Training Program for Health Professionals Greater Boston Physicians for Social Responsibility www.igc.org/psr/ September 2002 Developmental disabilities in children are the subject of growing public health concern.* This presentation examines the contribution of toxic chemicals to those disabilities. These problems clearly result from complex interactions among genetic, environmental, nutritional, and social factors that impact children during vulnerable periods of development. Among these contributing factors, toxic exposures deserve special scrutiny because they are preventable causes of harm. Today’s presentation is based on a review of research compiled in the May 2000 report, In Harm’s Way: Toxic Threats to Child Development, by the Greater Boston Physicians for Social Responsibility. It summarizes highlights of laboratory, clinical, and epidemiologic research. This body of work suggests that exposures to common chemicals, during windows of vulnerability may contribute to learning and behavior problems in children. The implications are profound, and suggest that by preventing exposure to known and suspected toxicants, we can prevent needless disability. *(For the purpose of today's discussion, we use the term "developmental disability" to refer generally to learning, behavior, and developmental problems.)

PROGRAM OUTLINE Section I. Neurodevelopmental Disabilities Section II. Links Between Chemicals and Disabilities Section III. Magnitude of the Chemical Threat This discussion will address three general topics. First, we’ll focus on the problem of childhood disability itself. Next, we’ll focus on the science linking household and environmental chemicals to disability. We’ll introduce some basic concepts in toxicology (persistence, bioconcentration, toxicity, dosing pattern), and then review the links between a variety of substances and disabilities. Finally, we’ll put these toxic threats in context within the modern chemical landscape. We’ll consider the untold numbers, quantities, and combinations of untested substances to which the fetus and child are routinely exposed. Finally we’ll address the regulatory vacuum that permits what’s been called “a vast toxicologic experiment”(1) to be conducted on the public. 1. Needleman HL, Landrigan PJ. Raising Children Toxic Free. NY, Farrar, Straus and Giroux, 1994.

Section I. Outline: Neurodevelopmental Disabilities Clinical/Public Health Dimensions The Research/Evidence Problem Conceptual Framework Clinical Traits Syndromes Underlying Cellular Biology In this first section we begin to explore the problem of childhood disability as a clinical and public health issue of considerable magnitude. We’ll consider the human face of these disorders as well as the vital statistics. Under the research/evidence problem, we’ll address the difficulties identifying causes and trends, including substantial uncertainties in trends that appear to be sharply on the rise. We’ll next present a unifying conceptual framework for understanding how multiple factors interact to influence neurodevelopment. We’ll discuss complementary perspectives on disabilities, which may be viewed as either traits or clinical syndromes. Finally, we’ll briefly review the cellular biology of brain development and its vulnerability to chemical disruption.

Prevalence of Learning and Behavioral Disabilities Public Health Dimensions Prevalence of Learning and Behavioral Disabilities Total: 17%, 12 million children Learning disabilities: 5-10% ADHD: 3-5% Autism: 0.05% We begin with the problem of developmental disabilities, looking first at the clinical and public health dimensions of the problem. Twelve million American children (17%) are reported to suffer from one or more of these disorders.(1) Five to ten per cent of children are reported to have a learning disability.(2) The prevalence of attention deficit disorder has traditionally been reported at 3-5%, (2) and autism as 0.05 %.(3,4) 1. Boyle CA, Decoufle P, Yeargin-Allsopp M. Prevalence and health impact of developmental disabilities in US children. Pediatrics March 93(3):399-403, 1994. 2. American Psychiatric Association. Diagnostic and Statistical Manual, Fourth Edition. Washington, DC 1994. 3. Fombone E. The epidemiology of autism: a review. Psychol Med Jul;29(4):769-786, 1999. 4. Gillberg C, Wing L. Autism: not an extremely rare disorder. Acta Psychiatr Scand 99(6):399-406, 1999.

Reported Trends: Real? Better reporting? Changing criteria? Public Health Dimensions Reported Trends: Real? Better reporting? Changing criteria? Learning disabilities 191% Children in special education: 1977-1994 ADHD 1 20% Reported prevalence >800% Ritalin use since 1971 The number of children in special education in the US increased 191% between 1977 and 1994.(1) There is a growing consensus that the public health impact of ADHD may be underestimated. Some prevalence estimates are as high as 20% of school-aged children. (2, 3, 4) The use of Ritalin is reported to have doubled every 4-7 years since 1971 to its current estimated use for 1.5 million children. (5) Are these increases real? Unfortunately, there is no good way to know with certainty. Surveillance of developmental disabilities is a difficult problem. There is no national database that compiles information on these disorders, although a national monitoring and tracking system is in development. Much of the reported increase is likely to be due to individuals using variable diagnostic criteria as well as improved recognition, treatment and reporting. However, some is also likely to be the result of a truly increased incidence. 1. Kavale KA, Forness RR. Co-variants in learning disability and behavior disorders: An examination of classification and placement issues. Advances in Learning and Behavioral Disabilities 12:1- 42, 1992. 2. Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities. Attention-Deficit/Hyperactivity Disorder: A Public Health Perspective conference, Atlanta, Georgia, September 23-24, 1999. 3. Centers for Disease Control and Prevention, National Center for Health Statistics. Prevalence of Attention Deficit Disorder and Learning Disability, May 2002. http://www/cdc/gov/nchs/data/series/sr_10/sr10_206.pdf 4. Rowland AS, Umbach DM, Stallone L, Naftel AJ, Bohlig EM, Sandler DP. Prevalence of medication treatment for attention deficit-hyperactivity disorder among elementary school children in Johnston County, North Carolina. Am J Public Health. 2002 Feb;92(2):231-4. 5. Safer D, Zito J, Fine E. Increase Methylphenidate usage for attention deficit disorder in 1990s. Pediatrics 98(6):1084-1088, 1996.

Trends, Prevalence, and Clusters Public Health Dimensions Trends, Prevalence, and Clusters Autism 100% Autism over 30 years 210% Autism in California DSS System: 1987-1998 400% Above nation: Prevalence in Brick Township, NJ Autism, once thought of as rare, has become a concern to public health agencies. A review of autism rates reported in the medical literature also showed a doubling of prevalence in the past two to three decades [from a rate of 0.05% to approximately 0.1%] (1) The number of children entered into the autism registry in the state of California increased by 210% between 1987 and 1998.(2) You can also see that while the annual increase in autism reporting in California regularly increases, reporting for cerebral palsy, epilepsy, and mental retardation has remained stable or increased only slightly. This observation suggests that the increases in autism reporting can not be attributed solely to families moving to California in order to avail themselves of special services. The prevalence of autism spectrum disorders, typically reported as 1-2/1000, has recently been reported to be as high as 6.7/1000.(3) According to the National Institute of Health’s National Institute of Child Health and Human Development (NICHD), dramatic increases in autism disorders in the U.S. and throughout the world clearly show that autism is not rare. (4) 1. Gillberg C, Wing L. Autism: not an extremely rare disorder. Acta Psychiatr Scand 99(6):399-406, 1999. 2. California Health and Human Services, Department of Developmental Services. Changes in the Population of Person's with Autism and Pervasive Developmental Disorders in California's Developmental Services System: 1987 through 1998. A Report to the Legislature, Mar 1999.  http://www.autism.com/ari/dds/dds.html 3. Centers for Disease Control. Brick Autism Project. www.cdc.gov/nceh/programs/cddh/dd/brick.htm 4. National Institute of Health, National Institute of Child Health and Human Development (NICHD). Autism Facts, Autism research at the NICHD, 2001. www.nichd.nih.gov/punlications/pubs/autism/facts/sub4.htm

Problem of Staggering Proportions Public Health Dimensions Problem of Staggering Proportions Whether new, newly recognized, or a combination of both, developmental disabilities are a problem of staggering proportions. Whether the rising numbers of cases represent new or simply newly-recognized developmental disabilities, these are problems of staggering proportions.

Associated Effects on Individuals, Families, and Communities Public Health Dimensions Associated Effects on Individuals, Families, and Communities Financial stress Emotional stress Suicide Substance abuse Employment problems Academic difficulties The burden that these disabilities places on children, families, and communities is enormous. Financial stress Emotional stress (1,2,3) Suicide (4,5) Substance abuse (3) Employment problems (2,6,7) Academic difficulties (3) 1. Cramer SC, Ellis E. Learning disabilities: Lifelong issues. Paul H. Brookes Publishing Company, Inc., Baltimore, MD 1996. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC 1994. 3. Dyson LL. The experience of families of children with learning disabilities: Parental stress, family functioning and sibling concept. Journal of Learning Disabilities 29(3):280-286, 1996. 4. Dickman GE. The link between learning disabilities and behavior. In Cramer SC, Ellis E.(eds). Learning disabilities: Lifelong issues. Paul H. Brookes Publishing Company, Inc., Baltimore, MD 1996, pp 215-228. 5. McBride HEA, Siegel LS. Learning disabilities and adolescent suicide. Journal of Learning Disabilitites 30(6):652-659, 1997. 6. Wagner M, Newman L, et al. In Cramer SC, Ellis E (eds). Learning disabilities: Lifelong issues. Paul H. Brookes Publishing Company, Inc., Baltimore, MD 1996 (introduction). 7. Alexander D. Learning disabilities as a public health concern. In Cramer SC, Ellis E (eds). Learning disabilities: Lifelong issues. Paul H. Brookes Publishing Company, Inc., Baltimore, MD 1996, pp 249-253.

Economic Implications Economic Dimensions Economic Implications $81.5 – 167 billion/yr $9.2 billion/yr Over $8,000/yr $80-100,000/yr Estimated U.S. costs of neuro-developmental deficits, hypo-thyroidism, related childhood disorders Est. costs of neurobehavioral disorders attributable to environmental pollutants Special education costs for a child with autism; costs of residential treatment The estimated economic costs of neurodevelopmental disorders is staggering. One report estimates that the costs of neurodevelopmental deficits, hypothyroidism, and related childhood disorders range from $81.5-$167 billion in the U.S. alone, depending on estimates of costs of special education and whether or not lost earning potential is included. (1) Using estimates of costs of just autism, mental retardation, and cerebral palsy, and conservatively estimating 10% of the total burden of those disorders attributable to environmental pollutants, the financial impact is $9.2 billion annually. (2) Special education costs for a child with autism spectrum disorder are over $8000/yr, with care in residential schools reaching $100,000/yr. (3) Children with ADHD incur medical costs twice those of children without ADHD, were more likely to have major injuries, asthma, and hospital inpatient and outpatient care. (4) Muir T, Zegarac M. Societal costs of exposure to toxic substances: economic and health costs of four case studies that are candidates for environmental causation. Environ Health Perspect 2001. Dec;109 Suppl 6:885-903. Review. 2. Landrigan PJ, Schechter CB, Lipton JM, Fahs MC, Schwartz J. Environmental pollutants and disease in american children: estimates of morbidity, mortality, and costs for lead poisoning, asthma, cancer, and developmental disabilities. Environ Health Perspect. 2002 Jul;110(7):721-8. 3. Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities. Autism Spectrum Disorders. www.cdc.gov/ncbddd/dd/ddautism.htm 4. Chan E, Zhan C, Homer CJ. Health care use and costs for children with attention-deficit/hyperactivity disorder: national estimates from the medical expenditure panel survey. Arch Pediatr Adolesc Med. 2002 May;156(5):504-11. ADHD doubles health care costs for children – comparable to costs for children with asthma.

Difficulties in Epidemiological Research The Research/Evidence Problem Difficulties in Epidemiological Research What makes evidence convincing? The current state of evidence – what do we know/not know? The surveillance problem is compounded by difficulties in epidemiological research in general. Unlike laboratory research with genetically similar animals in carefully controlled conditions, valid epidemiological research is more difficult to design and execute. Yet, we are often asked “where is the evidence in people?” It is, therefore, important to understand some of the inherent challenges in obtaining and interpreting epidemiological research. We’ll approach this discussion by considering what makes epidemiologic evidence convincing. We’ll also address the limits of current state of knowledge/evidence, and consider implications of “what we don’t know” when interpreting developmental neurotoxicology research. As we will later see, from an historical perspective, neurotoxic exposures thought to be safe have often been found to have adverse developmental impacts when more refined testing methods are used. “More toxic than previously recognized” is a recurrent theme in the developmental neurotoxicology literature.

Difficulties in DNT Epidemiological Research The Research/Evidence Problem Difficulties in DNT Epidemiological Research Latency: Long periods between when exposures occur and effects surface Windows of vulnerability Gene-environment interactions Susceptible sub-populations Multiple exposures Epidemiological shortcomings TEXT FOR ADVANCED DISCUSSION Epidemiological research, particularly in developmental neurotoxicology, (DNT), is difficult for a variety of reasons. To begin with, appropriate study and control populations are difficult to identify and recruit. These types of studies are difficult to design with both accurate exposure and outcome measurement. Long latency periods between the time of exposure (to parents or children during early development) and the time when effects are measurable (as childhood and/or adolescent disabilities) make cause- effect relationships difficult to establish. Adding a further complication, there are important biological windows of vulnerability during development. These are periods of development in which the brain is particularly vulnerable to disruption. If exposure to a chemical under investigation is measured outside a window of vulnerability, the exposure may appear to have no effect, even if profound effects occur during windows of vulnerability, as in the case of thalidomide. This complicates epidemiological research considerably, and requires that the precise timing, as well as the nature and size of exposures, must also be factored into the research design. Such information may be very difficult, if not impossible, to obtain. Genetic factors can alter the ability to handle environmental insults, resulting in susceptible sub- populations that are not ordinarily identified. Those individuals who are genetically susceptible to neurodevelopmental toxicants may, therefore, be lost in the general study population and disproportionate impacts to these individuals remain unrecognized. In the real world, people are ordinarily exposed to mixtures of chemicals rather than to individual compounds. Epidemiological studies of mixtures are much more difficult to design and execute than exposures to single chemicals. Interactive effects of chemicals may be extremely important but remain unidentified in studies that do not look for them. Finally, various kinds of bias and confounding influence the validity of epidemiological studies.

Epidemiology Shortcomings The Research/Evidence Problem Epidemiology Shortcomings Confounders Exposure misclassification Recall bias Difficult outcome classification OPTIONAL ADVANCED DISCUSSION POINTS: Confounders are factors that are associated with an exposure and are also by themselves predictive of rates for the disease under study. For example, where someone lives might influence both the likelihood of exposure to a chemical compound (a resident of a rural area may be more likely to be exposed to pesticides in drinking water), while they may also be exposed to other factors that increase or decrease risk of impaired learning skills (residents of the study area might have poor access to prenatal healthcare — increasing risk of adverse pregnancy outcome). In this case, pesticide exposure may not be directly causing developmental disabilities. Rather, the disabilities may be related to inadequate prenatal care and pesticide exposure is only a "marker" of that risk factor — a result of living in a rural area. Exposure misclassification is likely when exposures are estimated rather than actually measured. Exposure misclassification is common because it is often impossible to know what was in the environment at the time of exposure, much less measure the dose the person received. Exposure misclassification usually biases a study toward the null. That is, the study becomes less likely to find a positive correlation between an exposure and adverse outcome, even when such a correlation truly exists. Conversely, recall bias is likely to bias toward finding an effect when none really exists. It is the result of the greater likelihood of someone with an impairment or disability being more likely to recall an exposure in the past that they believe may have contributed to their disease than someone who is not impaired. Outcome measures that are insensitive may fail to identify subtle but important toxicologic effects.Varying criteria for outcome measurement make it difficult to compare one epidemiological study to another or to summarize a number of studies in a meta-analysis that has substantial statistical power to identify subtle effects.

Under-Recognition of Toxic Threats POTENTIAL ERROR IN PROSPECTIVE DNT Under-Recognition of Toxic Threats Confounding Statistical analysis Exposure measures Outcome measures Confounding Statistical power Statistical analysis Alpha error (type I) Epidemiological data can be collected and interpreted in ways that favor either finding an association between an exposure and a health effect when it does not truly exist, or, conversely, finding no association when it truly does exist.  These errors are known as false positives or false negatives, respectively.  Favoring either kind of error carries certain consequences. Studies with a bias towards false positives will tend to cause “false alarm”; bias toward false negatives will tend to cause “false assurance.” By convention, scientific research places a high priority on avoiding false positive errors. In general, it is considered more important to avoid false positive statements (that falsely state an association exists when it truly doesn’t) than to avoid false negative statements (that fail to recognize associations that actually do exist). This approach is fully justified when studying exposure-effect relationships in the laboratory. However, in many cases it is unlikely to provide a standard that is most protective of public health in the real world. Advanced Discussion Points This slide illustrates the substantial potential for false negative findings in prospective DNT studies. While we attempt to address confounding as standard epidemiologic practice, we're often unable to address or even recognize inadequate exposure and outcome assessments. In addition, statistical analysis is usually weighted to favor Type II errors (false negatives) over Type I errors (false positives). These and other factors create substantial potential for false negative studies. It is therefore especially important to maintain appropriate skepticism towards “negative” studies of suspected developmental neurotoxicants. Such results need to be carefully examined for factors biasing towards false negative findings, which may be falsely reassuring with regard to chemical exposures that may in fact pose significant public health risks. FALSE POSITIVES Beta error (type II) FALSE NEGATIVES False Alarm False Assurance

What Makes Evidence Convincing? MORE CONVINCING Controlled Clinical Trials Case-Control and Cohort Epidemiologic Studies Cross-Sectional Epidemiologic Studies LESS CONVINCING Before we examine the links between specific chemicals and disabilities, it’s useful to consider what makes epidemiologic evidence convincing, particularly when data are of limited quality, as is commonly the case in DNT studies. Because it is unethical to intentionally administer suspected toxic substances to pregnant women and children, we don’t have (and wouldn’t want) controlled clinical trials to tell us what substances are toxic. The next best data are those from prospective, well-designed epidemiological studies with accurate exposure and outcome measures, and control of multiple confounders and other sources of bias. But the effects of concern, such as reading or learning problems, often have long latencies and therefore require studies with very long time frames. Multiple, interactive contributors to developmental outcomes make epidemiological studies difficult to design and execute. In addition, exposures and outcomes are typically difficult to measure. For all these reasons, definitive epidemiological studies are very expensive, and time consuming, and are available for only a small number of potential neurodevelopmental toxicants. Epidemiologic studies that fail to show clear-cut harm from exposure to suspected toxicants should not be assumed to be definitive. Substances now known to be neurodevelopmental toxicants have typically required generations of study to establish currently recognized toxicity. With incremental improvements in exposure and outcome assessment methods, toxicity is typically demonstrated at progressively lower levels. Since adequate epidemiologic studies are available for only a few neurodevelopmental toxicants, we must often rely solely on laboratory animal studies to assess chemical toxicity. Animal studies also have important deficiencies that will be discussed later. Source: Schettler T, Solomon G, Valenti M, Huddle A. The role of science in public health decisions. In Generations at Risk: Reproductive Health and the Environment, MIT Press, Cambridge, MA 1999. Consistent animal toxicity

What Makes Evidence Convincing? The Research/Evidence Problem What Makes Evidence Convincing? Building Blocks for a Strong Epidemiology Study Short latency Specific outcomes Adequate sample size Control of confounding Precise exposure measures Well-defined outcome measures To summarize, the conditions that lend themselves to simple, convincing epidemiologic studies are not usually found in developmental problems as they occur in the real world. The inherent difficulty obtaining adequate human neurodevelopmental data is an important argument for a precautionary approach to substances with suspected developmental toxicity. In the policy arena, such a precautionary approach requires explicit recognition of the inherent difficulty establishing cause-effect relationships in developmental neurotoxicology.

Under-recognition of Toxic Threats: Epistemological Bias WHAT WE KNOW DON’T KNOW Known Effects Thousands of chemicals THE “UNKNOWN UNKNOWN” Long latency effects Billions of mixtures This slide addresses the significance of “what we don’t know” when evaluating potential developmental neurotoxicologic threats from chemicals. For any given toxicant, or group of toxicants, “what we know” may be a bigger or smaller portion of the true toxic threat. Since we don’t know ”what we don’t know,” it is not possible to evaluate the magnitude or significance of the unknown. However, ignoring enormous data gaps gives rise to false assurance and leads to complacency about preventable exposures. Historically, as we will see in a few minutes, neurodevelopmental impacts of exposures have often proven to be greater than “currently available knowledge” has indicated. It is important, therefore, to keep in mind that the “unknown” may be substantial and significant as we offer clinical advice or consider policy options. Whether the “known” is a substantial portion of the true toxic threat, as shown in this slide, or an even smaller portion, is something that can only be determined after the fact. Gene-environment interactions Windows of vulnerability

LEARNING, BEHAVIOR, AND DEVELOPMENT: A SPECTRUM OF ACADEMIC DISCIPLINES C L I N I C A L family practice developmental pediatrics adolescent medicine behavioral psychology educational psychology developmental psychology ob- gyn pediatrics psychiatry cognitive psychology We turn now from the discussion of evidence to a conceptual framework for thinking about disabilities. First, it is important to consider the wide variety of disciplines concerned with developmental disabilities as an issue in either research or clinical practice. Within many of these fields, there has been a recent explosion of developmental research. This has produced a glut of highly technical information not readily understood by those outside of the field in which the research was performed. A communication gap has resulted, dividing the fields of research and separating the domains of research, clinical practice, and public understanding. Developmental neurotoxicology (DNT) is one of the fields very actively researching disability. DNT is a branch of neuroscience that investigates the effects of early chemical exposures on brain development. Because DNT uses a specialized vocabulary, its findings have been somewhat inaccessible to the larger child development community. Promoting greater interdisciplinary understanding of this material is a matter of some urgency, because most toxicologic exposures and the risks they confer are inherently preventable. behavioral genetics developmental neuro- psychology neurotoxicology R E S E A R C H

Framework for Understanding TOXICANTS Traits/ Abilities NUTRITION NUTRITION This diagram serves as a unifying framework for several important concepts we’ll be discussing today. First let’s consider the etiologies of these disorders. As shown in the diagram, multiple causes interact in complex ways during windows of vulnerability to affect development. These causes include nutrition and chemical exposures during vulnerable periods in early life, genetic factors (which should not be viewed in isolation), and the social environment. While research typically focuses on one domain at time, it is increasingly recognized that complex interactions are most important. For example, several genes have been identified that influence susceptibility to environmental chemicals, including genes that affect lead absorption and metabolism (such as the vitamin D receptor and delta aminolevulenic acid dehydratase genes) (1-9), and genes that affect the metabolism of and susceptibility to organophosphate (OP) pesticides (such as the paroxonase and acetylcholinesterase genes). (10-13) Among the multiple causes of disability, chemical exposures deserve special scrutiny because they are preventable causes of harm. We turn our attention next to the developmental outcomes that result from interacting genetic, toxicologic, nutritional, and social influences. These outcomes, as shown at the right and bottom in the diagram, can be viewed as continuous traits, or as categorical diagnoses. 1. Smith CM, Wang X, Hu H, et al. A polymorphism in the delta-aminolevulinic acid dehydratase gene may modify the pharmacokinetics and toxicity of lead. Environ Health Perspect 103(3):248-253, 1995. 2. Bergdahl IA, Grubb A, Schutz A, et al. Lead binding to delta-aminolevulinic acid dehydratase in human erythrocytes. Pharmacology and Toxicology 81(4):153-158, 1997. 3. Wetmur JG. Influence of the common human delta-aminolevulinic acid dehydratase polymorphism on lead body burden. Environ Health Perspect 102 suppl 3:215-219, 1994. 4. Wetmur JG, Lehnert G, Desnick RJ. The delta-aminolevulinic acid dehydratase polymorphism higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes. Environmental Research 56(2):109-119,1991. 5. Claudio L, Lee T, Wolff MS, et al. A murine model of genetic susceptibility to lead bioaccumulation. Fundam Appl Toxicol 35(1):84-90, 1997. 6. Tomokuni K, Ichiba M, Fujisiro K. Interrelation between urinary delta-aminolevulinic acid, serum ALA, and blood lead in workers exposed to lead. Industrial Health 31(2):51-57, 1993. 7. Schwartz BS, Lee BK, Stewart W, et al. Delta-aminolevulinic acid dehydratase genotype modifiers four hour urinary lead excretion after oral administration of dimercaptosuccinic acid. Occupational and Environmental Medicine 54(4):241-246, 1997. 8. Sithisarankul P, Cadorette M, Davoli CT, et al. Plasma 5- amniolevulinic acid concentration and lead exposed children. Environmental Research 80(1):41-49,1999. 9. Sithisarankul P, Schwartz BS, Lee BK, et al. Aminolevulinic acid dehydratase genotype mediates plasma levels of the neurotoxin, 5-aminolevlinic acid, in lead-exposed workers. American Journal of Industrial Medicine 32(1):15-20, 1997. 10. Mutch E, Blain PG, Williams FM. Interindividual variations in enzymes controlling organophosphate toxicity in man. Human and Experimental Toxicology 11(2):109-116, 1992. 11. Costa LG, Li WF, Richter RJ, et al. The role of paraoxonase (PON1) in the detoxification of organophosphates and its human polymorphism. Chemico-Biological Interactions 119-120:429-38, 1999. 12. Genc S, Gurdol F, Guvene S, et al. Variations in serum cholinesterase activity in different age and sex groups. European Journal of Clinical Chemistry and Clinical Biochemistry 35(3):239-240, 1997. 13. Pilkington A, Buchanan D, Jamal GA, Gillham R, Hansen S, Kidd M, Hurley JF, Soutar CA.An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers. Occup Environ Med. 2001 Nov;58(11):702-10. GENETICS SOCIAL ENVIRONMENT Asperger’s syndrome Learning ?? disability ADHD Autism Developmental Syndromes

Traits/Abilities vs. Clinical Syndromes Clinical Traits Traits/Abilities vs. Clinical Syndromes TRAITS/LABELS Traits include a variety of cognitive, behavioral, and developmental characteristics, such as attention, memory, impulsivity, aggression, reading and verbal ability, executive function, social adjustment, and introversion/extroversion. These characteristics are possessed by all people, though to different degrees. Traits are considered “dimensional,” because they can be measured quantitatively using neuropsychological or neurophysiological tests, and the measurement can be expressed as a point along a continuum. Aggregates of these traits are often described using diagnostic labels that identify clinical syndromes. These syndromes include disorders such as attention deficit hyperactivity disorder (ADHD), autism, or learning disability. Such labels are useful for the purpose of providing management strategies. However, traits are often better suited to research since they can be readily defined, quantitatively measured, and are more amenable to animal models. As a result, a large body of scientific data has begun to describe the effects of chemicals or other influences on neurodevelopment in terms of traits, rather than clinical syndromes. In addition, traits provide a common denominator between different fields of research, and allow us to acknowledge influences on the cognitive and behavioral function of “normal” populations, as well as on those with diagnostic labels. Trait/Ability Attention ability Impulsivity Executive function Memory Social adjustment Reading and verbal skills Clinical Syndrome ADHD Learning disabilities Asperger’s syndrome Autism

Traits/Abilities vs. Clinical Syndromes Clinical Traits Traits/Abilities vs. Clinical Syndromes Trait/Ability Quantitative, dimensional Objective tests Animal models Apply to “normal” populations Definable criteria Useful research tools Clinical Syndrome Qualitative, categorical Clinical judgment (subjective) No animal models Different from “normal” Variable diagnostic criteria Provide management strategies OPTIONAL ADVANCED DISCUSSION POINTS: Clinical syndromes have additional limitations as outcome measures in research. First, their diagnostic criteria are in flux, making comparisons difficult over time and across studies. Also, clinical syndromes lack specific identifying features, since the predominant features of one syndrome may also appear in any of the other syndromes. For example, the attentional problems in ADHD are commonly found in children with other developmental diagnoses, as well as in medical and psychiatric disabilities, and in normal children. (1,2) This uncertainty in the use of diagnostic labels is reflected in the high frequency with which children fulfill criteria for multiple diagnoses. As many as 30% of parents report their children have been given three or more different diagnostic labels. (3) For example, large proportions of children with ADHD also have a learning disability (10-30%), a language disability (30-50%), or oppositional or conduct disorder. (30-80%) ADHD is also frequently associated with Asperger’s syndrome, obsessive compulsive disorder, tic disorders, and mental retardation. Overlapping symptoms and frequent co-morbidities create uncertainties in the use of diagnostic labels. As a result, the use of clinical syndromes (diagnostic labels) as outcome measures can contribute to uncertainty in research. 1. Stone WL, Ousley OY. Pervasive developmental disorders: autism. In Wolraich ML (ed): Disorders of Development and Learning. Second Edition. Mosby, St. Louis, MO, 1996. 2. Baumgaertel A, Copeland L, Wolraich ML. Attention deficit hyperactivity disorder: In Wolraich ML (ed): Disorders of Development and Learning. Second Edition. Mosby, St. Louis, MO, 1996. 3. Gorham KA, DesJardins C, Page R. et al. Effect on parents. In Hobbs N (ed): Issues in the Classification of Children, Vol.2, San Fransiciso, Jossey-Bass, 1974. p. 154-188. Cited in Assessment of Childhood Disorders. Third Edition. Mash EM, Terdal LG. (eds) Guilford Press, New York, NY, 1997, p. 16.

Neuronal Migration Underlying Cellular Biology Neuronal Migration Now that we’ve introduced multiple causes and alternative ways to view outcomes, we’ll briefly consider the cellular events underlying development. The complexity of these events makes the fetal and infant brain uniquely vulnerable to toxic disruption. Brain development begins early in fetal life and continues into adolescence. First the shape of the brain emerges. Throughout fetal life, brain cells proliferate, migrate to their appropriate locations, and differentiate into specialized cell types. This slide illustrates the complexity of this process. OPTIONAL ADVANCED DISCUSSION POINTS: Here we see neurons originate near the center of the brain (shown in the illustration as the ventricular zone, VZ) and migrate along radial glial guides (RG) to their final location closer to the surface of the brain (cortical plate, CP). As the neurons migrate they intercept nerve fibers from other portions of the brain (thalamus, TR; the opposite side of the brain CC). Later-developing neurons migrate to final positions closer to the brain surface, remaining in columns (outlined by cylinders) that correspond to columns from which they originated. (Adapted from Rakic 1988) (1) Once neurons reach their destinations, they form synapses, creating complex circuitry. Subsequently, neural circuits are refined and consolidated through programmed cell death (apoptosis), a process that continues into childhood and adolescence. 1. Rakic P. specification of cerebral cortical areas. Science 241(4862):170-176, 1988. Graphics: Adapted from above reference. Illustration by Steven Burdick Design.

Cellular Events in Neurodevelopment Underlying Cellular Biology Cellular Events in Neurodevelopment Events: Division Migration Differentiation Formation of synapses Pruning of synapses Apoptosis Myelination Active throughout childhood & adolescence Cell division, migration, differentiation, synapse formation, synapse pruning, apoptosis, and myelination occur during brain development, though the timing of the sequence of events differs somewhat in various portions of the brain. The sequence is genetically programmed, but mediated by a variety of neurotrophic biochemical compounds, including neurotransmitters, and subject to disruption by environmental influences. Interference with any stage of this process may alter subsequent stages and result in permanent impairments. Neurotoxic compounds can interfere with critical processes in these events, making the developing brain uniquely susceptible to exposure. Extensive studies of a few well-known neurodevelopmental toxicants, including lead, mercury, alcohol, and nicotine, reveal multiple mechanisms by which these compounds disrupt normal brain development. These include alterations in levels of neurotransmitters or other neurotrophic compounds and impairment of cell division, migration, differentiation, synapse formation, and apoptosis.

Time Lines of Developmental Processes in Humans Prenatal Period (Months) Postnatal Period (Years) 0 1 2 3 4 5 6 7 8 9 Birth 1 2 3 4 5 6 7 8 9 10 Cell radial glia,neurons glia Proliferation Migration brain, spinal cord ext. granular layer cerebellum of Neurons Subplate Neurons Synapse mz sp hp rf visual cortex association cortex Formation Myelination (see text) Key: mz – marginal zone; sp – subplate; hp – hippocampus; rf – reticular formation Brain development involves the production of 1 billion nerve cells and 1 trillion glial, or support, cells. Once produced neurons undergo migration, synaptogenesis, cell loss, and myelination. Pruning of synapses occurs through adolescence. The peak number of synapses is reached in early childhood. Inhibition at one stage can cause alterations throughout the cascade. Various aspects of myelination occur from around 5 months gestation through 10 years of life. Compared to other organs, the brain remains vulnerable to developmental disruption over a prolonged period of time, extending from shortly after conception, until well after birth. This slide shows how the timing of processes involved in normal brain development vary during fetal life, infancy, childhood, and adolescence. Notice, for example, how cellular migration tends to be compressed into fairly short timeframes compared to cell proliferation, synapse formation or myelination. The clinical effect of disruption of the process by a developmental neurotoxic compound depends not only on the size of the dose but also on the timing and duration. EXAMPLE: Effects of the developmental neurotoxin, methylmercury, in large populations of people, include mixtures of developmental delays, learning disabilities, attention deficits, seizures, and mental retardation, depending on the size, timing, and duration of exposure. EXAMPLE: Thalidomide caused autism in some children only when the exposure occurred between gestational days 20-24. The window of vulnerability to limb development defects is much longer. Source: Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from human and animal models. Environ Health Perspect 108 (Suppl 3):511-533, 2000. With author’s permission.

Human Brain Growth Rate Even within the brain, the growth and differentiation of specific areas differ. For example, brain growth rate for the diencephalon (thalamus and hypothalamus) peaks at birth whereas for the cerebellum it is between 1 and 1 1/2 yrs. This chart uses weight as a measure of brain growth. Herschkowitz et al., 1997; Neuropediatrics, 28:296-306. Herschkowitz et al., 1997; Neuropediatrics, 28:296-306.

Neural Proliferation (rodent) This slide shows the timing of cell proliferation in various areas of the rodent brain. Bursts of cellular proliferation occur early in the hippocampus, the hypothalamus (LHRH), and the cerebellum. Later, after birth, secondary rounds of cell proliferation occur in the hippocampus and cerebellum. Exposure to a neurotoxic teratogen can have variable effects, depending on timing. For example, exposure on day 15 of gestation to a chemical agent that disrupts cell proliferation will cause a failure to produce appropriate numbers of hippocampal pyramidal cells while the cerebellum and hypothalamus are spared. After birth, these animals are deficient in many tasks of learning and memory and are strikingly hyperactive. The same exposure at an earlier or later date may injure the cerebellum and cause different effects. These animals are often hypoactive. Day 12 injury can interfere with proliferation of hypothalamic cells that control the release of pituitary hormones which stimulate ovaries and testis development. Interference with cell division day 12 results in animals that have immature gonads and go though puberty later. P Rodier EHP 102(Suppl 2) 1994

Cellular Events in Neurodevelopment Underlying Cellular Biology Cellular Events in Neurodevelopment Summary: Critical sequence Vulnerable to disruption Size, timing, duration influence impact Downstream effects Susceptible throughout adolescence In summary, 1. Brain development is characterized by a critical sequence of events. 2. These complex events are vulnerable to disruption. 3. The clinical manifestation of disruption from developmental neurotoxins depends on the size, timing, and duration of exposure. 4. Even transient disruptions have downstream effects. 5. Developmental vulnerability extends from shortly after conception throughout adolescence.

Basic Toxicology: Exposure-related Concepts Persistence Bioconcentration Transient exposures Before we examine specific toxic threats, two concepts important for understanding toxic exposures should be reviewed. The first of these is persistence, the tendency of some substances to resist degradation, remain in the environment for as long as decades, or, in the case of metals, infinitely. Persistent harmful substances are represented by the red dots in the illustration. A related concept is the phenomenon of bioconcentration. This is a process that characterizes some persistent chemicals, in which the substance builds up over time in an organism and at higher levels of the food chain. Because of bioconcentration, substances dispersed into air or water reappear in relatively high concentrations in foods derived from animals that are long-lived (such as dairy products and meats) or high in the food chain (such as large predatory fish). When these foods are consumed by humans, they accumulate in us. This slide shows how a persistent, bioaccumulating chemical increases in concentration from a low level in the water, to higher levels in larger fish, to highest levels in people who eat the fish. In this way contaminants in water may be concentrated more than a million-fold in food consumed by people. Of particular concern, these bioconcentrated substances are typically passed from mother to fetus and nursing infant at vulnerable periods of development. Because of persistence and bioconcentration, pollutants that are virtually undetectable in ambient air and water have appeared as global contaminants in the food chain, as well as in human fat, breast milk, and fetal tissues. It is important to note, however, that chemicals that are not persistent or that do not bioconcentrate can also be a threat if they are encountered in sufficient concentrations, particularly during windows of vulnerability.  Therefore, persistent, bioconcentrating chemicals are not the only ones of concern.

Links: Chemicals and Disabilities Section II Outline Basic Toxicology Lead Mercury PCBs Pesticides In this next section we’ll focus on the science linking household and environmental chemicals to developmental disability. We’ll start by introducing some basic concepts in toxicology that are important in understanding chemical exposures. Then we will examine the state of the science concerning the most widely studied neurotoxicants: lead, mercury, PCBs, pesticides.

Basic Toxicology Toxicity-related Concepts: specific processes disrupted by neurodevelopmental toxicants proliferation radiation, ethanol, mercury, cholinesterase inhibitors migration radiation, mercury, ethanol differentiation ethanol, nicotine, mercury, lead synaptogenesis radiation, ethanol, lead, triethyl tin, parathion, PCBs gliogenesis & dec. thyroid, ethanol, lead myelinization apoptosis ethanol, lead, mercury signaling ethanol, cholinesterase inhibitors, mercury, lead, PCBs Toxic substances can interfere with one or several processes necessary for normal brain development. For example, lead can interfere with cell differentiation, synapse formation, myelinization, programmed cell death (apoptosis), and neurotransmitter levels. Similarly, mercury interferes with cell proliferation, migration, programmed cell death, and neurotransmitter levels. Therefore the size, timing, and duration of exposures will determine which processes are disrupted and how brain function will be impaired. Sources: 1. Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from human and animal models. Environ Health Perspect 108 (Suppl 3):511-533, 2000. 2. Olney JW, Farber NB, Wozniak DF, Jevtovic-Todorovic V, Ikonomidou C. Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain. Environ Health Perspect. 2000 Jun;108 Suppl 3:383-8. Review.

Neurodevelopmental Toxicants: The State of Knowledge Basic Toxicology Neurodevelopmental Toxicants: The State of Knowledge Only 12 chemicals tested for neurodevelopmental toxicity according to current EPA guidelines. Extensive data on effects of lead, mercury, polychlorinated biphenyls (PCBs), alcohol, nicotine. Less extensive but substantial data on neurotoxic pesticides, solvents other than alcohol. Still fewer data on other compounds including manganese, fluoride. Problem: Most data obtained for a few chemicals. No data available for majority. Before we look at the database for particular neurotoxic chemicals, we consider the state of the science in developmental neurotoxicity as a whole. Only 12 chemicals have been tested and reviewed for effects on brain development according to EPA's current guidelines, (so far as can be determined from all publicly available information). Extensive data is available on the effects of lead, mercury, PCBs, a few pesticides, alcohol, and nicotine. Studies of these substances provide important insights into mechanisms and impacts of neurodevelopmental toxicants. Though these data continue to expand, most potentially neurotoxic compounds remain inadequately studied, despite widespread exposures. Regulatory agencies fail to require systematic developmental neurotoxicity testing of additional compounds so that we remain ignorant of their potential impacts. Research funding continues to flow to studies of compounds known to be likely to cause adverse effects. As a result, we have a large amount of data on a few compounds and virtually none on most. We will, however, use the data from the well-studied compounds to illustrate the diverse impacts that neurotoxic compounds can have on the developing brain and make the case that more data are needed on a wide variety of substances.

REPORTED HARM DECLINING THRESHOLD OF HARM - LEAD 100 REPORTED HARM We’ll start with lead, the first, and perhaps best-understood example of a common chemical that harms learning and behavior. Because lead was one of the first pollutants recognized as harmful to a child’s brain, its well-documented, long history provides a useful case study in the science of toxicology, and in the political context of regulation. This history of lead tragically illustrates that the scientific understanding of neurodevelopmental toxicity emerges very slowly. The understanding of lead has advanced over the period of a full century, during which time the recognized “toxic threshold,” (the lowest exposure thought to be harmful), has relentlessly declined. While very high lead exposures were recognized to cause encephalopathy, coma, and death in children as early as 1900,(1,2) residual effects in survivors of childhood lead poisoning went unrecognized for decades. The enduring effects of lead poisoning on child development became apparent only with the publication of longer follow-up observations in the 1940s, which noted persistent impairments in intellect, behavior, and sensory-motor function. (3) Subsequent studies began to suggest that lower levels of lead exposure might be associated with neurological damage as well.(4) A specific toxic threshold for lead was established for the first time in the 1960s. At that time a toxic blood lead level was set at 60 micrograms/dl, only modestly below the level at which encephalopathy occurs (80 micrograms/dl).(5) With improvements in study design over the next 30 years, research revealed effects of lead on IQ at progressively lower levels of exposure.(6) After repeated downward revisions, the toxic threshold for lead was most recently set at 10 micrograms /dl, the “official” 1990 standard that still holds today. Subsequent analyses have quantified the risk of low-level lead exposure, estimating that an increase in blood lead from 10 to 20 micrograms /dl is associated with an average IQ loss of 2-3 points.(7,8) Recent epidemiologic studies suggest that there is no threshold below which lead exposure is without harmful effects, (9,10,11,12) and that for a given increment in blood lead, the associated impact on IQ is greater below a blood level of 10 micrograms/dl than above.(13) The fact that adverse effects from lead exposure are apparent well below the toxic threshold of 10 micrograms/dl is no surprise, considering that this currently recognized limit of “safe” exposure is nearly 13% of the blood lead concentration associated with encephalopathy, and 8% of the lethal blood lead level. Indeed, it would be surprising if some neurological harm were not occurring a mere one order of magnitude below the lethal exposure level. The growing profile of developmental impacts from low-level lead exposure is of substantial concern, considering that 4% of all American children (14) and as many as 36% of inner city African American children (15) exceed even the current, increasingly obsolete toxic threshold of 10 micrograms/dl. 1. Needleman HL. The future challenge of lead toxicity. Environ Health Perspect Nov 89:85-89, 1990. 2. Needleman HL. The development of understanding of the extent and nature of lead toxicity in children. Presented at the 17th International Neurotoxicology Conference, Little Rock, AK, Oct 17-20, 1999. 3. WHO. Inorganic Lead. Environmental Health Criteria 165. Geneva, 1995, p. 153. 4. WHO, Ibid. pp 153-154. 5. Needleman HL. The persistent threat of lead: medical and sociological issues. Curr Probl Pediatr Dec 18(12):697-744, 1988. 6. Needleman HL. The future challenge of lead toxicity. Environ Health Perspect Nov 89:85-89, 1990. 7. Schwartz, J. Low-level lead exposure and children’s IQ: a meta-analysis and search for a threshold. Environ Res 65: 42-55, 1994. 8. IPCS. Environmental Health Criteria 165: Inorganic lead. International Programme on Chemical Safety. Geneva, WHO, 1995. 9. Lanphear BP, Dietrich K, Auinger P, Cox C, Subclinical Lead Toxicity in U.S. Children and Adolescents, Pediatric Research 47: May 2000, p. 152A. 10. Schwartz J, Otto D: Lead and minor hearing impairment. Arch Environ Health Sep-Oct 46(5):300-5, 1991. 11. Lanphear, B: Adverse Neurobehavioral effects of blood lead levels below 10 micrograms/dl. Presented at the 17th International Neurotoxicology Conference, Little Rock, AK, Oct 17-20, 1999. 12. Rice DC: Developmental lead exposure: neurobehavioral consequences. In Slikker W. and Chang LW (eds): Handbook of Developmental Neurotoxicology. San Diego, CA: Academic Press, 1998, pp 553. 13. Canfield R. Did we miss the boat? Cognitive deficits in children with blood-lead levels below 10ug/dl. Children’s Health and the Environment 2000. The 18th International Neurotoxicology Conference. Colorado Springs, CO, Oct. 2000. 14. U.S. Environmental Protection Agency, Office of Children's Health Protection, Office of Policy, Economics and Innovation, National Center for Environmental Economics. America's children and the environment: A first view of available measures. EPA 240-R-00-006, Dec 2000. 15. Centers for Disease Control: Performance Plan, Lead Poisoning cdc.gov/od/perfplan/ppzk01.pdf, p 119. 2/03/00. 10 EXPOSURE – blood lead, ug/dl 1 0.1 1960 1970 1980 1990 2000 YEAR REPORTED Note: Exposures expressed in micrograms/deciliter (blood lead)

The Significance of Small Effects: EFFECTS OF A SMALL SHIFT IN IQ DISTRIBUTION IN A POPULATION OF 260 MILLION mean 100 6.0 million 6.0 million The effect of low lead exposures on IQ is relatively small for the average individual, reducing IQ by only a few points. It’s important to remember, however, that impacts that are marginal for the average individual can have profound effects when applied over large populations, in effect, shifting the population distribution curve for the parameter of concern. That parameter might be IQ, as in this case, or any other cognitive or behavioral function such as memory or attention. Such shifts have dramatic effects at the high and low ends of the distribution curve, often referred to as the “tails.” This is illustrated in a hypothetical population of 260 million with an average IQ of 100. The area under the left “tail” of the curve represents the 2.3% of the population with an IQ <70, the score used to define mental retardation. In a population of 260 million, about 6 million people would fall below this line.   Source: Weiss, B. Endocrine disruptors and sexually dimorphic behaviors; a question of heads and tails. Neurotox 18:581- 586, 1997. Graphics: adapted from above reference "mentally retarded" "gifted" 160 140 120 100 80 60 40 70 130 I.Q.

5 Point Decrease in Mean IQ 57% INCREASE IN "Mentally Retarded” Population This chart shows what happens when the average IQ is shifted by 5 points from 100 to 95. Now, 3.2% of the population, or 9.4 million people have an IQ below 70. This represents more than a 50% increase in the numbers of mentally retarded. The numbers of gifted, defined as those with IQ’s greater than 130, have declined by more than 50% from 6 million to 2.4 million. Thus a small shift in average IQ results in greatly increased need for special education and services, as well as diminished intellectual capacity within the population as a whole. Source: Weiss, B. Endocrine disruptors and sexually dimorphic behaviors; a question of heads and tails. Neurotox 18:581-586, 1997. Graphics: adapted from above reference 2.4 million 9.4 million "gifted" "mentally retarded" 160 140 120 100 80 60 40 70 130 I.Q.

Effects of Lead on Cognitive and Behavioral Traits ADHD LD OTHER hyperactivity reading, math fine motor impulsivity spelling visual motor distractibility pattern recognition aggressive dif. w. instructs word recognition antisocial conduct problems off-task executive function attention/vigilance social skills Recent studies also suggest that, in addition to undermining IQ, low-level lead exposure is associated with a wide range of adverse cognitive and behavioral effects. Many of these effects are associated with ADHD, such as hyperactivity, impulsiveness, and distractibility; others, such as impaired reading, math, and spelling skills are associated with learning disabilities. (1-8) Some of these effects have been observed at very low levels of exposure, and may occur in the absence of detectable IQ effects.(9-12) 1. Needleman HL, Reiss JA, Tobin MJ, et al. Bone lead levels and delinquent behavior. JAMA 275:363-369, 1996. 2. Thomson GO, Raab GM, Hepburn WS, et al. Blood-lead levels and children’s behaviour – results from the Edinburgh lead study. J Child Psychol Psychiatry Jul;30(4):515-528, 1989. 3. Silva PA, Hughes P, Williams S, et al. Blood lead, intelligence, reading attainment and behaviour in eleven year old children in Dunedin, New Zealand. J Child Psychol Psychiatry Jan29(1)43-52, 1988. 4. Tuthill RW. Hair lead levels related to children’s classroom attention-deficit disorder. Arch Environ Health 51:214-220, 1996. 5. Munoz H, Romiew I, Palazuelos E, et al. Blood lead level and neurobehavioral development among children living in Mexico City. Arch Environ Health May-Jun 48(3):132-139, 1993. 6. Yule W, Urbanowicz MA, et al. Teachers’ ratings of children’s behavior in relation to blood lead levels. Br. J. Dev. Psych. 2(295) . 7. Fergusson DM and Horwood. The effects of lead levels on the growth of word recognition in middle childhood. Intern J Epidemiol. 22, 891-897, 1993. 8. Yule W. The relationship between blood lead concentration, intelligence, and attainment. Dev Med Child Neurol 23, 567-576, 1981. 9. Winneke G, Kramer U, Brockhaus A, et al. Neuropsychologic studies in children with elevated tooth-lead concentrations II. Extended study. Int Arch Occup Environ Health 51(3):231-252, 1983. 10. Winneke G, Kramer U. Neuropsychological effects of lead in children: interactions with social background variables. Neuropsychobiology 11(3):195-202, 1984. 11. Silva, PA. Ibid. 12. Rice DC. Developmental lead exposure: neurobehavioral consequences. In Slikker W. and Chang LW (ed): Handbook of Developmental Neurotoxicology. San Diego, CA: Academic Press, 1998, p 544.

Association of Teacher Ratings With Student Lead Burden Class Dentine Lead (ppm) 1 <5.1 2 5.1-8.1 3 8.2-11.8 4 11.9-17.1 5 17.2-27.0 6 >27 Percent Class Distractible Nonpersistent Dependent Not Hyperactive Impulsive Organized This slide shows a dose-response relationship between lead and some ADHD-associated traits. The first graph shows data from Herbert Needleman’s 1979 cross-sectional study in which teachers evaluated student behavior in terms of distractibility, impersistence, dependence, disorganization, hyperactivity, impulsiveness, frustration, tendency to daydream, difficulty following directions, and general dysfunction. These behaviors proved to have striking correlations with lead exposure as assessed by dentine lead levels. The second graph shows comparable results from a similar study that used blood lead to assess exposure. (Blood levels range from 7 to 32 micrograms/dl; dentine levels ranged from <5.1 to >27 parts per million.) Graphics adapted from: Needleman H, et al. Deficits in psychologic and classroom performance of children with elevated dentine lead levels. NEJM 300:689-695, 1979. Yule W, et al. Teachers’ ratings of children’s behavior in relation to blood lead levels. Br J Dev Psych. 2:295, 1984. Class Blood Lead, (micrograms/dl) 1 7-10 2 11-12 3 13-16 4 17-32 Percent Class Distracted Persist Work Disorganized Hyperactive Impulsive Independent Organized

Blood lead levels in the U.S. population 1976 -1999 NHANES II, III, 99+ 18 16 14 12 10 Blood lead levels (mg/dL) 8 6 This graph shows declining gasoline lead levels in blue and the corresponding decline in children’s average blood lead levels in yellow. This represents a true, though partial, public health victory. It is an example of what we can do when we prioritize a problem and address it upstream by reformulating a product rather than trying to control releases. Today elevated blood lead levels remain a problem for a significant number of children, but the population-wide exposures resulting from air releases have been substantially reduced. 4 2 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 Year

An Overview of Mercury Wet Deposition Particulates & Vapor Combustion Dry Deposition Volcanoes Industry & Incinerators Landfills Like lead, mercury is a heavy metal that disrupts brain development. Unlike lead, however, the study of mercury effects on children is relatively young. The study of mercury’s neurodevelopmental effects began only about 50 years ago, and scientific consensus on low-dose toxicity has been achieved only in the last few years. (1,2) Mercury is usually released into the environment as a metal or an inorganic compound. Major human sources are coal-fired power plants and municipal and medical waste incinerators. Mercury released into the atmosphere often travels long distances before being deposited onto the earth’s surface. Bacteria present in sediments and water bodies convert mercury to methylmercury, which then bioaccumulates as it passes up the aquatic food chain. As a result of the growing burden of environmental mercury, certain fish including swordfish, shark, king mackeral, tileffish, fresh tuna and many freshwater fish consumed by pregnant women or women of reproductive age may pose a threat to the uniquely vulnerable fetal brain. 1. Environmental Protection Agency. Mercury Study Report to Congress: Vol I, 1997, available at: http://www.epa.gov/ttnuatw1/112nmerc/volume1.pdf. 2. National Academy of Sciences. Toxicological Effects of Methylmercury. Washington, D.C., National Academy Press, 2000. Graphics adapted from: Mercury in Massachusetts: An evaluation of sources, emissions, impacts and controls, Massachusetts Department of Environmental Protection: Office of Research and Standards, Bureau of Strategic Policy and Technology, June 1996. Farming WasteWater Releases Volatilization Ground-water Flow Runoff Pesticides Fertilizers Methylation Hg to HgCH3 Rain & Streams to Groundwater Sedimentation to Streams, lakes, vegetation, soil Bioaccumulation in Fish

Mercury Effects of Higher Dose Prenatal Exposure Mental retardation Seizures Cerebral palsy Disturbances of vision, hearing, sensation Abnormal gait Abnormal speech Disturbances of swallowing and sucking Abnormal reflexes The effects of methylmercury on the developing brain were first recognized in the tragic poisoning epidemic in Minimata Bay, Japan during the 1950s. In this episode, residents regularly consumed fish highly contaminated with methylmercury resulting from industrial discharges into the bay. Infants born to mothers who consumed the fish had a variety of neurological findings, including mental retardation and disturbances of gait, speech, sucking, swallowing, and reflexes,(1) while their mothers often showed no signs of mercury poisoning. Because methylmercury was not identified as the cause until very late in the course of the epidemic, mercury exposures were never quantified, and a toxic threshold for the effects seen at Minimata was never established. The quantitative study of methylmercury neurotoxicity began with a second major poisoning epidemic in Iraq in 1972. In this tragic incident, infants were born with severe disabilities, including mental retardation, cerebral palsy, seizures, blindness, and deafness, after their mothers consumed bread contaminated with a methylmercury fungicide. As in Minimata, many mothers of affected infants suffered minimal if any symptoms themselves. The first case reports of these severely retarded infants provided an apparent toxic threshold for mercury of greater than 34 micrograms/kilogram/day.(2,3) (This appeared to be a “no observed effect level,” or NOEL, for severe retardation at birth.) 1. Harada H. Congenital Minimata Disease: intrauterine methylmercury poisoning. Teratology 18:285- 288, 1978. 2. Amin-Zaki L, Elhassani S, Majeed MA, et al. Perinatal methylmercury poisoning in Iraq. Am J Dis Child 130, 1070-1078, 1976. 3. Amin-Zaki L, Elhassani S, Majeed MA, et al. Intra-uterine methylmercury poisoning in Iraq. Pediatrics 54(5) pp 587-595, 1974.

Mercury: Declining Threshold of Harm 0.01 0.1 1 10 100 Level associated with This graph displays the apparent toxic threshold for mercury as it was identified at various points in time over the past three decades. It illustrates the tendency for apparent toxic thresholds to decline with advancing knowledge. Exposure to mercury is shown in micrograms per kilogram per day on the vertical axis, and year is shown on the horizontal axis. The initial Iraqi toxic threshold is shown as the upper left-hand point on the graph. Within a few years of this observation, it became apparent that many children exposed prenatally to lower levels of mercury were delayed in learning to walk and talk, in spite of apparently “normal” development in infancy. (1) Subsequently, a variety of studies on diverse populations have established progressively lower thresholds for mercury effects by using increasingly sensitive exposure and outcome measures, and better statistical methods of analysis.(2-11) Recently, a large study in the Faroe islands has identified deficits in language, memory, and attention that occur at prenatal mercury exposures under 0.85 micrograms per kilogram per day. (This is the second square from the right-hand edge of the figure.) This exposure is less than 3% of the toxic threshold identified in the initial observations from the Iraqi epidemic. The presence of mercury effects below this level of 0.85 micrograms/kg/day implies that the actual threshold, if one exists, is lower. OPTIONAL ADVANCED DISCUSSION The black squares on the graph represent prenatal mercury exposures associated with adverse neurodevelopmental outcomes. The gray triangles represent World Health Organization (WHO), EPA, and Agency for Toxic Substances and Disease Registry (ATSDR) recommended limits for human mercury exposure. The standard issued by the FDA, it should be noted, regulates the level of mercury in fish, rather than in people. As a result, a wide variety of exposures may occur within the FDA regulatory limit, depending on how much and how often one eats fish, and the mercury level of the fish consumed. The indicated exposure is that of a 60 kg woman eating at the high end of fish consumption (100grams/day, the 95-97th percentile), eating fish that are contaminated at the FDA permitted limit. In this worst-case scenario, the woman is exposed to 1.65 mg/kilogram/day, or about 16.5 times EPA’s recommended safe limit. Notes: [1.] Studies of the neurodevelopmental effects of mercury generally use hair or blood levels as markers of exposure, since these are more accurate indicators of exposure than dietary surveys. Health-based guidelines, however, are expressed as recommended limits of dietary exposure. For the purpose of comparing data between studies, and for comparing effects levels with regulatory guidelines, exposures as indicated by hair and blood levels of mercury have been converted to approximate equivalent dietary exposures. The quantitative relationships between food intake hair and blood levels of mercury are described in the ATSDR Toxicological Profile for Mercury. (12) [2.] Study results that identified a range of exposures within which an effect was observed have been shown at the mid-point of that range. Due to differences in study methods, results are not strictly comparable between studies, and are shown here mainly to indicate general trends over time. 1. Marsh D. Fetal methylmercury poisoning: new data on clinical and toxicologic aspects. Trans Am Neurol Assoc 102:69-71, 1977. 2. Marsh DO, Myers GJ, Clarkson TW et al. Fetal methylmercury poisoning: clinical and toxicological data on 29 cases. Ann Neurol 7:348-353, 1980. 3. Marsh DO, Myers GJ, Clarkson TW, et al. Dose-response relationship for human fetal exposure to methylmercury. Clinical Toxicology, 18(11): 1311-1318, 1981. 4. McKeown-Eyssen GE, Ruedy J Neims A. Methyl mercury exposure in Northern Quebec II. Neurologic findings in children. Am J Epidemiol 118(4): 470-479, 1983. 5. WHO task group on environmental health criteria for methylmercury: Methylmercury, Environmental Health Criteria 101. Geneva, World Health Organization, 1990. 6. WHO Ibid. 7. Marsh DO, Clarkson TW, Cox C, et al. Fetal methylmercury poisoning. Arch Neurol 44:1017-1022, 1987. 8. Davidson PW, Myers GH, Cox C. Longitudinal neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from maternal fish ingestion: outcomes at 19 and 29 months. Neurotoxicology 16(4):677-688, 1995. 9. Grandjean P, Weihe P, White R. Cognitive Deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotox Teratol 19(6):417-428, 1997. 10. Sorensen N, Murata K, Budtz-Jorgensen, et al. Prenatal methylmercury exposure as a cardiovascular risk factor at seven years of age. Epidemiology 10(4):370-5, 1999. 11. Environmental Protection Agency. Mercury Study Report to Congress: Executive Summary, vol. I, p 3-39, 1997, available at: http://www.epa.gov/ttnuatw1/112nmerc/volume1.pdf 12. US Department of Health and Human Services, Agency for Toxic Substances and Disease Registry: Toxicologic Profile for Mercury, draft. Atlanta, 1998. harmful effect Regulatory standard (maximum safe exposure or high end exposure from allowed fish contamination) DAILY INTAKE (micrograms/kg/day Hg) FDA WHO ATSDR EPA 2000 1990 1980 1970 YEAR

Mercury Effects of Low Dose Prenatal Exposure Children with low prenatal mercury exposure Children with high prenatal mercury exposure Per cent of children with low test scores at age 7 years < 15 15-30 30-50 >50 µg/l lowest scores at age 7 years % Children with This graph shows some of the results of the Faroe Islands research. In this study, the mercury exposure of about 1000 children was evaluated prenatally and at the time of birth. Seven years later, impairments in attention, memory, and language were associated with increasing prenatal mercury exposure. (The analysis controlled for potential social, economic, medical, and toxicologic confounders.) The pale blue columns represent children in the lowest mercury exposure group. The red columns represent children in the highest mercury exposure group. The y-axis shows the percent of children in each exposure group that scored poorly (in the lowest quartile) in each cognitive category. Within each skill category, impairment increases with increasing mercury exposure. The results are particularly striking for attention, where the percent of children scoring poorly more than doubles between the lowest and highest exposure quartiles. The effects of mercury on attention, memory, and language are all significant at the p<0.05 level. Graphics adapted from: Grandjean P, Weihe P, White R et al. Cognitive Deficit in 7-yr Old Children with Prenatal Exposure to Methylmercury. Neurotoxicology and Teratology 19(6):417-428, 1997. Source: Grandjean, et. al., "Cognitive Deficit in 7-year-Old Children with Prenatal Exposure to Methylmercury", Neurotoxicology and Teratology, Vol. 19, No. 6, 1997 Figure shows prenatal mercury exposure levels of Faroese children with scores in the lowest quartile after adjustment for cofounders. For each of the five major cognitive functions, one neuropsychological test with a high psychometric validity was selected.

Mercury Exposures Advised Exposure Limit EPA Reference Dose (“safe” upper limit) – 0.1 microgram/kilogram/day Equivalent consumption limit Women: 1.5 oz. swordfish or 7 oz. tuna/week Child: 1 oz. tuna per 20 lb. body weight/week Based on extrapolations from the Iraqi study, the EPA currently defines a safe upper limit for dietary mercury exposure at 0.1 microgram per kilogram of body weight per day, a reference dose recently confirmed by the National Academy of Sciences. Exposures above this level pose increasing risks to fetal brain development. A woman of reproductive age exceeds this safe consumption limit by eating more than 1.5 ounces of swordfish or 7 ounces of tuna per week (based on average mercury concentrations of 1.0 and 0.2 microgram mercury per gram of fish, respectively). A 20 kilogram child exceeds the safe consumption limit by eating a mere half-ounce of swordfish per week, or 2.5 ounces of tuna per week. (1, 2) Note: See pages 62 – 63 of In Harm’s Way: Toxic Threats to Child Development for guidance on how to calculate safe consumption limits. 1. Environmental Protection Agency. Mercury Study Report to Congress: An Assessment of Exposure to Mercury in the United States. Vol IV, pp 155-160, 1997, available at: http://www.epa.gov/ttnuatw1/112nmerc/volume4.pdf 2. Environmental Protection Agency. Mercury Update: Impact on Fish Advisories. EPA-823-F-99-016 September 1999, available at: http://www.epa.gov/ostwater/fish/mercury.html  

Mercury Exposures Current exposures >10% of women of reproductive age exceed Reference Dose (RfD) 50% of women who eat fish exceed RfD on any given day Higher risk: Subsistence fishers, immigrants, Native Americans Biomonitoring data suggest that more than 10% of US women of reproductive age exceed the safe exposure limit. (1) An exposure assessment in New Jersey, based on dietary surveys, estimates that more than 20% of women of reproductive age exceed the limit, suggesting coastal populations may be at higher risk than suggested by the national average.(2,3) Exposure estimates specifically addressing risks to fish eaters suggest that on any given day, 50% of women of reproductive age who consume fish exceed the safe mercury exposure limit.(4) Based on a comprehensive review of relevant research, the National Academy of Sciences recently estimated that over 60,000 US children are born each year at risk for learning and other disabilities due to prenatal methylmercury exposure. (5) 1. Centers for Disease Control. Blood and hair mercury levels in young children and women of childbearing age, US 1999.Morbidity and Mortality Weekly Reports. 3/02/2001/50(08); 140-143. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5008a2.htm. 2. Stern AH, Korn LR, Ruppel BE. Estimation of fish consumption and methylmercury intake in the New Jersey population. J Expo Anal Environ Epidemiol Oct-Dec;6(4):503-525, 1996. 3. National Research Council. Toxicological Effects of Methylmercury.Washington, DC: National Academy Press. 2000. p 39. 4. Environmental Protection Agency. Mercury Study Report to Congress: Characterization of Human Health and Wildlife Risks from Mercury Exposure in the United States. Vol VII, p 6-29, 1997, available at: http://www.epa.gov/ttnuatw1/112nmerc/volume7.pdf. 5. National Research Council. op.cit. p 327.

PCBs From Factory to the Fetus AIR Dioxins PCBs: Dioxins: PCBs SOIL Dioxins and PCBs: Pathways of Exposure and Neurodevelopmental Effects AIR Dioxins PCBs: Transformers Landfills Hazardous Waste Sites Dioxins: PVC Manufacturing Medical/Municipal Incinerators PCBs SOIL WATER PCBs are a large group of fat-soluble chemicals produced from the 1920s to the late 1970s for use as lubricants and insulators in electrical equipment. Production has been banned in most of the industrialized world. However, an estimated two-thirds of the total amount produced has not yet been released to the environment.(1) Once emitted, PCBs can volatilize and travel long distances before settling on pastures and water bodies. Though PCB production has been banned in most of the industrialized world for decades, its persistence and bioaccumulation within the food chain have resulted in ubiquitous human exposures, particularly from the consumption of beef, dairy products, and fish that are relatively high in fat.(2) Because of its similar chemical properties, the pollutant dioxin is generally found along with PCBs in the food chain and in the human body. Dioxin and PCBs are passed during pregnancy from mother to fetus, and continue to be transmitted during breast feeding. Dioxin and PCBs thus illustrate one of the unforeseen pathways by which industrial chemicals may travel from the factory to the fetus. Like mercury and lead, the effects of PCBs on child development were not recognized until catastrophic epidemics drew attention to high-dose effects. These epidemics occurred in Japan and Taiwan in the early 1970s when thousands of people ingested rice oil accidentally contaminated with PCBs, as well as small amounts of other contaminants. As with other neurotoxicants, the developing fetus proved much more sensitive than the mother. Newborns who had been exposed had a variety of developmental effects, including reduced birth weight, hyperpigmentation, early tooth eruption, deformed nails, and gum hypertrophy.(3,4) In childhood, they also exhibited IQ impairment bordering on mental retardation, poor health, and increased behavior problems.(5-7) 1. DeVoogt P, Brinkman UAT. Production, properties and usage of polychlorinated biphenyls. In Kimbrough RD, Jensen A (eds): Halogenated Biphenyls, Terphenyls, Naphtalenes, Dibenzodioxins and Related Products. 2nd ed. Amsterdam:Elsevier, 1989. pp 3-46. 2. U.K. Joint Food Safety and Standards Group. 1997. Food Surveillance Information Sheet: Dioxins and Polychlorinated Biphenyls in Foods and Human Milk. Number 105. London, United Kingdom:Ministry of Agriculture, Fisheries and Food, Department of Health, Scottish Executive. Available at: http://archive.food.gov.uk/maff/archive/food/infsheet/1997/no105/105dioxi.htm 3. Kuratsune M. Yusho, with reference to Yu-Cheng. In Kimbrough RD, Jensen AA (eds): Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. 2nd ed. Amsterdam: Elsevier, 1989, pp 381-400. 4. Harada M: Intrauterine poisoning: Clinical and epidemiological studies of the problem. Bull Instit Constit Med (Kumamoto Univ.)25:1- 60, 1976. 5. Rogan WJ, Gladen BC, Hung KL, et al. Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science Jul 15;241(4863):334-6, 1988. 6. Yu ML, Hsu CC, Guo YL, et al. Disordered behavior in the early-born Taiwan Yu-Cheng children. Chemosphere 29;2413-2422, 1994. 7. Chen YC, Guo YL, Hsu CC, et al. Cognitive development of Yu-Cheng ("oil disease") children prenatally exposed to heat-degraded PCBs. JAMA Dec 9;268(22):3213-8, 1992. FOOD

PCBs Full-Scale IQ Subsequent research focused on populations with background, or near background exposures. This slide shows the effect of prenatal PCB exposure on full-scale IQ (upper chart) and reading/word comprehension among 11-year-old children in a large, prospective study in Michigan. (The y axis is the test score; the x axis is prenatal PCB exposure expressed in terms of the PCB concentration in maternal milk fat.) The most highly exposed children had IQ testing scores 6 points lower and were more than 3 times as likely to perform poorly on full-scale IQ tests, verbal comprehension, and freedom from distractibility when compared to children in the lowest exposure group. Graphics adapted from: Jacobson JL, Jacobson SW. Intellectual impairment in children exposed to PCBs in utero. NEJM 1996;335:783-789. Prenatal Exposure to Polychlorinated Biphenyls (PCBs) ug/g of fat

PCBs Reading Mastery -Word Comprehension The most highly exposed children were also more than twice as likely to be at least two years behind in reading comprehension. While mothers in this study were recruited to over-represent Lake Michigan fish-eaters, their serum and breast milk PCB levels were only slightly higher than the general population.(1) 1. Jacobson JL, Jacobson SW. Intellectual impairment in children exposed to PCBs in utero. NEJM 1996;335:783-789. Graphics adapted from above reference Prenatal Exposure to Polychlorinated Biphenyls (PCBs) ug/g of fat

PCBs: PERVASIVE DEVELOPMENTAL EFFECTS As exposure assessment has improved over the past several decades, persistent and pervasive adverse neurodevelopmental effects of prenatal PCB exposure have emerged at exposure levels typical of the general population. These effects have been demonstrated in large prospective cohort studies in the Netherlands, North Carolina, and Germany in addition to the Michigan study. In each of these studies, PCB effects were seen after controlling for large numbers of potentially confounding variables. In the newborn, the effects of low-level prenatal PCB exposure include decreased birth weight, head circumference, and gestational age, as well as motor immaturity, poor lability, and increased startle and decreased reflexes on the Brazelton Neonatal Behavioral Assessment.(1,2) 1. Fein GG, Jacobson JL, Jacobson SW, et al. Prenatal exposure to polychlorinated biphenyls: effects on birth size and gestational age. J Pediatr Aug;105(2):315-20, 1984. 2. Patandin S, Koopman-Esseboom C, de Ridder MA et al. Effects of environmental exposure to polychlorinated biphenyls and dioxins on birth size and growth in Dutch children. Pediatr Res Oct;44(4):538-45, 1998. Infant Birth weight Head circumference Gestational age Performance on Brazelton Neonatal Behavioral Assessment (BNBA) - motor immaturity, poor lability, startle

PCBs: PERVASIVE DEVELOPMENTAL EFFECTS Early Childhood Memory, attention, verbal ability, information processing Psychomotor development Sustained activity, high level play Withdrawn, depressed behavior Hyperactivity Preteen Word and reading comprehension Full scale and verbal IQ Memory and attention In infancy and early childhood, prenatal PCB exposure is associated with a variety of cognitive impairments (reduced memory and attention, decreased verbal ability, impaired information processing), developmental delays (reduced psychomotor development), and adverse behavioral and emotional effects (decreased sustained activity, decreased high-level play, increased withdrawn and depressed behavior, and increased activity level).(1-7) In preteen years, prenatal PCB exposure is associated with decreased word and reading comprehension, decreased full-scale and verbal IQ, and reduced memory and attention.(9)   1. Jacobson SW, Fein GG, Jacobson JL, et al. The effect of intrauterine PCB exposure on visual recognition memory. Child Dev Aug;56(4):853-860, 1985. 2. Jacobson JL, Jacobson SW, Humphrey HE. Effects of in utero exposure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children. J Pediatr Jan;116(1):38-45, 1990. 3. Jacobson J. Effects of prenatal PCB exp on cognitive processing efficiency and sustained attention. Dev Psychol 28:297-306, 1992. 4. Gladen BC, Rogan WJ, Hardy P, et al. Development after exposure to polychlorinated biphenyls and dichlorodiphenyl dichloroethene transplacentally and through human milk. J Pediatr Dec;113(6):991-995, 1988. 5. Rogan WJ, Gladen BC. PCBs, DDE, and child development at 18 and 24 months. Ann Epidemiol Aug;1(5):407-413, 1991. 6. Koopman-Esseboom C, Weisglas-Kuperus N, de Ridder MA, et al. Effects of polychlorinated biphenyl/dioxin exposure and feeding type on infants' mental and psychomotor development. Pediatrics May;97(5):700-6, 1996. 7. Patandin S, Lanting CI, Mulder PG, et al. Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age. J Pediatr Jan;134(1):33-41, 1999. 8. Patandin S. Effects of Environmental Exposure to PCBs and Dioxins on Growth and Development in Young Children. A Prospective Follow-Up Study of Breast-Fed and Formula–Fed Infants From Birth Until 42 Months of Age. Thesis, Rotterdam, 1999. 9. Jacobson JL, Jacobson SW. Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med Sep 12;335(11):783-9, 1996.

PCBs: Inadequate Margin of Safety BLOOD LEVELS (ppb) REPORTED 5 10 15 20 REPORTED HUMAN HEALTH EFFECTS EXPOSURES IN OFFSPRING Great Lakes fish eaters This chart illustrates the exposure levels (expressed as maternal blood PCB levels) at which these effects in children have been demonstrated. The left side of the figure shows the PCB blood levels in various populations, in which Great Lakes fish-eaters had the highest exposures. The exposures at which adverse effects have been demonstrated are indicated on the right side of the diagram, at the mid to low end of the exposure spectrum. Note: All health effects shown are associated with prenatal PCB exposure except hyperactivity which is associated with blood levels at 42 months of age. 1. Hovinga ME, Sowers M, Humphrey HE. Environmental exposure and lifestyle predictors of lead, cadmium, PCB, and DDT levels in Great Lakes fish eaters. Arch Environ Health 48(2):98-104, 1993. 2. Laden F, Neas LM, Spiegelman D, et al. Predictors of plasma concentrations of DDE and PCBs in a group of US women. EHP 107(1):75-81, 1999. 3. Schwartz PM, Jacobson SW, Fein G, et al. Lake Michigan fish consumption as a source of PCBs in human cord serum, maternal serum, and milk. AM J Public health 73(3):293-296, 1983. 4. Dar E, Kanarek MS, Anderson HA, Sonogni WC. Fish consumption and reproductive outcomes in Green Bay, Wisconsin. Environ Research 59(1):189-201, 1992. 5. Kuratsune M. Yusho, with reference to Yu-Cheng. In Kimbrough RD, Jensen AA (eds): Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins and Related Products. 2nd ed. Amsterdam: Elsevier, 1989 pp 381-400. 6. Harada M: Intrauterine poisoning: Clinical and epidemiological studies of the problem. Bull Instit Constit Med (Kumamoto Univ)25:1-60, 1976. 7. Rogan WJ, Gladen BC, Hung KL, et al: Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science Jul 15;241(4863):334-336, 1988. 8. Yu ML, Hsu CC, Guo YL, et al: Disordered behavior in the early-born Taiwan Yu-Cheng children. Chemosphere 29;2413-2422, 1994. 9. Chen YC, Guo YL, Hsu CC, et al: Cognitive development of Yu-Cheng ("oil disease") children prenatally exposed to heat- degraded PCBs. JAMA Dec 9;268(22):3213-8, 1992. 10. Fein GG, Jacobson JL, Jacobson SW, et al: Prenatal exposure to polychlorinated biphenyls: effects on birth size and gestational age. J Pediatr Aug;105(2):315-20, 1984. 11. Patandin S, Koopman-Esseboom C, de Ridder MA et al: Effects of environmental exposure to polychlorinated biphenyls and dioxins on birth size and growth in Dutch children. Pediatr Res Oct;44(4):538-545, 1998. 12. Jacobson SW, Fein GG, Jacobson JL, et al: The effect of intrauterine PCB exposure on visual recognition memory. Child Dev Aug;56(4):853-860, 1985. 13. Jacobson JL, Jacobson SW, Humphrey HE: Effects of in utero exposure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children. J Pediatr Jan;116(1):38-45, 1990. 14. Jacobson JL, Jacobson SW, Padgett R et al. Effects of prenatal PCB exposure on cognitive processing efficiency and sustained attention. Dev Psychol;28:297-306, 1992. 15. Jacobson JL, Jacobson SW: Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med Sep 12;335(11):783-9, 1996. 16. Gladen BC, Rogan WJ, Hardy P, et al: Development after exposure to polychlorinated biphenyls and dichlorodiphenyl dichloroethene transplacentally and through human milk. J Pediatr Dec;113(6):991-5, 1988. 17. Rogan WJ, Gladen BC: PCBs, DDE, and child development at 18 and 24 months. Ann Epidemiol. Aug;1(5):407-13, 1991. Koopman-Esseboom C, Weisglas-Kuperus N, de Ridder MA, et al: Effects of polychlorinated biphenyl/dioxin exposure and feeding type on infants' mental and psychomotor development. Pediatrics May,97(5):700-706, 1996. 18. Patandin S, Lanting CI, Mulder PG, et al: Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age. J Pediatr Jan;134(1):33-41, 1999. 19. Patandin Svati. Effects of Environmental Exposure to PCBs and Dioxins on Growth and Development in Young Children. A Prospective Follow-Up Study of Breast-Fed and Formula–Fed Infants From Birth Until 42 Months of Age. Thesis, Rotterdam, 1999. 20. Koopman-Esseboom C, Morse DC, Weisglas-Kuperus N, et al: Effects of Dioxins and PCBs on Thyroid Hormone Status of Pregnant Women and their Infants. Pediatr Res36:468-473, 1994. Great Lakes non-fish eaters Midwest and Decreased reflexes, memory, IQ, attention, & visual discrimination Northeast US women Michigan mothers North Carolina mothers Decreased attention, cognitive ability, high level play, & psychomotor development; Increased withdrawn/depressed, increased hyperactivity. Wisconsin women Dutch mothers

PCB Effects on Thyroid Hormone PCBs PCB Effects on Thyroid Hormone Altered thyroid hormone Mothers: Thyroid Hormone, Thyroid Stimulating Hormone (TSH) Infants: Thyroid Hormone, TSH Seals and Rats: Thyroid Hormone Developmental Implications Elevated maternal TSH during pregnancy, with or without reductions of thyroid hormone, associated with reduced IQ at age 7-9 yrs. A variety of data indicates that maternal PCBs also alter thyroid hormone status in mothers and infants. Animal data shows that PCBs reduce thyroid hormone in seals and in rat pups.(1) In humans, higher levels of maternal PCBs are associated with small but significant reductions in total thyroid hormone in both mothers and infants, as well as higher levels of thyroid stimulating hormone (TSH) in infants.(2) While these levels remain within normal limits, the changes are statistically significant. Thyroid hormone is critical to brain development, and even transient decreases in thyroxin in the central nervous system during critical developmental periods may alter neuronal branching and brain architecture. Recent research shows that elevated maternal TSH levels during pregnancy, with or without reductions of thyroid hormone, are associated with reduced IQ in offspring years later. (3) These observations suggest that the adverse developmental effects of PCBs may be at least partly mediated through impacts on thyroid hormone. OPTIONAL DISCUSSION: Details on Alteration of Thyroid Hormone (1) Seals: ¯ TT4, FT4, TT3 after in utero and lactational exposure Rats: ¯ TT4, FT4 after in utero, lactational exposure Humans: ¯ maternal T3,T4, ¯ infant T4, ­ infant TSH (human, WNL) 1. Jenssen BM. An overview of exposure to, and effects of, petroleum oil and organochlorine pollution in grey seals (Halichoerus grypus). Sci Total Environ 16;186(1-2):109-18, 1996. 2. Koopman-Esseboom C, Morse DC, Weisglas-Kuperus N, et al: Effects of dioxins and PCBs on thyroid hormone status of pregnant women and their infants. Pediatr Res 36:468-473, 1994. 3. Haddow JE, Palomaki GE, Allan WC, et al: Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med Aug 19;341(8):549-55, 1999.

PCB Neurodevelopmental Effects: Possible Mechanisms PCBs PCB Neurodevelopmental Effects: Possible Mechanisms Altered neurotransmitter levels Ah receptor mediated effects (dioxin-like PCBs) Disruption of production of growth factors and hormones including enzyme induction, modulation of growth factors, hormones Interference with thyroid hormone ­metabolism through enzyme induction interference with thyroid-hormone-mediated gene transcription displacement of thyroxin from carrier protein Optional Advanced Slide and Discussion: There are several possible mechanisms by which PCBs may interfere with neurodevelopment. PCBs alter levels of neurotransmitters, such as dopamine. The nature of the change depends on the particular PCB involved. (1,2) (There are 209 different kinds of PCBs, technically referred to as different “congeners”.) Some PCBs are similar in structure to the extremely potent, toxic compound, dioxin. Dioxin-like PCBs (co-planar PCBs) attach to the same receptor that mediates dioxin effects, the Ah receptor. The Ah-PCB complex passes into the cell nucleus where it binds to DNA, influencing the production and metabolism of a variety of growth factors, hormones, and hormone receptors. PCBs may interfere with thyroid hormone through a number of mechanisms including increasing metabolism through enzyme induction, interfering with thyroid hormone mediated gene transcription, and possibly by displacing thyroxin from a carrier protein. 1. Tilson HA. Neurochemical effects of PCBs-an overview. Neurotoxicol 18(3):727-744, 1997. 2. Seegal RF, Brosch KO, Okoniewski RJ. Effects of in utero and lactational exposure of the laboratory rat to 2,4,2’4’, and 3,4,3’4’-tetrachlorobiphenyl on dopamine function. Toxicol Appl Pharmacol 146(1):95-103, 1997. 3. Sewall CH, Flagler N, Vanden Heuvel JP, et al. Alterations in thyroid function in female Sprague-Dawley rats following chronic treatment with 2,3,7,8 TCDD. Toxicol Appl Pharmacol 132(2):237-244, 1995. 4. Zoeller RT. Effects of developmental exposure to PCBs on thyroid hormone action in the developing brain are not consistent with effects on circulating thyroid hormone. Abstract: Children’s Health and the Environment: Mechanisms and Consequences of Developmental Neurotoxicology. Little Rock AR, Oct 1999.

Organohalogen Compounds in Breast Milk in Sweden PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; PBDE, polybromonated diphenylether; TEQ, toxic equiv. Polybrominated diphenylethers (PBDE) are a family of flame retardants used in large numbers of consumer products including clothing, upholstery, and electronic equipment like televisions and computers. Chemically, PBDEs are structurally similar to PCBs. Like PCBs, some congeners are more toxic than others.Animal testing shows that impacts of PBDEs on the developing brain are similar to those of PCBs. In rodents, for example, single low-level exposures on day 10 of life lead to permanent hyperactivity and memory and learning impairment. PBDEs interfere with normal thyroid hormone function and alter neurotransmitter receptor levels in the brain. This slide shows trends of breast milk contamination with PCBs and dioxin and PBDEs in Sweden over 30 years. While PCB/dioxin levels are slowly dropping, PBDE levels have been rising at a rapid rate. In the late 1990’s Sweden enacted regulatory controls, including manufacturing restrictions on PBDEs, based on these observations. This regulatory action probably explains the initial decline in breast milk levels beginning at that time. Graphic: Adapted from Norén K and Meironyté D, 1998; Guvenius DM and Norén K, 2001 Ref: Darnerud PO, Eriksen GS, Johannesson T, Larsen PB, Viluksela M. Polybrominated diphenyl ethers: occurrence, dietary exposure, and toxicology. Environ Health Perspect 109 Suppl 1:49-68, 2001.

PBDE Levels in Humans Year This slide shows changes in PBDE levels in fat tissue in surgical specimens from several different countries. In the US, no regulatory controls have been put in place, and PBDE levels in adipose tissue in women in the Bay Area of California are substantially higher than in other countries. Whether or not these exposures are having any effect on the developing brain of children is unknown since, unlike for PCBs, no human neurotoxicity data are available. However, the observations raise interesting questions about when regulatory controls should be put in place. When the increasing exposure trend is identified? When health impacts are proven beyond doubt? Year PBDE, polybrominated diphenylethers. (She et al., 2001)

Pesticides Pesticides Physical, chemical or biological agent intended to kill an undesirable plant/animal pest Major classes: insecticides, fungicides, herbicides Most pesticides are synthetic agents new to humans and the environment Developed since 1940’s 891 pesticidal “active ingredients” licensed by US EPA* 523 used on food or feed Inherent toxicity 140 pesticides currently considered neurotoxic by EPA We next examine the links between pesticide exposures and neurodevelopmental disabilities. Definition: Pesticides are defined as any physical, chemical or biological agent intended to kill an undesirable plant or animal pest. Insecticides, fungicides and herbicides are the major classes of pesticides Most pesticides are relatively new, synthetic substances. Currently, there are 891 US EPA-licensed pesticidal active ingredients, including 523 licensed for use on food or animal feed. * (Other estimates put the number of active ingredients at closer to 1100, but it is difficult to determine exactly from the public EPA database.) (1) Pesticides have inherent toxicity in that they are intended to harm living organisms. Many are designed to poison the nervous system of target organisms.(2) EPA currently considers about 140 pesticides to be neurotoxic.(1) Since the nervous system of the insect is not unlike that of a mammal (3), the emerging human neurotoxicity of pesticides comes as no surprise. 1. Federal Register. 64(151):2945-42947, 1999. 2. Ecobichon, D. Toxic Effects of Pesticides. In Klaassen C. (ed) Casarett & Doull’s Toxicology: The Basic Science of Poisons, 5th ed, McGraw-Hill, 1996, p. 643. 3. O’Brien RD. Toxic Phosphorus Esters, Chemistry, Metabolism and Biological Effects. New York: Academic, 1960. * 1999 estimates

Acute, High Dose Toxicity Pesticides Acute, High Dose Toxicity US Poison Control (2000) 11,000 unintentional organophosphate (OP) exposures; 3000 treated in health care facility includes 4000 children < 6 yr World Health Organization 3 million acute, severe poisonings/yr 220,000 deaths/yr Many studies document substantial acute toxicity in humans from high-dose pesticide exposures. In 2000, US poison control centers received reports of over 11,000 unintentional exposures to organophosphate pesticides alone.(1) Among these, over 3000 people were treated in health care facilities, and 4000 involved children under 6 years of age. Globally, the World Health organization reports 3 million acute, severe pesticide poisonings, with as many or more cases unreported, and approximately 220,000 deaths annually.(2) 1. Litovitz, et al. 2000 American Association of Poison Control Centers Annual Report. The American Journal of Emergency Medicine, 19(5):337-395, 2001. 2. Ecobichon, D. Toxic Effects of Pesticides. In Klaassen C. (ed) Casarett & Doull’s Toxicology: The Basic Science of Poisons, 5th ed, McGraw-Hill, 1996, p. 643.

Acute Toxicity: Tip of the Iceberg? Pesticides Acute Toxicity: Tip of the Iceberg? Limits of acute poisoning data Incomplete coverage of U.S. population Unreported incidents Long term impacts of acute/high level exposures Limits of pesticide toxicity data Few studies of impact of chronic/low-dose exposures Few developmental/neurodevelopment studies State of evidence: Analagous, perhaps, to what was known about lead toxicity in early 1900s? While documentation of acute toxicity from high-dose pesticide exposures is substantial, there are important limits to these data: Poison Control Centers in the U.S. cover only about 80% of the population; Unreported incidents of unintentional exposures, of course, are not included or estimated; Estimates of acute poisoning do not reflect the potential for longer-term sequelae. Relative to toxicants examined earlier, there is little information on the long term or developmental effects of pesticide exposures, or effects from low-dose exposures. Neurodevelopmental impacts are particularly poorly studied and understood, which is perhaps surprising given the number of pesticides considered neurotoxic. The state of pesticide research might be compared to that of lead in the early 1900s, when acute toxicity had been noted, but long term effects were not yet described, and therefore were unrecognized. From the pesticide toxicity data that does exist, however -- much of it from animal toxicity studies -- there is ample cause for concern.

Background Pesticide Exposures Widespread Pesticides Background Pesticide Exposures Widespread While the high number of acute pesticide poisonings is worrisome, so too is the pervasive nature of background exposures. In a nine-month study of 238 families in Missouri in 1989, 98% of families used pesticides at least once per year. More than 80% used pesticides during pregnancy and 70% used them during the first 6 months of a child’s life. Most common uses were for pest control in the home (80%), herbicides for weed control in the yard (57%) and insecticide use for flea and tick control on pets (50%). (1) Limited biomonitoring data confirm that population background exposures are nearly universal. Urine samples collected from over 1000 adults as part of the NHANES II, the National Health and Nutrition Examination Survey II (1994), showed residues of chlorpyrifos (Dursban) in 82%, pentachlorophenol in 64%, lindane in 20% and 2,4-D in 12%. Over half of individuals tested had six or more pesticide residue in their urine. Limited data show child exposures to be even higher. The Minnesota Children’s Exposure Study (2000) found measurable residues of the chlorpyrifos metabolite, TCP, in 92% of 89 tested children. Mean urinary TCP levels were nearly four times higher than the mean adult value found in the NHANES III study. (2,3) Data on the presence of pesticides in food and the environment also indicate the potential for widespread exposure: Dust – Has often been found to contain a larger number and higher concentrations of pesticidal chemicals, than air, soil and food. Dust ingestion is estimated to account for 70% of infant pesticide exposure, and a major portion of toddler exposure.(4,5,6) Food – USDA found that about 72% of fruits and vegetables have detectable pesticide residues, with the majority of samples having more than one pesticide residue. Though most of these residues are within regulatory tolerance limits, it’s important to remember that with few exceptions, these tolerances are not based on neurodevelopmental endpoints. (7) In Homes – EPA’s Non Occupational Pesticide Exposure Study found most homes contained 3-9 pesticide residues, including pesticides that had been banned years before.(6,8) Air – Indoor air pesticide levels are 10-100X higher than outdoor air.(8) Drinking water – The supply for 14 million people in the Midwest is contaminated with triazine herbicides used in corn & soy fields, which are very persistent in ground water. A study of 144 drinking water systems in Ohio showed at least one triazine herbicide in each system. Some water systems contained up to five different herbicides. Groundwater on Long Island NY is contaminated with aldicarb, a carbamate insecticide. In general, surface water is more contaminated than ground water.(9,10,11) Water – USGS study from 1992-1996 showed more than 90% of water and fish samples from streams, and 50% of well water samples contained one, or more often, several pesticides.(12) 1. Davis, JR et al. Family pesticide use in the home, garden, orchard and yard. Arch Environ Contam Toxicol Apr;22(3):260-6, 1992. 2. Hill RH, Head SL, Baker S, et al. Pesticide residues in urine of adults living in the US: Reference range concentrations Environ Res 71:99-108, 1995. 3. Environmental Protection Agency, Memorandum, HED Preliminary Risk Assessment for the Registration Eligibility (RED) Document, Office of Prevention, Pesticides and Toxic Substances, Washington, DC, 10/18/99, p. 4. 4. Whitmore RW et al. Nonoccupational exposures to pesticides for residents of two US cities. Arch Environ Contam Toxicol 26: 1-13, 1993. 5. Fenske RA et al. Potential exposure and health risks of infants following indoor residential pesticide applications. Am J Public H 80: 689-693, 1990. 6. Simcox JN et al. Pesticides in household dust and soil: Exposure pathways for children of agricultural families. Environ Health Perspect 103:1126-1134, 1995. 7. USDA. Pesticide Data Program Progress Report. Washington DC, February, 1998. 8. Environmental Protection Agency. Nonoccupational Pesticide Exposure Study (NOPES) Final Report. EPA/600/3-90/003. Office of Research and Development 1/90. 9. Wargo J. Our Children’s Toxic Legacy. New Haven, CT. Yale University Press, 1996. 10. Schettler et al. Generations at Risk. MIT Press, 1998. p. 112. 11. Ohio EPA. Pesticide Special Study. http://www.epa.ohio.gov/ddagw/pestspst.html. 12. U.S. Geological Survey, 1999, The Quality of Our Nation's Waters-- Nutrients and Pesticides: U.S. Geological Survey Circular 1225, 82 p. available at: http://water.usgs.gov/pubs/circ/circ1225/ Reported use: 98% of families, 80% during pregnancy In Humans - detectable chlorpyrifos metabolites in 92% of children’s, 82% of adults’ urine samples In Food - detectable residues of at least one pesticide on 72% fruits/vegetables In Homes – 3 to 9 pesticide residues in typical home with 70% infant exposure from dust In Air - indoor air levels 10-100X higher than outdoor air In Water - >90% stream samples, 50% of wells

Agricultural Health Study Pesticides Rural Exposures: Agricultural Health Study Exposures to farmers and families of farmer pesticide applicators: 27% of applicators store pesticides in their home 94% of clothing worn for pesticide work is washed in the same machine as other laundry 40% of wives of applicators also mixed or applied pesticides Over 50% of children aged 11 or more do farm chores In 1994, the National Institutes of Health began the first large-scale study of pesticide applicators and their spouses. Over 89,000 individuals are participating in this Agricultural Health Study. The goals are to investigate the effects of environmental, occupational, dietary and genetic factors on the health of the agricultural population. Important findings about pesticide exposures have emerged indicating that take-home exposures from occupations may be subjecting pregnant women and children to pesticides, including known neurodevelopmental toxins. Gladen BC, Sandler DP, Zahm SH, Kamel F, Rowland AS, Alavanja MCR. Exposure opportunities of families of farmer pesticide applicators. American Journal of Industrial Medicine. Volume 34, Issue 6, 1998. Pages: 581-587 The Agricultural Health Study information can be found at http://www.aghealth.org

Prenatal Exposures: The Urban Environment Pesticides Prenatal Exposures: The Urban Environment Meconium assays in 20 newborns (Whyatt 2001): diethylphosphate (DEP); diethylthio-phosphate (DETP) Metabolites of chlorpyrifos, diazinon, parathion, organophosphate (OP) insecticides Detections: DEP in 19/20 (95%) of samples (range 0.8-3.2 ug/g) DETP in 20/20 (range 2.0-5.6 ug/g) In animal toxicity tests, chlorpyrifos, diazinon linked to adverse neurodevelopmental effects. A study of pesticide metabolite residues in the meconium (first stool) of newborns shows virtually universal exposure to organophosphates during in utero development. These data are particularly important since animal studies lead to the prediction that the human brain is likely to be particularly susceptible to impairment from organophosphate exposures during the third trimester of pregnancy.(1,2) In the rodent studies, single doses of an organophosphate pesticide on day 10 of life caused permanent changes in brain structure and resulted in hyperactivity and learning problems in the animals as adults. Developmental processes in the rodent brain on day 10 of life are comparable to those in the human fetal brain during the third trimester of pregnancy.(2) 1. Whyatt RM, Barr DB. Measurement of organophosphate metabolites in postpartum meconium as a potential biomarker of prenatal exposure: a validation study. Environ Health Perspect 2001 Apr;109(4):417-20 2. Ahlbom J, Fredriksson A, Eriksson P. Exposure to an organophosphate (DFP) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice.  Brain Res 677:13-19, 1995.

Minnesota Children's Pesticide Exposure Study Pesticides Minnesota Children's Pesticide Exposure Study Urinary metabolites in 90 urban and non-urban Minnesota children, 3-13 yrs old (Adgate 2001): Metabolite Parent Pesticides 3,5,6-trichloro-2-pyrifinol (TCPy) chlorpyrifos & related cmpds 1-naphthol (NAP) carbaryl or napthalene malathion dicarboxylic acid (MDA) malathion Detections in first-morning-void samples TCPy 93% 1-NAP 45% MDA 37% The 1997 Minnesota Children's Pesticide Exposure Study was the first biomonitoring study to examine evidence for exposure to pesticides in a representative sample of 102 children, 3-13 years old. (1). Biomonitoring was for urinary metabolites of commonly used insecticides and herbicides: chlorpyrifos and related compounds (TCPy), carbamates and related compounds (1-NAP), malathion (MDA), and atrazine (AM). Metabolite levels did not vary by sex, age, race, household income, or reported level of household pesticide use. Average TCPy levels were significantly higher in urban than in nonurban children (7.2 vs. 4.7 µg/L; p= 0.036). Levels of 1-NAP were lower than reported adult reference range concentrations, (2,3) whereas TCPy concentrations were substantially higher. Concentrations of MDA were detected more frequently and found at higher levels in children than in a recent sample of adults.(3) Overall, Minnesota children's TCPy and MDA levels were higher than in recent population-based studies of adults in the United States.(2,3) 1. Adgate JL et al. Measurement of Children's Exposure to Pesticides: Analysis of Urinary Metabolite Levels in a Probability-Based Sample. Environ Health Perspect (2001); 109:583-590. Online at http://ehpnet1.niehs.nih.gov/docs/2001/109p583-590adgate/abstract.html. 2. Results of the National Health and Nutrition Examination Survey III (NHANES III), which comprised a probability-based cross-sectional sample of 1,000 adults from 1988-94. See Hill R J, Head SL, Baker S, Gregg M, Shealy DB, Bailey SL, Williams CC, Sampson EJ, Needham LL. Pesticide residues in urine of adults living in the United States: reference range concentrations. Environ Res (1995); 71:99-106. 3. Results from a 1995 convenience survey of 80 adults in Maryland, as part of the National Human Exposure Assessment Survey (NHEXAS-MD)see MacIntosh DL, Needham LL, Hammerstrom KA, Ryan PB. A longitudinal investigation of selected pesticide metabolites in urine. J Expo Anal Environ Epidemiol (1999); 9:494-501.

Insecticide Sites of Action Organochlorines Pyrethroids Enzymes Axonal Membranes Ions (Na+, K+, Ca++, Cl-) Organophosphorus and Carbamate Esters Enzymes Neurotransmitters Optional Slide and Text for Advanced Discussion This illustration shows the target sites of the 4 main classes of neurotoxic insecticides. These targets are part of the same basic neuron “floor plan” shared by insects and mammals, including humans. Organophosphates (OPs) and carbamates inhibit acetylcholinesterase, an enzyme that regulates neurotransmitter levels at the synapse. Organochlorines and pyrethroids interfere with impulse transmission along the axon. 1. Ecobichon, D. Toxic Effects of Pesticides. In Klaassen C. (ed) Casarett & Doull’s Toxicology: The Basic Science of Poisons 5th ed, McGraw-Hill, 1996, p. 648. 2. O’Brien Rd. Toxic Phosphorus Esters, Chemistry, Metabolism and Biological Effects. NY, Academic, 1960. Graphics adapted from: Casarett and Doull’s Toxicology: The Basic Science of Poisons, 5th ed, ED: Klaassen, CD. McGraw Hill, New York, 1996. Figure 22-4. Potential sites of action of classes of insecticides on the axon and the terminal portions of the nerve. Casarett and Doull’s Toxicology: The Basic Science of Poisons, 5th Edition, Ed: Klaassen, CD. McGraw-Hill, New York, 1996. P. 649

Example of Pesticide Mechanism: Organophosphate (OP) Blocks function of cholinesterase Increases levels of acetylcholine, an important neurotransmitter Effecting: *Nerve impulse transmission *Brain growth and development The next series of slides details the effects and mechanism of action of one class of insecticides, the organophosphates. Organophosphates (OPs) have been widely used for pest control in the home, on lawns and gardens, and on crops. OPs kill insects by blocking the function of an important enzyme, acetylcholinesterase. This interferes with the metabolism of acetylcholine, (ACh), a neurotransmitter found in the human brain, as well as throughout the animal kingdom (including insects). As a result of this interference, levels of ACh build up in the brain. Since ACh is a neurotransmitter, this alters the transmission of nerve impulses. In the developing brain, ACh also acts as a morphogen, a substance that guides the growth of brain cells.(1,2) Therefore, altering the levels of ACh in the growing brain also interferes with the development of cellular architecture, causing permanent structural abnormalities. 1. Slotkin TA. Developmental cholinotoxicants: nicotine and chlorpyrifos. Environ Health Perspect 107 (suppl 1):71-80, 1999. 2. Das KP, Barone S Jr. Neuronal differentiation in PC12 cells is inhibited by chlorpyrifos and its metabolites: is acetylcholinesterase inhibition the site of action? Toxicol Appl Pharmacol 160(3):217-230, 1999.

Normal Functions of Acetylcholine & Acetylcholinesterase ACh Choline AChE + Acetate Transmits nerve impulse across synapse Morphogen in developing brain affecting: cell division differentiation Neurite growth synaptogenesis apoptosis Optional Slide and Text For Advanced Discussion: Organophosphates (OPs) act by inhibiting the enzyme acetylcholinesterase, (AChE) which normally breaks ACh down into choline and acetate. In the developing brain, ACh and AChE not only affect the transmission of nerve impulses, they also affect the growth and development of the brain (they are morphogenic). Normally, acetylcholine influences cell division, differentiation,(1) and synapse formation. (2) AChE induces neurite outgrowths.(3) 1. Slotkin TA. Developmental cholinotoxicants: nicotine and chlorpyrifos. Environ Health Perspect 107 (suppl 1):71-80, 1999. 2. Das KP, Barone S Jr. Neuronal differentiation in PC12 cells is inhibited by chlorpyrifos and its metabolites: is acetylcholinesterase inhibition the site of action? Toxicol Appl Pharmacol 160(3):217- 230, 1999. 3. Bigbee J, Sharma K, Gupta J, Dupree J. Morphogenic role for acetylcholinesterase in axonal outgrowth during neural development. Environ Health Perspect 107(suppl 1):71-80, 1999.

Organophosphate Pesticides (OP) Mechanisms of Toxicity 1. Normal: ACh Choline + Acetate AChE 2. With OP pesticide: ACh Choline + Acetate OP - AChE Optional Slide and Text For Advanced Discussion: When an organophosphate (OP) binds to acetylcholinesterase (AChE), the enzyme is inhibited, and acetylcholine (ACh) levels increase. At high OP exposures, marked increases in ACh cause multiple effects associated with acute OP poisoning. The full expression of this syndrome includes nausea, vomiting, excessive secretions, bronchospasm, respiratory distress, cardiovascular instability, and muscular paralysis. Carbamate insecticides, also commonly used in agriculture and in the home and garden, interfere with acetylcholinesterase activity as well, though the mechanism is somewhat different than that of organophosphates.

Disruption of ACh & AChE Function by Dursban ACh Choline + Acetate Dursban-AChE Transmission of nerve impulses Altered morphogenesis Cell division Differentiation Neurite growth Synaptogenesis Apoptosis Optional Slide and Text For Advanced Discussion: At much lower exposures, including doses at which there are no clinical symptoms, organophosphates (OPs) have a number of important effects on the developing nervous system. Because ACh guides the growth of developing neurons, even transient alterations in the levels of ACh may undermine the development of brain architecture.(1) Because AChE itself is a morphogen, the action of OPs (in binding AChE) also interferes with neurite growth.(2) In the case of chlorpyrifos (Dursban), until recently one of the most heavily used OPs, the OP itself impairs DNA synthesis, independently of its cholinergic effects. This effect of Dursban has been found to occur at levels of exposure that approximate those occurring in young children under some home conditions.(3,4,5) 1. Lauder JM, Schambra UB. Morphogenetic roles of acetylcholine. Environ Health Perspect 107 (Suppl 1):65-69, 1999. 2. Bigbee J, Sharma K, Gupta J, Dupree J. Morphogenic role for acetylcholinesterase in axonal outgrowth during neural development. Environ Health Perspect 107(suppl 1):71-80, 1999. 3. Campbell CG, Seidler FJ, Slotkin TA. Chlorpyrifos interferes with cell development in rat brain regions. Brain Res Bull 43:179-189, 1998. 4. Whitney KD, Seidler FJ, Slotkin TA. Developmental neurotoxicity of chlorpyrifos: cellular mechanisms. Toxicol Appl Pharmacol 13:53-62, 1995. 5. Guranathan S, Robson M, Freeman N et al. Accumulation of chlorpyrifos on residential surfaces and toys accessible to children. Environ Health Perspect 106:9-16., 1998. Noncholinergic Dursban effects: DNA synthesis, interfering with cell signaling cascades (cholinergic and noncholinergic cells)

Organophosphate Pesticide (OP) Effects in Laboratory Animals OP Cellular effect Behavior DFP muscarinic cholinergic hyperactivity receptors in brain at 4 mos. of age Dursban muscarinic cholinergic altered reflexes receptors in brain righting cliff avoidance brain weight auditory startle Diazinon delayed reflexes contact placing All low dose (<7 mg/kg/day) coordination Early developmental exposure endurance Developmental exposures to very small quantities of OP pesticides have been shown to adversely affect animal behavior, in toxicity studies conducted in laboratory animals. These studies involved small exposures ( < 7mg/kg/day) during gestation or early infancy in rodents. A variety of adverse effects were found in exposed animals including: hyperactivity; impairment of basic reflexes, such as the righting reflex and auditory startle; and impaired coordination and endurance. While the laboratory animals received doses that are orders of magnitude higher than typical human exposures, the behaviors evaluated are likely to be orders of magnitude less sensitive than the cognitive and behavioral effects of concern in children (as suggested by our experience with other, better studied, developmental neurotoxicants). Note: Below are the dosages associated with the observed effects noted in the slide. OP cellular effect behavior DFP muscarinic cholinergic hyperactivity 1.5 mg/kg, receptors in brain at 4 mos. of age PN d. 10 Dursban muscarinic cholinergic altered reflexes 6.25 mg/kg/d receptors in brain righting X 5 d gestation cliff avoidance 5 mg/kg/d d.6 brain weight auditory startle gestation-PN d. 11 Diazinon 0.18 mg/kg/d delayed reflexes through pregnancy contact placing coordination endurance

New Risk Assessments Raise Concerns Pesticides New Risk Assessments Raise Concerns Concerns raised by EPA risk assessments of individual OPs, resulting in: Dursban – over the counter sales banned Diazinon – banned indoors, phase out 4 yrs EPA assessment of cumulative OP risks: Only cumulative impact on cholinesterase inhibition considered No developmental neurotoxicity testing available for most of the 35 registered OPs Concern about unrecognized harm from pesticides is supported by the few risk assessments of individual pesticides that EPA has updated since 1996 (when Congress passed the Food Quality Protection Act, or FQPA, which greatly modified pesticide regulation). For example, all indoor household, lawn, garden and some food uses of two of the most widely used OP’s, chlorpyrifos and diazinon, were cancelled or scheduled for phase-out as a result of re-assessments released by EPA in June and December, 2000.(1,2) One of the major changes in pesticide regulation in The Food Quality Protection Act of 1996 was the requirement that EPA for the first time consider more than just risks from single chemicals, and begin to also consider the health risks posed by pesticides acting by common mechanism of toxicity. For such groups of pesticides, EPA treats cumulative risk as the risk of a common toxic effect associated with concurrent exposure by all relevant pathways and routes. The 35 still-registered organophosphate insecticides are the first group for which EPA is attempting such an assessment.(3) Note that this cumulative assessment includes no carbamate insecticides. As part of this assessment, EPA has made a science policy decision that the common toxic effect of the OPs is cholinesterase inhibition -- indeed, that is the the action for which these agents were intentionally designed to kill pests. Recent studies of animals exposed to chlorpyrifos, however, found developmental effects on DNA synthesis in noncholinergic cells.(3) Chlorpyrifos is one of the six OP pesticides for which a study of developmental neurotoxicity -- according protocols scientifically validated by EPA since 1991 -- has been completed, submitted to EPA, and reviewed for acceptability. 1. Environmental Protection Agency, Communications, Education, and Media Relations. Clinton-Gore administration acts to eliminate major uses of the pesticide Dursban to protect children and public health. Environmental News, June 8, 2000. 2. Environmental Protection Agency, Office of Pesticide Programs. Press Release on Diazinon risk assessment and agreement. 12/5/00. Organophosphate Pesticides: Documents for Diazinon available at: http:www.epa.gov/pesticides/op/diazinon.htm. 3. Environmental Protection Agency, Organophosphate Pesticides: Revised OP Cumulative Risk Assessment, downloaded 9/3/02 at http://www.epa.gov/pesticides/cumulative/rra-op/

Magnitude of the Chemical Threat Section III Outline: Magnitude of the Chemical Threat Production and Releases (Lack of) Regulatory Oversight Conclusions Finally, we’ll put these toxic threats in context within the modern chemical landscape. First we’ll consider the numbers of chemicals manufactured, and the reported releases of untested substances to the environment that increase the risk of fetal and childhood exposures. We’ll address the regulatory vacuum that permits what’s been called “a vast toxicologic experiment” to be conducted on the public. And we’ll consider the implications of this review.

The Chemical Environment Pervasive Exposures The Chemical Environment 80,000 chemicals in the Federal inventory 2,000 to 3,000 new chemicals introduced each year The few substances we’ve been discussing are unique in being well-studied and relatively well understood. In reality, few household and environmental chemicals to which the fetus and child are routinely exposed have undergone even minimal screening for their potential to cause developmental neurotoxicity -- adverse effects in the developing brain and nervous system -- prior to being put on the market. The potential for discovery that exposures to other commonly encountered chemicals could exert impacts similar to those seen with lead, mercury, and PCBs, for example, is troubling. Approximately 80,000 chemicals currently are registered for commercial use, and their numbers grow by an estimated 2,000 to 3,000 per year.(1) The great majority were synthesized in the past 50 years. They therefore are entirely new to the human environment, in an evolutionary time frame. 1. Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances: Endocrine Disruptor Screening and Testing Advisory Committee. Final Report. Washington D.C., 1998.

Toxics Release Inventory Top 20 Chemicals Over 2 Billion lbs of Neurotoxic Emissions in 2000 Despite vast ignorance as to the human health impacts, huge amounts of chemicals are being released into the environment each year. This chart shows a comparison of releases of only the top 20 chemicals from the Toxics Release Inventories (TRI) of 1997 and 2000. The TRI was established under the Emergency Planning and Community Right-to-Know Act of 1986 and requires certain industries to annually report emissions of more than 650 toxic chemicals. In the years 1998-2000, there were two changes to the reporting requirements. First, seven new industries, including metal mining and electric utilities, were required to begin reporting. Second, certain persistent and bioaccumulative toxins (PBTs) were added, and the threshold reporting requirement for them was lowered from 25,000 lbs. to 10-100 lbs. because they are toxic at very low doses. These PBTs include the neurotoxicants mercury, PCBs and dioxins (the dioxin reporting threshold was lowered to 0.1 gram). As shown, the addition of emissions from the seven new industries, plus PBT emissions, results in dramatic increases to the “TRI Top Twenty”, from 1997 to 2000. Total reported emissions tripled from 1.9 billion lbs. to 6.2 billion lbs., and known or suspected neurotoxicants more than doubled from 1 to over 2 billion lbs. Total PBT emissions for 2000 accounted for over 12 million lbs. (1,2) These data give us more useful information about biologically relevant releases of neurotoxicants than data from previous years, and point out the importance of having proper information available for analysis. 1. U.S. EPA. 2000 Toxics Release Inventory Public Data Release, available at www.epa.gov/tri. 2. Environmental Defense Fund “Scorecard” (www.scorecard.org) health effects of chemicals – neurotoxicity: compiled from 21 databases or references including EPA, National Institute of Occupational Safety and Health’s Registry of Toxic Effects of Chemical Substances, NJ Department of Health Services TRI fact Sheets and Casarett and Doull’s Toxicology: The Basic Science of Poisons. Edited by Klaassen C. 5th ed. McGraw Hill, 1996. Total Neurotoxicants Emissions TRI – Toxics Release Inventory

Developmental Testing of 2,863 Chemicals Produced > 1 million lbs/year Some Data On Developmental Toxicity 12 Tested for Neurodevelopmental Toxicity According to EPA Guidelines Indeed, for most of the nearly 3,000 chemicals produced in highest volume, (over one million pounds per year), the public record holds very little or no data on their toxicity from even basic standardized screening assays, and no data at all regarding effects on the developing nervous system.(1,2) Among these chemicals, only 12 (so far as can be determined from all publicly available information) have been adequately tested for their effects on the developing brain (developmental neurotoxicity testing), using the EPA guidelines validated for that purpose, and had those tests reviewed by EPA for quality.(3) 1. Pew Environmental Health Commission, 1999. Healthy From the Start. Why America Needs a Better System to Track and Understand Birth Defects and the Environment. p. 34. 2. US Environmental Protection Agency, Chemical Hazard Data Availability Study, available at: http://www.epa.gov/opptintr/chemtest/hazchem.pdf 3. Makris S, Raffaele K, Sette W, et al: A retrospective analysis of twelve developmental neurotoxicity studies submitted to the US EPA Office of Prevention, Pesticides, and Toxic Substances (OPPTS), draft, Nov 1998. No Data On Developmental Toxicity

Hazard Data - Chemicals Produced > 1 Million Pounds/Year 7% Full* Set of Basic Toxicity Tests: * Doesn’t Include Tests of Neurodevelopmental Effects Here we see EPA’s 1998 analysis of the lack of toxicity screening data for the vast majority of the nearly 3,000 chemicals produced at over one million pounds per year high, i.e. high production volume (HPV) chemicals. International authorities agree that testing in six basic endpoint areas (known as “basic tests” in the EPA analysis) is necessary for even a minimum level of understanding of a chemical’s toxicity. These tests cover: acute toxicity; chronic toxicity; developmental and reproductive toxicity; mutagenicity; ecotoxicity; and environmental fate. This basic level of testing and other information is called the Screening Information Data Set, or SIDS. While these tests do not fully measure a chemical’s toxicity, they do provide a minimum set of information that can be used to determine the relative hazards of chemicals and to judge if additional testing is necessary. EPA’s analysis found that absolutely no basic toxicity information, i.e., neither human health nor environmental toxicity, is publicly available for 43% of the high volume chemicals manufactured in the US, and that a full set of basic toxicity information is available for only 7% of these chemicals. For each chemical, the basic set of six SIDS screening tests costs about $205,000. Graphics and text adapted from: US Environmental Protection Agency, Chemical Hazard Data Availability Study: What Do We Really Know About the Safety of High Production Volume Chemicals? (1998), available at: www.epa.gov/opptintr/chemtest/hazchem.pdf

Failure to Evaluate Impacts on Children in Chemical Regulation (Lack of) Regulatory Oversight Failure to Evaluate Impacts on Children in Chemical Regulation Developmental neurotoxicity testing (DNT) not required DNT testing not in proposed voluntary testing schemes Even for chemicals with some toxicity data, database has important deficiencies. EPA regulations currently do not require that household and environmental chemicals be tested for possible effects on brain development before being “registered” or put on the market, or for renewing this registration for older chemicals. This is true even for registration of pesticides, one of the strictest areas of chemical regulation.(1-2) The American Chemistry Council, after negotiations with EPA, has established a voluntary screening program for high production volume chemicals. It is a tiered program that includes no requirements or commitments for neurodevelopmental testing. (3) Even for those few chemicals that have undergone some degree of examination, studies in both animals and humans have important deficiencies. 1. US Environmental Protection Agency. Draft Report of the Toxicology Workgroup of the EPA 10X Task Force, Toxicology Data Requirements for Assessing Risks of pesticide Exposure to Children’s Health, April 28, 1998, p.12. 2. Dr. Deborah Rice, statement. Seventeenth International Neurotoxicology Conference: Roundtable Discussion – Do the EPA Developmental Neurotoxicity Guidelines Detect Human Developmental Neurotoxicity? Little Rock, AR, Oct 20, 1999. 3. See Chemical Right-to-Know initiative at http://www.epa.gov/opptintr/chemrtk/index.htm.

Failure to Evaluate Impacts on Children (Lack of) Regulatory Oversight Failure to Evaluate Impacts on Children Deficiencies in animal studies: Underestimate human DNT by 100-10,000 fold (Hg, Pb, PCBs) Single genetic strains Test single chemical exposures (real exposures are to mixtures) To test 10% commercial chemicals in combinations of three requires 85 billion tests. Prospective epidemiological studies rarely available Deficiencies in Animal Studies: Animal studies commonly underestimate human vulnerability to neurotoxicants due to the obvious difficulty of testing uniquely human cognitive, language and behavioral functions within animal models. In the case of lead, mercury and PCBs, animal studies underestimated the levels of exposure that cause effects in humans by 100-10,000 fold.(1) In addition, the role of genetic variability in determining susceptibility to environmental exposures is ignored by the convention of using genetically similar animals for testing. Current testing protocols also underestimate toxic threats by exposing subjects to only one chemical at a time, though children are exposed to complex mixtures of chemicals throughout development.(2) It is now well established that such multiple chemical exposures can be far more damaging, or cause damage at lower levels of exposure, than single exposures generally addressed in animal models.(3-7) Testing chemicals in combinations, however, would exponentially increase the number of tests to be performed. For example, in order to test 10% of commercial chemicals, or 8000 chemicals, in combinations of three, 85 billion tests would be required. Comprehensive testing of chemical combinations is clearly not feasible. Finally as mentioned before, prospective epidemiological studies -- the best source of human toxicity information -- are costly, require very long time-frames, and are rarely available. 1. Rice D, Evangelista de Duffard A, Duffard R, et al. Lessons for neurotoxicology from selected model compounds: SGOMSEC joint report. Environ Health Perspect 104(suppl 2):205-215, 1996. 2. Schettler T, Solomon G, Valenti M et al. Generations at RisK: Reproductive Health and the Environment. MIT Press, Cambridge, MA, July 1999. 3. Bemis JC, Seegal RF. Polychlorinated biphenyls and methylmercury act synergistically to reduce rat brain dopamine content in vitro. Environ Health Perspect Nov;107(11):879-885 1999. 4. Porter WP, Jaeger JW, Carlson IH. Endocrine, immune and behavioral effects of aldicarb (carbamate), atrazine (triazine) and nitrate (fertilizer) mixtures at groundwater concentrations. Journal of Toxicology and Industrial Health 15:133-150, 1999. 5. Stewert P: PCBs/methylmercury. The Oswego study. Presented at Children’s Health and the Environment: Mechanisms and Consequences of Developmental Neurotoxicology, Little Rock, AR, Oct 17-20, 1999. 6. Thiruchelvam M, Richfield EK, Baggs RB, et al. The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease. J Neurosci Dec 15;20(24):9207-9214, 2000. 7. Jett DA, Navoa RV, Lyons MA : Additive inhibitory action of chlorpyrifos and polycyclic aromatic hydrocarbons on acetylcholinesterase activity in vitro. Toxicol Lett Apr 12;105(3):223-229, 1999.

Conclusions Emerging Themes With increasing scientific understanding, as neurodevelopmental effects emerge, estimates of toxic thresholds tend to fall. Animal testing for neurodevelopmental toxicity has underpredicted human vulnerability by a factor of 100-10,000 (HG, lead, PCBs). Subtle effects in individuals may carry profound impacts when expressed over a population. Adverse effects of some developmental neurotoxicants are synergistic or additive. Several critical concepts emerge from this review of available developmental neurotoxicity information, particularly with the benefit of an historical perspective. With increasing scientific understanding, as neurodevelopmental effects emerge, estimates of toxic thresholds tend to fall. Animal testing for neurodevelopmental toxicity has underpredicted human vulnerability by a factor of 100-10,000 (Hg, lead, PCBs). Developmental exposures that have subtle effects on the average individual have profound impacts if applied broadly over populations. Adverse effects of some developmental neurotoxicants are synergistic and additive. The impact of additive and synergistic effects on child development is currently unknown, but is potentially great. Optional Section for Advanced Discussion For example, additive effects are demonstrated in vitro by PCBs and mercury. Together these compounds reduce dopamine in brain tissue culture more than either toxicant acting alone.(1) Similarly, the effects of the pesticide Dursban have been shown to be additive with those of several polycyclic aromatic hydrocarbon compounds (such as pyrene and benzo(a)pyrene) commonly found in house dust.(2) An example of synergism is provided by the combined effects of the herbicide paraquat and the fungicide maneb. Together these pesticides injure the nigrostriatal dopamine system in laboratory animals – while acting alone each pesticide had little or no effect.(3) 1. Bemis JC, Seegal RF. PCBs and methylmercury act synergistically to reduce rat brain dopamine content in vitro. Env Health Perspect 107(11):879-885, 1999. 2. Jett da, Navoa RV, Lyons MA. Additive inhibitory action of chlorpyrifos and polycyclic aromatic hydrocarbons on acetylcholinesterase activity in vitro. Toxicol Lett Apr 12;105(3):223-229, 1999. 3. Cory-Slechta DA et al. Potentiated and preferential neurotoxicity of repeated exposures to combined paraquat and maneb on the nigrostriatal dopamine system: implications for Parkinson's disease. Reported at the 18th International Neurotoxicology Conference. Sept 23-26, 2000. Colorado Springs, Colorado.

Conclusions Guiding Principles 1. Disabilities are widespread. Chemical exposures are important preventable contributors to these conditions. 2. Apparent toxicity at high doses should be a red flag for possible harm from low-dose “background” exposures. Several guiding principles for public health and policies for regulating chemicals, generally, also emerge from this review. They consist of the following four important tenets: Disabilities are widespread. Chemical exposures are important preventable contributors to these conditions. Apparent toxicity at high doses should be a red flag for the very strong possibility of more widespread harm from low-level “background” exposures.

Conclusions Guiding Principles 3. Due to the slow rate at which “proof” of harm materializes, generations are at risk and may be harmed before adequate regulatory response occurs. An historical perspective indicates that knowledge of neurodevelopmental toxicity advances slowly. Due to the slow rate at which “proof” of harm materializes, generations are at risk and may be harmed before adequate regulatory response occurs.

Conclusions Guiding Principles 4. Protecting children from toxic threats will require a more flexible regulatory system capable of preventing as well as responding to widespread exposures and harm. Most importantly, Protecting children from toxic threats will require a more flexible regulatory system capable of preventing widespread exposures and harm before they occur, as well as responding to them after the fact.  

This “toxic iceberg” illustrates the limits of the current regulatory system. Current regulation addresses those few chemicals for which there is rigorous proof of harm, but such harm is likely to be the tip of the iceberg. There is a deeper level at which emerging harm can be identified but is not fully proven, despite clear warning signs. Below this, there are damages that occur with long latency periods, in which harmful exposure has occurred but the manifestation of the damage has yet to appear. And below this there are exposures that are doing harm but which will never be recognized due to the difficulties of detection. Since chemical exposures proliferate much faster than their neurodevelopmental toxicities can be understood, the true dimensions of the toxic threat will always be underestimated by "currently available knowledge".

Out of Summary: Out of Harm’s Way An historical review of toxic chemicals reveals a disturbing pattern. As a rule, these chemicals are recognized as harmful long after their use has become routine and exposures widespread. In some cases, toxic chemicals have become entrenched global contaminants by the time their human health consequences were understood. Because the fetus and developing child are most sensitive to the effects of these insidious exposures, our children in particular bear the risks of regulatory policies that largely consider chemicals safe until proven harmful.   While improved chemical testing is essential, there are inherent limits to toxicity testing. Therefore, with mounting evidence of toxic threats, it becomes increasingly important to protect the fetus and child from unnecessary chemical exposures. In the public policy arena, child development can be better protected by a more public health-oriented approach to the regulation of household and environmental chemicals. Such an approach would introduce appropriate precaution at all phases of the lifecycle of these substances, including their production, use, and disposal. Providers and parents have a leadership role to play in promoting such a vital change. Meanwhile, all who provide and care for the developing fetus and child can help reduce exposures to a wide variety of known and suspected neurodevelopmental toxicants that are commonly found in consumer products, food, the home and wider community. We cannot protect our children without protecting the environment in which they eat, drink and breathe, including our homes as well as the wider world. By safeguarding the environment in which we all live, we can take our children back, out of harm’s way.

This presentation was developed by Jill Stein MD, Ted Schettler MD MPH, David Wallinga MD MPA, Mark Miller MD MPH, and Maria Valenti. Other contributors to the presentation include John Andrews, Richard Clapp, Michelle Gottlieb, Terry Greene, and Marybeth Palmigiano. It was updated in September 2002. The authors of the presentation do not authorize changes, and are not responsible for the accuracy of material if changes have been made. It is based on the report In Harm’s Way: Toxic Threats to Child Development, by Ted Schettler MD MPH, Jill Stein MD, Fay Reich PsyD, Maria Valenti, and contributing author David Wallinga MD. Graphic design and illustrations by Stephen Burdick Design, photography by Robert Burdick. Greater Boston Physicians for Social Responsibility (GBPSR) May, 2000. The 140-page report can be viewed, downloaded, or ordered at: http://www.igc.org/psr/. For more information on this presentation and related training materials contact: GBPSR, 11 Garden St., Cambridge, MA 02138. 617-497-7440. psrmabo@igc.org.