threat to both human and environmental health. Recent studies suggest that several non-target organisms, from bees to mammals, show a wide variety of toxic effects of pesticides exposure, including impaired behavior, development and reproduction. Among mammals, bats are usually a neglected taxon among ecotoxicological studies, although they play important ecological and economical roles in forest ecosystems and agriculture through to seed dispersal and insect population control. Considering their wide variety of food habits, bats are exposed to environmental pollutants through food or water contamination, or through direct skin contact in their roosting areas. In order to better understand the risk posed by pesticides to bats populations, we compiled studies that investigated the main toxicological effects of pesticides in bats, aiming at contributing to discussion about the environmental risks associated with the use of pesticides.
[Oliveira, J.M. et al. (2020) How do pesticides affect bats? – A brief review of recent publications, Brazilian Journal of Biology. Available at: https://www.scielo.br/j/bjb/a/tnNtGd6GfzQFz6yNXNdzJPw/?lang=en. ] - Maternal chlormequat chloride exposure disrupts embryonic growth and produces postnatal adverse effects
Abstract
We showed previously that chlormequat chloride, a widely used plant growth regulator, could affect embryonic growth and growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis of rats. However, the potential effects of low dose chlormequat chloride exposure during pregnancy on embryonic and postnatal growth and development remain unclear. To further assess the risk of chlormequat chloride to human embryonic growth and postnatal health, we exposed maternal rats orally to the chemical during pregnancy at 5 mg/kg bw, a dose corresponding to the human acceptable daily intake (ADI) level set by World Health Organization (WHO), and determined the effects of chlormequat on embryo growth and postnatal health. We found that chlormequat chloride increased embryonic growth parameters, GH, and GH-releasing hormone (GHRH) levels, but did not affect somatostatin and IGF-1 on gestational day (GD) 11. In the pups of postnatal day (PD) 7, we observed increased head length, decreased body fat percentage, hypoglycemia, hyperlipidemia and hyperproteinemia. In conclusion, maternal exposure to chlormequat chloride during pregnancy disrupts the embryonic growth probably through its effects on growth regulators and even has adverse effects on postnatal health.
[Xiagedeer, B. et al. (2020) ‘Maternal chlormequat chloride exposure disrupts embryonic growth and produces postnatal adverse effects’, Toxicology, 442, p. 152534. doi:10.1016/j.tox.2020.152534. ] - Prenatal organophosphate insecticide exposure and infant sensory function.
Occupational studies suggest that exposure to organophosphate insecticides (OPs) can lead to vision or hearing loss. Yet the effects of early-life exposure on visual and auditory function are unknown. Here we examined associations between prenatal OP exposure and grating visual acuity (VA) and auditory brainstem response (ABR) during infancy. 30 OPs were measured in umbilical cord blood using gas chromatography tandem mass spectrometry in a cohort of Chinese infants. Grating visual acuity (VA) (n = 179-200) and auditory brainstem response (ABR) (n = 139-183) were assessed at 6 weeks, 9 months, and 18 months. Outcomes included VA score, ABR wave V latency and central conduction time, and head circumference (HC). Associations between sensory outcomes during infancy and cord OPs were examined using linear mixed models. Prenatal chlorpyrifos exposure was associated with lower 9-month grating VA scores; scores were 0.64 (95% CI: -1.22, -0.06) points lower for exposed versus unexposed infants (p = 0.03). The OPs examined were not associated with infant ABR latencies, but chlorpyrifos and phorate were both significantly inversely associated with HC at 9 months; HCs were 0.41 (95% CI: 0.75, 0.6) cm and 0.44 (95% CI: 0.88, 0.1) cm smaller for chlorpyrifos (p = 0.02) and phorate (p = 0.04), respectively.We found deficits in grating VA and HC in 9-month-old infants with prenatal exposure to chlorpyrifos. The clinical significance of these small but statistically significant deficits is unclear. However, the disruption of visual or auditory pathway maturation in infancy could potentially negatively affect downstream cognitive development.
[Silver MK, Shao J, Ji C, Zhu B, Xu L, Li M, et al. 2018. Int J Hyg Environ Health. pii: S1438-4639(17)30563-1.] - Association between Pesticide Profiles Used on Agricultural Fields near Maternal Residences during Pregnancy and IQ at Age 7 Years.
We previously showed that potential prenatal exposure to agricultural pesticides was associated with adverse neurodevelopmental outcomes in children, yet the effects of joint exposure to multiple pesticides is poorly understood. In this paper, we investigate associations between the joint distribution of agricultural use patterns of multiple pesticides (denoted as "pesticide profiles") applied near maternal residences during pregnancy and Full-Scale Intelligence Quotient (FSIQ) at 7 years of age. Among a cohort of children residing in California's Salinas Valley, we used Pesticide Use Report (PUR) data to characterize potential exposure from use within 1 km of maternal residences during pregnancy for 15 potentially neurotoxic pesticides from five different chemical classes. We used Bayesian profile regression (BPR) to examine associations between clustered pesticide profiles and deficits in childhood FSIQ. BPR identified eight distinct clusters of prenatal pesticide profiles. Two of the pesticide profile clusters exhibited some of the highest cumulative pesticide use levels and were associated with deficits in adjusted FSIQ of -6.9 (95% credible interval: -11.3, -2.2) and -6.4 (95% credible interval: -13.1, 0.49), respectively, when compared with the pesticide profile cluster that showed the lowest level of pesticides use. Although maternal residence during pregnancy near high agricultural use of multiple neurotoxic pesticides was associated with FSIQ deficit, the magnitude of the associations showed potential for sub-additive effects. Epidemiologic analysis of pesticides and their potential health effects can benefit from a multi-pollutant approach to analysis.
[Coker E, Gunier R, Bradman A, et al. 2017. Int J Environ Res Public Health. 14(5). pii: E506.] - 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.] - Behavioural disorders in 6-year-old children and pyrethroid insecticide exposure: the PELAGIE mother-child cohort.
The potential impact of environmental exposure to pyrethroid insecticides on child neurodevelopment has only just started to receive attention despite their widespread use. We investigated the associations between prenatal and childhood exposure to pyrethroid insecticides and behavioural skills in 6-year-olds.The PELAGIE cohort enrolled 3421 pregnant women from Brittany, France between 2002 and 2006. 428 mothers were randomly selected for the study when their children turned 6, and 287 (67%) agreed to participate. Children's behaviour was assessed using the Strengths and Difficulties Questionnaire (SDQ). Three subscales (prosocial behaviour, internalising disorders and externalising disorders) were considered. Five pyrethroid metabolites were measured in maternal and child urine samples collected between 6 and 19 gestational weeks and at 6 years of age, respectively. Increased prenatal cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCCA) concentrations were associated with internalising difficulties (Cox p value=0.05). For childhood 3-phenoxybenzoic acid (PBA) concentrations, a positive association was observed with externalising difficulties (Cox p value=0.04) and high ORs were found for abnormal or borderline social behaviour (OR 2.93, 95% CI 1.27 to 6.78, and OR 1.91, 95% CI 0.80 to 4.57, for the intermediate and highest metabolite categories, respectively). High childhood trans-DCCA concentrations were associated with reduced externalising disorders (Cox p value=0.03).The present study suggests that exposure to certain pyrethroids, at environmental levels, may negatively affect neurobehavioral development by 6 years of age.
[Viel JF, Rouget F, Warembourg C, Monfort C, et al. 2017. Occup Environ Med. 74(4):275-281.] - Effects of Neonicotinoid Pesticide Exposure on Human Health: A Systematic Review.
Numerous studies have identified detectable levels of neonicotinoids (neonics) in the environment, adverse effects of neonics in many species, including mammals, and pathways through which human exposure to neonics could occur, yet little is known about the human health effects of neonic exposure.In this systematic review, we sought to identify human population studies on the health effects of neonics. Eight studies investigating the human health effects of exposure to neonics were identified. Four examined acute exposure: Three neonic poisoning studies reported two fatalities (n = 1,280 cases) and an occupational exposure study of 19 forestry workers reported no adverse effects. Four general population studies reported associations between chronic neonic exposure and adverse developmental or neurological outcomes, including tetralogy of Fallot (AOR 2.4, 95% CI: 1.1, 5.4), anencephaly (AOR 2.9, 95% CI: 1.0, 8.2), autism spectrum disorder [AOR 1.3, 95% credible interval (CrI): 0.78, 2.2], and a symptom cluster including memory loss and finger tremor (OR 14, 95% CI: 3.5, 57). Reported odds ratios were based on exposed compared to unexposed groups.The studies conducted to date were limited in number with suggestive but methodologically weak findings related to chronic exposure. Given the wide-scale use of neonics, more studies are needed to fully understand their effects on human health.
[Cimino AM, Boyles AL, Thayer KA, Perry MJ. 2017. Environ Health Perspect. 125(2):155-162] - Neonicotinoid Insecticides Alter the Gene Expression Profile of Neuron-Enriched Cultures from Neonatal Rat Cerebellum
Neonicotinoids are considered safe because of their low affinities to mammalian nicotinic acetylcholine receptors (nAChRs) relative to insect nAChRs. However, because of importance of nAChRs in mammalian brain development, there remains a need to establish the safety of chronic neonicotinoid exposures with regards to children's health. Here we examined the effects of longterm (14 days) and low dose (1 μM) exposure of neuron-enriched cultures from neonatal rat cerebellum to nicotine and two neonicotinoids: acetamiprid and imidacloprid. Immunocytochemistry revealed no differences in the number or morphology of immature neurons or glial cells in any group versus untreated control cultures. However, a slight disturbance in Purkinje cell dendritic arborization was observed in the exposed cultures. Next we performed transcriptome analysis on total RNAs using microarrays, and identified significant differential expression (p < 0.05, q < 0.05, ≥1.5 fold) between control cultures versus nicotine-, acetamiprid-, or imidacloprid-exposed cultures in 34, 48, and 67 genes, respectively. Common to all exposed groups were nine genes essential for neurodevelopment, suggesting that chronic neonicotinoid exposure alters the transcriptome of the developing mammalian brain in a similar way to nicotine exposure. Our results highlight the need for further careful investigations into the effects of neonicotinoids in the developing mammalian brain.
[Kimura-Kuroda J, Nishito Y, Yanagisawa H, Kuroda Y, et al. 2017. Int J Environ Res Public Health. 13(10). pii: E987.] - 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.] - Polychlorinated Biphenyl and Organochlorine Pesticide Concentrations in Maternal Mid-Pregnancy Serum Samples: Association with Autism Spectrum Disorder and Intellectual Disability
Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are neurodevelopmental toxicants, but few studies have examined associations with autism spectrum disorder (ASD).We aimed to determine whether prenatal exposure to PCBs and OCPs influences offspring risk of ASD and intellectual disability without autism (ID).We conducted a population-based case-control study among Southern California births, including children with ASD (n = 545) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV-TR) criteria and ID (n = 181), as well as general population (GP) controls (n = 418). Concentrations of 11 PCB congeners and 2 OCPs measured in banked second-trimester serum samples were compared between the diagnostic groups. Logistic regression was used to calculate crude and adjusted odds ratios (AOR) for associations with ASD, and separately for ID, compared with GP controls, by quartiles of analyte concentrations in primary analyses.Geometric mean levels of several PCB congeners were higher in the ASD group than in the ID and GP groups. ASD risk was elevated for a number of PCB congeners, particularly for the highest vs. lowest quartile of PCB138/158 (AOR = 1.79; 95% CI: 1.10, 2.71) and PCB153 (AOR = 1.82; 95% CI: 1.10, 3.02), and for highest deciles of other congeners in secondary analyses. PCB138/158 was also associated with increased ID (AOR = 2.41; 95% CI: 1.18, 4.91), though no trend was suggested. OCPs were not associated with increased risk of ASD in primary analyses, whereas nonmonotonic increases in risk of ID were found with p,p´-DDE. Our results suggest higher levels of some organochlorine compounds during pregnancy are associated with ASD and ID.
[Lyall K, Croen LA, Sjödin A, Yoshida CK, et al. 2017. Environ Health Perspect. 125(3):474-480] - 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.] - Prenatal exposure to organophosphorus pesticides and childhood neurodevelopmental phenotypes.
Prenatal exposure to organophosphorus pesticides (OPs) has been associated with different neurodevelopmental outcomes across different cohorts. A phenotypic approach may address some of these differences by incorporating information across scales and accounting for the complex correlational structure of neurodevelopmental outcomes. Additionally, Bayesian hierarchical modeling can account for confounding by collinear co-exposures. We use this framework to examine associations between prenatal exposure to OPs and behavior, executive functioning, and IQ assessed at age 6-9 years in a cohort of 404 mother/infant pairs recruited during pregnancy. We derived phenotypes of neurodevelopment with a factor analysis, and estimated associations between OP metabolites and these phenotypes in Bayesian hierarchical models for exposure mixtures. We report seven factors: 1) Impulsivity and Externalizing, 2) Executive Functioning, 3) Internalizing, 4) Perceptual Reasoning, 5) Adaptability, 6) Processing Speed, and 7) Verbal Intelligence. These, along with the Working Memory Index, were standardized and scaled so that positive values reflected positive attributes and negative values represented adverse outcomes. Standardized dimethylphosphate metabolites were negatively associated with Internalizing factor scores (β^ - 0.13, 95% CI - 0.26, 0.00) but positively associated with Executive Functioning factor scores (β^ 0.18, 95% CI 0.04, 0.31). Standardized diethylphosphate metabolites were negatively associated with the Working Memory Index (β^ - 0.17, 95% CI - 0.33, - 0.03). Associations with factor scores were generally stronger and more precise than associations with individual instrument-specific items. Factor analysis of outcomes may provide some advantages in etiological studies of childhood neurodevelopment by incorporating information across scales to reduce dimensionality and improve precision.
[Furlong MA, Herring A, Buckley JP, Goldman BD, et al. 2017. Environ Res.158:737-747. ] - Prenatal exposure to pyrethroid pesticides and childhood behavior and executive functioning.
Several previous studies of pyrethroid biomarkers and behavior have reported associations between concurrent pyrethroid levels and adverse behavioral problems in children. One geospatial study reported associations between prenatal exposure to pyrethroids and autism. However, the association between prenatal pyrethroid biomarkers and childhood behavior is unknown. The Mount Sinai Children's Environmental Health Center is a prospective birth cohort with urinary pyrethroid biomarkers during pregnancy and behavioral measurements at 4, 6, and 7-9 years of age. Primiparous women were enrolled between 1998 and 2002. 162 mother/child pairs with complete exposure and behavioral outcomes data were used to investigate associations between detectable levels of prenatal pyrethroid metabolites and scores on the Behavioral Assessment System for Children and the Behavior Rating Inventory of Executive Function. Overall, detection frequencies of pyrethroid metabolites were low (<30%). In longitudinal mixed models, detectable levels of 3-PBA during pregnancy were associated with worse Internalizing (β -4.50, 95% CI -8.05, -0.95), Depression (β -3.21, 95% CI -6.38, -0.05), Somatization (β -3.22, 95% CI -6.38, -0.06), Behavioral Regulation (β -3.59, 95% CI -6.97, -0.21), Emotional Control (β -3.35, 95% CI -6.58, -0.12), Shifting (β -3.42, 95% CI -6.73, -0.11), and Monitoring (β -4.08, 95% CI -7.07, -1.08) scales. Detectable levels of cis-DCCA were associated with worse Externalizing (β -4.74, 95% CI -9.37, -0.10), Conduct Problems (β -5.35, 95% CI -9.90, -0.81), Behavioral Regulation (β -6.42, 95% CI -11.39, -1.45), and Inhibitory Control (β -7.20, 95% CI -12.00, -2.39). Although detection frequencies of pyrethroid metabolites were low, we found suggestive evidence that prenatal exposure to 3-PBA and cis-DCCA may be associated with a variety of behavioral and executive functioning deficits.
[Furlong MA, Barr DB, Wolff MS, Engel SM. 2017. Neurotoxicology. 62:231-238.] - Prenatal Residential Proximity to Agricultural Pesticide Use and IQ in 7-Year-Old Children.
Residential proximity to agricultural pesticide use has been associated with neural tube defects and autism, but more subtle outcomes such as cognition have not been studied.We evaluated the relationship between prenatal residential proximity to agricultural use of potentially neurotoxic pesticides and neurodevelopment in 7-year-old children.Participants included mothers and children (n=283) living in the agricultural Salinas Valley of California enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. We estimated agricultural pesticide use within 1 km of maternal residences during pregnancy using a geographic information system, residential location, and California’s comprehensive agricultural Pesticide Use Report data. We used regression models to evaluate prenatal residential proximity to agricultural use of five potentially neurotoxic pesticide groups (organophosphates, carbamates, pyrethroids, neonicotinoids, and manganese fungicides) and five individual organophosphates (acephate, chlorpyrifos, diazinon, malathion, and oxydemeton-methyl) and cognition in 7-year-old children. All models included prenatal urinary dialkyl phosphate metabolite concentrations.We observed a decrease of 2.2 points [95% confidence interval (CI): −3.9, −0.5] in Full-Scale IQ and 2.9 points (95% CI: −4.4, −1.3) in Verbal Comprehension for each standard deviation increase in toxicity-weighted use of organophosphate pesticides. In separate models, we observed similar decrements in Full-Scale IQ with each standard deviation increase of use for two organophosphates (acephate and oxydemeton-methyl) and three neurotoxic pesticide groups (pyrethroids, neonicotinoids, and manganese fungicides).This study identified potential relationships between maternal residential proximity to agricultural use of neurotoxic pesticides and poorer neurodevelopment in children.
[Gunier RB, Bradman A, Harley KG, Kogut K, Eskenazi B. 2017. Environ Health Perspect. 125(5):057002] - Residential proximity to agricultural fumigant use and IQ, attention and hyperactivity in 7-year old children
Our objective was to examine the relationship between residential proximity to agricultural fumigant use and neurodevelopment in 7-year old children. Participants were living in the agricultural Salinas Valley, California and enrolled in the Center for the Health Assessment of Mothers and Children Of Salinas (CHAMACOS) study. We administered the Wechsler Intelligence Scale for Children (4th Edition) to assess cognition and the Behavioral Assessment System for Children (2nd Edition) to assess behavior. We estimated agricultural fumigant use within 3, 5 and 8km of residences during pregnancy and from birth to age 7 using California's Pesticide Use Report data. We evaluated the association between prenatal (n = 285) and postnatal (n = 255) residential proximity to agricultural use of methyl bromide, chloropicrin, metam sodium and 1,3-dichloropropene with neurodevelopment. We observed decreases of 2.6 points (95% Confidence Interval (CI): -5.2, 0.0) and 2.4 points (95% CI: -4.7, -0.2) in Full-Scale intelligence quotient for each ten-fold increase in methyl bromide and chloropicrin use within 8km of the child's residences from birth to 7-years of age, respectively. There were no associations between residential proximity to use of other fumigants and cognition or proximity to use of any fumigant and hyperactivity or attention problems. These findings should be explored in larger studies.
[Gunier RB, Bradman A, Castorina R, Holland NT, et al. 2017. Environ Res. 158:358-365] - Sex-dependent effects of developmental exposure to different pesticides on spatial learning. The role of induced neuroinflammation in the hippocampus.
The use of pesticides has been associated with impaired neurodevelopment in children. The aims of this work were to assess: 1) the effects on spatial learning of developmental exposure to pesticides 2) if the effects are sex-dependent and 3) if hippocampal neuroinflammation is associated with the impairment of spatial learning. We analyzed the effects of developmental exposure to four pesticides: chlorpyrifos, carbaryl, endosulfan and cypermethrin. Exposure was from gestational day 7 to post-natal day 21 and spatial learning and memory was assessed when the rats were young adults. The effects of pesticides on spatial learning were pesticide and gender-dependent. Carbaryl did not affect spatial learning in males or females. Endosulfan and chlorpyrifos impaired learning in males but not in females. Cypermethrin improved spatial learning in the Morris water maze both in males and females while impaired learning in the radial maze only in males. Spatial learning ability was lower in control female rats than in males. All pesticides induced neuroinflammation, increasing IL-1b content in the hippocampus and there is a negative correlation between IL-1b levels in the hippocampus and spatial learning. Neuroinflammation would contribute to the effects of pesticides on spatial learning.
[Gómez-Giménez B, Llansola M, Hernández-Rabaza V, et al. 2017. Food Chem Toxicol. 99:135-148. ] - The Impact of Prenatal Organophosphate Pesticide Exposures on Thai Infant Neurodevelopment.
A birth cohort was begun to investigate the levels and sources of pesticide exposure in pregnant women living in Thailand, and to examine the effects of pesticide exposure on infant neurodevelopment at five months of age. Subjects were interviewed using questionnaires regarding their demographic characteristics, educational background, and work and home activities related to pesticide exposures. Spot urine samples were collected at 28 weeks gestation and analyzed by gas chromatography-mass spectrometry to determine maternal metabolite levels of organophosphate pesticides including dimethyl phosphate (DMP); total DEP (diethyl phosphate (DEP), diethyl thiophosphate (DETP), and diethyl dithiophosphate (DEDTP), and total DAP (the sum of all metabolite levels). At five months of age, infant development was evaluated using the Bayley Scales of Infant and Toddler Development-III (Bayley-III). Higher total DEP and total DAP metabolite levels from the mother at 28 weeks' gestation were significantly associated with reduced motor composite scores on the Bayley-III at five months of age. The total DEP levels were also significantly associated with reduced cognitive composite scores. Prenatal concentrations of maternal urinary metabolites were associated with infant cognitive and motor development. The results of several studies now suggest the need for public health intervention to reduce prenatal pesticide exposures from both agricultural and domestic use.
[Kongtip P, Techasaensiri B, Nankongnab N, et al. 2017. Int J Environ Res Public Health. 14(6). pii: E570.] - Urinary organophosphate insecticide metabolite concentrations during pregnancy and children's interpersonal, communication, repetitive, and stereotypic behaviors at 8 years of age: The home study.
Prenatal exposure to organophosphate insecticides may be associated with autism spectrum disorders and related behaviors. This association may be modified by single nucleotide polymorphisms in the paraoxonase (PON1) enzyme.
We examined the relationship of prenatal organophosphate insecticide biomarkers with reciprocal social, repetitive, and stereotypic behaviors in 8-year old children, and modification of this relationship by child PON1 polymorphisms.Among 224 pregnant women, we quantified concentrations of six nonspecific dialkyl phosphate (DAP) metabolites of organophosphate insecticides in two urine samples collected at ~16 and ~26 weeks gestation. When children were eight years old, we administered the Social Responsiveness Scale (SRS), a continuous measure of various dimensions of interpersonal behavior, communication, and repetitive/stereotypic behaviors. We estimated the association between a 10-fold increase in the sum of six DAP concentrations (ΣDAP) and SRS scores. We examined whether child PON1192 and PON1-108 genotypes modified this association.After covariate adjustment, ΣDAP concentrations were not associated with SRS scores [β=-1.2; 95% confidence interval (CI): -4.0, 1.6]. Among children with the PON1-108TT genotype, ΣDAP concentrations were associated with 2.5-point higher (95% CI: -4.9, 9.8) SRS scores; however, the association was not different from the 1.8-point decrease (95% CI: -5.8, 2.2) among children with PON1-108CT/CC genotypes (ΣDAP × PON1-108 p-value =0.54). The association between ΣDAP concentrations and SRS scores was not modified by PON1192 (ΣDAP × PON1192 p-value =0.89).In this cohort, prenatal urinary DAP concentrations were not associated with children's social behaviors; these associations were not modified by child PON1 genotype.
[Millenson ME, Braun JM, Calafat AM, Barr DB, et al. 2017. Environ Res. 157:9-16.] - Adverse Associations of both Prenatal and Postnatal Exposure to Organophosphorous Pesticides with Infant Neurodevelopment in an Agricultural Area of Jiangsu Province, China.
Prenatal exposure to organophosphorous (OP) pesticides has been found to be associated with adverse effects on child neurodevelopment, but evidence on potential effects induced by both prenatal and postnatal OP exposure in infants is limited.Our aim was to investigate the associations of both prenatal and postnatal OP exposure with birth outcomes and infant neurodevelopment.Exposure to OP in 310 mother-infant pairs was assessed by measuring dimethylphosphate (DM), diethylphosphate (DE), and total dialkylphosphate (DAP) metabolites in urines from pregnant women and their children at 2 years of age. The Gesell Developmental Schedules was administered to examine neurodevelopment of 2-year-old children.Based on the Gesell Developmental Schedules, the proportions of children with developmental delays were < 6%. Adverse associations between head circumference at birth and prenatal OP exposure were demonstrated. Both prenatal and postnatal OP exposure was significantly associated with increased risk of being developmentally delayed. Specifically, odds ratio (OR) value for prenatal DEs was 9.75 (95% CI: 1.28, 73.98, p = 0.028) in the adaptive area, whereas in the social area, OR values for postnatal DEs and DAPs were 9.56 (95% CI: 1.59, 57.57, p = 0.014) and 12.00 (95% CI: 1.23, 117.37, p = 0.033), respectively. Adverse associations were observed only in boys, not in girls.Both prenatal and postnatal OP exposure may adversely affect the neurodevelopment of infants living in the agricultural area. The present study adds to the accumulating evidence on associations of prenatal and postnatal OP exposure with infant neurodevelopment.
[Liu P, Wu C, Chang X, Qi X, Zheng M, Zhou Z. 2016. Environ Health Perspect. 124(10):1637-1643.] - An Observational Study to Evaluate Associations Between Low-Level Gestational Exposure to Organophosphate Pesticides and Cognition During Early Childhood.
Prenatal exposure to organophosphate pesticides, which is ubiquitous, may be detrimental to neurological development. We examined 327 mother/infant pairs in Cincinnati, Ohio, between 2003 and 2006 to determine associations between prenatal exposure to organophosphate pesticides and neurodevelopment. Twice during pregnancy urinary concentrations of 6 common dialkylphosphates, nonspecific metabolites of organophosphate pesticides, were measured. Aggregate concentrations of diethylphosphates, dimethylphosphates, and total dialkylphosphates were calculated. Bayley Scales of Infant Development, Second Edition-Mental and Psychomotor Developmental indices were administered at ages 1, 2, and 3 years, the Clinical Evaluation of Language Fundamentals-Preschool, Second Edition, at age 4, and the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, at age 5. Mothers with higher urinary total dialkylphosphate concentrations reported higher levels of socioeconomic status and increased fresh fruit and vegetable intake. We found no associations between prenatal exposure to organophosphate pesticides and cognition at 1-5 years of age. In our cohort, exposure to organophosphate pesticides during pregnancy was not associated with cognition during early childhood. It is possible that a higher socioeconomic status and healthier diet may protect the fetus from potential adverse associations with gestational organophosphate pesticide exposure, or that dietary exposure to the metabolites is innocuous and not an ideal measure of exposure to the parent compound.
[Donauer S, Altaye M, Xu Y, Sucharew H, et al. 2016. Am J Epidemiol. 184(5):410-8. ] - Pesticide exposure and neurodevelopment in children aged 6-9 years from Talamanca, Costa Rica.
Certain pesticides may affect children's neurodevelopment. We assessed whether pesticide exposure was associated with impaired neurobehavioral outcomes in children aged 6-9 years. We conducted a cross-sectional study in 140 children living near banana plantations and plantain farms in the Talamanca County, Costa Rica and assessed their neurobehavioral performance. Exposure was determined by analyzing urinary metabolites of chlorpyrifos (3,5,6-trichloro-2-pyridinol, TCPy), mancozeb (ethylenethiourea, ETU), and pyrethroids (3-phenoxybenzoic acid, 3-PBA). Repeated urine samples were obtained for 36 children. We estimated associations of pesticide concentrations with neurobehavioral outcomes using multivariable linear and logistic regression models. Median (25th-75th percentiles) TCPy, ETU, and 3-PBA concentrations were 1.4 (.7-3.1), 1.2 (.7-3.0), and .8 (.5-1.5) μg/L, respectively. Intraclass correlation coefficients (ICC) ranged between .32 and .67. After adjustment for potential confounders, higher urinary TCPy concentrations were associated with poorer working memory in boys (n = 59) (β per 10-fold increase in TCPy concentrations = -7.5, 95% CI: -14.4, -.7); poorer visual motor coordination (β = -1.4, 95% CI: -2.7, -.1); increased prevalence of parent-reported cognitive problems/inattention (adjusted OR per 10-fold increase in urinary concentrations = 5.8, 95% CI: 1.6, 22.9), oppositional disorders (aOR = 3.9, 95% CI: 1.0, 16.0), and ADHD (aOR = 6.8, 95% CI: 1.8, 28.6), and; decreased ability to discriminate colors (aOR = 6.6, 95% CI: 1.6, 30.3; the higher the score the worse). Higher ETU concentrations were associated with poorer verbal learning outcomes (β = -7.0, 95% CI: -12.7, -1.3). Higher 3-PBA concentrations were associated with poorer processing speed scores, particularly in girls (β = -8.8, 95% CI: -16.1, -1.4). Our findings indicate that children living near banana and plantain plantations are exposed to pesticides that may affect their neurodevelopment, which for certain domains may differ between boys and girls. We recommend the implementation of measures to reduce pesticide exposure in children living nearby banana plantations.
[van Wendel de Joode B, Mora AM, Lindh CH, et al. 2016. Cortex. 85:137-150. ] - Pesticides, Neurodevelopmental Disagreement, and Bradford Hill's Guidelines
Neurodevelopmental disorders such as autism affect one-eighth of all U.S. newborns. Yet scientists, accessing the same data and using Bradford-Hill guidelines, draw different conclusions about the causes of these disorders. They disagree about the pesticide-harm hypothesis, that typical United States prenatal pesticide exposure can cause neurodevelopmental damage. This article aims to discover whether apparent scientific disagreement about this hypothesis might be partly attributable to questionable interpretations of the Bradford-Hill causal guidelines. Key scientists, who claim to employ Bradford-Hill causal guidelines, yet fail to accept the pesticide-harm hypothesis, fall into errors of trimming the guidelines, requiring statistically-significant data, and ignoring semi-experimental evidence. However, the main scientists who accept the hypothesis appear to commit none of these errors. Although settling disagreement over the pesticide-harm hypothesis requires extensive analysis, this article suggests that at least some conflicts may arise because of questionable interpretations of the guidelines.
[Shrader-Frechette K, ChoGlueck C. 2016. Account Res. 1-13] - Prenatal exposure to multiple pesticides is associated with auditory brainstem response at 9months in a cohort study of Chinese infants
Pesticides are associated with poorer neurodevelopmental outcomes, but little is known about the effects on sensory functioning.Auditory brainstem response (ABR) and pesticide data were available for 27 healthy, full-term 9-month-old infants participating in a larger study of early iron deficiency and neurodevelopment. Cord blood was analyzed by gas chromatography-mass spectrometry for levels of 20 common pesticides. The ABR forward-masking condition consisted of a click stimulus (masker) delivered via ear canal transducers followed by an identical stimulus delayed by 8, 16, or 64 milliseconds (ms). ABR peak latencies were evaluated as a function of masker-stimulus time interval. Shorter wave latencies reflect faster neural conduction, more mature auditory pathways, and greater degree of myelination. Linear regression models were used to evaluate associations between total number of pesticides detected and ABR outcomes. We considered an additive or synergistic effect of poor iron status by stratifying our analysis by newborn ferritin (based on median split).Infants in the sample were highly exposed to pesticides; a mean of 4.1 pesticides were detected (range 0-9). ABR Wave V latency and central conduction time (CCT) were associated with the number of pesticides detected in cord blood for the 64ms and non-masker conditions. A similar pattern seen for CCT from the 8ms and 16ms conditions, although statistical significance was not reached. Increased pesticide exposure was associated with longer latency. The relation between number of pesticides detected in cord blood and CCT depended on the infant's cord blood ferritin level. Specifically, the relation was present in the lower cord blood ferritin group but not the higher cord blood ferritin group.ABR processing was slower in infants with greater prenatal pesticide exposure, indicating impaired neuromaturation. Infants with lower cord blood ferritin appeared to be more sensitive to the effects of prenatal pesticide exposure on ABR latency delay, suggesting an additive or multiplicative effect.
[Sturza J, Silver MK, Xu L, Li M, et al. 2016. Environ Int.92-93:478-85.] - Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism.
Autism spectrum disorders (ASD) are emerging as polygenic and multifactorial disorders in which complex interactions between defective genes and early exposure to environmental stressors impact on the correct neurodevelopment and brain processes. Organophosphate insecticides, among which chlorpyrifos (CPF), are widely diffused environmental toxicants associated with neurobehavioral deficits and increased risk of ASD occurrence in children. In the present study, we aimed at investigating whether the behavioral effects of gestational CPF administration are associated with brain increased oxidative stress and altered lipid mediator profile.Brain levels of F2-isoprostanes (15-F2t-IsoP), as index of in vivo oxidative stress, and prostaglandin E2 (PGE2), a major arachidonic acid metabolite released by immune cells and by specific glutamatergic neuron populations mainly in cortex and hippocampus, were assessed by specific enzyme-immuno assays in brain homogenates from BTBR T+tf/J and C57Bl6/J mice, exposed during gestation to either vehicle or CPF. Measures were performed in mice of both sexes, at different postnatal stages (PNDs 1, 21, and 70).At birth, BTBR T+tf/J mice exhibited higher baseline 15-F2t-IsoP levels as compared to C57Bl6/J mice, suggestive of greater oxidative stress processes. Gestational treatment with CPF-enhanced 15-F2t-IsoP and PGE2 levels in strain- and age-dependent manner, with 15-F2t-IsoP increased in BTBR T+tf/J mice at PNDs 1 and 21, and PGE2 elevated in BTBR T+tf/J mice at PNDs 21 and 70. At PND 21, CPF effects were sex-dependent being the increase of the two metabolites mainly associated with male mice. CPF treatment also induced a reduction of somatic growth, which reached statistical significance at PND 21.These findings indicate that the autistic-like BTBR T+tf/J strain is highly vulnerable to environmental stressors during gestational period. The results further support the hypothesis that oxidative stress might be the link between environmental neurotoxicants such as CPF and ASD. The increased levels of oxidative stress during early postnatal life could result in delayed and long-lasting alterations in specific pathways relevant to ASD, of which PGE2 signaling represents an important one.
[De Felice A, Greco A, Calamandrei G, Minghetti L. 2016. J Neuroinflammation. 13(1):149] - Prenatal Organophosphorus Pesticide Exposure and Child Neurodevelopment at 24 Months: An Analysis of Four Birth Cohorts.
Organophosphorus pesticides (OPs) are used in agriculture worldwide. Residential use was common in the United States before 2001.We conducted a pooled analysis of four birth cohorts (children's centers; n = 936) to evaluate associations of prenatal exposure to OPs with child development at 24 months. Using general linear models, we computed site-specific and pooled estimates of the association of total dialkyl (ΣDAP), diethyl (ΣDEP), and dimethylphosphate (ΣDMP) metabolite concentrations in maternal prenatal urine with mental and psychomotor development indices (MDI/PDI) and evaluated heterogeneity by children's center, race/ethnicity, and PON1 genotype.There was significant heterogeneity in the center-specific estimates of association for ΣDAP and ΣDMP and the MDI (p = 0.09, and p = 0.05, respectively), as well as heterogeneity in the race/ethnicity-specific estimates for ΣDAP (p = 0.06) and ΣDMP (p = 0.02) and the MDI. Strong MDI associations in the CHAMACOS population per 10-fold increase in ΣDAP (β = -4.17; 95% CI: -7.00, -1.33) and ΣDMP (β = -3.64; 95% CI: -5.97, -1.32) were influential, as were associations among Hispanics (β per 10-fold increase in ΣDAP = -2.91; 95% CI: -4.71, -1.12). We generally found stronger negative associations of ΣDAP and ΣDEP with the 24-month MDI for carriers of the 192Q PON1 allele, particularly among blacks and Hispanics. Data pooling was complicated by center-related differences in subject characteristics, eligibility, and changes in regulations governing residential use of OPs during the study periods. Pooled summary estimates of prenatal exposure to OPs and neurodevelopment should be interpreted with caution because of significant heterogeneity in associations by center, race/ethnicity, and PON1 genotype. Subgroups with unique exposure profiles or susceptibilities may be at higher risk for adverse neurodevelopment following prenatal exposure.
[Engel SM, Bradman A, Wolff MS, Rauh VA, Harley KG, Yang JH, Hoepner LA, et al. 2016. Environ Health Perspect. 124(6):822-30] - Prenatal Paraquat exposure induces neurobehavioral and cognitive changes in mice offspring.
In the present work, we investigated developmental toxicity of Paraquat (PQ), from the 1st or 6th day of mating and throughout the gestation period. We have examined several parameters, including toxicity indices, reproductive performance, sensorimotor development, as well as anxiety and cognitive performance of the offspring. Our results showed that exposure to 20mg/kg of Paraquat during the first days of pregnancy completely prevents pregnancy in treated mice, but from the 6th day of pregnancy, an alteration in fertility and reproductive parameters was observed. In offspring, the PQ was responsible for an overall delay of innate reflexes and a deficit in motor development. All exposed animals showed a decrease in the level of locomotor activity, increased levels of anxiety-like behavior and pronounced cognitive impairment in adulthood. These results demonstrated that Paraquat led to the onset of many behavioral changes that stem from the impairment of neuronal developmental processes in prenatally exposed mice.
[Ait-Bali Y, Ba-M'hamed S, Bennis M. 2016. Environ Toxicol Pharmacol. 48:53-62.] - Prenatal Residential Proximity to Agricultural Pesticide Use and IQ in 7-Year-Old Children.
Residential proximity to agricultural pesticide use has been associated with neural tube defects and autism but more subtle outcomes like cognition have not been studied.This study aimed to evaluate the relationship between prenatal residential proximity to agricultural use of potentially neurotoxic pesticides and neurodevelopment in 7-year old children.Participants included mothers and children (n=283) living in the agricultural Salinas Valley of California enrolled in the Center for the Health Assessment of Mothers and Children Of Salinas (CHAMACOS) study. We estimated agricultural pesticide use within one km of maternal residences during pregnancy using a geographic information system, residential location, and California's comprehensive agricultural Pesticide Use Report data. We used regression models to evaluate prenatal residential proximity to agricultural use of five potentially neurotoxic pesticide groups (organophosphates, carbamates, pyrethroids, neonicotinoids, and manganese fungicides) and five individual organophosphates (acephate, chlorpyrifos, diazinon, malathion and oxydemeton-methyl) and cognition in 7-year old children. All models included prenatal urinary dialkyl phosphate metabolite concentrations.We observed a decrease of 2.2 points (95% Confidence Interval (CI): -3.9, -0.5) in Full-Scale intelligence quotient (IQ) and 2.9 points (95% CI: -4.4, -1.3) in verbal comprehension for each standard deviation increase in toxicity-weighted use of organophosphate pesticides. In separate models, we observed similar decrements in Full-Scale IQ with each standard deviation increase of use for two organophosphates (acephate and oxydemeton-methyl) and three neurotoxic pesticide groups (pyrethroids, neonicotinoids, and manganese fungicides).This study identified potential relationships between maternal residential proximity to agricultural use of neurotoxic pesticides and poorer neurodevelopment in children.
[Gunier RB, Bradman A, Harley KG, et al. 2016. Environ Health Perspect. DOI: 10.1289/EHP504] - Prenatal Triclosan Exposure and Anthropometric Measures Including Anogenital Distance in Danish Infants.
Prenatal triclosan exposure is associated with reduced head circumference, a trait linked to cognitive impairment.
[Lassen et al. 2016. Environmental Health Perspectives doi: 10.1289/ehp.1409637.] - Research Review: Environmental exposures, neurodevelopment, and child mental health - new paradigms for the study of brain and behavioral effects.
Environmental exposures play a critical role in the genesis of some child mental health problems.We open with a discussion of children's vulnerability to neurotoxic substances, changes in the distribution of toxic exposures, and cooccurrence of social and physical exposures. We address trends in prevalence of mental health disorders, and approaches to the definition of disorders that are sensitive to the subtle effects of toxic exposures. We suggest broadening outcomes to include dimensional measures of autism spectrum disorders, attention-deficit hyperactivity disorder, and child learning capacity, as well as direct assessment of brain function.We consider the impact of two important exposures on children's mental health: lead and pesticides. We argue that longitudinal research designs may capture the cascading effects of exposures across biological systems and the full-range of neuropsychological endpoints. Neuroimaging is a valuable tool for observing brain maturation under varying environmental conditions. A dimensional approach to measurement may be sensitive to subtle subclinical toxic effects, permitting the development of exposure-related profiles and testing of complex functional relationships between brain and behavior. Questions about the neurotoxic effects of chemicals become more pressing when viewed through the lens of environmental justice.Reduction in the burden of child mental health disorders will require longitudinal study of neurotoxic exposures, incorporating dimensional approaches to outcome assessment, and measures of brain function. Research that seeks to identify links between toxic exposures and mental health outcomes has enormous public health and societal value.
[Rauh VA, Margolis AE. 2016. J Child Psychol Psychiatry. 57(7):775-93.] - Residential proximity to organophosphate and carbamate pesticide use during pregnancy, poverty during childhood, and cognitive functioning in 10-year-old children.
Low-income communities and communities of color have been shown to experience disproportionate exposure to agricultural pesticides, which have been linked to poorer neurobehavioral outcomes in infants and children. Few studies have assessed health impacts of pesticide mixtures in the context of socioeconomic adversity.We evaluated associations between both nearby agricultural pesticide use and poverty measures and cognitive abilities in 10-year-old children (n = 501) using data from a longitudinal birth cohort study linked with data from the California Pesticide Use Reporting system and the American Community Survey. Associations were assessed using multivariable linear regression.Children of mothers in the highest quartile compared to the lowest quartile of proximal pesticide use had lower performance on Full Scale IQ [β = -3.0; 95% Confidence Interval (CI) = (-5.6, -0.3)], Perceptual Reasoning [β = -4.0; (-7.6, -0.4)], and Working Memory [β = -2.8; (-5.6, -0.1)]. Belonging to a household earning an income at or below the poverty threshold was associated with approximately two point lower scores on Full Scale IQ, Verbal Comprehension, and Working Memory. Living in the highest quartile of neighborhood poverty at age 10 was associated with approximately four point lower performance on Full Scale IQ, Verbal Comprehension, Perceptual Reasoning, and Working memory.Residential proximity to OP and carbamate pesticide use during pregnancy and both household- and neighborhood-level poverty during childhood were independently associated with poorer cognitive functioning in children at 10 years of age.
[Rowe C, Gunier R, Bradman A, Harley KG, et al. 2016. Environ Res.150:128-37.] - The barrier, airway particle clearance, placental and detoxification functions of autism susceptibility genes.
Even taking problems of diagnosis into account, a five-fold increase in the incidence of autism in recent decades, in the absence of any known changes in the human gene pool suggests a strong environmental influence. Numerous pollutants have been implicated in epidemiological studies, including pesticides, heavy metals, industrial solvents, air pollutants, particulate matter, bisphenol A, phthalates and flame retardants. Many genes have been implicated in autism, some of which are directly related to detoxification processes. Many are also expressed prenatally in the frontal cortex when the effects of such toxins on neurodevelopment are most relevant. To gain access to the foetal brain, toxins must pass placental and blood/brain barriers and access to maternal or children's blood necessitates passage across skin, airway and intestinal barriers. Literature survey of a subset of 206 genes, defined as prime autism susceptibility candidates from an Autworks/Genotator analysis, revealed that most could be related to barrier function at blood/brain, skin, intestinal, placental or other interfaces. These genes were highly enriched in proteome datasets from blood/brain and placental trophoblast barriers and many localised to skin, intestinal, lung, umbilical and placental compartments. Many were also components of the exosomal/transcytosis pathway that is involved in the transfer of compounds across cells themselves, rather than between them. Several are involved in the control of respiratory cilia that sweep mucus and noxious particles from the airways. A key role of autism susceptibility genes may thus relate to their ability to modulate the access of numerous toxins to children, and adults and, during gestation, to the developing foetal brain.
[Carter CJ. 2016. Neurochem Int. 99:42-51] - ADHD-like behaviour in the offspring of female rats exposed to low chlorpyrifos doses before pregnancy
The aim of this study was to investigate how chronic low-dose chlorpyrifos exposure of female Wistar rats before and during pregnancy affects behavioural parameters in their offspring. Four months before pregnancy, we exposed three groups of rats to chlorpyrifos doses of 5, 10, and 15 mg kg-1 body weight every day for 30 days, whereas one group received a single 30 mg kg-1 dose on gestational day 6. When the offspring of the exposed rats grew up, we studied their anxiety rate, motor activity, and cognitive abilities using the respective behavioural tests: open field test, dark/light box, and the extrapolation escape test. The offspring of rats exposed before pregnancy had significantly higher activity rate than controls, and even showed motor agitation and hyperactivity signs. The offspring of rats exposed to the single dose had difficulties solving the extrapolation escape test and showed poorer short- and long-term memory performance. This confirmed that even pre-pregnancy chlorpyrifos exposure can cause neurobehavioral consequences in offspring. Even though the mechanisms of the observed changes remain unclear and need further investigation, these data seem alarming and may serve as an important argument for revising the terms of safe pesticide use.
[Grabovska S, Salyha Y. 2015. Arh Hig Rada Toksikol. 66(2):121-7] - Developmental neurotoxic effects of two pesticides: Behavior and biomolecular studies on chlorpyrifos and carbaryl.
In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. Authors studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8-12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development.
[Lee I, Eriksson P, Fredriksson A, et al. 2015. Toxicol Appl Pharmacol. pii: S0041-008X(15)30066-1.] - Effects of maternal chlorpyrifos diet on social investigation and brain neuroendocrine markers in the offspring - a mouse study.
Chlorpyrifos (CPF) is one of the most widely used organophosphate pesticides worldwide. Epidemiological studies on pregnant women and their children suggest a link between in utero CPF exposure and delay in psychomotor and cognitive maturation. Study's aim was to determine if developmental exposure to CPF affects social responsiveness and associated molecular neuroendocrine markers at adulthood.Pregnant CD1 outbred mice were fed from gestational day 15 to lactation day 14 with either a CPF-added (equivalent to 6 mg/kg/bw/day during pregnancy) or a standard diet. We then assessed in the offspring the long-term effects of CPF exposure on locomotion, social recognition performances and gene expression levels of selected neurondocrine markers in amygdala and hypothalamus.No sign of CPF systemic toxicity was detected. CPF induced behavioral alterations in adult offspring of both sexes: CPF-exposed males displayed enhanced investigative response to unfamiliar social stimuli, whereas CPF-exposed females showed a delayed onset of social investigation and lack of reaction to social novelty. In parallel, molecular effects of CPF were sex dimorphic: in males CPF increased expression of estrogen receptor beta in hypothalamus and decreased oxytocin expression in amygdala; CPF increased vasopressin 1a receptor expression in amygdala in both sexes.These data indicate that developmental CPF affects mouse social behavior and interferes with development of sex-dimorphic neuroendocrine pathways with potential disruptive effects on neuroendocrine axes homeostasis. The route of exposure selected in our study corresponds to relevant human exposure scenarios, our data thus supports the view that neuroendocrine effects, especially in susceptible time windows, should deserve more attention in risk assessment of OP insecticides.
[Venerosi A, Tait S, Stecca L, et al. 2015. Environ Health. 14:32.] - Occupational pesticide exposure in early pregnancy associated with sex-specific neurobehavioral deficits in the children at school age
Prenatal exposure to pesticides may affect neurodevelopment, while the impact of modern pesticides is unclear. From 1997-2001, women working in greenhouse horticultures were recruited at the beginning of their pregnancy. Based on detailed interview of the women and their employers, those categorized as occupationally exposed to pesticides were moved to unexposed work functions or went on paid leave, while women without any exposure were considered unexposed controls. Of the resulting birth cohort of 203 children, 133 (65%) were examined at age 6 to 11 years together with 44 newly recruited children of same age whose mothers were not occupationally exposed to pesticides in pregnancy. All children underwent a standardized examination including a battery of neurodevelopmental tests. Maternal occupational pesticide exposure in early pregnancy was associated with prolonged brainstem auditory evoked potential latencies in the children as a whole and with impaired neuropsychological function in girls, while no effect was apparent in boys. In girls, language and motor speed functions were significantly inversely associated with prenatal exposure, and a non-significant tendency toward decreased function was also seen for other neuropsychological outcomes. A structural equation model that combined all these test results showed an overall impaired neuropsychological function in girls prenatally exposed to pesticides. The findings suggest an adverse effect of maternal occupational pesticide exposure on their children's neurodevelopment, despite the fact that the exposures occurred solely during early pregnancy and under well regulated working conditions, where special measures to protect pregnant women were applied.
[Andersen HR, Debes F, Wohlfahrt-Veje C, et al. 2015. Neurotoxicol Teratol. 47:1-9.] - Pre- and postnatal exposures to pesticides and neurodevelopmental effects in children living in agricultural communities from South-Eastern Spain.
Childrens exposure to neurotoxic compounds poses a major problem to public health because oftheir actively developing brain that makes them highly vulnerable. However, limited information is available on neuropsychological effects in children associated with pre- and postnatal exposures to pesticides.Study's aim was to evaluate the association between current and pre- and postnatal exposures to pesticides and their effects on neurodevelopment in children aged 6–11 years living in agricultural communities from South-Eastern Spain.An ambispective study was conducted on 305 children aged 6–11 years randomly selected from public schools of the study area. Current exposure to organophosphate pesticides was assessed measuring children's urinary levels of dialkylphosphates (DAPs). Both prenatal and postnatal residential exposure to pesticides was estimated by developing a geographical information system (GIS) technology-based index that integrated distance-weighted measure of agricultural surface, time-series of crop areas per municipality and year, and land-use maps. Neuropsychological performance was evaluated with the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV).Greater urinary DAP levels were associated with a poorer performance on intelligence quotient and verbal comprehension domain, with effects being more prominent in boys than in girls. The influence of an increase in 10 ha per year in crop surface around the child's residence during the postnatal period was associated with decreased intelligence quotient, processing speed and verbal comprehension scores. As regards prenatal exposure to pesticides, a poor processing speed performance was observed. These effects were also more prominent in boys than in girls.Our results suggest that postnatal exposure to pesticides can negatively affect children's neuropsychological performance. Prenatal exposure was weakly associated to neurodevelopment impairment.
[González-Alzaga B, Hernández AF, Rodríguez-Barranco M, et al. 2015. Environ Int. 85:229-37. ] - Prenatal DDT and DDE exposure and child IQ in the CHAMACOS cohort.
Although banned in most countries, dichlorodiphenyl-trichloroethane (DDT) continues to be used for vector control in some malaria endemic areas. Previous findings from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort study found increased prenatal levels of DDT and its breakdown product dichlorodiphenyl-dichloroethylene (DDE) to be associated with altered neurodevelopment in children at 1 and 2years of age. In this study, we combined the measured maternal DDT/E concentrations during pregnancy obtained for the prospective birth cohort with predicted prenatal DDT and DDE levels estimated for a retrospective birth cohort. Using generalized estimating equation (GEE) and linear regression models, we evaluated the relationship of prenatal maternal DDT and DDE serum concentrations with children's cognition at ages 7 and 10.5years as assessed using the Full Scale Intelligence Quotient (IQ) and 4 subtest scores (Working Memory, Perceptual Reasoning, Verbal Comprehension, and Processing Speed) of the Wechsler Intelligence Scale for Children (WISC). In GEE analyses incorporating both age 7 and 10.5 scores (n=619), we found prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales (p-value>0.05). In linear regression analyses assessing each time point separately, prenatal DDT levels were inversely associated with Processing Speed at age 7years (n=316), but prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales at age 10.5years (n=595). We found evidence for effect modification by sex. In girls, but not boys, prenatal DDE levels were inversely associated with Full Scale IQ and Processing Speed at age 7years. We conclude that prenatal DDT levels may be associated with delayed Processing Speed in children at age 7years and the relationship between prenatal DDE levels and children's cognitive development may be modified by sex, with girls being more adversely affected.
[Gaspar FW, Harley KG, Kogut K, Chevrier J, et al. 2015. Environ Int. 85:206-12] - Prenatal exposure to a common organophosphate insecticide delays motor development in a mouse model of idiopathic autism
Autism spectrum disorders are characterized by impaired social and communicative skills and repetitive behaviors. Emerging evidence supported the hypothesis that these neurodevelopmental disorders may result from a combination of genetic susceptibility and exposure to environmental toxins in early developmental phases. This study assessed the effects of prenatal exposure to chlorpyrifos (CPF), a widely diffused organophosphate insecticide endowed with developmental neurotoxicity at sub-toxic doses, in the BTBR T+tf/J mouse strain, a validated model of idiopathic autism that displays several behavioral traits relevant to the autism spectrum. To this aim, pregnant BTBR mice were administered from gestational day 14 to 17 with either vehicle or CPF at a dose of 6 mg/kg/bw by oral gavages. Offspring of both sexes underwent assessment of early developmental milestones, including somatic growth, motor behavior and ultrasound vocalization. To evaluate the potential long-term effects of CPF, two different social behavior patterns typically altered in the BTBR strain (free social interaction with a same-sex companion in females, or interaction with a sexually receptive female in males) were also examined in the two sexes at adulthood. Our findings indicate significant effects of CPF on somatic growth and neonatal motor patterns. CPF treated pups showed reduced weight gain, delayed motor maturation (i.e., persistency of immature patterns such as pivoting at the expenses of coordinated locomotion) and a trend to enhanced ultrasound vocalization. At adulthood, CPF associated alterations were found in males only: the altered pattern of investigation of a sexual partner, previously described in BTBR mice, was enhanced in CPF males, and associated to increased ultrasonic vocalization rate. These findings strengthen the need of future studies to evaluate the role of environmental chemicals in the etiology of neurodevelopment disorders.
[De Felice A, Scattoni ML, Ricceri L, Calamandrei G. 2015. PLoS One. 10(3):e0121663] - Prenatal exposure to the organophosphate pesticide chlorpyrifos and childhood tremor.
The organophosphate insecticide chlorpyrifos (CPF), widely used for agricultural purposes, has been linked to neurodevelopmental deficits. Possible motor effects at low to moderate levels of exposure have not been evaluated.Prenatal exposure to CPF was measured in umbilical cord blood in a sample of 263 inner-city minority children, who were followed prospectively. At approximately 11 years of age (mean age 10.9 ± 0.85 years, range=9.0-13.9), during a neuropsychological assessment, children were asked to draw Archimedes spirals. These were rated by a senior neurologist specializing in movement disorders who was blind to CPF exposure level.Compared to all other children, those with prenatal CPF exposure in the upper quartile range (n=43) were more likely to exhibit mild or mild to moderate tremor (≥ 1) in either arm (p=0.03), both arms (p=0.02), the dominant arm (p=0.01), and the non-dominant arm (p=0.055). Logistic regression analyses showed significant CPF effects on tremor in both arms, either arm, the dominant arm (p-values <0.05), and the non-dominant arm (p=0.06), after adjustment for sex, age at testing, ethnicity, and medication. Prenatal CPF exposure is associated with tremor in middle childhood, which may be a sign of the insecticide's effects on nervous system function.
[Rauh VA, Garcia WE, Whyatt RM, Horton MK, et al. 2015. Neurotoxicology. 51:80-6. ] - Pyrethroid insecticide exposure and cognitive developmental disabilities in children: The PELAGIE mother-child cohort.
Pyrethroid insecticides are widely used in agriculture and in homes. Despite the neurotoxicity of these insecticides at high doses, few studies have examined whether lower-level exposures could adversely affect children's neurodevelopment. The PELAGIE cohort included 3421 pregnant women from Brittany, France between 2002 and 2006. When their children reached their sixth birthday, 428 mothers from the cohort were randomly selected, successfully contacted and found eligible. A total of 287 (67%) mothers agreed to participate with their children in the neuropsychological follow-up. Two cognitive domains were assessed by the Wechsler Intelligence Scale for Children: verbal comprehension and working memory. Five pyrethroid and two organophosphate insecticide metabolites were measured in maternal and child first-void urine samples collected between 6 and 19 gestational weeks and at 6years of age, respectively. Linear regression models were used to estimate associations between cognitive scores and urinary pyrethroid metabolite concentrations, adjusting for organophosphate metabolite concentrations and potential confounders. Maternal prenatal pyrethroid metabolite concentrations were not consistently associated with any children's cognitive scores. By contrast, childhood 3-PBA and cis-DBCA concentrations were both negatively associated with verbal comprehension scores (P-trend=0.04 and P-trend<0.01, respectively) and with working memory scores (P-trend=0.05 and P-trend<0.01, respectively). No associations were observed for the three other childhood pyrethroid metabolite concentrations (4-F-3-PBA, cis-DCCA, and trans-DCCA). Low-level childhood exposures to deltamethrin (as cis-DBCA is its principal and selective metabolite), in particular, and to pyrethroid insecticides, in general (as reflected in levels of the 3-PBA metabolite) may negatively affect neurocognitive development by 6years of age. Whatever their etiology, these cognitive deficits may be of importance educationally, because cognitive impairments in children interfere with learning and social development. Potential causes that can be prevented are of paramount public health importance.
[Viel JF, Warembourg C, Le Maner-Idrissi G, Lacroix A, et al. 2015. Environ Int. 82:69-75.] - Health Status of Children of Migrant Farm Workers: Farm Worker Family Health Program, Moultrie, Georgia
Objectives. We evaluated the health status of migrant farmworkers’ children served by the Farm Worker Family Health Program (FWFHP) in Moultrie, Georgia.Methods. We analyzed data from children aged 0 to 16 years examined through the FWFHP from 2003 to 2011 (n across years = 179–415). We compared their prevalence of overweight, obesity, elevated blood pressure, anemia, and stunting with that of children in the United States and Mexico.
Results. Across study years, prevalence of overweight, obesity, elevated blood pressure, anemia, and stunting ranged from 13.5% to 21.8%, 24.0% to 37.4%, 4.1% to 20.2%, 10.1% to 23.9%, and 1% to 6.4%, respectively. Children in the FWFHP had a higher prevalence of obesity than children in all comparison groups, and FWFHP children aged 6 to 12 years had a higher prevalence of elevated blood pressure than all comparison groups. Older FWFHP children had a higher prevalence of anemia than US children and Mexican children. Children in FWFHP had a higher prevalence of stunting than US and Mexican American children.
Conclusions. We observed an elevated prevalence of obesity, anemia among older age groups, and stunting in this sample of children of migrant workers.
[Nichols, M., Stein, A.D. and Wold, J.L. (2014) ‘Health status of children of migrant farm workers: Farm Worker Family Health Program, Moultrie, Georgia’, American Journal of Public Health, 104(2), pp. 365–370. Available at: https://ajph.aphapublications.org/doi/full/10.2105/AJPH.2013.301511. ] - Maternal perchlorate levels in women with borderline thyroid function during pregnancy and the cognitive development of their offspring: data from the Controlled Antenatal Thyroid Study
Objective: Thyroid dysfunction is associated with impaired cognitive development. Perchlorate decreases thyroidal iodine uptake, potentially reducing thyroid hormone production. It is unclear whether perchlorate exposure in early life affects neurodevelopment.Design: Historical cohort analysis.
Patients: From 2002 to 2006, 21,846 women at gestational age
Main outcome measures: Maternal urinary perchlorate, offspring IQ.
Results: Urine perchlorate was detectable in all women (median 2.58 μg/L); iodine levels were low (median 72 μg/L). Maternal perchlorate levels in the highest 10% of the population increased the odds of offspring IQ being in the lowest 10% OR = 3.14 (95% CI 1.38, 7.13) P = .006 with a greater negative impact observed on verbal OR = 3.14 (95% CI 1.42, 6.90) P = .005 than performance IQ. Maternal levothyroxine therapy did not reduce the negative impact of perchlorate on offspring IQ.
Conclusions: This is the first study using individual-level patient data to study maternal perchlorate exposure and offspring neurodevelopment and suggests that high-end maternal perchlorate levels in hypothyroid/hypothyroxinemic pregnant women have an adverse effect on offspring cognitive development, not affected by maternal levothyroxine therapy. These results require replication in additional studies, including in the euthyroid population.
[Taylor, P. et al. (2014) Maternal perchlorate levels in women with borderline thyroid function during pregnancy and the cognitive development of their offspring: data from the Controlled Antenatal Thyroid Study, The Journal of Clinical Endocrinology and Metabolism. Available at: https://pubmed.ncbi.nlm.nih.gov/25057878/.] - Prenatal exposure to organophosphate pesticides and neurobehavioral development of neonates: a birth cohort study in Shenyang, China.
The study aims to investigate the effect of the exposure to organophosphate pesticides (OPs) on the neonatal neurodevelopment during pregnancy in Shenyang, China. A cohort of the mothers (n=249) and their neonates participated in the study and information on each subject was obtained by questionnaire. Dialkyl phosphate (DAP) metabolites were detected in the urine of mothers during pregnancy to evaluate the exposure level to OPs. Neonate neurobehavioral developmental levels were assessed according to the standards of the Neonatal Behavioral Neurological Assessment (NBNA). The geometric means (GM) of urinary metabolites for dimethyl phosphate (DMP), dimethyl thiophosphate (DMTP), diethyl phosphate (DEP), and diethyl thiophosphate (DETP) in pregnant women were 18.03, 8.53, 7.14, and 5.64 µg/L, respectively. Results from multiple linear regressions showed that prenatal OP exposure was one of the most important factors affecting NBNA scores. Prenatal total DAP concentrations were inversely associated with scores on the NBNA scales. Additionally, a 10-fold increase in DAP concentrations was associated with a decrease of 1.78 regarding the Summary NBNA. Authors conclude, the high exposure of pregnant women to OPs in Shenyang, China was the predominant risk factor for neonatal neurobehavioral development.
[Zhang Y, Han S, Liang D, et al. 2014. PLoS One. 9(2):e88491] - Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals
Humans are increasingly and consistently exposed to a variety of endocrine disrupting chemicals (EDCs), chemicals that have been linked to neurobehavioral disorders such as ADHD and autism. Many of such EDCs have been shown to adversely influence brain mesocorticolimbic systems raising the potential for cumulative toxicity. As such, understanding the effects of developmental exposure to mixtures of EDCs is critical to public health protection. Consequently, this study compared the effects of a mixture of four EDCs to their effects alone to examine potential for enhanced toxicity, using behavioral domains and paradigms known to be mediated by mesocorticolimbic circuits (fixed interval (FI) schedule controlled behavior, novel object recognition memory and locomotor activity) in offspring of pregnant mice that had been exposed to vehicle or relatively low doses of four EDCs, atrazine (ATR - 10mg/kg), perfluorooctanoic acid (PFOA - 0.1mg/kg), bisphenol-A (BPA - 50 μg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD - 0.25 μg/kg) alone or combined in a mixture (MIX), from gestational day 7 until weaning. EDC-treated males maintained significantly higher horizontal activity levels across three testing sessions, indicative of delayed habituation, whereas no effects were found in females. Statistically significant effects of MIX were seen in males, but not females, in the form of increased FI response rates, in contrast to reductions in response rate with ATR, BPA and TCDD, and reduced short term memory in the novel object recognition paradigm. MIX also reversed the typically lower neophobia levels of males compared to females. With respect to individual EDCs, TCDD produced notable increases in FI response rates in females, and PFOA significantly increased ambulatory locomotor activity in males. Collectively, these findings show the potential for enhanced behavioral effects of EDC mixtures in males and underscore the need for animal studies to fully investigate mixtures, including chemicals that converge on common physiological substrates to examine potential mechanisms of toxicity with full dose effect curves to assist in interpretations of relevant mechanisms.
[Sobolewski M, Conrad K, Allen JL, Weston H, et al. 2014. Neurotoxicology. 45:121-30] - The association between prenatal exposure to organochlorine pesticides and thyroid hormone levels in newborns in Yancheng, China.
Organochlorine pesticides can interfere with the thyroid hormones that play an important role in early neurodevelopment. The present study, conducted in Yancheng City, Jiangsu Province, China, aimed to examine the association between the levels of organochlorine pesticides in maternal and cord sera and to assess the impact of prenatal exposure to organochlorine pesticides on thyroid hormone levels in cord serum. Eleven organochlorine pesticides in maternal and cord sera were measured in 247 mother-infant pairs recruited from Yancheng City between February 2010 and June 2010. The concentration of the thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) were determined in cord serum. Among the 11 tested organochlorine pesticides, the detectable levels of hexachlorobenzene (HCB), β-hexachlorocycolohexane (β-HCH) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) in both maternal and cord sera were above 50%. The levels of β-HCH and p,p'-DDE in maternal sera were positively associated with the levels in cord sera. After adjusting for confounders, the TSH level in cord serum samples was negatively associated with the HCB level. The data demonstrated that DDT, β-HCH and HCB residues bioconcentrate in maternal and cord sera. Moreover, the correlation analysis suggested that organochlorine pesticides in maternal blood can transfer through the placenta and affect newborn thyroid hormone levels.
[Li C1, Cheng Y1, Tang Q, et al. 2014. Environ Res.129:47-51] - A systematic review of neurodevelopmental effects of prenatal and postnatal organophosphate pesticide exposure.
This paper was aimed at analysing the scientific evidence published to date on potential neurodevelopmental and behavioural effects of prenatal and postnatal exposure to organophosphate (OP) pesticides. A systematic review was undertaken to identify original articles evaluating prenatal or postnatal exposure to OPs in children and effects on neurodevelopment and/or behaviour. Twenty articles met the inclusion criteria, 7 of which evaluated prenatal exposure to OPs, 8 postnatal exposure and 5 both pre- and postnatal exposure. Most of the studies evaluating prenatal exposure observed a negative effect on mental development and an increase in attention problems in preschool and school children. The evidence on postnatal exposure is less consistent, although 2 studies found an increase in reaction time in schoolchildren. Some paraoxonase-1 polymorphisms could enhance the association between OPs exposure and mental and psychomotor development. A large variability in epidemiological designs and methodologies used for assessing exposure and outcome was observed across the different studies, which made comparisons difficult. Prenatal and to a lesser extent postnatal exposure to OPs may contribute to neurodevelopmental and behavioural deficits in preschool and school children.
[González-Alzaga B, Lacasaña M, Aguilar-Garduño C, et al. 2013. Toxicol Lett. pii: S0378-4274(13)01425-2.] - Acetylcholinesterase activity and neurodevelopment in boys and girls.
Organophosphate exposures can affect children's neurodevelopment, possibly due to neurotoxicity induced by acetylcholinesterase (AChE) inhibition, and may affect boys more than girls. Authors tested the hypothesis that lower AChE activity is associated with lower neurobehavioral development among children living in Ecuadorian floricultural communities. In 2008, authors examined 307 children (age: 4-9 years; 52% male) and quantified AChE activity and neurodevelopment in 5 domains: attention/executive functioning, language, memory/learning, visuospatial processing, and sensorimotor (NEPSY-II test). Mean ± standard deviation AChE activity was 3.14 ± 0.49 U/mL (similar for both genders). The range of scores among neurodevelopment subtests was 5.9 to 10.7 U. Girls had a greater mean attention/executive functioning domain score than boys. In boys only, there were increased odds ratios of low neurodevelopment among those in the lowest tertile versus the highest tertile of AChE activity after adjustment for socioeconomic and demographic factors, height-for-age, and hemoglobin. Within these domains, attention, inhibition and long-term memory subtests were most affected.Overall, low AChE activity was associated with deficits in neurodevelopment, particularly in attention, inhibition, and memory in boys but not in girls. These critical cognitive skills affect learning and academic performance. Added precautions regarding secondary occupational pesticide exposure would be prudent.
[Suarez-Lopez JR1, Himes JH, et al. 2013. Pediatrics.132(6):e1649-58.] - Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of pre-senescent rats.
Pesticide exposure during brain development could represent an important risk factor for the onset of neurodegenerative diseases. The present study was designed to characterize the cognitive deficits in the animal model. When during late adulthood permethrin (PERM) treated rats were tested for spatial working memory performances in a T-maze-rewarded alternation task they took longer to choose for the correct arm in comparison to age matched controls. No differences between groups were found in anxiety-like state, locomotor activity, feeding behavior and spatial orientation task. Findings showing a selective effect of PERM treatment on the T-maze task point to an involvement of frontal cortico-striatal circuitry rather than to a role for the hippocampus.
[Nasuti C, Carloni M, Fedeli D, et al. 2013. Toxicology. 303:162-8] - Neurodevelopmental effects in children associated with exposure to organophosphate pesticides: a systematic review.
The aim of the present article is to synthesize reported evidence over the last decade on organophosphate (OP) exposure and neurodevelopmental effects in children. The eligibility criteria considered were studies assessing exposure to OP pesticides and neurodevelopmental effects in children from birth to 18 years of age, published between 2002 and 2012 in English or Spanish. All but one of the 27 studies evaluated showed some negative effects of pesticides on neurobehavioral development. A positive dose-response relationship between OP exposure and neurodevelopmental outcomes was found in all but one of the 12 studies that assessed dose-response. In the ten longitudinal studies that assessed prenatal exposure to OPs, cognitive deficits (related to working memory) were found in children at age 7 years, behavioral deficits (related to attention) seen mainly in toddlers, and motor deficits (abnormal reflexes) seen mainly in neonates. Evidence of neurological deficits associated with exposure to OP pesticides in children is growing. The studies reviewed collectively support the hypothesis that exposure to OP pesticides induces neurotoxic effects. Further research is needed to understand effects associated with exposure in critical windows of development.
[Muñoz-Quezada MT, Lucero BA, Barr DB, et al. 2013. Neurotoxicology. 39:158-68] - Prenatal p,p´-DDE exposure and neurodevelopment among children 3.5-5 years of age.
The results of previous studies suggest that prenatal exposure to bis[p-chlorophenyl]-1,1,1-trichloroethane (DDT) and to its main metabolite, 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE), impairs psychomotor development during the first year of life. However, information about the persistence of this association at later ages is limited. Authors assessed the association of prenatal DDE exposure with child neurodevelopment at 42-60 months of age. Study report McCarthy Scales of Children's Abilities for 203 children at 42, 48, 54, and 60 months of age. Maternal DDE serum levels were available for at least one trimester of pregnancy
After adjustment, a doubling of DDE during the third trimester of pregnancy was associated with statistically significant reductions of -1.37, -0.88, -0.84, and -0.80 points in the general cognitive index, quantitative, verbal, and memory components respectively. The association between prenatal DDE and the quantitative component was weaker at 42 months than at older ages. No significant statistical interactions with sex or breastfeeding were observed. Findings support the hypothesis that prenatal DDE impairs early child neurodevelopment; the potential for adverse effects on development should be considered when using DDT for malaria control.
[Torres-Sánchez L, Schnaas L, Rothenberg SJ, et al. 2013. Environ Health Perspect. 121(2):263-8] - Brain anomalies in children exposed prenatally to a common organophosphate pesticide
Study investigated associations between chlorpyrifos (CPF) exposure and brain morphology using magnetic resonance imaging in 40 children selected from a nonclinical, representative community-based cohort. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. A significant exposure × IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose–response relationship between CPF and cortical thickness.
[Rauh, V. A., F. P. Perera, M. K. Horton, R. M. Whyatt, et al. 2012. PNAS.109 (20): 7871-6.] - Cognitive, visual, and motor development of 7-month-old Guadeloupean infants exposed to chlordecone.
The insecticide chlordecone was extensively used in the French West Indies to control banana root borer. Its persistence in soils has led to the widespread pollution of the environment, and human beings are still exposed to this chemical. Chlordecone has been shown to impair neurological and behavioural functions in rodents when exposed gestationally or neonatally.The aim of the study was to evaluate the impact of prenatal and postnatal exposure to chlordecone on the cognitive, visual, and motor development of 7-month-old infants from Guadeloupe. Infants were tested at 7 months. Visual recognition memory and processing speed were assessed. Samples of cord blood and breast milk at 3 months were analyzed for chlordecone concentrations. Postnatal exposure was determined through breast feeding and frequency of contaminated food consumption by the infants. Cord chlordecone concentrations in tertiles were associated with reduced novelty preference on the FTII in the highly exposed group. Postnatal exposure through contaminated food consumption was marginally related to reduced novelty preference and longer processing speed. Detectable levels of chlordecone in cord blood were associated with higher risk of obtaining low scores on the fine motor development scale.These results suggest that pre- and postnatal low chronic exposure to chlordecone is associated with negative effects on cognitive and motor development during infancy.
[Dallaire R, Muckle G, Rouget F, et al. 2012. Environ Res. 118:79-85] - Does the home environment and the sex of the child modify the adverse effects of prenatal exposure to chlorpyrifos on child working memory?
In the current paper, the authors expanded the previous work on CPF to investigate how additional biological and social environmental factors might create or explain differential neurodevelopmental susceptibility, focusing on main and moderating effects of the quality of the home environment (HOME) and child sex. The study evaluate how the quality of the home environment (specifically, parental nurturance and environmental stimulation) and child sex interact with the adverse effects of prenatal CPF exposure on working memory at child age 7years. Results found a borderline significant interaction between prenatal exposure to CPF and child sex suggesting males experience a greater decrement in working memory than females following prenatal CPF exposure. In addition, a borderline interaction between parental nurturance and child sex was detected suggesting that, in terms of working memory, males benefit more from a nurturing environment than females. This is the first investigation into factors that may inform an intervention strategy to reduce or reverse the cognitive deficits resulting from prenatal CPF exposure.
[Horton, M.K., L.G. Kahn, F. Perera, D.B. Barr and V. Rauh. 2012. Neurotoxicology and Teratology. 34(5):534-41] - In utero exposure to dichlorodiphenyltrichloroethane and cognitive development among infants and school-aged children.
DDT continues to be used for control of infectious diseases in several countries. In-utero exposure to DDT and DDE has been associated with developmental and cognitive impairment among children. This study examined this association of in-utero DDT and DDE exposure with infant and child neurodevelopment was examined in 1100 subjects in the Collaborative Perinatal Project, a prospective birth cohort enrolling pregnant women from 12 study centers in the United States from 1959 to 1965. Maternal DDT and DDE concentrations were measured in archived serum specimens. Infant mental and motor development was assessed at age 8 months using the Bayley Scales of Infant Development, and child cognitive development was assessed at age 7 years, using the Wechsler Intelligence Scale for Children. Although levels of DDT and DDE were relatively high in this population, neither were related to Mental or Psychomotor Development scores on the Bayley Scales nor to Full-Scale Intelligence Quotient at 7 years of age. Categorical analyses showed no evidence of dose- response for either maternal DDT or DDE, and estimates of the association between continuous measures of exposure and neurodevelopment were indistinguishable from 0. Adverse associations were not observed between maternal serum DDT and DDE concentrations and offspring neurodevelopment at 8 months or 7 years in this cohort.
[Jusko TA, Klebanoff MA, Brock JW, Longnecker MP. 2012. Epidemiology. 23(5):689-98] - Organophosphate pesticide levels in blood and urine of women and newborns living in an agricultural community
Organophosphate pesticides are widely used and recent studies suggest associations of in utero exposures with adverse birth outcomes and neurodevelopment. Few studies have characterized organophosphate pesticides in human plasma or established how these levels correlate to urinary measurements. We measured organophosphate pesticide metabolites in maternal urine and chlorpyrifos and diazinon in maternal and cord plasma of subjects living in an agricultural area to compare levels in two different biological matrices. We also determined paraoxonase 1 (PON1) genotypes (PON1192 and PON1−108) and PON1 substrate-specific activities in mothers and their newborns to examine whether PON1 may affect organophosphate pesticide measurements in blood and urine.
Chlorpyrifos levels in plasma ranged from 0–1726 ng/mL and non-zero levels were measured in 70.5% and 87.5% of maternal and cord samples, respectively. Diazinon levels were lower (0–0.5 ng/mL); non-zero levels were found in 33.3% of maternal plasma and 47.3% of cord plasma. Significant associations between organophosphate pesticide levels in blood and metabolite levels in urine were limited to models adjusting for PON1 levels. Increased maternal PON1 levels were associated with decreased odds of chlorpyrifos and diazinon detection (odds ratio(OR): 0.56 and 0.75, respectively). Blood organophosphate pesticide levels of study participants were similar in mothers and newborns and slightly higher than those reported in other populations. However, compared to their mothers, newborns have much lower quantities of the detoxifying PON1 enzyme suggesting that infants may be especially vulnerable to organophosphate pesticide exposures.
[Huen, K. et al. (2012) Organophosphate pesticide levels in blood and urine of women and newborns living in an agricultural community, Environmental Research. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0013935112001740.] - Prenatal exposure to organochlorine compounds and neuropsychological development up to two years of life.
Polychlorinated biphenyls (PCB), hexachlorobenzene (HCB), and dichlorodiphenyl dichloroethylene (pp'DDE) are persistent, bioaccumulative, and toxic environmental pollutants with potential neurotoxic effects. Despite a growing body of studies investigating the health effects associated with these compounds, their specific effects on early neuropsychological development remain unclear. Study investigated such neuropsychological effects in a population-based birth cohort based in three regions in Spain (Sabadell, Gipuzkoa, and Valencia) derived from the INMA [Environment and Childhood] Project. The main analyses in this report were based on 1391 mother-child pairs with complete information on maternal levels of organochlorine compounds and child neuropsychological assessment (Bayley Scales of Infant Development) at age 14 months. Data found that prenatal PCB exposure, particularly to congeners 138 and 153, resulted in impairment of psychomotor development, but found no evidence for effects on cognitive development. Prenatal exposure to pp'DDE or HCB was not associated with early neuropsychological development. The negative effects of exposure to PCBs on early psychomotor development suggest that the potential neurotoxic effects of these compounds may be evident even at low doses.
[Forns J, Lertxundi N, Aranbarri A, Murcia M, et al. 2012. Environ Int. 45:72-7] - 7-Year Neurodevelopmental Scores and Prenatal Exposure to Chlorpyrifos, a Common Agricultural Pesticide
This is a longitudinal birth cohort study of inner-city mothers and children (Columbia Center for Children’s Environmental Health) to estimate the relationship between prenatal chlorpyrifos (CPF) exposure and neurodevelopment among cohort children at age 7 years. 265 children were sampled and researchers measured prenatal CPF exposure using umbilical cord blood plasma (picograms/gram plasma), and 7-year neurodevelopment. On average, for each standard deviation increase in exposure (4.61 pg/g), Full-Scale IQ declined by 1.4%, and Working Memory declined by 2.8%. These findings are important in light of continued widespread use of CPF in agricultural settings and possible longer-term educational implications of early cognitive deficits.
[Rauh V, Arunajadai S, Horton M, Perera F, Hoepner L, Barr DB, et al. 2011. Environ Health Perspect. doi:10.1289/ehp.1003160] - Impact of Prenatal Exposure to Piperonyl Butoxide and Permethrin on 36-Month Neurodevelopment
Research published February 7, 2011 in the online edition of the journal Peditatrics shows that children more highly exposed to pyrethroid insecticides and piperonyl butoxide (PBO), a synergist added to increase the potency of pyrethroids, are three times as likely to have a mental delay compared to children with lower levels. The study measured exposure to pesticides using maternal and umbilical cord plasma samples and in personal air samples, collected using backpack air monitors during pregnancy. Children were then tested for cognitive and motor development (using the Bayley Scales of Infant Development) at three years of age. Children with the highest prenatal exposures scored about 4 points lower on the test. That’s about the same intelligence loss caused by lead, Philip Landrigan, MD, a pediatrics professor and environmental health expert at New York’s Mount Sinai School of Medicine, told USA Today. Pyrethroid pesticides kill bugs by “being toxic to the developing brain,” Dr. Landrigan says. The results are “very believable and should be taken seriously.”
[Horton, et al. 2011. Pediatrics, Online February 7, 2011 (doi:10.1542/peds.2010-0133)] - Prenatal Exposure to Organophosphate Pesticides and IQ in 7-Year Old Children
Study conducted a birth-cohort study (CHAMACOS) among predominantly Latino farmworker families from an agricultural community in California and assessed exposure to OP pesticides by measuring dialkyl phosphate (DAP) metabolites in urine collected during pregnancy and from children at age 6 months and 1, 2, 3½ and 5 years. Averaged maternal DAP concentrations were associated with poorer scores for Working Memory, Processing Speed, Verbal Comprehension, Perceptual Reasoning, and Full Scale IQ. Children in the highest quintile of maternal DAP concentrations had an average deficit of 7.0 IQ-points compared with those in the lowest quintile.
[Bouchard MF, Chevrier J et al. 2011. Environ Health Perspect :-. doi:10.1289/ehp.1003185] - Prenatal Exposure to Organophosphates, Paraoxonase 1, and Cognitive Development in Childhood
Researchers examine the relationship between biomarkers of organophosphate exposure, PON1, and cognitive development at ages 12 and 24 months, and 6 to 9 years in this Mount Sinai Children’s Environmental Health Study. Prenatal exposurel was associated with a decrement in mental development at 12 months among blacks and Hispanics. In later childhood, increasing pesticide metabolites were associated with decrements in perceptual reasoning, with a monotonic trend consistent with greater decrements with increasing prenatal exposure. Findings suggest that prenatal exposure to organophosphates negatively impacts cognitive development, particularly perceptual reasoning, with evidence of effects beginning at 12 months and continuing through early childhood.
[Engel SM, Wetmur J, Chen J, Zhu C, Barr DB, Canfield RL, et al. 2011. Environ Health Perspect :-. doi:10.1289/ehp.1003183] - Trends in the Prevalence of Developmental Disabilities in US Children, 1997–2008
A new report by the American Academy of Pediatrics reveals that roughly one in six children in the U.S. have developmental disabilities, particularly those that are linked to environmental exposure, which showcases the need for stricter policies to reduce the use of pesticides and other toxic chemicals. The study is based on National Health Interview Surveys of children aged 3 to 17 years over the 12-year period of 1997-2008. Results show that boys have a higher prevalence overall and for a number of select disabilities compared with girls. Prevalence of any developmental disability increased from 12.84% to 15.04% over 12 years. Autism, attention deficit hyperactivity disorder, and other developmental delays increased, whereas hearing loss showed a significant decline. These trends were found in all of the sociodemographic subgroups, except for autism in non-Hispanic black children. Daily News
[Boyle, C. et al 2011. American Academy of Pediatrics, (doi: 10.1542/peds.2010-2989] - 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] - Mind, Disrupted: How Toxic Chemicals May Affect How We Think and Who We Are
First-ever biomonitoring report identifying toxic chemical pollution in people from the learning and developmental disability community. Report examines 61 toxic chemicals present in project participants in the context of rising rates of autism, attention-deficit hyperactivity disorder, and other learning and developmental disabilities.
[Gonzalez, S. et al. 2010. The Learning and Developmental Disabilities Initiative] - Neurobehavioral Deficits and Increased Blood Pressure in School-Age Children Prenatally Exposed to Pesticides
Prenatal exposure to pesticides at levels that do not cause adverse health effects in the mother can lead to delayed brain developmental in the child. A definite negative effect was found in children, whose mother had been exposed to pesticides during pregnancy. The effect was the strongest for motor coordination, spatial performance and visual memory. Children were 1.5 to 2 years behind in the development of these functions, which is a very marked shift at age 6-to-8 years, where brain development is particularly rapid. The researchers also found increased blood pressure, likely a result of adverse effect on brain nuclei responsible for regulation of cardiovascular functions.
[Harari, R. et al. 2010. Environ Health Perspect, 118:890–896] - PON1 and Neurodevelopment in Children from the CHAMACOS Study Exposed to Organophosphate Pesticides in Utero
Paraoxonase 1 (PON1) detoxifies oxon derivatives of some organophosphate (OP) pesticides, and its genetic polymorphisms influence enzyme activity and quantity.Study ained to determine whether PON1 genotypes and enzyme measurements were associated with child neurobehavioral development and whether PON1 modified the association of in utero exposure to OPs (as assessed by maternal DAPs) and neurobehavior.Children with the PON1−108T allele had poorer MDI scores and somewhat poorer PDI scores. Children were less likely to display PDD when they or their mothers had higher ARYase activity and when their mothers had higher POase activity.Study concludes PON1 was associated with child neurobehavioral development, but additional research is needed to confirm whether it modifies the relation with in utero OP exposure.
[Eskenazi B., K. Huen, A. Marks, K.G.Harley, A. Bradman, D.B. Barr, et al. 2010. Environ Health Perspect. 118: 1775-1781] - Prenatal Airborne Polycyclic Aromatic Hydrocarbon Exposure and Child IQ at Age 5 Years.
A mother’s exposure to urban air pollutants known as polycyclic aromatic hydrocarbons (PAHs) can adversely affect a child’s intelligence quotient or IQ. The Study found that children exposed to high levels of PAHs in New York City had full scale and verbal IQ scores that were 4.31 and 4.67 points lower than those of less exposed children.
[Perera, F. et al. 2009. Pediatrics, DOI: 10.1542/peds.2008-3506] - Neonatal Exposure to Low Doses of Diazinon: Long-Term Effects on Neural Cell Development and Acetylcholine Systems
Researchers gave diazinon (DZN) to newborn rats on postnatal days 1-4, using doses (0.5 or 2 mg/kg) spanning the threshold for barely detectable cholinesterase inhibition, then evaluated the lasting effects on indices of neural cell number and size, and on functional markers of acetylcholine (ACh) synapses (choline acetyltransferase, presynaptic high-affinity choline transporter, nicotinic cholinergic receptors) in a variety of brain regions. DZN exposure produced a significant overall increase in cell-packing density in adolescence and adulthood, suggestive of neuronal loss and reactive gliosis; however, some regions (temporal/occipital cortex, striatum) showed evidence of net cell loss, reflecting a greater sensitivity to neurotoxic effects of DZN. Deficits were seen in ACh markers in cerebrocortical areas and the hippocampus, regions enriched in ACh projections. In contrast, there were no significant effects in the midbrain, the major locus for ACh cell bodies.These results indicate that developmental exposures to apparently nontoxic doses of DZN compromise neural cell development and alter ACh synaptic function in adolescence and adulthood. The patterns seen here differ substantially from those seen in earlier work with chlorpyrifos, reinforcing the concept that the various organophosphates have fundamentally different effects on the developmental trajectories of specific neurotransmitter systems, unrelated to their shared action as cholinesterase inhibitors.
[Slotkin TA, Bodwell BE, Levin ED, Seidler FJ.2008. Environ Health Perspect. 116(3):340-8] - Prenatal and Childhood Exposure to Pesticides and Neurobehavioral Development: Review of Epidemiological Studies
This review of epidemiological studies focused on the neurobehavioural development of children exposed to pesticides imply that children's exposure to pesticides may bring about impairments in their neurobehavioral development. Children exposed to organophosphate pesticides (OP), both prenatally and during childhood, may have difficulties performing tasks that involve short-term memory, and may show increased reaction time, impaired mental development or pervasive developmental problems. In newborns, the effects of OP exposure are manifested mainly by an increased number of abnormal reflexes, while in adolescents, by mental and emotional problems. The studies investigating association between exposure to organochlorine pesticides and neurodevelopmental effects show inconsistent results. While some studies report impairments in mental and psychomotor functions, other studies do not confirm the above.The information deriving from epidemiological studies indicate a need to increase awareness among people and children exposed to pesticides about the association between the use of pesticides and neurodevelopmental impairments. Therefore, the principle of prudence should become a rule.
[Jurewicz, J and Wojciech H. 2008. Internatl J Occup Med and Environ Health. 21(2):121–132] - Prenatal Organochlorine Exposure and Measures of Behavior in Infancy Using the Neonatal Behavioral Assessment Scale (NBAS)
Findings provide evidence for an association between low-level prenatal PCB and DDE exposures and poor attention in early infancy.
[Sagiv SK, et al. 2008. Environ Health Perspect 116:666-673. doi:10.1289/ehp.10553] - In Utero p,p’-DDE Exposure and Infant Neurodevelopment: A Perinatal Cohort in Mexico
The goal of this study was to assess the prenatal DDE exposure window and its effect on the psychomotor development index (PDI) and mental development index (MDI) during the first year of life. Authors recruited 244 children whose pregnancies and deliveries were uncomplicated, and whose mothers were monitored throughout the pregnancy. Participating mothers were not occupationally exposed to DDT (dichlorodiphenyltrichloroethane) but were residents of a zone in Mexico with endemic malaria. Third-trimester DDE level was significantly higher than the level at baseline, first, and second trimesters, but the differences never exceeded 20%. Only DDE levels during the first trimester of pregnancy were associated with a significant reduction in PDI. DDE was not associated with MDI.
A critical window of exposure to DDE in utero may be the first trimester of the pregnancy, and psychomotor development is a target of this compound. Residues of DDT metabolites may present a risk of developmental delay for years after termination of DDT use.
[Torres-Sánchez, L, Rothenberg,S, Schnaas, L, et al. 2007. Environ Health Perspect. 115(3): 435–439.] - Developmental neurotoxicity of industrial chemicals.
Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.
[Grandjean P and Landrigan PJ.2006. Lancet.368(9553):2167-78] - Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First 3 Years of Life Among Inner-City Children
The purpose of this study was to investigate the impact of prenatal exposure to chlorpyrifos on 3-year neurodevelopment and behavior in a sample of inner-city minority children. As part of an ongoing prospective cohort study in an inner-city minority population, neurotoxicant effects of prenatal exposure to chlorpyrifos were evaluated in 254 children through the first 3 years of life. This report examined cognitive and motor development at 12, 24, and 36 months (measured with the Bayley Scales of Infant Development II) and child behavior at 36 months (measured with the Child Behavior Checklist) as a function of chlorpyrifos levels in umbilical cord plasma. Highly exposed children (chlorpyrifos levels of >6.17 pg/g plasma) scored, on average, 6.5 points lower on the Bayley Psychomotor Development Index and 3.3 points lower on the Bayley Mental Development Index at 3 years of age compared with those with lower levels of exposure. Children exposed to higher, compared with lower, chlorpyrifos levels were also significantly more likely to experience Psychomotor Development Index and Mental Development Index delays, attention problems, attention-deficit/hyperactivity disorder problems, and pervasive developmental disorder problems at 3 years of age. The adjusted mean 36-month Psychomotor Development Index and Mental Development Index scores of the highly and lower exposed groups differed by only 7.1 and 3.0 points, respectively, but the proportion of delayed children in the high-exposure group, compared with the low-exposure group, was 5 times greater for the Psychomotor Development Index and 2.4 times greater for the Mental Development Index, increasing the number of children possibly needing early intervention services.
[Rauh, V. et al. 2006. Pediatrics, 118(6) pp. e1845-e1859] - In Utero Exposure to Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) and Neurodevelopment Among Young Mexican American Children
Study investigated the relationship between prenatal exposure to dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) and neurodevelopment of Mexican farm-workers' children in California. Participants from the Center for the Health Assessment of Mothers and Children of Salinas study, a birth cohort study, included 360 singletons with maternal serum measures of p,p'-DDT, o,p'-DDT, and p,p'-DDE. Psychomotor development and mental development were assessed with the Bayley Scales of Infant Development at 6, 12, and 24 months. Results found a approximately 2-point decrease in Psychomotor Developmental Index scores with each 10-fold increase in p,p'-DDT levels at 6 and 12 months (but not 24 months) and p,p'-DDE levels at 6 months only. We found no association with mental development at 6 months but a 2- to 3-point decrease in Mental Developmental Index scores for p,p'-DDT and o,p'-DDT at 12 and 24 months, corresponding to 7- to 10-point decreases across the exposure range. Even when mothers had substantial exposure, breastfeeding was usually associated positively with Bayley scale scores. Prenatal exposure to DDT, and to a lesser extent DDE, was associated with neurodevelopmental delays during early childhood, although breastfeeding was found to be beneficial even among women with high levels of exposure. Countries considering the use of DDT should weigh its benefit in eradicating malaria against the negative associations found in this first report on DDT and human neurodevelopment.
[Eskenazi B, Marks AR, Bradman A, Fenster L, et al. 2006. Pediatrics.118(1):233-41.] - Pesticide Exposure and Stunting as Independent Predictors of Neurobehavioral Deficits in Ecuadorian School Children
Children in Ecuador whose mothers were exposed to pesticides while pregnant have diminished ability to copy geometric figures as part of a standardized Stanford-Binet test as compared to a control group, according to the epidemiological study. Adjusted regression analysis indicates that the exposed children experience a developmental delay on this aptitude of four years. The researchers also concluded that prenatal pesticide exposure may add to the already deleterious effects of malnutrition.
[Grandjean, P. et al. 2006. Pediatrics, 117(3) pp. e546-e556] - Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs.
Pyrethroid insecticides have been used for more than 40 years and account for 25% of the worldwide insecticide market. Although their acute neurotoxicity to adults has been well characterized, information regarding the potential developmental neurotoxicity of this class of compounds is limited. There is a large age dependence to the acute toxicity of pyrethroids in which neonatal rats are at least an order of magnitude more sensitive than adults to two pyrethroids. There is no information on age-dependent toxicity for most pyrethroids. In the present review authors examine the scientific data related to potential for age-dependent and developmental neurotoxicity of pyrethroids. As a basis for understanding this neurotoxicity, authors discuss the heterogeneity and ontogeny of voltage-sensitive sodium channels, a primary neuronal target of pyrethroids. Authors also summarize 22 studies of the developmental neurotoxicity of pyrethroids and review the strengths and limitations of these studies. These studies examined numerous end points, with changes in motor activity and muscarinic acetylcholine receptor density the most common. Many of the developmental neurotoxicity studies suffer from inadequate study design, problematic statistical analyses, use of formulated products, and/or inadequate controls. These factors confound interpretation of results. To better understand the potential for developmental exposure to pyrethroids to cause neurotoxicity, additional, well-designed and well-executed developmental neurotoxicity studies are needed. These studies should employ state-of-the-science methods to promote a greater understanding of the mode of action of pyrethroids in the developing nervous system.
[Shafer TJ, Meyer DA, Crofton KM.2005. Environ Health Perspect. 113(2):123-36.] - Summary health statistics for U.S. children: National Health Interview Survey, 2003.
This report presents both age-adjusted and unadjusted statistics from the 2003 National Health Interview Survey (NHIS) on selected health measures for children under 18 years of age, classified by sex, age, race, Hispanic origin, family structure, parent's education, family income, poverty status, health insurance coverage, place of residence, region, and current health status. The topics covered are asthma, allergies, learning disability, Attention Deficit Hyperactivity Disorder (ADHD), use of prescription medication, respondent-assessed health status, school-loss days, usual place of health care, time since last contact with a health care professional, unmet dental needs, time since last dental contact, and selected measures of health care access. In 2003, most U.S. children under 18 years of age had excellent or very good health (83%). However, 10% of children had no health insurance coverage, and 5% of children had no usual place of health care. Thirteen percent of children had ever been diagnosed with asthma. An estimated 8% of children 3-17 years of age had a learning disability, and an estimated 6% of children had ADHD.
[Centers for Disease Control and Prevention. 2005. Vital and Health Statistics 10 (223)] - In Utero Pesticide Exposure, Maternal Paraoxonase Activity, and Head Circumference.
Although the use of pesticides in inner-city homes of the United States is of considerable magnitude, little is known about the potentially adverse health effects of such exposure. Recent animal data suggest that exposure to pesticides during pregnancy and early life may impair growth and neurodevelopment in the offspring. To investigate the relationship among prenatal pesticide exposure, paraoxonase (PON1) polymorphisms and enzyme activity, and infant growth and neurodevelopment, authors conducted a prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City. In this report the effects of pesticide exposure on birth weight, length, head circumference, and gestational age among 404 births between May 1998 and May 2002 were evaluated. Pesticide exposure was assessed by a prenatal questionnaire administered to the mothers during the early third trimester as well as by analysis of maternal urinary pentachlorophenol levels and maternal metabolites of chlorpyrifos and pyrethroids. When the level of maternal PON1 activity was taken into account, maternal levels of chlorpyrifos above the limit of detection coupled with low maternal PON1 activity were associated with a significant but small reduction in head circumference. In addition, maternal PON1 levels alone, but not PON1 genetic polymorphisms, were associated with reduced head size. Because small head size has been found to be predictive of subsequent cognitive ability, these data suggest that chlorpyrifos may have a detrimental effect on fetal neurodevelopment among mothers who exhibit low PON1 activity.
[Berkowitz GS, Wetmur JG, Birman-Deych E, Obel J, et al. 2004. Environ Health Perspect.112(3):388-91.] - Arrested Development: A study on the Human Health Impacts of Pesticides
A study found a strong link between pesticide exposure and cognitive abilities among farmers' children in India. The study revealed serious mental development disorders that ranged from severely impaired analytical abilities, motor skills, concentration and memory among the children in the chemical-intensive cotton belts of India (A 2004 study reveals serious mental development disorders that range from severely impaired analytical abilities, motor skills, concentration and memory among the children in the chemical-intensive cotton belts of India.
[Kuruganti, K. 2003. Greenpeace. Bangalore India.] - Breastfeeding, exposure to organochlorine compounds, and neurodevelopment in infants.
Exposure to organochlorine compounds (OCs) occurs both in utero and through breastfeeding. Levels of hexachlorobenzene (HCB) found in the cord serum of newborns from a population located in the vicinity of an electrochemical factory in Spain were among the highest ever reported. This study looked at the association between exposure to OCs and breastfeeding on neurodevelopment in the 1-year-old infants of this population. A birth cohort including 92 mother-infant pairs was recruited between 1997 and 1999 in 5 neighboring villages. The mental and psychomotor development of each infant was assessed at 13 months. OCs were measured in cord serum. Dichlorodiphenyl dichloroethylene (p,p'DDE) cord serum levels were negatively associated with both mental and psychomotor development. For each doubling of a dose of p,p'DDE, study found a resultant decrease of 3.50 points on the mental scale and 4.01 points on the psychomotor scale. Long-term breastfeeding was associated with better performance on both the mental and motor scales. Short-term breastfed infants with higher p,p'DDE levels in cord serum were associated with the lowest scores on both the mental and the psychomotor scales. Prenatal exposure to p,p'DDE was associated with a delay in mental and psychomotor development at 13 months. No association was found for exposure to HCB. Long-term breastfeeding was found to be beneficial to neurodevelopment, potentially counterbalancing the impact of exposure to these chemicals through breast milk.
[Ribas-Fitó N, Cardo E, Sala M, et al. 2003. Pediatrics.111(5 Pt 1):e580-5.] - Pesticides and Polychlorinated Biphenyls (PCBs): An Analysis of the Evidence That They Impair Children's Neurobehavioral Development
This review presents evidence that children are uniquely vulnerable to toxins in the environment.It examines recent literature on the neurodevelopmental toxicity of certain
pesticides and of polychlorinated biphenyls (PCBs), and concludes by offering the hypothesis that neurodevelopmental toxicity caused by synthetic chemicals in the environment is potentially a widespread problem in American children, an issue that warrants rigorous study as well as evidence-based preventive intervention.
[Landrigan, P. 2001. Molecular Genetics and Metabolism. 73, 11–17] - In Harms Way: Toxic Threats to Child Development.
Animal studies link pesticides in the organochlorine, organophosphate (OP), and pyrethroid families to hyperactivity. OPs are also linked to developmental delays, behavioral disorders and motor dysfunction in animal studies.
[Shettler, T., et al., 2000. Greater Boston Physicians for Social Responsibility: Cambridge, MA.] - Pesticide exposure and risk of mild cognitive dysfunction
Little is known about the adverse effects of substances, such as pesticides and metals, on the development of mild cognitive dysfunction (MCD). Cross-sectional and prospective data from the Maastricht Aging Study were used to find out the potential neurotoxicity of particular substances. Exposure to pesticides, for example by arable farmers and gardeners, was associated with increased risks of MCD. Exposure to metals and organic solvents was not associated with MCD. Findings might reflect subtle changes in brain function among people exposed to pesticides.
[Bosma, H, van Boxtel, MPJ, Ponds, RWHM, et al. 2000. The Lancet. 356,9233:912-13] - Pesticides and Inner-city Children: Exposures, Risks, and Prevention.
The organophosphate insecticide chlorpyrifos and certain pyrethroids are the registered pesticides most heavily applied in cities. Illegal street pesticides are also in use, including tres pasitos (a carbamate), tiza china, and methyl parathion. In New York State in 1997, the heaviest use of pesticides in all counties statewide was in the urban boroughs of Manhattan and Brooklyn. Compounding these risks of heavy exposures are children's decreased ability to detoxify and excrete pesticides and the rapid growth, development, and differentiation of their vital organ systems. These developmental immaturities create early windows of great vulnerability. Recent experimental data suggest, for example, that chlorpyrifos may be a developmental neurotoxicant and that exposure in utero may cause biochemical and functional aberrations in fetal neurons as well as deficits in the number of neurons. Certain pyrethroids exert hormonal activity that may alter early neurologic and reproductive development. Assays currently used for assessment of the toxicity of pesticides are insensitive and cannot accurately predict effects to children exposed in utero or in early postnatal life. Protection of American children, and particularly of inner-city children, against the developmental hazards of pesticides requires a comprehensive strategy that monitors patterns of pesticide use on a continuing basis, assesses children's actual exposures to pesticides, uses state-of-the-art developmental toxicity testing, and establishes societal targets for reduction of pesticide use.
[Landrigan,PJ, Claudio,L, Markowitz, SB et al. 1999. Environ Health Perspect. 107(Suppl 3): 431–437.] - An Anthropological Approach to the Evaluation of Preschool Children Exposed to Pesticides in Mexico
In a comparative study in Mexico, children exposed to pesticides demonstrated decreases in stamina, coordination, memory, and the ability to draw familiar subjects.
[Guillette, E., et al. 1998. Environmental Health Perspectives, 106(6):347-353.] - Short-term oral and dermal toxicity of MCPA and MCPP
The herbicides 2-methyl-4-chlorophenoxy acetic acid (MCPA) and 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP or mecoprop) were tested for 90 days in rats. The compounds were added to the diet at levels of 0, 50, 400 and 3200 ppm. Growth, food intake, mortality, haematology, blood and liver chemistry, organ weights and histopathology were used as criteria.The main effects of both compounds were growth retardation and elevated relative kidney weights at levels of 400 ppm and more. The 50 ppm dose level can be considered as a non-toxic-effect level in the 90-day study.
In subacute dermal studies in rabbits during 3 weels the dosage were 0, 0.5, 1.0 and 2 g MCPA or MCPP per kg body weight. Thereafter followed a recovery period of 2 weeks. Growth, mortality, skin reaction, haematology, organ weights (MCPP) and histopathology were recorded and determined. Both compounds caused slight to moderate erythema at all dose levels, whereas elasticity of the skin was decreased. In both experiments the skin returned to normal during the recovery period. Weight loss was observed at all dose levels. In the MCPA experiments high mortality and histopathological changes in the liver, kidneys, spleen and thymus were recorded at the two highest dose levels. The cause of this could have been either the treatment with MCPA or a dysbacteria infection which developed during the experiment.
[Verschuuren, H. et al. (1975) Short-term oral and dermal toxicity of MCPA and MCPP, Toxicology. Available at: https://www.sciencedirect.com/science/article/abs/pii/0300483X75900360. ]