|Ehp Niehs Nih Members 2004 6826|
Ehp Niehs Nih Members 2004 6826
2002. This report appears in the May 2004 EHP. Severalstudies 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 zoologistTheo Colborn of the University of Florida that every childconceived today in the Northern Hemisphere is exposed tothese 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 compoundto another.the effects of pesticides on the developing brain havebeen investigated in human epidemiologic studies and inlaboratory experiments with animals. Vincent Garry, a professorof environmental medicine at the University of Minnesota,and his colleagues found that children born to applicatorsof the fumigant phosphine were more likely to display adverseneurological and neurobehavioral developmental effects.the herbicide glyphosate was also linked to neurobehavioraleffects, according to the same report, which appeared inthe June 2002 issue of EHP Supplements. Anotherepidemiologic study, reported in the March 2005 issue of NeuroToxicology, showedthat women who were exposed to organophosphate pesticidesin an agricultural community in California had childrenwho displayed adverse NeuroDevelopment al effects, and thathigher levels of pesticide metabolites in maternal urinewere associated with abnormal reflexes in the women’snewborn children.Many PCBs, PBDEs, and pesticides are the subject of the2001 Stockholm Convention on Persistent Organic Pollutants,which became international law in May 2004. the goal ofthe treaty is to rid the world of PCBs, dioxinsand furans, and nine highly dangerous pesticides, accordingto the United Nations Environment Programme. Implementationof the treaty has significant practical challenges, however,including the difficulty of eliminating one persistentpollutant without creating another (for example, when burningPCBs yields by-products such as dioxins and furans).Not Immune to HarmExposure to a neurotoxicant may not be the only way todisrupt the natural growth of the brain. Scientists arenow looking at the subtle physiological effects of immunotoxicantsand infectious agents on biological events during development.It turns out that mothers who experience an infectionduring pregnancy are at a greater risk of having a childwith a NeuroDevelopment al disorder such as autism or schizophrenia.For example, prenatal exposure to the rubella virus isassociated with neuromotor and behavioral abnormalitiesin childhood and an increased risk of schizophrenia spectrumdisorders in adulthood, according to an article in theMarch 2001 issue of Biological Psychiatry. Rubellahas also been linked to autism: some 8-13% of childrenborn 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 rubellavirus and mental retardation.Some epidemiologic studies have found an increased riskof schizophrenia among the children of women who were exposedto the influenza virus during the second trimester of pregnancy,according to a report in the February 2002 Current Opinionin Neurobiology. In the August 2004 Archives ofGeneral Psychiatry, Ezra Susser, head of epidemiologyat Columbia University’s Mailman School of PublicHealth, and his colleagues reported that the risk of themental disorder was increased sevenfold if the schizophrenicpatient’s mother had influenza during her first trimesterof pregnancy. A prospective birth cohort study in the April2001 Schizophrenia Bulletin found that secondtrimester exposure to the diphtheria bacterium also significantlyincreased the risk of schizophrenia.How might infectious agents cause these disorders? Accordingto John Gilmore, a professor of psychiatry at the Universityof North Carolina at Chapel Hill, maternal infections duringpregnancy can alter the development of fetal neurons inthe cerebral cortex of rats. the mechanism is far fromclear, but signaling molecules in the mother’s immunesystem, called cytokines, have been implicated. Speakingat the XXII International Neurotoxicology Conference, Gilmoredescribed in vitro experiments showing that elevatedlevels of certain cytokines--interleukin-1?,interleukin-6 and tumor necrosis factor-alpha (TNF---reducethe survival of cortical neurons and decrease the complexityof neuronal dendrites in the cerebral cortex. Ibelieve that the weight of the data to date indicates [thatthe maternal immune response] can have harmful effects, saysGilmore.Inflammatory responses in the mother may not be the onlyroute to modifying the fetal brain. the University of California,Davis, Center for Children’s Environmental Healthand Disease Prevention is conducting a large study of autisticchildren in California called CHARGE (Childhood AutismRisks from Genetics and the Environment), which suggeststhat 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. Autisticchildren have a significant reduction in plasma immunoglobulinsand a skewed profile of plasma cytokines compared to otherchildren, he says. We think that an immunesystem dysfunction may be one of the etiological coresof autism.He continues, We know that many of the thingsthat kids are exposed to these days are immunotoxicants.. . . We have evidence that ethylmercury and thimerosalalter the signaling properties of antigen-presenting cells,known as dendritic cells, at nanomolar levels. Sinceeach dendritic cell can activate 250 T cells, any dysregulationwill be magnified, he says. Add to that a geneticabnormality in processing immune information, and therecould be a problem. Such problems might extend to the central nervous system.the brains of individuals who have a NeuroDevelopment aldisorder also show evidence of inflammation. In the January2005 issue of the Annals of Neurology, Carlos Pardo,an assistant professor of neurology and pathologyat the Johns Hopkins University School of Medicine, andhis colleaguesreport finding high levels of inflammatorycytokines (interleukin-6, interleukin-8, and interferon-)in the cerebrospinal fluid of autistic patients.Glialcells, which serve as the brain’s innate immune system,are the primary sources of cytokines in the central nervoussystem. So it may not be surprising that Pardo’steam also discovered that glia are activated--showing bothmorphological and physiological changes--in postmortembrains of autistic patients.the recognition that the immune system is involved inNeuroDevelopment al disorders is changing people’sperceptions of these conditions. Historically, scientistshave focused on the role of neurons in all kinds of neurologicaldiseases, Pardo says, but they have generallybeen ignoring the [glia]. He adds, In autism,it could be that the [glia] are responding to some externalinsult, such as an infection, an intrauterine injury, ora neurotoxicant.According to Pardo, it’s still not clear whetherthe neuroimmune responses associated with autism contributeto the dysfunction of the brain or whether they are secondaryreactions to some neural abnormality. John Gilmore’swork [showing that cytokines can be harmful to brain cells]is quite interesting and important, he says. However, invitro studies may produce results that don’treflect what occurs under in vivo conditions. Cytokineslike TNF-maybe beneficial for some neurobiological functions at lowconcentrations, but may be extremely neurotoxic at highconcentrations.Lending Brain Power to Exposure Assessmentthe medical and scientific communities recognize thecolossal challenges involved in identifying the ultimatecauses of NeuroDevelopment al disorders. This is complicatedby the sheer numbers of potential exposures involved. Morethan 67% of the nearly 3,000 chemical compounds producedor imported in amounts exceeding 1 million pounds per yearhave not been examined with even basic tests for neurotoxicity,according to Toxic Ignorance, a 1997 analysis byEnvironmental Defense.In the past few years, several large projects have beenproposed, and funding by the NIH has been increased. Forexample, the NIH boosted its support for autism researchfrom $22 million in 1997 to $100 million in 2004. In 2001,the NIEHS and the EPA jointly announced the creation offour new children’s environmental health researchcenters (including the one at the University of California,Davis), which focus primarily on NeuroDevelopment al disorders.More recently, the proposed multibillion-dollar NationalChildren’s Study, which is cosponsored by the Departmentof Health and Human Services and the EPA, has been designedto follow nearly 100,000 children over the course of 21years. the investigators plan to study the effects of environmentalfactors on children’s growth and development, includingimpacts on learning, behavior, and mental health. Studyinvestigators hope to enroll the first participants inearly 2007.Scientists also see the need for designing better studies.In NeuroDevelopment al studies, as in any other field, thequality of a study is only as good as all of its parts.Jean Harry, head of the NIEHS Neurotoxicology Group, says, Youcan have a valid assessment of behavior, but in the absenceof good exposure data, a causative association with environmentalfactors will be compromised.In a bid to address the difficulties faced by epidemiologicstudies that look for NeuroDevelopment al effects from inutero chemical exposure, a working group of 20experts gathered in September 2005 under the auspices ofthe Penn State Hershey Medical Center, coincident withthe XXII International Neurotoxicology Conference. Thegoal of their day- Long session was to develop a schemeof best practices for the design, conduct, and interpretationof future investigations, as well as the practical inclusionof new technologies, such as imaging.At one point in the dialogue, the group recognized thatperhaps the greatest challenge in these studies was determininghow to evaluate in utero exposures to environmentalchemicals. Quite often the very nature of epidemiologicalstudies limits the ability to perform accurate exposureassessments, says Harry, who was part of the expertgroup. Such exposures may have occurred in the distantpast, they may have been unknown, or they may have beenin conjunction with many other compounds.the group therefore recommended that actual measurements,even if indirect, are better than methods based on subjectrecall. It also recommended that a well-defined hypothesisshould form the foundation of in utero studies forassessing NeuroDevelopment al outcomes. [These andother] conclusions will move the science forward by describingmethods that should improve interstudy comparisons, andthey offer ways in which research results should be reportedto the scientific and medical communities, saysJudy LaKind, an adjunct associate professor of pediatricsat the Hershey Medical Center and a member of the workshopsteering committee. the complete workshop report will bepublished in an upcoming issue of NeuroToxicology.Imagining the Big Picturethe challenges of addressing NeuroDevelopment al disordersare more than scientific. the difficulties come togetherat a crossroads where the communication of knowledge, thetreatment of patients, and the regulation of potentiallytoxic chemicals meet. Says Herbert, Evidence- Basedmedicine has not yet developed standards for assessing,or practices for treating, the impacts of chronic, multiplelow-dose exposures. Rather than waiting, she says,patients and parents of patients are turning to alternativemedicine to address their concerns.That’s not always a good thing, especially whenpatients and parents may be misinformed. Kathy Lawson,director of the Healthy Children Project at the LearningDisabilities Association of America, says there is a disconnectbetween scientific knowledge and the public’s awarenessof ways to reduce the incidence of some disorders. Inmy visits to various organizations, I’ve discoveredthat people are completely unaware that there is a connectionbetween environmental toxicants and their health, shesays. Even pediatricians often don’t knowabout these things, she adds.Educating the public is only part of the solution. EliseMiller, executive director of the nonprofit Institute forChildren’s Environmental Health, thinks that federalregulatory agencies do not adequately protect children’shealth. the Toxic Substances Control Act, whichwas passed thirty years ago, needs a major overhaul toensure neurotoxicants and other chemicals are prioritized,screened, and tested properly, she says. Currently,there are too many chemicals on the market and in the productswe use every day for which there is no toxicity data.Some politicians agree with these sentiments. In July2005, Senator Frank R. Lautenberg (D- NJ) introduced theChild, Worker, and Consumer Safe Chemicals Act, which initiallycalls for chemical manufacturers to provide health andsafety information on the chemicals used in certain consumerproducts, among them baby bottles, water bottles, and foodpackaging. If passed into law, the bill, coauthored bySenator James Jeffords (I-VT), would require all commerciallydistributed chemicals to meet the new safety measures by2020.the human brain is often touted as the most complex structurein the known universe. the developmental process that producesthis remarkable entity may also be among the most delicatein nature. As one scientist put it, the brain doesn’tlike to be jerked around. That kind of fragilitymakes it difficult for scientists to untangle genetic influencesfrom what often may be subtle environmental assaults. Evenso, the catalogue of harmful environmental agents willundoubtedly continue to grow as scientists learn more aboutthe interactions between the developing brain and its environment.the hope is that enough good minds will use that catalogueto create a future with healthier brains and more peaceof mind for parents and society alike.
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