Journal of Developmental & Behavioral Pediatrics:
In Harm’s Way: Toxic Threats to Child Development
STEIN, JILL M.D.; SCHETTLER, TED M.D., M.P.H.; WALLINGA, DAVID M.D., M.P.A.; VALENTI, MARIA
Greater Boston Physicians for Social Responsibility, Cambridge
Science and Environmental Health Network, Boston, Massachusetts
Institute for Agriculture and Trade Policy, Minneapolis, Minnesota
Greater Boston Physicians for Social Responsibility, Cambridge, Massachusetts
Address for reprints: Jill Stein, M.D., 17 Trotting Horse Drive, Lexington, MA 02421; e-mail: email@example.com.
ABSTRACT. Developmental disabilities result from complex interactions of genetic, toxicologic (chemical), and social factors. Among these various causes, toxicologic exposures deserve special scrutiny because they are readily preventable. This article provides an introduction to some of the literature addressing the effects of these toxicologic exposures on the developing brain. This body of research demonstrates cause for serious concern that commonly encountered household and environmental chemicals contribute to developmental disabilities. The developing brain is uniquely susceptible to permanent impairment by exposure to environmental substances during time windows of vulnerability. Lead, mercury, and polychlorinated biphenyls (PCBs) have been extensively studied and found to impair development at levels of exposure currently experienced by significant portions of the general population. High-dose exposures to each of these chemicals cause catastrophic developmental effects. More recent research has revealed toxicity at progressively lower exposures, illustrating a “declining threshold of harm” commonly observed with improved understanding of developmental toxicants. For lead, mercury, and PCBs, recent studies reveal that background-population exposures contribute to a wide variety of problems, including impairments in attention, memory, learning, social behavior, and IQ. Unfortunately, for most chemicals there is little data with which to evaluate potential risks to neurodevelopment. Among the 3000 chemicals produced in highest volume (over 1 million lbs/yr), only 12 have been adequately tested for their effects on the developing brain. This is a matter of concern because the fetus and child are exposed to untold numbers, quantities, and combinations of substances whose safety has not been established. Child development can be better protected by more precautionary regulation of household and environmental chemicals. Meanwhile, health care providers and parents can play an important role in reducing exposures to a wide variety of known and suspected neurodevelopmental toxicants that are widely present in consumer products, food, the home, and wider community.
REPORTED HIGH PREVALENCE OF DEVELOPMENTAL DISABILITY
Twelve million American children (17%) are reported to suffer from one or more developmental disabilities. * 1,2 Trends of these disorders over time are rising, although changes in reporting and diagnostic criteria are likely to explain some of the increase. For example, the numbers of children with learning disabilities, estimated to affect 5% to 10% of the public school population, 3,4 increased 191% between 1977 and 1994. The prevalence of attention deficit hyperactivity disorder (ADHD), previously estimated at 3% to 5% of school-aged children, has recently been reported to be as high as 12%. 5 Similarly, the prevalence of autism, previously reported as 0.5 to 1.0 case per thousand, is more recently reported as 2.0 cases per thousand. 6
The extent to which the unexpectedly high rates are attributable to improved recognition, reporting, altered diagnostic criteria, or true increases cannot be determined with available data. However, whether new or simply newly recognized, developmental disabilities are clearly an enormous burden to individuals, families, and society.
MULTIPLE ETIOLOGIES OF DEVELOPMENTAL DISABILITY INCLUDE PREVENTABLE TOXICOLOGIC CAUSES
An emerging body of evidence indicates that developmental disabilities result from complex interactions of genetic, toxicologic (chemical), and social factors. Among these various causes, toxicologic exposures deserve special scrutiny because they are readily preventable. There has been a recent explosion of research in developmental neurotoxicology, the science investigating the effects of early chemical exposures on the developing brain. This rather technical research, however, has been relatively inaccessible to the larger child development community and largely unknown to the wider public. In this brief article, we provide an introduction to some highlights of the developmental neurotoxicology literature. This growing body of research reveals substantial evidence that commonly encountered household and environmental chemicals contribute to the current burden of developmental disabilities. Such exposures are of particular concern for genetically susceptible individuals exposed during periods of developmental vulnerability. 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. The precise magnitude of the toxicologic component of disability has yet to be determined. Nonetheless, this substantial body of research—including laboratory animal, in vitro, and epidemiologic studies—underscores the need to eliminate developmental exposures to known and suspected developmental neurotoxicants wherever possible.
THEORETICAL FRAMEWORK FOR UNDERSTANDING TOXICOLOGIC INFLUENCES ON CHILD DEVELOPMENT
As one of several important early influences, toxicologic exposures interact with genetic and social factors to shape child development. Although developmental research typically focuses on only one of these domains at a time, it is increasingly recognized that complex interactions among these influences are most important. For example, several genes have been identified that influence susceptibility to environmental chemicals, including genes that affect lead absorption and metabolism (vitamin D receptor and delta aminolevulinic acid dehydratase genes 7) and genes that affect the metabolism of and vulnerability to organophosphate pesticides (genes coding for paroxonase and acetylcholinesterase 8–10). In effect, these genes modulate susceptibility to chemical exposures. New research designs, capable of addressing such interactions between genes and the environment (including both the chemical and social environment), are important for better understanding the causes of developmental disabilities.
LINKS BETWEEN CHEMICALS AND BRAIN DEVELOPMENT: WELL ESTABLISHED FOR A FEW COMMON CHEMICALS, UNSTUDIED IN MOST
Brain development begins early in fetal life and continues into adolescence. First, the general shape of the brain emerges. Throughout pregnancy, fetal brain cells proliferate, migrate to their appropriate locations, and differentiate into specialized cell types. Neurons 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. This sequence of events is genetically programmed but mediated by a variety of neurotrophic biochemical compounds, including neurotransmitters. Interference with any stage of this process may alter subsequent stages and result in permanent impairments.
The developing brain is, therefore, uniquely susceptible to exposure to neurotoxic compounds. 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.
For the purpose of this review, we focus on common household and environmental chemicals that impair development at levels of exposure experienced by significant portions of the general population. Our discussion is confined to a few examples of chemicals that have been extensively examined and found to be public health threats to neurodevelopment. In addition to these examples, however, a wealth of human and laboratory animal data documents the unique neurodevelopmental toxicity of alcohol, nicotine, and some drugs of abuse. These substances have been associated with a variety of neurodevelopmental problems including hyperactivity, attention deficits, learning disabilities, and IQ deficits. 11 More limited data raise concerns about the neurodevelopmental toxicity of additional commonly encountered chemicals, including some pesticides, metals, solvents, and others. With few exceptions, these chemicals of concern have not been adequately examined.
A historical perspective illustrates a fundamental theme in developmental neurotoxicology: The understanding of a given chemical advances slowly, and as it does, demonstrated toxicity tends to emerge at progressively lower levels of exposure. Although this review focuses on chemicals with a rich epidemiologic database, for most chemicals there are little or no human or laboratory neurodevelopmental toxicity data available. This is a matter of some concern because the fetus and child are already being exposed to untold numbers, quantities, and combinations of substances whose safety has not been established.
Declining Threshold of Harm: From Encephalopathy to IQ Impairment
Lead is one of the first and perhaps best understood examples of a common chemical that harms brain development. This understanding has continued to advance over the period of a full century, during which time the recognized “toxic threshold” (the lowest exposure thought to be harmful) has relentlessly declined. Whereas very high lead exposures were recognized to cause encephalopathy, coma, and death in children as early as 1900, 12,13 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. 14 Subsequent studies began to suggest that lower levels of lead exposure might be associated with neurological damage as well. 15
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 μg/dl, only modestly below the level at which encephalopathy occurs (80 μg/dl). 16 With improvements in study design over the next 30 years, research revealed effects of lead on IQ at progressively lower levels of exposure. 17 After repeated downward revisions, the toxic threshold for lead was most recently set at 10 μg/dl, the 1990 standard that still holds today. Subsequent meta-analyses have quantified the risk of low-level lead exposure estimating that an increase in blood lead from 10 to 20 μg/dl is associated with an average IQ loss of 2 to 3 points. 18,19
Significance of Small Effects: The Population Perspective
Although an IQ loss of a few points may have minimal significance for the average individual, it has profound implications when applied over large populations, 20 in effect, shifting the population distribution curve for IQ. When the population distribution curve for IQ, or any other neurobehavioral endpoint, is shifted by even a small amount there are dramatic effects at the high and low ends of the distribution, often referred to as the “tails.” As shown in a hypothetical example in Figure 1, a downward shift of a mere 5 points in the mean IQ results in a greater than 50% increase in the numbers of functionally mentally retarded individuals and a comparable decrease in the numbers of gifted individuals in the population. This small shift in average IQ therefore has enormous implications for society, translating, for example, into increased needs for special education and services, as well as a significantly diminished intellectual capacity within the population as a whole.
Emerging Links with Attention Deficits and Aggressive Behavior
Recent epidemiologic studies indicate that lead exposure is harmful even below the current 10 μg/dl standard. 21–25 Several studies suggest that there is no threshold below which lead exposure is without adverse effects, 26,27 and, importantly, that for a given increment in blood lead, the associated impact on IQ is greater below a blood level of 10 μg/dl than above. 28 Recent studies also suggest that, in addition to undermining IQ, low-level lead exposure is associated with impaired attention, hyperactivity, and antisocial and aggressive behavior. 27,29,30–33 Some of these effects have been observed at very low levels of exposure and may occur in the absence of detectable IQ effects. 30,34–36 The fact that adverse effects from lead exposure are apparently well below the toxic threshold of 10 μg/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.
Widespread Exposures at Levels of Concern
The growing profile of developmental impacts from low-level lead exposure is of substantial concern considering that 4% of all American children 37 and as many as 36% of inner-city black children 38 exceed even the current increasingly obsolete toxic threshold of 10 μg/dl. The emerging nonlinear dose-response profile, which indicates greatest proportional impact occurs at blood levels currently considered normal, is also of concern because this suggests subtle lead-induced impairments are occurring throughout the general population. This is not unexpected because what is called a “normal” lead level today is actually two to three orders of magnitude higher than preindustrial background levels. For a substance such as lead, which appears to have toxic effects at any level of exposure, it is not surprising that adverse effects are apparent even within this “normal” range of exposure.
Declining Threshold of Harm: From Catastrophic Retardation to Subtle Learning Impairments
Like lead, mercury is a heavy metal that disrupts brain development. One of the common forms of mercury, methylmercury, is a low-level contaminant in many species of fish. Although direct exposure data are not widely available, indirect assessments (using dietary surveys and fish-mercury contamination data) suggest that environmental mercury, like lead, puts substantial numbers of children at risk. At high levels of developmental exposure, methylmercury causes severe disability such as mental retardation and cerebral palsy, whereas the more commonly encountered low levels of exposure can contribute to attention, memory, and language impairments. Unlike lead, however, the study of mercury effects on children is relatively young, having begun only approximately 50 years ago, and scientific consensus on low-dose toxicity has been achieved only in the last few years. 39,40
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, fish consumed by pregnant women or women of reproductive age may pose a threat to the uniquely vulnerable fetal brain.
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, disturbances of gait, speech, sucking, swallowing, and reflexes, 41 whereas 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.
An apparent toxic threshold, implied in the first case reports of severely retarded infants, soon became obsolete. Within a few years it was evident that many children exposed prenatally to lower levels of mercury suffered delays in walking and talking despite apparently “normal” development in infancy. Subsequently, a variety of studies has established progressively lower thresholds for methylmercury effects by using increasingly sensitive methods of exposure and outcome assessment and improved statistical methods 42–44 (Fig. 2).
Most recently, a very large study in the Faroe Islands has identified deficits in language, memory, and attention 45 that occur at low levels of prenatal methylmercury exposure. These effects are associated with exposures that are less than 3% of the toxic threshold suggested by the earliest Iraqi observations. 46 However, even below the harmful exposure identified in the Faroe research, (0.85 μg/kg/d), a “discernible insidious effect” on language, memory, and attention was noted, 45 suggesting that the recognized threshold for neurological toxicity will continue declining as research methods continue to improve.
Widespread Exposures at Levels of Concern
Based on extrapolations from the Iraqi study, the EPA currently defines a safe upper limit for dietary mercury exposure at 0.1 μg/kg 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 μg mercury per gram of fish, respectively). A 20-kg child exceeds the safe consumption limit by eating a mere half-ounce of swordfish per week or 2.5 ounces of tuna per week. 47,48
Methylmercury exposure assessments suggest that 7% of U.S. women of reproductive age, as well as 20% of 3- to 6-year-old children, exceed the safe exposure limit. 49,50 An exposure assessment in New Jersey indicates 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. 51 Exposure assessments 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. 52 Based on a comprehensive review of relevant research, the National Academy of Sciences recently estimated that over 60,000 U.S. children are born each year at risk for learning and other disabilities due to prenatal methylmercury exposure.
Polychlorinated biphenyls (PCBs) are a large group of fat-soluble chemicals previously produced for industrial use as lubricants and insulators in electrical equipment. Although their production has been banned in most of the industrialized world for decades, their environmental 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. 53
Declining Threshold of Harm: From Retardation to Pervasive Subtle Developmental Impairments
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. 54,55 In childhood, they also exhibited IQ impairment bordering on mental retardation, poor health, and increased behavior problems. 56–58
In contrast with the earliest studies of high-dose PCB poisonings, subsequent research focused on populations with background, or near-background exposures, including large prospective cohorts in Michigan, North Carolina, The Netherlands, and Germany. As exposure assessment has improved over the past several decades, persistent and pervasive adverse effects of prenatal exposure have emerged at these exposure levels commonly experienced by the general population (Fig. 3). In the newborn, the effects of prenatal PCB exposure include decreased birth weight, head circumference, and gestational age, as well as motor immaturity, poor lability, increased startle and decreased reflexes on the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). 59,60 In early childhood, prenatal PCB exposure is associated with a variety of cognitive impairments (reduced memory and attention, decreased verbal ability, impaired information processing) and developmental delays (reduced psychomotor development), as well as adverse behavioral and emotional effects (decreased sustained activity, decreased high-level play, increased withdrawn and depressed behavior, increased activity level). 61–67 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. 68,69
Maternal PCB body burden also alters thyroid hormone status in mothers and infants. Higher 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 the infants. 70 Thyroid hormone is critical to brain development, and elevated maternal TSH levels during pregnancy, with or without reductions of thyroid hormone, are associated with reduced IQ in offspring years later. 71 These observations suggest that the adverse developmental effects of PCBs may be at least partly mediated through impacts on thyroid hormone. PCB exposures also modulate neurotransmitter levels, which may be another mechanism by which PCBs affect neurodevelopment.
Widespread Exposures at Levels of Concern
The pervasive effects of prenatal PCBs on development, behavior, and cognition have been established at background levels of population exposure, 72,73 clearly indicating widespread exposures are a cause for concern. The main route of PCB exposure is through the food chain. Because the half-lives of PCBs range from 5 to 15 years, 74 dietary PCB exposures need to be reduced throughout childhood and reproductive years to limit adverse developmental effects on the next generation. 68,75
Because breast milk contains relatively high levels of PCBs, breastfed infants are exposed to a substantial portion of a total lifetime dose of PCBs within the first few months of life. Although transplacental PCB exposures are quantitatively small compared with breast milk exposures, it is nonetheless these prenatal exposures that have proven harmful. PCB exposures in breast milk from mothers with relatively high PCB body burdens are not without some cognitive and immunologic effects, but these effects are compensated for by the cognitive and immunologic benefits of breastfeeding. 72,76,77 Considering all currently available knowledge regarding risks, benefits, and alternatives, breastfeeding continues to be recommended without qualification. 78,79 The benefits of breastfeeding can, however, be improved by the same dietary measures needed to reduce fetal exposure to maternal PCBs. 68 Intake of PCBs, as well as the companion pollutant dioxin, can be reduced by minimizing consumption of high-fat animal products, particularly cheeses and processed meats. These should be replaced by animal products that are low in fat, such as nonfat milk and lean meats, fish and poultry, and/or by vegetarian foods including grains, beans, fruits, and vegetables.
IN HARM’S WAY
Routine Exposure of Fetus and Child to Possibly Unsafe Industrial and Environmental Chemicals
The substances discussed above 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 adverse effects on the developing brain. The intensive study of the few well-scrutinized substances was in each instance triggered by a toxicologic catastrophe. In each case, subsequent research revealed progressively lower toxic thresholds, culminating in the discovery of toxicity at background population exposures with disturbing implications for public health. Were it not for the occurrence of high-dose epidemics, current population impacts of lead, mercury, and polychlorinated biphenyls (PCBs) might well be unrecognized today.
The potential for similar impacts from exposures to other commonly encountered chemicals is indeed troubling. Approximately 80,000 chemicals are currently in commercial use, 80 and the great majority were synthesized in the past 50 years. They are therefore entirely new to the human environment in the evolutionary time frame. Among these chemicals, only 12 have been adequately tested, according to the standards established by the Environmental Protection Agency (EPA), for their effects on the developing brain. 81 Indeed, for most of the 3000 chemicals produced in highest volume (over 1 million lbs/yr), the public record holds very little or no basic toxicologic screening data and no data at all regarding effects on the developing nervous system. 82 Meanwhile, the number of chemicals registered for production grows by 2000 to 3000 per year. 80 Despite vast ignorance as to the human health impacts, more than 2.5 billion pounds of toxic chemicals, nearly half of them known or suspected neurotoxicants, 83 were reported to have been directly emitted to the environment by large industrial facilities in 1997 alone. 84 These emissions provide a crude but nonetheless valuable indicator of potential exposures through air, food, and water contamination. Further potential for harmful exposure is created by the vast quantities of chemicals used in manufacturing and/or incorporated into products from which exposures may occur during transport, use, and after disposal. For example, in Massachusetts alone, over 500 million pounds of neurotoxic chemicals were used by industrial facilities in 1997. 85
Failure of Current Regulatory Framework to Protect Children
Currently there is no requirement to test chemicals for possible effects on brain development—not even in the registration of pesticides, one of the strictest areas of chemical regulation. 86 However, even for those few chemicals that have undergone some degree of examination, studies in both animals and humans have important deficiencies.
Prospective epidemiological studies, the best source of human toxicity information, are costly, require very long time frames, and are rarely available. Animal studies commonly underestimate human vulnerability to neurotoxicants because of the obvious difficulty 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- to 10,000-fold. 87 In addition, the importance of genetic variability in determining susceptibility to environmental exposures is ignored when using genetically similar animals for testing.
Current testing protocols also underestimate toxic threats by exposing subjects to only one chemical at a time, although children are exposed to complex mixtures of chemicals throughout development. 88 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. 89–93 Testing chemicals in combinations, however, would exponentially increase the number of tests to be performed. For example, to test 10% of commercial chemicals, or 8000 chemicals, in combinations of three, 85 billion tests would be required. 94 Comprehensive testing of chemical combinations is clearly not feasible.
Protecting Child Development from Toxic Threats
A 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.
Whereas 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 realm of public policy, 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 life cycle of these substances, including their production, use, and disposal. Meanwhile, providers, parents, and all who 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. 95
*For the purpose of this discussion, developmental disabilities are broadly defined to include learning, behavioral, emotional, sensory, speech, and neurodevelopmental impairments, as well as cerebral palsy and delays in growth and development. Cited Here...
1. Boyle CA, Decoufle P, Yeargin-Allsopp M: Prevalence and health impact of developmental disabilities in US children. Pediatrics 93:399–403, 1994
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC, 1994
4. Parrill M: Research implications for health and human services, in Cramer and Ellis (eds): Learning Disabilities, Lifelong Issues, Brookes Publishing Company, Baltimore, MD, 1996, pp 227–295
5. Rowland A: Prevalence and risk factors for ADHD in a North Carolina county: Study design and preliminary results. Presented at the Environmental Influences on Children Conference, New York, NY, May 1999
6. Gillberg C, Wing L: Autism: Not an extremely rare disorder. Acta Psychiatr Scand 99:339–406, 1999
7. Schwartz BS, Stewart WF, Kelsey KT, et al: Associations of tibial lead levels with BsmI polymorphisms in the vitamin D receptor in former organolead manufacturing workers. Environ Health Perspect 108:199–203, 2000
8. Mutch E, Blain PG, Williams FM: Interindividual variations in enzymes controlling organophosphate toxicity in man. Hum Exp Toxicol 11:109–116, 1992
9. Costa LG, Li WF, Richter RJ, et al: The role of paraoxonase (PON1) in the detoxification of organophosphates and its human polymorphism. Chem Biol Interact 119–120:429–438, 1999
10. Genc S, Gurdol F, Guvene S, et al: Variations in serum cholinesterase activity in different age and sex groups. Eur J Clin Chem Clin Biochem 35:239–240, 1997
11. Slikker W and Chang LW (eds): Handbook of Developmental Neurotoxicology. San Diego, CA, Academic Press, 1998
12. Needleman HL: The future challenge of lead toxicity. Environ Health Perspect 89:85–89, 1990
13. 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, AR, October 17–20, 1999
14. WHO: Inorganic Lead. Environmental Health Criteria 165. Geneva, Switzerland, World Health Organization, 1995, p 153
15. WHO: Inorganic Lead. Environmental Health Criteria 165. Geneva, Switzerland, Word Health Organization, 1995, pp 153–154
16. Needleman HL: The persistent threat of lead: Medical and sociological issues. Curr Probl Pediatr 18:697–744, 1988
17. Needleman HL: The future challenge of lead toxicity. Environ Health Perspect 89:85–89, 1990
18. Schwartz J. Low-level lead exposure and children’s IQ: A meta-analysis and search for a threshold. Environ Res 65:42–55, 1994
19. IPCS. Environmental Health Criteria 165: Inorganic lead. International Programme on Chemical Safety. Geneva, WHO, 1995
20. Weiss B: Endocrine disruptors and sexually dimorphic behaviors: A question of heads and tails. Neurotoxicology 18:581–586, 1997
21. Winneke G, Altmann L, Kramer U, et al: Neurobehavioral and neurophysiological observations in six year old children with low lead levels in East and West Germany. Neurotoxicology 15:705–713, 1994
22. Winneke G, Brockhaus A, Collet W, et al: Modulation of lead-induced performance deficit in children by varying signal rate in a serial choice reaction task. Neurotoxicol Teratol 11:587–592, 1989
23. Schwartz J, Otto D: Lead and minor hearing impairment. Arch Environ Health 46:300–305, 1991
24. Lanphear B: Adverse neurobehavioral effects of blood lead levels below 10 micrograms/dl. Presented at the 17th International Neurotoxicology Conference, Little Rock, AR, October 17–20, 1999
25. Rice DC: Developmental lead exposure: Neurobehavioral consequences, in Slikker W and Chang LW (eds): Handbook of Developmental Neurotoxicology. San Diego, CA, Academic Press, 1998, p 553
26. Schwartz J: Low-level lead exposure and children’s IQ: A meta-analysis and search for a threshold. Environ Res 65:42–55, 1994
27. 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 30:515–528, 1989
28. Canfield R: Did we miss the boat? Cognitive deficits in children with blood-lead levels below 10 ug/dl. Presented at the 18th International Neurotoxicology Conference. Colorado Springs, CO, September 23–26, 2000
29. Needleman HL, Reiss JA, Tobin MJ, et al: Bone lead levels and delinquent behavior. JAMA 275:363–369, 1996
30. 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 29:43–52, 1988
31. Tuthill RW: Hair lead levels related to children’s classroom attention-deficit disorder. Arch Environ Health 51:214–220, 1996
32. Munoz H, Romiew I, Palazuelos E, et al: Blood lead level and neurobehavioral development among children living in Mexico City. Arch Environ Health 48:132–139, 1993
33. Yule W, Urbanowicz MA, et al: Teachers’ ratings of children’s behavior in relation to blood lead levels. Br J Dev Psychol 2:295, 1984
34. 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 51:231–252, 1983
35. Winneke G, Kramer U: Neuropsychological effects of lead in children: Interactions with social background variables. Neuropsychobiology 11:195–202, 1984
36. Rice DC: Developmental lead exposure: Neurobehavioral consequences, in Slikker W and Chang LW (eds): Handbook of Developmental Neurotoxicology, San Diego, CA, Academic Press, 1998, p 544
37. US 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, December 2000
38. CDC Performance Plan, Lead Poisoning. Available at: cdc.gov/od/perfplan/ppzk01.pdf, p 119. Accessed February 3, 2000
40. National Academy of Sciences. Toxicological Effects of Methylmercury. Washington, DC, National Academy Press, 2000
41. Harada H: Congenital Minimata Disease: Intrauterine methylmercury poisoning. Teratology 18:285–288, 1978
42. Amin-Zaki L: Perinatal methylmercury poisoning in Iraq. Am J Dis Child 130:1070–1078, 1976
43. McKeown-Eyssen GE, Ruedy J, Neims A: Methyl mercury exposure in Northern Quebec II: Neurological findings in children. Am J Epidemiol 118:470–479, 1983
44. Cox C, Clarkson TW, Marsh DO, et al: Dose response analysis of infants prenatally exposed to methylmercury: An application of a single compartment model to single-strand hair analysis. Environ Res 49:318–332, 1989
45. Grandjean P, Weihe P, White R, et al: Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol and Teratol 19:417–428, 1997
46. Schettler T, Stein J, Reich F, et al: In Harm’s Way: Toxic Threats to Child Development. Cambridge, MA, Greater Boston Physicians for Social Responsibility, 2000
47. Schettler T, Stein J, Reich F, et al: In Harm’s Way: Toxic Threats to Child Development. Cambridge, MA, Greater Boston Physicians for Social Responsibility, pp 62–63, 2000
48. Environmental Protection Agency. Mercury Study Report to Congress: An Assessment of Exposure to Mercury in the United States. vol IV, p 155–160, 1997. Available at: http://www.epa.gov/ttnuatw1/112nmerc/volume4.pdf
. Accessed January 22, 2002.
50. Environmental Protection Agency. Mercury Study Report to Congress: Characterization of Human Health and Wildlife Risks from Mercury Exposure in the United States. vol VII, pp 6–32, 1997. Available at: http://www.epa.gov/ttnuatw1/112nmerc/volume7.pdf
. Accessed January 22, 2002.
51. Stern AH, Korn LR, Ruppel BE: Estimation of fish consumption and methylmercury intake in the New Jersey population. J Expo Anal Environ Epidemiol 6:503–525, 1996
52. Environmental Protection Agency. Mercury Study Report to Congress: Characterization of Human Health and Wildlife Risks from Mercury Exposure in the United States. vol VII, pp 6–29, 1997. Available at: http://www.epa.gov/ttnuatw1/112nmerc/volume7.pdf
. Accessed January 22, 2002.
54. 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, The Netherlands, Elsevier, 1989, pp 381–400
55. Harada M: Intrauterine poisoning: Clinical and epidemiological studies of the problem. Bull Instit Constit Med 25:1–60, 1976
56. Rogan WJ, Gladen BC, Hung KL, et al: Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science 241:334–336, 1988
57. Yu ML, Hsu CC, Guo YL, et al: Disordered behavior in the early-born Taiwan Yucheng children. Chemosphere 29:2413–2422, 1994
58. Chen YC, Guo YL, Hsu CC, et al: Cognitive development of Yu-Cheng (“oil disease”) children prenatally exposed to heat-degraded PCBs. JAMA 268:3213–3218, 1992
59. Fein GG, Jacobson JL, Jacobson SW, et al: Prenatal exposure to polychlorinated biphenyls: Effects on birth size and gestational age. J Pediatr 105:315–320, 1984
60. 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 44:538–545, 1998
61. Jacobson SW, Fein GG, Jacobson JL, et al: The effect of intrauterine PCB exposure on visual recognition memory. Child Dev 56:853–860, 1985
62. 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 116:38–45, 1990
63. Jacobson J: Effects of prenatal PCB exposure on cognitive processing efficiency and sustained attention. Dev Psychol 28:297–306, 1992
64. Jacobson JL, Jacobson SW: Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med 335:783–789, 1996
65. Gladen BC, Rogan WJ, Hardy P, et al: Development after exposure to polychlorinated biphenyls and dichlorodiphenyl dichloroethene transplacentally and through human milk. J Pediatr 113:991–995, 1988
66. Rogan WJ, Gladen BC: PCBs, DDE, and child development at 18 and 24 months. Ann Epidemiol 1:407–413, 1991
67. 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 97:700–706, 1996
68. 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 134:33–41, 1999
69. 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]. Erasmus University, Rotterdam, 1999
70. 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
71. Haddow JE, Palomaki GE, Allan WC, et al: Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341:549–555, 1999
72. Rice DC: Neurotoxicity produced by developmental exposure to PCBs. Ment Retard Dev Disabil Res Rev 3:223–229, 1997
73. Agency for Toxic Substances and Disease Registry. Public Health Implications of Exposure to Polychlorinated Biphenyls (PCBs). Available at: http://www.atsdr.cdc.gov/DT/pcb007.html
. Accessed January 22, 2002.
74. Wolff MS, Fischbein A, Selikoff IJ: Changes in PCB serum concentrations among capacitor manufacturing workers. Environ Res 59:202–216, 1992
75. Birnbaum Linda S: Dietary exposure to PCBs and dioxins in children. Environ Health Perspect 107:1, 1999
76. 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 97:700–706, 1996
77. Weisglas-Kuperus N, Patandin S, Aberbers GAM, et al: Immunologic effects of exposure to polychlorinated biphenyls and dioxins in dutch preschool children. Environ Health Perspect 108:1203–1207, 2000
78. Patandin S, Dagnelie PC, Mulder PG: Dietary exposure to polychlorinated biphenyls and dioxins from infancy until adulthood: A comparison between breast-feeding, toddler, and long-term exposure. Environ Health Perspect 107:45–51, 1999
79. American Academy of Pediatrics: Breastfeeding and the use of human milk. Pediatrics 100:1035–1039, 1997
80. US EPA, Office of Prevention, Pesticides and Toxic Substances: Endocrine Disruptor Screening and Testing Advisory Committee. Final Report. Washington, DC, US Environmental Protection Agency, 1998
81. 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, November 1998
82. Roe D, Pease W, Florini K, et al: Toxic Ignorance: The Continuing Absences of Basic Health Testing for Top Selling Chemicals in the United States, Environmental Defense Fund, 1997
83. Schettler T, Stein J, Reich F, et al: Chemicals, regulations, and the environment, in In Harm’s Way: Toxic Threats to Child Development. Cambridge, MA, Greater Boston Physicians for Social Responsibility, 2000, p 103
84. US Environmental Protection Agency, 1997 Toxics Release Inventory Public Data Release. Washington, DC, US Environmental Protection Agency, May 13, 1999
85. Schettler T, Stein J, Reich F, et al: Chemicals, regulations, and the environment, in In Harm’s Way: Toxic Threats to Child Development. Cambridge, MA, Greater Boston Physicians for Social Responsibility, 2000, p 105
86. Schettler T, Stein J, Reich F, et al: Executive summary, in In Harm’s Way: Toxic Threats to Child Development. Cambridge, MA, Greater Boston Physicians for Social Responsibility, 2000, p 6
87. 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
88. Schettler T, Solomon G, Valenti M, et al: Generations at Risk. Cambridge, MA, MIT Press, 1999
89. Bemis JC, Seegal RF: Polychlorinated biphenyls and methylmercury act synergistically to reduce rat brain dopamine content in vitro. Environ Health Perspect 107:879–885, 1999
90. Porter WP, Jaeger JW, Carlson IH: Endocrine, immune and behavioral effects of aldicarb (carbamate), atrazine (triazine) and nitrate (fertilizer) mixtures at groundwater concentrations. J Toxicol Indust Health 15:133–150, 1999
91. Stewert P: PCBs/methylmercury: The Oswego study. Presented at Children’s Health and the Environment: Mechanisms and Consequences of Developmental Neurotoxicology, Little Rock, AR, October 17–20, 1999
92. 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 20:9207–9214, 2000
93. Jett DA, Navoa RV, Lyons MA: Additive inhibitory action of chlorpyrifos and polycyclic aromatic hydrocarbons on acetylcholinesterase activity in vitro. Toxicol Lett 105:223–229, 1999
94. Montague P: Modern Environmental Protection, Pt. 4. Rachel’s Environment and Health Biweekly #707. Environmental Research Foundation, Annapolis, MD, September 2000
95. Schettler T, Stein J, Reich F, et al: In Harm’s Way: Toxic Threats to Child Development. Cambridge, MA, Greater Boston Physicians for Social Responsibility, 2000, pp 117–132
96. Weiss B: Endocrine disruptors and sexually dimorphic behaviors: A question of heads and tails. Neurotoxicology 18:581–586, 1997
97. Amin-Zaki L, Elhassani S, Majeed MA, et al: Perinatal methylmercury poisoning in Iraq. Am J Dis Child 130:1070–1078, 1976
98. Amin-Zaki L, Elhassani S, Majeed MA, et al: Intra-uterine methylmercury poisoning in Iraq. Pediatrics 54:587–595, 1974
99. Marsh D: Fetal methylmercury poisoning: New data on clinical and toxicologic aspects. Trans Am Neurol Assoc 102:69–71, 1977
100. Marsh DO, Myers GJ, Clarkson TW, et al: Fetal methylmercury poisoning: Clinical and toxicological data on 29 cases. Ann Neurol 7:348–353, 1980
101. Marsh DO, GJ Myers, Clarkson TW, et al: Dose-response relationship for human fetal exposure to methylmercury. Clin Toxicol 18:1311–1318, 1981
102. McKeown-Eyssen GE, Ruedy J, Neims A: Methyl mercury exposure in Northern Quebec II. Neurologic findings in children. Am J Epidemiol 118:470–479, 1983
103. WHO task group on environmental health criteria for methylmercury: Methylmercury, Environmental Health Criteria 101. Geneva, Switzerland, World Health Organization, 1990
104. WHO task group on environmental health criteria for methylmercury: Methylmercury, Environmental Health Criteria 101. Geneva, Switzerland, World Health Organization, 1990
105. Marsh DO, Clarkson TW, Cox C, et al: Fetal methylmercury poisoning. Arch Neurol 44:1017–1022, 1987
106. 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 16:677–688, 1995
107. Grandjean P, Weihe P, White R: Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 19:417–428, 1997
108. Sorensen N, Murata K, Budtz-Jorgensen, et al: Prenatal methylmercury exposure as a cardiovascular risk factor at seven years of age. Epidemiology 10:370–375, 1999
110. Agency for Toxic Substances and Disease Registry: Toxicologic Profile for Mercury, draft. Atlanta, GA, US Department of Health and Human Services, 1998
111. Rice DC: Neurotoxicity produced by developmental exposure to PCBs. Mental Retard Dev Disabil Res Rev 3:223–229, 1997
112. Hovinga ME, Sowers M, Humphrey HE: Environmental exposure and lifestyle predictors of lead, cadmium, PCB, and DDT levels in Great Lake fish eaters. Arch Environ Health 48:98–104, 1993
113. Laden F, Neas LM, Spiegelman D, et al: Predictors of plasma concentrations of DDE and PCBs in a group of US women. Environ Health Perspect 107:75–81, 1999
114. 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 73:293–296, 1983
115. Jacobson SW, Fein GG, Schwartz PM, et al: Perinatal exposure to an environmental toxin: A test of multiple effects model. Dev Psychobiol 20:523–532, 1984
116. Jacobson SW, Fein GG, Jacobson JS, et al: The effect of intrauterine PCB exposure on visual recognition memory. Child Dev 56:853–860, 1985
117. Jacobson JS, Jacobson SW, Humphrey HEB: Effects of exposure to PCBs and related compounds on growth and activity in children. Neurotoxicol Teratol 12:319–326, 1990
118. Jacobson JL, Jacobson SW, Humphrey HEB: Effects of in utero exposure to PCBs and related contaminants on cognitive functioning in young children. J Pediatr 116:38–45, 1990
119. Jacobson JL, Jacobson SW: Intellectual impairment in children exposed to PCBs in utero. N Engl J Med 335:783–789, 1996
120. Rogan WJ, Gladen BC, McKinney JD, et al: PCBs and DDE in human milk: Effects of maternal factors and previous lactation. Am J Public Health 76:172–177, 1986
121. Jensen AA: PCBs, PCDDs and PCDFs in human milk, blood and adipose tissue. Sci Total Environ 64:259–293, 1987
122. Rogan WJ, Gladen BC, McKinney JD, et al: Neonatal effects of transplacental exposures to PCBs and DDE. J Pediatr 109:335–341, 1986
123. Gladen BC, Rogan WJ: Effect of perinatal PCBs and dichlorodiphenyl dichloroethene transplacentally and through human milk. J Pediatr 113:991–995, 1988
124. Rogan WJ, Gladen BC: PCBs, DDE and children’s development at 18 and 24 months. Ann Epidemiol 1:407–413, 1991
125. Gladen BC, Rogan WJ: Effect of perinatal PCBs and DDE on later development. J Pediatr 119:58–63, 1991
126. Dar E, Kanarek MS, Anderson HA, Sonzogni WC: Fish consumption and reproductive outcomes in Green Bay, Wisconsin. Environ Res 59:189–201, 1992
127. Huisman M, Koopman-Esseboom C, Lanting CI, et al: Neurological condition in 18-month children perinatally exposed to PCBs and dioxins. Early Hum Dev 43:165–176, 1995
128. Koopman-Esseboom C, Weisglas-Kuperus N, de Ridder MAJ, et al: Effects of PCB/dioxin exposure and feeding type on infants’ mental and psychomotor development. Pediatrics 96:700–706, 1996
129. 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 134:33–41, 1999
Index terms: child development; environmental chemicals; lead; methylmercury; polychlorinated biphenyls
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