Workshop to identify critical windows of exposure for children's health: cancer work group summary

We considered whether there are discrete windows of vulnerability in the development of cancer and which time periods may be of the greatest importance. Cancer was considered broadly, including cancers in childhood as well as adult cancers that may have an in utero or childhood origin. We concluded that there was evidence from animal and epidemiologic studies for causal relationships for preconceptional, in utero, and childhood exposures and cancer occurrence in children and adults. However, the evidence is incomplete and all relevant critical windows may not have been identified. The comprehensive evaluation of the relative importance of specific time windows of exposure is limited. Improvements in the design of epidemiologic studies and additional animal studies of mechanisms are warranted.     

Workshop to identify critical windows of exposure for children's health: cardiovascular and endocrine work group summary

The work group on cardiovascular and endocrine effects was asked to review the current state of knowledge about children's windows of vulnerability to developmental toxicants and to recommend how that information may be used to improve risk assessment and public health. We considered differences between structural defects, where periods of vulnerability are rather well defined, and functional defects, where periods of vulnerability are quite elusive.     

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary

Fetuses, infants, and juveniles (preadults) should not be considered simply "small adults" when it comes to toxicological risk. We present specific examples of developmental toxicants that are more toxic to children than to adults, focusing on effects on the immune and respiratory systems. We describe differences in both the pharmacokinetics of the developing immune and respiratory systems as well as changes in target organ sensitivities to toxicants. Differential windows of vulnerability during development are identified in the context of available animal models. We provide specific approaches to directly investigate differential windows of vulnerability. These approaches are based on fundamental developmental biology and the existence of discrete developmental processes within the immune and respiratory systems. The processes are likely to influence differential developmental susceptibility to toxicants, resulting in lifelong toxicological changes. We also provide a template for comparative research. Finally, we discuss the application of these data to risk assessment.     

Workshop to identify critical windows of exposure for children's health: reproductive health in children and adolescents work group summary

This work group report addresses the central question: What are the critical windows during development (preconception through puberty) when exposure to xenobiotics may have the greatest adverse impact on subsequent reproductive health? The reproductive system develops in stages, with sex-specific organogenesis occurring prenatally and further maturational events occurring in the perinatal period and at puberty. Complex endocrine signals as well as other regulatory factors (genetics, growth factors) are involved at all stages. Evidence from animal models and human studies indicates that many specific events can be perturbed by a variety of toxicants, with endocrine-mediated mechanisms being the more widely studied. Prioritized research needs include basic studies on the cellular-molecular and endocrine regulation of sexual differentiation and development; increased efforts regarding potential adverse effects on development in females, including breast development; expanded animal studies on different classes of chemicals, comparing responses during development (prenatal and postnatal) with responses in adults; and, more extensive explorations regarding the reproductive biology and toxicology of puberty in humans.     

Identifying critical windows of exposure for children's health

Several authors have considered the importance of exposure timing and how this affects the outcomes observed, but no one has systematically compiled preconceptional, prenatal, and postnatal developmental exposures and subsequent outcomes. Efforts were undertaken to examine the information available and to evaluate implications for risk assessment for several areas: a) respiratory and immune systems, b) reproductive system, c) nervous system, d) cardiovascular system, endocrine system, and general growth, and e) cancer. Major conclusions from a workshop on "Critical Windows of Exposure for Children's Health" included a) broad windows of sensitivity can be identified for many systems but detailed information is limited; b) cross-species comparisons of dose to target tissue and better data on the exposure-dose-outcome continuum are needed; c) increased interaction among scientific disciplines can further understanding by using laboratory animal results in designing epidemiological studies and human data to suggest specific laboratory studies on mechanisms and agent-target interactions; and d) thus far, only limited attention has been given to peripubertal/adolescent exposures, adult consequences of developmental exposures, and genome-environment interactions. More specific information on developmental windows will improve risk assessment by identifying the most sensitive window(s) for evaluation of dose-response relationships and exposure, evaluation of biological plausibility of research findings in humans, and comparison of data across species. In public health and risk management, information on critical windows may help identify especially susceptible subgroups for specific interventions.     

The mammalian respiratory system and critical windows of exposure for children's health

The respiratory system is a complex organ system composed of multiple cell types involved in a variety of functions. The development of the respiratory system occurs from embryogenesis to adult life, passing through several distinct stages of maturation and growth. We review embryonic, fetal, and postnatal phases of lung development. We also discuss branching morphogenesis and cellular differentiation of the respiratory system, as well as the postnatal development of xenobiotic metabolizing systems within the lungs. Exposure of the respiratory system to a wide range of chemicals and environmental toxicants during perinatal life has the potential to significantly affect the maturation, growth, and function of this organ system. Although the potential targets for exposure to toxic factors are currently not known, they are likely to affect critical molecular signals expressed during distinct stages of lung development. The effects of exposure to environmental tobacco smoke during critical windows of perinatal growth are provided as an example leading to altered cellular and physiological function of the lungs. An understanding of critical windows of exposure of the respiratory system on children's health requires consideration that lung development is a multistep process and cannot be based on studies in adults.     

Critical windows of exposure for children's health: the reproductive system in animals and humans

Drugs and environmental chemicals can adversely affect the reproductive system. Currently, available data indicate that the consequences of exposure depend on the nature of the chemical, its target, and the timing of exposure relative to critical windows in development of the reproductive system. The reproductive system is designed to produce gametes in far greater excess than would seem to be necessary for the survival of species. Ten to hundreds of millions of spermatozoa are generated daily by most adult male mammals, yet very few of these germ cells succeed in transmitting their genetic material to the next generation. Although the number of oocytes produced in mammalian females is more limited, and their production occurs only during fetal life, most ovaries contain several orders of magnitude more oocytes than ever will be fertilized. Toxicant exposures may affect critical events in the development of the reproductive system, ranging from early primordial germ cell determination to gonadal differentiation, gametogenesis, external genitalia, or signaling events regulating sexual behavior. Although there are differences between the human reproductive system and that of the usual animal models, such models have been extremely useful in assessing risks for key human reproductive and developmental processes. The objectives for future studies should include the elucidation of the specific cellular and molecular targets of known toxicants; the design of a systematic approach to the identification of reproductive toxicants; and the development of sensitive, specific, and predictive animal models, minimally invasive surrogate markers, or in vitro tests to assess reproductive system function during embryonic, postnatal, and adult life.     

机动车尾气暴露与儿童神经行为功能关系

目的探讨机动车尾气暴露及相关因素对儿童神经行为功能的影响,并寻找神经行为功能受点人群。方法在福建省泉州市某区选择机动车尾气污染水平不同的2所小学,整群选取二、三年级学生进行问卷调查和神经行为功能测试,最终选择861名研究对象进行分析;采用卡方自动交互检测法(CHAID)分析儿童神经行为功能的主要影响因素及各因素之间可能存在的交互作用。结果二年级有被动吸烟的女童和二年级有被动吸烟且生活在污染区的男童神经行为功能受影响率最高,分别为72.55%和67.24%;机动车尾气暴露是影响三年级儿童神经行为功能的首要因素。结论机动车尾气及被动吸烟暴露的儿童应该被视为重点关注和保护人群;避免在居室内吸烟、减少机动车尾气污染等措施有利于儿童神经行为功能发育。     

Critical windows of exposure for children's health: cancer in human epidemiological studies and neoplasms in experimental animal models

In humans, cancer may be caused by genetics and environmental exposures; however, in the majority of instances the identification of the critical time window of exposure is problematic. The evidence for exposures occurring during the preconceptional period that have an association with childhood or adulthood cancers is equivocal. Agents definitely related to cancer in children, and adulthood if exposure occurs in utero, include: maternal exposure to ionizing radiation during pregnancy and childhood leukemia and certain other cancers, and maternal use of diethylstilbestrol during pregnancy and clear-cell adenocarcinoma of the vagina of their daughters. The list of environmental exposures that occur during the perinatal/postnatal period with potential to increase the risk of cancer is lengthening, but evidence available to date is inconsistent and inconclusive. In animal models, preconceptional carcinogenesis has been demonstrated for a variety of types of radiation and chemicals, with demonstrated sensitivity for all stages from fetal gonocytes to postmeiotic germ cells. Transplacental and neonatal carcinogenesis show marked ontogenetic stage specificity in some cases. Mechanistic factors include the number of cells at risk, the rate of cell division, the development of differentiated characteristics including the ability to activate and detoxify carcinogens, the presence of stem cells, and possibly others. Usefulness for human risk estimation would be strengthened by the study of these factors in more than one species, and by a focus on specific human risk issues.     

Use of gasoline exposure data and assessment. A summary report of work group III.

The overall consensus of the Work Group was that the workshop provided an excellent opportunity for discussion of the scientific issues pertaining to non-occupational exposures to gasoline as it related to public health officials, legal and regulatory agencies, and industrial (workplace) concerns. It was enlightening to discuss the implications of new and existing data and methods for determining the public's exposure to gasoline. The workshop resulted in a list of data needs and a vision of the future research that will be required to aid future users of exposure data.     

Workshop summary: connecting social and environmental factors to measure and track environmental health disparities

On May 24-25, 2005 in Ann Arbor, Michigan, the US Environmental Protection Agency, the National Institute of Environmental Health Sciences, and the University of Michigan sponsored a technical workshop on the topic of connecting social and environmental factors to measure and track environmental health disparities. The workshop was designed to develop a transdisciplinary scientific foundation for exploring the conceptual issues, data needs, and policy applications associated with social and environmental factors used to measure and track racial, ethnic, and class disparities in environmental health. Papers, presentations, and discussions focused on the use of multilevel analysis to study environmental health disparities, the development of an organizing framework for evaluating health disparities, the development of indicators, and the generation of community-based participatory approaches for indicator development and use. Group exercises were conducted to identify preliminary lists of priority health outcomes and potential indicators and to discuss policy implications and next steps. Three critical issues that stem from the workshop were: (a) stronger funding support is needed for community-based participatory research in environmental health disparities, (b) race/ethnicity and socioeconomic position need to be included in environmental health surveillance and research, and (c) models to elucidate the interrelations between social, physical, and built environments should continue to be developed and empirically tested.     

Seeking asylum in Denmark: refugee children's mental health and exposure to violence

AIMS: The aim of this study was to compare profiles of present mental health and previous exposure to violence among refugee children from the Middle East, whose asylum seeking families either did or did not obtain permission to stay in Denmark. METHODS: Shortly after arrival in Denmark, the parents of 311 Middle-Eastern children answered a structured interview on their children's exposure to organized violence and their mental health. The families were followed-up as concerns receipt of a residence permit. RESULTS: At arrival in Denmark, the children's patterns of previous exposure to violence and present mental health was generally similar irrespective of the family getting a residence permit, as was the case for 90 families (60.4%) with 190 children (61.1%). In both groups an overwhelming majority, eight to nine out of 10 children, had been exposed to conditions of war and had stayed in a refugee camp, and seven out of 10 had witnessed violence. Half of the children had a tortured parent. Considerably more children of families who did not get a residence permit had lost a parent (30.6% versus 13.7%; P<0.001). In both groups about two-thirds suffered from anxiety and about 30% from sleep problems, and children whose families did not later on get a residence permit more often appeared sad or miserable (43.8% versus 27.9%; P<0.005). CONCLUSIONS: The asylum-granting decision process seems to have divided the children into two groups with only superficial disparity as concerns their previous exposure to violence and their present mental health. There seems to be good reason to systematically integrate evidence on the children of refugee families in the treatment of applications for permission to stay.     

Using indicators to identify regions with critical maternal health conditions]

OBJECTIVE: In early 2000 the Ministry of Health and Social Welfare of Bolivia brought together a group of experts who, using available information, developed a method that made it possible to identify critical maternal and neonatal health sections of the country and to create a map of the health situation and of the existing health-services capacity in the 112 provinces of Bolivia. The objective of this piece is to describe the method that those experts created and applied. METHODS: Two indices were created, one for the health situation and the other for the existing health-services capacity. The steps followed in this process were: 1) identifying the variables included in each index, 2) weighting the variables in each index, 3) creating a mathematical formula for each index, 4) preparing a list with the data from each province for the chosen variables and with the percentage for each province for each index, obtained by using the respective formula, 5) setting three continuous-data categories for each index, and 6) defining the taxonomy that was possible by combining the results of the two indices. RESULTS: Applying this approach, a national map of the maternal health situation and of the existing capacity in each of the 112 Bolivian provinces was developed. This made it possible to choose a small number of provinces where the Ministry of Health and Social Welfare could work with other institutions to carry out joint interventions. The 9 selected provinces have a total of 26 municipalities, which include 17 health districts and which have 29% of the population of the country, 33% of the maternal deaths, and an estimated 35% of the early neonatal deaths. CONCLUSIONS: Using available information, this method generated a map of the overall maternal health situation in the 112 provinces of Bolivia and made it possible to identify critical geographical areas for health interventions.     

A critical examination of summary measures of population health

In the past decade, interest has been rising in the development, calculation and use of summary measures of population health, which combine information on mortality and non-fatal health outcomes. This paper reviews the issues and challenges in the design and application of summary measures and presents a framework for evaluating different alternatives. Summary measures have a variety of uses, including comparisons of health in different populations and assessments of the relative contributions of different diseases, injuries and risk factors to the total disease burden in a population. Summary measures may be divided into two broad families: health expectancies and health gaps. Within each family, there are many different possible measures, but they share a number of inputs, including information on mortality, non-fatal health outcomes, and health state valuations. Other critical points include calculation methods and a range of conceptual and methodological issues regarding the definition, measurement and valuation of health states. This paper considers a set of basic criteria and desirable properties that may lead to rejection of certain summary measures and the development of new ones. Despite the extensive developmental agenda that remains, applications of summary measures cannot await the final resolution of all methodological issues, so they should focus on those measures that satisfy as many basic criteria and desirable properties as possible.     

Model selection and Bayesian methods in statistical genetics: summary of group 11 contributions to Genetic Analysis Workshop 15

The research presented in group 11 of the Genetic Analysis Workshop 15 (GAW15) falls into two major themes: Model selection approaches for gene mapping (both Bayesian and Frequentist); and other Bayesian methods. These methods either allow relaxation of some of the common assumptions, such as mode of inheritance, for studying complicated genetic systems, or allow incorporation of additional information into the model. Over half of the groups applied model selection methods on all three data sets, using models in which genetic markers were used as predictors for linkage, phenotype expression, or transmission to an affected offspring. Most groups employed variations of Stochastic Search Variable Selection as the model selection method of choice. A brief review of this class of methods is given in this summary paper, followed by highlights of other methods and overall summaries of each contribution to the GAW15 presentation group 11. These group contributions exhibit the value of framing genetic problems in terms of model selection, and highlight the impact of variable selection for gene mapping.     

Human neurobehavioral effects of long-term exposure to styrene: a meta-analysis

Many reports in the literature suggest that long-term exposure to styrene may exert a variety of effects on the nervous system, including increased choice reaction time and decreased performance of color discrimination and color arrangement tasks. Sufficient information exists to perform a meta-analysis of these observations quantifying the relationships between exposure (estimated from biomarkers) and effects on two measures of central nervous system function: reaction time and color vision. To perform the meta-analysis, we pooled data into a single database for each end point. End-point data were transformed to a common metric of effect magnitude (percentage of baseline). We estimated styrene concentration from biomarkers of exposure and fitted linear least-squares equations to the pooled data to produce dose-effect relationships. Statistically significant relationships were demonstrated between cumulative styrene exposure and increased choice reaction time as well as increased color confusion index. Eight work-years of exposure to 20 ppm styrene was estimated to produce a 6.5% increase in choice reaction time, which has been shown to significantly increase the probability of automobile accidents. The same exposure history was predicted to increase the color confusion index as much as 1.7 additional years of age in men.     

Lessons learned for the assessment of children's pesticide exposure: critical sampling and analytical issues for future studies

In this article we examine sampling strategies and analytical methods used in a series of recent studies of children's exposure to pesticides that may prove useful in the design and implementation of the National Children's Study. We focus primarily on the experiences of four of the National Institute of Environmental Health Sciences/U.S. Environmental Protection Agency/ Children's Centers and include University of Washington studies that predated these centers. These studies have measured maternal exposures, perinatal exposures, infant and toddler exposures, and exposure among young children through biologic monitoring, personal sampling, and environmental monitoring. Biologic monitoring appears to be the best available method for assessment of children's exposure to pesticides, with some limitations. It is likely that a combination of biomarkers, environmental measurements, and questionnaires will be needed after careful consideration of the specific hypotheses posed by investigators and the limitations of each exposure metric. The value of environmental measurements, such as surface and toy wipes and indoor air or house dust samples, deserves further investigation. Emphasis on personal rather than environmental sampling in conjunction with urine or blood sampling is likely to be most effective at classifying exposure. For infants and young children, ease of urine collection (possible for extended periods of time) may make these samples the best available approach to capturing exposure variability of nonpersistent pesticides; additional validation studies are needed. Saliva measurements of pesticides, if feasible, would overcome the limitations of urinary metabolite-based exposure analysis. Global positioning system technology appears promising in the delineation of children's time-location patterns.     

Use of biomarkers to indicate exposure of children to organophosphate pesticides: implications for a longitudinal study of children's environmental health

Because of their history of widespread use in the United States and unknown long-term health effects, organophosphate pesticides (OPs) are being considered as a chemical class of interest in planning for the National Children's Study, a longitudinal study of children's environmental health. The availability and appropriate use of biomarkers to determine absorbed doses of environmental chemicals such as OPs are critical issues. Biomarkers of OP exposure are typically measured in blood and urine; however, postpartum meconium has been shown to be a promising matrix for assessing cumulative in utero exposure to the fetus, and studies are currently in progress to determine the utility of using saliva and amniotic fluid as matrices. In this article, we discuss the advantages and disadvantages of the currently available OP exposure monitoring methods (cholinesterase inhibition in blood, pesticides in blood, metabolites in urine and alternative matrices); study design issues for a large, long-term study of children's environmental health; and current research and future research needs. Because OPs are rapidly metabolized and excreted, the utility of one-time spot measurements of OP biomarkers is questionable unless background exposure levels are relatively stable over time or a specific time frame of interest for the study is identified and samples are collected accordingly. Biomarkers of OP exposure can be a valuable tool in epidemiology of children's environmental health, as long as they are applied and interpreted appropriately.