Estimation of cumulative lead releases (lead flux) from the maternal skeleton during pregnancy and lactation.

Recent longitudinal studies with human subjects and nonhuman primates using high-precision stable lead isotopes show that lead is mobilized from the maternal skeleton during pregnancy and the postpartum period. We have now calculated the cumulative lead release (lead flux in micrograms) mobilized from the skeleton during these periods by means of analysis of monthly PbB samples from recent immigrants to Australia. Results included a statistically significant inverse relationship (P = .006) between the lead flux and the time of conception after the arrival of the subjects in Australia. By using an area-under-the-curve approach to determine the added lead inputs to blood during pregnancy and nursing versus a baseline value, the net lead release to blood varied from 0.9 to 10.1 microg/d, which is equivalent to 0.3 to 4.03 mg of lead. With group PbB concentrations usually less than 3 microg/dL, the observed releases imply a high skeletal turnover of greater than 10% and possibly greater than 30% in some subjects during pregnancy and the postpartum period. These elevated rates in some subjects may partly arise from low daily calcium intakes, being one half to two thirds of that of recommended daily requirements. The lead flux calculated from a cumulative approach was compared with other approaches: first-order kinetics, bone turnover, bone x-ray fluorescence measurements, and the International Commission for Radiological Protection lead pharmacokinetic model. Calculated lead releases and remaining bone lead concentrations would likely not be detectable by current x-ray fluorescence methods.

Uses and limits of empirical data in measuring and modeling human lead exposure.

This paper examines the uses and limits of empirical data in evaluating measurement and modeling approaches to human lead exposure. Empirical data from experiment or observation or both have been used in studies of lead exposure. For example, experimental studies have elucidated and quantified physiologic or biokinetic parameters of lead exposure under controlled conditions. Observation, i.e., epidemiology, has been widely applied to study population exposures to lead. There is growing interest in the use of lead exposure prediction models and their evaluation before use in risk assessment. Empirical studies of lead exposure must be fully understood, especially their limits, before they are applied as "standards" or reference information for evaluation of exposure models, especially the U.S. Environmental Protection Agency's lead biokinetic model that is a focus of this article. Empirical and modeled datasets for lead exposure may not agree due to a) problems with the observational data or b) problems with the model; caution should be exercised before either a model or observational data are rejected. There are at least three sources of discordance in cases where there is lack of agreement: a) empirical data are accurate but the model is flawed; b) the model is valid but reference empirical data are inaccurate; or c) neither empirical data nor model is accurate, and each is inaccurate in different ways. This paper evaluates some of the critical empirical input to biokinetic models, especially lead bioavailability.

Risk and revisionism in arsenic cancer risk assessment.

Oral exposures of nonoccupational populations to environmental inorganic arsenic are associated with skin and internal cancers as well as various noncarcinogenic effects. Cancer risk assessments have been based largely on epidemiological studies of a large population exposed to inorganic arsenic in well water in Taiwan. Criticisms and skepticism of the use of the Taiwanese data for estimating arsenic cancer risks outside of Taiwan, including potential use by the U.S. Environmental Protection Agency for regulatory purposes, have been expressed on various grounds. The nature and extent of such criticisms have sharpened with recent findings in the exposed Taiwanese of increased incidence of internal cancers (bladder, kidney, liver, and lung), in addition to already-observed skin cancer, coupled with a good likelihood that these findings will produce more stringent arsenic regulation in the United States and elsewhere. These criticisms collectively posit a revisionist view that: 1) cancer incidence among the Taiwanese was amplified by a number of host and environmental factors not applicable elsewhere, 2) the cancer dose-response curve may not be linear at the lower exposures elsewhere, and 3) there is a toxicokinetic and metabolic threshold to cancer risk that was exceeded by the Taiwanese. However, a number of the arguments against wide use of the Taiwanese data are flawed and subject to challenge. We explore some of these arguments and their critical evaluation, particularly as they concern certain exposure, metabolic, and nutritional determinants of the cancer risk of inorganic arsenic in the Taiwanese.

New directions in the toxicokinetics of human lead exposure.

An important determinant of body lead (Pb) burden and Pb toxicity in exposed humans is Pb metabolism, or more correctly, Pb toxicokinetics. It affects the former through the quantitative processes of uptake, distribution and retention/excretion and the latter via delivery of toxic doses to cellular/molecular sites of action. Pb toxicokinetics has useful application in understanding Pb's behavior in populations. Several of these applications have been studied and results are presented for the toxicokinetic basis of dose-neurotoxic effect relationships in selected longitudinal studies and the use of toxicokinetic modeling for estimation of body lead burden in early populations. Three well-known, ongoing longitudinal studies of developmental neurotoxicity--in Boston, Cincinnati, and Port Pirie, Australia--involve cohorts who differ markedly as to their pre- and postnatal lead exposure profiles. Toxicokinetic examination of these exposure differences helps to explain the temporal variability seen in blood Pb-toxic effect relationships and supports a causal role for lead. Toxicokinetic models of Pb uptake and in-vivo behavior are increasingly being considered for estimating Pb-B levels in lieu of direct measurement. A linear biokinetic model, using reliable input data for natural/prehistoric levels of Pb in sources, was applied to estimation of prehistoric/preindustrial children's blood lead. A range of 0.06 to 0.12 microgram/dl was estimated for two lead intakes. These estimates are still two orders of magnitude (85 to 165-fold) lower than the newly issued CDC toxicity guideline for children of 10 micrograms/dl. Lastly, the toxicokinetics of lead in bone, particularly its resorption with metabolic stimuli, is of concern, particularly for "baby boom" women who are either of childbearing age or approaching menopause and who had greatly elevated environmental lead exposures in the 1940s to 1970s.

Defining lead as the premiere environmental health issue for children in America: criteria and their quantitative application.

The principal environmental health issue for American children is pervasive lead poisoning from the many decades of lead contamination. Available scientific evidence cementing lead's premiere ranking is voluminous, multifaceted, and compelling. This evidence, however, requires organization into a clear and coherent body of science before it can be fully recognized or comprehended by either the scientific community or the general public and its representatives: public health officials, regulators, policy makers, and legislators. An attempt at such organization is presented and begins with the premise that there exist clear, objective criteria by which a premiere environmental health issue can be defined. A second premise is that these criteria sort themselves into three categories which cover the full spectrum of toxic contaminant-population relationships. They are: (1) economic and sociopolitical, (2) scientific and public health, and (3) societal risk assessment criteria. The first set of criteria includes economic and historical centrality, primacy of economic over public health considerations, a relatively narrow decision-making framework, and controlled flow of information on the toxicant, especially its negative impacts. The second set of criteria is also orthodox in scope: the toxicant should be indestructible, should accumulate in both the environment and the body, and should be a multimedia contaminant; it should produce toxicity in numerous organs with little impediment; toxicity should be produced with low/no threshold in huge numbers of the most vulnerable; and finally, effects should persist in the critical target organ(s). There is a third, more globally encompassing, set of criteria important for present-day requirements for risk assessment; e.g., the contaminant should produce full-spectrum population-wide as well as individual toxicity. Evidence for societal harm should be compelling. It should typify the increasing importance of the elements of preventive over clinical medicine and the substance should bring to bear the cost-benefit analysis of macro plus micro health risk. Lead exposure and toxicity is conclusively shown to meet ALL of these criteria and is the premiere environmental health threat to America's children.

Determination of numbers of lead-exposed U.S. children by areas of the United States: an integrated summary of a report to the U.S. Congress on childhood lead poisoning.

In response to Congressional mandate and under the aegis of the Federal Agency for Toxic Substances and Disease Registry (ATSDR), a comprehensive report to Congress on childhood lead poisoning in the United States was prepared. We have examined numbers of lead-exposed U.S. children by socioeconomic/demographic strata for children 0.5 to 5 years of age; by children in U.S. lead-screening programs; and by enumerations of children 0.5 to 5 years old in the oldest (i.e., highest paint lead and lead plumbing) housing. Using blood lead (PbB) prevalence projection modeling and data of the Second National Health and Nutrition Examination Surgery (NHANES II), it is estimated for 1984 that 2.4 million black and white children 0.5 to 5 years old in metropolitan U.S. had PbB levels greater than 15 micrograms/dL. For all races and the entire nation, we estimate 3 to 4 million children will have PbB levels greater than 15 micrograms/dL. Inner-city, low-income children have the highest prevalences of PbB levels above this criterion level, but sizable numbers of all strata of children have elevated PbB levels when considering both base populations and prevalences for the specific strata (total of 30 strata). Lead screening programs indicate much lower numbers of exposed children compared to NHANES II-based projections, for various reasons that allow programs to underestimate true prevalences. Analysis of 1980 U.S. Census Bureau housing data for 318 standard metropolitan statistical areas show that 4.4 million children 0.5 to 5 years old live in the oldest U.S. housing (pre-1950). Of these, most are actually in the more affluent socioeconomic strata.

Determination of numbers of lead-exposed women of childbearing age and pregnant women: an integrated summary of a report to the U.S. Congress on childhood lead poisoning.

In a Congressionally mandated study carried out under the aegis of the U.S. Agency for Toxic Substances and Disease Registry (ATSDR) and summarized in this article, the authors have provided estimates of the numbers of American women of childbearing age and the numbers of American pregnant women whose lead exposure is sufficiently elevated to pose an intrauterine toxicity risk. Exposures associated with such risk were defined as blood lead (PbB) levels greater than 10, greater than 15, greater than 20, and greater than 25 micrograms/dL. Using PbB prevalence projection techniques based on the Second National Health and Nutrition Examination Survey (NHANES II), we first generated projected 1984 prevalences of these PbB levels in white and black women of childbearing age, ages 15 to 19 and 20 to 44. White women in the two age bands had rates of PbBs greater than 10 micrograms/dL of 9.2 and 9.7%, respectively. For black women, the corresponding rates were 8.2 and 19.7%, respectively. Combining these rates with standard metropolitan statistical areas (SMSAs) based 1980 Census and other population enumerations show, for example, that 4.4 million U.S. women of childbearing age are estimated to have had PbBs greater than 10 micrograms/dL. Pregnant black and white women in U.S. SMSAs are approximately 9% of the U.S. black and white childbearing age total, i.e. 3.6 million out of a 41.3 million SMSA total. Of these, 403,200 pregnant women were estimated to have PbB levels greater than 10 micrograms/dL.(ABSTRACT TRUNCATED AT 250 WORDS)

Methods for reducing lead exposure in young children and other risk groups: an integrated summary of a report to the U.S. Congress on childhood lead poisoning.

As part of a Congressionally mandated report on U.S. childhood lead poisoning prepared by the Federal government (U.S. Agency for Toxic Substances and Disease Registry [ATSDR]), the authors have analyzed the relative effectiveness of measures to reduce source-specific lead exposure of U.S. children. An integrated overview of this analysis is presented in this article. Two national actions, the Federally mandated phasedown of lead in gasoline by the U.S. Environmental Protection Agency and the voluntary phasedown of lead use in domestic food can production, are examples of centrally directed initiatives that have been relatively successful in limiting childhood lead exposure in the U.S. Efforts to abate lead-based paint exposure of children have largely failed. This is especially true for the nation's 21 million residential units with the highest lead content paint. Similarly, abatement of lead exposure from contaminated dusts and soils has generally been unsuccessful. Comprehensive measures to reduce lead exposure from drinking water in residences and public facilities, e.g., elementary schools, are only now being promulgated or implemented. The full extent of their effectiveness remains to be demonstrated. There are many miscellaneous but potentially severe exposure sources that are difficult to control but require attention, such as poorly glazed foodware and ethno-specific preparations.

Determination of numbers of lead-exposed American children as a function of lead source: integrated summary of a report to the U.S. Congress on childhood lead poisoning.

In 1986, the U.S. Congress [Section 118(f), Superfund Amendments and Reauthorization Act (SARA)] directed the Agency for Toxic Substances and Disease Registry to provide to it a quantitative assessment of the contributions of various sources of lead to childhood exposure. We provided both a quantitative response to the mandate and a critique of low-level lead sources for U.S. population segments. We also present here an integrated assessment of major and low-level lead sources. Significant sources of lead in childhood exposure include lead in paint, dust, soil, and drinking water. Approximately 6 million U.S. children less than 7 years old reside in the oldest housing, with highest exposure risk due to leaded paint. About 2 million in deteriorated units are at particularly high risk for exposure with ca. 1.2 million children in oldest, deteriorated housing estimated to have blood lead (PbB) levels above 15 micrograms/dl. Soil and dust lead are potential sources of exposure for 6-12 million children. Residential tap water lead is a measurable source for ca. 3.8 million children, of whom the U.S. EPA estimates ca. 240,000 have water-specific exposures at toxic levels. Leaded gasoline combustion mainly in past years has produced, and will continue to produce into the 1990s, significant numbers of exposed children with toxicologically elevated PbBs. For 1990, 1.25 million children will have their PbBs fall below 15 micrograms/dl. Food lead can cause significant exposure in certain cases.

Prenatal and postnatal effects of low-level lead exposure: integrated summary of a report to the U.S. Congress on childhood lead poisoning.

This article provides an integrated summary of a report to Congress from the Federal government (ATSDR) on childhood lead poisoning in the United States, with particular reference to low-level lead exposure and its effects on the fetus and the preschool child. As mandated by Section 118(f)(1)(C) of the 1986 Superfund Amendments and Reauthorization Act (SARA), ATSDR has examined the full spectrum of human in utero and postnatal lead toxicity, with emphasis on low-level neurotoxicity and adverse impacts on growth indices in risk populations. Especially important has been assessment of the relative persistence of these effects in later life as discernible from a number of longitudinal studies now under way around the world. Included in the Congressional report were discussions of dose-effect and dose-response relationships using blood lead levels as the indicator of lead dose.

Distribution and retention of organic and inorganic mercury in methyl mercury-treated neonatal rats.

Seven-day-old Long Evans rats received one mumol of 203Hg-labeled methyl mercury/kg sc and whole body retention and tissue distribution of organic and inorganic mercury were examined for 32 days postdosing. Neonates cleared mercury slowly until 10 days postdosing when the clearance rate abruptly increased. During the interval when whole body clearance of mercury was extremely slow, methyl mercury was metabolized to inorganic mercury. Peak concentration of mercury in kidney occurred at 2 days postdosing. At 32 days postdosing, 8% of mercury in kidney was in an organic from. Liver mercury concentration peaked at 2 days postdosing and organic mercury accounted for 38% at 32 days postdosing. Brain concentrations of mercury peaked at 2 days postdosing. At 10 days postdosing, organic mercury accounted for 86% of the brain mercury burden, and, at 32 days postdosing, for 60%. The percentage of mercury body burden in pelt rose from 30 to 70% between 1 and 10 days postdosing. At 32 days postdosing pelt contained 85% of the body burden of mercury. At all time points, about 95% of mercury in pelt was in an organic form. Compartmental analysis of these data permitted development of a model to describe the distribution and excretion of organic and inorganic mercury in methyl mercury-treated neonatal rats.

Sexual differences in the excretion of organic and inorganic mercury by methyl mercury-treated rats.

Adult male and female Long Evans rats received 1 mumole of methyl (203Hg) mercuric chloride per kilogram sc. Whole-body retention of mercury and excretion of organic and inorganic mercury in urine and feces were monitored for 98 days after dosing. Females cleared mercury from the body more rapidly than did males. The major route of mercury excretion was feces. By 98 days after dosing, cumulative mercury excretion in feces accounted for about 51% of the dose in males and about 54% of the dose in females. For both sexes, about 33% of the dose was excreted in feces as inorganic mercury. Cumulative excretion of organic mercury in feces accounted for about 18 and 21% of the dose in males and females, respectively. Urinary excretion of mercury was quantitatively a smaller route for mercury clearance but important sexual differences in loss by this route were found. Over the 98-day experimental period, males excreted in urine about 3.2% of the dose and females excreted 7.5%. Cumulative organic Hg excretion in urine accounted for 1.8% of the dose in males and 5.3% of the dose in females. These sexual differences in urinary and fecal excretion of organic and inorganic mercury following methyl mercury treatment were consistent with previous reports of sexual differences in mercury distribution and retention in methyl mercury-treated rats, particularly sexual differences in organic mercury uptake and retention in the kidney. Relationships between body burdens of organic or inorganic Hg and output of these forms of Hg in urine and feces were also found to be influenced by the interval after MeHg treatment and by sex. Relationship between concentration of Hg in liver and feces and in kidney and urine differed for organic and inorganic Hg and depended upon sexual status and interval after MeHg treatment. These findings emphasize that sexual differences in distribution, retention, and metabolism of methyl mercury are factors to be considered in estimations of hazards associated with exposure to this agent.