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Environews Focus

he notion that some substances inthe environment can damage the

nervous system has an ancient history.The neurotoxicity of lead was recog-nized more than 2,000 years ago by theGreek physician Dioscerides, whowrote, “Lead makes the mind give way.”In the intervening millennia manyother substances have been added to thelist of known or suspected neurotoxi-cants. Despite this accumulation ofknowledge, there is still much that isn’tunderstood about how neurotoxicants

affect the developing brain, especiallythe effects of low-dose exposures. Todayresearchers are taking a hard look atlow-dose exposures in utero and duringchildhood to unravel some of the mys-teries of impaired neurodevelopment.

About 17% of school-age childrenin the United States suffer from a dis-ability that affects their behavior, mem-ory, or ability to learn, according to astudy published in the March 1994issue of Pediatrics by a team fromthe Centers for Disease Control and

Prevention (CDC). The list of maladiesincludes attention deficit/hyperactivitydisorder (ADHD), autistic spectrumdisorders, epilepsy, Tourette syndrome,and less specific conditions such asmental retardation and cerebral palsy.All are believed to be the outcome ofsome abnormal process that unfolded asthe brain was developing in utero or inthe young child.

These disorders have an enormousimpact on families and society.According to the 1996 book Learning

Disabilities: Lifelong Issues, childrenwith these disorders have higher rates ofmental illness and suicide, and are morelikely to engage in substance abuse andto commit crimes as adults. The overalleconomic cost of neurodevelopmentaldisorders in the United States is esti-mated to be $81.5–167 billion peryear, according to a report publishedin the December 2001 issue of EHPSupplements.

Potentially even more disturbing isthat a number of epidemiologic studies

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Focus | New Thinking on Neurodevelopment

Environmental Health Perspectives • VOLUME 114 | NUMBER 2 | February 2006 A 101

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suggest that the incidence of certain disordersis on the rise. In the United States, the diag-nosis of autistic spectrum disorders increasedfrom 4–5 per 10,000 children in the 1980sto 30–60 per 10,000 children in the 1990s,according to a report in the August 2003Journal of Autism and Developmental Dis-orders. Similarly, notes a report in theFebruary 2002 issue of CNS Drugs, the diag-nosis of ADHD grew 250% between 1990and 1998. The number of children in specialeducation programs classified with learningdisabilities increased 191% between 1977and 1994, according to an article in Advancesin Learning and Behavioral Disabilities,Volume 12, published in 1998.

So what is going on? The short answeris that no one really knows. There’s noteven consensus on what the soaring ratesactually mean. Heightened public aware-ness could account for the surge in thenumbers, or it may be that physicians aregetting better at diagnosing the condi-tions. Some autism researchers believe therise in that condition’s prevalence simplyreflects changes in diagnostic criteria overthe last 25 years. On the other hand, somescientists believe that the rates of neurode-velopmental disease are truly increasing,and that the growing burden of chemicalsin the environment may play a role.

With that in mind, investigators areconsidering the effects of gene–environ-ment interactions. A child with a mildgenetic tendency toward a neurodevelop-mental disorder might develop withoutclinically measurable abnormalities in theabsence of environmental “hits.” However,children in industrialized nations developand grow up in a veritable sea of xenobiot-ic chemicals, says Isaac Pessah, director ofthe University of California, Davis, Centerfor Children’s Environmental Health andDisease Prevention. “Fortunately,” he says,“most of us have a host of defense mecha-nisms that protect us from adverse out-comes. However, genetic polymorphisms,

complex epistasis, and cytogenetic abnor-malities could weaken these defenses andamplify chemical damage, initiating afreefall into a clinical syndrome.”

Pessah cites the example of autism. Hesays susceptibility for autism is likely con-ferred by several defective genes, no one ofwhich can account for all the core symp-toms of social disinterest, repetitive andoverly focused behaviors, and problems incommunication. Could multiple genetic lia-bilities and exposure to a chemically com-plex environment act in concert to increasethe incidence and severity of the condition?

Despite the uncertainties, many scien-tists believe it would be wise to err on the

side of caution when it comes to a researchagenda. As Martha Herbert, a pediatricneurologist at Harvard Medical School,puts it, “Even though we may have neitherconsensus nor certainty about an autismepidemic, there are enough studies coming

in with higher numbers that we should takeit seriously. Environmental hypothesesought to be central to research now. Thephysiological systems that have beenharmed by environmental factors may alsopoint to treatment targets, and this mightbe a great way to help the children.”

The Parade of NeurotoxicantsAmong the most intensely studied neuro-toxicants are metals (lead, mercury, andmanganese), pesticides, polychlorinated

biphenyls (PCBs), and polybrominateddiphenyl ethers (PBDEs). A number ofthese compounds were identified as neuro-toxicants when individuals were exposed tohigh doses during occupational accidents orchildhood poisonings. Scientists are nowexploring the potential consequences oflow-dose exposures, especially to childrenand fetuses. Epidemiologic studies play acentral role, and these are often comple-mented by experimental work on animalsand cell cultures. These days, researchers arelooking not only at associations betweentoxicants and disease, but also at the under-lying cellular and molecular mechanisms.

Lead. Studies dating to the 1970s showthat children exposed to lead have deficitsin IQ, attention, and language. Inresponse, the CDC revised its limits foracceptable blood levels of the metal in sev-eral steps, from 60 micrograms per deciliter(µg/dL) in the 1960s to the current level of10 µg/dL, set in 1991. But many scientiststhink that limit is still too high. A studyreported in the September 2005 issue ofEHP found that there were significanteffects on a child’s IQ even when bloodlead concentrations were below 10 µg/dL.Upon the July 2005 release of the ThirdNational Report on Human Exposure toEnvironmental Chemicals by the CDC, JimPirkle, deputy director for science at theCDC’s Environmental Health Laboratory,stated, “There is no safe blood [lead] levelin children.”

Several groups have also found evidencethat lead exposure may shape a child’s socialbehavior. An article in the May 2000 issue

of Environmental Research reports a strongcorrelation, dating back to 1900, betweenviolent crime and the use of lead-basedpaint and leaded gasoline. The researchcomplements studies by Herbert Needle-man, a professor of psychiatry and pedi-atrics at the University of Pittsburgh Schoolof Medicine, who found that bone lead lev-els in young males were correlated withaggression and criminality. “Lead is signifi-cantly associated with a risk for delinquen-cy,” says Needleman. His research appeared

A 102 VOLUME 114 | NUMBER 2 | February 2006 • Environmental Health Perspectives

Percentage of school-age children in theUnited States who suffer from a disabilitythat affects their behavior, memory, or abilityto learn. Pediatrics, March 1994

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81.5 to 167Annual cost in billions of dollars for neuro-developmental disorders in the UnitedStates. EHP Supplements, December 2001

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in the November–December 2002 issueof Neurotoxicology and Teratology and the7 February 1996 issue of JAMA.

Another new area of research linksearly lead exposure to changes in theaging brain. Nasser Zawia, an associateprofessor of pharmacology and toxicologyat the University of Rhode Island,Kingston, and his colleagues foundincreased expression of amyloid precursorprotein (APP) and its product, β-amyloid(which is a hallmark of Alzheimer dis-ease), in aging rats that were exposed tolead shortly after birth. In contrast, oldrats that were exposed to lead did notshow an increased expression of APP andβ-amyloid. The work, published in the 26January 2005 issue of The Journal ofNeuroscience, suggests that early exposureto lead can “reprogram” gene expressionand regulation later in life. According toZawia, preliminary research also showsthat “monkeys exposed to lead as infantsexhibit similar molecular changes as wellas exaggerated Alzheimer’s pathology.”

Mercury. The current EnvironmentalProtection Agency (EPA) reference dose formethylmercury (an organic, toxic form ofmercury) is 0.1 micrograms per kilogramper day (µg/kg/day). Humans are exposedto methylmercury primarily through con-sumption of contaminated fish; a good70% of this contamination comes fromanthropogenic sources such as emissionsfrom coal-fired power plants. High-levelexposure to methylmercury in the womb islinked to a number of impairments, includ-ing mental retardation, cerebral palsy,seizures, deafness, blindness, and speechdifficulties. An article in the May 2005issue of EHP puts the economic cost to theUnited States of methylmercury-inducedtoxicity (in terms of lost productivity) at$8.7 billion annually.

The effects of low-dose exposures arenot so apparent. Two large epidemiologicstudies of fishing populations in the Faroe

Islands and the Seychelles have producedconflicting results regarding low-doseeffects. Both studies sought to examinethe association between methylmercuryexposure and neurodevelopment in chil-

dren whose mothers ate contaminatedseafood during pregnancy.

The leader of the Faroe Islands study,Philippe Grandjean, an adjunct professorof environmental health at the HarvardSchool of Public Health, and his col-

leagues reported in the November 1997issue of Neurotoxicology and Teratologythat 7-year-old Faroese children had sig-nificant cognitive deficits and neurologi-cal changes after prenatal exposure tomethylmercury. Grandjean’s team fol-lowed up on the children at age 14.According to a report in the February2004 issue of The Journal of Pediatrics, thechildren continued to have problems,including neurological changes anddecreased nervous control of the heart.

In contrast, the authors of theSeychelles study found little evidence oflasting harm on a cohort of 66-month-oldchildren, according to their report in the26 August 1998 issue of JAMA. A follow-up study, published in the 17 May 2003issue of The Lancet, similarly found nolasting effects on language, memory,motor skills, or behavioral function whenthe children were 9 years old.

The different outcomes of the two stud-ies are puzzling because the children ofboth populations appeared to be exposed tosimilar amounts of methylmercury. Severalexplanations have been proposed, including

the possibility that genetic differencesbetween the populations may alter their rel-ative predispositions to harm from mercuryexposure. The source of methylmercury isalso different in the two populations. TheFaroese are exposed primarily through theconsumption of pilot whale meat, whereasthe Seychelles population relies heavily onocean fish. According to Gary Myers, a pro-fessor of neurology and pediatrics at theUniversity of Rochester Medical Centerand one of the principal investigators of theSeychelles study, whale meat contains manyother contaminants (including PCBs)besides methylmercury. “There is also evi-dence,” he says, “that the effects of con-comitant PCB and mercury exposure aresynergistic.”

Researchers continue to look at whetherthere is a danger from methylmercury atthe levels of exposure achieved by fish con-sumption. Another layer of uncertainty wasadded with findings published in theOctober 2005 issue of EHP showing thatfish consumption during pregnancyappeared to boost infant cognition—butonly as long as mercury intake, as measuredin maternal hair, wasn’t too high.

The question of whether low levels ofmercury are harmful has also manifesteditself in a controversy over the use of vac-cines containing thimerosal, a preservative.Although thimerosal was removed frommany of these vaccines in 2001, childrenthat were immunized before that date couldhave received a cumulative dose of morethan 200 µg/kg of mercury with the routinecomplement of childhood vaccinations,according to a study in the May 2001 issueof Pediatrics. Thimerosal is nearly half ethyl-mercury by weight. Because ethylmercury isan organic form of mercury, there is somesuspicion that it acts like methylmercury inthe brain, although research published in


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4–5 to 30–60Increase from the 1980s to the 1990s in thenumber of U.S. children per 10,000 diagnosedwith autistic spectrum disorders. Journal of Autismand Developmental Disorders, August 2003

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Percentage of increase in the numberof U.S. children diagnosed with ADHDbetween 1990 and 1998. CNS Drugs,February 2002

the August 2005 issue of EHP suggests thatthe two forms differ greatly in how they aredistributed through and eliminated fromthe brain. Developing countries continue touse pediatric vaccines that containthimerosal. In the United States, thimerosalis still present in influenza vaccines, whichthe CDC recommends be given to pregnantwomen and children aged 6–23 months.

Advocacy groups, such as SafeMinds,have suggested that the decades-long rise inthe diagnosis of autism is related to thepresence of thimerosal in vaccines. In May2004, however, the Institute of Medicine(IOM) issued a report, Immunization SafetyReview: Vaccines and Autism, stating thatseveral epidemiological studies publishedsince 2001 “consistently provided evidenceof no association” between thimerosal-containing vaccines and autism. However,the IOM’s report has been severely criti-cized by a number of advocacy groups,including the National Autism Association,for relying too heavily on a specific set ofepidemiologic data while dismissing clini-cal evidence and other epidemiologic stud-ies that showed evidence of a link.

Despite the assurances of the IOM,some scientists continue to explore themechanisms underlying the potential neu-rotoxic effects of thimerosal. In the January2005 issue of NeuroToxicology, S. Jill James,a professor of pediatrics at the Universityof Arkansas for Medical Sciences, and her

colleagues report that the neuronal andglial cell toxicity of methylmercury andethylmercury (as dosed via thimerosal) areboth mediated by the depletion of theantioxidant peptide glutathione. Of thetwo cell types, neurons were found to beparticularly susceptible to ethylmercury-induced glutathione depletion and celldeath, according to James, and pretreat-ment of the cells with glutathione reducedthese effects. Other studies by James andher colleagues, reported in the December2004 issue of the American Journal of

Clinical Nutrition, showed that autistic chil-dren had lower levels of glutathione com-pared to normal controls, and may thereforehave had a significant reduction in the abil-ity to detoxify reactive oxygen species.

James says the abnormal profile “sug-gests that these children may have anincreased vulnerability to pro-oxidant envi-ronmental exposures and a lower thresholdfor oxidative neurotoxicity and immuno-toxicity.” Speaking at the XXII Internat-ional Neurotoxicology Conference inSeptember 2005, she presented evidencethat multiple genetic polymorphismsaffecting glutathione pathways may interactto produce a chronic metabolic imbalancethat could contribute to the developmentand clinical symptoms of autism. Her

paper in the American Journal of ClinicalNutrition reported that low glutathionelevels in many autistic children werereversible with targeted nutritional inter-vention, but the ramifications of this find-ing are still unclear.

Manganese. As an essential nutrient,manganese is required for normal develop-ment; the reference dose for manganese is0.14 mg/kg/day. Chronic occupationalexposure to high levels of this metal isassociated with manganism, a conditionreminiscent of Parkinson disease that is

characterized by tremors, rigidity, andpsychosis. The illness is seem primarilyamong miners.

Animal studies published in the August2005 issue of Neurotoxicology by David

Dorman, director of the division of biolog-ical sciences at the CIIT Centers for HealthResearch in Research Triangle Park, NorthCarolina, suggest that the fetus is protectedto a certain extent from maternally inhaledmanganese. According to Dorman, chil-dren are exposed to manganese primarily byingesting it, but he knows of no linkbetween childhood exposure to manganeseand later Parkinson disease.

Nevertheless, because manganese affectsthe adult brain, people suspect that thedeveloping brain may be even more suscep-tible to harm from this metal, and recentresearch has unveiled a new cause for con-cern: In the January 2006 issue of EHP,child psychiatry professor Gail Wassermanand colleagues from Columbia Universityreported that Bangladeshi children whodrank well water with high concentrationsof naturally occurring manganese haddiminished intellectual function. Theresearchers noted that the bioavailability ofmanganese in water is higher than that ofmanganese in food. They also pointed outthat about 6% of U.S. wells have a highenough manganese content to potentiallyput some children at risk for diminishedintellectual function.

The cellular and molecular mecha-nisms of manganese neurotoxicity are notwell understood. The dopaminergic systemin the basal ganglia, which is affected inParkinson disease, may be involved, butthis hypothesis is controversial. TomásGuilarte, a professor of molecular neuro-toxicology at the Johns Hopkins Bloom-berg School of Public Health, describedresearch on these systems in nonhumanprimates at the XXII International Neuro-toxicology Conference. According toGuilarte, unpublished positron-emission


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Percentage of increase in the number ofU.S. children in special education programsclassified with learning disabilities between1977 and 1994. Advances in Learning andBehavioral Disabilities, Volume 12, 1998

83Percentage of decrease in the CDCacceptable level for lead in blood from1960 to the current level, set in 1991.EHP, September 2005

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tomography studies of the basal gangliashow that “manganese does appear to havean effect on dopaminergic neurons.”Guilarte found that the more manganesethe animals received, the less dopamine wasreleased through the actions of ampheta-mine (which is used to induce the release ofthe neurotransmitter). “This does notmean that manganese causes Parkinson’sdisease, merely that it has an effect on thoseneurons,” he says. This is the first report ofan in vivo effect on dopamine release bymanganese.

PCBs, PBDEs, and pesticides. Manychemicals raise concerns because of theirpersistence in the environment and theirtendency to bioaccumulate in animal tis-sues. They are typically synthetic moleculesthat were designed for use in everydayproducts, such as electrical equipment,computers, furniture, and pesticides.

PCBs appear to be present in all parts ofthe food chain, and humans are exposed tothese molecules primarily through theingestion of animal fat. The toxicity ofthese chemicals was first recognized aftermass poisonings in Japan in 1968 andTaiwan in 1979. Children born to womenwho had ingested contaminated cooking oilin Taiwan had a number of developmentalabnormalities, including psychomotordelay and lower scores on cognitive tests,according to a report in the 15 July 1988issue of Science.

Since those earlier observations, severalstudies have described a connectionbetween prenatal exposure to PCBs anddelayed cognitive development and lowerIQ. For example, a study in the 10November 2001 Lancet reports thoseinfants and young children exposed toPCBs through breast milk scored lower ontests of psychomotor and mental develop-ment. The mothers were exposed to normalbackground levels of PCBs in Europe. Inresponse to such studies, the U.S. Food andDrug Administration set tolerance levels forPCBs in a number of consumer products,such as milk and manufactured dairy prod-ucts (1.5 parts per million), poultry (3.0parts per million), and baby food (0.2 partper million).

PBDEs are widely used as flame retar-dants in consumer products. The effects ofPBDEs on humans is not clear, but animaltoxicity studies described in volume 183(2004) of Reviews of Environmental Con-taminants and Toxicology show that PBDEscan cause permanent learning and memoryimpairments, hearing deficits, and behav-ioral changes. There is a growing concernabout PBDEs because they appear to beaccumulating in human tissues. Andreas

Sjödin, a toxicologist at the CDC, and col-leagues found a trend toward increasingconcentrations of PBDEs in human serumtaken from sample populations in thesoutheastern United States from 1985through 2002, and in Seattle, Washington,from 1999 through 2002. This reportappears in the May 2004 EHP. Severalstudies have also discovered PBDEs inhuman breast milk. The current EPA refer-ence dose for PBDEs is 2 mg/kg/day.

As for pesticides, it’s been suggested byzoologist Theo Colborn of the University ofFlorida that every child conceived today inthe Northern Hemisphere is exposed tothese chemicals from conception throughgestation and beyond. Some pesticidesappear to be more harmful than others, andso the reference dose varies somewhat fromone compound to another.

The effects of pesticides on the devel-oping brain have been investigated inhuman epidemiologic studies and in labo-ratory experiments with animals. Vincent

Garry, a professor of environmental medi-cine at the University of Minnesota, andhis colleagues found that children born toapplicators of the fumigant phosphinewere more likely to display adverse neuro-logical and neurobehavioral developmentaleffects. The herbicide glyphosate was alsolinked to neurobehavioral effects, accord-ing to the same report, which appeared inthe June 2002 issue of EHP Supplements.Another epidemiologic study, reported inthe March 2005 issue of NeuroToxicology,showed that women who were exposed toorganophosphate pesticides in an agricul-tural community in California had chil-dren who displayed adverse neurodevelop-mental effects, and that higher levels ofpesticide metabolites in maternal urinewere associated with abnormal reflexes inthe women’s newborn children.

Many PCBs, PBDEs, and pesticides arethe subject of the 2001 Stockholm Con-vention on Persistent Organic Pollutants,which became international law in May2004. The goal of the treaty is to “rid the

world of PCBs, dioxins and furans, andnine highly dangerous pesticides,” accord-ing to the United Nations EnvironmentProgramme. Implementation of the treatyhas significant practical challenges, how-ever, including the difficulty of eliminat-ing one persistent pollutant withoutcreating another (for example, whenburning PCBs yields by-products such asdioxins and furans).

Not Immune to HarmExposure to a neurotoxicant may not be theonly way to disrupt the natural growth ofthe brain. Scientists are now looking at thesubtle physiological effects of immunotoxi-cants and infectious agents on biologicalevents during development.

It turns out that mothers who experi-ence an infection during pregnancy are at agreater risk of having a child with a neuro-developmental disorder such as autism orschizophrenia. For example, prenatal expo-sure to the rubella virus is associated with

neuromotor and behavioral abnormalitiesin childhood and an increased risk of schiz-ophrenia spectrum disorders in adulthood,according to an article in the March 2001issue of Biological Psychiatry. Rubella hasalso been linked to autism: some 8–13% ofchildren born during the 1964 rubella pan-demic developed the disorder, according toa report in the March 1967 Journal ofPediatrics. The same study also noted a con-nection between the rubella virus and men-tal retardation.

Some epidemiologic studies have foundan increased risk of schizophrenia among thechildren of women who were exposed to theinfluenza virus during the second trimesterof pregnancy, according to a report inthe February 2002 Current Opinion inNeurobiology. In the August 2004 Archives ofGeneral Psychiatry, Ezra Susser, head of epi-demiology at Columbia University’sMailman School of Public Health, and hiscolleagues reported that the risk of the men-tal disorder was increased sevenfold if theschizophrenic patient’s mother had influenzaC

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sFocus | New Thinking on Neurodevelopment

8.7Annual cost in billions of dollars ofmethylmercury-induced toxicity (in termsof lost productivity). EHP, May 2005

during her first trimester of pregnancy. Aprospective birth cohort study in the April2001 Schizophrenia Bulletin found that sec-ond trimester exposure to the diphtheriabacterium also significantly increased therisk of schizophrenia.

How might infectious agents causethese disorders? According to JohnGilmore, a professor of psychiatry at theUniversity of North Carolina at ChapelHill, maternal infections during pregnan-cy can alter the development of fetal neu-rons in the cerebral cortex of rats. Themechanism is far from clear, but signalingmolecules in the mother’s immune system,called cytokines, have been implicated.Speaking at the XXII International Neuro-toxicology Conference, Gilmore describedin vitro experiments showing that elevatedlevels of certain cytokines—interleukin-1β, interleukin-6 and tumor necrosis fac-tor–alpha (TNF-α)—reduce the survivalof cortical neurons and decrease the com-plexity of neuronal dendrites in the cere-bral cortex. “I believe that the weight ofthe data to date indicates [that the mater-nal immune response] can have harmfuleffects,” says Gilmore.

Inflammatory responses in the mothermay not be the only route to modifying thefetal brain. The University of California,Davis, Center for Children’s EnvironmentalHealth and Disease Prevention is conduct-ing a large study of autistic children inCalifornia called CHARGE (ChildhoodAutism Risks from Genetics and theEnvironment), which suggests that thechild’s immune system may also beinvolved. According to Pessah, the studyprincipal investigator, children with autismappear to have a unique immune system.“Autistic children have a significant reduc-tion in plasma immunoglobulins and askewed profile of plasma cytokines com-pared to other children,” he says. “We thinkthat an immune system dysfunction may beone of the etiological cores of autism.”

He continues, “We know that many ofthe things that kids are exposed to thesedays are immunotoxicants. . . . We haveevidence that ethylmercury and thimeros-al alter the signaling properties of antigen-presenting cells, known as dendritic cells,

at nanomolar levels.” Since each dendriticcell can activate 250 T cells, any dysregu-lation will be magnified, he says. “Add tothat a genetic abnormality in processingimmune information, and there could be aproblem.”

Such problems might extend to thecentral nervous system. The brains ofindividuals who have a neurodevelopmen-tal disorder also show evidence of inflam-mation. In the January 2005 issue of theAnnals of Neurology, Carlos Pardo, an

assistant professor of neurology andpathology at the Johns Hopkins Univ-ersity School of Medicine, and his col-leagues report finding high levels ofinflammatory cytokines (interleukin-6,interleukin-8, and interferon-γ) in thecerebrospinal fluid of autistic patients.Glial cells, which serve as the brain’sinnate immune system, are the primarysources of cytokines in the central nervoussystem. So it may not be surprising thatPardo’s team also discovered that glia areactivated—showing both morphological

and physiological changes—in post-mortem brains of autistic patients.

The recognition that the immune sys-tem is involved in neurodevelopmentaldisorders is changing people’s perceptionsof these conditions. “Historically, scien-tists have focused on the role of neuronsin all kinds of neurological diseases,”Pardo says, “but they have generally beenignoring the [glia].” He adds, “In autism,it could be that the [glia] are respondingto some external insult, such as an infec-tion, an intrauterine injury, or a neuro-toxicant.”

According to Pardo, it’s still not clearwhether the neuroimmune responsesassociated with autism contribute to thedysfunction of the brain or whether theyare secondary reactions to some neuralabnormality. “John Gilmore’s work[showing that cytokines can be harmful tobrain cells] is quite interesting and impor-tant,” he says. “However, in vitro studiesmay produce results that don’t reflectwhat occurs under in vivo conditions.Cytokines like TNF-α may be beneficialfor some neurobiological functions at lowconcentrations, but may be extremelyneurotoxic at high concentrations.”

Lending Brain Power to ExposureAssessmentThe medical and scientific communitiesrecognize the colossal challenges involved

in identifying the ultimate causes ofneurodevelopmental disorders. This iscomplicated by the sheer numbers ofpotential exposures involved. More than67% of the nearly 3,000 chemical com-pounds produced or imported in amountsexceeding 1 million pounds per year havenot been examined with even basic testsfor neurotoxicity, according to ToxicIgnorance, a 1997 analysis by Environ-mental Defense.

In the past few years, several largeprojects have been proposed, and funding



6Percentage of U.S. wells with a high enoughmanganese content to potentially put somechildren at risk for diminished intellectual function.EHP, January 2006

7-foldThe increased risk of schizophrenia in off-spring if the mother had influenza during herfirst trimester of pregnancy. Archives ofGeneral Psychiatry, August 2004

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by the NIH has been increased. For exam-ple, the NIH boosted its support forautism research from $22 million in 1997to $100 million in 2004. In 2001, theNIEHS and the EPA jointly announcedthe creation of four new children’s envi-ronmental health research centers (includ-ing the one at the University ofCalifornia, Davis), which focus primarilyon neurodevelopmental disorders. Morerecently, the proposed multibillion-dollarNational Children’s Study, which iscosponsored by the Department ofHealth and Human Services and the EPA,has been designed to follow nearly100,000 children over the course of 21years. The investigators plan to study theeffects of environmental factors on chil-dren’s growth and development, includingimpacts on learning, behavior, and mentalhealth. Study investigators hope to enrollthe first participants in early 2007.

Scientists also see the need for design-ing better studies. In neurodevelopmentalstudies, as in any other field, the qualityof a study is only as good as all of its parts.Jean Harry, head of the NIEHS Neuro-toxicology Group, says, “You can have avalid assessment of behavior, but in theabsence of good exposure data, a causativeassociation with environmental factorswill be compromised.”

In a bid to address the difficultiesfaced by epidemiologic studies that lookfor neurodevelopmental effects from inutero chemical exposure, a working groupof 20 experts gathered in September 2005under the auspices of the Penn StateHershey Medical Center, coincident withthe XXII International NeurotoxicologyConference. The goal of their day-longsession was to develop a scheme of bestpractices for the design, conduct, andinterpretation of future investigations, aswell as the practical inclusion of newtechnologies, such as imaging.

At one point in the dialogue, thegroup recognized that perhaps the greatestchallenge in these studies was determin-ing how to evaluate in utero exposures toenvironmental chemicals. “Quite oftenthe very nature of epidemiological studieslimits the ability to perform accurateexposure assessments,” says Harry, whowas part of the expert group. “Such expo-sures may have occurred in the distantpast, they may have been unknown, orthey may have been in conjunction withmany other compounds.”

The group therefore recommendedthat actual measurements, even if indi-rect, are better than methods based onsubject recall. It also recommended that a

well-defined hypothesis should form thefoundation of in utero studies for assessingneurodevelopmental outcomes. “[Theseand other] conclusions will move the sci-ence forward by describing methods thatshould improve interstudy comparisons,and they offer ways in which researchresults should be reported to the scientif-ic and medical communities,” says JudyLaKind, an adjunct associate professor ofpediatrics at the Hershey Medical Centerand a member of the workshop steeringcommittee. The complete workshopreport will be published in an upcomingissue of NeuroToxicology.

Imagining the Big PictureThe challenges of addressing neurodevel-opmental disorders are more than scientif-ic. The difficulties come together at acrossroads where the communication ofknowledge, the treatment of patients, andthe regulation of potentially toxic chemi-cals meet. Says Herbert, “Evidence-basedmedicine has not yet developed standardsfor assessing, or practices for treating, theimpacts of chronic, multiple low-doseexposures.” Rather than waiting, she says,patients and parents of patients are turningto alternative medicine to address theirconcerns.

That’s not always a good thing, espe-cially when patients and parents may bemisinformed. Kathy Lawson, director ofthe Healthy Children Project at theLearning Disabilities Association ofAmerica, says there is a disconnectbetween scientific knowledge and the pub-lic’s awareness of ways to reduce the inci-dence of some disorders. “In my visits tovarious organizations, I’ve discovered thatpeople are completely unaware that thereis a connection between environmentaltoxicants and their health,” she says. “Evenpediatricians often don’t know about thesethings,” she adds.

Educating the public is only part of thesolution. Elise Miller, executive director of

the nonprofit Institute for Children’sEnvironmental Health, thinks that federalregulatory agencies do not adequately pro-tect children’s health. “The Toxic Sub-stances Control Act, which was passedthirty years ago, needs a major overhaul toensure neurotoxicants and other chemicalsare prioritized, screened, and tested prop-erly,” she says. “Currently, there are toomany chemicals on the market and in theproducts we use every day for which thereis no toxicity data.”

Some politicians agree with these sen-timents. In July 2005, Senator Frank R.Lautenberg (D–NJ) introduced the Child,

Worker, and Consumer Safe ChemicalsAct, which initially calls for chemicalmanufacturers to provide health and safe-ty information on the chemicals used incertain consumer products, among thembaby bottles, water bottles, and food pack-aging. If passed into law, the bill, coau-thored by Senator James Jeffords (I–VT),would require all commercially distributedchemicals to meet the new safety measuresby 2020.

The human brain is often touted asthe most complex structure in the knownuniverse. The developmental process thatproduces this remarkable entity may alsobe among the most delicate in nature. Asone scientist put it, “The brain doesn’tlike to be jerked around.” That kind offragility makes it difficult for scientists tountangle genetic influences from whatoften may be subtle environmentalassaults. Even so, the catalogue of harmfulenvironmental agents will undoubtedlycontinue to grow as scientists learn moreabout the interactions between the devel-oping brain and its environment. Thehope is that enough good minds will usethat catalogue to create a future withhealthier brains and more peace of mindfor parents and society alike.

Michael Szpir


67Percentage of high-production-volume chemicalsproduced in or imported into the United Statesthat have not been examined for neurotoxicity.Toxic Ignorance, 1997

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