Chemical Contributions to Neurodevelopmental Disorders

Abstract

Children increasingly receive diagnoses of neurodevelopmental disorders (NDDs). Causes are multifactorial, but growing consensus identifies environmental factors, especially chemical exposures, as primary drivers, with some individuals more genetically susceptible to these external pressures than others. Our current system of chemical management prioritizes rapid commercialization over disease prevention. This strategy privatizes economic benefits but socializes health costs. The evidence linking chemical exposure to neurodevelopmental risk merits greater attention by regulators. Public health concerns, particularly for children and other vulnerable groups, should be elevated in chemical risk assessment. The financial and emotional burden of preventable NDDs on U.S. children and their families calls for comprehensive policy attention.

Keywords

pollution endocrine disruption neurodevelopment neurotoxicity brain

Compelling evidence links chemical exposure to neurodevelopmental risk and merits policy changes which prioritize child health over economic interests.

Key Points

Chemical exposures measurably contribute to risk of neurodevelopmental disorders.

Policy changes which prioritize disease prevention over economic interests are needed to improve chemical management in the United States.

The chemicals of greatest concern constitute less than 1% of the 90,000+ chemicals in our environment.

Reducing developmental exposure to neurotoxicants is a manageable problem but requires policy changes that reduce bias, data exclusion, and outdated testing schemes.

Introduction

Prevalence of neurodevelopmental disorders (NDDs) is conspicuously rising, provoking some to label it a silent pandemic (Boyle et al., 2011; Grandjean & Landrigan, 2006, 2014). NDDs are a heterogeneous group of neuropsychiatric illnesses with various degrees of cognitive, language, social, motor, and affective deficits. According to the U.S. Centers for Disease Control and Prevention (CDC), in 2006-2008, an estimated one in six children suffered from some form of neurodevelopmental disability including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). NDDs emerge in childhood but typically persist a lifetime, making them long-term societal problems and a substantial economic burden across multiple sectors, especially schools. For example, the costs of caring for an autistic child averaged US$3000 per year in additional health costs, and US$8000 in additional school system costs (Lavelle et al., 2014). Total costs per year for U.S. children with ASD were estimated to be between US$11.5 billion and US$60.9 billion (2011 U.S. dollars) (Buescher, Cidav, Knapp, & Mandell, 2014), the bulk of which was borne by schools and other societal institutions. Families and caregivers of afflicted children also suffer immeasurable emotional burdens.

Effective therapies for most NDDs are lacking, so prevention especially matters. Causes are complex, but growing consensus implicates environmental factors, especially chemical exposures (Hertz-Picciotto & Delwiche, 2009; Landrigan, Lambertini, & Birnbaum, 2012), with some individuals more genetically susceptible to these external pressures than others (Volk et al., 2014; Woods et al., 2012). Mitigation of chemical risk factors is perhaps the most effective strategy for preventing environmentally contributed risk.

The Role of the Environment in NDD Risk

Although improvements in neurobehavioral assessment have clearly contributed to rapidly rising rates of ASD and other neurobehavioral disorders, they cannot fully account for the dramatic and rapid upswing (Hertz-Picciotto & Delwiche, 2009). Neither can genetics. NDDs resulting from genetic mutation (including Fragile X, Down’s Syndrome, Prader-Willis and Angleman Syndrome) are extremely rare. Similarly, while some disorders clearly have a heritable component, growing consensus holds that genetics may, at best, account for half of risk, with environment contributing the rest. For example, estimates from twin and other studies are wildly uneven but show that genetic factors contribute only an estimated 30% to 40% of ASD heritability (Huguet, Ey, & Bourgeron, 2013; Insel, 2009; Sandin et al., 2014). Similarly, although ADHD heritability is estimated to be as high as 75%, genome-wide association studies repeatedly fail to identify areas associated with significant risk. Candidate genes predict only minute increases in ADHD symptomology, highlighting the multifactorial nature of ADHD risk, including the environment (Faraone et al., 2005; Neale et al., 2010).

ASD and other NDDs mostly result from a confluence of sex-specific gene vulnerabilities layered with adverse, and critically timed, environmental interactions, including chemical exposures (Homberg et al., 2016; Sealey et al., 2016). Although identifying which chemicals, and how a “perfect storm” of genetic predispositions and environmental interactions manifests as clinical disease is challenging, it is not intractable. Significant advances on several fronts have identified chemicals of greatest concern.

The Chemosphere of Neurotoxicants

Our environment today contains upward of 90,000 chemicals, although a full accounting proves nearly impossible, even for regulators (such as the U.S. Environmental Protection Agency [EPA]) charged with monitoring their distribution, use, and toxicity (http://cen.acs.org/articles/95/i9/chemicals-use-today.html). Not all chemicals are harmful, but significant numbers are ever-present in our bodies. In 2001, the CDC via its National Biomonitoring Program began publishing an annual accounting of the chemicals it could detect in human fluids. The list contains 300+ chemicals and their metabolites, many in fetal-cord blood and breast milk—indicating that children are essentially born “pre-polluted” with hundreds of chemicals. Some chemicals have been studied for decades, but most have not been tested for any form of toxicity at all.

Classically, a neurotoxin is defined as a substance that is poisonous to neural tissue and can result in cell death. Not all chemicals that harm the developing brain fit that axiomatic definition. Endocrine disrupting chemicals (EDCs) are not “poisons” in the classical sense, but they can disrupt neural systems by altering the effects of hormones (Baccarelli, Pesatori, & Bertazzi, 2000; Gore et al., 2015). Disruption of gestational or neonatal thyroid hormone, for example, can result in severe neural outcomes including cretinism, retarded brain maturation, intellectual deficits, and cognitive impairment (Moog et al., 2017; Zoeller, 2007). Disruption of thyroid hormone signaling is particularly consequential because it is essential for many aspects of brain development. Maternal thyroid hormone levels can reflect insufficient dietary iodine, thyroid disease such as hypothyroidism, or exposure to EDCs such as polychlorinated biphenyls (PCBs) and PBDEs (Fonnum & Mariussen, 2009; Hagmar, 2003).

Most Americans, and even policy makers, do not realize that, in the United States, chemicals only rarely undergo any kind of formalized toxicity testing before being commercialized, and then almost never testing for neurodevelopmental or endocrine disrupting effects. Consequently, most published work assesses chemicals to which we are already ubiquitously exposed. Decades of research and rapid technological advances have yielded significant insight as to which of the 90,000+ chemicals in our chemosphere are most harmful to childhood neurodevelopment.

Animal, cell, and in vitro studies have identified over 1,000 industrial chemical neurotoxicants. Epidemiological studies have associated 200+ chemicals with neurotoxicity in humans (Heyer & Meredith, 2017). Only a handful of chemicals have been specifically shown to induce developmental neurotoxicity in humans (Table 1). In a pair of reviews spanning two decades, Philippe Grandjean and Philip Landrigan highlighted six chemicals with particularly strong links to NDDs: arsenic, lead, methylmercury, toluene, PBDEs, and some PCB congeners (Grandjean & Landrigan, 2006, 2014). According to additional substantial evidence, organophosphate pesticides, such as chlorpyrifos, which are potently neurotoxic and even fatal at high doses, also harm the developing brain at low doses (Saunders et al., 2012; Venerosi, Ricceri, Tait, & Calamandrei, 2012).

Table 1.

A Representative Listing of Some of Most Well-Studied Compounds With Evidence of Developmental Neurotoxicity in Humans.

Chemical	Neurodevelopmental outcomes in children
Arsenic	Cognitive and memory deficits.
BPA	Emotional problems in children including increased internalizing problems in boys and increased anxious and depressive behaviors in girls.
Chlorpyrifos	Cognitive and emotional deficits; associated with higher prevalence of ADHD.
Lead	Cognitive and emotional deficits including elevated aggression.
Methyl mercury	Cognitive and emotional deficits.
PBDEs	Cognitive and emotional deficits; decreased IQ; positive association with ASD-related behaviors for some congeners.
PCBs and dioxins	Cognitive and motor deficits; decreased IQ; some evidence of disruption to sexually dimorphic behaviors including play.
Organophosphate pesticides	Cognitive deficits; associated with higher prevalence of ASD and ADHD.
Phthalates	Lower IQ; problems with attention, hyperactivity, and social communication; decreased masculine play in boys.
Pyrethroid pesticides	Cognitive deficits; associated with higher prevalence of ADHD.

Note. Although some, such as the PCBs and PBDEs, have been phased out of use, others, such as some organophosphate and pyrethroid pesticides, BPA, and phthalates, remain in high use. BPA = bisphenol A; ADHD = attention deficit hyperactivity disorder; PBDE = polybrominated diphenyl ether; ASD = Autism spectrum disorders.

A 2015 U.S. EPA review identified 100 neurotoxicants of concern (Mundy et al., 2015). Evidence for adverse effects in humans was available for 22 of them. The list included four of the six neurotoxicants highlighted in the Grandjean and Landrigan reviews (lead, methylmercury, PBDEs, and PCBs), chlorpyrifos, and four known teratogens (chemicals that cause birth defects).

Lack of concordance between lists generated by scientific and regulatory groups results from multiple factors, most significantly differences in the types and sources of data selected for consideration. Generally, scientific reports tend to be more inclusive than regulatory ones, and they use a different scheme for identifying, evaluating, and weighting data (Mandrioli & Silbergeld, 2016; McCarty, Borgert, & Mihaich, 2012; Myers et al., 2009; Tweedale, 2017; “The Weight of Evidence,” 2010; Woodruff & Sutton, 2014; Zoeller & Vandenberg, 2015). From a policy perspective, even using the most inclusive lists of suspected developmental neurotoxicants, controlling exposure would require action on less than 1% of the estimated 90,000+ chemicals on the market. This list includes compounds linked to a myriad of other diseases including cancer, neurodegeneration, obesity, and heart disease (Gore et al., 2015; World Health Organization [WHO] & United Nations Environment Programme [UNEP], 2012). Thus, improved management of this small but highly impactful subset of problematic compounds would have sweeping public health benefits.

Unfortunately, the U.S. current regulatory system avoids restricting toxic chemicals already on the market because most regulatory bodies require unequivocal proof of an “adverse outcome.” For regulatory purposes, an adverse outcome is typically a pathologic lesion or major functional impairment (Keller et al., 2012; Solecki et al., 2017). Thus, outcomes such as language delay, decrements in IQ, and other subclinical difficulties of learning, memory, and social cognition would not qualify as “adverse” under most codified definitions. In addition, cost–benefit analyses tend to prioritize the economic value of a compound over potential long-term health effects when making decisions about potentially restricting their use (Tweedale, 2017). The recent controversy surrounding chlorpyrifos (pesticide) exemplifies this prioritization of corporate interests over public health ones. Because of such challenges, in the rare instances when toxic chemicals (including tetraethyl lead, PCBs, and PBDEs) have been phased out, the process was slow and contentious (Vogel, 2013).

Barriers to Linking Exposure to Disease Risk: Evidence of Harm

Lack of data linking individual chemical exposures to increased risk of clinically defined NDDs such as ASD and ADHD has been cited as a significant barrier to regulatory action on chemicals suspected of being developmental neurotoxicants. This is an enormous challenge and, quite possibly, an impossible task. We all are exposed to a complex mixture of hundreds, if not thousands, of chemicals every day, so this complicates isolating and tracking the consequences of particular chemical exposures in individuals or populations. Exposure profiles also vary considerably based on lifestyle, geographic location, age, and other factors. The classic, double-blinded exposure paradigm used for pharmaceuticals and other therapeutic interventions obviously cannot be used for toxicology because the result is some level of harm, or even death. Requiring proof of harm for regulatory action is ultimately an unethical standard because it requires significant injury, in this case to children, and the manifestation of a clinically defined disorder. Yet, unfortunately, this is how the U.S. system currently works.

There is some compelling epidemiological evidence linking specific chemicals to NDDs and/or their hallmark features. Recent reviews link ASD risk to several chemicals, including pesticides, phthalates, PCBs, solvents, air pollutants, fragrances, glyphosate, and heavy metals (Kalkbrenner, Schmidt, & Penlesky, 2014; Sealey et al., 2016; Ye, Leung, & Wong, 2017). Elevated prenatal levels of trans-nonachlor (a component of the pesticide chlordane) and PBDE-28 (a fire retardant) have been linked to compromised sociality, but not ASD itself (Braun et al., 2014). Prenatal phthalate (plasticizer) exposure has been associated in some studies to poorer aptitude in language, social cognition, social communication, and social awareness in children (Huang et al., 2017; Miodovnik et al., 2011), but not a mental health disorder specifically. Animal studies largely confirm the human data, and also generate insight as to possible mechanisms (Fujiwara, Morisaki, Honda, Sampei, & Tani, 2016; Gore, Martien, Gagnidze, & Pfaff, 2014; Landrigan et al., 2012; Messer, 2010).

Robust evidence links pyrethroid pesticides, the most commonly used household insecticide, with ADHD, with the association strongest for boys. For example, a national sample of 687 prepubescent children found that boys with elevated urinary levels were more than twice as likely to have the hallmark ADHD symptoms of impulsivity and hyperactivity (Wagner-Schuman et al., 2015). Similar linkages have been reported in other children and in mice (Richardson et al., 2015). Of additional concern, in some animal models, perinatal exposure to pyrethroid and other pesticides linked to ADHD leads to a Parkinson’s-like disease in adults (Bouchard, Bellinger, Wright, & Weisskopf, 2010; Nasuti et al., 2014).

PCBs have long and unequivocally been associated with cognitive deficits including lower IQ (Winneke, 2011), but also fine-motor deficits, greater impulsivity, compromised verbal and auditory working memory, and decreased attention. They have not, however, been linked to a specific clinically defined disorder. Similarly, a 2014 study linked organophosphates and PBDEs with measurable IQ loss in European populations (Bellanger, Demeneix, Grandjean, Zoeller, & Trasande, 2015). Of additional concern, some PCB metabolites can also alter thyroid activity. Because PCBs can be gestationally and lactationally transferred, they pose multigenerational human health concerns (Fonnum & Mariussen, 2009).

Barriers to Linking Exposure to Disease Risk: Lack of Understanding About the Biological Basis of Neurodevelopmental Disease

A general lack of understanding regarding the biological basis of ASD, ADHD, and other NDDs, and why they have a sex-biased prevalence, adds to the difficulty of evaluating how chemical exposures contribute to risk. Although neural disease clearly begins during “development,” it can be difficult to define precisely when that period begins and ends because brain development proceeds well beyond childhood (Heyer & Meredith, 2017). In addition, the specific “critical windows” when the brain is most vulnerable to chemical insult remain incompletely defined. Technological advances in the past decade, especially in brain imaging, have revealed that myelination, synaptic remodeling, and other aspects of brain organization continue well into early adulthood—especially deep within cortical structures fundamental for reasoning, impulse control, and executive function. Ultimately, the finely tuned adult brain has pruned down approximately half the number of synapses it had at age 2.

Protracted, phased development allows the brain to organize responsively to myriad physical and experiential cues including nutrition, illness, culture, parental care, and peer relationships (Boyce, 2016; Heyer & Meredith, 2017; Homberg et al., 2016; Ye et al., 2017). Unequivocally, environment influences the decades-long process of brain morphogenesis via multiple mechanisms including epigenetics (Broad, Rocha-Ferreira, & Hristova, 2016; Keverne, 2014; Oro, 2004; Yeo, Patisaul, & Liedtke, 2013). This flexibility is not only adaptive but also leaves the developing brain vulnerable to insult. Even subtle perturbation of nervous system ontogeny can have profound, lifelong consequences on learning, social interactions, memory, mood, risk of substance abuse, and other adverse behaviors. Because much remains to be understood regarding the etiology of ASD, ADHD, and other NDDs, the National Academy of Sciences and other groups have advocated using fundamental aspects of mammalian brain development as “endpoints” in risk assessment, rather than clinical disorders themselves, as evidence of developmental neurotoxicity (National Academies of Sciences, Engineering, and Medicine, 2017).

Our laboratory has focused on brain sex differences. We have repeatedly found, using a rodent models, that perinatal exposure to EDCs capable of altering estrogen signaling, such as bisphenol A (BPA) or soy phytoestrogens, can eliminate or reverse sex differences in brain nuclei critical for sex-specific physiology and behavior (Patisaul & Adewale, 2009; Rebuli & Patisaul, 2016). In collaboration with the National Center for Toxicological Research (a division of the Food and Drug Administration [FDA]), we found that even at doses well below that considered “safe” by FDA and other regulatory agencies, prenatal BPA exposure can alter estrogen receptor levels in the hypothalamus and other sexually dimorphic brain nuclei in the rat (Arambula, Belcher, Planchart, Turner, & Patisaul, 2016; Cao et al., 2013). Other groups have also reported BPA and other EDC-related effects on brain sexual differentiation and sexually dimorphic behaviors including anxiety, exploration, and reproductive behavior (Chapin et al., 2008; Diamanti-Kandarakis et al., 2009; Food and Agriculture Organization of the United States [FAO] & WHO, 2011; Gore et al., 2015; vom Saal et al., 2007; Wolstenholme, Rissman, & Connelly, 2011; WHO & UNEP, 2012). In addition, rapidly growing evidence from various experimental models shows that fetal EDC exposure can have wide-ranging effects on fundamental neural processes (Gore et al., 2014), all implicated in ASD and other NDDs.

Conclusion

That chemicals can maim or kill us is not a novel concept. Humans have recognized the toxicity of compounds, synthetic and natural, for thousands of years—knowledge we have leveraged to great advantage in war and medicine. We are not always quick to accept, however, the consequences of chronic low-dose exposure, or the heightened vulnerability of subgroups (e.g., pregnant women). For classic neurotoxicants (including poisons and venoms), effects are typically rapid and obvious. We have exploited their properties for centuries and even used them in chemical weapons. Organophosphates are a model example of where the line between chemical weapon and commercially valuable pesticide is precariously thin. For other poisons, such as alcohol (ethanol), our tolerance of long-term consequences has been more myopic, often deliberately. Fetal alcohol syndrome (FAS) is one of the most preventable causes of craniofacial deformities and mental retardation. Although historical accounts linking excessive parental drinking with neural deficiencies in children date back centuries, FAS was not formally recognized as a clinical disorder until 1973 (Jones & Smith, 1973). In addition, misconceptions persisted. For example, despite all evidence to the contrary, effects on afflicted children were repeatedly ascribed to the drinking habits of the father, not the mother, and to some ethnic groups but not others.

Policy making must act in light of the science, despite lingering controversy and convenient beliefs. With alcohol, lead, methylmercury, chlorpyrifos, and other potent neurotoxicants, decision makers still search for a “safe” nonzero dose. Convenient blindness to the deleterious effects of ethanol was arguably a consequence of its social value. Because most people enjoy it without evidence of immediate harm, they can dismiss cogent evidence of long-term consequences and rationalize that acute, high doses are toxic but chronic intakes of lower doses is risk-free and, in some cases, even potentially beneficial. Similarly, organophosphates and other neurotoxicants have broad utility and commercial value. Consequently, despite undeniably adverse effects at high exposures, their economic and other benefits create the tempting hubris that we can identify an exposure level that is “safe.” Risk assessment must resist this hubris and be particularly vigilant about prioritizing child health.

Toxicity testing should be proactive rather than reactive, preventive rather than corrective. Ineffective, expensive, and outdated testing paradigms within the sphere of regulatory toxicology impede identifying and managing chemicals that contribute to risk of NDDs. Effectively screening new compounds and the 90,000+ chemicals already in commerce for developmental neurotoxicity is impossible using only traditional, animal-intensive methods (McCarty et al., 2012; Myers et al., 2009; Solecki et al., 2017; Tweedale, 2017; “The Weight of Evidence,” 2010). Moreover, although EDCs clearly contribute to NDDs, the current system of regulatory testing and risk assessment was not designed to assess these risks, nor has it kept pace with emerging technology to appropriately and reliably test for EDC activity (Gore et al., 2015; Zoeller & Vandenberg, 2015). Traditional, formalized “guideline” tests have crude endpoints developed decades ago to identify teratogens like thalidomide, but not outcomes or behaviors associated with an NDD like autism, which has profound social deficits but no defining neuropathology.

One solution is development of high-throughput approaches that leverage emerging in vitro technology and a more diverse range of neurotoxicological endpoints (McPartland, Dantzker, & Portier, 2015; Reif et al., 2016). New mandates and timelines in the Toxic Substances Control Act (TSCA) reform law necessitate accelerating and broadening implementation of these approaches. Adoption will require revising what constitutes an “adverse” outcome to include neurodevelopmental processes and decrements in cognition, sociality, learning, and memory.

Risk assessment has been slow to evolve, resistant to using scientific data collected outside of traditional testing schemes, and lacking in transparency. For example, in its 2014 Updated Review of Literature and Data on BPA (CAS RN80-05-7), the FDA evaluated 36 studies with evidence for potential neurotoxicity but deemed only one useful for risk assessment. That one paper was done by an industry-funded lab and found no effects. The discounted papers were mostly from academic labs and focused on more relevant exposure windows and endpoints. Not surprisingly, the FDA concluded BPA causes no harm at current exposure levels. By contrast, reports by the Endocrine Society and expert panels convened by the WHO and others warn that BPA poses at least some risk, especially to the developing brain (Chapin et al., 2008; Diamanti-Kandarakis et al., 2009; FAO & WHO, 2011; Gore et al., 2015; vom Saal et al., 2007; WHO & UNEP, 2012).

Ultimately all decisions occur under uncertainty. Abundant evidence in animals and humans indicates that pesticides, brominated fire retardants, and some EDCs are developmental neurotoxicants and yet there continues to be calls for more research, purportedly to resolve uncertainty. Magnified uncertainties prolong the review of scientific data and set the bar for regulatory action insurmountably high. FAS was finally identified as the consequence of maternal alcohol consumption using two manuscripts describing only eight (Jones & Smith, 1973) and 12 cases (Ulleland, 1972). For comparison, between January 2008 and December 2013, eight of 10 epidemiological studies, collectively examining over 1,000 children, reported evidence linking developmental BPA exposure and neurobehavioral outcomes in children. The FDA study described above discounted 35 of 36 experimental studies using hundreds of animals published between October 24, 2011, and July 23, 2013. Prior, related assessments had discounted hundreds more.

For BPA and many compounds, abundance of data is not the problem. Instead, regulators must adopt strategies that more comprehensively minimize evaluation bias by systematically analyzing all available data. Recognizing that data will always be uneven in quality and imperfectly replicated, systematic review and other methods that quantitatively account for bias and study quality are proving valuable (Beronius, Hanberg, Zilliacus, & Ruden, 2014; Murray & Thayer, 2014; Woodruff & Sutton, 2014).

Effective regulatory policy balances human health interests, economic interests, corporate interests, and societal interests to manage risk in a way that is cost-effective, in the public interest, transparent, and rational. Current chemical management policies are too heavily weighted toward protecting economic interests and should prioritize public health and mitigate exposures that pose a risk to the developing brain. The substantial direct and indirect economic costs of rising rates of childhood NDDs emphasizes the pressing need to identify effective interventions that make best use of societal resources, including preventive policies.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Chemical Contributions to Neurodevelopmental Disorders

Abstract

Keywords

Tweet

Key Points

Introduction

The Role of the Environment in NDD Risk

The Chemosphere of Neurotoxicants

Barriers to Linking Exposure to Disease Risk: Evidence of Harm

Barriers to Linking Exposure to Disease Risk: Lack of Understanding About the Biological Basis of Neurodevelopmental Disease

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References