, 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.
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 CNS.15
Moreover, the developing human brain is exceptionally sensitive to injury caused by toxic chemicals,6
and several developmental processes have been shown to be highly
vulnerable to chemical toxicity. For example, in-vitro studies suggest
that neural stem cells are very sensitive to neurotoxic substances such
as methylmercury.16 Some pesticides inhibit cholinesterase function in the developing brain,17 thereby affecting the crucial regulatory role of acetylcholine before synapse formation.18 Early-life epigenetic changes are also known to affect subsequent gene expression in the brain.19
In summary, industrial chemicals known or suspected to be neurotoxic to
adults are also likely to present risks to the developing brain.
Figure 1
shows the unique vulnerability of the brain during early life and
indicates how developmental exposures to toxic chemicals are
particularly likely to lead to functional deficits and disease later in
life.
Figure 1 Full-size image (27K) Download to PowerPoint
Effect of neurotoxicants during early brain development
Exposures
in early life to neurotoxic chemicals can cause a wide range of adverse
effects on brain development and maturation that can manifest as
functional impairments or disease at any point in the human lifespan,
from early infancy to very old age.
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
neurotoxicity are probably permanent.23
Brain imaging of young adults who had raised lead concentrations in
their blood during childhood showed exposure-related decreases in brain
volume.24 Lead exposure in early childhood is associated with reduced school performance25 and with delinquent behaviour later in life.26, 27
Developmental
neurotoxicity due to methylmercury occurs at much lower exposures than
the concentrations that affect adult brain function.28
Deficits at 7 years of age that were linked to low-level prenatal
exposures to methylmercury were still detectable at the age of 14 years.29 Some common genetic polymorphisms seem to increase the vulnerability of the developing brain to methylmercury toxicity.30
Functional MRI scans of people exposed prenatally to excess amounts of
methylmercury showed abnormally expanded activation of brain regions in
response to sensory stimulation and motor tasks (figure 2).31
Because some adverse effects might be counterbalanced by essential
fatty acids from seafood, statistical adjustment for maternal diet
during pregnancy results in stronger methylmercury effects.32, 33
Figure 2 Full-size image (74K) Download to PowerPoint
Functional MRI scans show abnormal activation in the brain
Average
activation during finger tapping with the left hand in three
adolescents with increased prenatal methylmercury exposure (A) and three
control adolescents (B). The control participants activate the premotor
and motor cortices on the right, whereas participants exposed to
methylmercury activate these areas bilaterally.31
Prenatal
and early postnatal exposures to inorganic arsenic from drinking water
are associated with cognitive deficits that are apparent at school age.34, 35
Infants who survived the Morinaga milk arsenic poisoning incident had
highly raised risks of neurological disease during adult life.36
The developmental neurotoxicity of polychlorinated biphenyls has been consolidated and strengthened by recent findings.37
Although little new information has been published about the
developmental neurotoxicity of toluene, much has been learned about the
developmental neurotoxicity of another common solvent, ethanol, through
research on fetal alcohol exposure. Maternal consumption of alcohol
during pregnancy, even in very small quantities, has been linked to a
range of neurobehavioural adverse effects in offspring, including
reduced IQ, impaired executive function and social judgment, delinquent
behaviour, seizures, other neurological signs, and sensory problems.38
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
additional developmental neurotoxicants.
Cross-sectional
data from Bangladesh show that exposure to manganese from drinking
water is associated with reduced mathematics achievement scores in
school children.39 A study in Quebec, Canada, showed a strong correlation between manganese concentrations in hair and hyperactivity.40
School-aged children living near manganese mining and processing
facilities have shown associations between airborne manganese
concentrations and diminished intellectual function41 and with impaired motor skills and reduced olfactory function.42 These results are supported by experimental findings in mice.43
A
meta-analysis of 27 cross-sectional studies of children exposed to
fluoride in drinking water, mainly from China, suggests an average IQ
decrement of about seven points in children exposed to raised fluoride
concentrations.44
Confounding from other substances seemed unlikely in most of these
studies. Further characterisation of the dose—response association would
be desirable.
The occupational health literature45
suggests that solvents can act as neurotoxicants, but the
identification of individual responsible compounds is hampered by the
complexity of exposures. In a French cohort study of 3000 children,
investigators linked maternal occupational solvent exposure during
pregnancy to deficits in behavioural assessment at 2 years of age.46
The data showed dose-related increased risks for hyperactivity and
aggressive behaviour. One in every five mothers in this cohort reported
solvent exposures in common jobs, such as nurse or other hospital
employee, chemist, cleaner, hairdresser, and beautician. In
Massachusetts, USA, follow-up of a well-defined population with prenatal
and early childhood exposure to the solvent tetrachloroethylene (also
called perchlorethylene) in drinking water showed a tendency towards
deficient neurological function and increased risk of psychiatric
diagnoses.47
Acute
pesticide poisoning occurs frequently in children worldwide, and
subclinical pesticide toxicity is also widespread. Clinical data suggest
that acute pesticide poisoning during childhood might lead to lasting
neurobehavioural deficits.48, 49
Highly toxic and bioaccumulative pesticides are now banned in
high-income nations, but are still used in many low-income and
middle-income countries. In particular, the organochlorine compounds
dichlorodiphenyltrichloroethane (DDT), its metabolite
dichlorodiphenyldichloroethylene (DDE), and chlordecone (Kepone), tend
to be highly persistent and remain widespread in the environment and in
people's bodies in high-use regions. Recent studies have shown inverse
correlations between serum concentrations of DDT or DDE (which indicate
accumulated exposures), and neurodevelopmental performance.50, 51
Organophosphate
pesticides are eliminated from the human body much more rapidly than
are organochlorines, and exposure assessment is therefore inherently
less precise. Nonetheless, three prospective epidemiological birth
cohort studies provide new evidence that prenatal exposure to
organophosphate pesticides can cause developmental neurotoxicity. In
these studies, prenatal organophosphate exposure was assessed by
measurement of maternal urinary excretion of pesticide metabolites
during pregnancy. Dose-related correlations were recorded between
maternal exposures to chlorpyrifos or other organophosphates and small
head circumference at birth—which is an indication of slowed brain
growth in utero—and with neurobehavioural deficits that have persisted
to at least 7 years of age.52—54
In a subgroup study, MRI of the brain showed that prenatal chlorpyrifos
exposure was associated with structural abnormalities that included
thinning of the cerebral cortex.55
Herbicides and fungicides might also have neurotoxic potential.56 Propoxur,57 a carbamate pesticide, and permethrine,58 a member of the pyrethroid class of pesticides, have recently been linked to neurodevelopmental deficits in children.
The
group of compounds known as polybrominated diphenyl ethers (PBDEs) are
widely used as flame retardants and are structurally very similar to the
polychlorinated biphenyls. Experimental evidence now suggests that the
PBDEs might also be neurotoxic.59
Epidemiological studies in Europe and the USA have shown
neurodevelopmental deficits in children with increased prenatal
exposures to these compounds.60—62
Thus, the PBDEs should be regarded as hazards to human neurobehavioural
development, although attribution of relative toxic potentials to
individual PBDE congeners is not yet possible.
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 obscure associations that might actually be present.63
Guidance from experimental neurotoxicity studies is therefore crucial.
In the assessment of potential developmental neurotoxicants, we have
used a strength of evidence approach similar to that used by the
International Agency for Research on Cancer for assessing
epidemiological and experimental studies.
Phthalates
and bisphenol A are added to many different types of plastics,
cosmetics, and other consumer products. Since they are eliminated
rapidly in urine, exposure assessment is complicated, and such
imprecision might lead to underestimation of the true risk of
neurotoxicity. The best-documented effects of early-life exposure to
phthalates are the consequence of disruption of endocrine signalling.64
Thus, prenatal exposures to phthalates have been linked to both
neurodevelopmental deficits and to behavioural abnormalities
characterised by shortened attention span and impaired social
interactions.65
The neurobehavioural toxicity of these compounds seems to affect mainly
boys and could therefore relate to endocrine disruption in the
developing brain.66
In regard to bisphenol A, a prospective study showed that point
estimates of exposure during gestation were linked to abnormalities in
behaviour and executive function in children at 3 years of age.67
Exposure to air pollution can cause neurodevelopmental delays and disorders of behavioural functions.68, 69
Of the individual components of air pollution, carbon monoxide is a
well-documented neurotoxicant, and indoor exposure to this substance has
now been linked to deficient neurobehavioural performance in children.70 Less clear is the reported contribution of nitrogen oxides to neurodevelopmental deficits,71
since these compounds often co-occur with carbon monoxide as part of
complex emissions. Tobacco smoke is a complex mixture of hundreds of
chemical compounds and is now a well-documented cause of developmental
neurotoxicity.72
Infants exposed prenatally to polycyclic aromatic hydrocarbons from
traffic exhausts at 5 years of age showed greater cognitive impairment
and lower IQ than those exposed to lower levels of these compounds.68
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 autism spectrum disorder.78
The
persistent decrements in intelligence documented in children,
adolescents, and young adults exposed in early life to neurotoxicants
could presage the development of neurodegenerative disease later in
life. Thus, accumulated exposure to lead is associated with cognitive
decline in the elderly.79
Manganese exposure may lead to parkinsonism, and experimental studies
have reported Parkinson's disease as a result of developmental exposures
to the insecticide rotenone, the herbicides paraquat and maneb, and the
solvent trichloroethylene.80 Any environmental exposure that increases the risk of neurodegenerative disorders in later life (figure 1) requires urgent investigation as the world's population continues to age.81
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 production volume
chemicals.
Our updated literature review
shows that since 2006 the list of recognised human neurotoxicants has
expanded by 12 chemicals, from 202 (including ethanol) to 214 (table 1 and appendix)—that
is, by about two substances per year. Many of these chemicals are
widely used and disseminated extensively in the global environment. Of
the newly identified neurodevelopmental toxicants, pesticides constitute
the largest group, as was already the case in 2006. In the same 7-year
period, the number of known developmental neurotoxicants has doubled
from six to 12 (table 2).
Although the pace of scientific discovery of new neurodevelopmental
hazards is more rapid today than in the past, it is still slower than
the identification of adult neurotoxicants.
Table 1Table image
Industrial chemicals known to be toxic to the human nervous system in 2006 and 2013, according to chemical group
Table 2Table image
Industrial chemicals known to cause developmental neurotoxicity in human beings in 2006 and 2013, according to chemical group
The
gap that exists between the number of substances known to be toxic to
the adult brain and the smaller number known to be toxic to the much
more vulnerable developing brain is unlikely to close in the near
future. This discrepancy is attributable to the fact that toxicity to
the adult brain is usually discovered as a result of acute poisoning
incidents, typically with a clear and immediate association between
causative exposure and adverse effects, as occurs for workplace
exposures or suicide attempts. By contrast, the recognition of
developmental neurotoxicity relies on two sets of evidence collected at
two different points in time: exposure data (often obtained from the
mother during pregnancy), and data for the child's postnatal
neurobehavioural development (often obtained 5—10 years later). Because
brain functions develop sequentially, the full effects of early
neurotoxic damage might not become apparent until school age or beyond.
The most reliable evidence of developmental neurotoxicity is obtained
through prospective studies that include real-time recording of
information about exposure in early life followed by serial clinical
assessments of the child. Such research is inherently slow and is
hampered by the difficulty of reliable assessment of exposures to
individual toxicants in complex mixtures.
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 range as, or even greater than, the losses associated with medical
events such as preterm birth, traumatic brain injury, brain tumours, and
congenital heart disease (table 3).94
Table 3Table image
Total
losses of IQ points in US children 0—5 years of age associated with
major risk factors, including developmental exposure to industrial
chemicals that cause neurotoxicity
Loss
of cognitive skills reduces children's academic and economic
attainments and has substantial long-term economic effects on societies.4
Thus, each loss of one IQ point has been estimated to decrease average
lifetime earnings capacity by about €12 000 or US$18 000 in 2008
currencies.96
The most recent estimates from the USA indicate that the annual costs
of childhood lead poisoning are about US$50 billion and that the annual
costs of methylmercury toxicity are roughly US$5 billion.97
In the European Union, methylmercury exposure is estimated to cause a
loss of about 600 000 IQ points every year, corresponding to an annual
economic loss of close to €10 billion. In France alone, lead exposure is
associated with IQ losses that correspond to annual costs that might
exceed €20 billion.98 Since IQ losses represent only one aspect of developmental neurotoxicity, the total costs are surely even higher.
Evidence
from worldwide sources indicates that average national IQ scores are
associated with gross domestic product (GDP)—a correlation that might be
causal in both directions.99
Thus, poverty can cause low IQ, but the opposite is also true. In view
of the widespread exposures to lead, pesticides, and other
neurotoxicants in developing countries, where chemical controls might be
ineffective compared with those in more developed countries,100, 101
developmental exposures to industrial chemicals could contribute
substantially to the recorded correlation between IQ and GDP. If this
theory is true, developing countries could take decades to emerge from
poverty. Consequently, pollution abatement might then be delayed, and a
vicious circle can result.
The antisocial
behaviour, criminal behaviour, violence, and substance abuse that seem
to result from early-life exposures to some neurotoxic chemicals result
in increased needs for special educational services,
institutionalisation, and even incarceration. In the USA, the murder
rate fell sharply 20 years after the removal of lead from petrol,102
a finding consistent with the idea that exposure to lead in early life
is a powerful determinant of behaviour decades later. Although poorly
quantified, such behavioural and social consequences of
neurodevelopmental toxicity are potentially very costly.76
Prevention
of developmental neurotoxicity caused by industrial chemicals is highly
cost effective. A study that quantified the gains resulting from the
phase-out of lead additives from petrol reported that in the USA alone,
the introduction of lead-free petrol has generated an economic benefit
of $200 billion in each annual birth cohort since 1980,103
an aggregate benefit in the past 30 years of over $3 trillion. This
success has since been repeated in more than 150 countries, resulting in
vast additional savings. Every US$1 spent to reduce lead hazards is
estimated to produce a benefit of US$17—220, which represents a
cost-benefit ratio that is even better than that for vaccines.4
Furthermore, the costs associated with the late-life consequences of
developmental neurotoxicity are enormous, and the benefits from
prevention of degenerative brain disorders could be very substantial.
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 National Center for
Computational Toxicology and an initiative—the Tox 21 Program—to promote
the evolution of toxicology from a mainly observational science to a
predominantly predictive science.107
In-vitro methods have now reached a level of predictive validity that means they can be applied to neurotoxicity testing.108
Some of these tests are based on neural stem cells. Although these cell
systems do not have a blood—brain barrier and particular metabolising
enzymes, these approaches are highly promising. As a further option,
data for protein links and protein—protein interactions can now be used
to explore potential neurotoxicity in silico,109 thus showing that existing computational methods might predict potential toxic effects.110
In
summary, use of the whole range of approaches along with clinical and
epidemiological evidence, when available, should enable the integration
of information for use in at least a tentative risk assessment. With
these methods, we anticipate that the pace of scientific discovery in
developmental neurotoxicology will accelerate further in the years
ahead.
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 and were recently underlined by the US National Research Council,111
are: large gaps in the testing of chemicals for developmental
neurotoxicity, which results in a paucity of systematic data to guide
prevention; and the huge amount of proof needed for regulation. Thus,
very few chemicals have been regulated as a result of developmental
neurotoxicity.
The presumption that new chemicals and technologies are safe until proven otherwise is a fundamental problem.111
Classic examples of new chemicals that were introduced because they
conveyed certain benefits, but were later shown to cause great harm,
include several neurotoxicants, asbestos, thalidomide,
diethylstilboestrol, and the chlorofluorocarbons.112
A recurring theme in each of these cases was that commercial
introduction and wide dissemination of the chemicals preceded any
systematic effort to assess potential toxicity. Particularly absent were
advance efforts to study possible effects on children's health or the
potential of exposures in early life to disrupt early development.
Similar challenges have been confronted in other public health
disasters, such as those caused by tobacco smoking, alcohol use, and
refined foods. These problems have been recently termed industrial
epidemics.113
To control the pandemic of developmental neurotoxicity, we propose a coordinated international strategy (panel).
Mandatory and transparent assessment of evidence for neurotoxicity is
the foundation of this strategy. Assessment of toxicity must be followed
by governmental regulation and market intervention. Voluntary controls
seem to be of little value.11
Panel
Recommendations for an international clearinghouse on neurotoxicity
The
main purpose of this agency would be to promote optimum brain health,
not just avoidance of neurological disease, by inspiring, facilitating,
and coordinating research and public policies that aim to protect brain
development during the most sensitive life stages. The main efforts
would aim to:
- Screen industrial chemicals present in human exposures for neurotoxic effects so that hazardous substances can be identified for tighter control
- Stimulate and coordinate new research to understand how toxic chemicals interfere with brain development and how best to prevent long-term dysfunctions and deficits
- Function as a clearinghouse for research data and strategies by gathering and assessing documentation about brain toxicity and stimulating international collaboration on research and prevention
- Promote policy development aimed at protecting vulnerable populations against chemicals that are toxic to the brain without needing unrealistic amounts of scientific proof
The
three pillars of our proposed strategy are: legally mandated testing of
existing industrial chemicals and pesticides already in commerce, with
prioritisation of those with the most widespread use, and incorporation
of new assessment technologies; legally mandated premarket evaluation of
new chemicals before they enter markets, with use of precautionary
approaches for chemical testing that recognise the unique vulnerability
of the developing brain; and the formation of a new clearinghouse for
neurotoxicity as a parallel to the International Agency for Research on
Cancer. This new agency will assess industrial chemicals for
developmental neurotoxicity with a precautionary approach that
emphasises prevention and does not require absolute proof of toxicity.
It will facilitate and coordinate epidemiological and toxicological
studies and will lead the urgently needed global programmes for
prevention.
These new approaches must
reverse the dangerous presumption that new chemicals and technologies
are safe until proven otherwise. They must also overcome the existing
requirement to produce absolute proof of toxicity before action can be
started to protect children against neurotoxic substances. Precautionary
interpretation of data about developmental neurotoxicity should take
into account the very large individual and societal costs that result
from failure to act on available documentation to prevent disease in
children.114 Academic research has often favoured scepticism and required extensive replication before acceptance of a hypothesis,114
thereby adding to the inertia in toxicology and environmental health
research and the consequent disregard of many other potential
neurotoxicants.115
Additionally, the strength of evidence that is needed to constitute
“proof” should be analysed in a societal perspective, so that the
implications of ignoring a developmental neurotoxicant and of failing to
act on the basis of available data are also taken into account.
Finally,
we emphasise that the total number of neurotoxic substances now
recognised almost certainly represents an underestimate of the true
number of developmental neurotoxicants that have been released into the
global environment. Our very great concern is that children worldwide
are being exposed to unrecognised toxic chemicals that are silently
eroding intelligence, disrupting behaviours, truncating future
achievements, and damaging societies, perhaps most seriously in
developing countries. A new framework of action is needed.
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 “neurotoxins”, all of which were searched for with the
limiters “All Child: 0—18 years, Human”. We also used references cited
in the publications retrieved.
Contributors
Both authors did the literature review, wrote and revised the report, and approved the final version.
Conflicts of interest
PG
has provided paid expert testimony about mercury toxicology for the US
Department of Justice. PJL has provided paid expert testimony in cases
of childhood lead poisoning. We declare that we have no other conflicts
of interest.
Acknowledgments
This
work was supported by the National Institutes of Health, National
Institute for Environmental Health Sciences (ES09584, ES09797, and
ES11687). The funding source had no role in the literature review,
interpretation of data, writing of this Review, or in the decision to
submit for publication. The contents of this paper are solely the
responsibility of the authors and do not represent the official views of
the National Institutes of Health. We thank Mary S Wolff (Icahn School
of Medicine at Mount Sinai, New York, NY, USA) and Linda S Birnbaum (US
National Institute of Environmental Health Sciences, Research Triangle
Park, NC, USA) for their critical reading of the report.
Supplementary Material
Supplementary appendix
PDF (352K)
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a Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark
b Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA
c Icahn School of Medicine at Mount Sinai, New York, NY, USA
Correspondence to: Dr Philippe Grandjean, Environmental and
Occupational Medicine and Epidemiology, Harvard School of Public Health,
401 Park Drive E-110, Boston, MA 02215, USA
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