United States         Environmental Criteria and
Environmental Protection    Assessment Office
Agency            Research Triangle Park, NC 27711
                                   EPA-600/8-83/028aF
                                   June 1986
Research and Development
Air Quality
Criteria for  Lead
Volume I  of IV

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                           EPA-600/8-83/028aF
                                       June 1986
Air Quality Criteria for Lead
          Volume I of  IV
      U.S. ENVIRONMENTAL PROTECTION AGENCY
         Office of Research and Development
      Office of Health and Environmental Assessment
      Environmental Criteria and Assessment Office
         Research Triangle Park, NC 27711

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                                   NOTICE

     Mention  of  trade  names  or  commercial  products  does  not  constitute
endorsement or recommendation for use.
                                       n

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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 1985 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.
                                       m

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                                           CONTENTS
                                                                                          Page
VOLUME I
  Chapter 1.  Executive Summary and Conclusions 	    1-1

VOLUME II
  Chapter 2.   Introduction 	    2-1
  Chapter 3.   Chemical and Physical Properties 	    3-1
  Chapter 4.   Sampling and Analytical Methods for Environmental Lead 	    4-1
  Chapter 5.   Sources and Emissions 	    5-1
  Chapter 6.   Transport and Transformation 	:	    6-1
  Chapter 7.   Environmental Concentrations and Potential Pathways to Human Exposure ..    7-1
  Chapter 8.   Effects of Lead on Ecosystems 	    8-1

VOLUME III
  Chapter 9.   Quantitative Evaluation of Lead and Biochemical  Indices of Lead
               Exposure in Physiological Media 	    9-1
  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
                                              iv

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                                       TABLE OF CONTENTS
                                           CHAPTER 1
                               EXECUTIVE SUMMARY AND CONCLUSIONS
LIST OF FIGURES 	        ix
LIST OF TABLES 	        xi
LIST OF ABBREVIATIONS 	       xii
MEASUREMENT ABBREVIATIONS 	        xv
GLOSSARY VOLUME II 	       xvi
GLOSSARY VOLUME III 	       xix
GLOSSARY VOLUME IV 	        xx
AUTHORS AND CONTRIBUTORS 	      xxii
CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE 	     xxiii
PROJECT TEAM 	       xxv

 1.  EXECUTIVE SUMMARY AND CONCLUSIONS 	      1-1
     1.1  INTRODUCTION 	      1-1
     1.2  ORGANIZATION OF DOCUMENT 	      1-2
     1.3  CHEMICAL AND PHYSICAL PROPERTIES OF LEAD 	      1-3
     1.4  SAMPLING AND ANALYTICAL METHODS FOR ENVIRONMENTAL LEAD 	      1-5
          1.4.1  Sampling Techniques 	      1-6
          1.4.2  Analytical Procedures 	      1-9
     1.5  SOURCES AND EMISSIONS 	      1-11
     1.6  TRANSPORT AND TRANSFORMATION 	      1-19
          1.6.1  Atmospheric Transport 	      1-19
          1.6.2  Deposition 	      1-24
          1.6.3  Transformation 	      1-28
     1.7  ENVIRONMENTAL CONCENTRATIONS AND POTENTIAL PATHWAYS
          TO HUMAN EXPOSURE 	      1-32
          1.7.1  Lead in Air 	      1-32
          1.7.2  Lead in Soil and Dust 	      1-35
          1.7.3  Lead in Food 	      1-36
          1.7.4  Lead in Water 	      1-37
          1.7.5  Baseline Exposures to Lead 	      1-38
          1.7.6  Additional Exposures 	      1-42
                 Urban atmospheres 	      1-42
                 Houses wi th i nteri or 1 ead pai nt 	      1-44
                 Family gardens 	      1-44
                 Houses with lead plumbing 	      1-44
                 Residences near smelters and refineries 	      1-45
                 Occupational exposures 	      1-45
                 Secondary occupational exposure 	      1-46
                 Special habits or activities 	      1-46
          1.7.7  Summary 	      1-47
     1.8  EFFECTS OF LEAD ON ECOSYSTEMS 	      1-50
          1.8.1  Effects on Plants 	      1-53
          1.8.2  Effects of Microorganisms 	      1-56
          1.8.3  Effects on Animals 	      1-57
          1.8.4  Effects on Ecosystems 	      1-59

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                           TABLE OF CONTENTS (continued).
1.9  QUANTITATIVE EVALUATION OF LEAD AND BIOCHEMICAL INDICES OF LEAD
     EXPOSURE IN PHYSIOLOGICAL MEDIA 	      1-61
     1.9.1  Determinations of Lead in Biological  Media 	      1-62
            Measurements of lead in blood 	      1-63
            Lead in plasma 	      1-63
            Lead in teeth 	      1-63
            Lead in hair 	      1-64
            Lead i n uri ne 	      1-64
            Lead i n other ti ssues 	      1-64
            Quality assurance procedures in lead  analyses 	      1-64
     1.9.2  Determination of Biochemical Indices  of Lead Exposure in
            Biological  Media 	     1-65
            Determination of Erythrocyte Porphyrin (Free Erythrocyte
            Protoporphyrin, Zinc Protoporphyrin)  	     1-65
            Measurement of Urinary Coproporphyrin 	     1-66
            Measurement of Delta-Aminolevulinic Acid Dehydrase Activity 	     1-67
            Measurement of Delta-Aminolevulinic Acid in Urine and
            Other Media 	     1-67
            Measurement of Pyrinridine-5'-Nucleotidase Activity 	     1-68
            Measurement of Plasma 1,25-dihydroxyvitamin D 	     1-68
1.10 METABOLISM OF LEAD 	     1-69
     1.10.1 Lead Absorption in Humans and Animals 	     1-69
            Respiratory absorption of lead 	     1-69
            Gastrointestinal absorption of lead 	     1-70
            Percutaneous absorption of lead 	     1-71
            Transplacental transfer of lead 	     1-71
     1.10.2 Distribution of Lead in Humans and Animals 	     1-71
            Lead in Blood 	     1-71
            Lead Levels in Tissues 	     1-72
                     Soft tissues 	     1-72
                     Mineralizing tissue 	     1-73
                     Chelatable lead 	     1-74
                     Animal studies 	     1-74
     1.10.3 Lead Excretion and Retention in Humans and Animals 	     1-75
            Human studies 	     1-75
            Animal studies 	     1-76
     1.10.4 Interactions of Lead with Essential Metals and Other Factors 	     1-76
            Human studies 	     1-76
            Animal studies 	     1~76
     1.10.5 Interrelationships of Lead Exposure with Exposure Indicators
            and Tissue Lead Burdens 	     1-77
            Temporal charactersitics of internal  indicators of lead exposure 	     1-78
            Biological  aspects of external exposure/internal indicator
            relationships 	     1-78
            Internal indicator/tissue lead relationships 	     1-78
     1.10.6 Metaboli sm of Lead Alkyls 	     1-79
            Absorption of lead alkyls in humans and animals 	     1-79
            Biotransformation and tissue distribution of lead alkyls 	     1-80
            Excretion of lead alkyls 	     1-80
                                         VI

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                           TABLE OF CONTENTS (continued).
1.11 ASSESSMENT OF LEAD EXPOSURES AND ABSORPTION IN HUMAN POPULATIONS 	     1-80
     1.11.1 Levels of Lead and Demographic Covariates
            in U.S.  Populations 	     1-81
     1.11.2 Time Trends in Blood Lead Levels Since 1970	     1-85
            Studies in the United States 	     1-85
            European Studi es 	     1-87
     1.11.3 Gasoline lead as an Important Determinant of Trends in Blood Lead
            Levels 	     1-87
     1.11.4 Blood Lead versus Inhaled Air Lead Relationships 	     1-95
     1.11.5 Studies Relating Dietary Lead Exposures (Including Water) to
            Blood Lead 	     1-102
     1.11.6 Studies Relating Lead in Soil and Dust to Blood Lead 	     1-103
     1.11.7 Additional Exposures 	     1-104
1.12 BIOLOGICAL EFFECTS OF LEAD EXPOSURE 	     1-105
     1.12.1 Introduction 	     1-105
     1.12.2 Subcellular Effects of Lead 	     1-105
     1.12.3 Effects of Lead on Heme Biosynthesis, Erythropoiesis, and
            Erythrocyte Physiology in Humans and Animals 	     1-108
     1.12.4 Neurotoxic Effects of Lead 	     1-116
            Internal Lead Levels at Which Neurotoxic Effects Occur 	     1-116
            The Question of Irreversibility 	     1-118
            Early Development and the Susceptibility to Neural Damage 	     1-118
            Utility of Animal Studies in Drawing Parallels to the Human
            Condition 	     1-119
     1.12.5 Effects of Lead on the Kidney 	     1-121
     1.12.6 Effects of Lead on Reproduction and Development 	     1-122
     1.12.7 Genotoxic and Carcinogenic Effects of Lead 	     1-124
     1.12.8 Effects of Lead on the Immune System 	     1-124
     1.12.9 Effects of Lead on Other Organ Systems 	     1-125
1.13 EVALUATION OF HUMAN HEALTH RISKS ASSOCIATED WITH EXPOSURE TO LEAD AND
     ITS COMPOUNDS 	     1-125
     1.13.1 Introduction 	     1-125
     1.13.2 Exposure Aspects:  Levels of Lead in Various Media of Relevance to
            Human Exposure 	     1-126
            Ambient Air Lead Levels 	     1-126
            Levels of Lead in Dust 	     1-127
            Level s of Lead i n Food 	     1-127
            Lead Levels in Drinking Water 	     1-129
            Lead in Other Media 	     1-129
            Cumulative Lead Intake From Various Sources 	     1-129
     1.13.3 Lead Metabolism:  Key Issues for Human Health Risk Evaluation 	     1-130
            Differential Internal Lead Exposure Within Population Groups 	     1-130
            Indices of Internal Lead Exposure and Their Relationship to
            External Lead Levels and Tissue Burdens/Effects 	     1-132
            Proportional Contributions of Lead in Various Media to Blood
            Lead in Human Populations 	     1-136
     1.13.4 Biological Effects of Lead Relevant to the General Human Population .     1-138
            Criteria for Defining Adverse Health Effects 	     1-139
            Dose-Effect Relationships for Human Adults 	     1-140
            Dose-Effect Relationships for Children 	     1-142


                                         vii

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                           TABLE OF CONTENTS (continued).
     1.13.5 Dose-Response Relationships for Lead Effects in Human Populations ...     1-150
     1.13.6 Populations at Risk	     1-154
            Children as a Population at Risk	     1-154
            Pregnant Women and the Conceptus as a Population at Risk 	     1-155
            Description of the U.S.  Population in Relation to Potential
            Middle-Aged White Males (aged 40-59) as a Population at Risk 	     1-156
            Lead Exposure Risk 	     1-157
     1.13.7 Summary and Conclusions 	     1-158
1.14 REFERENCES 	     1-161

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                                        LIST OF  FIGURES


"igure                                                                                   Page

 1-1   Metal  complexes  of  lead  	    1-4
 1-2   Softness  parameters of metals  	    1-5
 1-3   Pathways  of lead exposure  from the  environment  to man, main compartments
       involved  in partitioning of internal body burden of absorbed/retained
       lead,  and main routes of lead  excretion  	    1-12
 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 	    1-14
 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  	    1-18
 1-7   Trend  in  lead content of U.S.  gasolines,  1975-1984  	    1-20
 1-8   Lead consumed in gasoline  and  ambient lead concentrations, 1975-1984  	    1-21
 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) 	    1-25
 1-10  Lead concentration  profile  in  snow  strata of northern  Greenland  	    1-26
 1-11  Variation of lead saturation capacity with cation exchange capacity in
         soil at selected  pH values 	    1-31
 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  (D!-D4)  which have a high binding
         capacity for this metal.   When the flow of nutrients at I,  II, III,  the
         rate of flow of inorganic nutrients to primary producers is  reduced  	    1-51
 1-13  Geometric mean blood lead  levels by race and age for younger  children  in  the
         NHANES II study,  and  the Kellogg  Silver Valley,  ladho  study  and New  York
         childhood screening  studies  	    1-83
 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  	    1-86
 1-15  Time dependence of blood lead for blacks, aged  24 to 35  months,  in New York
         City and Chicago 	    1-88
 1-16  Parallel  decreases in  blood lead values  observed  in the  NHANES II study
         and amounts of lead  used in gasoline  during  1976-1980  	    1-90
 1-17  Change in 206Pb/207Pb  ratios in petrol,  airborne particulate  and
         blood from 1974 to 1981 	    1-92
 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  	    1-96
                                              IX

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                                 LIST OF FIGURES  (continued).


Figure                                                                                   Page

 1-19  Geometric mean blood  lead  levels of New York City children (aged 25-36
         months) by ethnic group,  and estimated amount of lead present in gasoline
         sold in New York, New  Jersey, and Connecticut vs. quarterly sampling
         period, 1970-1976 	    1-97
 1-20  Effects of lead (Pb)  on  heme  biosynthesis  	    1-109
 1-21  Illustration of main  body  compartments involved in partitioning, retention
       and excretion of absorbed  lead and selected target organs for lead toxicity  ...    1-134
 1-22  Multi-organ impact of reductions of heme body pool by  lead 	    1-141
 1-23  Dose-response for elevation of EP as  a function of blood lead level  using
       probit analysis 	:	    1-152
 1-24  Dose-response curve for  FEP as a function  of blood lead level:  in sub-
       populations 	    1-152
 1-25  EPA calculated dose-response  for ALA-U 	    1-153

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                                        LIST OF TABLES


Table                                                                                     Page

 1-1   Estimated atmospheric lead emissions to the atmosphere for the United
       States,  1984 	      1-17
 1-2   Summary of surrogate and vegetation surface deposition of lead 	      1-28
 1-3   Estimated global deposition of atmospheric lead 	      1-29
 1-4   Atmospheric lead in urban, rural, and remote areas of the world 	      1-34
 1-5   Background lead in basic food crops and meats 	      1-37
 1-6   Summary of environmental concentrations of lead 	      1-38
 1-7   Summary of base!ine human exposures to lead 	      1-43
 1-8   Summary of potential additive exposures to lead 	      1-49
 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 	      1-84
 1-10  Summary of pooled geometric standard deviations and estimated
       analytic errors 	      1-85
 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 	      1-91
 1-12  Estimated contribution of leaded gasoline to blood lead by inhalation
       and non-inhalation pathways 	      1-94
 1-13  Summary of blood inhalation slopes (p) 	      1-99
 1-14  Relative baseline human lead exposures expressed per kilogram body weight 	      1-128
 1-15  Contributions from various media to blood lead levels (ug/dl) of U.S.
       children (age = 2 yrs):  Background levels and incremental contributions
       from air 	      1-137
 1-16  Summary of lowest observed effect levels for key lead-induced health effects
       in adults 	      1-143
 1-17  Summary of lowest observed effect levels for key lead-induced health effects
       in children 	      1-144
 1-18  EPA-estimated percentage of subjects with ALA-U exceeding limits for
       various blood lead levels 	      1-153
 1-19  Provisional estimate of the number of individuals in urban and rural
       population segments at greatest potential risk to lead exposure 	      1-158

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                                     LIST OF ABBREVIATIONS
AAS
Ach
ACTH
ADCC
ADP/0 ratio
AIDS
AIHA
All
ALA
ALA-D
ALA-S
ALA-U
APDC
APHA
ASTM
ASV
ATP
B-cells
Ba
BAL
BAP
BSA
BUN
BW
C.V.
CaBP
CaEDTA
CaNa,EDTA
CBD *
Cd
CDC
CEC
CEH
CFR
CMP
CNS
CO
COHb
CP-U

c6ah
D.F.
DA
6-A LA
DCMU
DPP
DNA
DTH
EEC
EEG
EMC
EP
Atomic absorption spectrometry
Acetylcholine
Adrenocorticotrophic hormone
Antibody-dependent cell-mediated cytotoxicity
Adenosine diphosphate/oxygen ratio
Acquired immune deficiency syndrome
American Industrial Hygiene Association
Angiotensin II
Aminolevulinic acid
Aminolevulinic acid dehydrase
Aminolevulinic acid synthetase
Aminolevulinic acid in urine
Ammoniurn pyrrolidine-dithiocarbamate
American Public Health Association
Amercian Society for Testing and Materials
Anodic stripping voltammetry
Adenosine triphosphate
Bone marrow-derived lymphocytes
Barium
British anti-Lewi site (AKA dimercaprol)
benzo(a)pyrene
Bovine serum albumin
Blood serum urea nitrogen
Body weight
Coefficient of variation
Calcium binding protein
Calciurn ethylenediaminetetraacetate
Calcium sodium ethylenediaminetetraacetate
Central business district
Cadmium
Centers for Disease Control
Cation exchange capacity
Center for Environmental Health
reference method
Cytidine monophosphate
Central nervous system
Carbon monoxide
Carboxyhemoglobin
Urinary coproporphyrin
plasma clearance of p-aminohippuric acid
Copper
Degrees of freedom
Dopamine
delta-aminolevulinic acid
[3-(3,4-dichlorophenyl)-l,l-dimethylurea
Differential pulse polarography
Deoxyribonucleic acid
Delayed-type hypersensitivity
European Economic Community
Electroencephalogram
Encephalomyocardi ti s
Erythrocyte protoporphyrin

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                              LIST OF ABBREVIATIONS (continued).


EPA                      U.S.  Environmental Protection Agency
FA                       Fulvic acid
FDA                      Food and Drug Administration
Fe                       Iron
FEP                      Free erythrocyte protoporphyrin
FY                       Fiscal year
G.M.                     Grand mean
G-6-PD                   Glucose-6-phosphate dehydrogenase
GABA                     Gamma-aminobutyric acid
GALT                     Gut-associated lymphoid tissue
GC                       Gas chromatography
GFR                      Glomerular filtration rate
HA                       Humic acid
Hg                       Mercury
hi-vol                   High-volume air sampler
HPLC                     High-performance liquid chromatography
i.m.                     Intramuscular (method of injection)
i.p.                     Intraperitoneally (method of injection)
i.v.                     Intravenously (method of injection)
IAA                      Indol-3-ylacetic acid
IARC                     International Agency for Research on Cancer
ICD                      International classification of diseases
ICP                      Inductively coupled plasma emission spectroscopy
IDMS                     Isotope dilution mass spectrometry
IF                       Interferon
ILE                      Isotopic Lead Experiment (Italy)
IRPC                     International Radiological Protection Commission
K                        Potassium
LDH-X                    Lactate dehydrogenase isoenzyme x
LCgQ                     Lethyl concentration (50 percent)
LD?Q                     Lethal dose (50 percent)
LH                       Luteinizing hormone
LIPO                     Laboratory Improvement Program Office
In                       Natural logarithm
LPS                      Lipopolysaccharide
LRT                      Long range transport
mRNA                     Messenger ribonucleic acid
ME                       Mercaptoethanol
MEPP                     Miniature end-plate potential
MES                      Maximal electroshock seizure
MeV                      Mega-electron volts
MLC                      Mixed lymphocyte culture
MMD                      Mass median diameter
MMED                     Mass median equivalent diameter
Mn                       Manganese
MND                      Motor neuron disease
MSV                      Moloney sarcoma virus
MTD                      Maximum tolerated dose
n                        Number of subjects or observations
N/A                      Not Available
                                              XTM

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                              LIST OF ABBREVIATIONS (continued).
NA
NAAQS
NAD
NADB
NAMS
NAS
NASN
NBS
NE
NFAN
NFR-82
NHANES II
Ni
NTA
OSHA
P
P
PAH
Pb
PBA
Pb(Ac)?
PbB   c
PbBrCl
PBG
PFC
pH
PHA
PHZ
PIXE
PMN
PND
PNS
P.O.
ppm
PRA
PRS
PWM
Py-5-N
RBC
RBF
RCR
redox
RES
RLV
RNA
S-HT
SA-7
S.C.
son
S.D.
SDS
S.E.M.
Not Applicable
National ambient air quality standards
Nicotinamide Adenine Dinucleotide
National Aerometric Data Bank
National Air Monitoring Station
National Academy of Sciences
National Air Surveillance Network
National Bureau of Standards
Norepinephrine
National Filter Analysis Network
Nutrition Foundation Report of 1982
National Health Assessment and Nutritional Evaluation Survey II
Nickel
Ni tri1otri acetoni tri1e
Occupational Safety and Health Administration
Phosphorus
Significance symbol
Para-aminohippuric acid
Lead
Air lead
Lead acetate
concentration of lead in blood
Lead (II) bromochloride
Porphobilinogen
Plaque-forming cells
Measure of acidity
Phytohemaggluti ni n
Polyacrylamide-hydrous-zirconia
Proton-induced X-ray emissions
Polymorphonuclear leukocytes
Post-natal day
Peripheral nervous system
Per os  (orally)
Parts per million
Plasma  renin activity
Plasma  renin substrate
Pokeweed mitogen
Pyrimi de-5'-nucleoti dase
Red blood cell; erythrocyte
Renal blood flow
Respiratory control ratios/rates
Oxidation-reduction potential
Reticuloendothelial system
Rauscher leukemia virus
Ribonucleic acid
Serotonin
Simian  adenovirus
Subcutaneously (method of injection)
Standard cubic meter
Standard deviation
Sodium  dodecyl sulfate
Standard error of the mean
                                               xiv

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                              LIST OF ABBREVIATIONS (continued).
SES
SCOT
slg
SLAMS
SMR
Sr
SRBC
SRMs
STEL
SW voltage
T-cells
t-tests
TBL
TEA
TEL
TIBC
TML
TMLC
TSH
TSP
U.K.
UMP
USPHS
VA
WHO
XRF
X^
Zn
ZPP
Socioeconomic status
Serum glutamic oxaloacetic transaminase
Surface immunoglobulin
State and local air monitoring stations
Standardized mortality ratio
Strontium
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-ammonium
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
Zinc
Erythrocyte zinc protoporphyrin
                                   MEASUREMENT ABBREVIATIONS
dl
ft
g
g/gai
g/ha-mo
km/hr
1/min
mg/km
Mg/m3
mm
|jm
umol
ng/cm2
nm
nM
sec
t
deciliter
feet
gram
gram/gallon
gram/hectare-month
kilometer/hour
liter/minute
mi 11i gram/ki1ometer
microgram/cubic meter
millimeter
micrometer
micromole
nanograms/square centimeter
nanometer
nanomole
second
tons
                     xv

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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.
                                       xvi

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hydroponically grown plants - plants which are grown with their roots immersed
                              in a nutrient-containing solution instead of
                              soil.

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.

LC50 - 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 urn) 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.
                                      xvn

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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.
                                     xviii

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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 urn) 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.
                                     xix

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                             GLOSSARY VOLUME IV


ADP/0 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

demyelination - 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 represser

hepatocyte - a parenchymal liver cell
                                      xx

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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, heal thy-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
                  cells

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 i

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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 Agency
MD-52
Research Triangle Park, NC  27711

Contributing Authors:

Dr. 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.  Eli as
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
                                      xxi i

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                            SCIENCE ADVISORY BOARD
                    CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE
     The substance of this document and its addendum was reviewed by the Clean
Air Scientific Advisory Committee of the Science Advisory Board in public
sessions.
                             SUBCOMMITTEE ON LEAD
Chairman

Dr. Morton Lippmann
Professor
Department of Environmental Medicine
New York University Medical Center
Tuxedo, New York  10987
Executive Secretary

Mr. Robert Flaak
Science Advisory Board (A-101F)
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, D.C.  20460
                                 Panel Members
Dr. Carol R. Angle
Professor of Pediatrics and
  Director UNMC Toxicology Program
University of Nebraska Medical Center
COP - Room 4037A
42nd and Dewey Avenue
Omaha, Nebraska  68105

Dr. J. Julian Chisolm, Jr.
Associate Professor of Pediatrics
The Kennedy Institute
707 North Boardway
Baltimore, Maryland  21205

*Dr. Anita S.  Curren
Commissioner
Westchester County Health Department
112 East Post Road
White Plains,  New York  10601

Dr. Ben B. Ewing
Professor of Environmental Engineering
Institute for Environmental Studies
University of Illinois
408 S. Goodwin
Urbana, Illinois  61801
Dr. Robert Frank
Professor of Environmental Health
  Sciences
Johns Hopkins School of Hygiene
  and Public Health
615 N. Wolfe Street
Baltimore, Maryland  21205

Professor A. Myrick Freeman III
Department of Economics
Bowdoin College
Brunswick, Maine  04011

Dr. Robert Goyer
Deputy Director
NIEHS
P. 0. Box 12233
RTP, North Carolina  27709

Dr. Paul B.  Hammond
Professor of Environmental Health
University of Cincinnati College of Medicine
Kettering Laboratory
3223 Eden Avenue
Cincinnati,  Ohio  45267-0056
                                     xxm

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Dr. Lloyd G. Humphreys
Professor Emeritus
University of Illinois
Urbana-Champaign
603 East Daniel
Champaign, Illinois  61820

Dr. Warren B. Johnson
Director, Atmospheric Science Center
SRI International
333 Ravenswood Avenue
Menlo Park, California  94025

Dr. Paul Kotin
Adjunct Professor of Pathology
University of Colorado Medical School
4505 S. Yosemite #339
Denver, Colorado  80237

Dr. Timothy Larson
Environmental Engineering and
   Science Program
Department of Civil Engineering
FX-10
University of Washington
Seattle, Washington  98195

Dr. Kathryn R. Mahaffey
Chief,  Priorities Research and
   Analysis Branch (C-15)
NIOSH
4676 Columbia Parkway
Cincinnati, Ohio  45226

Professor M. Granger Morgan
Head,  Department  of Engineering
   and  Public Policy
Carnegie-Mellon University
Pittsburgh,  Pennsylvania  15253
Professor Roger G.  Noll
Department of Economics
Stanford University
Stanford, California  94305

Dr. D. Warner North
Principal
Decision Focus Inc., Los Altos
  Office Center, Suit 200
4984 El Camino Real
Los Altos, California  94022

Dr. Robert D. Rowe
Vice President, Environmental
  and Resource Economics
Energy and Resource Consultants, Inc.
Boulder, Colorado  80302

^Professor Richard M. Royal 1
Department of Biostatisties
Johns Hopkins University
615 North Wolfe Street
Baltimore, Maryland  21205

Dr. Ellen K. Silbergeld
Chief Toxics Scientist
Toxic Chemicals Program
Environmental Defense Fund
1525  18th Street,  N.W.
Washington,  D.C.   20036

Dr. James H. Ware
Associate Professor
Harvard  School of  Public Health
Department of Biostastics
677 Huntington Avenue
Boston,  Massachusetts  02115

Dr. Jerry Wesolowski
Air and  Industrial  Hygiene  Laboratory
California Department  of Health
2151  Berkeley Way
Berkeley, California   94704
                                      xxiv

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                         PROJECT TEAM FOR DEVELOPMENT
                                      OF
                         Air Quality Criteria for Lead
Dr. David E.  Weil, Project Manager
  and Coordinator for Chapters 1 and 13, Volume I and IV, and Addendum
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, N.C.  27711

Dr. J.  Michael Davis
Coordinator for Chapters 9, 10, and 12, Volumes III and IV
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, N.C.  27711

Dr. Robert W. Eli as
Coordinator for Chapters 3, 4, 5, 6, 7, and 8, Volume II
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, N.C.  27711

Dr. Lester D. Grant
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, N.C.  27711

Dr. Dennis J. Kotchmar
Coordinator for Chapter 11, Volume III
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, N.C.  27711
                                      xxv

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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 criteria
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 varying
     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  atmo-
spheric 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
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  descriptive;  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  December, 1985,  has been  reviewed  thoroughly  for  information  relevant to air quality
criteria  for  lead;  however, the document is not  intended as a complete and detailed review of
                                            1-1

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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.
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—its 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 and  distribution  of  the present  materials,  this Draft
Final  version  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  following:  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.   In  addition to  the  above materials,  there  is  appended  to  Chapter I an addendum
specifically  addressing:   the  complex  relationship between blood lead  level  and blood pres-
sure;  and the  effects of fetal and pediatric exposures on growth and neurobehavioral develop-
ment.
      An  effort has  been made to  limit the document to a highly critical assessment of the sci-
entific  data base through December, 1985.   The  references  cited do not constitute an exhaus-
tive bibliography of all  available lead-related literature, but they are thought to be suffi-
cient 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 infor-
mation 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

                                             1-2

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Quality Planning and  Standards  in documentation prepared as a part of the process of revising
the National Ambient Air Quality Standard (NAAQS) for Lead.
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 tetraethyllead (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 moiety in an organometallic 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 1-la) 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,
that  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
that 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 ami no acids,  peptides,  and nucleotides  are  known.    The simplest structure
of  this type  occurs  with  the  amino  acid glycine,  as represented  in Figure 1-lb  for  a 1:2
(metal:ligand)  complex.   The importance  of  chelating agents in the  present context is their
widespread use  in the treatment of lead and other metal poisoning.
                                            1-3

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H3C
\
\
Vt
H3C
(a)

CH3
i
CH3

H2O
l
CL ^0. NH2
? \/ V
Pb
CH2 / \ .C^
\ / X ^^ ^
NH2 ^0-^ ^0
H2O
(b)
                           Figure 1-1. Metal complexes of lead.

     Metals are  often classified  according  to some  combination of  their  electronegativity,
ionic 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  1-2).  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.
                                            1-4

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CLASS B OR COVALENT INDEX, X'mr
a.u
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
• I I I I I I I I " I " I
, Au-
f >
• Ag" W
-••Pt" • B.' •
	 • Pb(IV) 	
• Ti" Hg"
_0Cu T' CLASS B _
* Pb" • Sbllll)
- £S *cu" * 	 ~
0Co" In" * 0
— * »Ni" ' • • fe>- Sn(IV) 	
Cr"
Ti" »Tp Zn"
— Mn"» v" Ga' * BORDERLINE ~
_ Gd" Lu>' 	
I9" . ••» •*''• •
Cs- Ba" • • yl. A)J.
V •••Ca" U" -
\Na- Sr" •
• Be"
~ L' CLASS A
1 1 I I I I I ! ,.l ,,l
                                    6    8    10    12   14   16
                                    CLASS A OR IONIC INDEX, Z'/r
20   23
                                Figure 1-2. 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.
                                            1-5

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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
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 of 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 ijg/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  described 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.
                                             1-6

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     Airborne lead  is  primarily inorganic participate 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  ug/m3.
Some samplers measure lead deposition expressed in (jg/cm2; some instruments separate particles
by size.  As a general rule, particles smaller in mass median aerodynamic diameter (MMAD) than
2.5 (jm  are  classified as "fine," and those larger than 2.5 \im 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 tech-
nique, 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 rela-
tively 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 fluores-
cence,  analysis  can  be performed directly  on  the filter  if  the filter material  is suitable.
                                            1-7

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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
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 rain
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
cooling.
     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, 1983).
Containers used  for sample collection  and storage should be fabricated  from essentially lead-
                                                               is;)
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

                                            1-8

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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.

1.4.2  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.,  1976)].   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
                                            1-9

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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).
     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 (jg/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  (XRF)  allows   simultaneous  identification of several elements,  in-
cluding  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 emission 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, in-
cluding  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 pro-
viding compositional  information on individual  lead particles, thus  permitting the  study  of
dynamic chemical changes and perhaps allowing improved source  identification.
                                            1-10

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     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.
     Colorimetric 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
     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 partic-
ular importance to the human environment are emissions of lead to the atmosphere.   The sources
                                            1-11

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of these emissions and  the  pathways of lead through the environment  to man are shown in Figure
1-3.   This  figure shows natural  inputs to soil by crustal weathering  and anthropogenic inputs
to the  atmosphere from automobile  emissions and stationary industrial  sources.   Natural emis-
sions of  lead  to the  atmosphere from  volcanoes  and windblown  soil are  of  minor importance.
                         INDUSTRIAL
                         EMISSIONS
  CRUSTAL
WEATHERING
                                                                       SURFACE AND
                                                                      GROUND WATER
                                       FECES
               Figure 1-3. Pathways of lead from the environment to man, main compartments
               involved in partitioning of internal body burden of absorbed/retained lead, and
               main routes of lead excretion.
                                               1-12

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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.
     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  versus  anthropogenic  lead  inputs.   Other  studies  have  shown the  same
magnitude of increasing  deposition  in freshwater marine sediments.   The  pond and marine sedi-
ments  also  document  the  shift in isotopic composition of atmospheric lead caused by increased
commercial  use of  the  New Lead Belt  in  Missouri,  where the ore body has an isotopic  composi-
tion substantially different from other ore  bodies of the world.
     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
that began  in  the  1920's did not reach the  South Pole until the mid-19501s.   This interpreta-
tion agrees with  that  of Maenhaut et al.  (1979), who found atmospheric concentrations  of lead
of  0.000076 ug/m3  at the same  location.  This  concentration is about 3-fold higher than  the
0.000024 ug/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
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
efficiency,  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
                                            1-13

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         1750
1775
1950
1975
         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 a). (1969) (O), Shirahata et al. (1980) (D), Edgington
         and Bobbins (1976) (A ), Ng and Patterson (1982) ( A ), and Rolfe (1974) ( • ).
gasoline combustion.   From this  knowledge of the chronological record, it is possible  to sort
out contemporary  anthropogenic  emissions from natural sources  of atmospheric  lead.
     Natural  lead  enters  the  biosphere  from lead-bearing minerals in  the  lithosphere.   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 ug/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 ug/m3 (U.S.
                                             1-14

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    Q  10'
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       10°
                                                                   SPANISH PRODUCTION
                                                                        OF SILVER
                                                                      IN NEW WORLD
                                               EXHAUSTION
                                               OF ROMAN
                                               LEAD MINES
                                                                            INDUSTRIAL
                                                                            REVOLUTION
  SILVER
PRODUCTION
IN GERMANY
              DISCOVERY OF
              CUPELLATION
                                      INTRODUCTION
                                       OF COINAGE
                                            RISE AND FALL
                                             OF ATHENS
                                                    \
                                                   ROMAN REPUBLIC
                                                     AND EMPIRE
H—J\      I       I      I
                                                           I       I
                                                                  I	I
           5500   5000  4500   4000   3500   3000   2500    2000   1500   1000    500
                                      YEARS BEFORE PRESENT
        Figure 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 5-1.
        Source:  Adapted from Settle and Patterson (1980).
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  metric  t/yr over the  10-year period, with  storage bat-
teries  and gasoline additives accounting for approximately  70 percent of  total use.   Certain
                                              1-15

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products, especially batteries,  cables,  plumbing,  weights,  and ballast, contain  lead that is
economically recoverable 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.
     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 recipi-
ent.  Estimated  lead emissions  to the atmosphere are shown  in Table  1-1.   Mobile and station-
ary  sources of  lead  emissions,  although found throughout the  nation,  tend to be concentrated
in  areas  of high  population density, and near  smelters.  Figure  1-6 shows  the approximate
locations of major  lead mines,  primary and secondary smelters  and  refineries,  and alkyl  lead
paints (International Lead Zinc Research Organization, 1982).
     The majority of lead  compounds found in the  atmosphere  result  from leaded gasoline  com-
bustion.  Several  reports  indicate  that transportation  sources contribute  about 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  urn in diameter).  Parti-
cles in this size category are subject to growth  by coagulation and,  when airborne, can remain
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 is emitted as  small particles  (<0.25 (jm MMAD), and approximate-
ly  40  percent is  emitted as  larger particles   (>10  urn MMAD)  (Ter  Haar  et  al.,  1972).   The
remainder of  the lead  consumed  in  gasoline combustion  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.
                                            1-16

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         TABLE  1-1.   ESTIMATED  ANTHROPOGENIC  LEAD  EMISSIONS  TO  THE  ATMOSPHERE  FOR  THE
                                      UNITED  STATES,  1984
Source Category
Gasoline combustion
Waste oil combustion
Solid waste disposal
Coal combustion
Oil combustion
Gray iron production
Iron and steel production
Secondary lead smelting
Primary copper smelting
Ore crushing and grinding
Primary lead smelting
Zn smelting
Other metallurgical
Lead alkyl manufacture
Lead acid battery manufacture
Portland cement production
Miscellaneous
Total
Annual (1984)
emissions,
(t/yr)
34,881
781
352
265
115
54
427
278
29
116
1150
116
11
224
112
70
35
39,016a
Percentage of
total U.S.
emissions
89.4%
2.0
0.9
0.7
0.3
0.1
1.1
0.7
0.1
0.3
2.8
0.3
0.1
0.6
0.3
0.2
0.1
100%
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:   Updated from Battye (1983).

     The use of  lead  additives in gasoline, which increased  in volume for many years,  is now
decreasing both because automobiles designed to use unleaded fuel  constitute the major portion
of the  automotive  population  and because of two  regulations  promulgated  by the U.S.  Environ-
mental  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 reduc-
tion or phase-down of the lead content in leaded gasoline.   The trend in lead content for U.S.
                                            1-17

-------
I
I—»
CO
- -r-1
1 	
I
1
1

~l
I
1
i
                                     -J.J1
                                                          \
                                                                         MINES (11)
                                                                         SMELTERS AND REFINERIES (5)
                                                                       O SECONDARY SMELTERS AND REFINERIES (39)
                                                                       • LEAD ALKYL PLANTS (4)
                                      Figure 1-6.  Locations of major lead operations in the United States.

                                      Source: International Lead Zinc Research Organization (1985).

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gasolines is shown  in  Figure 1-7.   Of the total gasoline pool, which includes both leaded and
unleaded fuels, the  average  lead content decreased 73 percent,  from  an  average of 1.62 g/gal
in  1975  to  0.44  g/gal  in 1984.  The  current  allowable  lead content of  unleaded  gasoline  is
0.1 g/gal (F.R., 1985;  March 7).
     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
1984, the lead  consumed  in gasoline decreased 73 percent (from 167,400 to 46,000 metric tons)
while the corresponding  composite  maximum quarterly average of ambient lead decreased 71 per-
cent (from 1.23 to 0.36 |jg/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.
     A new locus for lead emissions emerged in the mid-1960s with the opening of the "Viburnum
Trend" or "New Lead Belt" in southeastern Missouri.  The  presence of eight mines and three ac-
companying lead  smelters  in this  area makes  it the  largest  lead-producing  district  in the
world.
1.6  TRANSPORT AND TRANSFORMATION
1.6.1  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 at the tailpipe are
typically around  24,000 |jg/m3,  while lead values  in  city  air are usually between  0.1  and 10
ug/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
                                            1-19

-------
    240
    200  -
    1.50
Z
O
u
    1.00
    0.50 -
    0.00
             SALES WEIGHTED TOTAL
             GASOLINE POOL
             (LEADED AND UNLEADED
             'AVERAGE
          1975    1976     1977     1978     1979    1980

                                   CALENDAR YEAR
1981
1982
1983
                 1984
           Figure 1-7. Trend in lead content of U.S. gasolines, 1975-1984.

           Source:  U.S. Environmental Protection Agency (1985).
                                        1-20

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    180
    160
    140
§   120
O


ILl"
O
W
    100
O    80
LU
5
D

Z
O
U    60
     40
     20
                                   LEAD CONSUMED IN GASOLINE
                                                                          1.2
         LEAD CONCENTRATION
                                        I       I       I      I
                                                                           03
                                                                          0.2
                                                                          0.1
                                                                                O
                                                                                u
            1975   1976   1977   1978   1979   1980   1981    1982   1983   1984


                                  CALENDAR YEAR




     Figure 1-8.  Lead consumed in gasoline and ambient lead concentrations, 1975-1984.


     Source:  U.S. Environmental Protection Agency (1985, 1986).
                                            1-21

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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  urn);  the  accumulation mode (0.1-2 (jm);  and the  large particle mode (>2 urn).
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
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  that 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
                                            1-22

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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 11 mines and 5 primary
smelters and  refineries  shown in  Figure 1-6  are  not  located in  urban areas.   Most of the 39
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 ug/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
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 (Stolzenburg  et  al. ,  1982).   Sievering et al.
(1980) used the method of Stolzenburg 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 ug/m3,  whereas the  two rural sites  were about 0.15 ug/m3.   The average particle
size  became smaller toward  the rural  sites,  as the MMAD  shifted downward from 0.5  to  0.1 urn.
                                            1-23

-------
     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  degree 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  interhemispheric 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.
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.
 1.6.2  Deposition
      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
                                             1-24

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   1000
£  2000
ID
+*
0)


i
0  3000
   4000
   5000
                         • DISSOLVED Pb

                         D PARTICULATE Pb
       0   2   4   6   8   10   12   14  16   0
               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).
                     1-25

-------
                 0.20

                 0 18

                 0.16

                 0 14

                 0 12

                 0.10

                 0 08

                 0.06

                 0.04

                 0.02
                                   I  ' '  ' '  I '  ' '  ' I  ' '  ' ' I ' ' ' ' I '  '
                        JLi_
-'~r.  ... i  .... I  .... l .... I  .
                      800
                                  1750
          1800     1850
          	A. D.	
                                                        1900
                                                                1950
                                       AGE OF SAMPLES

                    Figure 1*10. Lead concentration profile in snow strata
                    of Northern Greenland.
                    Source: Murozumi et al. (1969).

move from the  main airstream through the  boundary layer 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 trans-
fer  to  a surface.  These mechanisms  are  a function  of  particle size,  windspeed,  and surface
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
                                             1-26

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Chamberlain (1966).   The models of Slinn  (1982)  and Davidson et al.  (1982)  are  particularly
useful  for lead  deposition.   Slinn1s  model considers a multitude of vegetation parameters to
find several  approximate solutions for particles in the size range of 0.1-1.0 urn MMAD,  estima-
ting 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 V, of 0.05-1.0 cm/sec;  deposi-
tion velocities are specific for each vegetation type.   Both models  show a decrease in deposi-
tion velocity  as  particle  size decreases down to about 0.1-0.2 (jm MMAD; as diameter decreases
further from 0.1 to 0.001 urn MMAD, 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 com-
parable 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 approximate
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.   The amount of lead  removed by wet deposition is approximately
208,000  metric  t/yr  (Table  1-3).   The  deposition flux  for  each  vegetation type  shown on
Table 1-3  totals  202,000 metric 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
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
-------
              TABLE 1-2.   SUMMARY OF SURROGATE AND VEGETATION SURFACE DEPOSITION OF LEAD
Depositional surface
     Flux,
ng Pb/cm2/day
Air cone,
  ng/m3
Deposition velocity,
       cm/sec         Reference
Tree leaves (Paris)              0.38
Tree leaves (Tennessee)       0.29-1.2
Plastic disk (remote          0.02-0.08
  California)
Plastic plates                0.29-1.5
  (Tennessee)
                      13-31
                       110
                                        0.086
                 0.05-0.4
                 0.05-0.06
Tree leaves (Tennessee) — 110 0.005
Snow (Greenland) 0.004 0.1-0.2 0.1
Grass (Pennsylvania) --- 590 0.2-1.1
Coniferous forest (Sweden) 0.74 21 0.41
4
5
6
7
1. Servant, 1975
2. Lindberg et al . , 1982
3. Elias and Davidson, 1980
4. Lindberg and Harriss, 1981
5. Davidson et al . , 1981c, 1981b
6. Davidson et al. , 1982
7. Lannefors et al. , 1983
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) PbO-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
                                            1-28

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                 TABLE 1-3.   ESTIMATED GLOBAL DEPOSITION OF ATMOSPHERIC LEAD
                                   Mass of water,
                                     1017 kg/yr
Lead concentration,
     10-6 g/kg
Lead deposition,
   106 kg/yr
Wet
To oceans
To continents
Dry
To oceans, ice caps, deserts
Grassland, agricultural
areas, and tundra
Forests




4.1 0.4
1.1 0.4
Area Deposition rate
1012 m2 10-3 g/m2-yr
405 0.2
46 0.71
59 1.5
Total dry:
Total wet:
Global:

164
44
Deposition
106 kg/yr
89
33
80
202
208
410
Source:   This report.


ratio is  usually about  0.22.   Habibi et  al.  (1970) studied the composition  of auto exhaust

particles as a function of particle size.   Their main conclusions follow:


     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  |jm MMAD 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 PbO-PbS04, respectively.
                                            1-29

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     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:

                     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
 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
                                             1-30

-------
                                pH = 8
                         	pH = 6
                         	pH = 4
                           25
50
75
                                         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).

uptake.   In  normal  soils,  only a small  fraction of the  total  lead is in exchangeable  form
(about 1 yg/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
                                            1-31

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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
biological   methylation of  lead  was  found  under any  condition.    Chemical  alkylation  from
methylcobalamine was found  to occur in the  presence  of  sulfide  or of  aluminum ion;  chemical
methylation was independent of the presence of bacteria.
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.

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 that 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
                                             1-32

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of this data  base,  the conditions that 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 concentrations is  apparent from Table 1-4, which  summarizes  data ob-
tained from  numerous  independent measurements.   Concentrations vary  from 0.000076  ug/m3  in
remote areas to over 10 ug/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 ug/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  that 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.
     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 (Yocom,
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 ug/m3 at fixed locations, the average per-
sonal exposure was  0.16 ug/m3.   The  authors  suggest  that the use of fixed monitors to assess
exposure is inadequate at either indoor or outdoor locations.
                                            1-33

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TABLE 1-4.   ATMOSPHERIC LEAD IN URBAN, RURAL, AND REMOTE AREAS OF THE WORLD
Location
Urban
New York
Boston
St. Louis
Houston
Chicago
Los Angeles
Ottowa
Toronto
Montreal
Brussels
Turin
Riyadh, Saudi Arabia
Rural
New York Bight
United Kingdom
Italy
Belgium
Illinois
Remote
White Mtn. , CA
High Sierra, CA
Olympic Nat. Park, WA
Great Smoky Mtns. Nat.
Park, TN
Glacier Nat. Park, MT
South Pole
Thule, Greenland
Thule, Greenland
Prins Christian-
sund, Greenland
Dye 3, Greenland
Eniwetok, Pacific Ocean
Kumjung, Nepal
Bermuda
Abastumani Mtns. USSR
Sampling period

1978-79
1978-79
1973
1978-79
1979
1978-79
1975
1975
1975
1978
1974-79
1983

1974
1972
1976-80
1978
1973-74

1969-70
1976-77
1980

1979
1981
1974
1965
1978-79

1978-79
1979
1979
1979
1973-75
1979
Lead cone. ,
(ug/m3)

1.1
0.8
1.1
0.9
0.8
1.4
1.3
1.3
2.0
0.5
4.5
5.5

0.13
0.13
0.33
0.37
0.23

0.008
0.021
0.0022

0.015
0.0046
0.000076
0.0005
0.008

0.018
0.00015
0.00017
0.00086
0.0041
0.019
Reference

NEDS, 1982
NEDS, 1982
NEDS, 1982
NEDS, 1982
NEDS, 1982
NEDS, 1982
NAPS, 1971-1976
NAPS, 1971-1976
NAPS, 1971-1976
Roels et al . , 1980
Facchetti and Geiss, 1982
El-Shobokshy, 1984

Duce et al . , 1975
Cawse, 1974
Facchetti and Geiss, 1982
Roels et al. , 1980
Hudson et al . , 1975

Chow et al. , 1972
Eli as and Davidson, 1980
Davidson et al. , 1982

Davidson et al . , 1985
Davidson et al. , 1985
Maenhaut et al. , 1979
Murozumi et al . , 1969
He i dam, 1983

He i dam, 1983
Davidson et al . , 1981c
Settle and Patterson, 1982
Davidson et al. , 1981b
Duce et al . , 1976
Dzubay et al . , 1984
                                  1-34

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1.7.2  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  that 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 (jg/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).
     A definitive  study  that 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.
                                            1-35

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Except near roadsides  and  smelters,  only a few micrograms  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 may be of both atmospheric and  soil  origin.   As with soils, lead on vegetation surfaces
decreases exponentially with distance away from roadsides  and smelters.  This deposited 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  ug/g,  all  of which  is  soil lead.    Aboveground parts not  exposed to
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.
                                             1-36

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               TABLE 1-5.   BACKGROUND LEAD IN BASIC FOOD  CROPS  AND MEATS
                                      (pg/g fresh weight)
Crop
Wheat
Potatoes
Field corn
Sweet corn
Soybeans
Peanuts
Onions
Rice
Carrots
Tomatoes
Spinach
Lettuce
Beef (muscle)
Pork (muscle)
Natural
Pb
0.0015
0.0045
0.0015
0.0015
0.021
0.005
0.0023
0.0015
0.0045
0.001
0.0015
0.0015
0.0002
0.0002
Indirect
atmospheric
0.0015
0.0045
0.0015
0.0015
0.021
0.005
0.0023
0.0015
0.0045
0.001
0.0015
0.0015
0.002
0.002
Direct
atmospheric
0.034
--
0.019
--
--
--
—
0.004
--
—
0.042
0.010
0.02
0.06
Totalt
0.037
0.009
0.022
0.003
0.042
0.010
0.0046
0.007
0.009
0.002
0.045
0.013
0.02*
0.06*
 Except as indicated, data are from Wolnik et al.  (1983,  1985).
*Data from Penumarthy et al.  (1980).
1.7.4  Lead i_n_ 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
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.   Groundwater
typically ranges from 1 to 100 ug Pb/1  (National  Academy of Sciences, 1980).
                                            1-37

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     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  in  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 ug/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.

                 TABLE 1-6.  SUMMARY OF ENVIRONMENTAL CONCENTRATIONS OF LEAD
Medium
Air (urban)
Air (rural)
Soil total
Food crops
Surface water
Ground water
Natural
lead
(ug/m3)
(ug/m3)
(ug/g)
(ug/g)
(Mg/g)
(|jg/g)
0
0

0
0
0
. 00005
.00005
8-25
.0025
.00002
.003
Atmospheric
lead
0
0
3
0
0

.3 - 1.1
.15 - 0.3
- 5
.002 - 0.045
.005 - 0.030
--
Total
lead
0.3 -
0.15 -
10 - 30
0.002 -
0.005 -
0.001 -
1.1
0.3

0.045
0.030
0.1
                                            1-38

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     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 that 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.
     Besides  the  atmospheric  lead in environmental components,  there are two other industrial
components that  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.   Dusts are different from soil, in
that soil  derives from  crustal  rock and  typically  has  a  lead concentration  of  10-30  ug/g,
whereas dusts come  from  both natural and anthropogenic sources  and vary in lead concentration
from 1000 to  10,000 ug/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
ug/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
                                            1-39

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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 that 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  that 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,  suggested 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 was
thought  to  represent a  contribution of 20  percent to  the total  lead consumption in  foods
(F.R.,  1979,  August 31).   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 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 ug/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 of 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

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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 ug/day
for  adults  and  children.   This  estimate  assumes  that about  90 percent of  the direct atmo-
spheric  lead,  solder lead,  and  lead of  undetermined origin would be  removed  from  the diet,
leaving  8 |jg/day from  these sources and  3  H9/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 (jg 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.   Lead in
standing water from houses newer than five years (copper pipes) averaged 31 ug/1, while houses
less than 18 months old averaged about 70 ug/1.  Houses older than five years and houses with
galvanized pipe  averaged  less  than 6 ug/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
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 ug/g,  whereas  urban street dusts
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range from 1,000  to  20,000 ug/g.   For the purpose  of  estimating potential  human exposure, an
average value of  90  |jg/g in street dust is assumed for baseline exposure and 1500 ug/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  ug/g.   A value of 300  ug/g is
assumed.  The only natural  lead in dust would be  some fraction of that derived from soil lead.
A value of 10  ug/g  seems  reasonable, since  some  of the  soil lead is  of  atmospheric  origin.
Children ingest about  five times  as  much dust as adults,  with 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 in-
crease  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
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  ug  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 ug/g in  urban
environments.
                                            1-42

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                         TABLE 1-7.   SUMMARY OF BASELINE HUMAN EXPOSURES TO LEAD
                                                 (|jg/day)
Source
Child-2 yr old
Inhaled air
Food, Water &
beverages
Dust
Total
Percent
Adult female
Inhaled air
Food, Water &
beverages
Dust
Total
Percent
Adult male
Inhaled air
Food, Water &
beverages
Dust
Total
Percent
Total
lead
consumed

0.5

25.1
21.0
46.6
100%

1.0

32.0
4.5
37.5
100%

1.0

45.2
4.5
50.7
100%
Soil
Natural
lead
consumed

0.001

0.71
0.6
1.3
2.8%

0.002

0.91
0.2
1.2
3.1%

0.002

1.42
0.2
1.6
3.1%
Indirect
atmospheric
lead*

-

1.7
-
1.7
3.5%

-

2.4
-
2.5
6.6%

-

3.5
-
3.5
6.8%
Direct
atmospheric
lead*

0.5

10.3
19.0
29.8
64.0%

1.0

12.6
2.9
17.4
46.5%

1.0

19.3
2.9
23.2
45.8%
Lead from
solder or
other metals

-

11.2
-
11.2
24.0%

-

8.2
-
13.5
36.1%

-

18.9
-
18.9
37.2%
Lead of
undetermined
origin

-

1.2
1.4
2.6
5.6%

-

1.5
1.4
2.9
7.8%

-

2.2
1.4
3.6
7.0%
*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 prior to human consumption.

Source:   This report.

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     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 ug/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 ug/g; the  average  concentration at
ten feet was  slightly  more than  400 ug/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 |jg/g was  increased  to 2000 ug/g for
houses  with interior lead-based  paints.   The additional 1700  (jg/g  would add 85 jjg  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.
      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
direct  atmospheric deposition  onto  aboveground plant parts  or onto soil, or by the flaking of
lead-containing  paint  chips  from houses.  Air concentrations  and particle  size distributions
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 |jg/g  lead on  the surface of a
leafy vegetable  such as  lettuce during a 21-day growing period.  It appears that a significant
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  ug  lead/day.   Water lead levels in the 131 homes
studied ranged  from  less than 50 to  over  500 ug/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

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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  lead  concentrations  within  2 km of  lead
smelters and refineries average 5-15 ug/m3.   Considering both inhaled air and dust, a child in
this circumstance would  be  exposed to 1300  ug lead/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 ug  lead/g can account for 1,000 ug/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.
     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 lead/cm2  of  coating) produces breathing-zone concentrations of
lead  reaching 15,000  ug/m3,  far  in  excess of the  current occupational short-term  exposure
limit in  the United  States  (450 ug/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 ug/m3  and ranged as high as 2400 ug/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 ug/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  and  the plastics  industries,  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
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Department of Employment, Chief  Inspector  of Factories  (1972).   The  source  of this problem is
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 ug/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  ug/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 also 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  ug/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  concentration of 510 ug/m3  after 22 minutes of sanding an  outdoor post coated with paint
containing 2.5 mg  lead/cm2.   After only five minutes of  sanding  an indoor window  sill contain-
ing 0.8-0.9  mg  lead/cm2,  the air contained 550  ug/m3.  Garage mechanics may  also  be exposed to
excessive  lead  concentrations.   Clausen and Rastogi  (1977) report airborne lead  levels  of
0.2-35.5 ug/m3  in  ten garages in Denmark; the  greatest concentration was measured in a paint
workshop.   Used motor oils  were  found to contain 1500-3500 ug lead/g, while one  brand of gear
oil,  unused,  contained  9280  ug/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  alky!  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 ug,  with a median
of 410 ug.   In all cases,  the trousers were worn under coveralls.   Dust  samples from 25 house-
holds of smelter workers ranged  from 120 to 26,000  ug/g, with a median of 2,400 ug/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 food/kg body wt,  or three  times the  consumption
of an 80 kg adult male,  who eats 39 g/kg.

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     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  that  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.
     On  the  other hand, 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 degrees 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 ug/cm2  in  lead-based paint
pigments.  A gram of urban soil may have 150-2000 |jg lead.
     Lead is  also present  in tobacco.  The World  Health Organization (1977) estimates  a lead
content  of 2.5-12.2  |jg  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/day.   Even at 0.1 (jg/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
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
(jg/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.

1.7.7  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  lead should be measured  in terms of the  total  amount of
lead emitted to the biosphere.   American industry contributes several hundred thousand tons of
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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  ug  of lead are consumed daily by
each American.
     Beyond 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 ug/m3), use  and efficiency of respirators, length of time  of exposure, dust
control techniques, and worker training in occupational hygiene.
                                            1-48

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                  TABLE 1-8.   SUMMARY OF POTENTIAL ADDITIVE EXPOSURES TO LEAD
                                           (|jg/day)
    Exposure
  Total
  lead
consumed
Atmospheric
   lead
 consumed
  Other
  lead
sources
Baseline exposure:
Child
 Inhaled air
 Food, water & beverages
 Dust

Total baseline
    0.5
   25.1
   21.0

   46.6
     0.5
    10.3
    19.0

    29.7
   15.6
    2.0

   17.6
Additional exposure due to:
 Urban atmospheres1
 Family gardens2
 Interior lead paint3
 Residence near smelter4
 Secondary occupational5

Baseline exposure:
Adult male
  Inhaled air
  Food, water & beverages
  Dust

Total baseline
   91
   48
  110
  880
  150
    1.0
   45.2
    4.5

   50.7
    91
    12

   880
     1.0
    20.3
     2.9

    24.2
   36
  110
   34.4
    1.6

   36.0
Additional exposure due to:
Urban atmospheres1
Family gardens2
Interior lead paint3
Residence near smelter4
Occupational6
Secondary occupational5
Smoking7
Wine consumption8

28
120
17
100
1100
44
30
100

28
30

100
1100

27
?


17




3
7
Includes lead from household (1000 ug/g) and street dust (1500 ug/g) and inhaled air
 (0.75 ug/m3).
2Assumes soil lead concentration of 2000 ug/g; all fresh leafy and root vegetables, and sweet
 corn of Table 7-12 replaced by produce from garden.  Also assumes 25% of soil lead is of
 atmospheric origin.
3Assumes household dust rises from 300 to 2000 ug/g.  Dust consumption remains the same
 as baseline.
4Assumes household and street dust increase to 10,000 ug/g.
5Assumes household dust increases to 2400 ug/g.
6Assumes 8-hr shift at 10 ug Pb/m3 or 90% efficiency of respirators at 100 ug Pb/m3, and
 occupational dusts at 100,000 ug/m3.
70ne and a half packs per day.
8Assumes unusually high consumption of one liter per day.
                                            1-49

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1.8  EFFECTS OF LEAD ON ECOSYSTEMS
     To function properly,  ecosystems  require  an adequate supply of energy,  which continually
flows through the systems, and an adequate supply of nutrients,  which for the most part,  cycle
within the ecosystem.   There is evidence that lead can interfere with both of these processes.
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  trans-
ferred 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  similar  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 introduced  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/ha-yr  and,  from  atmospheric  deposition,  about 0.02 g/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 ecosystems
and along roadways.   There is, however,  wide variation in the amount of lead transferred 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
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                                                                       GRAZERS
 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 concentration in the  preceding reservoir.  Lead
accumulates in decomposer reservoirs (D.,-D4) which have a high binding capacity for this
metal. When the flow of nutrients is reduced at I, II, or III, the rate of flow of inorganic
nutrients to primary producers is reduced.

Source: Adapted from Swift et al. (1979).
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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 southeastern
Missouri.   Factors  causing great variation are  remoteness  from source (leading  to  lower 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.
     In soils  with  lead  concentrations  within  the  range of natural  lead  (15-30  ug/g),  only
trace  amounts  of  lead  are absorbed by plants.   The amount absorbed increases when the concen-
tration of  lead   in  soil  increases or when the  binding capacity of soil  for  lead decreases.
Uptake by root systems does not necessarily mean  the lead reaches the stems, leaves or fruits.
Rather, the process should be seen as a soil-plant continuum that strongly favors retention of
lead by the soil  and the root system.
     The  soil-root continuum  is a complex structure that consists  of  the soil  particles, the
soil  solution, the  mutigel   or other  remnants  of  root exudates,  the epidermal cells  with
elongated  root hairs,  and  the root cortical  cells.  The walls of the epidermal  cells are  a
loose  matrix  of  cellulose and hemicellulose fibers.  Much  of  this continuum is of biological
origin  and contains  compounds active in ion exchange,  such  as hemicelluloses and pectic  sub-
stances  that   are  heavily endowed  with  -COOH  groups,  and proteins  that also  have charged
groups.   As a  cation moves from the soil particle to the root cortex,  whether by mass flow or

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diffusion, it is  continually  proximate  to root structures with a high binding capacity.   Lead
is more  tightly bound at these  sites than other cations, even  calcium.   Consequently,  rela-
tively little lead passes  through the roots into the shoot.   It appears that most of the soil
lead  is  retained within the  root.   However,  some  plants may allow more  lead  to translocate
than others.
     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.
     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  lug/1.   Of  this  amount,
approximately 0.02 ug/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 ug/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
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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  the  following:   (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.
     The  translocation 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 a lead con-
centration  of 1 ug/g,  increasing  to 50  percent  inhibition  at 3 (jg/g.   Bazzaz et  al.  (1974,
1975)  observed  reduced net photosynthesis that may  have been  caused indirectly by lead inhi-
biting carbohydrate synthesis.
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     The stunting of  plant  growth may be by the inhibition of the growth hormone IAA (indole-
3-ylacetic acid) by  lead.   Lane et al.   (1978)  found  that 10 (jg/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
mitochondria  as  well  as  stimulation  of exogenous  NADH oxidation with  related mitochondrial
swel1 ing.
     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  ug lead/g
sol. with  no  added  calcium,  grew  at  about half  the control  rate with  17  ug  calcium/g sol.
This relation persisted up to 25 ug lead/g sol.  and 500 ug calcium/g  sol.
     These studies of the physiological  effects  of lead on plants all show some effect at con-
centrations of 2-10  ug/g  in the nutrient medium  of  hydroponically-grown agricultural  plants.
It  is  certain  that  no effects would have  been  observed at these concentrations  had  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 sur-
rounding 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  Agrostis tenuis (Karataglis,  1982)  and  Festuca  rubra (Wong, 1982)
under  controlled laboratory  conditions.   Root elongation was used as  the index of  tolerance.
At  lead concentrations  of  36 ug/g  nutrient  solution,  all  populations  of A.  tenuis  were com-
pletely inhibited.   At 12 ug/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  ug/g,  the control  populations achieved 10 per-
cent of their normal  growth, and tolerant populations  achieved 42 percent.  There were no mea-
surements of lead below 6  ug/g.
     The plant effect studies support the conclusion that inhibition  of plant growth  begins at
a lead concentration  of less  than 1 ug/g soil moisture and becomes completely inhibitory at a
level   between  3  and  10 ug/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 ug/g.
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     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 (jg lead/g  or greater.   Concentrations approach-
ing 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 lead concentrations of 750 |jg/g soil  and nitrifi-
cation inhibition at 1000 ug/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 concentrations of
2000-5000 ug/g,  forest  floor nutrient cycling processes may  be seriously disturbed near lead
smelters.   This  is especially  important  because  approximately  70 percent of plant  biomass
enters  the decomposer 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  subsequent 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 ug/g or  as high as  5000 ug/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  (Op),  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,
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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 (jg/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.

1.8.3  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 animals.
The type  of  food an animal eats determines the rate of lead  ingestion.  In the case  of herbi-
vores, 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, inges-
tion of lead by a carnivore depends mostly on deposition on herbivore fur and somewhat less on
lead in herbivore tissue.
     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  species,  confirming  the earlier work  of  Quarles  et al.
(1974)  which  showed  body  burdens  of granivores
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was no evidence  of  toxic effects on the earthworms.   Ash and Lee (1980)  cleared the digestive
tracts of earthworms  and still  found direct correlation of lead in earthworms with soil  lead;
in  this  case,  soil  lead was  inferred  from  fecal  analyses.   Ireland and Richards  (1977)  also
found  some  localization of  lead  in  subcellular  organelles of the  chloragogue  and intestinal
tissue.  In view of the fact that chloragocytes are believed to be involved with waste storage
and glycogen  synthesis,  the authors concluded that  this  tissue  is used to  sequester lead in
the manner of vertebrate livers.
     Chmiel  and Harrison (1981) showed that the bones of small  mammals  had  the highest concen-
trations of  lead, with kidneys and livers  somewhat  less.   They  also showed greater bone con-
centrations  in  insectivores than  herbivores,  both at control  and  contaminated  sites.   Clark
(1979) found  lead concentrations  in shrews, voles, and brown bats from roadside habitats near
Washington,  D.C., to  be higher than any previously reported.   There are  few studies reporting
lead  in  vertebrate  tissues  from  remote sites.   Elias et al. (1976, 1982) reported tissue con-
centrations in voles, shrews, chipmunks, tree squirrels, and pine martens from the remote High
Sierra.  Bone  concentrations were  generally only 2 percent  of  those reported  from roadside
studies  and  10 percent of the controls  of  roadside  studies, indicating that  the  controls in
the roadside studies were themselves contaminated to a large degree.
     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  lead/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 sur-
faces,  and   somewhat  indirectly  by the  uptake of  lead through plant  roots.   Many  of  these
animals  consume  more  than  1 mg  lead/kg-day in  habitats near smelters  and  roadsides,  but no
toxic  effects  have been  documented.   Animals of the decomposer food chain  are  affected in-
directly 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  accumulate  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 (jg/1.   Full  life  cycles were
studied  to estimate population productivity.  Although individual growth rates were not affec-
ted,  increased  mortality,  especially  at  the  egg  hatching stage,  effectively  reduced  total
biomass  production  at  the population level.  Production was 50 percent at a lead concentration
of  36  ug/1 and 0 percent.at 48 ug/1.
      Aquatic  animals  are affected by  lead  at  water  concentrations lower than previously con-
sidered  safe (50 pg/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

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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
erythrocytes and the inhibition of the enzyme ALA-D required for hemoglobin synthesis.   At low
exposures,  fish compensate by  forming additional  erythrocytes,  which  often  do not  reach
maturity; at higher exposures, the fish become anemic.  Symptoms of neurological 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 con-
centration.

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 vege-
tation 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.
     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.
     Babich et  al.  (1983)  introduced the concept of  ecological dose as it applies to the ef-
fects of metals on ecological processes in soil.   The inhibition of microbe-mediated processes
can be  used to quantify the  effects of environmental pollutants on  natural  ecosystems.   The
ecological  dose of  50  percent  (EcD50)  is the  concentration  of a  toxicant that  inhibits  a
microbe-mediated ecologic  process  by 50 percent.  Since  microbes are  an  integral part of the
biogeochemical   cycling  of  elements and the flow of energy  through an  ecosystem,  they are an
important indicator  of  the  productivity of  the ecosystem.  This concept  is  superior to the
lethal  dose  (LD) concept  because  it  is  based on an  assemblage  of heterogeneous populations
that are  important  to the ecosystem and that might be comparable to similar population assem-
blages of  other ecosystems.  The  LD  concept  relies  on  the elimination of single population
that may be insignificant to the ecosystem or not comparable to other ecosystems.
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     The amount  of lead that  causes litter  to  be resistant  to  decomposition is  not  known.
Doelman and  Haanstra  (1979) 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 ug/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 (1979) even at the lowest  experimental concentration  of  lead, leading  to the con-
clusion 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
versus  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 estimating   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.
      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.
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     Of the  450,000 metric  tons  emitted annually  on  a global basis, 115,000 metric  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  highway,  up  to 10,000 ug lead  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 ug/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 ug/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 the 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:  sample collection  and shipment, laboratory han-
dling,  instrumental analysis, and criteria for internal and external quality control.
     From  a  historical  perspective,  the definition of  "satisfactory analytical  method"  for
lead has  been  changing steadily as new  and  more sophisticated equipment has become available
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,  in   conjunction  with  "ultra-clean"
facilities  and  sampling  methods,   to  demonstrate  conclusively  not  only  the true  extent  of
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anthropogenic input of  lead  to the environment over the  years  but also the  relative  limita-
tions 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 isotope-dilution mass
spectrometry (IDMS).   The accuracy and  unique precision  of  IDMS arise from  the fact  that all
manipulations are  on a weight  basis  involving simple procedures,  and  measurements entail  only
lead isotope ratios and  not  the  absolute  determinations of the  isotopes involved, which great-
ly reduces  instrumental  corrections  and  errors.  Reproducible results to  a precision of one
part in 104-105 are  routine  with  appropriately designed  and  competently operated instrumenta-
tion.   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,  required level  of operator expertise,  and time  and effort
 involved  for  measurements by  IDMS,  this methodology  mainly serves for analyses that  either
 require extreme accuracy  and precision,  e.g.,  geochronometry,  or  for  the  establishment  of
 analytical reference material  for general testing  purposes  or the validation of other method-
 ologies.

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     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.   The Delves  cup  procedure,  which  employes  flame
microanalysis, can be  applied to blood lead with an apparent operational sensitivity of about
10  ug/dl  blood and  a relative precision of approximately 5 percent in the range of blood lead
seen  in populations  in  industrialized areas.   The  flameless, or electrothermal, method of AAS
enhances  sensitivity 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.   Metal  exchange reagents
have  been employed  in  lieu of  the ashing  step  to  liberate lead from  binding  sites, although
this  substitution is  associated with less  precision.   For the  ashing method,  relative preci-
sion  is approximately  5  percent; in terms of accuracy and sensitivity, problems appear at low
lead  levels,  e.g.,  5 ug/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,  employed  in an  ultra-clean  facility.
Atomic absorption spectrometry  (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, samples
must  be solubilized  after careful surface cleaning to remove contamination; solubilization 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
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 Jjn situ measurement of lead by X-ray fluorescence spectrometry in children.

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Lead measured  in this  fashion  allows observation  of  ongoing lead accumulation,  rather  than
waiting for exfoliation.
     Lead in Hair.   The  analysis  of lead in  hair  as  an exposure indicator offers  the advan-
tages of being  a noninvasive procedure that  uses  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 exter-
nally 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 using hair as  an external indicator of
exposure.  However, 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 con-
tent 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,  the analysis of  hair  lead  is best used with the simultaneous mea-
surement of blood lead.
     Lead in Urine.  The 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 other mineral elements pres-
ent.   Urine lead  levels  are most  useful  and also  somewhat easier to  determine  in  cases of
chelation mobilization  or chelation therapy, where levels are high enough to permit good pre-
cision  and  dilution 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, which is 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.
     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
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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 with-
in or  outside  the  laboratory.   The reference method is  assumed to be accurate for the parti-
cular  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 analyses  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 tnis  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 Protopor-
phyrin).  With  lead  exposure,  erythrocyte  protoporphyrin  IX  accumulates  because  of impaired
placement of  divalent iron  to form  heme.   Instead,  divalent zinc occupies  the place of the
native  iron.   Depending  upon the method of  analysis,  either metal-free erythrocyte porphyrin
(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
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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 hematof1uorometer.   Because of  the  high  sensitivity  of such
measurement, relatively small blood samples are required,  with liquid samples or blood collec-
ted 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 hematof1uorometer 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  hematof1uorometer  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  hematof1uorometer 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 pg  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 and  give  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  (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 sam-
ple  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 sam-
pling.
     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 because aminoacetone can interfere with colorimetric mea-
surement.   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-dimethylamino-
benzaldehyde  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/milliter 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-oxohexanoic
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.   Currently, 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 and uses radioisotopes and radiometric
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-
cytidinemonophosphate.  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-activity  in  a  liquid scintillation counter.  This  method  shows  a  good
correlation with the earlier 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  1,25-dihydroxyvitamin D  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 the following:

     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
     There are  four'ways in which lead may be absorbed by the body.   The amount of lead enter-
ing the bloodstream via these routes of absorption is influenced 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  in-
volves  lead  uptake  from  food and beverages as well  as lead  deposited in the upper respiratory
tract and eventually swallowed.  It also includes ingestion  of non-food  material, primarily 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 organisms,  in-
cluding 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 versus approx-
imately 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  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.   For example,  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 this differ-
ence  can be  ascribed to  a  difference in  dietary  composition.   In nonhuman primates,  infant
monkeys absorb  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, the
GI  absorption  rate  of lead appears to be  independent  of the  quantity  of  lead  already  in the
gut  up  to a level  of at  least 400 jjg.  In animals, dietary lead levels between 10 and 100 ppm
result in reduced absorption of  lead from the GI tract.
     Percutaneous Absorption of  Lead.   Absorption of inorganic lead compounds through the skin
is  of  much  less significance than absorption through respiratory and GI routes.  On the other
hand,  absorption through skin is  far more  significant than other routes of  exposure  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 occurs  readi-
ly;  this  uptake is  apparent by  the 12th week of gestation in humans and increases throughout
fetal  development.   Cord blood contains  significant  amounts of  lead, correlating with but
somewhat  lower  than maternal  blood lead levels.    Further  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) of  the  erythrocyte lead is bound within the  cell,  primarily associated with hemoglobin
(particularly HbA2), with approximately  5  percent bound to a  10,000-dalton fraction,  20 per-
cent 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 ug/dl  blood  lead.
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     Whole blood  lead  in  daily equilibrium with other compartments in adult humans appears to
have a biological  half-life  of 25-28 days and  amounts  to  about 1.9 mg in total  lead content,
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 ug/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
associated  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-
tional^  exposed  is generally below 0.5 ug/g wet weight, with higher values for  aorta and kid-
ney  cortex.   Brain tissue  lead  level  is  generally below 0.2  ug/g  wet  weight  and  shows 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 consistent with the regional distribution in experimental animals.
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     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
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  when
one  takes  into account the 40-fold  increase  in  skeletal  mass that children undergo.  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  is  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
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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.
     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  the  component  of
teeth that is perhaps the most responsive 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 assessing long-term exposure.
     Chelatable lead.  Mobile lead  in  organs  and systems is potentially more active  toxicolog-
ically  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-
mobilizable is  difficult to define fully, but it most  likely  includes a labile lead compart-
ment within bone as well  as within soft  tissues.   Support for this  view includes the follow-
ing:  (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)  jri
vitro studies  of lead mobilization in  bone  organ explants under  closely  defined conditions;
(4) tracer-modeling 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 define 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
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brain because of  a  poorly developed brain barrier system as well  as from enhanced body reten-
tion of lead by young animals.
     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  the clearance rates
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 simi-
larity 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 rate of biliary clearance
is about 50 percent that of renal clearance.
     Lead  accumulates  in  the  human  body, 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 ug 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
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lead concentrations have  been  gathered.   This parameter itself represents  a  40-fold mass in-
crease.   Thus, this significant skeletal  growth rate has an impact on an obvious question:   if
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 versus 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
     The toxicological  behavior of  elements  such as  lead  is affected 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  deficiencies  in  a  number  of  nutritional  components.   Various surveys
have indicated  that iron,  calcium,  zinc,  and  vitamin deficiencies  are widespread  among the
pediatric population,  particularly the poor.   A number of reports have documented the associ-
ation of lead absorption with suboptimal  nutritional  states for iron and calcium, with 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

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both  increased GI  absorption and  retention,  indicating  that  the lead-calcium  interaction
operates  at  both   the  gut  wall  and within  body  compartments.   Lead  appears to  traverse
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.  Jji  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 for calcium,  iron,  and phosphate versus lead up-
take,  vitamin  D 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
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various indicators in internal exposure;  and  (3) the relationship of various internal  indica-
tors of exposure to target tissue lead burdens.
     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., as in the case 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
possibility 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 j_n  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 curvilinearity 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 blood
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 ug/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
                                           1-78

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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.
     At present, the  measurement  of  plumburesis  associated  with  challenge  by a single  dose  of
a  lead-chelating  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  ug/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 fashion,  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  pose 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.
                                           1-79

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     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
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  mammalian  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.   Alky!  lead  is
rapidly  cleared  from  blood,  and 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 trialkyl
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  in
terms of  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 in-
dices 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 (see Section 1.9).   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.
                                           1-80

-------
     The main discussion in Chapter 11 is structured to achieve four main  objectives:

     (1)  Elucidation of patterns of internal  lead exposures  in U.S.  populations  and  identi-
          fication 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  environ-
          ment 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  Nubian samples  (dated
3300-2900 B.C.)  averaged 0.6  ug lead/g for  bone and  0.9  ug lead/g for  teeth.   More recent
Peruvian  Indian  samples  (12th  Century)  had  teeth lead levels  of 13.6  M9/9-   Contemporary
Alaskan Eskimo samples had a mean of 56.0 ug/g, while Philadelphia samples had a  mean of 188.3
ug/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  ug/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  ug/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 and  Michaelson,  1980; McDowell et al. ,  1981;  Mahaffey et al. ,  1982;  Annest et  al.,
1982;  Annest and Mahaffey,  1984).   The national  estimates are  based on 9933  persons whose
blood  lead  levels  ranged from 2.0  to 66.0  ug/dl.   The median blood lead  for the entire  U.S.
population for the years of the NHANES II study ,(1976-1980) is 13.0 ug/dl.
     Age  appears  to be one of the most important demographic covariates of blood lead levels,
with blood  lead  levels in children 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
                                           1-81

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Figure 1-13.   Blood lead  levels  in non-occupationally  exposed  adults may  increase  slightly
with age due to skeletal lead accumulation.
     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 asso-
ciated 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 ug/dl  in rural  populations  to  12.8 ug/dl  in urban populations of 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.  Fur-
thermore,  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.
     Knowledge of  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 percen-
tiles  in  the  tail  of the  distribution, which  represents  those individuals at highest risk of
excess exposure.
     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.   A somewhat larger
geometric  standard  deviation of 1.42 maybe derived from the NHANES II  study when only  gasoline
and  industrial air  lead  emission  exposures are assumed to be controllable  sources of varia-
tion.
                                           1-82

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  40
  35
  30
1
  25
Q
O
O

GO
  20
  15
. IDAHO STUDY

 NEW YORK SCREENING - BLACKS
• NEW YORK SCREENING - WHITES
• NEW YORK SCREENING - HISPANICS
• NHANES II STUDY - BLACKS
 NHANES II STUDY - WHITES
                                               \.
                                                       \
                                                                                 J
                                           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 at., 1982), the Kellogg Silver Valley, Idaho Study (Yankel et
     al., 1977), and the New York Childhood Screening Studies (Billick et al., 1979).
                                       1-83

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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 UNITED STATES BY AGE AND RACE, UNITED STATES 1976-80
Race and age
All races
All ages
6 months-5 years
6-17 years
18-74 years - men:
women:
Whites
All ages
6 months-5 years
6-17 years
18-74 years - men:
women:
Blacks
All ages
6 months-5 years
6-17 years
18-74 years - men:
women:

Urban,
21 million

14.0*
16.8
13.1
16.9
12.2

14.0
15.6
12.6
16.9
12.4

14.4
20.8
14.6
17.4
11.8
Degree of urbanization
Urban,
<1 million

12.8
15.4
11.7
15.7
11.0

12.5
14.4
11.4
15.4
10.8

14.8
19.2
13.6
18.6
12.4

Rural

11.9
13.0
10.7
15.1
9.8

11.8
12.7
10.5
14.8
9.8

14.4
16.5
13.0
18.3
11.3
*Values are geometric means in |jg/dl.

Source:  Annest and Mahaffey, 1984; Annest et al. (1982).
                                           1-84

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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 1970's and  has continued into 1980.  This  downward trend
has occurred as 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 candidate.

  TABLE 1-10.   SUMMARY OF POOLED GEOMETRIC STANDARD DEVIATIONS AND ESTIMATED ANALYTIC ERRORS
Study
NHANES II
N.Y. Childhood
Pooled geometric standard deviations
Inner-city Inner-city Adult
Black children White children females
1.37a 1.39a 1.36b
1.41 1.42

Adult
males
1.40b
Estimated
analytic
error
0.021
(c)
Screening Study
Tepper- Levin
Azar et al .
1.30
1.29
0.056U
0.042d
Note:   To calculate an estimated person-to-person GSD,
       compute Exp [(In(GSD))2 - Analytic Error)^].
aA geometric standard deviation of 1.42 may be derived when only gasoline and industrial air
 lead emission exposures are assumed to be controllable sources of variability.
 pooled across areas of differing urbanization.
cnot known, assumed to be similar to NHANES II.
dtaken from Lucas (1981).

     Blood  lead  data  from the NHANES  II  study  demonstrate well that, on  a  nationwide basis,
there has been a significant downward trend over time (Annest et al., 1983a).   Mean blood lead
levels dropped from  14.6 ug/dl  during the first  six months of the survey to 9.2 ug/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
decreased  for  all  three  racial  groups and  for  almost  all age groups in  the  period 1970-76.
                                           1-85

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                25
             =5  20
             1
i
00
UJ

§
O
UJ
O
O
2
m
ui
o
DC
UJ
                15
                10
      WINTER 1976
          (FEB.)
WINTER 1977
   (FEB.)
WINTER 1978
   (FEB.)
FALL 1978 WINTER 1979
  (OCT.)      (FEB.)
WINTER 1980
   (FEB.)
                                                                      I
                                   10       15       20       25       30       35

                                                 CHRONOLOGICAL ORDER. 1 unit = 28 days
                                                                          40
                                                          45
                                            50
                                                                                                    55
                     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).

-------
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.
     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 0.0-37.0
ug/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;   Okubo  et al. , 1983).   These papers  cover a variety of exposure  situations  and popula-
tions.  All  of  them obtained  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, however,  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 was a substantial reduction in
reported  blood lead levels.   A  cautionary  note  must be  made, however,  that the  analytic  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  Gasoline  Lead as an Important Determinant 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.
                                           1-87

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      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).

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     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.  (1983b) 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 United  States during the  same time period (see Figure  1-16).   The associa-
tions persisted 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  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 Facchetti  and Geiss (1982) and  Facchetti  (1985), was a mas-
sive  study that  attempted  to utilize differing proportions of the isotopes  in geologic forma-
tions to  infer the  proportion of  lead in gasoline  that  is  absorbed by the  body.   The other
study (Manton, 1977; Manton,  1985) utilized existing  natural  shifts in isotopic  proportions in
an attempt to do the same thing.
     The ILE was 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 blood lead isotopic  ratios were
1.1591 ± 0.0043 in rural  areas and 1.1627 ± 0.0022 in Turin in 1975.   In Turin school children
in 1977-78,  blood  lead  isotopic ratios tended to  be somewhat lower than  the ratios  for Turin
adults.
     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 ug/m3 in Turin  (from
0.88-4.54 ug/m3  depending  on location of  the  sampling  site), about 0.56 (jg/m3  in the nearby
communities (0.30-0.67 (jg/m3), and about 0.30 ug/m3 in distant locations.
                                           1-89

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   100
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                                            I



                                  LEAD USED IN

                                     • GASOLINE
 AVERAGE

 BLOOD

LEAD LEVELS
                                             A
              1976
                     1977
 1978



YEAR
1979
1980
                                                                                        16
                                                                                                    15
                                                                                         14
                                                                                                    11
                                                                                         10
                                                                                              •o
                                                                                              CO
                                                                                         13   O

                                                                                              ui

                                                                                              O
                                                                                              O

                                                                                         12   2
                                                                                              m
                                                                                              ui
                                                                                              O
                                                                                              DC
                                                                                              U)
           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).

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      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


Overall (all races)
All
All
By

By


black6
whites
sex: Male
Female
age: 0.5-5 yr
6-17 yr
18-74 yr
Coefficients for
January-June
and July-December
0.920
0.678
0.929
0.944
0.912
0.955
0.908
0.920
6-month Periods
Apri 1 -September ,
and October-March
0.938
0.717
0.955
0.960
0.943
0.969
0.970
0.924
Averages
0.929
0.698
0.942
0.952
0.928
0.962
0.939
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).

 Averages 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.

eBlacks could not be analyzed according to sex and age subgroups because of inadequate sample
 sizes.

Source:  Annest et al. (1983b).
                                           1-91

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    1.20
   1.18
   1.16
   1.14
o
(SI
 a.
to
   1.10
   1.08
   1.06
              12      24     36
                                     48
                           TIME, months


                              60      72
                                                            84
                                                                    96
                                                                           108
                                                                                  120
                                                                                          132
         -PHASE
"t,
                      PHASE 1	»•
                                O GASOLINE

                                D BLOOD. ADULTS. TURIN

                                A BLOOD, ADULTS, >25 km

                                O BLOOD. ADULTS. <£5 km

                                • BLOOD. SCHOOL CHILDREN

                                • BLOOD. TRAFFIC WARDENS

                                A AIRBORNE PARTICULATE. TURIN

                                  AIRBORNE PARTICULATE, RURAL
                                      -PHASE 2-
                                                                  - PHASE 3-
                                                     I
I
   1.04

    1974     1975   1976    1977    1978   1979    1980    1981    1982    1983    1984


                                                  Yt-AR


    Figure 1-17.  Change in 2^6p(D/207p[3 ratios in gasoline, tolood, and airborne participate from

    1974 to 1984.
   Source:  Facchetti (1985).
                                             1-92

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     Isotope  ratios  in the  blood of  63  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 21.4 ± 10.4 percent  in  Turin  to 11.4 ± 7.3  percent  in the
nearby  countryside,  and to  10.1 ±  9.3  percent in the  remote countryside  (Facchatti,  1985).
     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.   The  results are
shown in Table 1-12 based upon a concept outlined in Facchetti and Geiss (1982).  As concluded
earlier,  an  assumed  value  of p=1.6 is  plausible for predicting the amount  of lead absorbed
into blood at air lead concentrations less than 2.0 ug/m3.   The predicted values for airborne
lead derived  from leaded gasoline range from 0.28 to 2.79 (jg/dl in blood due to direct inhala-
tion.   The total  contribution to blood lead from gasoline lead is much larger, from 3.21-4.66
ng/dl,  suggesting that  the  non-inhalation total contribution of  gasoline  increases from 1.88
ug/dl in  Turin to 2.33  ug/dl in the  near  region  and 2.93 ug/dl in the more distant  region.
The non-inhalation sources include ingestion of dust and soil lead and lead in food and drink-
ing water.  Efforts are being made to quantify their magnitude.   The average direct inhalation
of lead in the air from gasoline is 9-19 percent of the total intake attributable to gasoline
in the countryside and an estimated 60 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  Isotopic  Lead Experiment  comes  very close.   The experimental  intervention  consisted of
replacing the normal  206Pb/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
no need to carry  out detailed aerometric and ecological modeling 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.   Non-
inhalation sources include  ingestion of dust and  soil,  and  lead in food and drinking  water.
The  higher water  lead concentrations  in the  country and consumption of wine containing lead
may  be  factors unaccounted  for  in the analysis.  Dietary  lead  thus may in  part  explain the
large excess  of gasoline  lead isotope  ratio  in  blood  beyond that expected  from inhalation of
*
 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.

                                           1-93

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            TABLE 1-12.   ESTIMATED CONTRIBUTION  OF  LEADED  GASOLINE  TO  BLOOD  LEAD
                           BY INHALATION  AND  NON-INHALATION  PATHWAYS





Location
Turin
<25 km
>25 km

Air lead
fraction
from
gaso-
line3
0.873
0.587
0.587


Air
lead
cone. ,
|jg/m3
2.0
0.56
0.30

Lead
fraction
from
gaso-
linec
0.214
0.114
0.101

Mean
blood
lead d
cone. ,
ug/di
21.77
25.06
31.78
Blood
lead
from
gaso-
line.
Mg/dl
4.66
2.86
3.21

Lead
from
gasol ine,:
in air,
M9/dl
2.79
0.53
0.28
Non-
inhaled
lead from
gaso-
line.
|jg/dl
1.88
2.33
2.93


Estimated
fraction
gas-lead .
Inhalation
0.60
0.19
0.09
 Fraction of air lead in Phase 2 attributable to  lead  in  gasoline.
 Mean air lead in Phase 2.
GMean fraction of blood lead in Phase 2 attributable to  lead  in  gasoline.
 Mean blood lead concentration in Phase 2.
Estimated 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); Facchetti  (1985).
ambient air  lead;  this  could occur both from gasoline  lead  entering the food chain and being
added during food processing and preparation.   The 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 exposures of the subjects,
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  206Pb/204Pb  in the air varied with  seasons  in Dallas,
Texas; therefore,  the  ratio of those isotopes should vary in the blood.   By comparing the ob-
served variability, estimates could then be made of the amount of lead in air that is absorbed
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

                                            1-94

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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 the following:   (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) changes  in  total environmental  lead  exposure.   However,  information was  only  partially
available 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 versus 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.
                                           1-95

-------
E

§
a
UJ
>
UJ
_l

O
<
UJ
_l

O
O
O

ffi


<
UJ


u
UJ


O
UJ

O
    10
        I I  I  |  I  I  I  |  I  I  I  |  I  I  I  | I  I  I  |  I  I  I  |  I  I  I
    35
    30
25 -/
20
    15
                           ——— BLACK

                           — — — HISPANIC

                           — • — AIR LEAD
                    vM           v/   * X-
                    V  \   /       \'    \   / >
              A  A
   -      V     V
                                              \    A
                                            2.5  UJ


                                                0

                                                UJ


                                                cc

                                            2.0  <
                                                                  1.5
                                                                  1.0
        1 J  I  I  I  I  I  I  I I I  I  I  I  I  I  I  I  I  I  I  I  I  I I  I  I
                                                              0.0
     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.
       Source:  Billick et al. (1980).

-------
   30
o
o
O
O
O
ffl  20
ui
5
o
ui

O
ui
C3
   10
                                      BLACK


                                 — — HISPANIC

                                      GASOLINE LEAD
    nl  I  I  I  I  II  I  I  I  I  I  I  I I  I I  I  I  I  I  I  I  I  I  I  I  I  loo

    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.
     Source: Billick et al. (1980).

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     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
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 ug/m3  or  less,  there is no statistically signifi-
cant difference  between curvilinear  and  linear blood lead-inhalation relationships.   At air
lead exposures of 10 ug/m3 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 ug/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 ug/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 ug/dl  per ug/m3.   There are  some  advantages in  using these
experimental  studies on adult  males,  but certain deficiencies are  acknowledged.   The Kehoe
study exposed  subjects  to  a wide range of  lead 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  (jg/m3) add
much  uncertainty to  the  estimate.    The  Rabinowitz study controlled well  for diet and other
factors  and,  since  stable  lead  isotope tracers  were  used,  there  was no  baseline problem.
However,  the  actual  air  lead  exposure of  these  subjects outside  the metabolic ward was not
well  determined.
                                            1-98

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                       TABLE  1-13.   SUMMARY  OF  BLOOD  INHALATION  SLOPES  (p)
                                       (ug/dl  per  ug/m3)
Population
Children




"*

Adult
Male







Study
Angle and Mclntire
(1979) Omaha, NE
Roels et al. (1980)
Belgium
Yankel et al. (1977);
Walter et al . (1980)
Idaho
Azar et al . (1975).
Five groups
Griffin et al .
(1975) NY
prisoners
Gross
(1979)
Rabinowitz et al.
(1973, 1976, 1977)
Study
type N
Population 1074

Population 148

Population 879


Population 149

Experiment 43


Experiment 6

Experiment 5

Model sensitivity
Slope of slope
1.92 (1.

2.46 (1.

1.52 (1.


1.32 (1.

1.75 (1.


1.25 (1.

2.14 (2.

40-4.40)b'C'd

55-2.46)b)C

07-1.52)b)C>d


08-1.59)C'd

52-3. 38)e


25-1. 55)C

14-3. 51)f

 Selected from among the most plausible statistically equivalent models.   For nonlinear
 models,  slope at 1.0 |jg/m3.
DSensitive to choice of other correlated predictors such as dust and soil  lead.
"Sensitive to linear versus nonlinear at low air lead.
 Sensitive to age as a covariate.
"Sensitive to baseline changes in  controls.
 Sensitive to assumed air lead exposure.
                                           1-99

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     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
for  children.   Slope estimates  for  children from  population  studies are used  in which  some
other important  covariates  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/rn3).   The relationship is  in fact
not  linear, but  increases more rapidly  in the upper range of  air  lead exposures,  and  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 ug/dl
per  ug/m3.
     Chapter  II  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  versus total  (both direct and in-
direct) air lead slope for children  may be approximately double the slope (~2.0) estimated for
the direct  contribution due to inhaled air lead  alone.
                                           1-100

-------
     The following statements  summarize  the  situation briefly:   (1) The  experimental  studies
at  lower  air lead levels  (3.2 ug/m3 or less) and  lower  blood  levels (typically 30 ug/dl  or
less)  have  linear  blood lead  inhalation relationships with  slopes  p.  of 0-3.6 for most  sub-
jects.   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 (jg/m3)  and  blood lead levels  are higher  (above 40 ug/dl)
show a  much  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  ug/m3)  and  blood leads  of  30-40 ug/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  differ-
ences  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  exposures.   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 situa-
tions  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  estimates 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 esti-
mates.   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 aggregate analyses (direct and indirect air impacts) typically yield slope values in the
range of 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
                                           1-101

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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.

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  levels 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  and studies  on infants provide estimates that  are  in close agreement.   While only one
individual study  has  been  done on 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  lead  levels  in their diets  (>300  ug/day).   Although the
fitted  cube  root  equations give  high slopes at lower dietary lead levels, the  linear slope of
the  United Kingdom  Central  Directorate on Environmental Pollution (1982) study is probably an
underestimate of  the  slope at lower dietary  lead  levels.   Most of the dietary intake supple-
ments  used in  these two studies were so high that many of the subjects had blood lead concen-
trations  much  in excess  of  30 ug/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  and also probably underestimates to
some extent the value of the  slope.
     The  slope  estimates  for adult  dietary  lead  intake are an  approximately 0.02 ug/dl in-
crease  in  blood lead per ug/day  intake, but  consideration of blood lead kinetics may increase
this  value  to  about 0.04 (jg/dl per ug/day  intake.  Such values are somewhat lower (about 0.05
ug/dl  per ug/day) than  those  estimated from population studies extrapolated to typical dietary
                                            1-102

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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.
     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 water lead 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  (jg/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 cor-
rect in certain situations,  especially at higher water lead levels (>100 ug/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 re-
sulting 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).
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     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 |jg/dl in blood  lead for each  increase  of 1000
ug/g in  soil  lead  concentration.  This range is  similar  to  the  range  of 1.0 to 10.0  reported
by Duggan  (1980, 1983).   Two studies providing good data  for slope estimates are the  Stark et
al.  (1982)  study and  the Angle and  Mclntire (1982)  study.   These two  studies gave slope esti-
mates of 2.2 and  6.8 ug/dl  per 1000  ug/g, respectively.
     The relationship  of  house  dust  lead  to blood lead  is even more difficult  to  obtain.
Three studies have  data permitting  such calculations.   The median value of 1.8  (jg/dl  per 1000
ug/g for children 2-3 years old in  the  Stark study may also represent a reasonable value for
use here.

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), paints with high  levels  of lead were most  frequently
found in pre-1940 residences.  One cannot assume,  however, that high-level  leaded paint is ab-
sent 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.
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The habit of  cigarette  smoking is a  source  of  lead exposure.   Other sources include the fol-
lowing:  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, in-
terdependent fashion.
     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 ef-
fects  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, or 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  the  effects  of lead on the activity of various enzymes are concerned, many of
the  available  studies  examined  the j_n vitro behavior of relatively pure enzymes and have only
marginal relevance to  various effects j_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
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such effects  in  the  summary sections below which deal  with lead's effects on particular organ
systems.   This section  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 affec-
ted by lead  in  numerous 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 i_n
vivo and  jm  vitro.   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 expo-
sures.
     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  i_n  vivo  using mitochondria of both  brain and  non-neural
tissues.   In  some  cases,  the lead  exposure  level  associated  with such changes has  been rela-
tively low.   Several  studies document the  relatively greater  sensitivity  of this organelle in
young versus  adult animals  in terms of mitochondrial  respiration.   The cerebellum  appears to
be  particularly  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 metabolic activity that occurs in the young rat  at 10-21 days postnatally.
     Ijn 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  ug/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  vivo  accumulation of  lead  in  mitochondria  of kidney,  liver,
spleen, and  brain  tissue,  with one study showing that  such uptake was slightly more than that
which  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  ui vitro.
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Significant decreases in mitochondria!  respiration  i_n vitro using both  NAD-1inked  and succi-
nate substrates  have been  observed for brain  and  non-neural  tissue mitochondria in  the  pre-
sence of lead  at  micromolar  levels.   There appears  to be substrate specificity in the inhibi-
tion 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 mitochon-
dria 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
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 ijn 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
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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
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 the following:  (1)  stimulation  of mitochondrial delta-amino-
levulinic  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), which catalyzes  formation of porphobilinogen from two  units  of ALA; and (3) inhibi-
tion  of  insertion of  iron (II)  into  protoporphyrin IX  to  form heme,  a  process mediated by
ferrochelatase.
     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 jji vitro at  levels as  low as 5.0 pM or 1.0 ug 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  ug/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
                                           1-108

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                                    MITOCHONDRION
MITOCHONDRIAL
GLYCINE
-f
SUCCINYL-CoA






1

ALA SYNTHETASE
MEMBRANE
HEME
i
FERRO-
CHELATASE :

k xPb
^ \
• ? \
1
(INCREASE) iRON+PROTOPORPHYRIN -*4f~

Pb (DIRECTLY
1 7
OR i
BY DEREPRESSION) '
i

AMINOLEVULINIC ACID
(ALA)

ALA
DEHYDRASE
(DECREASE)


•* 	 Pb
r
r > _



'
•*— Pb


COPROPORPHYRIN

(INCREASE)
t
I
                                                                     IRON
                     PORPHOBILINOGEN
                        Figure 1-20.  Effects of lead (Pb) on heme biosynthesis.
levels appears  to  be much less  than  the effect of ALA-D activity  inhibition.   ALA-D activity
is  significantly  depressed at  40 M9/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 j_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
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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  |jg/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
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
ug/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.
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     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 zinc protoporphyrin  (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  erythro-
poietic 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
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
(jg/dl.   In children 10-15 years old,  the  threshold is about 16  ug/dl; 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  ug/dl,  as a  second group under 4 years old, indicating that  iron deficiency was not
a  factor  in  the study.  At  25 ug/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 ug/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  ug/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
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blood lead below  30  ug/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 (jg/dl  corresponded to
EP elevations of  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  |jg/dl,  which  was  the previously  accepted  cut-off value
(now 25  ug/dl)  for  undue  lead exposure  specified  by  the Centers  for  Disease  Control.   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
with impaired activity  of  detoxifying enzyme systems such as aniline hydroxylase and aminopy-
rine demethylase.   It is also responsible for reduced 6p-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  has heme biosynthetic capability  and that  not only is such capability reduced in
the  presence of  lead,  but  production  of porphyrinic material  is  increased.   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  impaired 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  a  great  deal  of  data   documenting  lead-associated effects on
mitochondria.   The  relative value of  the  lead-ZPP  relationship in  erythropoietic  tissue as an
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index of this effect in other tissues hinges on the relative sensitivity of the erythropoietic
system compared 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-
rin 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
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 ug/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  ug/dl in adults and somewhat lower (~40 ug/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-5'-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.
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     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  re-
sponse 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 ug/dl  blood lead.   Lead's inhi-
bition 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.
     Tetraethyl  lead  and tetramethyl  lead, components of leaded  gasoline,  undergo transforma-
tion j_n  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

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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 i_n 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 j_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 uM ALA.  This i_n 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 i_n  vivo  effects of lead on neurotransmitter function cannot be duplicated with jji
vitro 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.
     A number  of  studies strongly suggest that  lead-impaired  heme production itself may be a
factor  in  the  lead'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
neonatal rats are exposed to lead.
     Awareness of the interactions of lead and  the vitamin D-endocrine system has been grow-
ing.  A  recent study has found that  children with blood lead levels  of 33-120  ng/dl showed
significant  reductions  in  serum  levels  of  the hormonal  metabolite  1,25-dihydroxyvitamin D
(1,25-(OH)2D).  This   inverse  dose-response relationship was  found throughout  the  range  of
measured blood  lead  values  (12-120  ug/dl), and  appeared to be the  result of lead's effect on
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the production  of  the  vitamin D hormone.  The  1,25-(OH)2D  levels  of children with blood lead
levels of  33-55 (jg/dl  corresponded  to  the  levels  that  have  been observed  in  children with
severe renal  dysfunction.   At  higher  blood lead  levels  (>62 ug/dl), the  1,25-(OH)2D values
were similar  to those  that have been measured  in  children  with various  inborn metabolic dis-
orders. Chelation therapy of the lead-poisoned children (blood lead levels >62 ug/dl) resulted
in a return to  normal 1,25-(OH)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-(OH)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 the following:   (1)  the internal
exposure levels, as  indexed by blood lead levels,  at  which  various neurotoxic effects occur;
(2)  the persistence or reversibility of  such  effects;  and  (3)  populations that  appear to be
most  susceptible  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 levels
as low as 100 ug/dl.  In children, the effective blood lead  level for producing encephalopathy
or death is lower, starting at approximately 80-100 ug/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 encephalopathic symptoms can develop or death can occur
in apparently asymptomatic  individuals or in those apparently only mildly affected by elevated

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lead body  burdens.   Rapid deterioration often  occurs,  with convulsions or coma  suddenly  ap-
pearing with progression to death within 48 hours.   This strongly suggests  that even in appar-
ently asymptomatic individuals, rather severe neural  damage probably exists at high blood lead
levels even though it is not yet overtly manifested in obvious encephalopathic 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 encephalopathic 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
CMS and peripheral nerve dysfunction)  are detectable in some human adults at blood lead levels
as  low  as 40-60 ug/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  pg/dl  (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 expo-
sure levels, several studies  point toward average  5-point IQ decrements occurring in asympto-
matic  children  at  average blood  levels  of  50-70 ug/dl.   Other evidence  is indicative  of
average  IQ  decrements  of about 4 points being  associated with blood levels  in  a 30-50 ug/dl
range.   Below 30 ug/dl,  the evidence for IQ decrements is quite mixed,  with some studies show-
ing  no   significant  associations with  lead  once  other  confounding  factors are  controlled.
Still, the  1-2  point differences  in  IQ generally  seen with  blood  lead  levels  in  the  15-30
(jg/dl range  are suggestive of lead effects  that  are often dwarfed by  other  socio-hereditary
factors.   Moreover,  a  highly  significant  linear relationship between IQ  and blood  lead over
the range of 6  to 47 ug/dl found  in  low-SES Black children  indicates  that  IQ  effects may be
detected without  evident  threshold even at these  low levels, at least  in  this population of
children.   In addition,  other behavioral  (e.g.,  reaction time,  psychomotor  performance)  and
electrophysiological (altered  EEC patterns,  evoked  potential measures, and  peripheral  nerve
conduction velocities are consistent with a dose-response function relating neurotoxic effects
to  lead  exposure  levels  as low as 15-30 ng/dl and  possibly lower.  Although the comparability
of  blood  lead concentrations  across  species is  uncertain (see discussion below),  studies show
neurobehavioral  effects in  rats  and monkeys at  maximal  blood lead levels below 20 pg/dl; some
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studies demonstrate  residual  effects long after  lead exposure has terminated and  blood lead
levels have returned to approximately normal  levels.
     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, FEP,  or  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.
     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;  a  five-year follow-up  of some of the same children revealed the
presence of  altered  brain stem auditory evoked potentials.   Current  population  studies, how-
ever, will  have  to be supplemented by longitudinal studies of the effects of lead on develop-
ment  in  order  to address  the  issue of  the reversibility or persistence of the  neurotoxic
effects of  lead  in humans more satisfactorily.   (See the Addendum to this document for a dis-
cussion  of  recent  results  from prospective  studies linking perinatal  lead exposure to post-
natal mental development.)
     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.
      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

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lead.   Various lines of evidence suggest that the order of susceptibility to lead's effects is
as follows:   (1) young  >  adults and (2) female  >  male.   Animal  studies also  have  pointed to
the perinatal  period of  ontogeny  as a  particularly  critical  time for a  variety  of  reasons:
(1) it is  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.
One analysis of lead-exposed children suggests that differing effects on cognitive performance
may be a  function  of the different  ages at  which children are  subjected  to  neurotoxic expo-
sures.  Nevertheless, 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  (see  Addendum), increased
opportunity  for exposure  because  of normal  mouthing behavior,   and  increased rates  of lead
absorption due to various factors, e.g., nutritional deficiences.
     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.
     Studies  using  rodents and monkeys have  provide  a variety of evidence of neurobehavioral
alteration induced  by  lead  exposure.   In  most cases  these effects  suggest  impairment in
"learning,"  i.e, the processes of appropriately  modifying one's  behavior in response to  infor-
mation  from  the  environment.   Such behavior involves the  ability to receive,  process, and
remember information in various  forms.  Some  studies  indicate behavioral alterations of  a more
basic  type,  such as delayed development of certain reflexes.  Other evidence  suggests changes
affecting  rather complex behavior in the form of social interactions.
     Most  of  the  above effects  are evident  in rodents and  monkeys  with blood  lead  levels
exceeding  30 ug/dl, but  some  effects  on learning ability  are apparent  even  at maximum  blood
lead exposure levels below 20  pg/dl.  Can these  results with animals be generalized 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 [jg/dl  in a  suckling rat equivalent to 30 ug/dl  in  a three-year-old
child?   Until an  answer  is  available  for this  question,  i.e.,  until  the function describing
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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.   Nevertheless, interesting  parallels in
hyper-reactivity and increased response  variability do exist  between different  species, and
deficits  in  performance on various tasks  are indicative of  altered CNS  functions,  which are
likely to parallel  some type of altered CNS function in humans 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  neuropathologic  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 i_n  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
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  mitochondria! function
and protein  synthesis.
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     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 J_n
vitro studies, may be in the information they can provide on basic mechanisms involved in lead
neurotoxicity.  A  number of j_n  vitro studies show that  significant,  potentially deleterious
effects on nervous  system  function occur at j_n  situ  lead concentrations of 5  uM 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.   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 ug/dl, and some are suggestive of renal effects, possibly occurring even at levels as
low as 30 ug/dl.   In children, the relatively sparse evidence available points  to the manifes-
tation of  nephropathy  only at quite high blood  lead levels (usually exceeding  100-120 ug/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 investi-
gated, although  a few studies indicate that children diagnosed as being acutely lead poisoned
experience lead nephropathy effects  lasting throughout adulthood.
     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 re-
versible  lesions  such  as nuclear inclusion  bodies, cytomegaly,  swollen  mitochondria, and in-
creased 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
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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.
     Among  the  questions  remaining to be  answered more definitively  about the effects of lead
on the kidneys  is the lowest blood lead  level  at which renal effects  occur.  In this regard it
should be  noted that 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 measurements  are  a   less  satisfactory indicator because they may  not  accurately
reflect cumulative  absorption some time after exposure  to  lead  has terminated.   Other ques-
tions  include the following:  Can a distinctive lead-induced renal lesion be identified either
in  functional   or  histologic terms?   What biologic measurements are  most reliable  for the
prediction  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  mechanism  of  lead-induced hypertension  and renal  injury?   What are the contribu-
tions  of  environmental  and genetic factors  to  the  appearance of  renal  injury due  to  lead?
Conversely,  the most difficult question of all  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,
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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  s_e.   Early  studies  of pregnant  women exposed to  high
levels of lead indicated toxic, but not teratogenic, effects on the conceptus.   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  performance  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 ug/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
deleterious  effects  in young  children  as blood  lead levels approach  or exceed  25-30  ug/dl.
Industrial exposures  of men to lead at levels  resulting  in blood lead values  of  40-50 ug/dl
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
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
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(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 levels as well.   (Recent  studies,  most of which are prospective epidemiological inves-
tigations,  on the relationship between relatively low-level lead exposure and effects on fetal
and  child  development,  along with  supporting experimental  evidence  on possible  underlying
mechanisms  are reviewed in an Addendum to  this document.)

1.12.7  Genotoxic and Carcinogenic Effects of Lead
     It is hard  to  draw clear conclusions concerning what role  lead  may play in the induction
of  human  neoplasia.   Epidemiological  studies  of lead-exposed  workers provide  no  definitive
findings.   However,  statistically significant  elevations  in respiratory tract  and digestive
system cancer  in workers exposed to lead  and  other  agents warrant some concern.   Since  lead
acetate can produce renal tumors  in some experimental animals,  it seems reasonable to conclude
that at least  this  particular lead compound should  be regarded  as a  carcinogen and prudent to
treat it as  if  it  were also  a human  carcinogen (as  concluded by the International  Agency for
Research on  Cancer).    However,   this  statement is  qualified  by noting that lead has  been
observed to  increase  tumorigenesis  rates  in animals only at relatively high  concentrations,
and therefore it does  not appear to be a  potent carcinogen.   Iji vitro  studies  further support
the  genotoxic  and  carcinogenic  role  of lead,  but  also  indicate  that lead is  not  potent in
these systems either.

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  that,  although  not
inducing 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  the
effects of  lead 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.
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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.   However,  some work does  suggest
that humans and  animals show significant increases in  blood  pressure following chronic expo-
sure to  low levels  of lead (see Addendum to  this  document for a detailed discussion  of  the
relationship between blood  lead and  blood  pressure  and  the possible  biological  mechanisms
which may be responsible  for this association).   It should also be noted that overt gastroin-
testinal  symptoms associated  with   lead  intoxication  have  been  observed  to  occur in  lead
workers at  blood lead levels as low as  40-60 ug/dl.   These findings suggest that effects  on
the  gastrointestinal  and  cardiovascular systems may  occur at relatively low  exposure  levels
but remain to be more conclusively demonstrated by further scientific investigations.   Current
evidence indicates that various endocrine processes may be affected by lead  at relatively high
exposure  levels.   However,  little  information exists on endocrine effects at  lower exposure
levels,  except  for   alterations  in  vitamin-D  metabolism previously   discussed  earlier  as
secondary to heme synthesis effects and occurring at  blood lead levels  ranging below 30 ug/dl
to as  low as  12 ug/dl.  (Evidence  relating endocrine function to various  recently reported
lead-associated effects on  human fetal and child development, including effects on growth and
stature, is reviewed in the Addendum to this document.)
1.13   EVALUATION  OF HUMAN  HEALTH  RISKS ASSOCIATED  WITH EXPOSURE TO  LEAD AND  ITS COMPOUNDS
1.13.1  Introduction
     This section attempts to integrate key information and conclusions discussed in preceding
sections into a  coherent  framework by which interpretation and judgments can be made concern-
ing 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
identification of those effects  most  relevant to various segments of the general  U.S.  popula-
tion and the  placement  of such effects in a dose-effect/dose-response framework.   With regard
to the latter, a crucial issue has to  do with the relative response of various segments 'of  the
population in terms of observed effect levels as indexed by some exposure indicator.  Further-
more,   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 of  specific population
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groups that can  be  expected to experience a particular effect at various  lead exposure levels
(i.e., "responders") 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 ug
lead/day.    This  level  of  exposure is  referred  to as the baseline exposure  for  the American
population 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  interior  or exterior  house paint.
      Ambient  Air Lead Levels.   Monitored  ambient air lead concentration  values  in  the United
States  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 Aero-
metric  Data Bank,  consisting of measurements  by  state  and local agencies in conjunction with
compliance  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 ug Pb/m3, while  the majority of the
non-urban  locations have  annual   figures below 0.2 ug  Pb/m3.   Over  the  interval   1976-1982,
there has   been  a  downward  trend  in these  averages,  mainly attributable  to decreasing  lead
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
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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  be-
comes 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-
mined.
      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 United States were shown  in
one  study  to  range from 150 to 500 ug/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 M9/g and higher.  In residential areas, exterior dust
lead  levels  are approximately  1000 ug/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 ug/g.   Some  soils  adjacent to  houses
with  exterior  lead-based paints may have lead concentrations greater than 10,000 ug/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 en-
vironment  or near  a smelter  (see earlier Table 1-8).
      Levels of Lead in Food.  The route  by  which  adults  and older children  in the baseline
population  of the United  States receive  the  largest proportion  of  lead  intake  is through
foods, with  reported estimates  of the  dietary lead intake for Americans ranging from 40 to 60
ug/day.   The  added exposure from living in an urban environment is about 28 ug/day for adults
and 91 ug/day  for  children,  all of which can be  attributed to atmospheric lead.
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     TABLE 1-14.   RELATIVE BASELINE HUMAN LEAD EXPOSURES  EXPRESSED  PER  KILOGRAM BODY WEIGHT*
                                  Total
                                  lead
                                consumed,
                                 ng/day
                 Total  lead consumed
                    per kg body wt,
                       ug/kg-day
                   Atmospheric lead
                    per kg body wt,
                       ug/kg-day
Child (2-yr-old)
 Inhaled air
 Food and beverages
 Dust

               Total

Adult female
 Inhaled air
 Food and beverages
 Dust

               Total

Adult male
 Inhaled air
 Food and beverages
 Dust

               Total
 0.5
25.1
21.0

46.6
 1.0
32.0
 4.5

37.5
 1.0
45.2
 4.5

50.7
0.05
2.5
2.1

4.65
0.02
0.64
0.09

0.75
0.014
0.65
0.064

0.73
0.05
1.0
1.9

2.95
0.02
0.25
0.06

0.33
0.014
0.28
0.04

0.334
*Body weights:   2-year-old child = 10 kg;  adult female = 50 kg;  adult male = 70 kg.

Source:   This report.


     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 ug Pb/day, respectively,  in milk
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
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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 |jg/g  (50 ug/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  |jg/l 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  ug/g was  greater where water was plumbo-solvent.
     Most  drinking water,  and  the  beverages produced from  drinking water,  contain  0.007-
0.011 ug  lead/g.   The exceptions are  canned juices  and  soda  pop, which range  from  0.018  to
0.040 ug/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 chips  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 there,
particularly  for  children  with  pica.   Census  data,   for example,   indicate  that  there  are
approximately  27 million residential  units  in  the United States  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/m3.
     Cumulative  Human Lead  Intake From Various Sources.   Table  1-7   earlier  illustrated  the
baseline  of human lead  exposures in  the  United  States 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  conservative estimates  because  a  part of  the lead of  undetermined  origin may  originate
from atmospheric lead not yet accounted  for.
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     From Table 1-14,  it  can be seen that young children have a dietary lead intake rate that
is fivefold 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 three-
fold.  Overall,  then,  the rate of  lead  entry  into the  bloodstream 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
atmospheric fraction of the  baseline exposure  is sixfold 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  tissue  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.   Item 2 deals
with the adequacy of  current means  of  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 versus adults also occurs at the time  when:  (1) humans are developmen-
tal ly more  vulnerable  to  the effects of toxicants  such as lead  in terms of  metabolic activity;
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 versus  adults  in terms of lead  exposure
 implications   is  a more  metabolically active skeletal system in children.   Turnover  rates  of

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bone elements such as calcium and phosphorus are greater in children than in adults,  with cor-
respondingly greater  mobility of  bone-sequestered  lead.   This  activity is  a  factor in  the
observation 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 0,  furthermore,  there may exist an increasingly adverse  inter-
active cycle between  lead effects  on 1,25-dihydroxyvitamin D and associated increased absorp-
tion 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; the extreme  manifestation of  this  behavior  is  called  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 contami-
nated 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 embryological  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.  In addition, certain emerging information  (noted
in Section 13.5  and  described in detail in the  Addendum  to  this document) indicates that in-
creases in  blood pressure are associated  with blood lead concentrations  ranging  from  >30-40
ug/dl down to  possibly  as low as  7  ug/dl;  this association appears to be particularly  robust
in white  males,  aged  40-59.   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 differences in
exposure  control—occupational versus 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 i_n  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 jn 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 re-
flecting 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  chelatable
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  showing 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  moderately
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;  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  either that 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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                                 SPINAL CORD
                          PERIPHERAL
                           NERVES
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
blood (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 ^g/d\, 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 ng/d\, 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.
                                             l-13-i

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shows  an  approximate  twofold 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  twofold,  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
disposition 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
discordance may underlie  the  observation that severe lead neurotoxicity in children  is assoc-
iated 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 ug/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-
cal ly  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  25  ug/dl,  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 also  in accord 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 j_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  individual
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 United States, 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,  especially  in urban chil-
dren, which  represent the  population  group in the United  States  at  greatest risk  for  lead
exposure and its toxic effects.
     Table 1-15 tabulates the relative direct and indirect contributions  of air lead  to blood
lead at  different ambient  air-lead  levels for calculated typical  background  levels  of  lead
from food, water,  and dust  for U.S.  children.  Calculations  and  assumptions used in  deriving
the estimates shown in Table 1-15  are summarized in footnotes to  that table.   The  dietary  con-
tributions listed  in the table,  for example, are  based on:   (1) the estimated average back-
ground levels  of  lead (from non-air and air sources) in  food ingested per  day by  U.S. chil-
dren, as  delineated  in Table 7-19;  and (2) the value of 0.16 (jg/dl  of  blood lead  increase per
ug/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 less  than one
million population or  more  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  ug/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 urban areas in the United  States (population >1 million) are available
from  Table 7-2.   The air   lead  levels during  1976-1979  averaged 1.08 ug/m3 for  all  cities
listed in Table 7-2  and 1.20 ug/m3  for eight cities in the table  that  were included  in the
NHANES II study (i.e., Boston, New York, Philadelphia,  Detroit, Chicago, Houston,  Los  Angeles,
and Washington,  DC).  The  Table 1-15 blood  lead  values of 12.6-14.6 ug/dl  estimated  for air
lead  levels  of 1.0-1.25 ug/m3 approximate the observed NHANES  II  average  of  16.8 ug/dl  for
children  in large  urban areas with average air lead levels of 1.08-1.20 ug/m3.   The NHANES II
blood  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
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         TABLE 1-15.   CONTRIBUTIONS FROM VARIOUS MEDIA TO BLOOD LEAD LEVELS (ug/dl)  OF
   U.S.  CHILDREN (AGE = 2 YEARS):   BACKGROUND LEVELS AND INCREMENTAL CONTRIBUTIONS FROM AIR


                        	Air lead, ug/m3	
     Source             0         0.25      0.50       0.75       1.00       1.25       1.50

Background-non air
Food, Water and
  Beverages3            2.37      2.37      2.37       2.37       2.37       2.37       2.37
Dust0                   0.30      0.30      0.30       0.30       0.30       0.30       0.30
Subtotal                2.67      2.67      2.67       2.67       2.67       2.67       2.67

Background-air
Food, Water and
  Beverages0            1.65      1.65      1.65       1.65       1.65       1.65       1.65

Ingested dust (with Rb
deposited
Inhaled air
Total
from air)
e
0.00
0.00
4.32
1.57
0.50
6.39
3.09
1.00
8.41
4.
1.
10.
70
50
52
6.
2.
12.
27
00
59
7.
2.
14.
84
50
66
9.40
3.00
16.72
aFrom Table 7-19, (25.1 - 10.3) ug/day x (0.16 from Ryu et al.,  1983) = 2.37 ug/dl .

 From Chapter 7, 1/10 dust not atmospheric.   Using Angle et al.  (1984) low area (Area S)
 for soil and house dust and their regression equation, we have:   (1/10) x (97 ug/g x
 0.00681 + 324 ug/g x 0.00718) = 0.30 ug/dl.   Alternatively,  the consumption from non air
 would be (1/10) x (97 ug/g soil dust + 324 ug/g house dust)  x 0.05 grams ingested  of
 each = 2.1 ug ingested.   Using Ryu et al.  (1983), 2.1 x 0.16 = 0.34 ug/dl added to blood.

cAs in (a) above, but using 10.3 instead of (25.1 - 10.3) yields 1.67 ug/dl .   Values are
 derived for component of background Pb in food from past deposition from air onto  soil  and
 into other media leading into human food chain (not expected to change much except over
 long-term).

 The regression equations of Angle et al.  (1984) are used, as well  as levels of soil dust
 and house dust in the low area (S) and high area (C) of that study.   For example,  the
 increase at 1.0 ug/m3 in air would result in increases in soil  as  follows:

                                   '      x   <519 - 97>   = 526
 Similarly the increase in house dust would be:

                                I        x   C625 - 324)  = 374
 The effect on blood lead would be (526 x 0.00681) + (374 x 0.00718) = 6.27 ug/dl.
eUsing the 2.0 slope from Angle et al.  (1984), i.e., 1.93 rounded up.
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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 percent) to be  comparable  to the 1976-1980 period,  then  the  blood lead levels of children
exposed to 1.25  ug/m3  air  lead would  increase to  15.5  ug/dl,  a  value even closer to the mean
of  16.8 (jg/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 which can  be potentially viewed  as  adverse health
effects likely to  occur among  the general  population at  or near existing  ambient air concen-
trations of lead in  the United States.  Key information regarding  observed health effects and
their implications are discussed below for  adults and children.
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     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 not only
involved 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 versus 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  the following:   (1) impaired normal functioning
of  a specific  tissue or  organ  system itself; (2) reduced reserve capacity of  that tissue or
organ  system in  dealing with   stress due to other  causative  agents;  (3) the  reversibility/
irreversibility of the  particular effect(s);  (4)  the relative frequency of  a  given effect; (5)
the  presence  of the effect  in  a vulnerable segment of  the  population; and (6)  the cumulative

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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  hepatic  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)  the biological  reversibility
or  irreversibility  characteristic of the particular  effect  in a  given  organism;  and  (2)  the
generally  less-recognized  concept  of  exposure  reversibility or  irreversibility.   Severe
central nervous  system damage  resulting  from intense, high level   lead  exposure is generally
accepted  as  an  irreversible effect of  lead  exposure;  however,  the reversibility/irreversibi-
lity of certain more  difficult-to-detect  neurological  effects occurring at lower lead exposure
levels, remains  a matter of some controversy.  The concept of exposure reversibility/irrever-
sibility  can  be illustrated by the case  of urban children of low socioecomomic status  showing
disturbances in heme  biosynthesis and erythropoiesis.   Biologically, these various effects  may
be  considered  reversible;  the extent to  which actual  reversibility occurs, however, is deter-
mined  by  the feasibility of removing these  subjects  from their particular lead exposure  set-
ting.   If such  removal from exposure  is unlikely  or does not occur,  then  such effects will
logically persist and,  de  facto, 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.
      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
                                            1-140

-------
ERYTHROPOIETIC
EFFECTS
NEURAL
EFFECTS *
RENAL ENDOCRIN?
EFFECTS
REDUCED
SYNTHESIS


ANEMIA - REDUCED
TO ALL TISSUES
-*
/
REDUCED HEMOPROTEINS
(eg . CYTOCHROMES)

REDUCED 1 25IOHI2-
VITAMIN 0

Hf PATIC
EFFECTS
REDUCED HEME FOR
HEME REGULATED
TRANSFORMATIONS

— »"
'
/
/
1
t
\
\
\
/'
\
\
IMPAIRED I/
CELLULAR If •
ENERGETICS |\
\
DISTURBED IMUNO
REGULATORY ROLE
OF CALCIUM
/
EXACERBATION OF
HYPOXIC EFFECTS OF
OTHER STRESS AGENTS

EFFECTS ON NEURONS
AXONS.AND
SCHWANN CELLS
*
IMPAIREDMVELINATION
AND NERVE CONDUCTION

IMPAIRED DEVELOPMENT
OF NERVOUS SYSTEM

IMPAIRED MINERAL
TISSUE HOMEOSTASIS
/
DISTURBED CALCIUM
METABOLISM
/.
\
IMPAIRED CALCIUM
ROLE AS SECOND
MESSENGER
\
DISTURBED ROLE IN
TUMORIGENESIS
CONTROL

IMPAIRED
DETOXIFICATION
OF XENOBIOTICS

IMPAIRED METABOLISM
OF ENDOGENOUS
AGONISTS

A
/'
\
IMPAIRED CALCIUM
ROLE IN CYCLIC
NUCLEOTIDE METABOLISM

IMPAIRED DETOXIFICATION
OF ENVIRONMENTAL
TOXINS

IMPAIRED
DETOXIFICATION
OF DRUGS

/
ALTERED METABC' ISM
OF TRYPTOPHAN
(
\
IMPAIRED
HYDROXYLATION
OF CORTISOl
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 (	*-).
                                               1-141

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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 encephalopathic  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 (jg/dl.  Often  associated  with  encephalopathic  symptoms  at these  or  higher blood lead
levels 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 ug/dl, 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  the  following:   (1) slowed nerve conduction  velocities  indicative of peri-
pheral  nerve dysfunction  (at  levels as low  as  30-40  (jg/dl);  (2)  altered testicular  function
(at  40-50  ug/dl);  and  (3) reduced hemoglobin production (at approximately 50 ug/dl) and other
signs  of  impaired heme synthesis  evident  at  still  lower blood lead levels.   All of these ef-
fects  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,  as does evidence for  elevated blood pressure  in middle-aged
white  males (aged 40-59);  the  significance  of this and  evidence  of impairment of other  bio-
chemical  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,
 it can be  seen that  lead  impacts many different organ systems and biochemical/physiological

                                            1-142

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                           TABLE 1-16.   SUMMARY OF LOWEST OBSERVED EFFECT LEVELS FOR KEY LEAD-INDUCED HEALTH EFFECTS IN ADULTS
Lowest
effect
100-120

80
60

50


40

30


25-30

15-20

<10
observed A
level (PbB)
ug/dl

ug/dl
ug/dl

Mg/dl


ug/dl

ug/dl


Mg/dl

Mg/dl

Mg/dl
Heme synthesis and
hematological effects


Frank anemia


Reduced hemoglobin
production

Increased urinary ALA and
elevated coproporphyrins



Erythrocyte protoporphyrin
(EP) elevation in males
Erythrocyte protoporphyrin
(EP) elevation in females
ALA-D inhibition
Neurological Effects on Reproductive Cardiovascular
effects the kidney function effects effects
Encephalopathic signs Chronic
and symptoms nephropathy

-r- F
f
Overt subencephalopathic A
neurological symptoms
t
Peripheral nerve dysfunction —
(slowed nerve conduction)
1










emale reproductive
effects
Itered testicular
function
1
-I-

Elevated blood
pressure
(White males,)
aged 40-59


i
?
 PbB = blood lead concentrations.



Source:  This report.

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                          TABLE 1-17.  SUMMARY OF LOWEST OBSERVED EFFECT LEVELS FOR KEY LEAD-INDUCED HEALTH EFFECTS IN CHILDREN
Lowest
effect
80-100
70
60
50
40

30
15
10
observed
level (PbB)a
Mg/dl
Mg/dl
Mg/dl
(jg/dl
|jg/dl

Mg/dl
Mg/di
Mg/di
Heme synthesis and
Hematological effects

Frank anemia

Reduced hemoglobin
synthesis
Elevated coproporphyrin
Increased urinary ALA

Erythrocyte protoporphyin
elevation
ALA-D inhibition
1
Py-5-N activity
inhibition
*
Neurological Renal system Gastrointestinal
effects effects effects
Encephalopathic Chronic nephropathy Colic, other overt
signs and symptoms (aminoaciduria, etc.) gastrointestinal symptoms
i
Peripheral neuropathies -*-

Peripheral nerve dysfunction
(slowed NCV's)
CNS cognitive effects
(IQ deficits, etc.)
? Vitamin D metabolism
interference
Altered CNS electrophysiological
responses I
T
t
. PbB = blood lead concentrations.
 Py-5-N = pyrimidine-B'-nucleotidase.

Source:  This report.

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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
encephalopathic signs  and symptoms.    In  children,  effective  blood lead levels for  producing
encephalopathy or  death  are  lower  than  for adults,  starting at  approximately 80-100 ug/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 have been detected
in  some  children at  levels  as  low  as  40-60 ug/dl).   Chronic nephropathy,  indexed  by amino-
aciduria, is  most  evident at high exposure levels producing blood lead levels  over 100 ug/dl,
but may  also  exist at lower  levels  (e.g.,  70-80  ug/dl).   In  addition, colic  and  other  overt
gastrointestinal symptoms  clearly occur at similar or still  lower blood  lead  levels in  chil-
dren,  at least down to 60 ug/dl.  Frank  anemia is  also evident by 70 ug/dl,  representing  an
extreme  manifestation  of  reduced hemoglobin synthesis observed at blood lead levels as low  as
40 ug/dl, along with  other signs of marked  heme  synthesis inhibition at that  exposure level.
All  of these  effects  are reflective  of  the widespread 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 ug/dl.   All of these effects are widely  accepted as  clearly
adverse  health effects.
     Additional  studies  demonstrate  evidence for further,   important  health  effects occurring
in  non-overtly lead-intoxicated  children at similar  or   lower blood lead levels  than  those
indicated above for overt  intoxication  effects.    Among the most important of the  effects dis-
cussed  in  Chapter  12 are neuropsychological   and  electrophysiological  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 ug/dl.  As  for CMS
effects,  none  of the available studies  on the subject, individually, can be said to prove con-
clusively  that significant cognitive  (IQ) or  behavioral  effects occur in  children at  blood
lead levels <30 ug/dl.  However, the most recent neurobehavioral studies of CNS cognitive (IQ)
effects  collectively  demonstrate associations  between neuropsychologic deficits and low-level
lead  exposures in young  children resulting in blood lead levels  ranging to  below 30 ug/dl.
The  magnitudes of average observed  IQ  deficits generally  appear to  be approximately 5 points
at  mean  blood lead levels of 50-70  ug/dl,  about 4 points  at  mean blood lead  levels of 30-50
ug/dl,  and 1-2 points at  mean  blood lead  levels of  15-30 |jg/dl.   Somewhat  larger decrements
have  been  reported  for  the latter blood  lead  range  among  children of  lower  socioeconomic
status families.
                                           1-145

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     Additional recent studies  have  obtained  results  at blood lead values  mainly in the 15-30
|jg/dl range  indicative of  small,  but not unimportant,  effects of lead on the ability to focus
attention, appropriate 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 confound-
ing variables.  This caution is particularly warranted  in view of other well-conducted studies
that have appeared in the literature which did not find statistically significant associations
between lead and  similar  effects  at blood  lead  levels below 30 ug/dl.   Still,  because such
latter  studies  even  found  some  small  effects  remaining  after  correction for  confounding
factors,  lead cannot  be  ruled  out as an etiological  factor contributing  to  the  induction of
such effects  in the 15-30 ug/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 the range of 30-50 ug/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 lead  levels  in the range of 30-55 ug/dl and analo-
gous  associations  at  blood lead levels  below  30  ug/dl  (with no  evident threshold  down to 15
ug/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 persis-
tence  of  such effects even  in  the face  of later declines in blood lead 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 associ-
ated  with IQ decrements.
      While  the precise medical or health  significance  of the neuropsychological and electro-
physiological  effects found by the  above studies to be  associated  with low-level lead expo-
sures  is  difficult to fully define at this time, the  IQ deficits and other  behavioral changes
likely  impact the intellectual development, school performance,  and  social  development  of the
affected  children sufficiently so as to be regarded as  adverse.   This is especially true  if
such impaired intellectual development  or school performance and disrupted  social  development
are reflective of persisting,  long-term  effects of low-level  lead exposure in early childhood.
The issue of persistence  of such  lead effects still remains  to  be more clearly  resolved, with
some study  results  reviewed  in Chapter 12 and  mentioned  above suggesting relatively  short-
 lived  or  markedly decreasing   lead  effects  on neuropsychological  functions over a  few years

                                            1-146

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from early  to later childhood  and  other studies suggesting that significant  low-level  lead-
induced neurobehavioral and  EEC effects  may,  in fact, persist  into  later childhood.   Despite
any remaining  ambiguities  of the above  type,  however,  the medical community  has  highlighted
(CDC,  1985) lead-induced neurobehavioral  effects (e.g.,  IQ deficits  and other neuropsychologic
effects) as one basis for viewing pediatric blood lead levels below 25-30 |jg/dl as  being asso-
ciated with unacceptable risk for lead-induced toxicity.
     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 lead 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
probably 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 earlier, in Chapter 12 and Section 13.4,  lead affects  heme synthe-
sis at  several points  in its metabolic pathway, with consequent impact on the normal  function-
ing 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 ug/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 in-
directly  in  terms of  consequent 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 ug/dl, with  no  clear threshold evi-
dent.    Correlations  between  erythrocyte  and hepatic ALA-D activity inhibition in  lead workers
at blood  lead levels  in the  range  of  12-56 [jg/dl  suggest that ALA-D activity in  soft tissues
                                           1-147

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(e.g., brain, liver, kidney,  etc.) may be inhibited at similar blood  lead  levels  at  which  ery-
throcyte ALA-D activity inhibition 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-
rent commonly-accepted blood  lead  level  of 40 ug/dl.   Such  increases  in blood and urinary ALA
are detectable in humans  at  blood lead levels below 30 ug/dl, with no clear  threshold evident
down to  15-20  ug/dl,  although other data exist which  fail  to show  any relationship  below 40
ug/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
lead 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 lead  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 ug/dl  in adults and  approximately 15 ug/dl for
young  children,  with  significant  EP elevations (>l-2 standard deviations  above  reference  nor-
mal  EP  mean  levels) occurring in 50  percent  of all  children studied  as blood lead approaches
or moderately exceeds 30 ug/dl.
     Medically,  small  increases in  EP  levels were  previously not  viewed  as being  of great
concern  at  initial  detection  levels  around  15-20  ug/dl in  children.  However,  EP increases
become more worrisome when markedly greater, significant elevations  occur  as  blood lead levels
reach  20 to 30 ug/dl  and additional  signs  of significantly deranged heme synthesis  begin to
appear,  along with indications of functional disruption of  various organ  systems.  Previously,
such  other  signs of  significant  organ  system  functional  disruptions had only  been credibly
detected at blood lead levels distinctly in excess of 30 ug/dl, e.g.,  inhibition  of hemoglobin
synthesis  starting  at 40 ug/dl and  significant  nervous system effects at 50-60 ug/dl.   This
served  as  a  basis  for CDC's  1978 statement establishing  30 ug/dl  blood lead  as  a criteria
level  for  undue  lead exposure for young children.   At the  present  time,  however, the medical
community  (CDC,  1985) accepts EP elevations  associated  with  PbB levels  of 25 ug/dl or higher
as being unacceptable  in pediatric populations.
                                           1-148

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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-(OH)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-(OH)2-vitamin D
is a particularly  robust one,  with blood lead levels of 30-50 |jg/dl resulting in decreases in
the hormone that overlap comparable degrees of  decrease  seen  in  severe  kidney 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 ug/dl (i.e., to
levels below  5  ug/dl  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 ug/dl, 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  a  better   indicator  of more  widespread  impacts on  pyrimidine metabolism in
general  in additional organs and tissues  besides blood, such  that lead exposures lower than 30
pg/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) the persistence of
lead-induced neurobehavioral alterations  well  into adulthood long  after termination  of peri-
natal 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
persistence in brain tissues after termination of external lead exposure  and  blood lead levels
return to  "normal";   and  (3)  evidence from  various  j_n vivo and JH  vitro studies indicating
that, at  least on a subcellular-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 ef-
fects on nervous system  functioning and  other important physiological processes as blood lead
levels increase above 15-20 (jg/dl  and reach 20  to 30  ug/dl, the rationale for considering 30
ug/dl as  a "maximum  safe"  blood lead level (as  was  the case  in setting the 1978  EPA lead
NAAQS) was  called  into  question  and substantial  impetus provided for revising  the  criteria
level downward.   At  this time,  it  is  difficult  to identify  specifically  what  blood lead
criteria level  would be  appropriate  in   view  of the  existing  medical information.   Clearly,
                                           1-149

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however, 30 |jg/dl  does  not  afford 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 ug/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 ug/dl  range are  also
associated with  the onset  of  deleterious effects  in  several  organ  systems which  are either
individually or  collectively seen  as being adverse.  These and  other  considerations  have led
the medical community  (CDC,  1985)  to define 25 ug/dl PbB as  a level  associated with unaccept-
able risk for pediatric lead toxicity.
     At levels  below 25-30  ug/dl,  many of  the different smaller effects reported as being
associated with  lead  exposure  might be  argued as separately  not being  of clear medical signi-
ficance, 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) can,  at some point distinctly below  25-30  ug/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  ug/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
ug/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
consideration.   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
population groups.

                                           1-150

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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 ug  Pb/dl in blood  lead.   Also,  statis-
tically significant reduction  in  hemoglobin production  occurs at a  lower blood lead level  in
children (40 ug/dl) than in adults (50 ug/dl).
     Elevation in  erythrocyte  protoporphyrin  for a given  blood lead level is greater in chil-
dren and  women than in adult  males,  children  being somewhat more sensitive  than  women.   The
current threshold  for  detectable  EP elevation in terms of  blood  lead levels for children was
estimated  at  approximately  16-17  ug/dl in  the recent studies of  Piomelli et  al.  (1982).   In
adult males, the corresponding blood lead value is 25-30 |jg/dl.
     Coproporphyrin elevation in urine first occurs at a blood lead  level  of  40 ug/dl and this
threshold  appears  to  apply  for  both  children and  adults.   It also appears  that  urinary ALA
shows  a  correlation with  blood  lead  levels  to  below  40  ug/dl,  but since there  is no clear
agreement  as  to the  meaning of elevated  ALA-U  below  40  ug/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.
     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 have  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  ug/dl).   Dose-response curves  for  adult  men and
women  as  well  as children prepared  by Reels  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 al.
(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
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.
                                           1-151

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        LU

        ui iou
        H  90

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           40
           30
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                                       i    i    r
                                   OMEAN+1S.D.
                                   a MEAN+2S.D.
                                     MEAN ALA-U = 0.32 FOR
                                      BLOOD LEAD < 13 ug/dl
                               I	I
                                     I	I
I
                 10   20   30   40   50    60   70    80

                        BLOOD LEAD LEVEL, fig/dl
                                                     90
          Figure 1-25. EPA-calculated dose-response curve for ALA-U.

          Source: Azar et al. (1975).
           TABLE 1-18.   ERA-ESTIMATED  PERCENTAGE OF  SUBJECTS
      WITH ALA-U EXCEEDING LIMITS  FOR VARIOUS BLOOD LEAD LEVELS
Blood  lead  levels,
       10
       20
       30
       40
       50
       60
       70
                                             Azar et al. (1975),
                                             percent population

                                                      2
                                                      6
                                                     16
                                                     31
                                                     50
                                                     69
                                                     84
                                1-153

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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, three such populations are definable:   they are preschool  age children
(^6 years  old),  especially those living in  urban settings,  pregnant women,  and white males
aged 40-59, although  the evidence concerning  this latter group is much more limited than that
for the  other two.   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 concep-
tus.  Also, for  reasons  not as yet  fully understood, the  limited information available indi-
cates that  middle-aged white males  appear  to be differentially more  at  risk for manifesting
elevations  in  blood  pressure  in response to  lead  exposure  (see the Addendum to this document
for a complete discussion of the evidence supporting this).
     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 versus adults are noted.   The significant elements of difference
include  the following:   (1) greater intake of  lead by  infants and young  children into  the re-
spiratory  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
                                            1-154

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in the efficiency  of  lead 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 versus
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 incon-
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 ^e 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
                                           1-155

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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 arising 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.
     Middle-Aged White Males  (Aged 40-59) as a Population at Risk
     Recently-emerging  epidemiological  evidence  indicates that  increased blood  pressure is
associated with  blood lead concentrations  ranging from >30-40 ug/dl  down to blood  lead levels
possibly  as  low  as  7 M9/d1-   Tnis  relationship appears  to  be  particularly significant for
middle-aged white  males (aged 40-59), although a considerable degree of uncertainty surrounds
the  statistical  analyses  of  the studies giving  rise to this  conclusion.  A detailed critique
of  the various  analyses  which have  been  performed  on  the available epidemiological studies
concerning the blood lead/blood pressure relationship,  as well  as a discussion of the plaus-
ible  biological mechanisms  underlying  this relationship, are  presented  in  Section I of the
Addendum  to this  document.
     The  specific magnitudes of risk obtained for serious cardiovascular outcomes  in relation
to  lead  exposure,  estimated on  the basis  of  lead-induced  blood pressure  increase, depends
crucially upon the size of  the coefficients estimated for the blood  lead/blood pressure  asso-
ciation.  Given the  fact  that significant uncertainty exists in regard  to the most  appropriate
blood-lead  blood-pressure coefficient(s)  to use in attempting  to project serious  cardiovas-
cular  outcomes, the  further  analysis of additional  large-scale epidemiological data sets will
be  necessary  in order to  resolve more precisely  the  quantitative  relationship(s)  between  blood
 lead and blood  pressure.    It  is  possible, however, to  identify at  this  time the population
 subgroup  of middle-aged white males  (aged 40-59) as  being yet another group  at  general  risk  in
 terms  of  manifesting notable health  effects  in  response  to lead  exposure.
                                            1-156

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     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  preschool  children (up to 6 years  of age), especially those living in
                                      V
urban settings, women of child-bearing age (defined here as ages 15-44), and white males,  aged
40-59.   These  data,  which  are presented below in Table 1-19, were obtained from a provisional
report by  the  U.S.  Bureau  of the  Census (1984).  Data  from the 1980 Census  indicates  that
approximately  61 percent of the  populace lives  in  urban  areas (defined as central cities and
urban fringe).   Assuming that the 61 percent  estimate for  urban residents also  applies to
children of preschool age,  then approximately 15,495,000 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 versus non-urban settings.   (NOTE:  The age distribution
of the percentage of urban residents 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 deficit 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 condi-
tion is  defined as  serum  iron  concentration  (<40 ug/dl)  or as  transferrin  saturation  (<16
percent),  respectively.   Hence,  of the  22,029,000  children  ^5 years of age  (Table 1-19), as
many as 4,846,000  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  1984
(56,602,000)  into  the  total  number  of  live  births  in  1984 (3,697,000;   National  Center for
Health Statistics, 1985),  it  may be  seen  that  approximately 7 percent of this segment of the
population may  be at increased risk at any given time.
     As  for white males,  aged 40-59, defined  as  being  at  risk  notably  for increased blood
pressure in  association with  elevated blood lead levels, approximately 20 million individuals
can be estimated to  be at potential risk based on the 1980 Census data.
                                           1-157

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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
Population segment
Preschool children
Total
Women of
child-bearing age
Total
White males
Total
Actual age,
(yr)
0-4
5
6
15-19
20-24
25-29
30-34
35-39
40-44
40-44
45-49
50-54
55-59
Total number in U.S.
population
(1984)
18,453,000
3,576,000
3,374,000
25,403,000
9,019,000
10,481,000
10,869,000
10,014,000
9,040,000
7,179,000
56,602,000
6,064,000
4,960,000
4,600,000
4,760,000
20,384,000
Urban
population*
11,256,000
2,181,000
2,058,000
15,495,000
5,502,000
6,393,000
6,630,000
6,109,000
5,514,000
4,379,000
34,527,000
3,699,000
3,026,000
2,806,000
2^904,000
12,435,000
*An urban/total  ratio of 0.61 was used for all  age groups.   "Urban"  includes central  city
 and urban fringe populations (U.S.  Bureau of the Census,  1983).
Source:   U.S.  Bureau of the Census (1984), Table 6.

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.  Cur-
          rent blood  levels  of populations in industrialized societies  best reflect this
          impact of  man's  activities,  such lead levels  being many fold  higher than blood
          lead  levels  found  in  contemporary populations   remote  from industrial  activi-
          ties.
                                           1-158

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(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  clinical/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  an 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 25  ug/dl "maximum safe
     level"  for pediatric exposures.

(5)  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  is  pregnant women,  because of exposure of the  fetus to lead in
     the  absence of any effective biological (e.g., placenta!) barrier during gesta-
     tion.   A third group  at  increased risk  would appear to be white males,  aged
     40-59,   in  that  blood  pressure elevations  appear  to be significantly correlated
     with elevations in blood lead level  in this group.
                                      1-159

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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 (jg/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.
                                       1-160

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1.14  REFERENCES


American  Society  for Testing and Materials  (1975b)  Tentative method of  test  for lead in  the
     atmosphere  by  colorimetric  dithizone  procedure;  D 3112-72T.  Annu.   Book  ASTM  Stad.
     1975: 633-641.

Anderson,  K.  E. ;  Fishbein, A.; Kestenbaum,  D. ;  Sassa, S. ; Alvares,  A.  P.;  Kappas, A. (1977)
     Plumbism  from  airborne  lead in  a firing  range:  an unusual  exposure  to  a toxic  heavy
     metal. Am. J. Med. 63: 306-312.

Angle,  C.  R.; Mclntire,  M.  S.  (1979) Environmental  lead  and children:  the  Omaha study.  J.
     Toxicol.  Environ. Health 5: 855-870.

Annest, J. L.  (1983) Trends in the blood lead levels of the U.S. population: the second
     National  Health and  Nutrition Examination  Survey (NHANES  II)  1976-1980.   In:  Rutter,  M.;
     Russell  Jones,  R. ,  eds.   Lead versus  health:  sources and effects  of low  level  lead  ex-
     posure.  New York, NY: John Wiley  and Sons; pp. 33-58.

Annest, J.  L. ;  Casady,  R. J. ; White, A. A.  (1983) The NHANES  II study:  analytic error and  its
     effects on national  estimates of  blood  lead levels:  United States,  1976-80.  Available  for
     inspection  at:  U.S.   Environmental  Protection Agency,  Environmental Criteria  Assessment
     Office, Research Triangle Park, NC.

Annest, J. L.; Mahaffey,  K. R.; Cox, D. H.;  Roberts, J. (1982)  Blood lead levels for persons 6
     months -  74 years of age:  United States,  1976-80.  Hyattsville, MD: [U.S.  Department of
     Health  and  Human Services.   (Advance data  from  vital  and  health statistics  of  the
     National Center for  Health Statistics:  no.  79.)]

Annest, J. L.;  Pirkle, J. L.;  Makug,  D.;   Neese, J.  W.;  Bayse,  D.  D.;   Kovar, M.  G.  (1983)
     Chronological  trend   in blood  lead levels  between 1976 and  1980.  N.  Engl. J. Med.   308:
     1373-1377.

Ash, C.  P.  J.;  Lee, D. L.  (1980) Lead, cadmium,  copper  and  iron  in earthworms from  roadside
     sites. Environ. Pollut. Ser. A 22: 59-67.

Azar,  A.;  Snee,  R.  D.; Habibi,  K.  (1975)  An epidemiologic approach to  community air  lead ex-
     posure  using personal  air samplers.  In:   Lead.   Environ.  Qual. Saf.  Suppl. 2:  254-290.

Barltrop,  D.  (1975)  Significance of lead-contaminated soils  and dusts  for  human populations.
     Arh. High. Rada Toksikol. Suppl.  26:  81-96.

Battye,  B.  (1983) Lead emissions inventory, 1981 [Memo  to  John  Haines].  January  31. Avail-
     able  for  inspection  at:  U.S.  Environmental Protection Agency, Environmental Criteria and
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  LEAD EFFECTS ON CARDIOVASCULAR FUNCTION, EARLY
DEVELOPMENT, AND STATURE:   AN ADDENDUM TO U.S.  EPA
       AIR QUALITY CRITERIA FOR LEAD (1986)
                  September, 1986
   Environmental Criteria and Assessment Office
     Office of Research and Development (ORD)
       U.S. Environmental Protection Agency
         Research Triangle Park, NC  27711

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                                   CONTENTS
1.   INTRODUCTION 	       1

2.   LEAD EFFECTS ON THE CARDIOVASCULAR SYSTEM 	       1
    2.1   Cardiotoxic Effects in Overtly Lead-Intoxicated
          Human Adults and Children 	       1
    2.2   Epidemiologic Studies of Blood Lead/Blood Pressure
          Relationships 	       2
    2.3   Mechanisms Potentially Underlying Lead-Induced
          Hypertension Effects 	      18
          2.3.1   Role of Disturbances in Ion Transport by Plasma
                  Membranes 	      18
          2.3.2   Role of Renin-Angiotensin in Control  of Blood
                  Pressure and Fluid Balance; Possible Role of
                  Kallikrein-Kinin in Control of Blood Pressure 	      20
    2.4   Experimental Studies of Lead Effects on Blood Pressure
          and the Renin-Angiotensin System 	      22
          2.4.1   Acute In Vivo Lead Exposure 	      22
          2.4.2   Chronic Lead Exposure 	      23
          2.4.3   Renin Secretion by Kidney Slices In Vitro 	      26
          2.4.4   Effects of Lead on Vascular Reactivity 	      26
          2.4.5   Effects of Lead on Noradrenergic Hormones 	      27
          2.4.6   Effects of Lead on Cardiac Muscle 	      27
    2.5   Summary of Lead-Related Effects on the Cardiovascular
          System 	      29

3.   EFFECTS OF LEAD ON DEVELOPMENT AND GROWTH 	      31
    3.1   Fetal Exposure Effects 	      31
          3.1.1   Results of Recent Human Studies 	      32
          3.1.2   Interpretation of Findings from Human Studies 	      40
    3.2   Effects of Lead on Postnatal Growth 	      49
          3.2.1   Epidemiologic Observations 	      49
          3.2.2   Animal Toxicology Studies  	      51
    3.3   Possible Mechanisms of the Effects of Lead on Growth
          and Development 	      52
          3.3.1   Genetic and Extrinsic Factors 	      52
          3.3.2   Endocrine Factors	      52
          3.3.3   Additional Factors Affecting Growth 	      55
    3.4   Summary and Conclusions Regarding  Lead Effects on
          Growth and Development 	      55

4.  REFERENCES  	      57

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                                LIST OF FIGURES
Number

 A-l
 A-2
Systolic blood pressure for 7371 middle-aged men
categorized according to blood lead concentration 	
Relationships among variables affecting 6-month MDI and
PDI scores, as revealed through structural  equation
analysis 	
Page


 11


 37
                                LIST OF TABLES
Number
                                                                Page
 A-l     Body weight, blood pressure, and lipid values of lead
         workers and referents 	       5
 A-2     Systolic blood pressure means in relation to blood lead
         concentrations 	       7
 A-3     Coefficient for the natural log of blood lead concen-
         tration (In PbB) vs.  blood pressure (BP) in men with
         and without adjustment for site variables 	      16
 A-4     Estimates of relative risk of pre-term delivery (by last
         menstrual date) based on multiple logistic analysis of
         maternal blood lead concentrations at delivery 	      34
 A-5     Covariate-adjusted Bayley Mental Development Index
         scores of infants classified by umbilical cord blood lead
         1 evel s 	      36
 A-6     Partial linear regression coefficients for 24-month
         Bayley MDI scores against each blood lead measure, with
         and without maternal  IQ in the model 	      39
 A-7     Lead-related variance increments for neonatal neurological
         measures 	      40
 A-8     Percent additional variance accounted for by different
         indices of lead exposure for various neurobehavioral tests,
         as determined by stepwise multiple regression analyses
         after correction for confounding 	      41
 A-9     Summary of recent studies on the relationship between
         prenatal lead exposure and congenital malformations 	      41
 A-10    Summary of recent studies on the association of prenatal
         lead exposure with gestational age and birth weight 	      44
 A-ll    Summary of recent studies on the relationship between
         prenatal lead exposure and Bayley Mental Development
         Index scores 	    47

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AUTHORS AND CONTRIBUTORS


     The  following  people  served  as authors  or otherwise  contributed to
preparation of the present addendum.   Names are listed in alphabetical order.

Dr. J. Michael Davis
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Dr. Lester D. Grant, Director
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Dr. Peter Petrusz
Department of Anatomy
University of North Carolina School of Medicine
Chapel Hill, NC   27514

Dr. David J. Svendsgaard
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Dr. Winona Victery
Applied Pathology Section
Biometry and Risk Assessment Program
National Institute of Environmental Health Sciences
Research Triangle Park, NC   27709

Dr. David E. Weil
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711


REVIEWERS

     Drafts  of this  Addendum were  circulated for public  comment and for review
by  the  Clean Air  Scientific Advisory  Committee  (CASAC) of  EPA's  Science
Advisory Board (SAB).   Members  of  the CASAC Subcommittee on  Lead listed in the
front matter of  the main  1986  document Air Quality  Criteria  for Lead also
reviewed the present Addendum to the 1986 document.
                                      IV

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1.    INTRODUCTION

     The 1977  EPA criteria document,  Air Quality  Criteria  for  Lead  (EPA-600/8-77-071)  has
been updated and  revised  pursuant to Sections 108-109  of  the  Clean Air Act,  as  amended,  42
U.S.C.  7408 and  7409.   As part of this  process,  EPA released  two external  review  drafts  of
the  revised  Criteria Document, Air  Quality Criteria  for  Lead  (EPA-600/8-82-028A&B),  which
were made  available  both for public  comment  and  peer review  by  the Clean  Air Scientific
Advisory Committee  (CASAC) of the Agency's  Science Advisory Board.   A final  version  of  the
updated criteria  document incorporating  revisions  made in  response  to public  comments  and
CASAC  review  of earlier  drafts  has  been completed  (U.S.  EPA,  1986),  and  will be  used as  a
basis  for  review  and,  as  appropriate,  revision of  the  National  Ambient Air Quality Standard
(NAAQS) for lead.
     Not fully  evaluated   in  the  revised Criteria Document,  however,  are  recently  published
papers  concerning: (1) the relationship between blood lead  levels and  cardiovascular effects;
and  (2) lead  exposure  effects on early development and stature.   The  present Addendum to  the
revised document, Air  Quality Criteria for Lead  (U.S.  EPA,  1986),  evaluates newly  published
information concerning both of these  topics.
2.  LEAD EFFECTS ON THE CARDIOVASCULAR SYSTEM
     Lead has  long  been  reported to be associated with cardiovascular effects, in both human
adults and children.   This  section assesses pertinent  literature  on  the subject, including:
(1) studies of cardiotoxic effects in overtly lead-intoxicated individuals;  (2) epidemiologic
studies  of  associations  between  lead  exposure  and  increased   blood  pressure,  including
observations  for  non-overtly  intoxicated  subjects;  (3)  toxicologic  data providing  experi-
mental evidence  for lead-induced  cardiovascular effects  in  animals  and (4)  information  on
possible mechanisms of action underlying lead's cardiovascular effects.
2.1  Cardiotoxic Effects in Overtly Lead-Intoxicated Human Adults and Children
     Structural and functional  changes  suggestive  of lead-induced cardiac abnormalities have
been described  for both  adults and children,  always  in individuals with clinical  signs  of
overt intoxication.  For  instance,  in  reviewing five fatal cases  of lead poisoning in young
children, Kline  (1960)  noted that degenerative  changes  in  heart muscle were  reported  to  be
the proximate  cause  of  death;  it was not  possible,  however,  to establish that  the observed
changes  were  directly  due to  lead intoxication  per  se.   In  another study,  Kosmider  and
Petelenz (1962)  found  that 66  percent  of a  group  of  adults  over 46 years old  with chronic
                                             A-l

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lead poisoning had electrocardiographic  abnormalities,  a  rate  four  times  the  adjusted normal
rate for that age group.   Additional  evidence for a possible  etiological  role  of  higher level
lead exposure in  the  induction  of disturbances  in cardiac function  derives  from  observations
of the disappearance  of electrocardiographic abnormalities following chelation therapy in the
treatment of many cases  of  lead encephalopathy  (Myerson and  Eisenhauer,  1963; Freeman, 1965;
Silver and  Rodriguez-Torres,  1968).   The  latter investigators, for example,  noted  abnormal
electrocardiograms in 21  (70 percent)  of  30   overtly  lead-intoxicated children  prior  to
chelation therapy, but abnormal  electrocardiograms  remained  for only four (13 percent) after
such  therapy  (Silver and  Rodriguez-Torres,  1968).    None  of the  above  studies   provide
definitive  evidence  that lead  induced  the observed  cardiotoxic  effects, although  they are
highly suggestive of an  etiological  role  of  lead in  producing such effects.  Some  recently
reported  human   autopsy  study  results   (Voors  et  al.,  1982)   showing  associations  between
heart-disease mortality  and elevated aortic lead levels also point  toward  possible  involve-
ment of lead in cardiotoxic  disease processes.
2.2  Epidemiologic Studies of Blood Lead/Blood Pressure Relationships
     Hypertension or, more  broadly,  increased blood pressure represents  the single main type
of cardiovascular effect  long  studied as possibly being associated with  excessive lead expo-
sure.  As  long  ago  as 1886, Lorimer  reported  that  high blood lead levels increased the risk
of hypertension.   However,  from  then until  recently,  relatively mixed  and  often apparently
contradictory  results have  been  reported  concerning   lead-hypertension  effects.  That  is,
numerous  investigators  reported  significant  associations   between  hypertension  and  lead
poisoning (Oliver, 1891; Legge, 1901; Vigdortchik, 1935; Emmerson,  1963;  Dingwall-Fordyce and
Lane, 1963;  Richet  et al.,  1966; Morgan, 1976; Beevers, et al. ,  1976), whereas other studies
failed to  find  a statistically significant association at p <0.05  (Belknap,  1936; Fouts and
Page,  1942;  Mayers,  1947;  Brieger and  Rieders,  1959; Cramer and Dahlberg,  1966;  Malcolm,
1971;  Ramirez-Cervantes  et al.,  1978).   The  potential contribution of  lead  to hypertension
was  difficult  to resolve  based  on  the  results  of such studies, due to many methodological
differences  and  problems  (e.g.,  lack of comparable definitions of lead  exposure and prospec-
tive control populations,  variations in how hypertension was  defined or measured as the key
health endpoint, etc.).
     In contrast to  the generally confusing array of results derived from the above studies,
a  more  consistent pattern of  results has begun to emerge from recent investigations of rela-
tionships  between  lead  exposures and increases in blood pressure or hypertension.  A variety
                                             A-2

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of  study designs  or approaches  have  been  used  in the  recent  studies  and  relationships
examined between a wide  range of blood lead levels and increases in blood pressure in various
clinically-defined, occupationally-exposed, or general population groups.
     In a case-control  pilot study of clinically-defined groups, Khera et al.  (1980)  measured
lead and cadmium levels  in single-draw blood and urine samples from 50 patients being seen at
General Hospital, Birmingham, UK for moderate or severe cardiac condition and/or hypertension
and  from 75 other  patients with  no known cardiovascular  symptoms.   After  excluding  small
numbers  of  women,  non-Caucasians,  and patients <30  yrs  old,  data for the remaining  38 male
cardiovascular patients were  compared to those for  48  matched normotensive  controls.   Urine
metal  levels  were highly  variable (24  hr  samples  being  needed to  overcome  diurnal  varia-
tions),  but average  levels were higher  in cardiovascular  (PbU x = 0.34 u mol/1) than normo-
tensive  (PbU x  = 0.27  u mol/1) patients.   The cardiovascular patients also  had higher blood
lead levels (x  = 2.17,  range 0.43-4.0 u mol/1) than the normotensives (x = 1.4, range 0.58 -
2.2  u  mol/1).*  Hypertensive  patients  (N = 13)  had somewhat  higher mean blood lead levels
than other  cardiovascular  disease  patients (N = 25), and both of these groups had distinctly
higher  PbB  values than  the 48 normotensive  subjects.   Furthermore, blood  lead levels were
consistently notably higher for cardiovascular patients than normotensive subjects when com-
pared  within  4 different age groups  (i.e.,  30-39, 40-49,  50-59, and >60 yrs).   The authors
noted  that  smoking habits  were net determined well  enough to allow for firm conclusions, but
overall  results showed little change  for smoking and lead levels, whereas cadmium levels were
distinctly  higher in  smokers  and  ex-smokers.   These  descriptive  pilot study  results,  not
formally analyzed  for  statistical  significance, qualitatively  suggest higher lead burdens in
cardiovascular  disease  (especially  hypertensive)  patients  than  in  matched  normotensive
control  subjects, but do not permit any firm conclusions as to whether lead causally contrib-
uted to  the etiology of the cardiovascular disease states.
     Batuman  et  al.  (1983),  in  another  study  of  clinically-defined  groups,  evaluated
chelatable  lead burdens in 48 male  patients  seen  for  essential  hypertension  at a Veterens
Administration  Hospital  in New Jersey.   Patients  (N = 27) having essential hypertension with
reduced  renal   function  (serum creatinine level  >1.5  mg/dl)  had  significantly  (p <0.001)
larger  amounts  of chelatable  lead  (x  = 860  ±  101  ug Pb/3 days)  in  their  urine after EDTA
challenge than  did 21  essential hypertension patients without  renal disease (x = 340 ± 39 ug
Pb/3  days).   EDTA test  urine  lead levels for the latter  normal  renal  function hypertension
*Note  that  1 u mole/1 s  20.7  ug/dl  blood lea_d.  Thus, the mean blood lead levels (x) = 44.9
 ug/dl  for  the  cardiovascular patients and  x = 29.0  ug/dl  for  the  normotensive subjects.
                                             A-3

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patients  did  not  differ significantly  from 22  control  patients with  known renal  failure
etiologies.   The authors interpreted their study as suggesting a possible  etiological  role of
lead  in  the renal disease of  some  patients  designated as having essential  hypertension  (in
this  case patients  not currently  occupationally  exposed  to  lead  but  having  lead  burdens
indicative  of  likely past high exposures).  The  fact  that  control  patients with  known  non-
gout  etiology  did  not  have elevated  lead levels, as  well  as  evidence  from other  studies
(Wedeen,  1982;  Wedeen et al.,  1985; Weeden, 1986),  indicate  that  renal  failure  associated
with  hypertension did not  result  in impaired renal excretion  of Pb  and  consequent increased
accumulation of  greater  lead  body stores as  a possible explanation  for the observed results.
     Another approach  employed  in   recently  reported   studies  of blood-lead  blood-pressure
relationships has been  the  study  of groups of  workers  with  varying  levels of lead exposure.
As part of the Glostrup study in Denmark, Kirkby and Gyntelberg (1985)  evaluated  the coronary
risk  profiles for 96 heavily-exposed lead smelter workers employed  between 9 and 45 years in
comparison  to  that  of  a  non-occupationally  exposed reference group matched with  respect to
age,  sex,  height, weight,  socioeconomic status, and alcohol/tobacco  consumption.   The  lead
workers had mean blood  lead (PbB x) levels  of  51 ± 16  (S.D.) ug/dl, while  the  mean for the
referent  control  group  was  11 ± 3 (S.D.) ug/dl.  Blood pressure was  taken both with the  sub-
ject  in the supine position (with a random zero  sphygmomanometer) and in  the sitting position
(with  a  more usual  mercury  sphygmomanometer);  systolic ankle and arm blood pressure levels
were  also measured  by the Doppler ultrasound technique; resting electrocardiograms with  nine
leads  were  recorded and coded  according to   the  Minnesota  Code by  a  trained expert;  and
participants were administered an extensive  questionnaire including questions on  subjective
symptoms, chest  pain,  alcohol  and tobacco usage,  cardiovascular disease  among relatives and
other  pertinent  information.   Table A-l shows  the  results obtained  for  the lead workers and
the referent group for body weight, blood pressure measurements, and lipids.
      Statistical  analyses of results were carried out by Mann-Whitney and chi-square tests of
significance for differences  between the comparison groups.   No significant differences  were
obtained  for alcohol consumption, smoking habits,  or other  life-style factors;  nor was  body
weight significantly different between the groups.  In regard to blood pressure determined by
sphygmomanometer, no significant differences  were obtained (at p <0.05) for systolic pressure
in  either  the   supine  or  sitting  positions,   whereas  diastolic pressure  was  significantly
elevated  for  lead workers  in both  the  supine  (+4 mm  Hg) and  sitting (+5  mm Hg)  positions.
Systolic  pressure monitored by  more sensitive  ultrasound techniques  was,  however, signifi-
cantly  elevated  in  the  left (but  not  right) arm and  the dorsal arteries  of  both right and
left  feet.   As   for other  cardiovascular risk  factors,  a  significantly   (p <0.01) higher
percentage  (20  percent) of lead workers had ischemic electrocardiographic  (ECG) changes  than

                                             A-4

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   Table A-l.   Body weight, blood pressure, and lipid values of lead workers and referents.
                                    (NS = not significant)
Lead Employees

Body weight (kg)
Blood pressure (mm Hg)
Sitting position
Systolic
Diastolic
Supine position
Systolic
Diastolic
Ultrasound systolic pressure
Right arm
Left arm
Right dorsal artery of foot
Left dorsal artery of foot
Lipids
Total cholesterol (mg%)
Triglycerldes (mmol/1)
High-density lipoprotein cholesterol
(mg%)
Mean
78.6


135
86

135
83

135
144
165
164

247.1
1.24

50.5
SO
11.9


21
12

18
12

18
19
28
27

50.1
0.87

9.5
Referents
Mean
76.0


133
82

129
78

133
135
154
155

247.1
1.33

54.9
SD
11.2


20
11

18
12

17
19
22
23

51.6
1.33

11.6
Level of
signifi-
cance
NSa


NS
0.04

NS
0.005

NS
0.03
0.05
0.03

NS
NS

0.004
aNS = not significant at p <0.05.
bl mm Hg = 0.133 kPa.
Source:   Kirkby and Gyntelberg (1985)

did referent control  subjects  (6  percent); but no  significant  differences  were observed for
percentages having angina  pectoris  or intermittent claudication or  in  regard to serum lipid
levels  (except  for  lower  mean  high-density  lipoprotein  cholesterol  for the  lead  workers).
The lead workers with ECG changes had significantly higher blood pressure levels than refer-
ents with  ECG  changes  for both  systolic  and diastolic  measures in both supine  and  sitting
positions  (p  <0.05  for  all  four comparisons).   The authors  concluded that  long-term  lead
workers in this study have higher  coronary risk profiles  than a comparable referent  group and
that these  findings  may indicate a  greater  risk  for major cardiovascular  diseases,  such  as
myocardial  infarction or stroke.
     Overall,  the Kirkby and Gyntelberg (1985) study appears to have been carefully  conducted
and to  have yielded  results  with  a  considerable  degree  of internal  consistency in  regard  to
blood-pressure  determinations obtained by several  different procedures.   Also, these findings
do point toward higher cardiovascular risk for lead smelter workers,  most clearly in terms  of

                                             A-5

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increased blood pressure.   The evidence for increased blood pressure  and  other cardiovascular
risk factors  being specifically due  to lead exposure  is  less  clear,  given  that  a  correla-
tional  analysis between blood lead  levels,  zinc  protoporphyrin,  and blood pressure levels was
reported as yielding  no  statistically significant correlations  and  the  workers  were exposed
to  other  toxic agents  in  the workplace  (e.g.,  antimony,   smoke  and dust) that  might  exert
cardiovascular effects.  On  the  other hand,  neither did other factors  with known association
with high blood  pressure  (e.g.,  body weight,  smoking,  etc.) explain  the  differences  observed
between  the  lead  worker  and referent  control  groups,  and  insufficient description of  the
correlational  analysis was provided  to allow evaluation of  its  soundness.   If lead  exposure
did  contribute  to the  observed  higher blood pressure  values seen in the  lead  workers,  the
magnitude of  the  effect  did not appear  to  be very large,  e.g.,  a  difference of 4-5  mm Hg
diastolic increase associated with  a difference  in mean blood lead level  of ~40 |jg/dl or 0.1-
0.125 mm Hg per ug/dl  blood lead.
     Another recently reported study (deKort et  al., 1986)  examined blood pressure in occupa-
tional ly exposed  workers  (from  a plant processing  lead and cadmium  compounds used as stabi-
lizers  in the plastic industry) in  relation to a control group of workers (from a plant where
insulation materials are produced).   Data were included only for workers  employed longer than
1 yr in  each  plant and not  being treated  for hypertension.  Blood lead  (PbB), blood cadmium
(CdB) and  urine  cadmium  (CdU)  were  determined  by atomic  absorption  (AA)  spectrophotometry,
blood pressure  by random-zero sphygmomanometer, and information  concerning medical  history,
medications, smoking habits,  and other personal  characteristics  by questionnaire.   Chi-square
and  two-tailed  Student's  t-tests were  used  to  test for significant differences  between the
comparison  groups.  Data  were  included in  the analyses  for 53 male workers in the  lead-
exposed group  and for 52  persons for the control  group.  The former were,  on  an average, 3.9
years  older (p  <0.05) and  had been  at work  3.9  years   longer  than  control  subjects,  but
smoking habits  were  comparable.   Blood lead values for the exposed group averaged 47.4 (jg/dl
(ranging  up  to  60-70  (jg/dl),  whereas  the  control  group  averaged 8.1 |jg/dl  (none exceeding
20  pg/dl).   Statistical analyses showed  blood pressure  levels to  be positively correlated
with PbB and CdU  but not CdB.  The correlation for systolic pressure and  PbB remained signif-
icant  after  controlling for  confounding  variables.  The  authors concluded  that a  positive
relationship  existed  between blood  lead  and blood  pressure at  levels  near  or  below 60-70
ug/dl.
     Besides the  above studies  of  occupationally lead-exposed  workers,  Moreau et al. (1982)
reported  findings for 431 male civil  service employees  (aged 24 to 55 yrs) belonging to the
Paris  police  department.   For  each  subject  examined during  a  routine medical visit (during
May, 1980  to  February, 1981), blood pressure was measured by a  mercury apparatus, blood lead
levels determined by  AA spectrometry,  and information  on  alcohol  and tobacco usage obtained
                                             A-6

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 by  questionnaire.   Statistical  analyses were  carried  out,  using  log  PbB  values which appeared
 to  be normally distributed.  Significant correlations  between  blood lead and systolic blood
 pressure were  found, even after taking into account age, wine consumption, and tobacco usage.
 Correcting  for body mass  (ratio weight/height2)  did not alter  the results.   A weaker, but
 significant, association was  reported for diastolic pressure in  relation  to PbB  levels.   In a
 letter  concerning the  same  data set, Orssaud  et al. (1985) later  reported additional analyses
 in  which  systolic blood pressure values were adjusted for body  mass index, age, and alcohol
 consumption  using an analysis  of covariance.  The  results are summarized in Table A-2,  with
 systolic blood pressure values  (both unadjusted and adjusted) grouped in  relation to the  same
 blood lead classes  used by  Pocock et al. (1984), as discussed later.

      Table  A-2.  Systolic  blood pressure means in relation to blood lead concentrations.
Blood
lead
(umol/1)
<0.60
0.61-0.89
0.90-1.19
1.20-1.49
1.50-1.79
>1.80
Systolic
Mean (and 2 SE)
(mm Hg)
127 (3.6)
130 (1.8)
133 (2.4)
139 (4.8)
143 (13.6)
130 (5.4)
blood pressure
Adjusted
mean
129
130
132
138
142
129
No. of
subjects
46
212
126
34
7
6
Source:  Orssaud et al. (1985)

     Overall,  the  blood  pressure means differ significantly  (p  <0.001)  by blood lead group,
increasing consecutively from the first group (<0.60 (jmol/1 = 12.4 ug/dl) to the fourth (1.20
to 1.49 |j mol/1 = 24.8 to 30.8 M9/dl).  The means for the last two groups (>1.50 u mol/1 = 31
(jg/dl)  are  based on  very  small  N's  and were  not  viewed by the  authors  as  yielding useful
information.   The overall correlation between blood lead level and systolic pressure was 0.23
(p  <0.001);  correlations  for  the  age  classes  24  to  34  years  (N = 145),  34 to  44 years
(N = 143), and 45  to 55  years  (N = 142)  were 0.29  (p <0.001), 0.20  (p <0.05),  and 0.14
(N.S.), respectively.  Adjusting for  alcohol  consumption and body mass  index, it was noted,
did not alter  these  results.   The authors concluded that blood pressure was related to blood
lead values,  the correlation  being  highest  in  young subjects but decreasing with  age.   In
general, the  results are highly suggestive of increases in systolic pressure being associated
with blood  lead values in  adult males across a range  of  -12 to  30 ug/dl, the increase  not
being particularly large (about 9 mm Hg or 0.5  mm  Hg per ug/dl  blood lead).   However, it is
not clear  as to why  tobacco  consumption  (although  measured) was  apparently  not  included in

                                             A-7

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the statistical  analyses  and to what extent  its  inclusion  would have affected the  reported
results.   Nor  is  it  completely  clear as to what results  were obtained for  diastolic  pressure
in the  analyses reported  on  later by  Orssaud  et al.  (1985).   For  example,  do  the  weaker
associations for blood  lead-diastolic pressure  reported  by  Moreau et  al.  (1982)  become  non-
significant or no longer evident when adjustments  are made for other  factors,  as evaluated in
the analyses reported by Orssaud for systolic  pressure  results?
     More recently,  Weiss et al.  (1986)  examined blood-lead  blood-pressure  relationships  in a
longitudinal  study  of  a  cohort of 89  Boston,  MA policemen.   During baseline examination,
blood  lead  determinations  were obtained  (AA spectrophometry)  and  three  consecutive  blood
pressure  measurements  taken,  using  a  random-zero  instrument.   With  the  subject  seated,
systolic  blood  pressure and fifth  phase diastolic  pressure were  measured on the left  arm.
Triplicate  blood  pressure measurements  were also taken  at  years 3,  4,  and 5.  Multivariate
analyses showed that, after correction for previous  systolic blood  pressure, body  mass index,
age,   and smoking,  high  blood  lead level was  a  significant predictor  of subsequent  blood
pressure  elevation.   More  specifically,  auto-regressive analyses were  performed for  blood
lead  and  blood pressure  data  from 70  subjects providing 162 pairs  of  data  (by  consecutive
examination)  for  the systolic  regression.   There was a significant  association  (p  = 0.036)
between high  (^30 ug/dl)  blood  lead and subsequent  elevation  in blood pressure (coefficient
= 5.804) but not for low (20 to  29 (jg/dl) blood  lead  (coefficient = 0.224).  Similar  analyses
for 172 pairs of data from 72 subjects for diastolic  pressure revealed no significant associ-
ation between blood lead and diastolic pressure.   Further iterative cross-validation  analyses
(assessing  the  impact of  a few influential  data points)  improved the  relationship between
systolic pressure and other independent variables (e.g., body mass index,  age, etc.) but did
not dramatically alter the relationship  with high  blood lead (coefficient = 4.467,  p  <0.097).
Overall,  the  authors concluded  that these data  suggest a  relationship between  blood  lead
levels  and  systolic  (but  not  diastolic) blood  pressure.    The stronger  association  found
between  lead  and systolic  pressure than between  lead and  diastolic  pressure is  consistent
with  the  observations by  Moreau  et al.  (1982)  and Orssaud  et al.   (1985)  for  Paris  civil
servants.  However,  the latter had generally lower blood  lead levels  than the  high lead group
of Boston policemen  (^30  ug/dl) for which Weiss  et  al.  (1986)  found significant  blood lead-
systolic pressure associations.
     One  other American  study,   available  thus  far  only in  abstract  form (Hodgson  et  al.  ,
1985),  evaluated blood-lead  blood-pressure  relationships  in  a cohort  of lead  workers  and
controls  (all  white  males of similar socioeconomic  status).  Separate equations  were gener-
ated for systolic and diastolic  blood pressure as  dependent  variables and blood lead  and zinc
protoporphyrin  levels as independent variables,  controlling  for age,  body mass index, average

                                             A-8

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daily alcohol consumption,  smoking,  exercise frequency, and an  index  of lifetime cumulative
lead exposure  (for lead  workers).   Overall R2  ranged from 0.09  to 0.30; no  index  of lead
exposure  accounted for  more than  2 percent  of the  total  variance;  and  none of the lead
coefficients were significant (even at p <0.10).   Unfortunately,  insufficient information was
reported  in  the  published abstract to allow adequate  assessment of important aspects of the
study (e.g., size of the study groups, how well matched they were,  etc.).
     In addition  to the  above  recent studies of clinically-defined populations  or specific
worker  cohorts,  Kromhout and Couland (1984)  and  Kromhout et al.   (1985)  evaluated a cohort
drawn from the more general population.   More specifically, data on trace metals and coronary
disease risk  indicators  were collected  in 1977  for  152 men (aged 57-67 yrs)  in  the  town of
Zutphen,  The Netherlands.   Blood lead,  blood  cadmium,  serum  zinc,  and  serum  copper were
determined by AA  spectrometry;  serum lithium was determined by  flame  emission spectrometry.
Also, the following coronary heart  disease risk  indicators  were measured:   total and high
density lipoprotein  cholesterol,  smoking  habits,  Quetelet index  (weight/height2), and sys-
tolic and diastolic blood  pressure.   A  standard  protocol  and  mercury  sphygmomanometer was
employed  by  a  single  internist  in obtaining blood pressure readings from the right arm while
the subjects were  in  a supine position.   The  first  reading was taken at  the  beginning, and
the second and  third  at the end  of  the  medical  examination;  only the  systolic and diastolic
(fifth phase) values  of the third reading were  recorded.   Resting heart rate was calculated
from  an  electrocardiogram.   Statistical  analyses   were  carried  out  using  SPSS  package
programs,   including calculation  of correlation coefficients, ANOVA, and multiple regression
analyses.   For  skewed  distribution  variables,  log transformations were  used,  but no  differ-
ences were found  between analyses using transformed or  untransformed  variables.   The levels
of  coronary  heart disease  risk  indicators were  generally high in  the elderly  cohort; and
blood lead levels  exceeded  30 ug/dl   in 8.6  percent  and 40 ug/dl in 1.3 percent of the study
group.   In  addition to  several  significant  associations found between  the other  metals and
various risk  indicators, blood lead  was  found to be  statistically  significantly  related to
cigarette  smoking  (p  <0.03),  but more markedly  related  to  both  systolic and diastolic blood
pressure.   Using multiple regression analyses correcting for age and body mass index,  the PbB
regression coefficients  were reduced from  0.24 (p <0.01)  to  0.21 (p  <0.01) for systolic
pressure  and  from  0.18 (p <0.05) to  0.15  (p  <0.05)  for diastolic.  However,  in  testing the
stability  of the results by excluding the highest blood lead (52.5  ug/dl) subject  with hyper-
tension (218/138  mm Hg), a  borderline  significant  correlation was found  between  blood lead
and  systolic  pressure,  whereas   the  blood lead-diastolic  pressure coefficient  became non-
significant.   Neither  blood  lead  coefficient for systolic or diastolic  pressure  was  signif-
icant after  multiple  regression  analyses  were  conducted  that  include other  determinants
                                             A-9

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(e.g.,  age  and  body  mass  index)  in  the model  when  the  data  for the  same  highest-lead
individual  was  excluded;  but the  coefficients  between blood  pressure  and age or body  mass
index were unaffected by  his  exclusion.   The  authors  concluded that  blood  lead is  probably  a
less important determinant of blood pressure than  age  or body mass  index.
     The  above  recent studies provide  generally consistent  evidence  of  increased blood pres-
sure being  associated  with elevated  lead body burdens in  adults, especially as  indexed by
blood lead levels  in various  cohorts  of  working men.   None  of  the  individual  studies  provide
definitive evidence  establishing  causal  relationships between  lead  exposure and  increased
blood pressure.   Nevertheless,  they collectively  provide  considerable qualitative  evidence
indicative of significant associations  between blood lead and blood pressure levels.   Partic-
ularly  striking  are  the  distinct  dose-response  relationship  seen for  systolic  pressure
(correcting for  age, body  mass,  etc.)  by Moreau et al.  and  the findings of significant asso-
ciations between  blood  lead  and  systolic pressure after extensive  and conservative statisti-
cal analyses  by Weiss  et al.   However, estimates  of quantitative relationships between blood
lead levels and blood  pressure  increases derived  from such  study results  are subject to  much
uncertainty,  given the  relatively  small  sample sizes and limited  population groups  studied.
Two larger-scale  recent  studies  of general  population groups,   reviewed next,  provide better
bases for estimation of quantitative blood-lead blood-pressure  relationships.
     In  one  such  recent  study,  Pocock  et al.  (1984) evaluated relationships between blood
lead concentrations, hypertension,  and renal  function indicators in a clinical  survey of 7735
middle-aged men (aged  40-49)  from  24 British towns.   Each  man's blood pressure was  measured
while  seated  twice in  succession  by  means  of a  London School  of Hygiene sphygmomanometer.
Diastolic  pressure was  recorded at  phase V  disappearance  of  sounds.   The mean  of  the two
readings  of  blood pressure was  adjusted for  observed variation within each  town  to correct
for  any  differences among three observers.   Results  for  7371  men included  in data  analyses
indicated  correlation  coefficients  of   r = +0.03  and  r = +0.01  for  associations  between
systolic  and  diastolic  blood  pressure,  respectively,  and  blood  lead  levels.   The  systolic
blood pressure  correlation, though small in magnitude, was  nevertheless statistically signif-
icant  at p <0.01.   However,  analyses of  covariance  using data for men categorized according
to  blood lead concentrations only suggested  increases  in blood pressure  at lower blood lead
levels;  no further significant  increments  in  blood  pressure  were  observed at higher blood
lead levels either before  or after adjustment for factors such as age, town, body mass index,
alcohol  consumption,  social  class, and  observer  (see Figure A-l).   Evaluation of prevalence
of  hypertension defined  as  systolic  blood pressure  over   160 mm  Hg revealed no significant
overall  trend;  but of  those men  with blood  lead  levels over 37  ug/dl,  a larger proportion
(30 percent)  had  hypertension when  compared  with  the  proportion  (21 percent) for all other

                                             A-10

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                            418(21)   675(20)   349(25)     95(25)     22(171     22(30)
                                   NUMBER(PERCENT) WITH SYSTOLIC BP>160 mmHg

                     Figure A-1. Systolic blood pressure for 7,371 middle-aged men categorized according
                     to blood lead concentration.
                     Conversion: SI to customary units -- Lead: 1 nmo\tLs*2Q.7 /jg/100 ml.
                     Source: Pocock et al. (1984).
men combined (p =0.08).   Similar results  were obtained  for diastolic hypertension defined as
>100  mmHg,  i.e.,  a  greater proportion (15 percent) of  men with blood  lead levels  over 37
pg/dl  had  diastolic  hypertension in  comparison with the  proportion (9 percent)  for all other
men  (p =0.07).   Pocock et al.  (1984)  interpreted their  findings  as  being  suggestive  of
increased  hypertension  at blood lead  levels  over  37 Lig/dl, but  not  at lower  concentrations
typically  found  in  British  men.   However, more  recent  analyses  reported  by  Pocock  et al.
(1985)  for the same  data indicate  highly  statistically  significant associations  between both
systolic  (p =0.003)  and  diastolic  (p <0.001)  blood  pressure  and  blood  lead  levels,  when
adjustments  are made  for variation due to site  (town) in multiple regression  analyses.   The
regression coefficients for log  blood lead versus systolic and diastolic pressure were +2.089
and +1.809,  respectively, when adjusted for town as well  as body mass, age,  alcohol, smoking,
social  class and  observer.   Noting the small  magnitude  of the association observed  and the
difficulty   in  adjusting for  all  potentially  relevant   confounders,  Pocock et  al  (1985)
                                               A-11

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cautioned against prematurely concluding that elevated body lead burden has  a causal  influence
on blood pressure.
     Relationships between blood lead and blood pressure among American adults have also been
recently evaluated  in  another  large-scale  study,  as reported by Harlan et al.  (1985),  Pirkle
et al.   (1985),  Landis  and  Flegal  (1986),  and  Schwartz (1985a,b; 1986a,b).   These  analyses
were based  on  evaluation  of  NHANES  II  data, which  provide careful  blood lead and  blood
pressure  measurements  on  a large-scale  sample  representative  of  the U.S.  population  and
considerable information  on  a  wide variety of potentially confounding variables as well.   As
such, these analyses avoided the problem of selection bias,  the healthy-worker effect,  work-
place exposures to other toxic agents, and problems with appropriate  choice  of control  groups
that often  confounded  or  complicated  earlier,  occupational  studies  of blood-lead  blood-
pressure relationships.  Three blood pressure readings were recorded  for each subject:   while
seated  early in  the examination, supine midway in  the  examination,  and seated near the end.
First and  fifth phase sounds  were taken as systolic and  diastolic  pressures,  respectively.
The  second  seated  blood  pressure  was  used  in statistical analyses, but analyses  using  the
first  seated  pressure  or a mean  of the  first and second  seated pressure yielded  similar
results.  Blood  lead  values,  determined by  AA spectrometry, were transformed  to  log  values
used in statistical analyses.
     Relationships  between  blood  pressure  and other variables  were evaluated  in  two  ways.
First,   men  and  women were stratified into normotensive  and  hypertensive categories and mean
values  for relevant variables contrasted across the categories.  For  ages 21-55 yr, diastolic
high blood  pressure (>90 mm Hg) male  subjects (N = 475) had significantly  (p <0.005)  higher
PbB  levels,  body  mass  index values, and  calcium foods than  did  normotensive male  subjects
(N = 1,043).  Similar  results  were obtained for aged 21-55  yr diastolic high blood pressure
females  (N  =  263)   in  comparison  to normotensive  females  (N = 1,316).  For ages  56-74 yr
subjects, significantly  (p  <0.05)  higher PbB  levels were  found for  female  subjects (but not
males)  defined  as  having  isolated  systolic  high blood  pressure  (i.e., systolic  >160  and
diastolic <90 mm Hg).  Simple correlation analyses and step-wise multiple regression analyses
were carried  out  as a second  statistical  evaluation approach; PbB  values  were entered  into
predictive  models  for  systolic and diastolic  pressure as  well  as  several  other pertinent
variables  (such as  age,  body mass  index,  etc.)   entered  sequentially  according to greatest
magnitude of  variance  explained for the dependent variable.   The simple correlation analyses
reported  by Harlan et al.  (1985)  demonstrated  statistically significant linear associations
(p <0.001) between  blood  lead concentrations and blood pressure (both systolic and diastolic)
among males and  females,  aged 12 to  74 years.   Using multiple regression analyses controlling
for  a number of  other  potentially  confounding  factors,  however, the blood-lead blood-pressure

                                             A-12

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 associations remained significant  for males but  not  for women after adjusting  for the effects
 of other pertinent variables.
     Additional analyses of NHANES  II data reported  by Pirkle et al.  (1985) focussed on white
 males  (aged 40 to  59 years)  in order  to  avoid the  effects  of  collinearity between blood
 pressure and  blood  lead concentrations  evident  at earlier ages and because of less extensive
 NHANES  II data being available for  non-whites.   In the subgroup studied, Pirkle et al. (1985)
 found  significant  associations  between blood lead and blood pressure even after including in
 multiple  regression  analyses all  known factors  previously  established as  being correlated
 with  blood pressure.   The  relationship also  held when  tested  against  every  dietary and
 serologic variable measured  in  the NHANES II study.  Inclusion of both curvilinear transfor-
 mations and interaction terms altered little the coefficients for blood pressure associations
 with  lead  (the  strongest relationship was observed  between the natural log of blood lead and
 the blood  pressure  measures).  The  regression coefficients for log blood lead versus systolic
 and  diastolic  blood pressure were 8.436 and 3.954, respectively.  No  evident threshold was
 found  below which  blood lead level was  not  significantly related to blood pressure across a
 range  of  7 to  34  M9/dl.   In fact,  the dose-response relationships  characterized  by Pirkle
 et al.  (1985)  indicate that  large initial  increments  in blood pressure  occur at relatively
 low blood  lead  levels,  followed by leveling off of  blood pressure increments at higher blood
 lead levels.  Pirkle et al. (1985) also found lead to be a significant predictor of diastolic
 blood  pressure  greater  than or equal   to  90 mmHg,  the  criterion  blood pressure  level  now
 standardly  employed  in the  United States  to define hypertension.  Additional  analyses  were
 performed by Pirkle  et  al.  (1985) to estimate the likely public health implications of their
 findings concerning blood-lead,  blood-pressure relationships.   Changes in blood pressure that
 might result from a specified change in blood lead levels were first estimated.  Then coeffi-
 cients  from the  Pooling Project and Framingham studies (Pooling Project Research Group,  1978
 and  McGee  and  Gordon,  1976,  respectively)  of  cardiovascular disease  were  used  as  bases:
 (1) to  estimate the  risk  for incidence of serious  cardiovascular  events  (myocardial  infarc-
 tion, stroke, or death)  as a consequence of lead-induced blood pressure increases and (2) to
 predict the change in  the  number of serious  outcomes  as  the result of a 37 percent decrease
 in blood lead levels  for adult white males  (aged  40-59  years) observed during the  course of
 the NHANES II  survey (1976-1980).
     Questions  have been raised by Gartside (1985) and  E.I.  Du Pont de Nemours (1986)  regard-
 ing the  robustness  of  the  findings derived  from the analyses  of NHANES  II  data  discussed
above and as to  whether certain  time trends in the NHANES  II  data  set  may have contributed to
 (or account  for) the  reported  blood-lead  blood-pressure relationships.   Gartside  reported
analyses of HNANES  II data  which found that the  size and  level  of  statistical  significance of
coefficients obtained varied depending  upon  specific data aggregations  used in analyzing the
                                             A-13

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data.  The  largest and  most  significant coefficients  for  blood lead versus  blood  pressure
were  obtained  by Gartside  for  data aggregated by  age  groups that approximated that  of  the
40-59  yr male  aggregation described  by Pirkle et  al.  (1985),  with  coefficients  for  most
younger  cohorts  group aggregated  by  varying 20 yr age intervals  (e.g.,  21-40,  22-42  yrs,
etc.)  or  older  groups not always being significant at p <0.05.   As for the time trend issue,
both blood lead and blood pressure declined substantially during the 4-yr NHANES II study and
different geographic sites were sampled without revisitation of the same site over the survey
period.   Thus,  variations  in  the sampling sites over time,  coincident with changes  in blood
lead  and/or  blood  pressure,  might contribute to any observed associations  between blood lead
and blood pressure.  E.I. Du Pont de Nemours (1986) reported that multiple  regression coeffi-
cients decreased in magnitude and some became non-significant at p <0.05 when geographic site
was  adjusted  for in analyses  of NHANES  II  data,  including  analyses for the male group (aged
12-74) reported on by Harlan et al. (1985) and for males (aged 40-59) reported on by Pirkle et
al.  (1986).   For example,  E.I.  Du Pont  de  Nemours  reported unpublished reanalyses of NHANES
II  data  confirming significant  associations for both aged 12-74 yrs males  and 40-59 yr males
between  log  PbB and systolic or diastolic blood pressure unadjusted for geographic site, but
smaller  coefficients  (nonsignificant  for diastolic) when geographic site was included in the
analysis.   However,  neither the Gartside  nor  E.I.  Du Pont de  Nemours  analyses adjusted for
all  of the  variables that were  selected  for stepwise inclusion in the  Harlan  et  al.  (1985)
and  Pirkle et al.  (1986) published analyses  by means of a priori decision rules for inclusion
of  variables having  significant  associations  with blood pressure.  Also,  other differences
existed   in  regard  to   specific  aspects  of  the   modeling   approaches  employed,  making  it
extremely difficult  to  assess clearly the potential  impact  of variation in selection of age
groups and geographic site adjustment on NHANES II analyses results.
      In  order to more definitively assess the robustness of the Harlan et al. (1985) findings
and,   also,   to  evaluate  possible time-trend  effects confounded  by  variations  in  sampling
sites, Landis and  Flegal (1986)  carried out  further analyses  for NHANES  II males, aged 12-74,
using a  randomization  model-based  approach  to  test  the   statistical  significance  of  the
partial  correlation between blood lead and  diastolic blood pressure, adjusting for age, body
mass  index,  and  the 64 NHANES  II sampling sites.  The resulting  analyses  confirm that the
significant  association  between blood lead  (PbB) and blood pressure (BP) cannot be dismissed
as   spurious  due to  concurrent  secular trends in  the two  variables  over  the NHANES study
period.   Simple linear and multiple  regression coefficients  between log PbB and diastolic BP
for all  males  (aged  12-74) were  0.15  and  4.90,  respectively;  for  various groups broken out by
age (<20, 21-39,  >40 yrs)  and body mass  index  levels, the respective coefficients  ranged from
0.04 to  0.15 and  from 1.29 to  3.55 (predominantly  between  2.3  and  3.6), displaying  consider-
able  consistency  across  age-body mass  comparison  groups.   Also,  the  most  stringent or
                                             A-14

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"conservative"   approach   used  to  calculate  a  randomized  model  statistic  controlling  for
effects  due  to 64  sampling sites  yielded  a  test  statistic of  4.64  (still  significant  at
P <0.05).
     In order to  address  the  "site" issue more definitively, Schwartz  (1985a,b; 1986a,b) has
also carried out  a  series of additional  reanalyses  of the NHANES II data.   These unpublished
analyses confirm  that the  regression  coefficients  remain significant for both systolic and
diastolic blood pressure  when site is included as a  variable in multiple  regression analyses.
Of several different  approaches  used by Schwartz, the most direct was  holding all aspects of
the original  Pirkle et  al.  (1985) analyses the  same  except for the addition  of a variable
controlling  for  the  64   geographic  sites sampled  in  NHANES II.   Using this  approach,  the
cofficients for log  PbB  in relation to either diastolic or systolic BP dropped somewhat from
those  of the original analyses  when  site  was controlled  for  (i.e.,  from  8.44  to 5.09 for
systolic and from 3.95 to 2.74 for  diastolic  blood pressure),  but the coefficients for each
still   remained  significant  at  p  <0.05.  When still  other approaches were used to control for
site along with variations in other variables included in the analyses, statistically signif-
icant  results were  still  consistently  obtained both for  males  aged 40-59 and for males aged
20-74.    The  results  obtained  by  Schwartz via reanalysis of NHANES II data (unadjusted versus
adjusted for geographic site) are presented in Table A-3 in comparison  to results reported by
E.I.  Du  Pont de Nemours  and in relation  to  the findings presented by  Pocock for British men
(also  unadjusted versus adjusted for site).
     Overall,  the  analyses  of  data  from  the  two large-scale  general population  studies
(British Regional Heart  Study  and U.S. NHANES II Study) discussed above  collectively provide
highly  convincing evidence  demonstrating small  but statistically  significant associations
between  blood  lead  levels and  increased  blood  pressure  in  adult men.   The strongest associ-
ations  appear   to  exist   for  males  aged  40-59 and  for systolic  somewhat  more  so  than for
diastolic  pressure.   Virtually all  of the  analyses  revealed positive  associations  for the
40-59  aged group,  which  remain or become significant  (at p <0.05) when  adjustments are made
for geographic  site.   Furthermore,  the  results of these large-scale  studies  are consistent
with similar findings of  statistically significant associations between blood lead levels and
blood  pressure  increases  as  derived  from  other   recent   smaller-scale  studies  discussed
earlier, which  also mainly found  stronger  associations for systolic pressure  than for dia-
stolic.  None of the observational studies in and of themselves can be  stated as definitively
establishing causal  linkages between  lead  exposure and  increased blood  pressure of hyper-
tension.   However,  the plausibility of the observed associations reflecting causal relation-
ships  between  lead  exposure  and  blood  pressure  increases  is  supported   by:    (1)  the
consistency of  the  significant associations  that have now been found by numerous independent
investigators  for a variety of  study populations;  and  (2)  by  extensive  toxicological data
                                             A-15

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     Table A-3.   Coefficients  for the  Natural  Log of Blood  Lead Concentration (logPbB)  vs.
           Blood Pressure (BP) in Men  With  and Without  Adjustment  for Site  Variables
  Analysis
Performed by
     Study
     Group
Unadjusted
 for Site
                                                                   Coefficient of
                                                                   logPbB  vs.  BP
Adjusted
for Site
Pocock et al.
  (1984, 1985)
Schwartz (1985a,b)
E.I.  Du Pont
  de Nemours(1986)
Schwartz (1986a,b)
E.I. Du Pont
  de Nemours (1986)
British Regional
 Heart Study
White males aged 40-59
     Systolic (n=7371)
     Diastolic (n=7371)

NHANES II
Males aged 20-74
     Systolic (n=2254)
     Diastolic (n=2248)

NHANES II
Males aged 12-74
     Systolic (n=2794)
     Diastolic (n=2789)

NHANES II
White males aged 40-59
     Systolic (n=543)
     Diastolic (n=565)

NHANES II
White males aged 40-59
     Systolic (n=553)
     Diastolic (n=575)
                                                              1.68**
                                                              0.30
                                                              5.23***
                                                              2.96***
                                                              3.43***
                                                              2.02***
                                                              8.44**
                                                              3.95**
                                                              6.27**
                                                              4.01**
                   2.09**
                   1.81***
                   3.23**
                   1.39*
                   1.95*
                   0.36
                   5.01*
                   2.74*
                   3.46*
                   1.93*
  *p < 0.05
 **p < 0.01
***p < 0.001


(see  below)  which clearly  demonstrate  increases  in  blood pressure for  animal  models under
well-controlled  experimental  conditions.   The  precise  mechanisms  underlying relationships

between  lead  exposure  and  increased  blood  pressure,  however,  appear  to  be  complex  and

mathematical  models  describing  the  relationships  still  remain  to   be  more  definitively

characterized.   At present,  log  PbB-BP models  appear  to fit  best the  available  data,  but

linear relationships  between  blood lead and blood pressure cannot be ruled out at this time.

The most  appropriate  coefficients characterizing PbB-BP relationships also remain to be more

precisely  determined,  although  those  reported by Landis and Flegal (1986) and those in Table

A-3 obtained  by  analyses adjusting for  site appear to be the currently best available and most
                                             A-16

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reasonable estimates of the  likely strength of the association (i.e.,  generally in the range
of 2.0-5.0  for log  PbB  versus systolic  and 1.4  to  2.7  for log PbB  versus  diastolic blood
pressure).
     Blood lead levels  that may be associated with increased blood pressure also remain to be
more clearly defined.  However,  the collective evidence from the above studies points toward
moderately elevated blood lead levels (>30 ug/dl) as being associated most clearly with blood
pressure increases,  but  certain evidence (e.g.,  the  NHANES II data analyses  and  the Moreau
et  al.  study  results) also  indicates significant  (and  apparently stronger)  relationships
between blood  pressure elevations  and still lower blood lead levels that range, possibly, to
as low as 7 ug/dl.
     The quantification  of likely  consequent  risks for serious  cardiovascular outcomes, as
attempted by  Pirkle et al.  (1985),  also  remains to  be  more precisely  characterized.   The
specific magnitudes  of risk  obtained for serious cardiovascular outcomes in relation to lead
exposure, estimated  on the basis  of  lead-induced  blood pressure  increases,  depend crucially
upon:   the  form of  the  underlying  relationship  and size of  the coefficients  estimated for
blood-lead blood-pressure  associations;  lead exposure levels at which significant elevations
in  blood  pressure  occur;  and  coefficients  estimating  relationships between  blood  pressure
increases  and  specific  more  serious cardiovascular  outcomes.   As noted  above  uncertainty
still exists regarding the most appropriate model and blood-lead blood-pressure coefficients,
which makes it difficult  to  resolve which specific coefficients should be used in attempting
to  project  more serious  cardiovascular  outcomes.  Similarly,  it is  difficult to determine
appropriate blood  lead  levels at which  any  selected  coefficients might be  appropriately
applied in models  predicting more serious cardiovascular outcomes.   Lastly, the selection of
appropriate models  and coefficients  relating  blood pressure increases to  more serious out-
comes is also  fraught  with uncertainty.   Questions exist regarding the general applicability
of coefficients derived from the  Pooling Projects and Framingham Study to the men aged 40-59
in  the  general U.S. population.   Further  analyses  of additional  large  scale epidemiologic
data  sets  may  be  necessary  in order to determine more precisely quantitative relationships
between  blood-lead  and  blood-pressure,  and more serious  cardiovascular outcomes  as well.
     The findings  discussed  here,  while  pointing toward  a likely causal effect  of lead in
contributing to increased blood pressure need to be placed in broader perspective in relation
to  other  factors   involved in  the  etiology  of hypertension.   The  underlying  causes  of in-
creased blood  pressure or "hypertension"  (diastolic  blood  pressure above 90  mm  Hg), which
occurs  in  as  many  as 25 percent of  Americans,  are not yet  fully delineated  (Frolich, 1983;
Kaplan, 1983).   However,  it is very clear that many factors contribute to development of this
disease,  including  hereditary traits,  nutritional  factors  and environmental  agents.   The
relative roles of various dietary and environmental factors in influencing blood pressure and
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the mechanisms by which  they  do so are a matter  of intense investigative effort and  debate
(see  proceedings  of  conference "Nutrition  and Blood  Pressure:  Current  Status of  Dietary
Factors and Hypertension," McCarron and  Kotchen,  1983).   The contribution of  lead,  compared
to many other factors evaluated in various  analyses discussed above,  appears  to be  relatively
small, usually  not  accounting  for  more  than 1-2  percent  of the variation explained  by  the
models employed when other significant factors are controlled for in  the analyses.
2.3  Mechanisms Potentially Underlying Lead-Induced Hypertension Effects
     This  section discusses  plausible biochemical-physiological  mechanisms  by  which  lead
potentially influences the cardiovascular  system to induce increased blood pressure, followed
by  the  evaluation of experimental  evidence concerning the contribution of  lead  exposure to
development of hypertension.
     Blood  pressure  is  determined  by  interaction  of two factors:  cardiac  output  and total
peripheral  resistance.  An  elevation  of either or both results in an increase in blood pres-
sure.  A subsequent defect in a critical regulatory function (e.g., renal  excretory function)
may  influence  central nervous  system regulation  of  blood pressure, leading  to  a permanent
alteration  in  vascular  smooth muscle  tone  which sustains  blood pressure  elevation.   The
primary  defect  in the pathophysiology of hypertension  is  thought to be due to alteration in
calcium  binding  to plasma membranes of cells; this change in calcium handling may in turn be
dependent  upon  an  alteration  in  sodium  permeability  of the  membrane  (Blaustein,  1977;
Rasmussen,  1983;  Postnov  and Orlov, 1985;  Hilton,  1986).   This change  affects several path-
ways capable of elevating pressure: one is  a direct alteration of the sensitivity of vascular
smooth  muscle  to  vasoactive  stimuli; another is  indirect,  via alteration of neuroendocrine
input to vascular  smooth muscle (including  changes  in renin secretion rate).

2.3.1   Role of Disturbances in  Ion  Transport by Plasma Membranes
     Many  stimuli  activate target  cells  in the mammalian body  via changes  in  ion permeabili-
ties  of the plasma membrane, primarily for sodium, potassium,  and calcium  ions (Carafoli and
Penniston,  1985);  the change  in calcium ion concentration is the  primary intracellular signal
controlling muscle  contractions,  hormone  secretion,  and other  diverse  activities.   Extra-
cellular fluid contains high  concentrations of sodium and calcium, while intracellular potas-
sium is high.   Intracellular calcium  is  present  in two forms, bound and  free ion, with the
concentration  of  the  free ion normally  about  0.1 uM.   These concentration gradients across
cell  membranes are maintained  via  the  action of membrane-bound  energy-requiring or voltage-
dependent   exchange  pumps.   For  sodium  and  potassium, the  regulatory  pump is  a  sodium/
potassium-dependent  ATPase which  extrudes  sodium  in exchange  for  potassium ions and in the
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process  is  important  in  maintaining the  cell  membrane potential.   For  calcium,  there is a
membrane potential-dependent  sodium/calcium exchange pump which extrudes  one  calcium ion in
exchange for  three  sodium ions.  In addition, there are calcium ATPase pumps located at cell
membranes and at intracellular membrane storage  sites  (endoplasmic  reticulum and mitochon-
dria).  As  calcium  ions move in and out of the cell and in and out of intracellular storage
sites,  the  intracellular free  calcium  ion  ([Ca2+]) changes from  its  resting  value to some-
thing higher  or lower.  The ion interacts with several calcium-binding proteins which in turn
activate cell contractile or secretory processes.
     It has  been  postulated (Blaustein and Hamlyn, 1983) that sodium pump inhibition by some
endogenous  factor (thought  to be a hormone) could be ultimately causatory for development of
both essential and volume-expanded hypertension by affecting vascular tone or resistance.   As
explained above,  the  sodium pump maintains and restores the membrane potential subsequent to
depolarization events.  Decreased  sodium pump activity may directly increase membrane perme-
ability to  calcium  and  increase  reactivity to calcium-dependent  stimuli.   Small  changes in
the distribution of intracellular and extracellular sodium ions affect the membrane potential
and cause a much  larger decrease in activity  of the sodium/calcium exchange pump, resulting
in a proportionately  much greater elevation in  intracellular  free calcium ion which in turn
increases  reactivity  to  calcium-activated  stimuli.   Some  of  the  newest  antihypertensive
therapeutic agents  (calcium  channel  blockers)  act to lower  intracellular [Ca2+]  by reducing
movement  of  extracellular  calcium  into  cells,  thereby  reducing  activation of  processes
requiring such  movement.    Diuretic  drugs  may  reduce the  postulated rise  in  intracellular
sodium  concentration   related  to  the  decreased  Na+/K+-ATPase activity  and thereby  reduce
elevated intracellular calcium by stimulation of the Na/Ca exchange pump.
     If lead exposure could be shown  to affect sodium transport (which then indirectly alters
vascular resistance)   or  to directly  affect vascular  resistance  (by changing calcium  ion
permeability  or  transport),  it could  contribute  to  the  development of hypertension.   In
sections previously  presented  in the  revised criteria  document  (U.S. EPA, 1986),  abundant
experimental  evidence  was discussed which  indicates that  lead  affects both; that  is,  lead
inhibits cell  membrane-bound  Na+/K+-ATPase as  well as  interferes with  normal processes  of
calcium transport across  membranes of  various  tissue types  (see  sections  12.2.3  and 12.3.2.2
of U.S.  EPA,  1986,  for discussion).   Highlighted  concisely  below  is  evidence  that lead acts
to alter  sodium  balance  and calcium-activated  cell activities of vascular  smooth  muscle.
Changes  in  either or  both  of these  could  be expected  to  produce changes in  blood  pressure
regulation.
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2.3.2  Role of Renin-Angiotensin in Control  of Blood Pressure  and  Fluid  Balance;
       Possible Role of Kallikrein-Kinin in  Control  of Blood Pressure
     One major endogenous  factor  regulating  total  peripheral  resistance  of  the  vascular
smooth muscle  is  angiotensin  II (All),  a small  peptide generated  in plasma via  the action of
a renal  hormone, renin.   Renin is synthesized and stored in  juxtaglomerular (JG)  cells of the
kidney and is  released  when JG cells receive stimuli  indicating a decrease in arterial  pres-
sure, as sensed by cardiovascular baroreceptors  and  transmitted to the central nervous system
(CNS) with subsequent activation of  efferent p-adrenergic signals to the  kidney.   Changes in
the  intracel lular  calcium ion  concentration  of the  JG cell   are  thought to be  involved in
renin  release  (Churchill,  1985),  with  an  increase  in  intracellular  [Ca2+]  producing  a
decrease in renin secretion, while  a  decrease in intracellular [Ca2+] produces an increase in
renin release.
     Renin is  the  first enzyme in  a series which splits a  small  peptide,  angiotensin I (AI)
from angiotensinogen, or  renin substrate,  a large protein  synthesized  by  liver  and found in
circulation.   AI  is  converted  to  All by angiotensin converting enzyme (ACE), an  enzyme  found
in plasma and  lung tissue.   All is degraded  to  AIII  and other breakdown  products by various
proteolytic enzymes.   Renin is cleared from  plasma by  the liver.
     All acts to  increase total  peripheral  resistance by:   (1)  direct  action  on  vascular
smooth muscle to increase vasoconstriction (it is 10 to 40 times more potent than norepineph-
rine and acts to elevate cytosolic  calcium of vascular smooth  muscle to  activate  the contrac-
tion of actin  and myosin);  and (2) indirectly,  by acting on the area postrema of the medulla
oblongata to  increase the  discharge  rate of sympathetic neurons (which  increases norepineph-
rine release,  decreases  its  reuptake,  and increases vascular  sensitivity  to norepinephrine).
     All also  influences  renal  function and overall  salt and  fluid balance in  several  ways:
(1)  Renal  hemodynamics:   glomerular filtration  rate  is  altered  by All-related  changes  in
renal blood  flow  or  indirectly by  increased  noradrenergic transmission  to the  kidney  re-
sulting from  CNS action  of  AIL   (2)   Salt  and water  metabolism:   All-induced  changes in
renal sympathetic tone alter reabsorption of sodium  and potassium;  All stimulates aldosterone
secretion which affects sodium and  potassium balance;  All may  have direct  action  on the  renal
tubules to  increase electrolyte and water reabsorption.   In addition,  All appears to  act
directly on the CNS to increase thirst.
     The renin-angiotensin system thus has a major influence on regulation of blood pressure;
for  this reason,  investigators interested in hypertension have studied  the system in detail.
Because renal  disease  may be  an  important  initiating event in  subsequent development of
hypertension and  because  lead  is  an  important renal  toxicant, some  investigative reports of
patients with lead  intoxication  have evaluated  blood  pressure  changes  and changes in  the
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renin-angiotensin system.   For example,  Sandstead  et al.  (1970)  found  that  dietary sodium
restriction produced  smaller increases  in  plasma renin  activity  and  aldosterone  secretion
rates in lead-poisoned  men  than expected.  The mechanism  of  action  on the renin-aldosterone
system was  not known.   Gonzalez et al.  (1979) studied renin activity, aldosterone, and plasma
potassium levels  in a  group of lead-intoxicated patients,  who  had low plasma renin activity
(PRA) in  response to  a furosemide challenge  (a  volume-depleting stimulus)  and  were hyper-
kalemic (evidence that  aldosterone  levels were low).  Bertel et  al.  (1978) also presented a
clinical case  report  of  reduced  beta-adrenoceptor-mediated  function  in one  lead-toxic  man
(blood  lead >250  ug/dl) with hypertension (160-170/100-105 mm  Hg).   Prior to administration
of the  test dose  of isoprenaline, the patient  had  high  plasma norepinephrine levels and low
PRA  activity.   The  dose  of isoprenaline required  to increase heart  rate 25  beats/min was
15-fold greater than that required in control subjects.
     Recently, Campbell  et  al.  (1985)  found lead-related  increases  in  the concentrations of
PRA  and angiotensin I  in lead-exposed normotensive men.   Mean plasma renin activity in these
men  was 8.3 ± 5.0 ng/ml/h,  a value they note is slightly high for normotensive not on sodium
restriction;  all subjects with PRA >12 ng/ml/h had blood  lead concentration of >2 umol/1, the
accepted upper  limit  for the general  population.   Al was  positively correlated with PRA; it
appeared that  angiotensin converting  enzyme was  augmented  with   lead  exposure,  possibly by
substrate induction due to increased Al concentration.
     These  authors point  out that their  findings appear  to be  in conflict with others which
find depressed or unaltered  renin activity in lead poisoning; however,  the studies may not be
comparable  because the  men  in this study had  chronic sub-clinical lead exposure as compared
to  chronic  heavy  lead  exposure.   None  of  the  subjects  in this  study had  excessive  lead
exposure—rather, exposure  which  would  be  considered  "normal".   Yet  they  tended  to  have
elevated PRA,  which  may reflect  possible  low-grade  stimulation  of  the renin-angiotensin-
aldosterone system  that, if continued  through  chronic  cumulative  exposure,  might  affect
blood pressure in sensitive  individuals.
     There  is  another  hormone  system  which  has  postulated  effects  in  regulation  of  blood
pressure:   the  kallikrein-kinin  system  (Carratero and Scicli,  1983).   Kallikreins  (found in
plasma,  urine  and several  glands,  including the  kidney) are proteases  which  release kinins
from plasma  substrates called  kininogens.   Kinins,   thought  to be antagonistic  to  All,  are
vasoactive  peptides which may  participate in blood  pressure  regulation  by altering vascular
tone and regulating sodium  and water loss.   Kinins  are  inactivated  by plasma kininases (one
of which is angiotensin I converting enzyme).  Urinary  kallikreins  can be measured by their
esterolytic activity on  synthetic  substrates.   Many reports  suggest that urinary kallikrein
is decreased  in patients with  essential hypertension,  although  others do not  find such an
association,  and indeed find normal  excretion rates.
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     Boscolo et al.,  (1981)  studied  urinary kallikrein activity and plasma renin activity in
22 men  occupationally exposed to  lead.   Eight  of  these men who suffered  from  hypertension
and/or  nephropathy  had  low  or  absent PRA;  this finding may  be related to the  presence of
renal disease rather than be contributory to it.   The remaining 14 non-symptomatic men showed
normal or reduced urinary kallikrein  and variable PRA.   The  authors  concluded that the slight
but significant correlation  between  renin and kallikrein that was  found in the  lead-exposed
patients might  be the result of a correlated physiological  response of these renal  enzymes
due to  an  effect  of lead on one or  more components of the  blood pressure  regulating system.
     The paucity  of  experimental  data  linking  lead  and  changes  in the  renin-angiotensin
system  stimulated most of  the  following experimental studies,  although  many questions remain
unanswered.
2.4   Experimental Studies of Lead Effects on Blood Pressure and the Renin-Angiotensin System
     Several questions  can be  posed  regarding how  lead  might  affect  the  renin-angiotensin
system, such as:

     (1)  Does lead affect sodium handling by the renal  tubule?
     (2)  Does lead directly affect renin release?  If so,  is All elevated to
          an appropriate level?  Do normal homeostatic mechanisms function to
          adjust renin levels under conditions of fluid and electrolyte loss?
     (3)  Does lead alter renin synthesis (as measured by  renal renin content)?
     (4)  Does lead affect rate of production of All by altering angiotensin
          converting enzyme activity?
     (5)  Does lead alter All catabolism?
     (6)  Does lead affect renin substrate production?
     (7)  Does lead affect renin clearance by the liver?
     (8)  Does lead affect vascular reactivity directly?
     (9)  Does lead directly affect aldosterone release?
    (10)  Does lead alter  noradrenergic  activity (either  in adrenal glands or systemically)?

Many of these questions have been addressed by studies discussed below.

2.4.1  Acute In Vivo Lead Exposure
     Lead  injected  iv  in dogs and rats,  at  doses as low as  0.1 mg/kg (whole blood lead < 5
|jg/dl  and  renal  lead  of 1.2 pg/9) produced over the next several hours significant increases

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in plasma renin activity  (PRA)  and in excretion of sodium,  other cations,  and water (Mouw et
al.,   1978).   There was  no  change  in  glomerular filtration  rate;  therefore, the  increased
sodium  excretion  could  be  attributed to  decreased sodium  reabsorption.   The mechanism  of
lead's  action  on  tubular reabsorption was  not  determined,  but it was suggested  (though  not
evaluated) that lead could affect mitochondrial  ATP production necessary  for active  transport
processes or act  directly  on  carrier molecules  or enzymes,  e.g., Na /K -ATPase,  specifically
involved in tubular transport.   In this  report, the mechanism  by which  lead increased renin
secretion was not determined.
     In a subsequent study,  Goldman et al.  (1981) found that the rise in  PRA after acute lead
injection was  not due  to  increased renin  secretion in  six of nine dogs;  rather,  there  was
elimination  of hepatic  renin clearance, without  evidence  for  other  interference  in  liver
function.  In the remaining three dogs, renin secretion increased; this was thought  to be  due
to lead activation of  normal  mechanisms for renin secretion, although  none  of  the classic
pathways  for   influencing  renin secretion  were altered.   The  authors postulated  that  lead
might  produce  alterations  in  cytosolic  calcium  concentration  in   renin-secreting  cells.
(Further evidence  that  cytosolic  calcium concentration is  indeed  important in renin release
has been  reviewed  in  detail  by Churchill,  1985.)  In addition, although  angiotensin II (All)
levels  in  lead-exposed animals were elevated because  of  increased PRA,  the  All  levels  were
not  increased  proportionately  as  much  as  the PRA,  leading to  a further  suggestion  that
angiotensin-converting  enzyme  (which converts  Al  to All)  might be suppressed or  that  All-
degrading  enzyme   could  be  enhanced;  this  was  not tested  in  the experiment.   The authors
postulate that there  may be  multiple  actions of lead  on the  renin-angiotensin  system which
may help explain confusion about the ability of  lead to cause hypertension.  At certain expo-
sure  conditions,  there  could  be elevated PRA without simultaneous inhibition of angiotensin-
converting enzyme,  thereby  contributing  to hypertension,  while  higher doses  or  longer expo-
sure  might  inhibit  converting  enzyme  and  thereby  cause loss  of  hypertension.   Neither
hypothesis was addressed in this experiment.

2.4.2   Chronic Lead Exposure
     The literature of experimental findings of  lead-induced changes in the renin-angiotensin
system  and blood  pressure  in  animals  is complicated by  apparently inconsistent results when
comparing one  study to another.   All studies report changes in the renin-angiotensin system,
yet some  studies  fail to find an effect on blood pressure and others do  report hypertension.
Doses  and  exposure periods employed vary  widely,  but in  general,  hypertension  is observed
most  consistently with  relatively  low  doses  over relatively  long exposure periods.   The
papers  reviewed here make specific mention of lead dose employed and blood lead concentration
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achieved (if measured).   For comparison with human exposure findings,  it is helpful to recog-
nize that blood lead concentrations seldom exceed 40 ug/dl  in the general  population.
     Perry and  Erlanger  (1978)  found that chronically feeding rats either cadmium or lead at
doses of 0.1,  1.0,  or 5.0 ppm produces statistically significant increases in systolic blood
pressure.    Blood  lead  concentrations were  not  determined  in  this  experiment.   There  were
dose-dependent  changes  in blood  pressure,  measured at  3  months, and  the  increase observed
with 5  ppm Pb was  observed  at  3, 9, and 18 months  of observation.   Body burden  of  lead in
rats fed 0.1 ppm Pb was estimated to be 0.4 mg  at 18 months.   The mechanisms for this finding
were not discussed  but the implications for human  populations  exposed to very  low doses of
these metals  were pointed  out.   Victery et al.  (1982a) reinvestigated  the  question,  using
lead doses  of 100  and  500 ppm  administered in  the  drinking water to rats  beginning while
animals were J_n utero and continuing through six months of  age.   At 3^  mo  of age, the male
rats drinking  100 ppm lead  first demonstrated  a statistically significant  increase  in  sys-
tolic  blood  pressure  (152 ±3.7 vs.  135 ±5.6  mm  Hg);  this  difference persisted  for  the
remainder of  the  experiment.  Animals  drinking  500  ppm  had lower pressures  which were  not
significantly  different  from  controls.   Female  rats  drinking 100 ppm did  not  demonstrate
pressure changes.    At termination of  the  experiment  PRA was significantly  decreased by  100
ppm  lead  exposure,  but  not  at  500  ppm.   All  values  tended to  be  lower  (controls:  22  ± 8
pg/ml,   100  ppm:  13 ± 7,  500  ppm: 10 ± 2).  There  was a dose-dependent  decrease  in  AII/PRA
ratio for lead-exposed rats.   Renal  renin was  depressed in lead-exposed animals.   The hyper-
tension observed  in  these  animals was not secondary to overt renal disease (as opposed to an
effect  on  renal  cell metabolism),  as evidenced  by  lack of changes  in  renal  histology  and
plasma creatinine.
     With regard  to possible mechanisms  of the  lead-induced hypertension,  the  animals  had
low-renin hypertension (which  is characteristic  of  30 percent of  people  with hypertension).
Thus, elevated  renin  was  not responsible for maintenance  of  the hypertension.  Volume expan-
sion may be  a  factor, as suggested  by slight  increases  in body weight and decreased hemato-
crit  (also  possibly  related  to  lead  effects  on heme  synthesis).  There  was no  change in
plasma  sodium  and  potassium,  although more sensitive determinations  of fluid  balance  and
exchangeable  sodium were  not  done.   A second  potential  hypertensive mechanism,  increased
vascular responsiveness to catecholamines,  was  examined and is discussed below.
     Victery et al.  (1983)  examined  changes in the renin-angiotensin  system of rats exposed
to  lead  doses of 5,  25, 100,  or 500 ppm  during gestation  until 1 month of  age.   All  had
elevated plasma renin activity,  while those at  100 and 500  ppm also had increased renal  renin
concentration.   Lead-exposed  animals anesthetized to  obtain the  blood sample secreted  less
renin than control animals.   It appears that lead has  two  chronic effects  on renin secretion,
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one inhibitory  and  one  stimulatory;  the magnitude  of  effect on  PRA reflects the  dose  and
timing of the lead exposure as well  as the physiological  state of the animal.
     In another study, Victery  et al.  (1982b) reported that  rats  fed 5  or 25 ppm lead for 5
months (blood lead  of  5.6  and 18.2 ug/dl,  respectively)  did  not develop hypertension but at
25 ppm had  significantly decreased  PRA.   Both groups of  animals  had a decrease in the All to
PRA ratio.   Thus,  lead  exposure  at  levels  generally present  in  human  population  caused
observable effects  in  renin  synthesis,  and produced changes  in  All  concentration which were
consistent with either inhibition of  conversion of AI to  All  or  enhanced All  catabolism.   No
measurements of ACE activity were made.   The failure to observe hypertension in these animals
may have  been due to a  number of factors,  but additional studies may be  required to verify
this finding.
     lannaccone et  al.   (1981)  administered 50 ppm  lead  to  male rats for  160 days  (average
blood  lead  of  38.4 ug/dl)  and found  a  marked increase in arterial  pressure  of lead-exposed
animals  (systolic/diastolic:   182±6/138±7 mmHg)  versus pressures in  controls  of  128±5/98±3.
No measurements  of hormone  levels  were  performed;  determination  of  vascular reactivity in
these animals is discussed  below.
     Male pigeons  fed a diet containing added  calcium   (100  ppm),  magnesium  (30 ppm), lead
(0.8  ppm),   or  cadmium  (0.6  ppm)  in  a  2x4  factorial  design  for  a six-month  period were
observed  for alterations in  aortic  blood pressure and atherosclerotic changes (Revis et al.,
1981).  Diastolic pressures  were 25 mm Hg higher in pigeons  exposed to Mg, Pb, or Cd than in
Ca-exposed pigeons.   Systolic pressure was greatest in Cd-exposed birds.   Calcium in the diet
resulted  in  lowered systolic  pressures  in  animals  exposed  to  combinations  of other metals
(presumably  by  decreasing  their  gastrointestinal  absorption).    Similarly, there  was  a
decrease  in  number and  size of  aortic  plaques  in  presence  of  calcium  and an increase with
lead exposure.
     Keiser  et  al.  (1983b) tested lead-exposed rats  (500 or  1000  ppm for 3-4 mo, blood lead
levels of 41 and  55 ug/dl)  for  the  ability of the liver to  clear exogenous renin and a test
substance (sulfobromophthalein) following nephrectomy.  They  found no difference from control
clearance times.   Thus,  elevations  in  plasma renin observed  in chronically  exposed animals
must  be  the result  of  increased renin  secretion.   However,   the finding  of  decreased renin
activity  after  some long-term exposure  periods  (see above)  illustrates  that  lead must also
act  in  an   inhibitory   way  to  decrease  renin   secretion,  and  the  finding  of  decreased,
increased, or unchanged  renin activity depends on the balance of the stimulatory and inhibi-
tory input to the juxtaglomerular cells.
     In a preliminary  experiment, there were  no  differences  in  urinary  kallikrein excretion
rates in  lead-exposed and control rats (Victery and Vander, unpublished findings).

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2.4.3  Renin Secretion by Kidney Slices In Vitro
     The effects of  renin-secretion  stimuli  on the ability of kidney slices to secrete renin
j_n  vitro  either  after  chronic  j_n  vivo  or  j_n vitro  exposure to  lead  have been  studied
by  several  investigators.   Keiser et  al.  (1983a)  reported that rabbit  kidney cortex slices
exposed to  10-5  or  10-6  M lead  secreted  significantly  less  renin than  controls.   Slices
obtained from  lead-exposed  rabbits (500 or 1000 ppm  for 7 wk, with blood  lead levels of 66
and 109 ug/dl  respectively) secreted significantly more  renin  w  vitro  than controls.  They
postulated  that lead  could compete  with Ca2+ for  influx  into  juxtaglomerular  cells  and
thereby stimulate  renin release.   Responsiveness  to a  beta-adrenergic  stimulus  was  less in
the  higher-dose slices.   Since p-adrenergic  stimuli  are thought  to  act via  reduction of
intracellular  [Ca2+] (by increased Ca efflux or intracellular sequestration),  it was proposed
that  lead  may interfere with  these  calcium  fluxes  and interfere with  the  response  to p
agonists.
     Meredith  et al.  (1985) found somewhat contradictory  results, with  lead  able to provoke
renin  secretion  from rabbit kidneys both i_n  vivo  and iji vitro (at comparable dose levels to
that  used  by  Keiser).  Calcium  channel  blockers  attenuated this  response.   These  authors
propose that  lead  is able  to act  at  the  cellular level to stimulate renin secretion.  Since
most  experimental  evidence suggests  that  increased  intracellular  calcium  decreases renin
release, whereas  calcium efflux  stimulates  renin  secretion,  the authors  further postulate
that  lead  uptake  by the juxtaglomerular cells promotes  calcium efflux which then  leads to an
increase in renin secretion.

2.4.4  Effects of Lead on Vascular Reactivity
     Piccinini et al.  (1977) and Favalli et al. (1977)  studied the effects of  lead on calcium
exchanges  in  the isolated  rat tail  artery;  lead  in concentrations  of up to 15 umol  i_n vitro
produced  contractions which  required  the  presence  of  calcium  in the perfusion solution.
Therefore, calcium  influx was not  affected by  lead.  The fact  that tissue calcium  content  was
increased  is   compatible with  the sites  of  lead action  at  the  cell membrane; lead  inhibits
calcium  extrusion,  and  at  intracellular stores,  lead  decreases  calcium-binding capacity.
Both processes produce an increase in  intracellular  exchangeable calcium.
     Tail  arteries  obtained from  the  hypertensive  rats in the study performed by Victery et
al.  showed  an increased  maximal  contractile force  when tested  i_n  vitro  with the alpha-
adrenergic  agents  norepinephrine  and methoxamine  (Webb  et al.,  1981).   This  finding is
apparently  related  to  an  increase in the  intracellular  pool  of  activator  calcium in  the
smooth muscle  cells  in the  artery.   This  change may  also be  responsible  for  decreased relaxa-
tion  of the muscle  after induced contractions.
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     lr\ vivo tests  of  cardiovascular reactivity in rats  exposed  to 50 ppm  lead  (blood  lead
38.4 ±3.6 ug/dl)  for  160 days  were performed  by lannaccone et  al.  (1981).   Systolic  and
diastolic blood  pressure  readings  obtained  under  anesthesia were 182 ± 6/138 ± 7 mm  Hg  for
lead-exposed rats  versus  128 ± 5/98 ± 3  for controls.   Humoral agents,  i.e.,  norepinephrine
and angiotensin  II  (but  not  bradykinin and angiotensin I),  produced significant increases in
systolic and diastolic pressure.   This  suggests there is decreased  conversion  of AI to  AIL
At high doses,  epinephrine produced an equal  increase  in pressure  in lead-exposed and control
animals;  at  lower  doses,  only  slight  increases  in  mean  arterial  pressure were  observed.
Bilateral carotid artery occlusion under conditions of autonomic  blockade produced a two-fold
greater  decrease in blood pressure and heart  rate in lead-exposed rats.   The  data suggest
that  the lead-related  increase  in  arterial pressure  is  due  at  least  in part  to greater
sympathetic tone, with the metal affecting neural control  of blood pressure.

2.4.5  Effects of Lead on Noradrenergic Hormones
     Lead exposure  alters the  levels  of noradrenergic hormones  in  the  young  animal exposed
via maternal milk from birth until day 21 of age (Goldman et al.,  1980).   Lead concentrations
in the  drinking  water  of up to  2000  ppm produced  blood  lead levels  in  pups of 47 ± 3 ug/dl
with dose-dependent  increases  in adrenal and plasma norepinephrine.  There were also changes
in  several  enzymes which  alter turnover  rates  of norepinephrine.  Baksi  and  Hughes  (1983)
investigated the effect  of 6-wk tetraethyl  lead exposure (at 0.2, 2.0,  and 5  ug Pb/g food)
on adrenal catecholamine levels and found significant decreases in dopamine (perhaps due  to a
decrease  in  synthesis)  and significant increases in norepinephrine and epinephrine.   Both of
these  groups  of  authors  felt that  the  change   in  adrenal  catecholamines  could  directly or
indirectly be responsible for the hypertension observed in lead-exposed animals.

2.4.6  Effects of Lead on Cardiac Muscle
     Lead has  been  hypothesized  to contribute  to  cardiomyopathy  (Asokan,  1974)  and to  have
cardiotoxic properties.   Rats  fed 1 percent lead acetate for 6 weeks (with blood lead levels
of  112 ± 5  ug/dl)  had structural  changes  in  the  myocardium.   These  included myofibrillar
fragmentation  and separation with  edema fluid, dilation of  the  sarcoplasmic  reticulum,  and
mitochondrial  swelling.   These  changes  were  observed  before  any  measured  changes  in
myocardial electrolyte concentrations.
     Williams  et al.  (1977a,b) exposed young rats  to  2000  ppm lead via maternal  milk,  from
birth to 21 days  of age (blood lead at 21 days of age was 43 |jg/dl but was not different from
controls  at 170-200  days).    Animals  were  studied for  cardiovascular response  to norepi-
nephrine at 170-200 days of age.  There were no differences in the blood pressure increase in
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response to norepinephrine,  but there was a five- to ten-fold increase in cardiac arrhythmias
in lead-exposed animals.   There were no differences in the basal  or norepinephrine-stimulated
cyclic AMP levels in cardiac tissue.
     In a subsequent study (Hejtmancik and Williams, 1979),  it was reported that only part of
the arrhythmogenic  activity of norepinephrine  in  lead-exposed rats was due to  reflex vagal
stimulation; there  was  also a direct  cardiac  effect,  probably at the  alpha receptor level.
Lead appeared to have no effect on beta receptors.
     Kopp et  al.  (1978) developed an  j_n  vitro system for monitoring the  cardiac electrical
conduction system (electrocardiogram  or  ECG)  and systolic tension, and demonstrated that HI
vitro  lead  (3  x 10-2 mM) or cadmium  (3  x 10-2 mM) depressed systolic  tension  and prolonged
the  P-R  interval   of  the  ECG.   Both  ions  increased  conduction  times  in the  His  bundle
electrograms but  conduction blocks occurred  at different  sites  (atrioventricular  node  for
cadmium and distal to the His-Purkinje cell junction for lead).
     In a subsequent paper,  Kopp  and Barany (1980) found that cadmium or lead  added to heart
tissue perfused i_n  vitro  (3 x  10-3 mM and 3  x 10-4 mM, respectively) inhibited the positive
inotropic activation of  the  heart by calcium  and isoproterenol,  and the concomitant increase
in phosphorylation  of cardioregulatory proteins.   There was no effect  of  lead or cadmium on
the positive chronotropic effects  of the beta-adrenergic agonist.
     Hearts obtained from  rats exposed to low  levels  of cadmium and/or lead  (5 ppm)  for 20
months were found to have  similar changes in  the  heart's  electrical  conduction system (Kopp
et al., 1980)  with  significant prolongation of the  P-R  interval.   In lead-fed animals,  this
was due to increased conduction time through the His-Purkinje cell system.
     Williams et  al. (1983)  suggested that much of  the  negative  inotropic effect of lead on
cardiac tissue  and  ECG  abnormalities  can be related to  lead's  interference with calcium ion
availability and/or membrane translocation.    In  addition,  even  those  lead exposure-related
effects that appear to  occur through autonomic nerves  may  be  understood in terms of effects
on calcium ion, which is required  for neurotransmitter release.
     Evis et al. (1985)  studied the effects of chronic low lead treatment (5 and 25 ppm,  with
blood  lead  levels  < 10 pg/dl)  and  hypertension (spontaneously  hypertensive  rats)  on  blood
pressure and the  severity  of cardiac arrhythmias in rats.   The animals  were studied up to 16
months of age  and the  authors  reported that there were no consistent lead-related effects on
ischemia-induced  cardiac arrhythmias,  blood  pressure,  or  P-R   interval  in  the  electro-
cardiogram.
     Prentice and Kopp (1985) examined functional  and metabolic responses of the perfused rat
heart  produced  by  lead with varying  calcium  concentrations in the perfusate.   Lead altered
spontaneous  contractile  activity,  spontaneous electrical  properties and  metabolism  of  the
heart tissue.   The exact mechanisms were not completely resolved but did involve disturbances
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in cellular calcium metabolism,  although not by any single mechanistic model.   Other possible
actions of lead were discussed,  and they included:   (1)  lead-induced disturbances in calcium-
dependent  enzymatic  processes;  (2)  altered  calcium   binding  and  calcium  activation  of
phosphorylation-dependent  events  linked  to  transduction  of  chemical  energy  to  produce
mechanical  work;  (3)  modified   calcium  release and  sequestration  by  intracellular  storage
sites; and (4) disruptions in cellular energy production and utilization.
     In addition, hearts perfused with 30 uM lead had reduced coronary blood flow,  presumably
by lead  acting  to  directly constrict the vascular  smooth  muscle  or by interference with the
local  metabolic stimuli  for vasodilatation.   Increases  in perfusate  calcium  concentration
partially  reversed  this effect,  although  at  the  highest calcium  levels (5.0  mM), coronary
blood  flow was  again  reduced.   These  authors concluded  that their present  findings  were
consistent  with those  of others  which  showed increased  vascular  reactivity and  that  the
chronic  lead  exposure-related changes  in blood pressure may  be related to  localized actions
of lead on vascular beds and arterial smooth muscle.
2.5  Summary of Lead-Related Effects on the Cardiovascular System
     Blood pressure is regulated and affected by many interactive forces and control systems;
some of  these  have been shown to be affected by lead exposure.   Understanding of the effects
of  lead  on  each system is still preliminary,  but  sufficient evidence indicates that changes
which  occur  in the  presence of lead  can promote  development  of  hypertension.   To briefly
summarize, lead can directly inhibit renal tubule reabsorption of sodium, probably via action
on  the Na+/K+-ATPase.   Sodium/potassium-ATPase  inhibition  may  occur in other  cell  types as
well.   This  may  alter the  concentrations  of  intracellular  sodium and calcium  ions.   Some
volume  depletion  may  occur  which  may  act  to  elevate plasma renin  activity.   The effect of
lead  exposure  on  plasma  renin activity  can  be stimulatory, inhibitory,  or without effect,
depending  on  the  length  of exposure  and  the  exposure level.   Lead exposure  reduces  the
increase  in  PRA  that  occurs with  noradrenergic stimulation.  Hepatic  clearance  of renin is
not  affected by lead exposure and  is  thus  apparently not responsible for an increase in PRA
during chronic  lead exposure.  Depending on the length and dose of  lead exposure, renal renin
concentration  is  elevated  followed by decreased concentrations.   Changes  in renin secretion
rate  in  animals do not appear to  be  well  correlated with changes  in blood pressure and may,
in  fact, reflect altered homeostatic responses elicited to regulate pressure.
     Additional changes  observed  during lead exposure include the  following:  in response to
elevations  in   PRA,  All  is  elevated,  but the  levels are inappropriately  low;  this does not
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appear  to  be due  to  a  lead-related  decrease  in ACE  (angiostensin-converting enzyme),  but
rather  to  increased  catabolism.   Aldosterone  levels  are also inappropriately  low,  possibly
due to  a lead-related defect  in calcium  ion-dependent  release  of aldosterone.   Adrenergic
hormones  are elevated.   Vascular  smooth  muscle   isolated  from  lead-exposed  animals  has
increased reactivity to  noradrenergic  stimuli,  probably  due to an increase  in intracellular
calcium  ion  concentration.   There  appears  to be  increased  sympathetic  activity  in  lead-
exposed  animals.   Cardiac  arrhythmias  are  usually observed  to  be more  frequent  in  lead-
exposed animals.
     Although the exact  mechanisms  involved in lead-induced changes in  renin  secretion rate
have not been examined,  it  is  likely that lead could  be  affecting  the  cytosolic free calcium
ion of  the juxtaglomerular cells.   When  there is  a  stimulation  of  renin release,  there  is
presumably a decrease  in intracellular  [Ca2+]  due  to lead blockage of calcium entry through
voltage-sensitive calcium channels.   After  lead  enters the  juxtaglomerular cells,  lead could
enhance  or block calcium exit  via Na/Ca  exchange pumps,  or  increase  or decrease  the  intra-
cellular sequestration of calcium in  storage compartments.   It is  not  yet  clear whether lead
stimulates or  antagonizes  calcium  fluxes  that occur in  the JG  cells;  therefore it  is  not
possible  to  state  definitely  which  of  these  possibilities is  correct.   Renin  release  in
response to  adrenergic  stimuli  binding to  receptor-operated calcium  channels  appears  to  be
inhibited.   The  reasons  for this are not  known,  but lead may decrease  the  number of  receptor
sites  or change the  intracellular  calcium  response  which   is normally  elicited  when  these
channels are stimulated.  For  example,  if intracellular  free calcium  ion  levels are already
elevated and  there were to be a smaller decrease  in [Ca2+] than  normal due  to  blocking  of
calcium  efflux  via the  Na/Ca  exchange pumps  or  lowered pumping into  intracellular stores,
renin secretion would be less  under  conditions  of adrenergic  stimulation.
     The  changes in  vascular  reactivity  which have  been   reported  in animals  chronically
exposed  to lead  are  probably  the key finding  which can  lead to  an understanding of  how lead
can contribute to development  of hypertension.   The  vascular  smooth muscle  changes are neces-
sary and sufficient  in themselves  to account for the  increase in  blood pressure and  the fact
that these  changes are  observed in animals exposed  to  relatively low lead levels  makes  it
increasingly important to evaluate  these  findings  in  additional  experimental  studies.   There
may be  additional  changes  in  the  entire  sympathetic  neural control  of vascular  tone which
acts to  amplify the contractile response to any endogenous vasoconstrictor  substance.
     Two  authors (Audesirk,  1985,  and  Pounds,  1984)  have  recently  reviewed  experimental
evidence on  the  influence  of  lead on calcium movements at the subcellular  level in a variety
of  cell types  (including  neurons,  neuromuscular   synapses,  and  hepatocytes).    The  reader
should  consult   these  reviews  for  experimental  documentation of  the  postulated  changes  in
calcium-activated systems.   Lead may interact with  any process normally influenced by calcium
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ions and, depending on the system, lead may act as a calcium antagonist or as an agonist.   In
addition, lead interferes with the function of many proteins, especially enzymes such as Na/K
ATPase and the mitochondrial  respiratory enzymes.  These interactions  may  influence calcium
ion  concentrations  and  movements.   If  lead  interferes  with  calcium ion  movement through
calcium channels, either by blocking entry or blocking efflux, there will  be a decrease or an
increase in cytosolic  free  calcium  ion.   Lead may alter the distribution and uptake rates of
calcium  ion  in cell storage  sites  with  the result that mitochondrial  and  endoplasmic reti-
culum levels can  be increased or decreased; this in turn would affect cytosolic free calcium
levels.   Lead  binds  to calcium-binding sites on  calcium  regulatory  proteins (calmodulin, in
particular [Cheung,  1984])  and  thereby can alter enzyme  systems  such as Ca-specific ATPase,
which would then alter calcium efflux from the cytosol.
     This  review  has discussed  some  of  the major  experimental data  concerning lead-related
changes  in blood-pressure  regulatory  systems.   Further research  efforts  are  necessary to
evaluate more  fully cellular mechanisms  by which lead exposure produces its  effects.   Lead
(even at very  low levels) produces  measurable effects on the renin-angiotensin system.  With
the blood  pressure  changes  observed in lead-exposed animals, changes in renin are not estab-
lished to  be  the  cause  of hypertension;  rather, hypertension is  more likely  to  be  due to
changes  in vascular  reactivity  and  level of sympathetic tone, both of which may be dependent
on lead-related changes in intracellular calcium ion concentration.
3.  EFFECTS OF LEAD ON DEVELOPMENT AND GROWTH
     The  effects  of  lead exposure  early in  development  have recently  become a matter  of
increasing interest and  potential  concern in  light of  certain  newly published epidemiologic
observations.    Coupled  with  earlier findings  from human  and experimental  animal  studies,
these  recent  results  point  toward  a number  of  deleterious effects  on  various aspects  of
development and growth  associated with  relatively  low exposure  levels  encountered  by  the
general population.   For convenience, the  findings are  grouped  here under  the  headings  of
fetal exposure effects and postnatal  growth effects.
3.1  Fetal Exposure Effects
     Numerous  investigations  evaluating the  effects  of intrauterine lead exposure  on fetal
development  are  reviewed in Section 12.6  of  the revised Criteria Document  (U.S  EPA,  1986).
Animal  studies  reviewed there tended to  use  rather high exposure levels and  were  sometimes
confounded by  nutritional  variables, but  such  studies  collectively provide  clear  evidence
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that prenatal  lead  exposure  can cause a number of  fetotoxic  and teratogenic effects.   Among
the specific effects  observed  are  reduced heme synthesis and  decreased fetus size or weight.
Changes  in  heme metabolism—reduced  ALA-D  activity,  in particular--have also  been  reported
for humans  peri natal ly,  even  at  average blood  lead  levels  of  only 8  and  10 (jg/dl  in  the
infants  and their  mothers,  respectively  (Lauwerys et  al.,   1978).   Some  additional  human
studies  have  provided evidence suggestive  of an association  between  prenatal  lead  exposure
and shortened  gestation,  decreased birth weight,  or  stillbirths (e.g., Fahim  et al.,  1976;
Nordstrom et  al. ,  1979;  Khera et al. ,  1980b),  but others have found  no  significant associ-
ation  between   such  effects  and  prenatal  lead  exposure (e.g.,  Clark,  1977;  Alexander  and
Delves, 1981; Roels et al., 1978).
     Part of  the difficulty  in drawing conclusions  from many  of  the human  studies,  espe-
cially the  earlier  ones,  derived  from the problems in accurately measuring blood lead levels
(see  Chapter 9 of  the  revised 1986  Criteria Document)  and  in identifying  and  controlling
confounding  variables.   In addition,  the power  of these early studies was  often limited by
the  small   number  of subjects employed.   More  recently,  several  new human  studies,  using
improved analytic  techniques  and,  in  general, rather large numbers of subjects, have focused
on  possible associations  of  prenatal  lead exposure and  various developmental  outcomes in
fetuses,  infants,  or young  children.   These  studies,  most  of  them  longitudinal in design,
have  generally  estimated  prenatal  lead exposure through  maternal  or cord blood  lead concen-
trations and have followed (or are still following) the children's postnatal  exposure through
periodic  blood lead  measurements.  The studies have  also been  careful  to  consider various
confounding factors that could affect developmental endpoints.

3.1.1  Results  of Recent Human Studies
      Using  logistic regression modeling techniques, Needleman et al. (1984)  found an associa-
tion  between umbilical cord blood lead  levels and certain minor congenital anomalies based on
hospital  records  for  4354 infants born in  Boston.   Their analysis controlled for a  number of
demographic, socioeconomic, and other possible confounders, including coffee, alcohol, tobac-
co,  and  marijuana use,  and variables such  as gestational age, birth weight, maternal parity,
and  age.   The  most common anomalies  included hemangiomas and lymphangiomas  (14/1000 births),
hydrocele  (27.6/1000  males),  minor skin anomalies  such  as  skin tags and papillae (12.2/1000
births),  and undescended testicles (11/1000  males).  A  statistically  significant association
was  found  between  cord  blood  lead  levels  and  the occurrence  of  minor malformations taken
collectively.   However,  no individual  type of malformation showed a significant  relationship
to lead exposure,  nor  were major  malformations  found  to  be significantly  related to lead.
Birth weight and gestational  age also  showed no evidence of being  related  to  lead  exposure.

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On the other  hand,  first trimester bleeding, premature  labor,  and  neonatal  respiratory dis-
tress were all significantly reduced at higher exposure levels of lead.
     Moore et al.  (1982)  reported that gestational age  was  significantly  reduced as a func-
tion  of  increasing  cord or maternal  blood lead  levels in a  cross-sectional  study  of  236
mothers and  their infants in Glasgow,  Scotland.   Blood lead levels were  relatively high in
the 11 cases  of  premature birth (gestational age  less  than 38 weeks) that were  observed in
this  study:   maternal  levels  averaged about 21 ug/dl  and cord levels about 17 ug/dl  (geomet-
ric means).   Overall,  the geometric mean blood  lead  level  for the  mothers was approximately
14 pg/dl and  for the infants was  approximately  12  ug/dl.   Stepwise forward multiple regres-
sion  analyses using  log-transformed blood lead  levels  revealed  significant  negative coeffi-
cients for length  of gestation  against maternal, blood lead (-0.056, p <0.01) as well as cord
blood lead (-0.047, p <0.05).   Other variables considered in the analyses included:   mother's
age,  social   class,  birth weight,  and  total  parity,  of  which only  total  parity  was  also
significant.   First-flush  household water  lead  levels were positively  associated with both
maternal  and cord blood lead levels (p <0.001).
     A recent paper by Bryce-Smith (1986) noted that both birth weight and  head circumference
were reduced as a function of placental lead levels in a cohort of 100 normal  infants born in
Yorkshire, England.   Placental  lead concentrations averaged between 1 and  a little more than
2  ug/g.   Zinc and cadmium levels  also showed significant relationships to birth  weight  and
head  circumference.   Little  information is provided on  the  details of the work,  but  a full
account of the study is said to  be in preparation for publication.
     A longitudinal study of the effects of lead exposure on child development is underway in
the lead smelter  town and environs of  Port  Pirie,  South Australia.  McMichael  et al.  (1986)
enrolled 831  pregnant women and  followed 774 of the pregnancies to completion (spontaneous
abortion,  stillbirth,  or  live birth).   Venous blood lead concentrations were measured in the
mothers at  least  three  times  during  pregnancy:  at  14-20  weeks,   around  32 weeks,  and at
delivery.   In addition,  cord  blood lead was measured.   Blood  lead  levels  were significantly
higher in the Port Pirie women  than in those from adjacent towns and countryside (e.g., 11.2
ug/dl at delivery  in Port Pirie versus  7.5  ug/dl  outside).   Mean blood lead values did  not
vary  systematically  through  the course of pregnancy.    Information  on  demographic and socio-
economic characteristics, medical  and  reproductive history, smoking and drinking habits,  and
other variables  was  collected by a standardized questionnaire-interview.  A  number  of preg-
nancy  outcomes  were  assessed.   Most  notably,   multivariate  analysis  showed  that  pre-term
delivery was significantly related to maternal blood lead at delivery.   Pre-term delivery was
defined as  birth  before the  37th week of  pregnancy, and  was measured  by  date  of  last
menstrual  period  as  well as by the Dubowitz et  al.  (1970) assessment  of  neonatal  maturity.
As  shown  in   Table A-4,  the relative  risk  of pre-term  delivery increased over four-fold at
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Table A-4.   Estimates of relative risk of pre-term delivery  (by last menstrual  date)  based on
         multiple logistic analysis of maternal  blood lead concentrations  at delivery.
Maternal
  PbB                                               Relative risk
(ug/dl)                    Including stillbirthsExcluding stillbirths
  ^8                                1.0                                      1.0
>8, 511                             2.1                                      2.7
>11, 514                            3.0                                      6.1
  >14                               4.4*                                     8.7
^Significantly different from 1.0 based on 95% confidence interval  of 1.2-16.8;  confidence
 intervals not reported for relative risks excluding stillbirths.
Source:  McMichael et al.  (1986)

blood  lead levels above 14 ug/dl.  If cases of late fetal death are excluded, the association
is  even  stronger and  the  relative risk  due  to lead exposure even greater  (see  Table A-4).
     McMichael  et al.  assessed a number  of  other  outcomes  as well.  Of  774 pregnancies, 23
ended  in spontaneous  abortion  before  the  20th  week.   All  but  one of these miscarriages
occurred  in  the  higher-exposure Port Pirie  group.   Thus,  although  the  Port  Pirie  mothers
constituted less  than 80 percent of the study population, they accounted for about 96 percent
of  the spontaneous  abortions.   McMichael  et al. ,  however, limited their statistical analysis
to  the Port  Pirie group alone and found no significant association between  spontaneous abor-
tions  and maternal  blood lead  levels,  mother's age, blood pressure, or  certain  other vari-
ables.   Of  740 non-twin pregnancies greater  than  20 weeks,  11 ended in  stillbirth.   Ten of
the 11 occurred in Port Pirie women.  The proportion of stillbirths was  17.5/1000 live births
in  Port Pirie versus  5.8/1000  outside  Port  Pirie  and 8.0/1000 for  South Australia overall.
Interestingly,  maternal  blood  lead  levels  at  14-20 weeks  did  not differ  appreciably for
stillbirth versus live birth pregnancies, but  at  delivery  the  maternal  blood  lead level for
stillbirths was significantly lower (7.9 ug/dl) than that for live births (10.4 ug/dl).
     As  for  neonatal  morphology, the incidence of  low birth  weight (i.e.,  <2500 g at gesta-
tional  age  37 weeks or more) was  greater in the Port Pirie  group  (3.9  percent) than in the
non-Port  Pirie group  (1.8 percent).  However,  both  maternal  blood lead at delivery and  cord
blood  lead  were consistently lower (although  not  significantly  so) in  low birthweight preg-
nancies.   Head  circumference  was  significantly  inversely  related  to  maternal  blood   lead
(-0.03 cm per  ug Pb/dl),  but  the authors  suggested  that this  finding  -could have  been an
artifact  of  procedural differences between hospitals.   Crown-heel  length was not  associated
with  lead exposure.   After controlling for certain  risk  factors, such as smoking and  alcohol
usage, no association  between  lead exposure and the  occurrence  of congenital  anomalies was
evident.   Difficulty  in conceiving and premature  rupture of  membranes  showed  no association
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with  lead  exposure;  but for  15  deliveries  with incomplete  placental  membranes, the  mean
maternal blood  lead  level  at  delivery was  13.4 ug/dl,  versus  10.7 ug/dl  for all  other
pregnancies.
     Other recent prospective studies have also assessed physical development but have placed
particular emphasis  on neurobehavioral  aspects  of child development.  The  Bayley Scales  of
Infant  Development  have  been  frequently used to assess mental  and psychomotor development in
these studies because they are well suited for children 2 to 30 months of age and have satis-
factory reliability and validity.
     Bellinger  et  al.  (1984) were the  first  to report effects  on  Bayley  Mental  Development
Index (MDI)  scores  that  were inversely related to cord blood lead levels.   The subjects were
216  middle-  to upper-middle-class Boston  children,  90  percent of whom had  cord  blood lead
levels  below 16 ug/dl (the highest being 25 ug/dl).  Subjects were grouped into three catego-
ries:   low  (mean  = 1.8  ug/dl);  mid  (mean  =  6.5  ug/dl); and high  (mean =  14.6  ug/dl).
Multivariate  regression  analyses  were  used  to model  effects  on  the  MDI.   Of the  several
covariates examined,  HOME scores  (Bradley  and Caldwell,  1979)  and length  of gestation were
identified as  confounders of the association between  cord  blood lead and the MDI; both were
positively correlated  with  cord blood  lead and  with  the  MDI,  but not significantly  so.  The
effect  of  this positive  relationship was  to  reduce the degree of association  between cord
blood  lead  levels  and MDI  scores.    Thus,  when  length  of gestation  and HOME scores  were
partialled out, the bivariate  correlation between cord blood lead and the MDI increased from
-0.11 to  -0.19.  In terms of  covariate-adjusted MDI scores, the difference  between  low and
high lead groups was nearly 6 points (see Table A-5).
     As  the  longitudinal  study  by  Bellinger  et al.  (1985;   1986a,b)  has continued,  the
association  between higher  cord blood  lead and  lower Bayley MDI scores has  persisted  to 24
months,  at  which  point  the  deficit  in MDI  performance was  still  approximately  5 points
(Table  A-5).   No  association was found using postnatal blood lead levels, nor did the Bayley
Psychomotor  Development Index show an effect.
     Some  of  the  first  results  of  a  longitudinal  study  of   inner-city  children   born  in
Cincinnati,  Ohio,  have been reported  by  Dietrich et al.  (1986).   These  are interim results
for  185 subjects from  a cohort of  approximately 400  subjects.   The investigators  measured
blood lead concentrations of the mothers at the first prenatal visit (PbB-Pre),  generally in
either  the first  or second  trimester of pregnancy,  and of the  infants at 10 days, 3 months,
and  6 months after  birth (PbB-1,  -3,  and  -6).   The  mean PbB-Pre was  8.3  ug/dl  (range: 1-27
ug/dl); infant  PbB-1,  -3,  and -6 mean  averages were 4.9, 6.3,  and 8.1, respectively  (overall
range:  1-36  ug/dl).   The Mental Development Index,  Psychomotor  Development Index  (PDI), and
Infant  Behavior Record (IBR)  of the  Bayley  Scales  were  administered at  6  months.   Multi-
variate analyses  indicated  an  inverse  association between  blood lead levels at 3 months and
                                             A-35

-------
  Table A-5.   Covariate-adjusted Bayley Mental  Development Index  scores  of  infants  classified
                             by umbilical  cord  blood lead  levels.
Cord PbB
(pg/dl)
<3
6-7
£10
Parameter estimatet
± standard error
p-value
95% confidence
interval


110
107
105
-2

-1

6
.8+1
.111
.Oil
.9 + 0
0.0019
.1 to


.2*
.3
.4
.9

-4.7


114
114
107
-3

-1

12
.6 i 1
.Oil
.3 + 1
.6 ± 1
0.0015
.4 to
Age (months)

.5
.6
.6
.1

-5.8

114.
115.
110.
-2.

0.
18
3 ±
4 ±
3 ±
0 ±
0.15
7 to

1.8
1.9
2.0
1.4

-4.6

117
118
111
-2

-0
24
.2 ± 1.7
.8 ± 1.8
.8 ± 1.8
.7 ± 1.3
0.038
.2 to -5.2
*Mean ± standard error
tParameter estimate represents the estimated difference in  mean  covariate-adjusted MDI  scores
 of adjacent exposure categories.   The lowest and highest exposure  categories  may be compared
 by multiplying the parameter estimate by two.
Source:  Bellinger et al.  (1985)

performance on the  MDI,  PDI,  and Attention/Motor Maturity  factor of the  IBR.   However,  these
effects were  evident only  for  the White  infants,  who  constituted  about 15 percent of  the
study  population.   Otherwise,  no effect  was evident  for prenatal  or  postnatal  exposure,
either in White or Black infants.
     Further analyses using a method  known as structural equation  modeling (based on regres-
sion techniques)  indicated  that prenatal  lead exposure had an indirect effect on MDI and  PDI
scores through  its effects on  gestations! age  and/or birth  weight (measured  as continuous
variables).  That  is, higher  PbB-Pre  levels were associated with reduced gestational age  and
reduced birth weight (p  <0.05 in each  case), which in turn  were  both significantly associated
with reduced MDI  and PDI  scores (see  Figure A-2).   Thus, although  the  net effect of prenatal
lead  exposure  was  evident in  neurobehavioral   deficits,  the  outcome was mediated through
decreases  in  gestational  age  and/or  birth weight.   (Gestational  age and birth  weight were
independently  affected  by  lead exposure,  even  though  gestational  age  may  have determined
birth  weight  to  some extent).   PbB-1 showed a  similar relationship to  MDI  scores,  but  the
regression coefficients were  not  as  large as for PbB-Pre.   Structural  equation analyses also
indicated  that  tobacco  and alcohol  usage may reduce  birth  weight  both directly and (through
association with prenatal  blood lead)  indirectly.  However, the  effect  of prenatal blood lead
                                             A-36

-------
           TOBACCO AND
          ALCOHOL USAGE
  MENTAL
DEVELOPMENT
   INDEX
                                                                          PSYCHOMOTOR
                                                                          DEVELOPMENT
                                                                             INDEX
      Figure A-2. Relationships among variables affecting 6-month MDI and PDI scores, as revealed through
      structural equation analyses. Arrows represent hypothesized relational pathways, with covariate-adjusted
      parameter estimates (and standardized regression coefficients) indicated for each. All relationships are
      significant at p<0.05 (one-tail test).
      Source:  Dietrich et at. (1986).
on  gestational age  and  birth weight,  and  hence MDI  and PDI scores,  remained  statistically
significant  even  after  adjustment for  alcohol and tobacco  usage.   Race was not  a  significant
confounder  or covariate for  prenatal  lead exposure  according  to  the  authors' multivariate
regression analyses  and therefore was not evaluated in the  structural equation models.
     It should be noted that Dietrich et  al.  (1986) also  found that higher 6-month blood lead
levels were  significantly  associated with  higher Bayley  scores, particularly the  PDI.   They
interpreted  this   association as  the result of  motorically  advanced infants'   (indicated  by
higher  PDI  scores)  coming  into greater  contact  with lead in their immediate  surroundings.
Post hoc  analyses supported this view, for those infants with the  greatest increase  in  blood
                                               A-37

-------
lead levels between  3  and 6 months tended to  have  higher PDI  scores  at 6  months (r = +0.21,
p <0.01).   As  summarized  by  the authors, "while low  level  fetal  exposure to  lead  may  both
directly  (in   the  case  of  white  subjects)   and  indirectly  (for all  infants)  compromise
neurobehavioral status at 6 months,  more precocious  infants may actually display higher blood
lead levels when postnatally  exposed  to sources of  lead  in  their  physical  environment."  It
remains to be  seen  what the ultimate developmental  outcome is for such children.
     In  a  continuation  of the Port Pirie study  described above, Vimpani et al.  (1985)  have
reported preliminary  results  of  testing  592   children  at age 24  months on the  MDI  and PDI
Bayley Scales.   In addition  to  prenatal maternal and cord blood lead  levels,  capillary blood
lead levels at 6,  15,  and 24 months were assessed.   Geometric mean  blood lead  levels  rose
sharply from about  14 ug/dl at 6 months  to around 21  ug/dl at 15 months.  About 20 percent of
the subjects had estimated blood lead concentrations  above 30 ug/dl  at 24 months, after which
levels declined slightly.  Among  the  sociodemographic variables assessed were  mother's  age,
each parent's  education  level  and  workplace, marital  status, and the  child's  birth  rank.
HOME and maternal  IQ  were assessed when  the  children  reached 3  years of age.
     Pearson correlation coefficients between  MDI scores and blood  lead measures were statis-
tically  significant  at all  sampling  stages  except  for  delivery  and cord blood.   Multiple
regression analyses  using  a  number  of sociodemographic and other potential  covariates (e.g.,
5-minute Apgar score, size for gestational age, mouthing behavior,  maternal  IQ) entered prior
to  blood lead  indicated  that reduced  MDI scores  were significantly  associated  with higher
integrated postnatal  blood  lead  levels  but  not with prenatal  or perinatal  levels.   As shown
in Table A-6,  regression  coefficients for specific postnatal  sampling  points  (6, 15, and 24
months)  were mixed  in their significance levels, the  highest  occurring at 6  months  and the
lowest at  24  months  (after  controlling  for  maternal  IQ).   At the time of this preliminary
report,  maternal  IQ  had  not  been measured   for the  entire  cohort;  HOME  scores  were not
included in any of  the reported analyses.
     A recent  study  by  Ernhart  et al. (1985a, 1986)  has also addressed the issue of prenatal
lead exposure  and  postnatal  neurobehavioral  function.   Maternal and  cord  blood samples were
obtained at the time of delivery in  a  Cleveland, Ohio,  hospital.   The mean blood lead level
for 162  umbilical  cord  samples  was 5.8 ug/dl  (range:  2.6-14.7 ug/dl); mean blood lead level
for 185  maternal samples  was  6.5 ug/dl  (range: 2.7-11.8 ug/dl).  Of these  totals, there were
132 mother-infant  pairs of  data,  for  which  the correlation of blood  lead levels  was 0.80.
In  addition  to size, minor morphological  anomalies,  and 1- and 5-minute  Apgar performance,
the infants were evaluated on the Brazelton  Neonatal  Behavioral Assessment Scale (NBAS) and
part of  the   Graham-Rosenblith  Behavioral Examination for Newborns (G-R).   The NBAS Abnormal
                                             A-38

-------
   Table A-6.  Partial linear regression coefficients for 24-month Bayley MDI scores against
              each blood lead measure, with and without maternal IQ in the modelt
PbB Index
Average Prenatal
Del ivery
Cord
6 months
15 months
24 months
Integrated Postnatal
Ignoring
maternal IQ
-0.250
0.181
0.053
-0.231*
-0.084
-0.152*
-0.240*
Control 1 ing
For maternal
-0.064
0.001
0.026
-0.396*
-0.103
-0.061
-0.310*
IQ

tModel contains 13 sociodemographic and neonate factors
*Statistically significantly different from zero at p <0.05 (one-tailed)
Source:  Vimpani et al. (1985)

Reflexes  scale  focused  on  neonatal  neuromuscular  indicators  such  as walking,  standing,
Babinski reflexes, and ankle clonus.  The G-R scales included a Neurological Soft Signs scale
(jitteriness,  high-pitched/weak  cry,  hypersensitivity,  etc.)  and  a  Muscle   Tonus  scale.
Several  covariates  were   incorporated  in  the  hierarchical  regression analysis,  including
alcohol, tobacco and drug use, nutrition, gestational age, and parental size measures.
     Of the 17 neonatal outcomes examined, three measures showed significant relationships to
blood  lead  measures.   Abnormal  Reflexes  and Neurological Soft Signs  showed  significant in-
creases  in  the amount  of variance that  cord  blood lead accounted  for; Muscle  Tonus  scores
showed  significant effects only  for  maternal  blood lead levels  (see Table A-7).   Further
analyses using data solely from mother-infant pairs showed only Neurological Soft Signs to be
significantly related to cord blood lead; maternal blood lead showed no significant relation-
ship  (Table  A-7).   This  dissociation  of maternal  and cord blood  lead  effects,  despite the
rather  high  correlation of the  two independent  variables,  was  viewed by  Ernhart  et  al.  as
evidence  of  possible  increased fetal accumulation of  lead.  With regard to  morphological
anomalies, Ernhart  et  al.  found no evidence  of any effects  related to  lead.   However,  they
did  find clear evidence  of such  effects  related  to  maternal  alcohol  consumption (Ernhart
et al., 1985b).
     A brief report  on later  outcomes in this  same cohort  mentions a statistically signifi-
cant effect of  the  Neurological  Soft  Signs measure  on  Bayley MDI  scores at  12  months (Wolf
et al.,  1985).  Apart  from this indirect effect of cord blood lead, no effects  on MDI  scores
at 6-24  months  or  Stanford-Binet  IQ  scores  at 36  months  were  attributed to  prenatal  lead
exposure.  A  more detailed account of the  later stages of  this  prospective  study will  be
needed to evaluate its  findings and their implications.

                                             A-39

-------
       Table A-7.   Lead-related variance increments  for neonatal  neurological  measures.
Variable

Covariate
Variance
Cord PbB
Pb Effect
Variance
Maternal PbB
Pt
Covariate
Variance
Pb Effect
Variance
Pt
                                      All  Available Data*
Abnorm.  Refl.
Neur.  Soft Sign
Muscle Tonus
0.07
0.05
0.13
0.033
0.038
0.008
0.023
0.016
0.260
0.07
0.04
0.09
0.002
0.004
0.024
0.563
0.408
0.035
                              Restricted Data (132 paired cases)
Abnorm. Refl.
Neur. Soft Sign
Muscle Tonus
0.09
0.06
0.12
0.006
0.056
0.015
0.373
0.008
0.162
0.09
0.06
0.12
0.001
0.007
0.016
0.717
0.354
0.153
tp values <0.05 are underlined.
*For cord PbB, n = 162; for maternal  PbB,  n = 185.
Source:  Ernhart et al. (1985a)

     The predictive value  of  different markers of lead exposure  for  neurobehavioral perfor-
mance  has  been specifically  addressed by Winneke et al.   (1985a,b).   Of an  original  study
population  of  383  children born in Nordenham,  F.R.G.,  114  subjects were followed  up  at age
6-7 years.   The mean average maternal  blood lead level was  9.3 ug/dl (range:  4-31 ug/dl); the
mean cord blood  lead  level was  8.2 ug/dl  (range:  4-30 ug/dl).   Because of the high degree of
correlation between cord  blood  and maternal  blood lead (r  =  0.79),  the two were combined to
form an  estimate  of perinatal exposure.   Cord  blood  versus blood lead levels at  age  6-7 yr
correlated  at  r =  0.27.   Stepwise multiple  regression analyses  by  Winneke  et  al.  (1985a)
indicated that maternal  blood  lead  levels  accounted  for  nearly as much of  the  variance in
neurobehavioral test scores at age 6-7 years as did contemporary blood lead levels (see Table
A-8).   Cord blood  lead alone,  however,  showed less  impact on  later  performance.   Combining
maternal and  cord  blood  lead levels to form an estimate  of perinatal exposure resulted in a
significant association with only version 10 of the Wiener (Vienna) reaction performance test
(Winneke et al., 1985b).

3.1.2   Interpretation of Findings from Human Studies
     As  reviewed  above,  three  recent studies have investigated  an association  between pre-
natal  lead  exposure and  congenital  morphological  anomalies (Table A-9).   All three studies
                                             A-40

-------
  Table A-8.  Percent additional variance accounted for by different indices of lead exposure
  for selected neurobehavioral tests, as determined by stepwise multiple regression analyses
                               after correction for confounding.
Test
wise
Verbal IQ
Performance IQ
Full-scale IQ
Wiener Reaction Performance
Version 12 errors
Version 10 errors
Cued Reaction Time (3-sec)
Lift-off latency
Push button latency

Perinatal
PbB

+0.2t
+0.0
-0.1

+2.8**
+7.5***

-2.5*
+3.8**
Marker of Lead Exposure
Cord
PbB

-0.1
+1.8
+0.3

+0.7
+3.0**

-1.4
-0.7

Current
PbB

+0.3
-2.4*
-0.3

+4 3***
+11.0***

+0.0
-0.1
tSign (+ or -) indicates direction of effect.

*p <0.10      **p <0.05      ***p <0.01

Source:   Winneke et al.  (1985a)
   Table A-9.  Summary of recent studies on the relationship between prenatal lead exposure
                                 and congenital malformations.
Reference
Ernhart et al.
Needleman et al
McMichael et al

(1985a, 1986)
. (1984)
. (1986)
n
185
162
4354
749
Pb-Exposure
Index
delivery
cord
cord
prenatal
delivery
cord
Avg. PbB
(Mg/dl)
6.5
5.8
6.5
11.0
11.0
10.0
Malformations
0
0
+*
0
0
0
Symbols:   0, no evident relationship; +, positive relationship; -, negative relationship; *,
statistically significant at p <0.05.
                                             A-41

-------
used  regression analyses  to  control   for  numerous  possible  covariates  and  confounders,
including mother's age, parity,  and  tobacco  and alcohol usage.  Nutritional  information was
collected by McMichael   et al.  (1986) and by  Ernhart et  al.  (1985a,  1986),  but apparently not
by Needleman et al.  (1984).
     Of the three studies,  only  Needleman et al.  (1984) reported significant effects related
to  lead  exposure.   The sole deleterious effect was  for minor malformations as  a  group,  not
individually.    Unpredicted  significant  reductions   in  first  trimester  bleeding,  premature
labor, and  neonatal  respiratory  distress were also  associated with  higher blood lead levels.
This  study  was  a  retrospective  analysis;  that  is, the  investigators  themselves did  not
examine the infants  but  instead  relied on the routine observations  of hospital  staff pediat-
ric  residents,  as  recorded  in chart notes.   While  ensuring  that  the data were  collected in
blind  fashion,  this  method  suffers from a lack of  precision and  uniformity  that  could  have
affected the results in various ways.  Diagnosing  malformations, particularly minor malforma-
tions,  involves  judgment  by a clinician as  to  the  degree  of departure from  normality.   The
fact  that  neither  major malformations (which would  be  more  obvious) nor  any  specific  minor
malformation  showed a significant  relationship  to blood  lead  level  in  the analyses  of
Needleman et al. suggests that diagnostic criteria were  not consistently employed.   This  lack
of  precision could  be  the basis for the nonspecificity  of  their reported  effect (i.e.,  minor
malformations  taken  as a whole  but not  individually).   Clearly,  it would  be  preferable to
have  specialists in  teratology make  the diagnoses on the basis of  predetermined criteria for
minor as well  as major malformations.  Prior  determination  of diagnostic criteria and assign-
ment  as  to  their severity would also  eliminate the  possibility of grouping certain outcomes
to  achieve  statistical significance.   On  the other  hand,  diagnostic  imprecision would not
appear,  in  itself,  to  bias  the  investigation so  as  to  promote detection  of a spurious  asso-
ciation where none existed.
     The multiplicity and apparently exploratory nature  of the statistical analyses performed
by  Needleman  et al., coupled with the prima facie  implausibility  of a protective effect of
lead  (for  first  trimester  bleeding,  premature  labor,  and  neonatal  respiratory  distress),
suggest  the possibility  that  their findings  were simply due to  chance, i.e., an artifact of
conducting  multiple  statistical  tests.  However,  lead may have highly  specific and indepen-
dent  effects   within  a  given  organ  system   (Silbergeld,  1983),  so  qualitatively different
outcomes  are  not   wholly  unlikely.   In  addition,  as discussed  further  below,  seemingly
paradoxical effects  of prenatal  lead  exposure could be  due to misleading indicators of expo-
sure.   For  example,  if in some cases the fetus served as a sink for the mother's body burden,
then  the  maternal  blood lead  level  could  be lower  than that  registered  in  the cord.   Thus,
the mother  might be "protected" at  the  expense of  the  fetus, or vice  versa, depending upon
the dynamics of the mother-fetus transfer  of  lead at any particular stage of gestation.
                                             A-42

-------
     McMichael  et  al.  (1986)  followed 749 pregnancies prospectively  to  completion  but also
apparently  used hospital  records to  obtain  data on  congenital  malformations.   Apart from
noting that 40  (5.4 percent) of the infants had anomalies at birth (29 of which were classi-
fied  as  minor),  they simply  stated,  "After  controlling for  the  putative risk  factors  of
maternal  age, gravidity,  social  status,  smoking and alcohol usage, no association with blood
lead  level  at 14-20 weeks or later was  apparent."   Unfortunately, not enough information is
provided in their  report on their methods or analyses to judge the validity of their conclu-
sion on this point.
     The investigation by Ernhart et al. (1985a, 1986) was part of a prospective study using
cord and maternal blood samples taken at the time of delivery and employing a detailed proto-
col  for  the  detection  of birth anomalies.  Their  success in detecting an effect of maternal
alcohol  consumption (Ernhart et  al.,  1985b)  suggests  that their  methodology was basically
adequate to detect  a  teratological effect.  However, the maternal and cord blood lead levels
observed by Ernhart et al. (1986) averaged only 6.5 and 5.8 ug/dl, respectively, with maximum
values of  11.8  and 14.7 ug/dl.   This  restricted  range  of variation  in blood  lead levels
coupled with a comparatively small number of subjects (n = 185) and the relatively infrequent
occurrence of congenital  anomalies (often less than 1-2 percent of births) would have made it
difficult to detect an effect of lead in any case.
     The evidence  available  from the above three  studies allows  no definitive conclusion at
this  time  regarding the  existence  of  an association between  commonly  encountered levels  of
prenatal   lead  exposure   in  humans  and  the  occurrence  of  congenital  anomalies.   Further
prospective studies with large subject populations and clearly adequate statistical power are
needed to resolve this question.   For example, if the natural occurrence of a malformation is
2  percent,  5402  subjects per group would  be  required  to  find a relative risk of 1.5 with an
alpha of 0.05 and a beta of 0.10 (Schlesselman and Stolley, 1982).
     More evidence  is  available  that  bears  on  the  issue of prenatal  lead  exposure  and the
developmental  outcomes  measured  as  birth weight  and  gestational  age.   All of  the  studies
summarized  in Table A-10  included gestational  age  and  birth  weight  as variables  in their
analyses,  but the  only   significant  findings  for birth  weight   came  from Dietrich  et al.
(1986).   No  evidence  of an  association  was  reported  by  Ernhart  et  al.  (1985a,  1986),
Needleman et  al.  (1984),  and Moore et al. (1982).   Although Bellinger et al. (1984) found no
evidence of an  effect  on birth weight per  ^e,  they did  report an  exposure-related  trend  in
the  percentage  of  small-for-gestational-age infants  (1.2, 2.4, and 8.1 percent for the low,
mid, and high blood lead categories).
     The findings  of McMichael  et al.  (1986)  are not entirely  clear with regard  to birth
weight.  The  proportion  of  pregnancies  resulting in  low-birthweight   singleton  infants for
Port Pirie women  (whose  blood lead levels  averaged  10.4  M9/dl) was more than twice that for
                                             A-43

-------
   Table A-10.   Summary of recent studies on the association  of  prenatal  lead exposure with
                               gestational  age and birth  weight.
Reference


n
Ernhart et al . (1985a, 1986) 185
162
Bellinger
Needleman
Dietrich
McMichael
Moore et
et al.
et al.
et al.
et al.
(1984)
(1984)
(1986)
(1986)
al. (1982)
216
4354
185
749
236
Pb-Exposure
Index
delivery
cord
cord
cord
prenatal
delivery
cord
delivery
cord
Avg. PbB Gestational
((jg/dl ) Age
6.
5.
6.
6.
8.
11.
10.
14.
12.
5 ?
8 ?
5 +
5 0
3 -*
0 -*
0 -*
0 -*
0 -*
Birth
Wt.
0
0
_i
0
_*
+2
+2
0
0
Symbols:   0, no evident relationship;   +,  positive relationship;   -,  negative relationship;  *,
statistically significant at p <0.05;   ?,  not reported.
1Birth weight showed no relationship,  but  the trend in percentage  of  small-for-gestational-
 age infants was nearly statistically  significant at p <0.05.
2See text for possible explanation of  reduced blood lead levels  in mothers  whose infants
 were low in birth weight.

non Port Pirie women (average blood lead level  5.5 ug/dl).   Yet  in both groups the mean blood
lead levels (maternal as well as cord) for low-birth weight pregnancies were lower than those
for birth  weights greater than  2500  g.   Multiple regression analysis  showed  no  significant
association  between  low  birth weight  and  maternal  blood lead.   Note that,  unlike  others
who used  birth weight as a  continuous  variable,  McMichael  et al. categorically  defined  low
birth weight  as  less than  2500 g at  37 weeks  or greater gestational  age.   This  dichotomous
classification might have  made  detection  of subtle effects on  birth  weight  more difficult.
However,  using  "small-for-dates"  (i.e.,  weight  less  than  the  tenth percentile  for  the
appropriate gestational age) in multiple logistic regression analysis revealed no evidence of
intrauterine growth retardation.
     It  is  interesting that McMichael et  al.  found low birth weight  as well  as  stillbirths
associated with  lower  maternal  blood  lead level  (stillbirths significantly so, birth weight
not).   These  seemingly anomalous findings could be explained by a greater than normal  trans-
fer of  lead from the mother to the fetus  and/or placenta in such  cases.  As noted in Section
10.2.4 of the revised Criteria Document (U.S. EPA, 1986) and further  confirmed by some of  the
                                             A-44

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studies reviewed here, maternal  and cord blood lead levels are in general  highly correlated,
with maternal  levels  at birth  typically  being somewhat greater than  cord  levels.   However,
average blood  lead levels  at  birth may  not accurately reflect  individual  circumstances  or
past exposure  levels.  For  example, Ong et  al.  (1985)  analyzed maternal  and cord blood lead
concentrations for 114 women  at delivery and found that, although the two were significantly
correlated  (r =  0.63),  in  roughly one-fourth  of the  cases  the cord  blood lead  level  was
higher than the mother's.   The dissociation of maternal  and fetal blood lead noted by Ernhart
et  al.  (1985a,  1986)  in  their  statistical  analyses might  also reflect  increased transfer
and/or absorption of lead from the mother to fetus in certain individuals.
     In  addition,  exposure  levels during  the  course  of  pregnancy  may  not  be accurately
indexed by  blood lead  levels  at parturition.  Various studies indicate that average maternal
blood lead levels during pregnancy may tend to decline (Alexander and Delves, 1981; Bonithon-
Kopp et  al. ,  1986),  increase (Gershanik  et  al. ,  1974;  Manton, 1985),  or  show no consistent
trend (Barltrop, 1969;  Lubin  et al.,  1978).   These  divergent results may simply reflect the
likelihood that  the  maternal  blood lead pool  is  subject both to increase  as  bone stores  of
lead  are  mobilized  during pregnancy  (Buchet  et al. ,  1978;  Manton,  1985;  Silbergeld and
Schwartz, 1986) and to decrease as lead is transferred to the placenta and fetus.
     Apparently, then,  under  some  conditions  the  fetus  may be exposed to  higher levels  of
lead  than  indicated  by the  mother's  blood lead  concentration.   This conclusion  does not
establish  that birth weight is  reduced  by intrauterine exposure to  lead.   It does suggest,
however,  that  attempts  to  detect effects of prenatal lead exposure—including not only birth
weight, but morphological   anomalies,  pregnancy outcomes, and  postnatal  development—may  be
complicated  if,  for some  reason,  a  disequilibrium exists  between  maternal and  fetal  body
burdens at the  time  of  blood  lead measurement.   Further research  is  needed  on the dynamic
relationship  between  mother and fetus as  lead is mobilized and transferred from one  to the
other during gestation.
     For  gestational age,  Dietrich et al. (1986),  Moore  et  al. (1982), and McMichael  et al.
(1986) reported  significant negative  relationships with prenatal lead exposure;  in contrast,
Needleman  et  al.  (1984)   reported no association,  and Bellinger et al.   (1984)  reported a
positive  (nonsignificant)  relationship between  prenatal  lead  exposure and gestational age.
Note,  however, that infants  of less  than 34 weeks  gestational  age  were  excluded from the
study by  Bellinger and his colleagues.  This selection criterion would interfere with detec-
tion  of  a  reduction  in  gestational age.  Thus,  the evidence as a  whole  from these studies
indicates  that gestational age  appears to  be reduced as prenatal  lead  exposure  increases,
even  at   blood lead  levels below 15 ug/dl.   Based on  the  parameter  estimates  of Dietrich
et  al. (1986), the reduction in gestational  age  amounts to 0.6 week per natural log unit of

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blood  lead  increase.   In terms of risk estimates,  according  to McMichael  et al.  (1986)  the
risk of pre-term  delivery  increases  signficantly by at least  4-fold as  either the cord blood
lead or mother's blood lead concentration  at delivery increases from ^8  to  >14 ug/dl•
     Further evidence of a deleterious effect of prenatal  lead exposure  on  infant development
comes from studies using the Mental  Development Index of the Bayley Scales  of Infant Develop-
ment (Table  A-11).   Bellinger  and  his colleagues  have reported persistent  deficits  of  4-7
points in MDI  scores  at ages 6 to 24 months, and have found that these  deficits consistently
relate to the children's blood lead levels measured at birth in the umbilical cord (Bellinger
et al., 1984,  1985,  1986a,b).   Dietrich et al. (1986) have also reported deficits on 6-month
MDI  scores  that  relate  to prenatal  maternal blood lead levels.  In both of these studies  the
results were  statistically significant after  proper allowance  for various  factors  such as
SES, HOME scores, tobacco and alcohol usage, etc.   Both studies also provide estimates of  the
magnitude of the effects on MDI scores.  Parameter estimates from Bellinger et al. range from
-2  to  -3.6  points  for  each  increment in cord  blood  lead classification  (see  Table A-5).
Consistent with  these  figures  is the estimate  of  -2.25 points per natural log unit maternal
blood  lead  as  derived from the  structural  equation analyses  of Dietrich  et  al.  (see Figure
A-2).
     Vimpani et  al.  (1985)  found evidence  more  clearly relating  MDI  deficits to postnatal
lead exposure  than to  prenatal exposure.   They ascribed  an average 4-point drop in 24-month
MDI  scores  to  a  mean  increase  of  10 ug/dl  in blood  lead levels at  6 months after birth.
Note,  however,  that they also  found a negative relationship   between MDI  scores  and average
prenatal  exposure,  although not  a  statistically  significant  relationship.   Since postnatal
blood  lead  levels increased by about 50 percent from 6 months to 15 months in the Port Pirie
study,  later  increases  in  exposure  may  have  overwhelmed the  more subtle  effects  of lower
prenatal  exposure levels.   It  should  be  remembered that the   same  cohort  of subjects showed
significantly  reduced  gestational   age   and  possibly  other  effects as   a  result  of these
prenatal  exposure levels  (McMichael  et  al.,  1986).   Also,   earlier  testing  on  the Bayley
Scales  (e.g.,  at 6 months of age) might  have  revealed a stronger effect of prenatal exposure
than could be  detected at 24 months  after birth.
     The  prospective study of  Ernhart et  al.  (1985a, 1986)   has  thus  far provided evidence
relating  neonatal performance  on a  Neurological  Soft  Signs  scale (jitteriness, hypersensi-
tivity,  etc.)  to  prenatal  lead  exposure  as reflected  in  cord blood  lead  levels.   A brief
follow-up report by  Wolf et al.  (1985) indicates that lowered Bayley MDI scores at one year
of  age appear  to be a  statistically significant  sequela  of the  cord  blood lead effect on
Neurological Soft Signs shortly  after birth.   Finally,  Winneke et al.  (1985)  noted a highly
significant  relationship between perinatal blood  lead  levels  and  one  measure  of psychomotor
performance at 6-7 years after  birth.
                                             A-46

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          Table A-11.   Summary of recent studies on the relationship between prenatal
                   lead exposure and Bayley Mental  Development Index scores.
Reference
Bellinger et al. (1984,
1985, 1986a,b)



Dietrich et al. (1986)



Vimpani et al. (1985)






Pb-Exposure
n Index
216 cord
6-mo PN
12-mo PN
18-mo PN
24-mo PN
185 prenatal
10- day PN
3-mo PN
6-mo PN
592 prenatal
delivery
cord
6-mo PN
15-mo PN
24-mo PN
integr. PN
Avg. PbB
(ug/dl) 6-mo
6.5 -*
6.2 0
7.7
?
7
8.3 -*1
4.9
6.3 -*2
8.1 +*3
?
ii4
104
~145
~215
~215
?
Bayley MDI Scores
12-mo 18-mo 24-mo
_* _ _*
000
000
0 0
0




-
0
0
_*
-
-
_*
Symbols:  0, no evident relationship;  + ,  positive relationship;  -, negative relationship;
 *, statistically significant at p <0.05;   ?, not reported;   PN, postnatal.
Effect of prenatal (i.e., maternal) blood lead on MDI mediated through effects on
 gestational age and/or birth weight.
2Effect of blood lead at 3 months significant only for White children (15 percent
 of study population).
3Authors interpret positive relationship as due to greater lead exposure in  developmentally
 advanced children.
4Blood lead levels for Port Pirie mothers  only, as reported  by McMichael et  al.  (1986).
5Geometric means estimated from graph.

     The  exposure  levels at  which  the above  neurobehavioral  deficits  are  observed can be
inferred from some of the reported analyses.   Based on the blood lead classifications used by
Bellinger et al.  (1984) and the 95 percent confidence intervals for the effects they reported
(see Table A-5),  significant declines in Bayley MDI scores occurred at cord  blood lead levels
of 10 ug/dl  and  above.   Dietrich et al.  (1986) did not group the prenatal  blood lead concen-
tration  in  their study,  and  thus  it  is  not  possible  to state a precise exposure  level at
which their  effects  occurred.   However,  with a mean of 8.3  and standard deviation of 3.8,  it
appears that over  95  percent  of their study population had  blood lead levels below 16 ug/dl.
Vimpani  et  al.  (1985)  noted that subjects whose  blood  lead concentrations  consistently fell
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in the top quartile  at  6,  15, and 24 months  had significantly lower MDI scores  compared to
the remainder of the cohort.   Although the  authors  did not  describe  the  distribution of blood
lead levels  in their study,  they  did  note that about 20  percent  of the subjects  had blood
lead levels  in excess  of  30 ug/dl  at  age 2  years,  which was  the point of peak  exposure.
Thus, their  levels  appear to  be somewhat  higher  than those  of  the other  studies reviewed
here.  However, the  prenatal  levels for  this cohort were  considerably lower,  averaging around
11 ug/dl  in Port Pirie mothers and  about 8  ug/dl  outside  Port  Pirie  (McMichael  et al., 1986).
     The  neurobehavioral  effects  noted by  Ernhart  et  al.   (1985a,  1986)  and  Wolf  et  al.
(1985),  although "small" by the authors' characterization,  were significantly related to cord
blood lead levels that averaged only 5.8 ug/dl  and  ranged upward to  only 14.7 ug/dl.  Winneke
et al.(1985) reported that  errors  in reaction test performance were associated  with maternal
blood lead  levels averaging  9.3  ug/dl  and  cord blood lead  levels averaging 8.2  ug/dl.   A
scatter plot of the  mother-cord blood lead  concentrations indicates  that, except for a couple
of  outliers,  nearly all of  the values  were  clearly below 20 ug/dl and  generally  did  not
appear to  exceed about  15  ug/dl.    All   of  these studies taken together suggest  that neuro-
behavioral deficits,  including  declines in Bayley  Mental Development Index  scores  and other
assessments  of neurobehavioral  function,  are  associated with  prenatal  blood  lead exposure
levels on the order  of 10 to 15 ug/dl and possibly  even lower, as  indexed by maternal or cord
blood lead concentrations.
     The  evidence reviewed  in  this  section supports  the  conclusion that  fetal  exposure to
lead at  relatively   low  and  prevalent concentrations  can have undesirable  effects  on infant
mental development,  length  of  gestation,  and possibly  other aspects  of  fetal  development.
Further  research  is needed  to  assess the  complex  dynamic relationship  between  maternal  and
fetal  body  lead  burdens,  particularly with  regard  to  possible  individual differences in
transfer and/or  uptake  from  mother to  fetus.  Further research  is  also needed to assess the
possible  contribution  of paternal  lead exposure to these effects  (cf.  Uzych,  1985; Trasler
et al., 1985;  Brown, 1985).  At present, however, perinatal blood lead levels at least as low
as  10 to  15  ug/dl clearly warrant concern for deleterious effects  on early postnatal as well
as  prenatal  development.  The  persistence of certain  types  of effects remains to be more
fully  investigated  as  the  present  long-term  prospective  studies  proceed.   For example, it
remains  to be  evaluated as  to  whether delays  in cognitive  development indicated  by decre-
ments in  MDI scores are reflected in later childhood by lowered IQ scores or poorer academic
performance.   The evidence  from other  studies reviewed  in the 1986  Criteria Document (U.S.
EPA,  1986) is  indicative  of decrements in IQ  measured  in  schoolage  children,  even at PbB
levels below 30 ug/dl.   Note that additional evidence for IQ decrements being associated with
blood  lead levels below 30  ug/dl  (Hazakis  et  al,  1986)  and,  possibly, as low as 10-15 ug/dl
(Fulton  et al,  1986)  in schoolage  children  was presented at  a  recent Edinburgh  symposium.
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3.2  Effects of Lead on Postnatal Growth
3.2.1  Epidemiologic Observations
     Among the earliest  indications  of lead effects on  stature  in children are observations
reported  by  Nye  (1929)  regarding  "runting," along  with squint  and  foot drop,  as  physical
signs  characteristic  of overtly  lead-poisoned  Australian  children  seen  in  the  1920's.
Remarkably,  since  then  very few  systematic evaluations  of  possible  stunting  of  physical
growth have  been  included  among the health  endpoints  examined  in the numerous epidemiologic
studies of lead effects on early human development.
     In one  such  study,  Mooty et al.  (1975)  obtained  physical  measurements (weight, height)
for children  (2-4  years  old) chosen according to low  and  high blood lead  levels  (x ± S.D.=
20.4 ± 4.3  and 56.9 ± 8.3 (jg/dl,  respectively).  The  21 high-lead children,  with blood lead
levels in  the  range 50-80  pg/dl, were both  shorter  (x = 32.1 percentile on  Stuart's Boston
Growth Charts)  and weighed  less (x =  43.8 percentile) than  the 26 low-lead children with
blood leads of 10-25 M9/dl  (height = 41.1 percentile, weight = 48.7 percentile).   The average
age for the  control  group,  which was  composed of 12 Puerto Rican, 8 Black,  and 5 Caucasian
children,  was  34  months;  the high-lead group had a  mean age of 33 months and  was composed of
4 Puerto  Rican,  17 Black,  and no Caucasian children. Because of the slightly  younger age and
lack  of  Caucasian  children   in  the  high-lead  group  (as  well  as other differences,  e.g.,
dietary intakes),  it  is  not  possible to clearly determine  the  relative contribution of lead
to the observed smaller stature of the high-lead  subjects versus other factors.
     In a  later  study,  Johnson  and Tenuta  (1979)  studied  the  growth  and diets  of 43 low-
income Milwaukee children  (aged  1-6 years) in relation to  their blood lead  levels.  Children
with  low  (12-29  ug/dl;  N = 15),  moderate  (30-49  ug/dl;   N = 16),  and high  (50-67 ug/dl;
N = 12) blood lead levels had average daily calcium intakes of 615,  593, and  463 mg, respec-
tively.   Also, there  was a relative decrease (p  <0.075) in individual height  percentile with
increasing blood  lead  level  (high-lead children  had means  of  25.7 percentile for height and
42.2 percentile  for  weight;  no  specific data were  reported for other lead groups) and higher
incidence  of  pica  (eating  of plaster and paint) on  the part of the children  with blood lead
levels ranging from  30 to  67 (jg/dl.   Unfortunately,  the specific racial composition  and mean
ages of the  different  blood  lead groups were not reported,  making it impossible to determine
the relative  contribution  of such  factors  (or  the  differences  in  calcium intake  or other
dietary factors)  to the observed smaller stature  among  the  high-lead children.
     In another  study,  Routh et al.  (1979)  examined a sample  of nonurban children (N = 100;
mainly from  lower socioeconomic status  families in North  Carolina) with  developmental  and
learning  disabilities   for   previously   undiagnosed  lead  intoxication.   One  child  with
"moderately"  elevated  blood  lead  (according to  the then-existing CDC  classification,  50-79
ug/dl)  and  nine  with  "minimal"  elevations (30-49  ug/dl) were  identified.    Of  these  10
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children, seven  were microencephalic (defined as  head  circumferences  at or below  the  third
percentile for the  child's  age on standard growth charts).   This  was  a markedly greater pro-
portion of microencephaly than that seen among the remaining children  with  blood lead levels
below  29  pg/dl  (17  of  62;  25 percent).   Most of the microencephaly  syndrome  children were
Black.  Five of the elevated blood-lead children  also showed more  general  growth retardation,
in that  their  height, weight,  or both were at or below the  third  percentile for age and sex.
These results, as are those from the previously discussed studies, are  suggestive of possible
stunting of growth  due  to lead exposure early in  development resulting in  blood lead levels
generally above 30 (jg/dl.   However, again it is not possible to clearly separate the relative
contribution of lead from other factors (racial,  dietary, etc.) that may have affected growth
of the children studied by Routh et al.  (1979).
     Much stronger  evidence  for  lead exposure producing retardation of  growth  and decreased
stature  has  more recently  emerged in the  1980's from both  animal toxicology  studies  (dis-
cussed  below)  and  evaluation  of  larger scale  epidemiologic data sets.   In  regard to  the
latter,  Schwartz  et al.  (1986) have reported  results of analyses of data from the NHANES II
study described earlier in relation to evaluation of blood lead/blood pressure relationships.
More  specifically,  Schwartz  et al. (1986) analyzed  results  for anthropometric  measurements,
as well  as  numerous other factors  (age, race, sex,  dietary,  etc.) likely to affect rates of
growth and development,  among the NHANES II children.
      Linear regressions of adjusted data from 2695 children  (aged  7 yrs or younger) indicated
that  9 percent of the  variance in  height, 72  percent of the variance in weight, and 58 per-
cent  of  the  variance in chest circumference were  explained by the following five variables:
age,  race,  sex,  blood  lead, total calories or protein,  and  hematocrit or transferrin satura-
tion.   The  step-wise multiple regression  analyses further  indicated  that  blood lead levels
were  a statistically significant predictor of childrens1  height (p <0.0001), weight (p <0.001)
and chest circumference (p <0.026), after controlling for age in months, race, sex and nutri-
tional  covariates.   The  strongest relationship was found between  blood lead and height, with
threshold regressions indicating no evident threshold for the relationship down to the lowest
observed  blood  lead level of  4 ug/dl.  At their average age  (59 months), the mean blood lead
level  of the  children  appears  to  be  associated  with a reduction  of about  1.5  percent below
the height expected  if their blood  lead level had been zero.  Similarly, the relative impacts
on weight and chest  circumference were of the same magnitude.
      Overall,  the above  findings  of Schwartz et al.  (1986)  appear  to  be highly credible,
being based  on well-conducted  statistical  analyses of a large-scale national survey data set
(which  was  subjected to rigorous  quality assurance procedures) and having  taken into account
numerous  potentially  confounding  variables.   Other  recent  results  newly   emerging  from
independent, well-conducted prospective studies of prenatal  and early postnatal  lead exposure
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effects on  human development, also  appear  to substantiate the likelihood of  lead  retarding
early  growth,  as reviewed above.  For  example,  Dietrich  et al. (1986)  report  that prenatal
maternal blood  lead levels  and  early  postnatal  (10-day)  blood lead  levels were negatively
correlated with  birth  weight (p <0.001) and  gestational  age  (p <0.05)  for 185  infants  from
low  socio-economic  inner-city Cincinnati families.   The  plausibility of  reported  epidemio-
logic  findings  of  associations  between early  lead  exposure  and  retardation  of growth  re-
flecting a causal  relationship  is  supported by animal toxicology results concisely  discussed
below.

3.2.2  Animal Toxicology Studies
     The impairment of physical  growth or stature as  an effect of lead exposure during prena-
tal  or early postnatal life has been well  established by animal studies  (see  below).   How-
ever,  although  preceeding   sections  of  the  Addendum cite  several   recent  epidemiological
studies which  strongly support  the  notion  that  lead exposure during early development  can
lead  to  retardation   of  growth  in   humans  as  well,  additional  carefully  designed  animal
toxicology studies  are needed  to better substantiate  and  further  extend the  epidemiological
findings.
     A computer search for the relevant animal experimental studies published  during the  last
decade yielded 43  papers  which  described significant retardation of growth (measured by  gain
in weight  or length)  after  low-level  exposure during intrauterine life,  during  early post-
natal  life,  or  both.   An additional   22  papers specifically stated that growth of  the lead-
exposed animals  was  not affected.   However, a  close examination of  this  latter  group  of
studies revealed that  in the great  majority of  the cases the  treatment started  too  late
(e.g.,  after weaning)  or  the doses were too  low (e.g.,  less  than 10  ppm in  drinking water).
On balance,  then,  it  seems very clear  that  low-level chronic  lead exposure during pre-  and
early  postnatal  development does  indeed result  in  retarded  growth  even  in  the absence  of
overt  signs of lead poisoning.
     One study on  rats,  by Grant et  al. (1980), provides  detailed experimental  data relating
external  lead  exposure doses to consequent  blood  lead  levels  and growth rate  measured  in
terms  of  both weight  and  length.  Continuous prenatal and postnatal   exposures to  lead  were
accomplished via  lead adulteration of  the  drinking  water:  (1) of  dams  prior  to  conception,
throughout pregnancy,  and nursing;  and (2)  of  the  drinking water consumed post-weaning  by
their  offspring  through  180  days (6  months).   Females from lead exposure groups with average
blood  lead  levels  in  the range of  18-48  ug/dl were  significantly shorter  in  crown-to-rump
length from  postnatal  days  7 to 180; lead-exposed males  exhibited only a transient retarda-
tion of growth and were not significantly different in length  from control  animals by the end
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of the 180  day  observation period.   Decreased body weight (with no decrease in food consump-
tion per  unit of  body  weight)  was  found in  animals  with blood lead levels of  40-60  ug/dl,
whereas deficits  in  rate  of neurobehavioral  development and indications  of specific organic
or  functional  alterations (Fowler  et  al.,  1980)  were  observed at blood lead levels  in the
range of 20-40 ug/dl.
3.3  Possible Mechanisms of the Effects of Lead On Growth and Development
     Considering  the  numerous  reports  of  growth  impairment  in  lead-exposed  experimental
animals,  as  well  as  emerging  evidence concerning  similar  effects in human  subjects,  it is
surprising to  find that  out  of the more than  60  studies  alluded  to above,  none  was speci-
fically designed  to  investigate the mechanism of lead-induced growth retardation,  and only a
very few  even  commented upon  possible, speculative mechanisms.   Thus, it can clearly be con-
cluded that experimental studies specifically addressing this question are needed.
     What  are  the mechanisms  to  be considered?   At  the low dose levels  of  interest (those
relevant  to  human populations),  general  malaise  resulting  from severe poisoning  or one or
more  of  its  manifestations,  e.g.,  marked damage  to  blood, brain,  kidney,  or the cardio-
vascular  system,   are  not  likely to  be   important.   On the  other  hand, consideration  of
established  factors  that affect the regulation  of normal  growth may enable  one  to identify
measurable parameters that are  likely to be affected by lead.
     Growth  is  a complex  phenomenon that  is  accompanied  by an orderly  sequence  of matura-
tional  changes  which  involve  accretion of protein and increases in length and size, not just
weight.   While  growth  hormone  (GH) is the  most  abundant hormone of the pituitary gland, and
its  primacy  in  controlling postnatal somatic growth is unquestioned, growth is also affected
by  thyroid  hormones,   androgens,  estrogens,  glucocorticoids,  and  insulin.    Extrinsic  and
genetic factors also play a part in regulating growth.

3.3.1  Genetic  and Extrinsic Factors
     Food  supply  is  the  most  important  extrinsic factor  affecting growth.   Food must be
adequate  in  proteins,  essential   vitamins,  minerals,  and   calories.   Several studies  have
demonstrated that nutritional  deficits aggravate the effects of lead poisoning (e.g., Bell &
Spickett,  1983; Hsu,  1981;  Leeming &  Donaldson,  1984; Ashraf &  Fosmire,  1985;  Wool ley and
Woolley-Efigenio, 1983; Harry et al., 1985).

3.3.2   Endocrine  Factors
     The  major  hormones that are  involved  in  postnatal  growth  are GH, thyroid hormones, and
androgens.   These  should be measured in the blood of lead-exposed animals during the  critical
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stages  of  life and correlated with growth and developmental parameters.  Practically none of
this  information  is available at this  time.   Of the many animal studies reviewed (plus many
other  human  studies),  none  included  GH  measurements  in  the  lead-exposed  growth-impaired
subjects.   However,  known facts regarding neuroendocrine control  of GH secretion and poten-
tial  effects  of lead on  such neuroendocrine regulatory mechanisms provide plausible hypothe-
ses regarding ways by which lead-induced growth  retardation could be mediated.
     The  secretion  of  GH  from  the  pituitary is  controlled  by  the  hypothalamus.   Two
neuropeptides,  a  stimulating  one (GRF) and an  inhibiting  one  (SRIF), have been isolated and
characterized.  In addition, dopamine (DA) appears to be important in GH regulation, although
its effects (which may be exerted at  several different levels) are not entirely clear.   These
substances  can  now be  assayed in blood and  in small pieces of tissue, and the neurons which
produce them can be identified by immunohistochemical methods.   It is not yet known in detail
how  GH secretion  is regulated.  GH  itself can  inhibit its  own  secretion  via  a so-called
short-loop  feedback mechanism.  The anatomical substrate for such a mechanism has been demon-
strated when  it was shown  that  blood in some of the  hypothalamo-hypophysial portal  vessels
does actually flow upward, from the pituitary to the hypothalamus.   This blood supply reaches
the  area  of  the  arcuate nucleus where  the  GRF-containing neurons  are  located.   SRIF  may
influence GH  release  not  only directly at the  level  of the pituitary  but  also  via interac-
tions within  the  median  eminence, and  through  innervation  of  the  GRF-producing cells in the
arcuate nucleus.   The  reverse  interaction  may  also  occur,  i.e., GRF, via  axon collaterals
ending  in the  vicinity  of SRIF-producing neurons in the anterior periventricular area of the
hypothalamus,  may  influence the  production  and release of SRIF.   Finally,  somatomedin  (SM)
may play  an important role in  the  GH-regulating feedback mechanisms  (cf.  Underwood  and  van
Ryk,  1985,  and discussion below).  Direct  injection  of SM into the  cerebral  ventricles  has
been shown  to  inhibit  GH  secretion.   This can occur by at least two mechanisms:   stimulation
of SRIF production  in  the hypothalamus, and inhibition  of  the synthesis  of GH in the pitui-
tary in response to GRF.
     Endogenous opiates (enkephalins  and  endorphins)  are also  known to stimulate the release
of GH, probably through activation of hypothalamic mechanisms  (e.g.,  Casanueva et al.,  1980).
In the only study which looked at the effects  of perinatal  lead exposure on  enkephalin levels
in one  brain  region,  namely the striatum (Winder et  al.,  1984),  up to a  50 percent decrease
was found;  however,  enkephalin  levels  in the hypothalamus of  lead-intoxicated  animals  were
not investigated.
     Although the  effects of lead  on  the  nervous  system have been  studied  extensively,  no
study has  so far attempted to  determine its  influence on hypothalamic releasing or inhibiting
factors, including GRF  and SRIF.   One recent study addressed the question  of how chronic  lead

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treatment influenced the dopaminergic control  of prolactin,  a pituitary hormone whose regula-
tion is similar to that of GH (Govoni et al.,  1984).   Although DA content in the hypothalamus
was unchanged, the  content  of one of its metabolites,  dihydroxyphenyl  acetic acid,  showed a
highly significant decrease.   The amount of  DA receptors in  the pituitary was also decreased.
These  findings  explain,  at  least  partially, previous  findings that  circulating  prolactin
levels were  elevated in chronically lead-exposed rats (Govoni et al. ,  1978).   The importance
of  DA  in the  control  of normal  growth is  emphasized  by a  recent  study by  Huseman  et  al.
(1986),  in  which they  establish  endogenous dopaminergic dysfunction  as a  possible  cause  of
human growth  hormone  deficiency  and short stature.   According to these authors, decreased GH
production can result  from  decreased dopaminergic or noradrenergic tone in the hypothalamus,
from decreased GRF  production by hypothalamic neurons,  and  finally from decreased pituitary
responsiveness to  GRF  and/or  DA.   All  these  parameters can  now  be  measured  and  should  be
carried out in studies of chronically lead-exposed animal models.
     As  pointed  out above,  it has  become  clear that  many  (but not  all) effects of  GH  are
mediated  by  peripherally produced  growth  factors called somatomedins  (SM).   These  interact
with  receptors  in target  tissues,  the  most  important of which from  the  point of view  of
linear growth is cartillage.   Only one study (Rohn et al., 1982) is so far available in which
SM  levels were correlated with  lead intoxication  in 21 children before  and  after chelation
therapy.  Somatomedin levels in these children were found to be increased, and became further
elevated  after  chelation; plasma  GH or other  pituitary hormones were  not  determined.   The
mechanism of the changes found in this study is not clear, but the most likely explanation is
that  some sort  of compensatory  overproduction  of  SM  was  occurring.   Again,  experimental
studies of the appropriate design would  be most useful.
     Somatomedin secretion  is  reduced in  diabetes and  can be  restored by insulin treatment.
The overlapping  biological  activities of  insulin and SM  might be due to the fact that these
two hormones react with each other's receptors.   Insulin is  clearly the primary stimulator of
somatic  growth  in  the fetus, and  in  postnatal  life  insulin  deficiency (diabetes) is associ-
ated  with growth  failure,   while  hyperinsulinism  is  accompanied  by overgrowth  in several
conditions.  None of the references  found in the literature  survey alluded to above addressed
the question of whether lead affects insulin secretion in the fetus or during early postnatal
life.
     With  regard to  thyroid  function,  impairment of  the iodine-concentrating  mechanism  by
lead  has  been shown in rats (Sandstead, 1967) and in man (Sandstead et al., 1969).  In addi-
tion,  one of two patients  studied had  decreased secretion  of  thyroxine.   Since the iodine-
uptake  deficit was  readily corrected by the  injection  of thyroid stimulating hormone (TSH),
it  can be assumed  that TSH  deficiency was  at  least a  factor  in  these patients.   However,
                                             A-54

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neither in this nor in any other studies were direct measurements of thyroid hormone (or TSH)
levels have  been  performed at the ages  when  the involvement of these  hormones  in growth is
critical.
     Androgens  in  lead-exposed  animals have been measured only in one recent study (Sokol et
al., 1985) which  was  designed to evaluate  the  effects  of lead on the hypothalamo-pituitary-
testicular axis  in post-pubertal  (52- to 82-day  old)  rats.   Significantly reduced levels of
testosterone  were  found both  in  testicular  tissue  and  in  blood.   Also,  the  weight  of the
ventral prostate (a sensitive indicator of androgen activity) was reduced.
     The  androgens responsible for  the  peripubertal  growth spurt orginate from the adrenal
cortex,  which  (perhaps  through the  hypothalamo-pituitary  axis)  is  also affected by lead
(Sandstead et  al., 1970b).   However,  other steroids besides  androgens  may also be important
here.   For  example,  the inhibition  of  growth  in  immature  animals  is  one of  the  cardinal
effects  of glucocorticoids.   Again,  specific studies assessing the  possible  involvement of
the adrenal gland  in the effect of lead on growth are completely lacking.

3.3.3  Additional  Factors Affecting Growth
     There are additional  growth  factors  other  than  those  discussed  above.   These include
some broad-spectrum,  hormone-like  growth factors such as epidermal  growth factor, platelet-
derived  growth factor,  and  fibroblast growth  factor,  as well  as  more  restricted,  tissue-
specific  growth  factors  such  as  nerve growth  factor,  erythropoietin,  colony-stimulating
factors,  and  lymphocyte  growth  factors (interleukins).   The great importance of these  growth
factors -- besides their specific roles in particular tissues and growth processes -- lies in
the fact that several  of them (or their receptors) have been found to be related to oncogenes
and  their products,  i.e.,  substances that are  responsible  for malignant transformation of
cells.   These  or  similar  substances  are now  being recognized with  increasing  frequency as
normal  constituents  of  cells  and  regulators of  normal  cell growth.   The loss  of  cellular
control over  the  production  or function of these substances  may be  responsible for malignant
growth.   These  growth factors and  related  gene products  have been  recognized  only  recently
and are the subject of intensive current research.  Thus,  it is  not  surprising that they have
not yet  been correlated with lead toxicity.   However,  given the general  effects  of lead on
body growth,  it seems  quite  likely  that  one or more  of these  growth factors  or  oncogene
products may be influenced by lead toxicity.
3.4  Summary and Conclusions Regarding Lead Effects on Growth and Development
     The  earlier  epidemiologic  studies  discussed  above  (Mooty  et  al.,  1975; Johnson  and
Tenuta, 1979;  Routh et  al.,  1979) provided  suggestive evidence  for  lead effects  on early
                                             A-55

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growth and stature.   However,  it is difficult to apportion  relative  degrees  of contribution
of lead to observed growth deficits in comparison to other factors  due to the  manner in which
the data  from these small scale  studies  were  reported.   Much stronger  evidence  has  emerged
from the  Schwartz  et  al.  (1986) evaluation of the large-scale NHANES  II  nationwide data set,
and some  additonal data  are  beginning to  emerge  from  prospective studies, such  as  that  of
Dietrich et al.  (1986).
     The  plausibility  that the  observed  epidemiological  associations between  lead exposure
and retarded  growth reflect  causal  relationships  is supported  by certain limited parallel
experimental   toxicology  observations  in numerous animal studies,  including especially find-
ings  reported in  the  rat by Grant  et al.  (1980),  albeit at blood  lead  levels  distinctly
higher than the  lower values  in the  range  of  blood lead  levels  of children  included in the
Schwartz  et   al.  (1986)   analysis.   Furthermore, the possibility  of  lead  effects on neur-
oendocrine mechanisms mediating  lead-induced  retardation  of growth  is also  supported  by
certain studies, e.g., those  of Petrusz et al. (1979) and others,  showing effects of lead in
neuroendocrine functions  in animals  and man.  In view  of  the lack of thorough  evaluation of
lead effects  on  GH and other plausible mechanisms affecting growth,  much remains to be done,
however,  with regard to  more fully  characterizing  quantitative relationships  between lead
exposure  and  growth  retardation  in children, as  well  as  determining the specific  physio-
logical mechanisms underlying such effects.
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