United States
Environmental Protection
Agency
Environmental Criteria and
Assessment Office
Research Triangle Park NC 27711
EPA-600/8-83-028B
September 1984
External Review Draft
Research and Development
v>EPA
Air Quality
Criteria for Lead
Volume I of IV
Review
Draft
(Do Not
Cite or Quote)
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
-------
Draft
Do Not Cite or Quote
EPA-600/8-83-028B
September 1984
External Review Draft
Air Quality Criteria for Lead
Volume I of IV
NOTICE
This document is a preliminary draft It has not been formally released by EPA and should not at this stage
be construed to represent Agency policy It is being ciurculated for comment on its technical accuracy and
policy implications
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U S Environmental Protection Agency
Research Triangle Park, NC 27711
-------
NOTICE
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
i i
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ABSTRACT
The document evaluates and assesses scientific information on the health
and welfare effects associated with exposure to various concentrations of lead
in ambient air. The literature through 1983 has been reviewed thoroughly for
information relevant to air quality criteria, although the document is not
intended as a complete and detailed review of all literature pertaining to
lead. An attempt has been made to identify the major discrepancies in our
current knowledge and understanding of the effects of these pollutants.
Although this document is principally concerned with the health and
welfare effects of lead, other scientific data are presented and evaluated in
order to provide a better understanding of this pollutant in the environment.
To this end, the document includes chapters that discuss the chemistry and
physics of the pollutant; analytical techniques; sources, and types of
emissions; environmental concentrations and exposure levels; atmospheric
chemistry and dispersion modeling; effects on vegetation; and respiratory,
physiological, toxicological , clinical, and epidemiological aspects of human
exposure.
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CONTENTS
Page
VOLUME I
Chapter 1. Executive Summary and Conclusions
VOLUME II
Chapter 2. Introduction 2-i
Chapter 3. Chemical and Physical Properties 3-1
Chapter 4 Sampling and Analytical Methods for Environmental Lead 4-1
Chapter 5. Sources and Emissions
Chapter 6. Transport and Transformation j
Chapter 7. Environmental Concentrations and Potential Pathways to Human Exposure . 7-1
Chapter 8. Effects of Lead on Ecosystems
VOLUME III
Chapter 9 Quantitative Evaluation of Lead and Biochemical Indices of Lead
Exposure in Physiological Media g_l
Chapter 10. Metabolism of Lead 10-1
Chapter 11. Assessment of Lead Exposures and Absorption in Human Populations 11-1
Volume IV
Chapter 12. Biological Effects of Lead Exposure 12-1
Chapter 13. Evaluation of Human Health Risk Associated with Exposure to Lead
and Its Compounds 13-1
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TABLE OF CONTENTS
CHAPTER 1
EXECUTIVE SUMMARY AND CONCLUSIONS
Page
LIST OF FIGURES vi i
LIST OF TABLES " x
1 EXECUTIVE SUMMARY AND CONCLUSIONS 1-1
1.1 INTRODUCTION " i-i
1.2 ORGANIZATION OF DOCUMENT 1-3
1.3 CHEMICAL AND PHYSICAL PROPERTIES OF LEAD 1-4
1.4 SAMPLING AND ANALYTICAL METHODS FOR ENVIRONMENTAL LEAD 1-6
1.4.1 Sampling Techniques 1-6
1 4.2 Analytical Procedures 1-10
1.5 SOURCES AND EMISSIONS ' 1-12
1.6 TRANSPORT AND TRANSFORMATION 1-21
1.6.1 Atmospheric Transport 1-21
1.6.2 Deposition 1-26
1.6.3 Transformation 1-28
1.7 ENVIRONMENTAL CONCENTRATIONS AND POTENTIAL PATHWAYS
TO HUMAN EXPOSURE 1-31
1.7.1 Lead in Air 1-32
1.7.2 Lead in Soil and Dust 1-34
1.7.3 Lead in Food 1-35
1.7.4 Lead in Water 1-36
1.7.5 Baseline Exposures to Lead 1-37
1.7.6 Additional Exposures 1-41
Urban atmospheres 1-43
Houses with interior lead paint 1-43
Family gardens 1-44
Houses with lead plumbing 1-44
Residences near smelters and refineries 1-44
Occupational exposures 1-44
Secondary occupational exposure 1-46
Special habits or activities 1-46
1.7.7 Summary 1-47
1 8 EFFECTS OF LEAD ON ECOSYSTEMS 1-49
1.8.1 Effects on Plants 1-52
1.8.2 Effects of Microorganisms 1-54
1.8.3 Effects on Animals 1-55
1.8.4 Effects on Ecosystems 1-57
1.9 QUANTITATIVE EVALUATION OF LEAD AND BIOCHEMICAL INDICES OF LEAD
EXPOSURE IN PHYSIOLOGICAL MEDIA 1"59
1.9 1 Determinations of Lead in Biological Media 1-60
Measurements of lead in blood 1-61
Lead in plasma 1-61
Lead in teeth 1-61
Lead in hair I~fa2
Lead in urine 1-62
Lead in other tissues 1-62
Quality assurance procedures in lead analyses 1-63
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TABLE OF CONTENTS (continued).
Page
1 9.2 Determination of Biochemical Indices of Lead Exposure in
Biological Media 1-63
Determination of Erythrocyte Porphyrin (Free Erythrocyte
Protoporphyrin, Zinc Protoporphyrin) 1-63
Measurement of Urinary Coproporphyrin 1-64
Measurement of Delta-Aminolevulinic Acid Dehydrase Activity 1-65
Measurement of Delta-Aminolevulinic Acid in Urine and
Other Media 1-65
Measurement of Pyrimidine-51-Nucleotidase Activity 1-66
Measurement of Plasma 1,25-dihydroxyvitamin D 1-66
1.10 METABOLISM OF LEAD "!!!!!!!' 1-67
1.10.1 Lead Absorption in Humans and Animals 1-67
Respiratory absorption of lead 1-67
Gastrointestinal absorption of lead 1-68
Percutaneous absorption of lead 1-69
Transplacental transfer of lead 1-69
1.10 2 Distribution of Lead in Humans and Animals 1-69
Lead in Blood 1-69
Lead Levels in Tissues 1-70
Soft tissues 1-70
Mineralizing tissue 1-71
Chelatable lead 1-72
Animal studies 1-72
1.10.3 Lead Excretion and Retention in Humans and Animals 1-73
Human studies 1-73
Animal studies 1-74
1.10.4 Interactions of Lead with Essential Metals and Other Factors 1-74
Human studies 1-74
Animal studies 1-74
1.10.5 Interrelationships of Lead Exposure with Exposure Indicators
and Tissue Lead Burdens 1-75
Temporal charactersitics of internal indicators
of lead exposure 1-76
Biological aspects of external exposure-
internal indicator relationships 1-76
Internal indicator-tissue lead relationships 1-76
1.10.6 Metabolism of Lead Alkyls 1-77
Absorption of lead alkyls in humans and animals 1-77
Biotransformation and tissue distribution of lead alkyls 1-78
Excretion of lead alkyls 1-78
1.11 ASSESSMENT OF LEAD EXPOSURES AND ABSORPTION IN HUMAN POPULATIONS 1-78
1.11.1 Levels of Lead and Demographic Covariates
in U.S Populations 1-79
1.11.2 Time Trends in Blood Lead Levels Since 1970 1-81
Studies in the United States 1-81
European Studies 1-86
1.11.3 Determinants of Trends in Blood Lead Levels 1-86
1.11.4 Blood Lead vs. Inhaled Air Lead Relationships 1-93
1.11 5 Studies Relating Dietary Lead Exposures (Including Water) to
Blood Lead 1-100
vi
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TABLE OF CONTENTS (continued).
Page
1 11.6 Studies Relating Lead in Soil and Dust to Blood Lead 1-101
1.11.7 Additional Exposures 1-102
1.12 BIOLOGICAL EFFECTS OF LEAD EXPOSURE !!!!!!!!!!!!!!!!!!.'!!!.'! 1-102
1.12.1 Introduction 1-102
1 12.2 Subcellular Effects of Lead 1-103
1.12.3 Effects of Lead on Heme Biosynthesis, Erythropoiesis, and
Erythrocyte Physiology in Humans and Animals 1-105
1 12.4 Neurotoxic Effects of Lead 1-113
Internal Lead Levels at Which Neurotoxic Effects Occur 1-114
Early Development and the Susceptibility to Neural Damage 1-115
The Question of Irreversibility 1-116
Utility of Animal Studies in Drawing Parallels to the Human
Condition 1-116
1 12.5 Effects of Lead on the Kidney 1-118
1.12.6 Effects of Lead on Reproduction and Development 1-120
1.12.7 Genotoxic and Carcinogenic Effects of Lead 1-121
1.12.8 Effects of Lead on the Immune System 1-121
1.12.9 Effects of Lead on Other Organ Systems 1-122
1.13 EVALUATION OF HUMAN HEALTH RISKS ASSOCIATED WITH EXPOSURE TO LEAD AND
ITS COMPOUNDS 1-122
1.13.1 Introduction 1-122
1.13.2 Exposure Aspects: Levels of Lead in Various Media of Relevance to
Human Exposure 1-123
Ambient Air Lead Levels ]-123
Levels of Lead in Dust 1-124
Levels of Lead in Food 1-125
Lead Levels in Drinking Water 1-126
Lead in Other Media 1-126
Cumulative Lead Intake From Various Sources 1-127
1.13.3 Lead Metabolism: Key Issues for Human Health Risk Evaluation 1-127
Differential Internal Lead Exposure Within Population Groups 1-127
Indices of Internal Lead Exposure and Their Relationship to
External Lead Levels and Tissue Burdens/Effects 1-129
Proportional Contributions of Lead in Various Media to Blood
Lead in Human Populations 1-133
1.13.4 Biological Effects of Lead Relevant to the General Human Population . 1-135
Criteria for Defining Adverse Health Effects 1-136
Dose-Effect Relationships for Human Adults 1-139
Dose-Effect Relationships for Children 1-139
1.13.5 Dose-Response Relationships for Lead Effects in Human Populations ... 1-147
1.13.6 Populations at Risk 1-151
Children as a Population at Risk 1-151
Pregnant Women and the Conceptus as a Population at Risk 1-152
Description of the U.S. Population in Relation to Potential
Lead Exposure Risk 1-153
1.13.7 Summary and Conclusions 1-154
1.14 REFERENCES 1-157
vi i
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LIST OF FIGURES
Figure Page
1-1 Pathways of lead exposure from the environment to man 1-2
1-2 Metal complexes of lead 1-5
1-3 Softness parameters of metals 1-6
1-4 Chronological record of the relative increase of lead in snow strata,
pond and lake sediments, marine sediments, and tree rings. The data
are expressed as a ratio of the latest year of the record and should
not be interpreted to extend back in time to natural or uncontaminated
levels of lead concentration 1-13
1-5 The global lead production has changed historically in response to
major economic and political events. Increases in lead production
(note log scale) correspond approximately to historical increases
in lead emissions shown in Figure 1-4 1-15
1-6 Locations of major lead operations in the United States 1-17
1-7 Trend in lead content of U.S. gasolines, 1975-1982 1-19
1-8 Lead consumed in gasoline and ambient lead concentrations, 1975-1983 1-20
1-9 Profile of lead concentrations in the central northeast Pacific. Values
below 1000 m are an order magnitude lower than reported by Tatsumoto and
Patterson (1963) and Chow and Patterson (1966) 1-24
1-10 Lead concentration profile in snow strata of northern Greenland 1-25
1-11 Variation of lead saturation capacity with cation exchange capacity in
soil at selected pH values 1-30
1-12 This figure depicts cycling process within major components of a terrestrial
ecosystem, i.e. primary producers, grazers, and decomposers. Nutrient and
non-nutrient elements are stored in reservoirs within these components.
Processes that take place within reservoirs regulate the flow of elements
between reservoirs along established pathways. The rate of flow is in
part a function of the concentration in the preceding reservoir Lead
accumulates in decomposer reservoirs which have a high binding capacity
for this metal. It is likely that the rate of flow away from these
reservoirs has increased in past decades and will continue to increase
for some time until the decomposer reservoirs are in equilibrium with the
entire ecosystem. Inputs to and outputs from the ecosystems as a whole
are not shown 1-50
1-13 Geometric mean blood lead levels by race and age for younger children in the
NHANES II study, and the Kellogg Silver Valley, Iadho study and New York
childhood screening studies 1-80
1-14 Average blood lead levels of U S. population 6 months - 74 years. United
States, February 1976 - February 1980, based on dates of examination of
NHANES II examinees with blood lead determinations 1-84
1-15 Time dependence of blood lead for blacks, aged 24 to 35 months, in New York
City and Chicago 1-85
1-16 Parallel decreases in blood lead values observed in the NHANES II study
and amounts of lead used in gasoline during 1976-1980 1-87
1-17 Change in 206Pb/207Pb ratios in petrol, airborne particulate and
blood from 1974 to 1981 1-90
1-18 Geometric mean blood lead levels of New York City children (aged 25-36
months) by ethnic group, and ambient air lead concentration vs.
quarterly sampling period, 1970-1976 1-94
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LIST OF FIGURES (continued).
Figure
Page
1-19 Geometric mean blood lead levels of New York City children faaed 2S-3S
sold i^ Sew6JoJkC New^rc^ 6St^ted amount of 1ead Present in gasoline
pen od" !5?0-W6 . ^VS" «I«rter1y sampling
1 20 Lead effects heme biosynthesis l-95
1-?? M,trat'°" °' main b
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LIST OF TABLES
Tab1e Page
1-1 Estimated atmospheric lead emissions for the United States, 1981 and
the world 1-16
1-2 Summary of surrogate and vegetation surface deposition of lead 1-27
1-3 Estimated global deposition of atmospheric lead 1-28
1-4 Atmospheric lead in urban, rural, and remote areas of the world 1-33
1-5 Background lead in basic food crops and meats 1-36
1-6 Summary of environmental concentrations of lead 1-38
1-7 Summary of baseline human exposures to lead 1-42
1-8 Summary of potential additive exposures to lead 1-48
1-9 Weighted geometric mean blood lead levels from NHANES II survey by
degree of urbanization of place of residence in the U.S. by age
and race, United States 1976-80 1-82
1-10 Summary of pooled geometric standard deviations and estimated
analytic errors 1-83
1-11 Person correlation coefficients between the average blood lead levels
for six-month periods and the total lead used in gasoline production
per six months, according to race, sex, and age 1-88
1-12 Estimated contribution of leaded gasoline to blood lead by inhalation
and non-inhalation pathways 1-91
1-13 Summary of blood inhalation slopes (p) (jg/dl per pg/m3 1-97
1-14 Relative baseline human lead exposures expressed per kilogram body weight .. . 1-125
1-15 Percent contributions from various media to blood lead levels (pg/dl)
of U.S. children (age = 2 yrs) ]-134
1-16 Summary of lowest observed effect levels for key lead-induced health effects
in adults 1-140
1-17 Summary of lowest observed effect levels for key lead-induced health effects
in children 1-141
1-18 EPA-estimated percentage of subjects with ALA-U exceeding limits for
various blood lead levels . . . .' 1-150
1-19 Provisional estimate of the number of individuals in urban and rural
population segments at greatest potential risk to lead exposure 1-154
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LIST OF ABBREVIATIONS
AAS
Ach
ACTH
ADCC
ADP/O ratio
AIDS
AIHA
All
ALA
ALA-D
ALA-S
ALA-U
APOC
APHA
ASTM
ASV
ATP
B-cel1s
Ba
BAL
BAP
BSA
BUN
BW
C V.
CaBP
CaEDTA
CaNa.EDTA
CBD *
Cd
CDC
CEC
CEH
CFR
CMP
CNS
CO
COHb
CP-U
C .
cBah
D.F.
DA
6-ALA
DCMU
DPP
DNA
DTH
EEC
EEG
EMC
EP
Atomic absorption spectrometry
Acetylcholi ne
Adrenocorticotrophic hormone
Antibody-dependent cell-mediated cytotoxicity
Adenosine diphosphate/oxygen ratio
Acquired immune deficiency syndrome
American Industrial Hygiene Association
Angiotensin II
Ami nolevuli ni c
Ami nolevuli nic
Aminolevuli nic
Ami nolevuli ni c
dehydrase
synthetase
in urine
acid
acid
acid
acid
Ammonium pyrrolidine-dithiocarbamate
American Public Health Association
Amercian Society for Testing and Materials
Anodic stripping voltammetry
Adenosine triphosphate
Bone marrow-derived lymphocytes
Barium
British anti-Lewisite (AKA dimercaprol)
benzo(a)pyrene
Bovine serum albumin
Blood serum urea nitrogen
Body weight
Coefficient of variation
Calcium binding protein
Calcium ethylenediami netetraacetate
Calcium sodium ethylenediaminetetraacetate
Central business district
Cadmi um
Centers for Disease Control
Cation exchange capacity
Center for Environmental Health
reference method
Cytidine monophosphate
Central nervous system
Carbon monoxide
Carboxyhemoglobi n
Urinary coproporphyrin
plasma clearance of p-aminohippuric acid
Copper
Degrees of freedom
Dopami ne
delta-aminolevulinic acid
[3-(3,4-dichlorophenyl)-l,l-dimethyl urea
Differential pulse polarography
Deoxyribonucleic acid
Delayed-type hypersensitivity
European Economic Community
Electroencephalogram
Encephalomyocardi tis
Erythrocyte protoporphyrin
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LIST OF ABBREVIATIONS (continued).
EPA
FA
FDA
Fe
FEP
FY
G.M.
G-6-PD
GABA
GALT
GC
GFR
HA
Hg
hi-vol
HPLC
i. m.
i.p.
i. v.
IAA
IARC
ICO
ICP
IDMS
IF
ILE
IRPC
K
LDH-X
LCc
LD
LH~
LIPO
1 n
LPS
LRT
mRNA
ME
MEPP
MES
MeV
MLC
MMD
MMED
Mn
MND
MSV
MTD
n
N/A
50
50
U.S. Environmental Protection Agency
Fulvic acid
Food and Drug Administration
Iron
Free erythrocyte protoporphyrin
Fiscal year
Grand mean
G1ucose-6-phosphate dehydrogenase
Gamma-aminobutyric acid
Gut-associated lymphoid tissue
Gas chromatography
Glomerular filtration rate
Humic acid
Mercury
High-volume air sampler
High-performance liquid chromatography
Intramuscular (method of injection)
Intraperitoneal^ (method of injection)
Intravenously (method of injection)
Indol-3-ylacetic acid
International Agency for Research on Cancer
International classification of diseases
Inductively coupled plasma emission spectroscopy
Isotope dilution mass spectrometry
Interferon
Isotopic Lead Experiment (Italy)
International Radiological Protection Commission
Potassium
Lactate dehydrogenase isoenzyme x
Lethyl concentration (50 percent)
Lethal dose (50 percent)
Luteinizing hormone
Laboratory Improvement Program Office
Natural logarithm
Lipopolysaccharide
Long range transport
Messenger ribonucleic acid
Mercaptoethanol
Miniature end-plate potential
Maximal electroshock seizure
Mega-electron volts
Mixed lymphocyte culture
Mass median diameter
Mass median equivalent diameter
Manganese
Motor neuron disease
Moloney sarcoma virus
Maximum tolerated dose
Number of subjects or observations
Not Avai1able
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LIST OF ABBREVIATIONS (continued).
NA Not Applicable
NAAQS National ambient air quality standards
NAD Nicotinamide Adenine Dinucleotide
NADB National Aerometric Data Bank
NAMS National Air Monitoring Station
NAS National Academy of Sciences
NASN National Air Surveillance Network
NBS National Bureau of Standards
NE Norepinephrine
NFAN National Filter Analysis Network
NFR-82 Nutrition Foundation Report of 1982
NHANES II National Health Assessment and Nutritional Evaluation Survey II
Ni Nickel
NTA Nitri1otriacetonitrile
OSHA Occupational Safety and Health Administration
P Phosphorus
P Significance symbol
PAH Para -aminohippuric acid
Pb Lead
PBA Air lead
Pb(Ac>2 Lead acetate
PbB concentration of lead in blood
PbBrCl Lead (II) bromochloride
PBG Porphobilinogen
PFC Plaque-forming cells
pH Measure of acidity
PHA Phytohemagglutinin
PHZ Polyacrylamide-hydrous-zi rconi a
PIXE Proton-induced X-ray emissions
PMN Polymorphonuclear leukocytes
PND Post-natal day
PNS Peripheral nervous system
P.O. Per os (orally)
ppm Parts per million
PRA Plasma renin activity
PRS Plasma renin substrate
PWM Pokeweed mitogen
Py-5-N Pyrimide-5'-nucleotidase
RBC Red blood cell, erythrocyte
RBF Renal blood flow
RCR Respiratory control ratios/rates
redox Oxidation-reduction potential
RES Reticuloendothelial system
RLV Rauscher leukemia virus
RNA Ribonucleic acid
S-HT Serotonin
SA-7 Simian adenovirus
S.C Subcutaneously (method of injection)
scm Standard cubic meter
S.D Standard deviation
SDS Sodium dodecyl sulfate
S E.M. Standard error of the mean
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LIST OF ABBREVIATIONS (continued).
SES
SGOT
sig
SLAMS
SMR
Sr
SRBC
SRMs
STEL
SW voltage
T-cel1s
t-tests
TBL
TEA
TEL
TIBC
TML
TMLC
TSH
TSP
U.K.
UMP
USPHS
VA
V^R
WHO
XBF
v-
Zn
ZPP
Socioeconomic status
Serum glutamic oxaloacetic transaminase
Surface immunoglobulin
State and local air monitoring stations
Standardized mortality ratio
Stronti um
Sheep red blood cells
Standard reference materials
Short-term exposure limit
Slow-wave voltage
Thymus-derived lymphocytes
Tests of significance
Tri-n-butyl lead
Tetraethyl-ammoni um
Tetraethyllead
Total iron binding capacity
Tetramethyllead
Tetramethyllead chloride
Thyroid-stimulating hormone
Total suspended particulate
United Kingdom
Uridine monophosphate
U.S. Public Health Service
Veterans Administration
Deposition velocity
Visual evoked response
World Health Organization
X-Ray fluorescence
Chi squared
Zi nc
Erythrocyte zinc protoporphyrin
MEASUREMENT ABBREVIATIONS
dl deciliter
ft feet
g gram
g/gal gram/gallon
g/ha-mo gram/hectare-month
km/hr kilometer/hour
1/min liter/minute
mg/km milligram/kilometer
|jg/m3 microgram/cubic meter
mm millimeter
(jm micrometer
pmol micromole
ng/cm2 nanograms/square centimeter
nm nanometer
nM nanomole
sec second
t tons
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GLOSSARY VOLUME II
A horizon of soils - the top layer of soil, immediately below the litter layer;
organically rich.
anorexia - loss of appetite.
anthropogenic - generated by the activities of man.
apoplast - extracellular portion of the root cross-section.
Brownian movement - the random movement of microscopic particles,
carnivore - meat-eating organism.
catenation - linkage between atoms of the same chemical element.
cation exchange capacity (CEC) - the ability of a matrix to selectively exchange
positively charged ions.
chemical mass balance - the input/output balance of a chemical within a defined
system.
coprophilic fungi - fungi which thrive on the biological waste products of
other organisms.
detritus - the organic remains of plants and animals.
dictyosome - a portion of the chloroplast structurally similar to a stack of
disks.
dry deposition - the transfer of atmospheric particles to surfaces by sedimen-
tation or impaction.
ecosystem - one or more ecological communities linked by a common set of
environmental parameters.
electronegativity - a measure of the tendency of an atom to become negatively
charged.
enrichment factor - the degree to which the environmental concentration of an
element exceeds the expected (natural or crustal)
concentration.
galena - natural lead sulfide.
gravimetric - pertaining to a method of chemical analysis in which the
concentration of an element in a sample is determined by weight
(e.g., a precipitate).
herbivore - plant-eating organism.
humic substances - humic and fulvic acids in soil and surface water.
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hydroponically grown plants - plants which are grown with their roots immersed
in a nutrient-containing solution instead of
soi 1.
Law of Tolerance - for every environmental factor there is both a minimum and
a maximum that can be tolerated by a population of plants
or animals.
leaf area index (LAI) - the effective leaf-surface (upfacing) area of a tree as
a function of the plane projected area of the tree canopy.
'-^*50 ~ concentration of an agent at which 50 percent of the exposed population
dies.
lithosphere - the portion of the earth's crust subject to interaction with the
atmosphere and hydrosphere.
mass median aerodynamic diameter (MMAD) - the aerodynamic diameter (in pm) at
which half the mass of particles in
an aerosol is associated with values
below and half above.
meristematic tissue - growth tissue in plants capable of differentiating into
any of several cell types.
microcosm - a small, artificially controlled ecosystem.
mycorrhizal fungi - fungi symbiotic with the root tissue of plants.
NADP - National Atmospheric Deposition Program.
photolysis - decomposition of molecules into simpler units by the application
of light.
photosystem I light reaction - the light reaction of photosystem converts light
to chemical energy (ATP and reduced NADP).
Photosystem I of the light reaction receives ex-
cited electrons from photosystem II, increases
their energy by the absorption of light, and
passes these excited electrons to redox
substances that eventually produce reduced
NADP
primary producers - plants and other organisms capable of transforming carbon
dioxide and light or chemical energy into organic compounds.
promotional energy - the energy required to move an atom from one valence
state to another.
saprotrophs - heterotrophic organisms that feed primarily on dead organic
material.
stoichiometry - calculation of the quantities of substances that enter into
and are produced by chemical reactions.
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stratospheric transfer - in the context of this document, transfer from the
troposphere to the stratosphere.
symplast - intracellular portion of the root cross-section.
troposphere - the lowest portion of the atmosphere, bounded on the upper level
by the stratosphere.
wet deposition - the transfer of atmospheric particles to surfaces by precipi-
tation, e.g., rain or snow.
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GLOSSARY VOLUME III
aerosol - a suspension of liquid or solid particles in a gas
BAL (British Anti~Lewisite) - a chelating agent often used in the treatment of
metal toxicity
biliary clearance - an excretion route involving movement of an agent through
bile into the GI tract
Brownian diffusion - the random movement of microscopic particles
chelatable" or systemically active zinc - fraction of body's zinc store
available or accessible to
removal by a zinc-binding agent
chi-square goodness-of-fit tests - made to determine how well the observed
data fit a specified model, these tests
usually are approximately distributed as a
chi-square variable
first-order kinetics - a kinetic process whose rate is proportional to the
concentration of the species undergoing change
geochronometry - determination of the age of geological materials
hematocrit - the percentage of the volume of a blood sample occupied by cells
intraperitoneal - within the body cavity
likelihood function - a relative measure of the fit of observed data to a
specified model. In some special cases it is equivalent
to the sum of squares function used in least squares
analysis.
mass median aerodynamic diameter (MMAD) - the aerodynamic diameter (in pm) at
which half the mass of particles in
an aerosol is associated with values
below and half above
multiple regression analysis - the fitting of a single dependent variable to a
linear combination of independent variables using
least squares analysis is commonly called multiple
regression analysis
plumburesis - lead excreted in urine
R2 - this statistic, often called the multiple R squared, measures the proportion
of total variation explained. A value near 1 means that nearly all of the
variation is explained, whereas a value near zero means that almost none of
the variation is explained.
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GLOSSARY VOLUME IV
ADP/O ratio - a measure of the rate of respiration; the ratio of adenosine
diphosphate concentration to oxygen levels increases as
respiration is impaired
active transport - the translocation of a solute across a membrane by means of
an energy-dependent carrier system capable of moving against
a concentration gradient
affective function - pertaining to emotion
asthenospermia - loss or reduction of the motility of spermatozoa
azotemia - an excess of urea and other nitrogenous compounds in the blood
basal ganglia - all of the large masses of gray matter at the base of the
cerebral hemispheres, including the corpus striatum, subthalamic
nucleus, and substantia nigra
basophilic stippling - a histochemical appearance characteristic of immature
erythrocytes
cognitive function - pertaining to reasoning, judging, conceiving, etc.
corpuscular volume - red blood cell volume
cristae - shelf-like infoldings of the inner membrane of mitochondria
cytomegaly - markedly enlarged cells
demyellnation - destruction of the protective myelin sheath which surrounds
most nerves
depolarization - the electrophysiological process underlying neural transmission
desaturation kinetic study - a form of kinetic study in which the rate of release
of a species from its binding is studied
desquamation - shedding, peeling, or scaling off
disinhibition - removal of a tonic inhibitory effect
endoneurium - the delicate connective tissue enveloping individual nerve fibers
within a nerve
erythrocyte - red blood cell
erythropoiesis - the formation of red blood cells
feedback derepression - the deactivation of a repressor
hepatocyte - a parenchymal liver cell
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hyalinization - a histochemical marker characteristic of degeneration
hyperkalemia - a greater than normal concentration of potassium ions in the
circulating blood
hyperplasia - increased numbers of cells
hypertrophy - increased size of cells
hypochromic - containing less than the normal amount of pigment
hyporeninemic hypoaldosteronism - pertaining to a systemic deficiency of renin
and aldosterone
inclusion bodies - any foreign substance contained or entrapped within a cell
isocortex - cerebral cortex
lysosomes - a cytoplasmic, membrane-bound particle containing hydrolyzing
enzymes
macrophage - large scavenger cell that ingests bacteria, foreign bodies, etc.
(Na , K )-ATPase - an energy-dependent enzyme which transports sodium and
potassium across cell membranes
natriuresis - enhanced urinary excretion of sodium
normocytic - refers to normal, healthy-looking erythrocytes
organotypic - disease or cell mixture representative of a specific organ
oxidative phosphorylation - the generation of cellular energy in the presence
of oxygen
paresis - partial or incomplete paralysis
pathognomic feature - characteristic or indicative of a disease
polymorphonuclear leukocytes - leukocytes (white blood cells) having nuclei of
various forms
respiratory control rates (RCRs) - measure of intermediary metabolism
reticulocytosis - an increase in the number of circulating immature red blood
eel 1 s
synaptogenesis - the formation of neural connections (synapses)
synaptosomes - morphological unit composed of nerve terminals and the attached
synapse
teratogenic - affecting the development of an organism
teratospermia - a condition characterized by the presence of malformed
spermatozoa
XX
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AUTHORS AND CONTRIBUTORS
Chapter 1: Executive Summary
Principal Author
Dr. Lester D. Grant
Director
Environmental Criteria and Assessment Office
Environmental Protection Aqency
MD-52
Research Triangle Park, NC 27711
Contributing Authors.
Or. J. Michael Davis
Environmental Criteria and
Assessment Office
MD-52
Research Triangle Park, NC 27711
Dr. Vic Hasselblad
Biometry Division
Health Effects Research Laboratory
MD-55
Research Triangle Park, NC 27711
Dr. Paul Mushak
Department of Pathology
School of Medicine
University of North Carolina
Chapel Hill, NC 27514
Dr. Robert W. Elias
Environmental Criteria and
Assessment Office
MD-52
Research Triangle Park, NC 27711
Dr. Dennis J. Kotchmar
Environmental Criteria and
Assessment Office
MD-52
Research Triangle Park, NC 27711
Dr. David E. Weil
Environmental Criteria and
and Assessment Office
MD-52
Research Triangle Park, NC 27711
XX1
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1. EXECUTIVE SUMMARY AND CONCLUSIONS
1 1 INTRODUCTION
This criteria document evaluates and assesses scientific information on the health and
welfare effects associated with exposure to various concentrations of lead in ambient air
According to Section 108 of the Clean Air Act of 1970, as amended in June, 1974, a cri-
teria document for a specific pollutant or class of pollutants shall-
accurately reflect the latest scientific knowledge useful in indicating
the kind and extent of all identifiable effects on public health or welfare which
may be expected from the presence of such pollutant in the ambient air, in varyinq
quantities
Air quality criteria are of necessity based on presently available scientific data, which
in turn reflect the sophistication of the technology used in obtaining those data as well as
the magnitude of the experimental efforts expended. Thus, air quality criteria for atmos-
pheric pollutants are a scientific expression of current knowledge and uncertainties Speci-
fically, air quality criteria are expressions of the scientific knowledge of the relationships
between various concentrations-~averaged over a suitable time period-~of pollutants in the
same atmosphere and their adverse effects upon public health and the environment. Criteria
are issued as a basis for making decisions about the need for control of a pollutant and as a
basis for development of air quality standards governing the pollutant. Air quality criteria
are descnptive, that is, they describe the effects that have been observed to occur as a
result of external exposure at specific levels of a pollutant. In contrast, air quality
standards are prescriptive, that is, they prescribe what a political jurisdiction has deter-
mined to be the maximum permissible exposure for a given time in a specified geographic area
This criteria document is a revision of the previous Air Quality Criteria Document for
Lead (EPA-600/8-77-017) published in December, 1977 This revision is mandated by the Clean
Air Act (Sect 108 and 109), as amended U.S.C. §§7408 and 7409. The criteria document sets
forth what is known about the effects of lead contamination in the environment on human health
and welfare. This requires that the relationship between levels of exposure to lead, via all
routes and averaged over a suitable time period, and the biological responses to those levels
be carefully assessed Assessment of exposure must take into consideration the temporal and
spatial distribution of lead and its various forms in the environment. Thus, the literature
through July, 1984 has been reviewed thoroughly for information relevant to air quality cri-
teria for lead, but the document is not intended as a complete and detailed review of all
literature pertaining to lead. Also, efforts are made to identify major discrepancies in our
current knowledge and understanding of the effects of lead and its compounds
SUMPB/D 1-1 9/6/84
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Lead is a naturally occurring element that may be found in the earth's crust and in all
components of the biosphere. It may be found in water, soil, plants, animals, and humans
Because lead also occurs in ore bodies that have been mined for centuries by man, this metal
has been distributed throughout the biosphere by the industrial activities of man Of parti-
cular importance to the human environment are emissions of lead to the atmosphere. The
sources of these emissions and the pathways of lead through the environment to man are shown
in Figure 1-1. This figure shows natural inputs to soil by crustal weathering and
anthropogenic inputs to the atmosphere from automobile emissions and stationary industrial
sources. Natural emissions of lead to the atmosphere from volcanoes and windblown soil are of
minor importance.
AUTO
EMISSIONS
INDUSTRIAL
EMISSIONS
CRUSTAL
WEATHERING
AMBIENT
AIR
SOIL
SURFACE AND
GROUND WATER
PLANTS
ANIMALS
PAINT
PIGMENTS
SOLDER
INHALED
AIR
DRINKING
WATER
FOOD
SOFT
BLOOD
TISSUE
BONES
*ER
KIDNEY
^ \
FECES URINE
Fipjre 1-1 Pathway! of lead front the environment to man, main compartments
involved in partitioning of internal body burden of absorbed/retained lead, and
main routn of lead excretion
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From these emission sources, lead moves through the atmosphere to various components of
the human environment. Lead is deposited on soil and plants and in animals, becoming incor-
porated into the food chain of man. Atmospheric lead is a major component of household and
street dust, lead is also inhaled directly from the atmosphere.
1 2 ORGANIZATION OF DOCUMENT
This document focuses primarily on lead as found in its various forms in the ambient
atmosphere, in order to assess its effects on human health, however, the distribution and bio-
logical availability of lead in other environmental media have been considered. The rationale
for structuring the document was based primarily on the two major questions of exposure and
response The first portion of the document is devoted to lead in the environment--1ts physi-
cal and chemical properties; the monitoring of lead in various media; sources, emissions, and
concentrations of lead, and the transport and transformation of lead within environmental
media. The latter portion is devoted to biological responses and effects on human health and
ecosystems
In order to facilitate printing, distribution, and review of the present draft materials,
this Second External Review Draft of the revised EPA Air Quality Criteria Document for Lead is
being released in four volumes. The first volume (Volume I) contains this executive summary
and conclusions chapter (Chapter 1) for the entire document. Volume II contains Chapters 2-8,
which include, the introduction for the document (Chapter 2); discussions of the above listed
topics concerning lead in the environment (Chapters 3-7), and evaluation of lead effects on
ecosystems (Chapter 8). The remaining two volumes contain Chapters 9-13, which deal with the
extensive available literature relevant to assessment of health effects associated with lead
exposure
An effort has been made to limit the document to a highly critical assessment of the sci-
entific data base through July, 1984. The references cited do not constitute an exhaustive
bibliography of all available lead-related literature, but they are thought to be sufficient
to reflect the current state of knowledge on those issues most relevant to the review of the
ambient air quality standard for lead.
The status of control technology for lead is not discussed in this document. For informa-
tion on the subject, the reader is referred to appropriate control technology documentation
published by the Office of Air Quality Planning and Standards (OAQPS), U.S. EPA. The subject
of "adequate margin of safety" stipulated in Section 108 of the Clean Air Act also is not
explicitly addressed here, this topic will be considered in depth by EPA's Office of Air
Quality Planning and Standards in documentation prepared as a part of the process of revising
the National Ambient Air Quality Standard (NAAQS) for Lead.
SUMPB/D !-3 9/6/84
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1.3 CHEMICAL AND PHYSICAL PROPERTIES OF LEAD
Lead is a gray-white metal of silvery luster that, because of its easy isolation and low
melting point, was among the first of the metals to be extensively utilized by man Lead was
used as early as 2000 B.C. by the Phoenicians. The most abundant ore is galena, from which
metallic lead is readily smelted. The metal is soft, malleable, and ductile, a poor
electrical conductor, and highly impervious to corrosion. This unique combination of physical
properties has led to its use in piping and roofing, and in containers for corrosive liquids
The metal and the dioxide are used in storage batteries, and organolead compounds are used in
gasoline additives to boost octane levels. Since lead occurs in highly concentrated ores from
which it is readily separated, the availability of lead is far greater than its natural abun-
dance would suggest. The great environmental significance of lead is the result both of its
utility and of its availability
The properties of organolead compounds (i.e., compounds containing bonds between lead and
carbon) are entirely different from those of-the inorganic compounds of lead. Because of their
use as antiknock agents in gasoline and other fuels, the most important organolead compounds
have been the tetraalkyl compounds tetraethyl1ead (TEL) and tetramethyllead (TML). These lead
compounds are removed from internal combustion engines by a process called lead scavenging, in
which they react in the combustion chamber with halogenated hydrocarbon additives (notably
ethylene dibromide and ethylene dichloride) to form lead halides, usually bromochlorolead(II)
The donor atoms in an organometal1ic complex could be almost any basic atom or molecule,
the only requirement is that a donor, usually called a ligand, must have a pair of electrons
available for bond formation. In general, the metal atom occupies a central position in the
complex, as exemplified by the lead atom in tetramethyllead (Figure l-2a) which is tetra-
hedrally surrounded by four methyl groups. In these simple organolead compounds, the lead is
usually present as Pb(IV), and the complexes are relatively inert. These simple ligands,
which bind to metal at only a single site, are called monodentate ligands. Some ligands,
however, can bind to the metal atom by more than one donor atom, so as to form a heterocyclic
ring structure. Rings of this general type are called chelate rings, and the donor molecules
which form them are called polydentate ligands or chelating agents. In the chemistry of lead,
chelation normally involves Pb(II) A wide variety of biologically significant chelates with
ligands such as amino acids, peptides, and nucleotides are known. The simplest structure
of this type occurs with the amino acid glycine, as represented in Figure l~2b for a 1 2
(metal:1igand) complex. The importance of chelating agents in the present context is their
widespread use in the treatment of lead and other metal poisoning
SUMPB/D
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h2o
I
P*3
H3C
ch3
h2o
(a)
(b)
Figure 1-2. Metal complexes of lead.
Metals are often classified according to some combination of their electronegativity,
iomc radius, and formal charge. These parameters are used to construct empirical classifi-
cation schemes of relative hardness or softness. In these schemes, "hard" metals form strong
bonds with "hard" anions and, likewise, "soft" metals bond with "soft" anions. Some metals
are borderline, having both soft and hard character. Pb(II), although borderline, demon-
strates primarily soft character (Figure 1-3). The term Class A may also be used to refer to
hard metals, and Class B to soft metals. Since Pb(II) is a relatively soft (or class B) metal
ion, it forms strong bonds to soft donor atoms like the sulfur atoms in the cysteine residues
of proteins and enzymes. In living systems, lead atoms bind to these peptide residues in pro-
teins, thereby changing the tertiary structure of the protein or blocking a substrate's
approach to the active site of an enzyme. This prevents the proteins from carrying out their
functions. As has been demonstrated in several studies (Jones and Vaughn, 1978; Williams and
Turner, 1981; Williams et al., 1982), there is an inverse correlation between the LD50 values
of metal complexes and the chemical softness parameter.
The role of the chelating agents is to compete with the peptides for the metal by forming
stable chelate complexes that can be transported from the protein and eventually be excreted
by the body. For simple thermodynamic reasons, chelate complexes are much more stable than
monodentate metal complexes, and it is this enhanced stability that is the basis for their
ability to compete favorably with proteins and other ligands for the metal ions.
It should be noted that both the stoichiometry and structures of metal chelates depend
upon pH, and that structures different from those manifest in solution may occur in crystals.
It will suffice to state, however, that several ligands can be found that are capable of suf-
ficiently strong chelation with lead present in the body under physiological conditions to
permit their use in the effective treatment of lead poisoning.
SUMPB/D
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ft
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1 5
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05
- Au
i—i—i—r
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//
# Ag
"•T.
—• Cu
Pd'
Hg'
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• Bi>
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CLASS B
>Cu'
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Sn'® ^
Cd*«
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BORDERLINE
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J I I I 1 I L
CLASS A
0 2 4 6 8 10 12 14 16 20 23
CLASS A OR IONIC INDEX. Z'/r
Figure 1-3. Softness parameters of metals.
Source: Nieboer and Richardson (1980).
1.4 SAMPLING AND ANALYTICAL METHODS FOR ENVIRONMENTAL LEAD
Lead, like all criteria pollutants, has a designated Reference Method for monitoring and
analysis as required in State Implementation Plans for determining compliance with the lead
National Ambient Air Quality Standard. The Reference Method uses a high volume sampler (hi-
vol) for sample collection and atomic absorption spectrometry (AAS), inductively coupled
plasma emission spectroscopy (ICP), or X-ray fluorescence (XRF) for analysis.
For a rigorous quality assurance program, it is essential that investigators recognize
all sources of contamination and use every precaution to eliminate them. Contamination occurs
on the surfaces of collection containers and devices, on the hands and clothing of the inves-
tigator, in.the chemical reagents, in the laboratory atmosphere, and on the labware and tools
used to prepare the sample for analysis.
1.4.1 Sampling Techniques
Sampling strategy encompasses site selection, choice of instrument used to obtain repre-
sentative samples, and choice of method used to preserve sample integrity In the United
SUMPB/D 1-6 9/6/84
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States, some sampling stations for air pollutants have been operated since the early 1950's.
These early stations were a part of the National Air Surveillance Network (NASN), which has
now become the National Filter Analysis Network (NFAN). Two other types of networks have been
established to meet specific data requirements. State and Local Air Monitoring Stations
(SLAMS) provide data from specific areas where pollutant concentrations and population densi-
ties are the greatest and where monitoring of compliance to standards is critical The
National Air Monitoring Station (NAMS) network is designed to serve national monitoring needs,
including assessment of national ambient trends. SLAMS and NAMS stations are maintained by
state and local agencies and the air samples are analyzed in their laboratories. Stations in
the NFAN network are maintained by state and local agencies, but the samples are analyzed by
laboratories in the U.S. Environmental Protection Agency, where quality control procedures are
rigorously maintained.
Data from all three networks are combined into one data base, the National Aerometric
Data Bank (NADB). These data may be individual chemical analyses of a 24-hour sampling period
arithmetically averaged over a calendar period, or chemical composites of several filters used
to determine a quarterly composite. Data are occasionally not available for a given location
because they do not conform to strict statistical requirements.
In September, 1981, EPA promulgated regulations establishing ambient air monitoring and
data reporting requirements for lead comparable to those already established in May, 1979 for
the other criteria pollutants. Whereas sampling for lead is accomplished by sampling for
total suspended particulate (TSP), the designs of lead and TSP monitoring stations must be
complementary to insure compliance with the NAMS criteria for each pollutant. There must be
at least two SLAMS sites for lead in any area that has a population greater than 500,000 and
any area where lead concentration currently exceeds the ambient lead standard (1.5 |jg/m3) or
has exceeded it since January 1, 1974.
To clarify the relationship between monitoring objectives and the actual siting of a mon-
itor, the concept of a spatial scale of representativeness was developed. The spatial scales
are discribed in terms of the physical dimensions of the air space surrounding the monitor
throughout which pollutant concentrations are fairly similar. The time scale may also be an
important factor. Siting criteria must include sampling times sufficiently long to include
average windspeed and direction, or a sufficient number of samples must be collected over
short sampling periods to provide an average value consistent with a 24-hour exposure.
Airborne lead is primarily inorganic particulate matter but may occur in the form of or-
ganic gases Devices used for collecting samples of ambient atmospheric lead include the
standard hi-vol sampler and a variety of other collectors employing filters, impactors,
impingers, or scrubbers, either separately or in combination, that measure lead in pg/nr
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Some samplers measure lead deposition expressed in Mg/cm2, some instruments separate particles
by size. As a general rule, particles smaller in aerodynamic diameter than 2.5 Mm are class-
ified as "fine", and those larger than 2.5 as "coarse." The present SLAMS and NAMS employ
the standard hi-vol sampler (U.S Environmental Protection Agency, 1971) as part of their
sampling networks. As a Federal Reference Method Sampler, the hi-vol operates with a specific
flow rate of 1600-2500 m3 of air per day.
When sampling ambient lead with systems employing filters, it is likely that vapor-phase
organolead compounds will pass through the filter media. The use of bubblers downstream from
the filter containing a suitable reagent or absorber for collection of these compounds has
been shown to be effective. Organolead may be collected on iodine crystals, adsorbed on acti-
vated charcoal, or absorbed in an iodine monochloride solution.
Sampling of stationary sources for lead requires the use of a sequence of samplers in the
smokestack. Since lead in stack emissions may be present in a variety of physical and chemical
forms, source sampling trains must be designed to trap and retain both gaseous and particulate
lead.
Three principal procedures have been used to measure mobile source emissions, specifi-
cally auto exhaust aerosols: a horizontal dilution tunnel, plastic sample collection bags, and
a low residence time proportional sampler. In each procedure, samples are air-diluted to
simulate roadside exposure conditions. The air dilution tube segregates fine combustion-
derived particles from larger lead particles. Because the total exhaust plus dilution airflow
is not held constant in this system, potential errors can be reduced by maintaining a very
high dilution air/exhaust flow ratio. In the bag technique, auto emissions produced during
simulated driving cycles are air-diluted and collected in a large plastic bag. This technique
may result in errors of aerosol size analysis because of condensation of low vapor pressure
organic substances onto the lead particles. To minimize condensation problems, a third
technique, a low residence time proportional sampling system, has been used. This technique
may be limited by the response time of the equipment to operating cycle phases that cause
relatively small transients in the exhaust flow rate.
In sampling for airborne lead, air is drawn through filter materials such as glass fiber,
cellulose acetate, or porous plastic. These materials often include contaminant lead that can
interfere with the subsequent analysis. The type of filter and the analytical method to be
used often determine the sample preparation technique. In some methods, e.g., X-ray fluo-
rescence, analysis can be performed directly on the filter if the filter material is suitable.
The main advantages of glass fiber filters are low pressure drop and high particle collection
efficiency at high flow rates. The main disadvantage is variability in the lead blank, which
makes their use inadvisable in many cases. Teflon® filters have been used since 1975 by
Dzubay et al. (1982) and Stevens et al. (1978), who have shown these filters to have very low
SUMPB/D 1-8 g/6/84
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lead blanks (<2 ng/cm2). The collection efficiencies of filters, and also of impactors, have
been shown to be dominant factors in the quality of the derived data.
Other primary environmental media that may be affected by airborne lead include precipi-
tation, surface water, soil, vegetation, and foodstuffs. The sampling plans and the sampling
methodologies used in dealing with these media depend on the purpose of the experiments, the
types of measurements to be carried out, and the analytical technique to be used.
Lead concentration at the start of a rain event is higher than at the end, and ram
striking the canopy of a forest may rinse dry deposition particles from the leaf surfaces
Rain collection systems should be designed to collect precipitation on an event basis and to
collect sequential samples during the event. Two automated systems have recently been used.
The Sangamo Precipitation Collector, Type A, collects rain in a single bucket exposed at the
beginning of the rain event (Samant and Vaidya, 1982). A second sampler, described by Coscio
et al (1982), also remains covered between rain events; it can collect a sequence of eight
samples during the period of rain and may be fitted with a refrigeration unit for sample
cooli ng
Because the physicochemical form of lead often influences environmental effects, there is
a need to differentiate among the various chemical forms of lead in aqueous samples. Complete
differentiation among all such forms is a complex task that has not yet been fully accom-
plished. The most commonly used approach is to distinguish between dissolved and suspended
forms of lead. All lead passing through a 0.45 (jm membrane filter is operationally defined as
dissolved, while that retained on the filter is defined as suspended (Kopp and McKee, 1979)
Containers used for sample collection and storage should be fabricated from essentially lead-
free plastic or glass, e.g., conventional polyethylene, Teflon®, or quartz. These containers
must be leached with hot acid for several days to ensure minimum lead contamination (Patterson
and Settle, 1976).
The distance from emission sources and depth gradients must be considered in designing
the sampling plan for lead in soil. Depth samples should be collected at not greater than 2
cm intervals to preserve vertical integrity. Because most soil lead is in chemical forms un-
available to plants, and because lead is not easily transported by plants, roots typically
contain very little lead and shoots even less. Before analysis of plants, a decision must be
made as to whether or not the plant leaf material should be washed to remove surface contami-
nation from dry deposition and soil particles. If the plants are sampled for total lead
content (e.g., if they serve as animal food sources), they cannot be washed; if the effect of
lead on internal plant processes is being studied, the plant samples should be washed. In
either case, the decision must be made at the time of sampling, as washing cannot be effective
after the plant materials have dried.
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14.2 Analytical Procedures
The choice of analytical method depends on the nature of the data required, the type of
sample being analyzed, the skill of the analyst, and the equipment available. For general
determination of elemental lead, atomic absorption spectroscopy (AAS) is widely used and re-
commended. Optical emission spectrometry and X-ray fluorescence (XRF) are rapid and inexpen-
sive methods for multielemental analyses. X-ray fluorescence can measure lead concentrations
reliably to 1 ng/m3 using samples collected with commercial dichotomous samplers. Other
analytical methods have specific advantages appropriate for special studies.
With respect to measuring lead without contamination during sample handling, several in-
vestigators have shown that the magnitude of the problem is quite large. It appears that the
problem may be caused by failure to control the blank or by failure to standardize instrument
operation (Patterson, 1983; Skogerboe, 1982). The laboratory atmosphere, collecting con-
tainers, and the labware used may be primary contributors to the lead blank problem
(Patterson, 1983; Skogerboe, 1982). Failure to recognize these and other sources of contami-
nation such as reagents and hand contact is very likely to result in the generation of arti-
ficially high analytical results. Samples with less than 100 ng lead should be analyzed in a
clean laboratory especially designed for the elimination of lead contamination. Moody (1982)
has described the construction and application of such a laboratory at the National Bureau of
Standards.
For AAS, the lead atoms in the sample must be vaporized either in a precisely controlled
flame or in a furnace. Furnace systems in AAS offer high sensitivity as well as the ability
to analyze small samples. These enhanced capabilities are offset in part by greater difficul-
ty in analytical calibration and by loss of analytical precision [lead analyses of 995 parti-
culate samples from the NASN were accomplished by AAS with indicated precision of 11 percent
(Scott et al , 1976a)]. Disks (0.5 cm2) are punched from air filters and analyzed by inser-
tion of nichrome cups containing the disks into a flame. Another application involves the use
of graphite cups as particle filters with the subsequent analysis of the cups directly in the
furnace system. These two procedures offer the ability to determine particulate lead directly
with minimal sample handling.
Techniques for AAS are still evolving. An alternative to the graphite furnace, evaluated
by Jin and Taga (1982), uses a heated quartz tube through which the metal ion in gaseous
hydride form flows continuously. Sensitivities were 1-3 ng/g for lead. The technique is
similar to the hydride generators used for mercury, arsenic, and selenium. Other nonflame
atomization systems, electrodeless discharge lamps, and other equipment refinements and tech-
nique developments have been reported (Horlick, 1982). More specialized AAS methods for the
determination of tetraalkyl lead compounds in water and fish tissue have been described by
Chau et al (1979) and in air by Birnie and Noden (1980) and Rohbock et al. (1980)
SUMPB/D 1-10 9/6/84
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Optical emission spectroscopy is based on the measurement of the light emitted by ele-
ments when they are excited in an appropriate energy medium. The technique has been used to
determine the lead content of soils, rocks, and minerals at the 5-10 pg/g level with a rela-
tive standard deviation of 5-10 percent, this method has also been applied to the analysis of
a large number of air samples. The primary advantage of this method is that it allows simul-
taneous measurement of a large number of elements in a small sample. In a study of environ-
mental contamination by automotive lead, sampling times were shortened by using a sampling
technique in which lead-free porous graphite was used both as the filter medium and as the
electrode in the spectrometer.
More recent activities have focused attention on the inductively coupled plasma (ICP)
system as a valuable means of excitation and analysis (Garbarino and Taylor, 1979). The ICP
system offers a higher degree of sensitivity with less analytical interference than is typical
of many of the other emission spectroscopic systems. Optical emission methods are inefficient
when used for analysis of a single element, since the equipment is expensive and a high level
of operator training is required. This problem is largely offset when analysis for several
elements is required, as is often the case for atmospheric aerosols.
X-ray fluorescence (XF) allows simultaneous identification of several elements, including
lead, using a high-energy irradiation source. This technique offers the advantage that sample
degradation can be kept to a minimum. On the other hand, X-ray emission induced by charged-
particle excitation (proton-induced X-ray emission or PIXE) offers an attractive alternative
to the more common techniques. The excellent capability of accelerator beams for X-ray emis-
sion analysis is partially due to the relatively low background radiation associated with the
excitation; this is the basis of the electron microprobe method of analysis. When an intense
electron beam is incident on a sample, it produces several forms of radiation, including
X-rays, whose wavelengths depend on the elements present in the material and whose intensities
depend on the relative quantities of these elements. The method is unique in providing com-
positional information on individual lead particles, thus permitting the study of dynamic che-
mical changes and perhaps allowing improved source identification.
Isotope dilution mass spectrometry (IDMS) is the most accurate measurement technique
known at the present time. No other techniques serve more reliably as a comparative refer-
ence; it has been used for analyses of subnanogram concentrations of lead in a variety of sam-
ple types (Chow et al. , 1969, 1974; Facchetti and Geiss, 1982, Hirao and Patterson, 1974;
Murozumi et al., 1969, Patterson et al., 1976; Rabinowitz et al., 1973) The isotopic compo-
sition of lead peculiar to various ore bodies and crustal sources may also be used as a means
of tracing the origin of anthropogenic lead.
SUMPB/D
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Colonmetric or spectrophotometric analysis for lead using dithizone (diphenylthiocarba-
zone) as the reagent has been used for many years. It was the primary method recommended by a
National Academy of Sciences (1972) report on lead, and the basis for the tentative method of
testing for lead in the atmosphere by the American Society for Testing and Materials (1975b)
Prior to the development of the IDMS method, colorimetric analysis served as the reference by
which other methods were tested.
Analytical methods based on electrochemical phenomena are found in a variety of forms.
They are characterized by a high degree of sensitivity, selectivity, and accuracy derived from
the relationship between current, charge, potential, and time for electrolytic reactions in
solutions. Anodic stripping voltammetry (ASV) is a two step process in which the lead is pre-
concentrated onto a mercury electrode by an extended but selected period of reduction. After
the reduction step, the potential is scanned either linearly or by differential pulse to oxi-
dize the lead and allow measurement of the oxidation (stripping) current.
The majority of analytical methods are restricted to measurement of total lead and cannot
directly identify the various compounds of lead. Gas chromatography (GC) using the electron
capture detector has been demonstrated to be useful for organolead compounds. The use of
atomic absorption as the GC detector for organolead compounds has been described by De Jonghe
et al. (1981), while a plasma emission detector has been used by Estes et al. (1981). In ad-
dition, Messman and Rains (1981) have used liquid chromatography with an atomic absorption
detector to measure organolead compounds. Mass spectrometry may also be used with gas chroma-
tography (Mykytiuk et al., 1980).
1 5 SOURCES AND EMISSIONS
The history of global lead emissions has been assembled from chronological records of de-
position in polar snow strata, marine and freshwater sediments, and the annual rings of trees.
These records aid in establishing natural background levels of lead in air, soils, plants,
animals, and humans, and they document the sudden increase in atmospheric lead at the time of
the industrial revolution, with a later burst during the 1920's when lead-alkyls were first
added to gasoline. Pond sediment analyses have shown a 20-fold increase in lead deposition
during the last 150 years (Figure 1-4), documenting not only the increasing use of lead since
the beginning of the industrial revolution in western United States, but also the relative
fraction of natural vs. anthropogenic lead inputs. Other studies have shown the same magni-
tude of increasing deposition in freshwater marine sediments. The pond and marine sediments
document the shift in isotopic composition of atmospheric lead caused by increased com-
mercial use of the New Lead Belt in Missouri, where the ore body has an isotopic composition
substantially different from other ore bodies of the world.
SUNPB/° 1-12 9/6/84
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1.0
09
08
07
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S 06
t-
z
LLI
= 05
3
U
2 04
o
| 03
02
0 1
0
1750 1775 1800 1825 1850 1875 1900 1925 1950 1975
YEAR
Figure 1-4. Chronological record of the relative increase of lead in snow strata, pond
and lake sediments, marine sediments, and tree rings. The data are expressed as a
ratio of the latest year of the record and should not be interpreted to extend back in
time to natural or uncontaminated levels of lead concentration.
Source: Adapted from Murozumi et al. (1969) (O), Shirahata et al. (19801(D), Edgington
and Robbins (1976) ( A ), Ng and Patterson (1982) ( ~ ). and Rolfe (1974) ( • ).
Perhaps the best chronological record is that of the polar ice strata of Murozumi et al
(1969), which extends nearly three thousand years back in time (Figure 1-4). At the South
Pole, Boutron (1982) observed a 4-fold increase of lead in snow from 1957 to 1977 but saw no
increase from 1927 to 1957. The author suggested the extensive atmospheric lead pollution
which began in the 1920's did not reach the South Pole until the mid-1950's. This interpreta-
tion agrees with that of Maenhaut et al. (1979), who found atmospheric concentrations of lead
of 0.000076 pg/m3 at the same location This concentration is about 3-fold higher than the
0.000024 pg/m3 estimated by Patterson (1980) and Servant (1982) to be the natural lead concen-
tration in the atmosphere. In summary, it is likely that atmospheric lead emissions have
increased 2000-fold since the pre-Roman era, that even at this early time the atmosphere may
SUMPB/D
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9/6/84
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have been contaminated by a factor of three over natural levels (Murozumi et al 1969), and
that global atmospheric concentrations have increased dramatically since the 1920's.
The history of global emissions may also be inferred from total production of lead. The
historical picture of lead production has been pieced together from many sources by Settle and
Patterson (1980) (Figure 1-5). Until the industrial revolution, lead production was deter-
mined largely by the ability or desire to mine lead for its silver content. Since that time,
lead has been used as an industrial product in its own right, and efforts to improve smelter
sfficiency, including control of stack emissions and fugitive dusts, have made lead production
more economical This improved efficiency is not reflected in the chronological record
because of atmospheric emissions of lead from many other anthropogenic sources, especially
gasoline combustion. From this knowledge of the chronological record, it is possible to sort
out contemporary anthropogenic emissions from natural sources of atmospheric lead.
Lead enters the biosphere from lead-bearing minerals in the lithosphere through both
natural and man-made processes. Measurements of soil materials taken at 20-cm depths in the
continental United States show a median lead concentration of 15-16 (jg Pb/g soil. In natural
processes, lead is first incorporated in soil in the active root zone, from which it may be
absorbed by plants, leached into surface waters, or eroded into windborne dusts.
Calculations of natural contributions using geochemical information indicate that the
natural particulate lead level is less than 0.0005 jjg/m3 (National Academy of Sciences, 1980),
and probably lower than the 0.000076 |jg/m3 measured at the South Pole (Maenhaut et al , 1979).
In contrast, lead concentrations in some urban environments may range as high as 6 pg/m3 (U S
Environmental Protection Agency, 1979, 1978). Evidently, most of this urban particulate lead
originates from man-made sources.
Lead occupies an important position in the U.S. economy, ranking fifth among all metals
in tonnage used. Approximately 85 percent of the primary lead produced in this country is
from native mines, although often associated with minor amounts of zinc, cadmium, copper,
bismuth, gold, silver, and other minerals (U S. Bureau of Mines, 1972-1982). Missouri lead
ore deposits account for approximately 80-90 percent of the domestic production. Total utili-
zation averaged approximately 1.36xl06 t/yr over the 10-year period, with storage batteries
and gasoline additives accounting for ~70 percent of total use. Certain products, especially
batteries, cables, plumbing, weights, and ballast, contain lead that is economically recover-
able as secondary lead. Lead in pigments, gasoline additives, ammunition, foil, solder, and
steel products is widely dispersed and therefore is largely unrecoverable. Approximately
40-50 percent of annual lead production is recovered and eventually recycled.
SUMPB/D
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9/6/84
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I I
SPANISH PRODUCTION
OF SILVER
IN NEW WORLD
INDUSTRIAL
REVOLUTION
EXHAUSTION SILVER
OF ROMAN PRODUCTION
LEAD MINES IN GERMANY
INTRODUCTION
OF COINAGE
DISCOVERY OF
CUPELLATION
RISE AND FALL
OF ATHENS
\
ROMAN REPUBLIC
AND EMPIRE
/
5500 5000 4500 4000 3500 3000 2500 2000 1500 1000
YEARS BEFORE PRESENT
500
¦ 9 J* production has changed historically in response to
IS£»r«r?r V P°!,t,cal events. Increases in lead production (note log
in Figure appr0x,mate'*to historical increases in lead emissions shown
Source: Adapted from Settle and Patterson (1980).
Lead or its compounds may enter the environment at any point during mining, smelting,
processing, use, recycling, or disposal. Estimates of the dispersal of lead emissions into
the environment by principal sources indicate that the atmosphere is the major initial
recipient. Estimated lead emissions to the atmosphere are shown in Table 1-1. Mobile and
stationary sources of lead emissions, although found throughout the nation, tend to be con-
centrated in areas of high population density, and near smelters. Figure 1-6 shows the ap-
proximate locations of major lead mines, primary and secondary smelters and refineries, and
alkyl lead paints (International Lead Zinc Research Organization, 1982)
SUMPB/D
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TABLE 1-1 ESTIMATED ATMOSPHERIC LEAD EMISSIONS FOR THE
UNITED STATES (1981) AND THE WORLD (1979)
Source Category
Annual
U.S.
Emissions
(t/yr)
Percentage of
U.S. Total
Emissions
Annual
Global
Emi ssions
(t/yr)
Gasoline combustion
61,000
91.4%
273,000
Waste oil combustion
Sol id waste di sposal
Coal combustion
Oil combustion
Wood combustion
830
319
950
226
1.2
0.5
1.4
0 3
8,900
14,000
6,000
4,500
Gray iron production
Iron and steel production
Secondary lead smelting
Primary copper smelting
Ore crushing and grinding
Primary lead smelting
Other metallurgical
Zn smelting
Ni smelting
295
533
631
30
326
921
54
0 5
0.8
0.9
0.1
0.5
1.4
0.1
50,000
770
27,000
8,200
31,000
16,000
2,500
Lead alkyl manufacture
Type metal
Portland cement production
245
85
71
0 4
0.1
0.1
7,400
Miscellaneous
233
0.3
5,900
Total
66,749a
100%
449,170
Inventory does not include emissions from exhausting workroom air, burning of lead-painted
surfaces, welding of lead-painted steel structures, or weathering of painted surfaces
Source For U.S. emissions, Battye (1983); for global emissions, Nriagu (1979).
The majority of lead compounds found in the atmosphere result from leaded gasoline com-
bustion. Several reports indicate that transportation sources contribute over 90 percent of
the total atmospheric lead. Other mobile sources, including aviation use of leaded gasoline
and diesel and jet fuel combustion, contribute insignificant lead emissions to the atmosphere
Automotive lead emissions occur as PbBrCl in fresh exhaust particles. The fate of emit-
ted lead particles depends upon particle size Particles initially formed by condensation of
lead compounds in the combustion gases are quite small (well under 0.1 pm in diameter) Parti-
cles in this size category are subject to growth by coagulation and, when airborne, can remain
SUMPB/D
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9/6/84
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I
MINES 115)
~ SMELTERS AND REFINERIES (7)
O SECONDARY SMELTERS AND REFINERIES (56)
• LEAD ALKYL PLANTS (4)
Figure 1-6. Locations of major lead operations in the United States.
Source International Lead Zinc Research Organization (1982)
-------
suspended in the atmosphere for 7-30 days and travel thousands of miles from their original
source Larger particles are formed as the result of agglomeration of smaller condensation
particles and have limited atmospheric lifetimes
During the lifetime of the vehicle, approximately 35 percent of the lead contained in the
gasoline burned by the vehicle will be emitted as small particles [<0.25 pm mass median aero-
dynamic diameter (MMAD)], and approximately 40 percent will be emitted as larger particles
(>10 pm MMAD) (Ter Haar et al., 1972) The remainder of the lead consumed in gasoline combus-
tion is deposited in the engine and exhaust system.
Although the majority (>90 percent on a mass basis) of vehicular lead compounds are emit-
ted as inorganic particles (e g., PbBrCl), some organolead vapors (e.g., lead alkyls) are also
emitted. The largest volume of organolead vapors arises from the manufacture, transport, and
handling of leaded gasoline. Such vapors are photoreactive, and their presence in local atmo-
spheres is transitory. Organolead vapors are most likely to occur in occupational settings
and have been found to contribute less than 10 percent of the total lead present in the atmo-
sphere.
The use of lead additives in gasoline, which increased in volume for many years, is now
decreasing as automobiles designed to use unleaded fuel constitute the major portion of the
automotive population. The decline in the use of leaded fuel is the result of two regulations
promulgated by the U.S. Environmental Protection Agency (F.R., 1973 December 6) The first
required the availability of unleaded fuel for use in automobiles designed to meet federal
emission standards with lead-sensitive emission control devices (e g , catalytic converters),
the second required a reduction or phase-down of the lead content in leaded gasoline The
trend in lead content for U.S. gasolines is shown in Figure 1-7. Of the total gasoline pool,
which includes both leaded and unleaded fuels, the average lead content has decreased 63 per-
cent, from an average of 1 62 g/gal in 1975 to 0 46 g/gal in 1983.
Data describing the lead consumed in gasoline and average ambient lead levels (composite
of maximum quarterly values) versus calendar year are plotted in Figure 1-8. Between 1975 and
1982, the lead consumed in gasoline decreased 64 percent (from 165,600 to 59,800 metric tons)
while the corresponding composite maximum quarterly average of ambient lead decreased 66 per-
cent (from 1.23 to 0.42 pg/m3). This indicates that control of lead in gasoline over the past
several years has effected a direct decrease in peak ambient lead concentrations.
Solid waste incineration and combustion of waste oil are principal contributors of lead
emissions from stationary sources. The manufacture of consumer products such as lead glass,
storage batteries, and lead additives for gasoline also contributes significantly to station-
ary source lead emissions Since 1970, the quantity of lead emitted from the metallurgical
industry has decreased somewhat because of the application of control equipment and the clos-
ing of several plants, particularly in the zinc and pyrometallurgical industries.
SUMPB/D 1.-18 9/6/84
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LEADED FUEL
SALES-WEIGHTED TOTAL
GASOLINE POOL
(LEADED AND UNLEADED
AVERAGE 'I
UNLEADED FUEL
1975
1976
1977
1981
1978 1979 1980
CALENDAR YEAR
Figure 1-7. Trend in lead content of U.S. gasolines, 1975-1983.
Source: U.S. EPA (1984a).
1982
1983
1-19
-------
180
160 —
i—i—r
¦ LEAD CONSUMED IN GASOLINE
LEAD CONCENTRATION
140 —
in
5 120
100
a 80
uj
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AMBIENT AIR
1.2
1.1
1 0
09
08
0.7
06
05
04
40 —
03
20
J L
02
0 1
1975 1976 1977
1978 1979 1980
CALENDAR YEAR
1981 1982 1983
Figure 1-8. Lead consumed in gasoline and ambient lead concen-
trations, 1975-1983.
Source: U.S. EPA (1984a).
1-20
-------
A new locus for lead emissions emerged in the nnd-1960s with the opening of the "Viburnum
Trend" or "New Lead Belt" in southeastern Missouri The presence of ten mines and three ac-
companying lead smelters in this area makes it the largest lead-producing district in the
wor 1 d
1 6 TRANSPORT AND TRANSFORMATION
16 1 Atmospheric Transport
At any particular location and time, the concentration of lead found in the atmosphere
depends on the proximity to the source, the amount of lead emitted from sources, and the de-
gree of mixing provided by the motion of the atmosphere. Lead emissions from auto exhaust are
typically around 10,000 pg/m3, while lead values in city air are usually between 0 1 and 10
pg/m3. These reduced concentrations are the result of dilution of effluent gas with clean air
and the removal of particles by wet or dry deposition. Characteristically, lead concentra-
tions are highest in confined areas close to sources and are progressively reduced by dilution
or deposition in districts more removed from sources. In parking garages or tunnels, atmos-
pheric lead concentrations can be ten to a thousand times greater than values measured near
roadways or in urban areas In turn, atmospheric lead concentrations are usually about 2h
times greater in the central city than in residential suburbs. Rural areas have even lower
concentrations. Particle size distribution stabilizes within a few hundred kilometers of the
sources, although atmospheric concentration continues to decrease with distance. Ambient
organolead concentrations decrease more rapidly than inorganic lead, suggesting conversion
from the organic to the inorganic phase during transport.
Whitby et al (1975) placed atmospheric particles into three different size regimes, the
nuclei mode (<0 1 pm), the accumulation mode (0.1-2 pm), and the large particle mode (>2 pm)
At the source, lead particles are generally in the nuclei and large particle modes. Large
particles are removed by deposition close to the source and particles in the nuclei mode dif-
fuse to surfaces or agglomerate while airborne to form larger particles of the accumulation
mode Thus it is in the accumulation mode that particles are dispersed great distances
Particles in air streams are subject to the same principles of fluid mechanics as par-
ticles in flowing water The first principle is that of diffusion along a concentration gra-
dient If the airflow is steady and free of turbulence, the rate of mixing is determined by
the diffusivity of the pollutant By making generalizations of windspeed, stability, and sur-
face roughness, it is possible to construct models using a variable transport factor called
eddy diffusivity (K), in which K varies in each direction, including vertically. There is a
family of K-theory models that describe the dispersion of particulate pollutants The
simplest K-theory model produces a Gaussian plume, called such because the concentration of
SUMPB/D 1-21 9/6/84
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the pollutant decreases according to a normal or Gaussian distribution in both the vertical
and horizontal directions These models have some utility and are the basis for most of the
air quality simulations performed to date Another family of models is based on the conserva-
tive volume element approach, where volumes of air are seen as discrete parcels having conser-
vative meteorological properties The effect of pollutants on these parcels of air, which may
be considered to move along a trajectory that follows the advective wind direction, is ex-
pressed as a mixing ratio. None of the models have been tested for lead, and all require sam-
pling periods of two hours or less in order for the sample to conform to a well-defined set of
meteorological conditions; in most cases, such a sample would be below the detection limits
for lead. The common pollutant used to test models is S02, which can be measured over very
short, nearly instantaneous, time periods. The question of whether gaseous S02 can be used as
a surrogate for particulate lead in these models remains to be answered.
Dispersion within confined situations, such as parking garages, residential garages, and
tunnels, and away from expressways and other roadways not influenced by complex terrain fea-
tures depends on emission rates and the volume of clean air available for mixing These fac-
tors are relatively easy to estimate and some effort has been made to describe ambient lead
concentrations which can result under selected conditions. On an urban scale, the routes of
transport are not clearly defined, but can be inferred from an isopleth diagram, i e , a plot
connecting points of identical ambient concentrations These plots always show that lead con-
centrations are maximum where traffic density is highest.
Dispersion beyond cities to regional and remote locations is complicated by the fact that
there are no monitoring network data from which to construct isopleth diagrams, that removal
by deposition plays a more important role with time and distance, and that emissions from many
different geographic locations and sources converge Dispersion from point sources such as
smelters and refineries results in a concentration distribution pattern similar to urban
dispersion, although the available data are notably less abundant. The 15 mines and 7 primary
smelters and refineries shown in Figure 1-6 are not located in urban areas. Most of the 56
secondary smelters and refineries are likewise non-urban. Consequently, dispersion from these
point sources should be considered separately, but in a manner similar to the treatment of
urban regions. In addition to lead concentrations in air, concentrations in soil and on vege-
tation surfaces are often used to determine the extent of dispersion away from smelters and
refineries.
Beyond the immediate vicinity of urban areas and smelter sites, lead in air declines
rapidly to concentrations of 0.1-0 5 pg/m3 Two mechanisms responsible for this change are
dilution with clean air and removal by deposition. Some attempts have been made to reconcile
air concentrations and deposition in remote locations with emission sources. Source reconcil-
iation is based on the concept that each type of natural or anthropogenic emission has a
SL)MpB/D i-22 9/6/84
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unique combination of elemental concentrations Measurements of ambient air, properly
weighted during multivariate regression analysis, should reflect the relative amount of
pollutant derived from each of several sources (Stolzenberg et al , 1982) Sievering et al
(1980) used the method of Stolzenberg et al (1982) to analyze the transport of urban air from
Chicago over Lake Michigan. They found that 95 percent of the lead in Lake Michigan air could
be attributed to various anthropogenic sources, namely auto emissions, coal fly ash, cement
manufacture, iron and steel manufacture, agricultural soil dust, construction soil dust, and
incineration emissions. Cass and McRae (1983) used source reconciliation in the Los Angeles
Basin to interpret 1976 NFAN data based on emission profiles from several sources. Their
chemical element balance model showed that 20-22 percent of the total suspended particle mass
could be attributed to highway sources.
Harrison and Williams (1982) determined air concentrations, particle size distributions,
and total deposition flux at one urban and two rural sites in England. The urban site, which
had no apparent industrial, commercial, or municipal emission sources, had an air lead concen-
tration of 3 8 pg/m3, whereas the two rural sites were about 0.15 pg/m3. The average particle
size became smaller toward the rural sites, as the MMAD shifted downward from 0.5 to 0 1 pm.
Purdue et al. (1973) measured both particulate and organic lead in atmospheric samples
They found that the vapor phase lead was about 5 percent of the total lead in most samples
It is noteworthy, however, that in an underground garage, total lead concentrations were
approximately five times those in ambient urban atmospheres, and the organic lead increased to
approximately 17 percent.
Knowledge of lead concentrations in the oceans and glaciers provides some insight into
the degrees of atmospheric mixing and long range transport Patterson and co-workers have
measured dissolved lead concentrations in sea water off the coast of California, in the
Central North Atlantic (near Bermuda), and in the Mediterranean The profile obtained in the
central northeast Pacific by Schaule and Patterson (1980) is shown in Figure 1-9 These
investigators calculated that industrial lead currently is being added to the oceans at about
10 times the rate of introduction by natural weathering, with significant amounts being
removed from the atmosphere by wet and dry deposition directly into the ocean Their data
suggest considerable contamination of surface waters near shore, diminishing toward the open
ocean
Ninety percent of the particulate pollutants in the global troposphere are injected in
the northern hemisphere (Robinson and Robbins, 1971). Since the residence times for particles
in the troposphere are much less than the lnterhemispheric mixing time, it is unlikely that
significant amounts of particulate pollutants can migrate from the northern to the southern
hemisphere via the troposphere. Murozumi et al. (1969) have shown that long range transport
of lead particles emitted from automobiles has significantly polluted the polar glaciers
SUMPB/D 1-23 9/6/84
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1000
• DISSOLVED Pb
~ PARTICULATE Pb
O 3000
4000
~ o
5000 3-fc
CONCENTRATION, ng Pb/kg
Figure 1-9. Profile of lead concentrations in the
central northeast Pacific Values below 1000 m are
an order of magnitude lower than reported by
Tatsumoto and Patterson (1963) and Chow and
Patterson (1966).
Source: Schaule and Patterson (1980)
1-24
-------
They collected samples of snow and ice from Greenland (Figure 1-10) and the Antarctic The
authors attribute the gradient increase after 1750 to the Industrial Revolution and the accel-
erated increase after 1940 to the increased use of lead alkyls in gasoline. The most recent
levels found in the Antarctic snows were, however, less than those found in Greenland by a
factor of 10 or more.
Evidence from remote areas of the world suggests that lead and other fine particle com-
ponents are transported substantial distances, up to thousands of kilometers, by general
weather systems. The degree of surface contamination of remote areas with lead depends both
on weather influences and on the degree of air contamination. However, even in remote areas,
man s primitive activities can play an important role in atmospheric lead levels
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0 06
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0 02 —
800
1750
1800
1850
1900
1950
h-B C A D —H
AGE OF SAMPLES
Figure 110. Lead concentration profile in snow
strata of Northern Greenland.
Source: Murozumi et al. (1969).
SUMPB/D
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9/6/84
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1.6 2 Peposi tion
Before atmospheric lead can have any effect on organisms or ecosystems, it must be trans*
ferred from the air to a surface. For natural ground surfaces and vegetation, this process
may be either dry or wet deposition. Transfer by dry deposition requires that the particle
move from the main airstream through the boundary laysr to a surface. The boundary layer is
defined as the region of minimal air flow immediately adjacent to that surface. The thickness
of the boundary layer depends mostly on the windspeed and roughness of the surface Airborne
particles do not follow a smooth, straight path in the airstream. On the contrary, the path
of a particle may be affected by micro-turbulent air currents, gravitation, or its own iner-
tia. There are several mechanisms that may alter the particle path sufficient to cause
transfer to a surface These mechanisms are a function of particle size, windspeed, and sur-
face characteristics.
Particles transported to a surface by any mechanism are said to have an effective deposi-
tion velocity (V^) which is measured not by rate of particle movement but by accumulation on a
surface as a function of air concentration. Several recent models of dry deposition have
evolved from the theoretical discussion of Fuchs (1964) and the wind tunnel experiments of
Chamberlain (1966). The models of SI inn (1982) and Davidson et al. (1982) are particularly
useful for lead deposition. Slinn's model considers a multitude of vegetation parameters to
find several approximate solutions for particles in the size range of 0.1-1.0 ^m, estimating
deposition velocities of 0.01-0.1 cm/sec. The model of Davidson et al. (1982) is based on
detailed vegetation measurements and wind data to predict a of 0.05-1.0 cm/sec; deposition
velocities are specific for each vegetation type. Both models show a decrease in deposition
velocity as particle size decreases down to about 0.1-0.2 pm; as diameter decreases further
from 0.1 to 0.001 |jm, deposition velocity increases.
Several investigators have used surrogate surface devices to measure dry deposition
rates. The few studies available on deposition of lead on vegetation surfaces show rates
comparable to those of surrogate surfaces and deposition velocities in the range predicted by
the models discussed above (Table 1-2) These data show that global emissions are in approxi-
mate balance with global deposition. The geochemical mass balance of lead in the atmosphere
may be determined from quantitative estimates of inputs and outputs. Inputs amount to
450,000-475,000 metric tons annually (Table 1-1) The amount of lead removed by wet deposi-
tion is approximately 208,000 t/yr (Table 1-3). The deposition flux for each vegetation type
shown on Table 1-3 totals 202,000 t/yr. The combined wet and dry deposition is 410,000 metric
tons, which compares favorably with the estimated 450,000 - 475,000 metric tons of emissions
Concentrations of lead in ground water appear to decrease logarithmically with distance
from a roadway Rainwater runoff has been found to be an important transport mechanism in the
SUMPB/D
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9/6/84
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TABLE 1-2. SUMMARY OF SURROGATE AND VEGETATION SURFACE DEPOSITION OF LEAD
Depositional Surface
F1 ux
ng Pb/cm2/day
Air Cone
ng/m3
Deposition Velocity
cm/sec
Reference
Tree leaves (Paris)
0.38
—
0 086
1
Tree leaves (Tennessee)
0.29-1.2
—
—
2
Plastic disk (remote
Callfornia)
0.02-0.08
13-31
0.05-0.4
3
Plastic plates
(Tennessee)
0 29-1.5
110
0.05-0.06
4
Tree leaves (Tennessee)
110
0.005
4
Snow (Greenland)
0.004
0.1-0.2
0 1
5
Grass (Pennsylvania)
590
0.2-1.1
6
Coniferous forest (Sweden)
0.74
21
0.41
7
1. Servant, 1975
2. Lindberg et al., 1982
3. Elias and Davidson, 1980
4 Lindberg and Harriss, 1981
5. Davidson et al., 1981
6. Davidson et al., 1982
7. Lannefors et al , 1983
removal of lead from a roadway surface in a number of studies. Apparently, only a light rain-
fall, 2-3 mm, is sufficient to remove 90 percent of the lead from the road surface to sur-
rounding soil and to waterways. The lead concentrations in off-shore sediments often show a
marked increase corresponding to anthropogenic activity in the region. Rippey et al. (1982)
found such increases recorded in the sediments of Lough Neagh, Northern Ireland, beginning
during the 1600's and increasing during the late 1800's. Data on recent lead levels indicate
an average anthropogenic flux of 72 mg/m2-yr, of which 27 mg/m2>yr could be attributed to
direct atmospheric deposition. Prior to 1650, the total flux was 12 mg/m2-yr, so there has
been a 6-fold increase since that time Ng and Patterson (1982) found prehistoric fluxes of
1-7 mg Pb/m2-yr to three offshore basins in southern California, which have now increased 3 to
9-fold to 11-21 mg/m2*yr. Much of this lead is deposited directly from sewage outfalls,
although at least 25 percent probably comes from the atmosphere.
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TABLE 1-3. ESTIMATED GLOBAL DEPOSITION OF ATMOSPHERIC LEAD
Mass of Water Lead Concentration Lead Deposition
1017 kg/yr 10-6 g/kg 106 kg/yr
Wet
To oceans
To continents
4.1
1.1
o o
164
44
Dry
Area
1012 m2
Deposition rate
10-3 q/m2-yr
Deposition
106 kq/yr
To oceans, ice caps, deserts
405
0.2
89
Grassland, agricultural
areas, and tundra
46
0.71
33
Forests
59
1.5
Total dry:
Total wet:
Global:
80
202
208
410
Source: This report.
1.6 3 Transformation
Lead is emitted into the air from automobiles as lead halides and as double salts with
ammonium halides (e.g., PbBrCl • 2NH4C1). From mines and smelters, PbS04, Pb0-PbS04, and PbS
appear to be the dominant species In the atmosphere, lead is present mainly as the sulfate
with minor amounts of halides. It is not completely clear just how the chemical composition
changes in transport.
The ratio of Br to Pb is often cited as an indication of automotive emissions From the
mixtures commonly used in gasoline additives, the mass Br/Pb ratio should be 0.4-0.5 How-
ever, several authors have reported loss of halide, preferentially bromine, from lead salts in
atmospheric transport; both photochemical decomposition and acidic gas displacement have been
postulated as mechanisms. The Br/Pb ratios may be only crude estimates of automobile emis-
sions, this ratio would decrease with distance from the highway from 0.39 to 0 35 at less
proximate sites and 0.25 in suburban residential areas. For an aged aerosol, the Br/Pb mass
ratio is usually about 0.22. Habibi et al. (1970) studied the compos ltion of auto exhaust
particles as a function of particle size. Their main conclusions follow:
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1 The chemical composition of emitted exhaust particles is related to particle
size.
2 There is considerably more soot and carbonaceous material associated with fine-
mode particles than with coarse-mode particles. Particulate matter emitted
under typical driving conditions is rich in carbonaceous material.
3 Only small quantities of 2PbBrCl*NH4C1 were found in samples collected at the
tailpipe from the hot exhaust gas. Lead-halogen molar ratios in particles of
less than 10 pm MMED indicate that much more halogen is associated with these
solids than the amount expected from the presence of 2PbBrCl-NH4C1.
Lead sulfide is the main constituent of samples associated with ore handling and fugitive
dust from open mounds of ore concentrate. The major constituents from sintering and blast
furnace operations appeared to be PbS04 and Pb0*PbS04) respectively.
Atmospheric lead may enter the soil system by wet or dry deposition mechanisms. Lead
could be immobilized by precipitation as less soluble compounds [PbC03, Pb(P04)2], by ion ex-
change with hydrous oxides or clays, or by chelation with humic (HA) and fulvic (FA) acids.
Lead immobilization is more strongly correlated with organic chelation than with iron and
managanese oxide formation (Zimdahl and Skogerboe, 1977). The total capacity of soil to im-
mobilize lead can be predicted from the linear relationship developed by Zimdahl and Skogerboe
(1977) (Figure 1-11) based on the equation:
-6 _ 5 .5
N = 2.8 x 10 (A) + 1.1 x 10 (B) - 4.9 x 10
where N is the saturation capacity of the soil expressed in moles/g soil, A is the cation ex-
change capacity of the soil in meq/100 g soil, and B is the pH.
The soil humus model also facilitates the calculation of lead in soil moisture using
values available in the literature for conditional stability constants (K) with fulvic acid.
The values reported for log K are linear in the pH range of 3-6 so that interpolations in the
critical range of pH 4-5.5 are possible (Figure 1-11). Thus, at pH 4.5, the ratio of com-
Plexed lead to ionic lead is expected to be 3.8 x- 103. For soils of 100 pg/g, the ionic lead
in soil moisture solution would be 0.03 pg/g. It is also important to consider the stability
constant of the Pb-FA complex relative to other metals. At normal soil pH levels of 4 5-8,
lead is bound to FA + HA in preference to many other metals that are known plant nutrients
(Zn, Mn, Ca, and Mg).
Soils have both a liquid and solid phase, and trace metals are normally distributed be-
tween these two phases. In the liquid phase, metals may exist as free ions or as soluble com-
plexes with organic or inorganic ligands. Since lead rarely occurs as a free ion in the
liquid phase, its mobility in the soil solution depends on the availability of organic or
SUMPB/D 1-29 9/6/84
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50
45
r 40
o
o>
"S>
I 30
E
>
t 2.5
u
<
0.
< 2.0
z
o
a:
3
< 1.0
V)
0
0
0 25 50 75 100 125
CEC. meq/100 g
Figure 1-11. Variation of lead saturation capacity with cation exchange
capacity in soil at selected pH values.
Source: Data from Zimdahl and Skogerboe (1977).
inorganic ligands. The liquid phase of soil often exists as a thin film of moisture in inti-
mate contact with the solid phase. The availability of metals to plants depends on the equi-
librium between the liquid and solid phase. In the solid phase, metals may be incorporated
into crystalline minerals of parent rock material and secondary clay minerals or precipitated
as insoluble organic or inorganic complexes. They may also be adsorbed onto the surfaces of
any of these solid forms. Of these categories, the most mobile form is in soil moisture,
where lead can move freely into plant roots or soil microorganisms with dissolved nutrients.
The least mobile is parent rock material, where lead may be bound within crystalline struc-
tures over geologic periods of time; intermediate are the lead complexes and precipitates
Transformation from one form to another depends on the chemical environment of the soil The
water soluble and exchangeable forms of metals are generally considered available for plant
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uptake In normal soils, only a small fraction of the total lead is in exchangeable form
(about 1 pg/g) and none exists as free lead ions. Of the exchangeable lead, 30 percent exists
as stable complexes, 70 percent as labile complexes.
An outstanding characteristic of lead is its tendency to form compounds of low solubility
with the major anions of natural water. The hydroxide, carbonate, sulfide, and more rarely
the sulfate may act as solubility controls in precipitating lead from water. The amount of
lead that can remain in solution is a function of the pH of the water and the dissolved salt
content. A significant fraction of the lead carried by river water may be in an undissolved
state. This insoluble lead can consist of colloidal particles in suspension or larger undis-
solved particles of lead carbonate, -oxide, -hydroxide, or other lead compounds incorporated
in other components of particulate lead from runoff, it may occur either as sorbed ions or
surface coatings on sediment mineral particles or be carried as a part of suspended living or
nonliving organic matter.
The bulk of organic compounds in surface waters originates from natural sources
(Neubecker and Allen, 1983). The humic and fulvic acids that are primary complexing agents in
soils are also found in surface waters at concentrations of 1-5 mg/1 , occasionally exceeding
10 mg/1. The presence of fulvic acid in water has been shown to increase the rate of solution
of lead sulfide 10-60 times over that of a water solution at the same pH that did not contain
fulvic acid. At pH values near 7, lead-fulvic acid complexes are present in solution
The transformation of inorganic lead, especially in sediment, to tetramethyllead (TML)
has been observed and biomethylation has been postulated. However, Reisinger et al. (1981)
have reported extensive studies of the methylation of lead in the presence of numerous bac-
terial species known to alkylate mercury and other heavy metals. In these experiments no bio-
logical methylation of lead was found under any condition.
1.7 ENVIRONMENTAL CONCENTRATIONS AND POTENTIAL PATHWAYS TO HUMAN EXPOSURE
In general, typical levels of human lead exposure may be attributed to four components of
the human environment: inhaled air, dusts of various types, food, and drinking water. A base-
line level of potential human exposure is determined for a normal adult eating a typical diet
and living in a non-urban community. This baseline exposure is deemed to be unavoidable by
any reasonable means Beyond this level, additive exposure factors can be determined for
other environments (urban, occupational, smelter communities), for certain habits and activi-
ties (smoking, drinking, pica, and hobbies), and for variations due to age, sex, or socio-
economic status.
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1.7 1 Lead in Air
Ambient airborne lead concentrations may influence human exposure through direct inhala-
tion of lead-containing particles and through ingestion of lead which has been deposited from
the air onto surfaces. Our understanding of the pathways of human exposure is far from com-
plete because most ambient measurements are not taken in conjunction with studies of the con-
centrations of lead in man or in components of his food chain.
The most complete set of data on ambient air concentrations may be extracted from the
National Filter Analysis Network (NFAN) and its predecessors. In remote regions of the world,
air concentrations are two or three orders of magnitude lower than in urban areas, lending
credence to estimates of the concentrations of natural lead in the atmosphere. In the context
of this data base, the conditions which modify ambient air (as measured by the monitoring net-
works) to air inhaled by humans cause changes in particle size distributions, changes with
vertical distance above ground, and differences between indoor and outdoor concentrations
The wide range of concentration is apparent from Table 1-4, which summarizes data ob-
tained from numerous independent measurements. Concentrations vary from 0.000076 pg/m3 in
remote areas to over 10 pg/m3 near sources such as smelters. Many of the remote areas are far
from human habitation and therefore do not reflect human exposure However, a few of the
regions characterized by small lead concentrations are populated by individuals with primitive
lifestyles, these data provide baseline airborne lead data to which modern American lead expo-
sures can be compared.
The remote area concentrations reported in Table 1-4 do not necessarily reflect natural,
preindustrial lead. Murozumi et al. (1969) and Ng and Patterson (1981) have measured a 200-
fold increase in the lead content of Greenland snow over the past 3000 years. The authors
state that this lead originates in populated mid-latitude regions, and is transported over
thousands of kilometers through the atmosphere to the Arctic. All of the concentrations in
Table 1-4, including values for remote areas, have been influenced by anthropogenic lead emis-
sions It seems likely that the concentration of natural lead in the atmosphere is between
0.00002 and 0.00007 pg/m3. A value of 0 00005 will be used for calculations regarding the
contribution of natural air lead to total human uptake.
The effect of the 1978 National Ambient Air Quality Standard for Lead has been to reduce
the air concentration of lead in major urban areas. Similar trends may also be seen in urban
areas of smaller population density. There are many factors which can cause differences
between the concentration of lead measured at a monitoring station and the actual inhalation
of air by humans. Air lead concentrations usually decrease with vertical and horizontal dis-
tance from emission sources, and are generally lower indoors than outdoors.
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TABLE 1-4 ATMOSPHERIC LEAD IN URBAN, RURAL, AND REMOTE AREAS OF THE WORLD
Location
Sampling period Lead conc. (pg/m3) Reference
Urban
New York
Boston
St. Louis
Houston
Chicago
Los Angeles
Ottawa
Toronto
Montreal
Brussels
Turi n
Rural
New York Bight
United Kingdom
Italy
Belgium
Remote
White Mtn., CA
High Sierra, CA
Olympic Nat. Park, WA
South Pole
Thule, Greenland
Thule, Greenland
Prins Christian-
sund, Greenland
Dye 3, Greenland
Eniwetok, Pacific Ocean
Kumjung, Nepal
Bermuda
1978-79
1978-79
1973
1978-79
1979
1978-79
1975
1975
1975
1978
1974-79
1974
1972
1976-80
1978
1969-70
1976-77
1980
1974
1965
1978-79
1978-79
1979
1979
1979
1973-75
1.1
0.8
1.1
0.9
0.8
1.4
1.3
1.3
2.0
0.5
4.5
0.13
0.13
0.33
0.37
0.008
0.021
0.0022
0.000076
0.0005
0.008
0.018
0 00015
0.00017
0.00086
0.0041
NEDS, 1982
NEDS, 1982
NEDS, 1982
NEDS, 1982
NEDS, 1982
NEDS, 1982
NAPS, 1975
NAPS, 1975
NAPS, 1975
Roels et al.
1980
Facchetti and Geiss, 1982
Duce et al., 1975
Cawse, 1974
Facchetti and Geiss, 1982
Roels et al., 1980
Chow et al., 1972
Elias and Davidson, 1980
Davidson et al., 1982
Maenhaut et al , 1979
Murozumi et al., 1969
Heidam, 1983
Heidam, 1983
Davidson et al., 1981c
Settle and Patterson, 1982
Davidson et al., 1981b
Duce et al., 1976
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Because people spend much of their time indoors, ambient air data may not accurately in-
dicate actual exposure to airborne lead. Some studies show smaller indoor/outdoor ratios
during the winter, when windows and doors are tightly closed. Overall, the data suggest
indoor/outdoor ratios of 0.6-0.8 are typical for airborne lead in houses without air condi-
tioning. Ratios in air conditioned houses are expected to be in the range of 0.3-0.5 (Yocum,
1982). Even detailed knowledge of indoor and outdoor airborne lead concentrations at fixed
locations may still be insufficient to assess human exposure to airborne lead. The study of
Tosteson et al (1982) included measurement of airborne lead concentrations using personal
exposure monitors, carried by individuals going about their day-to-day activities. In con-
trast to the lead concentrations of 0.092 and 0.12 pg/m3 at fixed locations, the average per-
sonal exposure was 0.16 pg/m3. The authors suggest the inadequacy of using fixed monitors at
either indoor or outdoor locations to assess exposure.
17.2 Lead in Soil and Dust
Studies have determined that atmospheric lead is retained in the upper 2-5 cm of undis-
turbed soil, especially soils with at least 5 percent organic matter and a pH of 5 or above.
There has been no general survey of this upper 2-5 cm of the soil surface in the United
States, but several studies of lead in soil near roadsides and smelters and a few studies of
lead in soil near old houses with lead-based paint can provide the backgound information for
determining potential human exposures to lead from soil. Because lead is immobilized by the
organic component of soil, the concentration of anthropogenic lead in the upper 2-5 cm is
determined by the flux of atmospheric lead to the soil surface. Near roadsides, this flux is
largely by dry deposition and the rate depends on particle size and concentration. In
general, deposition flux drops off abruptly with increasing distance from the roadway This
effect is demonstrated in studies which show surface soil lead decreases exponentially up to
25 m from the edge of the road. Roadside soils may contain concentrations of atmospheric lead
ranging from 30 to 2000 pg/g in excess of natural levels within 25 meters of the roadbed, all
in the upper layer of the soil profile.
Near primary and secondary smelters, lead in soil decreases exponentially within a 5-10
km zone around the smelter complex. Soil lead contamination varies with the smelter emission
rate, length of time the smelter has been in operation, prevailing windspeed and direction,
regional climatic conditions, and local topography.
Urban soils may be contaminated from a variety of atmospheric and non-atmospheric
sources. The major sources of soil lead seem to be paint chips from older houses and deposi-
tion from nearby highways Lead in soil adjacent to a house decreases with distance; this may
be due to paint chips or to dust of atmospheric origin washing from the rooftop (Wheeler and
Rolfe, 1979)
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A definitive study which describes the source of soil lead was reported by Gulson et al
(1981) for soils in the vicinity of Adelaide, South Australia. In an urban to rural transect,
stable lead isotopes were measured in the top 10 cm of soils over a 50 km distance. By their
isotopic compositions, three sources of lead were identified: natural, non-automotive indus-
trial lead from Australia, and tetraethyl lead manufactured in the United States. The results
indicated most of the soil surface lead originated from leaded gasoline.
Lead may be found in inorganic primary minerals, on humic substances, complexed with
Fe-Mn oxide films, on secondary minerals, or in soil moisture. All of the lead in primary
minerals is natural and is bound tightly within the crystalline structure of the minerals.
The lead on the surface of these minerals is leached slowly into the soil moisture
Atmospheric lead forms complexes with humic substances or on oxide films, that are in equi-
librium with soil moisture, although the equilibrium strongly favors the complexing agents
Except near roadsides and smelters, only a few pg of atmospheric lead have been added to each
gram of soil Several studies indicate that this lead is available to plants and that even
with small amounts of atmospheric lead, about 75 percent of the lead in soil moisture is of
atmospheric origin.
Lead on the surfaces of vegetation may be of atmospheric origin. In internal tissues,
lead maybe a combination of atmospheric and soil origin. As with soils, lead on vegetation
surfaces decreases exponentially with distance away from roadsides and smelters This de-
posited lead is persistent. It is neither washed off by rain nor taken up through the leaf
surface. Lead on the surface of leaves and bark is proportional to air lead concentrations
and particle size distributions. Lead in internal plant tissues is directly, although not
linearly, related to lead in soil.
1.7.3 Lead in Food
In a study to determine the background concentrations of lead and other metals in agri-
cultural crops, the Food and Drug Administration (Wolnik et al., 1983), in cooperation with
the U.S. Department of Agriculture and the U.S. Environmental Protection Agency, analyzed over
1500 samples of the most common crops taken from a cross section of geographic locations.
Collection sites were remote from mobile or stationary sources of lead. Soil lead concentra-
tions were within the normal range (8-25 pg/g) of U.S. soils. The concentrations of lead in
crops are shown as "Total" concentrations on Table 1-5. The total concentration data should
probably be seen as representing the lowest concentrations of lead in food available to
Americans. The data on these ten crops suggest that root vegetables have lead concentrations
between 0.0046 and 0.009 pg/g, all of which is soil lead. Aboveground parts not exposed to
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TABLE 1-5. BACKGROUND LEAD IN BASIC FOOD CROPS AND MEATStt
Crop
Natural
Pb
Indirect
Atmospheric
Direct
Atmospheric
Total^t
Wheat
0.0015
0.0015
0.034
0.037
Potatoes
0.0045
0.0045
--
0.009
Field corn
0.0015
0.0015
0.019
0.022*
Sweet corn
0.0015
0.0015
--
0.003
Soybeans
0.021
0.021
—
0.042
Peanuts
0.050
0 050
--
0.010
Onions
0.0023
0.0023
--
0.0046*
Rice
0.0015
0.0015
0.004
0.007*
Carrots
0.0045
0.0045
—
0.009*
Tomatoes
0.001
0.001
—
0.002*
Spi nach
0.0015
0.0015
0.042
0.045*
Lettuce
0.0015
0.0015
0.010
0.013
Beef (muscle)
0.0002
0.002
0.02
0.02**
Pork (muscle)
0.0002
0.002
0.06
0.06**
^All units are in |jg/g fresh weight.
^Except as indicated, data are from Wolnick et al. (1983)
*Preliminary data provided by the Elemental Analysis Research Center, Food and Drug
Administration, Cincinnati, OH
**Data from Penumarthy et al. (1980)
significant amounts of atmospheric deposition (sweet corn and tomatoes) have less lead inter-
nally. If it is assumed that this same concentration is the internal concentration for above-
ground parts for other plants, it is apparent that five crops have direct atmospheric deposi-
tion in proportion to surface area and estimated duration of exposure. The deposition rate of
0.04 ng/cm2*day in rural environments could account for these amounts of direct atmospheric
lead. Lead in food crops varies according to exposure to the atmosphere and in proportion to
the effort taken to separate husks, chaff, and hulls from edible parts during processing for
human or animal consumption. Root parts and protected aboveground parts contain natural lead
and indirect atmospheric lead, both of which are derived from the soil. For exposed above-
ground parts, any lead in excess of the average of unexposed aboveground parts is considered
to have been directly deposited from the atmosphere.
1.7.4 Lead in Water
Lead occurs in untreated water in either dissolved or particulate form. Because atmos-
pheric lead in rain or snow is retained by soil, there is little correlation between lead in
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precipitation and lead in streams that drain terrestrial watersheds. Rather, the important
factors seem to be the chemistry of the stream (pH and hardness) and the volume of the stream
flow The concentration of lead in streams and lakes is also influenced by the lead content
of sediments. At neutral pH, lead moves from the dissolved to particulate form; the particles
eventually pass to sediments. At low pH, the reverse pathway is generally the case. Hard-
ness, which is a combination of the Ca and Mg concentration, can also influence the solubility
of lead; at higher concentrations of Ca and Mg, its solubility decreases
For groundwater, chemistry is also important, as is the geochemical composition of the
water-bearing bedrock. Municipal and private wells typically have a neutral pH and somewhat
higher than average hardness. Lead concentrations are not influenced by acid rain, surface
runoff, or atmospheric deposition. Rather, the primary determinant of lead concentration is
the geochemical makeup of the bedrock that is the source of the water supply. Ground water
typically ranges from 1 to 100 ng Pb/1 (National Academy of Sciences, 1980).
Whether from surface or ground water supplies, municipal waters undergo extensive chem-
ical treatment prior to release to the distribution system. Although there is no direct ef-
fort to remove lead from the water supply, some treatments, such as flocculation and sedimen-
tation, may inadvertently remove lead along with other undesirable substances. On the other
hand, chemical treatment to soften water increases the solubility of lead and enhances the
possibility that lead will be added to water as it passes through the distribution system.
For samples taken at the household tap, lead concentrations are usually higher in the initial
volume (first daily flush) than after the tap has been running for some time. Water standing
in the pipes for several hours is intermediate between these two concentrations. (Sharrett et
al., 1982; Worth et al., 1981).
1.7.5 Baseline Exposures to Lead
Lead concentrations in environmental media that are in the pathway of human consumption
are summarized on Table 1-6. Because natural lead is generally three to four orders of magni-
tude lower than anthropogenic lead m ambient rural or urban air, all atmospheric contribu-
tions of lead are considered to be of anthropogenic origin. Natural soil lead typically
ranges from 10 to 30 vg/g, but much of this is tightly bound within the crystalline matrix of
soil minerals at normal soil pHs of 4-8. Lead in the organic fraction of soil is part natural
and part atmospheric. The fraction derived from fertilizer is considered to be minimal In
undisturbed rural and remote soils, the ratio of natural to atmospheric lead is about 1:1,
perhaps as high as 1:3. This ratio persists through soil moisture and into internal plant
tissues.
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TABLE 1-6. SUMMARY OF ENVIRONMENTAL CONCENTRATIONS OF LEAD
Natural
Atmospheri c
Total
Medi um
Lead
Lead
Lead
Air urban
(pg/m3)
0.00005
0.3 - 1.1
0.3 - 1 1
rural
(pg/m3)
0.00005
0.15 - 0.3
0.15 - 0.3
Soil Total
(|jg/g)
8-25
3 - 5
10 - 30
Food Crops
(pg/g)
0.0025
0.002 - 0.045
0.002 - 0.045
Surface water (jjg/g)
0 00002
0.005 - 0.030
0 005 - 0.030
Ground water
(pg/g)
0.003
--
0.001 - 0.1
In tracking air lead through pathways of human exposure, it is necessary to distinguish
between atmospheric lead that has passed through the soil, called indirect atmospheric here,
and atmospheric lead that has deposited directly on crops or water. Because indirect atmos-
pheric lead will remain in the soil for many decades, this source is insensitive to projected
changes in atmospheric lead concentrations.
Initially, a current baseline exposure scenario is described for an individual with a
minimum amount of daily lead consumption. This person would live and work in a nonurban en-
vironment, eat a normal diet of food taken from a typical grocery shelf, and would have no
habits or activities that would tend to increase lead exposure. Lead exposure at the baseline
level is considered unavoidable without further reductions of lead in the atmosphere or in
canned foods. Most of the baseline lead is of anthropogenic origin.
To arrive at a minimum or baseline exposure for humans, it is necessary to begin with the
environmental components (air, soil, food crops, and water) that are the major sources of lead
consumed by humans (Table 1-6). These components are measured frequently, even monitored
routinely in the case of air, so that much data are available on their concentrations But
there are several factors which modify these components prior to actual human exposure. We do
not breathe air as monitored at an atmospheric sampling station; we may be closer to or
farther from the source of lead than is the monitor; we may be inside a building, with or
without filtered air; water we drink does not come directly from a stream or river, but often
has passed through a chemical treatment plant and a distribution system. A similar type of
processing has modified the lead levels present in our food.
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Besides the atmospheric lead in environmental components, there are two other industrial
components which contribute to this baseline of human exposure- paint pigments and lead
solder. Solder contributes directly to the human diet through canned food and copper water
distribution systems. Paint and solder are also a source of lead-bearing dusts. The most
common dusts in the baseline human environment are street dusts and household dusts. They
originate as emissions from mobile or stationary sources, as the oxidation products of surface
exposure, or as products of frictional grinding processes. Ousts are different from soil, in
that soil derives from crustal rock and typically has a lead concentration of 10-30 pg/g,
whereas dusts come from both natural and anthropogenic sources and vary in lead concentration
from 1000 to 10,000 pg/g.
The route by which many people receive the largest portion of their daily lead intake is
via foods Several studies have reported average dietary lead intakes in the range of 100-500
pg/day for adults, with individual diets covering a much greater range (Nutrition Foundation,
1982). The sources of lead in plants and animals are air, soil, and untreated waters. Food
crops and livestock contain lead in varying proportions from the atmosphere and natural
sources From the farm to the dinner table, lead is added to food as it is harvested, trans-
ported, processed, packaged, and prepared. The sources of this lead are dusts of atmospheric
and industrial origin, metals used in grinding, crushing, and sieving, solder used in packag-
ing, and water used in cooking. It is assumed that this lead is all of direct atmospheric
origin. Direct atmospheric lead can be deposited directly on food materials by dry deposi-
tion, or it can be lead in dust which has collected on other surfaces, then transferred to
foods. For some of the food items, data are available on lead concentrations just prior to
filling of cans In the case where the food product has not undergone extensive modification
(e.g , cooking or added ingredients), the added lead was most likely derived from the atmos-
phere or from the machinery used to handle the product.
From the time a product is packaged in bottles, cans, or plastic containers until it is
opened in the kitchen, it may be assumed that no food item receives atmospheric lead. Most of
the lead which is added during this stage comes from the solder used to seal some types of
cans Estimates by the Food and Drug Administration, prepared in cooperation with the
National Food Processors Association, suggest that lead in solder contributes more than 66
percent of the lead in canned foods where a lead solder side seam was used. This lead is
thought to represent a contribution of 20 percent to the total lead consumption in foods The
contribution of the canning process to overall lead levels in albacore tuna has been reported
by Settle and Patterson (1980). The study showed that lead concentrations in canned tuna are
elevated above levels in fresh tuna by a factor of 4000. Nearly all of the increase results
from leaching of the lead from the soldered seam of the can; tuna from an unsoldered can is
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elevated by a factor of only 20 compared with tuna fresh from the sea. It is assumed that no
further lead is added to food packaged in plastic or paper containers, although there are no
data to support or reject this assumption.
Studies that reflect contributions of lead added during kitchen preparation showed that
lead in acidic foods stored refrigerated in open cans can increase by a factor of 2-8 in five
days if the cans have a lead-soldered side seam not protected by an interior lacquer coating
(Capar, 1978). Comparable products in cans with the lacquer coating or in glass jars showed
little or no increase.
As a part of its program to reduce the total lead intake by children (0-5 years of age)
to less than 100 pg/day by 1988, the U.S. FDA estimated lead intakes for individual children
in a large-scale food consumption survey (Beloian and McDowell, 1981). Between 1973 and 1978,
intensive efforts were made by the food industry to remove sources lead from infant food
items. By 1980, there had been a 47 percent reduction in the lead concentration of food con-
sumed by children in the age group 0-5 months and a 7 percent reduction for the 6- to 23-month
age group. Most of this reduction was accomplished by the removal of soldered cans used for
infant formula.
Because the U.S. FDA is actively pursuing programs to decrease lead in adult foods, it is
probable that there will be a decrease in total dietary lead consumption over the next decade
independent of projected decreases in atmospheric lead concentration. With both sources of
lead minimized, the lowest reasonable estimated dietary lead consumption would be 10-15 pg/day
for adults and children. This estimate assumes about 90 percent of the direct atmospheric,
solder lead, and lead of undetermined origin would be removed from the diet, leaving 8 pg/day
from these sources and 3 pg/day of natural and indirect atmospheric lead.
There have been several studies in North America and Europe of the sources of lead in
drinking water, and a concentration of 6-8 pg Pb/1 is often cited in the literature for speci-
fic locations. A recent study in Seattle, WA by Sharrett et al. (1982) showed that the age of
the house and the type of plumbing determined the lead concentration in tap water. Standing
water from houses newer than five years (copper pipes) averaged 31 pg/1, while houses less
than 18 months old averaged about 70 pg/1. Houses older than five years and houses with gal-
vanized pipe averaged less than 6 pg/1. The source of the water supply, the length of the
pipe, and the use of plastic pipes in the service line had little or no effect on the lead
concentrations. It appears certain that the source of lead in new homes with copper pipes is
the solder used to join these pipes, and that this lead is eventually leached away with age.
Ingestion, rather than inhalation, of dust particles appears to be the greater problem in
the baseline environmental exposure, especially ingestion during meals and playtime activity
by small children Although dusts are of complex origin, they may be conveniently placed into
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a few categories relating to human exposure. Generally, the most convenient categories are
household dusts, soil dust, street dusts, and occupational dusts. It is a characteristic of
dust particles that they accumulate on exposed surfaces and are trapped in the fibers of
clothing and carpets. Two other features of dusts are important. First, they must be de-
scribed in both concentration and amount. For example, the concentration of lead in street
dust may be the same in a rural and urban environment, but the amount of dust may differ by a
wide margin. Secondly, each category represents some combination of sources. Household dusts
contain some atmospheric lead, some paint lead, and some soil lead; street dusts contain
atmospheric, soil, and occasionally paint lead. For the baseline human exposure, it is
assumed that humans are not exposed to occupational dusts, nor do they live in houses with
interior leaded paints. Street dust, soil dust, and some household dust are the primary
sources for baseline potential human exposure
In considering the impact of street dust on the human environment, the obvious question
arises as to whether lead in street dust varies with traffic density. It appears that in non-
urban environments, lead in street dust ranges from 80 to 130 pg/g, whereas urban street dusts
range from 1,000 to 20,000 pg/g. For the purpose of estimating potential human exposure, an
average value of 90 pg/g in street dust is assumed for baseline exposure and 1500 pg/g in the
discussions of urban environments.
Household dust is also a normal component of the home environment. It accumulates on all
exposed surfaces, especially furniture, rugs, and windowsills. Most of the dust values for
nonurban household environments fall in the range of 50-500 pg/g. A value of 300 pg/g is
assumed. The only natural lead in dust would be some fraction of that derived from soil lead.
A value of 10 pg/g seems reasonable, since some of the soil lead is of atmospheric origin.
Children ingest about 5 times as much dust as adults, most of the excess being street dusts
from sidewalks and playgrounds. Exposure to occupational lead by children would be through
clothing brought home by parents.
The values for baseline exposure derived or assumed in the preceeding sections are sum-
marized on Table 1-7. These values represent only consumption, not absorption of lead by the
human body.
1.7 6 Additional Exposures
There are many conditions, even in nonurban environments, where an individual may
increase his lead exposure by choice, habit, or unavoidable circumstance. These conditions
are discussed below as separate exposures to be added as appropriate to the baseline of human
exposure described above. Most of these additive effects clearly derive from air or dust, few
are from water or food. Ambient air lead concentrations are typically higher in an urban than
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TABLE 1-7 SUMMARY OF BASELINE HUMAN EXPOSURES TO LEADt
Soi 1
Total
Natural
Indi rect
Direct
Lead from
Lead of
lead
lead
atmospheric
atmospheric
solder or
undetermined
Source
consumed
consumed
lead*
lead*
other metals
origin
Child-2 yr old
Inhaled air
0.5
0 001
-
0.5
-
-
Food
18.9
0.9
0.9
9.2
5.8
2.1
Water & beverages
6.9
0.01
1.8
1 0
4.1
-
Dust
21 0
0.6
——
19 0,
-
1.4
Total
47.3
1.5
2.7
29.7
9.9
3.4
Percent
100%
3.2%
5.8%
62.8%
20.9%
7.3%
Adult female
Inhaled air
1 0
0.002
-
1.0
-
-
Food
25.3
1.2
1.2
12.3
7.8
2.8
Water & beverages
10.7
0.01
2.7
1.6
6.4
-
Dust
4.5
0.2
2.9
-
1.4
Total
41.5
1.4
3.9
17.8
14.2
4.2
Percent
100%
3.4%
9.4%
42.9%
34.2%
10.1%
Adult male
Inhaled air
1.0
0.002
-
1.0
-
-
Food
35.8
1.7
1.7
17.5
11.1
3.8
Water & beverages
18.9
0.1
4.7
2.8
11.3
-
Dust
4.5
0.2
2.9
-
1.4
Total
60.2
2.0
6.4
24.2
22.4
5.2
Percent
100%
3.3%
10.6%
40.2%
37.2%
8.7%
*Indirect atmospheric lead has been previously incorporated into soil, and will probably remain in the
soil for decades or longer Direct atmospheric lead has been deposited on the surfaces of vegetation
and living areas or incorporated during food processing shortly before human consumption.
^Units are in pg/day
Source- This report
-------
a rural environment. This factor alone can contribute significantly to the potential lead
exposure of Americans through increases in inhaled air and consumed dust. Produce from urban
gardens may also increase the daily consumption of lead. Other contributing factors not
related only to urban living are houses with interior lead paint or lead plumbing, residences
near smelters or refineries, or family gardens grown on high-lead soils. Occupational expo-
sures may also be in an urban or rural setting. These exposures, whether primarily in the oc-
cupational environment or secondarily in the home of the worker, would be in addition to other
exposures in an urban location or from the special cases of lead-based paint or plumbing.
Urban atmospheres. The fact that urban atmospheres have more airborne lead than nonurban
atmospheres contributes not only to lead consumed by inhalation, but to increased amounts of
lead in dust as well. Typical urban atmospheres contain 0.5-1.0 (jg Pb/m3 Other variables
are the amount of indoor filtered air breathed by urban residents, the amount of time spent
indoors, and the amount of time spent on freeways. Dusts vary from 500 to 3000 pg/g in urban
environments.
Houses with interior lead paint. In 1974, the Consumer Product Safety Commission collec-
ted household paint samples and analyzed them for lead content (National Academy of Sciences,
National Research Council, 1976). The paints with the greatest amounts of lead were typically
found in the kitchens, bathrooms, and bedrooms. Peeling and flaking paint contributes to
potential human exposure via habitual or inadvertent consumption of paint chips. But powder
from painted walls also contributes to the lead concentration of household dust. Flaking
paint can also cause elevated lead concentrations in nearby soil. For example, Hardy et al.
(1971) measured soil lead levels of 2000 pg/g next to a barn in rural Massachusetts. A steady
decrease in lead level with increasing distance from the barn was shown, reaching 60 pg/g at
fifty feet from the barn. Ter Haar and Aronow (1974) reported elevated soil lead levels in
Detroit near eighteen old wood frame houses painted with lead-based paint. The average soil
lead level within two feet of a house was just over 2000 pg/g, the average concentration at
ten feet was slightly more than 400 pg/g. The same authors reported smaller soil lead eleva-
tions in the vicinity of eighteen brick veneer houses in Detroit. Soil lead levels near
painted barns located in rural areas were similar to urban soil lead concentrations near
painted houses, suggesting the importance of leaded paint at both urban and rural locations
The baseline lead concentration for household dust of 300 pg/g was increased to 2000 pg/g for
houses with interior lead based paints. The additional 1700 pg/g would add 85 pg Pb/day to
the potential exposure of a child. This increase would occur in either an urban or nonurban
environment and would be in addition to the urban residential increase if the lead-based
painted house were in an urban environment.
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Family gardens. Several studies have shown potentially higher lead exposure through the
consumption of home-grown produce from family gardens grown on high lead soils or near sources
of atmospheric lead. In family gardens, lead may reach the edible portions of vegetables by
deposition of atmospheric lead directly onto aboveground plant parts or onto soil, or by the
flaking of lead-containing paint chips from houses. Air concentrations and particle size dis-
tributions are the important determinants of deposition to soil or vegetation surfaces. It is
unlikely that surface deposition alone can account for more than 2-5 pg/g lead on the surface
of a leafy vegetable such as lettuce during a 21-day growing period. It appears that a signi-
ficant fraction of the lead in both leafy and root vegetables derives from the soil.
Houses with lead plumbing. The Glasgow Duplicate Diet Study (United Kingdom Central
Directorate on Environmental Pollution, 1982) reports that children approximately 13 weeks old
living in lead-plumbed houses consume 6-480 pg Pb/day. Water lead levels in the 131 homes
studied ranged from less than 50 to over 500 pg/1. Those children and mothers living in the
homes containing high water lead levels generally had greater total lead consumption and
higher blood lead levels, according to the study. Breast-fed infants were exposed to much
less lead than bottle-fed infants. The results of the study suggest that infants living in
lead-plumbed homes may have exposure to considerable amounts of lead. This conclusion was
also demonstrated by Sherlock et al. (1982) in a duplicate diet study in Ayr, Scotland
Residences near smelters and refineries. Air concentrations within 2 km of lead smelters
and refineries average 5-15 pg/m3 Considering both inhaled air and dust, a child in this
circumstance would be exposed to 1300 pg Pb/day above background levels. Exposures to adults
would be much less, since they consume only 20 percent of the dusts children consume
Occupational exposures. The highest and most prolonged exposures to lead are found among
workers in the lead smelting, refining, and manufacturing industries (World Health Organiza-
tion, 1977). In all work areas, the major route of lead exposure is by inhalation and inges-
tion of lead-bearing dusts and fumes. Airborne dusts settle out of the air onto food, water,
the workers' clothing, and other objects, and may be subsequently transferred to the mouth
Therefore, good housekeeping and good ventilation have a major impact on exposure. Even tiny
amounts (e g. , 10 mg) of dust containing 100,000 pg Pb/g can account for 1,000 pg/day lead
exposure.
The greatest potential for high-level occupational exposure exists in the process of lead
smelting and refining. The most hazardous operations are those in which molten lead and lead
alloys are brought to high temperatures, resulting in the vaporization of lead, because con-
densed lead vapor or fume has, to a substantial degree, a small (respirable) particle size
range.
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When metals that contain lead or are protected with a lead-containing coating are heated
in the process of welding or cutting, copious quantities of lead in the respirable size range
may be emitted. Under conditions of poor ventilation, electric arc welding of zinc silicate-
coated steel (containing 4.5 mg Pb/cm2 of coating) produces breathing-zone concentrations of
lead reaching 15,000 pg/m3, far in excess of the current occupational short-term exposure
limit in the United States (450 pg/m3). In a study of salvage workers using oxy-acetylene
cutting torches on lead-painted structural steel under conditions of good ventilation, breath-
ing-zone concentrations of lead averaged 1200 pg/m3 and ranged as high as 2400 pg/m3.
At all stages in battery manufacture except for final assembly and finishing, workers are
exposed to high air lead concentrations, particularly lead oxide dust. Excessive concentra-
tions, as great as 5400 pg/m3, have been quoted by the World Health Organization (1977) The
hazard in plate casting, which is a molten-metal operation, is from the spillage of molten
waste products, resulting in dusty floors.
In both the rubber products industry and the plastics industry there are potentially high
exposures to lead. The potential hazard of the use of lead stearate as a stabilizer in the
manufacture of polyvinyl chloride was noted in the 1971 Annual Report of the United Kingdom
Department of Employment, Chief Inspector of Factories (1972). The source of this problem is
the dust that is generated when the lead stearate is milled and mixed with the polyvinyl
chloride and the plasticizer. An encapsulated stabilizer that greatly reduces the occupa-
tional hazard was reported by Fischbein et al. (1982). Sakurai et al. (1974), in a study of
bioindicators of lead exposure, found ambient air concentrations averaging 58 pg/m3 in the
lead-covering department of a rubber hose manufacturing plant.
The manufacture of cans with leaded seams may expose workers to elevated environmental
lead levels Bishop (1980) reports airborne lead concentrations of 25-800 pg/m3 in several
can manufacturing plants in the United Kingdom. Between 23 and 54 percent of the airborne
lead was associated with respirable particles. Firing ranges may be characterized by high
airborne lead concentrations, hence instructors who spend considerable amounts of time in such
areas may be exposed to lead. Anderson et al. (1977) discuss plumbism in a 17-year-old male
employee of a New York City firing range, where airborne lead concentrations as great as 1000
pg/m3 were measured during sweeping operations. Removal of leaded paint from walls and other
surfaces in old houses may pose a health hazard. Feldman (1978) reports an airborne lead con-
centration of 510 pg/m3 after 22 minutes of sanding an outdoor post coated with paint contain-
ing 2.5 mg Pb/cm2. After only five minutes of sanding an indoor window sill containing
0.8-0.9 mg Pb/cm2, the air contained 550 pg/m3. Garage mechanics may also be exposed to exces-
sive lead concentrations. Clausen and Rastogi (1977) report airborne lead levels of 0 2-35.5
pg/m3 in ten garages in Denmark; the greatest concentration was measured in a paint workshop
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Used motor oils were found to contain 1500-3500 pg Pb/g, while one brand of gear oil, unused,
contained 9280 pg Pb/g. The authors state that absorption through damaged skin could be an
important exposure pathway. Other occupations involving risk of lead exposure include stained
glass manufacturing and repair, arts and crafts, and soldering and splicing.
Workers involved in the manufacture of both tetraethyl lead and tetramethyl lead, two
alkyl lead compounds, are exposed to both inorganic and alkyl lead. The major potential
hazard in the manufacture of tetraethyl lead and tetramethyl lead is from skin absorption, but
this is guarded against by the use of protective clothing
Secondary occupational exposure. The amount of lead contained in pieces of cloth 1 cm2
cut from bottoms of trousers worn by lead workers ranged from 110 to 3,000 pg, with a median
of 410 pg. In all cases, the trousers were worn under coveralls. Dust samples from 25 house-
holds of smelter workers ranged from 120 to 26,000 pg/g, with a median of 2,400 pg/g.
Special habits or activities. The quantity of food consumed per body weight varies
greatly with age and somewhat with sex. A two-year-old child weighing 14 kg eats and drinks
1.5 kg food and water per day. This is 110 g/kg, or 3 times the consumption of an 80 kg adult
male, who eats 39 g/kg.
Children place their mouths on dust collecting surfaces and lick non-food items with
their tongues. This fingersucking and mouthing activity are natural forms of behavior for
young children which expose them to some of the highest concentrations of lead in their envi-
ronment. A single gram of dust may contain ten times more lead than the total diet of the
child.
Pica is the compulsive, habitual consumption of non-food items. In the case of paint
chips and soil, this habit can present a significant lead exposure for the afflicted person.
There are very little data on the amounts of paint or soil eaten by children with varying de-
grees of pica and exposure can only be expressed on a unit basis. A single chip of paint can
represent greater exposure than any other source of lead. For example, Billick and Gray
(1978) report lead concentrations of 1000-5000 pg/cm2 in lead-based paint pigments. A gram of
urban soil may have 150-2000 pg lead
Lead is also present in tobacco. The World Health Organization (1977) estimates a lead
content of 2.5-12.2 pg per cigarette; roughly 2-6 percent of this lead may be inhaled by the
smoker The National Academy of Sciences (1980) has used these data to conclude that a typi-
cal urban resident who smokes 30 cigarettes per day may inhale roughly equal amounts of lead
from smoking and from breathing urban air. The average adult consumption of table wine in the
U.S. is about 12 g. Even at 0 1 pg/g, which is ten times higher than drinking water, wine
does not appear to represent a significant potential exposure. At one liter/day, however,
lead consumption would be greater than the total baseline consumption. McDonald (1981) points
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out that older wines with lead foil caps may represent a hazard, especially if they have been
damaged or corroded. Wai et al. (1979) found the lead content of wine rose from 200 to 1200
jjg/liter when the wine was allowed to pass over the thin ring of residue left by the corroded
lead foil cap. Newer wines (1971 and later) use other means of sealing.
17 7 Summary
Ambient airborne lead concentrations showed no marked trend from 1965 to 1977 Decreases
from 1977 to 1982 reflect the smaller lead emissions from mobile sources in recent years
Airborne size distribution data indicate that most of the airborne lead mass is found in sub-
micron particles. Atmospheric lead is deposited on vegetation and soil surfaces, entering the
human food chain through contamination of grains and leafy vegetables, of pasture lands, and
of soil moisture taken up by all crops. Lead contamination of drinking water supplies appears
to originate mostly from within the distribution system.
Environmental contamination by le^d should be measured in terms of the total amount of
lead emitted to the biosphere. American industry contributes several hundred thousand tons of
lead to the environment each year: 61,000 tons from petroleum additives, 44,000 tons from am-
munition, 45,000 tons in glass and ceramic products, 16,000 tons in paint pigments, 8,000 tons
in food can solder, and untold thousands of tons of captured wastes during smelting, refining,
and coal combustion. These are uses of lead which are generally not recoverable; thus, they
represent a permanent contamination of the human or natural environment. Although much of
this lead is confined to municipal and industrial waste dumps, a large amount is emitted to
the atmosphere, waterways, and soil, to become a part of the biosphere.
Potential human exposure can be expressed as the concentrations of lead in those environ-
mental components (air, dust, food, and water) that interface with man. It appears that, with
the exception of extraordinary cases of exposure, about 100 |jg of lead are consumed daily by
each American. For the total American population, this amounts to only 8 tons/year, or
0.0001-0 01 percent of the total environmental contamination.
8eyond the baseline level of human exposure, additional amounts of lead consumption are
largely a matter of individual choice or circumstance. Most of these additional exposures
arise directly or indirectly from atmospheric lead, and in one or more ways probably affect
90 percent of the American population. In some cases, the additive exposure can be fully
quantified and the amount of lead consumed can be added to the baseline consumption (Table
1-8). These may be continuous (urban residence) or seasonal (family gardening) exposures.
Some factors can be quantified on a unit basis because of wide ranges in exposure duration or
concentration. For example, factors affecting occupational exposure are air lead concentra-
tions (10-4000 pg/m3), use and efficiency of respirators, length of time of exposure, dust
control techniques, and worker training in occupational hygiene
SUMPB/D 1-47 9/6/84
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TABLE 1-8 SUMMARY OF POTENTIAL ADDITIVE EXPOSURES TO LEAD
Total
Atmospheric
Other
lead
1 ead
lead
consumed
consumed
sources
(pg/day)
(pg/day)
(pg/day)
Baseline exposure:
Chi Id
Inhaled air
0.5
0.5
-
Food, water & beverages
25.8
10.2
15.6
Dust
21.0
19.0
2 0
Total baseline
47.3
29.7
17 6
Additional exposure due to:
Urban atmospheres1
91
91
Family gardens2
48
12
36
Interior lead paint3
110
110
Residence near smelter4
2200
2200
Secondary occupational5
150
Baseline exposure:
Adult male
Inhaled air
1.0
1.0
_
Food, water & beverages
54.7
20.3
34 4
Dust
4.5
2.9
1 6
Total baseline
60.2
24.2
36.0
Additional exposure due to:
Urban atmospheres1
28
28
Family gardens2
120
30
17
Interior lead paint3
17
Residence near smelter4
250
250
Occupational6
1100
1100
Secondary occupational5
44
Smoking7
30
27
3
Wine consumption8
100
?
?
includes lead from household (1000 (jg/g) and street dust (1500 pg/g) and inhaled air
(0 75 pg/m3).
2Assumes soil lead concentration of 2000 pg/g; all fresh leafy and root vegetables, sweet
corn of Table 7-13 replaced by produce from garden. Also assumes 25% of soil lead is of
atmospheric origin.
^Assumes household dust rises from 300 to 2000 pg/g Dust consumption remains the same
as baseline.
4Assumes household and street dust increases to 25,000 pg/g.
5Assumes household dust increases to 2400 pg/g
6Assumes 8-hr shift at 10 pg Pb/m3 or 90% efficiency of respirators at 100 pg Pb/m3, and
occupational dusts at 100,000 pg/m3
70ne and a half packs per day
sAssumes unusually high consumption of one liter per day
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1 8 EFFECTS OF LEAD ON ECOSYSTEMS
Two principles govern ecosystem functions- (1) energy flows through an ecosystem; and
(2) nutrients cycle within an ecosystem. Energy usually enters the ecosystem in the form of
sunlight and leaves as heat of respiration. Unlike energy, nutrient and non-nutrient elements
are recycled by the ecosystem and transferred from reservoir to reservoir in a pattern usually
referred to as a biogeochemical cycle. The reservoirs correspond approximately to the food
webs of energy flow (see Figure 1-12). Although elements may enter (e g., weathering of soil)
or leave the ecosystem (e.g., stream runoff), the greater fraction of the available mass of
the element is usually cycled within the ecosystem. The boundaries of ecosystems may be as
distinct as the border of a pond or as arbitrary as an imaginary circle drawn on a map Many
trace metal studies are conducted in watersheds where some of the boundaries are determined by
topography For atmospheric inputs to terrestrial ecosystems, the boundary is usually defined
as the surface of vegetation, exposed rock, or soil. Non-nutrient elements differ little from
nutrient elements in their biogeochemical cycles. Quite often, the cycling patterns are simi-
lar to those of a major nutrient. In the case of lead, the reservoirs and pathways are very
similar to those of calcium.
Atmospheric lead is deposited on the surfaces of soil, vegetation, and water. Lead may
also be introudced to natural ecosystems as spent ammunition. In agricultural and other eco-
systems more directly influenced by the activities of man, lead may enter as components of
fertilizers, pesticides, and paint chips, or by the careless disposal of lead-acid batteries
or other industrial products. The movement of lead within ecosystems is influenced by the
chemical and physical properties of lead and by the biogeochemical properties of the ecosys-
tem In the appropriate chemical environment, lead may undergo transformations that affect
its solubility (e.g., formation of lead sulfate in soils), its bioavailability (e g. , chela-
tion with humic substances), or its toxicity (e.g., chemical methylation).
In prehistoric times, the contribution of lead from weathering of soil was probably about
4g Pb/ha-yr and, from atmospheric deposition, about 0.02 g Pb/ha-yr. Weathering rates are
presumed to have remained the same, but atmospheric inputs are believed to have increased to
180 g/ha-yr in natural and some cultivated ecosystems, and up to 3000 g/ha-yr in urban ecosy-
stems and along roadways. There is, however, wide variation in the amount of lead trans-
ferred from the atmosphere to terrestrial ecosystems. For example, Elias et al. (1976) found
15 g/ha-yr in a remote subalpine ecosystem of California; Lindberg and Harriss (1981) found
150 g/ha-yr in the Walker Branch watershed of Tennessee; Smith and Siccama (1981) report
270 g/ha-yr in the Hubbard Brook forest of New Hampshire; Getz et al. (1977c) estimated 240
g/ha-yr by wet precipitation alone in a rural ecosystem largely cultivated, and 770 g/ha-yr in
an urban ecosystem; Jackson and Watson (1977) found 1,000,000 g/ha-yr near a smelter in south-
eastern Missouri Factors causing great variation are remoteness from source leading to lower
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GRAZERS
CARNIVORES
HERBIVORES
CARNIVORES
PRIMARY
PRODUCERS
DECOMPOSERS
DETRITUS
INORGANIC
NUTRIENTS
Figure 1-12. This figure depicts cycling processes within the major components of a
terrestrial ecosystem, i.e. primary producers, grazers and decomposers. Nutrient and
non-nutrient elements are stored in reservoirs within these components. Processes
that take place within reservoirs regulate the flow of elements between reservoirs
along established pathways. The rate of flow is in part a function of the concentra-
tion in the preceding reservoir. Lead accumulates in decomposer reservoirs which
have a high binding capacity for this metal. It is likely that the rate of flow away
from these reservoirs has increased in past decades and will continue to increase for
some time until the decomposer reservoirs are in equilibrium with the entire
ecosystem. Inputs to and outputs from the ecosystem as a whole are not shown.
Source: Adapted from Swift et al. (1979).
1-50
-------
air concentrations, difference in particle size and greater dependence on wind as a mechanism
of deposition and type of vegetation cover. For example, deciduous leaves may, by the nature
of their surface and orientation in the wind stream, be more suitable deposition surfaces than
conifer needles.
Many of the effects of lead on plants, microorganisms, and ecosystems arise from the fact
that lead from atmospheric and weathering inputs is retained by soil. (One effect of cultiva-
tion is that atmospheric lead is mixed to a greater depth than the 0-5 cm of natural soils)
Although no firm documentation exists, it is reasonable to assume from the known chemistry of
lead in soil that other metals may be displaced from binding sites on organic matter and that
the chemical breakdown of inorganic soil fragments may be retarded by the interference of lead
with the action of fulvic acid on iron bearing crystals. Soil cation exchange capacity, a
major factor, is determined by the relative size of the clay and organic fractions, soil pH,
and the amount of Fe-Mn oxide films present (Nriagu, 1978a). Of these, organic humus and high
soil pH are the dominant factors in immobilizing lead. Under natural conditions, most of the
total lead in soil would be tightly bound within the crystalline structure of inorganic soil
fragments, unavailable to soil moisture. Available lead, bound on clays, organic colloids,
and Fe-Mn films, would be controlled by the slow release of bound lead from inorganic rock
sources. Because lead is strongly immobilized by humic substances, only a small fraction
(perhaps 0.01 percent in soils with 20 percent organic matter, pH 5.5) is released to soil
moisture.
Atmospheric inputs and those from the weathering of soil determine the concentration of
lead in the nutrient media of plants, animals, and microorganisms. It follows that the con-
centration of lead in the nutrient medium determines the concentration of lead in the organism
and this in turn determines the effects of lead on the organism. The fundamental nutrient
medium of a terrestrial ecosystem is the soil moisture film which surrounds organic and inor-
ganic soil particles. This film of water is in equilibrium with other soil components and
provides dissolved inorganic nutrients to plants.
Hutchinson (1980) has reviewed the effects of acid precipitation on the ability of soils
to retain cations. Excess calcium and other metals are leached from the A horizon of soils by
rain with a pH more acidic than 4.5. Most soils in the eastern United States are normally
acidic (pH 3.5-5.2) and the leaching process is a part of the complex equilibrium maintained
in the soil system. By increasing the leaching rate, acid rain can reduce the availability of
nutrient metals to organisms dependent on the top layer of soil. It appears that acidifica-
tion of soil may increase the rate of removal of lead from the soil, but not before several
major nutrients are removed first. The effect of acid rain on the retention of lead by soil
moisture is not known.
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Atmospheric lead may enter aquatic ecosystems by wet or dry deposition or by the ero-
sional transport of soil particles. In waters not polluted by industrial, agricultural, or
municipal effluents, the lead concentration is usually less than 1 jjg/1. Of this amount,
approximately 0.02 pg/1 is natural lead and the rest is anthropogenic lead, probably of atmos-
pheric origin (Patterson, 1980). Surface waters mixed with urban effluents may frequently
reach lead concentrations of 50 pg/1, and occasionally higher. In still water, lead is
removed from the water column by the settling of lead-containing particulate matter, by the
formation of insoluble complexes, or by the adsorption of lead onto suspended organic parti-
cles. The rate of sedimentation is determined by temperature, pH, oxidation-reduction poten-
tial, ionic competition, the chemical form of lead in water, and certain biological activities
(Jenne and Luoma, 1977). In the sediments of streams, rivers, and lakes, lead appears to be
immobile, in the sense that it is not easily transported by redissolution in fresh water
1.8.1 Effects on Plants
Some physiological and biochemical effects of lead on vascular plants have been detected
under laboratory conditions at concentrations higher than those normally found in the environ-
ment. The commonly reported effects are the inhibition of photosynthesis, respiration, or
cell elongation, all of which reduce the growth of the plant (Koeppe, 1981). Lead may also
induce premature senescence, which may affect the long-term survival of the plant or the eco-
logical success of the plant population. Most of the lead in or on a plant occurs on the sur-
faces of leaves and the trunk or stem. The surface concentration of lead in trees, shrubs,
and grasses usually exceeds the internal concentration by a factor of at least five (Elias et
al, 1978). The major effect of surface lead at ambient concentrations seems to be on subse-
quent components of the grazing food chain and on the decomposer food chain following litter-
fall (Elias et al., 1982).
Two defensive mechanisms appear to exist in the roots of plants for removing lead from
the stream of nutrients flowing to the above-ground portions of plants. Lead may be deposited
with cell wall material exterior to the individual root cells, or may be sequestered in organ-
elles within the root cells. Any lead not captured by these mechanisms would likely move with
nutrient metals from cell to cell through the symplast and into the vascular system. Uptake
of lead by plants may be enhanced by symbiotic associations with mycorrhizal fungi. The three
primary factors that control the uptake of nutrients by plants are: (1) the surface area of
the roots, (2) the ability of the root to absorb particular ions, and (3) the transfer of ions
through the soil. The symbiotic relationship between mycorrhizal fungi and the roots of
higher plants can increase the uptake of nutrients by enhancing all three of these factors
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The trans 1ocation of lead to aboveground portions of the plant is not clearly understood.
Lead may follow the same pathway and be subject to the same controls as a nutrient metal such
as calcium There may be several mechanisms that prevent the translocation of lead to other
plant parts. The primary mechanisms may be storage in cell organelles or adsorption on cell
walls Some lead passes into the vascular tissue, along with water and dissolved nutrients,
and is carried to physiologically active tissue of the plant. Evidence that lead in contami-
nated soils can enter the vascular system of plants and be transported to aboveground parts
may be found in the analysis of tree rings. These chronological records confirm that lead can
be translocated in proportion to the concentrations of lead in soil.
Because most of the physiologically active tissue of plants is involved in growth, main-
tenance, and photosynthesis, it is expected that lead might interfere with one or more of
these processes. Indeed, such interferences have been observed in laboratory experiments at
lead concentrations greater than those normally found in the field, except near smelters or
mines (Koeppe, 1981). Inhibition of photosynthesis by lead may be by direct interference with
the light reaction or the indirect interference with carbohydrate synthesis. Miles et al.
(1972) demonstrated substantial inhibition of photosystem II near the site of water splitting,
a biochemical process believed to require manganese. Devi Prasad and Devi Prasad (1982) found
a 10 percent inhibition of pigment production in three species of green algae at 1 pg/g, in-
creasing to 50 percent inhibition at 3 pg/g. Bazzaz et al. (1974, 1975) observed reduced net
photosynthesis that may have been caused indirectly by inhibition of carbohydrate synthesis.
The stunting of plant growth may be by the inhibition of the growth hormone IAA (mdole-
3-ylacetic acid). Lane et al. (1978) found that 10 pg/g lead as lead nitrate in the nutrient
medium of wheat coleoptiles produced a 25 percent reduction in elongation. Lead may also
interfere with plant growth by reducing respiration or inhibiting cell division Miller and
Koeppe (1971) and Miller et al. (1975) showed succinate oxidation inhibition in isolated mito-
chondria as well as stimulation of exogenous NADH oxidation with related mitochondrial
swelling.
Hassett et al. (1976), Koeppe (1977), and Malone et al. (1978) described significant
inhibition by lead of lateral root initiation in corn. The interaction of lead with calcium
has been shown by several authors, most recently by Garland and Wilkins (1981), who demon-
strated that barley seedlings (Hordeum vulgare), which were growth inhibited at 2 (jg Pb/g sol
with no added calcium, grew at about half the control rate with 17 pg Ca/g sol. This relation
persisted up to 25 pg Pb/g sol. and 500 pg Ca/g sol.
These studies of the physiological effects of lead on plants all show some effect at con-
centrations of 2~10 pg Pb/g in the nutrient medium of, hydroponically-grown agricultural
plants. It is certain that no effects would have been observed at these concentrations had
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the lead solutions been added to normal soil, where the lead would have been bound by humic
substances. There is no firm relationship between soil lead and soil moisture lead because
each soil type has a unique capacity to retain lead and to release that lead to the soil
moisture film surrounding the soil particle. Once in soil moisture, lead seems to pass freely
to the plant root according to the capacity of the plant root to absorb water and dissolved
substances.
Some plant species have developed populations tolerant to high lead soils Using popu-
lations taken from mine waste and uncontaminated control areas, some authors have quantified
the degree of tolerance of Aqrostis tenuis (Karataglis, 1982) and Festuca rubra (Wong, 1982)
under controlled laboratory conditions. Root elongation was used as the index of tolerance.
At 36 pg Pb/g nutrient solution, all populations of A. tenuis were completely inhibited. At
12 |jg Pb/g, the control populations from low lead soils were completely inhibited, but the
populations from mine soils achieved 30 percent of their normal growth (growth at no lead in
nutrient solution). At 6 pg/g, the control populations achieved 10 percent of their normal
growth, tolerant populations achieved 42 percent. There were no measurements below 6 pg/g.
These studies support the conclusion that inhibition of plant growth begins at a lead concen-
tration of less than 1 pg/g soil moisture and becomes completely inhibitory at a level between
3 and 10 pg/g. Plant populations that are genetically adapted to high lead soils may achieve
50 percent of their normal root growth at lead concentrations above 3 pg/g.
Even under the best of conditions where soil has the highest capacity to retain lead,
most plants would experience reduced growth rate (inhibition of photosynthesis, respiration,
or cell elongation) in soils containing 10,000 pg Pb/g or greater. Concentrations approaching
this value typically occur around smelters and near major highways. These conclusions pertain
to soil with the ideal composition and pH to retain the maximum amount of lead. Acid soils or
soils lacking organic matter would inhibit plants at much lower lead concentrations.
1.8.2 Effects on Microorganisms
It appears that microorganisms are more sensitive than plants to soil lead pollution and
that changes in the composition of bacterial populations may be an early indication of lead
effects. Delayed decomposition may occur at 750 pg Pb/g soil and nitrification inhibition at
1000 pg/g.
Tyler (1972) explained three ways in which lead might interfere with the normal decompo-
sition processes in a terrestrial ecosystem. Lead may be toxic to specific groups of decom-
posers, it may deactivate enzymes excreted by decomposers to break down organic matter, or it
may bind with the organic matter to render it resistant to the action of decomposers. Because
lead in litter may selectively inhibit decomposition by soil bacteria at 2000-5000 pg/g,
forest floor nutrient cycling processes may be seriously disturbed near lead smelters This
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is especially important because approximately 70 percent of plant biomass enters the de-
composer food chain. If decomposition of the biomass is inhibited, then much of the energy
and nutrients remain unavailable to subsequent components of the food chain. There is also
the possibility that the ability of soil to retain lead would be reduced, as humic substances
are byproducts of bacterial decomposition. Because they are interdependent, the absence of
one decomposer group in the decomposition food chain seriously affects the success of sub-
sequent groups, as well as the rate at which plant tissue decomposes. Each group may be
affected in a different way and at different lead concentrations. Lead concentrations toxic
to decomposer microbes may be as low as 1-5 pg/g or as high as 5000 pg/g. Under conditions of
mild contamination, the loss of one sensitive bacterial population may result in its replace-
ment by a more lead-tolerant strain. Delayed decomposition has been reported near smelters,
mine waste dumps, and roadsides. This delay is generally in the breakdown of litter from the
first stage (0^) to the second (O2), with intact plant leaves and twigs accumulating at the
soil surface. The - substrate-concentrations at which lead inhibits decomposition appear to be
very low
The conversion of ammonia to nitrate in soil is a two-step process mediated by two genera
of bacteria, Nitrosomonas and Nitrobacter. Nitrate is required by all plants, although some
maintain a symbiotic relationship with nitrogen-fixing bacteria as an alternate source of ni-
trogen. Those which do not would be affected by a loss of free-living nitrifying bacteria,
and it is known that many trace metals inhibit this nitrifying process. Lead is the least of
these, inhibiting nitrification 14 percent at concentrations of 1000 pg/g soil. Even a 14
percent inhibition of nitrification can reduce the potential success of a plant population, as
nitrate is usually the limiting nutrient in terrestrial ecosystems.
18.3 Effects on Animals
Forbes and Sanderson (1978) have reviewed reports of lead toxicity in domestic and wild
animals. Lethal toxicity can usually be traced to consumption of lead battery casings, lead-
based paints, oil wastes, putty, linoleum, pesticides, lead shot, or forage near smelters.
Awareness of the routes of uptake is important in interpreting the exposure and accumulation
in vertebrates. Inhalation rarely accounts for more than 10-15 percent of the daily intake
of lead (National Academy of Sciences, 1980); food is the largest contributor of lead to ani-
mals. The type of food an herbivore eats determines the rate of lead ingestion. More than 90
percent of the total lead in leaves and bark may be surface deposition, but relatively little
surface deposition may be found on some fruits, berries, and seeds that have short exposure
times. Roots intrinsically have no surface deposition. Similarly, ingestion of lead by a
carnivore depends mostly on deposition on herbivore fur and somewhat less on lead in herbivore
tissue.
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The type of food eaten is a major determinant of lead body burdens in small mammals.
Goldsmith and Scanlon (1977) and Scanlon (1979) measured higher lead concentrations in insec-
tivorous species than in herbivorous, confirming the earlier work of Quarles et al. (1974)
which showed body burdens of granivores
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While it is impossible to establish a safe limit of daily lead consumption, it is reason-
able to generalize that a regular diet of 2-8 mg Pb/kg*day body weight over an extended period
of time (Botts, 1977) will cause death in most animals. Animals of the grazing food chain are
affected most directly by the accumulation of aerosol particles on vegetation surfaces, and
somewhat indirectly by the uptake of lead through plant roots. Many of these animals consume
more than 1 mg Pb/kg-day in habitats near smelters and roadsides, but no toxic effects have
been documented. Animals of the decomposer food chain are affected indirectly by lead in soil
which can eliminate populations of microorganisms preceeding animals in the food chain or
occupying the digestive tract of animals and aiding in the breakdown of organic matter.
Invertebrates may also accumultate lead at levels toxic to their predators.
Borgmann et al. (1978) found increased mortality in a freshwater snail, Lymnaea palutris,
associated with stream water with a lead content as low as 19 pg/1. Full life cycles were
studied to estimate population productivity. Although individual growth rates were not af-
fected, increased mortality, especially at the egg hatching stage, effectively reduced total
biomass production at the population level. Production was 50 percent at 36 pg/1 and 0 per-
cent at 48 Pb/1-
Aquatic animals are affected by lead at water concentrations lower than previously con-
sidered safe (50 (jg Pb/1) for wildlife. These concentrations occur commonly, but the contri-
bution of atmospheric lead to specific sites of high aquatic lead is not clear. Hematological
and neurological responses are the most commonly reported effects of extended lead exposures
in aquatic vertebrates. Hematological effects include the disabling and destruction of mature
red blood cells and the inhibition of the enzyme ALA-D required for hemoglobin synthesis. At
low exposures, fish compensate by forming additional red blood cells. These red blood cells
often do not reach maturity. At higher exposures, the fish become anemic. Symptoms of neuro-
logical responses are difficult to detect at low exposure, but higher exposure can induce
neuromuscular distortion, anorexia, and muscle tremors. Spinal curvature eventually occurs
with time or increased concentration.
1.8 4 Effects on Ecosystems
Recent studies have shown three areas of concern where the effects of lead on ecosystems
may be extremely sensitive First, decomposition is delayed by lead, as some decomposer
microorganisms and invertebrates are inhibited by soil lead. Secondly, some ecosystems exper-
ience subtle shifts toward lead tolerant plant populations. Thirdly, the natural processes of
calcium biopurification are circumvented by the accumulation of lead on the surfaces of
vegetation and in the soil reservoir. These problems all arise because lead in ecosystems is
deposited on vegetation surfaces, accumulates in the soil reservoir, and is not removed with
the surface and ground water passing out of the ecosystem.
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Terrestrial ecosystems, especially forests, accumulate a tremendous amount of cellulose
as woody tissue of trees Few animals can digest cellulose and most of these require symbio-
tic associations with specialized bacteria. It is no surprise then, that most of this cellu-
lose must eventually pass through the decomposer food chain. Because 80 percent or more of
net primary production passes through the decomposing food chain, the energy of this litter is
vital to the rest of the plant community and the inorganic nutrients are vital to plants.
The amount of lead that causes litter to be resistant to decomposition is not known.
Doelman and Haanstra (1979a) demonstrated the effects of soil lead content on delayed decom-
position: sandy soils lacking organic complexing compounds showed a 30 percent inhibition of
decomposition at 750 pg/g, including the complete loss of major bacterial species, whereas the
effect was reduced in clay soils and non-existent in peat soils. Organic matter maintains the
cation exchange capacity of soils. A reduction in decomposition rate was observed by Doelman
and Haanstra (1979a) even at the lowest experimental concentration of lead, leading to the
conclusion that some effect might have occurred at even lower concentrations.
When decomposition is delayed, the availability of nutrients may be limited for plants.
In tropical regions or areas with sandy soils, rapid turnover of nutrients is essential for
the success of the forest community. Even in a mixed deciduous forest, a significant portion
of the nutrients, especially nitrogen and sulfur, may be found in the litter reservoir (Likens
et al. 1977). Annual litter inputs of calcium and nitrogen to the soil account for about 60
percent of root uptake. With delayed decomposition, plants must rely on precipitation and
soil weathering for the bulk of their nutrients. Furthermore, the organic content of soil may
decrease, reducing the cation exchange capacity of soil.
It has been observed that plant communities near smelter sites are composed mostly of
lead-tolerant plant populations. In some cases, these populations appear to have adapted to
high lead soils, since populations of the same species from low lead soils often do not thrive
on high lead soils. In some situations, it is clear that soil lead concentration has become
the dominant factor in determining the success of plant populations and the stability of the
ecological community.
Biopurification is a process that regulates the relative concentrations of nutrients vs
non-nutrient elements in biological components of a food chain. In the absence of absolute
knowledge of natural lead concentrations, biopurification can be a convenient method for esti-
mating the degree of contamination. It is now believed that calcium reservoirs in members of
grazing and decomposer food chains were contaminated by factors of 30-500, i.e., that 97-99.9
percent of the lead in organisms is of anthropogenic origin. Burnett and Patterson (1980)
have shown a similar pattern for a marine food chain.
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Ecosystem inputs of lead by the atmospheric route have established new pathways and
widened old ones. Insignificant amounts of lead are removed by surface runoff or ground water
seepage. It is likely that the ultimate fate of atmospheric lead will be a gradual elevation
in lead concentration of all reservoirs in the system, with most of the lead accumulating in
the detrital reservoir Because there is no protection from industrial lead once it enters
the atmosphere, it is important to fully understand the effects of industrial lead emissions
Of the 450,000 tons emitted annually on a global basis, 115,000 tons of lead fall on
terrestrial ecosystems Evenly distributed, this would amount to 0.1 g/ha-yr, which is much
lower than the range of 15-1,000,000 g/ha*yr reported in ecosystem studies in the United
States. Consequently, it is apparent that lead has permeated these ecosystems and accumulated
in the soil reservoir, where it will remain for decades. Within 20 meters of every major high-
way, up to 10,000 pg Pb have been added to each gram of surface soil since 1930 (Getz et al.,
1977b). Near smelters, mines, and in urban areas, as much as 130,000 pg/g have been observed
in the upper 2.5 cm of soil (Jennett et al., 1977). At increasing distances up to 5 km away
from sources, the gradient of lead added since 1930 drops to less than 10 pg/g (Page and
Ganje, 1970), and 1-5 pg/g have been added in regions more distant than 5 km (Nriagu, 1978a).
In undisturbed ecosystems, atmospheric lead is retained by soil organic matter in the upper
layer of soil surface. In cultivated soils, this lead is mixed with soil to a depth of 25 cm
The ability of an ecosystem to compensate for atmospheric lead inputs, especially in the
presence of other pollutants such as acid precipitation, depends not so much on factors of
ecosystem recovery, but on undiscovered factors of ecosystem stability. Recovery implies that
inputs of the perturbing pollutant have ceased and that the pollutant is being removed from
the ecosystem. In case of lead, the pollutant is not being eliminated from the system nor are
the inputs ceasing. Terrestrial ecosystems will never return to their original, pristine
levels of lead concentrations
1.9 QUANTITATIVE EVALUATION OF LEAD AND BIOCHEMICAL INDICES OF LEAD EXPOSURE IN PHYSIOLOGICAL
MEDIA
A complete understanding of a toxic agent's biological effects (including any statement
of dose-effect relationships) requires quantitative measurement of either that agent in some
biological medium or a physiological parameter associated with exposure to the agent. Quanti-
tative analysis involves a number of discrete steps, all of which contribute to the overall
reliability of the final analytical result; i.e., sample collection and shipment, laboratory
handling, instrumental analysis, and criteria for internal and external quality control.
From an historical perspective, the definition of "satisfactory analytical method" for
lead has been changing steadily as new and more sophisticated equipment has become available
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and understanding of the hazards of pervasive contamination along the analytical course has
increased. The best example of this change is the current use of the definitive method for
lead analysis, isotope-dilution mass spectrometry (IDMS), in tandem with "ultra-clean" facili-
ties and sampling methods, to demonstrate conclusively not only the true extent of anthropo-
genic input of lead to the environment over the years but also the relative limitations of
most of the methods used today for lead measurement.
1.9.1 Determinations of Lead in Biological Media
The low levels of lead in biological media, even in the face of excessive exposure, and
the fact that sampling of such media must be done against a backdrop of pervasive lead contam-
ination necessitates that samples be collected and handled carefully. Blood lead sampling is
best done by venous puncture and collection into low-lead tubes after careful cleaning of the
puncture site. The use of finger puncture as an alternative method of sampling should be
avoided, if feasible, given the risk of contamination associated with the practice in indus-
trialized areas. While collection of blood onto filter paper enjoyed some popularity in the
past, paper deposition of blood requires special correction for hematocrit/hemoglobin level
Urine sample collection requires the use of lead-free containers as well as addition of a
bactericide. If feasible, 24-hr sampling is preferred to spot collection. Deciduous teeth
vary in lead content both within and across type of dentition. Thus a specific tooth type
should be uniformly obtained for all study subjects and, if possible, more than a single
sample should be obtained from each subject.
Many reports over the years have purported to offer satisfactory analysis of lead in
blood and other biological media, often with severe inherent limitations on accuracy and pre-
cision, meager adherence to criteria for accuracy and precision, and a limited utility across
a spectrum of analytical applications. Therefore, it is only useful to discuss "definitive"
and, comparatively speaking, "reference" methods presently used.
In the case of lead in biological media, the definitive method is IDMS. The accuracy and
unique precision of IDMS arise from the fact that all manipulations are on a weight basis in-
volving simple procedures, and measurements entail only lead isotope ratios and not the abso-
lute determinations of the isotopes involved, which greatly reduces instrumental corrections
and errors. Reproducible results to a precision of one part in 104-105 are routine with
appropriately designed and competently operated instrumentation. Although this methodology is
still not recognized in many laboratories, it was the first breakthrough, in tandem with
"ultra-clean" procedures and facilities, in definitive methods for indexing the progressive
increase in lead contamination of the environment over the centuries. Given the expense, re-
quired level of operator expertise, and time and effort involved for measurements by IDMS,
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this methodology mainly serves for analyses that either require extreme accuracy and preci-
sion, e g. , geochronometry, or for the establishment of analytical reference material for
general testing purposes or the validation of other methodologies.
While the term "reference method" for lead in biological media cannot be rigorously ap-
plied to any procedures in popular use, the technique of atomic absorption spectrometry (AAS)
in its various configurations, or the electrochemical method, anodic stripping voltammetry
(ASV), come closest to meriting the designation. Other methods that are generally applied in
metal analyses are either limited in sensitivity or are not feasible for use on theoretical
grounds for lead analysis.
Measurement of Lead in Blood Atomic absorption spectrometry, as applied to analysis of
whole blood, generally involves flame or flameless micromethods. One macromethod, the Hessel
procedure, still enjoys some popularity. Flame microanalysis, the Delves cup procedure,
applied to blood lead appears to have an operational sensitivity of about 10 pg Pb/dl blood
and a relative precision of approximately 5 percent in the range of blood lead seen in popula-
tions in industrialized areas. The flameless, or electrothermal, method of AAS enhances sen-
sitivity about tenfold, but precision can be more problematic because of chemical and spectral
interferences.
The most widely used and sensitive electrochemical method for lead in blood is ASV. For
most accurate results, chemical wet ashing of samples must be carried out, although this pro-
cess is time consuming and requires the use of lead-free reagents. The use of metal exchange
reagents has been employed in lieu of the ashing step to liberate lead from binding sites, al-
though this substitution is associated with less precision. For the ashing method, relative
precision is approximately 5 percent. In terms of accuracy and sensitivity, problems appear
at low levels, e.g., 5 pg/dl or below, particularly if samples contain elevated copper levels
Lead in Plasma. Since lead in whole blood is virtually all confined to the erythrocyte,
plasma levels are quite low and extreme care must be employed to measure plasma levels relia-
bly The best method for such measurement is IDMS, in tandem with ultra-clean facility use.
AAS is satisfactory for comparative analyses across a range of relatively high whole blood
values.
Lead in Teeth. Lead measurement in teeth has involved either whole tooth sampling or
analysis of specific regions, such as dentine or circumpulpal dentine. In either case, sam-
ples must be solubilized after careful surface cleaning to remove contamination; solubiliza-
tion is usually accompanied by either wet ashing directly or ashing subsequent to a dry-ashing
step.
Atomic absorption spectrometry and ASV have been employed more frequently for such deter-
minations than any other method. With AAS, the high mineral content of teeth argues for pre-
liminary isolation of lead via chelation/extraction. The relative precision of analysis for
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within-run measurement is around 5-7 percent, with the main determinant of variance in
regional assay being the initial isolation step. One change from the usual methods for such
measurement is the i_n situ measurement of lead by X-ray fluorescence spectrometry in children.
Lead measured in this fashion allows observation of ongoing lead accumulation, rather than
waiting for exfoliation.
Lead in Hair. Hair as an exposure indicator for lead offers the advantages of being non-
invasive and a medium of indefinite stability. However, there is still the crucial problem of
external surface contamination, which is such that it is still not possible to state that any
cleaning protocol reliably differentiates between externally and internally deposited lead.
Studies that demonstrate a correlation between increasing hair lead and increasing sever-
ity of a measured effect probably support arguments for hair being an external indicator of
exposure. It is likely then, that such measurement using cleaning protocols that have not
been independently validated will overstate the relative accumulation of "internal" hair lead
in terms of some endpoint and will also underestimate the relative sensitivity of changes in
internal lead content with exposure. One consequence of this would be, for example, an
apparent threshold for a given effect in terms of hair lead which is significantly above the
actual threshold. Because of these concerns, hair is best used with the simultaneous measure-
ment of blood lead.
Lead in Urine. Analysis of lead in urine is complicated by the relatively low levels of
the element in this medium as well as the complex mixture of mineral elements present. Urine
lead levels are most useful and also somewhat easier to determine in cases of chelation mobil-
ization or chelation therapy, where levels are high enough to permit good precision and dilu-
tion of matrix interference.
Samples are probably best analyzed by prior chemical wet ashing, using the usual mixture
of acids. Both ASV and AAS have been applied to urine analysis, with the latter more routine-
ly used and usually with a chelation/extraction step.
Lead in Other Tissues. Bone samples require cleaning procedures for removal of muscle
and connective tissue and chemical solubilization prior to analysis. Methods of analysis are
comparatively limited and flameless AAS is the technique of choice.
In vivo lead measurements in bone have been reported with lead workers using X-ray fluo-
rescence analysis and a radioisotopic source for excitation. One problem with this approach
with moderate lead exposure is the detection limit, approximately 20 ppm. Soft organ analysis
poses a problem in terms of heterogeneity in lead distribution within an organ (e.g., brain
and kidney). In such cases, regional sampling or homogenization must be carried out Both
flame and flameless AAS appear to be satisfactory for soft tissue analysis and are the most
widely used analytical methods.
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Quality Assurance Procedures in Lead Analyses. In terms of available information, the
major focus in establishing quality control protocols for lead has involved whole blood meas-
urements. Translated into practice, quality control revolves around steps employed within the
laboratory, using a variety of internal checks, and the further reliance on external checks,
such as a formal continuing multi-laboratory proficiency testing program.
Within the laboratory, quality assurance protocols can be divided into start-up and rou-
tine procedures. The former involves establishment of detection limits, within-run and
between-run precision, analytical recovery, and comparison with some reference technique
within or outside the laboratory. The reference method is assumed to be accurate for the par-
ticular level of lead in some matrix at a particular point in time. Correlation with such a
method at a satisfactory level, however, may simply indicate that both methods are equally
inaccurate but performing with the same level of precision proficiency. More preferable is
the use of certified samples having lead at a level established by the definitive method.
For blood lead, the Centers for Disease Control (CDC) periodically survey overall accu-
racy and precision of methods used by reporting laboratories. In terms of overall accuracy
and precision, one such survey found that ASV as well as the Delves cup and extraction varia-
tions of AAS performed better than other procedures. These results do not mean that a given
laboratory cannot perform better with a particular technique; rather, such data are of assist-
ance for new facilities choosing among methods.
Of particular value to laboratories carrying out blood lead analysis are the external
quality assurance programs at both the State and Federal levels. The most comprehensive pro-
ficiency testing program is that carried out by the CDC. This program actually consists of
two subprograms, one directed at facilities involved in lead poisoning prevention and screen-
ing (Center for Environmental Health) and the other concerned with laboratories seeking certi-
fication under the Clinical Laboratories Improvement Act of 1967, as well as under regulations
of the Occupational Safety and Health Administration's (OSHA) Laboratory Improvement Program
Office. Judging from the relative overall improvements in reporting laboratories over the
years of the programs' existence, the proficiency testing programs have served their purpose
well. In this regard, OSHA criteria for laboratory certification require that eight of nine
samples be analyzed correctly for the previous quarter. This level of required proficiency
reflects the ability of a number of laboratories to actually perform at this level.
1.9.2 Determination of Biochemical Indices of Lead Exposure in Biological Media
Determination of Erythrocyte Porphyrin (Free Erythrocyte Protoporphyrin, Zinc
Protoporphyrin). With lead exposure, erythrocyte protoporphyrin IX accumulates because of
impaired placement of divalent iron to form heme. Divalent zinc occupies the place of the
native iron. Depending upon the method of analysis, either metal-free erythrocyte porphyrin
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(EP) or zinc protoporphyrin (ZPP) is measured, the former arising from loss of zinc in the
chemical manipulation Virtually all methods now in use for EP analysis exploit the ability
of the porphyrin to undergo intense fluorescence when excited by ultraviolet light. Such
fluorometric methods can be further classified as wet chemical micromethods or direct mea-
suring fluorometry using the hematofluorometer Because of the high sensitivity of such mea-
surement, relatively small blood samples are required, with liquid samples or blood collected
on filter paper.
The most common laboratory or wet chemical procedures now in use represent variations of
several common chemical procedures: (1) treatment of blood samples with a mixture of ethyl
acetate/acetic acid followed by a repartitioning into an inorganic acid medium, or (2) solu-
bilization of a blood sample directly into a detergent/buffer solution at a high dilution
Quantification has been done using protoporphyrin, coproporphyrin, or zinc protoporphyrin IX
plus pure zinc ion. The levels of precision for these laboratory techniques vary somewhat
with the specifics of analysis. The Piomelli method has a coefficient of variation of 5 per-
cent, while the direct ZPP method using buffered detergent solution is higher and more vari-
able.
The recent development of the hematofluorometer has made it possible to carry out EP mea-
surements in high numbers, thereby making population screening feasible. Absolute calibration
is necessary and requires periodic adjustment of the system using known concentrations of
EP in reference blood samples. Since these units are designed for oxygenated blood (i.e.,
capillary blood), use of venous blood requires an oxygenation step, usually a moderate shaking
for several minutes. Measurement of low or moderate levels of EP can be affected by interfer-
ence with bilirubin. Competently employed, the hematofluorometer is reasonably precise,
showing a total coefficient of variation of 4.1-11.5 percent. While the comparative accuracy
of the unit has been reported to be good relative to the reference wet chemical technique, a
very recent study has shown that commercial units carry with them a significant negative bias,
which may lead to false negatives in subjects having only moderate EP elevation. Such a bias
in accuracy has been difficult to detect in existing EP proficiency testing programs By com-
parison to wet methods, the hematofluorometer should be restricted to field use rather than
becoming a substitute in the laboratory for chemical measurement, and this field use should
involve periodic split-sample comparison testing with the wet method.
Measurement of Urinary Coproporphyrin. Although EP measurement has largely supplanted
the use of urinary coproporphyrin (CP-U) analysis to monitor excessive lead exposure in
humans, this measurement is still of value in that it reflects active intoxication The
standard analysis is a fluorometric technique, whereby urine samples are treated with buffer,
and an oxidant (iodine) is added to generate CP from its precursor. The CP-U is then parti-
tioned into ethyl acetate and re-extracted with dilute hydrochloric acid. The working curve
is linear below 5 (jg CP/dl urine.
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Measurement of Delta-Aminolevulinic Acid Dehydrase Activity. Inhibition of the activity
of the erythrocyte enzyme delta-aminolevulinic acid dehydrase (ALA-D) by lead is the basis for
using such activity in screening for excessive lead exposure. A number of sampling and sample
handling precautions attend such analysis. Since zinc (II) ion will offset the degree of
activity inhibition by lead, blood collecting tubes must have extremely low zinc content,
which essentially rules out the use of rubber-stoppered blood tubes. Enzyme stability is such
that the activity measurement is best carried out within 24 hr of blood collection. Porpho-
bilinogen, the product of enzyme action, is light labile and requires the assay be done in
restricted light. Various procedures for ALA-D measurement are based on measurement of the
level of the chromophoric pyrrole (approximately 555 nm) formed by condensation of the porpho-
bilinogen with p-dimethylaminobenzaldehyde.
In the European Standardized Method for ALA-D activity determination, blood samples are
hemolyzed with water; ALA solution is then added, followed by incubation at 37°C, and the
reaction terminated by a solution of mercury (II) in trichloroacetic acid. Filtrates are
treated with modified Ehrlich's reagent (p-dimethylaminobenzaldehyde) in trichloroacetic/
perchloroacetic acid mixture. Activity is quantified in terms of micromoles ALA/min per liter
of erythrocytes.
One variation in the above procedure is the initial use of a thiol agent, such as dithio-
threotol, to reactivate the enzyme, giving a measure of the full native activity of the
enzyme. The ratio of activated/unactivated activity versus blood lead levels accommodates
genetic differences between individuals.
Measurement of Delta-Aminolevulinic Acid in Urine and Other Media. Levels of delta-
aminolevulinic acid (6-ALA) in urine and plasma increase with elevated lead exposure Thus,
measurement of this metabolite, generally in urine, provides an index of the level of lead
exposure. ALA content of urine samples (ALA-U) is stable for about 2 weeks or more with
sample acidification and refrigeration. Levels of ALA-U are adjusted for urine density or
expressed per unit creatinine. If feasible, 24-hr collection is more desirable than spot
sampli ng.
Virtually all the various procedures for ALA-U measurement employ preliminary isolation
of ALA from the balance of urine constituents. In one method, further separation of ALA from
the metabolite aminoacetone is done. Aminoacetone can interfere with colorimetric measure-
ment ALA is recovered, condensed with a beta-dicarbonyl compound, e.g., acetyl acetone, to
yield a pyrrole intermediate. This intermediate is then reacted with p-dimethylaminobenzalde-
hyde in perchloric/acetic acid, followed by colorimetric reading at 553 nm. In one variation
of the basic methodology, ALA is condensed with ethyl acetoacetate directly and the resulting
pyrrole extracted with ethyl acetate. Ehrlich's reagent is then added as in other procedures
and the resulting chromophore is measured spectrophotometrically.
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Measurement of ALA in plasma is much more difficult than in urine, since plasma ALA is at
nanogram/mi"11 iter levels. In one gas-liquid chromatographic procedure, ALA is isolated from
plasma, reacted with acetyl acetone and partitioned into a solvent that also serves for pyro-
lytic methylation of the involatile pyrrole in the injector port of the chromatograph, making
the derivative more volatile. For quantification, an internal standard, 6-amino-5-oxohexanoi c
acid, is used. While the method is more involved, it is more specific than the older colori-
metric technique.
Measurement of Pyrimidine-5'-Nucleotidase Activity. Erythrocyte pyrimidine-5'-nucleo-
tidase (Py5N) activity is inhibited with lead exposure. Presently two different methods
are used for assaying the activity of this enzyme. The older method is quite laborious in
time and effort, whereas the more recent approach is shorter but uses radioisotopes and radio-
metric measurement.
In the older method, heparinized venous blood is filtered through cellulose to separate
erythrocytes from platelets and leukocytes. Cells are then freeze-fractured and the hemo-
lysates dialyzed to remove nucleotides and other phosphates. This dialysate is then incubated
in the presence of a nucleoside monophosphate and cofactors, the enzyme reaction being termi-
nated by treatment with trichloroacetic acid. The inorganic phosphate isolated from added
substrate is measured colorimetrically as the phosphomolybdic acid complex.
In the radiometric assay, hemolysates obtained as before are incubated with pure 14C~CMP
By addition of a barium hydroxide/zinc sulfate solution, proteins and unreacted nucleotide are
precipitated, leaving labeled cytidine in the supernatant. Aliquots are measured for 14C ac-
tivity in a liquid scintillation counter. This method shows a good correlation with the ear-
lier technique.
Measurement of Plasma 1.25-dihydroxyvitamin D. Measurement techniques for this vitamin D
metabolite, all of recent vintage, consist of three main parts: (1) isolation from plasma or
serum by liquid-liquid extraction, (2) preconcentration of the extract and chromatographic
purification using Sephadex LH-20 or Lipidex 5000 columns, as well as high performance liquid
chromatography (HPLC) in some cases, and (3) quantification by either of two radiometric bind-
ing techniques, the more common competitive protein binding (CPB) assay or radioimmunoassay
(RIA). The CPB assay uses a receptor protein in intestinal cytosol of chicks made vitamin
D-deficient.
In one typical study, human adults had a mean level of 31 picograms/ml. The limit of
detection was 5 picograms/analytical tube, and within-run and between-run coefficients of
variation were 17 and 26 percent, respectively. In a recent interlaboratory survey involving
15 laboratories, the level of variance was such that it was recommended that each laboratory
should establish its own reference values.
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1.10 METABOLISM OF LEAD
Toxicokinetic parameters of lead absorption, distribution, retention, and excretion rela-
ting external environmental lead exposure to various adverse effects are discussed in this
section. Also considered are various influences on these parameters, e.g., nutritional
status, age, and stage of development. A number of specific issues regarding lead metabolism
by animals and humans are addressed, including:
1. How does the developing organism (from gestation to maturity) differ from the adult
in toxicokinetic response to lead intake?
2. What do these differences in lead metabolism portend for relative risk of adverse
effects?
3. What are the factors that significantly change the toxicokinetic parameters in ways
relevant to assessing health risk?
4. How do the various interrelationships among body compartments of lead translate to
assessment of internal exposure and changes in internal exposure?
1.10.1 Lead Absorption in Humans and Animals
The amounts of lead entering the bloodstream via various routes of absorption are influ-
enced not only by the levels of the element in a given medium but also by various physical and
chemical parameters and specific host factors, such as age and nutritional status.
Respiratory Absorption of Lead. The movement of lead from ambient air to the bloodstream
is a two-part process: deposition of some fraction of inhaled air lead in the deeper part of
the respiratory tract and absorption of the deposited fraction. For adult humans, the deposi-
tion rate of particulate airborne lead as likely encountered by the general population is
around 30-50 percent, with these rates being modified by such factors as particle size and
ventilation rates. All of the lead deposited in the lower respiratory tract appears to be ab-
sorbed, so that the overall absorption rate is governed by the deposition rate, i.e., approxi-
mately 30-50 percent. Autopsy results showing no lead accumulation in the lung indicate total
absorption of deposited lead.
All of the available data for lead uptake via the respiratory tract in humans have been
obtained with adults. Respiratory uptake of lead in children, while not fully quantifiable,
appears to be comparatively greater on a body-weight basis. A second factor influencing the
relative deposition rate in children is airway dimensions. One report has estimated that the
10-year-old child has a deposition rate 1.6- to 2.7-fold higher than the adult on a weight
basis.
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The chemical form of the lead compound inhaled does not appear to be a major determinant
of the extent of alveolar absorption of lead. While experimental animal data for quantitative
assessment of lead deposition and absorption for the lung and upper respiratory tract are
limited, available information from the rat, rabbit, dog, and nonhuman primate support the
findings that respired lead in humans is extensively and rapidly absorbed. Over the range of
air lead encountered by the general population, absorption rate does not appear to depend on
air lead level.
Gastrointestinal Absorption of Lead. Gastrointestinal (GI) absorption of lead mainly
involves lead uptake from food and beverages as well as lead deposited in the upper respira-
tory tract and eventually swallowed. It also includes ingestion of non-food material, primar-
ily in children via normal mouthing activity and pica. Two issues of concern with lead uptake
from the gut are the comparative rates of such absorption in developing versus adult organ-
isms, including humans, and how the relative bioavailability of lead affects such uptake.
By use of metabolic balance and isotopic (radioisotope or stable isotope) studies, var-
ious laboratories have provided estimates of lead absorption in the human adult on the order
of 10-15 percent. This rate can be significantly increased under fasting conditions to 45
percent, compared to lead ingested with food. The latter figure also suggests that beverage
lead is absorbed to a greater degree since much beverage ingestion occurs between meals
The relationship of the chemical/biochemical form of lead in the gut to absorption rate
has been studied, although interpretation is complicated by the relatively small amounts given
and the presence of various components in food already present in the gut. In general, how-
ever, chemical forms of lead and their incorporation into biological matrices seem to have a
minimal impact on lead absorption in the human gut Several studies have focused on the ques-
tion of differences in GI absorption rates for lead between children and adults Such rates
for children are considerably higher than for adults: 10-15 percent for adults vs. approxi-
mately 50 percent for children. Available data for the absorption of lead from nonfood items
such as dust and dirt on hands are limited, but one study has estimated a figure of 30 per-
cent. For paint chips, a value of about 17 percent has been estimated.
Experimental animal studies show that, like humans, the adult animal absorbs much less
lead from the gut than the developing animal Adult rats maintained on ordinary rat chow ab-
sorb 1 percent or less of the dietary lead. Various animal species studies make it clear that
the newborn absorbs a much greater amount of lead than the adult, supporting studies showing
this age dependency in humans. Compared to an absorption rate of about 1 percent in adult
rats, the rat pup has a rate 40-50 times greater Part, but not most, of the difference can
be ascribed to a difference in dietary composition. In nonhuman primates, infant monkeys ab-
sorb 65-85 percent of lead from the gut, compared to 4 percent for the adults.
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The bioavailability of lead in the GI tract as a factor in its absorption has been the
focus of a number of experimental studies. These data show that: (1) lead in a number of
forms is absorbed about equally, except for lead sulfide; (2) lead in dirt and dust and as
different chemical forms is absorbed at about the same rate as pure lead salts added to a
diet; (3) lead in paint chips undergoes significant uptake from the gut; and (4) in some
cases, physical size of particulate lead can affect the rate of GI absorption. In humans, GI
absorption rate of lead appears to be independent of quantity in the gut up to a level of at
least 400 ^g. In animals, dietary levels between 10 and 100 ppm result in reduced absorption.
Percutaneous Absorption of Lead. Absorption of inorganic lead compounds through the skin
is of much less significance than absorption through respiratory and GI routes. In contrast,
absorption through skin is far more significant than through other routes for the lead alkyls
(see Section 1.10.6). One recent study using human volunteers and 203Pb-labeled lead acetate
showed that under normal conditions, skin absorption of lead alkyls approached 0.06 percent.
Transplacental Transfer of Lead. Lead uptake by the human and animal fetus readily
occurs, such transfer going on by the 12th week of gestation in humans, and increasing
throughout fetal development. Cord blood contains significant amounts of lead, correlating
with but somewhat lower than maternal blood lead levels. Evidence for such transfer, besides
the measured lead content of cord blood, includes fetal tissue analyses and reduction in
maternal blood lead during pregnancy. There also appears to be a seasonal effect on the
fetus, with summer-born children showing a trend to higher blood lead levels than those born
in the spring.
1.10 2 Distribution of Lead in Humans and Animals
In this subsection, the distributional characteristics of lead in various portions of the
body (blood, soft tissue, calcified tissue, and the "chelatable" or potentially toxic body
burden) are discussed as a function of such variables as exposure history and age.
Lead in Blood. More than 99 percent of blood lead in humans is associated with the
erythrocytes under steady-state conditions, but it is the very small fraction transported in
plasma and extracellular fluid that provides lead to the various body organs. Most (~50 per-
cent) erythrocyte lead is bound within the cell, primarily associated with hemoglobin (partic-
ularly HbA2), with approximately 5 percent bound to a 10,000-dalton fraction, 20 percent to a
heavier molecule, and 25 percent to lower-weight species. Several studies with lead workers
and patients indicate that the fraction of lead in plasma versus whole blood increases above
approximately 50-60 jjg/dl blood lead.
Whole blood lead in daily equilibrium with other compartments in adult humans appears to
have a biological half-life of 25-28 days and comprises about 1.9 mg in total lead content,
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based on isotope studies. Other data from lead-exposed workers indicate that half-life
depends on mobile lead burden. Human blood lead responds rather quickly to abrupt changes in
exposure. With increased lead intake, blood lead achieves a new value in approximately 40-60
days, while a decrease in exposure may be associated with variable new blood values, depending
upon the exposure history. This dependence presumably reflects lead resorption from bone.
With age, furthermore, a moderate increase occurs in blood lead during adulthood. Levels of
lead in blood of children tend to show a peak at 2-3 years of age (probably caused by mouthing
activity), followed by a decline. In older children and adults, levels of lead are sex-
related, with females showing lower levels than males even at comparable levels of exposure.
In plasma, virtually all lead is bound to albumin and only trace amounts to high-weight
globulins. Which of these binding forms constitutes an "active" fraction for movement to
tissues is impossible to state. The most recent studies of the erythrocyte/plasma relation-
ship in humans indicate an equilibrium between these blood compartments, such that levels in
plasma rise with levels in whole blood in fixed proportion up to approximately 50-60 jjg/dl,
whereupon the relationship becomes curvilinear.
Lead Levels in Tissues. Of necessity, various relationships of tissue lead to exposure
and toxicity in humans must generally be obtained from autopsy samples. Limitations on these
data include questions of how such samples represent lead behavior in the living population,
particularly with reference to prolonged illness and disease states. The adequate characteri-
zation of exposure for victims of fatal accidents is a problem, as is the fact that such
studies are cross-sectional in nature, with different age groups assumed to have had similar
exposure in the past.
Soft tissues. After age 20 most soft tissues (in contrast to bone) in humans do not show
age-related changes. Kidney cortex shows an increase in lead with age, which may be associ-
ated with the formation of nuclear inclusion bodies. Absence of lead accumulation in most
soft tissues results from a turnover rate for lead similar to that in blood.
Based on several autopsy studies, soft-tissue lead content for individuals not occupa-
tionally exposed is generally below 0.5 pg/g wet weight, with higher values for aorta and kid-
ney cortex. Brain tissue lead level is generally below 0 2 pg/g wet weight with no change
with increasing age, although the cross-sectional nature of these data would make changes in
low levels of brain lead difficult to discern. Autopsy data for both children and adults
indicate that lead is selectively accumulated in the hippocampus, a finding that is also con-
sistent with the regional distribution in experimental animals.
Comparisons of lead levels in soft-tissue autopsy samples from children with results from
adults indicate that such values are lower in infants than in older children, while children
aged 1-16 years had levels comparable to those for adult women. In one study, lead content of
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brain regions did not materially differ for infants and older children compared to adults.
Complicating these data somewhat are changes in tissue mass with age, although such changes
are less than for the skeletal system.
Subcellular distribution of lead in soft tissue is not uniform. High amounts of lead are
sequestered in the mitochondria and nucleus of the cell. Nuclear accumulation is consistent
with the existence of lead-containing nuclear inclusions in various species and a large body
of data demonstrating the sensitivity of mitochondria to injury by lead.
Mineralizing tissue. Lead becomes localized and accumulates in human calcified tissues,
i.e , bones and teeth. This accumulation in humans begins with fetal development and con-
tinues to approximately 60 years of age. The extent of lead accumulation in bone ranges up to
200 mg in men ages 60-70 years, while in women lower values have been measured. Based upon
various studies, approximately 95 percent of total body lead is lodged in the bones of human
adults, with uptake distributed over trabecular and compact bone. In the human adult, bone
lead is both the most inert and the largest body pool, and accumulation can serve to maintain
elevated blood lead levels years after exposure, particularly occupational exposure, has
ended.
By comparison to human adults, only 73 percent of body lead is lodged in the bones of
children, which is consistent with other information that the skeletal system of children is
more metabolically active than that of adults. Furthermore, bone tissue in children is less
dense than in adults. While the increase in bone lead level across childhood is modest, about
two-fold if expressed as concentration, the total accumulation rate is actually 80-fold,
taking into account a 40-fold increase in skeletal mass. To the extent that some significant
fraction of total bone lead in children and adults is relatively labile, in terms of health
risk for the whole organism it is more appropriate to consider the total accumulation rather
than just changes in concentration.
The traditional view that the skeletal system was a "total" sink for body lead (and by
implication a biological safety feature to permit significant exposure in industrialized popu-
lations) never did agree with even older information on bone physiology, e.g., bone remodel-
ling. This view is now giving way to the idea that there are at least several bone compart-
ments for lead, with different mobility profiles. Bone lead, then, may be more of an insid-
ious source of long-term internal exposure than a sink for the element. This aspect of the
issue is summarized more fully in the next section. Available information from studies of
uranium miners and human volunteers who ingested stable isotopes indicates that there is a
relatively inert bone compartment for lead, having a half-life of several decades, as well as
a rather labile compartment that permits an equilibrium between bone and tissue lead.
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Tooth lead also increases with age at a rate proportional to exposure and roughly propor-
tional to blood lead in humans and experimental animals. Dentine lead is perhaps the most
responsive component of teeth to lead exposure since it is laid down from the time of eruption
until shedding. This characteristic underlies the usefulness of dentine lead levels in asses-
sing long-term exposure.
Chelatable lead Mobile lead in organs and systems is potentially more active toxicolog-
lcally in terms of being available to biological sites of action. Hence, this fraction of
total body lead burden is a more significant predictor of imminent toxicity. In reality,
direct measurement of such a fraction in human subjects would not be possible. In this
regard, chelatable lead, measured as the extent of plumburesis in response to administration
of a chelating agent, specifically CaNa2EDTA, is now viewed as the most useful probe of undue
body burden in children and adults.
A quantitative description of the inputs to the body lead fraction that is chelant-mobi-
lizable is difficult to define fully, but it most likely includes a labile lead compartment
within bone as well as within soft tissues. Support for this view includes. (1) the age
dependency of chelatable lead, but not lead in blood or soft tissues; (2) evidence of removal
of bone lead in chelation studies with experimental animals; (3) i_n vitro studies of lead
mobilization in bone organ explants under closely defined conditions, (4) tracer-modelling
estimates in human subjects, and (5) the complex nonlinear relationship of blood lead and lead
intake through various media. Data for children and adults showing a logarithmic relationship
of chelatable lead to blood lead and the phenomenon of "rebound" in blood lead elevation after
chelation therapy regimens (without obvious external re-exposure) offer further support.
Animal studies. Animal studies have helped to sort out some of the relationships of lead
exposure to i_n vivo distribution of the element, particularly the impact of skeletal lead on
whole body retention. In rats, lead administration results in an initial increase of lead
levels in soft tissues, followed by loss of lead from soft tissue via excretion and transfer
to bone. Lead distribution appears to be relatively independent of dose Other studies have
shown that lead loss from organs follows first-order kinetics except for loss from bone, and
that the skeletal system in rats and mice is the kinetically rate-limiting step in whole-body
lead clearance.
The neonatal animal seems to retain proportionally higher levels of tissue lead compared
to the adult and manifests slow decay of brain lead levels while showing a significant decline
over time in other tissues. This decay appears to result from enhanced lead entry to the
brain because of a poorly developed brain barrier system as well as from enhanced body reten-
tion of lead by young animals.
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The effects of such changes as metabolic stress and nutritional status on body redistri-
bution of lead have been noted. Lactating mice, for example, are known to demonstrate tissue
redistribution of lead, specifically bone-lead resorption with subsequent transfer of both
lead and calcium from mother to pups.
1.10.3 Lead Excretion and Retention in Humans and Animals
Human Studies. Dietary lead in humans and animals that is not absorbed passes through
the GI tract and is eliminated with feces, as is the fraction of air lead that is swallowed
and not absorbed. Lead entering the bloodstream and not retained is excreted through the
renal and GI tracts, the latter via biliary clearance. The amounts excreted through these
routes are a function of such factors as species, age, and exposure characteristics.
Based upon the human metabolic balance data and isotope excretion findings of various in-
vestigators, short-term lead excretion in adult humans amounts to 50-60 percent of the ab-
sorbed fraction, with the balance moving primarily to bone and some fraction (approximately
half) of this stored amount eventually being excreted. This estimated overall retention
figure of 25 percent necessarily assumes that isotope clearance reflects that for body lead in
all compartments. The rapidly excreted fraction has a biological half-life of 20-25 days,
similar to that for lead removal from blood, based on isotope data. This similarity indicates
a steady rate of lead clearance from the body. In terms of partitioning of excreted lead
between urine and bile, one study indicates that the biliary clearance is about 50 percent
that of renal clearance.
Lead accumulates in the human body with age, mainly in bone, up to around 60 years of
age, when a decrease occurs with changes in intake as well as in bone mineral metabolism. As
noted earlier, the total amount of lead in long-term retention can approach 200 mg, and even
much higher in the case of occupational exposure. This rate corresponds to a lifetime average
retention rate of 9-10 pg Pb/day. Within shorter time frames, however, retention will vary
considerably because of such factors as development, disruption in the individuals' equilib-
rium with lead intake, and the onset of such states as osteoporosis.
The age dependency of lead retention/excretion in humans has not been well studied, but
most of the available information indicates that children, particularly infants, retain a sig-
nificantly higher amount of lead than adults. While autopsy data indicate that pediatric sub-
jects at isolated points in time actually have a lower fraction of body lead lodged in bone,
which probably relates to the less dense bones of children as well as high bone mineral turn-
over, a full understanding of longer term retention over childhood must consider the exponen-
tial growth rate occurring in children's skeletal systems over the time period for which bone
lead concentrations have been gathered. This parameter itself represents a 40-fold mass
increase. This significant skeletal growth rate has an impact on an obvious question. if
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children take in more lead on a body-weight basis than adults, absorb and retain more lead
than adults, and show only modest elevations in blood lead compared to adults in the face of a
more active skeletal system, where does the lead go? A second factor is the assumption that
blood lead in children relates to body lead burden in the same quantitative fashion as in
adults, an assumption that remains to be proven adequately.
Animal Studies. In rats and other experimental animals, both urinary and fecal excretion
appear to be important routes of lead removal from the organism. The relative partitioning
between the two modes is species- and dose-dependent. With regard to species differences,
biliary clearance of lead in the dog is but 2 percent of that for the rat, while such excre-
tion in the rabbit is 50 percent that of the rat.
Lead movement from laboratory animals to their offspring via milk constituents is a route
of excretion for the mother as well as a route of exposure for the young. Comparative studies
of lead retention in developing vs. adult animals such as rats, mice, and nonhuman primates
make it clear that retention is significantly greater in the young animal. These observations
support those studies showing greater lead retention in children. Some recent data indicate
that a differential retention of lead in young rats persists into the post-weaning period,
calculated as either uniform dosing or uniform exposure.
1.10.4 Interactions of Lead with Essential Metals and Other Factors
Toxic elements such as lead are affected in their toxicokinetic or toxicological behavior
by interactions with a variety of biochemical factors, particularly nutrients.
Human Studies. In humans the interactive behavior of lead and various nutritional fac-
tors is expressed most significantly in young children, with such interactions occurring
against a backdrop of rather widespread deficiencies in a number of nutritional components.
Various surveys have indicated that iron, calcium, zinc, and vitamin deficiencies are wide-
spread among the pediatric population, particularly the poor. A number of reports have docu-
mented the association of lead absorption with suboptimal nutritional states for iron and cal-
cium, reduced intake being associated with increased lead absorption.
Animal Studies. Reports of lead-nutrient interactions in experimental animals have
generally described such relationships for a single nutrient, using relative absorption or
tissue retention in the animal to index the effect. Most of the recent data are for calcium,
iron, phosphorus, and vitamin D. Many studies have established that diminished dietary calci-
um is associated with increased blood and soft-tissue lead content in such diverse species as
the rat, pig, horse, sheep, and domestic fowl. The increased body burden of lead arises from
both increased GI absorption and increased retention, indicating that the lead-calcium inter-
action operates at both the gut wall and within body compartments. Lead appears to traverse
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the gut via both passive and active transfer. It involves transport proteins normally operat-
ing for calcium transport, but is taken up at the site of phosphorus, not calcium, absorption.
Iron deficiency is associated with an increase of lead in tissues and increased toxicity,
effects that are expressed at the level of lead uptake by the gut wall. In vitro studies
indicate an interaction through receptor-binding competition at a common site, which probably
involves iron-binding proteins. Similarly, dietary phosphate deficiency enhances the extent
of lead retention and toxicity via increased uptake of lead at the gut wall, as both lead and
phosphate are absorbed at the same site in the small intestine. Results of various studies of
the resorption of phosphate along with lead have not been able to identify conclusively a
mechanism for the elevation of tissue lead. Since calcium plus phosphate retards lead absorp-
tion to a greater degree than simply the sums of the interactions, an insoluble complex of all
these elements may be the basis of this retardation.
Unlike the inverse relationship existing f.or calcium, iron, and phosphate vs. lead up-
take, vitamin 0 levels appear directly related to the rate of lead absorption from the GI
tract, since the vitamin stimulates the same region of the duodenum where lead is absorbed. A
number of other nutrient factors are known to have an interactive relationship with lead:
1. Increases in dietary lipids increase the extent of lead absorption, with the extent
of the increase being highest with polyunsaturates and lowest with saturated fats,
e.g., tristearin.
2. The interactive relationship of lead and dietary protein is not clear cut, and
either suboptimal or excess protein intake will increase lead absorption.
3. Certain milk components, particularly lactose, greatly enhance lead absorption in
the nursing animal.
4. Zinc deficiency promotes lead absorption, as does reduced dietary copper.
Taken collectively, human and animal data dealing with the interaction of lead and nutri-
ents indicate that children having multiple nutrient deficiencies are in the highest exposure
risk category.
1.10.5 Interrelationships of Lead Exposure with Exposure Indicators and Tissue Lead Burdens
Three issues involving lead toxicokinetics evolve toward a full connection between lead
exposure and its adverse effects: (1) the temporal characteristics of internal indices of
lead exposure; (2) the biological aspects of the relationship of lead in various media to
various indicators in internal exposure; and (3) the relationship of various internal indica-
tors of exposure to target tissue lead burdens.
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Temporal Characteristics of Internal Indicators of Lead Exposure. The biological half-
life for newly absorbed lead in blood may be as short as weeks, several months, or even
longer, depending on the mobile lead burden in the body. Compared to mineral tissues, this
medium reflects relatively recent exposure. If recent exposure is fairly representative of
exposure over a considerable period of time, e.g., exposure of lead workers, then blood lead
is more useful than for cases where exposure is intermittent or different across time, as in
the case of lead exposure of children. Accessible mineralized tissue, such as shed teeth,
extend the time frame back to years of exposure, since teeth accumulate lead with age and as a
function of the extent of exposure. Such measurements are, however, retrospective in nature,
in that identification of excessive exposure occurs after the fact and thus limits the possi-
bility of timely medical intervention, exposure abatement, or regulatory policy concerned with
ongoing control strategies.
Perhaps the most practical solution to the dilemma posed by the different temporal
characteristics of tooth and blood lead analyses is ijn situ measurement of lead in teeth or
bone during the time when active accumulation occurs, e.g., 2- to 3-year-old children. Avail-
able data using X-ray fluorescence analysis do suggest that such approaches are feasible and
can be reconciled with such issues as acceptable radiation hazard risk to subjects.
Biological Aspects of External Exposure/Internal Indicator Relationships. The literature
indicates clearly that the relationship between lead in media relevant for human exposure and
blood lead is curvilinear when viewed over a relatively broad range of blood lead values
This curvi1inearity implies that the unit change in blood lead per unit intake of lead in some
medium varies across this range of exposure, with comparatively smaller blood lead changes
occurring as internal exposure increases.
Given our present knowledge, such a relationship cannot be taken to mean that body uptake
of lead is proportionately lower at higher exposure, because it may simply mean that b-lood
lead becomes an increasingly unreliable measure of target-tissue lead burden with increasing
exposure While the basis of the curvilinear relationship remains to be identified, available
animal data suggest that it may be related to the increasing fraction of blood lead in plasma
as blood lead increases above approximately 50-60 jjg/dl.
Internal Indicator/Tissue Lead Relationships. In living human subjects, direct deter-
mination of tissue lead burdens or how these relate to adverse effects in target tissues is
not possible. Some accessible indicator (e.g., measurements of lead or a biochemical surro-
gate of lead such as erythrocyte protoporphyrin in a medium such as blood), must be employed
While blood lead still remains the only practical measure of excessive lead exposure and
health risk, evidence continues to accumulate that such an index has some limitations in
either reflecting tissue lead burdens or changes in such tissues with changes in exposure
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At present, the measurement of plumburesis associated with challenge by a single dose of
a 1ead-che1 atlng agent such as CaNa2EDTA is considered the best indicator of the mobile,
potentially toxic fraction of body lead. Chelatable lead is logarithmically related to blood
lead, such that an incremental increase in blood lead is associated with an increasingly
larger increment of mobilizable lead. The problems associated with this logarithmic relation-
ship may be seen in studies of children and lead workers in whom moderate elevation in blood
lead levels can disguise levels of mobile body lead. In one recent multi-institution study of
210 children, for example, 12 percent of children with blood lead 30-39 pg/dl, and 38 percent
with levels of 40-49 jjg/dl, had a positive EDTA-challenge response and required further eval-
uation or treatment. At blood lead levels such as these, the margin of protection against
severe intoxication is reduced The biological basis of the logarithmic chelatable-lead/
blood-lead relationship rests, in large measure, with the existence of a sizeable bone lead
compartment that is mobile enough to undergo chelation removal and, hence, potentially mobile
enough to move into target tissues.
Studies of the relative mobility of chelatable lead over time indicate that, in former
lead workers, removal from exposure leads to a protracted washing out of lead (from bone re-
sorption of lead) to blood and tissues, with preservation of a bone burden amenable to subse-
quent chelation. Studies with children are inconclusive, since the one investigation directed
to this end employed pediatric subjects who all underwent chelation therapy during periods of
severe lead poisoning. Animal studies demonstrate that changes in blood lead with increasing
exposure do not agree with tissue uptake in a time-concordant fasion, nor does decrease in
blood lead with reduced exposure signal a similar decrease in target tissue, particularly in
the brain of the developing organism.
1 10 6 Metabolism of Lead Alkyls
The lower alkyl lead components used as gasoline additives, tetraethyl lead (TEL) and
tetramethyl lead (TML), may themselves poise a toxic risk to humans. In particular, there is
among children a problem of sniffing leaded gasoline.
Absorption of Lead Alkyls in Humans and Animals. Human volunteers inhaling labeled TEL
and TML show lung deposition rates for the lead alkyls of 37 and 51 percent, respectively,
values which are similar to those for particulate inorganic lead. Significant portions of
these deposited amounts were eventually absorbed. Respiratory absorption of organolead bound
to particulate matter has not been specifically studied as such.
While specific data for the GI absorption of lead alkyls in humans and animals are not
available, their close similarity to organotin compounds, which are quantitatively absorbed,
would argue for extensive GI absorption In contrast to inorganic lead salts, the lower lead
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alkyls are extensively absorbed through the skin and animal data show lethal effects with per-
cutaneous uptake as the sole route of exposure.
Biotransformation and Tissue Distribution of Lead Alkyls The lead alkyls TEL and TML
undergo monodealkylation in the liver of mamm?l ian species via the P-450-dependent mono-
oxygenase enzyme system. Such transformation is very rapid. Further transformation involves
conversion to the dialkyl and inorganic lead forms, the latter accounting for the effects on
heme biosynthesis and erythropoiesis observed in alkyl lead intoxication. Alkyl lead is
rapidly cleared from blood, shows a higher partitioning into plasma than inorganic lead with
triethyl lead clearance being more rapid than the methyl analog.
Tissue distribution of alkyl lead in humans and animals primarily involves the tnalkyl
metabolites. Levels are highest in liver, followed by kidney, then brain. Of interest is the
fact that there are detectable amounts of trialkyl lead from autopsy samples of human brain
even in the absence of occupational exposure. In humans, there appear to be two tissue com-
partments for triethyl lead, having half-times of 35 and 100 days.
Excretion of Lead Alkyls. With alkyl lead exposure, excretion of lead through the renal
tract is the main route of elimination. The chemical forms being excreted appear to be
species-dependent. In humans, trialkyl lead in workers chronically exposed to alkyl lead is a
minor component of urine lead, approximately 9 percent.
1-11 ASSESSMENT OF LEAD EXPOSURES AND ABSORPTION IN HUMAN POPULATIONS
Chapter 11 describes the effect of environmental lead exposure on human populations The
effect discussed is a change in an internal exposure index that follows changes in external
exposures. The index of internal lead exposure most frequently cited is blood lead level, but
other indices such as levels of lead in tooth and bone are also presented. Blood lead level
estimates the body's recent exposure to environmental lead, while teeth and bone lead levels
represent cumulative exposures
Measurement of lead in blood and other physiological media has been accomplished via a
succession of analytical procedures over the years. With these changes in technology there
has been increasing recognition of the importance of controlling for contamination in the sam-
pling and analytical procedures These advances, as well as the institution of external
quality control programs, have resulted in markedly improved analytic results. A generalized
improvement in analytic results across many laboratories occurred during Federal Fiscal Years
1977-1979
The main discussion of scientific evidence in Chapter 11 is structured to achieve four
main objectives-
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(1) Elucidation of patterns of internal lead exposures in U.S. populations and
identification of important demographic covariates.
(2) Characterization of relationships between external and internal exposures to
lead by exposure medium (air, food, water, or dust).
(3) Identification of specific sources of lead which result in increased internal
exposure levels.
(4) Estimation of the relative contributions of various sources of lead in the
environment to total internal exposure as indexed by blood lead level.
A question of major interest in understanding environmental pollutants is the extent to
which current ambient exposures exceed background levels. Ancient Nubians samples (dated
3300-2900 B.C.) averaged 0.6 pg lead/g for bone and 0.9 (jg lead/g for teeth. More recent
Peruvian Indian samples (12th Century) had teeth lead levels of 13.6 pg/g. Contemporary
Alaskan Eskimo samples had a mean of 56.0 pg/g, while Philadelphia samples had a mean of 188.3
pg/g. These data suggest an increasing pattern of lead absorption.
Studies of current populations living in remote areas far from urbanized cultures show
blood lead levels in the range of 1-5 pg/dl In contrast to the blood lead levels found in
remote populations, data from current U.S. populations have geometric means ranging from <10
to 20 pg/dl depending on age, race, sex, and degree of urbanization. These higher current
exposure levels appear to be associated with industrialization and widespread commercial use
of lead, e.g., as gasoline additives
1.11.1 Levels of Lead and Demographic Covariates in U.S. Populations
The National Center for Health Statistics has provided the best currently available pic-
ture of blood lead levels among United States residents as part of the second National Health
and Nutrition Examination Study (NHANES II) conducted from February, 1976 to February, 1980
(Mahaffey et al., 1980, McDowell et al., 1981; Annest et al., 1982). The national estimates
are based on 9933 persons whose blood lead levels ranged from 2.0 to 66.0 pg/dl. The median
blood lead for the entire U.S. population is 13.0 pg/dl.
Age appears to be one of the most important demographic covariates of blood lead levels.
Blood lead levels in children are generally higher than those in non-occupationally exposed
adults. Children aged 2-3 years tend to have the highest blood lead levels. The age trends
in blood lead levels for children under 10 years old, as seen in three studies, are presented
in Figure 1-13. Blood lead levels in non-occupationally exposed adults may increase slightly
with age due to skeletal lead accumulation
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40
35
30
o
<
IDAHO STUDY
NEW YORK SCREENING - BLACKS
NEW YORK SCREENING - WHITES
- NEW YORK SCREENING - HISPANICS
NHANES II STUDY - BLACKS
NHANES II STUDY - WHITES
25
Q
O
O
/
20
V
V\
"V
\
15
oL
5
AGE, yr
10
Figure 1-13. Geometric mean blood lead levels by race and age for younger children in the
NHANES II Study (Annest et al., 1982), the Kellogg Silver Valley, Idaho Study (Yankel et
al., 1977), and the New York Childhood Screening Studies (Billick et al., 1979).
1-30
-------
Sex has a differential impact on blood lead levels depending on age. No significant dif-
ference exists between males and females less than seven years of age. Males above the age of
seven generally have higher blood lead levels than females.
Race also plays a role, in that blacks generally have higher blood lead levels than
either whites or Hispanics, and urban black children (aged 6 mo.-5 yr.) have markedly higher
blood lead concentrations than any other racial or age group. Possible genetic factors
associated with race have yet to be fully untangled from differential exposure levels and
other factors as important determinants of blood lead levels.
Blood lead levels also seem to increase with degree of urbanization. Data from NHANES II
show that blood lead levels in the United States, averaged from 1976 to 1980, increase from a
geometric mean of 11.9 pg/dl in rural populations to 12.8 pg/dl in urban populations less than
one million and increase again to 14.0 (jg/dl in urban populations of one million or more (see
Table 1-9). Results obtained from the NHANES II study show that urban children generally have
the highest blood lead levels of any non-occupationally exposed population group. Further-
more, black urban children have significantly higher blood lead levels than white urban
children. Several case control studies of children have shown that blood lead levels are
related to hand lead levels, house dust levels, lead in outside soil, interior paint lead
level, and history of pica.
The distributional form of blood lead levels in a population is important because the
distributional form determines which measure of central tendency (arithmetic mean, geometric
mean, median) is most appropriate. It is even more important in estimating percentiles in the
tail of the distribution, which represents those individuals at highest risk of excess expo-
sure
Based on examination of NHANES II data, as well as results of several other studies, it
appears that the lognormal distribution is the most appropriate for describing the distribu-
tion of blood lead levels in populations thought to be homogenous in terms of demographic and
lead exposure characteristics. The lognormal distribution appears to fit well across the
entire range, including the upper tail of the distribution. The geometric standard deviation
for four different studies are shown in Table 1-10. The values, including analytic error, are
about 1.4 for children and possibly somewhat smaller for adults. This allows an estimation of
the upper tail of the blood lead distribution, the group at higher risk.
1 11.2 Time Trends in Blood Lead Levels Since 1970
Studies in the United States. Recent U.S. blood lead levels show that a downward trend
has occurred consistently across race, age, and geographic location. The downward pattern
commenced in the early part of the 19701s and has continued into 1980. The downward trend has
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TABLE 1-9. WEIGHTED GEOMETRIC MEAN BLOOD LEAD LEVELS
FROM NHANES II SURVEY BY DEGREE OF URBANIZATION OF PLACE OF
RESIDENCE IN THE U.S. BY AGE AND RACE, UNITED STATES 1976-80
Degree of urbanization
Race and age
Urban,
^1 mi 11 ion
Urban,
<1 mi 11i on
Rural
All races
Geometric mean (pg/dl)
All ages
14.0
12.8
11.9
6 months-5 years
6-17 years
18-74 years
16.8
13.1
14.1
15.3
11.7
12.9
13.1
10.7
12.2
Whites
All ages
14.0
12.5
11.7
6 months-5 years
6-17 years
18-74 years
15.6
12.7
14.3
14.4
11.4
12.7
12 7
10.5
12.1
Blacks
All ages
14.4
14.7
14.4
6 months-5 years
6-17 years
18-74 years
20.9
14.6
13.9
19.3
13.6
14.7
16.4
12.9
14.9
Source: Annest et al. (1982).
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TABLE 1-10. SUMMARY OF POOLED GEOMETRIC STANDARD DEVIATIONS AND ESTIMATED ANALYTIC ERRORS
Pooled Geometric Standard Deviations
Estimated
Study
Inner City Inner City
Black Children White Children
Adul t
Females
Adul t
Males
Analytic
Error
NHANES II
1.37 1.39
1. 36a
1.40a
0.021
N Y. Childhood
Screening Study
1.41 1.42
-
-
(b)
Tepper-Levi n
-
1.30
-
0.056C
Azar et al.
-
-
1.29
0.042C
Note: To calculate an estimated person-to-person GSD,
compute Exp [(ln(GSD))2 - Analytic Error)^].
apooled across areas of differing urbanization.
bnot known, assumed to be similar to NHANES II.
ctaken from Lucas (1981)
occurred from a shift in the entire distribution and not just via a truncation in high blood
lead levels. This consistency suggests a general causative factor and attempts have been made
to identify the causative element. Reduction of lead emitted from the combustion of leaded
gasoline is a prime suspect
Blood lead data from the NHANES II study demonstrates well that, on a nationwide basis,
there has been a significant downward trend over time (Annest et al., 1983). Mean blood lead
levels dropped from 15.8 pg/dl during the first six months of the survey to 10.0 jjg/dl during
the last six months. Mean values from these national data presented in six month increments
from February, 1976 to February, 1980 are displayed in Figure 1-14.
Billick and colleagues (Billick et al., 1979) have analyzed the results of blood lead
screening programs conducted by the City of New York. Geometric mean blood lead levels de-
creased for all three racial groups and for almost all age groups in the period 1970-76
Figure 1-15 shows that the downward trend covers the entire range of the frequency distribu-
tion of blood lead levels. The decline in blood lead levels showed seasonal variability, but
the decrease in time was consistent for each season.
Gause et al. (1977) present data from Newark, New Jersey, which reinforces the findings
of Billick and coworkers. Gause et al. studied the levels of blood lead among 5- and 6-year-
old children tested by the Newark Board of Education during the academic years 1973-74,
1974-75, and 1975-76 Blood lead levels declined markedly during this three-year period
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WINTER 1976
(FEB.)
WINTER 1977
(FEB.)
WINTER 1978 FALL 1978 WINTER 1979
(FEB) (OCT.) (FEB)
WINTER 1980
(FEB)
ui
lU
0
5
10
15
20
25
30
35
40
45
50
55
CHRONOLOGICAL ORDER, 1 unit = 28 days
Figure 1-14. Average blood lead levels of U.S. population 6 months-74 years. United States,
February 1976-February 1980, based on dates of examination of NHANES II examinees with
blood lead determinations.
Source: Annest et al. (1983).
-------
i—i—i—i—r
CHICAGO
NEW YORK
I I
J I I I I I »»!»
1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980
YEAR (Beginning Jan. 1)
Figure 1-15. Time dependence of blood lead for blacks, aged 24 to 35
months, in New York City and Chicago.
Source: Adapted from Billick (1982).
1-35
-------
Rabinowitz and Needleman (1982) report a more recent study of umbilical cord blood lead
levels from 11,837 births between April, 1979 and April, 1981 in the Boston area. The overall
mean blood lead concentration was 6.56 ± 3.19 (standard deviation) with a range of 0 0-37.9
pg/dl. A downward trend in umbilical cord blood lead levels was noted over the two years of
the study
European Studies. There has been a series of publications from various workers in
England who have been examining the question of whether or not time trends in blood lead
levels exist there as well as in the United States (Oxley, 1982; Elwood, 1983a, 1983b, Quinn,
1983). These papers cover a variety of exposure situations and populations. All of them ob-
tained findings analogous to those described above for the United States, in that there has
been a general decline in blood lead levels over the decade of the 1970's; they differ, how-
ever, with regard to the magnitude of the decline, when the decline began, and to what extent
the decline may be attributable to a particular source of lead.
In an international study, Friberg and Vahter (1983) compared data on blood lead levels
obtained in 1967 with data for 1981. For areas of the world where there were data collected by
Goldwater and Hoover (1967) as well as the UN/WHO study, there has been a substantial reduc-
tion in reported blood lead levels A cautionary note must be made, however, that the analy-
tic and human sampling procedures are not the same in the two studies. Therefore these data
should be thought of as providing further but limited evidence supporting a recent downward
trend in blood lead levels worldwide.
1.11.3 Determinants of Trends in Blood Lead Levels
Explanations have been sought for declining trends in blood lead levels observed among
population groups in the United States and certain other countries since the early 1970s.
Extensive evidence points towards gasoline lead as being an important determinant of changes
in blood lead levels associated with exposures to airborne lead of populations in the United
States and elsewhere.
A striking feature of the NHANES II data was a dramatic decline in nationwide average
blood lead levels in the United States during the period (1976-1980) of the survey In evalu-
ating possible reasons for the observed decrease in the NHANES II blood lead values, Annest
(1983) and Annest et al. (1983) found highly significant associations between the declining
blood lead concentrations for the overall U.S population and decreasing amounts of lead used
in gasoline in the U.S. during the same time period (see Figure 1-16) The associations per-
sisted after adjusting for race, age, sex, region of the country, season, income, and degree
of urbanization (see Table 1-11) Analogous strong associations (r = 0 95, p < 0 001) were
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GJ
110
100
(A
z
o
® 90
O
O
E
UJ
0.
X 80
»-
z
o
s
<0
ec 70
111
Q.
O
Ul
(A
3
Q
<
UJ
O
l-
60
50
LEAD USED IN
GASOLINE
AVERAGE
BLOOD
LEAD LEVELS
1976
1977
1978
YEAR
1979
1980
16
15
14
13
12
11
9
/V.
Figure 1-16. Parallel decreases in blood lead values observed in the NHANES II Study and
amounts of lead used in gasoline during 1976-1980.
Source: Annest (1983).
-------
TABLE 1-11. PEARSON CORRELATION COEFFICIENTS BETWEEN THE AVERAGE BLOOD LEAD LEVELS
FOR SIX-MONTH PERIODS AND THE TOTAL LEAD USED IN GASOLINE PRODUCTION
PER SIX MONTHS, ACCORDING TO RACE, SEX, AND AGE3
Coefficients for 6-month Periods
January-June Apri1-September .
And July-December And October-March Averages
Overall (all races)
0 920
0.938
0.929
All black9
0 678
0.717
0 698
All whites
0.929
0.955
0 942
By sex: Male
0 944
0.960
0.952
Female
0.912
0.943
0.928
By age 0.5-5 yr
0 955
0.969
0.962
6-17 yr
0.908
0.970
0.939
18-74 yr
0.920
0.924
0 922
The lead values used to compute the averages were preadjusted by regression analysis to
account for the effects of income, degree of urbanization, region of the country, season,
and when appropriate, race, sex, and age.
^All correlation coefficients were statistically significant (P < 0.001) except those for
blacks (P < 0.05).
cAverages were based on six-month periods, except for the first and last, which covered only
February 1976 through June 1976 and January 1980 through February 1980, respectively.
^Averages were based on six-month periods, except for the last, which covered only October
1979 through February 1980.
Blacks could not be analyzed according to sex and age subgroups because of inadequate sample
sizes.
Source: Annest et al (1983).
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also found for blood lead levels for white children aged 6 mo.-5 yr. in the NHANES II sample
and gasoline lead usage.
Two field investigations have attempted to derive an estimate of the amount of lead from
gasoline that is absorbed by the blood of individuals. Both of these investigations used the
fact that the isotopes of lead are stable; thus, the varying proportions of the isotopes pre-
sent in blood and environmental samples can indicate the source of the lead. The Isotopic
Lead Experiment (ILE), reported in Fachetti and Geiss (1982), is a massive study that attemp-
ted to utilize differing proportions of the isotopes in geologic formations to infer the pro-
portion of lead in gasoline that is absorbed by the body The other study (Manton, 1977) uti-
lized existing natural shifts in isotopic proportions in an attempt to do the same thing
The ILE is a large scale community trial in which the geologic source of lead used in
antiknock compounds in gasoline was manipulated to change the isotopic composition of lead in
the atmosphere (Garibaldi et al., 1975; Facchetti, 1979). The isotopic lead ratios obtained
in the samples analyzed are displayed in Figure 1-17. It can easily be seen that the airborne
particulate lead rapidly changed its isotope ratio in line with expectation. Ratios in the
blood samples appeared to lag somewhat behind. Background lead isotopic ratios were 1 1603 ±
0.0028 in rural areas and 1.1609 ± 0.0015 in Turin in 1975. In Turin school children in
1977-78, a mean isotopic ratio of 1.1347 was obtained.
Preliminary analysis of the isotope ratios in air lead has allowed the estimation of the
fractional contribution of gasoline lead in the city of Turin, in small communities within 25
km of Turin, and in small communities beyond 25 km (Facchetti and Geiss, 1982). At the time
of maximal use of Australian lead isotope in gasoline (1978-79), about 87.3 percent of the air
lead in Turin and 58.7 percent of the air lead in the countryside was attributable to gaso-
line. The determination of lead isotope ratios was essentially independent of specific air
lead concentrations. During that time, air lead averaged about 2.0 pg/m3 in Turin (from 0 88-
4.54 pg/m3 depending on location of the sampling site), about 0.56 pg/m3 in the nearby commun-
ities (0.30-0.67 pg/m3), and about 0.30 pg/m3 in distant locations.
Isotope ratios in the blood of 35 subjects also changed, and the fraction of lead in
blood attributable to gasoline could be estimated independently of blood level concentration
The mean fraction decreased from 23.7 ± 5.4 percent in Turin to 12.5 ±7.1 percent in the
nearby countryside, and to 11.0 ± 5.8 percent in the remote countryside.
These results can be combined with the actual blood lead concentrations to estimate the
fraction of the gasoline uptake that is attributable to direct inhalation and that which is
not. The results are shown in Table 1-12 (based on a suggestion by Dr. Fachetti). As con-
cluded earlier, an assumed value of p=1.6 is plausible for predicting the amount of lead ab-
sorbed into blood at air lead concentrations less than 2.0 pg/m3 The predicted values for
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1 20
1 18
1 16
1.14
1.12
1 10
1 08
1 06
I I I I I I II I I I I I I I I I
*) BASED ON A LIMITED NUMBER OF SAMPLES
- Pb 206/Pb 207
• ADULTS < 25 km
BLOOD a ADULTS > 25 km
O ADULTS TURIN
~ TRAFFIC WARDENS-TURIN
¦ SCHOOL CHILDREN-TURIN
AIRBORNE
PARTICULATE
• TURIN
A COUNTRYSIDE
O PETROL
Phase 0
Phase 1
Phase 2
Phase 3
I I l I I i
74
75
76
77
78
79
80
81
Figure 1-17. Change in Pb-206/Pb-207 ratios in petrol, airborne particulate,
and blood from 1974 to 1981.
Source: Facchetti and Geiss (1982).
1-90
-------
TABLE 1-12. ESTIMATED CONTRIBUTION OF LEADED GASOLINE TO BLOOD LEAD
BY INHALATION AND NON-INHALATION PATHWAYS
Air Lead
Lead
Mean
Blood
Lead
Non-
Estimated
Fraction
Air
Fraction
Blood
Lead
From
Inhaled
Fraction
From
Lead .
From
Lead .
From
Gasolioe
Lead From
Gas-Lead .
Gaso-
Cone
Gaso-
Cone.
Gaso-
In Air
Gaso-
Inhalation
Location
11 ne
1 i ne
1 i ne
11 ne9
(pg/m3)
(pg/dl)
(|jg/dl)
(pg/dl)
(pg/dl)
Turi n
0 873
2.0
0.237
21.77
5.16
2.79
2 37
0.54
<25 km
0.587
0.56
0.125
25.06
3.13
0.53
2.60
0 17
>25 km
0.587
0.30
0.110
31.78
3.50
0.28
3 22
0 08
aFraction of air lead in Phase 2 attributable to lead in gasoline
^Mean air lead in Phase 2, pg/m3
cMean fraction of blood lead in Phase 2 attributable to lead in gasoline.
^Mean blood lead concentration in Phase 2, pg/d1
eEstimated blood lead from gasoline = (c) x (d)
^Estimated blood lead from gas inhalation = p x (a) x (b), p = 1.6.
^Estimated blood lead from gas, non-inhalation = (f)-(e)
^Fraction of blood lead uptake from gasoline attributable to direct inhalation = (f)/(e)
Data from Facchetti and Geiss (1982), pp. 52-56.
airborne lead derived from leaded gasoline range from 0.28 to 2.79 pg/dl in blood due to
direct inhalation. The total contribution to blood lead from gasoline lead is much larger,
from 3 50-5.16 pg/dl, suggesting that the non-inhalation total contribution of gasoline
increases from 2.37 pg/dl in Turin to 2.60 |jg/dl in the near region and 3.22 pg/dl in the more
distant region. The non-inhalation sources include ingestion of dust and soil lead and lead
in food and drinking water. Efforts are being made to quantify their magnitude The average
direct inhalation of lead in the air from gasoline is 8-17 percent of the total intake attri-
butable to gasoline in the countryside and an estimated 68 percent in the city of Turin.
The strongest kind of scientific evidence about causal relationships is based on an ex-
periment in which all possible extraneous factors are controlled The evidence derived from
the I sotoplc Lead Experiment comes very close. The experimental intervention consisted of
replacing the normal 2obPb/207Pb isotope ratio by a very different ratio. There is no plausi-
ble mechanism by which other concurrent lead exposure variables (e.g., food, water, beverages,
paint, industrial emissions) could have also changed their isotope ratios Hence the very
large changes in isotope ratios in blood were responding to the change in gasoline There was
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no need to carry out detailed aerometric and ecological modelling to track the leaded gasoline
isotopes through the various environmental pathways. In fact, EPA analyses* show that inhala-
tion of community air lead will substantially underestimate the total effect of gasoline lead,
at least in the 35 subjects whose blood leads were tracked in the ILE Preliminary Study
Spengler et al. (1984) showed that part of the extra exposure could possibly be attributed to
higher-than-ambient air lead concentrations inside motor vehicles, e.g , on the trip to work,
however, no data are presently available to confirm this hypothesis. Dietary lead is also an
explanation for the large excess of gasoline lead isotope ratio in blood beyond that expected
from inhalation of ambient air lead; this could occur both from gasoline lead entering the
food chain and being added during food processing and preparation. The 35 subjects in the ILE
study cannot be said to represent some defined population, and it is not clear how the results
can be extended to U.S. populations. Turin's unusual meteorology, high blood lead levels, and
the "reversed" urban-rural gradient of blood lead levels in the subjects in the ILE study
indicate the need for future research. However, in spite of the variable gasoline lead expo-
sures of the subj'ects, there is strong evidence that changes in gasoline lead produce large
changes in blood lead.
Manton (1977) conducted a long term study of 10 subjects whose blood lead isotopic com-
position was monitored for comparison with the isotopic composition of the air they breathed
Manton had observed that the ratio of lead 206/204 in the air varied with seasons in Dallas,
Texas, therefore, the ratio of those isotopes should vary in the blood. By comparing the
observed variability, estimates could then be made of the amount of lead in air that is ab-
sorbed by the blood. From the Manton study it is estimated that between 7 and 41 percent of
the blood lead in study subjects in Dallas results from airborne lead Additionally these
data provide a means of estimating the indirect contribution of air lead to blood lead By
one estimate, only 10-20 percent of the total airborne contribution to blood lead in Dallas is
from direct inhalation.
Another approach to identifying the determinants of trends in blood lead levels over time
was taken in New York City Billick et al. (1979) presented several possible explanations for
observed declines in blood lead levels, as well as evidence supporting and refuting each The
suggested contributing factors were: (1) the active educational and screening program of the
New York City Bureau of Lead Poisoning Control, (2) a decrease in the amount of lead-based
paint exposure as a result of rehabilitation or removal of older housing stock, and (3)
A
Note. The term EPA analyses refers to calculations done at EPA. A brief discussion of the
methods used is contained in Appendix 11-B, more detailed information is available at EPA
upon request.
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changes in total environmental lead exposure However, information was only partially avail-
able for ambient air lead levels, air lead measurements for the entire study period were
available for only one station, which was located on the west side of Manhattan at a height of
56 m Superimposition of the air lead and blood lead levels indicated a similarity in both
upward cycle and decline. The authors cautioned against overinterpretation by assuming that
one air monitoring site was representative of the air lead exposure of New York City resi-
dents With this in mind, the investigators fitted a multiple regression model to the data to
try to define the important determinants of blood lead levels for this population. Age, eth-
nic group, and air lead level were all found to be significant determinants of blood lead
levels. The authors further point out the possibility of a change in the nature of the popu-
lation being screened before and after 1973. They reran this regression analysis separately
for years both before and after 1973 The same results were still obtained, although the
exact coefficients derived varied.
Billick et al. (1980) extended their previous analysis of the data from the single moni-
toring site mentioned earlier and examined the possible relationship between blood lead level
and the amount of lead in gasoline used in the New York City area. Figures 1-18 and 1-19 pre-
sent illustrative trend lines in blood leads for blacks and Hispanics and air lead and gaso-
line lead, respectively. Several different measures of gasoline lead were used: (1) mid-
Atlantic Coast (NY, NJ, Conn); (2) New York City plus New Jersey, and (3) New York City plus
Connecticut. The lead in gasoline trend line appears to fit the blood lead trend line better
than the air lead trend, especially in the summer of 1973.
1.11.4 Blood Lead vs. Inhaled Air Lead Relationships
The mass of data on the relationship of blood lead level and air lead exposure is compli-
cated by the need for reconciling the results of experimental and observational studies Fur-
ther, the process of determining the best form of the statistical relationship deduced is pro-
blematic due to the lack of consistency in the range of the air lead exposures encountered in
the various studies.
The model used is especially critical in situations where lead is present in relatively
low concentrations in one or more environmental media. A large number of statistical models
have been used to predict the contribution to blood lead level from various environmental
media. There is no question that the relationship between blood lead and environmental expo-
sure is nonlinear across the entire range of potential exposures, from very low to high
levels. At lower levels of exposure, however, various models all provide adequate descrip-
tions of the observed data. The choice of a model must be based at least in part on the
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I I I I I I I I III I I I I I I I I I I I I I I I I
- 35 —
BLACK
— HISPANIC
• AIR LEAD
Ol
3.
Q
<
O
O
o
<
LU
2
u
E
UJ
s
o
UJ
O
20
15
10
'J-
I ^ I x i V y
lV \ / \ / \
1
U ' • / *
'/\ \ ! \
h ^ V
/¦ /.
X- /* X- A
V/
of M I 1 I I I I I I I I I I I I I I I I I I I I I I I fn
1970 1971 1972 1973 1974 1975 1976
QUARTERLY SAMPLING DATE
Figure 1-18. Geometric mean blood lead levels of New York
City children (aged 25-36 months) by ethnic group, and am-
bient air lead concentrations versus quarterly sampling period
1970-1976.
>
<
>
o
-E
(O
1 0
Source: Billick et al. (1980).
1-94
-------
35
30
25
20
15
10
I I I | I I I | I I I | I I I | I I I | I I I | I I I
BLACK
HISPANIC
— • — GASOLINE LEAD
\ A /
\J \ I \ \
\ v Va v V \"/\
\ /\ / \ A V
V \ / v \ / \
\/ \
\ .. A
» • •
* V
60
50
a
>
u>
o
m
J»
O
4.0 o
3
(0
30
nT I I I I I I I I I l I I I I I I I I I I I I I I I I I Too
1970 1971 1972 1973 1974 1975 1976
QUARTERLY SAMPLING DATE
Figure 1-19. Geometric mean blood lead levels of New York
City children (aged 25-36 months) by ethnic group, and esti-
mated amount of lead present in gasoline sold in New York,
New Jersey, and Connecticut versus quarterly sampling period,
1970-1976.
0)
3
(0
Source: Billick et al. (1980).
1-95
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biological mechanisms, at the very least, no model should be adopted which is inconsistent
with biological reality.
Because the main purpose of this document is to examine relationships between lead in air
and lead in blood under ambient conditions, EPA has chosen to emphasize the results of studies
most appropriately addressing this issue. A summary of the most appropriate studies appears
in Table 1-13. At air lead exposures of 3 pg/m3 or less, there is no statistically signifi-
cant difference between curvilinear and linear blood lead-inhalation relationships. At air
lead exposures of 10 pg/m° or more, either nonlinear or linear relationships can be fitted
Thus, a reasonably consistent picture emerges in which the blood lead-air lead relationship
for direct inhalation is approximately linear in the range of normal ambient exposures (0 1-
2.0 pg/m3.) Therefore EPA has fitted linear relationships to blood lead levels in the studies
to be described with the explicit understanding that the fitted relationships are intended
only to describe changes in blood due to modest changes in air lead among individuals whose
blood lead levels do not exceed 30 pg/dl.
The blood-lead inhalation slope estimates vary appreciably from one subject to another in
experimental and clinical studies, and from one study to another. The weighted slope and stan-
dard error estimates from the Griffin et al. (1975) study (1.75 ± 0.35) were combined with
those calculated similarly for the Rabinowitz et al (1973, 1976, 1977) study (2.14 ± 0 47)
and the Kehoe (1961a,b,c) study (1 25 ± 0.35 setting DH = 0), yielding a pooled weighted slope
estimate of 1 64 ± 0.22 pg/dl per pg/m3. There are some advantages in using these experimen-
tal studies on adult males, but certain deficiencies are acknowledged. The Kehoe study ex-
posed subjects to a wide range of exposure levels while in the exposure chamber, but did not
control air lead exposures outside the chamber The Griffin study provided reasonable control
of air lead exposure during the experiment, but difficulties in defining the non-inhalation
baseline for blood lead (especially in the important experiment at 3 pg/m3) add much uncer-
tainty to the estimate The Rabinowitz study controlled well for diet and other factors and,
since they used stable lead isotope tracers, they had no baseline problem. However, the
actual air lead exposure of these subjects outside the metabolic ward was not well determined
Among population studies, only the Azar study provides a slope estimate in which indivi-
dual air lead exposures are known. However, there was no control of dietary lead intake or
other factors that affect blood lead levels, and slope estimates assuming only air lead and
location as covariables (1 32 ± 0 38) are not significantly different from the pooled experi-
mental studies.
There are no experimental inhalation studies on adult females or on children. The inha-
lation slope for women should be roughly the same as that for men, assuming proportionally
smaller air intake and blood volume. The assumption of proportional size is less plausible
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TABLE 1-13. SUMMARY OF BLOOD INHALATION SLOPES (p)
pg/dl per Mg/m3
Study Model Sensitivity*
Population Study Type N Slope of Slope
Children
Angle and Mclntire
(1979) Omaha, NE
Population
1074
1.92
(1.40-4.40)1'2,3
Roels et al. (1980)
Belgium
Population
148
2.46
(1.55-2 46)1,2
Yankel et al. (1977);
Walter et al. (1980)
Idaho
Population
879
1.52
(1.07-1.52)1'2,3
Adul t
Male
Azar et al. (1975).
Five groups
Population
149
1.32
(1.08-1.59)2,3
Griffin et al.
(1975) NY
prisoners
Experiment
43
1.75
(1.52-3.38)4
Gross
(1979)
Experiment
6
1.25
(1.25-1.55)2
Rabinowitz et al.
(1973, 1976, 1977)
Experiment
5
2.14
(2.14-3.51)5
^Selected from among the most plausible statistically equivalent models. For nonlinear
models, slope at 1.0 ^jg/m3.
^Sensi tive
to
choice of other correlated predictors such as dust and soil lead
2Sensitive
to
linear vs. nonlinear at low air lead.
^Sensitive
to
age as a covariate.
4Sensi tive
to
baseline changes in controls.
^Sensitive
to
assumed air lead exposure.
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for children. Slope estimates for children from population studies are used in which some
other important covanates of lead absorption were controlled or measured, e.g. , age, sex,
dust exposure in the environment or on the hands. Inhalation slopes were estimated for the
studies of Angle and Mclntire (1979) [1.92 ± 0.60], Roels et al. (1980) [2.46 ± 0.58], and
Yankel et al. (1977) [1.53 ± 0.064)]. The standard error of the Yankel study is extremely low
and a weighted pooled slope estimate for children would reflect essentially that study alone
In this case the small standard error estimate is attributable to the very large range of air
lead exposures of children in the Silver Valley (up to 22 (jg/m3). The relationship is in fact
not linear, but increases more rapidly in the upper range of air lead exposures. The slope
estimate at lower air lead concentrations may not wholly reflect uncertainty about the shape
of the curve at higher concentrations. The median slope of the three studies is 1.92 pg/dl
per |jg/m3.
Chapter 11 evaluates the effects of atmospheric lead on blood lead in a disaggregate
manner broken down according to exposure media, including direct inhalation of atmospheric
lead, ingestion of particulate lead that has fallen out as dust and surface soil, and air lead
ingested in consuming food and beverages (including lead absorbed from soil and added during
processing and preparation). Disaggregate analyses based on various pathways for environmen-
tal lead of the type presented appear to provide a sensitive tool for predicting blood lead
burdens under changes of environmental exposure. However, some authors, e.g. , Brunekreef
(1984) make a strong argument for the use of air lead as the single exposure criterion. Their
argument is that exposure to air lead is usually of sufficient duration that the contributions
along other pathways have stabilized and are proportional to the air lead concentration. In
that case, the ratio between blood lead and air lead plus dust, food, and other proportional
increments must be much larger than for air lead by direct inhalation alone.
The range of p values that Brunekreef (1984) reports is very large, and typical values of
3-5 are larger than those adjusted slopes (1.52-2.46) derived by EPA in preceding sections.
If the aggregate approach is accepted, then the blood lead vs. total (both direct and indir-
ect) air lead slope for children may be approximately double the slope (-2.0) estimated for
the direct contribution due to inhaled air lead alone.
To summarize the situation briefly: (1) The experimental studies at lower air lead
levels (3.2 pg/m3 or less) and lower blood levels (typically 30 |jg/dl or less) have linear
blood lead inhalation relationships with slopes P1 of 0-3.6 for most subjects. A typical
value of 1.64 ± 0.22 may be assumed for adults. (2) Population cross-sectional studies at
lower air lead and blood lead levels are approximately linear with slopes p of 0 8-2.0. (3)
Cross-sectional studies in occupational exposure situations in which air lead levels are
higher (much above 10 pg/m3) and blood lead levels are higher (above 40 pg/dl) show a much
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more shallow linear blood lead inhalation relation. The slope p is in the range of 0.03-0.2.
(4) Cross-sectional and experimental studies at levels of air lead somewhat above the higher
ambient exposures (9-36 pg/m3) and blood leads of 30-40 pg/dl can be described either by a
nonlinear relationship with decreasing slope or by a linear relationship with intermediate
slope, approximately p = 0.5. Several biological mechanisms for these differences have been
discussed (Hammond et al., 1981; O'Flaherty et al. , 1982; Chamberlain, 1983; Chamberlain and
Heard, 1981). Since no explanation for the decrease in steepness of the blood lead inhalation
response to higher air lead levels has been generally accepted at this time, there is little
basis on which to select a formula for interpolating from low air lead to high air lead expo-
sures. The increased steepness of the inhalation curve for the Kellogg/Silver Valley study is
inconsistent with the other studies presented. It may be that smelter situations are unique
and must be analyzed differently, or it may be that the curvatuve is the result of imprecise
exposure estimates. (5) The blood-lead inhalation slope for children is at least as steep as
that for adults, with a median estimate of 1.92 from three major studies. These slope esti-
mates are based on the assumption that an equilibrium level of blood lead is achieved within a
few months after exposure begins. This is only approximately true, since lead stored in the
skeleton may return to blood after some years. Chamberlain et al. (1978) suggest that long
term inhalation slopes should be about 30 percent larger than these estimates. Inhalation
slopes quoted here are associated with a half-life of blood lead in adults of about 30 days.
O'Flaherty et al. (1982) suggest that the blood-lead half-life may increase slightly with
duration of exposure, but this has not been confirmed (Kang et al. , 1983). (6) Slopes which
include both direct (inhalation) and indirect (via soil, dust, etc.) air lead contributions
are necessarily higher than those estimates for inhaled air lead alone. Studies using aggre-
gate analyses (direct and indirect air impacts) typically yield slope values in the range 3-5,
about double the slope due to inhaled air lead alone.
Other studies, reviews, and analyses of the study are discussed in Section 11.4, to which
the reader is referred for a detailed discussion and for a review of the key studies and their
analyses.
It must not be assumed that the direct inhalation of air lead is the only air lead con-
tribution that needs to be considered. Smelter studies allow partial assessment of the air
lead contributions to soil, dust, and finger lead. Useful ecological models to study the pos-
sible propagation of lead through the food chain have not yet been developed. The direct in-
halation relationship does provide useful information on changes in blood lead as responses to
changes in air lead on a time scale of several months. The indirect pathways through dust,
soil, and the food chain may thus delay the total blood lead response to changes in air lead,
perhaps by one or more years.
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1 11.5 Studies Relating Dietary Lead Exposures (Including Water) to Blood Lead
Dietary absorption of lead varies greatly from one person to another and depends on the
physical and chemical form of the carrier, on nutritional status, and on whether lead is in-
gested with food or between meals. These distinctions are particularly important for consump-
tion of leaded paint, dust, and soil by children. Typical values of 10 percent absorption of
ingested lead into blood have been assumed for adults and 25-50 percent for children.
It is difficult to obtain accurate dose-response relationships between blood lead levels
and lead level in food or water. Dietary intake must be estimated by duplicate diets or fecal
lead determinations. Water lead levels can be determined with some accuracy, but the varying
amounts of water consumed by different individuals adds to the uncertainty of the estimated
relationships
Quantitative analyses relating blood lead levels and dietary lead exposures have been re-
ported. Studies on infants provide estimates that are in close agreement. Only one indivi-
dual study is available for adults, another estimate from a number of pooled studies is also
available. These two estimates are in good agreement. Most of the subjects in the Sherlock
et al. (1982) and United Kingdom Central Directorate on Environmental Pollution (1982) studies
received quite high dietary lead levels (>300 (jg/day). The fitted cube root equations give
high slopes at lower dietary lead levels. On the other hand, the linear slope of the United
Kingdom Central Directorate on Environmental Pollution (1982) study is probably an underesti-
mate of the slope at lower dietary lead levels. Most of the dietary intake supplements used
in these two studies were so high that many of the subjects had blood lead concentrations much
in excess of 30 pg/dl for a considerable part of the experiment. Blood lead levels thus may
not completely reflect lead exposure, due to the previously noted nonlinearity of blood lead
response at high exposures. For these reasons, the Ryu et al. (1983) study is the most
believable, although it only applies to infants.
The slope estimates for adult dietary intake are an approximately 0.02 (jg/dl increase in
blood lead per pg/d intake, but consideration of blood lead kinetics may increase this value
to about 0.04 (jg/dl per fjg/d intake. Such values are somewhat lower (about 0.05 pg/d 1 per
pg/d) than those estimated from population studies extrapolated to typical dietary intakes,
the value estimated for infants is much larger (0.16). Estimates for adults should be taken
from the experimental studies or calculated from assumed absorption and half-life values
The relationship between blood lead and water lead is not clearly defined and is often
described as nonlinear. Water lead intake varies greatly from one person to another It has
been assumed that children can absorb 25-50 percent of lead in water. Many authors chose to
fit cube root models to their data, although polynomial and logarithmic models were also used.
Unfortunately, the form of the model greatly influences the estimated contributions to blood
lead levels from relatively low water lead concentrations.
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Although there is close agreement in quantitative analyses of relationships between blood
lead levels and dietary lead concentrations, there is a larger degree of variability in
results of the various water lead studies. The relationship is curvilinear but its exact form
is yet to be determined. At typical levels for U.S. populations, the relationship appears to
be linear. The only study that determines the relationship based on lower water lead values
(<100 pg/1) is the Pocock et al. (1983) study. The data from this study, as well as the
authors themselves, suggest that the relationship is linear for this lower range of water lead
levels. Furthermore, the estimated contributions to blood lead levels from this study are
quite consistent with the polynomial models from other studies. For these reasons, the Pocock
et al (1983) slope of 0.06 is considered to represent the best estimate. The possibility
still exists, however, that the higher estimates of the other studies may be correct in cer-
tain situations, especially at higher water lead levels (>100 pg/1).
1.11.6 Studies Relating Lead in Soil and Dust to Blood Lead
The relationship of exposure to lead contained in soil and house dust and the amount of
lead absorbed by humans, particularly children, has been the subject of a number of scientific
investigations. Some of these studies have been concerned with the effects of exposures
resulting from the ingestion of lead in dust (Duggan and Williams, 1977; Barltrop, 1975;
Creason et al., 1975); others have concentrated on the means by which the lead in soil and
dust becomes available to the body (Sayre et al., 1974). Sayre et al. (1974) demonstrated the
feasibility of house dust as a source of lead for children in Rochester, NY. Two groups of
houses, one inner city and the other suburban, were chosen for the study. Lead-free sanitary
paper towels were used to collect dust samples from house surfaces and the hands of children
(Vostal et al., 1974). The medians for the hand and household samples were used as the cut-
points in the chi-square contingency analysis. A statistically significant difference between
the urban and suburban homes for dust levels was noted, as was a relationship between house-
hold dust levels and hand dust levels (Lepow et al., 1975).
Studies relating soil lead to blood lead levels are difficult to compare. The relation-
ship obviously depends on depth of soil lead, age of the children, sampling method, cleanli-
ness of the home, mouthing activities of the children, and possibly many other factors. Vari-
ous soil sampling methods and sampling depths have been used over time; as such they may not
be directly comparable and may produce a dilution effect of the major lead concentration con-
tribution from dust, which is located primarily in the top 2 cm of the soil.
Increases in soil lead significantly increase blood lead in children. From several
studies EPA estimates an increase of 0.6-6.8 pg/dl in blood lead for each increase of 1000
pg/g in soil lead concentration. The values from the Stark et al. (1982) study may represent
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a reasonable median estimate, i.e., about 2.0 pg/dl for each 1000 jjg/g increase in soil lead.
Household dust also increases blood lead, children from the cleanest homes in the Kellogg/
Silver Valley Study had 6 pg/dl less lead in blood, on average, than those from the households
with the most dust.
1.11.7 Additional Exposures
A major source of environmental lead exposure for many members of the general population
comes from lead contained in both interior and exterior paint on dwellings. The amount of
lead present, as well as its accessibility, depends upon the age of the residence (because
older buildings contain paint manufactured before lead content was regulated) and the physical
condition of the paint. In a survey of lead levels in 2370 randomly selected dwellings in
Pittsburgh, PA (Shier and Hall, 1977), paint with high levels of lead were most frequently
found in pre-1940 residences. One cannot assume, however, that high level lead paint is
absent in dwellings built after 1940. In the case of the houses surveyed in Pittsburgh, about
20 percent of the residences built after 1960 have at least one surface with more than 1.5
mg/cm2 lead. In fiscal year 1981, the U.S. Centers for Disease Control (1982), screened
535,730 children and found 21,897 with lead toxicity. Of these cases, 15,472 dwellings were
inspected and 10,666 (approximately 67 percent) were found to have leaded paint.
A number of specific environmental sources of airborne lead have been identified as
having a direct influence on blood lead levels. Primary lead smelters, secondary lead smel-
ters, and battery plants emit lead directly into the air and ultimately increase soil and dust
lead concentrations in their vicinity. Adults, and especially children, have been shown to
exhibit elevated blood lead levels when living close to these sources. Blood lead levels in
these residents have been shown to be related to air, as well as to soil or dust exposures
The habit of cigarette smoking is a source of lead exposure. Other sources include the
following, lead based cosmetics, lead-based folk remedies, and glazed pottery.
1 12 BIOLOGICAL EFFECTS OF LEAD EXPOSURE
1 12.1 Introduction
Lead has diverse biological effects in humans and animals. Its effects are seen at the
subcellular level of organellar structures and processes as well as at the overall level of
general functioning that encompasses all systems of the body operating in a coordinated,
interdependent fashion
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This review not only seeks to categorize and describe the various biological effects of
lead but also attempts to identify the exposure levels at which such effects occur and the
mechanisms underlying them. The dose-response curve for the entire range of biological
effects exerted by lead is rather broad, with certain biochemical changes occurring at rela-
tively low levels of exposure and perturbations in other systems, such as the liver, becoming
detectable only at relatively high exposure levels. In terms of relative vulnerability to
deleterious effects of lead, the developing organism generally appears to be more sensitive
than the mature individual.
It should be noted that lead has no known beneficial biological effects. Available evi-
dence does not demonstrate that lead is an essential element
1.12.2 Subcellular Effects of Lead
The biological basis of lead toxicity is its ability to bind to ligating groups in bio-
molecular substances crucial to various physiological functions, thereby interfering with
these functions by, for example, competing with native essential metals for binding sites,
inhibiting enzyme activity, and inhibiting or otherwise altering essential ion transport
These effects are modulated by: 1) the inherent stability of such binding sites for lead; 2)
the compartmentalization kinetics governing lead distribution among body compartments, among
tissues, and within cells; and 3) the differences in biochemical organization across cells and
tissues due to their specific functions. Given the complexities introduced by items 2 and 3,
it is not surprising that no single unifying mechanism of lead toxicity across all tissues in
humans and experimental animals has yet been demonstrated.
Insofar as effects of lead on activity of various enzymes are concerned, many of the
available studies concern i_n vitro behavior of relatively pure enzymes with marginal relevance
to various effects i_n vivo. On the other hand, certain enzymes are basic to the effects of
lead at the organ or organ system level, and discussion is best reserved for such effects in
the summary sections below dealing with lead's effects on particular organ systems. This sec-
tion is mainly concerned with organellar effects of lead, especially those which provide some
rationale for lead toxicity at higher levels of biological organization. Particular emphasis
is placed on the mitochondrion, because this organelle is not only affected by lead in numer-
ous ways but has also provided the most data bearing on the subcellular effects of lead
The critical target organelle for lead toxicity in a variety of cell and tissue types
clearly is the mitochondrion, followed probably by cellular and intracellular membranes The
mitochondrial effects take the form of structural changes and marked disturbances in mitochon-
drial function within the cell, particularly in energy metabolism and ion transport These
effects in turn are associated with demonstrable accumulation of lead in mitochondria, both j_n
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V1 vo an<^ JLO V1tro. Structural changes include mitochondrial swelling in a variety of cell
types as well as distortion and loss of cristae, which occur at relatively moderate lead
levels. Similar changes have also been documented in lead workers across a range of
exposures.
Uncoupled energy metabolism, inhibited cellular respiration using both succinate and
nicotinamide adenine dinucleotide (NAD)-linked substrates, and altered kinetics of intracellu-
lar calcium have been demonstrated jn vivo using mitochondria of brain and non-neural tissues
In some cases, the lead exposure level associated with such changes has been relatively low
Several studies document the relatively greater sensitivity of this organelle in young vs
adult animals in terms of mitochondrial respiration. The cerebellum appears to be particular-
ly sensitive, providing a connection between mitochondrial impairment and lead encephalopathy
Lead s impairment of mitochondrial function in the developing brain has also been consistently
associated with delayed brain development, as indexed by content of various cytochromes. In
the rat pup, ongoing lead exposure from birth is required for this effect to be expressed,
indicating that such exposure must occur before, and is inhibitory to, the burst of oxidative
metabolism activity that occurs in the young rat at 10-21 days postnatally.
Jn vivo lead exposure of adult rats also markedly inhibits calcium turnover in a cellular
compartment of the cerebral cortex that appears to be the mitochondrion. This effect has been
seen at a brain lead level of 0.4 (jg/g. These results are consistent with a separate study
showing increased retention of calcium in the brain of lead-dosed guinea pigs. Numerous re-
ports have described the j_n vi vo accumulation of lead in mitochondria of kidney, liver,
spleen, and brain tissue, with one study showing that such uptake was slightly more than
occurred in the cell nucleus. These data are not only consistent with deleterious effects of
lead on mitochondria but are also supported by other investigations i_n vi tro Significant
decreases in mitochondrial respiration vi tro using both NAD-linked and succinate substrates
have been observed for brain and non-neural tissue mitochondria in the presence of lead at
micromolar levels. There appears to be substrate specificity in the inhibition of respiration
across different tissues, which may be a factor in differential organ toxicity. Also, a
number of enzymes involved in intermediary metabolism in isolated mitochondria have been
observed to undergo significant inhibition of activity with lead.
Of particular interest regarding lead's effects on isolated mitochondria are ion trans-
port effects, especially in regard to calcium Lead movement into brain and other tissue
mitochondria involves active transport, as does calcium. Recent sophisticated kinetic
analyses of desaturation curves for radiolabeled lead or calcium indicate that there is
striking overlap in the cellular metabolism of calcium and lead. These studies not only
establish the basis for the easy entry of lead into cells and cell compartments, but also pro-
vide a basis for lead's impairment of intracellular ion transport, particularly in neural cell
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mitochondria, where the capacity for calcium transport is 20-fold higher than even in heart
mitochondria.
Lead is also selectively taken up in isolated mitochondria i_n vitro, including the mito-
chondria of synaptosomes and brain capillaries. Given the diverse and extensive evidence of
lead's impairment of mitochondrial structure and function as viewed from a subcellular level,
it is not surprising that these derangements are logically held to be the basis of dysfunction
of heme biosynthesis, erythropoiesis, and the central nervous system. Several key enzymes in
the heme biosynthetic pathway are intramitochondrial, particularly ferrochelatase Hence, it
is to be expected that entry of lead into mitochondria will impair overall heme biosynthesis,
and in fact this appears to be the case in the developing cerebellum. Furthermore, rela-
tively moderate levels of lead may be associated with its entry into mitochondria and conse-
quent expressions of mitochondrial injury.
Lead exposure provokes a typical cellular reaction in humans and other species that has
been morphologically characterized as a lead-containing nuclear inclusion body. While it has
been postulated that such inclusions constitute a cellular protection mechanism, such a
mechanism is an imperfect one. Other organelles, e.g., the mitochondrion, also take up lead
and sustain injury in the presence of nuclear inclusion formations.
In theory, the cell membrane is the first organelle to encounter lead and it is not
surprising that cellular effects of lead can be ascribed to interactions at cellular and
intracellular membranes in the form of disturbed ion transport. The inhibition of membrane
(Na ,K )-ATPase of erythrocytes as a factor in lead-impaired erythropoiesis is noted in
Section 1.12.3. Lead also appears to interfere with the normal processes of calcium transport
across membranes of different tissues. In peripheral cholinergic synaptosomes, lead is
associated with retarded release of acetylcholine owing to a blockade of calcium binding to
the membrane, while calcium accumulation within nerve endings can be ascribed to inhibition of
membrane (Na+,K+)-ATPase.
Lysosomes accumulate in renal proximal convoluted tubule cells of rats and rabbits given
lead over a range of dosing. This also appears to occur in the kidneys of lead workers and
seems to represent a disturbance in normal lysosomal function, with the accumulation of lyso-
somes being due to enhanced degradation of proteins because of the effects of lead elsewhere
within the cell.
1.12.3 Effects of Lead on Heme Biosynthesis, Erythropoiesis, and Erythrocyte Physiology in
Humans and Animals
The effects of lead on heme biosynthesis are well known because of their clinical promi-
nence and the numerous studies of such effects in humans and experimental animals The
process of heme biosynthesis starts with glycine and succinyl-coenzyme A, proceeds through
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formation of protoporphyrin IX, and culminates with the insertion of divalent iron into the
porphyrin ring to form heme. In addition to being a constituent of hemoglobin, heme is the
prosthetic group of many tissue hemoproteins having variable functions, such as myoglobin, the
P-450 component of the mixed-function oxygenase system, and the cytochromes of cellular
energetics. Hence, disturbance of heme biosynthesis by lead poses the potential for multiple-
organ toxicity
In investigations of lead's effects on the heme synthesis pathway (Figure 1-20), most
attention has been devoted to (1) stimulation of mitochondrial delta-aminolevullnic acid
synthetase (ALA-S), which mediates formation of delta-aminolevulinic acid (ALA); (2) direct
inhibition of the cytosolic enzyme, delta-aminolevulinic acid dehydrase (ALA-D >, wh\ch
catalyzes formation of porphobilinogen from two units of ALA; and (3) inhibition of insertion
of iron (II) into protoporphyrin IX to form heme, a process mediated by ferrochelatase.
MITOCHONDRIAL MEMBRANE
MITOCHONDRION
HEME
GLYCINE
+
SUCCINYL-CoA
FERRO
CHELATASE
If
Pb
V
Fe - PROTOPORPHYRIN
d-ALA SYNTHETASE
(INCREASE)
^ Pb (DIRECTLY OR BY
DEREPRESSION!
t
t
l i
d-ALA
d-ALA
DEHYDRASE
(DECREASE)
r-pb
COPROPORPHYRIN
(INCREASE)
Pb
PORPHOBILINOGEN (PBG)
Figure 1-20. Lead effects on heme biosynthesis.
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Increased ALA-S activity has been found in lead workers as well as in lead-exposed ani-
mals, although an actual decrease in enzyme activity has also been observed in several experi-
mental studies using different exposure methods. It appears, then, that the effect on ALA-S
activity may depend on the nature of the exposure. Using rat liver cells in culture, ALA-S
activity was stimulated i_n vitro at levels as low as 5.0 pM or 1.0 pg Pb/g preparation. The
increased activity was due to biosynthesis of more enzyme. The blood lead threshold for sti-
mulation of ALA-S activity in humans, based on a study using leukocytes from lead workers,
appears to be about 40 pg Pb/dl. Whether this apparent threshold applies to other tissues
depends on how well the sensitivity of leukocyte mitochondria mirrors that in other systems.
The relative impact of ALA-S activity stimulation on ALA accumulation at lower lead exposure
levels appears to be much less than the effect of ALA-D activity inhibition. ALA-D activity
is significantly depressed at 40 pg/dl blood lead, the point at which ALA-S activity only
begins to be affected.
*
Erythrocyte ALA-D activity is very sensitive to inhibition by lead. This inhibition is
reversed by reactivation of the sulfhydryl group with agents such as dithiothreitol, zinc, or
zinc and glutathione. Zinc levels that achieve reactivation, however, are well above physio-
logical levels. Although zinc appears to offset the inhibitory effects of lead observed in
animal studies and in human erythrocytes |n vitro, lead workers exposed to both zinc and lead
do not show significant changes in the relationship of ALA-D activity to blood lead when com-
pared with workers exposed just to lead. Nor does the range of physiological zinc levels in
nonexposed subjects affect ALA-D activity. In contrast, zinc deficiency in animals signifi-
cantly inhibits ALA-D activity, with concomitant accumulation of ALA in urine. Because zinc
deficiency has also been demonstrated to increase lead absorption, the possibility exists for
the following dual effects of such deficiency on ALA-D activity: (1) a direct effect on acti-
vity due to reduced zinc availability; and (2) increased lead absorption leading to further
inhibition of activity.
Erythrocyte ALA-D activity appears to be inhibited at virtually all blood lead levels
measured so far, and any threshold for this effect in either adults or children remains to be
determined. A further measure of this enzyme's sensitivity to lead is a report that rat bone
marrow suspensions show inhibition of ALA-D activity by lead at a level of 0.1 pg/g suspen-
sion. Inhibition of ALA-D activity in erythrocytes apparently reflects a similar effect in
other tissues. Hepatic ALA-D activity in lead workers was inversely correlated with erythro-
cyte activity as well as blood lead levels. Of significance are experimental animal data
showing that (1) brain ALA-D activity is inhibited with lead exposure, and (2) this inhibition
appears to occur to a greater extent in developing animals than in adults, presumably reflec-
ting greater retention of lead in developing animals. In the avian brain, cerebellar ALA-D
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activity is affected to a greater extent than that of the cerebrum and, relative to lead con-
centration, shows inhibition approaching that occurring in erythrocytes.
Inhibition of ALA-D activity by lead is reflected by elevated levels of its substrate,
ALA, in blood, urine, and soft tissues. Urinary ALA is employed extensively as an indicator
of excessive lead exposure in lead workers. The diagnostic value of this measurement in pedi-
atric screening, however, is limited when only spot urine collection is done; more satisfac-
tory data are obtainable with 24-hr collections. Numerous independent studies document a
direct correlation between blood lead and the logarithm of urinary ALA in human adults and
children; the blood lead threshold for increases in urinary ALA is commonly accepted as 40
(jg/dl. However, several studies of lead workers indicate that the correlation between urinary
ALA and blood lead continues below this value, one study found that the slope of the dose-
effect curve in lead workers depends on the level of exposure.
The health significance of lead-inhibited ALA-D activity and accumulation of ALA at lower
lead exposure levels is controversial. The "reserve capacity" of ALA-D activity is such that
only the level of inhibition associated with marked accumulation of the enzyme's substrate,
ALA, in accessible indicator media may be significant. However, it is not possible to quan-
tify at lower levels of lead exposure the relationship of urinary ALA to target tissue levels
nor to relate the potential neurotoxicity of ALA at any accumulation level to levels in indi-
cator media. Thus, the blood lead threshold for neurotoxicity of ALA may be different from
that associated with increased urinary excretion of ALA.
Accumulation of protoporphyrin in erythrocytes of lead-intoxicated individuals has been
recognized since the 1930s, but it has only recently been possible to quantitatively assess
the nature of this effect via development of sensitive, specific microanalysis methods. Accu-
mulation of protoporphyrin IX in erythrocytes results from impaired placement of iron (II) in
the porphyrin moiety in heme formation, an intramitochondrial process mediated by ferrochela-
tase. In lead exposure, the porphyrin acquires a zinc ion in lieu of native iron, thus form-
ing ZPP, which is tightly bound in available heme pockets for the life of the erythrocytes.
This tight sequestration contrasts with the relatively mobile nonmetal, or free, erythrocyte
protoporphyrin (FEP) accumulated in the congenital disorder erythropoietic protoporphyria.
Elevation of erythrocyte ZPP has been extensively documented as exponentially correlated
with blood lead in children and adult lead workers and is presently considered one of the best
indicators of undue lead exposure. Accumulation of ZPP only occurs in erythrocytes formed
during lead's presence in erythroid tissue; this results in a lag of at least several weeks
before its buildup can be measured. The level of ZPP accumulation in erythrocytes of newly
employed lead workers continues to increase after blood lead has already reached a plateau
This influences the relative correlation of ZPP and blood lead in workers with short exposure
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histories. Also, the ZPP level in blood declines much more slowly than blood lead, even after
removal from exposure or after a drop in blood lead. Hence, ZPP level appears to be a more
reliable indicator of continuing intoxication from lead resorbed from bone.
The threshold for detection of lead-induced ZPP accumulation is affected by the relative
spread of blood lead and corresponding ZPP values measured. In young children (<4 yr old),
the ZPP elevation associated with iron-deficiency anemia must also be considered. In adults,
numerous studies indicate that the blood lead threshold for ZPP elevation is about 25-30
pg/dl. In children 10-15 years old, the threshold is about 16 jjg/d1; for this age group, iron
deficiency is not a factor. In one study, children over 4 years old showed the same thresh-
old, 15.5 pg/dl, as a second group under 4 years old, indicating that iron deficiency was not
a factor in the study At 25 pg/dl blood lead, 50 percent of the children had significantly
elevated FEP levels (2 standard deviations above the reference mean FEP).
At blood lead levels below 30-40 pg/dl, any assessment of the EP-blood lead relationship
is strongly influenced by the relative analytical proficiency of measurements of both blood
lead and EP. The types of statistical analyses used are also important. In a recent detailed
statistical study involving 2004 children, 1852 of whom had blood lead values below 30 jjg/dl,
segmental line and probit analysis techniques were employed to assess the dose-effect thres-
hold and dose-response relationship. An average blood lead threshold for the effect using
both statistical techniques was 16.5 pg/dl for the full group and for those subjects with
blood lead below 30 pg/dl. The effect of iron deficiency was tested for and removed. Of par-
ticular interest was the finding that blood lead values of 28.6 and 35.7 pg/dl corresponded to
EP elevations more than 1 or 2 standard deviations, respectively, above the reference mean in
50 percent of the children. Hence, fully half of the children had significant elevations of
EP at blood lead levels around 30 pg/dl, the currently accepted cut-off value for undue lead
exposure. From various reports, children and adult females appear to be more sensitive to
lead's effects on EP accumulation at any given blood lead level; children are somewhat more
sensitive than adult females.
Lead's effects on heme formation are not restricted to the erythropoietic system. Recent
studies show that the reduction of serum 1,25-dihydroxyvitamin D seen with even low-level lead
exposure is apparently the result of lead-induced inhibition of the activity of renal
1-hydroxylase, a cytochrome P-450 mediated enzyme. Reduction in activity of the hepatic
enzyme tryptophan pyrrolase and concomitant increases in plasma tryptophan as well as brain
tryptophan, serotonin, and hydroxyindoleacetic acid have been shown to be associated with
lead-induced reduction of the hepatic heme pool. The heme-containing protein cytochrome P-450
(an integral part of the hepatic mixed-function oxygenase system) is affected in humans and
animals by lead exposure, especially acute intoxication. Reduced P-450 content correlates
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with impaired activity of detoxifying enzyme systems such as aniline hydroxylase and aminopy-
rine demethylase. It is also responsible for reduced 60-hydroxylation of Cortisol in children
having moderate lead exposure.
Studies of organotypic chick and mouse dorsal root ganglion in culture show that the ner-
vous system not only has heme biosynthetic capability, but such preparations elaborate porphy-
rinic material in the presence of lead. In the neonatal rat, chronic lead exposure resulting
in moderately elevated blood lead is associated with retarded increases in the hemoprotein
cytochrome C and with disturbed electron transport in the developing cerebral cortex. These
data parallel effects of lead on ALA-D activity and ALA accumulation in neural tissue. When
both of these effects are viewed in the toxicokinetic context of increased retention of lead
in both developing animals and children, there is an obvious and serious potential for im-
paired heme-based metabolic function in the nervous system of lead-exposed children.
As can be concluded from the above discussion, the health significance of ZPP accumula-
tion rests with the fact that it is evidence of impaired heme and hemoprotein formation in
many tissues that arises from entry of lead into mitochondria. Such evidence for reduced heme
synthesis is consistent with many data documenting lead-associated effects on mitochondria.
The relative value of the lead-ZPP relationship in erythropoietic tissue as an index of this
effect in other tissues hinges on the relative sensitivity of the erythropoietic system com-
pared with other organ systems. One study of rats exposed over their lifetime to low levels
of lead demonstrated that protoporphyrin accumulation in renal tissue was already significant
at levels of lead exposure which produced little change in erythrocyte porphyrin levels
Other steps in the heme biosynthesis pathway are also known to be affected by lead, al-
though these have not been as well studied on a biochemical or molecular level. Coproporphy-
ria levels are increased in urine, reflecting active lead intoxication. Lead also affects the
activity of the enzyme uroporphyrinogen-I-synthetase in experimental animal systems, resulting
in an accumulation of its substrate, porphobilinogen. The erythrocyte enzyme has been report-
ed to be much more sensitive to lead than the hepatic species, presumably accounting for much
of the accumulated substrate. Unlike the case with experimental animals, lead-exposed humans
show no rise in urinary porphobilinogen, which is a differentiating characteristic of lead
intoxication versus the hepatic porphyrias. Ferrochelatase is an intramitochondrial enzyme,
and impairment of its activity either directly by lead or via impairment of iron transport to
the enzyme is evidence of the presence of lead in mitochondria.
Anemia is a manifestation of chronic lead intoxication and is characterized as mildly
hypochromic and usually normocytic. It is associated with reticulocytosis, owing to shortened
cell survival, and the variable presence of basophilic stippling. Its occurrence is due to
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both decreased production and increased rate of destruction of erythrocytes. In young chil-
dren (<4 yr old), iron deficiency anemia is exacerbated by lead uptake, and vice versa. Hemo-
globin production is negatively correlated with blood lead in young children, in whom iron
deficiency may be a confounding factor, as well as in lead workers. In one study, blood lead
values that were usually below 80 ng/dl were inversely correlated with hemoglobin content. In
these subjects no iron deficiency was found. The blood lead threshold for reduced hemoglobin
content is about 50 jjg/dl in adults and somewhat lower (~40 pg/dl) in children.
The mechanism of lead-associated anemia appears to be a combination of reduced hemoglobin
production and shortened erythrocyte survival due to direct cell injury. Lead's effects on
hemoglobin production involve disturbances of both heme and globin biosynthesis. The hemoly-
tic component to lead-induced anemia appears to be caused by increased cell fragility and in-
creased osmotic resistance. In one study using rats, the hemolysis associated with vitamin E
deficiency, via reduced cell deformability, was exacerbated by lead exposure. The molecular
basis for increased cell destruction rests with inhibition of (Na , K )-ATPase and pyrimi-
dine-51-nucleotidase. Inhibition of the former enzyme leads to cell "shrinkage" and inhibi-
tion of the latter results in impaired pyrimidine nucleotide phosphorolysis and disturbance of
the activity of the purine nucleotides necessary for cellular energetics.
In lead intoxication, the presence of both basophilic stippling and anemia with a hemo-
lytic component is due to inhibition by lead of the activity of pyrimidine-5'-nucleotidase
(Py-5-N), an enzyme that mediates the dephosphorylation of pyrimidine nucleotides in the
maturing erythrocyte. Inhibition of this enzyme by lead has been documented in lead workers,
lead-exposed children, and experimental animal models. In one study of lead-exposed children,
there was a negative correlation between blood lead and enzyme activity, with no clear
response threshold. A related report noted that, in addition, there was a positive correlation
between cytidine phosphate and blood lead and an inverse correlation between pyrimidine
nucleotide and enzyme activity.
The metabolic significance of Py-5-N inhibition and cell nucleotide accumulation is that
they affect erythrocyte stability and survival as well as potentially affect mRNA and protein
synthesis related to globin chain synthesis.
Based on one study of children, the threshold for the inhibition of Py-5-N activity
appears to be about 10 pg/dl blood lead. Lead's inhibition of Py-5-N activity and a threshold
for such inhibition are not by themselves the issue. Rather, the issue is the relationship of
such inhibition to a significant level of impaired pyrimidine nucleotide metabolism and the
consequences for erythrocyte stability and function. The relationship of Py-5-N activity
inhibition by lead to accumulation of its pyrimidine nucleotide substrate is analogous to
lead's inhibition of ALA-D activity and accumulation of ALA.
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Tetraethyl lead and tetramethyl lead, components of leaded gasoline, undergo transforma-
tion u] vivo to neurotoxic trialkyl metabolites as well as further conversion to inorganic
lead. Hence, one might anticipate that exposure to such agents may result in effects commonly
associated with inorganic lead, particularly in terms of heme synthesis and erythropoiesis.
Various surveys and case reports show that the habit of sniffing leaded gasoline is associated
with chronic lead intoxication in children from socially deprived backgrounds in rural or
remote areas. Notable in these subjects is evidence of impaired heme biosynthesis, as indexed
by significantly reduced ALA-D activity. In several case reports of frank lead toxicity from
habitual leaded gasoline sniffing, effects such as basophilic stippling in erythrocytes and
significantly reduced hemoglobin have also been noted.
The role of lead-associated disturbances of heme biosynthesis as a possible factor in
neurological effects of lead is of considerable interest due to: (1) similarities between
classical signs of lead neurotoxicity and several neurological components of the congenital
disorder acute intermittent porphyria; and (2) some of the unusual aspects of lead neuro-
toxicity. There are three possible points of connection between lead's effects on heme
biosynthesis and the nervous system. Associated with both lead neurotoxicity and acute inter-
mittent porphyria is the common feature of excessive systemic accumulation and excretion of
ALA. In addition, lead neurotoxicity reflects, to some degree, impaired synthesis of heme and
hemoproteins involved in crucial cellular functions; such an effect on heme is now known to be
relevant within neural tissue as well as in non-neural tissue.
Available information indicates that ALA levels are elevated in the brains of lead-
exposed animals and arise through ui situ inhibition of brain ALA-D activity or through trans-
port of ALA to the brain after formation in other tissues. ALA is known to traverse the
blood-brain barrier. Hence, ALA is accessible to, or formed within, the brain during lead
exposure and may express its neurotoxic potential.
Based on various i_n vitro and i_n vivo neurochemical studies of lead neurotoxicity, it
appears that ALA can inhibit release of the neurotransmitter gamma-aminobutyric acid (GABA)
from presynaptic receptors at which ALA appears to be very potent even at low levels. In an
i_n vitro study, ALA acted as an agonist at levels as low as 1.0 jjM ALA. This ui vitro obser-
vation supports results of a study using lead-exposed rats in which there was inhibition of
both resting and K -stimulated release of preloaded 3H-GABA from nerve terminals. The obser-
vation that iji vivo effects of lead on neurotransmitter function cannot be duplicated with i_n
V1^ro preparations containing added lead is further evidence of an effect of some agent (other
than lead) that acts directly on this function. Human data on lead-induced associations
between disturbed heme synthesis and neurotoxicity, while limited, also suggest that ALA may
function as a neurotoxicant.
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A number of studies strongly suggest that lead-impaired heme production itself may be a
factor in the toxicant's neurotoxicity. In porphyric rats, lead inhibits tryptophan pyrrolase
activity owing to reductions in the hepatic heme pool, thereby leading to elevated levels of
tryptophan and serotonin in the brain. Such elevations are known to induce many of the neuro-
toxic effects also seen with lead exposure. Of great interest is the fact that heme infusion
in these animals reduces brain levels of these substances and also restores enzyme activity
and the hepatic heme pool. Another line of evidence for the heme-basis of lead neurotoxicity
is that mouse dorsal root ganglion in culture manifests morphological evidence of neural
injury with rather low lead exposure, but such changes are largely prevented with co-
administration of heme. Finally, studies also show that heme-requiring cytochrome C produc-
tion is impaired along with operation of the cytochrome C respiratory chain in the brain when
neonate rats are exposed to lead.
There has recently been a growing awareness of the interactions of lead and the vitamin
O-endocrine system. A recent study has found that children with blood lead levels of 33-120
|jg/dl showed significant reductions in serum levels of the hormonal metabolite 1,25-dihydroxy-
vitamin D (1,25-(0H)2D). This inverse dose-response relationship was found throughout the
range of measured blood lead values, 12-120 pg/dl, and appeared to be the result of lead's
effect on the production of the vitamin D hormone. The 1,25-(0H)2D levels of children with
blood lead levels of 33-55 pg/dl corresponded to the levels that have been observed in chil-
dren with severe renal dysfunction. At higher blood lead levels (>62 jjg/dl), the 1,25-(0H)2D
values were similar to those that have been measured in children with various inborn metabolic
disorders. Chelation therapy of the lead-poisoned children (blood lead levels >62 jjg/dl) re-
sulted in a return to normal 1,25-(0H)2D levels within a short period.
In addition to its well known actions on bone remodeling and intestinal absorption of
minerals, the vitamin D hormone has several other physiological actions at the cellular level.
These include cellular calcium homeostasis in virtually all mammalian cells and associated
calcium-mediated processes that are essential for cellular integrity and function. In addi-
tion, the vitamin D hormone has newly recognized functions that involve cell differentiation
and essential immunoregulatory capacity. It is reasonable to conclude, therefore, that
impaired production of 1,25-(0H)2D can have profound and pervasive effects on tissues and
cells of diverse type and function throughout the body.
1.12.4 Neurotoxic Effects of Lead
An assessment of the impact of lead on human and animal neurobehavioral function raises a
number of issues. Among the key points addressed here are: (1) the internal exposure levels,
as indexed by blood lead levels, at which various neurotoxic effects occur; (2) the persis-
tence or reversibility of such effects; and (3) populations that appear to be most susceptible
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to neural damage. In addition, the question arises as to the utility of using animal studies
to draw parallels to the human condition.
Internal Lead Levels at which Neurotoxic Effects Occur Markedly elevated blood lead
levels are associated with the most serious neurotoxic effects of lead exposure (including
severe, irreversible brain damage as indexed by the occurrence of acute or chronic encephalo-
pathic symptoms, or both) in both humans and animals. For most adult humans, such damage
typically does not occur until blood lead levels exceed 120 (jg/dl. Evidence does exist, how-
ever, for acute encephalopathy and death occurring in some human adults at blood lead as low
as 100 jjg/dl. In children, the effective blood lead level for producing encephalopathy or
death is lower, starting at approximately 80-100 pg/dl. It should be emphasized that, once
encephalopathy occurs, death is not an improbable outcome, regardless of the quality of medi-
cal treatment available at the time of acute crisis. In fact, certain diagnostic or treatment
procedures themselves may exacerbate matters and push the outcome toward fatality if the
nature and severity of the problem are not diagnosed or fully recognized. It is also crucial
to note the rapidity with which acute encephalopathy symptoms can develop or death can occur
in apparently asymptomatic individuals or in those apparently only mildly affected by elevated
lead body burdens. Rapid deterioration often occurs, with convulsions or coma suddenly
appearing with progression to death within 48 hours. This strongly suggests that even in
apparently asymptomatic individuals, rather severe neural damage probably exists at high blood
lead levels even though it is not yet overtly manifested in obvious encephalopathy symptoms.
This conclusion is further supported by numerous studies showing that overtly lead intoxicated
children with high blood lead levels, but not observed to manifest acute encephalopathy symp-
toms, are permanently cognitively impaired, as are most children who survive acute episodes of
frank lead encephalopathy.
Recent studies show that overt signs and symptoms of neurotoxicity (indicative of both
CNS and peripheral nerve dysfunction) are detectable in some human adults at blood lead levels
as low as 40-60 ^ig/dl, levels well below blood lead concentrations previously thought to be
"safe" for adult lead exposures. In addition, certain electrophysiological studies of peri-
pheral nerve function in lead workers, indicate that slowing of nerve conduction velocities in
some peripheral nerves are associated with blood lead levels as low as 30-50 jjg/d 1 (with no
clear threshold for the effect being evident) These results are indicative of neurological
dysfunctions occurring at relatively low lead levels in non-overtly lead intoxicated adults
Other evidence confirms that neural dysfunctions exist in apparently asymptomatic chil-
dren at similar or even lower levels of blood lead. The body of studies on low- or moderate-
level lead effects on neurobehavioral functions in non-overtly lead intoxicated children, as
discussed in Chapter 12, presents an array of data pointing to that conclusion At high
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exposure levels, several studies point toward average 5-point IQ decrements occurring in
asymptomatic children at average blood levels of 50-70 pg/dl Other evidence is indicative of
average IQ decrements of about 4 points being associated with blood levels in a 30-50 jjg/dl
range. Below 30 pg/dl, the evidence for IQ decrements is quite mixed, with most studies show-
ing no significant associations with lead once other confounding factors are controlled.
Still, the 1-2 point differences in IQ seen with blood lead levels mainly in the 15-30 pg/dl
range in some studies are suggestive of possible, very small lead effects that are typically
dwarfed by other socio-hereditary factors. On the other hand, given the weak, highly equivo-
cal evidence for such effects possibly being associated with lead exposures in that blood lead
range (and their already very small size, if due to lead), then it is unlikely that any signi-
ficant relationships between lead and IQ decrements of presumably even smaller or zero magni-
tude would be convincingly detectable at lower blood lead levels, i.e., below 15-30 pg/dl.
The lowest blood lead levels clearly associated with other types of altered behavioral
performance, both in apparently asymptomatic children and in developing rats and monkeys,
generally appear to be in the range of 30-50 pg/dl. However, certain behavioral (e.g ,
reaction-time and reaction-behavior deficits) and electrophysiological (altered EEG patterns,
evoked potentials, and peripheral nerve conduction velocities) effects indicative of CNS and
peripheral nerve functional perturbations have been reported for children at lower blood
levels and are suggestive of a continuous dose-response relationship between lead and neuro-
toxicity down to exposure levels as low as 15-30 pg/dl or, perhaps, somewhat lower.
Timing, type, and duration of exposure are important factors in both animal and human
studies. It is often uncertain whether observed blood lead levels represent the levels that
were responsible for observed behavioral deficits or electrophysiological changes. Monitoring
of lead exposures in pediatric subjects in all cases has been highly intermittent or non-
existent during the period of life preceding neurobehavioral assessment. In most studies of
children, only one or two blood lead values are provided per subject. Tooth lead may be an
important cumulative exposure index, but its modest, highly variable correlation to blood lead
or FEP and to external exposure levels makes findings from*various studies difficult to com-
pare quantitatively. The complexity of the many important covariates and their interaction
with dependent variable measures of modest validity, e.g., IQ tests, may also account for many
of the discrepancies among the different studies.
Early Development and the Susceptibility to Neural Damage. On the question of early
childhood vulnerability, the neurobehavioral data are consistent with morphological and bio-
chemical studies of the susceptibility of the heme biosynthetic pathway to perturbation by
lead. Various lines of evidence suggest that the order of susceptibility to lead's effects
is: (1) young > adults and (2) female > male. Animal studies also have pointed to the peri-
natal period of ontogeny as a particularly critical time for a variety of reasons: (1) it is
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a period of rapid development of the nervous system; (2) it is a period where good nutrition
is particularly critical; and (3) it is a period where the caregiver environment is vital to
normal development. However, the precise boundaries of a critical period are not yet clear
and may vary depending on the species and function or endpoint that is being assessed. Never-
theless, there is general agreement that human infants and toddlers below the age of three
years are at special risk because of i_n utero exposure, increased opportunity for exposure
because of normal mouthing behavior, and increased rates of lead absorption due to various
factors, e.g., nutritional deficiences.
The Question of Irreversibility. Little research on humans is available on persistence
of effects. Some work suggests that mild forms of peripheral neuropathy in lead workers may
be reversible after termination of lead exposure, but little is known regarding the reversi-
bility of lead effects on central nervous system function in humans. A two-year follow-up
study of 28 children of battery factory workers found a continuing relationship between blood
lead levels and altered slow wave voltage of cortical slow wave potentials indicative of per-
sisting CNS effects of lead, and. a five-year follow-up of some of the same children revealed
the presence of altered brain stem auditory evoked potentials. Current population studies,
however, will have to be supplemented by prospective longitudinal studies of the effects of
lead on development in order to address the issue of the reversibility or persistence of the
neurotoxic effects of lead in humans more satisfactorily.
Various animal studies provide evidence that alterations in neurobehavioral function may
be long lived, with such alterations being evident long after blood lead levels have returned
to control levels. These persistent effects have been demonstrated in monkeys as well as rats
under a variety of learning performance test paradigms. Such results are also consistent with
morphological, electrophysiological, and biochemical studies on animals that suggest lasting
changes in synaptogenesis, dendritic development, myelin and fiber tract formation, ionic
mechanisms of neurotransmission, and energy metabolism.
Utility of Animal Studies in Drawing Parallels to the Human Condition. Animal models are
used to shed light on questions where it is impractical or ethically unacceptable to use human
subjects This is particularly true in the case of exposure to environmental toxins such as
lead In the case of lead, it has been effective and convenient to expose developing animals
via their mothers' milk or by gastric gavage, at least until weaning. In many studies, expo-
sure was continued in the water or food for some time beyond weaning. This approach simulates
at least two features commonly found in human exposure: oral intake and exposure during early
development. The preweaning period in rats and mice is of particular relevance in terms of
parallels with the first two years or so of human brain development.
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However, important questions exist concerning the comparability of animal models to
humans. Given differences between humans, rats, and monkeys in heme chemistry, metabolism,
and other aspects of physiology and anatomy, it is difficult to state what constitutes an
equivalent internal exposure level (much less an equivalent external exposure level) For
example, is a blood lead level of 30 pg/dl in a suckling rat equivalent to 30 pg/dl in a
three-year-old child? Until an answer is available to this question, i.e., until the function
describing the relationship of exposure indices in different species is available, the utility
of animal models for deriving dose-response functions relevant to humans will be limited.
Questions also exist regarding the comparability of neurobehavioral effects in animals
with human behavior and cognitive function. One difficulty in comparing behavioral endpoints
such as locomotor activity is the lack of a consistent operational definition. In addition to
the lack of standardized methodologies, behavior is notoriously difficult to "equate" or com-
pare meaningfully across species because behavioral analogies do not demonstrate behavioral
homologies. Thus, it is improper to assume, without knowing more about the responsible under-
lying neurological structures and processes, that a rat's performance on an operant condition-
ing schedule or a monkey's performance on a stimulus discrimination task corresponds to a
child's performance on a cognitive function test. Still, deficits in performance on such
tasks are indicative of altered CNS function which is likely to parallel some type of altered
human CNS function as well
In terms of morphological findings, there are reports of hippocampal lesions in both
lead-exposed rats and humans that are consistent with a number of behavioral findings suggest-
ing an impaired ability to respond appropriately to altered contingencies for rewards. That
is, subjects tend to persist in certain patterns of behavior even when changed conditions make
the behavior inappropriate. Other morphological findings in animals, such as demyelination
and glial cell decline, are comparable to human neuropathology observations mainly at rela-
tively high exposure levels.
Another neurobehavioral endpoint of interest in comparing human and animal neurotoxicity
of lead is electrophysiological function. Alterations of electroencephalographic patterns and
cortical slow wave voltage have been reported for lead-exposed children, and various electro-
physiological alterations both i_n vivo (e g. , in rat visual evoked response) and jn vitro
(e.g., in frog miniature endplate potentials) have also been noted in laboratory animals At
this time, however, these lines of work have not converged sufficiently to allow for strong
conclusions regarding the electrophysiological aspects of lead neurotoxicity.
Biochemical approaches to the experimental study of lead's effects on the nervous system
have generally been limited to laboratory animal subjects. Although their linkage to human
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neurobehavioral function is at this point somewhat speculative, such studies do provide in-
sight to possible neurochemical intermediaries of lead neurotoxicity. No single neurotrans-
mitter system has been shown to be particularly sensitive to the effects of lead exposure;
lead-induced alterations have been demonstrated in various neurotransmitters, including dopa-
mine, norepinephrine, serotonin, and y-aminobutyric acid. In addition, lead has been shown to
have subcellular effects in the central nervous system at the level of mitochondrial function
and protein synthesis.
Given the above-noted difficulties in formulating a comparative basis for internal expo-
sure levels among different species, the primary value of many animal studies, particularly i_n
vjjtro studies, may be in the information they can provide on basic mechanisms involved in lead
neurotoxicity. A number of i_n vitro studies show that significant, potentially deleterious
effects on nervous system function occur at i_n situ lead concentrations of 5 pM and possibly
lower, suggesting that no threshold may exist for certain neurochemical effects of lead on a
subcellular or molecular level. The relationship between blood lead levels and lead concen-
trations at such extra- or intracellular sites of action, however, remains to be determined.
Despite the problems in generalizing from animals to humans, both the animal and the human
studies show great internal consistency in that they support a continuous dose-response func-
tional relationship between lead and neurotoxic biochemical, morphological, electrophysiologi-
cal, and behavioral effects.
1-12.5 Effects of Lead on the Kidney
It has been known for more than a century that kidney disease can result from lead
poisoning. Identifying the contributing causes and mechanisms of lead-induced nephropathy has
been difficult, however, in part because of the complexities of human exposure to lead and
other nephrotoxic agents. Nevertheless, it is possible to estimate at least roughly the range
of lead exposure associated with detectable renal dysfunction in both human adults and chil-
dren. More specifically, numerous studies of occupationally exposed workers have provided
evidence for lead-induced chronic nephropathy being associated with blood lead levels ranging
from 40 to more than 100 (jg/dl, and some are suggestive of renal effects possibly occurring
even at levels as low as 30 |jg/dl In children, the relatively sparse evidence available
points to the manifestation of nephropathy only at quite high blood lead levels (usually
exceeding 100-120 pg/dl). The current lack of evidence for nephropathy at lower blood lead
levels in children may simply reflect the greater clinical concern with neurotoxic effects of
lead intoxication in children or, possibly, that much longer term lead exposures are necessary
to induce nephropathy The persistence of lead-induced nephropathy in children also remains
to be more fully investigated, although a few studies indicate that children diagnosed as
being acutely lead poisoned experience lead nephropathy effects lasting throughout adulthood.
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Parallel results from experimental animal studies reinforce the findings in humans and
help illuminate the mechanisms underlying such effects. For example, a number of transient
effects in human and animal renal function are consistent with experimental findings of
reversible lesions such as nuclear inclusion bodies, cytomegaly, swollen mitochondria, and
increased numbers of iron-containing lysosomes in proximal tubule cells Irreversible lesions
such as interstitial fibrosis are also well documented in both humans and animals following
chronic exposure to high doses of lead. Functional renal changes observed in humans have also
been confirmed in animal model systems with respect to increased excretion of amino acids and
elevated serum urea nitrogen and uric acid concentrations. The inhibitory effects of lead
exposure on renal blood flow and glomerular filtration rate are currently less clear in exper-
imental model systems; further research is needed to clarify the effects of lead on these
functional parameters in animals. Similarly, while lead-induced perturbation of the renin-
angiotensin system has been demonstrated in experimental animal models, further research is
needed to clarify the exact relationships among lead exposure (particularly chronic low-level
exposure), alteration of the renin-angiotensin system, and hypertension in both humans and
animals
On the biochemical level, it appears that lead exposure produces changes at a number of
sites. Inhibition of membrane marker enzymes, decreased mitochondrial respiratory function/
cellular energy production, inhibition of renal heme biosynthesis, and altered nucleic acid
synthesis are the most marked changes to have been reported. The extent to which these mito-
chondrial alterations occur is probably mediated in part by the intracellular bioavailability
of lead, which is determined by its binding to high affinity kidney cytosolic proteins and
deposition within intranuclear inclusion bodies.
Recent studies in humans have indicated that the EDTA lead-mobilization test is the most
reliable technique for detecting persons at risk for chronic nephropathy. Blood lead measure-
ments are a less satisfactory indicator because they may not accurately reflect cumulative
absorption some time after exposure to lead has terminated.
A number of major questions remain to be more definitively answered concerning the effect
of lead on the kidney. Can a distinctive lead-induced renal lesion be identified either in
functional or histologic terms? What biologic measurements are most reliable for the predic-
tion of lead-induced nephropathy? What is the incidence of lead nephropathy in the general
population as well as among specifically defined subgroups with varying exposure? What is the
natural history of treated and untreated lead nephropathy? What is the mechanism of lead-
induced hypertension and renal injury? What are the contributions of environmental and
genetic factors to the appearance of renal injury due to lead' At what level of lead in blood
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can the kidneys be affected? Is there a threshold for renal effects of lead? The most dif-
ficult question to answer may well be to determine the contribution of low levels of lead
exposure to possible exacerbation of renal disease of non-lead etiologies.
1.12 6 Effects of Lead on Reproduction and Development
The most clear-cut data described in this section on reproduction and development are
derived from studies employing high lead doses in laboratory animals. There is still a need
for more critical research to evaluate the possible subtle toxic effects of lead on the fetus,
using biochemical, ultrastructural, or behavioral endpoints. An exhaustive evaluation of
lead-associated changes in offspring should include consideration of possible effects due to
paternal lead burden as well. Neonatal lead intake via consumption of milk from lead-exposed
mothers may also be a factor at times. Moreover, it must be recognized that lead's effects on
reproduction may be exacerbated by other environmental factors (e.g., dietary influences,
maternal hyperthermia, hypoxia, and co-exposure to other toxins).
There are currently no reliable data pointing to adverse effects in human offspring fol-
lowing lead exposure of fathers per se. Early studies of pregnant women exposed to high
levels of lead indicated toxic, but not teratogenic, effects on the conceptus. Only one
recently reported study hints at minor birth anomalies possibly being associated with expo-
sures to low levels of lead (mean cord blood =15 (jg/dl) among women in the general population;
but the lack of significant associations being found between cord blood levels and (1) speci-
fic, individual types of minor anomalies or (2) any major anomalies argues for the need for
replication of the reported effects and raises questions about their medical significance.
Unfortunately, the collective human data regarding lead's effects on reproduction or in
utero development currently do not lend themselves to accurate estimation of exposure-effect
or no-effect levels. This is particularly true regarding lead effects on reproductive perfor-
mance in women, which have not been well documented at low exposure levels. Still prudence
would argue for avoidance of lead exposures resulting in blood lead levels exceeding 25-30
pg/dl in pregnant women or women of child-bearing age in general, given the equilibration
between maternal and fetal blood lead concentrations that occurs and the growing evidence for
deletarious effects in young children as blood lead levels approach or exceed 25-30 jjg/d1
Industrial exposure of men to lead at levels resulting in blood lead values of 40-50 pg/d1
also appear to result in altered testicular function.
The paucity of human exposure data forces an examination of the animal studies for indi-
cations of threshold levels for effects of lead on the conceptus. It must be noted that the
animal data are almost entirely derived from rodents. Based on these rodent data, it seems
likely that fetotoxic effects have occurred in animals at chronic exposures to 600-800 ppm
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inorganic lead in the diet. Subtle effects appear to have been observed at 5-10 ppm in the
drinking water, while effects of inhaled lead have been seen at levels of 10 mg/m3 With mul-
tiple exposure by gavage, the lowest observed effect level is 64 mg/kg per day, and for expo-
sure via injection, acute doses of 10-16 mg/kg appear effective. Since humans are most likely
to be exposed to lead in their diet, air, or water, the data from other routes of exposure are
of less value in estimating harmful exposures. Indeed, it appears that teratogenic effects
occur in experimental animals only when the maternal dose is given by injection.
Although human and animal responses may be dissimilar, the animal evidence does document
a variety of effects of lead exposure on reproduction and development. Measured or apparent
changes in production of or response to reproductive hormones, toxic effects on the gonads,
and toxic or teratogenic effects on the conceptus have all been reported. The animal data
also suggest subtle effects on such parameters as metabolism and cell structure that should be
monitored in human populations. Well-designed prospective human epidemiological studies
(beyond the few presently available) involving large numbers of subjects are still needed.
Such data could clarify the relationship of exposure periods, exposure durations, and blood
lead concentrations associated with significant effects and are needed for estimation of no-
effect 1evels as wel1
1 12.7 Genotoxic and Carcinogenic Effects of Lead
It is difficult to conclude what role lead may play in the induction of human neoplasia.
Epidemiological studies of lead-exposed workers provide no definitive findings. However, sta-
tistically significant elevations in cancer of the respiratory tract and digestive system in
workers exposed to lead and other agents warrant some concern. Since it is clear that lead
acetate can produce renal tumors in some experimental animals, it seems reasonable to conclude
that at least that particular lead compound should be regarded as a carcinogen and prudent to
treat it as if it were also human carcinogen (as per IARC conclusions and recommendations)
However, this statement is qualified by noting that lead has been seen to increase tumorigen-
esis rates in animals only at relatively high concentrations, and therefore does not seem to
be a potent carcinogen, ^n vitro studies further support the genotoxic and carcinogenic role
of lead, but also indicate that lead is not potent in these systems.
1.12 8 Effects of Lead on the Immune System
Lead renders animals more susceptible to endotoxins and infectious agents. Host suscep-
tibility and the humoral immune system appear to be particularly sensitive. As postulated in
recent studies, the macrophage may be the primary immune target cell of lead. Lead-induced
immunosuppression occurs in experimental animals at low lead exposures (blood lead levels in
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the 20-40 |jg/dl range) that, although they induce no overt toxicity, may nevertheless be
detrimental to health. Available data provide good evidence that lead affects immunity, but
additional studies are necessary to elucidate the actual mechanisms by which lead exerts its
immunosuppressive action Knowledge of lead effects on the human immune system is lacking and
must be ascertained in order to determine permissible levels for human exposure. However, in
view of the fact that lead affects immunity in laboratory animals and is immunosuppressive at
very low dosages, its potential for serious effects in humans should be carefully considered
1.12.9 Effects of Lead on Other Organ Systems
The cardiovascular, hepatic, gastrointestinal, and endocrine systems generally show signs
of dysfunction at relatively high lead exposure levels. Consequently, in most clinical and
experimental studies attention has been primarily focused on more sensitive and vulnerable
target organs, such as the hematopoietic and nervous systems. Recent work does suggest that
rats may show significant increases in systolic blood pressure following chronic exposure to
low levels of lead (5 ppm in drinking water). It should also be noted that overt gastrointes-
tinal symptoms associated with lead intoxication have been observed to occur in lead workers
at blood lead levels as low as 40-60 (jg/dl. These findings suggest that effects on the gas-
trointestinal and cardiovascular systems may occur at relatively low exposure levels but
remain to be more conclusively demonstrated by further scientific investigations. Current
evidence also points toward lead effects on various endocrine processes at relatively high
exposure levels, but little data is available presently that demonstrates lead effects on
endocrine processes at levels of exposure as low as 30 jjg/dl, other than the alterations in
vitamin-D metabolism discussed earlier as occurring secondary to heme synthesis effects seen
at blood lead levels ranging below 30 |jg/dl to as low as 12 pg/dl.
1.13 EVALUATION OF HUMAN HEALTH RISKS ASSOCIATED WITH EXPOSURE TO LEAD AND ITS COMPOUNDS
1.13.1 Introduction
This section attempts to integrate, concisely, key information and conclusions discussed
in preceding chapters into a coherent framework by which interpretation and judgments can be
made concerning the risk to human health posed by present levels of lead contamination in the
United States.
In discussion of the various health effects of lead, the main emphasis is on the identi-
fication of those effects most relevant to various segments of the general U S. population and
the placement of such effects in a dose-effect/dose-response framework. With regard to the
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latter, a crucial issue has to do with relative response of various segments of the population
in terms of observed effect levels as indexed by some exposure indicator. Furthermore, it is
of interest to assess the extent to which available information supports the existence of a
continuum of effects as one proceeds across the spectrum of exposure levels. Discussion of
data on the relative number or percentage of members (i.e., "responders") of specific popula-
tion groups that can be expected to experience a particular effect at various lead exposure
levels is also important in order to permit delineation of dose-response curves for the
relevant effects in different segments of the population. These matters are discussed in
Sections 1.13.4 and 1.13.5.
Melding of information from the sections on lead exposure, metabolism, and biological
effects permits the identification of population segments at special risk in terms of physio-
logical and other host characteristics, as well as heightened vulnerability to a given effect,
these risk groups are discussed in Section 1.13.6. With demographic identification of indivi-
duals at risk, one may then draw upon population data from other sources to obtain a numerical
picture of the magnitude of population groups at potential risk. This is also discussed in
Section 1.13.6.
1-13.2 Exposure Aspects: Levels of Lead in Various Media of Relevance to Human Exposure
Human populations in the United States are exposed to lead in air, food, water, and dust.
In rural areas, Americans not occupationally exposed to lead are estimated to consume 40-60 |jg
Pb/day. This level of exposure is referred to as the baseline exposure for the American popu-
lation because it is unavoidable except by drastic change in lifestyle or by regulation of
lead in foods or ambient air. There are several environmental circumstances that can increase
human exposures above baseline levels. Most of these circumstances involve the accumulation
of atmospheric dusts in the work and play environments. A few, such as pica and family home
gardening, may involve consumption of lead in chips of exterior or interior house paint.
Ambient Air Lead Levels. Monitored ambient air lead concentration values in the U.S. are
contained in two principal data bases: (1) EPA's National Air Sampling Network (NASN),
recently renamed National Filter Analysis Network (NFAN); and (2) EPA's National Aerometric
Data Bank, consisting of measurements by state and local agencies in conjunction with compli-
ance monitoring for the current ambient air lead standard.
NASN data for 1982, the most current year in the annual surveys, indicate that most of
the urban sites show reported annual averages below 0.7 (jg Pb/m3, while the majority of the
non-urban locations have annual figures below 0.2 pg Pb/m3. Over the interval 1976-1982,
there has been a downward trend in these averages, mainly attributable to decreasing lead
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content of leaded gasoline and the increasing usage of lead-free gasoline. Furthermore, exam-
ination of quarterly averages over this interval shows a typical seasonal variation, charac-
terized by maximum air lead values in summer and minimum values in winter.
With respect to the particle size distribution of ambient air lead, EPA studies using
cascade impactors in six U.S. cities have indicated that 60-75 percent of such air lead was
associated with sub-micron particles. This size distribution is significant in considering
the distance particles may be transported and the deposition of particles in the pulmonary
compartment of the respiratory tract. The relationship between airborne lead at the monitor-
ing station and the lead inhaled by humans is complicated by such variables as vertical gradi-
ents, relative positions of the source, monitor, and the person, and the ratio of indoor to
outdoor lead concentrations. Personal monitors would probably be the most effective means to
obtain an accurate picture of the amount of lead inhaled during the normal activities of an
individual. But the information gained would be insignificant, considering that inhaled lead
is generally only a small fraction of the total lead exposure, compared to the lead in food,
beverages, and dust. The critical question in regard to airborne lead is how much lead
becomes entrained in dust. In this respect, the existing monitoring network may provide an
adequate estimate of the air concentration from which the rate of deposition can be deter-
mi ned.
Levels of Lead In Dust. The lead content of dusts can figure prominently in the total
lead exposure picture for young children. Lead in aerosol particles deposited on rigid sur-
faces in urban areas (such as sidewalks, porches, steps, parking lots, etc.) does not undergo
dilution compared to lead transferred by deposition onto soils. Lead in dust can approach
extremely high concentrations and can accumulate in the interiors of dwellings as well as in
the outside surroundings, particularly in urban areas.
Measurements of soil lead to a depth of 5 cm in areas of the U.S. were shown in one study
to range from 150 to 500 pg Pb/g dry weight close to roadways (i.e., within 8 meters) By
contrast, lead in dusts deposited on or near heavily traveled traffic arteries show levels in
major U.S. cities ranging up to 8000 pg Pb/g and higher. In residential areas, exterior dust
lead levels are approximately 1000 pg/g or less if contaminated only by atmospheric lead
Levels of lead in house dust can be significantly elevated; a study of house dust samples in
Boston and New York City revealed levels of 1000-2000 pg Pb/g. Some soils adjacent to houses
with exterior lead-based paints may have lead concentrations greater than 10,000 pg/g
Forty-four percent of the baseline consumption of lead by children is estimated to result
from consumption of 0 1 g of dust per day, as noted earlier in Table 1-7 (and in Table 1-14 on
a body weight basis). Ninety percent of this dust lead is of atmospheric origin. Dust also
accounts for more than 90 percent of the additive lead attributable to living in an urban
environment or near a smelter (see earlier Table 1-8).
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TABLE 1-14. RELATIVE BASELINE HUMAN LEAD EXPOSURES EXPRESSED PER KILOGRAM BODY WEIGHT*
Total
Lead
Consumed
(pg/day)
Total Lead Consumed
Per Kg Body Wt
(pg/Kg-Day)
Atmospheric Lead
Per Kg Body Wt
(pg/Kg-Day)
Child (2 yr old)
Inhaled air
0.5
0.05
0.05
Food
18.9
1.9
0.92
Water and beverages
6.9
0.7
0.10
Dust
21.0
2.1
1.9
Total
47.3
4 75
2.14
Adult female
Inhaled air
1.0
0.02
0.02
Food
25.3
0.51
0.25
Water and beverages
10.7
0.21
0.03
Dust
4.5
0.09
0.06
Total
41.5
0.83
0.36
Adult male
Inhaled air
1.0
0.014
0.014
Food
35.8
0.51
0.25
Water and beverages
18.9
0.27
0.04
Dust
4.5
0.064
0.04
Total
60.2
0.86
0.344
*Body weights: 2 year old child = 10/kg; adult female = 50 kg; adult male = 70 kg.
Source: This report.
Levels of Lead in Food. The route by which adults and older children in the baseline
population of the U.S. receive the largest proportion of lead intake is through foods, with
reported estimates of the dietary lead intake for Americans ranging from 35 to 55 pg/day. The
added exposure from living in an urban environment is about 28 pg/day for adults and 91 pg/day
for children, all of which can be attributed to atmospheric lead.
Atmospheric lead may be added to food crops in the field or pasture, during transporta-
tion to the market, during processing, and during kitchen preparation. Metallic lead, mainly
solder, may be added during processing and packaging. Other sources of lead, as yet undeter-
mined, increase the lead content of food between the field and dinner table. American chil-
dren, adult females, and adult males consume 19, 25, and 36 pg Pb/day, respectively, in milk
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and nonbeverage foods. Of these amounts, 49 percent is of direct atmospheric origin, 31 per-
cent is of metallic origin, and 11 percent is of undetermined origin.
Processing of foods, particularly canning, can significantly add to their background lead
content, although it appears that the impact of this is being lessened with the trend away
from use of lead-soldered cans The canning process can increase lead levels 8-to 10-fold
higher than for the corresponding uncanned food items. Home food preparation can also be a
source of additional lead in cases where food preparation surfaces are exposed to moderate
amounts of high-lead household dust.
Lead Levels in Drinking Water Lead in drinking water may result from contamination of
the water source or from the use of lead materials in the water distribution system. Lead
entry into drinking water from the latter is increased in water supplies which are plumbo-
solvent, i.e., with a pH below 6.5. Exposure of individuals occurs through direct ingestion
of the water or via food preparation in such water.
The interim EPA drinking water standard for lead is 0.05 pg/g (50 pg/1) and several ex-
tensive surveys indicate that few public water supplies exceed this standard. For example, a
survey of interstate carrier water supplies conducted by EPA showed that only 0.3 percent ex-
ceeded the standard, whereas mean levels of approximately 4.0 pg/1 have been reported in 1971
and 1980 (as discussed in Section 7.2.3 1.1).
The major source of lead contamination of drinking water is the distribution system it-
self, particularly in older urban areas. Highest levels are encountered in "first-draw" sam-
ples, i.e., water sitting in the piping system for an extended period of time In a large
community water supply survey of 969 systems carried out in 1969-1970, it was found that the
prevalence of samples exceeding 0 05 pg/g was greater where water was plumbo-solvent.
Most drinking water, and the beverages produced from drinking water, contain 0.007-
0.011 pg Pb/g The exceptions are canned juices and soda pop, which range from 0 018 to
0 040 pg/g. About 15 percent of the lead consumed in drinking water and beverages is of
direct atmospheric origin; 60 percent comes from solder and other metals.
Lead in Other Media Flaking lead paint as well as paint clips and weathered powdered
paint in and around deteriorated housing stock in urban areas of the Northeast and Midwest has
long been recognized as a major source of lead exposure for young children residing in this
housing stock, particularly for children with pica. Census data, for example, indicate that
there are approximately 27 million residential units in the U.S. built before 1940, many of
which still contain lead-based paint Individuals who are cigarette smokers may inhale signi-
ficant amounts of lead in tobacco smoke. One study has indicated that the smoking of 30
cigarettes daily results in lead intake equivalent to that of inhaling lead in ambient air at
a level of 1.0 pg Pb/m3
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Cumulative Human Lead Intake From Various Sources. Table 1-7 earlier illustrated the
baseline of human lead exposures in the U.S. as described in detail in Chapter 7. These data
show that atmospheric lead accounts for at least 40 percent of the baseline adult consumption
and 60 percent of the daily consumption by a 2 yr old child. These percentages are conserva-
tive estimates because a part of the lead of undetermined origin may originate from atmos-
pheric lead not yet accounted for
From Table 1-14, it can be seen that young children have a dietary lead intake rate that
is 5-fold greater than for adults, on a body weight basis To these observations must be
added that absorption rates for lead are higher in children than in adults by at least 3-fold.
Overall, then, the rate of lead entry into the blood stream of children, on a body weight
basis, is estimated to be twice that of adults from the respiratory tract and six to nine
times greater from the GI tract. Since children consume more dust than adults, the atmos-
pheric fraction of the baseline exposure is six-fold higher for children than for adults, on a
body weight basis. These differences generally tend to place young children at greater risk,
in terms of relative amounts of atmospheric lead absorbed per kg body weight, than adults
under any given lead exposure situation.
1.13.3 Lead Metabolism: Key Issues for Human Health Risk Evaluation
From the detailed discussion of those various quantifiable characteristics of lead toxi-
cokinetics in humans and animals presented in Chapter 10, several clear issues emerge as being
important for full evaluation of the human health risk posed by lead:
(1) Differences in systemic or internal lead exposure of groups within the general popu-
lation in terms of such factors as age/development and nutritional status, and
(2) The relationship of indices of internal lead exposures to both environmental levels
of lead and tissues levels/effects.
Item 1 provides the basis for identifying segments within human populations at increased
risk in terms of exposure criteria and is used along with additional information on relative
sensitivity to lead health effects for identification of at-risk populations. The chief con-
cern with item 2 is the adequacy of current means for assessing internal lead exposure in
terms of providing adequate margins of protection from lead exposures producing health effects
of concern.
Differential Internal Lead Exposure Within Population Groups. Compared to adults, young
children take in more lead through the gastrointestinal and respiratory tracts on a unit body
weight basis, absorb a greater fraction of this lead intake, and also retain a greater propor-
tion of the absorbed amount. Unfortunately, such amplification of these basic toxicokinetic
parameters in children vs. adults also occurs at the time when (1) humans are developmen-
tally more vulnerable to the effects of toxicants such as lead in terms of metabolic activity,
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and (2) the interactive relationships of lead with such factors as nutritive elements are such
as to induce a negative course toward further exposure risk.
Typical of physiological differences in children vs. adults in terms of lead exposure im-
plications is a more metabolically active skeletal system in children. In children, turnover
rates of bone elements such as calcium and phosphorus are greater than in adults, with corre-
spondingly greater mobility of bone-sequestered lead. This activity is a factor in the obser-
vation that the skeletal system of children is relatively less effective as a depository for
lead than in adults.
Metabolic demand for nutrients, particularly calcium, iron, phosphorus, and the trace
nutrients, is such that widespread deficiencies of these nutrients exist, particularly among
poor children. The interactive relationships of these elements with lead are such that defi-
ciency states enhance lead absorption and/or retention. In the case of lead-induced reduc-
tions in 1,25~dihydroxyvitamin D, furthermore, there may exist an increasingly adverse inter-
active cycle between lead effects on 1,25-dihydroxyvitamin D and associated increased
absorption of lead.
Quite apart from the physiological differences which enhance internal lead exposure in
children is the unique relationship of 2- to 3-year-olds to their exposure setting by way of
normal mouthing behavior and the extreme manifestation of this behavior, pica. This behavior
occurs in the same age group which studies have consistently identified as having a peak in
blood lead. A number of investigations have addressed the quantification of this particular
route of lead exposure, and it is by now clear that such exposure will dominate other routes
when the child's surroundings, e.g., dust and soil, are significantly contaminated by lead
Information provided in Chapter 10 also makes it clear that lead traverses the human pla-
cental barrier, with lead uptake by the fetus occurring throughout gestation. Such uptake of
lead poses a potential threat to the fetus via an impact on the embryologital developement of
the central nervous and other systems. Hence, the only logical means of protecting the fetus
from lead exposure is exposure control during pregnancy.
Within the general population, then, young children and pregnant women qualify as well-
defined high-risk groups for lead exposure. Occupational exposure to lead, particularly among
lead workers, logically defines these individuals as also being in a high-risk category; work
place contact is augmented by those same routes and levels of lead exposure affecting the rest
of the adult population. From a biological point of view, lead workers do not differ from the
general adult population with respect to the various toxicokinetic parameters and any differ-
ences in exposure control--occupational vs. non-occupational populations--as they exist are
based on factors other than toxicokinetics.
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Indices of Internal Lead Exposure and Their Relationship To External Lead Levels and
Tissue Burdens/Effects. Several points are of importance to consider in this area of lead
toxicokinetics. (1) the temporal characteristics of indices of lead exposure, (2) the rela-
tionship of the indicators to external lead levels; (3) the validity of indicators of exposure
in reflecting target tissue burdens, (4) the interplay between these indicators and lead in
body compartments; and (5) those various aspects of the issue with particular reference to
children.
At this time, blood lead is widely held to be the most convenient, if imperfect, index of
both lead exposure and relative risk for various adverse health effects. In terms of expo-
sure, however, it is generally accepted that blood lead is a temporally variable measure which
yields an index of relatively recent exposure because of the rather rapid clearance of absor-
bed lead from the blood. Such a measure, then, is of limited usefulness in cases where expo-
sure is variable or intermittent over time, as is often the case with pediatric lead exposure
Mineralizing tissues (specifically, deciduous teeth), on the other hand, accumulate lead over
time in proportion to the degree of lead exposure, and analysis of this material provides an
assessment integrated over a greater time period.
These two methods of assessing internal lead exposure have obvious shortcomings. A blood
lead value will say little about any excessive lead intake at early periods, even though such
remote exposure may have resulted in significant injury. On the other hand, whole tooth or
dentine analysis is retrospective in nature and can only be done after the particularly vulne-
rable age in children—under 4-5 years--has passed. Such a measure, then, provides little
utility upon which to implement regulatory policy or clinical intervention.
It may be possible to resolve the dilemmas posed by these existing methods by in situ
analysis of teeth and bone lead, such that the intrinsic advantage of mineral tissue as a
cumulative index is combined with measurement which is temporally concordant with on-going
exposure. Work in several laboratories offers promise for such j_n situ analysis (see Chapters
9 and 10).
A second issue concerning internal indices of exposure and environmental lead is the
relationship of changes in lead content of some medium with changes in blood content. Much of
Chapter 11 is given over to description of the mathematical relationships of blood lead with
lead in some external medium—air, food, water, etc.--without consideration of the biological
underpinnings for these relationships.
Over a relatively broad range of lead exposure through some medium, the relationship of
lead in the external medium to blood lead is curvilinear, such that relative change in blood
lead per unit change in medium level generally becomes increasingly less as exposure in-
creases. This behavior may reflect changes in tissue lead kinetics, reduced lead absorption,
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or increased excretion. With respect to changes in body lead distribution, the relative
amount of whole blood lead in plasma increases significantly with increasing whole blood lead
content, i.e., the plasma erythrocyte ratio increases. Limited animal data would suggest that
changes in absorption may be one factor in this phenomenon. In any event, modest changes in
blood levels with exposure at the higher end of this range are in no way to be taken as
reflecting concomitantly modest changes in body or tissue lead uptake. Evidence continues to
accumulate which suggests that an indicator such as blood lead is an imperfect measure of
tissue lead burdens and of changes in such tissue levels in relation to changes in external
exposure (see Figure 1-21).
In Chapter 10, it is pointed out that blood lead is logarithmically related to chelata-
ble lead (the latter being a more useful measure of the potentially toxic fraction of body
lead), such that a unit change in blood lead is associated with an increasingly larger amount
of chelatable lead. One consequence of this relationship is that moderately elevated blood
lead values will tend to mask the "margin of safety" in terms of mobile body lead burdens.
Such masking is apparent in several studies of children where chelatable lead levels in
children showing moderate elevations in blood lead overlapped those obtained in subjects show-
ing frank plumbism, i.e., overt lead intoxication. In a multi-institutional survey involving
several hundred children, it was found that a significant percentage of children with moder-
ately elevated blood lead values had chelatable lead burdens which qualified them for medical
treatment.
Related to the above is the question of the source of chelatable lead. It is noted in
Chapter 10 that some sizable fraction of chelatable lead is derived from bone and this compels
reappraisal of the notion that bone is an "inert sink" for otherwise toxic body lead. The
notion of bone lead as toxicologically inert never did accord with what was known from studies
of bone physiology, i e., that bone is a "living" organ. The thrust of recent studies of che-
latable lead, as well as interrelationships of lead and bone metabolism, supports the view
that bone lead is actually an insidious source of long-term systemic lead exposure rather than
a protective mechanism which permits significant lead contact in industrialized populations
The complex interrelationships of lead exposure, blood lead, and lead in body compart-
ments is of particular interest in considering the disposition of lead in young children
Since children take in more lead on a weight basis, and absorb and retain more of this lead
than the adult, one might expect that either tissue and blood levels would be significantly
elevated or that the child's skeletal system would be more efficient in lead sequestration.
Average blood lead levels in young children are generally either similar to adult males or
somewhat higher than for adult females Limited autopsy data, furthermore, indicate that soft
tissue levels in children are not markedly different from adults, whereas the skeletal system
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tlADDER
Figure 1 21. illustration of main body compartments involved in partitioning, retention, and excretion
of absorbed lead and selected target organs for lead toxicity. Inhaled and ingested lead circulates via
lood (1) to mineralizing tissues such as teeth and bone (2), where long-term retention occurs reflective of
cumulative past exposures. Concentrations of lead in blood circulating to "soft tissue" target organs
such as brain (3), peripheral nerve, and kidney, reflect both recent external exposures and lead re-
circulated from internal reservoirs (e.g. bone). Blood lead levels used to index internal body lead
burden tend to be in equilibrium with lead concentrations in soft tissues and, below 30 #ig/dl, also
generally appear to reflect accumulated lead stores. However, somewhat more elevated current blood
lead levels may "mask" potentially more toxic elevations of retained lead due to relatively rapid declines
in blood lead in response to decreased external exposure. Thus, provocative chelation of some children
with blood leads of 30-40 *ig/dl, for example, results in mobilization of lead from bone and other
tissues into blood and movement of the lead (4) into kidney (5), where it is filtered into urine and
excreted (6) at concentrations more typical of overtly lead-intoxicated children with higher blood lead
concentrations.
1-131
-------
shows an approximate 2-fold increase in lead concentration from infancy to adolescence
Neglected in this observation is the fact that the skeletal system in children grows at an
exponential rate, so that skeletal mass increases 40-fold during the interval in childhood
when bone lead levels increase 2-fold, resulting in an actual increase of approximately 80-
fold in total skeletal lead. If the skeletal growth factor is taken into account, along with
growth in soft tissue and the expansion of vascular fluid volumes, the question of lead dis-
position in children is better understood. Finally, limited animal data indicate that blood
lead alterations with changes in lead exposure are poor indicators of such changes in target
tissue Specifically, it appears that abrupt reduction of lead exposure will be more rapidly
reflected by decreases in blood lead than by decreased lead concentrations in such target
tissues as the central nervous system, especially in the developing organism. This discord-
ance may underlie the observation that severe lead neurotoxicity in children is associated
with a rather broad range of blood lead values (see Section 12 4).
The above discussion of some of the problems with the use of blood lead in assessing tar-
get tissue burdens or the toxicologically active fraction of total body lead is really a sum-
mary of the inherent toxicokinetic problems with use of blood lead levels in defining margins
of safety for avoiding internal exposure or undue risk of adverse effects. If, for example,
blood lead levels of 30-50 pg/dl in "asymptomatic" children are associated with chelatable
lead burdens which overlap those encountered in frank pediatric plumbism, as documented in
several studies of lead-exposed children, then there is no margin of safety at these blood
levels for severe effects which are not at all a matter of controversy. Were it both logisti-
cally feasible to do so on a large scale and were the use of chelants free of health risk to
the subjects, serial provocative chelation testing would appear to be the better indicator of
exposure and risk. Failing this, the only prudent alternative is the use of a large safety
factor applied to blood lead which would translate to an "acceptable" chelatable burden. It
is likely that this blood lead value would lie well below the currently accepted upper limit
of 30 Mg/d1, since the safety factor would have to be large enough to protect against frank
plumbism as well as more subtle health effects seen with non-overt lead intoxication. This
rationale from the standpoint of lead toxicokinetics is in accord also with the growing data
base for dose-effect relationships of lead's effects on heme biosynthesis, erythropoiesis, and
the nervous system in humans as detailed in Sections 12.3 and 12.4 (see also Section 1.13 4,
below).
Further development and routine use of i_n situ mineral tissue testing at time points con-
cordant with on-going exposure and the comparison of such results with simultaneous blood lead
and chelatable lead measurement would be of significant value in further defining what level
of blood lead is indeed an acceptable upper limit.
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Proportional Contributions of Lead in Various Media to Blood Lead in Human Populations.
The various mathematical descriptions of the relationship of blood lead to lead in indi-
vidual media--air, food, water, dust, soil—are discussed in some detail in Chapter 11 Using
values for lead intake/content of these media which appear to represent the current exposure
picture for human populations in the U.S., these relationships are further employed in this
section to estimate proportional inputs to total blood lead levels in U.S. children. Such an
exercise is of help in providing an overall perspective on which routes of exposure are of
most significance in terms of contributions to blood lead levels seen especially in urban
children, the U.S. population group at greatest risk for lead exposure and its toxic effects
Table 1-15 tabulates the relative direct contributions of air lead to blood lead at dif-
ferent air-lead levels for calculated typical background levels of lead from food, water, and
dust for U.S. children. Also listed are the direct and indirect contributions of air lead to
blood lead at varying air lead levels for children, given calculated typical background levels
of blood lead. Calculations and assumptions used in deriving the estimates shown in Table
1-15 are summarized in footnotes to that table. The diet contributions listed in the table,
for example, are based on: (1) estimated average background levels of lead (from non-air and
air sources) in food ingested per day by U.S. children, as delineated in Table 7-25; and (2)
the value of 0.16 pg/dl of blood increase per pg/day food lead intake found by Ryu et al.
(1983) for infants. Similarly, values for other parameters used in Table 1-15 are obtained
from work discussed in Chapters 7 and 11.
It is of interest to compare (1) estimated blood lead values predicted in Table 1-15 to
occur at particular air lead concentrations with (2) actual blood lead levels observed for
U S. children living in areas with comparable ambient air concentrations. As an example,
NHANES II survey results for children living in rural areas and urban areas of more than one
million population or less than one million were presented in Table 11-5. For children (aged
0 5-5 yr) living in urban areas >1 million, the mean blood lead value was 16.8 pg/dl, a value
representative of average blood lead levels nationwide for preschool children living in large
urban areas during the NHANES survey period (1976 to February, 1980) Ambient air lead con-
centrations (quarterly averages) during the same time period (1976-1979) for a geographically
diverse sample of large U S. urban areas (population >1 million) are available from Table 7-3
The air lead levels during 1976-1979 averaged 1.08 |jg/m3 for all cities listed in Table 7-3
and 1 20 pg/m3 for six cities in the table that were included in the NHANES II study (i.e.,
Boston, New York, Philadelphia, Detroit, Chicago, Houston, Dallas, Los Angeles, and
Washington, DC). The Table 1-15 blood lead values of 12.7-14.8 pg/dl estimated for air lead
levels of 1 0-1.25 pg/m3 approximate the observed NHANES II average of 16.8 pg/dl for children
in large urban areas with average air lead levels of 1 08-1 20 pg/m-1. The NHANES II blood
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PERCENT CONTRIBUTIONS FROM VARIOUS MEDIA TO BLOOD LEAD LEVELS (ua/dl} OF
U.S. CHILDREN (AGE = 2 YEARS). BACKGROUND LEVELS AND INCREMENTAL CONTRIBUTIONS FROM AIR
Air Lead
(pq/m3)
Source
0
.25
50
.75
1.0
1.25
1 5
Background-non air
Food1
Water2
Dust3
Subtotal
1.55
.94
.30
2.79
1.55
.94
.30
2~79
1.55
.94
.30
2775
1.55
.94
.30
2775
1.55
.94
.30
2775
1.55
.94
30
2. 79
1 55
.94
.30
2779
Background-ai r
Food4
Water5
Subtotal
1.47
16
1.63
1 47
16
1.63
1.47
.16
1.63
1.47
.16
1.63
1.47
.16
1.63
1.47
.16
T753
1 47
16
1 63
Ingested Dust (with Pb
deposited from air)6
0.00
1.57
3.09
4.70
6.27
7 84
9.40
Inhaled air7
0 00
50
1.00
1.50
2.00
2.50
3.00
Total
4.42
6.49
8.51
10.62
12.69
14.76
16.82
- J """y x.jj (jy/ui.
From Table 7-25 (6.9 - 1 0) pg/day x (0.16 from Ryu et al., 1983) = 0.94 uq/dl.
n m?na^/n8 i/7 ^ f 2' 7"21 9ive a weighted mean concentration of liquids as
(0 °oi 1,8/8 ao M9/,) 10 x
3From Chapter 7, 1/10 dust not atmospheric. Using Angle et al. (1984) low area (Area S)
I nnln a house dust and their regression equation, we have- (1/10) x (97 ua/a x
0 8 p+f ^9/9^7°-°5718).T S 309Mg/dl. AKernatively, the cJ^t?on frSS^oS air
_ 5 1/10) X Vn !0llndust + 324 ^g/g house dust) x 0.05 grams ingested of
each - 2.1 pg ingested. Using Ryu et al. (1983), 2.1 x 0.16 = 0.34 Mg/dl added to blood.
ab°V?' b
-------
lead values for preschool children would be expected to be somewhat higher than the estimates
in Table 1-15 because the latter were derived from FDA data for 1981-1983, which were lower
than the FDA values for the 1976-1980 NHANES II period (see Chapter 7). FDA data for food,
water, and beverages for the 1976-1980 period are not in a form exactly comparable to the
1981-1983 data used in calculating background contributions in Table 1-15, but do suggest that
lead levels in those media declined by about 20 percent from the 1976-1980 period to 1981-
1983 If background contributions in Table 1-15 were corrected (i.e., increased by 20 per-
cent) to be comparable to the 1976-1980 period, then the blood lead levels of children exposed
to 1.25 pg/m3 air lead would increase to 15.6 pg/dl, a value even closer to the mean of
16.8 pg/dl found for NHANES II children living in urban environments (>1 million) during
1976-1980
1-13.4 Biological Effects of Lead Relevant to the General Human Population
It is clear from the wealth of available literature reviewed in Chapter 12 that there
exists a continuum of biological effects associated with lead across a broad range of expo-
sure. At rather low levels of lead exposure, biochemical changes, e.g., disruption of certain
enzymatic activities involved in heme biosynthesis and erythropoietic pyrimidine metabolism,
are detectable. Heme biosynthesis is a generalized process in mammalian species, including
man, with importance for normal physiological functioning of virtually all organ systems.
With increasing lead exposure, there are sequentially more intense effects on heme synthesis
as well as a broadening of effects to additional biochemical and physiological mechanisms in
various tissues. In addition to heme biosynthesis impairment at relatively low levels of lead
exposure, disruption of normal functioning of the erythropoietic and nervous systems are among
the earliest effects observed as a function of increasing lead exposure. With increasingly
intense exposure, more severe disruption of the erythropoietic and nervous systems occur and
additional organ systems are affected, resulting, for example, in manifestation of renal
effects, disruption of reproductive functions, and impairment of immunological functions At
sufficiently high levels of exposure, the damage to the nervous system and other effects can
be severe enough to result in death or, in some cases of non-fatal lead poisoning, long-
lasting sequelae such as permanent mental retardation.
As discussed in Chapter 12 of this document, numerous new studies, reviews, and critiques
concerning lead-related health effects have been published since the issuance of the earlier
EPA lead criteria document in 1977. Of particular importance for present criteria development
purposes are those new findings, taken together with information available at the writing of
the 1977 Criteria Document, which have bearing on the establishment of quantitative dose-
effect or dose-response relationships for biological effects of lead potentially viewed as
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adverse health effects likely to occur among the general population at or near existing
ambient air concentrates of lead in the United States. Key information regarding observed
health effects and their implications are discussed below for adults and children.
For the latter group, children, emphasis is placed on the discussion of (1) heme biosyn-
thesis effects, (2) certain other biochemical and hematological effects, and (3) the disrup-
tion of nervous system functions. All of these appear to be among those effects of most con-
cern for potential occurrence in association with exposure to existing U.S. ambient air lead
levels for the population group at greatest risk for lead-induced health effects (i.e
children ^6 years old). Emphasis is also placed on the delineation of internal lead exposure
levels, as defined mainly by blood-lead (PbB) levels likely associated with the occurrence of
such effects. Also discussed are characteristics of the subject effects that are of crucial
importance with regard to the determination of which might reasonably be viewed as constitu-
ting "adverse health effects" in affected human populations.
Criteria for Defining Adverse Health Effects. Over the years, there have been super-
imposed on the continuum of lead-induced biological effects various judgments as to which
specific effects observed in man constitute "adverse health effects". Such judgments involve
not only medical consensus regarding the health significance of particular effects and their
clinical management, but also incorporate societal value judgments. Such societal value judg-
ments often vary depending upon the specific overall contexts to which they are applied, e.g.,
in judging permissible exposure levels for occupational vs. general population exposures to
lead. For some lead exposure effects, e.g., severe nervous system damage resulting in death
or serious medical sequelae consequent to intense lead exposure, there exists little or no
disagreement as to these being significant "adverse health effects." For many other effects
detectable at sequentially lower levels of lead exposure, however, the demarcation lines as to
which effects represent adverse health effects and the lead exposure levels at which they are
accepted as occurring are neither sharp nor fixed, having changed markedly during the past
several decades. That is, from an historical perspective, levels of lead exposure deemed to
be acceptable for either occupationally exposed persons or the general population have been
steadily revised downward as more sophisticated biomedical techniques have revealed formerly
unrecognized biological effects and concern has increased in regard to the medical and social
significance of such effects.
It is difficult to provide a definitive statement of all criteria by which specific bio-
logical effects associated with any given agent can be judged to be "adverse health effects".
Nevertheless, several criteria are currently well-accepted as helping to define which effects
should be viewed as "adverse" These include: (1) impaired normal functioning of a specific
tissue or organ system itself, (2) reduced reserve capacity of that tissue or organ system in
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dealing with stress due to other causative agents; (3) the reversibi1ity/irreversibi 1lty of
the particular effect(s); (4) the relative frequency of a given effect, (5) presence of the
effect in a vulnerable segment of the population; and (6) the cumulative or aggregate impact
of various effects on individual organ systems on the overall functioning and well-being of
the individual.
Examples of possible uses of such criteria in evaluating lead effects can be cited for
illustrative purposes. For example, impairment of heme synthesis intensifies with increasing
lead exposure until hemoprotein synthesis is inhibited in many organ systems, leading to re-
ductions in such functions as oxygen transport, cellular energetics, neurotransmitter func-
tions, detoxification of xenobiotic agents, and biosynthesis of important substances such as
1,25-dihydroxyvitamin D In Figure 1-22, the far ranging impact of lead on the body heme pool
and associated disruption of many physiological processes is depicted, based on data discussed
in Sections 12.2 and 12.3. Furthermore, inspection of Figure 1-22 reveals effects that can be
viewed as intrinsically adverse as well as those that reduce the body's ability to cope with
other forms of toxic stress, e.g., reduced hepatic detoxification of many types of xenobiotics
and, possibly, impairment of the immune system. The liver effect can also be cited as an
example of reduced reserve capacity pertinent to consideration of the effects of lead, as the
reduced capacity of the liver to detoxify certain drugs or other xenobiotic agents results
from lead effects on hepatic detoxification enzyme systems.
In regard to the issue of reversibility/irreversibility of lead effects, there are really
two dimensions to the issue that need to be considered, i.e.: (1) biological reversibility or
irreversibility characteristic of the particular effect in a given organism; and (2) the gene-
rally less-recognized concept of exposure reversibi1ity or irreversibi1lty. Severe central
nervous system damage resulting from intense, high level lead exposure is generally accepted
as an irreversible effect of lead exposure; the reversibility/irreversibility of certain more
difficult-to-detect neurological effects occurring at lower lead exposure levels, however,
remains a matter of some controversy The concept of exposure reversibility/irreversibility
can be illustrated by the case of urban children of low socioecomomic status showing disturb-
ances in heme biosynthesis and erythropoiesis. Biologically, these various effects may be
considered reversible; the extent to which actual reversibility occurs, however, is determined
by the feasibility of removing these subjects from their particular lead exposure setting. If
such removal from exposure is unlikely or does not occur, then such effects will logically
persist and, defacto, constitute essentially irreversible effects.
The issues of frequency of effects and vulnerable segments of the population in whom
these effects occur are intimately related. As discussed later in Section 1.13.6, young chil-
dren—particularly inner city children--constitute a high risk group because they do show a
high frequency of certain health effects as summarized below.
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REDUCTION Of
H(Ml BOOt '001
ERYTHROPOIETIC
EXACERBATION Or
HYPOXIC EFFECTSOF
OTHER STRESS AGENTS
CAR0I0VASCUL4R
OVSf UNCTION ANO
OTHER HYPOXIC EFFECTS
RENAL ENOOCRINE
EFFECTS
IMPAIREO CALCIUM
ROLE IN CYCLIC
NUCLEOTIOE METABOLISM
Rf OUCEO HEME FOR
HEME RECUIATEO
! R ANSf ORMATlONS
ElEVATEO BRAIN
LEVELS Of TRYPTOPHAN
SEROTONIN ANOHIAA
IMPAIRED
HYOROXVIATJON
Of CORTISOL
Pb
REOUCEO HEMOPROTEINS
<•1 CYTOCHROMES)
IMPAIREO
CELLULAR
ENERGETICS
0ISTUR8EC ROLE IN
TUMOROGENESIS
CONTROL
OISTURBEO CALCIUM
METABOLISM
REOUCEO 1 Zl 10HI
VITAMIN 0
IMPAIREO
OETOXIFICATION
OF XENOBIOTICS
ANEMIA - REOUCEO
OXYGEN transport
TO AIL TISSUES
OISTURBEO IMUNO
REGULATORY ROIE
OF CALCIUM
IMP AIRE 0 ME T A BO L ISM
0'ZOOGENOUS
AGONISTS
IMPAIREO MYEL(NATION
ANO NERVE CONOUCTIQN
IMPAIREO CALCIUM
ROLEAS'ECONO
MESSENGER
IMPAIRED DEVELOPMENT
OF NERVOUS SYSTEM
IMPAIREO
DETOXIFICATION
OF DRUGS
IMPAIREO OETOXIFICATION
OF ENVIRONMENTAL
TOXINS
IMPAIREO MINERAL
TISSUE HOMEOSTASIS
EFFECTS ON NEURONS
AXONS ANO
SCHWANN CELLS
AL T(R( 0 ME T ABC ISM
OF TRYPTOPHAN
IMPAIREO BONE ANO
TOOTH DEVELOPMENT
OISTURBEO INOOLEAMINl
NEUROTRANSMITTER
FUNCTION
Figure 1-22. Multi-organ impact of reductions of heme body pool by lead. Impairment of heme
synthesis by lead (see Section 12 3) results in disruption of a wide variety of important physio-
logical processes in many organs and tissues. Particularly well documented are erythropoietic,
neural, renal-endocrine, and hepatic effects indicated above by solid arrows ( ^-) Plausible
further consequences of heme synthesis interference by lead which remain to be more conclu-
sively established are indicated by dashed arrows (
1-133
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Dose-Effect Relationships for Human Adults. The lowest observed effect levels (in terms
of blood lead concentrations) thus far credibly associated with particular health effects of
concern for human adults in relation to specific organ systems or generalized physiological
processes, e g., heme synthesis, are summarized in Table 1-16. That table should be viewed as
representing lowest blood lead levels thus far credibly associated with unacceptable risk for
a given effect occurring among at least some adults. As such, many other individuals may not
experience the stated effect until distinctly higher blood lead levels are reached due to wide
ranges of individual biological susceptibility, variations in nutritional status, and other
factors
The most serious effects associated with markedly elevated blood lead levels are severe
neurotoxic effects that include irreversible brain damage as indexed by the occurrence of
acute or chronic encephalopathy symptoms observed in both humans and experimental animals
For most human adults, such damage typically does not occur until blood lead levels exceed
100-120 mg/d1. Often associated with encephalopathy symptoms at such blood lead levels or
higher are severe gastrointestinal symptoms and objective signs of effects on several other
organ systems. Precise threshold(s) for occurrence of overt neurological and gastrointestinal
signs and symptoms of lead exposure in cases of subencephalopathic lead intoxication remain to
be established, but such effects have been observed in adult lead workers at blood lead levels
as low as 40-60 jjg/d1, notably lower than levels earlier thought to be "safe" for adult lead
exposure. Other types of health effects occur coincident with the above overt neurological
and gastrointestinal symptoms indicative of marked lead intoxication. These range from frank
peripheral neuropathies to chronic nephropathy and anemia.
Toward the lower range of blood lead levels associated with overt lead intoxication or
somewhat below, less severe but important signs of impairment in normal physiological func-
tioning in several organ systems are evident among apparently asymptomatic lead-exposed
adults, including: (1) slowed nerve conduction velocities indicative of peripheral nerve
dysfunction (at levels as low as 30-40 pg/d1), (2) altered testicular function (at 40-50
(jg/dl); and (3) reduced hemoglobin production (at approximately 50 (jg/dl) and other signs of
impaired heme synthesis evident at still lower blood lead levels. All of these effects point
toward a generalized impairment of normal physiological functioning across several different
organ systems, which becomes abundantly evident as adult blood lead levels exceed 30-40 (jg/dl
Evidence for impaired heme synthesis effects in blood cells exists at still lower blood lead
levels in adults, the significance of this and evidence of impairment of other biochemical
processes important in cellular energetics are discussed below in relation to children
Dose-Effect Relationships for Children. Table 1-17 summarizes lowest observed effect
levels for a variety of important health effects observed in children. Again, as for adults,
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TABLE 1-16 SUMMARY OF LOWEST OBSERVED EFFECT LEVELS FOR KEY LEAD-INDUCED HEALTH EFFECTS IN ADULTS
¦israra, -gas- ig-sas jmi&u ^{gg-
100 120 ug/dl Fnrpnhalnna*h »<- cmnc rk.A...
100-120 pg/dl
Encephalopathy signs
and symptoms
Chronic
nephropathy
80 pg/dl
Frank anemia
60 pg/dl
"f"
SO (jg/d)
Reduced hemoglobin
production
1
Overt subencephalopathic
neurological symptoos
i
Peripheral nerve dysfunction
(slowed nerve conduction)
Altered testicular
function
1
1
Overt gastrointestinal
symptoms (colic, etc )
40 pg/d
Increased urinary ALA and
elevated coproporphynns
-
J.
.1.
30 ijg/d
1
25-30 pg/dl
Erythrocyte protoporphyrin
(EP) elevation in sales
15-20 pg/dl
Erythrocyte protoporphyrin
(EP) elevation in females
<10 pg/dl
ALA-D inhibition
Abbreviations Pbfl = blood lead concentrations
Source This report
-------
TABLE 1-17 SUMMARY OF LOWEST OBSERVED EFFECT LEVELS FOR KEY LEAD-INDUCED HEALTH EFFECTS IN CHILDREN
Lowest Observed
Effect Level (PbB)
Heme Synthesis and
Hematological Effects
Neurological
Effects
Renal System
Effects
Gastrointestinal
Effects
80-100 pg/d1
70 (jg/dl
60 pg/dl
50 pg/dl
40 pg/dl
30 pg/dI
15 pg/dl
10 pg/dl
Frank anemia
Reduced hemoglobin
synthesis
Elevated coproporphyrin
Increased urinary ALA
Erythrocyte protoporphyin
elevation
ALA-D inhibition
Py-5-N activity
inhibition
t
Encephalopathy
signs and symptoms
Peripheral neuropathies
CNS cognitive effects
(IQ deficits, etc )
Peripheral nerve dysfunction
(slowed NCV's)
Altered CNS electrophysiological
responses
Chronic nephropathy
(aminoaciduria, etc )
Vitamin D metabolism
interference
Colic, other overt
gastrointestinal symptoms
Abbreviations PbB = blood lead concentrations, Py-5-N = pyrimidine-5'-nucleotidase.
Source This report
-------
it can be seen that lead impacts many different organ systems and biochemical/physiological
processes across a wide range of exposure levels. Also, again, the most serious of these
effects is the severe, irreversible central nervous system damage manifested in terms of
encephalopathy signs and symptoms. In children, effective blood lead levels for producing
encephalopathy or death are lower than for adults, starting at approximately 80-100 pg/dl
Permanent severe mental retardation and other marked neurological deficits are among lasting
neurological sequelae typically seen in cases of non-fatal childhood lead encephalopathy
Other overt neurological signs and symptoms of subencephalopathic lead intoxication are evi-
dent in children at lower blood lead levels (e g. , peripheral neuropathies detected in some
children at levels as low as 40-60 pg/dl). Chronic nephropathy, indexed by aminoaciduria, is
most evident at high exposure levels over 100 jjg/d1, but may also exist at lower levels (e.g
70-80 pg/dl). In addition, colic and other overt gastrointestinal symptoms clearly occur at
similar or still lower blood lead levels in children, at least down to 60 pg/dl. Frank anemia
is also evident by 70 pg/dl, representing an extreme manifestation of reduced hemoglobin syn-
thesis observed at blood lead levels as low as 40 pg/dl along with other signs of marked heme
synthesis inhibition at that exposure level. All of these effects are reflective of the wide-
spread marked impact of lead on the normal physiological functioning of many different organ
systems and some are evident in children at blood lead levels as low as 40 pg/dl. All of
these effects are widely accepted as clearly adverse health effects.
Additional studies demonstrate evidence for further, important health occurring
in non overtly lead intoxicated children at similar or lower blood lead levels than those
dicated above for widely recognized overt intoxication effects Among the most important and
controversial of the effects discussed in Chapter 12 are neuropsychological and electrophysio-
logical effects evaluated as being associated with low-level lead exposures in non-overtly
lead intoxicated children. Indications of peripheral nerve dysfunction, indexed by slowed
nerve conduction velocities (NCV), have been shown in children down to blood lead levels as
low as 30 pg/dl. As for CNS effects, none of the available studies on the subject, indivi-
dually, can be said to prove conclusively that significant cognitive (IQ) or behavioral
effects occur in children at blood-Pb levels <30 pg/dl. Rather, the collective neurobe-
havioral studies of CNS cognitive (IQ) effects can probably now be most reasonably interpreted
as being clearly indicative of likely associations between neuropsychologic deficits and low-
level lead exposures in young children resulting in blood-Pb levels ranging to as low as 30-50
pg/dl The magnitude of average observed IQ deficits appears to be approxiamtely 5 points at
mean blood lead levels of 50-70 pg/dl and about 4 points at mean blood lead levels of 30-50
pg/dl.
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Certain additional recent studies have obtained results at blood lead values mainly in
the 15-30 pg/dl range interpreted by some investigators as being indicative of small, but not
unimportant, effects of lead on cognitive functioning, the ability to focus attention, appro-
priate social behavior, and other types of behavioral performance. However, due to specific
methodological problems with each of these various studies (as noted in Chapter 12), much
caution is warranted that precludes conclusive acceptance of the observed effects being due to
lead rather than other (at times uncontrolled for) potentially confounding variables This
caution is particularly warranted in view of other well-conducted studies now beginning to
appear in the literature which did not find statistically significant associations between
lead and similar effects at blood lead levels below 30 jjg/dl. Still, because such latter
studies found 1-2 point IQ deficits remaining after correction for confounding factors, lead
cannot be totally ruled out as a possible etiological factor contributing to the induction of
such effects in the 15-30 jjg/dl range, based on existing published studies.
Also of considerable importance are studies which provide evidence of changes in EEG
brain wave patterns and CNS evoked potential responses in non-overtly lead intoxicated chil-
dren. The work of Burchfiel et al. (1980) indicates significant associations between IQ de-
crements, EEG pattern changes, and lead exposures among children with average blood lead
levels falling in a range of 30-50 jjg/dl. Research results provided by Otto et al (1981,
1982, 1983) also demonstrate clear, statistically significant associations between electrophy-
siological (SW voltage) changes and blood-Pb levels in the range of 30-55 (jg/dl and analogous
associations at blood-Pb levels below 30 pg/dl (with no evident threshold down to 15 pg/dl or
somewhat lower). In this case, the presence of electrophysiological changes observed upon
follow-up of some of the same children two years and five years later suggests persistence of
such effects even in the face of later declines in blood-Pb levels and, therefore, possible
long-term persistence of the observed electrophysiological CNS changes. However, the reported
electrophysiological effects in this case were not found to be significantly associated with
IQ decrements
The precise medical or health significance of the neuropsychological and electrophysiolo-
gical effects found by the above studies to be associated with low-level lead exposures is
difficult to state with confidence at this time. The IQ deficits and other behavioral changes
detected at blood lead levels above 30 pg/dl, although statistically significant, are gen-
erally relatively small in magnitude as detected by the reviewed studies, but nevertheless may
still impact the intellectual development, school performance, and social development of the
affected children sufficiently so as to be regarded as adverse. This would be especially true
if such impaired intellectual development or school performance and disrupted social develop-
ment were reflective of persisting, long-term effects of low-level lead exposure in early
childhood. The issue of persistence of such lead effects, however, remains to be more clearly
CHP1D/A 1-143 9/6/84
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resolved, with some study results reviewed in Chapter 12 and mentioned above suggesting rela-
tively short-lived or markedly decreasing lead effects on neuropsychological functions over a
few years from early to later childhood and other studies suggesting that significant low-
level lead-induced neurobehavioral and EEG effects may, in fact, persist into later childhood.
At levels below 30 pg/dl, observed IQ and other neuropsychologic effects are typically of even
smaller magnitude, lead's etiological role in producing them is less clearly established, and
their likely medical significance unclear (as is the case for electrophysiological changes
observed at levels below 30 pg/dl)
In regard to additional studies reviewed in Chapter 12 concerning the neurotoxicity of
lead, certain evidence exists which suggests that neurotoxic effects may be associated with
lead-induced alterations in heme synthesis, resulting in an accumulation of ALA in brain which
affects CNS GABA synthesis, binding, and/or inactivation by neuronal reuptake after synaptic
release. Also, available experimental data suggest that these effects may have functional
significance in the terms of this constituting one mechanism by which lead may increase the
sensitivity of rats to drug-induced seizures and, possibly, by which GABA-related behavioral
or physiological control functions are disrupted. Unfortunately, the available research data
do not allow credible direct estimates of blood-Pb levels at which such effects might occur in
rats, other non-human mammalian species, or man. Inferentially, however, one can state that
threshold levels for any marked lead-induced ALA impact on CNS GABA mechanisms are most pro-
bably at least as high as blood-lead levels at which significant accumulations of ALA have
been detected in erythrocytes or non-blood soft tissues (see below). Regardless of any dose-
effect levels inferred, though, the functional and/or medical significance of lead-induced ALA
effects on CNS mechanisms at low levels of lead exposure remains to be more fully determined
and cannot, at this time, be unequivocably seen as an adverse health effect.
Research concerning lead-induced effects on heme synthesis also provides information of
importance in evaluating what blood lead levels are associated with significant health effects
in children. As discussed in Section 1.12.3, lead affects heme synthesis at several points in
its metabolic pathway, with consequent impact on the normal functioning of many body tissues
The activity of the enzyme ALA-S, catalyzing the rate-limiting step of heme synthesis, does
not appear to be significantly affected until blood-lead levels reach or exceed approximately
40 pg/dl The enzyme ALA-D, which catalizes the conversion of ALA to porphobilinogen as a
further step in the heme biosynthetic pathway, appears to be affected at much lower blood-lead
levels as indexed directly by observations of ALA-D inhibition or indirectly in terms of con-
sequent accumulations of ALA in blood and non-blood tissues. More specifically, inhibition of
erythrocyte ALA-D activity has been observed in humans and other mammalian species at blood-
lead levels even below 10-15 yg/dl, with no clear threshold evident. Correlations between
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erythrocyte and hepatic ALA-D activity inhibition in lead workers at blood-lead levels in the
range of 12-56 pg/dl suggest that ALA-D activity in soft tissues (e.g., brain, liver, kidney,
etc.) may be inhibited at similar blood-lead levels at which erythrocyte ALA-D activity inhi-
bition occurs, resulting in accumulations of ALA in both blood and soft tissues.
Some studies indicate that increases in both blood and urinary ALA occur below the cur-
rently commonly-accepted blood-Pb level of 40 jjg/dl; such increases in blood and urinary ALA
are detectable in humans at blood-Pb levels below 30 (jg/dl, with no clear threshold evident
down to 15-20 pg/dl, although other data exist which fail to show any relationship below 40
ng/dl blood lead. Other studies have demonstrated significant elevations in rat brain,
spleen, and kidney ALA levels consequent to acute or chronic lead exposure, but no clear
blood-Pb levels can yet be specified at which such non-blood tissue ALA increases occur in
humans. It is reasonable to assume, however, that ALA increases in non-blood tissues likely
begin to occur at roughly the same blood-Pb levels associated with increases in erythrocyte
ALA levels.
Lead also affects heme synthesis beyond metabolic steps involving ALA, leading to the
accumulation of porphyrin in erythrocytes as the result of impaired iron insertion into the
porphyrin moiety to form heme. The porphyrin acquires a zinc ion in lieu of the native iron,
and the resulting accumulation of blood zinc protoporphyrin (ZPP) tightly bound to erythro-
cytes for their entire life (120 days) represents a commonly employed index of lead exposure
for medical screening purposes. The threshold for elevation of erythrocyte protoporphyrin
(EP) levels is well-established as being 25-30 pg/dl in adults and approximately 15 pg/dl for
young children, with significant EP elevations (>1-2 standard deviations above reference
normal EP mean levels) occurring in 50 percent of all children studied as blood-Pb approaches
or moderately exceeds 30 pg/dl.
Medically, small increases in EP levels have generally not been viewed as being of great
concern at initial detection levels around 15-20 pg/dl in children. However, EP increases
become more worrisome when markedly greater, significant EP elevations occur as blood-Pb
levels approach and exceed 30 pg/dl, and additional signs of significantly deranged heme syn-
thesis begin to appear, along with indications of functional disruption of various organ sys-
tems. Previously, such other signs of significant organ system functional disruptions had
only been credibly detected at blood-Pb levels distinctly in excess of 30 pg/dl, e.g., inhibi-
tion of hemoglobin synthesis starting at 40 pg/dl and significant nervous system effects at
50-60 pg/dl. This served as a basis for CDC establishment of 30 pg/dl blood-Pb as a criteria
level for undue lead exposure for young children and adoption by EPA of it as the "maximum
safe" blood-lead level, allowing some margin(s) of safety before reaching levels associated
with inhibition of hemoglobin synthesis or nervous system deficits, in setting the 1978 NAAQS
for lead.
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Recently, it has also been demonstrated in children that lead is negatively correlated
with circulating levels of the vitamin D hormone, 1,25-dihydroxyvitamin D, with the negative
association existing down to 12 ug/dl of blood lead. This effect of lead is of considerable
significance on two counts: (1) altered levels of l,25-(0H)2-vitamin D not only impact cal-
cium homeostasis (affecting mineral metabolism, calcium as a second messenger, and calcium as
a mediator of cyclic nucleotide metabolism) but also likely impact its known role in immuno-
regulation and mediation of tumorigenesis; and (2) the effect of lead on l,25-(0H)2-vitamin D
is a particularly robust one, with blood lead levels of 30-50 Mg/dl resulting in decreases in
the hormone that overlap comparable degrees of decrease seen in severe kTdney injury or cer-
tain genetic diseases.
Erythrocyte Py-5-N activity in children has also been demonstrated to be negatively im-
pacted by lead at exposures resulting in blood lead levels markedly below 30 Mg/dl (i e. , to
levels below 5 pg/d"f with no evident threshold). Extensive reserve capacity exists for this
blood enzyme, such that it is not markedly depleted until blood lead levels reach approximate-
ly 30-40 pg/d1, arguing for the Py-5-N effect in and of itself as perhaps not being particu-
larly adverse until such blood lead levels are reached. However, the observation of Py-5-N
inhibition is more arguably indicative of wider-spread impacts on pyrimidine metabolism in
general in additional organs and tissues besides blood, such that lead exposures lower than 30
(jg/dl resulting in measurable Py-5-N inhibition in erythrocytes may be of greater medical con-
cern when viewed from this broader perspective.
Also adding to the concern about relatively low lead exposure levels are the results of
an expanding array of animal toxicology studies which demonstrate: (1) persistence of lead-
induced neurobehavioral alterations well into adulthood long after termination of perinatal
lead exposure early in development of several mammalian species; (2) evidence for uptake and
retention of lead in neural and non-neuronal elements of the CNS, including long-term persis-
tence in brain tissues after termination of external lead exposure and blood lead levels
return to "normal"; and (3) evidence from various in-vivo and m-vitro studies indicating
that, at least on a subcel lular-molecular level, no threshold may exist for certain neuro-
chemical effects of lead.
Given the above new evidence that is now available, indicative of significant lead
effects on nervous system functioning and other important physiological processes as blood-Pb
levels increase above 15-20 pg/dl and approach or exceed 30-40 pg/dl, the rationale for con-
tinuing to view 30 pg/dl as a "maximum safe" blood-Pb level is called into question and sub-
stantial impetus is provided for revising the criteria level downward, i.e., to some blood-Pb
level below 30 (jg/dl At this time, it is difficult to identify specifically what blood-Pb
criteria level would be appropriate in view of the existing medical information. Clearly, 30
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pg/dl can no longer be seen as affording any margin of safety before blood lead levels are
reached that are associated with unacceptable risk of notable adverse health effects occurring
in some children. This is based on at least two grounds" (1) blood lead levels in the 30-40
pg/dl range are now known to "mask" for some children markedly elevated chelatable body lead
burdens that are comparable to lead burdens seen in other children displaying overt signs and
symptoms of lead intoxication; and (2) blood lead levels in the 30-40 pg/dl range are also
associated with the onset of deletarious effects in several organ systems which are either
individually or collectively seen as being adverse.
At levels below 30 pg/dl, many of the different smaller effects reported as being asso-
ciated with lead exposure might be argued as separately not being of clear medical signifi-
cance, although each are indicative of interference by lead with normal physiological pro-
cesses. On the other hand, the collective impact of all of the observed effects (representing
potentially impaired functioning and depleted reserve capacities of many different tissues and
organs) may, at some point distinctly below 30 pg/dl, be seen as representing an adverse
pattern of effects worthy of avoidance with some added margin of safety. The onset of signs
of detectable heme synthesis impairment in many different organ systems at blood lead levels
starting around 10-15 pg/dl, along with indications of increasing degrees of pyrimidine meta-
bolism interference and signs of altered nervous system activity, could be viewed as such a
point Or, alternatively, the collective impact of such effects might be argued as becoming
sufficiently adverse to warrant avoidance (with a margin of safety) only when the various
effects come to represent marked deviations from normal as blood lead levels exceed 20-25
pg/dl and begin to approach the more clearly adverse 30 pg/dl level. Lastly, other arguments
have been advanced to the effect that any deviation from normal biochemical levels or physio-
logical functioning in any organ system should be viewed as adverse health effects to be
avoided, even at blood lead levels below 10 (jg/dl.
The frequency of occurrence of various effects among individual, affected children at
various blood lead levels may have important bearing on the ultimate resolution of the above
issue regarding the definition of blood-lead levels associated with adverse health effects in
pediatric populations. The porportion of children likely affected (i.e., responders) in terms
of experiencing particular types of effects at various lead levels is also an important con-
sideration Some information bearing on this latter point is discussed next.
1-13.5 Dose-Response Relationships for Lead Effects in Human Populations
Information summarized in the preceding section dealt with the various biological effects
of lead germane to the general population and included comments about the various levels of
blood lead observed to be associated with the measurable onset of these effects in various
populations groups.
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As indicated above, inhibition of ALA-D activity by lead occurs at virtually all blood
lead levels measured in subjects residing in industrialized countries. If any threshold for
ALA-D inhibition exists, it lies somewhere below 10 pg Pb/dl in blood lead.
Elevation in erythrocyte protoporphyrin for a given blood lead level is greater in
children and women than in adult males, children being somewhat more sensitive than women.
The threshold for currently detectable EP elevation in terms of blood lead levels for children
was estimated at approximately 16-17 pg/dl in the recent studies of Piomelli et al. (1982).
In adult males, the corresponding blood lead value is 25-30 jjg/dl.
Statistically significant reduction in hemoglobin production occurs at a lower blood lead
level in children (40 pg/dl) than in adults (50 pg/dl).
It appears that urinary ALA shows a correlation with blood lead levels to below 40 pg/dl,
but since there is no clear agreement as to the meaning of elevated ALA-U below 40 pg/dl, this
value is taken as the threshold for pronounced excretion of ALA into urine. This value
appears to apply to both children and adults. Whether this blood lead level represents a
threshold for the potential neurotoxicity of circulating ALA cannot now be stated and requires
further study.
Coproporphyria elevation in urine first occurs at a blood lead level of 40 (jg/dl and this
threshold appears to apply for both children and adults.
A number of investigators have attempted to quantify more precisely dose-population
response relationships for some of the above lead effects in human populations. That is, they
have attempted to define the proportion of a population exhibiting a particular effect at a
given blood lead level. To date, such efforts at defining dose-response relationships for
lead effects have been mainly limited to the following effects of lead on heme biosynthesis,
inhibition of ALA-D activity; elevation of EP; and urinary excretion of ALA.
Dose-population response relationships for EP in children has been analyzed in detail by
Piomelli et al. (1982) and the corresponding plot at 2 levels of elevation (>1 S.D., >2 S.D )
is shown in Figure 1-23 using probit analysis. It can be seen that blood lead levels in half
of the children showing EP elevations at >1 and 2 S.D "s closely bracket the blood lead level
taken as the high end of "normal" (i.e., 30 pg/dl). Dose-response curves for adult men and
women as well as children prepared by Roels et al. (1976) are set forth in Figure 1-24. In
Figure 1-24, it may be seen that the dose-response for children remains greater across the
blood-lead range studied, followed by women, then adult males.
Figure 1-25 presents dose-population response data for urinary ALA exceeding two levels
(at mean + 1 S.D and mean + 2 S.D.), as calculated by EPA from the data of Azar et at
(1975). The percentages of the study populations exceeding the corresponding cut-off levels
as calculated by EPA for the Azar data are set forth in Table 1-18. It should be noted that
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<
D
O
>
a
z
(j
z
3
O
EP I - 2SD
C ^ NATURAL FREQUENCY
L
20 30 40 SO
BLOOD LEAD ug/dl
60
70
Figure 1-23. Dose-response for elevation of EP as a
function of blood lead level using probit analysis.
Geometric mean plus 1 S.D. = 33119/dl; geometric
mean plus 2 S.D. =¦ 53
Source: Piomelli et al. (1982).
100
(/)
-J
Ui
>
<
(/)
o
<
-J
3
&
O
a.
o
<
u
ac
AOULT FEMALES
CHILDREN / I
ADULT MALES
10 20 30 40
BLOOD LEAD LEVEL yg/dl
50
Figure 1-24. Dose-response curve for FEP as a
function of blood lead level in subpopulations.
Source: Roels et al. (1976).
1-149
-------
>
UJ
O
<
3
<
<
X
50
<
•j
2
UJ
U
s
A MEAN 2 S O
MEAN ALAU 0 32 FOR
BLOOD LEAD 13 *ig/dl
&
10
20
30
40
50
60
70
80
90
Bl OOO LEAD LEVEL ^g/dl
Figure 1-25. EPA calculated dose-response curve for
ALA-U.
Source: Azaretal. (1975).
TABLE 1-18. EPA-ESTIMATED PERCENTAGE OF SUBJECTS
WITH ALA-U EXCEEDING LIMITS FOR VARIOUS BLOOD LEAD LEVELS
Blood lead levels
(ng/dl)
Azar et al. (1975)
(Percent Population)
10
2
20
6
30
16
40
31
50
50
60
69
70
84
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the measurement of ALA in the Azar et al. study did not account for aminoacetone, which may
influence the results observed at the lowest blood lead levels.
1.13.6 Populations at Risk
Population at risk is a segment of a defined population exhibiting characteristics asso-
ciated with significantly higher probability of developing a condition, illness, or other ab-
normal status. This high risk may result from either (1) greater inherent susceptibility or
(2) exposure situations peculiar to that group. What is meant by inherent susceptibility is a
host characteristic or status that predisposes the host to a greater risk of heightened
response to an external stimulus or agent.
In regard to lead, two such populations are definable. They are preschool age children
(^6 years old), especially those living in urban settings, and pregnant women. Children are
such a population for both of the reasons stated above, whereas pregnant women are at risk
primarily due to the inherent susceptibility of the conceptus.
Children as a Population at Risk. Children are developing and growing organisms exhibi-
ting certain differences from adults in terms of basic physiologic mechanisms, capability of
coping with physiologic stress, and their relative metabolism of lead. Also, the behavior of
children frequently places them in different relationship to sources of lead in the environ-
ment, thereby enhancing the opportunity for them to absorb lead. Furthermore, the occurrence
of excessive exposure often is not realized until serious harm is done. Young children do not
readily communicate a medical history of lead exposure, the early signs of such being common
to so many other disease states that lead is frequently not recognized early on as a possible
etiological factor contributing to the manifestation of other symptoms.
Discussion of the physiological vulnerability of the young must address two discrete
areas. Not only should the basic physiological differences be considered that one would
expect to predispose children to a heightened vulnerability to lead, but also the actual
clinical evidence must be considered that shows such vulnerability does indeed exist.
In Chapter 10 and Section 1.13.2 above, differences in relative exposure to lead and body
handling of lead for children vs. adults are noted. The significant elements of difference
include: (1) greater intake of lead by infants and young children into the respiratory and
gastrointestinal (GI) tracts on a body weight basis compared to adults; (2) greater absorption
and retention rates of lead in children; (3) much greater prevalence of nutrient deficiency in
the case of nutrients which affect lead absorption rates from the GI tract; (4) differences in
certain habits, i.e., normal hand to mouth activity as well as pica resulting in the transfer
of lead-contaminated dust and dirt to the GI tract; (5) differences in the efficiency of lead
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sequestration in the bones of children, such that not only is less of the body burden of lead
in bone at any given time, but the amount present may be relatively more labile. Additional
information discussed in Chapter 12 suggests that the blood-brain barrier in children is less
developed, posing the risk for greater entry of lead into the nervous system.
Hematological and neurological effects in children have been demonstrated to have lower
thresholds in terms of blood lead levels than in adults. Similarly, reduced hemoglobin pro-
duction and EP accumulation occur at relatively lower exposure levels in children than in
adults, as indexed by blood lead thresholds. With reference to neurologic effects, the onset
of encephalopathy and other injury to the nervous system appears to vary both regarding likely
lower thresholds in children for some effects and in the typical pattern of neurologic effects
presented, e.g., in encephalopathy or other CNS deficits being more common in children vs.
peripheral neuropathy being more often seen in adults. Not only are the effects more acute in
children than in adults, but also the neurologic sequelae are usually much more severe in
children
The dietary habits of children as well as the diets themselves differ markedly from
adults and, as a result, place children in a different relationship to several sources of
lead. The dominance of canned milk and processed baby food in the diet of many young children
is an important factor in assessing their exposure to lead, since both those foodstuffs have
been shown to contain higher amounts of lead than components of the adult diet. The impor-
tance of these lead sources is not their relationship to airborne lead directly but, rather,
their role in providing a higher baseline lead burden to which the airborne contribution is
added.
Children ordinarily undergo a stage of development in which they exhibit normal mouthing
behavior, as manifested, for example, in the form of thumbsucking. At this time they are at
risk for picking up lead-contaminated soil and dust on their hands and hence into their mouths
where it can be absorbed.
There is, however, an abnormal extension of mouthing behavior, called pica, which occurs
in some children. Although diagnosis of this is difficult, children who exhibit this trait
have been shown to purposefully eat nonfood items. Much of the lead poisoning due to lead-
based paint is known to occur because children actively ingest chips of leaded paint.
Pregnant Women and the Conceptus as a Population at Risk. There are some rather mcon-
culsive data indicating that women may in general be at somewhat higher risk to lead than men
However, pregnant women and their concepti as a subgroup are demonstrably at higher risk. It
should be noted that, in fact, it really is not the pregnant woman per se who is at greatest
risk but, rather, the unborn child she is carrying Because of obstetric complications, how-
ever, the mother herself can also be at somewhat greater risk at the time of delivery of her
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child. With reference to maternal complication at delivery, information in the literature
suggests that the incidence of preterm delivery and premature membrane rupture relates to
maternal blood lead level. Further study of this relationship as well as studies relating to
discrete health effects in the newborn are needed.
Vulnerability of the developing fetus to lead exposure aris-ing from transplacental trans-
fer of maternal lead is discussed in Chapter 10. This process starts at the end of the first
trimester Umbilical cord blood studies involving mother-infant pairs have repeatedly shown a
correlation between maternal and fetal blood lead levels.
Further suggestive evidence, cited in Chapter 12, has been advanced for prenatal lead
exposures of fetuses possibly leading to later higher instances of postnatal mental retarda-
tion among the affected offspring The available data are insufficient to state with any cer-
tainty that such effects occur or to determine with any precision what levels of lead exposure
might be required prior to or during pregnancy in order to produce such effects.
Studies have demonstrated that women in general, like children, tend to show a heightened
response of erythorcyte protoporphyrin levels upon exposure to lead. The exact reason for
this heightened response is not known but may relate to endocrine differences between men and
women.
Description of the United States Population in Relation to Potential Lead Exposure Risk.
In this section, estimates are provided of the number of individuals in those segments of the
population which have been defined as being potentially at greatest risk for lead exposures.
These segments include pre-school children (up to 6 years of age), especially those living in
urban settings, and women of child-bearing age (defined here as ages 15-44). These data,
which are presented below in Table 1-19, were obtained from a provisional report by the U.S.
Bureau of the Census (1982), which indicates that approximately 61 percent of the populace
lives in urban areas (defined as central cities and urban fringe). Assuming that the 61 per-
cent estimate for urban residents also applies to children of preschool age, then approxi-
mately 14,206,000 children of the total listed in Table 1-19 would be expected to be at
greater risk by virtue of higher lead exposures generally associated with their living in
urban vs. non-urban settings. (NOTE: The age distribution of the percentage of urban resi-
dents may vary between SMSA's.)
The risk encountered with exposure to lead may be compounded by nutritional deficits (see
Chapter 10). The most commonly seen of these is iron deficiency, especially in young children
less than 5 years of age (Mahaffey and Michaelson, 1980). Data available from the National
Center for Health Statistics for 1976-1980 (Fulwood et al. , 1982) indicate that from 8 to 22
percent of children aged 3-5 may exhibit iron deficiency, depending upon whether this
condition is defined as serum iron concentration (<40 pg/dl) or as transferrin saturation
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TABLE 1-19. PROVISIONAL ESTIMATE OF THE NUMBER OF INDIVIDUALS IN URBAN AND
RURAL POPULATION SEGMENTS AT GREATEST POTENTIAL RISK TO LEAD EXPOSURE
Total Number in U S.
Actual Age
Population
Urban ^
Population Segment
(year)
(1981)
Population
Pre-school children
0-4
16,939,000
10,333,000
5
3,201,000
1,953,000
6
3,147,000
1,920,000
Total
23'2S7|000
14,2061000
Women of
15-19
10,015,000
6,109,000
child-bearing age
20-24
10,818,000
6,599,000
25-29
10,072,000
6,144,000
30-34
9,463,000
5,772,000
35-39
7,320,000
4,465,000
40-44
6,147,000
3,749,000
Total
b3,83b,UUU
32,838,UUU
Source. U.S. Bureau of the Census (1982), Tables 18 and 31.
*An urban/total ratio of 0.61 was used for all age groups. "Urban" includes central city
and urban fringe populations.
(<16 percent), respectively. Hence, of the 20,140,000 children ^5 years of age (Table 1-19),
as many as 4,431,000 would be expected to be at increased risk, depending on their exposure to
lead, due to iron deficiency.
As pointed out in the preceding section, the risk to pregnant women is mainly due to risk
to the conceptus. By dividing the total number of women of child-bearing age in 1981
(53,835,000) into the total number of live births in 1981 (3,646,000; National Center for
Health Statistics, 1982), it may be seen that approximately 7 percent of this segment of the
population may be at increased risk at any given time.
1.13.7 Summary and Conclusions
Among the most significant pieces of information and conclusions that emerge from the
present human health risk evaluation are the following:
(1) Anthropogenic activity has clearly led to vast increases of lead input into
those environmental compartments which serve as media (e g., air, water, food,
dust, and soil, etc.) by which significant human exposure to lead occurs.
Current blood levels of populations in industrialized societies best reflect
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this impact of man's activities, such lead levels being manifold higher than
blood lead levels found in contemporary populations remote from industrial
activities.
(2) Emission of lead into the atmosphere, especially through leaded gasoline com-
bustion, is of major significance in terms of both the movement of lead to
other environmental compartments and the relative impact of such emissions on
the internal lead burdens in industrialized human populations. By means of
both mathematical modeling of available cl inical/epidemiological data by EPA
and the isotopic tracing of lead from gasoline to the atmosphere to human blood
of exposed populations, the size of atmospheric lead contribution to human
blood lead levels in industrialized areas is estimated to be 25-50 percent
(3) Given this magnitude of relative contribution to human external and internal
exposure, reduction in levels of atmospheric lead would then result in signifi-
cant widespread reductions in levels of lead in human blood (an outcome which
is supported by careful analysis of the NHANES II study data). Reduction of
lead in food (added in the course of harvesting, transport, and processing)
would also be expected to produce significant widespread reductions in human
blood lead levels in the United States, as would efforts to decrease the num-
bers of American children residing in housing with interior or exterior lead-
based paint.
(4) A number of adverse effects in humans and other species are clearly associated
with lead exposure and, from a historical perspective, the observed "thres-
holds" for these various effects (particularly neurological and heme biosynthe-
sis effects) continue to decline as more sophisticated experimental and clini-
cal measures are employed to detect more subtle, but still significant effects
These include significant alterations in normal physiological functions at
blood lead levels markedly below the currently accepted 30 pg/dl "maximum safe
level" for pediatric exposures.
Preceding chapters of this document demonstrate that young children are at
greatest risk for experiencing lead-induced health effects, particularly in the
urbanized, low income segments of this pediatric population. A second group at
increased risk are pregnant women, because of exposure of the fetus to lead in
the absence of any effective biological (e g. , placental) barrier during gesta-
tion.
1-155 9/6/34
(5)
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(6) Dose-population response information for heme synthesis effects, coupled with
information from various blood lead surveys, e.g., the NHANES II study, indi-
cate that large numbers of American children (especially low income, urban
dwellers) have blood lead levels sufficiently high (in excess of 15-20 jjg/dl)
that they are clearly at risk for deranged heme synthesis and, possibly, other
health effects of growing concern as lead's role as a general systemic toxicant
becomes more fully understood.
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