Review of reviews on exposures to synthetic organic chemicals and children’s neurodevelopment: Methodological and interpretation challenges

Figures & data

Table 1. Criteria and descriptions used to evaluate epidemiologic reviews on associations of environmental chemical exposures with neurodevelopmental outcomes in children.

Criteria	Yes	Partial	No
Systematic inclusion/exclusion, search, retrieval, and review of studies	Detailed data on search and retrieval strategies including: explicit inclusion and/or exclusion criteria, PRISMA diagram (or similar information) summarizing search process; search terms and databases; information on excluded articles as part of full text review	General search strategies only (e.g., keywords and databases)	Search methods not presented
Structured evaluation of data quality	Each study evaluated using a specific set of criteria (e.g., with respect to study design, exposure assessment and outcome ascertainment methods, and control for confounding), results of assessment used in the analysis of the evidence	Study strengths and limitations reviewed in a nonsystematic narrative but without informing analysis and conclusions	No consideration of study quality
Systematic assessment of consistency	Consistency examined systematically across specific independently tested exposure–outcome associations (e.g., in side-by-side comparison tables where results are presented for each specific exposure–outcome combination)	Consistency addressed without focusing on specific exposure–outcome associations or without focus on independent observations	Simple narrative description of findings
Assessment of reporting and publication bias	An attempt to identify unpublished results (e.g., by searching gray literature or contacting the authors), and evaluation of selective reporting (e.g., by comparing tested and reported associations)	Only some of the criteria fulfilled (e.g., search for unpublished results mentioned in the Methods, but publication bias and selective reporting not addressed)	None of these issues addressed

Figure 1. PRISMA diagram. For the complete list of excluded articles and reasons for exclusions see Supplement 1.

Table 2. Summary of epidemiologic reviews evaluating the association of environmental chemical exposures with neurodevelopmental outcomes in children. Studies are organized alphabetically within subsections pertaining to the number of “yes,” “partial,” or “no” categorizations for the criteria in Table 1.

Publication	Exposure(s) and outcome(s) of interest (as stated by review authors)	Inclusion/exclusion, search and retrieval of articles	Structured evaluation of data quality	Systematic assessment of consistency and reasons for disagreement	Assessment of reporting and publication bias	Overall conclusions
Studies with ‘Yes’ for 2 criteria: see Figure 2,
Li et al. 2012	Exposure(s): CPF in pregnancy Outcome(s): neurobehavioral measures	Partial	Yes	Yes	Partial	“There was insufficient evidence that human developmental exposures to CPF produce adverse neurobehavioral effects in infants and children across different cohort studies that may be relevant to CPF exposure.” (p. 109)
Osunkentan and Evans 2015	Exposure(s): prolonged DDT/DDE exposures where indoor residual spraying was practiced Outcome(s): adverse neurodevelopmental outcomes	Yes	Yes	Partial	Partial	“For the three studies on neurodevelopment, evidence suggestive of negative impact of DDT was found.” (p. 1)
Prueitt et al. 2011	Exposure(s): CPF Outcome(s): adverse neurodevelopmental effects	Partial	Yes	Yes	Partial	“Overall, the epidemiology data are not sufficiently robust to support the hypothesis that chlorpyrifos is a causal factor in neurodevelopmental effects.” (p. 851)
Roth and Wilks 2014	Exposure(s): PBDEs, PFCs Outcome(s): neurodevelopmental and/or neurobehavioral effects in infants and children, such as adverse birth outcomes, cognitive deficits, developmental delay, and attention deficit hyperactivity disorders	Partial	Yes	Yes	No	“Collectively, the epidemiological evidence does not currently support a stronga causal association between PBDEs and PFCs and adverse neurodevelopmental and neurobehavioural outcomes in infants and children.”(p. 278)
Studies with “Yes” for one criterion: see Figure 2,
Burns et al. 2013	Exposure(s): OPs, OCs, carbamates, pyrethroids, and other pesticides in pregnant or nursing women or in infants or young children Outcome(s): neurobehavioral outcomes	Partial	Partial	Yes	No	“As a whole, the epidemiologic studies did not strongly implicate any particular pesticide as being causally related to adverse neurodevelopmental outcomes in infants and children.” (p. 127)
Cicchetti, Kaufman, and Sparrow 2004	Exposure(s): prenatal and postnatal PCBs Outcome(s): neurobehavioral, health-related, and cognitive deficits	No	Yes	No	Partial	“Studies deriving from the more recent cohorts used better research designs than those based on the early (about 1980) cohorts in Michigan and North Carolina, and produced occasional interesting hypotheses that need to be tested on new cohorts. However, the numerous claims and conclusions regarding the deleterious effects of maternal PCB exposure upon subsequent cognitive, neuropsychological, and behavioral development in their offspring, whether the exposure is in utero or postnatal, are not tenable; nor are the claims that PCBs affect the neuropsychological functioning of adults.” (p. 589)
González-Alzaga et al. 2014	Exposure(s): OPs Outcome(s): neurodevelopment and/or behavior	Partial	Partial	Yes	No	“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. Standardised methodologies are needed to allow results to be better compared and to perform a quantitative meta-analysis before drawing any final conclusions.” (p. 104)
Goodman et al. 2010	Exposure(s): prenatal and neonatal PCBs Outcome(s): neurodevelopment	Partial	No	Yes	Partial	“These analyses indicate that our ability to conduct weight-of-evidence assessments of the epidemiologic literature on neurotoxicants may be limited, even in the presence of multiple studies, if the available study methods, data analysis, and reporting lack comparability.” (p. 727)
Reiss et al. 2015	Exposure(s): low-level nonoccupational OP exposure Outcome(s): neurodevelopmental (e.g., mental and psychomotor) testing results	Partial	Partial	Yes	No	“In summary, associations observed between OP metabolites and birth outcomes in epidemiologic studies have been mostly weak or imprecise, inconsistent, temporally ambiguous, not clearly monotonic, not biologically plausible or coherent with toxicological evidence given the estimated degree of AChE inhibition at observed DAP concentrations, and not specific to any OP insecticide or health outcome.” (p. 638)
Studies with only a ‘Partial’ for two or more criteria: see Figure 2,
Berghuis et al. 2015	Exposure(s): PCBs, OH-PCBs, PBDE, DDE, phthalates, BPA, PFCs Outcome(s): neurodevelopmental outcome	Partial	No	Partial	No	“This review shows that exposure to POPs has effects on neurodevelopmental outcome in infants.” (p. 705) “Regarding exposure to other environmental chemicals, sex-specific effects have been reported after exposure to phthalates and their metabolites. Phthalates possibly also play a role in the pathogenesis of ASD, and there might be a genetic influence on the association between phthalate exposure and attentional problems in infants with ADHD. Exposure to BPA was found to be associated with child behavior, affecting boys and girls differently. No or inverse associations existed between exposure to PFCs and characteristics of attention-deficit/hyperactivity at school age.” (p. 705)
Boucher, Muckle, and Bastien 2009	Exposure(s): prenatal PCBs Outcome(s): cognitive profile	Partial	No	Partial	No	Prenatal PCB exposure appears to be related to a relatively specific cognitive profile of impairments.” (p. 7)
Ejaredar et al. 2015	Exposure(s): phthalates (urinary phthalate metabolites) Outcome(s): behavioral and cognitive impairment in children 0–12 years of age	Partial	Partial	No	Partial	“A systematic review of the literature supports the contention that prenatal exposure phthalates is associated with adverse cognitive and behavioral outcomes in children, including lower IQ, and problems with attention, hyperactivity, and poorer social communication.” (p. 51)
Eskenazi et al. 2008	Exposure(s): DDT/DDE, OPs Outcome(s): neurodevelopment	Partial	No	Partial	No	“Most studies have examined the association of DDE and neurodevelopment, although this literature shows inconclusive findings.” (p. 229)
Eskenazi et al. 2009	Exposure(s): DDT/DDE Outcome(s): neurodevelopmental effects	Partial	No	Partial	No	“These studies suggest that DDT, and less so DDE, may be associated with neurodevelopmental deficits.” (p. 1364)
Herbstman and Mall 2014	Exposure(s): prenatal and childhood PBDE Outcome(s): neurodevelopment	Partial	No	Partial	No	“Despite methodological, geographical, and temporal differences between studies, the majority of the epidemiologic evidence supports that early life exposure to PBDEs measured during pregnancy and/or during childhood is detrimental to child neurodevelopment in domains related to child behavior, cognition, and motor skills.” (p. 101)
Jacobson and Jacobson 1997	Exposure(s): prenatal PCBs Outcome(s): neurobehavioral effects	No	Partial	Partial	No	“Thus, a small reduction in a mean IQ score may reflect little effect on a majority of the sample accompanied by a substantial deficit in a small number of more vulnerable children.” (p. 415)
Julvez and Grandjean 2009	Exposure(s): occupational exposure during pregnancy; organic solvents, OC pesticides, OPs Outcome(s): developmental neurotoxicity risks in offspring	Partial	No	Partial	No	“The majority of recent occupational studies focused on organic solvents and pesticides, which were associated with neurobehavioral impairments in the progeny.” (p. 459)
Jurewicz and Hanke 2008	Exposure(s): OPs, OCs Outcome(s): neurobehavioral development	Partial	No	Partial	No	“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.” (p. 121)
Jurewicz, Polańska, and Hanke 2013a	Exposure(s): phthalates, BPA, brominated flame retardants Outcome(s): cognitive and behavioral development	Partial	Partial	No	No	“The results from the presented studies suggest that there are strong and rather consistent indications that the developing nervous system is particularly vulnerable to insult from low levels of exposure to widespread environmental contaminants such as: phthalates, bisphenol A, brominated flame retardants, polycyclic aromatic hydrocarbons, gas cooking” (p. 185)
Jurewicz, Polańska, and Hanke 2013b	Exposure(s): OPs, OC pesticides, PCBs Outcome(s): neurodevelopment	Partial	Partial	No	No	“The result of the presented studies show that exposure to the above-mentioned chemicals may impair the neurodevelopment of children.” (p. 465)
Kim et al. 2014	Exposure(s): brominated flame retardants Outcome(s): neurobehavioral and developmental disorders	Partial	No	Partial	No	“Although epidemiological data are limited, this overview of the evidence suggests a possible relationship between BFR exposure and serious health consequences, namely cancer, such as digestive system cancers and lymphoma, reproductive health effects, alteration in thyroid function, neurobehavioral and developmental outcomes in children, and diabetes.” (p. 17)
Koureas et al. 2012	Exposure(s): biomarkers of OPs, pyrethroids Outcome(s): neurodevelopment and neurobehavior	Partial	No	Partial	No	“With regard to OP pesticides, the studies reviewed suggested negative effects of prenatal exposure to these pesticides on neurodevelopment and male reproduction.” (p. 155) “In the only study that examined PYR exposure, no association was found between prenatal exposure and neurodevelopment… However, an association was found between prenatal piperonyl butoxide (a pyrethroid synergist) in personal air samples and the Mental Development Index (MDI) scores.” (p. 163)
Longnecker, Rogan, and Lucier 1997	Exposure(s): DDT, PCBs Outcome(s): neurologic effects, neurologic development	Partial	No	No	Partial	“Despite the occurrence of ambiguous or inconsistent findings within and across studies of neurologic development and PCB exposure, the data overall indicate that high prenatal PCB exposure encountered in general populations in developed countries may be adversely affecting children. The greater but later exposure from the mothers’ milk, however, is so far without consistent effect.” (p. 226) “High-level exposure to a mixture of PCBs and PCDFs causes neurobehavioral abnormalities, thus increasing the plausibility of subtle low-level effects. With only three studies of PCBs and abnormal findings at birth, however, the relation is far from established.” (p. 237)
Lyall, Schmidt, and Hertz-Picciotto 2014	Exposure(s): phthalates, PCBs, pesticides, PVCs Outcome(s): autism spectrum disorder	Partial	Partial	No	No	“Little research has assessed other persistent and non-persistent organic pollutants in association with ASD specifically.” (p. 443)
Muñoz-Quezada et al. 2013	Exposure(s): OPs Outcome(s): neurodevelopmental outcomes	Partial	Partial	Partial	No	“All studies except one cross-sectional study in China… provided evidence that exposure to OP pesticides was a risk factor for poor neurodevelopment, with the strongest linkages resulting from prenatal exposures.” (p. 164) “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.” (p. 158)
Mustieles et al. 2015	Exposure(s): BPA exposure during pregnancy Outcome(s): cognitive and/or behavior outcomes	Partial	No	Partial	No	“The epidemiologic studies conducted to date point in the same worrying direction [as animal studies], suggesting that prenatal exposure to BPA (and possibly postnatal BPA exposure) may be related to increased neurobehavioral problems in children. Although the very small number of human studies does not yet allow any conclusive link to be established, the results of our comparative analysis show that aggressive behavior and anxiety/depression symptoms are the problems most consistently associated with BPA exposure.” (pp. 181–182)
Quinete, Schettgen, and Bertram et al. 2014	Exposure(s): OH-PCBs and MeSO2-PCBs in human blood Outcome(s): neurodevelopment	Partial	No	No	Partial	“Health effects of PCB metabolites included carcinogenicity, reproductive impairment, and developmental neurotoxicity, being more efficiently transferred to the brain and across the placenta from mother to fetus in comparison to the parent PCBs.” (p. 11951)
Ribas-Fitó et al. 2001	Exposure(s): PCBs Outcome(s): neurological development	Partial	No	Yes	Partial	“These studies suggest a subtle adverse effect of prenatal PCBs exposure on child neurodevelopment. Differences in study design, inconsistency in some of the results, and the lack of adequate quantitative exposure data, do not allow the derivation of the degree of risk associated with neurodevelopmental effects at current levels of exposure.” (p. 537)
Rochester et al. 2013	Exposure(s): BPA Outcome(s): childhood behavior and neurodevelopment	Partial	Partial	Partial	No	“On the whole… studies strongly suggest that BPA is associated with neurobehavioral problems in children.” (p. 145)
Rossignol and Frye 2012	Exposure(s): environmental toxicants Outcome(s): autism spectrum disorders	Partial	Partial	No	No	“A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation, oxidative stress, mitochondrial dysfunction and toxicant exposures. The strongest evidence was for immune dysregulation/inflammation and oxidative stress followed by toxicant exposures and mitochondrial dysfunction.” (p. 398)
Schantz, Widholm, and Rice 2003	Exposure(s): congener-specific PCBs Outcome(s): neurodevelopment	No	Partial	Partial	No	“As the data from ongoing PCB studies assessing the mediators of neurobehavioral outcomes in children are published, the weight of evidence for PCB effects on neurodevelopment is growing. Studies in Taiwan, Michigan (USA), New York (USA), Holland, Germany, and the Faroe Islands have all reported negative associations between prenatal PCB exposure and measures of cognitive functioning in infancy or childhood. The German study also reported a negative association between postnatal PCB exposure and cognitive function in early childhood—a result that had not been found in previous studies. Only one published study in North Carolina (USA) has failed to find an association between PCB exposure and cognitive outcomes.” (p. 374)
Seegal 1996	Exposure(s): PCBs and related halogenated aromatic hydrocarbons Outcome(s): neurological and behavioral dysfunctions	No	Partial	Partial	No	At present data from four epidemiological studies are available in the literature. These studies describe potentially significant association between exposure to complex mixtures of HAHs or the developmental and cognitive dysfunctions seen in children born to mothers, via: (1) consumptions of contaminated rice oil, (2) contaminated fish or (3) exposure to environmental sources of PCBs (p. 710)
Weselak, Arbuckle, and Foster 2007	Exposure(s): periconceptual OPs, and DDT/DDE Outcome(s): developmental outcomes	Partial	Partial	No	No	“…there was limited or inadequate evidence to support causality for all associations examined” (p. 41)
Wigle et al. 2008	Exposure(s): PCBs, pesticides Outcome(s): neuropsychological deficits	Partial	Partial	Partial	No	“There were many relationships supported by limited epidemiologic evidence, ranging from several studies with fairly consistent findings and evidence of dose response relationships to those where 20 or more studies provided inconsistent or otherwise less than convincing evidence of an association. ….In most cases, relationships supported by inadequate epidemiologic evidence reflect scarcity of evidence as opposed to strong evidence of no effect.” (p. 373)
Studies with only 1 ‘Partial’: see Figure 2,
Arisawa, Takeda, and Mikasa 2005	Exposure(s): PCDDs, PCDFs, PCBs Outcome(s): neurodevelopment of infants	No	No	Partial	No	“Consistent results have been reported for the association between exposure to background levels of PCBs/dioxins, particularly trans-placental PCBs, and defective neurodevelopment of infants in the U.S. and Europe.” (p. 10)
Bellinger 2013	Exposure(s): chemicals including phthalates, BPA, PBDEs, PFCs, air pollution, and OPs during pregnancy Outcome(s): neurodevelopmental impacts	No	No	Partial	No	“For some chemicals of more recent concern, the available literature does not yet afford strong conclusions about neurodevelopment toxicity.” (p. 1)
Bjørling-Poulsen, Andersen, and Grandjean 2008	Exposure(s): OPs Outcome(s): developmental neurotoxicity	Partial	No	No	No	“Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides.” (p. 1)
Eaton et al. 2008	Exposure(s): CPF at current exposure levels Outcome(s): Adverse neurodevelopmental outcomes in humans	No	No	Partial	No	“The findings reviewed earlier for the three birth cohort studies suggest the possibility that prior chlorpyrifos exposures may be associated with adverse birth and neurodevelopmental outcomes; however, the evidence for this association is inconsistent between studies and the weight of available evidence argues against the proposed association as being of causal significance. While it is difficult at present to judge the significance, or lack thereof, of current levels of chlorpyrifos exposures in the United States on the development of the nervous system in humans, we cannot rule out chlorpyrifos-induced human neurodevelopmental perturbation.” (p. 108)
Engel and Wolff 2013	Exposure(s): EDs (e.g., PCBs, phthalates) Outcome(s): neurodevelopment	No	No	Partial	No	“Sufficient data exist to make a strong case for continued research aimed at investigating the role of EDs in child health and development. However, future epidemiologic research should base study designs on a cogent hypothesis with attention to the principles of causal inference.” (p. 15)
Grandjean and Landrigan 2006	Exposure(s): industrial chemicals Outcome(s): human neurotoxicity	Partial	No	No	No	“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 recognize the unique vulnerability of the developing brain are needed for testing and control of chemicals.” (p. 2167)
Jorissen 2007	Exposure(s): PCBs in breast milk Outcome(s): neurological effects	No	Partial	No	No	“At this point, there is no evidence of a threshold among the general population beyond which the risks of breastfeeding outweigh the benefits, nor is there any evidence demonstrating a clinically significant negative effect of postnatal exposure to PCBs via breast milk.” (p. 230)
Jurewicz and Hanke 2011	Exposure(s): phthalates Outcome(s): children’s neurodevelopment	Partial	No	No	No	“The findings of the reviewed studies indicate that children’s exposure to phthalates (MBzP, MECPP, MEHHP, MEOHP, MEHP, MCPP, MMP, MEP, MBP, MiBP, ΣDEHP, ΣDBP) may bring about impairments in the neurodevelopmental processes.” (p. 127)
Kimbrough and Krouskas 2003	Exposure(s): PCBs Outcome(s): neurobehavioral aspects	No	Partial	No	No	“Since the results reported in different studies are conflicting and are meliorated by breast feeding, parental education and the HOME score, the hypothesis of neurodevelopmental deficits resulting from in utero exposure of the fetus to PCBs is not supported by the data.” (p. 228)
LaKind, Berlin, and Mattison 2008	Exposure(s): dioxins in breast milk Outcome(s): neurodevelopment	No	No	Partial	No	“The current evidence does not support altering the World Health Organization recommendations promoting and supporting breastfeeding.” (p. 251)
Miodovnik et al. 2014	Exposure(s): phthalates (in urine) Outcome(s): neonatal and infant neurological status, mental and psychomotor development, cognitive development, behavior and emotional problems, play behavior, social impairment, ADHD, continuous performance test, parent report	No	No	Partial	No	“While the observed associations are based on limited studies with a broad range of endpoints, the implications of such outcomes are of concern from a public health standpoint and merit further investigation given the widespread nature of the exposure.” (p. 112)
Polańska, Jurewicz, and Hanke 2013	Exposure(s): prenatal and postnatal; OC pesticides, OPs, PCBs Outcome(s): ADHD or ADHD-related symptoms	Partial	No	No	No	“The outcome of the presented studies has proven an association between exposure to organochlorine pesticides and PCBs and ADHD-like behaviors: Alertness, quality of alert responsiveness, cost of attention, and other potential attention-associated measures including self-quieting and motor maturity. In addition, studies found that exposure to PCBs can be linked with a longer, more variant response time, impairment of response inhibition, poorer concentration and verbal, pictorial and auditory working memory and attention problems. Only one study did not find an association between ADHD and ADHD-like behaviors and PCBs exposure.” (p. 23)
Rohlman et al. 2008	Exposure(s): pesticides Outcome(s): neurobehavioral effects	No	No	Partial	No	“Although there are inconsistencies across the studies, the evidence suggests that there are performance deficits associated with exposure and an increase in the reporting of developmental and behavioral problems associated with exposure.” (p. 563)
Rosas and Eskenazi 2008	Exposure(s): in-utero OPs, OCs (DDT/DDE) Outcome(s): neurobehavioral development	No	No	Partial	No	“Given that the literature suggests a link between organochlorine and in-utero pesticide exposure and impaired child neurodevelopment, clinicians should educate parents about prevention of exposure, particularly in populations living in agricultural areas or where household use is common.” (p. 191)
Rossignol, Genuis, and Frye 2014	Exposure(s): environmental toxicants Outcome(s): autism spectrum disorders	Partial	No	No	No	“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.” (p. 1)
Schantz 1996	Exposure(s): PCBs Outcome(s): developmental neurotoxicity	No	Partial	No	No	“The fact that today’s children are being exposed to both PCBs and lead, as well as a multitude of other chemicals, many of which could be altering neuropsychological functioning in subtle ways, is a sobering thought, and one that bears our full and immediate attention.” (p. 225)
Sheets et al. 2016	Exposure(s): neonicotinoid insecticides Outcome(s): neurodevelopmental outcomes	Partial	No	No	No	“The collective information that is available shows no consistent pattern of effects among the six neonicotinoids or for any of these insecticides compared with nicotine.” (p. 186)
Studies with ‘No’ for all criteria: see Figure 2,
Colborn 2006	Exposure(s): CPF, glyphosate, phosphine Outcome(s): neurodevelopmental effects, autism, ADHD	No	No	No	No	“This is followed by a section on human epidemiology where only weak data are available linking neurodevelopmental impairment with pesticides.” (p. 10)
Czerska et al. 2013	Exposure(s): PBDE during pregnancy Outcome(s): mental and psychomotor development in infants	No	No	No	No	“Summarizing, exposure to PBDEs during BGS [brain growth spurt] may lead to the impaired neurodevelopment manifested by behavioral disorders and poorer mental and psychomotor development.” (p. 503)
Damstra 2002	Exposure(s): PCBs Outcome(s): neurological effects	No	No	No	No	“In summary, several humans studies show a range (severe to minor) of adverse effects but within the same continuum of motor and mental developmental delays or impairments.” (p. 462)
Ding and Bao 2014	Exposure(s): OPs pyrethroid Outcome(s): neurobehavioral development	No	No	No	No	Regarding US studies: “[The] inconsistent results across studies may arise from differences in exposure scenarios and in the method of exposure assessment… Nonetheless, growing evidence supports the adverse association between exposure to pesticides and children’s health consequences.” (p. 291)
Donaldson et al. 2010	Exposure(s): PCBs Outcome(s): neurobehavioral function	No	No	No	No	“Epidemiological studies have shown possible effects of contaminants on immune system function, neurodevelopment, sex hormone disruption, and oxidative stress” (p. 5224)
Evangelista De Duffard and Duffard 1996	Exposure(s): PCBs Outcome(s): developmental neurotoxicity	No	No	No	No	“Although there is little evidence to suggest that PCBs are directly neurotoxic in adults, there is considerable evidence indicating that these chemicals are developmental neurotoxicants.” (p. 254)
Grandjean and Landrigan 2014	Exposure(s): industrial chemicals Outcome(s): developmental neurotoxicity	No	No	No	No	“Since 2006, epidemiological studies have documented six additional developmental neurotoxicants—manganese, fluoride, chlorpyrifos, dichlorodiphenyltrichloroethane, tetrachloroethylene, and the polybrominated diphenyl ethers. We postulate that even more neurotoxicants remain undiscovered. To control the pandemic of developmental neurotoxicity, we propose a global prevention strategy.” (p. 330)
Korrick and Sagiv 2008	Exposure(s): early-life PCBs, OP pesticides Outcome(s): neurodevelopment	No	No	No	No	“Overall, epidemiologic studies support modest associations of primarily prenatal PCB exposures with differences in neuromotor development, decrements in cognition, and behavioral deficits, particularly regarding attention and impulse control.” (p. 1)
London et al. 2012	Exposure(s): prenatal and occupational pesticides, urinary metabolites of OPs Outcome(s): neurobehavioral deficits, ADHD, neurobehavioral performance of adolescents	No	No	No	No	“Given the association of organophosphates with behavioral problems in children, the rates of which have risen sharply in recent years, and the unknown but long-lasting effects on the developing brain, reducing exposure is critical.” (p. 895)
Mariussen and Fonnum 2006	Exposure(s): PCBs, DDT/DDE Outcome(s): neurobehavioral effects	No	No	No	No	“Epidemiological studies after accidental and environmental exposures have shown that polychlorinated biphenyls (PCBs) may affect neurological development and impair cognitive functions both in human and animals.” (p. 254) “Epidemiological studies on DDT/DDE-exposed children have not revealed substantial evidence of neurological or developmental abnormalities…” (p. 270)
Meeker 2012	Exposure(s): EDCs (e.g., PCBs, BPA, phthalates, pesticides) Outcome(s): child development	No	No	No	No	“Longitudinal and/or cross-sectional human studies have related exposure to EDCs, both in utero and during early childhood, with neurodevelopmental disorders such as decreased IQ, poorer memory, autism spectrum disorders, attention deficit/hyperactivity disorder, and other behavioral problems.” (p. 955)
Mikołajewska, Stragierowicz, and Gromadzińska 2015	Exposure(s): BPA Outcome(s): neurodevelopment	No	No	No	No	“These data indicate that exposure of pregnant women to BPA may either affect the behavior of children, or may be irrelevant. In general, however, the studies clearly suggest, that there is a relationship between the level of BPA and neurobehavioral problems in children.” (p. 226)
Miodovnik 2011	Exposure(s): PCBs, OPs, phthalates, BPA, PBDEs, PFCs Outcome(s): neurological, cognitive, and behavioral	No	No	No	No	“Definitive conclusions are a long way from being rendered for many of these chemicals.” (p. 69)
Nakai and Satoh 2002	Exposure(s): PCBs, PCDDs, PCDFs Outcome(s): neurotoxicity	No	No	No	No	“These cohort studies presented evidence of a delay in psychomotor development in children who were exposed to … PCBs during the perinatal periods” (p. 94)
Rauh et al. 2010	Exposure(s): CPF, other OPs Outcome(s): neurodevelopment	No	No	No	No	“Evidence is accumulating that the adverse consequences of early exposures to the OP pesticide CPF are serious and persistent, including a range of attentional, sensorimotor, impulse control and memory-related functions with implications for learning and school performance in children. Furthermore, these early low-dose exposures are well below the level known to be associated with the toxic consequences of acetylcholinesterase inhibition.” (p. 6)
Rice 1997	Exposure(s): developmental exposure to PCBs Outcome(s): neurotoxicity	No	No	No	No	“The congruence of findings between studies in humans and animal models, as well as the similarity of body burden at which neurotoxic effects are observed, support the hypothesis that PCB exposure produces neurotoxicity in the developing human at environmentally relevant levels.” (p. 228)
Safe 1992	Exposure(s): prenatal PCBs Outcome(s): development	No	No	No	No	“Recent studies have demonstrated that some developmental deficits in infants and children correlated with in utero exposure to PCBs; however, the etiologic agent(s) or structural class of PCBs responsible for these effects have not been delineated.” (p. 259)
Saravi and Dehpour 2016	Exposure(s): OC pesticides, PCBs Outcome(s): autism, impaired psychomotor and cognitive development, memory loss, impaired perceptual performance skills, ADHD	No	No	No	No	“A growing body of evidence suggests the role of OCs in disruption of normal neurodevelopment, etiology of autism, and impairment of psychomotor and mental functions, including memory, attention, and verbal skills in children.” (p. 261)
Saunders et al. 2012	Exposure(s): CPF Outcome(s): neurodevelopmental disorders in infants and children	No	No	No	No	“Policy makers must decide whether CPF’s negative effects are worth reconsidering and the possibility of a ‘silent epidemic’ is something they feel comfortable continuing to ignore” (p. 9)
Stein, Schettler, and Wallinga et al. 2002	Exposure(s): PCBs Outcome(s): developmental disabilities	No	No	No	No	“This body of research demonstrates cause for serious concern that commonly encountered household and environmental chemicals contribute to developmental disabilities.” (p. S13)
Weisglas-Kuperus 1998	Exposure(s): perinatal PCBs and dioxins Outcome(s): neurodevelopmental and behavioral outcome and neurobehavioral effects	No	No	No	No	“Cognitive and neuromotor changes, differences in immune response, reduced birthweight, microgenitalism, reduced fertility and changes in the male/female ratio may all be associated with human prenatal PCB/dioxin exposure. To consider the health of the offspring in exposed individuals is therefore of extreme importance.” (p. 1850)
Winneke, Walkowiak, and Lilienthal 2002	Exposure(s): prenatal or early postnatal PCBs Outcome(s): neurodevelopmental delay	No	No	No	No	“Associations between neurodevelopmental delay and prenatal or early postnatal PCB-exposure at environmental levels have been reported in several cohort studies. Adverse effects were found to be associated with early developmental PCB-exposure, although there are discrepancies between studies in terms of confounding, effective PCB-matrix, as well as spectrum and persistence of effects. From these cohort studies alone the causative role of PCBs in producing neurodevelopmental adversity still cannot be considered proven, but experimental findings do provide evidence for the developmental neurotoxicity of PCBs. The underlying mechanisms of this action is still unknown.” (p. 161)
Yolton et al. 2014	Exposure(s): OPs Outcome(s): ADHD and related behaviors	No	No	No	No	“To date, only three published studies have provided evidence of links between exposure to OPs and ADHD or related behaviors. However, these three studies have been the first to rigorously investigate this possible association, adding strength to the findings.” (p. 42)

3,5,6-TCP = 3,5,6-trichloropyridinol; ADHD = attention-deficit/hyperactivity disorder; BPA = bisphenol A; CPF = chlorpyrifos; DDE = dichlorodiphenyldichloroethylene; DDT = dichlorodiphenyltrichloroethane; ED = endocrine disruptor; HCB = hexachlorobenzene; OC = organochlorine; OP = organophosphate pesticide; PBDE = polybrominated diphenyl ether; PCB = polychlorinated biphenyl; PCDD = polychlorinated dibenzo(p)dioxin; PCDF = polychlorinated dibenzo(p)furan; PFC = perfluorinated chemical; STROBE = Strengthening the Reporting of Observational Studies in Epidemiology

Figure 2. Synopsis of percentage of environmental epidemiology reviews categorized as having fully, partially, or not meeting criteria on systematic inclusion/exclusion, search, retrieval and review of studies, structured evaluation of data quality, systematic assessment of consistency and assessment of reporting, and publication bias (see Table 1 for more details on criteria).

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