the June 2002 issue of EHP Supplements . Anotherepidemiologic 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- --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-) 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- 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.