United States
Environmental Protection
Agency
TECHNICAL SUPPORT DOCUMENT
ON LEAD
u jo, lc}yf{
FINAL QMFT
ECA0-C1N-G7
October. 1989
Prepared for
OFFICE OF SOL 10 WASTE ANO
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: 00 NOT CITE 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 1s in Internal draft for revlev purposes only and dots not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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PREFACE
The U.S. EPA 1s developing health-related guidance for lead that can be
applied to i wide range of different raedla (soil/dust, air, diet). This
report summarizes relevant Information on health effects of lead and or, lead
exposure and presents a description of a proposed modeling approach for
deriving Md1a-spec1 f1c criteria that can be tailored to specific exposure
scenarios or cases. The rationale for using a nodellng approach 1n place of
more traditional risk assessment strategies such as Reference Dose Is
discussed. Much of the Information presented 1n this report 1* taken from
recent and more comprehensive Agency reviews, Including the A1r Quality
Criteria Oocument (U.S. EPA, 1966a) and Review of the National Ambient A1r
Quality Standards for Lead (U.S. EPA, 1989a).
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EXECUTIVE SUMURY
This technical support document presents the rationale for an uptake/
bloklnetlc modeling approach to developing health criteria for leao.
Because of the apparent lack of a threshold for many of the noncancer
effects of lead In Infants and young children, coupled with multimedia
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 associated with
exposure to lead can be correlated with blood lead levels. The Uptake/
81ok1net1c Model described In this document, and described 1n greater detail
1n U.S. EPA (1989a), provides a method for predicting blood lead levels 1n ^
populations exposed to lead 1n the air, diet, drinking water. Indoor dust,
soil and paint, thus making Tt possible to evaluate the effects of regula-
tory decisions concerning each medium on blood lead levels and potential
health effects. This model, when Integrated with the Industrial Soruce
Complex for Dispersion model (U.S. EPA, 1986c), could be used to predict
site-specific distributions of blood lead levels 1n populations 1n the
vicinity of point sources.
Review of the available Information concerning the toxicokinetics and
health effects of lead 1n humans (and primates as well) leads to the conclu-
sion that Infants and young children are likely to be the most vulnerable
segment of human populations exposed to lead and, therefore, should be the
focus of risk assessment efforts. Studies In nonhuman primates provide
strong empirical support for this conclusion. The relatively high vulner-
ability of Infants and children results froa a combination of several
factors: 1) an apparent intrinsic sensitivity of developing organ systems
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to lead; 2) behavioral characteristics that Increase contact *1th l«ad from
dust and soil (for example, mouthing behavior and pica); 3) various physio-
logic factors that result 1n greater deposition of airborne lead 1n the
respiratory tract and greater absorption efficiency from the gastrointes-
tinal tract 1n children than in adults; and 4) transplacental transfer of
lead that establishes a lead burden 1n the Infant before birth, thus
Increasing the risk associated with additional exposure during Infancy and
childhood.
A diverse set of undesirable effects has been correlated with blood lead
levels 1n 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
yg/dl. Although considerable controversy remains regarding the biolog-
ical significance of some of the effects attributed to low lead exposure
(e.g., blood lead levels below 10 yg/dl) remains, the weight of evidence
1s convincing that 1n infants and children, exposure-effect relationships
extend to blood lead levels of 10-15 yg/dl and possibly lower.
The Uptake/B1ok1net1c Model provides a means for evaluating the relative
contribution of various media to establishing blood lead levels. The
results of such an analysis reveal that for areas having air lead levels
that are typical for urban areas 1n the United States (e.g., 0.25 yg/m3), and
where the predominant lead source 1s assumed to be a point source (e.g.,
saelter/sMkt stack). Ingested lead will be the single largest uptake source
1n 2-year-old children; uptake from the respiratory tract will be almost
Insignificant. Tht model also predicts that «26X of the 2-year-old
children living in such an environment and not exposed to lead-based paint
but exposed to dietary lead levels as projected for tht 1990 U.S. average
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*111 hav« blood ltad Wv.lj >10 pg/dl. Chlldrtn txpostd to Uad paint
cm b« txptcttd to hav« considerably Mghtr blood lead lavtls. Th« Uptake/
B1ok1n«t1c Kod«l providts * us*ful
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TABLE OF CONTENTS
Paga
1. INTRODUCTION 1-1
1.1. RFO METHOOOLOGY ANO RATIONALE FOR RFO 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 B1ok1net1c Models for Lead 1-5
1.1.5. Multimedia Exposure Analysis 1-6
2. HEALTH EFFECTS SUMMARY 2-1
2.1. OVERVIEW 2-1
2.2. TOXICOKINETICS: ABSORPTION, OISTRIBUTION/BOOY BUROEN,
METABOLISM AND EXCRE1I0N 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 2-24
2.3.3. Effects of Lead on the Kidney 2-29
2.3.4. Effects of Lead on Blood Pressure 2-31
2.3.5. Effects of Lead on Serum Vitamin D Levels .... 2-34
2.4. DEVELOPMENTAL/REPRODUCTIVE TOXICITY AND 6EN0T0XICITY . . . 2-35
2.4.1. Mental Development tn Infants and Children. . . . 2-35
2.4.2. Growth Deficits 2-45
2.4.3. Effects on Fertility and Pregnancy Outcome. . . . 2-46
2.4.4. GenotoxIcUy : 2-46
2.5. SUMMARY T . 2-47
3. EXPOSURE ASSESSMENT 3-1
3.1. BIOLOGICAL EFFECTS: ENVIRONMENTAL EXPOSURE 3-1
3.2. MULTIMEDIA LEAD EXPOSURES: AIR, SOIL. OUST, HATER,
PAINT 3-3
3.2.1. Lead 1n Air 3-5
3.2.2. Lead In Soil 3-7
3.2.3. Lead in Oust 3-8
3.2.4. Lead In Diet 3-9
3.2.5. Lead In Hater 3-9
3.2.6. Lead In Paint 3-10
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TABLE OF CONTENTS (cont.)
_Eiat_
3.3. MEDIA-SPECIFIC ESTIMATES FOR DIFFERENT LEVELS OF LEAD
UPTAKE 3-11
3.3.1. Uptake from Ambient A1r . 3-11
3.3.2. Dietary Lead Uptake 3-14
3.3.3. Uptake from Oust and Soil 3-16
3.3.4. Uptake of Lead from Drinking Hater 3-24
3.4. ENVIRONMENTAL EXPOSURE LEVELS ASSOCIATED HITH BLOOD
LEAD LEVELS , 3-25
3.4.1. Blood Lead/A1r Lead Relationships 3-25
3.4.2. Blood Lead/Dust and Soil Lead Relationships . . . 3-27
3.4.3. Blood Lead/Diet and Drinking Hater Lead
Relationships 3-27
3.5. SUMMARY 3-28
4. RISK CHARACTERIZATION 4-1
4.1. INTEGRATED LEAD UPTAKE/BIOKINETIC EXPOSURE MOOEL 4-1
4.1.1. Est1mates~cf Lead Uptake. ....... 4-2
4.1.2. Uptake of Lead from Ingested Paint 4-13
4.1.3. Uptake and Blood Lead Concentrations 4-14
4.2. CALCULATIONS OF PROJECTED MEAN BLOOO LEAD DISTRIBUTIONS:
LEAD UPTAKE LEVELS 4-17
4.3. SUMMARY 4-23
5. REFERENCES 5-1
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LIST OF TABLES
No. Title Page
2-1 Estimates of Regions': Deposition and Absorption In the
Adult Respiratory Tract of Ambient Air Lead Particles
Found Near Point Sources 2-7
2-2 Age Factor Adjustments for Calculating 0epos1t1on and
Absorption of Ambient Air Lead Particles (Found Near Point
Sources) In the Respiratory Tract of 2-Year-Qld Children. . . 2-9
3-1 Typical Lead Concentrations 1n Various Exposure Media .... 3-6
3-2 Age-Specific Estimates of Total Dietary Lead Intake
for 1990-1996 (vg/day) 3-15
4-1 Lead Intake and Uptake 1n 2- to 3-Year-01d Children Exposed
to Lead In Air, Diet, Oust, Soil and Orlnklng Water 4-3
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LIST OF FIGURES
Mo. Title ?a;£
2.1 Schematic Model of Lead Metabolism In 2-Year-Old Children,
with Corcpartmental Transfer Rate Constants 2-17
2-2 Child IQ as a Function of Blood Lead Level 1n Children
3-7 Years Old 2-21
2-3 British Ability Scales Combined Score (BASC, Means and
95% Confidence Intervals) as a Fucntlon 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 1n Children 5-9 Years Old 2-23
2-5 Effects of Lead on Heme Biosynthesis 2-25
2-6 Blood ALA-0 Activity as a Function of Blood Lead Level
In 158 Adults 2-26
2-7 Problt Oose-Response Functions for Elevated Erythroblast
Protoporphyrin as Function of Blood Lead Level In Children. . 2-28
2-8 Erythrocyte Pyrlmldlne 5'-Nucleotidase Activity (P5N Units)
as a Function of Blood Lead Level 1n 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
1n Adult Men 2-32
2-10 Serum 1,25-01hydroxycho1eca1c1fero1 (1,25-CC) Levels as a
Function of Blood Lead Levels 1n 50 Children, 2-3 Years Old . 2-36
2-11 Mental Development Index Score (Mean and SO) as a Function
of Age for Children 6rouped Into Three Ranges of Cord
Blood Lead Level; Low, <3 vg/di. Medium, 6-7 yg/dl.
High, 10-25 yg/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 1n 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. Air Lead Concentration
Monitored 1n Various Locations 3-19
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LIST OF FIGURES (cont.)
No. T1tit Page
4-1 Summary of Relationships Between Dally Lead Uptake and
Blood Lead for Infants, Adults and 2- to 3-Year-Old
Children, Derived from the Har'ey and iCielp (198S)
B1oJr.1net1c Model. 4-«6
4-2 Probability Percentile of Blood Lead Levels In 2-Year-Old
Children Living Near One or Mere Lead Potnt Sources and
Not Affected by Blood Lead . . 4-19
4-3 Probability 01str1but1cn of Blood Lead Levels 1n 2-Year-01d
Children Living Near One or More Lead Point Sources and
Not Affected by Blood Lead ... 4-20
4-4 Comparison of Distribution of Measured Blood Lead Levels
1n Children, 1-5 Years of Age, Living H1th1n 2.25 Miles
of a Lead Smelter with Levels Predicted from the Uptake/
B1ok1net1c Model 4-21
4-5 Comparison of Distribution of Measured Blood Lead Levels
1n Children, 1-5 Years of Age, Living Within 2.25 Miles
of a Lead Smelter with Levels Predicted froa the Uptake/
B1ok1net1c Model 4-22
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n
LIST OF ABBREVIATIONS
ALA-D 4-amlnolevulInlc acid dehydrase
ALA-S ^-aminolevulinic acid synthetase
bw body weight
ONA Deoxyribonucleic acid
EP Erythroblast protoporphyrin
6CI 6eneral Cognitive Inde*
G-R Graham-Rosenbleth Behavioral Examinations for Newborns
GSO Geometric standard deviation
KIO Kent Infant development scale
LOAEL Lowest-observed-adverse-effect level
MDI Mental development Index
MAO Mass median aerodynamic diameter
NBAS Neonatal behavioral assessment scale
NOAEL No-observed-adverse-effect level
OAQPS Office of Air Quality Planning and Standards
POI Psychomotor development Index
PSN Pyr1m1d1ne-5'-nucleot1dase
RfO Reference dose
S.E. Standard error
WPPSI Wechsler preschool and primary scale of Intelligence
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1. INTRODUCTION
1.1. RFO METHODOLOGY ANO RATIONALE FOR RFO DEPARTURE
The Agency has established the RfD for the purpose of quantitative risk
assessment of noncarclnogsnlc chemicals. The RfO Is an estimate with an
uncertainty of one or several orders of magnitude of ths highest continuous
3
oral (mg/kg/day) or Inhalation (mg/m ) exposure that can occur over the
human lifespan without the occurrence of adverse" noncarclnogenlc health
effects (U.S. EPA, 1987, 1988a). In developing an RfO for a specific
chemical, the best available scientific data on the health effects of the
chemical 1s 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 RfO.
The uncertainty factor reflects the degree of uncertainty associated with
extrapolating the NOAEL identified from analysis of relevant human toxlco-
loglcal studies to the most sensitive fraction of the 'healthy* human
population.
When human toxicologlcal data are Inadequate to base conclusions
regarding human NOAELs, NOAELs or LOAELs for the most sensitive animal
species as defined by well-designed animal studies are utilized to derive
the RfD. Ooses or exposure levels are adjusted by conversion factors to
account for alloewtrlc (e.g., body weight) and physiologic (e.g., breathing
rates) differences between animal and humans. The adjusted NOAELs or LOAELs
are then adjusted by an uncertainty factor to derive the RfO. 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. Considera-
tion 1s given to uncertainties associated with extrapolations made from less
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than Hf«t1mt exposures to 11 fstim* exposures. fro® lOAEls to NOAEls and for
differences 1n sensitivity between animals and humans.
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. Absenct of a Discernible Threshold for Health Effects of Lead. A
critical assumption Implicit to the RfD 1s the concept of threshold that 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).
Analyses of correlations between blood lead levels and ALA-D activity,
vitamin 0 and pyrlmldlne metabolism, neurobehavloral Indices, growth and
blood pressure 1nd1catt that the associations may persist through the lowest
blood lead levels in the populations tested (*10-15 pg/dft). Thus, it 1s
possible that If a threshold for the toxic effects of lead exists, 1t may
lie within a rang* of blood lead levels <10-15 yg/dft; however, the data
currently available art not sufficient to adequately define the dose-
responsc relationship for many of the toxic effacts of lead In populations
having blood lead levels <10 yg/dft. Hence, 1t Is not possible to
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confidently Identify a blood lead level below which no undesirable health
•ffccts would occur.
There 1s no widely accepted theoretical basis for the absence of a
threshold for many of the health effects associated with lead exposure.
Because the extensive experimental and human epidemiological studies
published to date have failed to establish a threshold, 1t 1s prudent to
assume, for regulatory purposes, that a threshold does not exist.
1.1.2. Mult1atd1a Exposure Scenarios. Humans art exposed to lead from a'
variety of media; the relative contribution of each medium to total lead
uptake changes with age and can vary In 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 1n many but not all
cases will be primarily related to air lead levels 1n the vicinity.
Examples of exposure scenarios 1n which levels 1n soil and dust might not be
related to air lead art situations Involving contamination of soil and dust
with leaded paint dusts and deposition of lead for stationery sources no
longer In operation. Most adults, on the other hand, art txposed primarily
from dietary (food and water) sources. Occupational txposurts, however,
may result 1n a significant contribution froa tht Inhalation, dermal or
Ingestion routt.
A vlablt risk asstssmtnt methodology for lead that 1s to bt of any use
1n making rtgulatory dtclslons or for dtvtloplng s1tt-sptc1f1c abatement
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strat«g1 «s must be flexible enough to Incorporate s1te-spec1f1c Information
on exposure sources arid demographic data. An Ideal methodology would
Incorporate such Information or would accept default values where oata arc
not available and yield quantitative estimates of risk. In terms of
predicted population distributions of blood lead levels.
RfO methodologies do not accommodate such considerations because they
are basically route-specific risk assessments. The RfO can be defined as an
estimate (with uncertainty spanning perhaps an order of magnitude) of a
dally exposure to the human population (including sensitive subgroups) that
1s likely to be without appreciable risks of deleterious effects during a
lifetime (U.S. EPA, 1988a). For example, an Inhalation RfO Is an estimate
of the air concentration to which the most sensitive human populations can
be exposed for a lifetime without appreciable risks to adverse effects and
1n the absence of exposures from other sources (e.g., the oral route). The
latter assumption renders the Inhalation RfO for lead relatively Insignifi-
cant 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 In our understanding of
dose-response relationships for lead 1n humans because many of the health
effects of lead 1n humans appear to correlate with blood lead levels. Thus,
blood lead (yg/dft) Is a more appropriate "benchmark" for exposure than a
level In ilr (mg/m3) or an oral exposure level (mg/kg/day) would be.
Although It Is uncltar If thresholds exist for many lead exposure
scenarios, significant concern Is associated with blood lead levels. By
estimating changes in blood lead level, on* may estimate change in risk of
experiencing health effects associated with the blood lead level. 8y
examining changes in blood lead distribution, estimates of population risk
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may be derived. It 1s possible to define critical ranges of blood lead
levels and associated effects. In this way, blood lead levels can be used
to define risk In 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
of the effects, such as neurobehavloral deficits associated with prenatal
exposure, needs further evaluation. Therefore, It is not anticipated that
critical ranges of blood lead as currently stated will have universal
acceptance, nor 1s It reasonable to assume these levels 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 In 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 parenting 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 BloklMtU Models for Lead. It Is currently feasible
to utilize bloklnetlc models to provide predictions of blood lead levels
that will result from any given range of route-Independent lead uptake rates
and v1ce-ver»a (U.S. EPA, 1989a). These models allow "benchmark" blood lead
levels to bt related quantitatively to route-Independent uptake rates and
can provide estimates of frequency distributions of blood lead levels
associated with any given uptake rate.
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1.1.5. Multlwdl* Exposure Analysis. S1te-spec1f1c data or interna-
tionally consistent default assumptions regarding exposure scenarios and
absorption efficiency for lead Intake from various media can be Incorpo-
rated.Into existing multimedia exposure analysis methods to yield estimates
of the relative contributions of air, dietary ana soil lead to any given
estimated lead uptake (U.S. EPA, 1989a). Output from a multimedia analysis
could b« used to explore the possible outcomes of regulatory decisions and
abatement strategics on the distribution of blood lead levels in 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 1n the vicinity of
the site. This would be a far more useful risk management tool than a
route-specific RfO.
In summary, the RfO 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 1n
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 1n blood
associated with frank toxicity have been established. There 1s little or no
argument that excessive exposure resulting 1n lead levels extending upwards
from 30-100 yg/dl 1s associated with a variety of overtly toxic effects
on the peripheral and central nervous systems, kidneys and cardiovascular
system.
In the most recent decade a shift has been seen In 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 in a significant fraction of the general population.
In particular, several factors have stimulated a renewed Interest in
exploring exposure-effect relationships 1n Infants and children. These
Include (1) an appreciation that potentially significant lead burdens can be
established In the fetus In utero: (2) that specific behavioral patterns of
infants (4 weeks to 1 year) and children (1 to 5 years) facilitate intake of
environmental lead; and (3) evidence that infants and children may be more
sensitive an4 thus more vulnerable to some of the toxic effects associated
with lead; several factors have stimulated renewed Interest .
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
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reproducible measures of physical and mental development has been a particu-
larly Important advancement In this area. While considerable concerns
remain regarding the biological significance of some of the effects
attributed to low lead exposure, the weight of evidence Is convincing that
In Infants and children, exposure-effect relationships extend to blood lead
levels of 10-15 vg/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 1n relation to the number of children
potentially exposed to environmental lead levels associated with blood lead
levels of 10-15 yg/dl, even small Increases In blood pressure may be of
considerable public health significance.
The review that follows summarizes key issues relating to the toxico-
kinetics and health effects of lead in humans that will have to be con-
sidered 1n developing a responsible regulatory policy for lead. This review
is 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 vg/dl). 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
1s contained 1n the Air Quality Criteria Oocument on Lead (U.S. EPA, 1986b),
1n subsequent addenda and related U.S. EPA documents (U.S. EPA, 1988a,b;
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ATSDR/U.S. EPA, 1988) and 1n the recent ATSOR report to the U.S. Congress
(ATSDR, 1988). The reader 1s referred to these documents for « rwr?
comprehensive treatment of the subjects and literature contained 1n this
Chapter.
2.2. TOXICOtCIHETICS: ABSORPTION, DISTRIBUTION/BOOY BURDEN. METABOLISM AMD
EXCRETION
Anthropogenic lead emissions to air consist primarily of lead 1n the
Inorganic form; therefore, the primary focus of this chapter Is the toxico-
kinetics of Inorganic lead. Organic lead compounds, notably tetraethyl,
tetramethyl, trlethyl and trlmethyl lead, are also released Into the air
during the combustion of leaded gasoline. Lead alkyl compounds will
generally be a minor component of lead released to air, but the toxlcolog-
1cal significance can be appreciable under certain circumstances (e.g.,
children who "sniff" leaded gasoline). For this reason, the toxicokinetics
of lead alkyls are also discussed 1n this chapter, with an emphasis on
Identifying Important differences between the toxicokinetics of Inorganic
lead and lead alkyls.
2.2.1. Absorption. Oral absorption 1s quantitatively the most signifi-
cant route of uptake of Inorganic lead In most human populations; the
exception 1s occupational exposures in which inhalation of airborne lead
results In significant uptake. Oral absorption can result from ingestion of
food, water and beverages as well as nonfood sources, such as soil and
dust. Percutaneous absorption 1s not considered a significant route of
absorption of inorganic lead. The rate and extent of absorption of
Inorganic lead- 1s 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
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body, and may vary with specific exposure scenarios. Biological variation
related to age and nutritional status will also Influence absorption.
ATkyl lead compounds (e.g., trlethyl, trlmethyl, tetraethyl and tetra-
methyl lead) arc more highly lipophilic than Inorganic 1aad and art readily
absorbad from tha lung and sMn. Extensive absorption from th* gastrointes-
tinal tract 1s pradlctad based on structural similarities between alkyl
leads and alkyl tins.
2.2.1.1. ABSORPTION FROM THE RESPIRATORY TRACT — Inorganic lead In
ambient air consists primarily of particulate aerosols, having a size dis-
tribution that 1s related to the characteristics and proximity to emission
sources. Nhlle lead particles 1n most urban and rural air are 1n the
sub-m1cron range, particle sizes In the vicinity of point sources can vary
considerably (>30 to <2 >i/r) with distance from the source and meteoro-
logical patterns (Oavldson and Osborne, 1984; Sledge, 1987). The number of
inhaled lead particles of a given size range will vary with ambient air
concentration and breathing rates. The latter can be expected to 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
tim) deposit In the nasopharyngeal regions of the human respiratory tract
where high alrstream velocities and airway geometry facilitate Inertlal
Impaction (Chamberlain et al., 1978; Chan and Llppmann, 1980). In the
tracheobronchial and alveolar regions, where alrstream velocities are lower,
2164A 2-4 10/21/89
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processes such is sedimentation and Interception become important for
deposition of smaller particles (<2 vi»>- Diffusion and electrostatic
precipitation become Important for sub-micron particles reaching the
alveolar region. Mouth breathing can be expected to Increase aerosol
deposition In the tracheobronchial and alveolar regions because the Inhaled
lead 1n the air bypasses the Mucociliary obstruction of airflow to bypass
the nasal region (HiIter et al., 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 pa 1n 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 subsequently absorbed fron_the gastrointestinal tract. Sneezing and
coughing will clear a fraction of this lead from the body; only a fraction
that 1s swallowed 1s absorbed 1n the gastrointestinal tract. Therefore,
absorption of lead initially deposited 1n the upper respiratory tract will
not be complete. Estimates for fractional absorption of large particles
(>2.5 pa) deposited In the upper respiratory tract range from 40-501
(Kehoe, 1961a,b.c; Chamberlain and Heard, 1981).
Particles deposited 1n the alveolar region can enter the systemic
circulation after dissolution 1n the respiratory tract or after Ingestion
phagocytic cells (e.g., macrophages). Available evidence Indicates that
lead part1d«s deposited In the alveolar region of the respiratory tract are
absorbed completely. Human autopsy results have shown that lead does not
accumulate In tht lung after repeated Inhalation. This suggests complete
absorption from th« alveolar region (Barry, 1975; Gross et al., 1975).
203
Chamberlain et al. (1978) exposed adult human subjects to ""Pb 1n engine
2164A 2-5 10/21/89
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exhaust, lead oxide or lead nitrate (<1 i* particle size) and observed
that 90% of the deposited lead was cleared from the lung wtthln ".4 days.
Morrow et al. (1980) reported 50% absorption of deposited lead Inhaled as
lead chloride or lead hydroxide (0.25*0.01 yg MAO) within 14 hours. An
analysis of the radioisotope dilution studies of Rab1now1tz et al. (1977) in
which adult human subjects were exposed dally to ambient air 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 1n the human respiratory tract have been combined with
Information on size distributions of ambient air lead aerosols to estimate
deposition and absorption eff1c4«ncles for inhaled lead In adults and
children (U.S EPA, 1986b; Cohen, 1987). An example of estimates of average
deposition and absorption for adults living 1n the vicinity of a stationary
industrial source are provided In Table 2-1. Summing the fractional absorp-
tion values for each region of lung yields an estimate of 37.7% for the
fractional absorption of Inhaled lead In adults living 1n the vicinity of an
Industrial source. For some urban and rural atmospheres, where sub-m1cron
particles dominate th« airborne lead mass, fractional absorption is
estimated closer to 15-30% (Cohen, 1987).
Breathing patterns, airflow velocity and airway geometry change with
age, giving rise to age-related differences In particle deposition
(Barltrop, 1972; James, 1978; Phalen et al., 1985). Depositions In various
regions of the respiratory tract in children may be higher or lower than in
adults, depending on particle size (Xu and Yu, 1986). For sub-m1cron
particles, fractional deposition 1n 2-year-old children has been estimated
as *1.5 times higher than that In adults (Xu and Yu, 1986). Estimates of
regional and total fractional absorption In children can be calculated by
2164A
2-6
10/31/89
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TABLE 2-1
Estlaates of Regional Deposition and Absorption In the Adult Respiratory Tract
of Aatolent Air Lead Particles Found Near Point Sources*
Average Absorption
Particle 1 Aabtent Lead Average Deposition Efficiency of X Absorption of
Size Range Distribution Efficiency Deposited Lead Inhaled Lead
(|i) Near Point Sources
ALV* T-Bc N-P* ALV T-B N-P ALV" T-B M-P
<1.0
12.5
0.15
0.05
0.003
1 0.4
0.4
1.9
0.25
0.015
1-2.5
12.5
0.25
0.10
0.20
1 0.4
0.4
3.1
0.5
1.0
2.5-15
20
0.20
0.25
0.40
1 0.4
0.4
4.0
2.0
3.2
15-30
40
ID
0.05
0.95
1 0.4
0.4
NC
0.B
15.2
>30
15
ID
ID
0.95
1 0.4
0.4
NC
NC
5.7
'Source: Cohen, 1987
'Alveolar
'Tracheobronchial
'Nasopharyngeal
'For <1.0 }* In alveolar region: 12.5 x 0.15 x 1 • 1.91
ID - Insufficient deposition; NC - not calculated
2I68A
10/21/89
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Baking age-sped f1c adjustmtnts 1n rtglonal fractional absorption for adults
that art presented 1n Table 2-1. Adjustment factors for 2-y«ar-old
ch1ldren, derlvtd from tht analysis of Xu and Yu (1986), art shown 1n Tabi#
2-2. Summing tht rtglonal valuts yltlds an tstlmatt of 421 for fractional
absorption of Inhaltd ltad 1n 2-ytar-o*id chlldrtn living ntar a stationary
Industrial sourct. For gtntral atmosphtrts In which sub-m1cron particles
dominate tht ltad mass distribution, an adjustment factor of 1.5 can bt
applitd to tht tstlmattd rangt of 15-301 for adults (Cohtn, 1987).
Alkyl ltad can occur 1n tht atmosphtrt as a vapor or associated with
atmospheric particulates (Harrison and Laxtn, 1978). The retention and
absorption of gaseous tetraethyl and tetramethyl ltad has bttn txamlned 1n
volunteers who Inhaltd *^Pb-1abt1td tetraalkyl ltad (Htard tt al., 1979).
Initial lung rtttntlon was 37 and 511 for tttratthyl and tetramethyl lead,
respectively. Of these amounts, 401 of tetraethyl lead and 201 of tetra-
methyl lead was exhaled within 48 hours; the remaining fraction (tetraethyl,
601; tetramethyl, 801) was absorbed. Respiratory absorption of particulate
alkyl lead has not been studied.
2.2.1.2. GASTROINTESTINAL ABSORPTION — The gastrointestinal tract Is
the primary site of absorption of lead 1n 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 Itad-btsed paint. Nonfood materials are particularly
Important sources of lead Intake 1n children because of normal mouthing
behavior and pica. Inhaled lead that 1s deposited 1n the upper respiratory
tract and subsequently swallowed also contributes to gastrointestinal Input
(U.S. EPA, 1986b. 1989a).
2164A 2-8 10/21/89
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TABLE 2-2
Age F actor Adjustments for Calculating Deposition and Absorption
of Ambient A1r Lead Particles (Found Near Point Sources)
1n the Respiratory Tract of 2-Year-01d Children*
Age Factor Adjustment % Absorption of
Particle Deposition Efficiency _ Inhaled Leadb
Size Range
(urn)
AIVC
T-Bd
N-P*
ALVf
T-8
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
10
0.5
1.0
NC
0.4
15.2
>30
10
ID
1.0
NC
NC
5.7
^Source: Xu and Yut 1986
^Summing the regional values yields an estimate of 42% for fractional
absorption of inhaled lead.
cAlveolar
^Tracheobronchial
•Nasopharyngeal
fFor <1.0 ym In alveolar region: 1.9% (from Table 5-1) x 1.5 • 2.9%
10 • Insignificant deposition; NC • not calculated
2164A
2-9
10/31/89
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Gastrointestinal absorption of lead varies with age, diet and
nutritional status as well as the chemical species and particle size of the
Ingested lead. Dietary balance studies have yielded estimates ranging from
7-151 for gastrointestinal absorption 1n adults (Kehoe, 196la,b,c;
Chamberlain et al., 1978; Rabinowltz et al., 1980). Absorption may be 3-5
times greater 1f oral Intake occurs during a period of fasting (Blake, 1976;
Chamberlain et al., 1978; Heard and Chamberlain, 1982).
Gastrointestinal absorption of dietary lead Is greater In Infants and
children than In adults. A balance study In Infants of ages 2 weeks to 2
years, yielded estimates of 421 for children with dietary Intakes of 25 yg
Pb/kg bw. Lower dietary Intakes were associated with highly variable
absorption (Zlegler et al., 1978). A study conducted with Infants and
children of ages 2 months to 8 years (dally intake, 10 t>g Pb/kg bw)
yielded estimates of 531 for gastrointestinal absorption (Alexander et al.,
1973).
Gastrointestinal absorption of lead Is 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
1n the Air Quality Criteria Oocument 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 in calcium. Iron, phosphate, copper, vitamin 0, protein or
fiber, or diets having a lipid content. This suggests that Individuals with
poor nutritional status may absorb more lead fro* environmental sources.
Gastrointestinal absorption of lead alkyls Is not likely to be an
Important route of uptake of environmental lead because of the relatively
2164A
2-10
10/21/89
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high volatility of l«&d alkyls. The exception would be 1n situations where
people art Ingesting groundwater contaminated with tetraethyl lead. Th«
addle 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,
extensive absorption 1s predicted based on Information regarding the gastro-
intestinal absorption of the structurally similar Group IV analogs, trlethyl
and trlmethyl tins (Barnes and Stoner, 1958).
2.2.1.3. PERCUTANEOUS ABSORPTION — Inorganic lead 1s not readily
absorbed through the skin. Values of 0-0.31 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., 1980). Thus, percutaneous absorption Is 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 tetranethyl 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 1n which evaporation was allowed to occur,
percutaneous absorption of tetraethyl lead was 6.5X (Laug and Kunze, 1948).
2.2.2. Tissue Distribution of Lead. Mineralized tissues (e.g., bone and
teeth) arc the single largest pool for absorbed lead, accounting for >951
of total lead burden In adults and slightly less 1n children (Barry, 1975,
1981). Lead not contained 1n mineralized tissue 1s distributed 1n soft
tissues, primarily blood, liver and kidneys. Small amounts accumulated in
2164A 2-11 10/21/89
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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; Bellinger et al.,
1987a; 01etr1ch et al., 1907).
Elimination half-lives for lead 1n soft tissues are relatively short
(weeks). Estimates of elimination half-lives for lead 1n blood in adults
range from 15-35 days (Chamberlain et al., 1975, 1978; Rablnowltz et al.,
1973, 1976). Studies using adult and juvenile baboons Indicate that elimi-
nation half-Hfe for kidney and liver, and probably other soft tissues, are
similar to that for blood (Harley and Knelp, 198S). Because of the
relatively short half-11fe, accumulation 1n soft tissue does not continue
over the lifetime exposure (Schroeder and Tipton, 1968; Barry and Nossman,
1970; Barry, 1975, 1981). The exception Is the kidney cortex. In which lead
can accumulate In nuclear Inclusion bodies In uremic or hypertensive persons
(Indrapraslt et al., 1974). Abrupt Increases 1n blood lead levels can be
expected to result 1n new higher steady-state levels In blood and other soft
tissues within 60-120 days (Tola et al., 1973; 6r1ff1n et al., 1975);
however, following a decrease In uptake, lead 1n bone and other tissue
stores slowly redlstrl- butes to blood. Thus, more time may be required to
achieve a new steady- state blood level after uptake decreases, depending on
the level and duration of prior exposure (Rablnowltz et al., 1977;
O'Flaherty et al., 1982; 6ross, 1981).
Elimination half-lives In 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
2164 A
2-12
10/31/89
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steady state In bone (Rab1now1tz et al., 1976; Holtzman, 1978). Bone lead
can provide a store for continuous release of lead to soft tissues In the
event that uptake decreases (O'Flaherty et al.. 1982). Metabolic stress
resulting In Increased bone turnover or deralnerallzaUon, such as that which
normally occurs during pregnancy or aging, nay accelerate release of lead
from bone (Manton, 198S; 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.
Limited studies on the subcellular distribution of lead In humans and
more extensive studies using animals have shown that lead accumulates 1n the
nucleus and mitochondria (Goyer et al., 1970; Cramer et al., 1974; Flood et
al., 1988). Approximately 75% of lead In erythrocytes 1s bound to hemo-
globtn and other Intracellular proteins; most of the remaining 25% 1s
thought to be associated with low molecular weight Ugands such as amino
acids and nonprotein thiols (Bruenger et al., 1973; Raghaven and Gonlck,
1977; Everson and Patterson, 1980; Ong and Lee, 1980; OeSllva, 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 yg/dl, and may approach 2% of whole blood lead
at blood lead levels >100 yg/dft (Wanton 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 tt al., 1960). In blood, partitioning of lead between the
plasma and erythrocyte fractions varies with animal species and metabolism.
Trlethyl and trlmethyl lead bind tightly to rat hemoglobin and concentrates
In erythrocytes In this species. Human erythrocytes have a relatively low
2164A 2-13 10/31/89
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affinity for tHtthyl and tr1m#thyl lead (Bylngton it al., 1980). Aft#r
exposure to tetraalkyl leads, trlalkyl leads art found 1n the plasma (Boeckx
•t al., 1977; Goldlngs and Stewart, 1982). After humans Inhale 203Pb-
labeled titratthyl and tetramethyl laid, lead distributes 1n whola blood
primarily 1n the plasma fraction (Heard at al., 1979). Clearance from whole
blood Is nearly complete within 10 hours and 1s followed by the reappearance
of lead 1n erythrocytes. The shift 1n distribution of lead from the plasma
to the erythrocyte fraction of whole blood may reflect dealkylatlon in
tissues and the appearance of dlalkyl or Inorganic lead 1n the blood, which
has a higher affinity for erythrocytes than do tetraalkyl or trlalkyl leads.
Lead distributes to a variety of tissues after exposure to lead alkyls.
Levels of lead are highest In liver followed by kidney and brain 1n humans
that have been exposed to tetraethyl and tetraaethyl lead (Bolanowska ct
al., 1967; Grandjean and Nlelson, 1979). The kinetics of elimination of
tr1ethyl lead 1n humans has been described by a two-compartment model having
half-lives of 35 and 100 days (Yamamura et al., 1975).
2.2.2.1. METABOLISM OF LEAD—Metabolism of inorganic lead consists
primarily of reversible Hgand 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 Let, 1980; OeSllva, 1981).
Tetraethyl and tttramtthyl Itad undtrgo oxidative dealkylatlon to the
corresponding trlalkyl derivatives, which art thought to bt the neurotoxic
forms of these compounds. Dealkylatlon of tetraalkyl lead occurs 1n a
variety of species. Including humans (U.S. EPA, 1986b). The convtrslon from
tetraalkyl to trlalkyl lead Is catalyzed by a cytochroe* P-450 dependent
monooxygenast system In liver mlcrosomts (K1om1 et al., 1977) and occurs
2164A 2-14 10/21/89
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rapidly. The maximum rate of conversion of tetraethyl lead to tr1ethyl i«ad
was estimated to b« 200 ^g/hour/j liver In rats (Cremer, 1959). Complete
dea'kylatlon to Inorganic load has- been sbowr 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.
2.2.2.2. EXCRETION OF LtAO — Lead that 1s absorbed from all routes
1s excreted 1n the feces by biliary secretion, and 1n the urine, 1n «l:2
proportions (Chamberlain et al., 1978). Approximately 50-601 of absorbed
lead 1s excreted with a half-life of 30-50 days. The remaining fraction 1s
distributed to tissues, primarily bone, and 1s excreted with a half-Hfe of
several years (Kehoe, 196la,bit-, Rab1now1tz et a1-, 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, *101 of
urinary lead 1s In the form of trlethyl lead (U.S. EPA, 1986b).
2.2.2.3. BIOKINETIC MOOELS — Several mathematical models have been
developed to describe uptake, distribution .and excretion of lead (RablnowUz
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 Itvtls of ltad 1n various physiological compartments that
would b« associated with a given rate of uptake or exposure level. The
various models that have been suggested differ In complexity with respect to
the number of physiological compartments described, and assumptions
regarding kinetics of exchange between compartments.
2164A 2-15 10/21/89
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Tht model proposed by Rablnowltz et *1. (1976) was based on the results
of radioisotope tracer studies using volunteers. The model spec1f1#d 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 1n adult
and juvenile baboons (Knelp et al., 1983). The model was subsequently
modified to Incorporate age-related changes 1n metabolism and physiology 1n
humans (Harley and Knelp, 1985). Figure 2-1 Illustrates the model for
2-year-old children. Three major tissue compartments that exchange with the
blood compartment are defined In the model: bone, liver, kidney and gastro-
intestinal tract. First-order rate constants for exchanges between blood
and tissues are defined along w4-th rate constants for transfers of lead from
liver to the gastrointestinal tract (e.g., biliary secretion) and from blood
Into the urine.
Harcus (1985a,b,c) proposed a more elaborate model based on measurements
obtained from a volunteer subject who Ingested lead (OeSllva, 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
1n plasma. A unique feature of this model Is that 1t addresses nonllnear-
1t1es 1n the relationship between lead 1n blood and lead 1n plasma.
Of th« various models that have been proposed, the Harley and Knelp
(1985) model Is unique 1n that It yields age-specific predictions for lead
levels In the major tissues given specified rates of lead uptake Into blood.
This makes It particularly suitable for applications to risk assessments in
which predictions concerning the distributions of blood lead levels among
2164A 2-16 10/21/89
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INTAKE Ql S —» EXCRETION
LIVER
BLOOD
BONE
KIDNEY
URINE EXCRETION
S
k„ - 0.13
kfl -6.11 i 10"*
k - 0.07
it
k , - 0.09
k - 0.02
14
k - 0.07
41
k f . 0.01
k,, - 0.14
FIGURE 2-1
Schematic Model of Lead Metabolism In 2-Year-01d Children,
with Conpartaental Transfer Rate Constants
2164A
2-17
10/21/89
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various age groups within exposed populations art essential. Furthermore,
because lead uptake 1s a primary Input to the model, the model can be used
In conjunction with multimedia uptake models to predict blood lead levels
associated with exposure levels In various environmental media. The Harley
and Knelp (1985) model has been successfully validated using available human
experimental and autopsy data (U.S. EPA, 1989a). Because this model was
developed specifically to predict tissue lead concentrations over time in
young children with continuous lead uptake, the'model was selected by the
Office of A1r 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 in 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 AMD TARGET ORGAN TOXICITY
2.3.1. Neurobehavioral Toxicity.
2.3.1.1. LEAD NEUROTOXICITY IN ADULTS — Severe lead neurotoxicity 1s
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 In the range of 40-60 pg/di (U.S. EPA, 1986b).
Nonovert symptoms of neurotoxicity that have been associated with lead
exposure 1n adults Include Impaired performance on psychoeetor tests,
decreased nerve conduction velocity and Impaired cognitive function (e.g.,
10). Blood lead levels associated with these effects range upwards from 30
yg/dft (U.S. EPA. 1986b).
2164A
2-18
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2.3.1.2. LEAD NEUROTOXICITY IN CHILDREN — Symptoms of overt neuro-
toxicity In children art similar to those that art observed In adults.
Based on a review of available data. U.S. EPA (1986b) concluded that overt
symptoms can be anticipated 1n the most sensitive children having blood lead
levels 220 tig/dft.
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-r1sk" 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
paint 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 2*0-60 yg/dft (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 1n 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 (If any) effects on 10
1n general populations, especially 1n comparison with the much
larger effects of other factors (e.g., social variables), at the
exposurt levels evaluated In these studies (blood lead levels
mainly In tht 15-30 »g/dl range); and 2) they are not
Incoe^atlbl* with findings of significant lead effects on 1Q at
average blood lead levels (230 yg/di).
2164 A
2-19
10/21/89
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Several large-scale studlts 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 ilO-15 vg/di. a
brief discussion of the key prospective studies of Mental development In
Infants and young children Is presented 1n 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 10 scores and contemporary blood lead
levels was seen over the entire range of 6-47 yg/di In 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 chlldrer
1n Edinburgh, Scotland, also Indicated a negative linear correlation between
blood lead and scores on tests of cognitive ability (Fulton et al., 1987).
The correlation extended across a range of 5-22 yg/dA mean blood lead
levels (Figure 2-3).
A more recent study examined data on nerve conduction velocity 1n
children living In 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 jig/di (Figure 2-4). Animal
studies provide the opportunity to examine neurobehavloral effects of lead
under controlled conditions, which are not possible 1n human studies.
Recent dita with nonhuman primates provide strong support for high
sensitivity to lead In newborns (Levin et al., 1988; Bushnell and Bowman,
1979a,b; Gilbert and R1ce, 1987).
2164A
2-20
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g
o
x
o
120
•
•
110
-
•
100
• •* • ••
^ \ .
90
80
• : .
•
70
• •
•
60
m
• i i
% ••
5 10 IS 20 25 30 35 40 45 50
BLOOD LEAD LEVEL (jig/dl)
FIGURE 2-2
Child 10 as a Function of Stood Ltad lavtl In Children 3-7 Y«ar» Old
Sourct: Schrotdtr and Hawk, 1987
2164A 2-21 10/21
-------
I
il
h
o
I
I
-10—
-20
Blood toad (ug/dl)
FIGURE 2-3
British Ability Scales Combined Scort (BASC, Means ind
951 Confidence Intervals) as a Function of Blood Lead Level
In Children 6-9 Years Old
Source: Fulton et al., 1967
2164A
2-22
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H'l J i i r
i—r—r
0.02050
g 0.02000
iti
a
* 0.01950
2
>»
| 0.01900
u
tti
>
$ 0.01850
Qwwlfftte
MatMy
0.01800
p-^n' i ¦ 1 1 1 ' 1 »—1 I l T
0 IS 25 35 45 55 €5 75
81.000 LCAO ICVCL <»«/«)
FIGURE 2-4
Mix 1 Ml Ntrv* Conduction T1m as a Function of Blood Lead Ltv«l
1n Chlldran 5-9 Ytars Old. (Data from 202 children art fit
to logistic, quadratic and "Hocfcty Stick" aodtls)
Sourct: Schwartz it al., 1988
2164 A
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2.3.2. Effects of Lead on He«e Biosynthesis ar.d Erythropoles's. The
process of htm# biosynthesis 1s outlined In Figure 2-5. Lead interfirei
with heme biosynthesis by decreasing the activity of the enzymes ALA-0 and
ferrochelatase. Increased activity of the enzyme ALA-S may also occur as a
secondary effect of feedback regulation. While these effects can be most
readily demonstrated In erythroblast, there Is evidence that Indicates lead
may derange heme biosynthesis 1n 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.
Significant Impairment of hemoglobin synthesis occurs In adults at
relatively high blood levels. The threshold for a decrease in blood
hemoglobin In adults and children 1s achieved at a blood lead level of 50
vg/di (Meredith et al., 1977; Flschbeln. 1977; Alvares et al., 1975).
Frank anemia In adults has been associated with levels >80 vg/di (Tola
et al., 1973; Grandjean, 1979; 1111s et al., 1978; Wada et al., 1973; Baker
et. al., 1979). The relationship between blood lead levels and heme
biosynthesis In 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-0 or levels of EP, a
substrate for ferrochelatase. Erythroblast AlA-0 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/di, suggesting that inhibition of ALA-0 may occur at
2164A
2-24
10/31/89
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MITOCHONDRION
MITOCHONDRIAL MEMBRANE
QtfCME
SUCCNYL-CoA
FERflO-
OELAIASC
ALA SYNTVCIASC
flNCKEASE)
RON*P*OTOPOftPHYft»4
4
RON
Pt (owecTur om
BY DEREPRESSION)
AMNOLEVUJNC ACD
(ALA)
ALA
OEHYORASE
(DECREASE)
COPROPORPHYRW
(NCREASE)
t
PORPHOSLMOOEN
FIGURE 2*5
Effects of Lead on Hnm Biosynthesis
Source: U.S. EPA, 1986b
2164A 2-25 10/21/89
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FIGURE 2-6
Blood ALA-0 Activity As a Function of Blood Lead Level In 158 Adults.
(Solid Circles, Medical Students; Open Circles, Workers 1n Print Shop; Solid
Squares, Autonoblle Repair Workers; Open Squares, Lead Saelters and
SMpscrapers)
Source: NAS. 1972
2164A 2-26 10/21/89
-------
these low blood lead levels (Hernberg and NUckanen, 1970; Hernberg et al.,
1970; Roels et al., 1975, 1976; Lauwerys et al., 1978; Chlsolm et al.,
1905). The dose-response relationship for ALA-D Inhibition at levels <20
vg/di 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 in
humans Is critically reviewed 1n several Agency documents (U.S. EPA, 1986a;
ATSOR/U.S. EPA, 1988). The threshold for elevated EP 1n children 1s =15
vg/di (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
Plomelll et al. (1982) Is shown In Figure 2-7. The dose-response relation-
ships for elevated EP in children and adults when examined across a range of
blood lead levels extending from 10-40 yg/dl Indicate that children are
more sensitive than adults and that adult females may be more sensitive than
males (Roels 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., 198S). Elevated protopor-
phyrin levels, although not necessarily an adverse effect per se, are
Indicative of disturbances In heme metabolism that may extend to other heme
proteins. _
The enzyme P5N 1s also Inhibited by lead (Paglla and Valentine, 1975).
This enzym catalyzes the dephosphorylatlon of pyr1m1d1ne nucleotide
monophosphates and plays an Important role 1n the regulation of the levels
of pyrlmldlne nucleotides within the erythroblast. The pathological
significance of Inhibition of PSN by lead Is unknown; however, congenital
deficiency of this enzym. In which <10% of normal activity Is present in
the erythroblast. Is associated with a syndrome of hemolytic anemia
2164A 2-27 10/31/89
-------
1 —
— V ^
MB
1
f C • NATURAL FREQUENCY —
0 * *
• M
1 ' l
i
III-
10 20 30 40 90
BLOOO LEAD. UQ/dL
to
70
FIGURE 2-7
Problt Dost-Rtspons* Functions for Eltvattd Erythroblist
Protoporphyrin as Function of Blood Lttd Ltvtl 1n Children.
(Geomttrlc Htan * 1 SO - 33 pg/dft; G«oa«tr1c Mtan ± 2 SO • 53 pg/dft)
Sourct: P1oa«111 «t *1., 1982
2164A 2-28 10/21/89
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(Valentine et *1., 1974). Thus, Inhibition of erythroblast P5N may
contribute to the anemia associated with relatively high blood lead levels
(280 yg/di) (ToU et at., 1973; Grandjean, 1979; L1l1s tt al., 1978;
Wada et al., 1973; Baiter et al., 1979). The Inhibition of P5N may also
contribute to a disruption of mRNA and protein biosynthesis 1n the
erythroblast.
Inhibition of P5N 1n human erythrocytes can be detected from measure-
ments of the levels of pyr1m1d1ne 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 pg/dl.
This suggests that significant Inhibition of P5N occurs at blood lead levels
>30 pg/da (Angle et al., 1982). Catalytic activity of erythrocyte P5N
Is Inversely correlated with blood lead 1n children (Angle and Hclntlre.
1978; Angle et al., 1982). The correlation persists when examined across a
range of blood lead levels extending from 7-80 yg/dl, 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 pyrlmldlne metabo-
lism 1n children with blood lead levels >10-15 and possibly at
lower levels.
2.3.3. Effects on the Kidney. Acute lead-Induced nephrotoxicity 1s
characterized by proximal tubular nephropathy. Characteristic lesions
described In both huaans and animals Include nuclear Inclusion bodies and
mitochondrial changes In the epithelial cells of pars recta of the proximal
tubule and impaired solute reabsorption (e.g., glucose, amino adds,
2164A
2-29
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7X
100-
FIGURE 2-B
Erythrocyte Pyrlaldlne 5'-Nucleotidase Activity (P5N Units)
as a Function of Blood Lead Level In 25 Children, 1-5 Years Old
Source: Angle et al., 1982
2164A
2-30
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phosphate). Chronic toxicity Is characterized by Interstitial fibrosis and
decreased glomerular filtration rate (Goyer, 1982; U.S. EPA, 1986b;
ATSCR/U.S. EPA, 1938).
Acute nephrotoxicity has been observed In children with lead encephalo-
pathy and 1s associated with relatively high blood lead levels (I.e., >80
yg/dl) (Ch1sol« et al., 1955; Chlsola 1962, 1968; Pueschel et *1., 1972;
U.S. EPA, 1986b). Chronic nephropathy, Indicated by nuclear Inclusion
bodies, mitochondrial changes, Interstitial fibrosis and glomerular changes,
has been associated with prolonged (210 years) occupational exposures and
blood lead levels >40-60 >xg/dft (L111 s et al., 1968; Cramer et al., 1974;
B1ag1n1 et al., 1977; Weeden 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 1n adults has been examined
In several epidemiological studies. Particularly notable are four large
epidemiology studies: 8RHS, NHANES II analysis and two studies conducted In
Hales. 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) is shown 1n Figure 2-9.
The BRHS study analyzed data on blood lead levels and blood pressure 1n
7735 middle-aged men (aged 40-49) froa 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 froa «10-40 yfl/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 m Hg systolic pressure and 1.25 on Hg diastolic
pressure.
2164A 2-31 10/21/89
-------
1
> > »
•10 1 2 3
Estimated changa in mean systolic blood prassura
(mm Hg) for a doubling of blood laad
BRHS (N.7371)
NHANESII (N.2254)
Catrphiliy (N«116*)
Walts (N.865)
FIGURE 2-9
Coroarlson of Study Rasults from Four Largar-Scala Ep1d««1ology Studl«s
of Ltad-Blood Prassura RalatlonsMps 1n Adult Han. BRHS, British
S«rt StSy ; mm IX. JM1.MI Mitt ndItatrlt on
Evaluation Surv.y (Sehwrtz. 1988); CaarpMlly stud'"
(Elwood at al.. 1988a,b). Show* art atans and 951 confldanca Halts.
Sourca: Pocock at al., 1988
2164A
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Several analysts 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 ever 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 yg/dl) was associated with an Increase of 2-3 mm
Hg systolic blood pressure.
Two surveys conducted In Males examined the relationship between blood
lead and blood pressure (Elwood et a1.t 1988a,b). The Welsh Heart Programme
analyzed data from 865 men and 856 women. Mean blood lead levels were 12
tig/di for men and 10 yg/dl for women. A regression analysis was
applied to the data. No statistically significant relationship between
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 statls- tlcally 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 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
2164A 2-33 10/31/89
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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 In 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 in
humans appears to extend to blood lead levels <20 vg/dl, and possibly to
as low as 7 yg/dt. This suggests that as blood lead level Increases >7
vg/dt to levels >20 wg/dl, the risk for Increased blood pressure
Increases. The precise function that describes the dose-effect relationship
over a range of blood lead levels <40 wg/dt 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 wg/dl). With such a low magnitude effect, detec-
tion of effects <10 yg/dl 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.S. Effects of Lead on Serua Vitamin 0 Levels. 1,2S-01hydroxy-
cholecalclferol, the active from 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 1n the mineralization of bone.
2164A 2-34 10/31/89
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Deficiencies 1n 1,25-d1hydroxycholtcalc1f#rol are associated with d«crtased
bone mineralization and clinical syndrom of rickets in children. 1,25-01-
hydroxycholecalclferol may also stimulate gastrointestinal absorption of
lead (Smith et al., 1978). Serum levels of 1,25-dihydroxycholecalcUerol
are Inversely correlated with blood lead tn 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 vg/dfc; however, the
dose-effect relationship has not been characterized (Figure 2-10). Based on
a linear regression analysis of data on serum 1,25-d1hydroxycholecalciferol
and blood lead levels 1n children as well as data on 1,25-d1hydroxycho1e-
caldferol levels 1n other vitamin 0 related clinical disorders 1n children,
1t has been predicted that Increasing the blood lead levels from 12
yig/dl to 60 yg/dft will lower serum 1,25-d1hydroxycholecalc1ferol to
clinically adverse levels (Hahaffey et al., 1982). Chronic depression of
serum 1,25-d1hydroxycholeca1c1ferol 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/dl should be considered
potentially undesirable with respect to changes 1n 1,25-d1hydroxychole-
calclferol levels In children.
2.4. DEVELOPMENTAL/REPRODUCTIVE TOXICITY AND GENOTOXICITY
2.4.1. Mental Development In Infants and Children. The effects of
prenatal and neonatal lead exposure on fetal and neonatal mental development
have been examined In several epidemiological studies. Four prospective
studies Initiated 1n the cities of Boston, Cincinnati, Cleveland and Port
P1r1e, Australia are particularly notable. Based on an extensive
2164A
2-35
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«•
>•
>•
UOOO »». M'*I
FIGURE 2-10
S»ru» 1,25-D1hydroxycho1«ca1c1f«ro1 Uvcls is a Function
of Blood Laad Ltvtls In 50 Children, 2-3 Ytars Old
Source: Mahaff«y «t al., 1982
2164A
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•valuation of these studies, the EPA concluded that "All of these studies
taken together suggest that neurobehavloral deficits. Including declines in
Bayley HOI scores and other assessments of neurobehavloral function, are
associated with prenatal blood lead exposure levels on the order of 10-15
yg/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 longitu-
dinal analysis of mental development In Infants (Bellinger et al., 1987a,b,
1989a). Infants were classified according to "low," "mid" or "high"
exposure groups, based on cord blood lead levels at birth: "low," <3
ng/di; "mid." 6-7 pg/dA; "high." 10-25 pg/dA. The Bayley HOI
was administered to each child at ages 6, 12, 18 and 24 months. Data were
collected on a large number of~soc1al and medical covariates. Including care
taking and parental Intelligence. A deficit of 4.8 points on the HOI was
detected 1n children whose blood lead levels were 10-25 pg/dA at birth,
as compared with children whose blood lead levels were <3 pg/di at birth
(Bellinger et al., 1987a). A plot of covarlated-adjusted HOI scores vs. age
at testing for each group In the Bellinger et al. (1987a) study 1s shown 1n
Figure 2-11.
Preliminary results of an analysis of data collected 1n a follow-up
study has been reported (Bellinger et al., 1987b, 1989b). At age 57 months,
scores on the McCarthy Scales GCI were Inversely associated with blood lead
level at age 24 months (3-25 pg/dA), but were not correlated with cord
blood lead levels it 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 sodoeconoeilc factors. It appeared to be
2164A 2-37 10/21/89
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FIGURE 2-11
Mental Development Index Scort (Covarlate adjusted. Mean and SO)
as a Function of Age for Children Grouped Into Three Ranges
of Cord Blood Lead level; Low, <3 pg/di; Medlua,
6-7 t>g/dl; High, 10-25 yg/di
Source: Bellinger et al., 1967a
2164A
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more likely that cognitive deficits persisted to age 57 months 1n children
with higher postnatal blood Wad levels or less favorable socioeconomic
factors or both.
The data reported thus far from tht Boston study Indicate that lead
levels within or exceeding the range 10-25 pg/dA are associated with
decrements or delays In mental development. This 1s consistent with a 10-15
vig/da range of concern for undesirable effects 1n children.
Cincinnati prospective study. The study Initiated 1n Cincinnati
consisted of a longitudinal analysis of mental and physical development 1n
Infants (OletMch et al., 1987, 1988). HOZ was measured at 3, 6, 12 and 24
months. Structural equation modeling, a form of regression analysis, was
used to examine statistical Interactions between HOI scores and both
prenatal blood lead levels (range 1-27 yg/dft), cord blood lead levels
(1-28 jig/dl) and neonatal (10-day) blood levels (1-22 yg/dft), as well as
several other possible covarlables. Including medical and socioeconomic
parameters. The analysis revealed a statistically significant relationship
between elevated prenatal and cord blood lead and lower HOI scores at 3 or 6
months of age. At 12 months of age. however, neither prenatal nor cord
blood levels were significantly related to HOI scores although the relation-
ship between neonatal (10-day) blood lead and HOI scores remained statisti-
cally significant. At 24 months, neither prenatal, cord blood nor neonatal
(10-day) blood lead levels were significantly related to HOI scores. Thus,
the effects on mental development detected 1n the Cincinnati study appeared
to be transient. The Investigators hypothesized that the transiency of the
decrements 1n HOI scores might reflect a "catch up" response of Infants
related to lower birth weights or gestational age In the Infants with higher
prenatal blood lead levels (Section 2.4.2.).
2164A 2-39 10/21/89
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Postural sway was measured In a small group of 6-year-old children from
the Cincinnati cohort (8hattacharya et al., 1988). Pea* blood ltvtl at 2
years (9-50 pg/dl) was significantly related to postural sway at 5
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
1n the Boston study; therefore, 1t 1s more difficult to categorize effects
associated with a specific range of blood lead levels between 1 and 28
yg/dl. Nevertheless, the study corroborates some of the Important
findings of the Boston study because both studies detected an apparent
effect of lead on mental development (HOI scores) during the first 12 monthr
1n Infants exposed to prenatal blood lead levels or neonatal blood lead
levels <25 ng/di. Thus, the study supports 10-15 pg/dft as a range
of concern for undesirable effects 1n children.
Cleveland prospective study. The longitudinal study Initiated 1n
Cleveland 1s unique because 1t exanlned a series of neurobehavloral measures
of neonatal sensorimotor function. The tests included the Brazelton NBAS
for Habituation, Orientation, Motor Performance, Range of State. Autonomic
Regulation and Abnormal Reflexes, and the 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/di) but not
maternal blood lead (3-12 yg/di). Tht results of follow-up studies at
6, 12, 24 and 36 months were somewhat equivocal with respect to the effects
of 1«ad on mental development (Ernhart et al., 1987). Lower scores on the
POI and HDI of the Bayley Scales, and the KIO at 6 months were significantly
2164A
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related to higher maternal blood lead <3-12 yg/da.) but not to cord blood
lead (3-15 yg/dl). Concurrent 6-month blood lead was positively associ-
ated with KID score (e.g., higher blood lead levels were associated with
higher ICIO scores). A portion of the Cleveland cohort was tested at 4
years, 10 months on the KPPSI. After accounting for covarlates, significant
effects of lead were not detected (Ernhart and Morrow-Tlucak, 1987).
The Cleveland study examined a cohort having a range of relatively low
blood lead levels (<15 yg/dft). This say 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 Is likely that >5GX of women 1n
this cohort consumed considerable amounts of alcohol during their preg-
nancy. It 1s possible that the alcohol-Induced effects on physical and
mental development of newborns mask any subtle effects of lead. Neverthe-
less, the study corroborates the major finding of the Boston and Cincinnati
studies; the existence of a positive relationship between HOI scores during
the first year of postnatal life and blood lead levels.
Port P1r1e prospective study. The Port P1r1e study examined cohorts
of Infants born to mothers living 1n the vicinity of a lead smelting
operation 1n Port Plrie, Australia, and infants from outside the Port PiHe
area. Maternal blood and cord lead levels were slightly but significantly
higher 1n the Port P1r1e cohort than 1n the cohort from outside Port Plrie;
mean cord blood lead was 10 vs. 6 yg/dft. Reduced HOI scores were
significantly associated with higher Integrated postnatal blood lead levels
and with 6-ettntti blood lead levels, but not with prenatal or delivery blood
lead levels. Mean blood lead levels 1n the children were 14 pg/dft at 6
months of age and 21 yg/di at 15 and 24 months of age (McMlchael et al.,
1986; V1mpan1 et al., 1985; Baghurst et al., 1987). The results of a linear
2164A 2-41 10/21/89
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regression analysis of the data Indicated an apparent 4-polnt deficit In MOI
for every 10 yg/dt increase 1n blood lead. After making adjustments for
maternal IQ and care-taking environment, this deficit, decreased te 2 points
for every 10-yg/di increase 1n blood lead. Follow-up study of these
children at 4 years of age Included the McCarthy Scales of Children's
Abilities. Deficits In 6CI 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/dt was associated
with a 7-polnt decrease In GCI score.
Mexico City prospective study. Preliminary results of a pilot study
1n Mexico City for a longitudinal Investigation of developmental outcomes
related to lead esposure 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 (MO); umbilical cord blood lead
(UC) was also sampled at delivery. Mean maternal blood lead levels were
1S.0 yg/dl at 36 weeks of pregnancy and IS.4 yg/di at delivery.
Mean cord-blood lead levels at delivery were 13.8 yg/dl. The Brazelton
NBAS was administered to the Infants at 48 hours and IS and 30 days after
birth.
The data were analyzed by calculating the trend of the NBAS subscale
scores over th« first 30 days by linear regression analysis and by computing
the difference In M36 and HO 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
blvarlate correlations were found between UC blood lead and the 30-day trend
In NBAS Abnormal Reflexes (r-0.299, p<0.05), between the M36-M0 blood lead
2164A
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-------
difference and Regulation of States (r-0.378, P<0.05), and between the MO-UC
blood lead difference and Abnormal Reflexes
-------
0 - I
• - J«
4 VMTfl
• Vmt*
• Yi
3-7
• - I
L -+—¦f
brtwx**., tM
OrtirtiM*. 1«7
•« *. lM7a
(«*.. 1M7
MeMdwl « *. IMS
' M *. tM7b
>«*. 1N
Hwk«tA.1M
Uniit, i«7
i r
i«
20
FIGURE 2-12
Comparison of Results fro« Prospective and Cross-Sectional Studies of
Hental Oevelopaent. [Shown Is the rang# of blood 1ud levels (solid lint)
for which significant statistical associations for various Indicts of «ental
development and blood lead level wtrt detected. Studies art organized
vertically according to the aga at which tha deficit or delay was observed.]
2164A
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blood lead levels <30 yg/dl. Thus, 1t 1s probable that as blood Wad
levels approach >30 }>g/dft, the risks for undesirable effects Increase.
It 1s more difficult to draw conclusions regarding tht enact
relationship over the range of blood lead levels extending <30 yg/dl.
Tne Boston study (Bellinger et al., 1987a) Indicates significant effects on
mental development related to blood lead levels within the. range 10-25
pg/dl. The Cincinnati (Dietrich ft al., 1987), Cleveland (Ernhart et
al., 1985, 1987) and Port Plrlt (Baghurst ft il., 1987; McKlchael «t al.,
1988) studies 1nd1cite effects within the ranges of 1-28, 3-15 and 8-32
yg/dl, respectively. Given the results of the these studies, 1t 1s
reasonable to conclude that any threshold that night exist 1s 1n the range
of 10-15 ng/di blood lead, and possibly lower.
2.4.2. Growth Deficits. The structural analysis used 1n the Cincinnati
prospective study Indicated th*-poss1b111ty that the decrement In HOI scores
night have been secondary to lead-related effects on either gestational age
at birth or fetal birth weight (Dietrich et al., 1987). A separate
regression analysis of the Cincinnati data examined the relationship between
prenatal blood lead levels (1-26 |xg/d&) and birth weight (Bornschelm et
al., 1989). Oecreased birth weight was related to Increased maternal blood
lead levels. Maternal age was Identified as a major covarlate; thus, H
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) 1n Infants, 3-15 months of age. was Inversely corre-
lated to postnatal blood lead Increases. Mean blood lead levels Increased
from 5.3 yg/dft at 3 months to 14.6 ug/di at 15 months (Shukla et
al., 1987).
2164A 2-45 10/21/89
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Effects of lead on pre- and postnatal growth art supported by stveral
other studies Including Schwartz et al. <1986), Hard tt al. (1987). FaMm »t
al. (1976) and Hud and Boudeve (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 outcone In populations living
near and distant from a lead smelter. The risk for pre-term delivery was
positively related to maternal blood lead, over a range of £-32 pg/di
(McMlchael et al., 1986). The relative risk for pre-term delivery was 4.4
for maternal lead levels >14 pg/dA (range 14-32 yg/dft, mean 17
tig/dft).
Depressed sperm production and development has been associated with
occupational exposure to lead. Based on studies by Uncrtnjan et al. (1975)
and Hlldt 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 pg/dl (U.S. EPA, 1986b).
2.4.4. Genotoxlclty. Studies relating to genotoxlclty of lead are
reviewed 1n the Air Quality Criteria Document for Lead (U.S. EPA, 1986b).
Structural chromosomal aberrations and Increased sister chromatid exchanges
1n peripheral lymphocytes have been associated with chronic exposure to lead
resulting In blood lead levels 1n the range of 24-89 yg/di, although
effects «tr« not observed over this range of blood levels In numerous
studies (U.S. EPA, 1986b). This may reflect the differences 1n exposure
duration 1n relation to lymphocyte proliferation and turnover. In one
study, Increased sister chromatid exchange was positively correlated with
2164A 2-46 10/21/89
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exposure duration and zinc protoporphyrin levels, but correlated poorly with
blood lead level (Grandjean et a1.» 1983).
Bacterial systems generally art regarded as Inappropriate for assaying
metal 1ons. The U.S. EPA (1989b) reviewed the data on chromosome aberra-
tions 1n 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
calcium-deficient diets have exhibited a higher Incidence of chromosomal
aberrations than lead-exposed animals on standard diets. Other studies
reviewed by the U.S. EPA (1989b) demonstrated that lead compounds Induce
cell transformation 1n Ba1b/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. SIM4ARY
Correlation and regression analyses of data on blood lead levels and
various health effects point to a spectrum of undesirable effects that
become apparent 1n populations having a range of blood lead levels extending
upward from 10-15 yg/dft. These Include effects on hem« metabolism and
erythrocyte pyr1m1d1ne nucleotide metabolism, serum vitamin 0 levels, mental
and physical development of Infants and children and blood pressure in
adults. Although correlations between blood lead levels and certain effects
persist when examined across a range of blood lead levels extending <10
>tg/dft, the risks associated with blood lead levels <10 ng/dl are
less certain. Although It 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
2164A 2-47 10/21/89
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blood levels 1n the range of 10-15 wg/dl or possibly lower are likely to
be associated with one or more undesirable effects. Therefore, regulatory
decisions regarding environmental lead should take Into account the evidence
for potentially adverse health effects at relatively low blood lead levels.
The results of studies on the effects of lead In children are summarized
In Figure 2-13. Evidence from several studies supports a relationship
between prenatal and postnatal lead exposure 1n 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
vg/dt or possibly lower. As blood lead levels Increase above the range
of 10-15 yg/di, the risk for more pronounced effects on all of the above
endpolnts Increases. At levels >30 vg/dl, the risk for nephrotoxic Ity
and overt neurological effects (e.g., encephalopathy) becomes 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 In that the
consequences of early dtlays or deficits 1n physical or mental development
may have long-term consequences over the lifetime of affected Individuals.
Furthermore, mouthing behavior 1s a significant mechanism for lead uptake in
infants. Thus, Infants and young children can be expected to be particu-
larly susceptible to changes 1n lead levels In dust and dirt (see Chapter 4
2164A
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¦RNHQIMf
kamtOCVtLOMCMT —¦ ¦ ¦ ¦ ¦ . .. ¦
C»t*UA«»
tmtrH.oMLomton m ¦¦
i
-------
for further discussion). For these reasons. Infants and children (up to 2
years) can be considered to be tht critical sensitive population on which to
focus regulatory decisions regarding environmental lead.
Currently available Information on the b1ok1net1cs of Inorganic lead
Indicate that oral exposure to lead 1n food and beverages end 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
chlldrtn. 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 Infants and children. These studies
(Cincinnati and Port P1r1e) 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
1s bone, which has a relatively long elimination half-life. Lead 1s slowly
released froei 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 levels decrease. Release of lead from bone may
be accelerated 1n conditions of metabolic stress, including pregnancy, in
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. Physiologically-based pharmaco-
kinetic models that Incorporate age-related changes In bont 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.
2154A 2-50 10/21/89
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3. EXPOSURE ASSESSMENT
3.1. BIOLOGICAL EFFECTS: ENVIRONMENTAL EXPOSURE
The emerging evidence of a constellation of biochemical effects, a'ong
with subtle health effects at low levels of lead exposure (^30 v9/di>.
1s considered Indicative that low-level lead exposure has a far-reaching
Impact on fundamental cellular enzymatic, energy transfer and calcium honeo-
statlc mechanisms. These effects can be expressed 1n infants and children
as deficits 1n neurobehavloral and physical developments, and 1n adults as
elevations 1n blood pressure. With higher levels of exposure (blood lead
levels >30 yg/dl), overt symptoms of lead toxicity appear 1n the form of
anemia, neurological Impairment (e.g., encephalopathy), reproductive abnor-
malities and nephropathy.
The highest risks for adverse health effects fro« exposure to environ-
mental lead 1n most populations are likely to be assocUted with infants and
young children. Hence, risk assessment efforts related to environmental
lead usually focus on this segment of the population. The exceptional
vulnerability of Infants and young children reflects an apparently Innate
sensitivity of developing organisms to lead, as well as a variety of physio-
logic and behavioral factors that facilitate their exposure to relevant
environmental media. It 1s Important to emphasize that exposure to humans
begins in utero with tht transplacental transfer of lead from mother to
fetus. Thus, infants ire born with an Initial lead burden that reflects
prior envlronaental exposure of the mother and, to some extent, in uterQ
exposure of the mother. Environmental exposure that begins with birth adds
to this preexisting burden and may be transferred to the next generation of
infants.
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Environmental exposure during the earliest period of Infancy (0-6
months) 1s derived largely from the diet and, to a lesser extent. Inhalation
of Indoor airborne lead. With the onset of floor activity and crawling,
oral Intake from Indoor and outdoor oust and 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
rear a lead point source (e.g., smoke stacks, smelter) Is derived fro
-------
In general, Inhalation 1$ a quantitatively minor rout* of exposure for
Infants and children. Nevertheless, chlldrsn may be more vulner&blt than
adults to exposure to alrbornt lead particles. Physiologic characteristics
of the respiratory tract of Infants and children result in higher deposition
efficiencies of inhaled airborne particles than in adults (Phalen et al.,
1985; Xu and Yu. 1986).
To fully appreciate the significant of dilldhood 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 1n adults. The relationships reported to exist between systemic
arterial blood pressure and concurrent blood lead level In 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 1n this
area cannot be overemphasized. Regardless of the outcome of such studies,
the long biological half-life 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, DUST, HATER, PAINT
Humans art typically exposed to lead 1n a variety of media as a result
of the transfer of airborne lead to soil, water and food (Figure 3-1). The
primary anthropogenic Inputs to the air art autaaobllt exhaust and Indus-
trial emissions. Natural inputs to tht air can Includt geological
2165A
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AUTO
EMISSIONS
INDUSTRIAL
EMISSIONS
CRUSTAL
WEATHERING
AMBIENT
AIR
SURFACE AND
GROUND WATER
SOIL
PLANTS
ANIMALS
r PAINT ^
PIGMENTS
SOLDER
INHALED
AIR
DRINKING
WATER
DUSTS
FOOO
HUMAN
SOFT
TISSUE
BLOOD
LIVER
KIDNEY
BONES
FECES URINE
FIGURE 3-1
Pathways of Lead from the Environment to Humans
Source: U.S. EPA, 1986b
2165A
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processes such as volcanic activity and crustal weathering. Emissions to
ambient air eventually deposit In 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 1n drinking water
delivery systems and In food containers. L«ad-ba.sed 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., 1982). Shown In Table 3-1 are typical levels of lead 1n various
media. Including ambient air, 1n 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 1n Infants and children, through Inges-
tion of dust and soil.
3.2.1. Lead In A1r. Hhereas, at one time, automobile exhaust accounted
for «901 of all air emissions 1n the United States, the recent phase-down
of lead content of gasoline and reductions in usage of leaded gasoline have
and will continue to substantially decrease the contribution of automobile
exhaust to air 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 1s emitted from vehicles
primarily as particles of inorganic lead, with a small percentage as
volatile lead alkyls. Of the automotive lead emissions deposited, «501 is
within less than a few kilometers of roadways, whereas smaller particles can
travel for thousands of kilometers (Huntzicker et al., 1975; U.S. EPA,
1986b).
2165A
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1A61C 3-1
Typical Lead Concentratims in Various Exposure Hedia'
NmUm Rural Area Urban Area Near Point Source(s)*
Aabient air (|tg/e»)c
6.1
6.1-6.3
6.3-3.6
U.S. CPA. 1969a
Indoor air (pgAu)
6.61-6.66
6.63-6.2
6.2-2.4
U.S. CPA. 1966b
Soil (pp«)
5-36
36-4566
156-15,666
U.S. CPA. 1966b; Hielke et a)., 1963
Street dust (ppa)°
66-136 (96)
166-5666 (1566)
(25.666)
Nriagu. 1976; U.S. CPA. )966b
House dust (ppi)a
56-566 (366)
56-3666 (1666)
166-26.666 (16,660)
U.S. CPA. 1969a; tandriqan et al..
Horse et al.,1979; Angle and Hclntire. 1979
lypical foods (ppa)
6.662-6.6
6.662-6.6
6.602-6.8
Hegel et al., 1966
Water (pg/d)
S-2166
S-2166
5-2100
U.S. CPA. 1969a; Gardels and Scrg. 1969
Paint' («g/cai)
<1 to >5
<1 to >5
<1 to >5
U.S. CPA. 1969a
"Source: U.S. IPA, 1969a
*Within 2-5 k« of sources including primary and secondary lead saelters, battery plants
'Represents quarterly averages Monitored in 1966
'Range of indoor/outdoor ratios used (6.3-6.6) fro* U.S. CPA (1966b) except near point sources where large particles predominate and infil-
tration into hoaes is low; ratio appears lo bo closer to 6.3 (Cohen and Coken, 1966).
"Values in parentheses represent estiaates provided In U.S. CPA (1966b) as typical averages.
'Since there may be several layers of load-based paint on a given surface, absolute concentration of lead is less useful tban ma/emt.
Surveys by HUD U Pittsburgh showed that >76X of pre-1946 dwelling units and 26X of post-1966 units had at least one surface with >1.5
og/coi load paint (HAS. 1966).
? I6#A
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Sources of Industrial emissions Include fugitive •missions from lead
mining, primary and secondary laad inciting, battery plants, and ccKbustior.
of oil, coal and municipal waste (U.S. EPA, 1986b). Dispersal of partlclas
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).
Concentrations In ambient air have declined over the last decade as a
result of the phasedown of leaded gasoline production and use, and reduc-
tions 1n emissions from stationary sources (U.S. EPA, 1989a).
3.2.2. Lead In Soil. Lead released to the air deposits on terrestrial
surfaces and enters the sol 1-r-where 1t can have several possible fates.
Lead can be retained in organic complexes near the soil surface. For
example. Insoluble lead species may be free or complexed metals adsorbed on
solid Inorganic or organic matrices. Studies of 1ead/so1l Interactions show
that soil fixation of lead 1s mainly affected by pH, cation exchange
capacity and organic matter content of soil. While 1t 1s true that, 1n a
variety of soils, lead appears most strongly asoclated with soil organic
carbon fraction (Zlmdahl and Skogerboe, 1977), no correlation 1s seen
between organic content and lead concentrations 1n "brown soils"
(Wojc1kowsk*-JUpust» and Tursk.1 , 1986). In addition, if little or no
organic content Is in the soil, other components can regulate lead
fixation. These Include hydrous manganese oxide (Forstner et al., 1981) and
hydrous ferric oxide (Swallow et al., 1980). Levels of lead 1n rural soils,
away from industrial emissions and roadbeds, range froei 5-30 yg lead/g
soil (see Table 3-1). Levels of lead near roadbeds can be much higher
2165A 3-7 10/24/89
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(30-2000 yg/g) and will vary with past and present traffic density and
vehicle speed (Page and Gange, 1970; Quarles ft al., 1974; Wheeler and
Rolfe, 1979). Much higher levels <>30,000 yg/g) can occur 1n the 1wnea4ate
vicinity of Industrial point sources (Yankel tt if., 1977; U.S. EPA, 1986b).
Lead in urban soils Includes lead from automotive and Industrial
amissions, as wall as from leaded paints. Lavals >2000 yg/g have been
reported 1n soil around wood-frame houses painted with leaded paint (Ter
Haar and Aronow, 1974; HIelke et al., 1983).
Lead bound to organic constituents In 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 (Prplc-Majlc et al., 1984).
3.2.3. Lead 1n Oust. Oust 1s an Important source of oral lead Intake 1n
Infants and children. The tern "dust" refers to house and outdoor dust;
house dust Is dust In the Interior of the building an
-------
Lead in house dust can bt derived froa 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
practices, the presence and condition 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 air and
the outdoor air lead concentration (U.S. EPA, 1986b). Lead can also enter
the house through contaminated clothing worn by parents (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 (Horse et al., 1979; Prp1c-MaJ1c et al., 1984).
3.2.4. Lead 1n Diet. Anthropogenic sources of lead 1n 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 froa 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). Oecllnes In atmospheric emissions froa automobiles and Industrial
point sources, 1n lead levels In water and 1n the use of lead solder 1n food
containers art expected to result 1n declining levels of lead In food (U.S.
EPA, 1989a; Cohen, 1988a,b).
3.2.5. Lead In Natar. Lead can enter ambient water froa atmospheric
deposition and surfact runoff, where 1t tends to fora Insoluble salts and
precipitates. Concentrations of lead In U.S. ambient water are typically
2165A 3-9 10/24/89
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low. Mean values ttnd to be *3-28 yg/1 (NAS, 1980; U.S. EPA, 1986b).
In contrast to ambient water, levels In drinking water can be much higher
(10-iOGG ug/£) because of leaching of lead from lead pipe and leaded
solder Joints. Lead concentrations 1n drinking water vary with the amount
of lead 1n the household plumbing and corrosiveness 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 il., 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 1s 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 >0.061 lead 1n 1977, the hazard persists 1n
homes and apartments constructed before the ban. In homes built before
1940, some Interior paints contained >501 lead. An estimated «201 of
housing units built between 1960 and 1974 have lead paint levels >0.7
mg/cm2 (ATSDR, 1988).
Infants and children are exposed to lead 1n paint from Ingesting and
Inhaling house dust contaminated with lead and from Ingesting paint chips
(paint pica). Exposure can occur outside "the house from Ingestion of street
and soil dust. Exposure is higher in houses «1th 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 In housing containing
lead-based paint: 235,000-842.000 children resided 1n homes with deterior-
ating surfaces (Pope, 1986; ATSDR, 1988). Since exposure to lead In paint
Is unrelated to atmospheric, soil or dietary levels of lead, efforts to
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reduce lead levels In these media will have little Impact on the Incidence
of Itad Intoxication associated with Uad paint.
3.3. MEDIA-SPECIFIC ESTIMATES FOR DIFFERENT LEVELS OF LEAD UPTAKE
B1ok1net1c models currently exist that predict age-specific blood Uad
levels associated with age-spedf1c uptake rates (Harley and Knelp, 1985).
This section discusses the major quantitative factors that must be Incorpor-
ated Into predictions of lead uptakes from specific environmental media.
Oefault assumptions and reference values Incorporated into an Uptake/
B1ok1net1c Model for lead (described 1n Section 4.1.) are also discussed.
In most populations, lead uptake occurs primarily as the result of Intake of
lead 1n 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 1n areas
contaminated with lead paint.
Uptake (Uj) of lead from a given exposure medium can be thought of as
the product of two separate processes, Intake (Ij) and absorption (Aj):
U, - I, . A,
where Intake (Ij) 1s the product of the concentration of lead In specific
media and the rati for the physiological mechanism of Intake (e.g.,
breathing rate).
Predictions of media-specific lead uptakes must take Into account
environmental fat* processes that determine concentrations of lead 1n
relevant media (see Section 3.2.), as well as behavioral and physiological
factors th4t affect intake and absorption from these media.
3.3.1. Uptaka froa Ambient Air. Humans are exposed to lead 1n indoor and
outdoor air. Uptake rates will be determined by the lead concentrations in
2165A
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Indoor and outdoor air, the time spent Indoors and outdoors and physio-
logical determinants of deposition and absorption 1n the respiratory tract.
A simple mathematical expression for this relationship Is as follows:
UA . V . OA . [PM™
where UA 1s uptake from air (yg/day), V Is the volume of afr breathed/
day (a3/day), DA 1s the product of the respiratory deposition and absorp-
tion fractions and Is the time-weighted average exposure concen-
tration (yg/m3).
3.3.1.1. INDOOR AND OUTDOOR AIR LEAD — As discussed 1n Section
3.3.1., numerous factors determine the concentration of lead 1n air at any
given location. 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 Incorpor-
ated Into predictive 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 air vents. Because the transport
processes are complex, relationships between outdoor and Indoor air lead
concentrations can be expected to vary from site to site. Factors that can
be expected to affect Indoor/outdoor ratios it 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 1n and out of the building and meteoro-
logical conditions.
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U.S. EPA (1986b) summarized data on Indoor and outdoor air lead levtls
and concluded that, at most sites, outdoor concentrations exceeded indoor
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 (Cohon and Cohen, '980).
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 1s 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 1n Pope (1985) and reflect data reported In various
studies (Hoffman et at., 1979; Rubinstein et ah, 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 (tPb]^) can be calculated as follows:
tPb3THA " (CPWAo * V * (CPb]A1 * TU * (1/24)
where CPb]^ tnd outdoor and indoor air concentrations
(yg/m3), respectively, and TQ and Tj art average times (hours/day)
spent outdoors and indoors.
3.3.1.3. MHALATXOH AND RESPIRATORY DEPOSITION AND ABSORPTION —
Intake of lead In t1r 1s determined by the voIum of air breathed each day.
which varies with age, body size and level of physical activity (U.S. EPA.
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1989c). Age-sped flc estimates of dally breathing volumes have been d«r1vtd
(Phalen tt *1. 1985), from which th§ following reference values for dally
breathing volumes In children were developed (U.S. EPA, 1989a):
Age (years): 0-1 1-2 2-3 3-4 4-5 5-6 6-7
Dally Volume (m3/day): 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 Uppaann, 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 part1de-s1ze-spec1f1c references values for these
parameters have been derived from existing experimental data.
3.3.2. Dietary Lead Uptake. Uptake of lead from the diet (Uq) can be
expressed as follows:
UD - >0 • A0
where Iq (yfl Pb/day) 1s thefntake from dietary sources and Aq 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 1n
atmospheric lead) (Cohen, 1988a,b). Projections for 1990 are presented in
Table 3-2.
Absorption of dietary lead varies with age, diet and nutritional status
(see Section 2.2.1.2.). Absorption Is an estimated 42-53X In Infants
2165A 3-14 . 10/24/89
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TABLE 3-2
Age-Spec1f1c Estimates of Total Dietary Lead Intake
for 1990-1996 (ng/day>*
Age
(years)
Metallic
Atmospheric
Other
Total
<1
3.4
0.8
3.3
7.5
1
4.0
3.8
8.9
2
5.6
1.2
3.6
10.4
3
5.8
1.2
3.7
8.9
4
5.9
1.1
3.8
8.9
5
6.1
1.2
4.0
9.3
6
6.3
1.3
4.3
9.8
•Source: Cohen, 1988a,b
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(Alexander et al., 1973; Zlegler et al.. 1978) and 7-15% In adults (Kehoe,
1961a,b,cf; Chamberlain et al., 1978; Rab1now1tz et al., 1980). There is
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 for saturable lead absorption have been experi-
mentally determined 1n the in vitro everted rat intestine (Aungst and Fung,
1981). The apparent Km for flux through the everted Intestine was reported
to be *125 yg/i, which Is substantially higher than the concentration
of lead 1n the Intestine that can be expected to occur from average dietary
Intake (<25 yg/l). However, other dietary metals may compete with 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 fro* Oust and Soil. Children are exposed to lead 1n Indoor
and outdoor dust and soil, primarily from Ingesting these materials as a
result of normal mouthing behavior and pica (abnormal .tendency to Ingest
nonfood materials). Thus, the average dally exposure will be determined by
lead levels In each medium and amounts of each medium that are Ingested
dally. Th« latter may vary with age, season, geographic location and
activity patterns. A simple expression for lead uptake from dust and soil
(UQS) Is as follows:
UDS " 0SING " A0S # lRb>0S
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where DSing 1s oral Intake of dust and soil
-------
¦any complex variables that can affect air/soil relationship for lt*d, such
as chemical and physical properties of the lead particles and soil, topo-
graphic and meteorological conditions, and the frequency of precipitation
and washing of streets and Interior surfacts.
The coefficients of the linear equations used to estimate sol 1/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 1s a 1og-ar1thm1c plot of average air
concentration versus average soil concentration for the data used 1n the
coefficient determinations for soil lead; the data are described 1n 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):
Log Soil Lead - a ~ b • Log A1r Lead
Log Oust Lead - c ~ d • Log Air Lead
where the coefficients a, b, c and d are 50.1, 579.0, 57.6 and 972.0,
respectively. The current Uptake/B1ok1net1c Model (Section 4.1.2.) uses
slightly modified coefficients of 53, 510, 60 and 844, respectively (Section
4.1.1.). The above equations were based on monitoring data for point source
sites such as smelters; however, 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 where indoor dust concentrations of lead are not greater than
concentrations 1n outdoor soil. Review of actual measurements of soil and
2165A
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10000
s
>3:
1
I
I
-J
a
1000 • r
100 -r
0.1 1
AIR CONCENTRATION (ng/m3)
FIGURE 3-2
Plot of Soil liad Concentration vs. A1r Ltad Conctntratlon
MonUortd In Various Locations
Sourct: U.S. EPA, 1986b
2165A 3-19 10/24/89
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house dust Wad reported at mining sites Indicated that, when soil lead was
<500 ppm, house dust lead concentrations were usually greater than
lead. Indicating the greater contribution of Indoor sources of load.
However, when soil lead was >100 ppm, house dust lead concentrations ranged
from 18-481 of soil lead concentrations (Steel* et al., 1989).
The use of the linear equations to estimate soil tnd dust lead levels
near primary and secondary lead smelters My underestimate current exposure
because of historical accumulations of relatively large particles at these
sites, regardless of current emissions controls (U.S. EPA, 1989a). These
sites will probably require separate estimates for current soil and dust
levels.
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 1s that lead
1n undisturbed soil matrix persists for an extremely long time; however,
soil lead concentrations 1n 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
gardening and new building construction can result 1n significant concentra-
tions of atmospherically deposited lead In deeper soils. Interior dust lead
concentrations will likely change over periods of weeks to months in
response to air lead changes, depending on 1nter1or-*xter1or 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 In air lead.
2165A 3-20 10/24/89
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The linear equations yield approximations based upon the bast available
monitoring data and Interpretations, but do not consider various complex
variables that may significantly affect soil and dust concentrations. The
use of adequately Measured soil and dust concentrations 1s preferable to use
cf the linear equations. However, 1n the absence of appropriate measurement
data, application of the linear equations In the Uptake/B1ok1net1c Model can
yield reasonable Initial approxlnations.
3.3.3.2. INTAKE OF OUST AND SOIL— Infants and children Ingest soil
and dust as a result of hand-to-mouth 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.
Hand-to-mouth activity reportedly occurs 1n *60% of children 1-2 years
old, and pica 1n «5% of children at this age; both activities decline 1n
years 3-6 (M111 lean et al., 1962; Barltrop, 1966).
Estimates of soil and dust Intake 1n children have been 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). A mass balance equation used to calculate soil
Ingestion (Ig) 1s as follows:
Is - <(C£H]f • F)/EF) - I0WMJS
where CM]p Is the concentration of the mineral In feces (mg/g feces), F is
the amount of feces excreted each day (g/day), EF Is the fraction of
Ingested mineral that 1s excreted In the feces, IQ 1s the dietary Intake
of the mineral (mg/day) and [M]s 1s the concentration of the mineral in
soil (mg/g). The above estimates can be generalized to dust and soil (i.e.,
dirt), assuming that concentrations In dust are similar to concentrations in
2165A
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soil. Estimates derived froa this mass balance approach art subject to
errors associated with estimates of gastrointestinal absorption and dietary
Intake of the Mineral.
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 soil/day based on
mass balances for aluminum, silicon and t1tan1u«, respectively. Clausing et
al. (1987) examined aluminum, silicon and titanium excretion In 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 1n the hospitalized children. The average estimated soil
Ingestion 1n the nursery school children for all three tracers was 56 mg
soil/day. If the values for dietary Intake froei 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).
Attempts to define reference values for dust and soil intake 1n children
must take Into account the range of soil pica that can occur 1n human
populations. Children with high tendenclfs for soil pica May Ingest 1000
times more soli than children with a low tendency for pica (£alabrese et
al., 1987; U.S. EPA, 1989c). Based on an analysis of available studies
(Binder et al., 1986; Clausing et al., 1987) and considerations of Calabrese
et al. (1987), the following values for average dally dust and soli
Ingestion have been developed:
Age (years): 0-1 1-2 2-3 3-4 4-5 5-6 6-7
Intake (mg/day): 0.005 0.05 0.20 0.20 0.05 0.05 0.05
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The above estlmtes My not apply to children with unusual tendencies
for soil pica which can result In much higher Intake of son (Calibres* et
al., 1989). Furthermore, the above values nay b« adjusted downwards 1n
future revisions of tht Uptake/81ok1net1c Model. In a study recently
brought to the attention of tht U.S. EPA, CaUbrese et a1. (1989) demon-
strated that failure to accurately measure ftcal weight and to consider
dietary Intake of tract metals My result 1n overestlMtlon of soil Intake
based on the measurements of the fecal content of tract metals. Calabrese
et al. (1989) reported a range of 24-68 mg/day for dust and soil Ingestion
In children (1-4 years old) based on fecal excretion of aluminum, silicon
and yttrium.
3.3.3.3. GASTROINTESTINAL ABSORPTION OF OUST AND SOIL LEAD — The
greatest source of uncertainty In the prediction of lead uptake froa dust
and soil Is the estlMtt of gastrointestinal absorption of lead. In vitro
studies have shown that the lead 1n dust and soil 1s solubWzed 1n acidic
solutions similar to that found In the stooach; however, In alkaline
solutions similar to Intestinal fluids, lead can reMln bound to soil (Day
et al., 1979; Harrison, 1979; Duggan and HIIHaas, 1977). Dietary balance
studies have yielded estlMtes of *421 for gastrointestinal absorption of
dietary lead 1n Infants and children (see Section 2.2.1.2.); however,
absorption efficiency My differ for lead 1n dust and soil.
Absorption of lead for dust and soil Is Influenced by thrtt Important
factors: chemical species, particle size and concentration 1n soil. Chancy
et al. (19ft) dtmonstrated that absorption of lead for soil varies with lead
concentration 1n soil.
216SA
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Particle size also determines the degree to which lead Is absorbed into
the body; the larger the particle size, the less the absorption. 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 et al., 1992). Thus,
absorption may be less In the stomach for the larger particles because the
particles do not remain 1n the stomach long enough to become completely
solublUzed. It Is, therefore, very Important when reviewing s1te-speclMc
data to determine the prevalent particle size on which the lead Is located.
In some locations where lead contamination In soil Is high, such as mining
areas, the particle sizes are much larger than 1n other locations, such as
smelter towns, possibly resulting 1n decreased bioavailability. Lead
species Is another critical factory in determining bioavailability. Barltrop
and Heek (1979) reported that lead sulfide 1s significantly 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/B1okonet1c Hodel and merits further Investiga-
tion. Applying Information on particle size, lead species and soil charac-
teristics In bioavailability estimates would prove very useful In further
validation of the model.
3.3.4 Uptake of Lead fro* Drinking Water. Uptake of lead from drinking
water (U^) can be expressed as follows:
where IW (yg/day) 1s the Intake from drinking water and A^ 1s the
fractional absorption of Ingested lead. Intake of lead from drinking water
can be expressed as follows:
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where tPb3y (nfl/l) 1* the Average dally concentration of lead in
drinking water and WjN(. Is the average amount of drinking water ingested
each day. The amount of drinking water Ingested will vary with numerous
factors Including age, body size, diet, physical activity, ambient tempera-
ture and humidity. Using data collected by the U.S. Department of
Agriculture 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 (i/day): 0.20 0.50 0.52 0.53 0.55 0.58 0.59
3.4. ENVIRONMENTAL EXPOSURE LEVELS ASSOCIATED WITH BL000 LEAD LEVELS
In the previous section, strategies for predicting uptake rates from
specific media (air, diet and dust/soil) were described, which, In
conjunction with bloklnetlc models, provide the basis for predicting
relationships between media-specific exposure levels and blood lead levels.
An alternative approach 1s to derive mathematical descriptions of these
relationships from the analysis of human experimental and epidemiological
data on environmental 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/Air Lead Relationships. The relationship between air
concentration and blood lead level in human populations reflects uptakes
directly froa 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; Norse et al., 1979; Angle and Hclntlre,
2165A
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1979; Brunekreef, 1984). The aggregate slop# factors, reflecting the
combined Impact of air lead uptake from all media on blood lead, range from
2-20 (ng/di)/(mg/m3) 1n young, moderately exposed children (U.S. EPA,
1986b, 1988a).
Experimental studies 1n which changes 1n blood lead levels are measured
1n human subjects exposed to lead aerosols yield estimates of slope factors
(blood lead/air lead) for Inhaled air lead. Several experimental studies of
• m
adults have been reported (Kahoe, 1961a,b,c; Griffin et al.. 1975;
Rab1now1tz 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/dft)/(mg/m^), and
1.9 (pg/dl)/(mg/m3) 1f subjects that were exposed to very high lead
levels (236 tig/dl) 1n 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 1n the population. If Information on noninhalation sources of exposure
1s sufficiently documented. Several studies 1n adult human populations have
been reported (Azar et al., 1975; Tepper and Levin, 197S; Nordman, 1975;
Johnson et al., 1975)• In these studies, various approaches are used to
account for nonair lead exposures. The range for blood lead/a1r lead slopes
are 1-2 (i»«/d4)/(mg/»3) (U.S. EPA, 1986b).
Tht EPA analyzed three studies of blood lead/air lead relationships in
children (U.S. EPA, 1986b). Estimated air disaggregate blood lead/air lead
slopes (yg/dfc)/(mg/a3) for the three studies are 1.92*0.60 (Angle and
2165A
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Hclntlre, 1979). 2.46*0.58 (Roels et *1., 1980) and 1.53*0.84 (Yanltel et
il., 1977; Halter tt al., 1980); the Median slop* Is 1.97 .
3.4.2. Blood Lead/Dust And Soil Lead Relationships. Few studies have
provided data on blood lead levels 1n children and levels 1n local soil and
dust, from which blood lead/dust lead and blood 1ead/so11 lead slope factors
can be estimated (Barltro? et il.. 1975; Yankel et al., 1977; Ner1 et al..
1978; Angle and Hclntlre, 1982; Stark et al., 1982). The range of mean
slope factors Is 0.6-6.8 (yg/dl)/(«g 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 Hclntlre, 1979).
B1ood/so11 lead slope factors vary, depending on the nature of source of
lead. For exanple, the average slope for Mining sites 1s an estlnated 1.7
yg/dl/mg Pb/g soil, whereas "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 Hater Lead Relationships. The U.S.
EPA (1986a) has sumurlzed studies relating dietary Intake and blood lead
levels. The relationships appear to be nonlinear at dietary Intakes >200
yg Pb/day. Hhen data are compared over the range of 100-200 yg dietary
Pb/day, blood 1ead/d1etary lead slope factors ranging froet 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 level and drinking water level is
nonlinear it water concentrations >100 yg Pb/i water. The U.S. EPA
(1986b) concluded that the best estimate for the slope factor associated
with first draw water concentrations <100 yg/i was 0.06 (yg Pb/da.
2165A
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bTood)/(yg Pb/i water) (Pocock et al., 1983). More recent analysis of
the rtlatlonshlp of blood lead and drinking water level supports the slope
factor of 0.2-0.25 tg 1 tad/a) water for
Infants and children (U.S. CPA, 1988b).
3.S. SUI#
-------
exposure source, levels of lead 1n each aedla, and behavioral and physiolog-
ical variables that Influtnct Intake and absorption. A b1ok1net1c model can
then b« used ta predict age-specific blood lead levels associated with
multimedia uptakes. This multimedia: Uptake/81ok1net1c 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 an Uptake/B1ok1net1c Model that estimates age-
speclflc blood lead levels associated with levels of continuous exposure to
air, dietary, drinking water, dust/soil and paint lead sources. The uptake
model accepts s1te-spec1f1c data or default values for lead levels 1n each
medium. This Information 1s combined with assumptions regarding behavioral
and physiological parameters that determine intake and absorption of lead
from each medium to yield estimated rates of lead uptake into the blood.
Behavioral and physiological parameters are adjusted for different ages and
Include such Hems as: time spent Indoors and outdoors; time spent sleeping;
diet; dust/soil Ingestion rates; dally breathing volumes; deposition
efficiency 1n the respiratory tract; and absorption efficiency 1n the
respiratory and gastrointestinal tracts.
The bloklnetlc model accepts uptake predictions and computes age-
speclflc blood lead levels based on a s1x-co®partment bloklnetlc model of
tissue distribution and excretion of lead. The model Incorporates default
assumptions regarding rate constants for transfers between blood and four
physiological compartments: bone, kidney, liver and gastrointestinal tract.
Transfers from blood to urine, liver to the gastrointestinal tract and
mother to fetus are considered, as well. These assumptions include adjust-
ments that reflect age-related changes 1n metabolism and physiology that
affect tht distribution and excretion of lead (e.g., bone turn-over rates).
The Uptake/11oklnetlc 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 end flexible 1n
that age-specific predictions can be wide for multimedia exposures. Uptika
from all sources by all absorption routes can be separately modeled. This
provides an estimate of th# relative Impact of changes In 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
s1te-spec1f1c data or revised defaults. Thus, the nod el 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 fro® four primary routes
of exposure to environmental lead: inhaled air lead, lead 1n the diet,
level 1n drinking water and lead 1n dust/soil. A separate calculation Is
presented for each of three air lead levels (25, 50 and 100 yg/m3) to
demonstrate how med1u»-spec1f1c uptake rates vary with changes 1n air lead.
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 In Section 4.1.2.
Formulas and default assumptions for each step 1n the uptake calcula-
tions art enumerated below (numbers refer to computational and Input steps
1n Table 4-1).
1. Air lead. The exposure concentrations (tig/m^) art Inputs to
the model. These can consist of site monitoring data or predictions based
on site-specific source analysis such as those derived from the Industrial
2166A 4-2 10/21/89
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I
TABLE 4-1
lead Intake and Uptake tn 2- to 3-Year-01d Children Exposed to Lead In Air,
Diet. Oust. Soil and Drinking Hater*
Input Paraaeter or Calculation
0.25
0.50
1.00
1. Air lead (pg/a*)
0.25
0.50
1.00
2. Breathing voluae (a'/day)
5
5
5
3. Lead Intake fro* air (pg/day)
1.25
2.5
5.0
4. X respiratory depotItlon/absorptIon
32
32
32
5. Total lead uptake froa Inhaled lead (pg/day)
0.4
0.8
1.6
6. Dietary lead Intake (pg/day)
29
29
29
7. X gastrointestinal absorption
50
50
50
8. Dietary lead uptake (pg/day)
14.5
I
14.5
14.5
9. Outdoor soli lead (pg/g>
180
308
563
10. Indoor dust lead (pg/g)
271
482
904
II. Aaount of dust and soil Ingested (g/day)
0.2
0.2
0.2
12. Weighting factors (soil/dust)
0.45-0.50
0.45-0.50
0.45-0.50
13. Lead Intake froa dust and soli (pg/day)
46
81
ISO
14. X gastrointestinal absorption
30
30
30
IS. Lead uptake froa dust and soil (pg/day)
13.8
24
45
16 Drinking water lead (pg//)
9
9
9
17. Drinking water Intake (//day)
0.5
0.5
0.5
18. Drinking water lead Intake (pg/day)
4.5
4.5
4.5
19. X absorption of lead fro* drinking water
50
50
50
20. Drinking water lead uptake (pg/day)
2.3
2.3
2.3
21. Total lead uptake froa respiratory and
gastrointestinal tract (pg/day)
31
41
63
'Children living near one or wore lead point sources and unaffected by lead paint
2I68A
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Source Complex 01 sperslon Model (U.S. EPA, 1986c). Sine# 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 consider-
ably with age, season, geographic location and cultural factors. Therefore,
1n estimating time-weighted average exposure concentrations, these factors
should be characterized 1n the population of Interest. Computational
strategies for estimating time-weighted exposure concentrations are
discussed 1n Sections 3.3.1.1 and 3.3.1.2.
2. BrtatMno 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 1n Section 3.3.1.3, breathing volume may vary considerably from
this value, depending on body size and physical activity.
3. Lead Intake from breathing air. Intake froei breathing 1s
calculated as follows:
'a • V • tW>JA
where V Is the dally breathing volume (m3/day) and CPblA 1s the exposure
concentration (yg/m3). Intake 1s calculated for the 0.25 yg/m3
exposure concentration as follows:
lower limit - (4 m3/day)(0.09 yg/|3) • 0.4 |ig/day
!a • (5 •3/day)(0.25 ng/m3) - 1.25 yg/day
4. Keiolritorv deposition/1 absorption of inhaled lead. As discussed
In Section 2.2.1.1., the deposition and absorption efficiencies of particles
1n the respiratory tract vary with particle size, which can be expected to
2166A
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relate to the nature of and proximity to the exposure source. The model
uses a default value of 31.5X for the estimated percent absorption of
Inhaled lead particles for 2- to 3-year-old children.
5. Total lead uptake from inhaled lead. Total lead uptake from
Inhalation of airborne lead (U^, yg/day) is calculated using the
equation In Section 3.3.1:
UA " '* • M
where IA Is the Intake of airborne lead by the respiratory tract (yg/day) and
OA Is the product of the respiratory deposition and absorption fractions.
For the example presented In Table 4-1 in which air lead Is assumed to be
0.25 yg/m3, the uptakes are calculated as follows:
UA • (1.25 wg/day)(0.32) . 0.4 wg/day
6. Dietary lead Intake. As discussed In 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. FDA, 1983,
1984; Pennington, 1983). For the purpose of making projections In time- or
s1te-spec1f1c estimates, a Multiple Source Food Model Is used to partition
dietary sources (Including water) into three categories: 1) metallic,
Including lead from solder Joints and pipes In plumbing and solder 1n food
cans; 2} atmospheric. Including deposition of atmospheric lead on food
before or after harvest, or during processing; and 3) other sources.
Oefault projections for the typical diet of children during the years
1990-1996 art presented In Table 3-2.
The values presented In Table 4-1 are based on data from dietary surveys
completed In 198$. However, current dietary levels may be lower because of
decreases of lead In canned food (Cohen, 1988«,b). Strategies for
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projecting survey data forward In time to account for these changes are
discussed In Section 3.3.2.
In the example presented 1n Table 4-1, the default projections do not
change with Increasing air lead. The basis for this assumption 1s that the
typical U.S. diet consists of foods harvested and processed In diverse
geographical locations. Thus, atmospheric contributions are not likely to
be related to local air lead levels. Exceptions to this can be antici-
pated. For example. In rural areas where consumption of home-grown
vegetables Is common, local air lead levels may be an Important determinant
of dietary Intake. In this case, site-specific estimates of dietary Intake
or adjustments to the atmospheric source category would be used 1n 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 Is Incorporated Into the calculations of
dietary and total lead uptakes.
7. X Gastrointestinal absorption of dietary lead. Gastrointestinal
absorption of lead 1s assumed to occur by nonsaturable (passive) and
saturable (active) mechanisms. The absorption coefficient (AQ) at any
given dietary Intake Is, therefore, the sum of the passive absorption
coefficient (AqP) and the active absorption coefficient (AqA), factored
by the concentration for lead In the gastrointestinal tract and the apparent
Km for acttv* absorption, as follows:
A0 ' A0P * <*0A/(U([Pb36I/K",3,)
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where:
Aq > dietary absorption coefficient;
Aqp ¦ coefficient for nonsaturable (passive) absorption;
Aga « coefficient for saturable (active) absorption;
[Pb]GI - concentration of lead in the gastrointestinal tract (ug/t); and
Km ¦ apparent Km for saturable absorption (yg/t).
The default values for 2- to 3-year old children that art used In the
model are as follows:
Aq > 0.5 for the default dietary Intake of 29 yg/day;
Aqp ¦ 0.15;
Aqa • 0.35 for the default dietary intake of 29 yg/day;
[Pb]gi - 12 yg/i for the default dietary Intake of 29 yg/day; and
Km - 100 yg/l.
8. Dietary uptake. Dietary uptake (Up) is calculated as follows:
UD " 1Q * A0
where IQ (yg Pb/day) 1s the Intake from dietary sources and AQ Is the
fractional gastrointestinal absorption of dietary lead. In the example
3
presented In Table 4-1 for outdoor air lead levels of 0.25 yg/m , the
calculation 1s as follows:
UD - (29 yg/day)(0.50) - 14.5 yg/day
9. Outdoor soil lead. The model accepts monitoring data for lead in
soil, or In the absence of data, estimates the geometric mean for dust and
soil lead based on the following calculation:
[Pb]s - 53 ~ 510 • [Pb]Ao
where £Pt>]qs0 *r* lead levels In soil (yg/g soil) and [Pb]^0 1* lead
3
concentration In outdoor air (yg/m ). The values 53 and 510 are
regression coefficients for monitoring data on air lead and soil lead (see
Section 3.3.3.1. for further discussion). In the example presented In Table
3
4-1, the lead level In soil associated with an air lead of 0.2S yg/m is
calculated as follows:
53 ~ 510 • 0.25 yg/m3 . 180 (yg/m3)
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Confidence limits on tht regression coefficients can also bt Incorporated
Into tht calculation to tstlmatt tht upptr and lowtr Halts of tht estimated
lead Itvtls 1n sol 1.
10. Indoor dutt lead. Tht dtfault calculation for Indoor dust lead
(CPblgj) 1s similar to that for soil:
CPb]0<| - 60 ~ 844 • [Pb]Ao
whtrt tPb]gj 1s tht ltad conctntratlon 1n Indoor dust (stt Section
3.3.3.1. for furthtr discussion).
11. Amount of d1rt Ingested. As dlscusstd In Section 3.3.3.2., the
amount of dirt (e.g., dust and soil) Ingtsttd on a dally basis can be
expected to vary with agt and tendency for soil pica. In tht txample
presented 1n Tablt 4-1, a valut of 0.20 mg/day Is assumtd for 2- to
3-ytar-old chlldrtn.
12. Weighting factors for soil and Indoor dust. .Tht rtlatlvt amounts
of soil and Indoor dust ltad that art Ingtsttd dtptnd on tint spent Indoors
and outdoors and activity patterns within tach tnvlronmtnt. Tht modtl uses
dtfault wtlghtlng factors of 0.45 for soil and 0.55 for Indoor dust.
13. Lead Intakt form Ingesting soil and Indoor dust. Tht combined lead
Intake from Indoor dust and soil (IqS) art calculattd as follows:
X0S " IS0IL * *DUST
where I$0il thi uount of so11 lt4d Ingtsttd and Iqujt 1s tht amount
of Indoor dust ltad Ingtsttd tach day.
Ltad tntik* froti soil *nd Indoor dust 4rt calculated
as follow:
ISOIL - CPblSOIL • OsiHG • <0-4*>
lOUST • CPb]DUST • D$inG • (0.55)
2166A
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where:
[Pb]$OIL ¦ concentration of lead In soil (yg/g);
(PbjOUST • concentration of lead In Indoor dust Ug/g);
"SING " amount of Indoor dust and soil Ingested (g/day);
0.55 - Indoor dust weighting factor; and
0.45 - soil weighting factor.
In the example presented 1n Table 4-1, the calculations are as follows:
^SOIL • (v9/fl) • (g/day) • 0.45 « 16.2 (yg/day);
5j ¦ 271 (yg/g) • 0.2 (g/d£y) • 0.55 ¦ 29.8 (yg/day);
Q5 ¦ 16.2 (yg/day) ~ 23.8 (yg/day) » 46 (yg/day).
14. X Lead absorption from dirt. Quantitative Information on
t
absorption efficiency of lead from Ingested dust and soil In humans- is
lacking. As discussed In Section 3.3.3.3., experiments with animals
indicate that lead Ingested 1n soil 1s absorbed less than lead in food; the
results of Uj, vitro studies Indicate that lead Is likely to be solublllzed
In human gastric fluids. To develop default values for the model, gastro-
intestinal absorption of solublllzed lead 1s assumed to occur by nonsatur-
able (passive) and saturable (active) mechanisms, similar to the assumption
regarding the absorption of dietary lead (see Section 3.3.2). The absorp-
tion coefficient for soil lead (A^) at any given dietary Intake is, there-
fore, the sum of the passive absorption coefficient (*sp) *nd the actWe
absorption coefficient (ASA), factored by the concentration for lead in
the gastrointestinal tract and the apparent Km for active absorption, as
follows:
AS - ASP * tASA/(U([Pb]GI/KB)3)>
where:
A$ ¦ absorption coefficient for soil lead;
A$p • coefficient for nonsaturable (passive) absorption;
A§a ¦ coefficient for saturable (active) absorption;
[Pb]Qj • concentration of soil lead in the gastrointestinal tract
(vfl/l); and
Km • apparent Kn for saturable absorption (yg/l).
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The default values for 2- to 3-year-old children who are used 1n the mod«1
art as follows:
Ac • 0.3 for th« default son lead Intake of 16.2 ug/day;
ASp -0.15;
Aca • 0.15 for the soil lead Intake of 16.2 pg/day;
CPblci ¦ 6 yg/4 for the default soil lead Intake of 16.2 wg/day; and
Kin - 100 yg/».
An Identical computation strategy 1s used to calculate the absorption
coefficient for Indoor dust lead. Default values for all the variables used
1n the Indoor dust lead calculations are Identical to those for soil lead.
15. Lead uptake from dust and soil. Lead uptake from Ingested d1 rt
(U0$) 1s calculated as follows:
UDS " XDS * *0S
where IQS 1s the Intake froa dust and soil (yg/day) and AQS 1s the
fractional absorption. In tht-example presented 1n Table 4-1, the calcula-
tion for exposures to 0.25 pg/«* lead 1n air 1s as follows:
UDS - (46 »g/day)(0.30) - 13.8 pg/day
16. Drinking water lead fuo/t). The default value for lead 1n
drinking water Is 9 tig/ft, which 1s the projected 1990-91 U.S. average
concentration (Cohen, 1988a).
17. Drinking water Intake. The default value for dally water Intake 1n
2- to 3-year-old children Is 0.52 t/day. -
18. Lead Intake froa drinking water. Lead Intake froei drinking water
Is calculated as follows:
IH • [Pb]H • Himc
where CPb1H (yg/ft) Is the average dally concentration of lead in
drinking water and MfN(. 1s the average aaount of drinking water Ingested.
2166A
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In the example presented In Table 4-1, the calculation of lead Intake from
3
drinking water for exposures to 0.25 yg/m air lead Is as follows:
Iw ¦ 9 (yg/l) • 0.52 (l/day) . 4.6 Ug/day).
19. X Gastrointestinal absorption of drinking water lead. The approach
taken for calculating gastrointestinal absorption of drinking water lead Is
Identical to that described previously for dietary lead. Absorption 1s
assumed to occur by nonsaturable (passive) and saturable (active) mecha-
nisms. The absorption coefficient for soil lead (*s) at any given dietary
Intake 1s, therefore, the sum of the passive absorption coefficient (Asp)
and the active absorption coefficient (*54)* factored by the concentration
for lead In the gastrointestinal tract and the apparent Km for active
absorption, as follows:
\ - Ayp ~ (A^/tHUPb^j/Km)3))
where:
Ay > absorption coefficient for drinking water lead;
Atyp - coefficient for nonsaturable (passive) absorption;
aUA • coefficient for saturable (active) absorption;
[POJqI ¦ concentration of lead In the gastrointestinal tract (yg/l);
and
Km • apparent Km for saturable absorption (yg/l).
The default values for 2* to 3-year old children used In the model are
as follows:
A« -0.5 for the default water lead intake of 4.4 yg/day;
Ayp ¦ 0.15;
Aua * 0*35 for the default Intake of drinking water lead of 4.4
yg/day;
[Pb]gi • 2 yg/t for the default water lead Intake of 4.4 yg/day; and
Km ¦ 100 yg/l.
20. Uptake of drinking water lead. Lead uptake from drinking water is
calculated as follows:
uw • \
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where IW Cpg/day) 1s the Intake from drinking water and ^ 1$ the
fractional absorption of Ingested lead. In the example presented 1n Tabl*
4-1, the calculation for exposure to 0.25 yg/m3 1«d Is as follows:
Uw ¦ 4,6 Cpg/day) • 0.5 - 2.3 (yg/day).
21. Total lead uptake. Total lead uptake (U?) Is the sun of uptakes
from breathing lead 1n air, diet, drinking water and dust/soil Ingestion:
uT • uA ~ u0 ~ uDS ~ %
In the example presented 1n Table 4-1, the total uptake associated with
exposure to 0.25 yg/m3 Is calculated as follows:
UT - 0.4 ~ 14.5 ~ 13.3 ~ 2.4 - 31 yg/day
The calculation of media-spedf1c uptakes presented 1n Table 4-1 shows
that the largest contribution to total uptake 1n 2- to 3-year-old children
Is from dust, soil and diet. The contribution of inhaled airborne lead 1s
relatively minor. Because of the relatively large contribution of dust and
soil lead to total uptake, predictions of total uptake will be highly sensi-
tive to changes In the values of Input parameters related to dust and soil.
For example. Increasing the default value for gastrointestinal absorption of
lead Ingested 1n dust and soil from a value of 25-501 Increases the
predicted lower limit for total uptake froei 8.1-12.1 yg/day. The default
value for dietary lead absorption would have to Increase to 721 to achieve a
similar Increase in total lead uptake. The results of studies on the
gastrointestinal absorption of dietary lead 1n infants and young children
suggest th*t It Is Improbable that the lower limit for gastrointestinal
absorption of dietary lead 1s as high as 721. However, 501 gastrointestinal
absorption of lead 1n dust and soil 1s plausible, given the paucity of data
concerning this parameter.
2166A
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Predictions of blood lead are also sensitive to Input data on lead
concentration 1n soil and dust. For example, the use of site monitoring
data for dust and soil lead, as opposed to default calculations based on air
lead/dust and soil lead relationships, may have substantial quantitative
Impact on the prediction of total lead uptake. Another situation where the
default calculations for air lead/soil dust lead relationships may not be
appropriate are sites where a smelter once operated but has ceased
operating. In this case, the air lead levels have dramatically decreased,
but high soil lead concentrations may persist for some period of time,
thereby heavily Influencing the Indoor dust concentrations. In this latter
case, the equation used 1n the document would underestimate Indoor dust
concentrations.
4.1.2. Uptake of Lead from Ingested Paint. In the example presented in
Table 4-1, It was assumed that the population of 2- to 3-year-old children
was not exposed to lead from paint. However, Ingestion of lead-based paint
chips can be a quantitatively important source for lead uptake 1n children
living or playing 1n areas In which decaying paint surfaces exist. Lead
levels in the Indoor dust of homes with lead paint can be 2000 »g/g (Hardy
et al., 1971; Ter Haar and Aronow, 1974). A child that Ingests 0.1 g of
indoor dust each day would have a paint lead Intake of 200 vg/day.
Although not Illustrated In the example, the model accepts Input of
age-specific estimates of Intake from lead paint and Incorporates these
values 1n the calculation of total lead uptake. The computation strategy Is
similar to th4t 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 solublllzed from paint 1n the
gastrointestinal tract.
2166A
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The effect of lead paint 1ngtst1on on total lead uptake can be
Illustrated In the following example. Keeping all other parameters in
Table 4-1 the same, an additional Intake of 200 vg/day of paint lead in a
2- to 3-year-old child Increases total lead uptake from 31-78 tig/day.
4.1.3. Uptake and Blood Lsad Concentrations. Knelp et al. (1983)
developed a b1ok1net1c model for lead from data obtained In single dose and
chronic lead exposure of Infant and juvenile baboons. Estimated physiolog-
ical 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 bloklnetlc model (Harley and Knelp, 1985) was
selected by the Office of A1r Quality Planning and Standards of U.S. EPA
(1989a) to estimate age-spedflc blood lead levels associated with a given
total lead uptake.
The Harley and Knelp (1985) model defines first-order rate constants for
exchanges between blood and four physiological compartments that contain
>951 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 In 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 bon« art adjusted to account for expected changes 1n the rate
of bone turn-over with age (Harley and Knelp, 1985). Similarly, age adjust-
ments 1n excretion of lead In the urine, the transfer of lead fro« blood to
liver and th» fractional absorption fro« the gastrointestinal tract are
Incorporated into the model.
2166A
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The model predicts levels of lead 1n blood, bone, kidney and liver
associated with continuous lifetime uptake rates for children of various
ages. While complete validation of the model in humans Is not possible,
comparisons can be made with the results of dietary studies In humans.
Shown 1n Figure 4-1 are relationships between blood lead levels and lead
uptake in 2-year-old children, as predicted by the blcklnetlc model of
Harley and Knelp (1985) and from several studies of dietary lead uptake in
Infants and adults (Sherlock et al., 1982; Ryu et al., 1983; U.S. EPA,
1989a). The Harley and Knelp (1985) Model predicts lower blood lead levels
than the uptake studies at low (<20 yg lead/day) lead uptakes. At higher
uptakes (>20 wg/day), predictions are within the range determined for
Infants (Ryu et al., 1983) and higher than those for adults (Sherlock et
al., 1982; Cools et al., 1976). —
The Harley and Knelp (1985) Model has been extended In several
directions, based on recent data, to develop the current version of the
Uptake/B1ok1netlc Model. These extensions Include the following:
1. additional compartmentatlon of the blood and bone lead pools
(Marcus, 1985a, c);
2. kinetic non-linearity 1n the uptake of lead by red blood cells at
high concentrations (Marcus,1985c);
3. transfer of lead from the mother to fetus.
The blood lead compartment is divided Into plasma and red blood cell
pools. Th« 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).
2166A
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*
,2:
Q
s
§
a!
Infants (Ryu/Lacey)
2-3 yr olds
(Biokinatic Modal)
Adults (Sfwtock/Cools)
20 40 60 80
LEAD UPTAKE (fig/day).
FIGURE 4-1
Summary of Relationships Batvaan Dally Lead Uptaka and Blood Had for
Infants (Ryu at al. 1983; lacay at *1., 1983). Adults (Sharlock at al..
1982; Cools at al., 1976), and 2- to 3-Yaar-01d CMIdran Oarlvad froa th«
Harlay and Knalp (1985) B1ofc1nat1c Modal.
Sourca: U.S. EPA, 1989a
2166A
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The bone compartment 1$ divided Into cortical and trabtcular pools.
Trabtcular bont develops tarlltr and has a fasttr 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 ia utero. and, thus, 1s 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 1n the model
to estimate newborn blood lead concentration. The current version of the
model uses a default maternal blood lead level of 7.5 yg/dft; however,
later versions will contain a maternal Uptake/B1ok1net1c Model 1n which
maternal blood lead levels will be estimated from exposures to air, diet,
drinking water and dust.
4.2. CALCULATIONS OF PROJECTED MEAN BLOOO LEAD DISTRIBUTIONS: LEAD UPTAKE
LEVELS
The Uptake/81oklnetlc Model predicts mean blood lead levels associated
with defined multimedia exposure levels. However, to assess the risks
associated with such exposures 1n 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 popula-
tion means. The friction 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, 1s defined by Its geometric mean and GSO. It is.
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 froa 1.3-1.4 (Tepper
2166A
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and levin, 1975; Azar et al.t 1975; BIIHck et *1., 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; COC, 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 GSO values (Roels et al., 1980; COC, 1983), and
the midpoint of 1.42 w111 be assumed as a reasonable best estimate."
Figures 4-2 and 4-3 show the frequency distribution for blood lead
levels In 2- to 3-year-old children living near a lead' point source with an
air lead level of 0.25 yg/a3, as predicted by the uptake/ bloklnetlc
node) and assuming a value of 1.42 for the GSO. Cumulative probability
percentiles for the lower and upper limit estimates of total lead uptake are
shown 1n Figure 4-2, and probability distribution for the upper limit
estimates are shown in Figure 4-3. Assuming an upper Hm1t total lead
uptake, «9X of the 2-year-old population Is predicted to have blood lead
levels >10 yg/dfc.
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 art shown In Figures 4-4 and 4-5. Hhen s1te-spec1fic
data for air, dust and soil lead were used In the model, predicted, and
2166A
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6mmtrie Ht* (01) > 7.31
1L0QB UAO CONCDtTMTlON (ug/dL)
24 to 38 Honths
FIGURE 4-2
Probability Ptrctntllt of Blood Ltad Ltvtls 1n 2-Ytar-01d Children
Living Ntar On* or More Lead Point Sources and Not Afftcttd by Blood Lead.
Ltad ltvtls 1n air art assuatd to bt 0.25 tig/an. Ltad uptakes wtrt
tstlnattd frcm tht uptakt nodtl (stt Tablt 4-1).
2166A
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8 30
Cutoff: if.f ug/d
t Above: 26.43
I Iclou: 73.57
6. Htan: 7.3!
8.25
>
H
¦
¦ e.i5
a
s
i
0
1
i
8 65
5
II
15
21
38
HOOD LIHO CONCDtTttTION <(*/&>
24 to 36 tenths
FIGURE 4-3
Probability Distribution of Blood Lead Levels In 2-Year-01d Children
Living Near One or More Lead Point Sources and Not Affected by Blood Laad.
Lead Levels In Air art Assumed to be 0.25 yg/a3* A value of 1.42 1s
assumed for GSO of the pradlctad Man blood laad 1 avals. The probability
distribution Is basad on tha pradlctad laad uptake (set Table 4-1).
2166A 4-20 10/21/89
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Uj
100
90
80
70
60
§ 50
£ 40
30
20
10
0
' 1 ' r^j
m
m
• i
r
• t
• M
• Observed
• §
• 1
0 Model Estimate
•6
• T
• B
• I
*
•6
• f
• I
• v
• j
• j
*
f •
J •
I •
j %
1 i I i
m
I.I.I,
10 20 30 40 50
BLOOD LEAD CONCENTRATION (jig/dl)
60
V
FIGURE 4-4
Comparison of Distribution of Measured Blood lead Levels 1n 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: (As amended from) U.S. EPA, 1989a
2166A
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100
UJ
-J
§
o
20
0
10
30
50
60
40
BLOOD LEAD CONCENTRATION (jig/dl)
FIGURE 4-5
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/Bloklnetlc Model. Oust and soil lead levels were
estimated using default calculations.
Source: (As amended from) U.S. EPA, 1989a
2166A
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observed mean blood lead levels and distributions were essentially Identical
up to the 90th percentile (Figure 4-4). Above tht 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 21 of those observed: however, the nodel again slightly
underpredlcted blood lead levels at the highest percentile (Figure 4*5).
4.3. SUMMARY
An Uptake/B1ok1net1c Model that can be used to predict blood lead levels
associated with multimedia exposures to lead 1n air, diet and dust/soil 1s
described. The model consists of two components. 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 In populations of children, assuming a log
normal distribution and a specified GSO. 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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5. REFERENCES
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