Document G6v20M7ZpwarjwbLraLzBNdk4

--_---- -- 11 1 :\ U S. DEPARTMENT OF COMMERCE National Technical Information Service PB-296 556 The Environmental Lead Problem An Assessment of Lead in Drinking Water from a Multi-Media Perspective MITRE Corp, McLean, VA METREK Div / Prepared far Environmental Protection Agency, Washington, DC Criteria and Standards Div May 79 VJ N33805 EPA-570/9-79-003 THE ENVIRONMENTAL LEAD PROBLEM: AN ASSESSMENT OF LEAD IN DRINKING WATER FROM A MULTI-MEDIA PERSPECTIVE MAY 1979 FINAL REPORT REPRODUCED BY NATIONAL TECHNICAL INFORMATION SERVICE U.S. DEPARTMENT OF COMMERCE SPRINBEIEUA YA. 22161 Prepared by THE MITRE CORPORATION Metrek Division McLean, Virginia 22102 A. DUP050033507 DISCLAIMER This report has been reviewed by the Office of Drinking Water, U.S. Environmental Protection Agency, and approved for publication, Approval does not signify that the contents necessarily reflect the views and policies of the U.S. Environmental Protection Agency, nor does mention of trade names or commercial products constitute en dorsement or recommendation for use. DUP050033508 BIBLIOGRAPHIC INFORMATION PB-296 556 The Environmental Lead Problem: An Assessment of Lead in Drinking Water from a Multi-Media Perspective, May 79 S, Drill, J. Konz, H. Mahar, and M. Morse. PERFORMER: MITRE Corp., McLean, VA, METREK Div. Contract EPA-68-01-4635 SPONSOR: Environmental Protection Agency, Washington, DC. Criteria and Standards Div. EPA/57O/979/OO3 Final rept. Human exposure to lead has been shown to be cumulative in nature. In order to assess the toxicological significance of environmental lead exposures, it is necessary to define the contributions to an individual's daily lead uptake from all possible exposure pathways. This paper defines and quantifies the major environmental sources of lead exposure, describes the absorption characteristics of lead compounds in man via each exposure route, determines the source contribution factors for daily lead uptake by each exposure pathway, and relates those contributions to an individual's blood-lead level. KEYWORDS: #Lead(Metal), *Potable water, ^Toxicology, Drinking water, *Water pollution effects(Humans)> *Toxic substances. Available from the National Technical Information Service, Springfield, Va. 22161 PRICE CODE: PC A08/MF A01 i j DUP050033509 EPA-570/9-79--003 May 1979 THE ENVIRONMENTAL LEAD PROBLEM: AN ASSESSMENT OF LEAD IN DRINKING WATER FROM A MULTI-MEDIA PERSPECTIVE by S. Drill, J, Konz, H, Mahar and M, Morse Metrek Division of The MITRE Corporation 1820 Dolley Madison Boulevard McLean, Virginia 22102 Contract No. 68-01-4635 Project Officer Charles L. Trichilo, Ph.D. Criteria and Standards Division Office of Drinking Water U.S. Environmental Protection Agency Washington, D.C. 20460 Criteria and Standards Division Office of Drinking Water U.S, Environmental Protection Agency Washington, D.C. 20460 i aJ DUP050033510 ABSTRACT Human exposure to lead has been shown to be cumulative in na ture. In order to assess the toxicological significance of environ mental lead exposures, it is necessary to define the contributions to an individual's daily lead uptake from all possible exposure path ways. This paper defines and quantifies the major environmental sources of lead exposure, describes the absorption characteristics of lead compounds in man via each exposure route, determines the source contribution factors for daily lead uptake by each exposure pathway, and relates those contributions to an individual's blood-lead level. ill Preceding page blank DUP050033511 ACKNOWLEDGEMENT The authors gratefully acknowledge Dr. K. Biddle, Dr, i.H. Blllick, Dr. K. Brldbord and V.E. Gray for the time and effort spent In reviewing the preliminary draft of this report and for their helpful comments and criticisms. We also wish to thank Dr. C.L. Trichilo for his continuous support and encouragement. iv DUP050033512 EXECUTIVE SUMMARY The MITRE Corporation/Metrek Division has been assisting the Criteria and Standards Division, Office of Drinking Water, in their assessment of the adequacy of the current interim standard for lead (Pb) in drinking water. In this assessment, the biological effects of lead exposure are reviewed, the major environmental sources of lead exposure (air, food, drinking water, soil/dust and paint) are quantified, the sensitive populations are identified and a relation ship between exposure levels and blood-lead levels is developed. The method employed in this study is to estimate the degree to which each major environmental source of lead exposure contributes to an individual's total daily lead uptake, based on probable exposure conditions (i.e., ambient lead levels) as well as individual biolog ical absorption rates for each exposure route. These source contri bution factors (percent contribution from each source to total daily lead uptake) identify the relative significance of each source in producing overall toxic consequences, and thus point out those areas where regulatory action will have the greatest effect. Since the blood-lead level is the value most widely reported in the literature to represent the extent of lead absorption, it is necessary to relate daily lead uptake to blood-lead values in order to define the toxicological impact associated with different levels of lead uptake. Environmental Lead Sources lead is a natural constituent of the earth's crust, but the presence of lead in the remainder of the environment is the result of extensive human use of lead. The chemical properties associated with the more common forms of lead result in low lead levels in natural waters. The majority of lead compounds found in the atmosphere result from leaded gasoline combustion. In 1975, the most recent year for which data are available, approximately 88.8 percent of the total atmospheric lead arose from this emission source. The next largest contributors, primary copper and lead smelting facilities, provided 2.5 and 1.7 percent of the total. localized atmospheric lead pollution resulting from industrial plants processing lead and its products can be quite severe, but the contribution of these plants to the pollution load across large areas is minimal. v DUP050033513 The ingestion of foodstuffs containing lead appears, on the average, to be the largest contribution to an adult's total daily lead intake. The source of lead in various foodstuffs may be natural bioaccumulation, deposition of airborne lead particles, or food processing and serving. Lead concentrations in finished drinking water collected at 969 public water supply systems in the United States ranged from an undetectable amount to 640 micrograms per liter (pg/1), Of the supply systems sampled, 37 sites (1.4 percent of the total) contained lead in concentrations exceeding the current national interim primary drinking water standard of 50 pg/l. Tap water tends to contain higher lead concentrations than water in distribution systems due to the use of lead pipe or lead-containing solder in home plumbing systems. Soil and dust contain a high concentration Of deposited lead particulates. Normal hand-to-mouth activity of children may lead to ingestion of high concentrations of lead compounds, which are then subject to absorption by the gastrointestional tract; bead levels in soil and dust in metropolitan areas have been reported as high as 12,000 pg/g. Leaded gasoline is the main contributor to these high lead levels. Lead-containing materials (e.g., paint, plaster, newsprint) are ingested by some children suffering from pica. Extremely high lead concentrations are found in the paint of Some on older dwellings. Toxicologic properties Environmental lead compounds can be absorbed into the blood stream from the lung after inhalation, from the gastrointestional tract after ingestion, or to a limited extent, from direct dermal contact. The absorption kinetics for each of these pathways are dependent upon a number of factors, including the physical and chemi cal nature of the lead compounds at the time of exposure and the pre sence of other modifying agents. Once inorganic lead is absorbed into the bloodstream, it is readily transported throughout in the body and does not normally retain any characteristics associated with its exposure or absorption route. Lead is present in virtually every organ of the human body* Over 90 percent of the lead stored in the adult body is located in the skeleton. Lead concentrations in the majority of soft tissues apparently reach an equilibrium level during the second decade of life and remain at this level indefinitely. Concentrations in the bones, aorta, liver, lungs, kidneys, pancreas and spleen continue to increase with age. vi DUP050033514 In adulta, approximately 90 percent of ingested lead is elim inated in the feces without prior gastrointestinal absorption. Absorption of lead via the gastrointestinal tract 13 greater in children, who therefore eliminate a substantially smaller proportion of their total intake as unabsorbed lead in the feces, the primary elimination route for lead absorbed by all routes is in the urine, representing about 95 percent of the total output of absorbed lead. The toxicological impact of lead is the cumulative result of exposure from many sources. Adverse health effects may result from continuous low-level exposure from the ambient environment. Toxic effects are essentially due to the mobile fraction of absorbed lead within the body. This mobile fraction is composed of lead from any recent exposure, as well as the background level of easily mobilized lead previously deposited in the soft tissues and soft (trabecular) bone, and to a lesser extent, to that portion mobilized from dense bone. Lead inhibits the synthesis of hemoglobin at several points throughout the heme synthetic pathway. The inhibition of the enzyme aminolevulinic acid dehydratase (ALAD) is believed to be the earliest known biological effect of lead intoxication. Anemia is often the earliest clinical sign of chronic and acute lead poisoning. This anemia is believed to be the result of decreased erythrocyte produc tion and increased destruction due to the interference of lead. Accumulation of lead in the body can lead to severe effects on the central nervous system. These central nervous system effects are most responsible for the morbidity and mortality associated with lead poisoning. Symptoms of neurological changes include ataxia (muscular coordination failure), clumsiness, weakness, stupor, coma and convul sions. There is a great deal of controversy concerning the subtle neurobebavioral effects of low-level lead exposure in asymptomatic humans In addition to the effects on the central nervous system, periph eral neuropathy due to lead poisoning has been reported. Peripheral nervous system paralysis is characterized by selective involvement of motor neurons and is manifested as weakness of the extensor muscles. There appear to be two distinct renal effects from chronic lead exposure, reversible proximal tubular damage and progressive, irre versible renal failure. Although dose-response relationships have not been defined, it appears that the effects occur only at levels above those which affect heme synthesis. vii DUP050033515 There are many tests which can be used for the detection of increased lead absorption. Tests which measure both tissue lead con tent and tissue metabolic effects are available. However, no single test can be used for the determination of total body burden or over all metabolic effects. At present, blood-lead concentration is the most widely used measure of tissue lead content. Two subgroups within the general population have been identi fied as being more sensitive and at greater risk to environmental lead exposure. Due to many factors, children under the age of four are especially susceptible to the toxic effects of lead. The fetus has also been identified as a lead-sensitive individual, due to the immature state of development of certain organs. Because transpla cental absorption is the major source of prenatal lead exposure, the pregnant female must be recognized as the exposure vehicle for the fetus. The blood-lead level in the fetus is approximately the same as that in the mother. Separate lead-uptake-to-blood-lead relation ships have been derived for children and pregnant women. The Center for Disease Control (CDC) set the blood-lead level of significant danger to children at 30 ng/dl. The level of 30 fig/dl set by the CDC is endorsed by the American Academy of Pediatrics and is now the target level defined by EPA as the level of undue lead exposure Results To evaluate the adequacy of the interim primary drinking water standard for lead, it is necessary to predict the blood-lead levels associated with various concentrations of lead in drinking water for identified sensitive populations, and to determine the extent to which altering the maximum allowable concentration of lead in drinking water may affect these populations. Through the combined use of the derived lead-uptake-to-bloodlead relationship and percent contribution values from the source contribution model, the relationship between various water-lead exposures and resulting blood-lead values can be drawn. The source contribution model represents any specific subunit of the total population by incorporation of the assumed characteristic exposure concentrations and physiologic factors associated with that subunit. The model has been applied to four hypothetical populations: adult males, pregnant females, nonpica children, and children with pica fOr paint. Source contribution factors and blood-lead levels in these populations have been calculated using the model. They are de scribed in the following paragraphs. viii The range of source contribution factors can be quite large, if one considers all the possible permutations of lead levels in the various media. In pregnant females, the source contribution factor for drinking water varies from about 6 to 70 percent. In children without pica# drinking water contributes between 2 and 74 percent of the daily lead uptake. For the child with pica for paint, drinking water contributes between 1 and 09 percent, depending on the concen tration of lead in soil/dust and paint. Analysis of the effect of varied water-lead intakes in reference to the critical threshold level of 30 pg/dl chosen by EPA and CDC reveals that urban children are the sensitive subgroup. Although water may comprise as much as 42 percent of the source contribution in rural children without pica who are exposed to lead in drinking water at the current standard, their total blood-lead level (12,3 (ig/dl) is well below the critical threshold level, Urban children without pica, at the current drinking water standard and above, all display blood-lead values equal to or exceeding the critical thresh old level. Urban children with pica for paint (with lead-containing paint at the current standard) display blood-lead levels of 30 pg/dl at water-lead levels below the standard, and blood-lead values well above the critical threshold level at water-lead levels above the standard. Urban children with pica (with lead-containing paint above the standard) display blood-lead levels well above the critical level at all water-lead levels. At the current wafer standard, water lead represents 8.5 and 8.2 percent of the total source contribution for urban children without pica and urban children with pica (lead-containing paint at the stan dard), respectively. In children with pica for paint exposed to lead-containing paint above the standard (8000 pg/g), water contrib utes 5.8 percent of the total daily lead uptake. Lowering the waterlead concentration from 50 to 10 pg/1 produces a decrease in the per cent contribution of water lead to total daily lead uptake from 5.8 to 1.2 percent, and a decrease in blood lead from an estimated 40.3 to 38.8 pg/dl. The blood-lead values of urban pregnant women at an air standard of 1.5 pg/rn^ vary only by 2.7 pg/dl from blood-lead values of preg nant rural women. The blood-lead level of these urban women at the current water standard is estimated to be 16,8 pg/dl, well below the 30 pg/dl level agreed on by EPA and CDC. The percent contribution of water to total lead uptake in urban women ranges from 6.4 percent (at 10 pg/1) to 25.5 percent at the standard (50 pg/1). The blood-lead level in those women varies by about 1,8 pg/dl (i.e,, from an esti mated 15.0 to 16.8 pg/dl) over this same range of water-lead concen trations. ix Blood-lead levels of D.S. children have been characterized as log-normally distributed, with a geometric standard deviation (GSD) of between 1.3 and 1.5 (EPA, 1978). Given the 30 pg/dl threshold level. One can identify the percent of the exposed population with blood-lead levels below 30 Hg/dl given a geometric mean blood-lead level. Or, if a selected percentage of the population is to be pro tected (as a safety margin), one can determine the particular geo metric mean which will insure that that percentage will not exceed 30 jjg/dl. This statistical treatment allows one to define the ex tent to which the "tails" of the frequency distribution extend beyond a particular blood-lead level. More than 99 percent of rural children without pica or with pica at low paint-lead levels, and all female adults are expected to fall below the 30 Mg/dl blood-lead guideline given drinking water lead at the current interim standard of 50 pg/dl. Decreasing drinking water-lead levels for these groups would have a negligible impact, since most individuals within these groups are already below the threshold. A larger proportion of the urban child population exceeds that 30 pg/dl blood-lead level, but the drinking water contribution is only a small fraction of their total daily lead uptake. Assuming drinking water lead at 50 pg/1, between 43.2 and 88.6 percent of the urban child population is expected to have blood lead in excess of 30 pg/dl (see Table 9-1). By reducing the lead level in drinking water to 10 jig/1, between 41.4 and 84.5 percent would exceed the 30 pg/dl threshold. The complete elimination of water lead from the uptake of the urban child yields an estimated mean blood-lead level of 28.1, 28.9, and 38.4 pg/dl for children without pica, with pica for paint at low paint-lead concentrations, and with pica at high paint-lead concen trations, respectively. The corresponding percentages of the popu lation falling below 30 pg/dl are 64.1, 61.0, and 17.0, respectively. Therefore, the total elimination of water lead in these groups adds 1.5 percent of the population to that portion already below the 30 pg/dl guideline. The effect upon the fetal population of reducing the water-lead standard is not as clearly defined by these manipula tions, since the blood-lead levels of the vast majority of the female population are already below 30 pg/dl. DUP050033518 TABLE OF CONTENTS LIST OF ILLUSTRATIONS LIST OF TABLES 1.0 INTRODUCTION 1.1 Background 1.2 Approach 2.0 ENVIRONMENTAL SOURCES OF LEAD EXPOSURE 2.1 Lead Concentrations in Ambient Air 2.2 Lead Concentrations in the Diet 2.3 Lead in Drinking Water 2.3.1 Lead in Potable Water Distribution Systems 2.3.2 Lead in Tap Water 2.4 Additional Sources of ChildhoodLead Exposure 2.4.1 Soil/Dust 2.4.2 Paint 2.4.3 Newsprint 2.5 Other Lead Sources 2.5.1 Lead-Glazed Utensils 2.5.2 Occupational Exposures 2.5.3 Smoking 3.0 ABSORPTION, RETENTION AND ELIMINATION OFLEAD IN HUMANS 3.1 Absorption Characteristics 3.1.1 Pulmonary Absorption 3.1.2 Gastrointestinal Absorption 3.1.3 Dermal Absorption 3.2 Retention Characteristics 3.3 Elimination Characteristics 3.4 Body Burden 4.0 TOXIC!T? OF LEAD 4.1 Biological Effects Associated with Lead Absorption 4.1.1 Hematopoietic Effects 4.1.2 Central and Peripheral NervousSystem Effects 4.1.3 Renal Effects 4.1.4 Carcinogenicity Page Xiii x*v 1 1 2 4 4 15 20 22 2^ 2^ 23 30 31 3* 33 31 32 33 33 34 37 40 41 46 47 49 50 50 54 57 59 xi DUP050033519 TABLE OF CONTENTS (Concluded) 4.2 Indices of Exposure/Effect 4.2*1 Lead Levels in Tissues 4.2.2 Tissue Metabolic Effects 4.2.3 Other Indices 4.3 Effects Levels 5.0 SENSITIVE POPULATIONS 5.1 Children 5.1.1 Increased Potential for Exposure to Lead 5.1.2 Metabolic Differences 5.1.3 Inherent Physiological Sensitivity 5.2 The Fetus and Pregnant Woman 5.2.1 Placental Transfer 5.2.2 Inherent Sensitivity: Immature Organogenesis 5.3 Threshold Levels 6.0 SOURCE CONTRIBUTIONS TO DAILY LEAD UPTAKE IN HUMANS 6.1 Basic Assumptions 6.2 Estimated Daily Lead Uptake from All Sources 7.0 LEAD UPTAKE/BLOOD-LEAD RELATIONSHIPS 7.1 Child Relationship 7.1.1 Comparison with Other Relationships 7.1.2 Major Assumptions 7.2 Adult Relationship 7*3 Comparison of the Relationships 8.0 WATER-LEAD/BLOOD-LEAD SCENARIOS 8.1 Water-Lead-to-Blood-Lead Relationship in Children 8.2 Water-Lead-to-Blood-Lead Relationship in Pregnant Women 8.3 Blood-Lead Contributions from Individual Sources 9.0 CONCLUSION 9.1 Approach 9.2 Effects of the Standard 10.0 REFERENCES Page 60 61 63 66 66 71 71 71 73 74 75 75 76 77 80 81 83 94 94 97 100 102; 107 109 109 114 117 120 121 121 131 xii V DUP050033520 LIST OF ILLUSTRATIONS r i i Figure Number Page 2-1 MAJOR ENVIRONMENTAL LEAD EXPOSURE PATHWAYS 5 2-2 SEASONAL PATTERNS AND TRENDS IN QUARTERLY AVERAGE URBAN LEAD CONCENTRATIONS (NASN DATA) 8 2-3 SIZE DISTRIBUTION AND LEAD CONTENT OF . AIRBORNE SUSPENDED PARTICULATES, EL PASO, . TEXAS (ALL SAMPLES COLLECTED IN SMELTER- TOWN, 250 METERS FROM THE SMELTER STACK) 12 3-1 LEAD RETENTION: THREE-COMPARTMENT MODEL 44 t 4-1 SITES OF LEAD INHIBITION IN THE NORMAL PATHWAY OF HEMOGLOBIN SYNTHESIS 51 7-1 TOTAL DAILY ABSORBED LEAD TO BLOOD-LEAD RELATIONSHIP FOR THE CHILD 98 ! i iI 7-2 RELATIONSHIPS BETWEEN LEAD UPTAKE VIA INGESTION AND BLOOD LEAD FOR THE CHILD 101 7-3 TOTAL DAILY ABSORBED LEAD TO BLOOD-LEAD RELATIONSHIP FOR THE FEMALE ADULT 106 .8-1 EFFECTS OF VARYING LEAD CONCENTRATIONS IN DRINKING WATER ON THE BLOOD-LEAD LEVELS OF A HYPOTHETICAL TWO YEAR OLD CHILD 110 8-2 EFFECTS OF VARYING LEAD CONCENTRATIONS IN DRINKING WATER ON THE BLOOD-LEAD LEVELS OF A HYPOTHETICAL FEMALE ADULT 116 9-1 EFFECT OF A REDUCTION IN MEAN BLOOD LEAD LEVELS ON THE NUMBER OF INDIVIDUALS EXCEEDING A THRESHOLD BLOOD LEAD LEVEL: LOG NORMAL DISTRIBUTION 123 9-2 PERCENT OF CHILD POPULATION WITH A BLOOD LEAD LEVEL < 30 pg/dl FOR A SPECIFIED GEOMETRIC MEAN BLOOD LEAD LEVEL (ASSUMING GEOMETRIC STANDARD DEVIATION OF 1.4) 125 xlii DUP050033521 LIST OF TABLES Table Humber 2-1 2-2 2-3 2-4 2-5 2-6 2-7 2-8 3-i 3-2 3-3 4-1 4-2 6-1 Page AVERAGE AMBIENT ATMOSPHERIC LEAD CONCENTRA TIONS: QUARTERLY COMPOSITES (pg/m3) 9 ATMOSPHERIC LEAD GRADIENTS ASSOCIATED WITH URBANIZATION LEAD CONTENT IN SELECTED FOODS 10 16 ESTIMATED DAILY LEAD INTAKE FROM FOOD: ADULTS 18 ESTIMATED DAILY LEAD INTAKE FROM FOOD: CHILDREN 21 LEAD CONCENTRATIONS IN DRINKING WATER SUPPLIES EXCEEDING NATIONAL INTERIM PRIMARY STANDARD (50 Hg/1) 25 LEAD CONCENTRATIONS IN HOUSEHOLD TAP WATER EXCEEDING NATIONAL INTERIM PRIMARY STANDARD (50 jAg/1) LEAD IN TAP WATER SAMPLES FROM HOUSEHOLDS IN SELECTED AREAS OF THE THE UNITED STATES 27 Ab s o r p t io n c h a r a c t e r is t ic s o f in h a l e d l e a d COMPOUNDS IN HUMANS 36 ABSORPTION CHARACTERISTICS OF INGESTED LEAD COMPOUNDS IN HUMANS 38 LEAD CONCENTRATIONS IN VARIOUS TISSUES OF CHILDREN AND MALE ADULTS (ppm WetWeight) 42 CORRELATION BETWEEN BLOOD LEAD AND OTHER TESTS 67 CLINICAL SIGNS OF LEAD INTOXICATION 69 BASIC ASSUMPTIONS EMPLOYED IN THE CALCULATION OF INDIVIDUAL SOURCE CONTRIBUTION FACTORS 82 xiv DUP050033522 Table Number 6-2 6-3 6-4 6-5 6-6 6-7 7-1 7-2 8-1 8-2 8-3 9-1 9-2 LIST OF TABLES (Concluded) Page REPRESENTATIVE ENVIRONMENTAL LEAD EXPOSURE LEVELS 84 CALCULATION SEQUENCE IN DETERMINING SOURCE CONTRIBUTION FACTORS: CHILDHOOD CASE 86 ESTIMATED DAILY LEAD UPTAKE IN ADULT MALES 87 ESTIMATED DAILY LEAD UPTAKE IN PREGNANT FEMALES 88 ESTIMATED DAILY LEAD UPTAKE IN CHILDREN WITHOUT PICA > 89 ESTIMATED DAILY LEAD UPTAKE IN CHILDREN WITH PICA FOR PAINT 91 ENVIRONMENTAL LEAD CONCENTRATION AND BLOOD LEAD IN CHILDREN: SELECTED SITES 95 RISE IN BLOOD LEAD LEVEL ASSOCIATED WITH in c r e a s e o f loo |Ag/i in w a t er l e a d c o n c e n t r a t io n 103 ESTIMATED DAILY LEAD UPTAKE AND BLOOD LEAD IN CHILDREN WITHOUT PICA 112 ESTIMATED DAILY LEAD UPTAKE AND BLOOD LEAD IN CHILDREN WITH FlCA FOR PAINT 113 ESTIMATED DAILY LEAD UPTAKE AND BLOOD LEAD IN PREGNANT FEMALES 115 SAFETY FACTORS ASSOCIATED WITH PROJECTED BLOOD-LEAD LEVELS FOR VARIOUS CHILD SUBPOPULATIONS 126 SAFETY FACTORS ASSOCIATED WITH PROJECTED BLOOD-LEAD LEVELS FOR VARIOUS PREGNANT FEMALE SUBPOPULATIONS 127 XV DUP050033523 1.0 INTRODUCTION The Office of Drinking Water (ODW) within the U.S. Environmental Protection Agency (EPA) in accordance with the Safe Drinking Water Act as amended has promulgated National Interim Primary Drinking Water Regulations, for a number of physical, chemical, biological and radiological contaminants in potable water systems. These interim standards, which specify maximum contaminant levels (MCLs) for sub stances in drinking water, will be replaced by final Primary Drinking Water Regulations as more definitive information describing the health risks associated with each contaminant is accumulated and analyzed. The MITRE Corporation, Metrek Division has assisted the Criteria and Standards Division, Office of Drinking Water, in their assessment of the adequacy of the current standard for lead (Pb) in drinking water (50 p.g/1). As part of this effort, MITRE has defined and quantified the major environmental sources of lead exposure, devel-oped estimates of total daily lead uptake in sensitive subgroups of the general population, defined blood-lead Levels resulting from the major environmental sources of exposure, and assessed the public health significance of various levels of lead in drinking water. 1.1 Background Lead is ubiquitous in the environment and humans are exposed in many ways. Lead in air can be traced to both stationary and mobile (e.g., automobiles) emission sources. Lead occurs naturally in water systems, but a substantial portion of the lead present in drinking water at the household tap is added in the water treatment and distribution processes. Lead also occurs naturally in trace quantities in various foods, but most of the lead in food is attributable to processing and handling. Children are exposed to 1 DUP050033524 additional sources of lead in soil/dust and other lead-containing nonfood materials. Both children and pregnant females have been identified as subgroups within the general population that are at greater risk from lead exposure than the remainder of the population* Lead accumulates in the human body--the majority in the bone, kidney and liver. Lead that has been stored in body compartments can be remobilized long after the initial absorption and produce adverse health effects. Even though the physiological effects of lead have been well-documented, there is still controversy surrounding toler able blood-lead levels and the significance of environmental sources of lead exposure. Because of the multiple pathways for lead exposure and the cumulative nature of lead exposure, it is necessary to take into account all the lead to which an individual is exposed when considering the implications of a lead drinking water standard. Occupational exposure, however, will not be discussed in this report. 1.2 Approach In order to properly assess the health significance of lead- contaminated drinking water, it is necessary to define an individ ual's total daily lead uptake from all sources, to assess the health impacts associated with that total daily uptake and to identify that proportion of the total daily uptake arising from the ingestion of drinking water* In this assessment the following steps were followed: Quantify the major environmental sources of lead exposure. Determine the absorption/retention/elimination character istics of those lead compounds commonly found in the environment. Develop estimates of total daily lead uptake in man based on ambient exposure levels and absorption/retention character istics. . 2 DUP050033525  Define the toxicological impacts associated with lead expo sure, especially the low level chronic effects for the identified sensitive populations, Assess the public health significance of various levels of lead in drinking water, given ambient lead contamination in other environmental media. The degree of exposure to lead in the environment varies sub stantially, and is dependent not only upon envirdnmental factors (e.g., lead concentrations in water) but also on individual host characteristics (e.g., age, dietary status). An individual's body lead burden reflects his or her Own exposure situation, which often cannot be approximated by "national average" lead concentrations in some medium. Such inherent variability has led MITRE/Metrek to develop a source contribution model that identifies and quantifies the effects of various environmental sources of lead exposure on ah individual's blood-lead level. This model permits one to examine all significant sources of lead exposure, and to define the change in blood lead as a result of any changes in exposure characteristics. In this way, various regulatory scenarios can be applied to the environmental lead problem, and thereby aid in the selection of the most cost-effective control option, based on incremental reduction in a population's blood-lead level. This document describes the development of the source contribution model, and applies specif ically to the health impacts of lead in drinking water. 3 2.0 ENVIRONMENTAL, SOURCES OF LEAD EXPOSURE Lead is a natural constituent of the earth's crust, but the pres ence of lead in the remainder of the environment is mainly the result of extensive use of lead and lead compounds by man. The chemical properties of the more common forms of lead result in low lead levels in natural waters. Because the toxicological effects associated with lead exposure can be considered cumulative, it is imperative to define and quantify all major sources of human lead exposure. Ambient air, food, and drinking water are the major sources of exposure for adults, while soil and dust, via normal hand-to-mouth activity, and various leadcontaining materials via pica* are significant additional sources of exposure for children. Inhalation and ingestion of lead-contain ing substances by adults and children appear to be the predominant routes of exposure, although dermal absorption may be significant in certain instances., Humans are exposed to lead and lead-containing compounds through the various environmental pathways illustrated in Figure 2-1. In the following sections, and in later chapters, the occurrence of lead in the major exposure pathways is exemplified, and lead levels in the significant exposure media that are representative of an average or range of hypothetical exposure conditions for selected populations are derived from the literature. 2.1 Lead Concentrations in Ambient Air The majority of lead Compounds found in the atmosphere result from leaded gasoline combustion. In 1975, the most recent year for which data are available, approximately 88.$ percent of the total atmospheric lead arose from that emission source. The next largest *The ingestion of nonfood material. 4 DUP050033527 VrOO*v 1 *-> 8U *xs <uo 8* M i 8 5 DUP050033528 FIGURE 2-1 MAJOR ENVIRONMENTAL LEAD EXPOSURE PATHWAYS contributors, primary copper and lead smelting facilities, provided 2.5 and 1.7 percent, respectively, of the total (EPA, 1978a). Local atmospheric lead pollution from industrial plants processing lead and its products can be severe, but their overall contribution to the pollution load across large areas is minimal (Atkins and Krueger, 1968). The National Air Sampling Network (NASN) has routinely col lected and analyzed airborne particulate samples for selected metals since the early 1960s. Their sampling protocol (Hi-vol filter samples) defines the total suspended particulate (TSP) material in ambient air. Recent studies have indicated, however, that the atmo- ' spheric lead constituent of TSP is comprised of particles whose mass median diameter (MMD) is approximately 0.2 to 1.43 p. Up to 74 percent of the particles are less than 1 p in diameter (Lee and von Lehmden, 1973; Harrison, 1973). It is widely believed that particles in this size range are easily respirable, and reach the innermost parts of the lung, since pulmonary deposition of inhaled particulate matter is greatest in the 0.01 to 2 p range (Task Group on Lung Dynamics, 1966), Virtually all lead deposited in the lung is eventually absorbed into the blood (Kehoe, 1961; NAS, 1972). In addition to inorganic lead particulate material, the atmosphere may contain organic lead vapors (e.g., lead alkyls) which are not detected by NASN sampling protocols. Most of these organic lead compounds arise, from the production, handling, and use of gasoline containing lead anti-knock additives. They are photpreactive and their presence in. local atmospheres is transitory. Studies have indicated that lead alkyls represent less than 10 percent of the total lead loading in the atmosphere (NAS, 1972). Therefore, any health hazard associated with organic lead exposure is most likely to. occur in an occupational setting (e.g., gasoline handling operations). 6 > r r , > > i. | j ' DUP050033529 According to HASH data, the levels of lead compounds in the atmosphere are slowly decreasing, mainly as a result of the decreased use of leaded gasoline. Figure 2-2 illustrates this gradual reduction in atmospheric lead. The data in Table 2-1 represent cumulative frequency distributions of atmospheric lead for all quarterly results by year at both urban and nonurban locations. As might be expected, urban atmospheres contain higher lead concentrations than nonurban atmospheres. In 1974, the arithmetic mean urban lead concentration was 0.89 pg/m^, as compared to the nonurban mean of 0.11 pg/m3, When nonurban locations are classed according to their proximity to large population centers, the lead concentrations decrease with distance from the urban environment, as seen in Table 2-2. The data in Figure 2-2 and Table 2-1 are average atmospheric lead concentrations reported by NASN. The data represent average quarterly composite samples taken at 300 urban and 35 nonurban sampling stations nationwide. There can be substantial geographical, diurnal, and seasonal variations not readily evident in the yearly averages data. Although the NASN annual averages are useful in identifying trends in air-lead levels, one should examine data from individual sampling sites or regional areas to identify those locations that experience higher than average lead concentrations. For example, the NASN data for the Burbank, California, sampling station indicate yearly averages ranging from 2.46 to 4.93 pg Vb/w? between 1970 and 1974. In`the same period, sampling in Los Angeles indicated an am bient lead concentration (yearly average) ranging from 2.12 to 4.63 pg/m3 (Akland, 1976). 7 DUP050033530 LEAD CONCENTRATIONS* (pg/m 3) * Ninetieth percentile indicates that 90 percent of all NASN stations reporting showed: lead concentrations at or below the particular value. SOURCE: Faoro and McMullen, 1977 FIGURE 2-2 SEASONAL PATTERNS AND TRENDS IN QUARTERLY AVERAGE URBAN LEAD CONCENTRATIONS (NASN DATA) 8 DUP050033531 t a o oS o 00 Hi- f- a ' 3s 00 ep r>. sO UO i p o oo s$9 *4t g *8 iu *3 9 ay U 3> O' CO CO CM O' H CM H O' CO H A H 9 co H 00 co O' 00 CO 00 CO o lA so VO uo sj <r .00 O' CO vO H CO vO p rH Hf CO CO CO o (A as O' rH as m P sr rH rH rH rH rH rH o O o CO r*. O' rH 00 -a- CO H rH o P rH rH rH op O ,d o* rH vr 00 Hf f> CO CO CO nr rH P O' in rH rH rH o o co CO eo VO CM CO m tn O' vO rs O' vo P ooQ d 06 0 1 05 m o' as VO f> CO rA CO tn o O' CO CO CaM\ CM OV r*s rH co CM co CO CO a OJ N CM CM rH o o poo o u rs r*. <r CO .rl 3 rH H CO CM rH vo CM O' CO CM 3 P CM o. VO vO CM rH CM CM CM H 4J CM CM ;rH rH .rH O o dO CO H O CO CO vO CM rH '} r <N oo i/'t O o sO fO H#* CO Sf CM o o o o rH rH rH 1 H *H rH rH rH od dPo 50 70 a sr CO CO r P rs a lA r--i r*- r- U0 o o m. 00 9 P o OV rs IH o rH H$ rH rH O O o d d d 'd d H U cd CO CO rs m CO 30 m H H CO o. o o O :H m a r- ih m A opOoo '1 o oO O o o d d d o ' CO CO ps. m rs rs CM vO tn vO o o o rH o -O' -a- <r co CO p. o O o ; ooPP oddd o g T3 ro CO to n* | .01 o H. o 8 8 8 MOO' rs'! 4J p .rH cCd *& B a ga ag o d o Od oo dd S a> OJ 05 CD a a -H 13 li 5 Ml SS 4J CO rs rn 00 as sr O' rH o UO O' Is* fN uo 1/0 Hf in l-s o O' CM oo CO |H rH i-H .rH $ a O rH CM CO <r 3 r*. rs l< rs rs. >4 O' O' O' O' O' rH t H rH r-H rH o ps rH rs rCsM CO rH 'O' rs O' O' O' O' O' rH *H H rH rH i 9 ua o a ; U rb a n U a ii- o Q *3 5C X 2So#"> ;\ 9 Example: In 1974, urban lead concentrations averaged 0.89 fig/m3, w ith a maximum reported q u a rte rly value o f 4.09 pg/m3; fo r 1974, 95% o f the reported lead concentration were _< 1,97 ug/m3. J !. DUP050033532 TABLE 2-2 ATMOSPHERIC LEAD GRADIENTS ASSOCIATED WITH URBANIZATION* Number of stations reporting Lead concentration Urban __________ _______ Nonurban Proximate Intermediate Remote 217 1.11 pg/m3 5 0.21 pg/m3 15 0.096 Pg/m3 10 0-022 Pg/m3 *1966-1967 NASN data SOURCE: Adapted from McMullen et al., 1970 i 10 DUP060033533 ,i In 1974 and 1975, there were fifty-six Air Quality Control. Regions (AQCRs)* that reported a lead concentration in excess of 1.5 pg/m3 in at least one quarterly composite sample (Preston, 1977). The maximum quarterly lead concentration of 32,0 pg/m^ was reported for the northern Idaho/eastern Washington AQCR. Over 50 percent of Its samples indicated lead at concentrations equal to or greater than 4 jig Pb/m3. These atmospheric lead measurements were substantiated by other unrelated monitoring surveys during the same period, which reported annual average lead concentrations ranging from 0.5 to 23 pg/m3 in the same geographical area (Yankel et al. , 1977; Idaho Department of Health and Welfare, 1977). The higher ambient lead levels were associated with a primary lead smelting operation located in the region. The particle size distribution of lead aerosols are dependent upon the emission source. Urban aerosols collected in several cities whose air pollution problems stem mainly from vehicular traffic contain lead particles with a mass median equivalent diameter of 0.25 (j l (Robinson and Ludwig, 1967). Over 90 percent of the leadcontaining particles are less than 1 p. in diameter (Jenkins, 1976)* The particle-size distribution of atmospheric lead particles col lected near a primary lead smelter is somewhat different (as seen in Figure 2-3).. A.larger portion of the lead-containing particles are in the >. 7.0 pi size region. These larger particles are not as likely to penetrate into the pulmonary regions of lungs. Rather, they are deposited in the. nasopharyngeal region, removed via the mucociliary escalator, and either swallowed or expectorated. It *AQCRs were required under the 1967 amendments to the Clean Air Act of 1963, and based on "jurisdictional boundaries, urban-industrial concentrations and other factors necessary to provide adequate implementation of air quality standards'' (EPA, 1972b). 11 DUP050033534 PERCENTAGE Mean: August 1972-July 1973; one set of samples each monthMeaii: January-July 1973; one set of samples each month SOURCE: Landrigan et al., 1975 FIGURE 2>3 SIZE DISTRIBUTION AND LEAD CONTENT OF AIRBORNE SUSPENDED PARTICULATES, EL PASO, TEXAS (ALL SAMPLES COLLECTED IN SMELTERTOWN, 250 METERS FROM THE SMELTER STACK) 12 DUP050033535 has been estimated that approximately 75 percent of the leadcontaining particulate material of an atmosphere, such as illustrated in Figure 2-3, would be nonrespirable (EPA, 1972a). Larger particles are also more apt to settle out of the atmosphere quickly. There fore, they contribute significantly to the lead levels in dust, soil, water, and vegetation in the vicinity of the source. In areas close to main transportation arteries, atmospheric lead concentrations can vary substantially. The level of atmospheric lead near a roadway has been shown to vary directly with the volume of vehicular traffic and the sise of the community traversed (Hall, 1972; Johnson et al., 1978; NAS, 1972). Mean atmospheric lead levels in the Los Angeles area have been shown to vary from 9.4 to 38.0 pLg/m^ according to proximity to freeways, time of day, day of the week, and sampling elevation* (NAS, 1972). Such sampling regimes may include both respirable lead particles and coarser, nonres pirable lead particles, since many of the larger particles would not necessarily have settled out of the atmosphere prior to sample collection. Empirical measurements in the immediate vicinity of freeways in Los Angeles have indicated that from 20 to 40 percent of the lead particles collected were larger than 2.14 p. in diameter (Atkins and Krueger, 1968). NASN quarterly composite samples of airborne lead concentrations for a given state or metropolitan area represent average lead concen trations recorded.by a hi-vol sampling network. The sampling sites, usually stationed on rooftops, do not accurately depict,the situation at street level. Heavily trafficked urban areas yield high low-level air-lead concentrations due to vehicular exhaust (Goldgraben, 1978). More than 50 percent of street level vehicular particulate air lead is deposited on nearby surfaces before transmission to higher altitudes can occur (this percentage is representative of highway *Sampling times ranged from 2 to 9 hours, but this variation did not appear largely responsible for the differences in reported levels. 13 DUP050033536 speeds; slower city traffic would be expected to raise the percentage of early lead deposition) (NAS, 1972; Huntzicker et al., 1975), Vertical gradient studies only exist for short-term analysis of lead concentrations. Reliable analysis should be based on long-term simultaneous measurement at low and high altitudes. Short-term low level urban vertical air analyses depict average lead concentrations of 8 pg/m3, while NASN annual averages indicate much lower air-lead values (<1 pg/nP) (Darrow and Schroeder, 1974; Edwards, 1975; EPA, 1977). The extent of this underestimation is not easily quantified, due to action of confounding microclimatic factors (e.g., street canyon effects, eddying, vehicle speed, and crosswind effects) (EPA, 1977). Horizontal dispersion studies of vehicular particulate lead near traffic arteries (vehicles at highway speeds) indicate deposition of greater than 50 percent of emitted lead within 150 feet of a highway, with concentrations decreasing with increasing distance (Daines et al., 1970; Lagerwerff and Specht, 1970; NAS, 1972). Horizontal dis placement of NASN sampling sites away from busy intersections would, again, underestimate particulate air lead concentrations character istic of exposure adjacent to street level sources in the urban environment. Other factors impacting those individuals exposed to street level vehicular lead particles include the resuspension of particulate lead deposited oh and near the road surface, and the effect of airborne street level lead containment within the indoor environment; Again, NASN samplers would be insensitive to these factors due to rooftop locations. The resuspension of settled vehicular lead on roadways by passing vehicles increases as a function of vehicle speed (Sehmel, 1976). Resuspension of 1 to 5 percent of lead deposited on roads by passing vehicles has been estimated (Sehmel, 1976), Air-lead levels in houses adjacent to heavily traveled roads are almost identical with outside street air-lead levels, and fluctuate with the same diurnal cycles (Butler and MacMurdo, 1974). ,, DUP050033537 2.2 Lead Concentrations in the Diet Although the ingestion of food containing lead appears, on the average, to be a large contributor to an adult's total daily lead intake, the exact quantity is a function of the type and size of the diet. The occurrence of lead in various foodstuffs inay.be.a result of natural bioaccumulation, deposition of airborne lead parti cles, and/or food processing and serving. Since most foods have been found to contain about 0.5 ppm of lead or less, intake depends more upon the size and nature of the diet than on a choice of particular foods (Schroeder and Balassa, 1961). However, some segments of the population with special dietary requirements, such as infants, may consume selected foods found high in lead content (s.gi, canned milk). As a result, they ingest more lead than might be expected based on average adult dietary constituents. The lead content of major food classes is presented in Table 2-3. To distinguish degrees of health risk associated with particular dietary habits, estimates of total dietary lead exposure have to reflect frequency distribution data on lead levels in specific food commodities in relation to the quantities actually ingested by vari ous sample populations. Several studies have estimated total daily ingested lead for several typical adult populations based on total food consumption, food class preference, and lead levels in the food stuffs (see Table.2-4). Each estimate of daily lead intake is based on various assumptions, as specified in the appropriate column of the table. In some instances 'two estimates of total dietary lead intake are provided; one including the lead contribution from beverages (FDA food category XII), in addition to all other food categories, and one excluding beverages. The revised estimate of daily .lead intake (i.e., excluding beverages) is provided, so that later calculations considering lead contributions from both food and drinking water will not result in double-counting. Since normal beverage; consumption 15 TABLE 2-3 LEAD CONTENT IN SELECTED FOODS FOOD CLASS* Dairy Products Raw cow's milk II |t II tt II it . I. It Human breast milk II It M II If If T.KAD CONTENT, (ppm) 0.02 0.091 0.05 0.04 0.012 0.05 0.026 Evaporated milk, canned It ft If ft I.V II It til II 0.02 0.11 0.81 0.05 Infant formula II II 0.08 0,42 Meat, Fish and Poultry Cured meats Grain and Cereal Products Potatoes Leaf vegetables 0.015 0.06 0.21 0.013 Q.012 0.37 (wet) 0.20 (dry) 0.10 0.004 0.12 0,04 0.003 0.054 0.05 0,3 0.08 REFERENCE FDA, 1975 Brubn and Franke, 1976 Lamm and Rosen, 1974 Mitchell and Aldous, 1974 Murthy and Rhea, 1971 Lamm and Rosen, 1974 Dillon et al., 1974 Mitchell and Aldous, 1974 Lamm and Rosen, 1974 Murthy and Rhea, 1971 Schroeder and Balassa, 1961 Lamm and Rosen, 1974 Murthy and Rhea, 1971 FDA, 1975; Kplbye et al., 1974 Kirkpatrick and Coffin, 1973 Schroeder and Balassa, 1961 Mahaffey et al., 1975 FDA, 1975; Kolbye et al,, 1974 Schroeder and Balassa, 1961 Garcia et al., 1974 Mahaffey et al., 1975 FDA, 1975; Kolbye et al., 1974 Schroeder and Balassa, 1961 Thomas et al., 1972 Mahaffey et al., 1975 FDA, .1975; Kolbye et al.,1974 Mahaffey et al., 1975 Schroeder and Balassa, 1961 Thomas et al., 197 2 16 DUP050033539 TABLE 2-3 (CONCLUDE]]) FOOD CLASS* LEAD CONTEST fpmn] REFERENCE VI Legume vegetables VII Root vegetables VIII Garden fruits Canned IX Fruits Canned ,X Oils, Fats, and Shortening XI Sugar and Adjuncts 0.265 0.02 0,26 0.11 0.131 0.04 0.11 0.12 0.02 0.06 0.U6 0.85 0.031 0.043 0.04 0.1 0.56 0.013 0.015 0,007 0.008 0.07 FDA, 1975; Kolbye et al., 1974 Schroeder and Balassa, 1961 Mahaffey et al., 1975 Mahaffey et al., 1975 FDA, 1975; Kolbye et al., 1974 Thomas et al., 1972 FDA, 1975; Kplbye et al., 1974 Mahaffey et al., 1975 Schroeder and Balassa, 1961 Thomas et al., 1972 Thomas et al., 1973 Thomas et al., 1975 FDA, 1975; Kolbye et al., 1974 Mahaffey et al., 1975 Schroeder and Balassa, 1961 Thomas et al,, 1973 Thomas et al., 1973 Mahaffey. et al., 1975 FDA 1975; Kolbye et al., 1974 Mahaffey et al., 1975 FDA, 1975; Kolbye et al., 1974 Schroeder and Balassa, 1961 XII Beverages ' All Beverages Beer Wine 0.004 0.003 0.01 0.01-0.29 0.08-0.66 0.05-1.5 Kolbye et al., 1974 Mahaffey et al., 1975 Hardy, 1965 de Treville, 1964 Hardy, 1965 de Treville, 1964 Food group category according to FDA, 1975 17 DUP050033540 I, NM f<l 0*h1* NcC4\ S do aOu<u. *2 13: (fAt) V4) o ^-S oo M 91 -*H e0 4-> a (ft >_ > W H* <i ? s s H M 4.93 (ft ft) iU<o ov B o (J *< ,C ** -! *d h > fl x 8 $ ja h v ?: H ' *> *2 8 4J 4Mdh1i '"00 A *afrt)t n=4J I(>Uft <NtSs H*d4 CQa 5 tOt <oOHC<9*>->4O4 2a i! 1 o#: g 7M 3 hi *H 8 *3 < No s en f i-4 H ll * SO ftl * 0 O g 9X *oH .2) dft) ufl )nJ Vq *o3. -So Ml *; 60:9 CmM Ud <Tk V> d <r <o f?(NiCN--T>)-fo5l < *s e& s I g33 22I Y*a. O Ot 9BStt)) 3 3fl s MV 4>) 4>) d jaat lie 3 B g u y >h 0c *Ma0 4*? 5S d , tt *fWVf(>ttf)tl4-|tfHdftJ)t) h->fcfrt*t) g-sl n ;t 8 8 10) 1o ESTIMATED DAILY LEAD INTAKE FROM FOOD: ADULTS fti "C al 18 DUP050033541 ,gs !1 ea3'a 3w iI sa s o- I R . 83 1 i SUHSJiI *a* 51 ^3 -n ^ , B 3 * 3 *3 3&s a|3 all It* i N * O S3 a Si e>w g*s o I I II * 5 4I-0 u2 > s 3u S3 ) N *4 O 1 o<si *tdJ !8UU 3 HO 8SO oo4) a u<8 U 13 41 00 U nit 3 eo^ J> *o fli IIS *a vHo cd * o> .* t4o> cod> s I H j* J3 33 3 Iu 3 19 DUP050033542 appears to provide lees lead uptake than equivalent amounts of water (see Table 2-3), it would be conservative to assume that all beverage lead intake was in the form of drinking water. Table 2-5 provides similar estimates for daily lead intake by children ranging in age from 6 months to several years. As noted in the appropriate columns, infants' diets varied from special formula to normal adult foods. In most instances, the drinking water category is only included in the data for children 2 years and older. 2.3 Lead in Drinking Water Lead is a natural, although often minor, constituent of surface and ground waters. The amount of lead dissolved in water depends upon the equilibrium constants of the chemical form(s) of lead present. These equilibrium constants depend, to some extent, upon the chemical characteristics of the water system. Studies of lead equilibrium solubilities of a variety of inorganic lead compounds show that water could contain from several micrograms to several hundred micrograms of lead per liter of water, depending upon the pH, temperature, and mineral content of the water (Durum, 1974; Hem and Durum, 1973). Empirical evidence indicates that surface and ground water used in domestic water supplies contains inorganic lead in concentrations averaging less than 10 jig/l (Ropp and Kroner, 1967), In a survey encompassing over 700 surface water sites in the United States and Puerto Rico, less than 0.5 percent of the samples exceeded 50 pg lead per liter of water (Hem and Durum, 1973). A larger proportion of the waters in the northeastern and southeastern states contained lead above the detection limit (1 pg/1), and the northeastern and southeastern states had the largest share of those samples reporting lead > 10 fig/1. Lead present in drinking water above that concentration found in the make-up water usually occurs as a result of the physical charac teristics of the water distribution System. The use of lead pipes 20 DUP050033543 ESTIMATED D A IL Y LEAD INTAKE FRCM FOOD: CHILDREN* 3 y o 1 i! iss I y|= 5 8 3 K sMiaiU ^*.1 4 h H <4 ,_< *< 5* 8H 3 I I s 4 1 3 1 1 y -s t1 3 5 .. . 1 IS I I <a eo . *j M j2 3 4Ji S >> ya 3 3 S Si of *d 11 a8-u8 5 *o 3 w *5 rcH>* r--<i .a t H TS i a a8 > Sr a: *** ' 1 88 21 M S-A DUP050033544 within the system (e.g., service line from water main to individual homes, home plumbing systems) provides an opportunity for the lead in contact with the water to go into solution. The degree of plumbosolvency of the water is a function of temperature, pH, and hardness (Moore, 1975; Waldron and Stofen, 1974). In general, acidic, softwater areas are particularly prone to high lead concentrations. In such areas, the acidity of the water increases its ability to dis solve the metal from lead pipes, and the low concentration of calcium impairs the formation of a calcium carbonate layer which, in hardwater districts, lines the pipes and impedes solution of the lead (Waldron and Stofen, 1974). Studies have indicated that the lead concentration in tap Water from a house using lead pipe in the plumbing system is a function of the total length of lead piping that the water traverses (Schroeder and Balassa, 1961; Waldron and Stofen, 1974; Moore, 1975, 1977). In addition, the use of lead-containing soldering alloys to join copper pipes, the use of lead storage tanks, and the grounding of electric wires to lead pipes (solution via electrolysis) increase the lead content in drinking water (Waldron and Stofen, 1974; Wong and Berrang, 1976; Goldberg, 1974). The lead content in tap water from homes with lead pipes in the plumbing system depends upon the length of time the water sits in the pipes. Lead concentrations are much higher in water that has remained in the pipes overnight than in samples taken after the system has been thoroughly flushed (Schroe der and Balassa, 1961; Wong and Berrang, 1976). 2.3.1 Lead in Potable Water Distribution Systems In a study by McCabe et al. (1970), lead concentrations in finished drinking water collected at 969 public water supply systems in the United States ranged from an undetectable amount to 640 pg/1. Of the supply systems sampled, 3? sites (1.4 percent of the total) contained lead in concentrations exceeding the current national 22 DUP050033545 interim primary drinking water standard of 50 pg/1 (McCabe et al. > 1970). In a similar survey that examined the water supplies of the 100 largest U.S. cities, Durfor and Becker (1964) found that 95 per cent contained lead at concentrations less than 10 pg/1, with a median value of 3.7 pg/1. The maximum reported lead concentration in that study was 61 pg/1. In a more recent survey of 592 interstate carrier water supplies (EPA, 1975), only two sites (0.3 percent of the total) reported lead levels in excess of 50 pg/1. In a recon naissance survey of 253 public water supplies, 79 sites did not detect lead concentrations greater than 1 jig/1. Of those 174 sites reporting measurable quantities of lead, the average was 6.2 pg/1, with a maximum of 34 pg/1 (Durham et al. > 1971). Additional surveys of individual U.S. water supplies have indi cated the presence of lead in potable water supplies at concentra tions exceeding 50 pg/1. In the nine-area* Community Water Supply Study (Bureau of Water Hygiene, 1970 a-d), several sites reported lead concentrations in excess of 50 pg/1, with a maximum value of 497 pg/1 occurring in one New York City suburban area. Studies at particular sites have indicated lead concentrations that exceeded the current interim standard in some water systems. In Colorado, for example, lead samples averaged 45 pg/1 in the systems surveyed, with a maximum reported level of 100 pg/l (Roberts et al., 1975). In eastern South Carolina (Georgetown County), 3 percent of the water supplies contained lead levels exceeding 50 pg/1 (Sandhu et al., 1975). Since these were not intended to be comprehensive surveys of potable water supplies in the particular geographical *Those sites included in the following Standard Statistical Metro politan Areas (SMSAs): San Bernardino-Riverside-Ontario, .Califor nia; Vermont; Kansas City, Missouri; Cincinnati, Ohio; New Orleans, Louisiana; Charleston, West Virginia; Charleston, South Carolina; Pueblo, Colorado; and New York, New York. 23 i ? DUP050033546 area, their frequency-of-occurrence data are not necessarily repre sentative of that area of the country. Lead levels in water supply systems are presented in Table 2-6. 2.3.2 Lead in Tap Water Tap water tends to contain higher lead concentrations than water in distribution systems due to the use of lead pipe or lead-containing solder in the plumbing systems. Table 2-7 provides lead levels in tap water collected from homes possessing a range of plumbing systerns. The lead levels vary from several hundred to several thousand micrograms of lead per liter of water. It is very difficult to estimate the average lead levels in households across the country, because of variations in the chemical properties of local water and home plumbing systems. However, several studies have attempted to gauge lead levels locally by collecting water from representative homes within a community water supply district (see Table 2-8). the variation in lead concentrations over time for a particular location can be partially explained by changes in treatment technique. 2.4 Additional Sources of Childhood Lead Exposure Lead-containing nonfood substances are deliberately ot inadver- tently ingested by some, individuals. This is especially prevalent and frequent in young children (Lourie et al, 1963; Day et el.., 1975; LepoW et al., 1974), many of whom display patterns of repet itive hand-to-mouth activity, mouthing behavior, or pica. Hand-to-mouth activity coupled with the presence of foreign substances (particularly soil,and dust) on the hands and ingestion of soil- and ' dust-contaminated food may both result in the ingestion of appre ciable quantities of lead. Mouthing of substances containing or contaminated with lead, or pica for such substances, may also be 24 -j j S i I | j j j ! j J j j ! DUP050033547 ]* 3 S d S3 M 4-1 sp a- 9 jt 1\ Ia U 1/1 IIgtnJ 8.1 !g fig| * uo uv tu ,* 3d V i-l 'pS.3ea &to JmR 9d <D *4 ,I Iso 23 S* 3 su } { ! I i i i i; O f*. SC54 i9ti K 25 DUP050033548 43 8 4J a a I1 1 .* Q) 60 H 10 44 0 5 O* 4! 44 *M 0 8 H Ot o O CO 1 vO SO AV 3 8 0 10 a 3 "B 0 8 p* 2 44 8 H1 M 0 44 0 0 j* > 3 1 10 vO I8 44 .a60 a 60 *0 3.H u O > % O 60 *8 (0 a * 5 *H *pH0 J8 Ji & 3CO m 44 I a a 5 TJ 0 0 a i 55 a s 6 *1 4 i *s 1u a.44 DO M-i 0 O pHH **aHH 3 a) *d 4<4u o s g 43 & 8 T* 43 -S ftf*. cm 0 O a >> I. a u% t" a w 4> a *5 0) g CO V "* S3 eap - h 44'. 3 3SSp. J*O& 5*H* S* O. ff- 0 .-4 u 'i ss 0 KH n tfj OH 9 n CO o as a r*.w g s o HW S 0 }a4t lu>vi- 44 o h 0.6 0<*o 8 s* w 60 vO a O OrMH u 0 IT* > 60 sO gs Js a 1 S r** OH o h 60 60 b *4 0 4a 0 * 33 OH 6J40 y 43 0 * 8 n 80 .1 si 3?1 oSHO <N r-4 SCOM OOCMH OotCrMv Oo*Tnt 8 OH CM 0o0 26 I DUP050033549 LEAD IN TAP WATER SAMPLES FROM HOUSEHOLDS IN SELECTED AREAS OF THE UNITED STATES SOURCE: Adapted from Lassovszky, 1978 s* AUJ r>. MSM> <10 SON srOs Pr*-KH X V. s> in ll 1| cm-*. Is>o rj SO ShO* sSo fr>> ** **. ** IO H P> H ris>. 1 s0 h- O >* r- co <t r> o o CO >0 CM ot-{ en c m m VO *H st <0 st CO O00O4CO OCO r*. <t 00 CM i 03 n s o r-* r> ! S* _ sO C\ CO so r- o co & *3 rH I3 *VD 44 JH <H C8tJ.T35 sCoO stnt scOo CoOo 00 3<D OJ H CM cMd . r m co o rmM st so i iI ooNcovmr iii (D'O t- oa T*., Si 3 mr* soo mc m oso E3 Q0> sr oo ws <n m so CM VCOM H CM st CO l/l to SO VO co UO mi hE ' riHd K> JJSs cd H .> 3 4Oi-H1 cud * 4doJ to o Hd cd 09 cd<Jgd <5 E Cd - *< * u gl >H *Mp 4O4 *d 0J tdo 43 < Si O O w HH cd A cu 09 H ,>US > a <3 zo ao 44 CO 0o9 to cod *rC3 o 27 >01> CO 44 SJ3hJ O <OM <U > to CD >4. T* CD V X--C)tf e9g 43 rH CO 44 5 T> " st 3 . . ff ^tO Ta3 *ti *j 0<0*3y)) *aH* u cd co CCOO <acu oi V 30 3tOo 43 U 41 U<U A0). CO n. r0H1 (0 Ha> oE a. CO B dn CO co a <k raH> T3 r4H) CU &0ccdo B to cu n 3 0(0) 403 3 403 CM CM c.drH C1O rH 43 >s o E r-l dH xt >0H1 <3U og. eg co W >CO CO TJ H T3 4<J-JU4 ,o 43 o a .acoi <y u 43O3 s5 CO E . -X5 CM rH frl*j O DUP050033550 a mechanism of lead exposure* The list of substances commonly mouthed or ingested by children displaying these behaviors has been shown to include paper (newspaper, wallpaper, toilet tissue, facial tissue, cardboard), dirt (soil, dust, clay, sand, ashes), paint and plaster, tobacco, and toiletries and cosmetics (Barltrop, 1966; Millican et al.1962). Some of these are known to contain lead. Concentrations of lead that have been measured in these substances are reported in the following sections. 2.4.1 Soil/Dust* Anthropogenic sources are responsible for the major portion of lead found in soil and dust. Natural occurrence of lead in the earth's crust accounts for an average of 15 pg/g (Durum et al., 1971). Mean rural soil and dust lead levels of 60 and 275 pg/g have been reported (Rolfe and Haney, 1975; Bethea and Bethea, 1975). However, lead levels in soil and dust in metropolitan areas are said to be as high as 20,000 pg/g (Jenkins, 1976). The mean interior house dust-lead level for an urban area was reported as 11,000 pg/g (Lepow et al., 1974). Metropolitan soil-lead levels as high as 3357 pg/g have been reported (NAS, 1972). The combustion of leaded gasoline is a major contributor to the high lead levels in urban soil and dust (NAS, 1972), Lead levels of about 75 to 730 pg/g have been found in soil adjacent to low and high traffic volume streets, respectively (Johnson et al,, 1978). Additional data from this study suggest a correlation between urban air-lead concentrations and lead levels in hand-wipe samples from children. Since urban atmospheric lead concentrations are related to traffic volume (Section 2.1), these indicate,a relationship between y 1 '" .............. ................. .....1.......... Soil and dust will he treated as a single entity in later calculations and therefore Will commonly be designatd "soil/dust". 28 DUP050033551 gasoline combustion and urban soil/dust-lead. Soil lead concen trations diminish with distance from roadways, but increase significantly near dwellings (Rolfe and Haney, 1975). Increased levels of soil lead near dwellings have been reportedly due to runoff of lead particulates from vehicular aerosol deposition (Rolfe and Haney, 1975), and from the weathering of paint on outer surfaces of dwellings (Ter Haar and Aronow, 1974). High interior dust lead levels (11,000 jxg/g) on unpainted surfaces were reported to be a result of outdoor vehicular aerosol contamination (Lepow et al., 1974). Soil concentrations near U.S. highways displayed decreased concentrations with increased distance from roadways, as well as with increased soil depth. Lead concentration reduction of 65 to 75 percent occurred within a distance of 24 meters from the road (from 32 to 8 |jig/g) where traffic densities ranged from 7500 to 48,000 cars per day (Lagerwerff and Specht, 1970). Industrial point sources (e.g., smelters and battery plants) are a major local source of soil/dust-lead contamination. Air and soil levels were shown to decrease with increased distance from a smelter site in El Paso, Texas. Soil lead concentrations within 1 mile of the smelter averaged 36,853 pg/g, but declined to 2726 pg/g at 1.1 to 2.0 miles and to 2151 Hg/,g at distances over 4 miles (Landrigan et at., 1975). A smelter study in Silver Valley, Idaho, displayed significantly increased air and soil-lead levels at distances of up to 16 miles from the source (Idaho Department of Health and Welfare, 1977). It is apparent that industrial point sources of lead emissions can affect soil levels for much greater distances than those induced by low level vehicle emissions. Lead particles are emitted from vehicles initially as halogenated compounds, of which lead chlorobromide is the most abundant. These lead particulates lose the halogens. Shift toward small parti cle sizes, and increase their water solubility during airborne trans port via chemical reactions which are enhanced by light and SO2. Lead oxide, lead carbonate, and lead sulfate are the major chemical 29 DUP050033552 forms prevalent after deposition of lead particles (Ter Haar and Bayard, 1971; EPA, 1977). These results are iii agreement with Olson and Skogerboe (1975)* who found the major lead contaminant of soil and dust to be lead sulfate. 2.4.2 Paint Ingestion of paint by children suffering from pica has been associated with numerous cases of childhood lead poisoning. Epide miological evidence indicates an association between elevated bloodlead levels and children with pica for paint (NAS, 1972). Pica for paint is of major concern. Extremely high lead concentrations are found in some older paint coatings and are still available as peeling and flaking paint (indoor and outdoor) on older dwellings, A survey of over 2000 dwellings in Pittsburgh revealed that at least 20 percent of the residences built after 1960 had at least one surface with an excess of 1.5 pg/cm^ lead (Shier and Hall, 1977). Smaller surveys in El Paso, Texas and Silver Valley, Idaho, found indoor paint-lead concentrations of >1 percent by weight (10,000 pg/g) (Landrigan et al., 1975; Idaho Department of Health and Welfare, 1977). Market surveys in 1971 showed 8 of 76 paints tested contained 2.6 to 10.8 percent lead. The Consumer Product Safety Commission found that only 2 percent of interior paints tested had lead levels exceeding 1 percent (NAS, 1976), The same survey found that 70.8 percent of oil-based paints and 96.1 percent of water-based paints contained less than 0.06 percent lead (the current paint standard). Regulation of the use of lead in house paints did not exist until 1955, when a 1 percent voluntary standard was adopted, A federal standard of 1 percent was imposed in the early 1970s, lowered to 0.5 percent in 1976, and further lowered to 0.06 percent (600 pg/g) in 1977. It is apparent that paint with lead levels' in excess of 1 percent (by weight) is still readily accessible to children who live in older dwellings (NAS, 1976), 30 DUP050033553 2.4.3 newsprint Newsprint can be comprised of up to 1 percent lead (by weight) (Hankin et al., 1974). Colored newsprint contains the greatest amounts of lead. Handling newsprint may result in appreciable dermal exposure; and, coupled with immature dietary habits (e.g,, the licking and sucking of fingers), newsprint may represent a source of ingested lead as well, ingestion of newspaper is common among children with pica. Indirect newsprint-related exposure can result from elevated air lead levels in homes where newspapers and magazines are used as fireplace fuel (Perkins and Oski, 1976). 2.5 Other Lead Sources 2.5.1 Lead-Glazed Utensils A number of persons have been poisoned by lead that has leached from glazed kitchen utensils. Studies have indicated that the amount of lead leaching into a beverage from the glaze of a ceramic vessel is a function of the temperature at which the glaze was fired, how* long the clrink has remained in the vessel, the pH of the drink, arid the number of times the vessel had been used previously. In one study, lead concentrations in a cola (pH 2,7) stored in a glazed mug increased by 2800 .|J.g/l. after two minutes and by 6600 (ig/1 after two hours of containment (Harris and Elsea, 1967). 2.5.2 Occupational Exposures Workers whose occupations entail chronic exposure to high lead levels (e.g., garage mechanics, police, smelter workers) have been shown to have higher mean blood-lead levels than other workers (EPA, 1972a; Johnson et al., 1975b). In some studies, more than 50 percent of such high risk populations have been shown to have blood-lead levels >40 pg/dl, far higher than the 1 to 5 percent representative of the average adult population (EPA, 1972a). 31 DUP050033554 Prudent' industrial hygiene practices can minimize excessive occupational lead exposure. Since this discussion is centered around the possible environmental lead exposure sources, as opposed to spe cific occupational categories, occupational lead exposures will not be discussed further. 2.5,3 Smoking Tobacco smoke is an additional source of respiratory lead expo sure. Reports indicate that inhaled cigarette smoke may provide from 20 to 66 pg of lead per pack (Schroeder and Balassa, 1961; Patterson, 1965). Contrasting information suggests that the high blood-lead levels in some individuals who smoke can be attributed to the contam ination of fingers and cigarettes from nontobacco sources and the deleterious effects of smoking upon lung clearance mechanisms (Tola and Nordman, 1977), 32 DUP050033555 3.0 ABSORPTION, RETENTION AND ELIMINATION OF LEAD IN HUMANS Lead is absorbed into the body via inhalation, ingestion, or dermal contact, enters the bloodstream, and is transported throughout the body. The concentration of lead in the body is a function of the level and duration of exposure, the rate of absorption, and the rate of elimination. Once lead has entered the bloodstream, it can be transported to most sites within the body. Lead is removed from the blood by excre tory mechanisms (e.g., kidney) or by gradual accumulation at various storage sites (e.g., soft tissue, bone). Toxic symptoms result when the lead concentration in a particular body compartment is sufficient to cause damage. When assessing the toxicological implications of environmental lead exposure, it is important to consider the expo sure route because the kinetics of absorption vary between routes. 3.1 Absorption Characteristics Environmental lead compounds can be absorbed into the blood stream from the lung after inhalation, from the gastrointestinal tract after Ingestion, or to a limited extent, from direct dermal \ contact. The absorption kinetics for each of these pathways are dependent upon a number of'factors, including the physical and chem ical nature of the lead compounds at the time of exposure and the presence of other modifying agents. Once inorganic lead is absorbed into the bloodstream (where it is mainly bound to erythrocytes [Butt et al., 1964]), it is readily transported to other locations in the body and does not normally retain any characteristics associated with its exposure or absorption route. Although inhalation and ingestion of lead-containing compounds are the predominant routes of intake, dermal absorption may be significant under certain circumstances 33 DUP050033556 (e.g,, occupational lead alkyl exposure). The three absorption routes are discussed in detail in the following sections. 3.1.1 Pulmonary Absorption To be absorbed into the bloodstream, inhaled lead material must be retained in the lpwer regions of the lung (pulmonary region) long enough to be solubilized. Lead vapors freely penetrate deeply into the lung, but the penetrability of lead-containing aerosols is dependent on several variables, the predominant one being particle size. Since most atmospheric lead compounds exist as a component of particulate matter, the uptake of lead vapors can be ignored (Smith, 1971). Physical retention of particulate matter in the lung is a func tion of particle size and breathing kinetics, while the chemical properties of the particle determine its solubility in body fluids, and hence its ultimate absorption* If particles are deposited in the upper regions of the respiratory tract (i.e., nasopharyngeal and tracheobronchial regions), they can be removed by the ciliated epithelium (mucocilary escalator) relatively quickly and expectorated or swallowed. Particles deposited in the pulmonary (i.e., alveolar) region, which is devoid of cilia, can be absorbed into the blood stream or phagocytized by alveolar macrophages and removed via the lymphatic system (Casarett and Doull, 1975). If a particle is larger than about 10 p in diameter, if is deposited by inertial impaction in the nasopharyngeal region and removed. Particles between 1 and 5 p often settle out in the tracheobronchial region and are similarly removed. Various lung deposition models suggest that the greatest retention in the' pulmonary region of the lung occurs for particles with an aerodynamic diameter in the 0.1 to 1 p range (Task Group on Lung Dynamics, 1966; Nozaki, 1966). As indicated in Section 2.1, the particle size distribution of ambient lead aerosols tends to be within the respirable range. 3.4 DUP050033557 However, one shouLd not assume that all of the respirable lead mate rial inhaled is subsequently absorbed into the bloodstream because the chemical form of the particle can affect the rate of absorption (Smith, 1971; Kehoe, 1969). The major species of atmospheric lead particles include various lead halide mixtures and lead oxide, phosphate, or sulfate (NAS, 1972). Since some of these compounds tend to be only slightly soluble in biological fluids, it is difficult to predict the degree to which they are actually absorbed within the lung. Empirical evidence, from lead balance and lead tracer studies, indicates chat from about 2Q to 50 percent of inhaled lead particles (i.e., those particles representative of urban atmospheres) are absorbed into the bloodstream (see Table 3-1). Xn some cases, both retention in the lung and absorption into the bloodstream were monitored; while in other cases, only particle retention was deter mined with subsequent absorption assumed; Based on these studies, 40 percent is a reasonable value for lead absorption into the blood stream from ambient lead aerosols in an adult. The absorption of lead from ambient aerosols by children is not as well defined. Several problems, including differences in respira tory physiology, metabolism, and body compartment size, make absorp tion projections, in children, based on data from adult, tenuous (Knelson, 1974), In addition, ambient monitoring data may not necessarily reflect the actual atmospheric dose to which a child (or an adult) is exposed, since there is often an increase in the particulate concentration gradient as one approaches ground level (see Section 2.1). Without definitive Clinical studies of atmo spheric lead retention and absorption in children, one must make projections based on adult data and modify them by known differences in ventilatory exchange. As a result, one must assume similar absorption and retention characteristics in adults and children but varying exposures. 35 o V Vl 3 .4 a> e d 60 -W _ . tt 35 53 03 . s i-4 tt *H ** *30 Je tt a-g 5o *4 *H | CO H CO A 53 3 *4 * 4J (0 rtHt 4V J- O.C H 4J O 2t+H * O V> A VI fj A a! O O to stt * tSt ?T H tttt . ^ *d ^ A tt tt tt |3 *0 rH 44 VI fS W +0 V* tat o tdt 9 o o GU OVJ 2ggn 1 >tt4 o,C A -H w tt u-i HO j UH Vi a O tt CO H A*H 4J _ o 80 *H m<u '*o 4 8-J s s1l & hOtt r'Htt 4VH4 4J o H 4 Hig -M 4 tt <o .o fi! tt of S 8 u4 fl *8 tdt Vo tt HC +j ctt do-S5 e vHi -M) *h d tt v> o JttS*B 4J p. H tt CO 0 >tt HI *w oJZ rH Ao Vi tt 4 *t* *o A 4J ill Vi u tt tt aa 4J tt tttt Oa IS Hvi fdtb MH US "OtMt *t4t S"8S . ft*i4 Vtt T_3 Mtt tttt '.t.ttt 1 * Is 2 tt A >O VI 00 S 5 *,s tt.G3 Vai 3 Is 3 ' f tt drH 01 T gA o H CM u O M tt tt VI tt C 1 8 g 8- O tt * 3p< nT* 38 3g-|' S iiM & rC *TJ 'v < Q *n X) VI a eo J<'2**24 ua jvg> tt P*<H tt O.iH cOn - *u.&A CO pq OrttH_ 3-g d* 3 g V* *H &p vj 2 8*3 *0 _ tt A V* *H rH tt O Vl 4H & tM 9' O A o to _ ,o j s e d a v* S O K A*H H tt tt VI Vci >> *tt ACT tt rH C o A tt ` .tt p - o (3 8 +j & o Percent retaJtned o n Oo in so 9* m o i In CM n en *<n . . vp 1 in CM -tt o m 36 o m DUP050033559 Inhaled lead-containing particles larger than one or two microns in diameter are usually collected in the nasopharyngeal or tracheo bronchial regions of the respiratory tract, removed via ciliary action and expectorated or swallowed. That fraction which is swal lowed may be absorbed in the gastrointestinal tract, but its contri bution relative to other sources of ingested lead is unknown. Some studies utilizing artificially generated aerosols have indicated that up to 40 percent of inhaled lead particles (mass median diameter of 2.9 (J-) deposited in the airways are transferred to the gastrointes tinal tract (Kehoe, 1961), However, gastrointestinal absorption of inhaled lead from ambient urban atmospheres is expected to be insig nificant given the particle-size distribution of such aerosols, 3.1.2 Gastrointestinal Absorption The absorption of lead-containing compounds in the gastrointes tinal (GI) tract is dependent upon the physical/chemical form of the material ingested, and can be affected by other factors including the Composition of the diet and the age and physiological status of the individual* Absorption of lead from the GI tract appears to be a passive diffusion process, but may be regulated to some extent by the mechanisms controlling calcium and phosphorous absorption (Casarett and Doull, 1975; Gruden and Stantic, 1975). In the average' adult, approximately 10 percent of ingested lead is actually absorbed into the bloodstream. As indicated in Table 3-2, however, empirical evidence indicates large variations in the GI absorption of lead in humans. In some studies, the lead absorption in particular individuals approached 70 percent of the total amount ingested, but in most instances, a value of approximately 10 percent was reported. Such variations may be a result of individual GI tract differences, discrepancies between experimental protocols (e.g., balance versus tracer studies), chemical dissimilarities between the form of lead administered, or analytical error (Blake, 1976; Wetherill el: al. , 1974). 37 DUP050033560 AP g tO i -( S* 1w I i * 33 ito4 o aw ** a I. - *H y3o1 I4J $ 0*rl Q*J S.*j- & r &*S.V H.ssP- O M 0 *0 *8 *4 u6a i*-* 0P 1?f1 > ** S h O *J SB HO a s >H"o0 3 SS i's g Sb i s ss Vu-w*4 vO SS sa <r M r> 3 is 1 i*8 3 a s 1& IH gg a 34 I. 38 5 ^ try t/y iu DUP050033561 In children, the G1 absorption of lead can vary, due in part to the source of the lead ingested and its physical/chemical charac- , teristics. Based on data shown in Table 3-2, it is conservatively assumed that approximately 50 percent of the lead in food and water is absorbed. This fivefold difference in the GI absorption rates of children and adults has been related to the differences in the metabolic behavior of lead at different ages (Kostial et al., 1971; Momcilovie and Kostial, 1974). Experiments involving weanling rate fed lead chloride confirm the finding of substantially increased GI absorption in the young (Kostial et al., 1971; Forbes and Reina, 1972), Children with pica may ingest a substantial amount of lead-con taining substances. Faint is a source of lead for some children with pica. The lead in paint is believed to be absorbed at a different rate than lead in food and water. Animal studies have shown that lead in paint is not absorbed as well as the simple inorganic salts present in other sources. The data indicate that the forms of lead contained in paint are absorbed only one-fourth to one-half as well as the lead salts. A 17-percent rate of absorption for lead in paint has been estimated (NAS, 1976). It must be emphasized that due to high variability of several factors, this absorption rate is only suitable for use on a group basis. No definitive studies have been conducted on the absorption rate for ingested lead from soil/dust. It appears that this is a major source.of lead and that many children ingest substantial amounts of soil/dust from normal hand-to-mouth activity. It is generally assumed that within the gastrointestinal tract lead is more easily separated from the physically absorbed soil fraction than from the chemically bound fraction in paint. Analysis of lead in soil/ dust and paint from an area impacted by a smelter showed that 20 to 60 39 DUP050033562 percent lead in surface soil was extractable in 0.1N HC1 (rep** resentative of the human stomach) compared with less than 10 percent extracted from paint samples (Roberts et al., 1974), A rate of 30 percent has therefore been selected as a representative figure for the absorption of lead from soil/dust, reflecting an absorption rate intermediate between dietary lead and paint lead uptake. A number of factors affect the degree of lead absorption in the 61 tract. Variations in the chemical form of the ingested lead material can alter the absorption rate. Lead tracer studies in fasting adults have indicated that lead nitrate is absorbed at about three times the rate of lead sulfide (i.e., 41 and 14 percent, respective ly) (Wetherill et al., 1974), Nutritional factors may also affect 61 absorption of lead (Barltrop and' Khoo, 1975a, b; 197$); short-term studies using 203pb tracer in rats detected a twentyfold increase in absorption for those animals fed diets deficient in minerals and a sevenfold increase for those on high-fat diets (Barltrop and Khoo, 1975a). There is also a pronounced tendency toward greater absorption when lead is ingested without food (Wetherill et al., 1974; Garber and Wei, 1974; Quarterman et al., 1976), Although it has been Suggested that lead in drinking water is absorbed in the 61 tract at twice the fate of lead in food (Patterson, 1965), definitive labora tory evidence of such a preferential absorption is currently unavail able, In the absence of such data, equivalent 61 absorption rates for load in food and water on the order of 10 percent in adults, and about 50 percent, in children, have been assumed, 3.1.3 Dermal Absorption In order to be absorbed through the skin, lead must either pass through the epidermal cell layer, the sweat or sebaceous glands, or the hair follicles. Uptake via the .sweat glands or hair follicles is not significant. The epidermal layers are not highly permeable and restrict the absorption of most inorganic lead compounds. However, 40 1 ' v j ! j '\ | f j j ! !. t j " ` DUP050033563 since the skin is a lipid barrier, organic lead compounds are able to pass through and be absorbed. Clinical studies have indicated that organic lead compounds (e.g., lead naphthenate, lead acetate) can cross the epidermal layers to varying degrees and result in elevated blood-lead levels (Rastogi and Clausen, 1976). Alkyl lead compounds are also readily absorbed through the skin (Gething, 1975), and have caused episodes of acute lead poisoning. The dermal absorption of lead compounds, however, does not appear to be a significant exposure route for the general population. Although organic lead compounds are quite capable of passing the skin barrier, the major source of exposure is occupational (e.g., garage mechanics, gasoline distributors). As mentioned in Section 2.1, alkyl lead concentrations in urban atmospheres are probably consider ably less than 10 percent of the inorganic lead values (MAS, 1972). 3.2 Retention Characteristics Postmortem analyses of tissue samples from persons with no occu pational exposure to lead have demonstrated the presence of the metal in virtually every organ of the human body (Barry, 1975; Gross et al., 1975),, The body burden of lead is not distributed uniformly; lead has an extremely high affinity for calcareous tissue (Table 3-3). Over 90 percent of the lead stored in the adult body is located in the skeleton.'. In one study (Barry, 1975), the average body burden of lead in 50 male adults was 164.8 mg, of which 155.5 rag (94.4 percent) was located in bone. Children were found to have both a substan tially lower body burden of lead and a lower percentage bf this body burden contained in their bones (Table 3-3). The average body burden of lead in 23 children (mean body weight 23 kg) was 12.3 mg, 72.5 percent of which (8,9 mg) was located in bone. However, concentra tions of lead in the majority of soft tissues-of children were either 41 TABLE 3-3 LEAP CONCENTRATIONS IN VARIOUS TISSUES OF CHILDREN AND MALE ADULTS (ppm Wet Weight) Tissue Tibia Rib Liver Kidney Cortex Medulla Prostate Spleen Lung Skin Thyroid Brain Cortex Stomach Heart Male Adults 23.4 8.85 1.03 ' 0,78 0.50 0.27 0.23 0.22 0.19 0.19 0.10 0.09 0.07 Children (2-9 Tears) 3.70 3.01 0.87 0.70 0.49 0.48 0.13 0.19 0.63 0.28 0.09 0.11 0.09 SOURCE: Adapted from Barry, 1975 42 'i DUP050033565 the same as o k higher than those in the corresponding tissues of adults (Table 3-3). Lead concentrations in the majority of soft tissues apparently reach an equilibrium level during the second decade of life and remain at this level indefinitely (Barry* 1975). Concentrations in the bones, aorta, liver, lungs, kidneys, pancreas and spleen continue to increase with age (Schroeder and Tipton, 1968). While some studies have reported that this increase continues indefinitely (Barry, 1975; Barry and llossman, 1970), others have noted a decrease in the lead burdens of many soft tissues beginning in about the . eighth decade (Cross et al., 1975; Schroeder and Tipton, 1968). This decrease in soft tissue-lead levels may reflect an atrophy of paren chymal cells and an increase in interstitial matter (e.g., fascia, fat) in these tissues that has been postulated to be a part of the aging process (Gross et al., 1975; Steiglitz, 1949). Decreases in bone-lead levels may be due to osteoporosis and/or the reduced lead exposure of older persons (Gross et al., 1975). The distribution and kinetics of lead in the body are approxi mated by a three-compartment model (Figure 3-1) (Rabinowitz et al., 1973; 1975). The model is based upon isotopic tracer studies of the relationships between lead intake, concentration in blood, and elimination in human subjects"; consequently, the. three compartments of the model represent physiological entities rather than distinct anatomical systems. Aside from blood, the majority of fluids and tissues of the body cannot be uniquely assigned to individual compartments .. The blood and certain soft tissues which exchange lead rapidly with the blood constitute compartment 1. , Lead which is absorbed through the pulmonary and gastrointestinal routes enters directly into this pool and is subsequently transported within compartment .1, exchanged with either of the remaining two compartments, or elimi nated in the urine. Compartment 2 accounts for a delay in the labeling of bile and other secretions relative to the labeling of 43 DUP050033566 44 DUP050033567 LEAD RETENTION: THREE-COMPARTMENT MODEL blood. This compartment, which contains less than half as much lead as compartment 1, is thought to represent a portion of the soft tissue not included in compartment 1 and perhaps the more actively exchanging skeletal components. Compartment 3 includes the remaining soft tissue and the majority of the skeletal material. Thus, this compartment contains most of the body burden of lead. Of the absorbed lead which reaches the blood, about 46 percent is subsequently transferred to the other two compartments. A small fraction of the lead transferred from the blood to soft tissue is subsequently returned to the blood but the vast majority is elimin ated by a variety of pathways. There appears to be no direct interchange of lead between soft tissue and bone (Rabinowitz et el., 1973). Varying estimates of the half-lives of lead in the first two compartments have been reported in the literature; 27 and 30 days for blood and soft tissue, respectively, in a 1973 study by Rabinowitz et al.j and 36 and 40 days in a subsequent paper by the same authors (Rabinowitz et al., 1975), Regardless of this discrep ancy, it is clear that the lifetimes of lead in the two compartments are quite similar. Furthermore, they are extremely short in comparison with the hdlf-life of lead in bone, which has been esti mated to be about 10^ days (27.5 years). Thus, the body burden of lead consists of two small and highly transient pools contained in the blood and soft tissues, and a long-lived, relatively immobile fraction contained in the skeleton. While the lead levels in the blood are quite sensitive to varia tions in uptake and therefore give a good indication of recent expo-, sure, they provide little insight into a person's lifetime exposure history. Bone or dentine lead levels are a poor indicator of recent exposure but a fairly good indicator of lifetime exposure (Gross, 1976; Kehoe,, 1969). An accurate chronology of lifetime lead exposure cannot be inferred from the distribution of lead in bone; however, 45 DUP050033568 the concentration and distribution of bone lead does provide a sub stantial amount of information. Because of the extremely slow turn over of compartment 3, the average concentration in this compartment more or less reflects a person's average lifetime exposure level (Barry, 1975). Furthermore, the distribution of lead within the skeleton is somewhat indicative of the nature of an individual's exposure history; soft, vascular bones such as the ribs and vertebrae contain a higher concentration of lead than dense bones such as the femur, after an acute high-level exposure, and a relatively low lead concentration following chronic low-level exposure (Kehoe, 1969). In humans, the adverse toxicological effects of lead are associated with the mobile fraction (i.e., that which is contained in com partments 1 and 2) (NAB, 1972). The lead outputs from compartment 3 normally represent an insignificant contribution to this mobile lead; however, under certain circumstances which are not clearly under stood, substantially higher quantities of skeletal lead can be reinobilized, Large quantities of lead are released from bone during chelation therapy and abnormal skeletal remodeling resulting from dietary deficiencies (calcium, phosphate, magnesium) and hormonal (parathyroid hormone, calcitonin) imbalance (Bethea and Bethea, 1975; Rosen and Wexler, 1977). Lead in the soft bones is presumably remobilized more readily than lead sequestered in the dense bones (Rabinowitz etal., 1974; Rosen and Wexler, 1977). In young children the likelihood of one of the aforementioned nutritional deficiencies (e.g., calcium deficiency) is very high. This suggests that children face an increased risk of remobilization of skeletal lead (EPA, 1977). 3.3 Elimination Characteristics In adults, approximately 90 percent of ingested lead is elim inated in the feces without prior gastrointestinal absorption (Kehoe, 1961; Wethexill et al., 1974). The rate of absorption of lead 46 "V 1 J > * ; > i \ 1 , DUP050033569 through the gastrointestinal tract is greater in children (Section 2.1.2), who therefore eliminate a substantially smaller proportion of their total intake as unabsorbed lead in the feces. The primary elimination route for lead absorbed by all routes is in the urine, representing about 95 percent of the total output of absorbed lead (Rabinowitz et al., 1973). Lead is excreted by the kidney into the urine, both by glomerular filtration and transtubular flow (Goyer and Mahaffey, 1972). Renal effects of lead (discussed in Section 4.1.3) may compound lead toxicity by interfering with urinary lead excretion. Direct transfer of lead to the urine takes place Bolely from compartment 1 (blood), and is the only direct route of excretion from this compartment. The remaining 5 percent of the Output of absorbed lead is from compartment 2 (soft tissues) in alimentary tract secretions, hair, nails, and perspiration (Rabinowitz et al., 1973). The rates and relative proportion of lead eliminated by all routes appear to be sensitive both to the dose and the chemical form of the lead, although these relationships are currently unclear (ERA, 1977). 3.4 Body Burden A great deal of emphasis has been placed on determining the human body burden of lead, perhaps because the toxic, effects of other metals, such as cadmium, are directly related to the overall body bur den (Friberg et al., 1974). However, the health effects of lead do not appear to be directly related to the. whole body content of lead; on the.contrary, the vast majority of the lead, in the body (that stored in bone) is believed to be essentially inactive (EPA, 1977). Furthermore, this inactive fraction is fairly insensitive to shorts term changes in lead uptake, which directly affect health, and thus the whole body burden can provide a misleading estimate of the lead-related health hazard. 47 DUP050033570 Lead is distributed differentially in the various tissues of the body. For analytical simplicity, these tissues can be grouped to gether on the basis of lead distribution characteristics and the body burden of lead represented as a limited number of distinct physiolog ical compartments (such as the three-compartment model described in Section 3.2). The lead content of many or all of the tissues is in constant flux, the magnitude of which can be radically different in different tissues (Rabinowitz et al., 1973, 1974, 1975; Wetherill et al., 1974). In the compartmental model, this flux is represented by rates of input to, transfer between, and excretion from the compart ment as a whole. When the rate of lead intake is constant for extended periods (-100 days) the concentration of.lead in blood reaches an approximate steady state (Wetherill et al., 1974), presumably indicating an equi librium in the overall body burden of lead* Modifications in daily lead intake, if maintained for a sufficient length of time, will result in changes in the lead concentrations in the three compartments and the attainment of a new equilibrium condition. The rates and magnitudes of these changes are dependent upon the rates of lead flux in the tissues and can theoretically be calculated from the three-compartment model by Inclusion of the appropriate parameters. Unfortunately, studies that have experimentally determined these parameters (Kopple at al., 1976; Rabinowitz et al., 1973, 1974, 1975; Wetherill et al., 1974) have used a very small number of subjects, all of whom were adult males, and a limited range of exposure conditions. Therefore, it is not certain whether these parameters are applicable to the adult male population as a whole. Furthermore, given the apparent differences in the behavior of lead in children and adults, it is almost certain that these parameters are not applicable to the child population. 48 . ' DUP050033571 4.0 TOXICITY OF LEAD The toxicological impact of environmental lead is a cumulative product of continuous low-level exposure. The possibility that adverse health effects may result from chronic exposure from the ambient environment is of major concern. Adverse toxicological effects are due essentially to the mobile fraction of absorbed lead within the body (EPA, 1977; Goyer and Mushak, 1977), Previously deposited fractions of lead are mobilized as a result of chelation therapy, normal skeletal remodeling and metabolism, and periods of physiological stress (Bethea and Bethea, 1975). Normal skeletal remodeling and growth is dependent upon the levels of parathyroid hormone, calcitonin, calcium, inorganic phosphate and magnesium (Rosen and Wexler, 1977). By altering the bodily concentrations of these metabolic factors, dietary metabolic imbalances (periods of physiological stress) can cause variation in the blood lead level through bone-lead mobilization. Two properties of lead are believed to be responsible for wide spread adverse health effects. Lead has an affinity for amino acids containing sulfur, resulting in deformation of protein structure. Lead also has a tendency'to bind to the mitochondria, leading to interference in the regulation of oxygen transport and energy generation (Needleman and Piomelli, 1978), Biochemical impairment of many enzyme systems has been found at very low lead exposure levels. In fact, recognition of low levels of exposure is generally a result of biochemical measurements of enzyme activities (Needleman and Piomelli, 1978). Although lead has been shown to produce enzyme interference effects at low concentrations, especially in infants and children, the amount of interference that can be tolerated by ah individual without subsequent harm is uncer tain. In vitro and in vivo studies have provided evidence of inhibi tory effects at minute blood-lead levels (about 5 pg/dl). It is 49 believed that a "no effect level" of enzyme inhibition by lead is nonexistent, but the physiological significance of low-level enzyme inhibition is questionable. Compensation for low lead level enzyme inhibition is thought to be achieved through a "reserve enzyme capa city" but the extent of this low level reserve capacity is as yet unclear, A total review of the literature has not been attempted for this discussion of lead toxicity; rather, a brief synopsis is provided. More in depth discussions of the health effects of lead can be found in several publications (e.g., EPA, 1977; WHO, 1977; Kehoe, 1961; NAS, 1972). 4.1 Biological Effects Associated with Lead Absorption Lead can affect a number of biological systems in man. The hematopoietic, nervous, and' renal Systems are the most sensitive to chronic low-level exposure. A number of other systems are also affected, but to a lesser degree. These include the reproductive, endocrine, hepatic, cardiovascular, immunologic and gastrointestinal systems. The discussion of health effects in this report will be limited to the three systems most sensitive to lead exposure and will focus on children. The carcinogenicity of lead compounds is also briefly discussed. 4.1.1 Hematopoietic Effects Lead inhibits the synthesis of hemoglobin at several points throughout the heme synthetic pathway (Figure 4-1). Synthesis of hemoglobin is completed within a few days after the red blood cells enter the bloodstream; therefore, inhibition of heme synthesis must take place before this point (Guyton, 1971b). The inhibition of the enzyme 6-aminolevu1inic acid dehydratase (ALAD) is believed to be the earliest known biological effect of lead intoxication (Hernberg, 50 DUP050033573 MITOCHONDRION CYTOPLASM KREBS ( V.CYCLE. SUCCINYL COENZYMR A + GLYCINE 5-AMIHOLEVULINIC ACID SYNTHETASE (ALAS) i1 4-AMINOLEVULINtC ACID (ALA) ^ 4-AMIMOLEVULINIC ACID DEHYDRATASE (ALAD) PORPHOBILINOGEN 1 OROPORPHYRINOGEN III J** possible inhibition X definite inhibition FIGURE 4-1 SITES OF LEAD INHIBITION IN THE NORMAL PATHWAY OF HEMOGLOBIN SYNTHESIS ^Precise site and mechanism of ZPP formation is unknown. SOURCE: Adapted from Baloh, 1974; NAS, 1972. 51 DUP050033574 1976). A result of this inhibition is a decline in heme synthesis due to a block in the utilization of 6-aminoleVulinic acid (ALA), However, a decrease in ALAD activity has also been reported for alco holics, diabetics, cancer patients and workers exposed to organic solvents (Yamaguchi et al., 1976) so this cannot be used as a defini tive indicator of early lead toxicosis. The degree of inhibition of ALAD activity increases with Increasing blood-lead levels. Partial inhibition becomes measurable at blood-lead levels as low as 5 to 10 pg/dl (Goyer and Mushak, 1977; Chisolm, 1971; Weasel and Dominski, 1977). There is no indication that this partial inhibition is harmful since heme levels are appar ently not affected. This suggests an enzyme reserve such as that discussed in Section 4.0. Above a blood-lead level of approximately 40 pg/dl, the increase in ALA excretion is exponential. The inhibi tion of ALAD activity accelerates as blood-lead levels increase from 40 to 80 pg/dl and higher (NAS, 1972). At blood-lead levels between 70 and 90 (lg/dl, ALAD activity is almost totally inhibited (Hernberg, 1976). The relationship between blood-lead levels and ALAD activity remains constant under varying exposure conditions (i.e., new expo sure, steady state, after termination of exposure) (Tola et al., 1973). Lead also interferes with the. final step in heme biosynthesis, the chelation of iron by protoporphyrin IX (PP). It is not clear whether this is due to the prevention of iron passage through the mitochondrial membrane (Needleman and Piomelli, 1978), interference with ferrochelatase activity (Lamola and Yamane, 1974), or a combina tion of these effects (EPA, 1977). The surplus PP created by the inhibition of iron chelation does not remain in the unchelated (free) form, but is chelated with zinc (Zn^*) to form zinc protoporphyrin IX (ZPP), and bound to globin (Lamola and Yamane, 1974). 52 DUP050033575 The elevated levels of PP measured in acidic solvent extracts of erythrocytes from patients with lead intoxication, led many investi-gatora to the erroneous conclusion that the porphyrin present in the red blood cells of these patients was free erythrocyte protoporphyrin (FEP). However, in vivo fluorometric measurements of whole blood and isolated erythrocytes have demonstrated that the omnipresent species in lead intoxication is actually ZPP (Lamola and Yamane, 1974; Blumberg et ai., 1977). This view is further supported by the fact that levels of ZPP measured in whole blood by a fluorometric technique are very similar to "FEP" levels determined by extraction methods and show an excellent linear correlation with these "FEP" values (the coefficients of correlation for linear relationships between ZPP levels and the FEP levels determined by two methods were 0.98 and 0.99) (Blumberg et al. 1977). Thus, it is thought that acidic solvents break down the ZPP chelate complex and produce the PP found in erythrocyte extracts. FEP values found in the literature have been reported as "FEP" in this study; however, it is believed that these values represent an indirect measurement of the levels of ZPP in the blood, rather than an indication of levels of free protoporphyrin IX in vivo. Blood-lead levels in children have been associated with specific hematologic changes (Table 4-2). At 15 [xg/dl there is a greater than 40 percent inhibition of ALAD activity. At 20 to 25 pg/dl, there is greater than 70 percent inhibition in ALAD activity. At 30 to 40 pg/dl, urinary excretion of ALA increases above 5 mg/1. At 20 to 25 Ug/dl, there is an increase in erythrocyte protoporphyrins. At 40 to 50 p-g/dl, there is a decreased hemoglobin level (Zielhuis, 1975). An increase in erythrocytic protoporphyrin is considered to be a sign of increased physiologic impairment since it is indicative of impaired mitochondrial function (WHO, 1977). 53 In addition to the enzymatic effects, a shortening of the life span of erythrocytes has been reported. The mechanisms responsible for the shortened life span are not clearly understood but may be the result of several physical effects. Observed effects resulting from exposure to low levels of lead include an increase in the osmatic resistance of erythrocytes, an increase in mechanical fragility and interference with a number of membrane functions, including functions which are important for maintaining cell integrity (Hernberg, 1976). The end result of the enzymatic as well as the physical effects on the hematological system is anemia, resulting from decreased erythrocyte production and increased cell destruction. This anemia is often the earliest manifestation of chronic and acute lead poisoning and is characterized by increased numbers of reticulocytes and basophilic stippled cells in the blood. The symptoms of this anemia are pallor, waxy sallow complexion, fatigue, irritability and head ache; irritabillity and decreased play activity may be signs in young children (NAS, 1972). It is believed that iron-deficient children may be more susceptible to the toxic effects of lead (NAS, 1972). In one study, the incidence of anemia rose sharply in children as the blood-lead level increased from 37 to 100 jig/dl. At bloodlead levels below 36 |j,g/dl, 14 percent of the children were anemic, compared to 36 percent with levels between 37 and 60 pg/dl (Betts et a!., 1973). However, the degree of anemia correlates poorly with blood-lead levels and does not become obvious until the level exceeds 80 pg/dl (Hernberg, 1976). In children, a threshold blood-lead level for anemia is about 40 pg/dl while for adults 50 pg/dl is considered the threshold level (EPA, 1977). 4,1,2 Central and Peripheral Nervous System Effects There is a great deal of concern over the neurological effects of lead. Some segments of the population, especially children, may be exposed to lead in quantities sufficient to cause neurological 54 DUP050033577 and behavioral impairment, although the actual levels necessary to produce such effects are in question (EPA, 1977). It is not known whether central nervous system (CNS) impairment can occur at levels below those which produce observable effects in the hematopoietic system (Qamstra, 1977). Central Nervous System: Accumulation of lead in the body can lead to severe effects on the central nervous system. These central nervous system effects are most responsible for the morbidity and mortality associated with lead poisoning. Symptoms of neurological changes include ataxia (muscular coordination failure), clumsiness, weakness, stupor, coma and convulsions (Hahaffey, 1977). The most severe effect of lead intoxication on the central ner vous system is acute encephalopathy (degenerative brain disease), Blindness, mental retardation, behavior disorders and death can result at this level of toxicity (NAS, 1976). The pathological changes may remain after therapy (Mahaffey, 1977) and can be con sidered irreversible. In an early, mild form, the subclinical signs of encephalopathy include psychomotor disturbances, impairment of intelligence functions and personality changes. Massive doses of lead corresponding to blood levels above 150 |Xg/dl are required for the development of acute encephalopathy. As the disease worsens, cerebral edema develops (Hernberg, 1976). Chronic exposure to lead can produce a progressive mental deter ioration in children. This is characterized by loss of motor skills hyperkinetic and aggressive behavior, and convulsions, and has been associated with blood-lead levels in excess of 60 pg/dl (EPA, 1977), There is a great deal of controversy concerning the subtle neurohehavioral effects of low-level lead exposure in asymptomatic humans. It appears that medically significant effects cdn he 55 DUP050033578 produced in adults from exposures yielding blood lead levels below 80 pg/di. In children, lover levels (i.e., about 40 pg/dl) are believed to produce neurological damage, possibly because of the underdeveloped state of the central nervous system (EPA, 1977). The frequency of neurologic effects appears to increase in children at blood-lead levels in the range of 50 to 60 pg/dl or above (NAS, 1976). Although this produces no major clinical effects, it has been argued that no damage to the central nervous system should be accepted. Central neruous system damage is believed to be more serious than the reversible effects on other systems since the nervous system has a poor regenerative capacity (Seppalainen et a!., 1975). Subclinical effects on intelligence and behavioral activity have been reported in children with blood-lead levels below 40 pg/dl (Goyer and Mushak, 1977). Exposure to concentrations below those levels which produce irreversible neurological dysfunctions has been postulated to be involved in the production of hyperactivity and fine motor deficits in children (Mahaffey, 1977). However, the view that these behavioral deficits are, or are related to, the cause of ele vated blood"*lead levels in these children is also tenable. In one study, the mean blood-lead level in 54 hyperactive children was 26.2 pg/dl while the mean blood-lead level in 37 controls was 22.2 pg/dl (David et al., 1972). Failure on fine motor tests occurred almost twice as frequently and mean IQ scores were significantly lower in children with blood-lead levels >40 pg/dl or those with blood lead >30 pg/dl having radiographically visible lead Lines in the long bones than in controls (de la Burde and Choate, 1972j 1975). Although many studies have been conducted to test low-level lead effects on the CN$, no conclusive evidence has been presented. It remains unknown whether psychological, emotional and neurological sequelae occur in asymptomatic children with blood-lead levels below those associated with clinical lead poisoning. 56 DUP050033579 Peripheral Hervous System: In addition to the effects on. the central nervous system, peripheral neuropathy due to lead poisoning has been reported. Peripheral nervous system paralysis is character ized by selective involvement of motor neurons and is manifested as weakness of the extensor muscles. At blood-lead levels of 80 to 120 pg/dl, a slowing of the conduction velocity of the nerves of the upper limbs and electromyographic abnormalities have been reported (Hernberg, 1976). Although peripheral neuropathy is considered rare in childhood lead poisoning, it has been suggested that this is because the effects are overshadowed by the clinical symptoms of encephalopathy. Feldman et al. (1973) observed a statistically significant (p < 0,002) decrease in peripheral nerve conduction velocity in a group of 24 children with blood-lead levels of 40 pg/dl or greater. In studies involving lead workers with mean blood-lead levels of 40 _+ 9 pg/dl, a slowdown of nerve conduction velocity in the upper extremities and electromyographic abnormalities (i.e., fibrillations and diminished number of motor units on maximal contraction) were reported (Seppalainen et al., 1975). 4.1.3 Renal Effects There appear to be two distinct renal effects from chronic lead exposure, reversible proximal tubular damage and progressive, irre versible renal failure. Although dose-response relationships have not been defined, it appears that the effects occur only at levels above those which affect heme synthesis (ftammond, 1977). Renal tubular dysfunction is manifested in children as Fanconi's syndrome, characterized by glycosuria (presence of abnormal amounts of glucose in urine), hypophosphatemia (an abnormally decreased amount of phosphate in the blood) and aminoaciduria (presence of amino acids in the urine). Aminoaciduria reportedly results from 57 DUP050033580 blood-lead levels above 80 H-g/dl (Chisolm, 1962); however, the exact level which produces this effect is unclear. The Faitconi Syndrome has been reported in one-third of the children in one study with acute encephalopathy and blood-lead levels above ISO pg/dl (NAS, 1972) . Studies indicate that chronic kidney damage is the result of high renal lead content for long periods of time. There is no evi dence to suggest that kidney damage occurs in asymptomatic cases; effects only occur in association with other symptoms of lead tox icity (Damstra, 1977). Prolonged and excessive exposure to lead can result in chronic lead nephropathy, although the level of exposure which causes this effect is not known (Hammond, 1977). Chronic lead nephropathy, a progressive and irreversible disease, is characterised by progressive azotemia (presence of urea in the blood), interstitial fibrosis, tubu lar degeneration and glomerular vascular changes in small arteries and arterioles of the kidney (Morgan et al., 1966). Renal insuffi ciency may be a sign of subclinical lead poisoning (Campbell et al., 1977). Renal failure may result from more extensive exposure (EPA, 1977). The formation of inclusion bodies, composed of a lead-protein complex containing approximately 50 pg iead/mg protein (Moore et al., 1973) , is one of the earliest effects of lead nephropathy (Hernberg, 1976). These inclusion bodies appear in renal proximal tubular cells as well as in other tissues (Hammond, 1977). The lead in the inclu sion bodies is 60 to 100 times more concentrated than in the whole kidney (Coyer and Mushak, 1977). These inclusion bodies may serve as a defense mechanism by binding the lead and thus lowering the concentration of lead in the cytoplasm (Goyer and Chisolm, 1972). Chronic renal injury from lead exposure can also produce gout (Emerson, 1968). Although the mechanism of interference with uric 58 ) DUP050033581 acid excretion is not known, it has been hypothesized that the rise in the serum urea level may result from a loss of glomeruli, leading to a reduction in the glomerular filtration rate (Campbell et al,, 1977). High levels of lead in drinking water (>100 pg/1) have reported ly been responsible for renal failure, hyperuricemia and gout in individuals drinking the water for 15 to 30 years (Beattie et al., 1972). 4.1,4 C arcinpgenfcitv A relationship between lead exposure and cancer in humans has not been demonstrated. However, very high doses of lead salts have been shown to be carcinogenic in laboratory animals by a number of investigators: lead phosphate in rats (Zollinger, 1953; Roe et al., 1965; Sunderman, 1971) and mice (Sunderman, 1971); lead acetate in rats (Boyland et al., 1962; Zawirska and Medras, 1968; Kanisawa and Schroeder, 1969; Sunderman, 1971; Coogan, 1973; Stiller, 1973) and mice (Van Each and Kroes, 1969; Sunderman, 1971); and lead subacetate in rats (Van Each et al., 1962; Mao and Molnar, 1967; Oyasu et al., 1970; Sunderman, 1971) and mice (Van Each and Kroes, 1969). Tumors of the kidney, both benign and malignant, were produced in all of these studies, regardless of the route of administration (orally in food or water, or by intraperitonesl and/or subcutaneous injection). High incidences of tumors of the testes, adrenal, thyroid, pituitary, prostate and lung have also been seen in rats and mice receiving these salts (Zawirska and Medras, 1968; Sunderman, 1971), and cere bral gliomas have been observed in 2 rats out of 17 receiving dietary lead subacetate (Oyasu et al., 1970). In contrast to the animal data, no significant relationship be tween exposure to lead and cancer in a human population has been reported, Dingyall-Fordyce and Lane (1963) conducted a follow-up study of 425 persons who had been exposed to lead in a storage bat tery factory. No evidence was found to suggest a correlation between 59 DUP050033582 lead absorption and malignant disease. In a more recent study (Cooper and Gaffey, 1975; Cooper, 1978), the Incidence of death from malignant neoplasms among battery plant workers and from lung cancer among smelter and battery plant workers was slightly higher than expected, although this increase was not statistically significant. A consistent feature of the animal studies is that the animals were subjected to very large quantities of the lead salts utilized. The lowest dietary concentration of a lead salt which produced cancer in the feeding studies was 0.1 percent. In the injection studies, the lowest lifetime dose received by rats that developed renal tumors Was 120 mg, IARC (1972) noted that the level of human exposure equivalent to the intake of lead acetate that has produced renal tumors in rats is 810 mg/day (550 mg Pb/day). This level greatly exceeds that at which severe, debilitating effects and even death will be produced. Thus, even if lead is a human carcinogen, the car cinogenic effects will presumably be greatly overshadowed by the sys temic toxic effects at the exposure levels generally encountered. Carcinogenicity cannot be considered a singular risk associated with lead exposure since the systemic effects constitute a major public health problem. 4.2 Indices of Exposure/Effect There are many tests which can be used for the detection of in creased lead absorption. Tests which measure both tissue lead con tent and tissue metabolic effects are available. However, no single test can be used for the determination of body burden or total meta bolic effects. At present, blood-lead concentration is considered the best available measure of tissue lead content; while free erythrocyte protoporphyrin (FEP) concentration is the best measure of tissue metabolic effects (Baloh, 1974). 60 DUP050033583 4.2.1 Lead Levels in Tissues The concentration of lead in several tissues has been used to indicate an individual's past exposure history to lead. Although blood-lead content is the most widely used criterion, tissues, urine, hair, teeth and bone have been sampled. Blood Lead: The blood-lead level is used both as an index of exposure and for the diagnosis of health effects. This value is the most widely accepted measure of recent exposure, as well as repre sentative of the actual mobilized fraction of lead responsible for the toxic effects in the body (Goyer and Mushak, 1977). A blood-lead level of 40 jig/dl is believed to be the maximum level at which no adverse health effects are found, although changes in enzyme activity have been observed below this value. Clinical manifestations of lead poisoning begin when blood-lead levels are consistently above 80 Ug/dl (Goyer and Mushak, 1977; NAS, 1976). Five methods are commonly used for the determination of bloodlead concentrations: spectrophotometry, flame atomic absorption. Delves cup, furnace atomic absorption, and anodic stripping voltam metry. These methods reportedly have the capability of producing results which are valid and reproducible within 5 percent precision or better. However, interlaboratory comparisons do not appear to confirm this degree of reproducibility. Discussions of the methods (Pierce et at., 1976) and the variability of the results of the methods (Lucas, 1977) have recently appeared in the literature. There are many sources of Variability involved, including sampling technique, storage time, contamination, and analytical procedure (Pierce et al., 1976). Studies indicate that up to 80 percent of the variability can be due to analytical method error (Lucas, 1977). Because of the wide variation in blood-lead measurements, it is com mon practice to run at least two analyses of the same blood sample. 61 DUP050033584 Even with these limitations, blood-lead analysis is still the most widely used test for the diagnosis of increased lead absorption. Many of the other test methods are based on a relationship to blood lead. (Jrine Lead; both blood-lead and urine-lead levels are accurate indicators of recent lead exposure. Urine-lead levels are considered less accurate in that they are susceptible to changing renal output or to dilution due to variable water content. In a steady state, urine lead is representative of blood lead. A "normal" value for urinary lead in young children is usually less than 55 p.g/24 hours. However, this value should not be used as an index of body burden since there can be complicating factors that affect lead excretion and give a false impression of the amout of lead in the body (Ealoh, 1974). Hair Lead; Hair lead analysis can be easily performed and can indicate chronic lead exposure. Since lead reacts with the sulfhydryl groups in hair protein as the hair emerges from the scalp, the concentration of lead at different sections can be indicative of episodic exposures to high lead levels (Goyer and Mushak, 1977). Contamination of hair by exogenous deposition poses a problem in evaluating the measurement. Although mean levels in children and adults are in the range of 20 to 30 p-g/g hair (Baloh, 1974), appro priate precautions (e.g,, careful washing of the hair sample) must be taken if the measurement is to be considered a reasonable indicator of exposure. tooth lead: Tooth lead analyses have been used to a limited degree as indicators of past heavy lead exposure. It is believed that the lead content of the tooth represents the total exposure up 62 DUP050033585 Co Che time of removal. The reliability of CooCh lead concentrations as an indicator of lead toxicity has not been evaluated (Baloh, 1974), Bone Lead; Bone is an ideal tissue to analyze for total body burden measurement, since more than 90 percent of the body burden of lead is deposited in the skeletal system of adults, and 60 to 65 per cent is deposited in the bone tissue of children. However, the value of such a determination is questionable since this bound lead is very slowly mobilized and does not represent a great danger. Correlation of bone-lead levels to the manifestations of toxic symptoms cannot be made, although bone-lead levels may single out those individuals highly susceptible to lead toxicity (Coyer and Mushak, 1977). Multiple bands of increased density in growing long bones (as seen by radiographic examination) indicate prolonged, increased absorption of lead (NAS, 1972). 4.2.2 Metabolic Effects Associated with Lead in Various Tissues It appears from the literature that there is a trend toward put ting more reliance on measurements of metabolic effects associated with absorbed lead in tissues rather than on blood-lead values. While the blood-lead level is considered a reliable index of recent lead exposure, it does not necessarily indicate the extent of leadinduced toxic effects. For this reason, considerable attention has been focused on measurements of the levels of intermediates and enzymes of the heme-synthetic pathway in the blood. Variability associated with blood-lead measurements has provided additional impetus for finding direct indices of lead toxicity. However, until these new methods have been tested and approved, blood-lead values will continue to be the most widely used measurement. Some of the tissue metabolic effects measurements have been correlated with blood-lead values. A table (Table 4-1) showing these reported asso ciations follows the discussion. 63 DUP050033586 tissue effects measurements include free erythrocyte protopor phyrin (FEP) and zinc protoporphyrin (ZPP) determinations, urine coproporphyrin (COPKO) measurement, urine 6-aminolevulinic acid (ALA) determination, and 6-aminolevulinic acid dehydratase (ALAD) activity measurements. These determinations are useful in detecting the subclinical effects of lead on hemoglobin synthesis. Since lead inhib its several enzymes essential to the synthesis of heme, measurement of heme precursors in the blood and urine can be indicative of metabolic effects associated with increased lead absorption. Zinc Protoporphyrin/Free Erythrocyte Protoporphyrin: Zinc pro toporphyrin (ZPP) appears in the blood as a result of chronic lead absorption. Since ZPP fluoresces when excited with high energy blue light, the compound can be fluorometrieally assayed. A rapid and reliable test for lead absorption based on this assay has been devised. This test can differentiate between lead poisoning, irondeficiency anemia, and other disorders Which may cause a rise in Zpp levels (Lamola et al., 1975a,b). Numerous investigators have reported levels of "free erythrocyte protoporphyrin" (FEP) based upon measurements of free protoporphyrin IX (PP) in acidic solvent extracts of Whole blood and isolated erythrocytes. However, the presence of PP in these extracts is ap parently a secondary effect of the extraction procedure on the ZPP present in the erythrocytes (Section 4.1.1), and therefore FEP is thought to be an indirect measurement of ZPP (Lamola and Yamane, 1974). A recent development has been the design of a portable hematofluorometer which can, in about five seconds, measure Zpp concen trations under field or laboratory conditions from a single drop of whole, unprepared blood. This appears to be a highly effective and efficient means of detecting the early signs of lead absorption and 64 DUP050033587 and could be useful as a mass screening technique. A discussion of this instrument has recently appeared in the literature (Blumberg et al., 1977). Urine Coproporphyria; Coproporphyrin (CQPRO) measurements are considered less specific than FEP measurements. Coproporphyria excretion begins to increase at approximately 35 to 40 pg/di bloodlead levels, but can be affected by conditions other than lead expo sure. Hepatic disorders, rheumatic fever, poliomyelitis, infectious mononucleosis, and alcoholism can all increase the C0PR0 level in urine (Baloh, 1974). Both sample collection and analysis of the COPRO test are sim ple. An approximate upper bound to the normal excretion rate for both adults and children is 0.2 pg/mi urine (Baloh, 1974). 6-AminoleVulinic Acid; Increased levels of 6-aminolevulinic acid (ALA) in urine have been associated with blood-lead levels of 40 to 50 pg/dl in adults (Hernberg et al, 1970). Since levels of concern can be below this, the concentration of ALA in urine is of limited utility. An upper normal level of excretion is difficult to define. Since the rate of both false negatives and false positives is high, the ALA test is not recommended for mass screening programs; 6-Aminolevulinic Acid Dehydratase: A more sensitive index of low level lead absorption is ALAD activity. This test can detect changes in lead concentrations down to blood-lead levels of approxi mately 5 pg/dl (Hernberg et al,, 1970). This test is believed to be the most sensitive indicator of biological effect. It has the advan tage of showing changes in lead absorption in asymptomatic humans (Goyer and Mushak, 1977). Although partial inhibition of ALAD activ ity does not cause any adverse health effects, presumably due to a large reserve capacity, it is reflective of early biochemical altera tions at low ambient environmental levels (Hernberg, 1976). 65 DUP050033588 The correlation of ALAD to blood-lead level is very good (Tola et al., 1973). Because of this close agreement, ALAS can be used to predict blood-lead values. 4.2.3 Other Indices Although not useful for monitoring or screening purposes, other indices can be used to assess lead absorption. Nerve-conduction velocity measurement can be a useful neurological test to detect early signs of lead exposure (Seppalainen et al., 1975; Singerman, 1976). Renal function tests and electron microscopic examination of the characteristic inclusion bodies are other possible measures of lead exposure (fash Group on Metal Toxicity, 1976). However, since renal function and nervous system damage are not evident before clin-^ ical symptoms appear, the determination of hematological changes remains a more useful tool for early detection of exposure (Singerman, 1976), 4.3 Effects Levels Specific toxic effects of recent lead exposure in humans are characteristic of exposure levels. These effects levels can be mea sured by many physiological indicators. Blood-lead levels are the most commonly reported index of the extent of recent lead exposure and of the active toxic fraction of lead in the body. There is a positive correlation between blood-lead levels of 5^ 80 pg/dl in adults and anemia and neurological impairment. Similar effects are seen in children with blood-lead levels of >. 50 to 60 (jig/dl (NAS, 1976), The more subtle manifestations of subclinicai behavioral dysfunction (e.g., hyperactivity, slowed learning ability) are not directly measurable by neurochemical tests, but are estimated with functional tests and correlated with hematopoietic chemical 66 DUP050033589 TABLE 4-1 1> j . ? 67 DUP050033590 measurements of the hemoglobin enzyme system. Since blood oxygencarrying capacity is effectively lowered with the onset of the inhibition of heme production, CHS degradation is expected to paral lel heme inhibition, because of the extreme sensitivity of the CNS to hypoxia. In vivo and in vitro studies reveal inhibition of ALAD at levels as low as 5 pg/dl (Hernberg et al., 1970; Chisolm et al., 1975), but it is believed that there is no complete absence of the enzymeinhibitory effect of lead at any level (Weasel and Dominski, 1977). This may be compensated for at low lead levels by a reserve enzyme capacity, but the individual effective range of this reserve is as yet unclear. Despite this possible reserve, blood-lead levels of 30 )jig/dl in women have resulted in definite ALAD inhibition (Hernberg et al., 1970). Table 4-2 presents a sample of the reported known low blood-lead level and acute high blood-lead level effects. 68 i DUP050033591 TABLE 4-2 CLINICAL SIGNS OF LEAD INTOXICATION Pb-Blood Level (ug/dl) 5-20 15 25-30 30-50 40-80 Effect Reference Normal background levels Partial inhibition of ALAD activity but no measurable increase in ALA excretion King (1971); Jenkins (1976) Jenkins (1976) Threshold level for in crease in EP. Piomelli (1978) Increase in protoporphyrin concentration in women and children Deleterious effects on red blood cells (change in osmotic resistance and mechanical fragility) FEP elevation of diagnostic importance Potential danger to children Hernberg (1976); NAS (1976) Hernberg (1976) Piomelli et ali (1973) Center for Disease Control (1975) First detectable increase in ALA excretion and FEP levels in body fluids; anemia increase in protoporphyrin concentration in men o Decreased ALAD activity Jenkins (1976) Hernberg (1976) Coyer and Mushak (1977) Decreased ALAD activity o Increase in urinary ALA, CP Increase in FEP ft Reticulocytosis Nerve conduction effects Inclusion bodies n Adverse metabolic effects on heme synthesis, early mild symptoms of plumbism Slight drop in hemoglobin level n Anemia Goyer and Mushak (1977) Goyer and Mushak (1977) Goyer and Mushak (1977) Goyer and Mushak (1977) Goyer and Mushak (1977) Goyer and Mushak (1977) Jenkins (1976); NAS (1976) NAS (1976) NAS (1976) 69 DUP050033592 TABLE 4-2 (CONCLUDED) Pb-Blood Level (yig/dl) >80 Effect Reference Increased risk of acute and chronic clinical effects Obvious anemia Reticulocytesis becomes measurable Shortening of erythrocyte life span NAS (1976) NAS (1976) Hernberg (1976) Hernberg (1976) Decreased ALAD activity Fivefold increase in urinary ALA, cap Increase in FEP Anemia Ataxia, coma, convulsions , Fanconi syndrome, chronic nephropathy Acute neurological disorders Coyer and Hushak (1977) Coyer and Hushak (1977) Goyer and Hushak (1977) Coyer and Hushak (1977) Coyer and Hushak (1977) Goyer and Hushak (1977) Coyer and Hushak (1977) 70 DUP050033593 5.0 SENSITIVE POPULATIONS Two subgroups within the general population have been identified as more sensitive and at greater risk to environmental lead ex posure than the average adult. Children under the age of four are especially susceptible to the toxic effects of lead. Fetuses have also been identified as a sensitive population and the pregnant female as their exposure vehicle based on the fact that the fetus is exposed to lead via transplacental absorption. 5.1 Children Children are known to be especially susceptible to acute and chronic lead poisoning. Empirical evidence indicates that children tend to become exposed to and absorb greater quantities of lead than do adults. In addition, clinical studies demonstrate'that young children are much more likely to suffer ill effects from lead expo sure than adults. The following paragraphs support the contention that children (from 1 to about 4 years of age) should be considered the critical receptor to environmental lead exposure and that regulatory actions should incorporate suitable safety factors during standard-setting procedures. 5.1.1 Increased Potential for Exposure to Lead There is an increased hazard to children from the ingestion of lead-contaminated materials. Normal hand-to-mouth activity (i.e., thumb sucking and finger licking) in young children is a significant mechanism of lead exposure. Lead contaminated soil and dust is a primary exposure source for children due to this activity (Lepow et al., 1974). Juvenile dietary habits are responsible for additional exposure to lead. These immature dietary habits include the retrieval and ingestion of dirt- or dust-contaminated foodstuffs (Day et al., 1975). 71 In addition, there is significant opportunity for increased lead exposure among children with pica and among children who mouth foreign objects* Pica, the repetitive ingestion of nonfood items, is a fairly common behavior pattern among young children. Two studies (Millican et al,, 1962; Barltrop, 1966) have described the incidence of pica and mouthing behavior in child populations. In both studies, the incidence rates for pica and mouthing were highest in the youn gest children studied (1 to 2 years) and decreased fairly steadily until 3 to 4 years of ilge. In addition, both studies reported that the incidence of these behaviors (particularly pica) in black child ren was generally substantially higher than in white children of the same age. Social, cultural, and economic differences between the populations almost certainly contributed to this difference* Thus a physiological etiology for the difference in incidence rates could not be inferred from these investigations* Among white children 1 to 2 years old, 28 percent had pica and about 82 percent displayed mouthing behavior; among blacks the rates were 57 and 78 percent for pica and mouthing, respectively (Millican et al., 1962). Among children 2 to 3 years old the rates were 20 and 52 percent for white children and 40 and 62 percent for blacks. The prevalence of pica among white children was low after age 3 (2 to 4 percent), but among black children it remained at about 20 percent up to age 6 (Millican et al., 1962). Estimates of lead intake by children with pica for paint range as high as 2.1 mg/day (MS, 1976), about ten, times greater than what one might expect from normal environmental sources (i.e., 100 to 200 pg/day from air, food, and water). Due to the variables involved (e.g., housing, socioeconomic condition), it is difficult to quantify the additional lead intake by children with pica, for the infant population in general, or for specific subsets within that popula tion. It is obvious, however, that in certain instances, children 72 DUP050033595 with pica for paint can absorb lead in amounts significantly greater than normal.. Respiratory characteristics of the child impose a greater poten tial for inhalation of airborne lead than those of the adult. Chil dren take part in greater physical activity than adults, thereby increasing their air intake, and breathe more through the mouth (due to greater physical activity and more frequent respiratory infec tions) thus employing a less effective filtering mechanism (American Lung Association, 1978). The child has an enhanced risk of exposure to lead via inhala tion since concentration gradients for airborne lead increase as one approaches ground level (Jenkins, 1976). Vehicular exhaust, a low altitude source of airborne particulate lead, is a major contributor to the inhaled component of lead uptake in' the child living in close proximity to heavily trafficked areas (NAS, 1972; Angle and MeIntire, 1975) , The child is also exposed to lead from dust that is resuspen ded by vehicular traffic (Jenkins, 1976). Resuspension is dependent upon vehicle speed, A range of 1 to 5 percent resuspension of depos ited particulates by passing vehicles has been estimated (Sehmel, 1976). 5.1.2 Metabolic Differences Children appear to have a gastrointestinal lead absorption rate that is four to five times higher than that of adults (Mahaffey, 1977; Alexander, 1974; NAS, 1976). This increased absorption rate, coupled with the potentially higher exposure dose (as a result of pica) can result in much higher blood-lead levels than expected in an adult. The daily uptake per unit body weight in children far exceeds that in adults. It should be noted that the studies showing roughly equivalent blood-lead concentrations in children and adults do not necessarily refute this point, since a child may be able to assim ilate blood lead into the soft tissues and bone at a more rapid rate than an adult (Jenkins, 1976). 73 DUP050033596 The relative proportion of the lead body burden in the slow exchange pool (i.e., in the dense bone matrix) is smaller in children than in adults. Only 60 to 75 percent of the lead body burden is located within a child's skeletal system, compared to 90 percent or more in the adult (Barry, 1975; SPA, 1977). This suggests that a larger amount of the absorbed lead can be concentrated in the soft tissues, where it may reach toxic concentrations, for example, brain tissue in neonatal rat tends to concentrate lead to a greater degree than in adults (NAS, 1976). Mechanisms for elimination of heavy metals are not well developed in the young, and this may ultimately result in higher soft tissue lead burdens in children than in adults at the same rate of lead uptake (per unit body mass)*. Studies have indicated that blood-lead levels in immature and adult rats were comparable after acute lead exposure, but were sustained longer in the immature rat (Bayley and Brown, 1974). 5.1.3 Inherent Physiological Sensitivity Studies in both laboratory animals and children have shown that the brain is highly vulnerable to irreversible damage during infancy and early childhood because of rapid growth rate of this organ (NAS, 1976). Due to this immature developmental state, infants may be especially sensitive to the detrimental effects of lead exposure. The infant's higher susceptibility is due in part to the rapid growth rate characteristic of organogenesis. Organ formation occurs from the second trimester of pregnancy through the fourth year postpartum. This period of rapid growth and increased stress sensitivity is considered the "growth spurt" (NAS, 1976). In humans the growth spurt is defined in terms of three brain components. Glial replication and differentiation continue through the first eighteen months after birth. Myelination extends through 74 t DUP050033597 the third and fourth years. Cerebellar growth extends through the eighteenth month postpartum and is most rapid during this period (NAS, 1976). This rapid growth rate increases susceptibility to a variety of stresses Such as nutritional deficiencies. Studies of infants with pyloric stenosis have shown that the brief starvation period encountered had permanent effects on their learning abilities and general adjustment ability 5 to 14 years later (Klein et al., 1975). Reduced IQ levels have been demonstrated in school age children who had experienced mainourishment during the initial two years postpartum (NAS, 1976). Long-term behavioral deficits were demonstrated in neonatal rats receiving oral administration of lead (Sabotka and Cook, 1974). Study groups of asymptomatic children with a history of pica for paint displayed poor learning ability, seizures, and hyperactivity (de la Burde and Choate, 1972). Similar findings are reported for symptomatic children (Byers and Lord, 1943). 5.2 The Fetus and Pregnant Woman Physiological sensitivity to lead may be at a maximum during fetal development. The pregnant female must be recognized as the exposure vehicle for the fetus since the placental transfer of lead is the main route of fetal lead uptake. In addition, the pregnant female may herself be more sensitive to lead due to increased food intake and changes in hormonal status* Hormonal imbalances which result from pregnancy (Guyton, 197la) may influence the mobilization of lead from bone* 5;2.1 Placental Transfer Lead has been shown to cross the placental barrier in laboratory animals (Kostial and Momcilpvie, 1974; McClain and Siekierka, 1975) as well as in humans (Baglan et al., 1974; Gershanik et al., 1974). There does not appear to be any significant difference between maternal and fetal blood-lead levels at any time during pregnancy 75 DUP050033598 (Gershanik et al., 1974), although placental blood-lead levels may be slightly (but not significantly) higher than levels in maternal or fetal blood (Baglan et al., 1974; Harris and Holley, 1972). Lead has been detected in the fetus as early as. the twelfth week of intrauter ine life and has been shown to increase throughout gestation. The lead content of the fetus at birth has been recorded as 300 jig; the equivalent of the daily intake for the normal adult (Barltrop, 1977). The transplacental passage of lead in blood is particularly important for two reasons. The fetus is highly sensitive to the neurological effects of lead exposure (due to lack of blood-brain barrier, efficient absorption, and rapid brain growth rates). Additionally, the newborn is starting life with a significant "background" blood-lead level. The observed positive correlation of urinary ALA levels with blood-lead levels in newborns indicates that heme-biosynthetic derangement must have begun in utero (EPA, 1977). Exposure of pregnant women to high water-lead concentrations has been correlated with the higher blood-lead concentrations in their men tally retarded offspring (Moore et al., 1977). This reinforces the association between lead exposure during pregnancy and subsequent neurological damage to the fetus, but the specific exposure, absorp tion, and retention levels and their corresponding specific effects are as yet unknown. 5.2.2 Inherent Sensitivity; Immature Organogenesis The fetus displays an immature developmental state, as well as a lack of development of a blood-brain barrier (Bridbord, 1978). The uptake (absorption) of lead has been shown to be six to eight times greater in the brain of suckling rats than in the brain of adult rats (Momcilovic and KostialL, 1974). Krigman and Hogan (1974) observed a fourfold increase of lead uptake in the brain of suckling rats as 76 -! .1 i i I j *y DUP050033599 compared to adults. The immature state of the fetal brain, central nervous system, and elimination systems results in increased sensitivity to very low concentrations of lead. In humans, neurological, development seems most pronounced from the second trimester of pregnancy until several years after birth (NAS, 1976). Permanent neurological damage may result if the individual is stressed during this sensitive span. The lack of development of the blood-brain barrier, in combination with the increased permeability of cerebral capillaries in the fetus, amplifies the sensitive state already created by immature brain-tissue development. Thus, while the brain and central nervous system of the fetus are inherently sensitive to concentrations which are nontoxic to mature systems, they are also prone to increased deposition of lead. Rapid brain growth rates of infants create a greater risk of lead-induced neurologic damage. This rapid growth rate takes the form of the growth spurt in humans, occurring during the second trimester of: pregnancy, through the initial four years poBtpartum. Permanent adverse effects on learning ability can result from the impact of lead on the brain during this growth spurt (NAS, 1976), Behavioral abnormalities (i.e., hyperactivity, aggressiveness, trem ors and repetitive grooming behavior), have been produced in rats exposed to lead during the growth spurt period (Michaelson and Sauerhoff, 1974), Suckling rats fed maternal milk dosed with lead during postnatal days 1 through 10 showed significantly slower learning than those fed equal doses of lead during days 11 through 21 (Brown, 1975). 5.3 Threshold Levels Threshold-lead levels are defined as those minimum blood-lead levels capable of inducing toxic response. In attempting to define a safe threshold level in terms of blood-lead levels, the most phys iologically receptive (sensitive) population to augmentations in this 77 level must be singled out end labeled as the highest risk group. The maximum safe threshold level must also accommodate variations in individual responsiveness to this lead level. Due to higher lead absorption rates,, unique sources of exposure and lack of mature development of excretory systems (yielding higher pooling in target tissues), fetuses and young children are the most physiologically receptive and sensitive individuals. Therefore, in defining a threshold level for lead, the lowest known toxic levels affecting this portion of the human population should be used. A suitable margin of safety must be incorporated into the determined threshold toxic effects level when setting any environmental standard. A conservative margin of safety should be employed in defining the allowable limits of exposure for the developing fetal central nervous system due to the proven neurotoxicity of lead (EPA, 1972a). ZPP elevation and corresponding impairment of heme synthesis at blood-lead levels above 30 pg/dl are regarded as unsafe for children and unacceptable by EPA (1978b). There are, however, contrasting opinions as to the actual impact of a rise in ZPP levels. ZPP ele vation may not indicate insufficient heme or hemoglobin production, although it does indicate an interference in the heme synthetic pathway. The rise in ZPP may be caused by other factors such as iron deficiency (EPA, 1978b). The Center for Disease Control (1975) set the level of signifi cant danger to children at 30 pg/dl, and considered FEP levels to be of significant diagnostic importance. The level of 30 ug/dl set by the CDC is endorsed by the American Academy of Pediatrics and is now the target level Set by EPA (1977) at which undue lead exposure begins. Although the maximum safe lead level has been set at 30 |g/dl by CDC, retrospective studies indicate that hyperactivity and altered motor activity may be correlated with blood-lead levels in children 78 DUP050033601 having blood-Lead Levels Lower than 30 jig/dl. These studies suggest that blood-lead values in the 25 to 30 Hg/dl range may initiate toxic effects in children but this position is based on the tentative hypothesis that lead is the cause of hyperactivity and altered motor activity in these children; in fact, this behavior may be the cause of or be correlated with the cause of the elevated blood-lead levels. Increased FEP levels have been recorded in women and children at the 25 to 30 jjLg/dl level (NAS, 1976; Zeilhuis, 1975). 79 DUP050033602 6.0 SOURCE CONTRIBUTIONS TO DAILY LEAD UPTAKE IN HUMANS The method employed in this study to estimate the degree to which each major environmental source of lead exposure contributes to an individual's total daily lead uptake is based on probable exposure conditions (i.e., ambient lead levels) as well as individual biological absorption rates for each exposure route. The method consists of a five-step process: definition of ambient concentrations of lead for the major exposure sources (i.e., air, food, drinking water, soil/ dust, paint) determination of daily lead intake according to the relationship:: Ii - C iPbli where Ij is the daily lead intake from source i (e.g., air, food, drinking water, paint, soil/dust), C| is the consump tion per day of each lead source i and [Pb] is the concen tration of lead in each source i s calculation of the amount of lead absorbed from each exposure source i: Ui " Ii * Ai where U is lead uptake for each exposure source i, Ij_ is the daily lead intake from each source i, and Aj is the percent absorption of lead, via the appropriate exposure route, for the particular source. s calculation of the total lead uptake from all sources, Ut: Ut *Z(li Ai) *2Ui determination of the proportion (Pi) of total daily uptake (Ug) provided by each of the five possible exposure sources (i.e., source contribution factors): Ui P i Ut 100 80 f A f j' l. * . j I ; [ * DUP050033603 6,1 Basic Assumptions Certain assumptions are required to define the amount of each source material consumed per day. Where appropriate. Reference Man* values are utilized for daily air and food consumption rates (see Table 6-1). Daily consumption rates for drinking water are those values suggested by NAS (1977) as conservative estimates. Hand-to-mouth activity (e.g., thumb sucking and finger licking) resulting in the ingestion of soil/dust is a normal behavioral char acteristic of children through five years of age (Piomelli, 1978). Within a lead-contaminated environment, hand-to-mouth activity and immature dietary habits (i.e., the retrieval of food from dusty surfaces or soil, and subsequent consumption), make soil/dust a major source of ingested lead for children. Under average urban conditions (after thirty minutes of normal playground activity) 5 to 50 mg of dirt from a child's hand can be transferred to a typical "sticky sweet," Ingestion of 2 to 20 sweets could result in an intake of 100 mg of soil/dust or more (Day et al., 1975), A small child playing in dirt easily ingests 10 mg of soil/dust with each episode of hand-to-mouth activity. A conservative estimate of ten hand-to-mouth activities a day would result in the ingestion of 100 mg of soil/dust a day (Lepow et al., 1974). Therefore, 100 mg per day would seem to be a reasonably conservative assumption for the ingested soil/dust of the two- to three-year-old. Pica occurs to some degree in a substantial percentage of chil dren between 12 and 36 months of age (NAS, 1976). Children exhibi ting pica for paint are of major concern, because of the high levels of lead in some paints, with older painted surfaces containing lead in concentrations greater than 1 percent. Pica for paint is believed *From the ICRP Reference Kan tables (International Committee on Radiological Protection [ICRP], 1975). 81 t -9 a im DUP050033605 to occur in episodes* possibly 2 to 3 times per week (NAS, 1976). It has been estimated that a child can consume somewhat greater than 1 gram within a 24-to 36-hour period, with cases reported of up to 20 grams within the same time period (Sachs, 1975) and that children with pica for paint may consume 1 to 3 grams per week (NAS, 1976). The low end of this range (1 g/wk) has been used in source contribu tion calculations as an estimate of paint intake in children with pica. Pulmonary and gastrointestinal absorption rates utilized in sub sequent calculations are also presented in Table 6-1. Host of these figures represent average absorption values for inhaled or ingested lead, as reported in the scientific literature. The absorption rate estimated for lead in soil/dust was intermediate between the absorp tion rates for lead in food and paint, since no value was found in the literature. Gastrointestinal absorption rates for children and adults are provided* 6.2 Estimated Daily bead Uptake from All Sources The relative contribution from each route of exposure (i.e., air, food, drinking water, soil/dust, paint) to dn individual's total daily uptake has been determined from the specified environmental lead occurrence data (Table 6-2) in the calculation sequence de scribed previously* Several concentrations of lead in drinking water have been utilized, along with representative ranges of lead in air, food, paint and soil/dust. Note that the values used represent average levels resulting from continuous, chronic exposure and do not reflect short term or episodic patterns of exposure (such as pica) which may be toxicologically significant. Table 6-2 provides those exposure values used in the calculations. Dietary lead levels reflect daily lead intake excluding any con tribution by beverages. In the studies cited (FDA, 1975), beverage intake for adults was less than half of the drinking water intake p */ i J | ! I i" i \ I i r i \ *l \ ! ; ? DUP050033606 REPRESENTATIVE ENVIRONMENTAL LEAD EXPOSURE LEVELS M| 0 O rt *Vg 2 0 a o *>i9o op w<aa0. rH 1a0 O 44 *P4 V4 44 dL mN a0a *9 0 a > rH *9 to o OoS a 8 O do *4 1 4V)i oO d O g u 0 5 4(R4 (3 44 44 - 44 * 4 Sk 0d U 0 43 44 0 44 *.H *4 0 R9 0 0 44 *0 0 P Vu a* 0 TJ 4J 0 8 0 0 0d0 Ha 9 0 .0 0 Vi 9 U * -* 9 44 fl0 .*h *9 0O0-I d0 d 0 44 X 60 H 0 0$ 0 0 0 8 Vi o 44 * <4 H *' 0 N to rH S' ftk % u V 4J > 0 0 y *o c .* 0 M g in VI d Vi | 0 H > Uk rH 0 to 00 *9 *d 03 cr M i4 0. S' 0 .s ua CM 44 -*0 O Vj-4- 0 d <*> - M *0 VI a .o> o u 0 7 d to O 44 as --i --4 44 a 0 H .3 Vi 0 N 44 *H 44 44 i is 0w 00 **H0 00 I,*AH NOCO C4 M 1. d 60 9 0 *H 0 0 0 0 0 60 d 60 a H 0 M 41 H E-4 0 O0 o > 0 1-4 0 0 44 9 44 W 00 H h 44 0 H 44 9 0 0 *0 0 W 0 g 0> CO I 0> 9 T 9 S5 1 44 0 Vi 0 S' *9 a 0 0 m d o 60 d s> a T3 * V0i *09 *R0 *9 d *ik S W U S * BUvO 44 N 000o Tj *H ft a, d co o 0< tj 2 S* ft B V 4J a *0a >to* 0 v ss Vi d s s 1 0 0 44 . 0 n d^. 0m IN 0 as 0 *H 44. 0 >% m0 WS 0K 0 *dh "eS 0> 0 d 404 0 *4 4b o Vi 06 P *0 d0 as 0 u dVi t-04 0 44 .3 * Mg VI & 00 0J n 0Vi iA.* 0 a* 00 rH 0o' "5O" *&o 00 vO COON IN rH to 0 44 PO 0< 0u pto o 04 wax1 a O 0 3 * 8 **- tn WWW 44 *9 rH rH 9 *H *<9 U 1 CB 50 50 O00V r---4I 50 3L rH *9 Vi ' 0 0 '9 60 C 00 V4 44 0 > 9 Vl V4 r4 H d< 0 <s 44 44 ud 0 a0 cL H h o . P SB 4 60 50 60 50 ilii m moo 50 60 i 0.oQ0 a 404 .d 00 36 0 r4 0 Ok M d Vi 0 44 0 O n 44 a 8 0X & uc 0 60 rH Vl d 09 0 rH O p4 H 43 4c4 44 u a r9l M *0 O 0 ftl < 44 f2 OO o rk fi 00 VI p *w UP ww ' 4J 05 d 9 O CO 84 i , i > DUP050033607 assumed in our calculations (0.9 and 2.0 1/day, respectively). The exclusion of beverage intake from the FDA estimates eliminated any double counting, since drinking water was entered in the calculations as a separate category. In addition, the lead concentrations in those beverages surveyed by the FDA were somewhat lower than the range of lead levels in water that were Subsequently utilised, so any errors imparted by these manipulations would be toward conservatism. Table 6-3 provides an example of the actual calculation sequence employed. The source contribution factors calculated for air, food and drinking water for the average adult male, based on the assumed sets of exposure conditions, are presented in Table 6-4. Hie factors for a pregnant female follow in Table 6-5. Using the model for the lowest hypothetical urban exposure con dition (lead in drinking water at 10 pg/1), representative intakes of 248 and 205 pg/day are indicated for the male and pregnant female, respectively. These values are in agreement with measured values (NAS, 1972; Coyer and Mushak, 1977; Tepper and Levin, 1975; Thompson, 1971; Goldberg, 1975). The source contribution factors for the aver age three-year-old child without pica and for the child with pica are given in Tables 6-6 and 6-7. Hie model indicates that urban exposure levels are much higher than has been reported by most studies. Those studies describing exposure conditions generally fail to include soil/dust levels, or underestimate the high concentrations of lead currently found in this exposure source (see Section 2.4). It should be noted that these tables represent presumed average values, and do not account for instances in which a particular environmental source is high. For example, ambient air lead concentrations averaged 0.89 Ug/m^ in 1974 (see Table 2-1), but the maximum repotted quarterly composite was 4.09 pg/m^. Obviously, in those instances the percent contribution from each source will shift to reflect these excursions. 85 J } { DUP050033609 * t* cu *> |I|I 3S is n in a> f~ QO dg r* co x+\ o O n d .* Is u jp i-3 ia 'ua 3h f8t- Ou Ho ;ss as-< V 5g -ei3<5 as* m qo ,48 3 2, OBJ} 5$* 3q i** p B T tc oo a- a *!g rtN M m a 8 <H 53 2 3 ij p8* Q- *60*3 2$ M m *5-3:3 3 MOW o < (M P t- s1 1 -i*? | to " <0 CO O oC"M Is. 3b Ppo* tJmt Q !K ua H CD o cn eo e *n 53 fH:00 0> 09 O O GO N H <n if h =*? "a t) ' B <1 4J|T!*S <Afi H |st all3! < fe Q H M 0 00 o 00 ^ a I- as. b o as, o o% o cp aW psO ^-CH- J34OJ <-4 Bo In a H <UJ,j-H9 W CM W sr a oo N K VO :(*. >4 n O (O *4 d 'it S' uSfjM t o a p co *4 q in \b o a p co -4 d as? o oo a co , a S' Sa *n^ 58 as. I Bf I -55 33s < f~a H CO oa a j-dBH uU V *4 O 13 B tf *1} M00 m a da 8 .je u H <wHhO?OW532Ho a * ssSs I'S2 U rM O U <84 3 W CM % 3 87 W CM S 3 DUP050033610 (X*P/Sit) s a m o a isro a a a a ta tanuu a r a i ATtva aaxviaxsa K tO CM 0 "1 pH CO pH SO C<t t o <n *n j I Q9 * t~i h co pH o as 45 eo bo 38- *85:5,2 3<S 4 . -o J.B4 4rJt iW i!g3*S -:IW P H n oo *6 -3 -H(A. "0s0. wi 0 H.;ip- * *"US.> o OPM tt eu S3 4 8ti-*S 3 tM.p H wp ST p n Ph to o r* N sO tnto Ph tp H pH :A Ot M A tO |H tO m tb ph sb S to OH ^s is 1 t0 a0 p .S aC sM . .|3s j 3 J "i. & am 3-S w-gSSS ass s 00 so .< so c -r o *2 u o -H v 4- g 4-3 tfl-H. *2 CO to >so O ft H "H. H M0 W *0^H0*00J 9.H ,h O w HOW O <h. a h 43 : I *& 3. S N g* a is *o M OtlSU t-*W H S O to n co o co no o to n o c*j cr p <o Os SO O irt .<5 SO m n Os so o *n QtO P> Os to 0 tO Os 0 .0 *2 iH tO o *W 2* a.s *8532 3a h S' Of 4J i-t a c <c ta U O vt^ .W a .s s 4L-3 o -h H*- . m s5^O 4S* t'- sis s SjS t' H O -H p i tjoj; a < h. p fn U 0 .0 W O Tl p U HOW O < >. Q H *M *0J1 _81 2 88 DUP050033611 519.3 Total 518.2 TABLE 6-6 Total 00 (ft cs 00 tn CS NO .00 Ifl is yo 00 in s s? 45 a <bo 8 cu Ul ,d5 h*H Isss 3 I0n CoA Cg ,Sl .|dla (So b ac w i is g j o h* s 3.25 .3 8 8 >.m. .~M3 ^^sa1?&W1b ' *fl 8I* ?w H HS C? b S-3 2 Ob .-bH> ?a a II r:-"I 4J r-i N a *r 0a0*s0 a3 "Sao o rert ab .iO6b lhoa o i i nm rH SD O OS ss 0 .* J *H ct-w o ei aMs"0- >. 4tgJ v3B( K^II a -u .u2i .i 3|jU o0 *HH 3.S.9, R* 8 Bb O*> si-Hr4, 34gJ.<UcH ai.J? 3 25 is in cs m cs m cs m cs m so o so o vo o eo a-3 a00*i0f 4b0*!3 4J*0* 4J -a4 uO bHsoOS-DH 'lO-sMOb|a-SH40J 4b o<O*3h^ aS -S< |a -5w4 l tOn H3O M^Jl U 9u 3|l|-3 sliT4 q h a * O OS M SM.S b. *oO^*Hh oI!*h a 1&& :bb &8C S 89 188.5 Total DUP050033612 DUP050033613 The range of calculated source contribution factors is quite large, if one considers all the possible permutations of lead levels specified for the various media. In adults, the source contribution factor for drinking water varies from about 5 to 70 percent. In children without pica, drinking water contributes between 2 and 74 percent of the daily lead uptake. For the child with pica for paint, drinking water contributes between 1 and 37 percent, depending on the concentration of lead in soil/dust and paint. In a child with pica for paint, soil/dust can account for as much as 82 percent of the daily lead uptake, while paint can contribute as much as 78 percent. The contribution from air varies from about 2 to 41 percent for an adult and is almost insignificant for a child. Ambient lead levels in air can be significantly higher than the values presented in Tables 6-4 through 6-7, so the assumed range in atmospheric concen trations is somewhat restricted. The contribution.of food to an individual"s total daily lead uptake varies from 24 to 87 percent for an adult, from 9 to 84 percent for a child without pica, and from 7 to 66 percent for a child with pica for paint. The total daily lead uptake in children is always higher than that predicted for adults. 93 DUP050033614 7.0 LEAD-UPTAKE/BLOOD-LEAD RELATIONSHIPS Blood lead is the most widely used indicator of recent lead exposure. It is also regarded as a reasonable surrogate for the biological response associated with lead absorption. Since this is the value most often reported in the literature to represent the . extent of lead absorption, it is necessary to relate daily lead uptake to blood-lead values in order to define the toxicological impact associated with the different levels of lead uptake determined by the source contribution model. Because children and fetuses have been identified as sensitive populations, it is necessary to derive this lead-uptake-to-blood-lead relationship for both children and pregnant women. 7.1 Child Relationship There are no comprehensive studies in the literature which re port a lead-uptake-to-blood-lead relationship for children. Although there are studies for adults, these can not be used to define a relationship for children due to the differences in exposure conditions and metabolic differences. Therefore, it has been necessary to derive a relationship from the combined data of a number of studies. Data from six epidemiological studies have been used to derive a relationship between lead-uptake and blood-lead values for children. These studies were selected because each specified an environmental lead level for most of the major sources of exposure, gave the levels for different exposure conditions (i.e., high and low exposure levels) and reported corresponding blood-lead levels for each exposure circum stance. Table 7-1 provides the data from these six studies. Since not all of the studies had values for every environmental source, it was necessary to assume values in such cases. Footnotes in the table 94 DUP050033615 MHOMp J 9 s wI p4 I H 1 I u:s uo 3 > 53 w 1 Hp /- 3 0 pH 44 T3 M '**' p O 6C 8 0* A o v~> hJ a. eQ *4OcG*Ji ^4*c>-oNNy 60 6t G JT fc>S>- <y H "O 4<40 Oh *M>K.1 63C. 0o-o0 cO O c m co Wd -6C- P^ 6C rH p. CO CM om in vo co Oooo ooO m co o *n O O' CM 3<3 00 St CO op as .S60t H H 0) 44 *J *H 3fi # 6C U P Op sj- vO *H *ood -Stoi*j1 U 6C TJCO-Goo O' O'. sf CO St pH aoma)om *a "0 raos coos r r-. stCO pH !> CO 00 O' O eM c m so -4 n nn nCO O' St CO 06 pH rH <t <f vo so co oo <s co Hrn co co vp o ri in m cp co 03 vO O CO ON S .-H CM pH ninpCpCOONN H P-H VD sO CO cr m sf o h* r> H \o Mf St pH CM CO CO fs| orHovoCMoofHir> *ot nCh ass.*f.occ omo.<sooncnh*p miCoM- *r~ooj 44oo*roo^ 44oo*oon ^oo coo hm cmo mff. m.o om <oM Ooo vO ooo M3 oop vo 1*. .IN sb in pH m uo 00 00 S- 43 O "o J3 o oo c m so r-. m w> 60 r-. 60 r*- vd sr so co o o O o ion oin on otn on ouN oin O *0 *8 *8 *o *C3 t u io *o *0 ?g CO CO CO CO C0i CO CO CO CO CO CO CO CO O' O' O' O' O' O' a> O' O' O' O' O' O' 0) 46 O a* n N-' O' g* 0 pH H o H pH 00 60 r- 8S-S 60 H wm p *rCt>t HpO^n IJHJ- UG o o H 3G to <8 ttutt *j Ta3 vG &. p H <33 p H V* >nj <u <9 O pH V>aJi 44 5et H ftt) H <u 5 to p 9 O 0 ^3 G0 4B3 H4J N 4t3o MHP *49) lO>N o W W pH 43 CO 95 O P o 60 c DUP050033616 BLOOD LEAD R e p o rte d (y g /d l) LEAD UPTAKE__________ T o ta l Via Ingestion (ug/kg/day) (pg/kg/day) (p %/day) ( tig /1) (iig/m 3) (n g /g ) (iig /g ) W ater A ir S o il/D u s t P a in t D rin kin g , ENVIRONMENTAL LEAP CONCENTRATION VO NO SO Sp 00 CO -sQ oo .<* sf ^' ao <r n M N \0 yO W 0\ 00 AO cr\ o n w* in s0 sf so TVjW O OO O O O OO O00vOO00vO rtM ***1M O O 0.0 O O OO OvOOvO 00 OO o o st .41om <u o o . *9 TJ *0 T3 ,TJ 1? *d U TO CO CO CO CO CO CO CO o n oS p> <?n .On On On 0v (0 I*"' >s-J/ ru>o* (401 OfHN .H <4b01O<<H9 4-1 _(O4ft 41 eO r00- d o n .<s09 M*eO /-oS. 4) 4) *o 01 H9 (a9 C00 (4 u > oH 4toJ 4C4-11i C0Ol 4(0J I *a 4X1 *4Ho4HJ1 0H TJ <2s 4oHJ .0 UCl C(9 4y01 4CJO 9Oo (>9> *0 00 a <o 9> u 40J <0O*Mo -r-H1 * *. . 0a0 *30 UOH M 04J S -0 0 0 0O *30 ,4J a 43 > 10 JrJt 0 TVoo34 40M>0 a5 6 41 Cl U4C1U *ta> vo *4 O* 41 <4-1 *0 "M0 00 40HJ 0H X41 0O T03 400J 4s1 0 0t9>0v r-f f0H00 > 4- 0 TJ 4to1 "0 00O y 0Oy fot. Cftl. SQ. 4) 4CH-1l HO0i *00 U oo P< 00 f0t. P. O V0 *00c 0 I BoV- 00 (0 41 41 41 00 fUt* 0M e <>41 fUOt- TJ 41 I -? j T4 96 Food DUP050033617 describe the values used. In determining the total lead absorbed, the absorption factors associated with the three-year-old, 15-kg child were used. These factors have been previously identified in Sections 3.0 and 6,0. Figure 7-1 shows the straight-line relationship (y =* 0.80x + 7.85; r * 0.73) derived using data points based on these studies. The relationship based on total uptake (Figure 7-1) appears to predict blood-lead values which agree with other reported values. For example, at the specified urban background levels for the child without pica (385.2 pg uptaks/day; see Table 6-6), this relationship predicts a blood-lead level of 28.4 pg/dl. Other studies (Adebonojo, 1974; Joselow et al., 1975) place the estimate in the range of 28 to 30 pg/dl. 7.1.1 Comparison with Other Relationships Since data from other studies relating absorbed lead to blood lead do so on the basis of ingested lead only, it Was necessary to derive another relationship based on that portion of the daily uptake associated with ingested lead only. To do this, that portion of the total daily uptake which was derived from the contribution by air was subtracted, and the remainder (total uptake via ingestion) was equated with the reported blood-lead levels. The amount to be subtracted was determined by using the source contribution factors identified in Tables 6-1 and 6-2, The values for lead uptake via ingestion Only were also provided in Table 7-1, Several studies have described an ingested lead-to-blood-lead re lationship for children. Two relationships which will be considered for comparison are those proposed by the National Academy of Sciences (1972) and by Moore et al. (1977). Clinical studies involving adult Volunteers have determined that the supplemental ingestion of 1 mg/day of lead as lead acetate or lead chloride produces a 17 pg/dl rise in blood-lead level over a period of several months (Kehoe, 1961). If one assumes a gastroin testinal absorption rate of 10 percent in adults, then the 1 mg/day 97 DUP050033618 (TP/Srt) aval aocra 98 FIGURE 7-1 TOTAL DAILY ABSORBED LEAD TO BLOOD-LEAD RELATIONSHIP FOR THE CHILD DUP050033619 intake rate corresponds to an uptake rate of 100 pg of lead per day. For the average (70 kg) adult, the lead absorbed daily to produce the 17 pg/dl rise in blood-lead levels would be about 1.43 pg Pb/kg/day. NAS (1976) assumed in developing their relationship that an increase in lead uptake of 1.43 yg/kg/day in children will also produce a 17 pg/dl rise in blood lead. Barltrop and Killala (1967) found that a group of two-to-three-year old children with a mean blood-lead level of 20 pg/dl excreted an average of 67.8 pg Pb/day/ person in the feces. Assuming that this fecal lead was the 50 percent of ingested lead that was not absorbed by the gastrointestinal tract, the daily uptake of ingested lead by the average (15 kg) child would be 4.5 pg/kg/day. The slope obtained from Kehoe (1961) data and these aver age lead uptake and blood-lead values were used by the NAS (1976) to specify a lead uptake-to-blood-lead relationship. It should be pointed out that the relationship considers only ingested lead and does not differentiate between lead in drinking water and lead in food. the relationship proposed by Moore et al. (1977) is based on a study involving neonates (10 days postpartum) to determine if any association existed between blood-lead levels and mental retardation. This study was carried out in Scotland, where drinking water-lead levels were in excess of .100 pg/1. In this study, blood-lead levels were compared to water-lead concentrations in the maternal home during pregnancy (Moore et al., 1977). No attempt was made to account for other sources of lead exposure (i.e., air, soil/dust, paint), or to determine the actual quantities of lead in the drinking water inges ted. This study does, however, provide an indication of the long-term impact of high lead levels in water on blood-lead levels of the indig enous population. 99 DUP050033620 Figure 7-2 illustrates how these relationships compare with the relationship developed from the six epidemiological studies on the basis of ingested lead only. It was assumed that the blood-lead values reported in the NAS (1976) and Moore et al. (1977) studies were actual measured values. Since these values represent the contributions from both ingested and inhaled lead, the reported blood-lead values from the six epidemiological studies were used in deriving MITRE*s ingested lead-only line. As can be seen in the figure, the slopes of the lines are different and the choice of curve will have a substantial effect on the value predicted for blood-lead concentration. The relationship developed from the six studies (uptake via ingestion only) appears to agree well with the relationship derived from the Moore et al. (1977) Study, However, since the data of the latter were obtained from ten-day-old infants, it is not certain how representative these data are, since the mother's blood-lead concen tration (as previously described) will have a major influence on the child's blood-lead concentration at this early stage of life. The NAS relationship predicts a much greater increase in bloodlead values than either of the other two relationships, with incre mental increases in the amount of lead absorbed. This difference may be partially explained by the fact that the relationship was developed by extrapolating adult data to conform with the intake and absorption characteristics of a three-year-old child, thereby ignoring any other metabolic differences between adults and children. 7,1.2 Major Assumptions Several assumptions are necessary when using this relationship. It is assumed that the relationship is approximately linear over a specific range of absorption values (about 4 to 50 pg/kg/day) and blood-lead values (i.e., 12 to 40 pg/dl), Other studies (Moore et al., 1977; Berlin et al., 1977; Goldberg, 1974) have suggested that the relationship may not be linear. It is further assumed that daily 100 DUP050033621 (tP/Srt) aval aooia 101 FIGURE 7-2 RELATIONSHIPS BETWEEN LEAD UPTAKE VIA INGESTION AND BLOOD LEAD FOR THE CHILD DUP050033622 intake values, as well as absorption rates for several environmental sources (i.e., food, soil/dust, paint) were fairly constant in the populations studied and approximated those used here. There are studies which indicate that these values are highly variable (King, 1971; Lin-Fu, 1972; Mahaffey, 1977; NAS, 1976; Roberts et al., 1974). The relationship was developed using data from six different studies and applying the best available values concerning average intake and absorption rates. In addition, the data used to derive the relationship were specific to children. As has been pointed out previously, it is necessary to use data obtained from children due to exposure and metabolic differences. Extrapolation of adult data leads to inaccurate predictions. 7.2 Adult Relationship The fetus has been identified as sensitive to lead. There is a close association between fetal and maternal blood-lead levels. Therefore, it is necessary to discuss the relationship between absorbed lead and blood lead for women. Although no studies were found which reported data relating absorbed lead to blood lead in pregnant women, several general statements concerning this relationship in adults can be found in the literature. Clinical studies suggest a blood-lead rise of 1.7 ng/dl for ev ery 100 ng of ingested lead (Kehoe, 1961). Data reviewed by Barltrop (1977) lead to the conclusion that blood-lead levels are increased by approximately 2 p.g/dl for each 100 |ig of ingested lead. Several investigators have correlated increases in water-lead concentrations with rises in blood-lead levels. These data have been compiled and presented by Berlin et al. (1977). Table 7-2 summarizes these data. These results were obtained for water concentrations around 100 l^g/1. The mean from these values is a rise of approximately a 2.5 pig/dl in blood lead for every 100 p.g/1 increase in water-lead concentration. 102 DUP050033623 I V- TABLE 7-2 RISE IN BLOOD LEAD LEVEL ASSOCIATED WITH INCREASE OF 100 Ug/1 IN WATER LEAP CONCENTRATION RISE IN BLOOD LEAD (UK/dl)____ __ 1.3 1,2 3.4 3.3 1.8 2.0 6.0 3.9 0.83 1.9 5.3 0.72 1.3 WATER LEAD SAMPLING PROTOCOL Running Sample First Flush Running Sample First Flush Running Sample Running Sample First Flush First Flush Full Flush First Flush First Flush SOURCE: Adapted from Berlin et al.t 1977. 103 DUP050033624 An additional study (EPA, 1977) suggested a range for the absorbed-lead-to-blood-lead relationship, this range was based on data from studies involving lead absorbed from food and water in adult populations* From these studies, it was estimated that for every 100 pg of ingested lead, a 6 to 18 pg/dl rise in blood lead would be expected. However, it is apparent that S relationship which assumes a rise in blood lead of approximately 2 pg/dl for every 100 pg of inges ted lead more closely approximates the majority of values reported in the literature. Therefore, this relationship will be considered representative. Hean blood-lead levels and corresponding estimated uptake values (through the source contribution model) were used as starting points for deriving a line to depict the adult absorbed-lead-to-blood-lead relationship. Reported values for average blood-lead levels in adults vary according to sex: female levels are lower than those of males. Three studies were used to define average blood-lead values for urban women. The three reported values were 13.8 pg/dl (based on 100 women [Goldsmith, 1974]), 13.8 pg/dl (based on 52 women [Johnson et al., 1975]), and 19.0 pg/dl (based on more than 400 women [Tepper and Levin, 1975]). An average of these values, about 15 pg/dl, was chosen as the representative blood-lead level for an urban woman. Representative urban environmental lead levels were used to define the intake one would expect for an urban female. Using these levels (i.e., air @ 1.5 pg/sr*, food @ 166 pg/day, and water @ 10 pg/1), an intake of 200 pg would be expected. This level is well within the range reported by a number of authors (HAS, 1972; Goyer and Mushak, 1977; Tepper and Levin, 1975; Thompson, 1971; Goldberg, 1975; Mahaffey, 1977) and is considered representative. Using the absorption values for adults, this intake would cor respond to an uptake of 31*47 pg Pb/day. Thus, a blood-lead level of DUP050033625 15 pg/dl would be expected to result from an uptake of 31.47 pg Pb/ day. Converting this to the pg/kg/day scale, assuming a body weight of 60 kg, would produce an uptake value of 0.524 pg/kg/day, Figure 7-3 shows the relationship derived when using these values. The line (y =* 14.lx + 7.67) passes through the point defined as the mean urban blood-lead level/mean urban absorption level, and has a slope based on the relationship of a 2 pg/dl rise in blood lead for every 100 pg of ingested lead. The ratio of 2 pg/dl rise in blood lead for every 100 pg of ingested lead was developed from data which reported a blood-lead range of up to about 30 to 35 pg/dl, For this reason, the relation ship is believed to be approximately linear up to this level. In at least one study of blood-lead levels associated with high drinkingwater-lead levels (Goldberg, 1975), it was suggested that a curvilinear relationship may be more representative at even lower blood-lead levels. However, until further data are produced, it will be assumed that the linear relationship is adequate for the ranges reported here. This relationship can be used to predict blood-lead levels for the female, pregnant female, and adult male since the scale allows for differing body weights. In addition, this relationship appears valid for the pulmonary intake route. EPA (1977) reports a ratio of rise in blood-lead levels to increase in ambient air lead concentrations of 2 pg/dl blood lead per 1 pg/m3 air lead. Assuming an increase in air lead concentration of 1 pg/m3, an average adult male would inhale 22,8 pg Pb/day, while an average adult female would inhale 21,1 pg/day. At a pulmonary absorption rate of 40 percent, the increase in uptake for the male would be 9,12 pg/day and the for the female, 8.44 pg/day. These increases in uptake correspond to increases in blood-lead levels of 1.8 pg/dl in the male and 1,7 pg/dl in the female. This compares favorably with the EPA prediction of a 2 pg/dl blood-lead increase for an increase of 1 pg/m3 in air lead. 105 1 (ug/kg/day) FIGURE 7-3 TOTAL DAILY ABSORBED LEAD TO BLOOD-LEAD RELATIONSHIP FOR THE FEMALE ADULT 106 DUP050033627 Thus, using this relationship, one can determine the estimated rise in blood lead which would be expected in an adult following an increase in the amount of lead absorbed from any environmental source, including drinking water. 7.3 Comparison of the Relationships None of the epidemiological or clinical studies reviewed by MITRE has unequivocally characterised the physiological basis or mathematical form of the lead-uptake-to-blood-lead relationship in either children or adults. Although many of these studies have con cluded that the relationships are adequately represented by linear functions, a number of authors have suggested that the relationships are nonlinear. The straight-line, lead-uptake-to-blood-lead relationships utilized by Metrek are based on data reporting lead intake levels and corresponding blood-lead levels and are presumed to have no more phys iological significance than that which is evidenced by their confor mity to these data. Linear functions were selected because: Cl) they appeared to adequately approximate experimental results (2) there was no overwhelming evidence to suggest that the relationship is nonlinear and no clearcut characterization of the form of such a relationship; and (3) they were simple to derive and manipulate. Since the equations have limited physiological significance, there is little or no justification for using them to extrapolate blood-lead values associated with uptake levels that are very far beyond the range of the available data or beyond the normal uptake ranges defined by the source contribution model (approximately 3 to 50 p.g/kg/day for children and 0.3 to 1.2 pg/fcg/day for adults). The relationships developed by MITRE predict that an incremental increase in lead uptake will produce a greater increase in blood lead in a pregnant woman than in a young child. However, since the two 107 DUP050033628 relationships are presumed to be valid only within specific, nonover1apping uptake ranges this observation does not necessarily signify physiological differences, other than in uptake rates, between children and pregnant females. A single nonlinear function could conceivably describe the actual lead-uptake-to-blood-lead relationship for both populations and would produce the observed results. However, it is likely that physiological differences are at least partially responsible for the observed difference in the slope of the relation* ships. Children may more readily accept lead into their relatively empty dense bone pool than adults, and thus retain a smaller fraction in the blood and tissues which exchange rapidly with it* Even if there were actual physiological differences resulting in two, more-or-less similar curves, these differences would not be apparent from the available data. The regions of the curves in closest proximity to each other represent extremely high lead intake levels for adults and extremely low intake levels for children; therefore, corresponding portions of the two curyea would never be manifested in a single population. 108 DUP050033629 8.0 WATER-LEAD/BLOOD-LEAD SCENARIOS To evaluate the adequacy of the interim primary drinking water standard for lead, it is necessary to predict the blood-lead levels associated with various concentrations of lead in drinking water for identified sensitive populations, and to determine the extent to which altering the maximum allowable concentration of lead in drinking water may affect these populations (via the toxicological consequences associated with changes in blood-lead levels). By combining the derived lead-uptake-to-blood-lead relationship with the percent contribution values from the source contribution model, the relationship between varied water-lead exposure and resultant blood-lead values can be drawn. In the source contribution model, any specific subunit of the total population is defined by representing the characteristic exposure concentrations and physiologic parameters associated with that subunit. Furthermore, the considerable variation from predicted average exposure levels seen in some subunits of the population, particularly children, and in certain regional or local situations (e.g., close proximity to smelting operations), can be accommodated by the model, since any set of environmental conditions can be utilized. 8.1 Water-Lead-to-Blood-Lead Relationship In Children Separate water-lead-to-blood-lead relationships have been defined for the following specific subunits of the child population: rural children without pica, rural children with pica for paint who are exposed to paint containing lead at the current standard, rural children with pica exposed to paint containing lead at levels above the standard, and urban children in the same three categories (Figure 8-1). The assumed exposure conditions are given on the figure; the 109 >! I 1 i i I i f. ji > i f ^Blood-lead levels calculated froo total uptake, hssed on exposure conditions shown. FIGURE 6-1 EFFECTS OF VARYING LEAD CONCENTRATIONS IN DRINKING WATER ON THE BLOOO-LEAD LEVELS OF A HYPOTHETICAL 2 YEAR OLD CHILD 110 * * DUP050033631 lead concentrations in drinking water is given on the abscissa. The six resultant relationships allow comparison of the effect on blood lead of increasing water-lead concentrations in urban and rural children. The relationships between water-lead exposure and blood-lead levels (Figure 8-1) share a common slope since each reflects the sane rate of change in total uptake* Therefore, each shows the same constant increase in blood lead over the range of water lead considered. The total blood-lead increase oyer the range of 10 to 200 jig/1 lead in water is 6,7 pg/dl, represented as a slope of 0.035 in each of the lines in Figure 8-1. The y-intefcept of each line has been determined by calculating the total lead uptake from ail sources except water and then calculating the expected blood lead at this uptake. Analysis of the effect of varied water-lead intakes in reference to the critical threshold level of 30 pg/dl, chosen by EPA and CPC, reveals urban children as the sensitive subgroup. Although water may comprise as much as 42 percent of the source contribution in rural children exposed to lead in drinking water at the current standard, their total blood lead (12.3 |xg/dl) is well below the critical threshold level (see Table 8-1), Urban children without pica, at the current drinking water standard and above, have blood-lead values near the critical threshold level* Urban children with pica for paint (with lead-containing paint at the current standard) have blood-lead levels of 30 pg/dl at water-lead levels below the current Standard (50 pg/1), and blood-lead values well above the critical threshold level at water-lead levels above the standard. Urban children with pica (with lead-containing paint above the standard) display blood-lead levels well above the critical level at water-lead levels below the current standard (Table 8-2). Ill DUP050033632 'So 'i:*if H 00 o\ Ok c m CM CM *1 n 4: rHH ;IX* CM VA Si 33 00 CO CO CO osCoOo s0o> CO H4- M0>.f St St o% rmH WITHOUT PICA *3 3 oa 00 00 OV CS CM CM CM M0 CO CO gj 5* 1 . 46 oa cd s-' < 3h5O 't*3(*!O rt CM CM CM P CM .* in m CO 00 00 eo s00 os r4 o sr H to 1-i o#^Aw2i 00 St CO CM Ok o H CM r-C f> # 1 <d 0, 4J AS! *a1 4J 3 5 rsi ul 3sO MO CO cq r* H H H H s. >* to 00 60 b0 00 A 3- 3 3- 3> O" lO H CM to O o O iM CM 112 1 p PS HH J H 3 O I u u(ou3 0* a3o M0 4H ssOO1 rO id H o o 03 * i 1 i } .* , ? DUP050033633 \ ESTIMATED DAILY LEAD UPTAKE AND BLOOD LEAD IN CHILDREN WITH P IC A FOR PAINT t4 i-Ot o 3J a\ oo CM ro 0 *4* Ot p CM p OO <r <r cc om sc mt vO uo CO St i-H be fi A 3s H ^4 fill0 *0 VU CTi p oo O 00 sf lO *t H H r4 H Ov to o\ o CO CO SCMt O KO CO CO sO st AO &i SO CO CO CO H to r-> !L j-3 H ro 8 ^ 33 CM 00 .# ov OO CM CO IN CO t ' Q\ 0V CM CO r> co .* oo CO st to rM * CM CM cost CO QS .* VO UO CO st 32 cd w P, Q) iH j2 <4 <d U 4J HP &] CO to <T> <ts Qr>\ CO to CO o P <M <* sr *0 oo *h h* |> cm O * AO oo ui CM CM VO St sf VO CO U") cmCoM fCi4*M g w /s 4 Ho 33 vp. CM HH H CM H. |s CM H rM CM H r> CO CM -* CM o> wo St St H CM cot oo oo H CM * H 0C H a id ^ a <-ut r-H ^4 4J9 4<J4 o cx H E> H 00 o CO K CM VO CO o 00 vp CM H .00 oo rs* Q> is. CM iH CO CO CM CO ft H CO H 00 CoO CoMo CM CO ,__,VH f351 *tf OO OO VO O 00 o vO CO O oo VO GO oo o so O 00 o vof> o 00 o5 U H H rS H S3j : --n , 00 bO 00 *N,, 00 00 a. A A a. a S o r-- H IO CM o to o oo rl CM ii 113 0) 4caj P3* 4? vC 3 H 0 u. 4oJ 10 P 3 3 3 a a o g g ou 8 <0 M O is * Qi r--1 ,0 nj H cu g CO MC DUP050033634 At the current water standard, water lead represents 8.5 and 8.2 percent of the total source contribution for urban children without pica and urban children with pica for paint (lead-containing paint at the standard), respectively. In children with pica, with leadcontaining paint above the standard (8000 pg/g), water lead provides 5.8 percent of the total daily lead uptake. Thus it is evident that water contributes only a small amount to the blood-lead level of children compared to other environmental exposures (i.e., soil/dust and paint). In pica children (paint lead at 8000 pg/g) lowering the water-lead concentration from 50 to 10 pg/1 produces a decrease in the percent contribution of water lead to total daily lead uptake from 5.8 to 1.2 percent. The decrease of 1.4 pg/dl blood lead, due to the lowering of water lead from 50 to 10 pg/1, is the same for each child subunit relationship as it is determined solely by the slope of the lines. In the rural low-intake situation (i.e., no pica) , the drop of 1.4 pg/dl is a result of a decrease in percent contribution of water from 41.9 to 12.6. 8.2 Water-Lead-t o-Blood-Lead Relationship in Pregnant Women The combined use of the derived lead-uptake-to-blood-lead relationship and the source contribution model yield a water-leadto-blood-lead straight-line relationship. Variations of lead concentrations in air are assumed to represent the rural-to-urban environmental gradient; while lead levels in food are assumed to remain relatively constant. Three air-lead concentrations were used to define the rural-to-urban gradient reflected in the total daily uptake value (Table 8-3). Using the derived uptake-to-blood-lead relationship, the blood-lead levels at these total daily uptake rates determined and were plotted against the varied water-lead concentrations (Figure 8-2). 114 DUP050033635 3~ 'g'Sa oa O r GO <H VI . m vD CTl <*> <M r*HH aDC* (S 0> rH ^ *<j0 <(0u Ho o j m Hm <o <T <n co or* 00I W 3 HiLO>h *J rH "0 O 0C oa p0H3 ^ 01 sO r- p H 00 . CO Nf in 00 OJ rH rH rH rH CM P 0 pH 4JCO CO ho a>* pH rH pH rH rH SO O Sf M CM cH s* SO .2.M3 -J Td pTH3 o oc .0roH3 o CO OH rH CS * r*HH0 *,0aC' *> tHCO ^-R) Ho ta-j VI V NN OH V> a u CO Sc q rH rO* il pH rH rH rH rH GO 00 .00 00 00 O. a a a rH *n 0H v> o rH cH 1X5 at <d 4oa-i. *c0d P 54ntsJ oo o<Mu o CO uo 4t rH CO EH ai 0 C/1 * DUP050033636 gM I XI 2 u. zo 2d ov 52!*. <u s x0OaV3 zui<S<a s*0" u s 31 a owj gs5 g<5 *2 o ^ Z 2 I- >oS 3 *E? (2g U. < > 05 X ShOu3i o9xs 4O0 fcf aIII s m 0) 4-1 pH o 3 nO (Q pH T3 to in C O <Sl <0 4J W 0) H a> 4-1 > s Q> 4) H H 13 % ft O H o U1 < 13 0 f-4 O H rH < CO a X> 116 ) DUP050033637 The three lines ih Figure 8-2 illustrate the effect of increas ing water-lead concentrations on three separate subgroups of the pregnant female population. It is apparent, as in Section 8.1, that the three lines share a common slope; thus they depict the same con stant increase in blood lead over the exposure range of water lead. The total increase in blood lead over the range of 10 to 200 jig/1 lead in water is 8.9 pg/dl, represented as a slope of 0.047. The y-intercepts are determined from the total uptake values computed by the source contribution model with water at zero, by their subsequent input into the derived-uptake-to-blood-lead relationship. Although the fetus population has been identified as a sensitive group, urban pregnant women have blood lead values which vary only by 2.7 pg/dl Cat the ambient air standard) from blood-lead values of pregnant rural women. The blood-lead level of these urban women at the current water standard is 16.8 p.g/dl, well below the 30 pg/dl level set on by EPA and CDC as the level of undue lead absorption. As presented in Table 8-3, the percent contribution of water to total lead uptake in pregnant urban women ranges from 6.4 percent (at 10 pg/1) to 25.5 percent at the standard (50 M-g/D Despite this percent contribution difference, the effect on blood lead of lowering the water-lead level from 50 to 10 p.g/1 is a decrease of only 1.8 pg/dl, a small fraction of the total blood lead. 8.3 Blood-Lead Contributions from individual Sources The straight-line relationships defined in this report between lead uptake and blood lead do not predict the expected blood-lead value of zero at a lead uptake of zero for either of the two sensitive populations considered. Perhaps this reflects significant deviations from linearity at low uptake values and the inability to accurately quantify all lead sources, especially at low levels. An implication of the nonzero intercepts is that an increase in lead uptake does not 117 DUP050033638 produce a proportionate increase in blood lead; for example, in the case of the urban pregnant woman (Table 8-2), with an air-lead concentration at the proposed standard, an increase in total daily uptake from 31.3 to 49.3 pig (58 percent) produces an increase in blood lead from 15 to 19.2 p.g/dl (only 28 percent). Assuming that subsequent to absorption lead taken up from the various environmental sources is indistinguishable to any physio logical process it is possible to determine the blood-lead level attributable to any one source. This assumption implies that the percent contribution of a source to total lead uptake is equivalent to its percent contribution to blood lead. Source contribution factors can then be used to determine blood-lead levels resulting from individual sources. These source contribution factors are shown in Tables 8-1 through 8-3. From data presented in these tables, it can be inferred that a constant uptake level from any one source does not contribute a constant amount of blood lead. Rather, a constant uptake may be responsible for different amounts of blood lead at different total uptake levels (as well as different percentages of the total blood lead). This effect is related to the nonzero y-intercepts of the lead-uptake-to-blood-lead relationships. In the pregnant female, with air lead at the proposed standard, there is a 58 percent increase in total lead uptake as lead in drinking water rises from 10 to 100 pg/1. A proportional increase in blood lead would lead to a value of 23.7 pg/dl; however, the defined relationship predicts a blood-lead level of 19.2 pg/dl, which is about 19 percent lower. Since uptake from the individual sources is indistinguishable, the blood lead attribut able to each source will be 19 percent lower than that expected on the basis of proportional increase in uptake. For example, the uptakes from food and air remain constant (a proportional increase of 0 percent); therefore, the blood lead associated with these sources will 118 DUP050033639 decrease by about 19 percent. Uptake from drinking water increases from 2 to 20 pg/dl (900 percent); a proportional increase in blood lead due to drinking water would give a value of 9.6 jig/dl, and a 19 percent reduction in this value would give an actual blood-lead level due to water of 7.8 jrg/dl. 119 DUP050033640 9.0 CONCLUSION The toxic effect of lead absorption is the cumulative result of exposure from many different sources. In order to define the toxicological impact associated with Specific environmental lead-source concentrations, it is necessary to jointly consider all of the major exposure sources. There are appreciable differences in exposure conditions between specific subsets of the population (e.g., adults vs. children, child ren with pica vs. children without pica, rural vs* urban populations) and these can be characterized by average exposure assumptions for the subpopulations in question. However, there is variability in the specific exposure conditions of individuals within these subpopulations which cannot be adequately quantified. The lead exposure of children with pica for paint is a striking example of this problem. Because of the wide variation in the lead concentrations ip paint and existing painted surfaces, and the presumed wide range in rates of paint ingestion by children suffering from pica, the use of estimates of average paint-lead concentrations and consumption rates cannot reflect the diversity of blood-lead levels seen in these children. This variability in exposure levels implies that there is con siderable variability in the source contribution factors for all of the major environmental lead exposure sources. The significance of varying the maximum allowable concentration of lead in any medium, measured in terms of the ability to thereby modify the blood-lead levels of the population (or one or more sensitive populations), is a function of the total daily lead uptake and the source contribution factor for that medium. Therefore, the effect of a standard for that medium will not be uniform; rather, it will differ greatly between individuals. 120 j. s ; < i ' % * ; ! , DUP050033641 9.1 Approach If all sources of environmental lead are considered, the most effective means of reducing the overall blood-lead value of a given population can be determined. Utilization of the source contribution model provides the necessary data, since the percent contributions from various environmental sources and the total lead uptake at different environmental levels have been outlined. The model shows which environmental sources are most responsible for the given blood-lead level and thus identifies those areas in which regulatory action will have the greatest impact on blood-lead levels. Large subsets of the population have been identified as being at a considerably higher risk from lead than the population as a whole. Therefore, it seems logical to approach the drinking-water lead standard from a sensitive population perspective. The standard can then be designed to directly benefit either or both of the sensitive populations, or a more sensitive subgroup (e,g., urban children, urban children with pica), Each of these options must be identified and discussed in terms of its impact on the final standard. 9.2 Effects of the Standard The intent of any reduction in a standard for lead should be to lower the blood-lead levels of the exposed population, and in particu lar to reduce the blood-lead levels of those subgroups of the general population who have a greater risk of lead exposure (children) or who are more sensitive to lead than the rest of the population (fetuses and children). Since the American Pediatrics Association and the Center for Disease Control (GDC) have suggested that 30 pg Pb/dl blood is that threshold above which clinically significant adverse effects are noted in exposed children, it ia prudent to assess the adequacy of the current standard in terms of the number of individuals whose blood lead falls above 30 pg/dl. 121 DUP050033642 According to our results, lead-contaminated drinking water gene rally contributes a small fraction of the total daily lead uptake, and therefore will have only limited impact on blood lead. For example, a reduction of drinking water lead from 50 pg/1 to 10 pg/1 is expected to lower the mean blood lead of the hypothetical child population by about 1.5 |xg/dl, or a pregnant female population's mean blood lead by 1,8 pg/dl. For high-risk youngsters (e.g*, urban, inner city children with pica) with blood-lead levels approaching 35 or 40 pg/dl, the utility of a regulation that reduces blood lead by 1.5 jig/dl might be questioned. However, for the population as a whole, a reduction of 1.5 pg/dl in the mean blood-lead level can be substantial. Blood-alead levels of U.S. children have been characterized as log-normally distributed, with a geometric.standard deviation (GSD) of between 1.3 and 1.5 (EPA, 1978b). Given the 30 pg/dl threshold level, one can identify the percent of the exposed population with blood-lead levels below 30 pg/dl given a geometric mean blood-lead level. Or, if a selected percentage of the population is to be protected (as a safety margin), one can determine the particular geometric mean which will insure that that percentage will not exceed 30 pg/dl. In effect, this statistical treatment allows one to define the extent to which the "tail" of the frequency distribution exceeds a particular bloodlead level. A reduction in mean blood-lead levels of the childhood population, regardless of how small in relation to an individual's blood lead, can affect a significant portion of the total population by displacing the frequency distribution. Thus fewer individuals Vill exceed a defined threshold level (see Figure 9-1). Using standard statistical methods applicable to log-normal distributions, one can calculate the mean (geometric) blood-lead level required if less than 99 percent of the observed population are to 122 DUP050033643 H ypothetical Frequency o f Occurrence x* x In Blood lead (Hg/dl) POT number of individuals with blood lead levels exceeding v Wa the threshold, given geometric mean of x KSS1 number of individual with blood lead levels exceeding bbSa the threshold, given geometric mean of x' FIGURE 9-1 EFFECT OF A REDUCTION IN MEAN BLOOD LEAD LEVELS ON THE NUMBER OF INDIVIDUALS EXCEEDING A THRESHOLD BLOOD LEAD LEVEL: LOG NORMAL DISTRIBUTION 123 DUP050033644 have a blood-lead level less than 30 ng/dl. Assuming a geometric standard deviation of 1.4 (Angle and Mclntire, 1978), and utilising the following relationships: In y - In Mg _____ (9-1) and F(z) (9-2) and M .0.5 In* s. S (9-3) where y * the CDC limit of 30 pg/dl Mg = the geometric mean Sg " the geometric standard deviation z = a standardized random variable F * fraction of the population with blood lead less than 30 pg/dl M = the arithmetic mean one can determine what fraction of the exposed population would have a blood-lead level less than 30 fig/dl, given various population mean blood-lead levels (see Figure 9-2). Using the relationship in Figure 9-2, and the source contribu tion model discussed previously, one can determine the proportion of the sensitive subpopulations with blood-lead levels below 30 ng/dl as different control scenarios are applied to lead in drinking water. Tables 9-1 and 9"2 indicate those percentages (people with blood-lead less than 30 jug/dl) for the various subgroups of both identified sensitive groups. 124 DUP050033645 Percent o f Population w ith Blood Lead Levels <30 (ig /d l Geometric Mean Blood Lead (Hg/dl) FIGURE 9-2 PERCENT OF CHILDHOOD POPULATION WITH A BLOOD LEAD LEVEL <3Qri|/dl FOR A SPECIFIED OEOMETRIC MEAN BLOOD LEAD LEVEL (ASSUMING GEOMETRIC STANDARD DEVIATION OF 1.4) 125 DUP050033646  ofPtUi p MoSO V4 >4 > w ,4 p !5 <O M 4 H OJ* T a o J P w*4 o p PC CL. oa. pa w a pM o B3 wo o PE$ J 2 put K 5 sc Pd H w ne p B C M U CO CO C CO Pd o H O < H W < CO p3 :^*e aoH '--*No H43J W^ P0COl Oco -OT.304J) "ooO' 1--1 <a<ou * a o -* 0) ** pQ w 3 f4 O rl 44 '"6n1, 3 0. H 0 cum o Pk 43 *o <0 3 >4 T O o H m d 5MVl X oo os <t VVJC\> CiTOi f*-4H it-dH I:X) cc<rnS> OfrO-* O-mO os <3S Os CO O* Os 00 AA <>--4 ,pd 00 X 0 CO N n co H H CM VV vo. sc noi oOin>*s ii-nnm tn <s oo cINo oMs otoo fN Os OS oo os ps 00 /S A CO CO CM 1* m m rH HHM v v/ OO 00 00 00 0. =L 00 00 >osp op XX oo oo o so O vO 00 00 H rM - u <s* $y oc <g> <a> 01 44 *> si M 44 dd dd H *H o H rl m CO 3 f4 CO CO ^ P- A (4 N. S <a <0 ft- (X u U4 3 {* 3 <X CO CO 4J o o u O 3 SO r< <u ft O u o o ft O *M *H JB O *H *H & JZ Pk ft. 3c PS CU Qj *o3o s 1--34 oo <oM 3 3 ft* 3' *N* d 0 rM 44 3 U 44 d o 3 3 3 V* 3 O w 0) 42 44 3* 43 fHO 3 44 O H "O 0) n a* CO d Cm 3e 0) 6M o H lA ^ 44 3 fC *^c 0 42 Gi n *4r4- M 00 Vi H w< 3 pfi 3 126 i.. ? ; 1 r :>- V i % .!' j '* DUP050033647 TABLE 9-2 SAFETY FACTORS ASSOCIATED WITH PROJECTED BLOOD-LEAD LEVELS FOR VARIOUS PREGNANT FEMALE SUBPOPULATIONS* RURAL (Air @ 0.11 Water @ 50 |ig/l Water @10 |xg/l URBAM (Air @ 1.5 g/m3) Water @ 50 jj.g/,1 Water @ 10 jjug/l Mean Blood Lead13 Population Below 30 ug/dl (%) 14.2 pig/dl 12.3 >99 > 99 16.S 15,0 > 99 > 99 aSg * 1.3 ^Arithmetic means as predicted by the source contribution/uptake to blood-lead model. J 27 DUP050033648 More than 99 percent of rural children without pica, rural children with pica at low paint lead levels, and all female adults are expected to fall below the 30 jxg/dl blood-lead guideline, given drinking water lead at the current interim standard of 50 pg/dl. Decreasing drinking water lead levels for these groups would have a negligible impact, since most individuals within those groups are already below the threshold. A larger proportion of the urban child population exceeds that 30 pg/dl blood-lead level; however, the drink ing water contribution is only a small fraction of their total daily lead uptake. Assuming drinking water lead at 50 p.g/1, between 43.2 and 88.6 percent of the urban child population is expected to have blood lead in excess of 30 pg/dl (see Table 9-1). By reducing the lead content of drinking water to 10 pg/l, between 37.4 and 84.5 percent would exceed the 30 pg/dl threshold, The complete elimination of water lead from the uptake of the urban child yields mean blood-lead levels of 28.1, 28.9 and 38*4 pg/dl for children without pica, with pica at low paint-lead concen trations, and with pica at high paint-lead concentrations, respec tively* The corresponding percentages of the population falling below 30 pg/dl are 64*1, 61.0 and 17.0, respectively. Therefore the total elimination of water lead in these groups adds 1.5 percent of the population to that portion already below the 30 pg/dl guideline. The reduction of water-lead concentration does not appear to greatly affect the blood-lead distribution of the child population. However, an additional 6 to 7 percent of the population over the 30 p-g/dl guideline will now fall within the "protected zone." The effect of reducing the water-lead standard upon the fetus population is not clearly defined by the 30 pg/dl threshold criterion. It is apparent upon viewing Table 9-2 that water-lead reduction, although lowering the mean blood-lead level somewhat, has a negligible effect on the proportion of the adult female population below the 30 pg/dl level. The majority of the female adult population is at no 128 ! > \ ' l \ DUP050033649 no apparent: hazard at the environmental concentrations considered. These blood-lead values (Table 9-2), although well below the threshold level, result in similar blood-lead levels in the newborn. Since the fetus and the newborn are at substantial risk, it may be prudent to reduce the maternal blood-lead levels. For the adult female population, any change in lead levels in drinking water will have a proportionately large effect on blood-lead levels (due to the large source contribution factor), even though those blood-lead levels are already substantially below the 30 pg/dl threshold level. 129 DUP050033650 Research Heeds Additional research is deeded in several areas in order to properly evaluate the validity of the results obtained by using the source contribution model: Rates of intake of soil/dust and paint by children and the rates of absorption of the lead in these sources have not been adequately characterised. There are only limited data regarding host and environmental factors that affect lead intake, uptake and toxicity (e.g., age, nutritional status, hormonal status, chemical form). e The toxicological differences between chronic and episodic exposures have not been properly evaluated. Comprehensive cost/risk/benefit analyses of all sources of lead exposure must be undertaken in order to determine the best overall regulatory approach. 130 DUP050033651 10.0 r e f e r e n c e s Adebonojo, F.O., 1974. "Hematologic; status of urban black children in Philadelphia: emphasis on the frequency of anemia and elevated blood lead levels." Clinical Pediatrics 13:874-888. Akland, G.S., 1976. Air flwaHty foy Metals. 1970-1974. from the National Air Surveillance Networks. IFA-600/4-76-041. U.S. Environ- mental Protection Agency, Washington, D.C. Alexander, F.W., 1974. "The uptake of lead by children in differing environments." Environmental Health Perspectives Experimental Issue No. 7:155-160. Alexander, F.W., H.T. Delves and B.E. Clayton, 1972. "The uptake and excretion by children of lead and other CORtflSlitUkttts." Int. Sympo sium of Environmental Health Aspects of bead. Amsterdam. American Lung Association, 1978. press Release for "Clean Air Week," 1-7 May 1978, dated 28 April 1978. New York, NSW York. Angle, C.R. and M.S. Mclntire, 1978. "Airborne lead and children-- the Omaha study." Archives of Environmental Health (in press). Angle, C.R. and M.S. Mcjntire, 1975. Lead; Environmental Sources and Red Cell Toxicity in Urban Children. EPA PB-249-0^1. U.S. Department of Commerce, National Technical Information Service Report. Atkins, P.R. and P. Krueger, 1968. The Natural Removal of Lead Pol lutants from a Suburban Atmosphere. Technical Report #98. Federal Water Pollution Control Administration, Washington, D.C. Baglan, R.J., A.B. Brill, A. Schulert, D. Wilson, K. Larsen, N. Dyer, M. Mansour, W. Schaffner, L. Hoffman and J. Davies, 1974. "Utility of placental tissue as an indicator of trace element exposure to adult and fetus." Environmental Research 8:64-70. Baloh, R.W., 1974* "Laboratory diagnosis of increased lead absorp tion." Archives of Environmental Health 28:198-208. Baltrop, D., 1966. "The prevalence of pica." American Journal of the Diseases of Children 112:116-123, Baltrop, D., 1977. "Health Hazards in Drinking Water"? Medical Aspects of Lead Hazard. WHO Working Party, London, 131 DUP050033652 Barltrop, D. and H.E. Khoo, 1975a. "Nutritional determinants of lead absorption." Trace Substances in Environmental Health. Volume IX. D.D. Hemphill (ed.). University of Missouri. Baltrop, D. and H.E. KhoO, 1975b. "The influence of nutritional fac tors on lead absorption." Postgraduate Medical Journal 51:795-800. Barltrop, D. and H.E. Khoo, 1976. "The influence of dietary minerals and fat on the absorption of lead." The Science of the Total Environ ment J5:265-273. Barltrop, D. and N.J.P. Killala, 1967. "Fecal excretion of lead by children." Lancet 2;1017-1019. Barry, P.S.I., 1975. "A comparison of concentrations of lead in human tissues," British journal of Industrial Medicine 32i119-139. Barry, P.S.I. and B.B. Mossman, 1970. "Lead concentrations in human tissues." British Journal of Industrial Medicine 27:339-351. Bayley, M. and D.R. Brpwn, 1974, "Low renal lead excretion in leadtreated immature rets." The Pharmacologist 16(2):207. Beattie, A.D., J.H. Dagg, A. Goldberg, I. Wang and J. Ronald, 1972. "Lead poisoning in rural Scotland." British Medical Journal 2:cl88. Berlin, A,, R. Amavis and M. Langevin, 1977. "Research on lead in drinking water in Europe." Working Group on Health Hazards from Drinking Water, 26-30 September 1977. London, England. Bethea, R.M. and N..J. Bethea, 1975. "Consequences of lead in the ambient environment:: an analysis." Residue Reviews 54:55-77. Betts, P.R., R, Astley, D.N. Raine, 1973. "Lead intoxication in children in Birmingham." British Medical Journal 16:402. Billick, I.H. and V.E, Gray, 1978. Lead Based Paint Poisoning Research: Review and Evaluation, 1971-1977. U.S. Department of Housing and Urban Development, Office of Policy Development and Research. U.S. Government Printing Office, Washington, D.C* Bird, D., 1971. The New York Times, August 4, 1971, p. 18. Blake, K.C.H., 1976. "Absorption of 2^3pb from gastrointestinal tract of man," Environmental Research 11:1-4. Blumberg, W.E., J. Eisinger, A.A. Lamola and D.M. Zuckerman, 1977, "The hematofluorometer." Clinical Chemistry 23(2):270-274. 132 DUP050033653 Bogen, D.C,, G.A. Welford and R.S. Morse, 1976. "General population exposure of stable lead and 210pb to residents of New York City." Health Physics 30(4):359-361. Booker, D.V., A.C. Chamberlain, D. Newton and A.N.B. Stott, 1969. "Uptake of radioactive lead following inhalation and injection." British Journal of Radiology 42:457-466. Boyland, E., C.E. Dukes, P.L. Grover and B.C.V. Mitchley, 1962. "The induction of renal tumours by feeding lead acetate to rats." British Journal of Cancer 16:283-288. Bridbord, K., 1978. "Occupational lead exposure and women." Preven tative Medicine 7_: 311-321. Brown, D.R., 1975. "Neonatal lead exposure in the rat: decreased learning as a function of age and blood lead 000060^311008." Toxi cology and Applied Pharmacology 32:628-637. Bruhn, J.C. and A,A. Franke, 1976. "Lead and cadmium in California raw milk." Journal of Dairy Science 59(10):1711-1717. de la Burde, B. and M.S. Choate, 1972. "Does asymptomatic lead expo sure in children have latent sequelae?" Journal of Pediatrics 81.: 1088-1091. de la Burde, B. and M.S. Choate, 1975. "Early asymptomatic lead exposure and development at school age." Journal of Pediatrics 37:638-462. Bureau of Water Hygiene, 1970a. Community Water Supply Study: Pueblo County, Colorado. Public Health Service, U.S. Department of Health, Education, and Welfare, Washington, D.C. Bureau of Water Hygiene, 1970b. Community Water Supply Study: Kansas City, Katisas-Missouri. Public Health Service, U.S. Department of Health, Education, and Welfare, Washington, D.C. Bureau of Water Hygiene, 1970c, Community Water Supply Study: San . Bernardino-Riverside-Ontario, California. Public Health Service, U.S, Department of Health, Education, and Welfare, Washington, D.C. Bureau of Water Hygiene, 1970d. Community Water Supply Study: New York SMSA. Public Health Service, U.S. Department of Health, Educa tion, and Welfare, Washington, D.C. 133 DUP050033654 Butler, J.D, and S.D. MacMurdo, 1974. "Interior and exterior atmo spheric lead concentrations of a house situated near an urban motor way." International Journal of Environmental Studies 6:181-184. Butt, E.U., R.E. Nusbaum, T.C. Gilmour and S.L. Didio, 1964. "trace metal levels in human serum and blood." Archives of Environmental Health 8:52-57. Byers, R.K. and E.E. lord, 1943. "Late effects of lead poisoning on mental development." American Journal of Diseases of Children 66: 471-494. Campbell, B.C., A.D. Beattie, M.R. Moore, A. Goldberg and A.G. Reid, 1977. "Renal insufficiency associated with excessive lead exposure." British Medical Journal 482-485. Casarett, l.J, and J. Doull, editors, 1975. toxicology? The Basic Science of Poisons. MacMillian Publishing Co., Inc., New York. Center for Disease Control (CDC), 1975. "Increased lead absorption and lead poisoning in young children." Journal of Pediatrics 87(3); 824-830. Center for Disease Control (CDC), 1978. Preventing Lead Poisoning in Young Children. U.S. Department of Health, Education, and Welfare, Center for Disease Control, Atlanta, Georgia. Chamberlain, A.C., W.S. Clough, M.J. Heard, D. Newton, A.N.B, Stott and C.C. Wells, 1975a. "Uptake of lead by inhalation of motor exhaust." Proceedings of the Royal Society of London B. 192;77-110. Chamberlain, A.C., W.S. Clough, M.J. Heard, D. Newton, A.N.B. Stott and A.C. Wells, 1975b. "Uptake of inhaled lead from motor exhaust." Postgraduate Medical Journal 51;790-794. Chisolm, J.J., Jr, 1962, "Aminoaciduria as a manifestation of renal tubular injury in lead intoxication and a comparison with patterns of aminoaciduria seen in other diseases." Journal of Pediatrics 60; 1-17* Chisolm, J.J., Jr., 1971. "Screening techniques for undue lead expo sure in children: biological and practical considerations." Journal of Pediatrics 79:719-725. Chisolm, J.J., M.B. Barrett and E.D, Mellits, 1975. "Dose-effect and dose-response relationships for lead in children." Journal of Pedia trics 87(6);1152-1160. 134 DUP050033655 Coogan, P. S, 1973. "Lead-induced renal carcinomas." Proceedings Inst. Medicine Chicago 29:309. Cooper, W.C., 1978. "Mortality of workers in lead production facili ties and lead battery plants." Paper presented at the Second Inter national Symposium on Environmental Lead Research, sponsored by International Lead Zinc Research Organization, Inc., and The Univer sity of Cincinnati, College of Medicine, 5--7 December 1978, Cooper, W.C. and W.R. Gaffey, 1975. "Mortality of lead workers." Journal of Occupational Medicine 17(2):100-107. Daines, R.H., H. Motto and D.M. Chilko, 1970, "Atmospheric lead: its relationship to traffic volume and proximity to highways." Envi ronmental Science and Technology 4.:318-322, Damstra, T., 1977. "Toxicological properties of lead." Environmen tal Health Perspectives 19;297-307. Darrow, D.K, and H.A. Schroeder, 1974. "Childhood exposure to envi ronmental lead." Advances in Experimental Medicine and Biology, Volume 48 M, Friedman (ed.).Plenum Press, New York. David, 0., S. Clark and K. Voeller, 1972. "Lead and hyperactivity," Lancet 2}900-903, Day, J.P., M, Hart and M.S. Robinson, 1975. "Lead in urban street dust," Mature .253:343-345. Dillon, H.E. D.J. Wilson and W. Schaffner, 1974, "Lead concentra tions in human milk." American Journal of the Diseases of Children 128:491-492. Dingwall-Fordyce, I. and R.E. Lane, 1963. "A follow study of lead workers." British Journal of Industrial Medicine 20:313-315. Durfor, C.W, and E. Becker, 1964, Public Water Supplies of the 100 Largest Cities in the U.S. Water Supply Paper #1812. U.S. Geological Survey, Washington, D.C. Durum, W.H.., 1974. Occurrence of Some Trace Metals in Surface Waters and Groundwaters. 16th Water Quality Conference. Durum, W.H, J.D, Hem and S.G. Heidel, 1971. Reconnaissance of Selected Minor Elements in Surface Waters of the United States, October 1970, Circular #643. U.S. Geological Survey, Washington, D.C. 135 DUP050033656 Edwards, H.W., 1975. "Environmental contamination by automotive lead." International Symposium Proceedings on Recent Advances in the Assessment of the Health Effects of Environmental Pollution, Volume 3. Commission of the European Communities, Luxemburg. Emmerson, B.T., 1969. "The clinical differentiation of lead gout from primary gout." Arthritis and Rheumatism 11:623-634. Faoro, R.B. and T.B. McMullen, 1977. National Trends in Trace Metals in Ambient Air. EFA-450/1-77-003. U.S. Environmental Protection Agency, Washington, D.C. Feldman, R.G., J. Haddow, L. Kopito and H. Schwachman, 1973. "Altered peripheral nerve conduction velocity; chronic lead intoxica tion in children." American Journal of the Diseases of Children 125(1):39-41. Food and Drug Administration (FDA), 1975. Compliance Program Evalua tion: FY 1974 Heavy Metals in Foods Survey. FDA #7320.130, Bureau of Foods, Washington, D.C. Food and Drug Administration (FDA), 1977. Compliance Program Evalua tion: FY 74 Total Piet Studies. FDA #7320.08. Bureau of Foods, Washington, D.C. . Forbes, G.B, and J.C. Reins, 1972, "Effect of age on gastrointes tinal absorption (Fa, Sn, Pb) in the rat." Journal of Nutrition 102(5):647--652; as cited in NAS, 1976. Friberg, L., M. Piscator, G.F. Nordberg and T* Kjellstrom, 1974, Cadmium in the Environment, 2nd edition. CRC Press, Cleveland, Ohio. Garber, B.T, and E Wei, 1974. "Influence of dietary factors on the gastrointestinal absorption of lead." Toxicology and Applied Pharma cology 27_: 685-691. Garcia, W.J., C.W. Blessin and G.E, Inglett, 1974, "Heavy metals in food products from corn." Cereal Chemistry 51:779-787. Gershanik, J.J., G.G. Brooks and J.A. Little, 1974. "Blood lead values in pregnant Women and their offspring." American Journal of Obstetrics and Gynecology 119(4);508-511. Gething, j., 1975. "Tetramethyl lead absorption: a report of human exposure to a high level of tetramethyl lead." British Journal of Industrial Medicine 32:329-333, 136 DUP050033657 Goldberg, A., 1974* "Drinking water as a source of lead pollution," Environmental Health Perspectives, May 1974. Goldberg, A., 1975. "Review of recent advances of lead in clinical research," Postgraduate Medical Journal 51:747-750. Goldgraben, G., 1978, The MITRE Corporation/Metrek Division, McLean, Virginia. Personal communication. Goldsmith, J.R., 1974. Food Chain and Health Implications of Air borne Lead, MTIS II PB-248 745, California State Health and Welfare Agency, Berkeley. Coyer, R.A. and J.J. Chisolm, 1972, "Lead," Chapter 8 In: Metallic Contaminants and Human Health, D.H.K. Lee, (ed.). Academic Press, New York. Goyer, R.A. and K.R. Mahaffey, 1972. "Susceptibility to lead toxicity," Environmental Health Perspectives. October. Goyer, R.A. and P. Mushak, 1977. "Lead toxicity laboratory aspects." Advances in Modern Toxicology, Volume 2: Toxicology of Trace Elements, R.A. Goyer and M.A. Mehlman (eds.). John Wiley and Sons, New York, Griffin, T.B., F. Coulston, H. Wills, J,C. Russel and J.H. Knelson, 1975, "Clinical studies of men continuously exposed to airborne particulate lead," Lead. T.B. Griffin and J.H. Knelson (eds.). Academic Press, New York. Gross, S.B., 1976, "Classifying lead body burdens using Z scores." Toxicology and Applied Pharmacology 38:345-355. Gross, S.B., E.A. Pfitzer, D.W. Yeager and R.A. Kehoe, 1975. "Lead inhuman tissues." Toxicology and Applied Pharmacology 32:638-651. Gruden, N. and M. Stantic, 1975. "Transfer of lead through the rat's intestinal wall." Science of the Total Environment 3:288-292. Guyton, A.G., 1971a. "Pregnancy and lactation." Chapter 82 In: Textbook of Medical Physiology, 4th edition. W.B. Saunders Company, Philadelphia. Guyton, A.C., 1971b. "Red blood cells and polycythemia." Chapter 8 In: Textbook of Medical Physiology, 4th edition. W.B, Saunders Company, Philadelphia. 137 DUP050033658 Hall, S.R,, 1972, "Pollution and poisoning." Environmental Science and Technology 6(1); 31-33. -- Hammond, P.B., 1977. "Exposure of humans to lead." Annual Revue of Pharmacology and Toxicology 17:197-214. Hankin, L., G.H. Heichel and R.A, Botsford, 1974, "Lead in wrappers of specialty foods as a potential hazard to children." Clinical Pediatrics 13(12):1064-1065. Hardy, H.L., 1965. "Lead," Symposium on Environmental Lead Contam ination. NTIS #PB-198-104. U.S. Public Health Service. Harris, P. and M.R. Holley, 1972. "Lead levels in cord blood." Pedi atrics 49:606. Harris, R. aiid W.R. Elsea, 1967. "Ceramic glaze as a source of lead poisoning," Journal of the American Medical Association 202(6):1297. Harrison, P.R., 1973. "Air pollution by lead and other trace metals." Advances in Experimental Medicine and Biology 40:173-237. Hem, J.D. and H.H. Durum, 1973. "Solubility and occurrence of lead in surface waters." Journal of the American Water Works Association 65(8):562-568. Hernberg, S., 1976. "Biochemical, subclinical and clinical responses to lead and their relationship to different expsosure levels, as indicated by the concentration of lead in blood." Effects and DoseResponse Relationships of Toxic Metals. G.F. Hordberg (ed.). ' Elsevier Scientific Publishing Company, New York. Hernberg, S., J. Nikkanen, G. Mellin and H. Lilius, 1970, "6-Aminolevulinic acid dehydratase as a measure of lead exposure." Axehives of Environmental Health 21:140-145. Huntzicker, J.J., S.K. Priedlander and C.l. Davidson, 1975. "Mate rial balance for automobile-emitted lead in Los Angeles basin." Environmental Science and Technology 9(5):448-456. Idaho Department of Health and Welfare, 1977. Shoshone Lead Health Project Work Summary, January 1976. Division of Health, Boise, Idaho. International Agency for Research on Cancer (IARC), 1972. IARC Mono graphs on the Evaluation of Carcinogenic Risk of Chemicals to Man, Volume 1. IARC, Lyon, France. 138 DUP050033659 International Committee on Radiological Protection (ICRP), 1975. Report of the Task Croup on Reference Man; Report #23. Pergamon Press, New York. Jenkins, D.W., editor, 1976. Design of Pollutant-Oriented integrated Monitoring Systems: A Test Case--Environmental Lead. EPA-600/4-76018. U.S. Environmental Protection Agency, Washington, D.C. Johnson, D.E., J.B. Tillery and R.J. Prevost, 1975a. "Levels of platinum, palladium and lead in populations of southern California." Environmental Health Perspectives 12:27-33. Johnson, D.E., J.B, Tillery and R.J. Prevost, 1975b. "Trace metals in occupationally and nonoccupationally exposed individuals." Envi ronmental Health Perspectives 10:151-158, Johnson, D.E., R.J. Prevost, J.B. Tillery, K.T, Kimball and J.M. Hosenfeld, 1978. Epidemiologic Study of the Effects of Automobile Traffic on Blood Lead Levels. EPA-600/I-78-055. U.S, Environmental Protection Agency, Office of Research and Development, Research Triangle Park, North Carolina. Joselow, M.M., J.E, Bauta, W. Pisher and J. Valentine, 1975, "Envi ronmental contrasts: blood lead levels of children in Honolulu and Newark." Journal of Environmental Health 37:10-13. Kanisawa, M. and H.A. Schroeder, 1969. "Life-term studies on the effect of trace elements on spontaneous tumors in mice and rats." Cancer Research 29:892-895. Karhausen, L., 1972. "Intestinal lead absorption." International Symposium on Environmental Health Aspects of Lead, Amsterdam. Kehoe, R.A., 1961. "The Harben Lectures, I960: the metabolism of lead in man in health and disease." Journal gf the Royal Institute of Public Health and Hygiene. April-August 1961. Kehoe, R.A., 1964. "Normal metabolism of lead." Archives of Environ mental Health 8:44-47. ......... Kehoe, R.A., 1969. "Toxicological appraisal of lead in relation to the tolerable concentration in the ambient air." Journal of the Air Pollution Control Association 19(9):690-701. ' King, 8.6., 1971. "Maximum daily intake of lead without excessive body lead-burden in children." American Journal of the Diseases of Children .122:337-340, 139 DUP050033660 Kirkpatrick, D.C. and D.E. Coffin, 1973. "Cadmium, lead and mercury content of various cured meats." Journal of the Science of Food and Agriculture 24: 1595-1598. Klein, P.S., G.B. Forbes and P.R. Nader, 1975. "Effects of starva tion in infancy (pyloric stenosis) on subsequent learning abilities.'1 Journal of Pediatrics 87:8-15. Knelson, J.H., 1974. "Problem of estimating respiratory lead dose in children." Environmental Health Perspectives Experimental issue No. 1:53-57. Kolbye, A.C., K.R. Mahaffey, J.A. Fiorino, P.C. Corneliussen and C.F. Jelinek, 1974. "Food exposures to lead." Environmental Health Per spectives Experimental Issue No. 7:65-74. Kopp, J.F. and R.C. Kroner, 1967. Trace Metals in Waters of the United States. U.S. Department'of the Interior, Federal Uater Pol lution Control Administration, Cincinnati, Ohio. Kopple, J.D., M.B. Rabinowitz and G.W. Wetherill, 1976. "The rela tive contributions of inspired and dietary lead to body lead burden." Clinical Implications of Air Pollution Research. A.J. Finkel (ed.). AMA/Publishing Science Group. Kostial, K. and B. Momcilovic, 1974. "Transport of lead-203 and calcium-47 from mother to offspring." Archives of Environmental Health 29(1):28-30. Kostial, K,, I. Simonovic and M, Pisonic, 1971. "Reduction of lead absorption from the intestine in newborn rats." Environmental Research 4:360-363. Krigman, M.R. and E.L. Hogan, 1974. "Effect of lead intoxication on the postnatal growth of the rat nervous system." Environmental Health Perspectives Experimental Issue No. 7:187-199. Lagerwerff, J.V. and A.W. Specht, 1970. "Contamination of roadside soil and vegetation with cadmium, nickel, lead and zinc." Environ mental Science and Technology 4_:583--586. Lamm, S.H. and J.F. Rosen, 1974. "Lead contamination in milks fed to infants: 1972-1973." Pediatrics 53(2):137-141. Lamola, A.A. and T. Yamane, 1974. "Zinc protoporphyrin in the erythrocytes of patients with lead intoxication and iron deficiency anemia." Science 186:936-938. 140 DUP050033661 Lamola, A.A., M. Joaelow and T. Yamane, 1975a. "Zinc protoporphyrin in the erythrocytes of patients with lead intoxication and iron deficiency anemia." Science 186:936-938. Lamola, A.A., M. Joaelow and T. Yamane, 1975b. "Zinc protoporphyrin (ZPP): a simple, sensitive fluorometric screening test for lead poisoning." Clinical Chemistry 21(1):93-97. Landrigan, P.J., S.H. Gehlbach, B.F. Rosenblum, J.M. Shoults, R.M. Candelaria, W.F. Barthel, J.A. Liddle, A.L. Smrek, N.W. Staehling and j.F. Sanders, 1975. "Epidemic lead absorption near an ore smelter." Hew England Journal of Medicine 292(3 ):123-129 Lassovszky, P., 1978. U.S. Environmental Protection Agency, Office of Water Supply, Washington, D.C. Personal Communication. Lee, R.E, and D.J. von Lehmden, 1973. "Trace metal pollution in the environment." Journal of the Air Pollution Control Association 23(1):853-857. Lepow, M.L,, L. Bruckman, R.A. Rubino, S. Markowitz, M. Gillette and J. Kapish, 1974. "Role of airborne lead in increased body burden of lead in Hartford children." Environmental Health Perspectives 7; 99-102. Lin-Fu, J.S., 1972* "Undue absorption of lead among children--a new look at an old problem." Mew England Journal of Medicine 286(13): 702-710. Lourie, R.S., E.M. Layman and F.K. Millican, 1963. "Why children eat things that are not food." Children 10:143-146. Lucas, J.M., 1977. Effect of Analytical Variability on Measurements of Population Blood Lead Levels. E.I. du Pont de Nemours 6 Company, Wilmington, Delaware. Mahaffey, K.R., 1977. "Relation between quantity of lead ingested and health effects of lead in humans." Pediatrics 59(3):448-456. Mahaffey, K.R.., P.E. Corneliussen, C.F. Jelinek and J.A* Fiorino, 1975, "Heavy metal exposure from foods." Environmental Health Perspectives, December 1975. Mao, P. and J.J. Molner, 1967. "The fine structure and histochem istry of lead-induced renal tumors in rats." American Journal of Pathology 50:571. 141 DUP050033662 McCabe, L.J., J.M. Symons, R.D. Lee and G.G. Robeck, 1970* "Survey of community water supply systems." Journal of the American Water Works Association 62:670-687. McClain, R.M* and J,J. Siekierka, 1975, "The placental transfer of lead-chelate complexes in the rat." Toxicology and Applied Pharma cology 31:443-451. McMullen, T.B., R.B. Faoro and G.B. Morgan, 1970. "Profile of pollu tant fractions in nonurban suspended particulate matter." Journal of the Air Pollution Control Association 20(6):369-372. Mehani, S., 1966. "Lead retention by the lungs of lead-exposed workers," Annals of Occupational Hygiene 9;165-171. Michaelson, I.A, and M.W. Sauerhoff, 1974. "Animal models of human disease: severe and mild lead encephalopathy in the neonatal rat." Environmental Health Perspectives Experimental Issue Mo, 7:201-225. Millican, F.K., E,M. Layman, R.S. Lourie, L.Y. Takahashi and C.C. Dublin, 1962. "The prevalence of ingestion and mouthing of nonedible substances by children. .Clinical Proceedings of the Children's Hospital 18(8):207-214. Mitchell, D.G, and K.M.Aldous, 1974. "Lead content in foodstuffs." Environmental Health Perspectives Experimental Issue No, 7:59-64. Momcilovic, B. and K, Kostial, 1974. "Kinetics of lead retention and distribution in suckling and adult rats." Environmental Research 8: 214-220. Moore, J.F., R.A. Goyer and M.H. Wilton, 1973. "Lead induced inclu sion bodies; solubility, amino acid content and acidic nuclear proteins." Laboratory Investigations 29:488-494. Moore, M.R., 1975. "Lead in drinking water and its significance to health." Drinking Water Quality and Public Health. Water Research Center. Moore, M.R., 1977, "Lead in drinking water in soft water areas-health hazards." Science of the Total Environment 7:109-115. Moore, M.R., P.A. Meredith and A. Goldberg, 1977. "A retrospective analysis of blood-lead in mentally retarded children." Lancet, April 2, 1977:717-719. Morgan, J.M., M.W. Hartley and R.E. Miller, 1966, "Nephropathy in chronic lead poisoning." Archives International Medicine 118:17-29. 142 DUP050033663 y Morse, R.S. and G.A* Welford, 1971* "Dietary intake o 210Pb." Health Physios 21;53-55 Murthy, G.K. and V.S. Rhea, 1971* "Cadmium, copper, iron, lead, manganese and zinc in evaporated milk, infant products and human milk." Journal of Dairy Science 54(7):1001-1005. National Academy of Sciences (NAS), 1972. Airborne Lead in Perspec tive. Committee on the Biologic Effects of Atmospheric Pollutants, National Research Council, Washington, D.C. National Academy of Sciences (NAS), 1976. Recommendations for the Prevention of Lead Poisoning in Children. Committee on Toxicology, Assembly of Life Sciences, National Research Council, Washington, D.C. National Academy of Sciences (NAS), 1977. Drinking Water and Health. Safe Drinking Water Committee, Washington, D.C. Needleman, H.L. and S. Piomelli, 1978. The Effects of Low Level Lead Exposure. Natural Resource Defense Council, Inc., Publication, April 25, 1978. Nozaki, K., 1966. "Method for studies on inhaled particles in human respiratory system and retention of lead fume." Industrial Health (Japan) 4:118-128. Olson, K.W. and R.K. Skogerboe, 1975. "Identification of soil lead compounds from automotive sources." Environmental Science and Tech nology 9(3):227-236. Oyasu, R., H.A, Battifora, R.A. Clasen, J.H. McDonald and G.M. Hass, 1970. "Induction of cerebral gliomas in rats with dietary lead sub acetate and 2-acetylaminofluorene." Cancer Research 30:1248-1261. Patterson, C.C., 1965. "Contaminated and natural lead environments of man." Archives of Environmental Health 11:344-360. Perkins, K.C. and E.A. Oski, 1976. "Elevated blood lead levels in a 6-month-old breast-fed infant: the role of newsprint logs." Pediatrics 57(3):426-427. Pierce, J.O., S.R. Koirtyohann, T.E. Clevenger and F.E. Lichte, 1976. The Determination of Lead in Blood...A Review and Critique of the State-of-the-Art, 1975. International Lead Zinc Research Organiza tion, Inc., New York. 143 DUP050033664 Piomelli, S., 1978. Director, Pediatric Hematology, New York Univer sity Medical Center,, New York, New York. Letter to J. Padgett, Director of Standards, Air Strategy Division, U.S, Environmental Pro tection Agency, Research Triangle Park, North Carolina, dated 14 March 1978. Piomelli, S. B. Davidow, V.F. Guinee, P. Young and G. Gay, 1973. "The FEP (free erythrocyte porphyrins) test: a screening micromethod for lead poisoning," Pediatrics 51(2):254-259, Preston, E., 1977. Ambient Lead Concentrations in the United States: Air Quality Control Regions with Monitoring Data. WP-12068. The " MITRE Corporation/Metrek Division, McLean, Virginia. Quarterman, J., J.W. Morrison and W.R. Humphries, 1976. "The effects of dietary lead content and food restriction on lead retention in rats." Environmental Research 12:180-187. Rabinowitz, M.B., G.W. Wetherill and J.D. Kopple, 1973. "Lead metabolism in the normal human: stable isotope studies." Science 182:725-727. Rabinowitz, M.B., G.W. Wetherill and J.D. Kopple, 1974. "Studies of human lead metabolism by use of stable isotope tracers." Environ mental Health Perspectives Experimental Issue No. 7:145-153. Rabinowitz, M., G.W. Wetherill and J. Kopple, 1975. "Absorption, storage and excretion of lead by normal humans." Trace Substances in Environmental Health, Volume IX, D.D. Hemphill (ed.). University of Missouri, Columbia, Missouri. Rastogi, S.C, and J. Clausen, 1976. "Absorption of lead through the skin." Toxicology 6:371--376. Roberts, E., R. Spewak, S, Stryker and S. Tracy, 1975. Collection and Analysis of Toxic Substances Data from State Agencies, Volume 4. M75-52. The MITRE Corporation/Metrek Division, McLean, Virginia. Roberts, T.M., T.C. Hutchinson, J. Paciga, A. Chattopadhyay, R.E. Jervis, J, Van Loon and D,K. Parkinson, 1974. "Lead contamination around secondary smelters: estimation of dispersal and accumulation by humans." Science 186:1120-1123. Robinson, E. and F.L. Ludwig, 1967. "Particle site distribution of urban lead aerosols." Journal of the Air Pollution Control Associa tion 17:664-669. 144 DUP050033665 Roe, F.J.C., E. Boyland, C.E. Dukes and B.C.V. Mitchley, 1965. "Failure of testosterone or xanthopterin to influence the induction of renal neoplasms by lead in rats." British Journal of Cancer 19:860-866. Rolfe, G.L. and A. Haney, 1975. An Ecosystem Analysis of Environ mental Contamination by Lead. Institute for Environmental Studies, Research Report #1, University of Illinois at Urbans, Champaign, Illinois. Rosen, J.F. and E.E. Wexler, 1977. "Studies of lead transport in bone organ culture." Biochemical Pharmacology 26:650-652. Sabotka, T.J. and M.P. Cook, 1974. "Postnatal lead acetate exposure in rats: possible relationship to minimal brain dysfunction," Amer ican Journal of Mental Deficiency 79:5-9. Sachs, H.K., 1975. Letter to Dr. J. Julian Chisolm, Jr. dated 18 October 1975; as cited in NAS, 1976. Sandhu, S.S., P. Nelson and W.J. Warren, 1975, "Potable water qual ity in rural Georgetown County," Bulletin of Environmental Contam ination and Toxicology 14(4):465-472. Schroeder, H.A. and J.J, BalasBa, 1961. "Abnormal trace metals in man: lead." Journal of Chronic Diseases 14(4):408-425. Schroeder, H.A. and I.R. Tipton, 1968. "The human body burden of lead." Archives of Environmental Health 17:965-978. Sehrnel, G.A., 1976. "Particle resuspension from an asphalt road caused by car and truck traffic." Proceedings of the Symposium on Atmosphere-Surface Exchange of Particulate and Gaseous Pollutants. Richland, Washington, ERDA Symposium Series (38):859-882. Seppaiainen, A.M., S. Tola, S. Hernberg and B. Kook, 1975, "Subclinical neuropathy at safe levels of lead exposure." Archives of Environmental Health 30:180-183, Shier, D,R and W,G Hall, 1977. Analysis of Housing Data Collected in a Lead-Based Paint Survey in Pittsburgh, Pennsylvania. National Bureau of Standards, Washington, D.C. Singerman, A., 1976, "Clinical signs versus biochemical effects for toxic metals." Effects and Dose-Response Relationships of Toxic Metals. C.F. Nordberg (ed.). Elsevier Scientific Publishing Company, Amsterdam. 145 i DUP050033666 Smith, R.G., 1971. "Health aspects of atmospheric exposure to lead." Medical Aspects of Air Pollution. SAE, Inc. Steiglitz, E.J., 1949. Geriatric Medicine. W.B. Saunders Company, Philadelphia. Stiller, D., 1973. "Topochemie tubularer Enzymanuster wahrend der experimentellen Cancerisierung. Untersuchungen zur Enzymhistochemie der chronischen Bleinephropathie der Ratte." Experimental Pathology 8:137-153. Stoewsand, G.S., 1972. Toxic Metals in Our Food Chain. Hew York State Association of Milk and Pood Sanitarians, New York, Strain, W.H., A, Flynn, E.G, Manson, F.R. Plecha, W.J. Pories and O.A. Hill, Jr., 1975, "Trace element content of household water." Trace Substances in Environmental Health. Volume IX. D.D. Hemphill (ed.). University of Missouri, Columbia, Missouri. Sunderman, F.W., Jr., 1971. "Metal carcinogenesis in experimental animals.11 Food and Cosmetics Toxicology 9:105-120. Task Group on Lung Dynamics, 1966, "Deposition and retention models for internal dosimetry of the human respiratory tract," Health Physics 12;173-307. Task Group on Metal Toxicity, 1976* "Dose." Effects and DoseResponse Relationships of Toxic Metals. G.F. Nordberg (ed.). Elsevier Scientific Publishing Company, Amsterdam. Tepper, L.B. and L.S. Levin, 1975. "A survey of air and population lead levels in selected American communities," Environmental Quality and Safety, Supplement II; Lead. Ter Haar, G. and R. Aronpw, 1974, "The use of tracer techniques and environmental sources for evaluation of the lead problem in children." Recent Advances in the Assessment of the Health Effects of Environmental Pollution, World Health Organization, Luxembourg. Ter Haar, G.L. and M.A, Bayard, 1971. "Composition of airborne par ticulates." Nature 232:553-554. Thomas, B., J.A. Roughan and E.D. Waters, 1972. "Lead and cadmium content of some vegetable foodstuffs," Journal of Food Science and Agriculture 23:1493-1498. 146 DUP050033667 Thomas, B,, J.A. Roughan and E.D. Waters, 1973. "head and cadmium content of some canned fruit and vegetables." journal of Food Sci ence and Agriculture 24:447-449. Thomas, B., J.W. Edmunds and S.J. Gurry, 1975. "Lead content of canned fruit." Journal of food Science and Agriculture 26:1-4. Thompson, J.A* > 1971. "Balance between intake and output of lead in normal individuals." British Journal of Industrial Medicine 2$:189194. Tola, S., S. Hernberg, S. Asp and J. Nikkanen, 1973. "Parameters indicative of absorption and biological effect in new lead exposure: a prospective study." British Journal of Industrial Medicine 30:134141. Tola, S. and C.H. Nordman, 1977. "Smoking and blood lead concentra tions in lead-exposed workers and an unexposed population*" Environ mental Research 13:250-255. Tolan, A. arid G.A.H, Elton, 1972. "Lead intake from food." Inter national. Symposium on Environmental Health Aspects of Lead, Amsterdam. Tolley, J.A., 1973. "Total lead in drinking water." Lancet 2(844): 1497-1498. de Treville, R.T.P., 1964. "Natural occurrence of lead." Archives of Environmental Health 8:212-221. Tsuchiya, K., 1977. Toxicology of Metals: Lead. EPA-600/1-77-022* U.S. Environmental Protection Agency, Washington, D.C. U.S, Environmental Protection Agency (EPA), 1972a. EPA's Position on the Health Effects of Airborne Lead. U.S. Environmental Protection Agency, Washington, D.C. U.S. Environmental Protection Agency (EPA), 1972b. Helena Valley, Montana. Area Environmental Pollution Study. Report #AP-91. U.S. Environmental Protection Agency, Office of Air Programs, Research Triangle Park, North Carolina. U.S. Environmental Protection Agency (EPA), 1975. Chemical Analysis of Interstate Carrier Water Supply Systems. EPA 430/9-75-005. U.S. Environmental Protection Agency, Washington, D.C. U.S. Environmental Protection Agency (EPA), 1977. Air Quality Cri teria for Lead. EPA-600/8-77-017. U.S. Environmental Protection Agency, Washington, D.C. 147 DUP050033668 U.S. Environmental Protection Agency (EPA), 1978a. Environmental Impact Statement [Lead]* U.S. Environmental Protection Agency, Office of Air, Noise, and Radiation, Office of Air Quality Planning and Standards, Research triangle Park, North Carolina, September. U.S. Environmental Protection Agency (EPA), 1978b. National Ambient Air Quality Standard for Lead. U.S. Environmental Protection Agency, Office of Air, Noise, and Radiation, Office of Air Quality Planning and Standards, Research triangle Park, North Carolina, September. Van Esch, G.J. and R. Kroes, 1969. "the induction of renal tumours by feeding basic lead acetate to mice and hamsters." British Journal of Cancer 23:765-770. Van Each, G.J., H. van Gendern and H.H. Vink, 1962. "The induction . of renal tumours by feeding basic lead acetate to rats." British Journal of Cancer 16:289-297. Waldron, H.A. and D. Stofen, 1974. Sub-Clinical Lead Poisoning. Academic Press, New York. Wessel, M.A. and A. Dominski, 1977. "Our children's daily lead." American Scientist 65;294-298. Wetherili, G.W., M.B. Rabinowitz and J.D. Kopple, 1974. "Sources and metabolic pathways of lead in normal humans," Recent Advances in the Assessment of the Health Effects of Environmental Pollution. Volume 2. Proceedings of the International Symposium, Paris, June 24-28, pp. 847-860. Wong, C.S. and P. Berrang, 1976. "Contamination of tap water by lead pipe and solder." Bulletin of Environmental Contamination and Toxi cology 15(5): 530-534. " World Health Organization (WHO), 1977. Environmental Health Criteria 3--lead. World Health Organization, Geneva. Yamaguchi, S., S, Kaku, Y. Hirota, S. Matuo, H. Matsumotp and N. Shimojo, 1976. "An appraisal of the Changes in delta-aminolevulinic acid dehydrase activity for an assessment of health effects at several levels of environmental lead." Effects of Dose-Response Relationships of Tokic Metals. G.F, Nordberg (ed). Elsevier Scientific Publishing Company, New York. Yankel, A., l.H. von Lindern and S.D. Walter, 1977. "The Silver Valley study: the relationship between childhood blood lead levels and environmental exposure." Journal of the Air Pollution Control Association 27(8):763-767. ' ''f ' ' . ' " 148 DUP050033669 Zawirska, B. and K. Medras, 1968. "Tumors and disorders of porphyrin metabolism in rats with chronic experimental lead poisoning." Zentbl. Allg. Path. 111:1-12. Ziegler, E.E., B.B. Edwards, R.L. Jensen, K.R. Mahaffey and S.J. Fomon, 1978. "Absorption and retention of lead by infants." Pediatric Research 12(1);29-34. Zielhuis, R.L., 1975. "Dose-response relationships for inorganic lead: X. biochemical and haematological responses; XI, subjective and functional responses-^chronic sequelae no-response levels." International Archives of Occupational Health 35:1,19. Zollinger, H.U., 1953. "Durch chronische Bleivergiflung erzeugte Nierenadenome und-carcinome bei Ratten und ihre Beziehungen zu den entsprechenden Neubildunger des Menschen." Virchows Arch. Path. Anaf. 323:694-710. 149 DUP050033670