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Human Developmental Neurotoxicology

2006 Edition, April 6, 2006

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Active, Most Current

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ISBN: 978-0-8247-2988-2
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Product Details:

  • Revision: 2006 Edition, April 6, 2006
  • Published Date: April 6, 2006
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 557
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:


Those who investigate the impacts of chemical exposures on children's neurodevelopment are not quite in the same dire epistemological straits as Yogi Berra. We at least suspect quite a lot of things. Rumsfeld's musings, although resembling a Zen koan in their obtuseness, are, nevertheless, more apt. Some questions have answers that most (although rarely all) observers would endorse. For example, if asked, "Is children's neurodevelopment adversely affected at levels of lead exposure that are not high enough to cause an overt encephalopathy?" most investigators would probably answer affirmatively. In Rumsfeld's system for classifying knowledge, this would be a "known known." An increase in the specificity with which a question is phrased will, however, often result in responses that are more variable, both in content and the respondent's level of certainty, suggesting that the issue in question would be better classified as a "known unknown." "What is the functional form of the dose-response relationship?", "To what extent do the expressions of nervous system toxicity depend on the age at which exposure occurs?" and "What is the natural history of lead-associated neurodevelopmental deficits under different degrees of postnatal environmental enrichment?" are examples of such questions. And then there are the "unknown unknowns." These bear on issues that we won't even think to ask questions about until we learn enough to appreciate the existence of a mystery that, heretofore, lay unrecognized.

These are not issues solely of academic interest. In the past two decades, children's abilities to process information, to reason, to learn, and to achieve a positive psychosocial adjustment have emerged as critical endpoints in risk assessments of chemical exposures. It is recognized that children with even subtle impairments of these skills, who cannot function near the peak of their potential, will not fare as well as those who do in a technological marketplace that places high value on analytic and communication skills and the ability to adapt quickly and effectively to shifting demands and opportunities. It is no longer adequate to make public health decisions based on risk assessments that use as critical endpoints frank neurological disease or mental retardation (to say nothing of endpoints such as the LD50–the dose at which 50% of animals in the "exposed" group die). Exposure standards will be insufficiently protective if based on using approaches that do not acknowledge the potential importance, both to the individual and to society, of "sub-clinical" effects, that is adverse impacts that are not severe enough to meet diagnostic criteria for a disease or that do not correspond to a pattern that is sufficiently common to have been canonized as a "diagnosis."

The increasing recognition of "subtle" effects of neurotoxicant exposures and their acceptance as worthy of concern has resulted in a steady evolution over the past 30 years in the study methodologies applied in human developmental neurotoxicology studies. Case series describing the severe neurological deficits of children who developed Congenital Minamata Disease after prenatal exposure to methyl mercury or who presented with a fulminant lead encephalopathy were sufficient to convince us of the serious neurotoxicities caused by high dose exposure to these metals. Studies that were more analytic, using a case-control design, became necessary when the goal was to determine whether the prevalence of clinically-defined childhood morbidities, for example diagnoses such as learning disabilities or attention deficit hyperactivity disorder, differed between children who were considered "exposed" or "unexposed" to some chemical. The effect measures applied in case-control studies were typically the odds ratio and relative risk, expressing the extent to which the morbidity was more likely to be present among children in the "exposed' than the "unexposed" group. When concern began to shift to possible subclinical impairments, it was necessary to mount cohort studies, in which participants were selected on the basis of exposure status rather than outcome status, and outcomes were often represented dimensionally rather than as diagnoses that were noted as being simply present or absent. Prospective studies were recognized as preferable to cross-sectional studies because they permitted an investigator to establish the temporal precedence of exposure vis a vis outcome, to characterize the natural history of exposure-outcome associations, and to identify age-dependent variations in susceptibility. In contrast to the odds ratio or relative risk statistics calculated in case-control studies, the effect measures calculated in cohort studies were more often the rate of change in the dimensional outcome per unit increase in an exposure index, providing new options for modeling dose-response and dose-effect relationships and developing points of departure for risk assessments.

Other recent trends in the evolution of human developmental neurotoxicology research are notable. At the same time that the endpoints considered important to society were broadened to include sub-clinical as well as clinical impairments within a particular health domain, the range of health domains of interest as possible targets of neurotoxicant exposures has also broadened. For a variety of reasons, neurotoxicological studies traditionally focused on cognitive morbidities, defined rather narrowly and often consisting solely of IQ, as the critical endpoints. Beginning in the 1980s, however, attention was drawn in the general pediatric literature to what was called "the new morbidity," referring to behavioral disorders and maladaptive psychosocial function. A concern with such disorders is increasingly reflected in neurotoxicological studies, with diagnoses such as juvenile delinquency, attention deficit hyperactivity disorder, and autism spectrum disorder serving as the endpoints of interest. Another trend is increasing sophistication of the methods used to address the critical issue of confounding bias by characterizing more accurately and comprehensively the panoply of factors that, apart from the chemical exposure of interest, can affect a child's health. Determining how a chemical exposure fits into the complex web of influences on child development, its effects perhaps being exacerbated by some of these other influences and mitigated by others, also became an important part of the evaluation of study hypotheses. These trends resulted in studies that have become increasingly complex and multidisciplinary, requiring, at least, the collaboration of toxicologists, developmental psychologists, epidemiologists, biostatisticians, and analytical chemists. The contributions of psychiatrists, sociologists and cultural anthropologists will be increasingly important as the range of endpoints of interest continues to broaden and the child development models used to evaluate chemical effects become richer in depth and complexity.

The purpose of this book is to describe the state-of-the-art in the design, conduct, and interpretation of human developmental neurotoxicology studies. Authors were asked to do more, however, than to describe current knowledge and methods in their fields of research. They were asked to address the question, "How can we do better?" and encouraged to identify the advances that need to be made in order to allow investigators to clarify the "known unknowns" and to identify the "unknown unknowns" that will be the foci of future research.

Chapters in section one focus on specific environmental chemical exposures, including mercury, PCBs, lead, and solvents. Although the first three are among the chemicals that have been most intensively studied, many knowledge gaps remain, continuing to inspire debate and to render the risk assessment process contentious. Because of the current world-wide concern about mercury toxicity, two chapters are devoted to this metal. Although there is some overlap in the topics covered, the chapters provide complementary perspectives on the conduct and interpretation of mercury studies as well as on their public health implications.

The chapters in section two focus on the developmental neurotoxicities associated with intentional exposures to chemicals or chemical mixtures. Some of these are medications administered therapeutically, such as anti-epileptic and chemotherapeutic drugs, while others are drugs used recreationally, including tobacco, alcohol, and cocaine. The potential adverse effects of exposures to recreational drugs generally receive much more attention than do the potential adverse effects of exposures to therapeutic drugs, perhaps due, at least in part, to differences in the risk-benefit calculus appropriate to these two classes of exposures. Exposure to therapeutic drugs occurs as a result of a decision that the avoidance of a health risk associated with a medical condition outweighs the risks associated with their use, which might be substantial (i.e., "side effects"). In contrast, use of recreational drugs, particularly during pregnancy, would not be expected to provide any health benefit to the fetus or child, which could make the risk of even subtle "side effects" on a child enough to tip the balance in favor of avoiding the exposure.

Chapters in section three focus on critical issues in the assessment of exposure and outcome. Separate chapters focus on the special considerations germane to the assessment of exposures to accumulative chemicals, such as many metals, and to the assessment of exposures to chemicals with relatively short biological residence times, such as organophosphate pesticides. Another chapter focuses on special issues that pertain to characterizing voluntary exposures, such as marijuana and cocaine. The chapters focusing on outcome assessment address considerations in assembling, modifying, and validating a battery of tests, the emerging role for neuroimaging modalities in assessing neurotoxicity, and the special challenges faced in studying the contributions of childhood neurotoxicant exposures to the development of adult neurologic disease.

Chapters in section four provide perspectives on several aspects of the analysis and interpretation of developmental neurotoxicity studies. These include the strategies used to identify potential confounding variables to include in regression models and the potential utility of analytic strategies such as structural equation modeling in characterizing the relationships among exposures, outcomes, confounders, and mediators. Another chapter shows how our understanding of exposure-outcome associations can be enriched by taking into account the broader social environment within a child that is developing and building multi-level models of complex inter-relationships. Two other chapters address issues pertaining to study interpretation, one focusing on how consideration of the experimental animal literature on a chemical's developmental neurotoxicity can inform both the choice of methods used in human studies, and the inferences drawn about behavioral mechanisms and, ultimately, about causality. A chapter that focuses on the effects of chemical exposures on thyroid hormone signaling pathways illustrates the daunting distance we have to go to bridge the yawning chasm that separates the observations made in epidemiologic studies of developmental neurotoxicity and an understanding of the biological mechanisms generating those observations.

The chapters in section five place the contributions of developmental neurotoxicity research in a broader context. Two chapters provide the perspectives of groups who could be characterized as "consumers" of such studies, namely those who use the data clinically to manage patients exposed to neurotoxic chemicals, and those who use the data as the basis for formulating public policy. They help us to understand ways in which this research can be designed, conducted, analyzed in ways that will make the data more useful to those who apply the findings. The final chapters alert us to the hazards that can arise in doing research that threatens industrial interests or that enriches investigators who place themselves in positions of conflict of interest. These caveats remind us of the quite profound effects that developmental neurotoxicity research have on people's health and livelihoods, and the special responsibilities we assume in undertaking such work.