New thinking on Neurodevelopment

[Guest guest]

Good to see Dr Pardo (JHU) is still doing research in this area.

New Thinking on Neurodevelopment

An article in the current issue of Environmental Health Perspectives

(EHP) reviews environmental considerations for neurodevelopmental

disorders, including autism. The article quotes Cure Autism Now-funded

researchers Martha Herbert and Pardo as they discuss abnormal

brain processes that could be triggered by environmental exposures to

neurotoxins, such as mercury. EHP is published by the National Institute

of Environmental Health Sciences.

The article is reproduced here with permission from EHP.

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, , 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 (µg/dL) in the 1960s to the

current level of 10 µg/dL, 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 µg/dL. 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, ß-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 ß-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 (µg/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 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 µg/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 ,

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 , and pretreatment of the cells with glutathione reduced these

effects. Other studies by 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.

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

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. Tomás Guilarte, a professor of molecular neurotoxicology

at the s 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. s Sjödin, 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. 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

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-1ß, interleukin-6 and tumor necrosis factor-alpha

(TNF-a)--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, , 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 ls of Neurology,

Pardo, an assistant professor of neurology and pathology at the

s Hopkins University School of Medicine, and his colleagues report

finding high levels of inflammatory cytokines (interleukin-6,

interleukin-8, and interferon-) 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. " 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-a 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, ), 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. 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 ,

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

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

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.

- Szpir

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