2
Adverse Health Effects of Exposure to Lead

Exposure to lead produces a variety of adverse health effects in sensitive populations through its impact on different organs and systems. The nature of the effects is a complex function of such factors as the magnitude of exposure, the physiologic and behavioral characteristics of the exposed person, and the relative importance of the lead-injured organ or system to overall health and well-being. The toxic effects of lead range from recently revealed subtle, subclinical responses to overt serious intoxication. It is the array of chronic effects of low-dose exposure that is of current public-health concern and that is the subject of this chapter. Overt, clinical poisoning still occurs, however, and is also discussed here. We have several reasons for emphasizing low-dose exposure. As recently noted by Landrigan (1989), the subtle effects of lead are bona fide impairments, not just inconsequential physiologic perturbations or slight decreases in reserve capacity. And the effects are associated with magnitudes of lead exposure that are encountered by a sizable fraction of the population in developed countries and thus are potentially found in very large numbers of people.

This chapter summarizes key points about the health effects of exposure of sensitive populations to lead. It deals specifically with various adverse effects of lead in sensitive populations (with emphasis on effects of low-dose exposure), persistence of some important health effects, molecular mechanisms of lead toxicity, and dose-effect relations. As described below, clinical lead poisoning differs between children and adults, in part because their organ systems are affected in different ways and to different extents. In addition, some people are more vulnerable



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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations 2 Adverse Health Effects of Exposure to Lead Exposure to lead produces a variety of adverse health effects in sensitive populations through its impact on different organs and systems. The nature of the effects is a complex function of such factors as the magnitude of exposure, the physiologic and behavioral characteristics of the exposed person, and the relative importance of the lead-injured organ or system to overall health and well-being. The toxic effects of lead range from recently revealed subtle, subclinical responses to overt serious intoxication. It is the array of chronic effects of low-dose exposure that is of current public-health concern and that is the subject of this chapter. Overt, clinical poisoning still occurs, however, and is also discussed here. We have several reasons for emphasizing low-dose exposure. As recently noted by Landrigan (1989), the subtle effects of lead are bona fide impairments, not just inconsequential physiologic perturbations or slight decreases in reserve capacity. And the effects are associated with magnitudes of lead exposure that are encountered by a sizable fraction of the population in developed countries and thus are potentially found in very large numbers of people. This chapter summarizes key points about the health effects of exposure of sensitive populations to lead. It deals specifically with various adverse effects of lead in sensitive populations (with emphasis on effects of low-dose exposure), persistence of some important health effects, molecular mechanisms of lead toxicity, and dose-effect relations. As described below, clinical lead poisoning differs between children and adults, in part because their organ systems are affected in different ways and to different extents. In addition, some people are more vulnerable

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations to lead toxicity and have increased  sensitivity, because they suffer from disease, lack proper nutrition, or lack adequate health care. These factors influence exposure patterns and the biokinetics of lead absorption. CLINICAL INTOXICATION IN CHILDREN Childhood lead poisoning involves injury in at least three organ systems: the central nervous system (specifically, the brain), the kidney, and the blood-forming organs. Other systems are also affected, but the nature of their toxic injury has not been as well characterized. Central Nervous System Effects The nature of lead-associated overt central nervous system injury in children differs with the degree of lead exposure. Blood lead concentrations of about 100–150 µg/dL are associated with a high  probability of fulminant lead encephalopathy. Before the widespread clinical use of chelation therapy, lead encephalopathy carried a high rate of mortality, about 65% (Foreman, 1963; NRC, 1972). The use of chelation therapy, pioneered by Chisolm and co-workers (NRC, 1972), has reduced mortality to 1 or 2%, or even less, if the poisoning is recognized and dealt with. The range of blood lead concentrations reported in association with encephalopathy is quite large (NRC, 1972), owing to such factors as individual differences in toxicokinetics and in timing of lead measurement and treatment. Children are much more sensitive than adults to the neurophatic effects of lead. The central nervous system is principally involved in children and the peripheral nervous system in adults (Chisolm and Harrison, 1956; NRC, 1972; Chisolm and Barltrop, 1979; Piomelli et al., 1984), and thresholds of blood lead concentration for neurofunctional measures are lower in children. The common neuropathologic findings in fatal childhood lead encephalopathy (Pentschew, 1965) are cerebral edema, structural derangement in capillaries, neuronal necrosis, and neuronal loss in isocortex and basal ganglia. Many children who survive an episode of lead encephalopathy have permanent neurologic sequelae, including retardation and severe behavioral

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations disorders (Byers and Lord, 1943; Perlstein and Attala, 1966; Rummo et al., 1979). Renal Effects Kidney injury in childhood plumbism is most often seen in overt poisoning and involves damage to the proximal tubule. In poisoning with encephalopathy, Chisolm (1962, 1968) has found the presence of the full, albeit transitory, Fanconi syndrome: glycosuria, aminoaciduria, hyperphosphaturia (with hypophosphatemia), and rickets. In overt toxicity after a range of exposures, aminoaciduria is the most consistent finding (Chisolm, 1962). In chronic high-dose lead exposure, aminoaciduria appears to be the most consistent nephropathic finding. In a group of children with blood lead concentrations of 40–120 µg/dL, Pueschel et al. (1972) found aminoaciduria in those with blood lead of 50 µg/dL or more. The role of childhood lead poisoning as a known contributor to early adult chronic nephritis found in Australia (e.g., Henderson, 1954; Emmerson, 1963) has not been identified in the United States (Tepper, 1963; Chisolm et al., 1976). Hematologic Effects Anemia is common in severe chronic lead poisoning and is reported to be associated with blood lead concentrations of 70 µg/dL and higher (NRC, 1972; CDC, 1978; Chisolm and Barltrop, 1979). However, reanalyses of the hematologic data of Landrigan et al. (1976) in children by Schwartz et al. (1990) indicated that anemia as indexed by hematocrit is present with blood lead concentrations below 70 µg/dL. Typically, the anemia is mildly hypochromic and normocytic and arises from a combination of reduced hemoglobin formation (resulting from either impaired heme synthesis or globin chain formation) and reduction in erythrocyte survival because of hemolysis (Waldron, 1966; Valentine and Paglia, 1980).

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations INTOXICATION IN ADULTS The most extensive adult studies are of workers occupationally exposed to lead in battery recycling, lead smelting, alkyl lead manufacturing, plumbing, and pipefitting. These studies are described in other reports (EPA, 1986a; ATSDR, 1988) of lead exposure and are not the focus of this report. This report examines principally the effects of lead exposure in pregnant women as a sensitive population. Other adult populations may be at increased risk of lead intoxication because of large exposures, but they are beyond the scope of this report. For this reason, only a brief summary of effects in adults is presented below. Central Nervous System and Other Neuropathic Effects Although lead poisoning after very large exposures in adults can produce central nervous system injury, the exposure threshold is much higher in adults than in children. Blood lead concentrations associated with adult encephalopathy are well above 120–150 µg/dL. The features of adult lead encephalopathy, which can be as abrupt in onset in adults as in children, have been described by Aub et al. (1926), Cantarow and Trumper (1944), and Cumings (1959). They include dullness, irritability, headaches, and hallucination, progressing to convulsions, paralysis, and even death. The more typical neuropathologic outcome of adult lead poisoning is peripheral polyneuritis involving sensory or motor nerves. There is often pronounced motor dysfunction, such as wrist drop and foot drop in the more advanced cases (Feldman et al., 1977). Changes include segmental demyelination and axonal degeneration (Fullerton, 1966), often with concomitant endoneural edema of Schwann cells (Windebank and Dyck, 1981). Renal Effects Occupational chronic lead nephropathy, the most important category of lead-associated kidney injury in adult populations, has been heavily studied for many years in Europe, but not as well in the United States.

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations In the studies of Wedeen et al.(1975, 1979), renal dysfunction has been established in U.S. lead workers, many of whom had no history of prior lead poisoning. Generally, the Fanconi syndrome of acute childhood poisoning is not seen in adults with chronic lead poisoning. Proximal tubular injury from lead in adults at early stages of nephropathy is difficult to detect in workers, because of extensive renal reserve (Landrigan et al., 1982). Hyperuricemia is frequent probably because of increased uric acid production (Granick et al., 1978). Lead has been clearly demonstrated to produce tubular nephrotoxicity in humans and rodents after acute or chronic exposure (Goyer and Rhyne, 1973; Wedeen et al., 1986; Ritz et al., 1988). Tubular proteinuria is a well-known manifestation of metal nephrotoxicity, but inconsistently reported in lead nephrotoxicity (Bonucci and Silvestrini, 1989; Goyer, 1989), perhaps because of the lack of sensitive and specific protein assays (Bernard and Becker, 1988). With the advent of two-dimensional gel electrophoresis (O'Farrell, 1975) and highly sensitive silver staining methods (Merril et al., 1981), it should be possible to separate various nonreabsorbed proteins from the urinary filtrate into lead-specific patterns at an early stage of tubular injury or monitor the low-molecular-weight proteins, such as retinol-binding protein, which is stable at the pH of normal urine (Bernard and Becker, 1988). Hematologic Effects Lead workers often show evidence of both marked impairment of heme biosynthesis and increased erythrocyte destruction (EPA, 1986a). Characteristic biochemical and functional indexes of those impairments include increased urinary delta-aminolevulinic acid and erythrocyte zinc protoporphyrin, increased cell fragility, and decreased osmotic resistance, which combine to produce anemia (Baker et al., 1979). REPRODUCTIVE AND DEVELOPMENTAL EFFECTS Reproductive and Early Developmental Toxicity Reproductive toxicity resulting from the high-dose lead exposure is

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations well established (Rom, 1976). Much of the early literature focused on an increased incidence of spontaneous abortion and stillbirth associated with lead exposure in the workplace (Paul, 1860; Legge, 1901; Oliver, 1911; Lane, 1949). In addition, lead was used as an abortifacient in England (Hall and Cantab, 1905). These outcomes, which are far less common today, presumably involve some combination of gametotoxic, embryotoxic, fetotoxic, and teratogenic effects and define the upper end of the spectrum of reproductive toxicity in humans. Since these earlier reports, industrial exposure of women of childbearing age was restricted by improved industrial hygiene practices, but a recent U.S. Supreme Court decision ruled exclusion illegal. The decision was based on the premise of equal access to the workplace, not on insufficiency of evidence of toxic harm. Epidemiologic studies of exposed women have reported reproductive effects of lead exposure in both nonoccupational groups (Fahim et al., 1976; Nordstrom et al., 1978a,b) and occupational groups (Panova, 1972). Deficiencies in the design of the studies prevent definitive conclusions, but the studies have helped to direct attention to a potential problem. Very early preimplantation loss can easily go undetected and might be occurring after moderate-dose and perhaps even low-dose exposure. With the advent of human chorionic gonadotropin assays, it is now possible to detect the onset of pregnancy and early fetal loss during the first 1–2 weeks of pregnancy. Savitz et al. (1989) used data from the National Natality and Fetal Mortality Survey, a probability sample of live births and fetal deaths to married women in 1980, to show that maternal employment in the lead industry was a risk factor for negative pregnancy outcomes, including stillbirth (OR = 1.6) and preterm birth (OR = 2.3). No systematic study has been conducted of the effects of increased lead stores on early fetal loss in women who may have incurred substantial lead exposures during their childhood or during a prior period of employment in a lead-related trade. Such studies are warranted, given the known reproductive toxicity of large exposure to lead. Several prospective studies have examined the issue of lead's involvement in spontaneous abortion, stillbirth, preterm delivery, and low birthweight. Women in the studies in Boston (Bellinger et al., 1991b), Cleveland (Ernhart et al., 1986), Cincinnati (Bornschein et al., 1989),

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations and Port Pirie (McMichael et al., 1986; Baghurst et al., 1987a) had average blood lead concentrations during pregnancy of 5–10 µg/dL; almost all had blood lead concentrations less than 25 µg/dL. The Glasgow (Moore et al., 1982) and Titova Mitrovica (Graziano et al., 1989; Murphy et al., 1990) cohorts had average blood lead concentrations of about 20 µg/dL. None of those studies reported an association between maternal blood lead concentrations and spontaneous abortion or stillbirth. However, the Cincinnati and Port Pirie studies found a lead-related decrease in duration of pregnancy, and the Glasgow, Cincinnati, and Boston studies reported a lead-related decrease in birthweight. The Boston study found an increased risk of intrauterine growth retardation, low birthweight, and small-for-gestational-age deliveries at cord blood lead concentrations of 15 µg/dL or more. The Port Pirie study found that the relative risk of preterm delivery increased 2.8-fold for every 10-µg/dL increase in maternal blood lead. In the Cincinnati study, gestational age was reduced about 0.6 weeks for each natural log unit increase in blood lead, or about 1.8 weeks over the entire range of observed blood concentrations. Even after adjustment for the reduced length of pregnancy, the Cincinnati study found reduced infant birthweight (by about 300 g) and birthlength (by about 2.5 cm), and the Port Pirie group reported reduced head circumference (by about 0.3 cm) (Baghurst et al., 1987b). Findings from some of the prospective studies have been extensively reviewed (Davis and Svendsgaard, 1987; Ernhart et al., 1989; Grant and Davis, 1989). However, some striking inconsistencies, yet to be explained, characterize the data on the relationship between prenatal lead exposure and fetal growth and maturation. For instance, in the large cohort (N = 907) of women residing in Kosovo (Factor-Litvak et al., 1991), no associations were seen between midpregnancy blood lead concentrations (ranging up to approximately 55 µg/dL) and either infant birthweight or length of gestation. Several studies have also looked for evidence of teratogenicity (Needleman et al., 1984; Ernhart et al., 1986; McMichael et al., 1986). Needleman et al. (1984), in a retrospective study of the association between cord blood lead and major or minor malformations in a cohort of 4,354 infants, found a significant increase in the number of minor anomalies observed per child, but no malformation was found to be associated with lead. Unexpectedly, several other factors, such as premature labor and neonatal respiratory distress, were found to be reduced

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations with increased blood lead. Both Ernhart et al. (1986) and McMichael et al. (1986) tried but failed to replicate these findings; however, these studies lacked the power to detect the small effects reported by Needleman et al. (1984). The Needleman et al. study is important because the minor anomalies in question might reflect general fetal stress and predict developmental disorders (Marden et al., 1964). Evidence is accumulating that relatively small increases in maternal blood lead during pregnancy can be associated with delayed or retarded growth. Shukla et al. (1987) reported that 260 infants from the Cincinnati prospective lead study experienced retardation in covariate-adjusted growth. More specifically, they found that infants born to women with lead concentrations greater than 8 µg/dL during pregnancy grew at a lower than expected rate if increased lead exposure continued during the first 15 months of life. Conversely, if postnatal lead exposure was small, the infants grew at a higher than expected rate; that suggests a catchup in growth after fetal growth suppression. No lead-related growth effects were observed in infants born to women with blood lead concentrations less than 8 µg/dL. In a later analysis of stature at 33 months of age, Shukla et al. (1991) reported that sustained increases in lead exposure above 20 µg/dL throughout the first 33 months of life are associated with reduced stature. However, prenatal exposure was no longer related to stature at 33 months of age. The reported indication of fetal toxicity is consistent with other previously discussed markers of lead-related fetal toxicity. It is also consistent with cross-sectional studies of lead's relation with physical size. Several points emerge from a review of those studies, apart from a lead-related retardation of growth itself. First, the specific manifestations of the fetal insult vary among cohorts and might reflect lead's interaction with such cofactors as adequacy of prenatal care, maternal age, ethnicity, and nutritional status. Second, the blood lead concentrations associated with adverse fetal development are low (10–15 µg/dL or even lower) and comparable with those found in a substantial fraction of women of childbearing age (ATSDR, 1988). The validity of the reported association between fetal lead exposure and markers of adverse fetal development is strengthened by the observed negative association between maternal or fetal blood lead concentrations and early physical growth and cognitive development (Bellinger et al., 1987; Dietrich et al., 1987a,b; Vimpani et al., 1989). Thus, the birth-outcome measures,

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations early physical-growth measures, and early measures of infant development can be viewed as potentially reflecting the fetal toxicity of lead. Gametotoxicity of lead has been studied primarily in male lead workers. Lancranjan et al. (1975) noted lead-associated disturbances of reproductive competence in lead workers; blood lead concentrations of about 40 µg/dL were associated with asthenospermia and hypospermia, and higher concentrations with teratospermia. Erectile dysfunction was observed in the lead workers, but did not seem dose-dependent. Zielhuis and Wibowo (1976) criticized the design and results of that study, noting potential underestimation of blood lead concentrations. Wildt et al. (1983) noted that lead-battery workers with blood lead concentrations over 50 µg/dL showed prostatic and seminal vesicular dysfunction compared with controls. However, their study had a number of methodologic problems concerning the measures of dysfunction and exposure monitoring (EPA, 1986a). More recently, Assennato and co-workers (1986) reported sperm count suppression in lead-battery workers in the absence of endocrine dysfunction. Rodamilans et al. (1988) found that duration of lead exposure of smelter workers was variably associated with endocrine testicular function: workers who had been employed for more than 3 years had decreases in serum testosterone, steroid-binding globulin, and free-testosterone index. In both studies, the mean blood lead concentrations were over 60 µg/dL. We have already noted longitudinal studies of lead's effects on growth and development in young children. Cross-sectional data are also available from a large population survey. Schwartz et al. (1986) reported that postnatal exposure of U.S. children affects later growth, according to analysis of the large NHANES II data set with respect to height, weight, and chest circumference as a function of blood lead concentration. The three growth milestones in children under 7 years old were significantly and inversely associated with blood lead concentration: height, p < 0.0001; weight, p < 0.001; and chest circumference, p < 0.026. The association was present over the blood lead concentration range of 5–35 µg/dL. These results are consistent with those of Frisancho and Ryan (1991), who found an inverse association between blood lead level and stature in a cohort of 1,454 5–12 year old children in the Hispanic HANES data set, and those of Lauwers and co-workers (1986) in Belgium, who noted statistically significant and inverse associations

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations among growth indexes and blood lead concentration in children up to the age of 8 years. Nonquantitatively, reduced stature has been seen in children chronically exposed to lead (Johnson and Tenuta, 1979). Angle and Kuntzelman (1989) in a retrospective pilot study examined 30 children with increased blood lead concentrations (over 30 µg/dL) and erythrocyte protoporphyrin relative to those in a control group. Growth velocity, higher in the high-lead group before 24 months of age, reverted to a net retardation after this age, compared with values in controls. In a longitudinal followup study (Markowitz and Rosen, 1990), lead-poisoned children showed reduced growth velocity, compared with that in age-matched control subjects. Furthermore, impaired growth velocities in the lead-poisoned children did not change substantially from baseline after chelation therapy. The data on children suggest that endocrinologic disturbances can occur at sensitive points in anthropometric development. Endocrine dysfunction in lead workers with relatively high lead exposure is known (Sandstead et al., 1970; Robins et al., 1983). Huseman and co-workers (1987) found that height in two lead-poisoned children dropped to below the tenth percentile during intoxication; both subjects demonstrated depressed thyroid-stimulating hormone (TSH) responses to thyrotropin-releasing hormone (TRH), and one showed depression in resting TSH concentrations. Cognitive and Other Neurobehavioral Effects Information about the effects of low-level exposure to lead has been obtained principally from two types of epidemiologic studies. One is the cross-sectional or retrospective cohort study, in which children's lead exposure and development are assessed at the same time or in which past lead exposure is estimated. The second type is the prospective longitudinal study, in which children's exposure and development are assessed on multiple occasions. Each type of study has strengths and weaknesses. For clarity, the findings from each type are discussed separately. Prospective Longitudinal Studies The findings pertaining to the association between indices of prenatal

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations lead exposure and early development are mixed. In some cohorts, prenatal exposures corresponding to maternal or cord blood lead concentrations of 10–20 µg/dL were associated with early developmental delays. In the Boston cohort, infants with cord blood lead concentrations between 10 and 25 µg/dL manifested a performance deficit of 4–8 points between 6 and 24 months of age, relative to infants with cord blood lead concentrations below 3 µg/dL (Bellinger et al., 1984a; 1986a,b; 1987). In the Cincinnati cohort, developmental scores at 3 and 6 months of age declined by 6–7 points for each increase of 10 µg/dL in prenatal lead concentrations in the range of 1–27 µg/dL (Dietrich et al., 1987a,b); in addition, 12-month Mental Development Index (MDI) scores were inversely related to infants' blood lead concentrations at 10 days of age. In the Cleveland cohort, increased cord blood lead concentrations were significantly associated with increased numbers of neurologic signs, and increased maternal blood lead concentrations with lower scores on the Bayley Scales and the Kent Infant Development Scale at age 6 months (Ernhart et al., 1986, 1987). Quite different results were reported from the Australian studies. In the Port Pirie study, developmental assessments were first administered at 2 years of age, at which time MDI scores from the Bayley Scales were not associated with average antenatal, maternal, or cord blood lead concentrations (Baghurst et al., 1987b; Wigg et al., 1988). In the Sydney cohort, neither maternal nor cord blood lead concentration was inversely related to any index of children's development at 6, 12, 24, 36, or 48 months (Cooney et al., 1989a,b). In fact, cord blood lead concentration was positively associated with infants' motor development even after adjustment for covariates. Exposure misclassification is a potential problem in this study. At 12, 18, and 24 months of age, half the children provided capillary (fingerstick) blood samples, and the other half venous blood samples. Given the potential difficulties associated with capillary samples, the mixing of sampling methods at several ages complicates the effort to establish the relative exposures of the children in the cohort. For example, the Sydney group found that at age 3 the average lead concentration in capillary samples was 30% greater than that in venous samples. Mahaffey et al. (1979) noted a similar positive bias of 20% for capillary versus venous samples in the NHANES II data. Although the impact of those differences on exposure assessment in the Sydney cohort is uncertain, the investigators' concern over contamination of the early capillary samples prompted the recruitment of an additional 123 children.

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations Carcinogensis Virtually all the attention to lead as a major public-health problem arises from its noncarcinogenic effects in humans and experimental animals. But questions have been raised about lead carcinogenicity and the topic is briefly summarized here. Available data are from occupational epidemiologic studies, short- and long-term experimental-animal tests, and biochemical and in vitro assessments of lead compounds. Various studies (Hiasa et al., 1983; Shirai et al., 1984; Tanner and Lipsky, 1984) have shown that dietary exposure to lead acetate at relatively high doses increases the development of renal cancer caused by several known organic renal carcinogens in rats. Hiasa et al. (1983) studied the promoting effects of a diet containing 1% lead acetate on the development of renal tubule-cell tumors after earlier exposure to N-ethyl-N-hydroxyl nitrosamine. They found a 70% incidence of renal tumors in animals given lead acetate and the  nitrosamine at 32 weeks and no increase of tumors in animals given either compound alone. Similar results with the nitrosamine were reported by Shirai et al. (1984), who concluded that lead acetate acted as a promoter, and with N-(4'-fluoro-4-biphenyl) acetamide by Tanner and Lipsky (1984), who demonstrated that lead acetate accelerated the onset and development of kidney tumors in rats after chronic exposure. Kasprzak et al., (1985) used a diet containing 1% lead acetate and supplemented with calcium acetate at 0–6% and showed that addition of calcium acetate to the diet tended to increase the incidence of renal tumors after 58 weeks of lead  acetate exposure from 45% to 71%, but decreased the accumulation of lead in the kidneys. The overall results indicate that lead can act both as a renal carcinogen in rodents and as a promoter of renal carcinogenesis caused by other organic renal carcinogens. The exact minimal doses of lead required to produce the effects are unknown. About a dozen occupational studies have considered lead exposure versus various types of cancers in such work categories as battery recycling, lead smelting, alkyl lead manufacturing, plumbing, and pipefitting. EPA (1986a) has examined the older studies, and they have been augmented by those of Fanning (1988) for battery operations, Gerhardsson et al. (1986) for alkyl lead production, and Cantor et al. (1986) for plumbing and pipefitting.

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations Results of some studies suggest a renal-cancer risk (Selevan et al., 1985; Cantor et al., 1986), but results of others do not (e.g., Cooper et al., 1985). In some cases (Selevan et al., 1988), an association with duration of exposure added plausibility to the findings. In contrast, results of numerous animal studies strongly support a renal-cancer potential for soluble lead salts (see EPA, 1986a; IARC, 1980, 1987), and at least 12 long-term studies (with various rat strains, a mouse strain, and both males and females) documented induction of renal tumors when animals were fed either lead acetate or subacetate (soluble forms of lead). Those animal data meet EPA's criteria for sufficient evidence of carcinogenicity, as published in ''Guidelines for Carcinogen Risk Assessment'' (EPA, 1986b). The mechanism of lead carcinogenicity in laboratory animals remains unclear. Lead is not mutagenic in most test systems, but it has been shown to be clastogenic, reducing the fidelity of DNA repair polymerases. As described above, lead compounds are also mitogens in rodent kidneys and have been shown to act as tumor promoters and co-carcinogens in various experimental studies. The inconclusive human data and established animal carcinogenicity led to a classification of lead as a probable human carcinogen (IARC, 1980, 1987) and an EPA carcinogen ranking of Group B2 (EP, 1986b). Since the U.S. population has an exposure of approximately 1 µg/kg of body weight per day, the EPA method for extrapolating animal data to humans could be used to estimate a lifetime cancer risk for lead approximately 10-5. Of course, the cancer risks would vary, depending on the extent of exposure if the linearized extrapolation is appropriate for lead based on biology. The noncarcinogenic effects of lead remain of predominant interest in sensitive populations, but the potential carcinogenic effects of lead should be considered as new information becomes available. Nephropathy The question arises whether lead has subclinical renal effects, as would be expected, given the array of toxic effects on other organ systems. Several obstacles frustrate efforts to answer the question epidemiologically or experimentally. First, there is a marked reserve capacity of the kidney to function in the face of toxic insult. It might be

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations some time before the reserve capacity is depleted when people are exposed to large concentrations; this has been shown in workers occupationally exposed to lead. Second, we do not know the mechanisms of nephrotoxic events at the cellular or subcellular level, e.g., in the proximal renal tubules. Finally, there is a dearth of biologic markers specific for lead's nephrotoxic action. Previous studies (Victery et al., 1984) have shown that lead-ion uptake in proximal renal tubule cells occurs via membrane binding or passive diffusion. Consequently, it is the kidney's intracellular handling of lead that defines the nephrotoxic dose-response relations for lead toxicity. One can look to several kinds of experimental studies to garner clues as to what is occurring in humans who have subclinical lead exposures. Of particular interest are data on leadbinding proteins in experimental systems. Oskarsson et al. (1982) showed that the lead-binding patterns in rat kidneys and brain, major target organs for lead toxicity, were consistent with binding to two proteins, which might thus be factors in the intracellular handling and availability of lead. Goering and Fowler (1984, 1985) showed that the inhibition of PBG-S (ALA-D) activity in the rat kidney is mediated by both lead biochelation and zinc availability; the former perhaps helps not only to account for relative resistance to lead in kidney PBG-S (Fowler et al., 1980; Oskarsson and Fowler,  1985a), a cytosolic enzyme otherwise quite sensitive to lead in other tissue (Fowler et al., 1980; Oskarsson and Fowler, 1985a), but such sequestration are linked to the presence of the lead binding proteins. ALA-S and ferrochelatase function were not, however, protected. These observations suggested that either other molecules or the lead-binding proteins were facilitating the mitochondrial uptake of lead, because the mitochondrial inner membrane has previously been shown (Oskarsson and Fowler, 1985a,b) to be highly impermeable to lead in vitro (Oskarsson and Fowler, 1987). Studies of Mistry et al. (1985) show a high affinity of these proteins for lead; other data (Fowler et al., 1985; Mistry et al., 1986; Shelton et al., 1986) indicate that they play a role in the intranuclear transport of lead and in lead-induced changes in renal gene expression and that their biologically active form is a cleavage fragment of alpha-2-microglobulin in the retinol-binding protein family (Fowler and Du Val, 1991) that undergoes aggregation, at least in vitro (Du Val and Fowler, 1989).

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations With experimental exposures to mercury (Woods and Fowler, 1977; Woods et al., 1984) or inorganic oxyarsenic (Woods and Fowler, 1978; Mahaffey et al., 1981), the resulting porphyrinuria appears to be derived from injury to the kidney itself. Other data are consistent with a lead-associated effect on renal heme formation. Ferrochelatase inhibition (a mechanism of erythrocyte protoporphyrin accumulation) occurs in the kidney (Fowler et al., 1980). The kidney is relatively rich in porphyrins (Zawirska and Medras, 1972; Maines and Kappas, 1977), and lead appears to inhibit the heme-requiring kidney 1-hydroxylase enzyme system (Rosen and Chesney, 1983; Reichel et al., 1989); one function of this system is the formation of 1,25-(OH)2-vitamin D, the hormonal metabolite of vitamin D. Short-term experimental-animal studies with intravenous lead have shown a high correlation between formation and dissolution of lead inclusion bodies in renal tubule cells and changes in total and specific gene regulation at these sites. Such changes in regulation are to be found in various subcellular fractions—mitochondrial, microsomal, cytosolic, and lysosomal fractions with a specific response for each organelle compartment (Mistry et al., 1987). Chronic exposures in experimental animals have produced similar results with regard to lead induction of specific stress proteins. Comparisons of such data with morphometric analyses of tubule cell populations and effects on heme biosynthesis might permit determination of which biologic markers are of greater utility in delineating specific lead-induced changes in cell functions. Knowledge of the intracellular handling such as the kidney and brain, is essential to an understanding of the mechanisms of lead toxicity in target cell populations in these tissues. Soluble, high-affinity lead-binding proteins in the kidney and brain of rats were first reported by Oskarsson et al. (1982). Those molecules were not identified in other nontarget tissues, so they might play a role in lead toxicity in these organs at low doses. Later studies (Goering and Fowler, 1984, 1985; Goering et al., 1986) demonstrated that semipurified preparations of the proteins play a major role in mediating lead inhibition of the heme biosynthetic pathway enzyme alpha-aminolevulinic acid dehydratase (porphobilinogen synthetase). Other studies (Mistry et al., 1985, 1986) demonstrated that the kidney lead-binding proteins had a high affinity for lead and were capable of facilitating the cell-free nuclear translocation and chromatin binding of 203Pb. Those molecules thus

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations appear to act as "receptors" for lead and to regulate its intranuclear uptake, chromatin binding, and changes in proximal tubule cell gene expression (Fowler et al., 1985; Shelton et al., 1986; Mistry et al., 1987; Hitzfeld et al., 1989; Klann and Shelton, 1989). More recent studies (DuVal et al., 1989; Fowler and DuVal, 1991)  have identified the renal lead-binding protein as a cleaved form of the protein alpha-2-microglobulin that locks the first 9-nitrogen-terminal residue and shown that the brain lead-binding protein is a chemically similar protein that is rich in aspartic and glutamic amino acids, but immunologically distinct. It appears that it is the cleared form of the alpha-2-microglobulin that is biologically active. Western blot studies (DuVal et al., 1989) have shown that that protein undergoes aggregation after in vitro exposure to lead. The data suggest that the protein can play an early role in the formation  of the pathognomonic cytoplasmic and intranuclear lead inclusion bodies. The inclusion bodies are the main intracellular storage sites for lead in proximal tubule cells after increased or chronic lead exposure (Goyer and Rhyne, 1973; Moore et al., 1973; Fowler et al., 1980; Shelton and Egle 1982; Oskarsson and Fowler 1985a,b; Klann and Shelton 1989). Previous studies have shown a marked kidney-specific macromolecular binding pattern for lead in renal proximal tubule cells. The binding is followed by several undefined intracellular events that result in the presence of large quantities of lead in renal proximal tubule cell nuclei. The precise sequence of events and relationships to other intracellular lead species have not been completely studied. Such data are central to an understanding of the bioavailability of lead to sensitive cellular processes. The bioactive lead species thus might be centrally involved in the mechanisms of toxicity. Further studies of how lead reacts with them should permit their use as biologic indicators of lead-induced nephropathy, provided that they are excreted in urine. Lead-induced alterations of renal gene expression (Fowler et al., 1985; Mistry et al., 1986; Shelton et al., 1986; Herberson et al., 1987; Hitzfeld et al., 1989) and inhibition of renal heme biosynthetic pathway enzymes with attendant development of metal-specific porphyrinuria patterns (Mahaffey and Fowler, 1977; Mahaffey et al., 1981) are examples of sensitive biochemical systems. Such responses have great potential as biologic indicators of nephropathy, once their relation to the pathophysiology of lead nephropathy is understood.

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations SUMMARY Exposure of various sensitive populations to lead induces a wide variety of adverse effects—in the central nervous system of children and fetuses, in various growth indexes of children, in the cardiovascular system of older people, in heme synthesis, and in calcium homeostasis and function. LOELs (lowest-observed-effect levels) for various lead effects are summarized in Table 2-4 for children and Table 2-5 for adults. The weight of the evidence gathered during the 1980s clearly supports the conclusion that the central and peripheral nervous systems of both children and adults are demonstrably affected by lead at exposures formerly thought to be well within the safe range. In children, blood lead concentrations around 10 µg/dL are associated with disturbances in early physical and mental growth and in later intellectual functioning and academic achievement. Studies of electrophysiologic end points have suggested some of the changes in brain function that might mediate the apparent effects. Despite impressive advances over the last decade in the methodologic rigor of studies of lead exposure and nervous system function, epidemiology remains limited by opportunity. Therefore, animal studies are critical for interpreting the human data. Factors that an epidemiologist must take account of with statistical analysis (an inevitably imperfect process) can be controlled experimentally with animals. For example, the influence of socioeconomic factors on performance can be eliminated, and the importance of timing, dose, and duration of exposure can be evaluated more precisely. The extensive evidence gathered in animal studies cannot be reviewed here, but some themes warrant enumeration. First, primates exposed to sufficient lead to produce a blood lead concentration of 25 µg/dL or less manifest a variety of memory, learning, and attentional deficits resembling those observed in humans. Second, the deficits appear to be permanent; they are evident for as long as 10 years in animals whose blood lead is maintained at approximately 15 µg/dL. Third, striking concordance of the human and animal data weighs heavily in favor of the hypothesis that low-dose lead exposure is responsible for some of the developmental and cognitive deficits observed in humans. Many of the

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations TABLE 2-4 Lowest-Observed-Effect Levels of Blood Lead for Effects in Children LOEL, µg/dL Neurologic Effects Heme-Synthesis Effects Other Effects <10 to 15 (prenatal and postnatal) Deficits in neurobehavioral development (Bayley and McCarthy Scales), electro-physiologic changes,a , b and lower IQc, d ALA-D inhibitione Reduced gestational age and birthweight; reduced size up to age 7–8 yra,b,e 15–20   Erythrocyte protoporphyrin increasea,e Impaired vitamin D metabolism, Py-5'-N inhibition a, e <25 Longer reaction time (studied cross-sectionally)b , e Reduced hematocrit (reduced Hb)f   30 Slower nerve conductione     40   Increasing CP-U and ALA-Uc   70 Peripheral neuropathiesa,e Frank anemiaa,e   80–100 Encephalopathya,e   Colic, other gastrointestinal effects, kidney effectse a Data from CDC, 1991. b Data from EPA, 1990a,b. c Data from Bellinger et al., 1992. d Data from Dietrich et al., 1993a. e Data from ATSDR, 1988. f Data from Schwartz et al., 1990.

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations TABLE 2-5 Lowest-Observed-Effect Levels of Blood Lead for Effects in Adults LOEL, µg/dL Heme Synthesis and Hematologic Effects Neurologic Effects Renal Effects Reproductive Effects Cardiovascular Effects <10 ALA-D inhibition         10–15         Increased blood pressure 15–20 Erythrocyte protoporphyrin increase in females         25–30 Erythrocyte protoporphyrin increase in males         40 Increased ALA-U and CP-U Peripheral nerve dysfunction (slower nerve conduction)       50 Reduced hemoglobin production Overt subencephalopathic neurologic symptoms   Altered testicular function  

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations LOEL, µg/dL Heme Synthesis and Hematologic Effects Neurologic Effects Renal Effects Reproductive Effects Cardiovascular Effects 60       Female reproductive effects   80 Frank anemia         100–120   Encephalopathic signs and symptoms Chronic nephropathy       Source: Adapted from EPA, 1986a, Vol. IV.

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations neurodevelopmental and possibly other toxic effects resulting from lead exposure might not be reversible. It is important to distinguish two aspects of reversibility. The first pertains to biologic plasticity, specifically an organism's ability to repair damage and recover functional capacity. The second pertains to the reality of exposure patterns. Impairment might persist, regardless of an organism's capacity for recovery, as long as exposure is maintained. In a practical sense, the impairment is irreversible. Therefore, the fact that an adverse effect is reversible in the biologic sense does not necessarily mean that it is without potential public-health importance. The key issue is whether exposure is reduced, and expression of an organism's recovery capacities thus permitted. This chapter documents that lead induces measurable increases in diastolic and systolic blood pressure in human populations and in experimental-animal models of environmentally induced blood-pressure changes. Lead exposure is not the only risk factor for hypertension, but is more amenable to reduction or prevention than behavioral factors that are refractory to change. Furthermore, the relation of lead to blood pressure persists across a dose-effect continuum, so reducing lead exposure of all magnitudes has public-health and societal ramifications. Lead's impact is noteworthy also because of the importance of associated cardiovascular morbidity and mortality, even for an agent that contributes less than a major risk. Through various processes, including toxicokinetic and intracellular disturbances, lead impairs calcium homeostasis and functions. The importance of impacts on calcium is that they impair calcium's central role in multiple cellular processes. Lead produces a cascade of effects on the heme body pool and affects heme synthesis. Some of the effects serve as early measures of body lead burden. Lead effects on cognition and other neurobehavioral measures need to be evaluated on a population-wide, as well as individual, basis. This evaluation should account for the whole statistical distribution of exposures and associated toxicity. Unfortunately, the direct identification and linkage of the critical and sensitive biological processes which are targets for these effects remains saltatory. There are many reasons why our ability to define the mechanism(s)

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Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations of action for lead toxicity lags behind our ability to detect and quantify the toxicological effects. In addition to the difficulties in defining a mechanism of action as discussed above, these reasons include: . Lead is a catholic toxicant producing adverse effects in most tissues and organs of the body, with a parallel effects on multiple organelles and metabolic processes. This situation makes it extremely difficult to identify and isolate the critical process(s) with sufficient experimental rigor. . There is frequently a long delay between the onset of lead exposure and the development of toxic manifestations, impairing identification of causal relationships between functional and cellular or biochemical events. . Lead causes nonspecific, decremental loss of tissue and organ function, with no important pathognomonic manifestations of toxicity. . The multifactorial nature of the toxicity in the nervous, cardiovascular, skeletal and other organ systems complicate establishing causal relationships between cellular and molecular processes and organ dysfunction. Nevertheless, these difficulties do not diminish the importance or necessity of these efforts. Continued efforts must be made to bridge experimental animal and human studies, at all level analysis, and to integrate the biochemical and molecular events impacting function at the level of the whole organisms.