Elsevier

The Lancet Neurology

Volume 13, Issue 3, March 2014, Pages 330-338
The Lancet Neurology

Review
Neurobehavioural effects of developmental toxicity

https://doi.org/10.1016/S1474-4422(13)70278-3Get rights and content

Summary

Neurodevelopmental disabilities, including autism, attention-deficit hyperactivity disorder, dyslexia, and other cognitive impairments, affect millions of children worldwide, and some diagnoses seem to be increasing in frequency. Industrial chemicals that injure the developing brain are among the known causes for this rise in prevalence. In 2006, we did a systematic review and identified five industrial chemicals as developmental neurotoxicants: lead, methylmercury, polychlorinated biphenyls, arsenic, and toluene. 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. Untested chemicals should not be presumed to be safe to brain development, and chemicals in existing use and all new chemicals must therefore be tested for developmental neurotoxicity. To coordinate these efforts and to accelerate translation of science into prevention, we propose the urgent formation of a new international clearinghouse.

Introduction

Disorders of neurobehavioural development affect 10–15% of all births,1 and prevalence rates of autism spectrum disorder and attention-deficit hyperactivity disorder seem to be increasing worldwide.2 Subclinical decrements in brain function are even more common than these neurobehavioural developmental disorders. All these disabilities can have severe consequences3—they diminish quality of life, reduce academic achievement, and disturb behaviour, with profound consequences for the welfare and productivity of entire societies.4

The root causes of the present global pandemic of neurodevelopmental disorders are only partly understood. Although genetic factors have a role,5 they cannot explain recent increases in reported prevalence, and none of the genes discovered so far seem to be responsible for more than a small proportion of cases.5 Overall, genetic factors seem to account for no more than perhaps 30–40% of all cases of neurodevelopmental disorders. Thus, non-genetic, environmental exposures are involved in causation, in some cases probably by interacting with genetically inherited predispositions.

Strong evidence exists that industrial chemicals widely disseminated in the environment are important contributors to what we have called the global, silent pandemic of neurodevelopmental toxicity.6, 7 The developing human brain is uniquely vulnerable to toxic chemical exposures, and major windows of developmental vulnerability occur in utero and during infancy and early childhood.8 During these sensitive life stages, chemicals can cause permanent brain injury at low levels of exposure that would have little or no adverse effect in an adult.

In 2006, we did a systematic review of the published clinical and epidemiological studies into the neurotoxicity of industrial chemicals, with a focus on developmental neurotoxicity.6 We identified five industrial chemicals that could be reliably classified as developmental neurotoxicants: lead, methylmercury, arsenic, polychlorinated biphenyls, and toluene. We also noted 201 chemicals that had been reported to cause injury to the nervous system in adults, mostly in connection with occupational exposures, poisoning incidents, or suicide attempts. Additionally, more than 1000 chemicals have been reported to be neurotoxic in animals in laboratory studies.

We noted that recognition of the risks of industrial chemicals to brain development has historically needed decades of research and scrutiny, as shown in the cases of lead and methylmercury.9, 10 In most cases, discovery began with clinical diagnosis of poisoning in workers and episodes of high-dose exposure. More sophisticated epidemiological studies typically began only much later. Results from such studies documented developmental neurotoxicity at much lower exposure levels than had previously been thought to be safe. Thus, recognition of widespread subclinical toxicity often did not occur until decades after the initial evidence of neurotoxicity. A recurring theme was that early warnings of subclinical neurotoxicity were often ignored or even dismissed.11 David P Rall, former Director of the US National Institute of Environmental Health Sciences, once noted that “if thalidomide had caused a ten-point loss of intelligence quotient (IQ) instead of obvious birth defects of the limbs, it would probably still be on the market”.12 Many industrial chemicals marketed at present probably cause IQ deficits of far fewer than ten points and have therefore eluded detection so far, but their combined effects could have enormous consequences.

In our 2006 review,6 we expressed concern that additional developmental neurotoxicants might lurk undiscovered among the 201 chemicals then known to be neurotoxic to adult human beings and among the many thousands of pesticides, solvents, and other industrial chemicals in widespread use that had never been tested for neurodevelopmental toxicity. Since our previous review, new data have emerged about the vulnerability of the developing brain and the neurotoxicity of industrial chemicals. Particularly important new evidence derives from prospective epidemiological birth cohort studies.

In this Review, we consider recent information about the developmental neurotoxicity of industrial chemicals to update our previous report.6 Additionally, we propose strategies to counter this pandemic and to prevent the spread of neurological disease and disability in children worldwide.

Section snippets

Unique vulnerability of the developing brain

The fetus is not well protected against industrial chemicals. The placenta does not block the passage of many environmental toxicants from the maternal to the fetal circulation,13 and more than 200 foreign chemicals have been detected in umbilical cord blood.14 Additionally, many environmental chemicals are transferred to the infant through human breastmilk.13 During fetal life and early infancy, the blood–brain barrier provides only partial protection against the entry of chemicals into the

New findings about known hazards

Recent research on well-documented neurotoxicants has generated important new insights into the neurodevelopmental consequences of early exposures to these industrial chemicals.

Joint analyses that gathered data for lead-associated IQ deficits from seven international studies20, 21 support the conclusion that no safe level of exposure to lead exists.22 Cognitive deficits in adults who had previously shown lead-associated developmental delays at school age suggest that the effects of lead

Newly recognised developmental neurotoxicants

Prospective epidemiological birth cohort studies make it possible to measure maternal or fetal exposures in real time during pregnancy as these exposures actually occur, thus generating unbiased information about the degree and timing of prenatal exposures. Children in these prospective studies are followed longitudinally and assessed with age-appropriate tests to show delayed or deranged neurobehavioural development. These powerful epidemiological methods have enabled the discovery of

Other suspected developmental neurotoxicants

A serious difficulty that complicates many epidemiological studies of neurodevelopmental toxicity in children is the problem of mixed exposures. Most populations are exposed to more than one neurotoxicant at a time, and yet most studies have only a finite amount of power and precision in exposure assessment to discern the possible effects of even single neurotoxicants. A further problem in many epidemiological studies of non-persistent toxicants is that imprecise assessment of exposure tends to

Developmental neurotoxicity and clinical neurology

Exposures in early life to developmental neurotoxicants are now being linked to specific clinical syndromes in children. For example, an increased risk of attention-deficit hyperactivity disorder has been linked to prenatal exposures to manganese, organophosphates,75 and phthalates.76 Phthalates have also been linked to behaviours that resemble components of autism spectrum disorder.77 Prenatal exposure to automotive air pollution in California, USA, has been linked to an increased risk for

The expanding complement of neurotoxicants

In our 2006 review,6 we expressed concern that additional developmental neurotoxicants might lie undiscovered in the 201 chemicals that were then known to be neurotoxic to human adults, in the roughly 1000 chemicals known to be neurotoxic in animal species, and in the many thousands of industrial chemicals and pesticides that have never been tested for neurotoxicity. Exposure to neurotoxic chemicals is not rare, since almost half of the 201 known human neurotoxicants are regarded as high

Consequences of developmental neurotoxicity

Developmental neurotoxicity causes brain damage that is too often untreatable and frequently permanent. The consequence of such brain damage is impaired CNS function that lasts a lifetime and might result in reduced intelligence, as expressed in terms of lost IQ points, or disruption in behaviour. A recent study compared the estimated total IQ losses from major paediatric causes and showed that the magnitude of losses attributable to lead, pesticides, and other neurotoxicants was in the same

New methods to identify developmental neurotoxicants

New toxicological methods now allow a rational strategy for the identification of developmental neurotoxicants based on a multidisciplinary approach.104 A new guideline has been approved as a standardised approach for the identification of developmental neurotoxicants.105 However, completion of such tests is expensive and requires the use of many laboratory animals, and reliance on mammals for chemicals testing purposes needs to be reduced.106 US governmental agencies have established the

Conclusions and recommendations

The updated findings presented in this Review confirm and extend our 2006 conclusions.6 During the 7 years since our previous report, the number of industrial chemicals recognised to be developmental neurotoxicants has doubled. Exposures to these industrial chemicals in the environment contribute to the pandemic of developmental neurotoxicity.

Two major obstacles impede efforts to control the global pandemic of developmental neurotoxicity. These barriers, which we noted in our previous review6

Search strategy and selection criteria

We identified studies published since 2006 on the neurotoxic effects of industrial chemicals in human beings by using the search terms “neurotoxicity syndromes”[MeSH], “neurotoxic”, “neurologic”, or “neuro*”, combined with “exposure” and “poisoning” in PubMed, from 2006 to the end of 2012. For developmental neurotoxicity, the search terms were “prenatal exposure delayed effects”[MeSH], “maternal exposure” or “maternal fetal exchange”, “developmental disabilities/chemically induced” and

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