United St»tss
Environm* it.i Protection
Agaricy
&EPA Research and
Development
TECHNICAL SUPPORT DOCUMENT
ON lEW
FIRST DRAFT
ECAO-CIN-757
Jinuary, 1991
Prepared for
OFFICE Of SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CUE OR QUOTE
NOTICE
This document 1s a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on its technical accuracy and policy implications.
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DISCLAIMER
This report Is an Internal draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
The U.S. EPA 1s developing health-related guidance for lead that can be
applied to a wide range of different media (soil/dust, air, diet). This
report summarizes relevant Information on health effects of lead and on lead
exposure and presents a description of a proposed modeling approach for
deriving med1a-spec1f1c criteria that can be tailored to specific exposure
scenarios or cases. The rationale for using a modeling approach 1n place of
more traditional risk assessment strategies such as Reference Dose 1s
discussed. Much of the Information presented 1n this report Is taken from
recent and more comprehensive Agency reviews, Including the A1r Quality
Criteria Document (U.S. EPA, 1986a) and Review of the National Ambient Air
Quality Standards for Lead (U.S. EPA, 1989a). The first draft of this
report was prepared by Syracuse Research Corporation under Contract No.
68-C8-0004. The literature search Vs current as of March, 1990. This
Technical Support Document (TSD) describes an Uptake/B1ok1net1c model of
lead that provides a method to predict blood lead levels In populations
exposed to lead In air, diet, drinking water, Indoor dust, soil and paint,
thus making 1t possible to evaluate the effects of regulatory decisions
concerning each medium on blood lead levels and potential health effects.
This model represents generalization of a model developed by OAQPS
(Integration of Harley and Knelp's B1ok1net1c model with OAQPS uptake model)
that has been used to predict site-specific distribution of blood lead
levels In populations In the vicinity of lead point sources.
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EXECUTIVE SUMMARY
This technical support document presents the rationale for an uptake/
bloklnetlc modeling approach to developing health criteria for lead.
Because of the lack of empirical evidence for a threshold for many of the
noncancer effects of lead In Infants and young children, coupled with multi-
media exposure scenarios, meaningful oral and Inhalation reference doses
cannot be developed for lead. Blood lead levels, however, provide an
Important and useful Index of risk because most toxicity endpolnts asso-
ciated w'Hh exposure to lead can be correlated with blood lead levels. The
Uptake/Bloklnetlc Model described 1n this document, and described In greater
detail 1n U.S. EPA (1989a), provides a method for predicting blood lead
levels In populations exposed to lead 1n the air, diet, drinking water,
Indoor dust, soil and paint, thus making it possible to evaluate the effects
of regulatory decisions concerning each medium on blood lead levels and
potential health effects. This model was developed by the Office of Air
Quality Planning and Standards (OAQPS). The model Integrated with the
Industrial Source Complex Dispersion Model (U.S. EPA, 1986c) has been used
to predict site-specific distributions of blood lead levels 1n populations
In the vicinity of lead point sources.
Infants and young children are the most vulnerable populations exposed
to lead and are the focus of the U.S. EPA's risk assessment efforts. The
relatively high vulnerability of Infants and children results from a combi-
nation of several factors: 1) an apparent intrinsic sensitivity of develop-
ing organ systems to lead; 2) behavioral characteristics that Increase-
contact with lead from dust and soil (e.g., mouthing behavior and pica);
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3) various physiologic factors resulting 1n greater deposition of airborne
lead In the respiratory tract and greater absorption efficiency from the
gastrointestinal tract 1n children than In adults; and 4) transplacental
transfer of lead that establishes a lead burden 1n the fetus, thus
Increasing the risk associated with additional exposure during Infancy and
c h1ldhood.
A diverse set of undesirable effects has been correlated with blood lead
levels In Infants and children. Impaired or delayed mental and physical
development, Impaired heme biosynthesis and decreased serum vitamin D levels
are correlated with blood lead levels across a range extending below 10
ug/dl. Although considerable controversy remains regarding the bio-
logical significance of some of the effects attributed to low lead exposure
(e.g., blood lead levels below 10 yg/di), the weight of evidence 1s
convincing that 1n Infants and children, exposure-effect relationships
extend to blood lead levels of 10-15 yg/di and possibly lower.
The Uptake/B1ok1net1c Model provides a means for evaluating the relative
contribution of various media to establishing blood lead levels (U.S. EPA,
1989a). The Uptake/B1ok1net1c Model provides a useful and versatile method
for exploring the potential Impact of future regulatory decisions regarding
lead levels 1n air, diet and soil.
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TABLE OF CONTENTS
Pa£e
1. INTRODUCTION 1-1
1.1. RfD METHODOLOGY AND RATIONALE FOR RfD DEPARTURE 1-1
1.1.1. Absence of a Discernible Threshold for Health
Effects of Lead 1-2
1.1.2. Multimedia Exposure Scenarios 1-3
1.1.3. Blood Lead as the Primary Index of Exposure . . . 1-4
1.1.4. Predictive B1ok 1 net 1c Models for Lead 1-5
1.1.5. Multimedia Exposure Analysis 1-5
2. HEALTH EFFECTS SUMMARY 2-1
2.1. OVERVIEW 2-1
2.2. TOXICOKINETICS: ABSORPTION, DISTRIBUTION/BODY BURDEN,
METABOLISM AND EXCRETION 2-3
2.2.1. Absorption 2-3
2.2.2. Tissue Distribution of Lead 2-11
2.3. SYSTEMIC AND TARGET ORGAN TOXICITY 2-18
2.3.1. Neurobehavloral Toxicity 2-18
2.3.2. Effects of Lead on Heme Biosynthesis and
Erythropolesls 2-21
2.3.3. Effects of Lead on the Kidney 2-29
2.3.4. Effects of Lead on Blood Pressure 2-29
2.3.5. Effects of Lead on Serum Vitamin D Levels .... 2-34
2.4. DEVELOPMENTAL/REPRODUCTIVE TOXICITY AND GENOTOXICITY . . . 2-36
2.4.1. Mental Development In Infants and Children. . . . 2-36-
2.4.2. Growth Deficits 2-45 •
2.4.3. Effects on Fertility and Pregnancy Outcome. . . . 2-46'
2.4.4. Genotox1c1ty 2-46'
2.5. SUMMARY 2-47
3. EXPOSURE ASSESSMENT 3-1
3.1. BIOLOGICAL EFFECTS: ENVIRONMENTAL EXPOSURE . . i 3-1
3.2. MULTIMEDIA LEAD EXPOSURES AIR. SOIL. OUST, WATER,
PAINT 3-3
3.2.1. Lead In A1r 3-5
3.2.2. Lead In Soil 3-7
3.2.3. Lead 1n Dust 3-8
3.2.4. Lead In Diet 3-9
3.2.5. Lead In Water 3-9
3.2.6. Lead In Paint 3-10
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TABLE OF CONTENTS (cont.)
Page
3.3. MEOIA-SPECIFIC ESTIMATES FOR DIFFERENT LEVELS OF LEAD
UPTAKE ; 3-11
3.3.1. Uptake from Ambient Air . 3-11
3.3.2. Uptake from the Diet. . 3-14
3.3.3. Uptake from Dust and Soil 3-16
3.3.4. Uptake of Lead from Drinking Water 3-29
3.4. ENVIRONMENTAL EXPOSURE LEVELS ASSOCIATED WITH BLOOO
LEAD LEVELS. . .' 3-30
3.4.1. Blood Lead/A1r Lead Relationships 3-30
3.4.2. Blood Lead/Dust and Soil Lead Relationships . . . 3-31
3.4.3. Blood Lead/Diet and Drinking Water Lead
Relationships 3-32
3.5. SUMMARY 3-33
4. RISK CHARACTERIZATION 4-1
4.1. INTEGRATED LEAD UPTAKE/BI OK INETIC EXPOSURE MODEL 4-1
4.1.1. Estimates of Lead Uptake 4-2
4.1.2. Uptake of Lead from Ingested Paint 4-17
4.1.3. Uptake and Blood Lead Concentrations 4-18
4.2. CALCULATIONS OF PROJECTED MEAN BLOOD LEAD DISTRIBUTIONS:
LEAD UPTAKE LEVELS 4-23
4.3. SUMMARY 4-29
5. REFERENCES 5-1
v 11
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LIST OF TABLES
No. TH le Page
2-1 Estimates of Regional Deposition and Absorption of
Ambient Air Lead Particles 1n the Adult Respiratory Tract
(Found Near Point Sources) 2-7
2-2 Age Factor Adjustments for Calculating Deposition and
Absorption of Ambient Air Lead Particles (Found Near Point
Sources) In the Respiratory Tract of 2-Year-01d Children. . . 2-8
3-1 Typical Lead Concentrations 1n Various Exposure Media .... 3-6
3-2 Age-Spec 1f1c Estimates of Total Dietary Lead Intake
for 1990-1996 (yg/day). . . . ' 3-15
3-3 Dally Soil Ingestion (mg/day) Based on Aluminum, Silicon,
-Titanium and Ylttrlum Mass Balance 3-25
4-1 Lead Intake and Uptake In 2- to 3-Year-01d Children Exposed
to Lead In Air, Diet, Dust, Soil and DrInking Water 4-3
vlll
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LIST OF FIGURES
No. Title Page
2-1 Schematic Model of Lead Metabolism 1n 2-Year-01d Children,
with Compartmental Transfer Rate Constants 2-17
2-2 Child IQ as a Function of Blood Lead Level in Children
3-7 Years Old 2-20
2-3 British Ability Scales Combined Score (BASC, Means and
95% Confidence Intervals) as a Function of Blood Lead
Levels 1n Children 6-9 Years Old 2-22
2-4 Maximal Nerve Conduction Time as a Function of Blood Lead
Level in Children 5-9 Years 0W 2-23
2-5 Effects of Lead on Heme Biosynthesis 2-24
2-6 Blood ALA-D Activity as a Function of Blood Lead Level
1n 158 Adults 2-26
2-7 Problt Dose-Response Functions for Elevated Erythrocyte
Protoporphyrin as Function of Blood Lead Level In Children. . 2-27
2-8 Erythrocyte Pyrlmldlne 5'-Nucleotldase Activity (P5N Units)
as a Function of Blood Lead Level In 25 Children, 1-5 Years
Old 2-30
2-9 Comparison of Study Results from Four Larger-Scale
Epidemiology Studies of Lead-Blood Pressure Relationships
In Adult Men 2-32
2-10 Serum 1,25-01hydroxycholecalc1ferol (1,25-CC) Levels as a
Function of Blood Lead Levels 1n 50 Children, 2-3 Years Old . 2-35
2-11 Mental Development Index Score (Covarlate Adjusted, Mean
and SD) as a Function of Age for Children Grouped Into Three
Ranges of Cord Blood Lead Level; Low, <3 pg/dl; Medium,
6-7 vg/dl; High, 10-25 Pg/dl 2-38
2-12 Comparison of Results from Prospective and Cross-Sectional
Studies of Mental Development 2-44
2-13 Summary of Studies Relating Blood Lead Levels and Effects
on Various Toxicity Endpolnts In Infants and Children .... 2-49
3-1 Pathways of Lead from the Environment to Humans 3-4
3-2 Plot of Soil Lead Concentration vs. A1r Lead Concentration
Monitored In Various Locations 3-19
1x
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LIST OF FIGURES (cont.)
No. Title Page
4-1 s Total Lead Uptake In 2- to 3-Year-01d 'Children Exposed
to Various Levels of Soil Lead as Predicted by the Lead
Uptake Model 4-14
4-2 Effect of Varying the Absorption Coefficients for Lead
1n Diet and Water (Ag>w) on Total Lead Uptake 1n 2- to
3-Year-01d Children as Predicted by the Lead Uptake Model . . 4-15
4-3 Effect of Varying the Concentration of Lead 1n Drinking
Water on Total Lead Uptake 1n 2- to 3-Year-01d Children
as Predicted by the Lead Uptake Model 4-16
4-4 Summary of Relationships Between Dally Lead Uptake and
Blood Lead for Infants, Adults and 2- to 3-Year-01d
Children, Derived from the Hawley and Knelp (1985)
B1ok1net1c Model 4-20
4-5 Probability Distribution of Blood Lead Levels In 2- to
3-Year-Old Children Exposed as Predicted by the Lead
Uptake/B1ok1net1c Model 4-25
4-6 Mean Blood Lead Levels In 2- to 3-Year-01d Children vs.
Total Lead Uptake as Predicted by the Lead B1 ok 1 net 1c
Model 4-26
4-7 Comparison of Distribution of Measured Blood Levels 1n
Children 1-5 Years of Age, Living within 2.25 Miles of a
Lead Smelter with Levels Predicted from the Uptake/
B1ok1net1c Model 4-27
4-8 Comparison of Distribution of Measured Blood Lead Levels
In Children, 1-5 Years of Age, Living within 2.25 Miles of
a Lead Smelter with Levels Predicted from the Uptake/
B1 ok 1 net 1 c Model 4-28
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LIST OF ABBREVIATIONS
ALA-D
4-am1nolevul1n1c acid dehydratase
ALA-S
j-amlnolevul1n1c acid synthetase
bw
body weight
DNA
Deoxyribonucleic acid
EP
Erythroblast protoporphyrin
GCI
General Cognitive Index
G-R
Graham-Rosenbleth Behavioral Examinations for Newborns
GSD
Geometric standard deviation
KID
Kent Infant development scale
LOAEL
Lowest-observed-adverse-effect level
MDI
Mental development Index
MMAD
Mass median aerodynamic diameter
NBAS
Neonatal behavioral assessment scale
NOAEL
No-observed-adverse-effeet level
OAQPS
Office of Air Quality Planning and Standards
POI
Psychomotor development Index
P5N
Pyr1m1d1ne-51-nucleotidase
RfD
Reference dose
S.E.
Standard error
WPPSI
Wechsler preschool and primary scale of Intelligence
x1
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1. INTRODUCTION
1.1. RfD METHODOLOGY AND RATIONALE FOR RfD DEPARTURE
The Agency has established the RfD for the purpose of quantitative risk
assessment of noncarclnogenlc chemicals. The RfD 1s an estimate (with
uncertainty spanning perhaps an order of magnitude) of the dally exposure to
the human population (Including sensitive subgroups) that 1s likely to be
without appreciable risk of deleterious effects during a lifetime (U.S. EPA,
1987, 1988a). In developing an RfD for a specific chemical, the best avail-
able scientific data on the health effects of the chemical are reviewed to
Identify the highest levels of exposure that are clearly not associated with
adverse health effects 1n humans. Typically, the highest NOAEL Is adjusted
by an uncertainty factor to derive the RfD. The uncertainty factor reflects
the degree of uncertainty associated with extrapolating the NOAEL Identified
from analysis of relevant human toxlcologlcal studies to the most sensitive
fraction of the "healthy" human population.
When human toxlcologlcal data are Inadequate to base conclusions regard-
ing human NOAELs, NOAELs or LOAELs for the most sensitive animal species, as
defined by well-designed animal studies, are used to derive the RfD. Doses
or exposure levels are adjusted by conversion factors to account for allo-
metrlc (e.g., body weight) and physiologic (e.g., breathing rates) differ-
ences between animals and humans. The adjusted NOAELs or LOAELs are then
adjusted by an uncertainty factor to derive the RfD. Uncertainty factors
for NOAELs derived from animal studies are larger than that for human
NOAELs, reflecting the greater uncertainty associated with extrapolating
dose-effect relationships from animals to humans. Consideration 1s given to
uncertainties associated with extrapolations made from less-than-1Ifetlme
exposures to lifetime exposures, from LOAELs to NOAELs and for differences
1n sensitivity between animals and humans.
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The RfD approach has yielded useful quantitative estimates of toxic
threshold for many chemicals, and thus, has been used as a "benchmark" on
which to consider regulatory decisions In relation to potential Impacts on
human health; however, for reasons that are enumerated below 1t Is Inappro-
priate to derive an RfD for risk assessments related to environmental lead.
1.1.1. Absence of a Discernible Threshold for Health Effects of Lead. A
critical assumption Implicit to the RfD Is the concept of threshold (I.e., a
dose level exists below which adverse -health effects will not occur). This
assumption precludes developing RfDs based on effects for which thresholds
have not been established from experimental or epidemiological data or for
chemicals for which theoretical considerations suggest the absence of a
threshold. Carcinogens fall Into the latter category; for example, theoret-
ical considerations suggest a finite probability that cancer could arise
from the Interactions of a single molecule of a mutagen with DNA (U.S. EPA,
1986a).
Unlike the case for carcinogens, there is no widely accepted theoretical
basis for the absence of a threshold for many of the health effects asso-
ciated with lead exposure. However, analyses of correlations between blood
lead levels and ALA-D activity, vitamin D and pyrlmldlne metabolism, neuro-
behavloral Indices, growth and blood pressure indicate that associations may
persist through the lowest blood lead levels In the populations tested
(<10-15 yg/dl). Thus, 1t 1s possible that 1f a threshold for the toxic
effects of lead exists, It may lie witnin a range of blood lead levels
<10-15 however, the data currently available are not sufficient
to adequately define the dose-response relationship for many of the toxic
effects of lead In populations having blood lead levels <10 pg/dl.
Hence, 1t Is not possible to confidently identify a blood lead level below
which no undesirable health effects would occur.
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The range 10-15 vig/dl for blood lead levels represents a "level of
concern." A level of concern 1s not the same as a threshold. In this case,
a level of concern represents a blood lead level associated with health,
effects that warrant attention from a medical or governmental regulatory
standpoint, and does not Imply that a biological or toxlcologlcal effect may
not occur at lower levels of exposure (Davis, 1990).
1.1.2. Multimedia Exposure Scenarios. Humans are exposed to lead from a
variety of media; the relative contribution of each medium to total lead
uptake changes with age and can vary 1n magnitude on a site-specific basis.
Infants are born with a lead burden that primarily reflects the mother's
past exposure and metabolic status during pregnancy. Infants and children
are exposed to lead primarily from Ingestion of food and beverages and from
Ingestion of nonfood sources by normal early mouthing behavior and pica.
The Impact of normal early mouthing behavior and pica will vary depending on
the levels of lead 1n house dust, soil and paint, which In many but not all
cases will be primarily related to historical air lead levels In the
vicinity; Examples of exposure scenarios In which levels In soil and dust
might not be related to historical air lead are situations Involving
contamination of soil and dust with leaded paint dusts or mine wastes. Most
adults are exposed primarily from dietary (food and water) sources. Occupa-
tional exposures also may result in a significant contribution from the
Inhalation, dermal or Ingestion route.
A viable risk assessment methodology for lead that 1s to be of any use
1n making regulatory decisions or for developing site-specific abatement
strategies must be flexible enough to incorporate site-specific Information
on exposure sources and demographic data In terms of predicted population
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distributions of blood lead levels, an Ideal methodology would Incorporate
such Information or would accept default values where data are not available
and yield quantitative estimates of risk.
RfD methodologies do not accommodate such considerations because they
are basically route-specific risk assessments. For example, an Inhalation
RfD Is an estimate of the air concentration to which the most sensitive
human populations can be exposed for a lifetime without appreciable risks of
adverse effects and in the absence of exposures from other sources (e.g.,
the oral route). The latter assumption renders the Inhalation RfD for lead
relatively Insignificant since Inhaled lead contributes only a fraction of
total lead uptake.
1.1.3. Blood Lead as the Primary Index of Exposure. The complex nature
of lead exposure has not prevented advances 1n our understanding of dose-
response relationships for lead In humans because many of the health effects
of lead 1n humans are correlated with blood lead levels. Thus, blood lead
(yg/dl) Is a more appropriate benchmark for exposure than a level In air
(mg/m3) or an oral exposure level (mg/kg/day).
Although 1t Is unclear 1f health thresholds exist for many lead exposure
scenarios, significant concern 1s associated with blood lead levels. By
estimating changes 1n blood lead level, one may estimate change In risk of
experiencing health effects associated with the blood lead level. By
examining changes In blood lead distribution, estimates of population risk
may be derived. It is possible to define critical ranges of blood lead
levels and associated effects. In this way, blood lead levels can be used
to define risk 1n a relative sense.
The nature of the effects associated with low level lead exposure are
such that a scientific consensus regarding biological significance of many
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of the effects, such as neurobehavlora1 deficits associated with prenatal
exposure, needs further validation. Therefore, 1t 1s not anticipated that
critical ranges of blood lead as currently defined will have universal
acceptance. Nor Is 1t reasonable that such definitions should be univer-
sally applied to all exposure situations for. risk assessment purposes. A
given range of blood lead levels 1s likely to be associated with a given
level of risk depending on other factors affecting the exposed population.
For example, a given blood lead level may be undesirable 1n Infants but of
less significance to adults.
A useful risk assessment methodology for lead should provide a popula-
tion distribution of blood lead levels and risk. The risk assessor can then
evaluate the risks associated with such distributions and the potential
benefits of prevention and abatement strategies given the definitions of
critical blood lead levels for specific effects of lead, as well as the
demographics and exposure sources for the population.
1.1.4. Predictive B1ok 1 net 1c Models for Lead. It 1s currently feasible
to utilize b1 ok 1ne11c models to provide predictions of blood lead levels
that will result from any given range of route-Independent lead uptake rates
and vice versa (U.S. EPA, 1989a). These models allow benchmark blood lead
levels to be related quantitatively to route-Independent uptake rates and
can provide estimates of frequency distributions of blood lead levels
associated with any given uptake rate.
1.1.5. Multimedia Exposure Analysis. S11e-spec 1f1c data or Internation-
ally consistent default assumptions regarding exposure scenarios and absorp-
tion efficiency for lead Intake from various media have been Incorporated
Into existing multimedia exposure analysis methods to yield estimates of the
relative contributions of air, dietary and soil lead to any given estimated
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lead uptake (U.S. EPA, 1989a). Output from a multimedia analysis could be
used to explore the possible outcomes of regulatory decisions and abatement
strategies on the distribution of blood lea'd levels 1n relevant human
populations. For example, a risk assessor could use these predictive models
to estimate the effects of having soil lead at a specific exposure site on
blood lead levels In 2-year-old children living In the vicinity of the site.
This would be a far more useful risk management tool than a route-specific
RfD.
In summary, the RfD approach 1s Inappropriate for lead based on our
current understanding of the dose-response relationship for the various
effects of lead and multimedia nature of lead exposure. Multimedia exposure
analysis coupled with predictive bloklnetlc models, however, provide a
powerful tool for developing an alternative and more useful alternative risk
assessment strategy for lead.
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2. HEALTH EFFECTS SUMMARY
2.1. OVERVIEW
A significant amount of Information regarding the toxicity of lead In
humans has been gathered over the past 60 years. The symptoms of overt
toxicity have been described and, for the most part, levels of lead In blood
associated with frank toxicity have been established. There 1s little or no
argument that excessive exposure resulting In blood lead levels extending
upwards from 30-100 pg/dl 1s associated with a variety of overtly toxic
effects on the peripheral and central nervous systems, kidneys and cardio-
vascular system.
In the most recent decade a shift has been seen 1n the emphasis of
research objectives from a focus on overt toxicity to exploration of the
more subtle physiologic, biochemical and neurobehavloral effects that may be
associated with blood lead levels <30 yg/dl -- levels that can be
anticipated to occur 1n a significant fraction of the general population.
In particular, several factors have stimulated a renewed Interest 1n
exploring exposure-effect relationships In Infants and children. These
Include 1) an appreciation that potentially significant lead burdens can be
established In the fetus J[n utero; 2) that specific behavioral patterns of
Infants (12 weeks to 1 year) and children (1-5 years) facilitate Intake of
environmental lead; and 3) evidence that Infants and children may be more
sensitive and thus more vulnerable to some of the toxic effects associated
with lead.
Research efforts during the last several years have greatly Improved our
understanding of the effects of low-level lead exposure. The advent of
prospective epidemiological study designs that Incorporate sensitive and
reproducible measures of physical and mental development have been a
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particularly Important advancement 1n this area. While considerable
concerns remain regarding the biological significance of some of the effects
attributed to low lead exposure, the weight of evidence 1s convincing that
In Infants and children, exposure-effect relationships extend to blood lead
levels of 10-15 yg/dl and possibly lower. Evaluations of the most
recent data on blood pressure In adults suggest that exposure to lead may
Increase blood pressure. When viewed In relation to the number of children
potentially exposed to environmental lead levels associated with blood lead
levels of 10-15 ug/dl, even small Increases In blood pressure are of
considerable public health significance.
The review that follows summarizes key Issues relating to the toxico-
kinetics and health effects of lead 1n humans that will have to be consid-
ered In developing a responsible regulatory policy for lead. This review 1s
not Intended to be comprehensive but rather an overview of the various
critical aspects of lead toxicity In humans, with more extensive discussions
of recent Information regarding effects associated with low levels (e.g.,
blood lead levels <10-15 pg/di). Issues relating to the toxicokinetics
of lead that are relevant to the validity of predictive models are also dis-
cussed. Discussions of overt toxicity have been abbreviated Intentionally,
and no attempt has been made to summarize the voluminous literature on
laboratory animals.
An enormous amount of scientific literature regarding the health effects
of lead In humans and animals has been published. Much of this Information
Is contained In the Air Quality Criteria Document on Lead (U.S. EPA, 1986b),
In subsequent addenda and related U.S. EPA documents (U.S. EPA, 1988a,b;
ATSDR/U.S. EPA, ,1988) and In the recent ATSDR report to the U.S. Congress
(ATSDR, 1988). The reader Is referred to these documents for a more compre-
hensive treatment of the subjects and literature contained 1n this chapter.
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2.2. TOXICOKINETICS: ABSORPTION, DISTRIBUTION/BODY BURDEN, METABOLISM AND
EXCRETION
Anthropogenic lead emissions to a 1 r consist primarily of lead In the
Inorganic form; therefore, the primary focus of this chapter Is on the
toxicokinetics of Inorganic lead. Organic lead compounds, notably
tetraethyl, tetramethyl, tr1 ethyl and trlmethyl lead, are also released Into
the a 1 r during the combustion of leaded gasoline. Lead alkyl compounds will
generally be a minor component of lead released to a 1 r, but the toxlco-
loglcal significance can be appreciable under certain circumstances (e.g.,
children who "sniff1" leaded gasoline). For this reason, the toxicokinetics
of lead alkyls 1s also discussed In this chapter; emphasis, however, Is
placed on Identifying Important differences between the toxicokinetics of
Inorganic lead and lead alkyls.
2.2.1. Absorption. Absorption of Ingested lead Is quantitatively the
most significant route of uptake of Inorganic lead 1n most human popula-
tions; the exception 1s occupational exposures 1n which Inhalation of
airborne lead results In significant uptake. Gastrointestinal absorption
can result from Ingestion of food, water and beverages as well as nonfood
sources, such as soil and dust. Percutaneous absorption Is not considered a
significant route of absorption of Inorganic lead. The rate and extent of
absorption of Inorganic lead Is Influenced by the physical and chemical
properties of environmental lead. Factors such as particle size and
solubility determine deposition patterns and dissolution rates within the
entry portals of the body, and may vary with specific exposure scenarios.
Biological variation related to age and nutritional status will also
Influence absorption.
Alkyl lead compounds (e.g., trlethyl, trlmethyl, tetraethyl and tetra-
methyl lead) are more highly lipophilic than inorganic lead and are readily
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absorbed from the lung and skin. Extensive absorption from the gastrointes-
tinal tract Is predicted based on structural similarities between alkyl
leads and alkyl tins.
2.2.1.1. ABSORPTION FROM THE RESPIRATORY TRACT -- Inorganic lead In
ambient a 1r consists primarily of particulate aerosols, having a size dis-
tribution that 1s related to the characteristics and proximity to emission
sources. Lead particles 1n most urban and rural a 1 r are 1n the submlcron
range. Particle sizes In the vicinity of point sources can vary consider-
ably with distance from the source and meteorological patterns (Davidson and
Osborne, 1984; Sledge, 1987). Particles >10 um make up a substantial
proportion of the air lead near point sources. The number of Inhaled lead
particles of a given size range will vary with ambient air concentration and
breathing rates, which vary with age and physical activity.
The entry of Inhaled lead Into the systemic circulation Involves the
processes of deposition and absorption. Amounts and patterns of deposition
of particulate aerosols In the respiratory tract are affected by the size of
the Inhaled particles, age-related factors that determine breathing patterns
(e.g., nose breathing vs. mouth breathing), airway geometry and alrstream
velocity within the respiratory tract. In general, large particles (>2.5
pm) deposit 1n the nasopharyngeal regions of the human respiratory tract
where high alrstream velocities and airway geometry facilitate Inertlal
Impaction (Chamberlain et al., 1978; Chan and Uppmann, 1980). In the
tracheobronchial and alveolar regions, where alrstream velocities are lower,
processes such as sedimentation and interception become important for
deposition of smaller particles (<2.5 um). Diffusion and electrostatic
precipitation become Important for submlcron particles reaching the alveolar
region. Mouth breathing can be expected to Increase aerosol deposition In
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the tracheobronchial and alveolar regions because air Inhaled through the
mouth bypasses the nasal region where Inertlal Impaction and mucociliary
Interception occur (Miller et al.f 1986).
Absorption of lead from the respiratory tract 1s Influenced by particle
size and solubility as well as the pattern of regional deposition.
Particles >2.5 ym In size that- are deposited primarily In the ciliated
airways of the nasopharyngeal and tracheobronchial regions of the respira-
tory tract can be transferred by mucociliary transport Into the esophagus
and swallowed; only a fraction of what 1s swallowed Is absorbed In the
gastrointestinal tract. Sneezing and coughing will clear a fraction of this
lead from the nasopharyngeal region. Therefore, absorption of lead
initially deposited In the upper respiratory tract will not be complete.
Estimates for fractional absorption of large particles (>2.5 ym) deposited
1n the upper respiratory tract range from 40-50% (Kehoe, 1961a,b,c;
Chamberlain and Heard, 1981).
Particles deposited 1n the alveolar region can enter the systemic
circulation after dissolution In the respiratory tract or after Ingestion by
phagocytic cells (e.g., macrophages). Available evidence Indicates that
lead particles deposited 1n the alveolar region of the respiratory tract are
absorbed completely. Human autopsy results have shown that lead does not
accumulate 1n the lung after repeated Inhalation. This suggests complete
absorption from the alveolar region (Barry, 1975; Gross et al., 1975).
Chamberlain et al. (1978) exposed adult human subjects to aosPb In engine
exhaust, lead oxide or lead nitrate (<1 ym particle size) and observed
that 90% of the deposited lead was cleared from the lung within 14 days.
Morrow et al. (1980) reported 50% absorption of deposited lead Inhaled as
lead chloride or lead hydroxide (0.25*0.01 yg MMAD) within 14 hours. An
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analysis of the :ad1o1sotope dilution studies of Rablnowltz et al. (1977) In
which adult human subjects were exposed dally to ambient a 1r lead Indicated
that -90% of the deposited lead was absorbed dally (U.S. EPA, 1986b).
Quantitative analyses of the relationship between aerosol particle size
and deposition In the human respiratory tract have been combined with
Information on size distributions of ambient a 1 r lead aerosols to estimate
deposition and absorption efficiencies for Inhaled lead 1n adults and
children (U.S EPA, 1986b; Cohen, 198/). An example of estimates of average
deposition and absorption for adults living In the vicinity of a stationary
Industrial source are provided In Table 2-1. Summing the fractional
absorption values for each region of lung yields an estimate of 38% for the
fractional absorption of Inhaled lead 1n adults living In the vicinity of an
Industrial source. For some urban and rural atmospheres, where submlcron
particles dominate the airborne lead mass, the estimated fractional absorp-
tion 1s 15-30% (Cohen, 1987).
Breathing patterns, airflow velocity and airway geometry change with
age, giving rise to age-related differences 1n particle deposition
(Barltrop, 1972; James, 1978; Phalen et al.P 1985). Depositions 1n various
regions of the respiratory tract 1n children may be higher or lower than 1n
adults, depending on particle size (Xu and Yu, 1986). For submlcron
particles, fractional deposition 1n 2-year-old children has been estimated
as -1.5 times higher than that 1n adults (Xu and Yu, 1986). Estimates of
regional and total fractional absorption in children can be calculated by
making age-specific adjustments in regional fractional absorption for adults
(Table 2-1). Adjustment factors for 2-year-old children, derived from the
analysis of Xu and Yu (1986), are shown in Table 2-2. Summing the regional
values yields an estimate of 42% for fractional absorption of Inhaled lead
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TABLE 2-1
Estimates of Regional Deposition and Absorption of Ambient Air Lead Particles 1n the Adult
Respiratory Tract (Found Near Point Sources)3
Average Absorption
Particle % Ambient Lead Average Deposition Efficiency of X Absorption of
Size Range Distribution Efficiency Deposited Lead Inhaled Lead
(11) Near Point Sources
ALVb T-Bc N-Pd ALV T-B N-P ALVe T-B N-P
<1.0 12.5 0.15 0.05
1-2.5 12.5 0.25 0.10
2.5-15 ?0 0.20 0.25
15 30 <0 ID 0.05
>30 15 10 ID
0.003 1 0.4 0.4 1.9 0.25 0.015
0.20 1 0.4 0.4 3.1 0.5 1.0
0.40 1 0.4 0.4 4.0 2.0 3.2
0.95 1 0.4 0.4 NC 0.8 15.2
0.95 1 0.4 0.4 NC NC 5.7
''Source: Cohen, 1987
bAl veolar
tracheobronchial
^Nasopharyngeal
eFor <1.0 jim In alveolar region: 12.5 x 0.15 x 1 = 1.9X
ID = Insufficient deposition; NC = not calculated
-------
TABLE 2-2
Age Factor Adjustments for Calculating Deposition and Absorption
of Ambient Air Lead Particles (Foundj Near Point Sources)
1n the Respiratory Tract of 2-Year-01d Children3
Age Factor Adjustment
X Absorption of
Particle
Deposition Efficiency
Inhaled Leadb
Size Range
ALVC T-8d N-Pe
(um)
ALVf T-B N-P
<1.0
1.5
1.5
1.5
2.9
0.4
0.02
1-2.5
1.3
1.7
1.5
4.0
0.9
1.5
2.5-15
0.5
1.4
2.0
2.0
2.8
6.4
15-30
ID
0.5
1 .0
NC
0.4
15.2
>30
ID
ID
1.0
NC
NC
5.7
aSource: Xu and Yu, 1986
^Summing the regional values yields an estimate of 42% for fractional
absorption of Inhaled lead.
CA1veolar
"^Tracheobronchial
Nasopharyngeal
^For <1.0 pm 1n alveolar region: 1.9X (from Table 5-1) x 1.5 = 2.9*
ID = Insignificant deposition; NC = not calculated
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In 2-year-old children living near a stationary Industrial source. For
general atmospheres In which submlcron particles dominate the lead mass
distribution, an adjustment factor of 1.5 can be applied to the estimated
range of 15-30% for adults (Cohen, 1987).
Alkyl lead can occur 1n the atmosphere as a vapor or associated with
atmospheric particulates (Harrison and Laxen, 1978). The retention and
absorption of gaseous tetraethyl and tetramethyl lead has been examined 1n
volunteers who Inhaled 203Pb-labeled tetraalkyl lead (Heard et al., 1979).
Initial lung retention was 37 and 51% for tetraethyl and tetramethyl lead,
respectively. Of these amounts, 40% of tetraethyl lead and 20% of tetra-
methyl lead was exhaled within 48 hours; the remaining fraction (tetraethyl,
60%; tetramethyl, 80%) was absorbed. Respiratory absorption of particulate
alkyl lead has not been studied.
2.2.1.2. GASTROINTESTINAL ABSORPTION — The gastrointestinal tract 1s
the primary site of absorption of lead In children and most adult popula-
tions, with the exception of those subject to occupational exposure (U.S.
EPA, 1986b). Sources of Input to the gastrointestinal tract Include lead
Ingested In food and beverages and lead Ingested In nonfood material such as
dust, soil and lead-based paint. Nonfood materials are particularly Impor-
tant sources of lead Intake In children because of normal mouthing behavior
and pica. Inhaled lead that 1s deposited In the upper respiratory tract and
subsequently swallowed also contributes to gastrointestinal Input (U.S. EPA,
1986b, 1989a).
Gastrointestinal absorption of lead varies with age, diet and nutri-
tional status as well as the chemical species and particle size of the
Ingested lead. Dietary balance studies have yielded estimates ranging from
7-15% for gastrointestinal absorption In adults (Kehoe, 1961a,b,c;
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Chamberlain et al., 1978; RablnoiOtz et al., 1980). Absorption may be 3-5
times greater 1f oral Intake occurs during a p;er1od of fasting (Blake, 1976;
Chamberlain et al., 1978; Heard and Chamberlain, 1982).
Gastrointestinal absorption of dietary lead 1s greater in Infants and
children than In adults. A balance study In Infants of ages 2 weeks to 2
years yielded estimates of 42% for children with dietary Intakes of >5 ug
Pb/kg bw. Lower dietary Intakes were associated with highly variable
absorption (Zlegler et al., 1978). A study conducted with Infants and chil-
dren of ages 2 months to 8 years (dally Intake, 10 yg Pb/kg bw) yielded
estimates of 53% for gastrointestinal absorption (Alexander et al., 1973).
Gastrointestinal absorption of lead 1s affected by a variety of dietary
and nutritional factors. The results of numerous studies of the effects of
diet on lead absorption and retention 1n humans and animals are summarized
In the A1r Quality Criteria Document for Lead (U.S. EPA, 1986b). Based on
the results of these studies, 1t can be predicted that Increased gastro-
intestinal absorption of lead may occur 1n populations consuming diets low
or deficient 1n calcium. Iron, phosphate, copper, vitamin D, protein or
fiber, or diets having a high lipid content. This suggests that Individuals
with poor nutritional status may absorb more lead from environmental sources.
Gastrointestinal absorption of lead alkyls Is not likely to be an
Important route of uptake of environmental lead because of the relatively
high volatility of lead alkyls. The exception would be 1n situations where
people are Ingesting groundwater contaminated with tetraethyl lead. The
acidic environment of the stomach will promote the conversion of tetraethyl
and tetramethyl lead to the corresponding trlalkyl derivatives (U.S. EPA,
1986b). Although the absorption of trlalkyl leads has not been studied,
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extensive absorption 1s predicted based on Information regarding the gastro-
intestinal absorption of the structurally similar Group IV analogs, tr1 ethyl
and trlmethyl tins (Barnes and Stoner, 1958).
2.2.1.3. PERCUTANEOUS ABSORPTION — Inorganic lead 1s not readily
absorbed through the skin. Values of 0-0.3% of administered dose were
reported for humans exposed to dermal applications of cosmetic preparations
containing lead acetate. The highest absorption was observed when the skin
was scratched (Moore et al.t 1980). Thus, percutaneous absorption 1s not
considered to be a significant route of uptake of Inorganic lead In humans,
relative- to gastrointestinal and respiratory tract absorption. This
contrasts with lead alkyls that are absorbed through the skin to a greater
extent than Inorganic lead.
Tetraethyl and tetramethyl lead are rapidly absorbed through the skin In
rabbits and rats (Kehoe and Thamann, 1931; Laug and Kunze, 1948). Evapora-
tion can be expected to compete with absorption for removal from skin;
however, even under conditions In which evaporation was allowed to occur,
percutaneous absorption of tetraethyl lead was 6.5% (Laug and Kunze, 1948).
2.2.2. Tissue Distribution of Lead. Mineralized tissues (e.g., bone and
teeth) are the single largest pool for absorbed lead, accounting for -95% of
total lead burden In adults and slightly less In children (Barry, 1975,
1981). Lead not contained In mineralized tissue 1s distributed In soft
tissues, primarily blood, liver and kidneys. Small amounts accumulated In
other soft tissues such as brain, although not quantitatively significant to
the overall distribution of the body burden, are of considerable toxlcologl-
cal Importance. Lead readily transfers across the placenta and distributes
to fetal tissues (Hor1uch1 et al., 1959; Barltrop, 1959; Lauwerys et al.,
1978; Kovar et al., 1984; Tsuchlya et al., 1984; Korpela et al., 1986).
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Elimination half-times for lead 1n soft tissues are relatively short
(weeks). Estimates of elimination half-times for lead 1n blood 1n adults
range from 15-35 days (Chamberlain et al., 1975, 1978; Rab1now1tz et al.,
1973, 1976). Studies of adult and Juvenile baboons Indicate that elimina-
tion half-times for kidney and liver, and probably other soft tissues, are
similar to that for blood (Harley and Knelp, 1985). Because of the rela-
tively short half-Hfe, accumulation In soft tissue does not continue over
the lifetime exposure (Schroeder and Tipton, 1968; Barry and Mossman, 1970;
Barry, 1975, 1981). The exceptions are the kidney cortex, 1n which lead
accumulates In nuclear Inclusion bodies (Indraprasit et al., 1974). Abrupt
Increases 1n blood lead levels can be expected to result In new higher
steady-state levels In blood and other soft tissues within 60-120 days (Tola
et al., 1973; Griffin et al., 1975); however, following a decrease 1n
uptake, lead 1n bone and other tissue stores slowly redistributes to blood.
Thus, more time may be required lo achieve a new steady-state blood level
after uptake decreases, depending on the level and duration of prior
exposure (Rab1now1tz et al., 1977; O'Flaherty et al., 1982; Gross, 1981).
Elimination half-times 1n children and adults for mineralized tissue,
such as bone, are considerably longer than for soft tissues (years). As a
result, a decade or more of constant exposure 1s required to achieve a
steady state In bone (Rablnowltz et al., 1976; Holtzman, 1978). Bone lead
can provide a store for continuous release of lead to soft tissues 1n the
event that uptake decreases (O'Flaherty et al., 1982). Metabolic stress
resulting 1n Increased bone turnover or demlneral1zat1on, such as that which
normally occurs during pregnancy or aging, may accelerate release of lead
from bone (Manton, 1985; Orasch et al., 1987; Zarlc et al., 1987; Sllbergeld
et al., 1988). Therefore, the potential exists for a portion of the bone
lead burden of the parent to be transferred to the fetus during pregnancy.
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Limited studies on the subcellular distribution of lead 1n humans and
more extensive studies In animals have shown that lead accumulates 1n the
nucleus and mitochondria (Goyer et al., 1970; Cramer et a 1., 1974; Flood et
al., 1988). Approximately 15% of lead 1n erythrocytes 1s bound to hemo-
globin and other Intracellular proteins; most of the remaining 25% Is
thought to be associated with low molecular weight llgands such as amino
acids and nonprotein thiols (Bruenger et al., 1973; Raghaven and Gonlck,
1977; Everson and Patterson, 1980; Ong- and Lee, 1980; DeSllva, 1981). Fetal
hemoglobin has a greater affinity for lead than adult hemoglobin (Ong and
Lee, 1980). The fraction of blood lead In serum Increases with Increasing
blood lead levels >40-50 pg/di, and may approach 2% of whole blood lead
at blood lead levels >100 pg/di (Manton and Cook, 1984).
Tissue distribution of lead after exposure to tetraethyl or tetramethyl
lead primarily reflects the distribution of the dealkylatlon products,
trlalkyl, dlalkyl and Inorganic lead (Cremer, 1959; Cremer and Calloway,
1961; Stevens et al., 1960). In blood, partitioning of lead between the
plasma and erythrocyte fractions varies with animal species and metabolism.
Tr1 ethyl and trlmethyl lead bind tightly to rat hemoglobin and concentrates
1n erythrocytes 1n this species. Human erythrocytes have a relatively low
affinity for trlethy1 and trlmethyl lead (By 1ngton et al., 1980). After
exposure to tetraalkyl leads, trlalkyl leads are found 1n the plasma (Boeckx
et al., 1977; Goldlngs and Stewart. 1902). After humans Inhale ao3Pb-
labeled tetraethyl and tetramethyl lead, lead distributes In whole blood
primarily 1n the plasma fraction (Heard «t al.. 1979). Clearance from whole
blood 1s nearly complete within 10 hours dnd 1s followed by the reappearance "
of lead In erythrocytes. The shift in distribution of lead from the plasma
to the erythrocyte fraction of whole blood may reflect dealkylatlon 1n
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tissues and the appearance of dlalkyl or Inorganic lead In the blood, vhlch
has a higher affinity for erythrocytes than do tetraalkyl and trlalkyl leads.
Lead distributes to a variety of tissues after exposure to lead alkyls.
Levels of lead are highest 1n liver followed by kidney and brain 1n humans
that have been exposed to tetraethyl and tetramethyl lead (Bolanowska et
al., 1967; Grandjean and Nielsen, 1979). The kinetics of elimination of
tr1 ethyl lead in humans has been described by a two-compartment model having
half-Hves of 35 and 100 days (Yamamura_et al., 1975 ).
2.2.2.1. METABOLISM OF LEAD — Metabolism of Inorganic lead consists
primarily of reversible Ugand reactions Including the formation of
complexes with amino acids and nonprotein thiols and binding to various
cellular proteins (Bruenger et al., 1973; Raghaven and Gonlck, 1977; Everson
and Patterson, 1980; Ong and Lee, 1980; DeSllva, 1981).
Tetraethyl and tetramethyl lead undergo oxidative dealkylatlon to the
corresponding trlalkyl derivatives, which are thought to be the neurotoxic
forms of these compounds. Dealkylatlon of tetraalkyl lead occurs In a
variety of species. Including humans (U.S. EPA, 1986b). The conversion from
tetraalkyl to trlalkyl lead Is catalyzed by a cytochrome P-450 dependent
monooxygenase system In liver microsomes (Klmmel et al., 1977) and occurs
rapidly. The maximum rate of conversion of tetraethyl lead to tr1ethy1 lead
was estimated to be 200 yg/hour/g liver In rats (Cremer, 1959). Complete
dealkylatlon to Inorganic lead has been shown to occur 1n a variety of
species, Including humans. The formation of Inorganic lead from tetraalkyl
leads may account for the hematological effects associated with chronic
exposure to alkyl leads, Including exposure of children who Inhale leaded
gasolIne.
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2.2.2.2. EXCRETION OF LEAD — Lead that 1s absorbed from all routes
Is excreted In the feces by biliary secretion, and 1n the urine, 1n -1:2
proportions (Chamberlain et a 1., 1978). Approximately 50-6054 of absorbed
lead 1s excreted with a half-time of 30-50 days. The remaining fraction 1s
distributed to tissues, primarily bone, and Is excreted with a half-time of
several years (Kehoe, 1961a,b,c; Rablnowltz et a 1 ., 1976; Chamberlain et
al.. 1978).
Lead 1s excreted primarily 1n the urine as dealkylated products after
exposure to lead alkyls. The chemical form that appears 1n urine may vary
with animal species. In humans exposed to tetraethyl lead, -10% of urinary
lead Is In the form of tr1 ethyl lead (U.S. EPA, 1986b).
2.2.2.3. BI0KINETIC MODELS — Several mathematical models have been
developed to describe uptake, distribution and excretion of lead (Rablnowltz
et al., 1976; Knelp et al., 1983; Marcus, 1985a,b,c). These models are
Important for risk assessment because they provide a basis for making
predictions about levels of lead In various physiological compartments that
would be associated with a given rate of uptake or exposure level. The
various models that have been suggested differ 1n complexity with respect to
the number of physiological compartments described, and assumptions
regarding kinetics of exchange between compartments.
The model proposed by Rablnowltz et al. (1976) was based on the results
of radioisotope tracer studies using volunteers. The model specified three
physiological compartments for lead distribution: blood, soft tissue (other
than blood) and bone.
The model proposed by Knelp et al. (1983) was based on kinetic constants -
derived from single Injection studies and chronic oral exposures In adult
and juvenile baboons (Knelp et al., 1983). The model was subsequently
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modified to Incorporate age-related changes In metabolism and physiology *ip
humans (Harley and Knelp, 1985). Figure 2!-l Illustrates the model for
2-year-old children. Three major tissue compartments that exchange with the
blood compartment are defined 1n the model: bone, liver, kidney and gastro-
intestinal tract. First-order rate constants for exchanges between blood
and tissues are defined along with rate constants for transfers of lead from
liver to the gastrointestinal tract (e.g., biliary secretion) and from blood
Into the urine.
Marcus (1985a,b,c) proposed a more elaborate model based on measurements
obtained ' from a volunteer subject who Ingested lead (DeSUva, 1981). In
addition to soft and hard tissue compartments, the model Includes an
expanded blood compartment containing four subcompartments: "deep" and
"shallow" pools 1n the erythrocyte, and a diffusible and protein bound pool
In plasma. A unique feature of this model Is, that 1t addresses nonllnearl-
tles 1n the relationship between lead 1n blood and lead 1n plasma.
Of the various models that have been proposed, the Harley and Knelp
(1985) model 1s unique In that 1t yields age-specific predictions for lead
levels In the major tissues given specified rates of lead uptake Into blood.
This makes 1t particularly suitable for applications to risk assessments 1n
which predictions concerning the distributions of blood lead levels among
various age groups within exposed populations are essential. Furthermore,
because lead uptake 1s a primary Input to the model, the model can be used
1n conjunction with multimedia uptake models to predict blood lead levels
associated with exposure levels In various environmental media. The Harley
l
and Knelp model has been successfully validated using available human
experimental and autopsy data (Harley and Knelp, 1985). Because this model
was developed specifically to predict tissue lead concentrations over time
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BONE
2
1 2
21
INTAKE
Gl 6
11
11
EXCRETION
BLOOD
UVER
1
I
3
' k
KIDNEY
URINE EXCRETION
5
k,s = 0.13
* «6.11 x 10'
1 3
0.07
k
3 1
= 0.03
k
1 j
c
0.08
k
1 4
= 0.02
s.
e
0.14
k
4 1
= 0.07
k
ti
¦
0.30
FIGURE 2-1
Schematic Model of Lead Metabolism in 2-Year-01d Children,
with Compartmental Transfer Rate Constants
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1n young children with continuous lead uptake, the model was selected by the
Office of Air Quality Planning and Standards (U.S. EPA, 1989a) for predict-
ing blood lead levels that would be associated with lead uptakes derived
from the Integrated lead uptake methodologies described 1n Chapter 4 of this
document. A more complete discussion of the Integration of the Harley and
Knelp (1985) model with lead uptake models 1s presented 1n Chapter 4.
2.3. SYSTEMIC AND TARGET ORGAN TOXICITY
2.3.1. Neurobehavloral Toxicity.
2.3.1.1. LEAD NEUROTOXICITY IN ADULTS — Severe lead neurotoxicity Is
characterized by overt symptoms of Irritability, shortening of attention
span, headache, muscular tremor, peripheral neuropathy, abdominal pain, loss
of memory and hallucinations. Delirium, convulsions, paralysis and death
can also occur. In adults, some of these overt symptoms may become apparent
at blood lead levels 1n the range of 40-60 pg/di (U.S. EPA, 1986b).
Nonovert symptoms of neurotoxicity that have been associated with lead
exposure In adults Include Impaired performance on psychomotor tests,
decreased nerve conduction velocity and Impaired cognitive function (s.g.,
IQ). Blood lead levels associated with these effects range upwards from 30
ug/dl (U.S. EPA. 1986b).
2.3.1.2. LEAD NEUROTOXICITY IN CHI LORE N — Symptoms of overt neuro-
toxicity 1n children are similar to those observed In adults. Nonovert
symptoms of neurotoxicity that have been reported 1n children Include
Impairments or abnormalities 1n psychomotor and cognitive function.
Numerous studies have examined psychomotor and cognitive function of
"high-risk" populations of children. Such populations are those typically"
Identified from clinical lead screening programs as having elevated blood
lead levels, children with previous histories of lead encephalopathy or
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pa-lut pica and children with possible occupational exposure (e.g., lead
pottery manufacture). Based on an extensive review of these data, the
Agency concluded that, although the evidence Is not conclusive, severe
psychomotor and cognitive deficits appear to be associated with blood lead
levels at the range of >40-60 pg/di (U.S. EPA, 1986b).
Studies of general pediatric populations (e.g., Infants and children
with no known history of excessive exposure or toxicity) provide Information
about subtle neurological effects In .children with lower blood lead levels
and body burdens than the studies of high-risk populations. An extensive
Agency review of these studies concluded the following (U.S. EPA, 1986b):
1) they are suggestive of relatively minimal (1f any) effects on IQ
1n general populations, especially In comparison with the much
larger effects of other factors (e.g., social variables), at the
exposure levels evaluated In these studies (blood lead levels
mainly In the 15-30 pg/di range); and 2) they are not Incompat-
ible with findings of significant lead effects on IQ at average
blood lead levels (>30 yg/da).
Several large-scale studies have been reported since completion of the
above analysis (U.S. EPA, 1986b) that Indicate effects on mental development
and cognitive ability associated with blood lead levels <10-15 yg/dl. A
brief discussion of the key prospective studies of mental development 1n
Infants and young children 1s presented In Section 2.4.1. of this document.
Two recent cross-sectional studies on cognitive ability 1n school-aged
children have been reported. As shown In Figure 2-2, an Inverse linear
association between Stanford-B1net IQ scores and contemporary blood lead
levels was seen over the entire range of 6-47 yg/dl 1n a study of
uniformly low socioeconomic status black children, 3-7 years old (Hawk et
al., 1986; Schroeder and Hawk, 1987). A study of 6- to 9-year-old children
1n Edinburgh, Scotland, also Indicated a negative linear correlation between
blood lead and scores on tests of cognitive ability (Fulton et al., 1987).
2164A
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120
10
100
• •
• •
_J 90
^ 80
o
70
60
5 10 15 20 25 30 35 40 45 50
BLOOD LEAD LEVEL (j/g/dl)
FIGURE 2-2
Child IQ as a Function of Blood Lead Level 1n Children 3-7 Years Old
Source: Schroeder and Hawk, 1987
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The correlation extended across a range of 5-22 yg/dl mean blood lead
levels (Figure 2-3).
A more recent study examined data on nerve conduction velocity 1n
children living 1n the vicinity of a lead smelter (Schwartz et al., 1988).
Based on "hockey stick," quadratic and logistic regression analyses of the
maximal nerve conduction velocity and blood lead level data 1n 202 children
(ages 5-9 years), a threshold for decreased maximal nerve conduction was
estimated to be within the range of 20-30 vg/dl (Figure 2-4).
Animal studies provide the opportunity to examine neurobehavloral
effects of lead under controlled conditions, which are not possible In human
studies. Recent data with nonhumari primates provide strong support for high
sensitivity to lead 1n newborns (Levin et al., 1988; Bushnell and Bowman,
1979a,b; Gilbert and Rice, 1987). Exposure to low levels of lead appears to
disrupt the normal maturation of the nervous system, which may cause
subsequent functional defeclts (Cookman et al., 1987, 1988).
2.3.2. Effects of Lead on Heme Biosynthesis and Erythropo1es1s. The
process of heme biosynthesis 1s outlined In Figure 2-5. Lead Interferes
with heme biosynthesis by decreasing the activity of the enzymes aminolevu-
linic acid dehydrase (ALA-D) and ferrochelatase. Increased activity of the
enzyme aminolevulinic acid synthetase (ALA-S) may also occur as a secondary
effect of feedback regulation. While these effects can be most readily
demonstrated in erythroblasts, there Is evidence that indicates lead may
derange heme biosynthesis In other tissues. Including the central nervous
system (Moore and Goldberg 1985; Sllbergeld, 1987). Thus, altered heme
metabolism In erythroblasts may be Indicative of similar disruptions In
other erythropoietic tissues that may contribute to more severe systemic or
neurological effects.
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20 —
i
i 10 —
-20 —
! ! ! I I ! !
5 10 15 20 25 30
Blood lead (ug/dl)
FIGURE 2-3
British Ability Scales Combined Score (BASC, Means and
95X Confidence Intervals) as a Function of Blood Lead Level
In Children 6-9 Years Old
Source: Fulton et al., 1987
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0 02C50
0 02000
Qwodrotie
z 001950
c
LogiUic
r C 019Jw r-
*oe*ty »iic«
^ 00165" -
ocieo:
o M
0 15
J L
! : i I : ! 7
25 35 4 5 55 65 75
BLOOD LEtD LEv£l
FIGURE 2-4
Maximal Nerve Conduction Time as a Function of Blood Lead Level
In Children, 5-9 Years Old. Data from 202 children are fit
to logistic, quadratic and 'Hockey Stick1 models
Source: Schwartz et al.. 1988
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MITOCHONDRION
MITOCHONDRIAL MEMBRANE
GLYCINE
HEME
SUCCINYL-CoA
FERRO-
CHELATASE
ALA SYNTHETASE
(INCREASE)
BONVPROTOPORPHYRIN
Pt> (DIRECTLY OR
BY DEREPRESSION)
AMINOLEVULINIC ACID
(ALA)
ALA
DEHYDRASE U* pb
(DECREASE)
COPROPORPHYRIN
(INCREASE)
t
PORPHOBILINOGEN
RON
FIGURE 2-5
Effects of Lead on Heme Biosynthesis
Source: U.S. EPA, 1986b
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Significant Impairment of hemoglobin synthesis occurs ln adults at rela-
tively high blood levels. The threshold for a decrease In blood hemoglobin
In adults and children Is achieved at a blood lead level of 50 yg/dl
(Meredith et al., 1977; Flschbeln, 1977 ; Alvares et a 1.. 1975 ). Frank
anemia 1n adults has been associated with levels >80 yg/dl (Tola et al.,
1973; Grandjean, 1979; L111 s et al., 1978; Wada et al., 1973; Baker et al.,
1979). The relationship between blood lead levels and heme biosynthesis 1n
other sensitive tissues, such as central nervous or cardiovascular tissues,
has not been characterized.
The effects of lead on erythroblast heme biosynthesis can be detected
from measurements of the activity of erythrocyte ALA-D or levels of erythro-
cyte protoporphyrin (EP), a substrate for ferrochelatase. Erythroblast
ALA-D activity Is Inversely correlated with blood lead level In Infants,
children and adults (Figure 2-6); the correlation persists when examined
across a range of blood lead levels <3-4 yg/dl, suggesting that Inhibi-
tion of ALA-D may occur at these low blood lead levels ' (Hernberg and
Nlkkanen, 1970; Hernberg et al., 1970; Roels et al., 1975, 1976; Lauwerys et
al., 1978; Chlsolm et al., 1985). The dose-response relationship for ALA-D
Inhibition at levels <20 yg/dl has not been completely characterized;
therefore, the existence of a threshold has not been verified.
The extensive Information regarding the effects of lead on EP levels 1n
humans Is critically reviewed In several Agency documents (U.S. EPA, 1986a;
ATSDR/U.S. EPA, 1988). The threshold for elevated EP In children 1s -15
yg/dl (Roels et al., 1976; Plomelll et al., 1982; Hammond et al., 1985;
Rablnowltz et al., 1986). A dose-response analysis based on the data from ~
PlomelH et al. (1982) 1s shown 1n Figure 2-7. The dose-response relation-
ships for elevated EP In children and adults when examined across a range of
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70C
&
«
x
1
4
<
>00 »> •'
FIGURE 2-6
Blood ALA-D Activity As a Function of Blood Lead Level 1n 158 Adults.-
Solid Circles, Medical Students; Open Circles, Workers In Print Shop; Solid
Squares, Automobile Repair Workers; Open Squares, Lead Smelters and
SMpscrapers
Source: NAS, 1972
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99
95
90
CO
_i
<
D
C
>
c
Z
u.
0
5 25
£ 75 -
50 —
10
5 (—
EP > X ~ 1 SD
EP > X ~ 2 SD
NATURAL FREQUENCY
10 20 30 40 50
BLOOD LEAD. ug/dL
60
70
FIGURE 2-7
Problt Dose-Response Function* for Elevated Erythrocyte
Protoporphyrin as Function of Blood Lead Level 1n Children.
Geometric Mean +• 1 SD ¦ 33 yg/di; Geometric Mean + 2 SD - 53 yg/dl
Source: Plomelll et a 1., 1982
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blood lead levels extending from 10-40 yg/di. Indicate that children are
more sensitive than adults and that adult females may be more sensitive than
males (Roe 1 s et al., 1976). The lower range of blood lead levels at which
EP levels become elevated Is below that associated with decrement In blood
hemoglobin levels and anemia (Hammond et al., 1985). Elevated protopor-
phyrin levels, although not necessarily an iadverse effect per se, are
Indicative of disturbances 1n heme metabolism that may extend to other heme
proteins other than hemoglobin.
The enzyme P5N 1s also Inhibited by lead (Paglla and Valentine, 1975 ).
This enzyme catalyzes the dephosphorylatlon of pyr1m1d1ne nucleotide mono-
phosphates and plays an Important role 1n the regulation of the levels of
pyrlmldlne nucleotides within the erythroblast. The pathological signifi-
cance of Inhibition of P5N by lead Is unknown; however, congenital defi-
ciency of this enzyme, In which <10% of normal activity Is present In the
erythroblast, 1s associated with a syndrome of hemolytic anemia (Valentine
et al., 1974). Thus, Inhibition of erythroblast P5N may contribute to the
anemia associated with relatively high blood lead levels (>80 pg/dl)
(Tola et al., 1973; Grandjean, 1979; L1lls et al., 1978; Wada et al., 1973;
Baker et al., 1979). The Inhibition of P5N may also contribute to a
disruption of mRNA and protein biosynthesis 1n the erythroblast.
Inhibition of P5N In human erythrocytes can be detected from measure-
ments of the levels of pyrlmldlne nucleotide monophosphate substrates for
this enzyme or from measurements of catalytic activity of erythrocyte
preparations. Levels of erythrocyte pyrlmldlne nucleotide monophosphate are
elevated 1n children that have blood lead levels exceeding 30 yg/da.
This suggests that significant Inhibition of P5N occurs at blood lead levels
>30 pg/dl (Angle et al., 1982). Catalytic activity of erythrocyte P5N
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1s Inversely correlated with blood lead 1n children (Angle and Mclntlre,
1978; Angle et al., 1982). The correlation persists when examined across a
range of blood lead levels extending from 7-80 pg/dt, suggesting that
Inhibition of P5N may occur at levels possibly <10 yg/di (Figure 2-8).
In conclusion, the available Information Indicates the potential for
undesirable effects on heme biosynthesis and erythroblast pyr1mld1ne metabo-
lism In children with blood lead levels >10-15 yg/di, and possibly at
lower levels.
2.3.3. Effects of Lead on the Kidney. Acute lead-Induced nephrotoxicity
Is characterized by proximal tubular nephropathy. Characteristic lesions
described 1n both humans and animals Include nuclear Inclusion bodies and
mitochondrial changes In the epithelial cells of the pars recta of the
proximal tubule and Impaired solute reabsorptlon (e.g.„ glucose, amino
acids, phosphate). Chronic toxicity 1s characterized by Interstitial
fibrosis and decreased glomerular filtration rate (Goyer, 1982; U.S. EPA,
1986b; ATSDR/U.S. EPA, 1988).
Acute nephrotoxicity has been observed In children with lead encephalo-
pathy and Is associated with relatively high blood lead levels (I.e., >80
vg/dl) (Chlsolm et al., 1955; Chlsolm 1962, 1968; Pueschel et al., 1972;
U.S. EPA, 1986b). Chronic nephropathy. Indicated by nuclear Inclusion
bodies, mitochondrial changes, Interstitial fibrosis and glomerular changes,
has been associated with prolonged (>10 years) occupational exposures and
blood lead levels >40-60 yg/dl (L111 s et al., 1968; Cramer et al., 1974;
Blaglnl et al., 1977; Wedeen et al., 1975, 1979; Buchet et al., 1980; Hong
et al., 1980).
2.3.4. Effects of Lead on Blood Pressure. The relationship between
concurrent blood lead levels and blood pressure In adults has been examined
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z
3
Z
i.
SO-
SO
60
70
•c
FIGURE 2-8
Erythrocyte Pyr1m1d1ne 51-Nucleotidase Activity (P5N Units)
as a Function of Blood Lead Level in 25 Children, 1-5 Years Old
Source: Angle et a 1.. 1982
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n several ep't Jem1olog1cal studies. Particularly notable are four large
epidemiology studies: the British Regional Heart Study (BRHS), the analysis
of the second National Health and Nutrition Evaluation Survey (NHANES II)
and two studies conducted In Wales. The estimated change 1n mean systolic
blood pressure for a doubling of blood lead, as assessed from analyses of
these four large-scale studies (Pocock et al., 1988) 1s shown 1n Figure 2-9.
The BRHS study analyzed data on blood lead levels and blood pressure In
7735 middle-aged men (aged 40-49) fcom 24 British towns (Pocock et al.,
1984, 1985, 1988). Systolic and diastolic blood pressure were positively
correlated with blood lead levels across a range of blood lead levels
extending from -10-40 yg/di. Based on a linear regression analysis of
the data. It was predicted that doubling of blood lead levels was associated
with an Increase of 1.45 mm Hg systolic pressure and 1.25 mm Hg diastolic
pressure.
Several analyses of data on blood pressure and blood lead levels from
NHANES II have been reported (Harlan et al., 1985; Plrkle et al., 1985;
Landls and Flegal, 1987). Systolic and diastolic blood pressure was posi-
tively correlated with blood lead levels over a range of blood lead levels
that extended from 7-34 yg/dl. Based on a linear regression analysis of
data from -20,000 subjects, It was predicted that a doubling of blood lead
levels (e.g., from 8-16 ng/dl) was associated with an Increase of 2-3 mm
Hg systolic blood pressure.
Two surveys conducted In Wales examined the relationship between blood
lead and blood pressure (Elwood et al., 1988a,b). The Welsh Heart Programme
analyzed data from 865 men and 856 women. Mean blood lead levels were 12
vg/dl for men and 10 yg/dl for women. A regression analysis was
applied to the data. No statistically significant relationship between
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I I 1 1 1 I
-10 1 2 3 4
Esvnatei change m mea~. systo'.c bbod p'essjre
(r.T Hg) for a doling of blood lead
BRHS (N.7371)
NHANE S II (N=225*;
Caerphilly (N=116^j
Wales (N.855;
FIGURE 2-9
Comparison of Study Results from Four Larger-Scale Epidemiology Studies
of Lead-Blood Pressure Relationships in Adult; Men. BRHS, British Regional
Heart Study (Pocock et al., 1988); NHANES II, National Health and Nutrition
Evaluation Survey (Schwartz, 1988); Caerphilly and Wales, Welsh Studies
(Elwood et al., 1988a,b)
Source: Pocock et al., 1988
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blood pressure and blood lead level was established. The Caerphilly
Collaborative Heart disease study analyzed data from 865 adult males living
In Caerphilly, Wales (Elwood et al., 1988b). Regression analysis did not
reveal a statistically significant relationship between blood pressure and
blood lead.
In addition to the four large-scale studies described above, preliminary
analysis of a cross-sectional study from Canada was recently reported (Nerl
et al., 1988). This study analyzed data from 2193 subjects. A statistic-
ally significant (p<0.01) relationship between blood lead levels and
diastolic blood pressure was reported. Several small-scale studies have
been reported that show significant relationships between occupational
exposure to lead and blood pressure (Sharp et al., 1988; Weiss et al., 1988;
Moreau et al., 1988).
Although the results of individual studies vary with respect to the
quantitative relationship between blood lead and blood pressure, the weight
of evidence provided by the several * large scale epidemiology studies and
numerous small scale epidemiology studies supports the existence of a
positive correlation between blood lead level and blood pressure. In
addition, the results of numerous animal studies support a dose-response
relationship between lead exposure and elevated blood pressure. Chronic
exposure to Inorganic lead Increases blood pressure 1n laboratory animals
(Vlctery, 1988), Increases plasma renin activity (Vander, 1988) and appears
to sensitize the vascular endothelium to pressor agents (Chal and Webb,
1988). The correlation between blood lead levels and blood pressure 1n
humans appears to extend to blood lead levels <20 ug/dl, and possibly to "
as low as 7 yg/di. This suggests that as blood lead level Increases >7
yg/dl to levels >20 pg/dl, the risk for Increased blood pressure
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Increases. The precise function that describes the dose-effect relationship
over a range of blood lead levels <40 yg/di has not been characterized.
This may reflect (1n part) the relatively small quantitative effect of blood
lead on blood pressure. Assuming a linear relationship between blood lead
level and blood pressure, the BRHS and NHANES II analyses predict an
Increase of 1-3 mm Hg systolic blood pressure for a doubling of blood lead
level (e.g., from 8-16 pg/dl). With such a low magnitude effect,
detection of effects <10 yg/di may not be possible even with large-scale
epidemiology studies, such as the NHANES II analysis. Nevertheless, a
sustained'Increase In blood pressure of only a few mm Hg may have a signifi-
cant public health Impact In terms of cardiovascular and related diseases
(Plrkle et al., 1985).
2.3.5. Effects of Lead on Serum Vitamin D Levels. 1,25-Dlhydroxychole-
calclferol, the active form of vitamin D, Is a hormone that plays an
Important role In the regulation of gastrointestinal absorption and renal
excretion of calcium and phosphorus' and In the mineralization of bone.
Deficiencies 1n 1,25-dlhydroxycholecalclferol are associated with decreased
bone mineralization and clinical syndrome of rickets In children. 1,25-01-
hydroxycholecalclferol may also stimulate gastrointestinal absorption of
lead (Smith et al., 1978). Serum levels of 1,25-d1hydroxycholecalc1ferol
are Inversely correlated with blood lead In children (Rosen et al., 1980;
Mahaffey et al., 1982). The correlation persists when examined across a
range of blood lead levels extending from 12-60 tig/di; however, the
dose-effect relationship has not been characterized (Figure 2-10). Based on
a linear regression analysis of data on serum 1,25-d1hydroxycholecalc1ferol
and blood lead levels 1n children as well as data on 1,25-d1hydroxychole-
calclferol levels 1n other vitamin D related clinical disorders 1n children,
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ic jc i. t «: •: ia.
UOOC »» !*¦
FIGURE 2-10
Serum 1,25-01hydroxycholecalclferol (1,25-CC) Levels as a Function
of Blood Lead Levels 1n 50 Children, 2-3 Years Old
Source: Hahaffey et al., 1982
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1t has been predicted that Increasing the tjlood lead levels from 12-60
ug/dl will lower serum 1,25-d1hydroxycho|lecalc1ferol to clinically
adverse levels (Mahaffey et al., 1982). Chronic depression of serum
1,25-d1hydroxycholecalc1ferol levels of a much smaller magnitude than that
associated with frank clinical disorders of calcium and phosphate metabolism
have the potential to alter bone development and growth In children;
therefore, blood lead levels >12 yg/di should be considered potentially
undesirable with respect to changes In 1,25-d1hydroxycholecalc1ferol levels
1n children.
2.4. DEVELOPMENTAL/REPRODUCTIVE TOXICITY AND GEN0T0XICITY
2.4.1. Mental Development 1n Infants and Children. The effects of
prenatal and neonatal lead exposure on perinatal status and postnatal mental
and motor development have been examined 1n several epidemiologic studies.
Four prospective studies Initiated In the cities of Boston, Cincinnati,
Cleveland and Port P1r1e, Australia are particularly notable. Based on an
extensive evaluation of these studies, the U.S. EPA concluded that "All of
these studies taken together suggest that neurobehavloral deficits,
Including declines In Bayley Mental Development Index {MO I) scores and other
assessments of neurobehavloral function, are associated with prenatal blood
lead exposure levels on the order of 10-15 pg/dl, and possibly even
lower, as Indexed by maternal or cord blood lead concentrations" (U.S. EPA,
1986b). Evaluations of more recent follow-ups reinforce this conclusion.
Boston prospective study. The Boston study consisted of a longitud-
inal analysis of mental development in Infants (Bellinger et al., 1987a,b,
1989a). Infants were classified according to "low," "mid" or "high" expo-
sure groups, based on cord blood lead level's at birth: low, <3 yg/dl;
mid, 6-7 yg/dl; high, 10-25 pg/di. The Bayley MDI was administered
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to each child at ages 6, 12, 18 and 24 months. Data were collected on a
large number of social and medical covarlates, Including care taking and
parental Intelligence. A deficit of 4.8 points on the MDI was detected 1n
children whose blood lead levels were 10-25 yg/dl at birth, as compared
with children whose blood lead levels were <3 yg/dl at birth (Bellinger
et al., 1987a). A plot of covarlated-adjusted MDI scores vs. age at testing
for each group 1n the Bellinger et al. (1987a) study 1s shown 1n Figure 2-11.
Preliminary results of an analysis of data collected In a follow-up
study has been reported (Bellinger et al., 1987b, 1989b). At age 57 months,
scores on the McCarthy Scales General Cognitive Index (GCI) were Inversely
associated with blood lead level at age 24 months (3-25 yg/dl), but were
not correlated with cord blood lead levels at birth. Improvement of
cognitive performance, as assessed from the GCI, appeared to be related to
concurrent blood lead as well as prenatal blood lead and socioeconomic
factors. For example, the Inverse association between 57-month GCI and
blood lead level was considerably larger among children with cord blood lead
levels of 10 yg/dl or slightly above. Thus, 1t appeared to be more
likely that cognitive deficits persisted to age 57 months 1n children with
higher postnatal blood lead levels or less favorable socioeconomic factors
or both.
The data reported thus far from the Boston study Indicate that lead
levels within or exceeding the range 10-25 yg/dl are associated with
decrements or delays In mental development. This Is consistent with a 10-15
yg/dl range of concern for undesirable effects in children.
Cincinnati prospective study. The study Initiated In Cincinnati
consisted of a longitudinal analysis of mental and physical development In
Infants (Dietrich et al., 1987, 1989). MDI was measured at 3, 6, 12 and 2+
2164 A
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Cord Stood L««d G'Ous
r
r
ACE AT TESTING (mythi)
FIGURE 2-11
Rental Development Index (Covarlate adjusted, Mean and SO) as a Function
of Age for Children 6rouped Into Three Ranges! of Cord Blood Lead Level;
Low, <3 yg/dl; Medium, 6-7 ug/dl; High, 10-25 yg/dl
Source: Bellinger et al., 1987a
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months. Structural equation modeling, a form of regression analysis, was
used to examine statistical Interactions between MDI scores and both
prenatal blood lead levels (range 1-27 yg/di), cord blood lead levels
(1-27 ug/di) and neonatal (10-day) blood levels (1-22 yg/di), as
well as several other possible covarlables,. Including medical and socio-
economic parameters. The analysis revealed a significant relationship
between elevated prenatal and cord blood lead and lower MDI scores at 3 or 6
months of age. At 12 months of age., however, neither prenatal nor cord
blood levels were significantly related to MDI scores although the relation-
ship between neonatal (10-day) blood lead and MDI scores remained statistic-
ally significant. An Inverse relationship between prenatal blood lead
levels and MDI scores through birth weight persisted out to 12 months
(Dietrich et al., 1989). At 24 months, neither prenatal, cord blood nor
neonatal (10-day) blood lead levels were significantly related to MDI
scores. Thus, the effects on mental development detected In the Cincinnati
study appeared to be transient. The Investigators hypothesized that the
transiency of the decrements 1n MDI scores might reflect a "catch up"
response of Infants related to lower birth weights or gestational age 1n the
Infants with higher prenatal blood lead levels (Section 2.4.2.).
Postural sway was measured 1n a small group of 6-year-old children from
the Cincinnati cohort (Bhattacharya et al., 1988). Peak blood level at 2
years (9-50 yg/dl) was significantly related to postural sway at 6
years. This suggests the possibility of persistent deficits In balance
related to childhood lead exposure.
The subjects 1n the Cincinnati study were not grouped by blood lead as ~
In the Boston study; therefore, it Is more difficult to categorize effects
associated with a specific range of blood lead levels between 1 and 28
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yg/dl. Nevertheless, the study corroborates some of the Important find-
ings of the Boston study because both studies detected an apparent effect of
lead on mental development (MDI scores) during the first 12 months In
Infants exposed to prenatal blood lead levels or neonatal blood lead levels
<25 pg/dl. Thus, the study supports 10-15 yg/dl as a range of
concern for undesirable effects 1n children.
Cleveland prospective study. The longitudinal study Initiated In
Cleveland 1s unique because 1t examined a series of neurobehavloral measures
of neonatal sensorimotor function. The tests Included the Brazelton
Neonatal Behavioral Assessment Scale (NBAS) for Habituation, Orientation,
Motor Performance, Range of State, Autonomic Regulation and Abnormal
Reflexes, and the Graham-Rosenbleth Behavioral Examination for Newborns
(G-R) for General Maturation, Soft Signs and Muscle Tonus (Ernhart et al.,
1986). The results of a multiple regression analysis Indicated that
decreased scores for G-R Soft Signs and NBAS were significantly related to
cord lead levels (2-15 pg/da) but not maternal blood lead (3-12
pg/dl). The results of follow-up studies at 6, 12, 24 and 36 months
were somewhat equivocal with respect to the effects of lead on mental
development (Ernhart et al., 1987). Lower scores on the POI and MDI of the
Bayley Scales, and the KID at 6 months were significantly related to higher
maternal blood lead (3-12 yg/dl) but not to cord blood lead (3-15
yg/dl). Concurrent 6-month blood lead was positively associated with
KID score (e.g., higher blood lead levels were associated with higher KID
scores). A portion of the Cleveland cohort was tested at 4 years, 10 months
on the WPPSI. After accounting for covariates, significant effects of lead
were not detected (Ernhart and Morrow-Tlucak, 1987).
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The Cleveland study examined a cohort having a range of relatively low
blood lead levels (<15 pg/di). This may explain why relatively few of
the Infant development Indices were found to be related to blood lead, even
though some of the tests were redundant. It 1s Hkely that >50% of women In
this cohort consumed considerable amounts of .alcohol during their pregnancy;
the alcohol-Induced effects on physical and mental development of newborns
may have masked any subtle effects of lead.
A brief report on outcomes In thl.s cohort noted a significant associa-
tion between performance on the G-R Neurological Soft Signs scale and
12-month MDI scores (Wolf et al., 1985). Thus, 1t Is possible to Infer a
relationship between cord blood lead levels and 12-month MDI performance In
the Cleveland study, although Ernhart et al. (1986, 1987) did not conclude
that such an association exists. Since the mean cord blood lead was 6
vg/dl and the maximum 15 yg/dl, any effect of prenatal lead exposure
necessarily occurred at blood lead levels <15 yg/di. From this perspec-
tive, the Cleveland study corroborates the major finding of the Boston and
Cincinnati studies: a positive relationship between MDI scores during the
first year of postnatal life and blood lead levels.
Port P1r1e prospective study. The Port PIr1e study examined cohorts
of Infants born to mothers living In the vicinity of a lead smelting opera-
tion In Port P1r1e. Australia, and Infants from outside the Port P1r1e area.
Maternal blood and cord lead levels were slightly but significantly higher
In the Port Plrle cohort than In the cohort from outside Port P1r1e; mean
cord blood lead was 10 vs. 6 yg/di. Reduced MDI scores were signifi-
cantly associated with higher Integrated postnatal blood lead levels and *
with 6-month blood lead levels, but not with prenatal or delivery blood lead
levels. Mean blood lead levels 1n the children were 14 yg/dl at 6
2164A
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months of age and 21 ng/da at 15 and 24 months of age (McMlchael et a 1.,
1986; V1mpan1 et al., 1985; Baghurst et a 1., 1987). The results of a linear
regression analysis of the data Indicated an apparent 4-po1nt deficit 1n MOI
for every 10 ug/dl Increase In blood lead. After making adjustments for
maternal IQ and care-taking environment, this deficit decreased to 2 points
for every 10 yg/dl Increase 1n blood lead. Follow-up study of these
children at 4 years of age Included the McCarthy Scales of Children's
Abilities. Deficits 1n GCI scores were associated with Increased Integrated
postnatal blood lead levels (McMlchael et al., 1988). Linear regression
analysis of data on blood lead and GCI scores Indicated that an Increase in
Integrated postnatal blood lead level from 10-30 yg/dl was associated
with a 7-po1nt decrease 1n GCI score.
Mexico City prospective study. PremlUnary results of a pilot study
In Mexico City for a longitudinal Investigation of developmental outcomes
related to lead exposure and other factors have been reported by Rothenberg
et al. (1989). Approximately 50 mothers were sampled for blood lead levels
at 36 weeks (M36) of pregnancy and delivery (MD); umbilical cord blood lead
(UC) was also sampled at delivery. Mean maternal blood "lead levels were
15.0 yg/da at 36 weeks of pregnancy and 15.4 pg/dl at delivery.
Mean cord-blood lead levels at delivery were 13.8 yg/dt. The Brazelton
NBAS was administered to the Infants at 48 hours and 15 and 30 days after
birth.
The data were analyzed by calculating the trend of the NBAS subscale
scores over the first 30 days by linear regression analysis and by computing
the difference In M36 and MD values or M36 and UC values. The relationships
among the various primary and secondary measures were then examined through
blvarlate correlations and multivariate repression analyses. Significant
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blvarlate correlations were found between UC blood lead and the 30-day trend
1n NBAS Abnormal Reflexes (r=0.299, p<0.05), between the M36-MD blood lead
difference and Regulation of States (r=0.378, p<0.05), and between the MD-UC
blood lead difference and Abnormal Reflexes (r= -0.451, p<0.01). The signs
of all the correlations reflected Impairment of functions. Stepwise
multiple regression modeling with all covarlates entered before the lead
variable revealed that the blood lead differentials for M36-MD and for MD-UC
accounted for a significant amount of the variance In the Abnormal Reflexes
trend {p~0.03 for each). Similarly, M36-MD accounted for a significant
amount of the variance (p=0.025). However, UC alone was no longer signifi-
cantly associated with Abnormal Reflexes. A major limitation of this study
was Us relatively small sample size (n=44).
The results of the most recent studies of lead and mental development
are summarized In Figure 2-12. The four prospective studies differed
greatly In design and scope, and discrepancies In the results are to be
anticipated given the complex nature of the endpolnts evaluated. Neverthe-
less, when taken together with the results of cross-sectional studies fHawk
et al., 1986; Ferguson et al., 1988a,b,c; Hatzakls et a 1., 1987; Lyngbye et
al., 1989; Fulton et al., 1987), corroborative evidence for effects on
physical and mental development In Infants and children exposed to lead 1s
provided. All four studies detected a relationship between elevated blood
lead levels and lower mental development (HOI scores) during the first 12
months 1n Infants exposed to prenatal or postnatal (or both) blood lead
levels <30 yg/dt. Thus, 1t 1s probdDle that as blood lead levels
approach >30 yg/dl, the risks for undesirable effects Increase. It Is -
more difficult to draw conclusions regarding the exact dose-effect relation-
ship over the range of blood lead levels extending <30 yg/dl. The
2164A
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!
| ¦ | ¦¦¦ m ¦nan • to
gUWI • m* a.
0 ¦ 6 Months
2
&
* 6-2* Monv"S '
i !
s
5 4 YMT
5
i
&
H
8
5 Yea-s
3 • 7 Years
6 • 9 Yea-s
E/rhart« at. 196£
Errtwi « aL. 196?
Ownen stat, 1967
Baftrger«1.1967a
Bagus ¦ *.. 1967
Mcwcnaa**. i9se
Botngaraa. i967tt
H»*aa 196c
Filar sal, 1967
10
20 30
Bleed Pb (ufl.'di)
40
SO
FIGURE 2-12
Comparison of Results From Prospective and Cross-Sectional Studies of
Mental Development. [Shown 1s the range of blood lead levels (solid line)
for which significant statistical associations; for various Indices of mental
development and blood lead level were detected. Studies are organized
vertically according to the age at which the deficit or delay was observed.]
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Boston study (Bellinger et al., 1987a) Indicates significant effects on
mental development related to blood lead levels within the range 10-25
yg/dl. The Cincinnati (Dietrich et al., 1987), Cleveland (Ernhart et
al., 1986, 1987) and Port P1 r 1 e (Baghurst et al., 1987; McHlchael et al.,
1988) studies Indicate effects within the ranges of 1-28, 3-15 and 8-32
yg/dl, respectively. Given the results of the these studies, It Is
reasonable to conclude that any threshold that might exist Is In the range
of 10-15 ug/dl blood lead, and possibly lower.
2.4.2. Growth Deficits. The structural analysis used In the Cincinnati
prospective study Indicated the possibility that the decrement In MDI scores
might have been secondary to lead-related effects on either gestational age
at birth or birth weight (Dietrich et al., 1987). A separate regression
analysis of the Cincinnati data examined the relationship between prenatal
blood lead levels (1-26 yg/dl) and birth weight (Bornscheln et al.,
1989). A dose-response analysis Indicated that decreased birth weight was
related to Increased maternal blood lead levels. The percentages of women
delivering Infants of low birth weight (<2750 g) were 19, 21 and 33%, corre-
sponding to maternal blood lead Intervals of 1-6, 7-12 and 13-18 yg/dl,
respectively. This analysis Indicated that concern for maternal blood lead
levels Is within the range of 10-15 yg/dl. Maternal age was Identified
as a major covarlate; thus, 1t appeared as If a given blood lead level was
associated with a larger decrement In birth weight In older women (e.g., 30
years) than In younger women (e.g., 18 years). In a subsequent analysis of
the Cincinnati data, growth rate (height) In Infants, 3-15 months of age,
was Inversely correlated to postnatal blood lead Increases. Mean blood lead
levels Increased from 5.3 yg/dl at 3 months to 14.6 yg/dl at 15
months (Shukla et al., 1987, 1989).
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Effects of lead on pre- arr* postnatal growth ar«» supported by several
other studies Including Lauwers et al. (1986),' Schwartz et al. (1986), Ward
et al. (1987), Fahlm et al. (1976) and Huel and Boudene (1981).
2.4.3. Effects on Fertility and Pregnancy Outcome. Severe occupational
exposure to lead has been associated with Increased Incidence of spontaneous
abortion (U.S. EPA, 1986b). However, early studies do not provide reliable
descriptions of dose-effect relationships. The Port P1r1e cohort study
described In Section 2.4.1. examined "pregnancy outcome In populations near
and distant from a lead smelter. The risk for pre-term delivery was
positively related to maternal blood lead, over a range of 8-32 yg/dl
(McMlchael et al., 1986). The relative risk for pre-term delivery was 4.4
for maternal lead levels >14 pg/dt (range 14-32 yg/di, mean 17 yg/dl).
Depressed sperm production and development has been associated with
occupational exposure to lead. Based on studies by Lancranjan et al. (1975)
and Wlldt et al. (1983), the Agency concluded that undesirable effects on
sperm or testes may occur In men as a result of chronic exposures leading to
blood lead levels of 40-50 yg/di (U.S. EPA, 1986b).
2.4.4. Genotox1c1ty. Studies relating to genotoxIcVty of lead are
reviewed In the Air Quality Criteria Document for Lead (U.S. EPA, 1986b).
Structural chromosomal aberrations and increased sister chromatid exchanges
In peripheral lymphocytes have been associated with chronic exposure to lead
resulting In blood lead levels in the range of 24-89 yg/dl, although
effects were not observed over this range of blood levels 1n numerous
studies (U.S. EPA, 1986b). This may reflect the differences In exposure
duration In relation to lymphocyte proliferation and turnover. In one
study, Increased sister chromatid exchange was positively correlated with
exposure duration and zinc protoporphyrin levels, but correlated poorly with
blood lead level (Grandjean et al., 1983).
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Bacterial systems generally arc regarded as Inappropriate for assaying
metal 1ons. The U.S. EPA (1989b) reviewed the data on chromosome aberra-
tions In higher organisms; alterations In chromosome structure appeared to
depend on factors such as harvest time following exposure, duration and
route of exposure, and test system. Furthermore, diet Influenced the
chromosome breakage Induced by lead in vivo. Lead-exposed animals on
calc1um-def1clent diets have exhibited a higher Incidence of chromosomal
aberrations than lead-exposed anlmal-s on standard diets. Other studies
reviewed by the U.S. EPA (1989b) demonstrated that lead compounds Induce
cell transformation In Balb/3T3 mouse cells and Fisher 344 rat embryo cells
Infected with the Rauscher murine leukemia virus. Collectively, these
studies suggest that lead produces undesirable effects on chromosomes.
2.5. SUMMARY
Correlation and regression analyses of data on blood lead levels and
various health effects point to a spectrum of undesirable effects that
become apparent In populations having a range of blood lead levels extending
upward from 10-15 vg/dl. These Include effects on heme metabolism and
erythrocyte pyrlmldlne nucleotide metabolism, serum vitamin 0 levels, mental
and physical development of Infants and children and blood pressure 1n
adults. Although correlations between blood lead levels and certain effects
persist when examined across a range of blood lead levels extending <10
ng/di, the risks associated with oiood lead levels <10 yg/dl are
less certain. Although 1t Is not possible to define with certainty the
risks associated with any given lead-related effect (e.g., neurobehavloral
deficits and Increased blood pressure), the weight of evidence suggests that
blood levels 1n the range of 10-15 ug/di or possibly lower are likely to
be associated with one or more undesirable effects. Therefore, regulatory
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decisions regarding environmental lead should take Into account the ev^.nnce
for potentially adverse health effects at relatively low blood lead levels.
The results of studies on the effects of lead 1n children are summarized
1n Figure 2-13. Evidence from several studies supports a relationship
between prenatal and postnatal lead exposure In Infants and young children,
as Indexed by blood lead levels, and a variety of diverse effects. These
include Impaired or delayed mental and physical development, decreased heme
biosynthesis and other biochemical effects on erythrocytes, and decreased
levels of serum vitamin D levels. Although a threshold for these effects
has not been established, the evidence suggests that 1t may lie within 10-15
yg/di or possibly lower. As blood lead levels Increase above the range
of 10-15 vg/di, the risk for more pronounced effects on all of the above
endpolnts Increases. At levels >30 yg/da, the risk for nephrotoxicity
and overt neurological effects (e.g., encephalopathy) becomed substantial.
Thus, Infants and children appear to be at least as sensitive to lead than
adults 1f the dose-effect relationship for these effects In children Is
compared with that for effects on blood pressure In adults.
Effects of lead on development are particularly disturbing 1n that the
consequences of early delays or deficits In physical or mental development
may have long-term consequences over the lifetime of affected Individuals.
Furthermore, mouthing behavior Is a significant mechanism for lead uptake In
Infants. Thus, Infants and young children can be expected to be particu-
larly susceptible to changes In lead levels in dust and dirt (see Chapter 4
for further discussion). For these reasons, Infants and children (up to 2
years) can be considered to be the critical sensitive population on which to
focus regulatory decisions regarding environmental lead.
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ENCEPHALObATHY
«PHRCTOXICfTV
SERUM VTTAMIN 0
EBV1MP0CY7E PiS
>cme biosynthesis
BIRTH WEIGHT
fcCVTAL DEVELOPMENT
« 2 VEARSI
METAL DEVELOPMENT ¦—| ¦ ffl-
(»Z YEARS)
I 1 i I 1
0 20 40 60 80
Blood Lead (ug/rr?)
FIGURE 2-13
Summary of Studies Relating Blood Lead Levels and Effects on Various
Toxicity Endpolnts In Infants and Children. Lines represent range of blood,
leads for which s1gn1f1cnat statistical associations were detected for each
effect. Solid squares Indicate mean blood levels for the population studied.
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Currently available Information on the isokinetics of 1norgan1: lead
Indicate that oral exposure to lead 1n food and beverages and nonfood
sources such as dust and soil will be the most quantitatively significant
route of uptake of environmental lead In most populations of Infants and
children. Therefore, abatement strategies that focus on these sources are
likely to be the most productive for lowering blood lead levels.
Numerous epidemiological studies have Indicated the Importance of fetal
lead exposure on lead burdens 1n 1-nfants and children. These studies
(Cincinnati and Port Plrle) also Indicate that children born with high lead
body burdens may be more vulnerable to further exposure 1n early childhood.
This further emphasizes the Importance of focusing regulatory policies on
children, who ultimately pass their lead burdens on to future generations.
Although the health effects of lead have been correlated with levels of
lead In blood, the largest physiological compartment for lead distribution
Is bone, which has a relatively long elimination half-time. Lead 1s slowly
released from bone and will distribute to other tissues when uptake levels
are decreased. As a result, new steady-state levels of lead In blood may be
achieved years after uptake decreases. Release of lead from bone may be
accelerated 1n conditions of metabolic stress. Including pregnancy, 1n which
resorption of bone occurs. The relatively slow turnover of bone lead must
be considered when evaluating the potential health Impact of decreasing
levels of lead In Important exposure media. Phys1olog1cally-based pharmaco-
kinetic models that Incorporate age-related changes In bone metabolism and
other physiological parameters that affect the distribution and excretion of
lead can be particularly useful for predicting the Impact of regulatory or
abatement decisions on blood lead levels.
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3. EXPOSURE ASSESSMENT
3.1. BIOLOGICAL EFFECTS: ENVIRONMENTAL EXPOSURE
The emerging evidence of a constellation of biochemical effects, along
with subtle health effects at low levels of lead exposure (<30 pg/di),
Is considered Indicative that low-level lead exposure has a far-reaching
Impact on fundamental cellular enzymatic, energy transfer and calcium homeo-
statlc mechanisms. These effects can be expressed In Infants and children
as deficits 1n neurobehavloral and physical developments, and 1n adults as
elevations In blood pressure. With higher levels of exposure (blood lead
levels >30 pg/dl), overt symptoms of lead toxicity appear In the form of
anemia, neurological Impairment (e.g., encephalopathy), reproductive
abnormalities and nephropathy.
The highest risks for adverse health effects from exposure to environ-
mental lead 1n most populations are likely to be associated with Infants and
young children. Hence, risk assessment efforts related to environmental
lead focus on this segment of the population. The exceptional vulnerability
of Infants and young children reflects an Innate sensitivity of developing
organisms to lead, as well as a variety of physiologic and behavioral
factors that facilitate their exposure to relevant environmental media.
Exposure to humans, however, begins _1_n utero with the transplacental
transfer of lead from mother to fetus. Thus, Infants are born with an
initial lead burden that reflects prior environmental exposure of the mother
and, to some extent, concomitant exposure to the mother during pregnancy.
Environmental exposure that begins with birth adds to this preexisting
burden and may be transferred to the next generation of Infants.
Environmental exposure during the earliest period of Infancy (0-6
months) Is derived largely from the diet and, to a lesser extent, Inhalation
of Indoor airborne lead. With the onset of floor activity and crawling.
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oral Intake from Indoor and outdoor dust a|nd soil begins to contribute
significantly and eventually becomes the single largest source of lead
uptake. An estimated 70% of total lead uptake! In 2-year-old children living
near a lead point source (e.g., smoke stacks and smelter) 1s derived from
Ingestion of dust and soil (U.S. EPA, 1989a). The Importance of dust and
soil reflects the behavioral tendencies of Infants and young children to
crawl and play on floors and soil surfaces and to engage In extensive
hand-to-mouth activity. The latter consists of thumb and finger-sucking and
placing objects from the environment Into their mouths. Pica, or excessive
and Intentional Ingestion of nonfood Items Including soil, plaster and wood,
occurs In some Infants and young children and can contribute substantially
to oral Intake of lead (Binder et al., 1986; Clausing et al., 1987;
Calabrese et al., 1989). Paint and plaster pica can be an extremely Impor-
tant exposure mechanisms for Infants and youngichildren living or playing 1n
or around structures containing deteriorating leaded paint or plaster.
In addition to behavioral characteristics that facilitate lead exposure,
nutritional factors may also contribute to the vulnerability of Infants and
young children to lead. The nutritional requirements for rapid physical
growth during the first 3 years render this age group susceptible to a
variety of nutritional deficits. Including Iron, copper and zinc deficien-
cies. As discussed 1n Section 2.2.1.2., deficiencies of these minerals are
associated with Increased gastrointestinal absorption of lead 1n animals.
In general, Inhalation Is a quantitatively minor route of exposure for
Infants and children. Nevertheless, children; may be more vulnerable than
adults to exposure to airborne lead particles. Physiologic characteristics
of the respiratory tract of Infants and children result 1n higher deposition
efficiencies of Inhaled airborne particles than 1n adults (Phalen et al.,
1985; Xu and Yu, 1986).
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To fully appreciate the significance of childhood lead exposure as a
critical focus of risk assessment methodology, the above considerations must
be placed 1n perspective with serious potential for long-term consequences
of neurobehavloral and developmental effects encountered at an early age.
This does not trivialize the Importance of long-term exposure and effects of
lead In adults. The relationships reported to exist between systemic
arterial blood pressure and concurrent blood lead level 1n adults suggest
that low-level environmental exposure .may have Important health consequences
for adults. It remains to be seen, however, whether such effects are
related to chronic exposure extending from childhood or Infancy to the
adult. The Importance of prospective epidemiological study designs In this
area cannot be overemphasized. Regardless of the outcome of such studies,
the long biological half-time of lead in bone and the potential for trans-
placental transfer of lead translates into additional risk factors for the
fetus and for the Infants of mothers exposed during childhood.
3.2. MULTIMEDIA LEAD EXPOSURES: AIR. SOIL. OUST. WATER, PAINT
Humans are typically exposed to lead in a variety of media as a rssu 11
of the transfer of airborne lead to soil, water and food (Figure 3-1). The
primary anthropogenic Inputs to the air are automobile exhaust and Indus-
trial emissions. Natural Inputs to the air can Include geological processes
such as volcanic activity and crustal weathering. Emissions to ambient air
eventually deposit 1n soil and ambient water, creating secondary exposure
sources that Include dust, soil, food and water. Additional Inputs to water
and food Include lead pipes and solder joints In drinking water delivery
systems and 1n food containers. Lead-based paint can also be an Important"
source of contamination of house and street dust. Other potential sources
of lead exposure Include cosmetics (surma) and folk medicines (Healy et al.,
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CRUSTAL
weathering
auto \ / industrial.
EMISSIONS J [ EMISSIONS
surface and
GROUNO WATER
AMBIENT
AIR
-{plumbing)
PLANTS
ANIMALS
PAIN
PIGMENTS
SOLDER
DRINKING
WATER
INHALED
AIR
OUSTS —
FOOD
SOFT
BLOOD
TISSUE
UVER
KIDNEY
V
FECES URINE
BONES
Pathways of Lead from the Environment to Humans
FIGURE 3-1
Pathways of Lead from the Environment to Humans
Source: U.S. EPA, 1986b
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1982). Shown 1n Table 3-1 are typical levels of lead 1n various media,
Including ambient air, in the United States (U.S. EPA, 1989a).
Although air emissions and lead paint are the primary anthropogenic
sources of environmental lead, oral Intake, rather than Inhalation, 1s
generally the predominant route of Intake for humans. Intake occurs through
Ingestion of food and beverages, and In Infants and children, through
Ingestion of dust and soil.
3.2.1. Lead 1n A1r. Whereas, at one time, automobile exhaust accounted
for -90% of all air emissions 1n the United States, the recent phase-down of
lead content of gasoline and reductions 1n usage of leaded gasoline have and
will continue to substantially decrease the contribution of automobile
exhaust to a 1r lead (U.S. EPA, 1986b). Lead 1n automobile exhaust origi-
nates from the combustion of gasoline containing organic lead additives,
primarily tetraethyl and tetramethyl lead. Lead Is emitted from vehicles
primarily as particles of Inorganic lead, with a small percentage as
volatile lead alkyls. Of the automotive lead emissions deposited, -50% Is
within less than a few kilometers of roadways, whereas smaller particles can
travel for thousands of kilometers (Huntzlcker et a 1 ., 1975; U.S. EPA,
1986b).
Sources of Industrial emissions Include fugitive emissions from lead
mining, primary and secondary lead smelting, battery plants, and combustion
of oil, coal and municipal waste (U.S. EPA, 1986b). Dispersal of particles
released from such processes depends on meteorological variables, Including
wind speed and direction and precipitation. The most abundant deposition
generally occurs within 10 km around emission sources, which can result In
high local concentrations of lead 1n dust, soil and ambient water (Yankel et
al., 1977).
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TABLE 3-1
Typical Lead Concentrations In Various Exposure Med1aa
Medium
Rural Area
Urban Area
Near Point Source{s)b
Reference
Ambient air (|ig/m*)c
0.1
0.1-0.3
0.3-3.0
U.S. EPA. 1989a
Indoor air (|ig/ma)
0.03-0.08
0.03-0.2
0.2-2.4
U.S. EPA. 1986b
Soil (ppm)
5-30
30-4500
150-15.000
U.S. EPA. 1986b; Mlelke et al.. 1983
Street dust (ppm)'
80-130 (90)
100-5000 (1500)
(25.000)
Nrlagu, 1978; U.S. £PA, 1986b
House dust (ppm)®
50-500 (300)
50-3000 (1000)
100-20,000 (10,000)
U.S. EPA, 1989a; Landrlgan et al.. 1975;
Horse et al., 1979; Angle and Hclntlre, 1979
Typical Foods (ppm)
0.002-0.8
0.002-0.8
0.002-0.8
Flegel et al., 1988
Water (wg/t)
5-2100
5-2100
5-2100
U.S. EPA, 1989a; Gardels and Sorg, 1989
Paint' (ag/ca')
A
•
V
<1 to >S
<1 to >5
U.S. EPA, 1989a
'Sourct: US (PA. 1989*
Within 2-5 km of sources Including primary and secondary lead smelters, battery plants
cRepresents quarterly averages monitored In 19B6
dRange of indoor/outdoor ratios used (0.3-0.8) from U.S. EPA (19B6b) except near point sources where large particles predominate and Infil-
tration into homes Is low; ratio appears to be closer to 0.3 (Cohen and Cohen, 1980).
eValues In parentheses represent estimates provided In U.S. EPA (1986b) as typical averages.
'Since there may be several layers of lead-based paint on a given surface, absolute concentration of lead is less useful than mg/cm3.
Surveys by HUD In Pittsburgh showed that >70% of pre-1940 dwelling units and 20% of post-1960 units had at least one surface with >1.5
mg/cm' lead paint (NAS, 1980).
-------
Concentrations 1n ambient air have declined over the last decade as a
result of the phasedown of leaded gasoline production and use, and reduc-
tions In emissions from stationary sources (U.S. EPA, 1989a).
3.2.2. Lead 1n Soil. Lead released to the air deposits on terrestrial
surfaces and enters the soil, where 1t carv have several possible fates.
Lead can be retained In organic complexes near the soil surface. For
example, Insoluble lead species may be free or adsorbed on solid Inorganic
or organic matrices. Studies of lead/.so1l Interactions show that soil fixa-
tion of lead 1s mainly affected by pH, cation exchange capacity and organic
matter content of soil. While 1t 1s true that, In a variety of soils, lead
appears most strongly associated with soil organic carbon fraction (Zlmdahl
and Skogerboe, 1977), no correlation 1s seen between organic content and
lead concentrations In "brown soils" (Wojclkowska-Kapusta and Turskl, 1986).
In addition, 1f little or no organic material 1s In the soil, other compo-
nents can regulate lead fixation. These Include hydrous manganese oxide
(Forstner et al., 1981) and hydrous ferric oxide (Swallow et al., 1980).
Levels of lead In rural soils, away from Industrial emissions and roadbeds,
range from 5-30 pg lead/g soil (see Table 3-1). Levels of lead near
roadbeds can be much higher (30-2000 vg/g) and will vary with past and
present traffic density and vehicle speed (Page and Gange, 1970; Quarles et
al., 1974; Wheeler and Rolfe, 1979). Much higher levels (>30,000 m
-------
sizes resulting from dispersal of mine tailings also tend to be larger
(10-1000 ym) than those produced from smelters. This may affect the
kinetics of lead transfer from soil Into the home (Steele et al., 1989).
Lead 1n urban soils Includes lead from automotive and Industrial
emissions, as well as from leaded paints. Levels >2000 vg/g have been
reported 1n soil around wood-frame houses painted with leaded paint (Ter
Haar and Aronow, 1974; Mlelke et al., 1983).
Lead bound to organic constituents 1n soil can remain 1n soil for long
periods of time. As a result, elevated levels can persist long after
sources of deposition have been reduced (Prp1c-HaJ1c et al., 1984).
3.2.3. Lead 1n Dust. Dust Is an Important source of oral lead Intake 1n
Infants and children. The term "dust" refers to house and outdoor dust;
house dust Is dust 1n the Interior of buildings and Includes such things as
material from fabrics (carpet) and paint, and soil tracked or blown Into the
house. Outdoor dust Includes anthropogenic materials deposited on outside
surfaces, referred to as "street dust," and the mobile uppermost layer of
natural soil, referred to as "soil dust" (U.S. EPA, 1986b). Atmospheric
lead from automotive and Industrial emissions are the primary contributors
to lead 1n outdoor dust. Paint can also be a significant source of lead In
outside dust around buildings painted with lead-based paint. Levels of lead
In outdoor dust vary with proximity to emission sources and meteorological
variables (Roels et al., 1980; Brunekreef et al., 1981; Yankel et al.,
1977). Outdoor dusts can be transported by wind and rain runoff (Laxen and
Harrison, 1977).
Lead In house dust can be derived from atmospheric deposition, transport
of outdoor dust and deterioration of lead-based paint surfaces. Lead levels
1n house dust are determined by a number of factors Including house cleaning
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practices, the presence and condltUn of lead-based paint surfaces, the
presence of upholstered furniture and carpet, the amount of dust and soil
transported Into the house, the permeability of the house to outdoor a 1r and
the outdoor air lead concentration (U.S. EPA, 1986b). Lead can also enter
the house as dust on clothing worn at work (I.e., secondary occupational
contamination) (CDC, 1989).
Lead 1n dust Is relatively mobile. Levels 1n outdoor dust near point
sources have been shown to decline- within 1-2 years after atmospheric
emissions decreased (Morse et al., 1979; Prp1c-MaJ1c et al., 1984).
3.2.4. Lead 1n Diet. Anthropogenic sources of lead In food Include
1) deposition of atmospheric lead onto crops, forage, feed, soils and water;
2) lead-based pesticides; and 3) harvesting, processing, transportation,
packaging, preparation and storage of food during which lead can enter the
food by atmospheric deposition or leaching from metal containers and
plumbing. Based on data from numerous studies of food consumption patterns
and lead levels In various foods (U.S. FDA, 1983, 1984), the U.S. EPA
developed a "Multiple Source Food Model" that establishes reference values
for lead contents of typical diets for children and adults (U.S. EPA,
1986b). Declines 1n atmospheric emissions from automobiles and Industrial
point sources, 1n lead levels In water and In the use of lead solder 1n food
containers are expected to result 1n declining levels of lead In food (U.S.
EPA, 1989a; Cohen, 1988a,b).
3.2.5. Lead 1n Hater. Lead can enter ambient water from atmospheric
deposition and surface runoff, where 1t tends to form Insoluble salts and
precipitates. Concentrations of lead In U.S. ambient water are typically
low. Mean values tend to be <3-28 yg/l (NAS, 1980; U.S. EPA, 1986b).
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In contrast with ambient water, levels In dr1rik1nc water can be much h^her
(10-1000 vq/l) because of leaching of lead from lead pipe and leaded
solder Joints. Lead concentrations In drinking water vary with the amount
of lead 1n the household plumbing and corroslveness of the water. Soft or
addle waters tend to be more corrosive and promote higher concentrations of
dissolved lead In the drinking water (Worth et al., 1981). Drinking water
can be a major source of lead Intake for Infants and young children who
consume large amounts of infant formula*prepared with household water.
3.2.6. Lead 1n Paint. Ingestion of lead-based paint Is one of the most
frequent causes of severe lead Intoxication In children (Chlsolm, 1984).
Although the U.S. Consumer Product Safety Commission banned the use of
household paints containing >0.06% lead In 1977, the hazard persists In
homes and apartments constructed before the ban. In homes built before
1940, some Interior paints contained >50% lead. An estimated -20% of
housing units built between 1960 and 1974 have lead paint levels >0.7
mg/cm2 (Pope, 1986; ATSDR, 1988).
Infants and children can be exposed to lead In paint from Ingesting and
Inhaling house dust contaminated with paint dust and from Intentionally
Ingesting paint chips (paint pica). Exposure can occur outside the house
from Ingestion of street and soil dust. Exposure Is higher In houses with
deteriorating surfaces (e.g., peeling of paint, cracked plaster). In 1980,
an estimated 6.2-13.6 million children under the age of 7 years resided 1n
housing containing lead-based paint; 235,000-842,000 children resided 1n
homes with deteriorating surfaces (Pope, 1986; ATSDR, 1988). Since exposure
to lead 1n paint Is unrelated to atmospheric, soil or dietary levels of
lead, efforts to reduce lead levels in these media will have little Impact
on the Incidence of lead Intoxication associated with lead paint.
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3.3. MEDIA-SPECIFIC ESTIMATES FOR DIFFERENT LEVELS OF LEAD UPTAKE
B1ok1net1c models have been developed that predict age-specific blood
lead levels associated with age-spec1f1c uptake rates (Harley and Knelp,
1985). This section discusses the major quantitative factors that must be
Incorporated Into predictions of lead uptakes from specific environmental
media. Default assumptions and reference values Incorporated Into an
Uptake/B1ok1net1c Model for lead (described 1n Section 4.1.) are also
discussed. Much of this discussion was taken from the recent OAQPS Staff
Report on lead exposure analysis methodology and validation (U.S. EPA,
1989a). In most populations, lead uptake occurs primarily as the result of
Intake of lead in air, diet, drinking water and dust; therefore, the
discussion 1s confined to these media. Intake of leaded paint chips can
contribute significantly to uptake 1n Infants and children living or playing
In areas contaminated with lead paint.
Uptake () of lead from a given exposure medium can be thought of as
the product of two separate processes, Intake (1^) and absorption (A^):
U1 = *1 ' A1
where Intake (1^) Is the product of the concentration of lead 1n any
specific media and the rate for the physiological mechanism of Intake (e.g.,
breathing rate).
Predictions of medla-speclf 1c lead uptakes must take Into account
environmental fate processes that determine concentrations of lead 1n
relevant media (see Section 3.2.), as well as behavioral and physiological
factors that affect Intake and absorption from these media.
3.3.1. Uptake from Ambient Air. Humans are exposed to lead In Indoor and
outdoor air. Uptake rates will be determined by the lead concentrations In
Indoor and outdoor air, the time spent Indoors and outdoors and physio-
logical determinants of deposition and absorption In the respiratory tract.
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A simple mathematical expression for this relationship ,1s as follows:
UA = v . OA • [Pb];THA
where U. 1s uptake from a 1 r Ug/day), V 1s the volume of air breathed/
A
day (m3/day), DA 1s the product of the respiratory deposition and absorp-
tion fractions and tPb]y^ the time-weighted average exposure concen-
tration (yg/m3).
3.3.1.1. INDOOR AND OUTDOOR AIR LEAD — Numerous factors determine
the concentration of lead 1n air at any given location (see Section 3.2.1.).
These Include distance and direction from emission sources, the nature of
the source and meteorological patterns that affect dispersion and deposition
of airborne lead. Many of these factors have been Incorporated Into predic-
tive models of airborne particulate dispersion, which can be used to predict
air lead levels associated with a given location near a point source (U.S.
EPA, 1986c).
Transport of lead from outdoors to Indoors accounts for virtually all
Indoor air lead 1n most modern buildings. Outdoor air lead enters buildings
through windows, doors, walls and a 1 r vents. Because the transport
processes are complex, relationships between outdoor and Indoor a 1 r lead
concentrations can be expected to vary from site to site. Factors that can
be expected to affect Indoor/outdoor ratios at a given site Include the
proximity to emission sources, which determines the size of outdoor air lead
particles, the permeability of entrance pathways (e.g., windows, doors,
walls) to lead, airflow patterns In and out of the building and meteoro-
logical conditions.
U.S. EPA (1986b) summarized data on Indoor and outdoor air lead levels
and concluded that, at most sites, outdoor concentrations exceeded Indoor
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concentrations. Indoor/outdoor concentration ratios ranged from 0.3-0.8,
with values 1n the lower end of the range near point sources, where lead
particles are larger (Cohen and Cohen, 1980).
3.3.1.2. TIME SPENT OUTDOORS — An estimate of dally exposure to lead
must be a time-weighted average of exposure to outdoor and Indoor lead;
therefore, Information on the relative amount of time spent In each environ-
ment Is required to estimate average exposure levels. Time spent outdoors
varies extensively with age, season, geographical location and a variety of
cultural and behavioral Influences. The following age-specific estimated
ranges for hours spent outdoors were derived from a literature review (U.S.
EPA, 1989a) summarized In Pope (1985) and reflect data reported 1n various
studies (Hoffman et al., 1979; Rubinstein et a 1 ., 1972; Suter, 1979; Koontz
and Robinson, 1982):
Age (years): 0-1 1-2 2-3 3-7
Time Outdoors (hours/day): 1-2 1-3 2-4 2-5
Based on Information on Indoor and outdoor air lead concentrations and the
average time spent outdoors and Indoors, an estimate of the time-weighted
average exposure concentration ([Pb]T1,.) can be calculated as follows:
IWA
tpb]7WA = «[Pb]Ao • Tq) ~ ([Pb]A1 • T1)) • (1/24)
where tPb]^0 and are outdoor and Indoor air concentrations
(vg/f3). respectively, and Tq and are average times (hours/day)
spent outdoors and Indoors.
3.3.1.3. INHALATION AND RESPIRATORY DEPOSITION AND ABSORPTION —
Intake of lead In air Is determined by the volume of air Inspired each day,
which varies with age, body size and level of physical activity (U.S. EPA,
1989c). Age-spec1f1c estimates of dally breathing volumes have been derived
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(Phalen et al., 1985), from which the foilowl|ng reference values for dally
breathing volumes 1n children were developed {Uj.S. EPA, 1989a):
Age (years): 0-1 1-2 2-3 3-4 4-5 5-6 6-7
Dally Volume (mVday): 2-3 3-5 4-5 4-5 5-7 5-7 6-8
The fraction of Inhaled lead that 1s deposited and absorbed varies with
airborne particle size and age (Chan and Llppmann, 1980; Phalen et al.,
1985; Xu and Yu, 1986). As 1s described In Section 2.2.1.1. (see Tables 2-1
and 2-2), age- and part1cle-s1ze-spec1f1c references values for these param-
eters have been derived from existing experimental data and physiological
models of the respiratory tract.
3.3.2. Uptake from the Diet. Uptake of lead from the diet (U^) can be
expressed as follows:
UD = !D * AD
where 1^ (pg Pb/day) Is the Intake from dietary sources and A^ 1s the
fractional gastrointestinal absorption (absorption coefficient) of dietary
lead. Dietary food Intake can be estimated from historical data on food
lead content (U.S. FDA, 1983, 1984) and data on food consumption
(Pennington, 1983). A Multiple Source Food Model has been developed that
partitions dietary sources Into three major categories: 1) metallic sources
Including lead solder 1n food cans and solder or pipe In drinking water
systems; 2) atmospheric lead deposited on food before and after harvest and
processing; and 3) sources for which an origin has not been established
(U.S. EPA, 1986b). These classifications allow projections for dietary
Intake based on projected adjustments 1n each category (e.g., a reduction In
atmospheric lead) (Cohen, 1988a,b). Projections for 1990 are presented 1n
Table 3-2.
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TABLE 3-2
Age-Spec1f1c Estimates of Total Dietary Lead Intake
for 1990-1996 (yg/
-------
Gastrointestinal absorption of dietary leaa varies with age, diet and
nutritional status (see Section 2.2.1.2.). Absorption Is an estimated
42-53% In Infants (Alexander et a 1., 1973; Zl'egler et al., 1978) and 7-15%
In adults (Kehoe, 1961a,b,c,; Chamberlain et al., 1978; Rablnowltz et al.,
1980). There 1s some evidence that gastrointestinal absorption of lead may
be a nonlinear process (Aungst and Fung, 1981; Marcus, 1989). Saturable and
nonsaturable absorption mechanisms have been described for essential metals;
thus, It Is reasonable to expect the existence of saturable and nonsaturable
mechanisms for lead. Kinetic constants (Kms) for saturable lead absorption
have been experimentally determined 1n the j_n vitro everted rat Intestine
(Aungst and Fung, 1981). The apparent Km for flux through the everted
Intestine was reported to be -125 ug/i. However, other dietary metals
may compete wUh lead for saturable absorption mechanisms (e.g., carrier-
mediated transport); therefore, the contribution of saturable mechanisms to
total absorption may depend on diet, nutritional status and the relative
magnitude of the Kms for each substrate for the saturable mechanism.
Kinetic constants for saturable lead absorption have not been determined In
primates.
3.3.3. Uptake from Dust and Soil. Children are exposed to lead in Indoor
and outdoor dust and soil, primarily fro« ingesting these materials as a
result of normal mouthing behavior and pica (abnormal tendency to Ingest
nonfood materials). Thus, the average daily exposure will be determined by
lead levels 1n each medium and amounts of e;ach medium that are Ingested
dally. The latter may vary with age, season, geographic location and
activity patterns. A simple expression for lead uptake from dust and soil
(Upg) 1s as follows:
UDS = °SING * *0S * [lPb]DS
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where DSj^g 1s oral Intake of dust and soil (g dust and soil/day),
1s the absorption fraction and [pb]os 1s the average exposure level (yg
Pb/g dust and son).
3.3.3.1. LEAD LEVELS IN DUST AND SOIL -- As discussed In Sections
3.2.2. and 3.2.3., levels of lead In dust and soil are determined by a
variety of factors related to the exposure source, meteorological condi-
tions, transport of dust Into the home and sources of lead 1n and around the
home (e.g., lead paint). The most desirable quantitative estimates for
localized areas are derived from adequate soil and dust monitoring data.
However, It Is Important that sufficient monitoring data are collected from
different local sites to produce meaningful estimates of the central
tendency of lead concentrations (e.g., arlthemetlc or geometric mean).
Since the lead concentration In soil may vary significantly between samples
collected In the same area, the use of a single sample to estimate lead
exposure to children may result In Inaccurate estimation of Ingested lead
uptakes.
In the absence of sufficient monitoring data, the geometric mean lead
concentration of soil and dust in certain sites can be estimated from
average lead concentration 1n the air using linear relationships described
In Appendix B of the U.S. EPA (1988a). This applies only to situations 1n
which air lead Is the primary source for soil lead. The derivation of these
relationships Include the following assumptions: 1) changes 1n the air
concentration will be followed by corresponding changes 1n soil lead and
Interior house dust lead concentrations; 2) the rate at which lead enters
soil/dust Is constant and equal to atmospheric deposition (plus other -
Inputs) minus soil removal; and 3) the environmental lead emissions have
been nearly constant for a sufficiently long time that lead levels in soil
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and dust arc In dynamic equilibrium. The derivation of the linear relation-
ships does not consider many complex variables that can affect air/soil
relationship for lead, such as chemical and physical properties of the lead
particles and soil, topographic and meteorological conditions, and the
frequency of precipitation and washing of streets and Interior surfaces.
The coefficients of the linear equations used to estimate soil/dust lead
from air lead were determined from monitoring data collected at sites where
both air lead levels and dust and surface soil concentrations were measured
and averaged over varying periods of time. The data used to determine the
coefficients were collected near lead point sources where emissions were
comparable with current lead exposure situations and lead contributed by new
houses and factories. Figure 3-2 Is a log arithmetic plot of average air
concentration versus average soil concentration for the data used 1n the
coefficient determinations for soil lead; the data are described In Appendix
A of the U.S. EPA (1988a). The raw data are fitted after a log transforma-
tion to yield geometric mean concentrations and the following linear
equations (U.S. EPA, 1989a):
[Pb]SOiL - a ~ b • [Pb]Ao
[PblDUST = c f d * ['Pb^Ao
where t Pb ] quST * ^b^S0IL an(* ^Pb^Ao are the concentrat1ons ^ead 1n
dust (vg/g), soil (vg/g) and outdoor air Ug/m3), respectively and
the coefficients a, b, c and d are 50.1, 579.0, 57.6 and 972.0, respectively.
The above equations are based on monitoring data for point source sites
such as smelters. The use of the linear equations to estimate soil and dust
lead levels near primary and secondary lead smelters may underestimate
current exposure because of historical accumulations of relatively large
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10000
I I
I I I I
> I I I I I
I I I I I I II
1000
¦ ¦
¦¦ * / ¦
100-r
¦ ¦¦
10+-
0.01 0.1 1
AIR CONCENTRATION (p.g/m3)
10
FI6URE 3-2
Plot of Soil Lead Concentration vs. A1r Lead Concentration
Monitored In Various Locations
Source: U.S. EPA. 1986b
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particles at these sites, regardless of currlent emissions controls (U.S.
EPA, 1989a). These sites will probably require separate estimates for
current soil and dust levels.
The relationship between air lead and soil and Indoor dust lead may
vary, depending on the lead emission source. For example, mining sites with
no history of smelter activity represent a situation 1n which the above
equations relating soil and dust lead with air lead may not apply. Review
of actual measurements of soil and house dust lead reported at mining sites
Indicated that, when soil lead was <500 ppm, house dust lead concentrations
were usually greater than soil lead, Indicating the greater contribution of
Indoor sources of lead. However, when soil lead was >1000 ppm, house dust
lead concentrations ranged from 18-48% of soil lead concentrations (Steele
et al., 1989). Thus, the air and soil lead levels at mining sites are not
Hkely to be related, and the relationship between soil lead and Indoor dust
lead levels may be nonlinear (Steele et al., 1989). Davles et al. (1985)
reported the following quantitative expression relating vegetable garden
soil lead and Indoor dust lead In a mining area:
[Pb]DUST = (0-3) * (l0g ™S0IL) + 'L65
The data on the time scales for soil and dust lead changes do not lead
to definite conclusions (U.S. EPA, 1989a). The current opinion Is that lead
1n undisturbed soil matrix persists for an extremely long time; however,
soil lead concentrations In disturbed (especially urban) environments will
change, on average, over periods of a few years to reflect changes 1n
surface deposition (U.S. EPA, 1989a). Although lead does deposit on the
surface of soils, significant lead concentrations have been found down to 12
Inches below the surface. This Indicates that human activities such as
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gardening and new building construction can result In significant concentra-
tions of atmospherically deposited lead In deeper soils. Interior dust lead
concentrations will likely change over periods of weeks to months 1n
response to air lead changes, depending on Interior-exterior access and
Interior recirculation or removal of dust as well as the primary sources of
dust and soil lead. Sources such as lead paint dust, mine-tailing and
smelters that have ceased to operate may continue to contribute lead to soil
and dust regardless of changes 1n air lead.
The linear and nonlinear equations yield approximations based upon the
best available monitoring data and Interpretations, but do not consider
various complex variables that may significantly affect soil and dust
concentrations. One approach to a more comprehensive model of Indoor dust
lead levels 1s to partition Indoor dust Into various source categories
Including air, soil, Indoor paint dusts, secondary occupational dusts and
hobbles (e.g., soldering). This approach has been Incorporated Into the
Uptake/Bloklnet1c Model as a user option (Section 4.1.1.). The multiple
source model sums the contributions of external environmental sources (I.e.,
air and soil) and "all other" sources to arrive at total Indoor dust lead.
The contributions of soil and air are calculated as follows:
'^'dust ' s ' [pb'sou
[">W ¦ a • Wao
where [P^quST* ^Pb^S0Il dnd ^Pb^Ao rePresent lead 1n dust (vg/g).
soil (yg/g) and outside air (yg/m3). respectively, and "s" (yg Pb/g
soil per yg Pb/g dust) and "a" (yg Pb/m3 air per yg Pb/g dust) are
conversion factors for soil and air. Other sources of Indoor dust lead are
added to the external environmental contribution to yield an estimate of
total Indoor dust lead. Including occupationally-der1ved dusts brought Into
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the home, Indoor dusts encountered outside tn;e primary nome (e.g., school,
day care and second home), and dusts from lead.based paint 1n the home.
Although a multiple-source model Is theoretically sound, much more
research 1s needed to develop empirical support for predictive quantitative
expressions of the relative contribution of each source to the levels of
lead 1n Indoor dust. Measurements of tracer elements In soil and Indoor
dusts provide data from which to derive an estimate for the soil-dust con-
version factor. Davis et al. (1990) measured the concentration of aluminum
and silicon In soil and Indoor dust and found the dust/soll ratios for both
metals to be -0.28. Assuming that Indoor aluminum and silicon are derived
entirely from transport of soil Into the house!, these data support a conver-
sion factor of 0.28 (s = 0.28). As noted above, the 0.28 conversion factor
will not be appropriate for all exposure sources. Monitoring data from mine
sites suggest that the relationship between soil lead and Indoor dust may be
nonllnear.
Empirical support for the air-dust conversion factor 1s difficult to
obtain because unique airborne dust tracers have not been Identified. An
a 1r-dus t conversion factor of 100 (1 wg Pb/g dust for each 100 vg
Pb/m3 air) was selected as an Interim default value for the multiple
source model until better data are available. It cannot be over emphasized,
however, that the use of adequately measured soil and dust concentrations Is
preferable to use of models or empirically derived equations.
3.3.3.2. INTAKE OF DUST AND SOIL -- Infants and children Ingest soil
and dust as a result of hand-to-moutn activity, consumption of food Items
that have been 1n contact with dust and soil, and soil pica. Considerable -
age-related and individual variation can be expected 1n these activities.
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Hand-to-nouth activity reportedly occurs 1n ~80K of children 1-2 years old,
and declines 1n years 3-6 {Mil 11 can et al., 1962; Barltrop, 1966).
Average soil Ingestion rates In young children have been estimated by
measuring the amount of soil or soil components on children's hands and from
assumptions regarding hand to mouth activity (LePow et al., 1975; Duggan and
Williams, 1977; Roels et al., 1980). Hawley (1985) summarized these data
and estimated that average soil Ingestion rates for 2- to 3-year-old
children range from 50-250 mg/day.
A more recent advance 1n this area has been the application of mass
balance studies, In which estimates of soil and dust Intake In children are
derived from measurements of the fecal excretion of poorly absorbed soil
minerals (e.g., aluminum, silicon and titanium) (Binder et al., 1986;
Clausing et al., 1987; Calabrese et al., 1989; Davis et al., 1990). A mass
balance equation used to calculate soil Ingestion (I
-------
Sedman (1989) analyzed data on fecal mineral excretion (Binder et al.,
1986), on mineral content of the diet and on food consumption 1n Infants and
young children (Pennington, 1983) to estimate soil Ingestion for 1- to
3-year-old children. Estimates were 40, 70 and 640 mg sol1/day based on
mass balances for aluminum, silicon and titanium, respectively. Clausing et
al. (1987) examined aluminum, silicon and titanium excretion 1n 18 nursery-
school children and 6 hospitalized children, ages 2-4 years. Estimates of
dietary Intake of each mineral were based on measurements of fecal excretion
of each mineral In the hospitalized children!. The average estimated soil
Ingestion- In the nursery school children for all three tracers was 56 mg
soil/day. If the values for dietary Intake from Clausing et al. (1987) are
applied to the Binder et al. (1986) data on fecal excretion, estimates of
soil Ingestion range from 80-135 mg soil/day for 1- to 3-year-old children
(U.S. EPA, 1989a).
The most comprehensive mass balance studies are those of Calabrese et
al. (1989) and Davis et al. (1990), In which] concurrent nonsoll Intakes of
the tracer elements were estimated for each subject In the study and
measurements of soil and house dust were used to estimate rates of Ingestion
of combined soil and house dust. The Calabrese et al. (1989) study,
Included 64 children ranging 1n age from 1-4 years. The Davis et al. (1990)
i
study examined 101 children ranging 1n age from 2-7 years. The results
reported for two tracer elements (aluminum and silicon) considered to be the
most reliable (8eck and Steele, 1990) are presented In Table 3-3. Estimated
mean combined soil-dust Ingestion rates for the two studies were 64 and 160
mg/day (Davis et al., 1990) and 154-483 mg/day (Calabrese et al., 1989). In
the Calabrese et al. (1989) study, one child out of 64 was Identified as
having an extremely high soil-dust Ingestion (5-8 g/day). When the data
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TABLE 3-3
Dally Soil Ingestion (mg/day) Based on Aluminum, Silicon,
Titanium and Y1ttr1um Mass Balance3
Element
Calabrese et al. (1989)
(n=64)
Davis et al. (1990)
(n=101)
Aluminum
154(30) «¦ 79
78b
64 (51)
S11 Icon
483(49) ~ 388
95b
160 (112)
T1 tanlum
170(30) f 86
268 (116)
YlttMum
65(11) ~ 91
NA
aValues are mean(median) + S.E.
bHean after deleting child with 5-8 g soil/day
NA = Not available
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were reanalyzed excluding this subject, the estimated mean soil Ingestion
rate for the group was 95 mg/day for aluminum and 78 mg/day for silicon
(Beck and Steele, 1990).
The results of the Calabrese et al. (1989) and Davis et al. (1990)
studies are In reasonable agreement with earlier mass-balance studies
(Binder et al., 1986; Clausing et al., 1987) and estimates obtained from
measurements of soil and soil components on the hands of children (Hawley,
1985). Thus, the current weight of empirical evidence supports a value of
-100 as an average soil-dust Ingestion rate In young children (ages 1-7
years). The results of the mass balance studies also suggest that the
distribution of soil Ingestion rates In the population may be highly skewed,
with a small percentage of Individuals exhibiting very high rates of Inges-
tion (I.e., pica for soil). This 1s evident from differences between the
mean and median values for soil Ingestion reported 1n the Calabrese et al.
(1989) and Davis et al. (1990) studies.
Given the skewed distribution of so 11-dust Ingestion rates, selecting
the most appropriate measure of central tendency, from which reference
values for soil-dust Ingestion can be established, 1s crucial. Basing the
reference values on the median soil-dust Ingestion rate rather than on the
arithmetic mean results In lower predicted soil lead exposures (and there-
fore lower predicted blood lead levels) because the median attaches no
weight to the level of exposure received by Individuals at the high end of
the soil-dust Ingestion distribution. Such an approach Is consistent with
current U.S. EPA risk assessment strategies for numerous other chemicals,
which are focused on the "general population" rather than on Individuals
expressing abnormal conditions or behavior that would promote exposure to a
toxic agent.
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The Issue 1s complicated by the fact that there 1s no clear consensus
regarding a quantitative definition of soil pica or the Incidence of
"abnormal" soil Ingestion behavior 1n children (U.S. EPA, 1989c). The
Incidence of abnormal soil Ingestion behavior Is estimated to range from
2-50% (U.S. EPA, 1989c). The wide range Is attributable to several factors,
Including the lack of a consensus among Investigators on a definition of
"abnormal" Ingestion behavior, as well as age, cultural, socioeconomic, and
disease related factors that may Influence Ingestion behavior 1n the various
populations of children. The only studies likely to provide definitive
Information on the distribution of soil Ingestion rates in the U.S. popula-
tion and are thus useful for risk assessment are the mass-balance studies,
1f applied to a sufficiently large sample. Studies that provide reliable
estimates of soil ingestion (Calabrese et al., 1989; Davis et al., 1990)
have been limited to relatively small sample sizes.
Until reliable estimates of the frequency distribution of soil Ingestion
rates for the U.S. population are developed, the reference value for soil
Ingestion 1n young children should be based on empirically derived arith-
metic means from the Calabrese et al. (1989) and Davis et al. (1990) studies
(—100 mg/day); however, extraordinarily high Ingestion rates reported by
Calabrese et al. (1989) {I.e., one child exceeding 5 g soil/day) should be
excluded. The reference value should be regarded as a default estimate to
be used In the absence of more specific data on soil Ingestion behavior In
the population being assessed. As such, 1t Is likely to overestimate
average soil Ingestion among some populations and underestimate soil inges-
tion In other study populations. The quantitative impact of such "errors"
on predicted distribution of blood lead levels are discussed in Section
4.1.1.
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3.3.3.3. GASTROINTESTINAL ABSORPTION OF. OUST AND SOIL LEAD — The
greatest source of uncertainty In the prediction of lead uptake from dust
and soil 1s the estimate of gastrointestinal absorption of lead. Iji vitro
studies have shown that the lead 1n dust and soil Is solublUzed 1n acidic
solutions similar to that found in the siomach; however, In alkaline
solutions similar to Intestinal fluids, lead can remain bound to soil (Day
et a 1 ., 1979; Harrison, 1979; Duggan and Williams, 1977). Dietary balance
studies have yielded estimates of 42-53% for gastrointestinal absorption of
dietary lead In Infants and children (see Section 2.2.1.2.); however,
absorption efficiency may differ for lead' 1n dust and soil. Two rat studies
have demonstrated that the bioavailability of soil lead Is less than that of
lead added to basal diets as lead acetate (Dacre and TarHaar, 1977; Chaney
et al., 1989). Diets supplemented with le;ad acetate are not entirely
analogous to diets 1n which environmental lead has been Incorporated Into
the dietary components; nevertheless, these results suggest that the absorp-
tion coefficient for soil may be lower than that for dietary lead. This may
not apply to all lead species and particle sizes and all soil types.
Absorption of lead for dust and soil Is Influenced by three Important
factors: chemical species, particle size and concentration In soil. Chaney
et al. (1988) demonstrated that absorption of lead from soil varies with
lead concentration In soil.
Particle size also determines the degree to which lead 1s absorbed Into
the body; the larger the particle size, the less the absorption (Barltrop
and Meek, 1979). For example, lead sulfide on larger particles eventually
dissolves In gastric fluid to the same concentration as lead sulfide on
smaller particles, but the process takes longer (100 vs. 200 minutes) (Healy
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et al., 1982). Thus, .ibsorptlon may be less In the stomach for the larger
particles because the particles do not remain In the stomach long enough to
become completely solublllzed. Therefore, It Is very Important when review-
ing site-specif 1c data to determine the prevalent particle size on which the
lead 1s located. In some locations where lead contamination In soil Is
high, such as mining areas, the particle sizes are much larger than In other
locations, such as smelter towns, possibly resulting In decreased bioavail-
ability. Lead species is another critical factor in determining bioavail-
ability. Barltrop and Meek (1979) reported that lead sulfide 1s signifi-
cantly less absorbed than lead acetate and lead oxides.
The Issue of bioavailability of lead for soil Is a major source of
uncertainty In the Uptake/Blokonetlc Model and merits further Investigation.
Applying Information on particle size, lead species and soil characteristics
In bioavailability estimates would prove very useful In further calibration
of the model.
3.3.4. Uptake of Lead from Drinking Water. Uptake of lead from drinking
water (Uy) can be expressed as follows:
uw = *w Aw
where IW (yg/day) Is the Intake from drinking water and Ay Is the frac-
tional absorption of Ingested lead. Intake of lead from drinking water can
be expressed as follows:
= [Pb]W ' WING
where (vQ/l) the average dally concentration of lead In
drinking water and Is the average amount of drinking water Ingested
each day. The amount of drinking water ingested will vary with numerous
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factors including age, body size, diet, physical activity, ambient tempera-
ture and humidity. Using data collected by the U.S. Department of Agricul-
ture In the 1977-1978 Nationwide Food Consumption Survey, average dally
Intake levels of drinking water have been derived (U.S. EPA, 1989c):
Age (years): 0-1 1-2 2-3 3-4 4-5 5-6 6-7
Ingestion (l/day): 0.20 0.50 0.52 0.53 0.55 0.58 0.59
3.4. ENVIRONMENTAL EXPOSURE LEVELS ASSOCIATED WITH BLOOD LEAD LEVELS
In the previous section, strategies for predicting uptake rates from
specific media (a 1r, diet and dust/soil) were described, which, In conjunc-
tion with bloklnetlc models, provide the basis for predicting relationships
between med1a-spec1f1c exposure levels and blood lead levels. An alterna-
tive approach 1s to derive mathematical descriptions of these relationships
from the analysis of human experimental and epidemiological data on environ-
mental exposure levels and blood lead. This section provides an overview of
the existing Information on relationships between levels In various media
and blood lead levels 1n humans. A more comprehensive discussion 1s
presented In other Agency documents (U.S. EPA, 1986b, 1989a).
3.4.1. Blood Lead/A1r Lead Relationships. The relationship between air
concentration and blood lead level In human populations reflects uptakes
directly from air by inhalation as well as oral uptakes of atmospheric lead
deposited on dust, soil, food and water. Several studies have provided data
on air lead levels and blood lead In human populations from which slope
factors (blood lead/air lead) can be derived (landrlgan et al., 1975; Roels
et al., 1976; Yankel et al., 1977; Morse et al., 1979; Angle and Mclntlre,
1979; Brunekreef, 1984). The aggregate slope factors, reflecting the"
combined Impact of air lead uptake from all media on blood lead, range from
2-20 (ug/dl)/(mg/m3) 1n young, moderately exposed children (U.S. EPA,
1986b, 1988a).
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Experimental studies In which changes In blood lead levels are measured
In human subjects exposed to lead aerosols yield estimates of slope factors
(blood lead/air lead) for Inhaled air lead. Several experimental studies of
adults have been reported (Kehoe, 1961a,b,c; Griffin et al.f 1975;
Rablnowltz et al., 1974, 1976, 1977; Chamberlain et al., 1978). The pooled
weighted estimate of the slope for the relationship between blood and air
lead for all of the studies Is 1.64+0.22 (S.E.) (yg/dl)/(mg/m3), and
1.9 (wg/dl)/(mg/m3) If subjects who were exposed to very high lead
levels (>36 yg/dl) In the Kehoe studies are excluded (U.S. EPA, 1986b,
1988a).
Analysis of cross-sectional data of blood lead/air lead relationships 1n
human populations can yield estimates of disaggregate blood lead/air lead
slope factors, reflecting the relationship between Inhaled lead and blood
lead In the population. If Information on noninhalation sources of exposure
Is sufficiently documented. Several adult human population studies have
been reported (Azar et al., 1975; Tepper and Levin, 1975; Nordman, 1975;
Johnson et al., 1975). In these studies, various approaches are used to
account for nonalr lead exposures. The range for blood lead/air lead slopes
are 1-2 (ng/di)/(mg/m3) (U.S. EPA, 1986b).
The U.S. EPA analyzed three studies of blood lead/air lead relationships
In children (U.S. EPA, 1986b). Estimated a 1 r disaggregate blood lead/air
lead slopes (vig/dt)/(mg/m3) for the three studies are 1.92+0.60 (Angle
and Mclntlre, 1979), 2.46+0.58 (Roels et al., 1980) and 1.53+0.84 (Yankel et
al., 1977; Halter et al;, 1980); the median slope Is 1.97 (yg/dl)/mg/ma).
3.4.2. Blood Lead/Dust and Soil Lead Relationships. Several studies have
provided data on blood lead levels In children and levels In local soil and
dust, from which blood lead/dust lead and blood lead/soil lead slope factors
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can be estimated (Barltrop et al., 1975; Yankel et al., 1977; Ner1 et al.,
1978; Angle and Mclntlre, 1982; Stark et al ., 1982). The range of mean
slope factors 1s 0.6-6.8 (yg/dl)/(mg Pb/g) soil (U.S. EPA, 1986b). The
range for blood lead/house dust lead slope 1s 0.2-7.2 (yg/dl)/(mg Pb/g)
dust (Stark et al., 1982; Yankel et al., 1977; Angle and Mclntlre, 1979).
Blood/soil lead slope factors vary, depending on the nature of source of
lead. A review of mining studies (Steele et al., 1989) Indicates that there
1s not a strong correlation between soil lead and blood lead (Heyworth et
al., 1981), that there are no elevated blood lead concentrations In areas
with very high soil lead concentrations (Heyworth et a "I., 1981), and that
slopes for mining sites are considerably lower than those for urban or
smelter sites (Barltrop et al., 1975; Barltrop and Strehlow, 1988;
Bornscheln et al., 1988). The estimated average slope for mining sites 1s
1.7 yg/dl/mg Pb/g soil; the average slopes for urban and smelter sites
were 3.2 and 4.2, respectively (Steele et al., 1989).
3.4.3. Blood Lead/Diet and Drinking Water Lead Relationships. The U.S.
EPA (1986a) has summarized studies relating j 1 etary Intake and blood lead
levels. The relationships appear to be nonlinear at dietary Intakes >200
yg Pb/day. When data are compared over the range of 100-200 yg dietary
Pb/day, blood lead/dietary lead slope factors ranging from 0.034-0.16 can be
obtained (Stulk, 1974; Cools et al., 1976; Schlegel and Kufner, 1979; Kehoe,
1961a,b,c; U.K. Directorate, 1982; Sherlock et al., 1982; Ryu et al., 1983).
The relationship between blood lead ievejl and drinking water level Is
nonlinear at water concentrations >i00 wg Pb/i water. The U.S. EPA
(1986b) concluded that the best estinute for the slope factor associated
with first draw water concentrations <100 yg/i was 0.06 (yg Pb/di
blood)/(yg Pb/t water) (Pocock et al . 1983). A more recent study was
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conducted by the Centers for Disease Control and the Department of Health of
the State of Hawal (Maes et al., 1989). This study examined a population In
Hawal 1n which historic exposure to airborne lead and lead In paint, dust
and soil are very low. A multiple linear regression model yielded a slope
factor of 0.024 pg/di blood/yg/1 water. A plecewlse linear model
yielded slope factors of 0.02 above 10 yg/i water and 0.13 below 10
vg/l water. More recent analysis of the relationship of blood lead and
dietary levels In Infants (Lacey et al., 1985; Ryu et al., 1983) supports a
slope factor of 0.2-0.25 (yg lead)/(di blood)/(yg lead/l) water for
Infants and children (U.S. EPA, 1988b).
3.5. SUMMARY
The primary source of environmental lead 1s atmospheric emissions from
automobiles and Industrial point sources that ultimately deposit 1n dust,
soil, ambient water and food. Direct contamination of soil with mine wastes
will be a major local source of exposure 1n some areas. Infants and
children appear to be the most vulnerable segments of the population to
environmental lead, because. In addition to Inhaling airborne lead and
ingesting dietary lead, they tend to Ingest dust and soil as part of their
normal behavior. Indeed, oral Ingestion of dust and soil can be the predom-
inant uptake mechanism 1n infants and young children. These same behavioral
tendencies place them at risk for Ingesting lead-based paint chips.
The biological effects of lead In Infants and children have been related
to blood lead levels, which are determined by the combined uptakes from the
respiratory and digestive tracts. Uptake from both routes can be expected
to vary appreciably with the nature and proximity of the exposure source, as -
well as age-related physiological variables that Influence Intake and
absorption efficiency.
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Although dust, son and dietary lead ane largely derived from atmo-
spheric deposition, simple relationships between airborne lead concentra-
tions and blood lead levels useful for derlWIng age-spec 1f1c and media-
specific risk assessments are not available. However, media- and age-
specific uptakes can be predicted using a multimedia uptake assessment
model, given certain assumptions regarding the nature and proximity to the
exposure source, levels of lead In each media, and behavioral and physio-
logical variables that Influence Intake and absorption. A b1ok 1ne11c model
can then be used to predict age-spec1flc blood lead levels associated with
multimedia uptakes. This multimedia l)ptake/B1oklnetlc Model approach Is
described 1n greater detail In Chapter 4.
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4. RISK CHARACTERIZATION
4.1. INTEGRATED LEAD UPTAKE/BIOKINETIC EXPOSURE MOOEL
This section describes the Uptake/B1ok1net1c Model developed by OAQPS
(U.S. EPA, 1989a) and New York University (Harley and Knelp, 1985) that
estimates age-specific blood lead levels associated with levels of continu-
ous exposure to air, dietary, drinking water, dust/soil and paint lead
sources. The uptake model accepts s1te-spec 1f1c data or default values for
lead levels In each medium. This Information 1s combined with assumptions
regarding behavioral and physiologic parameters that determine Intake and
absorption of lead from each medium to yield estimated rates of lead uptake
Into the blood. Behavioral and physiologic parameters are adjusted for
different ages and Include such Items as time spent Indoors and outdoors;
time spent sleeping; diet; dust/so 11 Ingestion rates; dally breathing
volumes; deposition efficiency In the respiratory tract; and absorption
efficiency 1n the respiratory and gastrointestinal tracts.
The bloklnetlc model accepts uptake predictions and computes age-
specific blood lead levels based on a six-compartment bloklnetlc model of
tissue distribution and excretion of lead. The model Incorporates default
assumptions regarding rate constants for transfers between blood and four
physiologic compartments: bone, kidney, liver and gastrointestinal tract.
Transfers from blood to urine, liver to the gastrointestinal tract and
mother to fetus are also considered. These assumptions Include adjustments
that reflect age-related changes in metabolism and physiology that affect
the distribution and excretion of lead (e.g., bone turn-over rates). The
Uptake/B1ok1net1c Model sums predicted uptakes over time to yield estimates
of blood lead levels associated with continuous uptakes over the lifespan.
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The uptake/bloklnetlc approach 1s extremely versatile and flexible 1n
that age-specific predictions can be made for multimedia exposures. Uptake
from all sources by all absorption routes can be separately modeled. This
provides an estimate of the relative Impact of changes 1n levels of specific
media on blood lead levels. The default assumptions and values on which
uptake rate and blood lead calculations are based can be replaced with
site-specific data or revised defaults. Thus,, the model can be updated as
new Information on exposure level, -Intake and uptake parameters become
available. This can be used to explore predictions regarding the Impact of
future trends 1n environmental lead levels resulting from proposed control
efforts and regulations.
4.1.1. Estimates of Lead Uptake. Presented 1n Table 4-1 Is the calcula-
tion scheme for deriving estimates of lead uptakes from four primary routes
of exposure to environmental lead: Inhaled air lead, lead 1n the diet, lead
In dust/soil and lead In drinking water. For Illustration, uptakes are
calculated for 2- to 3-year-old children (24-36 months of age) who were not
exposed to lead paint. However, the model will accept estimates of Intake
from Ingestion of lead 1n paint. This 1s discussed further 1n Section 4.1.2.
Formulas and default assumptions for each step 1n the uptake calcula-
tions are enumerated below (numbers refer to computational and Input steps
1n Table 4-1).
1. Outdoor Air Lead. The exposure concentrations (yg/m3) are
Inputs to the model. These can consist of site monitoring data or predic-
tions based on s1te-spec 1f1c source analysis such as those derived from the
Industrial Source Complex Dispersion Model {U.S;. EPA, 1986c).
2. Indoor Air Lead. The user is given the option of either entering
a value for Indoor air lead or estimating inooor air lead from outdoor air
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TABLE 4-1
Lead Intake and Uptake 1n 2- to 3-Year-01d Children Exposed
to Lead In A1r, Diet, Dust, Soil and Drinking Water*
Parameter
Default Value
1.
Outdoor air lead (yg/m3)
0.25
2.
Indoor air lead (pg/m3)
0.08
3.
Time spent outdoors (hour/day)
3
4.
Time weighted average (pg/m3)
0.10
5.
Breathing volume (m3/day)
5
6.
Lead Intake from breathing air (pg/day)
0.5
7.
X Respiratory deposition/absorption
32
8.
Lead uptake from air (pg/day)
0.2
9.
Lead Intake from diet (yg/day)
6.8
10.
% gastrointestinal absorption
50
11.
Lead uptake from diet (pg/da.y)
3.4
12.
Outdoor soil lead (pg/g)
200
13.
Indoor dust lead (pg/g)
200
14.
Dally soil-dust Ingestion (mg/day)
0.1
15.
Weighting factors (soil/dust)
45/55
16.
Lead Intake from dust and soil (pg/day)
20
17.
% gastrointestinal absorption
30
18.
Lead uptake from dust and soil (pg/day)
6.0
19.
Drinking water lead (pg/l)
4
20.
Drinking water Intake (i/day)
0.5
21.
Lead Intake from drinking water (pg/day)
2
22.
% gastrointestinal absorption
50
23.
Lead uptake from drinking water (pg/day)
1
24.
Total lead uptake (pg/day)
10.6
~Children not Ingesting lead paint
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lead. When the second option 1s selected, Indoor air lead 1s calculated as
follows:
[Pb]A1 = 0.30 • [P
where [Pbl^i and tPb^/\0 are tfle concentra
"a.
;1ons of lead 1n Indoor and
outdoor air, respectively, and 0.30 Is an empirically derived conversion
factor (see Section 3.3.1.1.). Indoor air lead Is calculated 1n Table 4-1
as follows:
[Pb]A1 = (0.30)(0.25 yg/m3) = 0.08 ug/m3
3. Time Spent Outdoors. Since .children may be exposed to lead 1n
both outdoor and Indoor air, exposure concentrations should reflect time-
weighted averages of exposure to both environments. The time-weighted
exposure level will be highly dependent on the amount of time children spend
outdoors. Activity patterns of children vary considerably with age, season,
geographic location and cultural factors. Therefore, 1n estimating time-
weighted average exposure concentrations, these factors should be charac-
terized In the population of Interest. The model defaults to a value of 3
hours/day for outdoor activity of 2- to 3-year-old children.
4. Time-weighted Average Air Lead Concentration. Computational
strategies for estimating time-weighted exposure concentrations are
discussed 1n Sections 3.3.1.1. and 3.3.1.2. In Table 4-1, the time-weighted
average air concentration {[Pb]) 1s calculated as follows:
[Pb]TWA= (([PblA0 ' V * ([Pb]A1 * V} * (1/24)
where Tq and T^ are the times spent outdoors and Indoors, respectively.
The calculation In Table 4-1 1s as follows:
CPb]TWA = (((0*25 hr)M(0.08l yg/m')(21 hr)))/24
= 0.10 yg/m3
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5. Breathing Volume. The model uses a default value of 5 m3/day
for the average dally breathing volume of 2- to 3-year-old children.
However, as discussed In Section 3.3.1.3., breathing volume may vary
considerably from this value, depending on body size and physical activity.
6. Lead Intake from Breathing Air. Intake from breathing (I ) Is
M
calculated as follows:
!A = V . [Pb]THA
where V Is the dally breathing volume (m3/day) and [Pb]ls
exposure concentration (yg/m3). Intake Is calculated 1n Table 4-1 as
fo1 lows:
1^ = (5 m3/day)(0.10 yg/m3) = 0.5 yg/day
7. Respiratory Deposition/Absorption of Inhaled Lead. The deposition
and absorption efficiencies of particles 1n the respiratory tract vary with
particle size, which may be related to the nature of the exposure source and
Its proximity (see Section 2.2.1.1.). The model uses a default value of 32%
for the estimated percent deposition and absorption of Inhaled lead
particles for 2- to 3-year-old children.
8. Lead Uptake from Inhaled Lead. Lead uptake from Inhalation of
airborne lead (U^, yg/day) Is calculated using the equation 1n Section
3.3.1.:
U - 1 • OA
A A
where 1^ Is the intake of airborne lead by the respiratory tract
(yg/day) and DA 1s the product of the respiratory deposition and absorp-
tion fractions. For the example presented in Table 4-1, uptake Is calcu-
lated as follows:
UA = (0.50 pg/day){0 3?) = 0.2 yg/day
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9. Dietary Lead Intake. As discussed 1n Section 3.3.2., typical
dietary lead Intakes for each age group are defined from the results of
Market Basket Surveys and analyses of food lead content (U.S. FOA, 1983,
1984; Pennington, 1983). The values presented 1n Table 4-1 are based on
data from dietary surveys completed 1n 1988. However, current dietary
levels may be lower because of decreases of lead 1n canned food (Cohen,
1988a,b). Strategies for projecting survey data forward 1n time to account
for these changes are discussed in Section 3.3l2.
In the example presented In Table 4-1, the default values for dietary
lead Intake used 1n the model do not change with Increasing air, soil or
water lead. The basis for this assumption Is that the typical U.S. diet
consists of foods harvested and processed In diverse geographical locations.
Thus, environmental contributions are not likely to be related to local
environmental lead levels. Exceptions to this can be anticipated. For
example. In rural areas where consumption of home-grown vegetables Is
common, local a 1 r or soil lead levels may be an Important determinant of
dietary Intake. In this case, s 1 te-spec 1f1c estimates of dietary Intake or
adjustments to the atmospheric source category could be used In the model In
place of default values. The model accepts data on the concentrations of
lead 1n home-grown fruits and vegetables, locally harvested fish and game
animals, and data on the estimated portion of the diet derived from each
food category. This Information 1s Incorporated Into the calculations of
dietary and total lead uptakes.
10. % Gastrointestinal Absorption of Dietary Lead. Empirical observa-
tions suggest that gastrointestinal absorption of dietary lead decreases
from a range of 40-50* In Infants to 7-15% 1n adults (see Section 3.2.2.).
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Since there Is evidence to suggest that saturable (passive) and nonsaturable
(active) mechanisms contribute to the gastrointestinal absorption of lead, a
comprehensive model of absorption should Include quantitative expressions
for both passive and active mechanisms. Both "linear" and "nonlinear
active-passive" models of gastrointestinal absorption have been Incorporated
Into the Lead Uptake/Bloklnetlc Model. The user 1s given a choice as to
which model Is to be used to estimate lead uptake. The linear model assumes
a constant absorption coefficient for dietary lead of 0.50, representing the
high end of the range of empirical observations In Infants. The following
relatively simple active-passive model has been Incorporated Into the
Uptake/Bloklnetlc Model (Marcus, 1990). The model assumes a "Michael 1s-
Menten type" of saturable function for the active component of lead absorp-
tion. The absorption coefficient (A^) at any given dietary Intake 1s
expressed as the sum of the passive absorption coefficient (ADp) and the
active absorption coefficient {AQA)r factored by the concentration for
lead In the gastrointestinal tract and the apparent Km for active absorp-
tion, as follows:
\ - A0P - ^[PbJg^Km)3))
where:
Ap = dietary absorption coefficient
A^ = coefficient for nonsaturable (passive) absorption
A^ = coefficient for saturable (active) absorption
[Pb]gj = concentration of lead In the gastrointestinal tract U9/1)
Km * apparent Km for saturable absorption (yg/l)
In the above model, the absorption coefficient decreases as the concen- _
tratlon of lead In the gastrointestinal tract ([PblPT) approaches and
ul
exceeds the Km for active absorption. The value of [Pb].T depends on both
Gl
Intake of lead and gastrointestinal volume, and thus will be age-dependent.
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The default values for 2- to 3-year-old children that are used In the
model are as follows:
Ag = 0.5 for the default dietary Vntake of 6.8 yg/day
V ¦ »•»
= 0.35 for the default dietary Intake of 6.8 yg/day
61 = ^ 'or *he ^efau^ dietary Intake of 6.8 yg/day
Km =100 mg/l
The relatively high value for Km of- 100 mg/l was selected to force the
model to be linear over anticipated dietary Intakes In children (I.e.,
constant saturable absorption coefficient). Thus, the values for saturable
and nonsaturable absorption coefficients sum to yield an absorption coeffi-
cient of 0.50, Identical to the default value used In the linear model.
However, the default outputs of the linear and active-passive models diverge
significantly If the value for the km 1s decreased. Although the active-
passive model Is theoretically sound and 1s a more accurate representation
of gastrointestinal absorption than one In which the lead absorption coeffi-
cient depends on Intake, strong empirical support for values for each param-
eter In the model is lacking. Default values, used 1n the Uptake/B1ok1net1c
Model were selected as reasonable estimates for these values and will be
revised as new Information becomes available.
11. Dietary Uptake. Dietary uptake (U^) 1s calculated as follows:
UD * !0 *D
where Ig (yg Pb/day) 1s the Intake '^on dietary sources and A^ 1s the
fractional gastrointestinal absorption of dietary lead. In the example
presented in Table 4-1, the calculation is as follows:
Up = (6.8 yg/day)(0.50) « 3.4 ug/day
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12. Soil Lead. The model accepts monitoring data for lead In soil; In
the absence of data, a default value of 200 yg/g Is used. Amounts and
patterns of lead distribution In soil vary considerably depending on the
nature of the lead source. Empirical relationships used to predict soil
lead levels associated with air lead sources and levels around mining sites
are discussed 1n Section 3.2.2. To Illustrate the computation scheme 1n the
lead Uptake Model, the default value of 200 yg/g 1s presented 1n Table 4-1.
13. Indoor Dust Lead. The Lead Uptake Model allows the user to select
from three options: 1) accept a default value of 200 yg/g; 2) Input
values In place of the default value, or 3) accept a multiple source model
that partitions Indoor dust lead Into several contributing sources. The
multiple source model sums the contributions of external environmental
sources (I.e., air and soil) and "all other" sources to arrive at total
Indoor air lead (see Section 3.2.2.). In the example presented 1n Table
4-1, option 1 1s used [I.e., Indoor dust lead 1s assumed to be equal to soil
lead (200 yg/g)].
14. Amount of Dirt Ingested. As discussed 1n Section 3.3.3.2., the
amount of d 1 rt (e.g., dust and soil) ingested dally can be expected to vary
with age and tendency for soil pica. In the example presented In Table 4-1,
a value of 0.10 mg/day Is assumed for 2- to 3-year-old children.
15. Weighting Factors for Soil and Indoor Dust. The relative amounts
of soil and indoor dust lead that are Ingested depend on time spent Indoors
and outdoors and activity patterns within each environment. The model uses
default weighting factors of 0.45 for son and 0.55 for Indoor dust.
16. Lead Intake from Ingesting Soil and Indoor Oust. The combined
lead intake from Indoor dust and soil (I) are calculated as follows:
!DS = 1 SOIL * 1 DUST
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where I$qjL Is the amount of soil lead Ingested and IgUST 1s the amount
of Indoor dust lead Ingested each day.
Lead Intake from soil (1 SOIL^ and 1ndoor dust ^DUST^ 3re ca1culated
as follows:
ISQIL . [Pb]S0IL • DSing • (0.45)
W = [Pb]0UST * dsing * <°-55>
where:
[Pb]Son = concentration of lead 1n soil (yg/g)
[Pb]DUST = concen*ra^on ^ead ^ndoor dust (yg/g)
DSTur = amount of Indoor dust and soil Ingested (g/day)
INb
0.55 = Indoor dust weighting factor
0.45 = soil weighting factor
In the example presented In Table 4-1, the calculations are as follows:
D$qil = 200 (yg/g) *0.1 (g/day) • 0.45 = 9 (yg/day)
Ddust = 200 (yg/g) • 0.1 (g/day) . 0.55 = 11 (yg/day)
ID$ = 9 (yg/day) * 11 (yg/day) = 20 (yg/day)
17. % Lead Absorption from D1rt. Quantitative Information on absorp-
tion efficiency of lead from Ingested dust and soil 1n humans 1s lacking.
As discussed In Section 3.3.3.3., experiments with animals Indicate that
lead 1n soil may be absorbed less than lead 1n food; the results of ]_n vitro
studies Indicate that lead Is likely to be solublUzed 1n human gastric
fluids. Both linear and nonlinear active-passive models of gastrointestinal
absorption of lead from Ingested water have been Incorporated Into the Lead
Uptake/Bloklnetlc Model (see discussion of gastrointestinal absorption of
dietary lead 1n this section for a description of the nonlinear active-
passive model). The user 1s given a choice about which model to use to
estimate lead uptake. The linear model assumes a constant absorption
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coefficient of 0.30 for soil-dust lead, which 1s lower than value of 0.50
assigned to dietary lead, reflecting the empirical evidence for lower
absorption from soil. The active-passive model 1s as follows:
ADS = A0SP * (ADSA/*1+^Pb]GI/Km)3))
where:
Ads = absorption coefficient for dust-soil lead
Aqsp = coefficient for nonsaturable (passive) absorption
Aq$a = coefficient for saturable (active) absorption
[Pb]Qj = concentration of dust-so11 lead 1n the gastrointestinal tract
(vg/l)
Km = apparent Km for saturable absorption (pg/l)
The default values for 2- to 3-year-old children who are used in the model
are as follows:
0.3 for the default dust-soil lead Intake of 20 yg/day
0.15
0.15 for the dust-soil lead intake of 20 pg/day
107 yg/l for the default dust-so 11 lead Intake of 20 vg/day
100 mg/t
The default value for the Km for active absorption has been set at 100
mg/l to force the model to linearity. Thus, the active and passive
absorption components sum to 0.30. which is identical to the default value
for the linear model.
18. Lead Uptake from Dust and Soil. Lead uptake from Ingested dirt
(Ujjg) Is calculated as follows:
DS
ADSP
adsa
[PbJ
Km
GI
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where Is the Intake from dust and soli (yg/day) and is the
fractional absorption. In the example presented In Table 4-1, the calcula-
tion Is as follows:
UDS = (20 yg/day)(0.30) = &-0 yg/day
However, when default values for the modell are used the outputs of the
linear and active-passive models diverge significantly 1f total Intake to
the GI tract exceeds 100 yg/day. This w1ljl occur when soil lead levels
exceed 1000 ppm.
19. Drinking Water Lead (yq/t). The default value for lead 1n
drinking water Is 4 yg/a.
20. Drinking Water Intake. The default value for dally water Intake
In 2- to 3-year-old children Is 0.5 i/day. This Includes tap water con-
sumed as water; tap water used to prepare food and beverages Is considered
1n the dietary section of the model.
21. lead Intake from Drinking Water. Lead Intake from drinking water
1s calculated as follows:
*W = ™W " WING
where (yg/l) Is the average dally concentration of lead 1n
drinking water and WjNg 1s the average amount of drinking water Ingested.
In the example presented In Table 4-1, the calculation of lead Intake from
drinking water 1s as follows:
Iy = 4 (wg/l) *0.5 (t/day) = 2 yg/day.
22. X Gastrointestinal Absorption of Drinking Water Lead. The
approach taken for calculating gastrointestinajl absorption of drinking water
lead 1s Identical to that described previously for dietary lead. The user
1s given the choice between a linear model or a nonlinear active-passive
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model. The default value for the absorption coefficient 1n the linear model
Is 0.50. The Km for active absorption 1s set to yield a sum of 0.50 for the
active and passive absorption components.
23. Uptake of Drinking Water Lead. Lead uptake from drinking water Is
calculated as follows:
UW = !W ' AW
where Iw (yg/day) Is the Intake from drinking water and Ay Is the
fractional absorption of Ingested lead. In the example presented In Table
4-1 1s as follows:
Uw = 2 (vg/day) • 0.5 = 1 ng/day.
24. Total Lead Uptake. Total lead uptake (U^) Is the sum of uptakes
from breathing lead In air, diet, drinking water and dust/soil Ingestion:
UT = UA + UD + UDS + UW
In the example presented 1n Table 4-1, the total uptake associated with
exposure to 0.25 yg/m3 Is calculated as follows:
UT = 0.2 + 3.4 f 6.0 * 2.3 = 10.6 yg/day
The calculation of media-specific uptakes presented 1n Table 4-1 shows
that the largest contribution to total uptake 1n 2- to 3-year-old children
1s from dust, soil and diet. The contribution of Inhaled airborne lead 1s
relatively minor. Because of the relatively large contribution of dust and
soil and diet lead to total uptake, predictions of total uptake will be
highly sensitive to changes In the values of Input parameters related to
these exposure media. Several examples are Illustrated In Figures 4-1
through 4-3.
Figure 4-1 shows the change In predicted total lead uptake In 2- to
3-year-old children as soil and dust lead Increases from 100-1200 yg/g.
2166A
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0.3 0.5 0.7 0.9
Soil and Dust Lead (n;g/g)
FIGURE 4-1
Total Lead Uptake In 2- to 3-Year-01d Children Exposed to Various Levels
of Soil Lead as Predicted by the Lead Uptake Model. Each line represents
the predicted lead uptake assuming different values for the gastrointestinal
absorption coefficients (Aqj) for dust and soil (10, 30 or 50%).
2166A
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25
0.3
0.9
0.5
0.7
1.1
0.1
Soil end Dust lead (mg/g)
FIGURE *-2
Effect of Varying the Absorption Coefficients for Lead In Diet and Hater
(Aq y) on Total Lead Uptake 1n 2- to 3-tear-Old Children as Predicted by
the'Lead Uptake Model
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[Pt]w = 4 ug/L
[Pb]w = 0 ug/L
25
20
1
0.1 0.3 0.5 0.7 0.9 1.1
Soil end Dust Lead (mg/g)
FIGURE 4-3
Effect of Varying the Concentration of Head 1n Drinking Water on Total
Lead Uptake 1n 2- to 3-Year-01d Children as Predicted by the Lead Uptake"
Model
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Three different values for the gastrointestinal absorption coefficient for
dust and soil were assumed In each plot (I.e., AQS = 10, 30 or 50% linear
absorption model). Values for all other parameters remained constant. The
figure Illustrates the sensitivity of the model to changes In the value of
the dust and soil absorption coefficients over a range that Is easily
accommodated by the currently available empirical data on gastrointestinal
absorption of lead.
The model 1s also highly sensitive to the values used for gastrointes-
tinal absorption of dietary lead. The model defaults to gastrointestinal
absorption coefficients of 50% for both diet and drinking water; however, a
value of 30% would not be entirely Inconsistent with currently available
empirical data. The effect modifying the absorption coefficients for diet
and drinking water from 50 to 30% 1n 2- to 3-year-old children 1s Illus-
trated 1n Figure 4-2. The result Is a downward parallel shift In the
uptake-soil lead relationship. Thus, the model predicts that at a soil lead
of 200 pg/g, decreasing the gastrointestinal absorption coefficients for
diet and drinking water from 50 to 30%, will decrease total lead uptake
by 30%.
The model predicts that uptake from drinking water will have the next
greatest Impact on total lead uptake, after dust-soil and dietary lead
uptakes are considered. However, the contribution of drinking water lead 1s
relatively small, compared with the contribution of dust-sol 1 and diet.
Hence, decreasing the concentration of lead 1n drinking water from 4 to 0
vq/l will have a relatively small effect on total lead uptake 1n 2- to
3-year-old children (see Figure 4-3).
4.1.2. Uptake of Lead from Ingested Paint. In the example presented 1n
Table 4-1, 1t was assumed that the population of 2- to 3-year-old children
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was not exposed to lead from paint. However, Ingestion of lead-based paint
chips can be a quantitatively Important source for lead uptake In children
living or playing In areas In which decaying paint surfaces exist. Lead
levels 1n the Indoor dust of homes with lead paint can be 2000 yg/g (Hardy
et al., 1971; Ter Haar and Aronow, 1974). A child who ingests 0.1 g of
Indoor dust each day would have a paint lead Intake of 200 yg/day.
Although not Illustrated In the example, the model accepts Input of age-
speclflc estimates of Intake from lead paint and Incorporates these values
In the calculation of total lead uptake. The computation strategy Is
similar to that used for calculating uptake from Ingestion of soil and
Indoor dust lead. Nonsaturable and saturable absorption mechanisms are
assumed to contribute to the uptake of lead solublUzed from paint In the
gastrointestinal tract.
The effect of lead paint Ingestion on total lead uptake can be Illus-
trated In the following example. Keeping all other parameters 1n Table 4-1
the same, an additional Intake of 200 yg/day of paint lead In a 2- to
3-year-old child Increases total lead uptake from 10-58 yg/day.
4.1.3. Uptake and Blood Lead Concentrations. Knelp et al. (1983)
developed a b1 ok 1 net 1c model for lead from data obtained 1n single dose and
chronic lead exposure of Infant and Juvenile baboons. Estimated physiologi-
cal and metabolic parameters for humans have been Incorporated Into the
model for baboons to develop a predictive model for humans (Harley and
Knelp, 1985). The resulting bloklneUc modei (Harley and Knelp, 1985) was
selected by the Office of Air Quality Planning and Standards of U.S. EPA
(1989a) to estimate age-specific blood lead levels associated with a given-
total lead uptake.
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The Harley and Kne'p (1985) model defines first-order rate constants for
exchanges between blood and four physiological compartments that contain
>95% of the lead body burden; bone, kidney, liver and gastrointestinal tract
(Heard and Chamberlain, 1984). Rate constants for transfer of lead from the
liver to the gastrointestinal tract and from blood to urine are also
specified 1n the model (see Figure 2-1). Rate constants are adjusted for
age-related changes 1n metabolism that affect the kinetics of distribution
and excretion of lead 1n children. For example, uptake and elimination rate
constants for bone are adjusted to account for expected changes In the rate
of bone turnover with age (Harley and Knelp, 1985). Similarly, age adjust-
ments In excretion of lead In the urine, the transfer of lead from blood to
liver and the fractional absorption from the gastrointestinal tract are
Incorporated Into the model.
The model predicts levels of lead In blood, bone, kidney and liver asso-
ciated with continuous lifetime uptake rates for children of various ages.
While complete validation of the model 1n humans 1s not possible, compari-
sons can be made with the results of dietary studies In humans. The follow-
ing data and discussion were taken from the recent OAQPS Staff Report on
lead exposure analysis methodology and validation (U.S. EPA, 1989a). Figure
4-4 compares the relationships between lead uptake and blood lead derived
from the various studies on Infants and adults. Despite the diverse nature
of the populations, study designs and methodologies, there 1s a fair degree
of consistency In the relationships. Each study found that a linear
function provided as good a fit, 1f not better, than other nonlinear forms
at the relatively low exposure levels investigated. Some experimental and
epidemiological data suggest, however, that the relationship between lead
concentrations In tissues and cumulative lead Intake Is only approximately
linear at low levels of Intake, and that successive Increments 1n Intake or
2166A 4-19 01/03/91
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Infants (Ryu'Lacey)
2-3 yr olds
(Biokmetc Model)
Adults (Sherlock.'Cools)
20 40 60
LEAD UPTAKE (^g/day)
100
FIGURE *-4
Summary of Relationships Between Dally Lead Uptake and Blood Lead for
Infants (Ryu et al., 1983; Lacey et al., 1983, 1985), Adults (Sherlock et
al., 1982; Cools et al., 1976) and 2- to 3-Y|ear-01d Children, Derived From
the Harley and Knelp (1985) B1ok1net1c Hodel
Source: U.S. EPA, 1989a
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exposure result In progressively smaller contributions to blood lead concen-
trations (Azar et al., 1975; Moore, 1977; Gross, 1981; Sherlock et a 1.,
1982). The curves drawn In Figure 4-4 for Infants and adults Include
smaller slopes for lead uptake values >20-40 ug/day. This curvilinear
relationship may be due to Increased renal clearance with higher blood lead
(Gross, 1981), distributional nonlInear1t1es that may be due to differences
1n lead binding sites In different tissues (Hammond et al., 1981; Marcus,
1985b; Wanton, 1985), or to a sizable pool of mobile lead In bone maintained
more or less Independently of uptake (Rablnowltz et al., 1977; Chamberlain,
1983). It appears, however, that none of the mechanisms Introduce signifi-
cant nonllnearltles at blood lead levels <30 ng/di, (Marcus, 1984,
1985a,c; Chamberlain, 1983) and that a linear mathematical model 1s valid
for relatively low to moderate lead exposures (U.S. EPA, 1986b). At levels
>30-40 pg/da, blood lead may be an inadequate Index for tissue lead
burdens In many children (P1ome111 et al., 1984) and linear models are
likely to lose their predictive power. For this reason, the relationships
depicted in Figure 4-4 are truncated at 30 ^g/dl. To estimate PbB
levels >30 yg/dl, which 1s now above the PbB level of health-related
concern for children, use of nonlinear models discussed In the criteria
document would be required (U.S. EPA, 1986b).
The Harley and Knelp (1985) Model has been extended In several
directions, based on recent data, to develop the current version of the
Uptake/Bloklnetlc Model. These extensions include the following:
1. additional compartmentat)on of the blood and bone lead pools
(Marcus, 1985a,c);
2. kinetic nonllnearlty 1n the uptake of lead by red blood cells
at high concentrations (Marcus, 1985c);
3. transfer of lead from the mother to fetus.
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The blood lead compartment 1s divided Into plasma and red blood cell
pools. The relationship between lead uptake and the concentration of lead
In whole blood may be nonlinear at concentrations >20 yg/dl (Marcus,
1985a,c; Marcus and Schwartz, 1987 ). This may result from decreased binding
of lead to erythrocytes at high lead concentrations (Barton, 1989).
The bone compartment Is divided Into cortical and trabecular pools.
Trabecular bone develops earlier and has a faster turnover (1-2 years) than
cortical bone. In children, a large portion of the body burden of lead Is
1n the more mobile trabecular bone pool.
The fetus receives lead from the mother Hi utero. and, thus. Is born
with a lead body burden that depends on that of the mother during pregnancy.
The ratio of newborn lead levels to maternal blood lead Is ~0.8-0.9 (U.S,
EPA, 1989a). A default ratio of 0.85 1s used In the model to estimate
newborn blood lead concentration. Maternal blood lead levels are estimated
from an uptake/b1ok1net1c model developed by Allen Marcus (Battelle-
Columbla) to emulate the uptake and bloklnetlcs of lead 1n the pregnant
woman. The essential components of the model are similar to those 1n the
model used to predict uptake and blood lead levels In the child, adjusted
for physiological values relevant to exposure and absorption. Intake from
air, diet, dust-soil Ingestion, drinking water, and occupational sources and
absorption coefficients for Inhaled and ingested lead from each medium are
used to calculate medium specific uptakes. Uptakes are summed to yield
total uptake, which 1s partitioned into the physiological compartments of
blood, bone, kidney and liver. Kinetic parameters for compartmental
transfers are adjusted for fetal age.
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4.2. CALCULATIONS OF PROJECTED MEAN BLOOD LEAD DISTRIBUTIONS: LEAD UPTAKE
LEVELS
The Uptake/Bloklnetlc Model predicts mean blood lead levels associated
with defined multimedia exposure levels. However, to assess the risks
associated with such exposures In a given population and evaluate potential
effects of regulatory or abatement decisions, the frequency distribution for
the population blood lead levels 1s a more useful parameter than population
means. The fraction of the population with the highest blood lead levels
will be the focus of regulatory and abatement decisions.
The distribution of blood lead levels 1s approximately log normal (U.S.
EPA, 1986b) and, thus, Is defined by Its geometric mean and GSD. It 1s,
therefore, possible to calculate the frequency distribution for blood lead
levels, given a mean blood lead level and estimated GSD for the population.
Estimated GSDs for blood lead levels 1n humans range from 1.3-1.4 (Tepper
and Levin, 1975; Azar et al., 1975; Bllllck et al., 1979). Schwartz (1985)
estimated a GSD of 1.428 for young children after removing the variance In
blood lead levels attributable to air lead exposure.
The OAQPS analyzed the NHANES II data on blood lead levels In adults;
estimated GSDs are 1.34-1.39 for adult women and 1.37-1.40 for adult men
(U.S. EPA, 1986b). The OAQPS (U.S. EPA, 1989a) also analyzed data from
various studies of blood lead levels In children living near lead point
sources (e.g., smoke stacks, smelters) (Baker et al., 1977; Yankel et al.,
1977; Roels et al., 1980; CDC, 1983; Hartwell et al., 1983; Schwartz et al.,
1986). The OAQPS concluded that
"Until additional data are available, a range of 1.30-1.53 will
therefore be assumed for children living near point sources as a
reasonable range of GSD values (Roels et al., 1980; CDC, 1983), and
the midpoint of 1.42 will be assumed as a reasonable best estimate."
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The Uptake/81ok1net1c Model assumes a GSD of 1.42 as a default v^lue.
It should be noted, however, that this value pertains to fairly homogeneous
populations (with respect to behavioral and pharmacokinetic factors) exposed
to similar mean levels of lead from the same sources. Other distributions
and levels of variability may be encountered in populations having subgroups
exposed to very different soil or a 1r lead concentrations.
Figure 4-5 shows the probability distribution of blood lead levels 1n
2- to 3-year-old children as predicted by the Uptake/81ok1net'ic Model and
assuming a GSD for blood lead of 1.42. The parameter values presented 1n
Table 4-1 were used to calculate uptake; maternal blood lead was assumed to
be 7.5 yg/dl. The model predicts a mean blood lead level of 2.98
vg/dl and that 0.02% of the children will have blood lead levels >10
vg/dl, the low end of the range of concern for adverse health effects
(I.e., 10-15 yg/di). Figure 4-6 shows the predicted relationship
between total lead uptake and mean blood lead level 1n 2- to 3-year-old
children. The numbers above each point on the; graph Indicate the percent of
children who are predicted to have blood lead levels >10 vg/dl-
Several validation exercises were undertaken to test the performance of
the Uptake/B1ok1net1c Model for predicting mean blood lead levels and
distributions In human populations (U.S. EPA, 1989a). Results of the most
extensive evaluation are shown In Figures 4r7 and 4-8. The Uptake/Blo-
k1 net 1c Model was used to predict blood lead levels In 299 children living
In the vicinity of lead smelter. The frequency distribution of the
predicted blood lead 1n Individual children was compared to the observed
distribution. When site-specific data for air, dust and soil lead were used -
in the model, predicted and observed mean blood lead levels and distribu-
tions were essentially Identical up to the 90tlj) percentile (see Figure 4-7).
2166A
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T *
«• L
• X
c o
V 0
A -
4
9 v
• w
• 6
- e
^ -
4 -
i i
k :
t. u
10.• u«/4L
e.82
99 .98
An: a.98
e 12 3496789 10 11
BLOOD LEAD CONCENTSAT ION
34 to 36 HonUt
FIGURE 4-5
Probability Distribution of Blood Lead Levels 1n 2- to 3-Year-01d
Children as Predicted by the Lead Uptake/B1ok1net1c Model. Uptake
parameters used to calculate blood leads are Shown In Table 4-1. Maternal
blood lead was assumed to be 7.5 yg/di. A value of 1.42 was assumed for
the GSD.
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74
2: 30 *0 50 6C
To'.ol ItsC Upt3i«« (nq/s;^)
FIGURE 4-6
Mean Blood Lead Levels In 2- to 3-Year-01d Children vs. Total Lead
Uptake as Predicted by the Lead B1ok1net1c Model. Maternal blood lead was'
assumed to be 7.5 yg/dft. A value of 1.42 was assumed for the GSD.
2166A
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Ul
100
90
80
70
p 60
£
LU 50
(J
£ 40
Cl
30
20
10
0
O Model Estimate
• Observed
10
20
30
40
50
60
BLOOD LEAD CONCENTRATION (jig/dl)
FIGURE 4-7
Comparison of Distribution of Measured Blood Levels In Children 1-5
Years of Age, Living Within 2.25 Miles of a Lead Smelter with Levels -
Predicted from the Uptake/Bloklnetlc Model. Measured dust and soil lead
levels were Included 1n the Input parameters to the model.
Source: U.S. EPA, 1989a
2166A
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100
O Model Estimate
• Observed
0
20
10
30
50
60
40
BLOOD LEAD CONCENTRATION (jig/dl)
FIGURfc
Comparison of Distribution of Measured B»ood lead levels In Ch11drf"J"^
Years of Age. Living HUhln 2.25 Ml«i of a Lead Smelter with Levels
Predicted from the Uptake/B1ok1net1c Model. Oust and soil lead levels wer
estimated using default calculations.
Source: U.S. EPA, 1989a
2166A
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Above the 90th percentile, the model slightly underpredlcted blood lead
levels. When default estimates of dust and soil lead were used In the
model, predicted mean blood lead levels were within 2% of those observed;
however, the model again slightly underpredlcted blood lead levels at the
highest percentile (see Figure 4-8).
4.3. SUMMARY
The Uptake/B1ok1net1c Model can be used to predict blood lead levels
associated with multimedia exposures to lead In air, diet, dust and soil.
The uptake model accepts monitoring data or estimated values for the levels
of lead 1n each media and predicts a range of lead uptake rates that will
result from exposure to each medium. The b1ok1net1c model accepts estimates
of total lead uptake and predicts mean levels of lead 1n blood, bone, liver
and kidney for children of different ages. Mean lead levels can then be
used to estimate frequency distributions for lead levels 1n populations of
children, assuming a log normal distribution and a specified GSD. The
results of several validation exercises Indicate that the Uptake/B1ok1net1c
Model accurately predicts mean blood lead levels associated with multimedia
exposures 1n children; however, It may underpredlct the highest level
expected to occur In an exposed population.
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