Executive Summary

Adverse health effects from exposure to lead are now recognized to be among industrialized society's most important environmental health problems. In the United States, more than 6 million preschool metropolitan children and 400,000 fetuses were believed to have lead concentrations above 10 micrograms per deciliter (µg/dL) of whole blood. That concentration has been designated by the U.S. Public Health Service as the maximum permissible concentration from the standpoint of protecting the health of children and other sensitive populations, and 20 µg/dL is the concentration at which medical intervention should be considered. A blood lead concentration of 10 µg/dL is low by comparison with the concentrations that have been associated with observable toxic reactions and that used to be widely permitted in the 1970s (e.g., 50–80 µg/dL). But it is hundreds of times higher than estimated blood lead concentrations in preindustrial peoples. For example, studies of bone samples of North American Indians and other preindustrial populations indicate that body burdens of lead in the general population today are 300–500 times greater than preindustrial background concentrations.

Science and society have been remarkably slow to recognize and respond to the full range of harm associated with lead exposure, but that is changing. Understanding of this public-health problem has involved a complex mixture of scientific knowledge, societal perception of risk, economic concerns based on lead's numerous uses, and a recognition that adverse health effects of lead are associated with lower exposures than previously believed. Current scientific studies in toxicology and epidemiology have shown that relatively low blood concentrations of lead may



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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations Executive Summary Adverse health effects from exposure to lead are now recognized to be among industrialized society's most important environmental health problems. In the United States, more than 6 million preschool metropolitan children and 400,000 fetuses were believed to have lead concentrations above 10 micrograms per deciliter (µg/dL) of whole blood. That concentration has been designated by the U.S. Public Health Service as the maximum permissible concentration from the standpoint of protecting the health of children and other sensitive populations, and 20 µg/dL is the concentration at which medical intervention should be considered. A blood lead concentration of 10 µg/dL is low by comparison with the concentrations that have been associated with observable toxic reactions and that used to be widely permitted in the 1970s (e.g., 50–80 µg/dL). But it is hundreds of times higher than estimated blood lead concentrations in preindustrial peoples. For example, studies of bone samples of North American Indians and other preindustrial populations indicate that body burdens of lead in the general population today are 300–500 times greater than preindustrial background concentrations. Science and society have been remarkably slow to recognize and respond to the full range of harm associated with lead exposure, but that is changing. Understanding of this public-health problem has involved a complex mixture of scientific knowledge, societal perception of risk, economic concerns based on lead's numerous uses, and a recognition that adverse health effects of lead are associated with lower exposures than previously believed. Current scientific studies in toxicology and epidemiology have shown that relatively low blood concentrations of lead may

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations be associated with toxic effects. The appropriate regulatory agencies have responded or have begun to respond by lowering the allowable (i.e., presumably safe) concentrations of lead in the population. Until the early 1970s in the United States, the acceptable concentration of lead in blood was 60 µg/dL in children and 80 µg/dL in adults. Early in 1990, after a series of intermediate lowerings of the acceptable concentration by various agencies and organizations, the Science Advisory Board of the U.S. Environmental Protection Agency (EPA) identified a blood lead concentration of 10 µg/dL as the maximum to be considered safe for individual young children, on the basis of available evidence. The U.S. Centers for Disease Control and Prevention (CDC) also recently lowered its lead-exposure guideline to 10 µg/dL and its guideline for medical intervention to 20 µg/dL. It should be noted that CDC, in a 1985 statement, explicitly identified lead toxicity in children at blood lead concentrations well below 25 µg/dL, but a lower concentration was not chosen as a guideline at that time, because of the logistics and feasibility of lead screening. As with the previous reduction in exposure limits, the advent of more sensitive and reliable analytic techniques has played a central role in these changes in permissible exposures. CHARGE TO THE COMMITTEE AND STRUCTURE OF THE REPORT This report was prepared by the National Research Council's Committee on Measuring Lead Exposure in Critical Populations, a committee of the Board on Environmental Studies and Toxicology. The study was sponsored by the Agency for Toxic Substances and Disease Registry (ATSDR). As part of its efforts to prepare this report, the committee summarized new scientific evidence on the low-dose toxicity of lead, and generally concurs with CDC in the selection of 10 µg/dL as the concentration of concern in children. Meeting this new guideline will require substantial improvement in methods for measuring lead in blood and monitoring other biologic markers of lead in tissues. If preventive techniques are to be successful, amounts and sources of lead must be identified. Developing analytic measurement techniques that are accurate and precise at such low concentrations is a difficult scientific challenge.

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations The committee was charged to examine one segment of the lead issue: the assessment of lead exposure in sensitive populations via various biologic markers of exposure and early effects. Chapters 2 and 3 of this report summarize the toxicity of lead and sources of exposure to lead for sensitive populations, defined in this report as infants, children, and pregnant women. Chapter 4 deals with lead in blood and other physiologic media and describes the monitoring of biologic markers that indicate that exposure to lead has occurred, markers of early toxic effects, and markers of susceptibility. Chapter 5 assesses techniques for quantitative measurement of the biologic markers of exposure and effect; it concludes by describing trends in monitoring lead exposure and the  effects on society of reducing exposure. Finally, Chapter 6 presents the committee's conclusions and recommendations to improve the monitoring of lead in sensitive populations. CONCLUSIONS Sensitive Populations As CDC has concluded, blood lead concentrations at or around 10 µg/dL present a public-health risk to sensitive populations on the basis of current evidence. The sensitive populations with respect to these adverse effects are infants, children, and pregnant women (as surrogates for fetuses). There is growing evidence that even very small exposures to lead can produce subtle effects in humans. Therefore there is the possibility that future guidelines may drop below 10 µg/dL as the mechanisms of lead toxicity become better understood. The adverse effects noted at approximately 10 µg/dL include Impairments of CNS and other organ development in fetuses. Impairments in cognitive function and initiation of various behavioral disorders in young children. Increases in systolic and diastolic blood pressure in adults including pregnant women. Impairments in calcium function and homeostasis in sensitive populations found in relevant target organ systems.

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations Somewhat higher blood lead concentrations are associated with impairment in biosynthesis of heme, a basic substance required for blood formation, oxygen transport, and energy metabolism. Some effects described above—cognitive dysfunction and behavioral disorders—might well be irreversible. One recent study showed persistence into early adulthood of childhood neurobehavioral effects due to lead. The revelation of adverse effects after modest exposures in study populations forces the question of what the aggregate impact on sensitive populations is, with respect to current exposures. Quantitative Methods for Analysis Exposure It is estimated that millions of infants, children, and pregnant women in the United States have blood lead concentrations above 10 µg/dL. And, the toxicity of lead is established across the spectrum of exposure concentrations starting as low as 10 µg/dL. The exposure span between these low-dose effects and the concentrations of lead associated with substantial risk of severe brain damage and death is a factor of only 10–15 for a child and probably less for a fetus. In contrast, safety margins of 10–100 for other toxic substances are commonly used with the lowest-observed-effect level (LOEL) in humans to establish an acceptable exposure of the general population. Sources and Accumulation With the reduction of lead in gasoline and foods, the remaining major sources of lead are Lead-based paint. Dust and soil. Drinking water. Occupational exposure.

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations Lead-based paint is the largest source of high-dose lead exposure for children. Dust and soil can be high-dose sources and can also constitute important sources of general population exposure. Drinking water is also a major source for the general population, and sometimes high concentrations of lead are found in drinking water. Lead in food is primarily a general population source. Although lead in food declined markedly during the 1980s, primarily because of the decrease in use of lead-soldered cans manufactured in the United States, imported canned foods continue to be high in lead. Gasoline lead was the major source of general population exposure in the 1970s, but regulatory action has reduced it by over 95%. Dust and soil lead is a legacy of past production of lead, as well as past uses in paint, gasoline, and other substances. Dust and soil lead continues to be replenished by the deterioration of lead-based paint and other sources. It serves as a compelling environmental reminder that lead is not biodegradable and will accumulate in areas with substantial loadings. In addition, stationary sources of lead, such as smelters, can be regionally important. RECOMMENDATIONS Sensitive Populations The committee had as a principal task the characterization of members of the population who are at increased risk for lead exposure and toxicity and are therefore members of a ''sensitive'' population. The committee identified a number of sensitive populations in which low-dose lead exposure assessments were necessary. They include infants, children, and pregnant women. Other populations are at risk because of potentially large exposures. The committee concluded, however, that the most sensitive populations are infants, children, and pregnant women; these populations are the focus of this report. (Lead workers have long been recognized to be at high risk because of excessive exposure.) Populations are defined as sensitive according to intrinsic and extrinsic factors or mixtures of the two. Age, sex, and genetic susceptibilities

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations typify intrinsic factors; relationships of subjects to external exposure sources define extrinsic factors. Mixtures of the two can exist, as in female workers who are exposed to lead in the workplace. Quantitative Methods for Analysis The principal markers of exposure are lead concentrations in various physiologic media, of which whole blood is the most commonly used for exposure assessment in sensitive populations. In very young children, lead in whole blood is an indicator mainly of recent exposure although there can be variable (but not dominant) input to total blood lead from past accumulation in the body. In adults and particularly lead workers, the past accumulation is a more prominent contributor to total blood lead. However, the historical input is determined by the slow kinetic component in blood-lead decay rates and thus, it is rarely the dominant contributor to total blood lead. Requirements for a longer-term measure of continuing lead exposure in sensitive populations necessitates use of in vivo measurements of lead in bone. Lead in shed teeth reflects lead accumulation over the period from tooth eruption to shedding in children and is useful for quantifying accumulation, but is inadequate as a basis for regulatory action, because it reflects exposure over a long period. Traditionally, impairments of steps in the biosynthesis of heme have been exploited as effect markers in sensitive populations. The accumulation of erythrocyte protoporphyrin (EP or ZPP) in whole blood was once the primary screening test to identify children with increased lead burdens. As blood lead concentrations of concern have continued to decline, however, this measure does not retain the necessary sensitivity or the specificity. One measure judged not to have meaning for systemic toxicity is inhibition in activity of porphobilinogen synthetase (ALA-dehydratase), an enzyme in the erythrocyte. Experimental animal studies have identified lead-binding proteins and stoichiometrically interactive processes of lead with calcium systems in various tissues. Their immediate relevance or feasibility for routine exposure screening in sensitive populations remains undefined. The committee recommends

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations That, because of the known relationship of the calcium messenger system to growth, development, and cognitive function, new methods be developed to characterize disturbances in the calcium messenger system associated with lead exposure. That research be conducted on the effects of lead on affected organ systems (e.g., the reproductive system and the genitourinary system) and on the toxicokinetic behavior of lead (particularly bone lead) in human populations. That research be conducted to improve the understanding of mechanisms of low-dose lead toxicity, with emphasis on lead's effects on gene expression, calcium signaling, heme biosynthesis, and cellular energy production. That research be conducted to examine further the persistence and reversibility of lead's effects. Exposure The presence of mean blood lead concentrations in the U.S. population close to those which produce adverse health effects illustrates the importance of correctly measuring lead concentrations in sensitive populations. The committee recognized that exposure guidelines for health protection may be further reduced in the future. The committee addressed measurement techniques for markers of both exposure and effect useful at low blood lead concentrations. Emphasis was placed on lead in physiologic media and EP, respectively. For the present and near future, the committee concluded that the primary screening tool to assess current lead exposure will be blood lead concentration, rather than EP concentration. At current body lead burdens of concern—i.e., those associated with the new CDC action level of 10 µg/dL—the EP technique is not sufficiently sensitive. (Evidence from diverse epidemiologic studies shows that the EP technique was not sufficiently sensitive even at the previous CDC guideline of 25 µg/dL.) Current measurement techniques are capable of producing accurate and precise blood lead measurements. They include atomic-absorption spectrometry (AAS), anodic-stripping voltammetry (ASV), and thermalionization mass spectrometry (TIMS), all of which can be applied at parts-per-billion concentrations of lead in biologic media. Use of those

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations methods assumes competence and strict attention to contamination control and other quality-assurance and quality-control (QA-QC) procedures. To achieve optimal methodologic utility and proficiency for routine and developmental needs, the committee particularly recommends That primary screening be done initially by measurement of lead in whole blood. That, given the current blood lead concentrations of concern, accurate and precise blood lead values be obtained, with strict attention to contamination control and other principles of QA-QC. That rigorous trace-metal clean techniques be established in sample collection, storage, and analysis. That a laboratory certification program be established, involving participation in external (blind) interlaboratory proficiency testing programs and analysis of lead in blood with concurrent analysis of appropriate reference materials. That, for more research-oriented purposes, standard reference materials be made available for such media as bone, blood, and urine, to allow laboratory evaluation of accuracy; this effort should be complemented by similar standards available for environmental media. That studies be conducted to explore the feasibility of applying ultraclean leadfree techniques to in vitro studies. That mass spectrometry with stable isotopes be used to investigate sources of environmental lead, as well as to examine lead metabolism in humans. Sources and Accumulation The committee identified the need for and acknowledged the rapidly developing availability of measurements for long-term lead accumulation during active exposure periods in sensitive populations, especially children and pregnant women. In so doing, it acknowledged that blood lead for routine purposes remains principally an index of recent exposure. In vivo K- and L-line x-ray fluorescence measurements of long-term accumulated lead in trabecular and cortical bone of sensitive populations have been developed and evaluated in some detail, and they may be feasible as routine screening tools for selected sensitive populations in the future. The committee recommends

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations That more sensitive techniques for quantifying body burdens of lead in workers via bone lead dosimetry be developed. That, when radiation techniques are used for bone lead determinations, great care be taken that doses to individual subjects and populations, particularly the human conceptus, be carefully quantified according to National Council on Radiation Protection and Measurement (NCRP) guidelines. The committee recognizes that the application of analytical techniques as described for the measurement of lead concentrations will require a large commitment of resources. Further, the establishment of new methods will require a significant investment of funds for research. However, the importance of the problem requires this commitment of manpower and funds.

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