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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations 6 Summary and Recommendations Society and science are working hard to comprehend and respond to lead as a major, persisting public-health issue that is of particular relevance to what are termed sensitive populations (i.e., populations that are at special risk for the subtle adverse health effects of chronic low-dose lead exposure): infants, children, and pregnant women (as surrogates for fetuses). This chapter presents recommendations on such matters as sources and pathways of lead exposure, the environmental epidemiology of lead in sensitive populations, methods of assessing exposure to lead with reference to markers of both exposure and effect, and adverse health effects of lead. SOURCES OF LEAD EXPOSURE An understanding of lead exposure in sensitive populations requires knowledge of the possible sources of exposure. This is especially important for lead, because it is found widely throughout the environment. However, for sensitive populations, there are some sources that are more important than others. These include lead in paint, gasoline, drinking water, solder (used to solder joints in water-distribution systems and used in imported food packaging), and in imported pottery. As noted previously, there are some continued uses of lead arsenate in agriculture, and it may be a contaminant in some dietary supplements, such as calcium preparations. Finally, this report did not address occupational exposure, but this may also be an important indirect source
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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations of exposure for some children in families whose parents work in lead industries. ADVERSE HEALTH EFFECTS OF LEAD The committee has identified infants, children, and pregnant women (as surrogates for fetuses) as sensitive populations at risk for the subtle adverse health effects of chronic low-dose lead exposure. In addition, adults occupationally exposed to lead and others having potentially large exposures face the risk of various forms of lead toxicity, including risk of lead-induced increases in blood pressure. However, the most sensitive populations at special risk for lead toxicity are infants, children, and pregnant women (as surrogates for fetuses). There has been a substantial change in our understanding of the health effects of lead since the mid-1970s. When the 1970s began, interest in lead was focused on symptomatic lead-poisoned children. Research beginning in the 1980's identified cognitive effects short of encephalopathy and numerous noncognitive end points of smaller and smaller lead exposures. Those changes have redefined the populations at risk and the risks themselves. The 1980s also saw the advent of prospective studies examining the cognitive effects of prenatal and postnatal exposure to lead. Such studies have been undertaken in populations with much smaller exposures than were previously examined. Despite the lower power implied by the smaller exposure range and exposures closer to the measurement error in the analytic techniques used, studies by Bellinger, Dietrich, and Vimpani and their co-workers have all found decrements in the Bayley Scales of Infant Development (used to judge extent of growth and development) and other developmental tests for infants associated with prenatal, postnatal, or perinatal lead exposure. The blood lead concentrations in these studies were usually 5–15 µg/dL. Associations found in a study group consisting mostly of people with a history of alcohol and drug abuse were weaker or insignificant, possibly because of difficulties in detecting the effects of lead in a population exposed to other toxic agents. Even in that group, the trends generally suggested decreased performance with increased lead exposure. Another development has been the use of end points other than full-scale
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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations IQ to measure the effects of lead on the central nervous system (CNS), such as teacher rating scales, reaction-time tests with an attention-span component, brain stem auditory evoked potentials, hearing thresholds, and other electroencephalographic measures. Some have found balance to be a sensitive early indicator of lead toxicity. The findings have added strength to the association with full-scale IQ, but it is noteworthy that the most consistent finding across all the studies of the CNS effects of lead is the association of increasing exposure with increasing reaction time, which apparently indicates an attention deficit. Similar effects have been noted in monkeys, again at lead concentrations of 5–15 µg/dL. One complex of recently identified end points involves disturbances in the growth and development of the fetus and child. That identification has been accompanied by increased evidence of metabolic disturbances on the subcellular level that provide clues to the possible mechanisms of lead toxicity. Recent studies indicate an inverse association of maternal lead exposure with birthweight or duration of pregnancy. For example, one study indicated that a change in maternal blood lead concentration from 4 to 8 µg/dL would be associated with a 0.6-week reduction in duration of pregnancy and a consequent 46-g reduction in birthweight. The joint teratogenic effects of alcohol, tobacco, and lead appear to be less than additive, and that could account for the lack of statistical significance in the finding of Ernhart and co-workers in a population with a history of alcohol abuse. Effects of lead on postnatal growth and development have been reported. Shortness of heavily exposed children (mean blood lead, 57 µg/dL) was noted by Mooty in 1975. In 1986, Schwartz and co-workers reported an association between lead and stature, with a 3-cm decline in height at age 5 as blood lead concentrations increased from 5 to 25 µg/dL. Prospective studies have confirmed an association of lead exposure with retarded postnatal growth in infants and children. Lead has also been associated with a delay in the age at which a child first sits up. Again, the findings suggest significant differences between blood lead concentrations of 5 and 15 µg/dL. Early epidemiologic assessments relied on traditional questionnaires (rote counting). If the majority of studies found an association, the effect was likely. The fact that the statistical analyses were highly
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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations sensitive to sample size was ignored, as were the sample sizes themselves. However, recent epidemiologic assessments have paid more attention to general trends and effect-size comparisons between studies and less attention to vote counting. Intuitively, five studies showing the same effect size are fairly convincing, whereas five studies with widely differing effect sizes are mostly suggestive of uncontrolled confounding. Meta-analysis is the common term for the more formal statistical methods for combining studies. Although the methods of meta-analysis must be applied cautiously, they promise an important improvement in the interpretation of the literature. MARKERS OF LEAD EXPOSURE AND EFFECT Lead has been shown to be a potent disturber of cellular calcium metabolism, preferentially binding to and activating or blocking calcium-binding proteins, such as calmodulin and calcitonin. Lead appears to produce increased intracellular calcium stores in every tissue studied, possibly with consequences for second-messenger functions. Recently, lead has been shown to activate protein kinase C at less than picomolar concentrations. No direct connection between those metabolic changes and disturbances in growth or cognitive functions has been established, but the existence of such changes adds considerable plausibility to the epidemiologic findings, particularly in view of the pervasive role of calcium in regulating cellular function. Molecular biologic markers for assessing individual differences in responsiveness to lead exposure are of increasing interest, because of the well-known individual variations in susceptibility at a given blood lead concentration. Radioimmunoassays for marker proteins, such as the renal and brain lead-binding proteins that have been found in the blood and urine of rodents, are of great potential value in elucidating the underlying causative factors of susceptibility to lead toxicity at the molecular level. The use of markers involves noninvasive or minimally invasive procedures. That is particularly important for gaining acceptance by public-health professionals and the public. It is clear that new marker techniques must be rapid, relatively simple, economically feasible, and associated with minimal health risks, if they are to gain widespread application.
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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations The committee concludes that a number of questions concerning the systemic compartmental mobility of lead remain, especially those related to methods of monitoring for lead exposure. The committee recommends that further studies be done to determine the factors that influence movement of lead into bone and from bone to blood and other target tissues; the early-effect indicators in lead exposure monitoring, including research on lead-binding proteins and their use in monitoring for small exposures; and in vivo lead and calcium interactions. TECHNIQUES TO MEASURE LEAD EXPOSURE AND EARLY TOXIC EFFECTS Continuous measurement of exposure, allowing more detailed investigation of potential dose-response relations, has been introduced. Improved analytic techniques have reduced errors in the measurement of lead exposure, as well as of some covariates. Biologic markers of exposure—such as blood lead, urinary lead, and bone lead—have always involved measurement of total lead in epidemiologically and clinically relevant biologic media. The existence of specific biochemical forms of lead in accessible physiologic media, their role in lead toxicokinetics and toxicity, and their comparative diagnostic value in in situ biochemical behavior are important and perhaps require more attention in the future. In the near term, such questions would have to be addressed through in vivo metal research. The potentially useful form-specific analysis in the near term for some segments of populations at risk has to do with speciation of inorganic versus biochemically stable organolead species in physiologic media with existing trace and ultratrace analytic methods. This approach is important for specific populations where environmental alkylation and accumulation occur or existence of alkyl lead forms would be problematic and where evidence exists of accumulation of different organolead species in tissues such as brain. The current trend in measurements for lead dosimetry and effects is toward noninvasive or minimally invasive procedures for blood, urine, or bone. For bone, the anatomic location of the measurement is typically the finger, tibia, or calcaneus, because the bone in those areas is
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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations close to the skin and x-ray absorption in soft tissue is minimized. Those anatomic locations might also be physiologically important because of apparent differences between the residence time of lead in compact versus cancellous bone, which could influence calculations of internal lead doses from bone lead stores. The regulatory and public-health implications of the advent of the techniques noted above concern the new ability to detect low-dose lead effects and to relate them more precisely to internal lead dosage. Further refinements and validation of the methods should permit societal decisions about low-dose lead in sensitive populations to be made on the basis of actual data, as opposed to calculated extrapolations, which can be based on uncorroborated assumptions. Clearly, the new methods have the potential to revolutionize public-health strategies in dealing with lead. The committee concludes that, at the current blood lead concentrations of concern, accurate and precise blood lead values can be obtained with current techniques, given strict attention to contamination control and other principles of quality assurance and quality control (QA/QC). For the present and near future, blood lead values, rather than those of erythrocyte protoporphyrin, will be the primary screening tool to assess current lead exposure. The committee recommends that the optimal screening method should be venous sampling. However, the committee recognizes that initial screening of small children will involve capillary blood sampling with strict attention to principles of contamination control. Under the latter circumstances, a confirmatory followup measurement on children whose measurements exceed the latest Centers for Disease Control and Prevention guidelines should be carried out on a venous blood sample obtained by venipuncture. The primary concerns associated with current measurements of lead concentrations in sensitive populations are unrecognized contamination and insufficient QA/QC. Several analytic techniques (atomic-absorption spectroscopy (AAS), anodic stripping voltammetry (ASV), and inductively coupled plasma mass spectrometry (ICP-MS)) are available for routine measurements of lead concentrations at parts-per-billion concentrations in clinical laboratories experienced in conducting those measurements regularly.
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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations The committee recommends the establishment of rigorous tracemetal cleanup techniques in sample collection, storage, and analysis in all clinical laboratories. The quality of those measurements should be documented with detailed QA/QC procedures, required participation in blind interlaboratory proficiency testing programs, and analysis of lead in blood with concurrent analyses of appropriate reference materials. There is a need for stored samples and standard reference materials (bone, water, blood, urine, dust, soil, and paint) to assess laboratory precision and adherence to QA/QC principles. Aliquots of representative samples also need to be stored for future intercalibrations. As the focus of epidemiologic studies has turned to smaller lead exposure, the problem of errors in the variables has become more severe, and the need for more careful measurements has markedly increased. Errors in measurement of variables other than lead similarly assume considerable importance. Before epidemiologic studies are begun, errors in variables (e.g., the standard deviation of the analytic measurement error in blood lead or IQ) must be systematically quantified. For L-line and K-line x-ray fluorescence (XRF) instruments, standard reference materials are needed for intralaboratory and interlaboratory measurements and QA/QC assessments. Standard reference materials should be used to evaluate the counting time necessary to achieve a quantitative lead peak of, e.g., 10 ppm, with 95% confidence limits, under the same operating conditions used for patient measurements. If L-line or K-line instruments are proposed for use in women of child-bearing age or pregnant women, the radiation risk to the human conceptus must be carefully quantified, according to NRC guidelines. Moreover, dosimetry measurements of both instruments should be calculated with strict adherence to National Council on Radiation Protection and Measurements procedures. The calculations should include determinations of absorbed- and scattered-dose rates, with radiation quality and tissue distribution weighting factors used for final calculations of the effective dose equivalent. The procedures should then provide confidence that risks associated with these techniques have been thoroughly examined. The committee recommends that federal agencies consider the need for further L-line and K-line XRF instrument development to decrease
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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations the counting time and enhance the detection limits without increasing radiologic risks. Both techniques may have future clinical utility to answer outstanding questions essential to protect the health of sensitive populations. Federal agencies, which are mandated to clear new medical devices for clinical use, should be cognizant of the sequence of XRF instrument assessments that are necessary to ensure radiologic safety and clinical utility of these instruments in sensitive populations. Recent advances in mass spectrometry have demonstrated the applicability of stable lead isotopes for investigating sources of environmental lead. The committee recommends that thermal-ionization mass spectrometry (TIMS) and ICP-MS be used to identify and trace unique sources of lead contamination that can be characterized by isotopic composition. The same instrumentation could be used to investigate lead metabolism in humans with relatively small (microgram) amounts of a stable lead isotope tracer. The refinement of other analytic techniques that are still in development should be promoted for surface-area analyses (e.g., secondary-ion mass spectrometry, SIMS) and microanalyses (e.g., laser microprobe mass spectrometry, LAMMA). In cells and tissues, lead has been shown to perturb the calcium messenger system. Although a direct connection between metabolic and dosimetric changes to disturbances in growth, development, vascular peripheral resistance, and cognitive function has yet to be fully established, the pervasive role of the calcium messenger in regulating diverse cellular functions provides considerable plausibility to epidemiologic findings. Given the inherent plausibility of those mechanistic and dosimetric observations, new initiatives and refinements in methods are needed to characterize further these and early toxic effects of lead on cells and tissues. Such new approaches and refinements in current techniques might become relevant in assessing lead exposure and toxic biochemical effects in sensitive populations. The committee finds a need to measure the biologically active chemical species of lead that produce toxic effects at low doses and their relationship to lead binding in major intracellular compartments, such as
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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations lead-binding proteins, intranuclear inclusion bodies, mitochondria, and lysosomes. In addition, there is a need to understand further the mechanisms of low-level lead toxicity in target tissues, with particular emphasis on lead-induced changes in gene expression, calcium, signaling, heme biosynthesis, and cellular energy production. Current tissue-culture studies involve a degree of lead contamination in media and various reagents. As a result, even so-called untreated control cells can be perturbed, to an extent, by ambient lead in tissue-culture media. To understand further lead's mechanistic effects at the cellular level, the committee recommends that studies be conducted to explore the feasibility of applying ultraclean lead-free techniques to in vitro studies.
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