Environmental Health Perspectives  [Printer-friendly version]
February 1, 2006

NEW THINKING ON NEURODEVELOPMENT

[Rachel's introduction: About 17% of school-age children in the
United States suffer from a disability that affects their behavior,
memory, or ability to learn. And the incidence of these disorders is
rising. What's that about? Why can't we do better by our kids?]

By Michael Szpir

The notion that some substances in the environment can damage the
nervous system has an ancient history. The neurotoxicity of lead was
recognized more than 2,000 years ago by the Greek physician
Dioscerides, who wrote, "Lead makes the mind give way." In the
intervening millennia many other substances have been added to the
list of known or suspected neurotoxicants. Despite this accumulation
of knowledge, there is still much that isn't understood about how
neurotoxicants affect the developing brain, especially the effects of
low-dose exposures. Today researchers are taking a hard look at low-
dose exposures in utero and during childhood to unravel some of the
mysteries of impaired neurodevelopment.

About 17% of school-age children in the United States suffer from a
disability that affects their behavior, memory, or ability to learn,
according to a study published in the March 1994 issue of Pediatrics
by a team from the Centers for Disease Control and Prevention (CDC).
The list of maladies includes attention deficit/hyperactivity disorder
(ADHD), autistic spectrum disorders, epilepsy, Tourette syndrome, and
less specific conditions such as mental retardation and cerebral
palsy. All are believed to be the outcome of some abnormal process
that unfolded as the brain was developing in utero or in the young
child.

These disorders have an enormous impact on families and society.
According to the 1996 book Learning Disabilities: Lifelong Issues,
children with these disorders have higher rates of mental illness and
suicide, and are more likely to engage in substance abuse and to
commit crimes as adults. The overall economic cost of
neurodevelopmental disorders in the United States is estimated to be
$81.5-167 billion per year, according to a report published in the
December 2001 issue of EHP Supplements.

Potentially even more disturbing is that a number of epidemiologic
studies suggest that the incidence of certain disorders is on the
rise. In the United States, the diagnosis of autistic spectrum
disorders increased from 4-5 per 10,000 children in the 1980s to 30-60
per 10,000 children in the 1990s, according to a report in the August
2003 Journal of Autism and Developmental Disorders. Similarly, notes a
report in the February 2002 issue of CNS Drugs, the diagnosis of ADHD
grew 250% between 1990 and 1998. The number of children in special
education programs classified with learning disabilities increased
191% between 1977 and 1994, according to an article in Advances in
Learning and Behavioral Disabilities, Volume 12, published in 1998.

So what is going on? The short answer is that no one really knows.
There's not even consensus on what the soaring rates actually mean.
Heightened public awareness could account for the surge in the
numbers, or it may be that physicians are getting better at diagnosing
the conditions. Some autism researchers believe the rise in that
condition's prevalence simply reflects changes in diagnostic criteria
over the last 25 years. On the other hand, some scientists believe
that the rates of neurodevelopmental disease are truly increasing, and
that the growing burden of chemicals in the environment may play a
role.

With that in mind, investigators are considering the effects of gene-
environment interactions. A child with a mild genetic tendency toward
a neurodevelopmental disorder might develop without clinically
measurable abnormalities in the absence of environmental "hits."
However, children in industrialized nations develop and grow up in a
veritable sea of xenobiotic chemicals, says Isaac Pessah, director of
the University of California, Davis, Center for Children's
Environmental Health and Disease Prevention. "Fortunately," he says,
"most of us have a host of defense mechanisms that protect us from
adverse outcomes. However, genetic polymorphisms, complex epistasis,
and cytogenetic abnormalities could weaken these defenses and amplify
chemical damage, initiating a freefall into a clinical syndrome."

Pessah cites the example of autism. He says susceptibility for autism
is likely conferred by several defective genes, no one of which can
account for all the core symptoms of social disinterest, repetitive
and overly focused behaviors, and problems in communication. Could
multiple genetic liabilities and exposure to a chemically complex
environment act in concert to increase the incidence and severity of
the condition?

Despite the uncertainties, many scientists believe it would be wise to
err on the side of caution when it comes to a research agenda. As
Martha Herbert, a pediatric neurologist at Harvard Medical School,
puts it, "Even though we may have neither consensus nor certainty
about an autism epidemic, there are enough studies coming in with
higher numbers that we should take it seriously. Environmental
hypotheses ought to be central to research now. The physiological
systems that have been harmed by environmental factors may also point
to treatment targets, and this might be a great way to help the
children."

The Parade of Neurotoxicants

Among the most intensely studied neurotoxicants are metals (lead,
mercury, and manganese), pesticides, polychlorinated biphenyls (PCBs),
and polybrominated diphenyl ethers (PBDEs). A number of these
compounds were identified as neurotoxicants when individuals were
exposed to high doses during occupational accidents or childhood
poisonings. Scientists are now exploring the potential consequences of
low-dose exposures, especially to children and fetuses. Epidemiologic
studies play a central role, and these are often complemented by
experimental work on animals and cell cultures. These days,
researchers are looking not only at associations between toxicants and
disease, but also at the underlying cellular and molecular mechanisms.

Lead. Studies dating to the 1970s show that children exposed to lead
have deficits in IQ, attention, and language. In response, the CDC
revised its limits for acceptable blood levels of the metal in several
steps, from 60 micrograms per deciliter (micrograms/deciliter) in the
1960s to the current level of 10 micrograms/deciliter, set in 1991.
But many scientists think that limit is still too high. A study
reported in the September 2005 issue of EHP found that there were
significant effects on a child's IQ even when blood lead
concentrations were below 10 micrograms/deciliter. Upon the July 2005
release of the Third National Report on Human Exposure to
Environmental Chemicals by the CDC, Jim Pirkle, deputy director for
science at the CDC's Environmental Health Laboratory, stated, "There
is no safe blood [lead] level in children."

Several groups have also found evidence that lead exposure may shape a
child's social behavior. An article in the May 2000 issue of
Environmental Research reports a strong correlation, dating back to
1900, between violent crime and the use of lead-based paint and leaded
gasoline. The research complements studies by Herbert Needleman, a
professor of psychiatry and pediatrics at the University of Pittsburgh
School of Medicine, who found that bone lead levels in young males
were correlated with aggression and criminality. "Lead is
significantly associated with a risk for delinquency," says Needleman.
His research appeared in the November-December 2002 issue of
Neurotoxicology and Teratology and the 7 February 1996 issue of JAMA.

Another new area of research links early lead exposure to changes in
the aging brain. Nasser Zawia, an associate professor of pharmacology
and toxicology at the University of Rhode Island, Kingston, and his
colleagues found increased expression of amyloid precursor protein
(APP) and its product, ?-amyloid (which is a hallmark of Alzheimer
disease), in aging rats that were exposed to lead shortly after birth.
In contrast, old rats that were exposed to lead did not show an
increased expression of APP and ?-amyloid. The work, published in the
26 January 2005 issue of The Journal of Neuroscience, suggests that
early exposure to lead can "reprogram" gene expression and regulation
later in life. According to Zawia, preliminary research also shows
that "monkeys exposed to lead as infants exhibit similar molecular
changes as well as exaggerated Alzheimer's pathology."

Mercury. The current Environmental Protection Agency (EPA) reference
dose for methylmercury (an organic, toxic form of mercury) is 0.1
micrograms per kilogram per day (micrograms/kg/day). Humans are
exposed to methylmercury primarily through consumption of contaminated
fish; a good 70% of this contamination comes from anthropogenic
sources such as emissions from coal-fired power plants. High-level
exposure to methylmercury in the womb is linked to a number of
impairments, including mental retardation, cerebral palsy, seizures,
deafness, blindness, and speech difficulties. An article in the May
2005 issue of EHP puts the economic cost to the United States of
methylmercury- induced toxicity (in terms of lost productivity) at
$8.7 billion annually.

The effects of low-dose exposures are not so apparent. Two large
epidemiologic studies of fishing populations in the Faroe Islands and
the Seychelles have produced conflicting results regarding low-dose
effects. Both studies sought to examine the association between
methylmercury exposure and neurodevelopment in children whose mothers
ate contaminated seafood during pregnancy.

The leader of the Faroe Islands study, Philippe Grandjean, an adjunct
professor of environmental health at the Harvard School of Public
Health, and his colleagues reported in the November 1997 issue of
Neurotoxicology and Teratology that 7-year-old Faroese children had
significant cognitive deficits and neurological changes after prenatal
exposure to methylmercury. Grandjean's team followed up on the
children at age 14. According to a report in the February 2004 issue
of The Journal of Pediatrics, the children continued to have problems,
including neurological changes and decreased nervous control of the
heart.

In contrast, the authors of the Seychelles study found little evidence
of lasting harm on a cohort of 66-month-old children, according to
their report in the 26 August 1998 issue of JAMA. A follow-up study,
published in the 17 May 2003 issue of The Lancet, similarly found no
lasting effects on language, memory, motor skills, or behavioral
function when the children were 9 years old.

The different outcomes of the two studies are puzzling because the
children of both populations appeared to be exposed to similar amounts
of methylmercury. Several explanations have been proposed, including
the possibility that genetic differences between the populations may
alter their relative predispositions to harm from mercury exposure.
The source of methylmercury is also different in the two populations.
The Faroese are exposed primarily through the consumption of pilot
whale meat, whereas the Seychelles population relies heavily on ocean
fish. According to Gary Myers, a professor of neurology and pediatrics
at the University of Rochester Medical Center and one of the principal
investigators of the Seychelles study, whale meat contains many other
contaminants (including PCBs) besides methylmercury. "There is also
evidence," he says, "that the effects of concomitant PCB and mercury
exposure are synergistic."

Researchers continue to look at whether there is a danger from
methylmercury at the levels of exposure achieved by fish consumption.
Another layer of uncertainty was added with findings published in the
October 2005 issue of EHP showing that fish consumption during
pregnancy appeared to boost infant cognition--but only as long as
mercury intake, as measured in maternal hair, wasn't too high.

The question of whether low levels of mercury are harmful has also
manifested itself in a controversy over the use of vaccines containing
thimerosal, a preservative. Although thimerosal was removed from many
of these vaccines in 2001, children that were immunized before that
date could have received a cumulative dose of more than 200
micrograms/kg of mercury with the routine complement of childhood
vaccinations, according to a study in the May 2001 issue of
Pediatrics. Thimerosal is nearly half ethylmercury by weight. Because
ethylmercury is an organic form of mercury, there is some suspicion
that it acts like methylmercury in the brain, although research
published in the August 2005 issue of EHP suggests that the two
forms differ greatly in how they are distributed through and
eliminated from the brain. Developing countries continue to use
pediatric vaccines that contain thimerosal. In the United States,
thimerosal is still present in influenza vaccines, which the CDC
recommends be given to pregnant women and children aged 6-23 months.

Advocacy groups, such as SafeMinds, have suggested that the decades-
long rise in the diagnosis of autism is related to the presence of
thimerosal in vaccines. In May 2004, however, the Institute of
Medicine (IOM) issued a report, Immunization Safety Review: Vaccines
and Autism, stating that several epidemiological studies published
since 2001 "consistently provided evidence of no association" between
thimerosal-containing vaccines and autism. However, the IOM's report
has been severely criticized by a number of advocacy groups, including
the National Autism Association, for relying too heavily on a specific
set of epidemiologic data while dismissing clinical evidence and other
epidemiologic studies that showed evidence of a link.

Despite the assurances of the IOM, some scientists continue to explore
the mechanisms underlying the potential neurotoxic effects of
thimerosal. In the January 2005 issue of NeuroToxicology, S. Jill
James, a professor of pediatrics at the University of Arkansas for
Medical Sciences, and her colleagues report that the neuronal and
glial cell toxicity of methylmercury and ethylmercury (as dosed via
thimerosal) are both mediated by the depletion of the antioxidant
peptide glutathione. Of the two cell types, neurons were found to be
particularly susceptible to ethylmercury-induced glutathione depletion
and cell death, according to James, and pretreatment of the cells with
glutathione reduced these effects. Other studies by James and her
colleagues, reported in the December 2004 issue of the American
Journal of Clinical Nutrition, showed that autistic children had lower
levels of glutathione compared to normal controls, and may therefore
have had a significant reduction in the ability to detoxify reactive
oxygen species.

James says the abnormal profile "suggests that these children may have
an increased vulnerability to pro-oxidant environmental exposures and
a lower threshold for oxidative neurotoxicity and immunotoxicity."
Speaking at the XXII International Neurotoxicology Conference in
September 2005, she presented evidence that multiple genetic
polymorphisms affecting glutathione pathways may interact to produce a
chronic metabolic imbalance that could contribute to the development
and clinical symptoms of autism. Her paper in the American Journal of
Clinical Nutrition reported that low glutathione levels in many
autistic children were reversible with targeted nutritional
intervention, but the ramifications of this finding are still unclear.

Manganese. As an essential nutrient, manganese is required for normal
development; the reference dose for manganese is 0.14 mg/kg/day.
Chronic occupational exposure to high levels of this metal is
associated with manganism, a condition reminiscent of Parkinson
disease that is characterized by tremors, rigidity, and psychosis. The
illness is seem primarily among miners.

Animal studies published in the August 2005 issue of Neurotoxicology
by David Dorman, director of the division of biological sciences at
the CIIT Centers for Health Research in Research Triangle Park, North
Carolina, suggest that the fetus is protected to a certain extent from
maternally inhaled manganese. According to Dorman, children are
exposed to manganese primarily by ingesting it, but he knows of no
link between childhood exposure to manganese and later Parkinson
disease.

Nevertheless, because manganese affects the adult brain, people
suspect that the developing brain may be even more susceptible to harm
from this metal, and recent research has unveiled a new cause for
concern: In the January 2006 issue of EHP, child psychiatry
professor Gail Wasserman and colleagues from Columbia University
reported that Bangladeshi children who drank well water with high
concentrations of naturally occurring manganese had diminished
intellectual function. The researchers noted that the bioavailability
of manganese in water is higher than that of manganese in food. They
also pointed out that about 6% of U.S. wells have a high enough
manganese content to potentially put some children at risk for
diminished intellectual function.

The cellular and molecular mechanisms of manganese neurotoxicity are
not well understood. The dopaminergic system in the basal ganglia,
which is affected in Parkinson disease, may be involved, but this
hypothesis is controversial. Tomas Guilarte, a professor of molecular
neurotoxicology at the Johns Hopkins Bloomberg School of Public
Health, described research on these systems in nonhuman primates at
the XXII International Neurotoxicology Conference. According to
Guilarte, unpublished positron-emission tomography studies of the
basal ganglia show that "manganese does appear to have an effect on
dopaminergic neurons." Guilarte found that the more manganese the
animals received, the less dopamine was released through the actions
of amphetamine (which is used to induce the release of the
neurotransmitter). "This does not mean that manganese causes
Parkinson's disease, merely that it has an effect on those neurons,"
he says. This is the first report of an in vivo effect on dopamine
release by manganese.

PCBs, PBDEs, and pesticides. Many chemicals raise concerns because of
their persistence in the environment and their tendency to
bioaccumulate in animal tissues. They are typically synthetic
molecules that were designed for use in everyday products, such as
electrical equipment, computers, furniture, and pesticides.

PCBs appear to be present in all parts of the food chain, and humans
are exposed to these molecules primarily through the ingestion of
animal fat. The toxicity of these chemicals was first recognized after
mass poisonings in Japan in 1968 and Taiwan in 1979. Children born to
women who had ingested contaminated cooking oil in Taiwan had a number
of developmental abnormalities, including psychomotor delay and lower
scores on cognitive tests, according to a report in the 15 July 1988
issue of Science.

Since those earlier observations, several studies have described a
connection between prenatal exposure to PCBs and delayed cognitive
development and lower IQ. For example, a study in the 10 November 2001
Lancet reports those infants and young children exposed to PCBs
through breast milk scored lower on tests of psychomotor and mental
development. The mothers were exposed to normal background levels of
PCBs in Europe. In response to such studies, the U.S. Food and Drug
Administration set tolerance levels for PCBs in a number of consumer
products, such as milk and manufactured dairy products (1.5 parts per
million), poultry (3.0 parts per million), and baby food (0.2 part per
million).

PBDEs are widely used as flame retardants in consumer products. The
effects of PBDEs on humans is not clear, but animal toxicity studies
described in volume 183 (2004) of Reviews of Environmental
Contaminants and Toxicology show that PBDEs can cause permanent
learning and memory impairments, hearing deficits, and behavioral
changes. There is a growing concern about PBDEs because they appear to
be accumulating in human tissues. Andreas Sjodin, a toxicologist at
the CDC, and colleagues found a trend toward increasing concentrations
of PBDEs in human serum taken from sample populations in the
southeastern United States from 1985 through 2002, and in Seattle,
Washington, from 1999 through 2002. This report appears in the May
2004 EHP. Several studies have also discovered PBDEs in human breast
milk. The current EPA reference dose for PBDEs is 2 mg/kg/day.

As for pesticides, it's been suggested by zoologist Theo Colborn of
the University of Florida that every child conceived today in the
Northern Hemisphere is exposed to these chemicals from conception
through gestation and beyond. Some pesticides appear to be more
harmful than others, and so the reference dose varies somewhat from
one compound to another.

The effects of pesticides on the developing brain have been
investigated in human epidemiologic studies and in laboratory
experiments with animals. Vincent Garry, a professor of environmental
medicine at the University of Minnesota, and his colleagues found that
children born to applicators of the fumigant phosphine were more
likely to display adverse neurological and neurobehavioral
developmental effects. The herbicide glyphosate was also linked to
neurobehavioral effects, according to the same report, which appeared
in the June 2002 issue of EHP Supplements. Another epidemiologic
study, reported in the March 2005 issue of NeuroToxicology, showed
that women who were exposed to organophosphate pesticides in an
agricultural community in California had children who displayed
adverse neurodevelopmental effects, and that higher levels of
pesticide metabolites in maternal urine were associated with abnormal
reflexes in the women's newborn children.

Many PCBs, PBDEs, and pesticides are the subject of the 2001 Stockholm
Convention on Persistent Organic Pollutants, which became
international law in May 2004. The goal of the treaty is to "rid the
world of PCBs, dioxins and furans, and nine highly dangerous
pesticides," according to the United Nations Environment Programme.
Implementation of the treaty has significant practical challenges,
however, including the difficulty of eliminating one persistent
pollutant without creating another (for example, when burning PCBs
yields by-products such as dioxins and furans). Not Immune to Harm

Exposure to a neurotoxicant may not be the only way to disrupt the
natural growth of the brain. Scientists are now looking at the subtle
physiological effects of immunotoxicants and infectious agents on
biological events during development.

It turns out that mothers who experience an infection during pregnancy
are at a greater risk of having a child with a neurodevelopmental
disorder such as autism or schizophrenia. For example, prenatal
exposure to the rubella virus is associated with neuromotor and
behavioral abnormalities in childhood and an increased risk of
schizophrenia spectrum disorders in adulthood, according to an article
in the March 2001 issue of Biological Psychiatry. Rubella has also
been linked to autism: some 8-13% of children born during the 1964
rubella pandemic developed the disorder, according to a report in the
March 1967 Journal of Pediatrics. The same study also noted a
connection between the rubella virus and mental retardation.

Some epidemiologic studies have found an increased risk of
schizophrenia among the children of women who were exposed to the
influenza virus during the second trimester of pregnancy, according to
a report in the February 2002 Current Opinion in Neurobiology. In the
August 2004 Archives of General Psychiatry, Ezra Susser, head of
epidemiology at Columbia University's Mailman School of Public Health,
and his colleagues reported that the risk of the mental disorder was
increased sevenfold if the schizophrenic patient's mother had
influenza during her first trimester of pregnancy. A prospective birth
cohort study in the April 2001 Schizophrenia Bulletin found that
second trimester exposure to the diphtheria bacterium also
significantly increased the risk of schizophrenia.

How might infectious agents cause these disorders? According to John
Gilmore, a professor of psychiatry at the University of North Carolina
at Chapel Hill, maternal infections during pregnancy can alter the
development of fetal neurons in the cerebral cortex of rats. The
mechanism is far from clear, but signaling molecules in the mother's
immune system, called cytokines, have been implicated. Speaking at the
XXII International Neurotoxicology Conference, Gilmore described in
vitro experiments showing that elevated levels of certain cytokines--
interleukin-1?, interleukin-6 and tumor necrosis factor-alpha (TNF-
alpha)--reduce the survival of cortical neurons and decrease the
complexity of neuronal dendrites in the cerebral cortex. "I believe
that the weight of the data to date indicates [that the maternal
immune response] can have harmful effects," says Gilmore.

Inflammatory responses in the mother may not be the only route to
modifying the fetal brain. The University of California, Davis, Center
for Children's Environmental Health and Disease Prevention is
conducting a large study of autistic children in California called
CHARGE (Childhood Autism Risks from Genetics and the Environment),
which suggests that the child's immune system may also be involved.
According to Pessah, the study principal investigator, children with
autism appear to have a unique immune system. "Autistic children have
a significant reduction in plasma immunoglobulins and a skewed profile
of plasma cytokines compared to other children," he says. "We think
that an immune system dysfunction may be one of the etiological cores
of autism."

He continues, "We know that many of the things that kids are exposed
to these days are immunotoxicants.... We have evidence that
ethylmercury and thimerosal alter the signaling properties of antigen-
presenting cells, known as dendritic cells, at nanomolar levels."
Since each dendritic cell can activate 250 T cells, any dysregulation
will be magnified, he says. "Add to that a genetic abnormality in
processing immune information, and there could be a problem."

Such problems might extend to the central nervous system. The brains
of individuals who have a neurodevelopmental disorder also show
evidence of inflammation. In the January 2005 issue of the Annals of
Neurology, Carlos Pardo, an assistant professor of neurology and
pathology at the Johns Hopkins University School of Medicine, and his
colleagues report finding high levels of inflammatory cytokines
(interleukin-6, interleukin-8, and interferon-gamma) in the
cerebrospinal fluid of autistic patients. Glial cells, which serve as
the brain's innate immune system, are the primary sources of cytokines
in the central nervous system. So it may not be surprising that
Pardo's team also discovered that glia are activated--showing both
morphological and physiological changes--in postmortem brains of
autistic patients.

The recognition that the immune system is involved in
neurodevelopmental disorders is changing people's perceptions of these
conditions. "Historically, scientists have focused on the role of
neurons in all kinds of neurological diseases," Pardo says, "but they
have generally been ignoring the [glia]." He adds, "In autism, it
could be that the [glia] are responding to some external insult, such
as an infection, an intrauterine injury, or a neurotoxicant."

According to Pardo, it's still not clear whether the neuroimmune
responses associated with autism contribute to the dysfunction of the
brain or whether they are secondary reactions to some neural
abnormality. "John Gilmore's work [showing that cytokines can be
harmful to brain cells] is quite interesting and important," he says.
"However, in vitro studies may produce results that don't reflect what
occurs under in vivo conditions. Cytokines like TNF-alpha may be
beneficial for some neurobiological functions at low concentrations,
but may be extremely neurotoxic at high concentrations." Lending Brain
Power to Exposure Assessment

The medical and scientific communities recognize the colossal
challenges involved in identifying the ultimate causes of
neurodevelopmental disorders. This is complicated by the sheer numbers
of potential exposures involved. More than 67% of the nearly 3,000
chemical compounds produced or imported in amounts exceeding 1 million
pounds per year have not been examined with even basic tests for
neurotoxicity, according to Toxic Ignorance, a 1997 analysis by
Environmental Defense.

In the past few years, several large projects have been proposed, and
funding by the NIH has been increased. For example, the NIH boosted
its support for autism research from $22 million in 1997 to $100
million in 2004. In 2001, the NIEHS and the EPA jointly announced the
creation of four new children's environmental health research centers
(including the one at the University of California, Davis), which
focus primarily on neurodevelopmental disorders. More recently, the
proposed multibillion-dollar National Children's Study, which is
cosponsored by the Department of Health and Human Services and the
EPA, has been designed to follow nearly 100,000 children over the
course of 21 years. The investigators plan to study the effects of
environmental factors on children's growth and development, including
impacts on learning, behavior, and mental health. Study investigators
hope to enroll the first participants in early 2007.

Scientists also see the need for designing better studies. In
neurodevelopmental studies, as in any other field, the quality of a
study is only as good as all of its parts. Jean Harry, head of the
NIEHS Neurotoxicology Group, says, "You can have a valid assessment of
behavior, but in the absence of good exposure data, a causative
association with environmental factors will be compromised."

In a bid to address the difficulties faced by epidemiologic studies
that look for neurodevelopmental effects from in utero chemical
exposure, a working group of 20 experts gathered in September 2005
under the auspices of the Penn State Hershey Medical Center,
coincident with the XXII International Neurotoxicology Conference. The
goal of their day-long session was to develop a scheme of best
practices for the design, conduct, and interpretation of future
investigations, as well as the practical inclusion of new
technologies, such as imaging.

At one point in the dialogue, the group recognized that perhaps the
greatest challenge in these studies was determining how to evaluate in
utero exposures to environmental chemicals. "Quite often the very
nature of epidemiological studies limits the ability to perform
accurate exposure assessments," says Harry, who was part of the expert
group. "Such exposures may have occurred in the distant past, they may
have been unknown, or they may have been in conjunction with many
other compounds."

The group therefore recommended that actual measurements, even if
indirect, are better than methods based on subject recall. It also
recommended that a well-defined hypothesis should form the foundation
of in utero studies for assessing neurodevelopmental outcomes. "[These
and other] conclusions will move the science forward by describing
methods that should improve interstudy comparisons, and they offer
ways in which research results should be reported to the scientific
and medical communities," says Judy LaKind, an adjunct associate
professor of pediatrics at the Hershey Medical Center and a member of
the workshop steering committee. The complete workshop report will be
published in an upcoming issue of NeuroToxicology. Imagining the Big
Picture

The challenges of addressing neurodevelopmental disorders are more
than scientific. The difficulties come together at a crossroads where
the communication of knowledge, the treatment of patients, and the
regulation of potentially toxic chemicals meet. Says Herbert,
"Evidence-based medicine has not yet developed standards for
assessing, or practices for treating, the impacts of chronic, multiple
low-dose exposures." Rather than waiting, she says, patients and
parents of patients are turning to alternative medicine to address
their concerns.

That's not always a good thing, especially when patients and parents
may be misinformed. Kathy Lawson, director of the Healthy Children
Project at the Learning Disabilities Association of America, says
there is a disconnect between scientific knowledge and the public's
awareness of ways to reduce the incidence of some disorders. "In my
visits to various organizations, I've discovered that people are
completely unaware that there is a connection between environmental
toxicants and their health," she says. "Even pediatricians often don't
know about these things," she adds.

Educating the public is only part of the solution. Elise Miller,
executive director of the nonprofit Institute for Children's
Environmental Health, thinks that federal regulatory agencies do not
adequately protect children's health. "The Toxic Substances Control
Act, which was passed thirty years ago, needs a major overhaul to
ensure neurotoxicants and other chemicals are prioritized, screened,
and tested properly," she says. "Currently, there are too many
chemicals on the market and in the products we use every day for which
there is no toxicity data."

Some politicians agree with these sentiments. In July 2005, Senator
Frank R. Lautenberg (D-NJ) introduced the Child, Worker, and Consumer
Safe Chemicals Act, which initially calls for chemical manufacturers
to provide health and safety information on the chemicals used in
certain consumer products, among them baby bottles, water bottles, and
food packaging. If passed into law, the bill, coauthored by Senator
James Jeffords (I-VT), would require all commercially distributed
chemicals to meet the new safety measures by 2020.

The human brain is often touted as the most complex structure in the
known universe. The developmental process that produces this
remarkable entity may also be among the most delicate in nature. As
one scientist put it, "The brain doesn't like to be jerked around."
That kind of fragility makes it difficult for scientists to untangle
genetic influences from what often may be subtle environmental
assaults. Even so, the catalogue of harmful environmental agents will
undoubtedly continue to grow as scientists learn more about the
interactions between the developing brain and its environment. The
hope is that enough good minds will use that catalogue to create a
future with healthier brains and more peace of mind for parents and
society alike.