Document NE7beqx8j20OkmY6Y8Gye8j9y
PB87-142402
AIR QUALITY CRITERIA FOR LEAD VOLUME III OF IV 3
{U, s.) Environmental Protection Agency Research Triangle Park, NC
Jun 86
RECEIVED
4 m 51989
, HASKELL LIBRARY
DEPARTMENT OF COMMERCE Technical Information Service
ffns.
N 29317
United States t Environmental Protection Agency |
Environmental Criteria end Assessment Office. Research Triangle Park. NC 27711
EPA-600/8-83/028cF June 1986
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Research land Pevglopment
Air Quality Criteria for Lead
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PB87-142402
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FINAL d r af f
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Volume III of IV
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June 1986
Air Quality Criteria for Lead
Volume III 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
DUP040012157
.DISCLAIMER
This document has been reviewed in accordance with U.S. Envir.onm.enta] Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation*
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DUP040012158
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 fair'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 discreparvcies in pur
current knowledge and understanding of the effects of these pollutants.
Although this document is pTincipaTly ebacerned w^th the health and
welfare effects of lead, other scientific data are presented and evaluated in
order to provide .a better understanding of this pollutant ;in the environment.
To this end, the document includes chapters that discuss the chemistry and
physics of the pollutant; analytical techniques; sources, and types of
emissions; environmental!, concentrations and exposure levels; atmospheric
Chemistry and dispersion modeling; effects on vegetation; and respiratory,
physiological, toxicological, clinical, and epidemiological aspects of human
exposure,
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CONTENTS
VOLUME I Chapter 1. Executive Summary and Cone!usipns ............... .........................
VOLUME II * -Chapter;2. Chapter 3, Chapter 4. Chapter 5.
Chapter 6.
Chapter 7, Chapter S.
Introduetl on
.,,,.....,,..,......___ _
Chemical and Physical Properties
i;
Sampling and Analytical Methods for Environmental Lead
Sources and Emissions .. ...,.... . .....,,...
Transport and Transformation .,v,.:..;V-..,.....,.
Environmental Concentrations and Potential Pathways to Human
Effects of Lead on Ecosystems
___ 1__________
ure
VOLUME III Chapter 9.
Chapter 10, Chapter 11,
Quantitative Evaluation of Lead and Biochemical Indices of Lead
Exposure in Physi ol ogical Media .......................... /................. ...... Metabolism of Lead _____________________________ _________________ Assessment of Lead Exposures and Absorption in Human Populations
Volume IV Chapter 12. Chapter 13.
Biological Effects of Lead Exposure
j____ ________12-1
Evaluation of Human Health Risk Associated with Exposure to Lead
and Its Compounds ....................... ..................... ........ ..................................... .
Page
1-1
2-1 3-1 4-1 5-16-1 7-1 8-1
9-1 10-1
11-1
13-1
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IV DUP040012160
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TABLE OF CONTENTS
9. QUANTITATIVE EVALUATION OF LEAD,AND BIOCHEMICAL INDICES OF LEAD EXPOSURE
in p h y s io l o g ic a l me d ia
..................... .......................................... .Vi.,
9.1 INTRODUCTION
9.2 DETERMINATIONS OF LEAD IN BIOLOGICAL MEDIA ................... ................ .
9.2.1 Sampling and Sample-Hand!ing Procedures for Lead
in Biological Media?',
9.2.1.1 Blood Sampling......................... ................. ..... .. .
9.2.1.2 Urine Sampling ................................... ......................
9.2.1.3 Hair Sampling
1.______
9.. 2.1.4 Mineralized Tissue........... ................. .......
9.2.1..5 Sample Handling in the Laboratory .........___...
9.2.2 Methods of Lead Analysis ........
,
9.2,2.11 Lead Analysis in Whole Blood........
9.2.212 Lead in Plasma ................. -........... .................... .............
9.2.2.`3 Lead Id Teeth___ _______________ ,___ ....____
9.2.2:4 Lead ijti Hal t ........................ f ._______________
9.2.2.5 Lead in Uripe...................... ........................................
9.2.2.6 Lead in Other Tissues ______________________
9.2.3 Quality Assurance Procedures in Lead Analysis .......................
9.3 DETERMINATION OF ERYTHROCYTE PORPHYRIN (FREE ERYTHROCYTE
PROTOPORPHYRIN, ZINC PROTOPORPHYRIN) .................
9.3.1 Methods of Erythrocyte Porphyrin Analysis
9.3.2 Inter!aboratory Testing of Accuracy and Precision in
EP Measurement___!'................. ........... _________...------
9.4 MEASUREMENT OF URINARY COPROPORPHYRIN........... ......................................
9.5 . MEASUREMENT OF DELTA-AMINOLEVULINIC ACID DEHYDRASE ACTIVITY ......
9.6 MEASUREMENT OF DELTA-AMINOLEVULINIC ACID IN URINE AND OTHER MEDIA
9.7 MEASUREMENT OF PYRIMIDINE-5'-NUCLEOTIDASE ACTIVITY ....................... .
9.8 MEASUREMENT OF PLASMA 1,25-DIHYDR0XYV1TAMIN 0 J... I......... ..........
9.9 SUMMARY .. . ... ............................................ ........................................... ....
9.9.1 Determinations o'f Lead in Biological Media ______
9.9.2 Determination of Erythrocyte Porphyrin (Free Erythrocyte
Protoporphyrin, Zinc Protoporphyrin^ .______ _________________
9.9.3 Measurement of Urinary Coproporphyrln
...... ....................................
9.9.4 Measurement of Delta-Aminolevulinic Acid Dehydrase Activity ......
9.9.5 Measurement of Delta-Aminolevulinic Acitj in Urine and Other Media
9.9.6 Measurement of Pyrimidine-5'-Nucleotidase Activity............____
9.9.7 Measurement of Plasma 1,25-Oihydrpxyvitsjnriri D................. ..
9.10 REFERENCES
10. METABOLISM OF LEAD ......................................................
10.1 INTRODUCTION........................... .......................... 10.2 LEAD ABSORPTION IN HUMANS AND ANIMALS .........
10,2.1 Respiratory Absorption of Lead _____ 10.2.1.1 Human Studies ____ ______
10.2.1.2 Animal Studies ______ ____ 10.2,2 Gastrointestinal Absorption of Lead
10.2.2.1 Hyman Studies ...............
TO.2.2.2 Animal Studies ................ . 10.2.3 Percutaneous Absorption of Lead .... 10.2.4 Transplacental Transfer of Lead ....
V
9-1 9-1 9--2
9-2 9-3 - 9-4 9-4. 9-5 : 9-5 9-6 ;o-7 9-11 9-12 9-13 9-14 9-15 9-16
9-20 9-20
9-23 9-25 9-25 9-27 9-29 9-30 9-31 9-32
19-35 19-36 9-36 ; 9-37 1,9-38 19-38 9-39
10-1 10-1 10-1
10-1
10-2
10-6
10-6 10-6 10-10 10-13 10-14
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DUP040012161
I i TABLE OF CONTENTS (continued).
10.3 DISTRIBUTION OF LEAD IN HUMANS AND ANIMALS ...................................... .
10.3.1 Lead in Blood .............___......---------------- ..........
10.3.2 Lead Levels in Tissues
................................
10.3.2.1 Soft Tissues ...........................___
10.3.2.2 Mineralizing Tissue .....................................
10.3.3 Chelstable Lead
^, .v..
10.3.4 Mathematical Descriptions of Physiological Lead Kinetics
10.3.5 Animal Studies .............................................. ..................... .
10.4 LEAD EXCRETION AND RETENTION IN HUMANS AND ANIMALS ..............
10.4.1 Human Studies ............... ......................................................
10.4.2 Animal Studies ............... .1
________......
10.5 INTERACTIONS OF LEAD WITH ESSENTIAL METALS AND OTHER FACTORS
10.5.1 Human Studi es................. ..... ................................. ..
1Q.;5.2 Animal Studies ....... t........ ................................ .
10.5.2.1 Interactions of Lead with Calcium .........___
10.5.2.2 Interactions of Lead with Iron ... .'4. .............
10.5.2.3 Lead Interactions with Phosphate......................
10.5-.2.4 Interactions of Lead with Vitamin 0 ...........
10.5.2.5 Interactions of Lead with Lipids ...........
10.5.2.6 Lead Interaction with Protein
.
10.5.2.T Interactions of Lead with Milk Components
10.5.2.8 Lead Interactions with Zirtc and Copper ........
10.6 INTERRELATIONSHIPS OF LEAD EXPOSURE, EXPOSURE INDICATORS,
' AND TISSUE LEAD BURDENS ...................... j........................... ..
10.6.1 Temporal Characteristics of Internal Indicators
of Lead Exposure........................................
.10.6.2 Biological Aspects of External Exposure/Internal
Indicator Relationships .....i..,.................. .........____
10.6.3 Internal [ndicator/Tissue Lead Relationships ........___
10.7 METABOLISM OF LEAD ALKYLS ..............?..........................____
10.7.1 Absorption of Lead Alkyls in Humans and Animals .........
1 10.7.1.1 Gastrointestinal. Absorption .....___..___ .....
10.7.1.2 Percutaneous Absorption of Lead Alkyls
10.17.2 Biotransferaation andTissue Distribution of Lead Alkyls
10.7.3 Excretion of lidad Alkyls___j............................... .............. .
10.8 SUMMARY
10.8.1 Lead Absorption in Humans and> Animals------ -------- ...
1 10.8.1.1 Respiratory Absorption of Lead .............
. * 10.8.1.2 Gastrointestinal Absorption of Lead .....
10.-8.1.3 Percutaneous Absorpiion of Lead...........
10.8.1.4 Transplacental Transfer of Lead .........
10.8.2 Distribution of Lead in Humans and Animals ..............
10.8.2.1 Lead in Blood ............................................ ..
10.8.2.2 Lead Levels in Tissues .............------
10.8.2.2.1 Soft Tissues ............___
10.8.2.2.2 Mineralizing Tissue .....__ _
10.8.2.2.3 Chelatable Lead .........___
10.8.2.2.4 Animal Studies ................. .
10.8.3 Lead Excretion and Retention in Humans and Animals
10,8.3,1 Human Studies ......_______ ____________
VI
Page
10-14 10-15 - 10-19 10-20 10-23 10-24 10-26 10-31 10-32 10-32 10-38 10-41 10-41 10-44 10-44 10-48 10-48 10-49 10-49 10-50 10-50 10-50
10-51
10-52
10-53 10-54 10-57 ,10-57 10-57 10-5.8 10-58 10-59 10-60 10-60 10-60 10-61 10-62 10-62 10-62 10-62 10-63 * 10-63 ID-64 10-65 10-65
10-66 ' 10-66
DUP040012162
TABLE OF CONTENTS (continued).
10.8.. 3.2 Animal Studies ..__ _____ ,. .1... 1.......,..,',..,...
10.8.4 interactions of dead with Essential Metals and: Other Factors
10.8.4.1 Hunan.^Studies ....................,...............
10.8.4.2 Animal Studies,,,,,..........____ .______
10.8.5 Interrelationships of Lead Exposure with Exposure indicators
and Tissue Lead,Burdens ......... 1^....J..............
10.8.5.1 Temporal Characteristics of Internai Indicators of
Lead Exposure . . . . . .......... ,.... ..............................
10.8.5.2 Biological Aspects of External Expdsufe/Internal
Indicator Relationships
i,,.
10.8.5.3 Internal Indicator/Tissue Lead Relationships
10.8.6 Metabolism of Lead Alkyls ......... ,j...............................
10.8.6.1 Absorption of Lead Alkyls in Humans and Animals ...
10.8.6.2 Biotransformation and Tissue Distribution of
Lead Alkyls i,,
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10.8.6.3 Excretion of Lead Alkyls .........,
............
1Q.9 REFERERCES.........
11. ASSESSMENT OF LEAD EXPOSURES AND ABSORPTION IN HUMAN POPULATIONS
11.1 INTRODUCTION ................... J............... ,.......... ... ................ ...............................
11.2 METHODOLOGICAL CONSIDERATIONS
...... ........................ ........... ...................
11.2.1 Analytical Problems
____ .......... ................ ...........
11.2.2 Statist!cal Approaches
............................................. ......
11.2.3 Confounding of Relevant Variables................. ...............
11.3 LEAD IN HUMAN POPULATIONS........... ............................................................... .
11.3.1 Introduction .....________...________________ _
i 11.3.2 ,Ancient and Remote Populations ...._____ ,___ ......................J,,
11.3.2.1 Ancient Popul ations ................. ................. ... .j..
11.3.2.2 Remote. Populations .................. ......... !.,
11.3.3 Levels of L-ead and Demographic Covariates in U.S. and Other
Populations1......,,,............................... d..........................
11.3.3.1 fhe NH^NES II Study .......................,J_________________
11.3.3.2 fibs Childhood Blood Lead Screening Programs___
11.3.3.3 levels^of Leadjand Demographic Covariates Worldwide .
11.3.4 Distributional ftapedtsof Population Blood lead levels-----
11.3.5 Time frendsii iih Blood Lead Levels Since 1970
........,. .............
11.3.5.1 fime Trends in jNHANES II Study Data ,.......,
i 11.3.5.2 Time TfeiidS in'theChildhood Lead Poisoning Screening
Progranjs
,i.________________________ ,..,.
11.3.5.3 Newark_______:.............................. ..................,,........ ..
11.3.5.4 Bostorr ....________
11.3,5.5' Lead Studies in the United Kingdom _______ _
11.3.5,6 Other Studies ...................................................... ..................
11.3.6 Gasoline Let as an Important Determinant of Trends in Blood
Lead LeveIs ............. ................... ................. .........................................
11.3.6.1 NHANES II Study Oata ................ ........................................
11.3.6.2 laotdpe Studies ....................... ..................................
11,3,6,2,1 Italy ................. ....... ..............
1$, 3.6.2.2 Uni ted States
--------- .....------
11.3.6.3 Studies of Childhood Blood Lead Poisoning Control
Programs _____ ______ _____ _______...............................
11.3.6.4 Frankfurt, West Germany
........... ... ................
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10-67 10-67 10-67 10-67
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10-68
10-69
10-69 10-69 10-70 10-70
10-71 10-71 .10-72
11-1 11-1 11-4 11-4 .11-5 11- 6 11-8 .11-8 11-8 11-10 11-13
11-14 11-14 11-20 11-24 .11-24 11-31 11-3,1
11-34 11-37 11-37 11-40 11-41
11-42 11-42 11-45 11-45 1.1-52
11-55 11-60
DUP040012163
TABLE OF CONTENTS (continued).
11.4 STUDIES RELATING EXTERNAL DOSE TO INTERNAL EXPOSURE ...................................
11.4.1 Air Studies ....................................................................................... .........
11.4.1.1 The Griffin et al. Study......................... ..... .j.,.,.
11.4.1.2 The Rabinowitz et al. Study..................................................
11.4.1.3 The Chamberlain et al. Study .................................. ...,
11.4.1.4 The Kehoe Study ................................... .....,:.,
11.4.1.5 The Azar et al. Study
11.4.1.6 Si1ver Val1ey/Kal1ogg, Idaho Study ..........,
11.4.1.7 Omaha, Nebraska Studies .............. .... ............,.................. ..
11.4 1.8 Roels et al. Studies
.
11.4.1.9 Other Studies Relating Blood Lead Levels to
Air Exposure ......... _____________________ ..........,.
11.4.1.10 Summary1 of Blood Lead versus Inhaled Air Lead Relations
11.4.2 Dietary Lead Exposures Including Water.
11.4:2.1 Lead Ingestion from Typical Diets
___ ....------
11.4.2.1.1 Ryu Study on Infants and. Toddlers -------- ....
11.4.2.1.2 Rabinowitz Infant Study L..........................
11.4.2.1.3 Rabi nowi tz Adul t Study--------------- ------- ----
11.4.2.1.4 H'uierflidnt Study
...... ......................
11.4.2.1.5 Sherlock Studies ......................,J................
11.4.2.jL.6 Central Directorate on Environmental
Pollution Study
11.4.2.1.7 Pocock Study ...
11.4.2.1.8 Thomas Study ...
11.4.2.1.9 Elwood Study .....
11.4.2.2 Lead Ingestion from Experimental Dietary Supplements
11.4.2.2.1 Kehoe Study
11.4:2.2.2 Stui k Study _________________ j.........
11.4.2.2.3 Cools Study
............
11.4.2.2.4 Schlegel Study ............. ...................... ,,,
11.4.2.2.5 Chamberlai n Study.___
11.4.2.3 Inadvertent Lead Ingestion From Lead Plumbing .....
11.4.2.3.1
Jfuidles
.
11.4.2.3.2
Sfufies _____________ ... 1.
...
11.4.2.3.3 Thomas Study _______________________ ____
11.4.2.3.4 Worth Study ......................................
11.4.2.4 Summary!of Dietary Lead Exposures, Including Water
11.4.3 Studies Relating lead in Soil and Dust to Blood Lead .------ -
11.4.3.1 Omaha, Nebraska Studies ........................................... .
11.4.3.2 Stark Study ..................................................... .
11.4.3.3 The Silver Valley/Kellogg Idaho Study ...
11.4.3.4 Blood Lead Levels oT Dutch City Children
11.4.3.5 Charney Study..........................
11.4.3.6 Charleston Studies ..................... .
11.4.3.7 Elarltrop Studies .... ......................
11.4.3.8 The British Columbia Studies ...
11.4.3.9 The Baltimore Charney Study: A Controlled Trial of
Household Oust Lead Reduction ,.
11.4.3.10 Gallacher Study ................... .
11.4.3.11 Other Studies of Soil and Dusts
11.4.3.12 Summary of Soil and Dust Lead ..
11.4.4 Paint Lead Exposures ......................... ...........
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11-63 11-66 11-67 11-71 2L1-74 11-76 11-78 11-8.1 11-89 11-91
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11-94 11-99 11-106 11-108 11-108 11-110 11-111
11-111
11-111
11-114 11-115 11-119 11-119 11-119 11-119 11-120
11-122
11-122
11-122
11-122
11-122 11-124 11-126 11-127 11-127 11-134 11-134 11-134 11-137 11-137 11-138 11-141 * 11-142 11-143
11-145 11-146 * 11-147 11-151 li-isi
DUP040012164
TABLE OF CONTENTS (continued).
11.5 SPECIFIC SOURCE STUDIES
------- v:
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11,5,1 Primary Smelter populations
.s,,1.
11.5.1.1 El Paso, Texas,.,...................... ..,,...,,,.,
11.5.1.2 CDC-EPA Study
,
11.5.1.3 Meta Valley, Yugoslavia ,^_______.....
11.5.1.4 Kosovo iproyinee, Yugos1avia
11.5.1.5 the Cavalleri Study
11.5.1.-6 Hartwell Study ......,,..,,,,.
11.5.2 Battery Plants
.,........____ ______,,.,,
11.5.3 Secondary Smelters ..,,.,, ,,>..........
11.5.4 Secondary Exposure of Children ,. .1,.,. !*.,......,
11.5.5 Mi seel 1aneous Studi es _________,,., JL
>,
11.5.5.1 Studies Using ipdirect Measures of,.4ir Exposure
11.5.5.1.1 Studies in the United States _______
11.5.5.1.2 British Studies ........ ...........................
11.5.5.2 Miscellaneous Sources of Lead........:____ _____
11.6 SUMMARY AND CONCLUSIONS .......................... ..............................................
11.7 REFERENCES ........................ ................................................. .......................
APPENDIX 11A.............................>.____________.................................................. ..
appen d ix i i b ............................ ............................................................................ ..
APPENDIX 11C......... .................... *........ ..............................4,."..................
Page
11-161 11-161 11-161 xli-163 11-163 11-165 11-165 11-166 llr 166 11-166 11-170 11-177 11-177 11-177 .11-179 11-181 11-183 11-193 11A-1 118-1 11C-1
ix DUP040012165
LIST OF FIGURES
Figure
10-1 Effect of particle size on lead deposition rate in the lung _____________
10-2 The curvilinear relationship of serum lead to blood lead .1.,.
10-3 Schematic model of lead metabolism in infant baboons, with compartmenta]
transfer coefficients .....____ _
,%>'............ .... .
10-4 A compartmental model for lead biokinetics with multiple pools for blood
lead___ ________________ ___________..................................................... .......
10-5 Fitting of nonlinear blood lead model to data of D.eSiiva {1981). Broken
line incorporates an intercept term of 0.25; solid line does not
incorporate intercept term ..................................I..5_________
10-6 Renal clearance (ratio of urinary lead to blood lead) from (A) King et al.
1979; (B) Williams et al., 1969; (C) Gross, 1981; (D) DeVoto and.
Spinazzola, 1973; (E) Azar et al., 1975; (G) Chamberlain et al.., 1978 ....
11-1 Pathways of lead from the environment to and withijn man ...,. .............
11-2 Estimated lead concentrations in bones (pg/g) from 5500 years before
present (BP) to the present time ....____ I,........
11-3 Geometric mean blood lead levels by race and age for younger children in
the NHANES II study. EPA calculations front data furnished by the National
Center for Health Statistics ......... ...............................................................v___
11-4 Geometric mean blood lead values'by race and age for younger children in
the New York City screening program (1970-1976) ...................
11-5 Unweighted geometric mean blood lead level for malle and female nonsmoking
teachers (pg/dl) for several countries ................... 1...... ................... 1.............
11-6 . Histograms of blood lead levels with fitted lognormal curves for the
NHANES II study. All subgroups are white non-SMSA residents with family
incomps over $6000/year........... .................... ....................................
11-7 ' Average blood lead levels of U.S. population aged 6 months-74 years,
United States February 1976-February 1980, based on dates of examination
of NHANES II examinees with blood lead determinations ...___ ....................
11-8 Reduction in medn blood lead levels, according to race, sex,, and age.
Data on sex and .age are for whites ............... ................................................
11-9 Time-dependence ,of blood lead levels for blacks, aged 25 to .36 months, in
New York City and Chicago .............................. ____________ ___...................
11-10 Modeled umbilical cord b.lood lead levels by date qf sample collection for
infants in Boston ........... ............................________..j.,____ __________
11-11 Parallel'decreases in blood lead values observed in the NHANES II study
and amounts of lead used in gasoline during 1976-1980 ....._______________
11-12 Change in 20sPb/207Pb rati os in petrol, airborne pjar.ti.culate and blood
froim 1974 to 1984 ................................ ....................... .................................. ...........
11-13 Estimated direct! and indirect contributions of leail in gasoline to blood
lead in Italian inen based on EPA analysis of I.LE delta (Table 11-16) _____
-11-14' Geometric mean blood 'ead levels of New York City children (aged 25-36
months) by ethnic group, and ambient air lead concentration versus
quarterly sampling period, 1970-1976
........................... ................. .
11-15 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 versus quarterly sampling
period, 1970-1976 ........................................ ............................... .........................
11-16 Geometric mean blood levels for blacks and Hispanics in the 25- to 36-month
age group and rooftop quarterly averages for ambient city-wide lead
level s ................,..... ...... .......................................------------------------------------- --,.
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10-4 10-18 . 10-28 10-29
10-30
1.0-35 11-3
11-12
11-19 11-23 11-25
11-28
11-32 11-33 13.-35 lk-38 11-43
i
'ljl-47 li-51
11-58
11-59
11-61
DUP040012166
LIST OF FIGURES (continued).
Figure
2.3* 17
11-18
11-19
11-20 11-21 11-22 11-23 11-24 11-25 11-25 11-27
11-28
11-29 11-3:0 11-31 11-32 11-33
11B-1
llC-1 11C-2 llC-3 IIC-4 11C-5
Time dependence of blood Feed and gas lead for blacks, aged 25 to 36
months, in New York
-------.
Data plots for individual subjects as a function of time for Kehoe
subjects, as presented by Gross (1979) .................................. ................... ......
Blood lead versus air lead relationships derived from Kehoe inhalation
studies: Linear relationship holds for low exposures, quadratic for high
exposures. 95 percent confidence bands are also shown _______________
Monthly ambient air 'lead concentrations in Kellogg, Idaho, 197:1
through 1975
..................................................................................
Fitted equations to the Kellogg Idaho/$i1ver Valley,- adjusted blood lead
data
........
Blood lead! concentrations versus weekly lead intake for bottle-fed
infants .. i............................................... ......I,,.,.,.,,,.......------------------ ......
Mean blood! lead for men grouped by first draw water concentration _.....
Average blood lead levels. Phase I ......... ................................................................
Average blood lead levels. Phase II ............... .A........................... ..................... .
Lead in blood (mean values and range) in volunteers. In the lower curve
the average daily lead dose of the exposed group is shown ...........____ _
Cube root regression of bloqd lead on first flush water lead. This shows
mean S.Os. of blood lead for pregnant women grouped in 7 intervals of
first flush water lead .................................... ..... ___________,
Relation of blood lead (adult female) to first flush water lead in combined
estates. (Numbers are coincidental points; 9 = 9 or more.) Curve a,-
present data; curve b, data of Moore et al, (1.979) ____ ________,------- -
Cumulative distribution of lead levels i-n dwelling units ...........................
Correlations of children's blood lead levels;with fractions of surfaces
within a dwelling having lead concentrations?82 mg/cm2 _____............
Arithmetic mean air lead levels by traffic vplume, Dallas, 197.6' .....
Blood lead concentration and traffic density'by sex and age, Dallas,
1976 .......................................................................f ..........
Geometric mean blood 1ead levels by pace endjage for younger children
in the NHANES II study, and the KellQgg/Silvpr Valley and New York
Childhood Screening Studies ..........................................................____________ _
Residual sum of squares for nonlinear regression models for Azar data
(N=149) ............................................................................ __________________
Individual values of blood Pb-206/207 ratio for subjects follow-up in Turin
(12 subjects) ................. .................... ...................... ......................................
individual]values of blood Pb-206/207 ratio for subjects follow-up in
Costagneto! (4 subjects) ...............,....___ .
.................
Individual.values of blood.Pb-206/207 ratio for subjects follow-up in
Duento and Fiano (6 subjects) ...................................... ............... ............................
individual values of blood Pb-206/207 ratio for subjects follow-up in Nole
and Santeno (9 subjects) ____ ____...................................................
Individual values of blood Pb-206/207 ratio for subjects follow-up in Viu
(4 subjects) ............................................ ......................................... ...................... ...
Essa
11-62 11-77
11-79 11-33 11-88 11-116 11-118 11-121 11-121 11-123
11-125
V i-. 1
b
11-128 11-155
11-157 11-178
11-180
11-184 11B-2 IIC* 2 iie-3 11C-3 11C "4 llC-4
xi DUP040012167
LIST OF TABLES
Table
10-1 10-2 10-3 10-4 .11-1 11-2
11-3
11-4
11-5
11-6
11-7
11-8
11-9
11-10 11-1.1 11-12
1.1-13
11-14 11-15 11-16 11-17 11-18 11-19 11-20
11-21 11-22
Deposition of lead in the human respiratory tract .........................
Distribution of lead in brain regions of humans and animals ..... ............
Daily lead excretion and retention data for adults and infants ..............
Effect of nutritional factors on lead uptake in animals
Summary of Representative Studies of Past Exposures tp Lead ................... .
NHANES II blood, lead levels of persons 6 months-74 years, with weighted
arithmetic mean, standard error of the mean, weighted geometric mean,
median, and percent distribution, by race 'and age, United States,
1976-80 ........................................... ................... .> ...,......;
NHANES II blood lead levels of males 6 manths-74 years, with weighted ;
arithmetic mean, standard error of the mean, weighted geometric mean,
median, and percent distribution, by face and age, United States,
i
1976-80 ............................ ......................... ....... ............ :...................... J............
NHANES II blood lead levels of females 6 months-74 years, with weighted
arithmetic mean, standard error of the mean, weighted geometric mean, ;
median, and percent distribution, 'by race and age, United States,
1976-80 ........................................................................................4..............................
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 ....................................................................................
Annual geometric mean blood lead levels from the New York blood lead 1
screening studies of Biliick et al. (1979). Annual geometric means 1
ard calculated from quarterly geometric means estimated by the method of
Hasselblad et al. (1980) ............................................................ .... ....... .:........
Summary of unweighted blood lead levels in whites not living in an
SMSA, with family income greater than $6,000 ............. .............. ..............................
Summary of fits to NHANES II blood lead levels of whites not
living in an SMSA, with income greater than $6,000,. for five
different two-parameter distributions................................................ .
Estimated mean square errors resulting from analysis of variance on
various subpopulations of the NHANES II data using unweighted data .......___
Characteristics of childhood lead poisoning screening data '..................L............
'Distribution of blood lead levels for: 13- to 48-tacnth-O'ld blacks
j
byjseason and year for New York screening data ........ ...........................- T...........
Comparison of median blood lead levels (pg/dl) in several countries from
studies of Goldwater and Hoover (19671) and Friberg and Vahfcer (1983)
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, arid afce-----------i........................................ I.........
Estimated-contribution of leaded gasoline to blood lead by inhalation and
non-ir.halation pathways ............... ______________ ;.........,.
Assumed air lead concentrations for model................................................... .......
Regression model for blood lead attributable to gasoline ....................... ..............
Rate of change of 206Pb/204Pb and 206Pb/207Pb in air and blood, and
percentage cf airborne lead in blood of subjects 1, 3, 5, 6 and 9 ......------
Calculated blood lead uptake from air lead using Manton isotope study ........
Respired and other inputs of airborne Pb to blood for some Dallas residents
in 1975 .............................................................................. ....................... .......... -.............
Mean air lead concentrations during the various blood sampling periods at
the measurement sites described in the text (pg/in) ................................... ....
Griffin et al. (1975) experiment inhalation slope estimates
Griffin et al. (1975) experiment mean residence time in blood ..........--------
xii
Pag,e
10-3
10-21 10-34 10-45 11-11
>
11-16
11-17
11-18
11-21
11-22
11-26
11-27
11-30 11-36
. 11-36
' 11-42
11-44
11-49 11-50 11-51
11-54 11-54
11-55
11-63 11-70 11-70
DUP040012168
!
1
5 . -
LIST OF TABLES (continued).
Table
11-23 Air lead concentrations (pg/ma) for two subjects in the Rabinowitz studies .
11-24 Estimates of 1 nhalation slops, p, for Rabinowi tz studi e.s
f.
11-25 Linear slope for blood lead versus air lead at low air lead exposures in
Kehoe1 s subjects .................................................................... .....
11-26 Geometric mean air and bipod lead levels (pg/100 g) for five city-
occupation groups (data calculated by ERA) ..... i^.
.11-27 Geometric mean blood lead levels by area compared with estimated air lead
levels for 1- to 9-year-old. children living near Idaho-smelter ..............
11-28 Geometric mean blood lead, levels by age and area for subjects living near
the Idaho smelter............... _____________ ______________ s....................
11-29 Age-specific regression coefficients for the analysis of.log (blood lead)
1 evel sin the Idaho smel ter study ........... ............................._____
11-30 Estimated coefficients and standard errors for the Idaho smelter study ____ _
11-31 Air, dustfall and blood lead concentrations in Omaha, NE, study, 1970-1977 ..
11-32 Mean airborne and blood lead levels recorded during five distinct surveys
(1974 to 2978) for study populations of 11-year old children living less
than 1 km or 2.5 km from a lead smelter, or living in a rural or urban area
11-33 Geometric mean air lead and adjusted blood lead levels for II communities
"in studv of Tepper and Levin (1975) as reported by Kasselblad and
Nelson (1975) ....................I............ ......................... ...............................................
11-34 Mean air and blood lead valuejs for five zones in Tokyo study
,
11-35 Blood lead-air lead slopes for several population studies as calculated
by Snee ................................................... . . .............\ . ................ ..............,....
11-36 Characteristics of studies on the relationship between air lead and blood
1 ead in chi 1 dren ________..........___..................____ _
II-37 A selection of recent analyses on occupational 8-hour exposures to high
air 1 ead levels ...................................................... .
J.
III-38 f
Cross-sectional observational study with measured individual ai'ir lead exposure ___ _____ ............................................ _________________________...........
Ur39 Cross-sectional observational studies on children with estimated
ai r exposures........................................ .................................... ...........................
Ilf40 eLxopnogsiuturedsina..l .e..x.p.e.r.im..e.n.t.a.l 1s.t.u.1d.i.e.s..w..i.t.h..m..e.a.s.u..re.d...in..d.i.v.i.d..u.a.lj..a..i.r..l.e.a.d... ........
I-lj-41 Household consumption of canned foods, pounds per week
.L..................
Ilf 42 Blood .'lead levels ard lead intake values for infants in the study
of Ryu et al................. . .L.1................... ...............................................
lljt-43
Influence of level of lead in water on blood lead level in blood and p 1 acenta ____ ____ __L........................... ..................._____I_________ ______...
Ilf44 Distributions of observed blodd"lead values in Ayr .......____ ..... ......................
II-45 81ood lead and kettle water lead concentrations for adult women1 living
in Ayr ..................... J.................................................. .........................
11-46 Relationship of blood lead and water lead in 910 men aged 40-59 from
24 Briti sh towns ....................................... ............................................ .......................
11-47 Dose-response ^analysis for blood lead levels in .the Kehoe study as
analyzed by Gross (1981) -----........... ......................... .......................... .............
11-48 Blood lead levels of 771 persons in relation to lead content of drinking
water, Boston, MA.................. .....................................;.............. .................. ..............
11-49 Studies relating blood lead levels (pg/dl) to dietary intakes (pg/day) ...___
Page
11-72 11-73
.11-78
: fs.
<
11-80 1.
11-84 s
11-84
11-85 11-87
11-90 ?
11-93
11-96 11-96
11-98
11-100
11-101
11-102
11-103
11-104 11-109
11-110 -
11-112 11-113 11-113 * :
11-117
11-120
11-129 11-130
xi i i
DUP040012169
I[ *
.1
*
`LIST OF TABLES (continued),
Table
,s
Page
11-50 Studies involving blood lead levels (pg/dl) and experimental dietary
intakes ............................................................................................... . . . .l,____
1.1-131
11-51 Studies relating blood lead levels (pg/dl) to first-flush water leadf(pg/l) --
11-132
11-52 Studies relating blood lead levels (pg/dl) to running water lead (pg/i) ..
11-133
. _
11-53 Coefficients andstandard errors for Omaha study model ..
, T1-T35
11-54 Multiple regression models for blood lead of children in New Haven, ,
Connecticut, September 1974 - February 1977 ............................ 11-136
11-55 Air Lead Levels in the Rotterdam Area .................................. 11-139
11-56 Blood lead levels in pg/100 ml for children who participated in blood
survey and environmental siirvey........................ 11-139
11-57 School variables(arithmetic means) for measured lead concentrations ..,.......... ,
1.1-139
11-58 Results of lsad measurements reported by Brunekreef et al, (1913) ....................
11-140
11-59 Coefficients andstandard errors from model of Charleston study ...... . ............ .,
11-142
11-60 Mean blood and soil lead concentrations in English study i...................... ,
11-143
11-61 Lead concentration of surface soil and children's blood by residential
area of trai 1, Briti sh Col umbia .:................ ................. ..................
11-145
11-62 Analysis of relationship between soil lead and blood lead Tit children ........
11-150
11-63 Estimates of the contribution of soil lead to blood lead ..........,.................
11-152
11-64. Estimates, of the contribution of housedust to blood lead in children.,...........
11-153
11-65 Results ojf screening and housing inspection in childhood lead poisoning
control project by fiscal year .................................................... .
.1-11-161
11-66 Mean blood lead levels in Selected Yugoslavian populations, by estimated
weekly time-weighted air lead exposure ___________________________ ..
11-164
11-67 Levels of lead recorded in:, Hartwell et al. (1983) study ......................
11-167
11-68 Spearman correlations of lead in air, water, dust, soil, and paint with
lead levels in'blood: by site and age groups, 1978-1979
............. ................
11-167
; 11-69 Environmental parameters and methods: Arnhem lead study, 1978 ......................
11-169
s 11-70 Geometric mean blood lead levels for children based on reported
'] occupation of father, history of pica, and distance of residence
i from smelter (micrograms per deciliter) ........................ ............................................. . 11-171
i 11-71 Sources of 1 ead ..........................................
.............
11-182
11-72 Summary of blood lead pooled geometric standard deviations and estimated
j
analyti c errors ................. 1................:..................................... ..........................,
11-185
i 11-73 Estimated contribution of leaded gasoline to blood-lead by inhalation
; - and non-inhalation pathways ........... ....... ......... I. ' 11-187
;-11-74 Summary of blood inhalation slopes, (p)pg/dl per pg/pi3
11-188
ii
xiy
DUP040012170
AAS Ach ACTH ADCC ADP/O ratio
AIDS AIHA All ALA ALA-D ALA-S ALA-U APDC APHA ASTM ASV ATP B-cells Be
BAL BAP BSA
BUN BU C.V. CaBP CaEDTA CaNa-EOTA CBD c Cd COC CEO CEH CFR CMP CNS CO COHb CPE, CR-U
cBah
O.F. DA 6-ALA DCMU
DPP ONA DTH EEC
EE6 EMC
!
.t
LIST OF ABBREVIATIONS
Atomic absorption spectrometry
Acetylcholine
Adrenocbrticotrophic hormone
Anti body-dependent ceil-mediated cytotoxicity
Adenosine diphosphate/oxygen ratio
Acquired immune deficiency syndrome
American Industrial Hygiene Association
Angiotehsin II
Aminolevulinic acid
i
Aminolevulinic acid dehydrase ;
Aminolevulinic acid synthetase :
Aminolevulinic acid in urine j
Ammonium pyrrolidine-dithiaearbamate
American Public Health Association
Amercian Society for Testing and Materials
Anodic stripping voltammetry
4
Adenosine triphosphate
Bone marrow-derived lymphocytes;
Barium ,
Britishanti-Lewisite (AKA dimefcaprol)
benzo(a)pyre;ne
j
Bovine serum albumin
!
Blood serum urea nitrogen
;
Body weight
Coefficient of variation
. Calcium binding protein
j Calcium ethylenediaminetetraacetate
; Calcium sodium ethylenediaminetetraacetate
1 Central business district
' Cadmium
i Centers for Disease Control
j
; Cation exchange capacity
1
j Center for Environmental Health]-
] reference.method
]
Cytidine-monophosphate
; Central.nervous system
| Carbon monoxide
|
! Carboxyhemoglobin
'
j Competitive protein bidding '
` Urinary coproporphyria
plasma clearance of p-aminohippuric acid
Copper
Degrees of freedom
Dopamine
delta-aminolevulinic acid
[3-(3,4-dichlorophenyl)-1,1-dimethyl urea
Differential pulse polarography
Deoxyribonucleic acid
Delayed-type hypersensitivity
European Economic Community
Electroencephalogram
Encephalomyocarditi s
xv
EP EPA FA FDA Fe FEP FY G.M. G-6-PD
GABA GALT-
GC GFR GI HA HANES I Hb
Hg hi-vol HPLC i.m.
i.p. i.v. IAA IARC ICD ICP IDMS IF ILE IRPC K LDH-X
1LCnPcnv Ljf5r0u LIPO
Ira LPS LRT
mRNA
ME MEPP MES MeV MLC
MMD MMAD Mn
MNO MSV MTO
LIST OF ABBREVIATIONS (continued).
.Erythrocyte protoporphyrin
LI.S. Environmental Protection Agency
Fulvie acid
Food and Drug Administration
Iron
.Free erythrocyte protoporphyrin
Fiscal year
Grand mean
.
Glucose-6-phosphate dehydrogenase
Gamma-aminobutyric acid j -
Gut-associated lymphoid tissue.
Gas chromatography
Glomerular filtration rate j
.Gastrointestinal
j
.Humic acid
I
-;jHealth Assessment and Nutrition Evaluation Survey
Hemoglobin
Mercury
High-volume air sampler
High-performance liquid chromatography
Intramuscular (method of injection)
Intraperitoneally (method of injection)
Intravenously (method of injection)
Indol-3-ylacetic acid
International Agency for Research on Cancer
International classification .of diseases
Inductively coupled plasma emission spectroscopy
Isotope dilution mass spectrometry
] Interferon
Isotopic Lead Experiment (Italy)
-International Radiological Protection Commission
Potassium
.
Lactate dehydrogenase isoenzyme x
{ Lethyl concentration (50' percent)
3 Lethal dose (50 percent) |
; Luteinizing hormone
;
Laboratory Improvement Program Office
j Natural logarithm'
- i Lipopolysaccharide
>
i Long range transport
\
: Messenger ribonucleic acid :
Mercaptoethanol
Miniature end-plate potential
Maximal electroshock seizure
Mega-electron volts.
Mixed lymphocyte culture
Mass median diameter
Mass median aerodynamic diameter
Manganese
Motor neuron disease
Moloney sarcoma virus
Maximum tolerated dose
xv i
DUP04QQ12172
n N/A NA . NAAQS NAD
NA0& NAMS NAS NASN
NBS
NE JNFAN NFR-.82 NHANES II Ni NTA OSHA P
P PAH
Pb PBA Pb(Ac)? PbB * PbBrCI PRg PFC pH PHA PHZ PIXE PMN PNB PNS P,Q.' ppm PRA" PRS PWMPy.SN RBC RBF RCR redox RES RL.V
RNA S-HT SA-7
$..
son S.O.
: ] `1
! i i l .
LIST OF ABBREVIATIONS (continued).
Number of subjects or observations
Not Available
'
Not Applicable
National ambient air .qualify staMards
Nicotinamide Adenine Oinucleotitie ' .
National Aerometrie Data Bank
National Air Monitoring Station
National Academy of Science?
National Air Surveillance Rdtwprk . .
*
National Bureau of Standards ...
Norepinephrine
National Filter Analysis Network
Nutrition Foundation Report oflSISl
`
National Health Assessment and Nutritional Evaluation SuKvey II
Nickel
!
Ni tri1otriacetonitri1e
Occupational Safety and Health Admini
Phosphorus
Significance symbol
Para-aminohippuri.c acid
Lead
Air lead
Lead acetate
..concentration of lead in blood
Lead (II) bromochloride
Porphobilinogen
Plaque-forming cells )
Measure of acidity ' I
Phytohemagglutinin
Polyacryl ami de-hydrousizi rc.onia
Proton-induced ray emissions
Polymorphonuclear leukocytes
Post-natal day
!
Peripheral nervous system .
Per os (orally)
-
Parcs per million
Plasma renin activity r
Plasma renin substrate]
Pokeweed mitogen .
j
Pyri;mide-5'-nucleotidase
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 inj'ection)
Standard cubic meter
Standard deviation
xyii
4
DUP040012173
SDS S.E.M. SES SCOT sig' .SLAMS . SMR Sr SRBC SRMs STEL SW voltage T-cells t-tests TBL 1 TEA. TEL' TIBC TML TMLC TSH, TSP i U.KJ UMP USPHS VA V, v |r
WHO KEF r Zn ZPP 1
i*
ii i d! i .ft ;
g g/gai g/ha-mo km/hr 1/fflin mg/km pg/m3 tnm pm pmol ng/cm2 nm
LIST OF ABBREVIATIONS (continued).
Sodium dodecyl sulfate
Standard error of the mean Socioeconomic status
Serum glutamic oxaloacetic transaminase
Surface immunoglobulin: State and local air monitoring stations
Standardized mortality ratio 1 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
'f
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
i `
MEASUREMENT ABBREVIATIONS
i
1 deciliter i
feet gram
,,'
-'
gram/gal 1on gram/hectare-month kilometer/hour
liter/mi n.ute milligram/ki1ometer
microgram/cybic meter millimeter
micrometer
micromole nanograms/square centimeter
nanometer
XV T 1 1
DUP040012174
! {
i
LIST OF ABBREVIATIONS (continued),
nM sec
nanomole second ...
it tons
!
II
i i' j t
XIX
DUP040012175
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 y'' bile into the 01 tract
Brownian diffusi on - 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 goodnfess-of-fit tests - made to determine how well the observed i 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
j. geochronometry -{determination of the age of geological materials
hematocrit - the percentage of the volume of a blood sample occupied by cells
intraperitoneal - within the body cavity
likelihood function - a relative measure of the fit of observed data to a
specified model. In some special cases it is equivalent
to the sum of squares function used in least squares
; analysis.
?
mass median aerodynamic diameter (MMAD)
the aerodynamic diameter (in pm) at which half the mass of particles in ah 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
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.
xx DUP040012176
AUTHORS, CONTRIBUTORS, AND REVIEWERS
Chapter 9: Quantitative Evaluation of Lead ;and Biochemical Indices of Lead Exposure in 'Physiological Media L
Principal Author
'
Or. Paul Mushak .
*;
Department of Pathology
School of Medicine
University of North Carolina'
Chapel Wiil, HC .27514
.. .. ;
-
The .following persons reviewed, this chapter at EpA's request.. The evaluations
and conclusions contained herein, however., are ndt necessarily those of the
reviewers.................... ................. -
..............j.......................
Dr. Carol Angle Department of Pediatrics University of Nebraska
College of Medicine Omaha, N 6810.5
Dr. A. Cl Chamberlain Environmental and Medical : Sciences Division
Atomic Energy Research ; Establishment
riarwel1 0X11 England:
Or. Lee Annest , Division of Health Examin. Statistics National Center for Health Statistics
.3700 East-West Highway Hyattsvi 1 1 e, MD .20782
j
Dr. Neil Chernoff
Division of Developmental Biology
MD-67
-
U.S. Environmental Protection
Agency
Research Triangle Park, NC 27711
Or. Donald Barltrop
Department of Child Health
Westminister Children's Hospital
London SW1P 2NS|
T
England
Dr. Julian Chisolm Baltimore City Hospital 4,940 Eastern Avenue Baltimore, MD 21224
i
I
; ?
;
Dr, Irv Billickj
Gas Research Institute 8600 West Bryn Mawr Avenue ..Chicago, IL 60631 -r 1 .
.
Mr. Jerry Cole
International Lead-Zinc Research
' Organization
.
292 Madison Avenue
New York, NY .10017
j ,
Dr. Joe Boone Clinical Chemistry and
Toxicology Section Centers for Disease Control Atlanta, GA 30.333
Dr. Max Costa Department of Pharmacology University of Texas Medical
School
Houston, TX 77025
Dr. Robert Bornschetn University of Cincinnati
Kettering Laboratory
Cincinnati, OH 45267
Dr. Anita Curran Commissioner of Health
Westchester County White Plains, NY 10607
xxi
DUP040012177
.}
Dr. Jack Dean Immunobiology Program and
Immunotoxicology/CeH Biology program CUT P.Q. Box 12137 Research Triangle Park, NC 277.09
Dr. H. T. Delves
Chemical Pathology and Human Metabolism
Southampton General Hospital Southampton S09 4XY England
Dr. Fred deSerres
Assoc. Director for Genetics
NIERS
-'
P.O. Box 12233
Research Triangle Park, NC 27709
Dr. Robert Dixon Laboratory of Reproductive and
Bevelbpmental Toxicology NfERS
P.O. Box 12233 Research Triangle Park, NG 27709
Dr. Claire Ernhart Department of Psychiatry
Cleveland Metropolitan General Hospital Cleveland, OH 44109
Dr. Sergio Fachetti Section Head - Isotope Analysis Chemistry Division joint Research Center . 121020 Ispra Varese, Italy
Dr. Virgjil Perm Department of Anatomy and Cytology Dartmouth Medical School Hanover, NH 03755
Dr. Alf Fischbein Environmental Sciences Laboratory Mt. Sinai School of Medicine New York, NY 10.029
Dr. Jack Fowle Reproductive Effects Assessment Group U.S, Environmental Protection Agency RD-689 Washington, DC 20460
xxii
Dr. .Bruce Fowler Laboratory .of Pharmacology NJ.EHS
f.6. Box 12233
Research Triangle Park, NC
27709
Dr. Warren Galke
Department of- .Biostatlstics and Epidemiology ;.
Schoo1 of'AlT i e|f Heal th East Carolina Ijntversity Gf.eeiiv iT i ei., jNC
Mr, Eric Gdldstein
Natural Resources Defense Council, Inc. :
122 E. 42nd Street New York, f:NY 1016.8/
Or, Harvey Gonick
10:33 Gayley Avenue
Suite .11.6
i
Los Angeles, A 90024
Dr. Robert Goyer Deputy Director NIEHS P.O. Box 12233 Research triangle Park,NC
27709
D.r, Stanley Gross
Hazard.Eva1uation Division
Toxicology Branch
.
U.S. Environmental Protection
Agency
Washington, DC- 2046.0
Dr, Paul Hammond University e.f Cincinnati Kettering Laboratory Cincinnati, OH 45267_
i !
Dr, Ronald D. Hood Department of Biology The University of Alabama University, AL 3548.6
Or. V. Houk
Centers for Disease Control 160.0 Clifton Road, NE Atlanta, GA 30333
DUP040Q12178
Dr. Loren D. Kol1er 'School of Veterinary Medicine University of Idaho Moscow, ID 83843
Dr. Kri.st.al Ko.stial
\
Institute for Medical .Research
and Occupational Health
Yu-4100 Zagreb
Yugoslavia
-
Dr... Lawrence Rapper Department of Biostatistics
UNCj School of Public Health . Chapel Hill, NC 27514
j`
'
Dr.| Phillip Landri.gari
Division of Surveillance, Hazard Evaluation and Field Studies
Taft Laboratories - MIQSH Cincinnati, OH 45226 .
J*.
Or, David Lawrence Microbiology and Immunology Dept. Albany Medical College of Union
University Albany, NY 12208
Dr. Jane Lin-Fu
'
Office of Maternal and Child Health ;
Department of Health and Human Services
Rockville, MD 20857
.
OrJ Don Lynam Ai r] Conservation Ethyl Corporation
451] Florida Boulevard Batjm Rouge., LA 7.0.801
Or.!Kathryn Mahaffey
Division pf Nutrition
j
Food and Drug Administration
1090 Tusculum Avenue
Cincinnati, OH 45226
Dr. Ed McCabe Department of Pediatrics University of Wisconsin Madison, Wl 53706
Dr. Chuck Nauman Exposure Assessment Group. ' U.5, Environmental .Protectiqn
Agency Washington, DC 20460
Dr, Herbert 1., Need) eman dejpartment ,of Psychiatry: , Children1s Hospital of Pittsburgh Pittsburgh, PA. .15213
Dr. H, Mitchel1 Perry
V.A, Medical Center $t. Louis, MO 63131
Or. Jack Pierrard
1
:E. I. duPdnt de Nemours and
Company, Inc..
Petroleum Laboratory
Wilmington, DE 19898
Or. Sergio Piomelli 1 Columbia University Medical School Division of Pediatric Hematology
and Oncology New York, NY 10032
Dr. Magnus Piscator
Department of Environmental Hygiene
The KaroTjnska Institute 104 01
Stockholm
Sweden
< ..
Or. Robert Putnam
1
International Lead-Zinc;
Research Organization' -
232 Madison Avenue
New York, NY 10017 j
' Dr. Michael Rabinowitz [
Children's Hospital Medical Center
.300 Longwood Avenue Boston, MA 02115
#
i
J
xxiii
DUP040012179
Dr, Harry RoeIs Unite de Tbxicologie
Industrie!le et Medicale Universite de Louvain Brussels, Belgium
Dr. John Rosen
Division of Pediatric Metabolism
Albert Einstein College of Medicine Montefiore Hospital and Medical Center 111 East 210 Street Bronx, NV 10467
Dr. Michael Rutter
Department of Psychology Institute of Psychiatry DeCrespigny Park London SE5 8AL England
Dr. Stephen R. Schroeder Division for Disorders ,
of Development and Learning Biological Sciences Research Center Universitv of North Carolina Chapel Hill, NC 27514
Dr, Anna-Maria Seppalainen
Institutes of Occupational Health.
Tyoterv.eyslaitos
Haartmaniokaty 1
.00290 Helsinki 29
_,
Finland
i
i
1
Or, Ellen Silbergeld Environmental Defense Fund
1525 18th Street , ; MW Washington, DC 20086
Dr Ron Snee E. I. duPont Nemoursand.
Company, Ihe,:., Engineering .Depaftjnent L3167 Wiljnington, 0.E . 19f9S:
Or, Gary. Ter Hear
Toxicology and .industrial .
Hygiene i:
.:
Ethyl Corporation
45.1 Florida Boii!eyard
Baton Rouge, LA 70801
Dr. Ian von Lindern Department of Chemical Engineering
University of Idaho Moscow, Idaho -.83843
Dr, Richard P, Wedeen V.A, Medical Center T.remont Avenue
East Orange, M0 07019
xxiv
I
Chapter 10: Metabolism of Lead
Principal Author
Dr. Paul. Mushak
L
Department of Pathology
School of Medicine
University of North Carol!ha
Chapel Hill, NC 27514 |
.
Contributing Author
:
*
Dr. Alan Marcus Department of Mathematics' * Washington State University Pullman., WA 99164-2930:
The following persons reviewed this chapter at EPA's request. The evaluations
and conclusions contained herein, however. are not necessarily those of the reviewers.
Dr. Carol Angle
Department of Pediatrics
University of Nebraska j
College of Medicine !
Omaha., NE 68105'
,.-!j .
Dr. Robert Bornschein
University of Cincinnati Kettering Laboratory Cincinnati, OH 4.5267
Dr. Lee Annest Division of Health Examin. Statistics
National Center for Health Statistics 3700 East-West Highway Hyattsvine, MO 20782 ~
>,
Dr. Donald Baritrop
j-
Department of Child Health
Westminister .Children's Hospital
London SW1F 2NS
` , ,.;
England
j
f
Dr. jrv Billick
Gas Research Institute
8600 West Bryn Mawr Avenue
Chicago, IL 60631
Or. A. C. Chamberlain Environmental and Medical
Sciences Division Atomic Energy Research
Establishment Harwell 0X11 England i
Dr. Neil Chernoff Division of Developmental Biology MD-67 U.S, Environmental Protection
Agency j Research Tjriangle. Park, NC 27711,
Dr,-Julian Chisolm Baltimore City Hospital 4940 Eastern Avenue Baltimore, MO 21224
Dr. Joe Boone Clinical Chemistry and
Toxicology Section
Centers for Disease Control Atlanta, GA 3033.3
Mr. Jerry Cole International Lead-Zinc Research
Organization
292 Madison Avenue New York, NY .10017
:
I
--
v
\
5 'X
r
;
a *
' ? i i }
i .
. !-
.1 j
XXV
DUP040012181
Dr, Max Costa Department of Pharmacology University of Texas Medical School Houston, TX 77025
Dr. Anita Curran Commissioner of Health Westchester County White Plains, NY 10607
Dr. Jack Dean 5
Immunobiology -Program and
Immunotoxicolpgy/Cel1 Biology program
CUT
T
P.0, Box .12137 j
Research Triangle Park, NC 27709
Dr. H.T. Delvesf
Chemical Pathology and Human Metabolism
Southampton General Hospital
Southampton SQ9 4XY
England
\
Dr. Fred deSerres Assoc. Director for Genetics NIEHS
P.O. Box 12233 Research Triangle Park, NC 27709
Dr. Robert Dixon
Laboratory of Reproductive and
Developmental Toxicology
NIEHS.
I
P.O. Box .1223,3 !
Research Triangle Park, NC 27709
Or. Claire Ernhart Department of Psychiatry Cleveland Metropolitan General Hospital Cleveland, OH 44109
Dr. Sergio Fachetti Section Head - Isotope Analysis Chemistry 0ivision Joint Research Center 121020 Ispra Varese, Italy
Dr. Virgil Ferm Department of Anatomy and Cytology Dartmouth Medical School Hanover, NH 03755
xxv i
Dr. Alf Fisehbein
Environmental Sciences Laboratory Mt. Sinai School of Medicine New York, NY 10029
Dr. Jack Fowle
. . _.
Reproductive Effects. .Assessment Group1
U.S. Environmentai.Protection Agency
RD-689
Washington, DC 20460
Dr, BruCe Fowler Laboratory of Pharmacology NIEHS ;
P.O. Bbx 12233 ' Research Triangle Park, NC
27709
Dr, Warilfen Galke Department of Biostatistics
and Epidemiology School "of Allied Health East .Carolina University Greenville, NC 27834
Mr. Eric Goldstein Natural Resources Defense
Council, Inc. 122 E. 42nd Street New York, NY 10168
Dr. Harvey Goniek 1033 Gayley Avenue Suite 116 Los Angeles, CA 90024
Dr. Robert Goyer
Deputy Director -
NIEHS
.
P.,0. Box 12.233
Research Triangle Park, NC
27709
Dr, Stanley Gross Hazard Evaluation Division Toxicology Branch
U.S. Environmental Protection Agency
Washington, 0C 20460
Dr, Paul Hammond University of Cincinnati Kettering Laboratpry
Cincinnati, OH 45267
DUP040012182
Dr. Ronald 0, Hood Department of Biology the University of Alabama .
University, At 3548$
Dr, Ed McCabe
Department pf Pediatrics Uni versjty. of. Wi sconsin
Madison, WI 53706,
Dr. V. liouk
Centers for Disease Conirpli
1600 Clifton Road, ME
Atlanta, GA .30333
Dr. Chuck Neuman Exposure Assessment Group
U.S. Environmental ProtAetion Agency Washington, DC 20460
Dr. Loren 0. Roller
!'
School of Veterinary Medicihe
University of Idaho"
Moscow, ID 83843
Dr. Kristal Kostial
Institute for Medical Research and Occupational Health -
Yu-4100 Zagreb Yugoslavia
Drv Herbert L- Neddleman; ... Department of Psychiatry :; ' j Children's Hospital of Pittsburgh Pittsburgh, PA 15213
.1
J Dr, ;H. .Mitchell Perry I V.A. Medical Center
5t. Louis, M0 6.3131'
1
Dr. Lawrence Kupper Department of Biostatistics UNC School of Public Health?
Chape] Hill, NC 27.514
; Dr, Jack Pierrard
E, I, duPont d.e Nemours and Company, Inc. ;
j Petroleum Laboratory I Wilmington, DE 19898
Dr. Phillip. Landrigan Division of Surveillance,
Hazard Evaluation and Field Studies
Taft Laboratories - NIQSH CincinnatiOH 45226
i
Dr. David Lawrence
Microbiology and Immunology Dept..
Albany Medical College' of Union
University:
:
Albany, NY 12208
Dr. Sergio Piomelli ' Columbia University Medical School Division of Pediatric Hematology
and Oncology New York, NY 10032
Dr. Magnus Piseator
i Department of Environmental Hygiene
; The Karolinska Institute 104 01?
j Stockholm
s
i Sweden
'
Dr.' Jane Lin-Fu..
Office of Maternal and Child Health Department of Health and Human Services Rockville, MD 20857
;' Dr, Robert Putnam 1 International Lead-Zinc
Research Organization ! 29.2 Madison Avenue
New York, NY 10017
j
Dr. Don Lynam
Air Conservation Ethyl Corporation 451 Florida Boulevard Baton Rouge, LA 70801
Or. Harry RoeIs
Unite de Toxicologie
Industrielie et Medicate Universite de Louvain Brussels, Belgium
Dr, Kathryn Mahaffey Division of Nutrition
Food and Drug Administration 1090 Tusculum Avenue Ci ncinnati, OH 45226
xxvii
Or. John Rosen Division of Pediatric Metabolism Albert Einstein College of Medicine Montefiore Hospital and Medical Center 111 East 210 Street Bronx, NY 10467
i
f
{
i
; ! i
1
DUP040012183
}.
Dr. Michael Rutter Department of Psychology Institute of Psychiatry OeCrespigny Park London SE5 SAL England
Dr. Stephen R. Schroeder Division for Disorders
of Development and Learning ,. Biological Sciences Research Center University of North Carolina Chapel Hill, NC 27514
Dr. Anna-Maria Seppalainen Institutes of Occupational Health Tyoterveyslaitos Haartmaninkatu 1 00290 Helsinki 29 Finland
Dr. Ellen Silbergeld Environmental Defense Fund 1525 18th Street, NW Washington, DC 20036
'
j l j J
j 1
Dr. Ron Snee , . - .
E-I. dupont Nemours and Company,, Inc;
Engineering Department L3167
Wilmington, 0E 19898
Dr. 6ary Ter Haar
Toxicology and Industrial
hygiene
;
Etlofl Corporation ;
451 Fierida Boulevard
Baton Rouge, LA 70801
Dr. Ian von Lindern Department of Chemical'
Engineering: University of Idaho
Moscow, ID 83843
Dr, Richard P, Wedeen V.A, Medical Center Tremont Avenue
East Orange, NJ 07019
i. i
xxviii
DUP040012184
Chapter 11: Assessment of Lead Exposures and Absorption in Human Populations
Principal Authors
;
Dr. Warren Galke
Department of Biostatistihs>and Epidemiology
School of Allied Health }
East Carolina University
Greenville, NC 27834
*
Dr, Vic Uasselblad
;
Biometry Division^ ;
MD-55 '
U.S. Environmental Protection
Agency
v:
Research Triangle Park, NC 27711
(-Qr, Alan Marcus
'Department of Mathematics Washington State University
i Pullman, WA S'0i64-293i0' V
i Contributing Author;
| Dr. Dennis Kdtchmar Environmental Criteria and Assessment Office : MO"52 U.S. Environmental Protection Agency Research Triangle Park:, NC 27711
#
i The foil owing persons reviewed this chapter at EPA's request. The evaluations
.and cphclusiohs contained herein, however, are not necessarily those of the reviewers. .............
Dr, Carol Angle Department of Pediatrics University of Nebraska College of Medicine
Omaha, NE 68105 -
; i
Dr. Joe Boone Clinical Chemistry and
Toxicology Section Centers for Disease Control Atlanta, GA 3033.3
IDr,'Lee Annest
j
;Divisi.pn of Health Examin, Statistics
jNational .Center for Health Statistics
13700 East-West Highway -
i
Hyattsville, MO 20782
Dr. Robert Bornschein
University of Cihcir|nati Kettering Laboratory Cincinnati, OH 45267
br. Donald Baritrop
department of Child Health
Westminister Children's Hospital
London SW1P-2NS
-
*
England
! !
Dr, A, C. Chamberlain '
Environmental and Medical Sciences Division ;
Atomic Energy Research Establishment
Harwell 0.X11
England
Dr. Irv Billick
Gas Research institute 8600 West Bryn Mawr Avenue Chicago, IL 60631
Or. Neil Chernoff
Division of Developmental Biology
MD-67 U.S. Environmental Protection
Agnecy Research Triangle Park, NC 27711
xxix
Dr. Julian Chisolm Baltimore City Hospital 4-940 Eastern Avenue Baltimore, MD .21224
Or.- Virgil Ferm
Department of Anatomy and Cytology Dartmouth Medical School Hanover, NH 0.375.5 .. .
Mr. Jerry Cole
Dr. Alf Fischbein
International Lead-Zinc Research Organization .Environmental Sciences Laboratory
292 Madison Avenue.
' : Mt. Sinai. School of Medicine
Hew Ycrk, NY 10017
New York, NY 10029
Dr. Max Costa Department of Pharmacology University of Texas Medical School Houston, TX 77025
Dr. Jack FoWle ;
Reproductive Effects Assessment Group
U.S. Environmental Protection Agency
RD-689
Washington, DC 2.0460 '
Dr.. Anita Curran
Commissioner of Health Westchester County White Plains., NY 10607
Dr, Bruce Fowler Laboratory of Pharmacology NIEHSt
P.0. Box 1223.3 Research' Triangle Park, NC
27709
Dr. Jack Dean Immunobi ol.ogy Program. and
Immunotoxico1ogy/Cel1 8io1ogy Program CUT-
P.0. Box 12137 Research triangle Park, NC 277.09
Dr. Fred deSerres i Assoc. Director for Genetics NIEHS P.0. Box 12233 Research Triangle Park NC 27709
Dr. Robert Dixon.
|
Laboratory of Reproductive and
Developmental toxicology
NIEHS
;.
P.0. Box 1223.3
j
Research Triangle ParkL NC 27709
Mr. Eric. Goldstein Natural Resources Defense
Council, Inc, School ot Allied Health 122 E. 42nd Street
New York, NY 10168
Dr. Harvey Gonick.
.1033 Gayley Avenue
Suite 116
.
Los Angeles, CA 90024
Or. Robert Goy.er Deputy Oirector NIEHS
P.0. Box:12233
Research'Triangle Park, NC
27709
Or, Claire Ernhart Department of Psychiatry
Cleveland Metropolitan General Hospital Cleveland, OH 44109
Or. Stanley Gross
Hazard Evaluation Division Toxicology Branch U.S. Environmental Protection Agency Washington, DC 20460
Or. Sergio Fachetti Section Head - Isotope Analysis Chemistry' pivision Joint Research Center .121020 Ispra Varese, Italy
Or. Paul Hammond University of Cincinnati Kettering Laboratory 3223 Eden Avenue Cincinnati, OH 45267
XXX
DUP040012186
Dr. .Ronald 0. Hood
Department of Biology
:\
The University of Alabama
University, AL 35486
Dr. V. Houk
Centers for Disease Control :
1600 Ciiiften Road, NE - 7
Atlanta, GA 30333
i
Dr. Loren Koller School of Veterinary Medicine University of Idaho Moscow, ID 83843
Dr. Kristal Kostial j
' Institute for MedicaljResearch
and Occupational Health
Yu-4100 Zagreb
Yugoslavia
'
.Dr, Lawrence Kupper
k;
Department of Biostatistics
UHC School of Public Health
Chapel Hill, NC 27514
Dr, Phi Hip Landrigan
Division of Surveillance, Hazard Evaluation and Field Studies
Taft Laboratories - NIOSH Cincinnati, OH 45226
Dr, David Lawrence .Microbiology and Immunology Dept.
Albany Medical College of Union University Albany, NY .12208'
Dr. Jane Li.n~Fu
j
Office of Maternal and Child Health
Department of Health and Human Services
Rockville, MD 20857 :
Dr. Don Lynam
Air Conservation .Ethyl Corporation 451 Florida Boulevard
Baton Rouge, LA 70801
Dr. Kathryn Mahaffey Division of Nutrition Fodd: and Drug Administration 1090 Tusculum Avenue Cincinnati, pH ' 45226
Dr. Ed McCabe Department of Pediatrics University of Wiscohsin Madison, WI 53706;
Dr. Paul Mushak Department of pathology UNC School of Medicine Chapel Hi11, NC 27514
Or. Chuck Nauman `: Exposure Assessment Group U.S, Environmental Protection
Agency Washington, DC 20460
, Dr. Herbert L. Need!eman .Children's Hospital of Pittsburgh Pittsburgh, PA . 15213
Dr. H. Mitchell Perry V.A. Medical Center St, Louis, M0 63131
Dr, Charles G. Pfieffer Engineering Department Engineering Services Division E 1, duPont', Incorporated Wilmingion, DE 19898
Dr, Jack Pierrard E.I. duPont de Nemours and
Company, Inc. Petro 1 eum Labpratory Wi1mington, DE 19898
Dr. Sergio Piomelli Columbia University Medical School Division of Pediatric Hematology
and Oncology New York, NY 1003.2
xxxi
}
Dr. Magnus Piscater Department of Environmental Hygiene The Karolinska Institute 104 01 Stockholm Sweden
Dr. Robert Putnam International Lead-Zinc
Research Organization 292 Madison- Avenue New York, NY 10017
Dr. Michael Rabinpwitz Children's Hospital Medical Center 300 Longwood Avenue Boston, MA j02115
Dr. Harry Reels Unite de Toxicol ogle
Industrielle et Medicale Universite de Louvain Brussels,. Belgium
Dr. .John Rosen ` Division of Pediatric Metabolism Albert Einstein College of Medicine Montefiore Hospital and Medical Center 111 East 210 Street Bronx, NY 10467
Dr. Stephen ft, Schroeder' ' Division for Disorders
of Development and Learning Biological Sciences .Research Center University bf North Carolina Chapel Hill, NC 27514
Dr. Anna-Maria Seppalainen Institutes of Occupational Health Tyoterveyslaitos Haartmaninkatu 1 00290 Helsinki 29 Finland
Dr. Ellen SiTb.ergeld Environmental Defense Fund 1525 18th Street, NW Washington, DC 200.36
Dr. Ron Snee :
:.
E.I. duPont Nemours and
Company, Inc.
Engineering DepartmentL3267
Wilmington, DE 19898 -
j i
Dr. Garf/ Ter Hear Toxicology and Industrial
Hygiene
Ethyi Corporation,
451 Florida Boulevard. Baton Rouge, LA 70801
; i
Or. Tan von Lindern Department of Chemical Engineering University of Idaho i ;Moscow:, ID, 83843
Dr, Richard P. Weeden j V.A. Medical Center
; Tremont Avenue j East Orange, NJ . .07019
I xxx i i
'DUP040012188
9, QUANTITATIVE EVALUATION OF LEAD AND BIOCHEMICAL INDICES OF LEAD EXPOSURE IN PHYSIOLOGICAL MEDIA
9.1 INTRODUCTION
?
' :
To understand the effects of an agent on an organism and, in particular, to formulate
statements of dose-effect relationships, one must be able to assess quantitatively the organ
ism's degree of exposure to the substance. In the case of lead, internal biologically based
measures provide a more accurate indication of exposure than do .external measures such as am
bient air concentrations. Internal measuresmay be either direct--e.g., the level of lead in
a biological medium such as bipod, calcified tissue, etc,--or indirect--e.g., the level of
some biochemical parameter or `'indicator" closply associated with internal lead exposure.
This chapter examines the merits and weaknesses- of vari.ous;imeasurement methods as they are
currently'used to assess lead exposure.
Quantitative analysis involves a number pf- discrete steps, .all of which are important
contributors to the quality of ithe final result; (1) sample collection and transmission to
the laboratory; (2) laboratory manipulation of samples, physically and chemically, before ana
lysis by instruments;- (3) instrumental analysis.and quantitative measurement; and (4) esta
blishment of relevant criteria-fbr accuracy and precision, namely, internal and external qua
lity assurance checks. Each of these steps is discussed in this chapter in relation to the
measurement of lead exposure.
Clearly, the definition of "satisfactory analytical .method" for lead has changed over the X
years, paralleljng (I) the evolution of more sophisticated instrumentation and procedures, (2) J
a greater awareness of such factors as background contamination and loss of the element from .-
samples, and (3)t development of hew statistical methods .to .analyze data. For example', current. ;
methods of lead analysis,- such ..as anodic stripping voltammetry, background-corrected atomic . -
absorption spectrometry, and particularly isotope-dilution mass .spectrometry:, are more sensi
tive and spec- ifjic than the older clas- sical approaches. Increasing use of the new< e'r methods would tend to result -in lower lead values being reported for a given sample. Whether this
trend in analytical improvement'can be isolated from other variables such as temporal changes
in exposure is another matter.
Because lead is ubiquitously distributed as a contaminant, the constraints (i\e. , ultra-
clean, ultra-trace analysis) placed upon a laboratory attempting analysis of geochemical sam
ples of pristine origin, or of extremely low lead levels in biological samples such as plasma,
are quite severe (Patterson, 1980), Very few laboratories can credibly claim such capability.
9-1
DUP040012189
Ideally., similar standards of quality should be adhered to, across the rest of the analytical
spectrum. With many clinical, epidemiological, and experimental studies, however, these
standards may be unrealistic given the practical limitations and objectives of the studies,.
Laboratory performance is but one part of the quality equation; the problems of sampling are '
equally important but less subject to tight control- The necessity of rapidly obtaining a
blood sample in cases of suspected lead poisoning, or of collecting hundreds or thousands of
blood samples in urban populations, limits the number of sampling safeguards that can be rea
listically achieved. Sampling in this context will always be accompanied by a certain amount
of analytical "suspicion." Furthermore, a certain amount of biological lead analysis data is
employed for comparative purposes, as in,experimental studies concerned with the relative in
crease in tissue burden of lead associated with increases in doses dr severity of effects. In
addition, any major compromise of an analytical .prdtpcol inay be siatistically discernible,.
Thus, analysis of biological media for lead must be done un^er protocols that minimize the
risk of inaccuracy. Specific accuracy and precision characteristics of a method in a parti
cular report should be noted to permit some judgment On the part of the reader about the In
fluence of methodology on the reported refults.
.
1i
The choice of measurement method and medium for analysis is dictated both by the type of
information' desired and by technical or logistical considerations. As noted elsewhere in this
document. Whole blood lead reflects recent or continuing exposure," whereas lead in mineralized
tissue,) such as deciduous teeth, reflects an exposure period of months and years. While urine
lead values are not particularly good correlates of.lead exposure under steady-state condi
tions in populations at large, such measurements may be of considerable clinical value. In ac
quiring.; blood samples, the choice of venipuncture or finger puncture will be governed by such
factors-as cost and! feasibility,..contamination risk, and the biological quality of the sample.
The use] of biological indicators that strongly correlate with lead burden may be more desira
ble, since they provide evidence of actual response and, together with blood lead data, pro
vide a less risky diagnostic tool for assessing lead'exposure.
ii !1 <j
< .;
9.2 DETERMINATIONS OF LEAD IN .BIOLOGICAL MEDIA
3.2.1 Sampling and Sample Handling Procedures for Lead in Biological. Media Lead analysis In biological media requires careful sample collection and handling for two
reasons.: (1) lead occurs at trace levels in most indicators of subject exposure, even under conditions of high lead exposure; and (2) such samples must be obtained against a backdrop of "
9-2
DUP040012190
pervasive contamination, the full,, extent of which may still be unrecognized by many laborato
ries.
The reports of Speecke et a].. (1976), Patterson arid Settle (1976), Murphy (1976), Berman
(1976), and Settle and Patterson^(1980) review detailed aspects of the problems of sampling
and subsequent sample handling in the laboratory. These reports indicate that the normal pre
cautions taken during sampling (detailed below for clinical and epidemiological studies)
should hot be considered absolute* but rather as what is practical and feasible. They further
indicate.that the inherent Sensitivity or accuracy of a given method or'instrument may be less
of : a determining factor in the overall analysis than the quality of sample Collection and
hani dling.* 9.3,1.1 Blood Sampling. Samples for blood lead determination may bej Pol)acted by venipunc
ture (venous blood) or fingertip puncture (capillary blood). Collection of capillary versus
venous blood is usually decided by a number of factors, including the feasibility of obtaining
samples during the screening of many subjects and the difficulty of securing subject com
pliance, particularly in the case^f children and their parents. Furthermore, capillary blood
may be collected as discrete quantities in small-volume capillary tubes or as spots on filter
paper disks. With capillary tubes, obtaining good mixing with anticoagulant to avoid clotting
is important, as is the problem of lead contamination pf the tube. The use of filter paper
requires the selection of paper with uniform composition, low lead content, and uniform blood
dispersal characteristics,
]
Whether venous or capillary blood is collected, much care must be exercised in cleaning
the site, before puncture as well as in selecting lead"free receiving containers. Cooke et al.
(1374) employed vigorous scrubbing with a low-lead soap solution and,rinsing with deionized
water, while Marcus et al. (1975) carried out preliminary cleaning with an ethanplic citric
aci;d solution followed by rinsing with 70-percent sthanoi. Vigor in cleaning the puncture
site is probably as important as ,the choice of any particular cleaning agent, Marcus et al.
(1977) have noted that in one procedure for puncture site preparation, where the site is
coviered with wet paper towels, contamination will occur if the paper towels are made from re--
cycled paper. Recycled paper retains' a significant amount of lead.
In theory, capillary and venous blood lead levels should be virtually identical. However,
the literature indicates that some differences, which mainly reflect sampling problems, do
arise in the case of capillary blood, A given amount of contaminant has a greater impact on a
100-pi fingersttck sample than on a 5-ml sample of venous blood. Finger-coating techniques
may reduce some of the contamination (Mitchell et al., 1974). An additional problem is the
presence of lead in the anticoagulants used to coat capillary tubes. Also, lower values of
capillary versus venous blood lead may reflect "dilution11 of the sample by extracellular fluid
9-3
DUP040012191
from excessive compression of the puncture site. When Joselow and Bogden (1972) compared a
method using finger puncture and spotting onto filter paper with a procedure using venous
blood and Bessel's procedure (1968) for flame atomic absorption Spectrometry (see Section
9.2.2.1), they obtained a correlation coefficient of r= 0,9 (range, 20-46 pg/dl). Similarly,
Cooke et al. (1974) found an r value of 0,8 (no range given), while MiichelT et al, (.1974) ob
tained a value of 0.92 (10-92 pg/dl). Mahaffey et al. (1979) found that capillary blood
levels in a comparison test were approximately 20 percent higher than corresponding venous
blood levels in the same subjects, presumably reflecting sample contamination. Similar eleva
tions have been described by DeSi.lva and Damian (1980), Carter (1978) has found that blood
samples with lower hemoglobin levels may spread onto filter paper differently from normal
hemoglobin samples, requiring correction; in .quantification tjo obtain 'reliable values, this
complication should be kept in mind When considering children, who are frequently prone to
iron-deficiency anemia.
The relative freedom of the blood container from interior surface lead and the presence
of lead in the anticoagulant to be added to the blood are important considerations in venous
sampling. For studies focusing on "normal11 ranges, such tubes may add some lead to blood and
still meet certification requirements, The "low-lead" heparinized blood tubes commercially
available (blue stopper Vacutainer, Bectpo-Dickinson) were found to contribute less than 0.2
pg/dl to whole blood samples (Rabinowitz and Needleinan, 1988). Nackowski et aT. (1977) sur
veyed a large variety of commercially available blood tubes for lead and other metal contami
nation. .Lead uptake by blood oyer time from the various tubes was minimal with the "low-lead11
Vacutainer tubes and with all but four of the other tube types. In the large survey of
Mahaffey et al, (1979), 5-tol Monoject (Sherwood) or 7-ml lavender-top Vacutainer (Secton-
Diekinson) tubes were Satisfactory. However, when more precision is needed, tubes are best ;
recleaned in the laboratory: and lead-free anticoagulant added (although this would be less
convenient for sampling efficiency than the commercial tubes), In addition, blank levels for
every batch of samples should bo verified.
!
)
9.2.1.2 Urine Sampling, Urine samples require collection using lead-free containers and caps
as well as the addition of a low-lead bactericide if samples are to. be stored. White not
always feasible, 24-hr samples should be obtained because they level out any effect of vari
ation in excretion over time. If spot sampling is done, lead levels should he expressed per.
unit creatinine, or corrected for a constant specific gravity, if greater than 1.010.
9.2.1.3 Hair Sampling, The usefulness of hair lead analysis depends on the manner of samp
ling. Hair samples should be removed from subjects by a consistent method, either by a pre- ^
determined length measured from the skin or by using the entire hair. Hair should be placed
in air-tight containers for shipment or storage. For segmental analysis, the entire hair
1ength is required.
9-4 '
DUP040012192
i"' t*.V
it 11
9.2.1.4 Mineralized Tissue. An important consideration in deciduous tooth collection is con-
sistency in the type of teeth collected from various subjects.. Fosse and Justesen (1978} re
ported no difference in lead content between molars and incisors, and Chatman and Wilson ;
(1975) reported comparable whole.tooth levels for cuspids, Incisors, and molars.. On the other i
hand, Mackie et al. (1977) and Lockeretz (1975) noted levels varying with tooth type, with a
statistically significant difference (Mackie et al., 1977) between second molars (lowest
levels) and incisors (highest levels). That the former two studies found rather low overall
lead levels across groups, while Mackie et al. (1977) reported higher values, suggests that
dentition differences in lead content may be magnified at relatively higher levels of ex
posure. Delves et al. (.1982), comparing pairs of central incisors or pairs of central and
lateral incisors from the same child, found that lead content may even vary within a specific
type of tooth. These data suggest the desirability of acquiring two, teeth per subject to get
an .average lead value.
Teeth containing fillings or extensive decay are best eliminated from analysis. Mackie
et al, (1977) discarded decayed,teeth if the extent of decay exceeded approximately 3.0 per-
cent.
i
;
i ,- -
9.2.1.5 Sample Handling*in the laboratory. The effect of storage on lead content is a poten
tial problem with blood samples. ' During storage, dilute aqueous solutions .of lead surrender a
sizable portion of the lead content to the Container surface, whether glass or plastic, unless
the sample is acidified (I.ssaq and Zielinski, 1974; Unger land Green, 1977), Whether there is
,a comparable effect, or comparable extent of such an .effect, with blood is not clear. Unger
and Green (.1977) claim that lead1 loss from blood to containers parallels that seen with aque
ous
solutions,
but; theiri
data
do
\
pot
support
this
assertion.
'>
Moore and Meredith (1977) used
isotopic lead spiking (23Pb) with and without carrier in various containers ,at differing tern-
I '?
*;
peratures to monitor leald stability in .blood over time, the only material'loss occurred with-
.
soda glass at room temperature-after IS days. Nackows.ki et al. (1977) found that ''low-lead'1 . - ;
blood tubes, while qultelsatisfactory in terms of sample cqntamination, began tp show transfer
of lead to the- container, wall after 4,days, Meranger et al.. (1981) studied movement of lead,
spiked to various levels, to containers of various composition as a function of temperature
and time.' In all cases, reported lead loss to containers was significant. " However, problems
exist with the above reports. Spiked samples, probably are not incorporated into the same bio
chemical environment as lead Inserted in vivo. Also, Nackowski et al. (1977) did not indicate
whether the blood samples were kept frozeh or refrigerated between testing intervals. i
Mitchell et al. (1972) found that the effect of blood storage depends on the method of analy
sis, with lower recoveries of lead from aged blood using the Hesse! (1968) method.
9-5
DUP040012193
Lerner (1975) collected blood samples (.35 originally) from a si ogle subject into lead-"
free tubes and, after freezing, forwarded them in blind fashion to a certified testing labor
atory over a period of 9'months. Four samples were lost, and.one was rejected as grossly con
taminated (4 standard deviations from mean). Of the remaining 30 samples, the mean was 10.3*
pg/dl wit! a standard deviation (5.D.) of 3.9. The analytical method had a precision of.3.5
pg/dl (S.D. = 1) at normal levels of lead, suggesting that the overall stability of the sam
ples' lead content was good. Boone et al. (197.9) reported that samples frozen for periods of
less than 1 year showed no effect of storage* while Piscator (1902) noted no change in low
levels (<10 pg/dl) when samples were stored at -20C for 6 months. Based on the above data,
blood samples to be stored for any period of time should be frozen rather than refrigerated,
with care taken; to prevent breaking the tube during freezing. Teeth and hair samples, when
stored in containers to minimize contamination, are indefinitely stable.
i
The actual Is ite of analysis should be as free from lead as possible. Given the limited
availability of an "ultra-clean" facility such as that described by Patterson and Settle
(1976), the next desirable level of laboratory is the "Class 100" facility, in which fewer
than ISO airborne particles are greater than 0.5 pm in .diameter. These facilities employ high-
efficiency particulate air filtering and; laminar air flow`.(with movement away from sample
handling areas). Totally inert surfaces in the working area and ah antechamber for removing
contaminated clothes, appliance cleaning, etc.are other necessary features.
ATI plastic and glass ware coming into contact with samples should be cleaned rigorously
and stored away from dust contact,, and materials such as ashing vessels should permit minimal
lead leaching. In this regard, Teflon or quartz ware is preferable to other plastics or boro-
silicate glass (Patterson and Settle, 1976)
Reagents, particularly for chemical degradation of biological samples, should be both
certified and periodically tested for quality. 'Several commercial grades of reagents are
available, although precise work may require doubly purified materials from the National
Bureau of Standairds (NBS). These reagents should b e stored with a minimum of surface_ contami-
nation around thjs top of the containers.
,
,j
For a more detailed discussion of appropriate laboratory practices, the reader may con
sult LaFleur (1976). '
'
9.2.2 Methods.of Lead Analysis Detailed technical discussion of the array of instruments available to measure lead in
blood and other media is outside the scope of this chapter (see Chapter 4). This discussion is structured more appropriately to those aspects of methodology dealing with relative sensi-tivity, specificity, accuracy, and precision. While acceptance of international standardized
9-6
DUP040012194
(SI) units for expressing lead levels in various.media is increasing, units familiar to clini
cians and epidemiologists will be used here. (To convert pg Pb/dl blood to SI units [pmoles/
liter], multiply by 0.048.)
Many reports over the years; have purported to offer satisfaptpry analysis of lead in bib-
logical media, but in fact have shown rather meager adherence to criteria for accuracy and
precision or have shown a lack ..of demonstrable utility across a wide spectrum of analytical
applications. Therefore, discus-sion in this section is confined to "definitive11 and reference
methods for lead analysis, except for a brief treatment of the traditional but now widely sup
planted colorimetric method.
Using the definition of Cali and Reed .(1976), a definitive method is one in which all
major or significant parameters are related by solid evidence to the absolute mass of the ele
ment with a high degree of confidence:. A reference method, by contrast, is one of demonstra
ted accuracy, validated by a definitive method, and arrive# at by consensus through perfor
mance testing by a number of different laboratories. In the case of lead in biological media,
the definitive method is isotope-dilution mass spectrometry (IDM5). IDMS is so accurate be`'
cause all manipulations are on a weight basis involving simple procedures. The measurements
entail only ratios and not the absolute determinations of the isotopes involved, which greatly
reduces instrumental corrections or errors. No interferences occur from sample matrix or
other elements,, and the method does not depend on recovery. Reproducible results to a pre
cision of one part in 104 or 10s are routine with specially designed instruments.
In terms of reference methods for lead in biological media, such a label is commonly
attached to atomic absorption spectrometry.(AAS) in its various Instrumentation/ methodology
configurations and to the elejCtrochemiGa] .technique., anodic stripping voltammetry (ASV).
These have been termed reference methods inspfar as their precision and accuracy can be veri
fied or calibrated against IDMS.\
.I
Other methods that are recogftnized for ge' n( eral trace-m_ etal analysis- are not fully applicapie to biological lead or have inherent shortcomings. X-ray fluorescence analysis lacks the.
requisite sensitivity for media with.low lead content, and the associated sample preparation
may present,a high contaminations risk. A notable exception may be X-ray fluorescence analysis
of teeth or bone In situ as discussed below. Neutron-activation analysis is the method of
choipe with many elements, but it is not technically feasible for lead analysis because of the
absence of long-lived isotopes.
9.2.2.1 Lead Analysis in Whole Blood. The first generally accepted technique for quantifying
lead in whole blood and other biological media was a colorimetric method that involved spec-
trophotometric measurement based on the binding of lead to a chromogeoic agent to yield a
chromophoric complex. The complex!ng agent has typically been dithizone, 1,5-diphenylthio-
carbazone, yielding a lead complex that is spectrally measured at 510 nm.
* t f '
f i* ;
* \
9-7
DUP040012195
Two variations of the spectropbotometric technique used when measuring low levels of lead have keen the procedures of the U.S. Public Health Service (USPHS) (Rational Academy of Sciences, 1972) and of the American Public Health Association (APHA) (1955), In both, venous blood or urine is wet ashed using concentrated nitric acid of low lead content followed by ad- * justment of the ash with hydroxylamine and sodium citrate to a pH of; 9-10, Cyanide ion is added and the solution extracted with dithizone in chloroform. Back extraction remove/ the lead into dilute nitric acid; the acid layer is treated With ammonia, then cyanide, and re extracted with dithizone in chloroform. The extracts are read in a spectrophotometer at 510 nm. Bismuth interference is handled (APHA variation) by removal with dithizone at pH 3.4. According to L.erner (1975), the analytical precision in the "normal" range is about 3.5 pg/dl ($,D. ?= 1), using 5 ml of sample.
The most accurate and precise metjhod for lead measurement in blood is IDM5. As typified by the report of Hachlan et al. (137B), whole blood samples are accurately weighed, and a weighed aliquot of 20ePb-enriched,isotope solution is added. After sample decomposition with ultra-pure nitric and perchloric acids, satiiflles are evaporated, residues are taken up in di lute lead-free hydrochloric acid (Hl), and lead is isolated using anion-exchange columns,. Column eluates are evaporated with tlje above acids, and lead is deposited onto high-purity platinum wire from dilute perchloric acid. The 206Pb/208Pb ratio is then determined by ther mal ionization mass spectrometry. Samples without added isotope and reagent blanks are also carried through the procedure. In terms of precision, the 95-per.cent.confidence level for leadjsamples overall is within 0,15 percent- Because of the expense incurred by the require ments for operator expertise, the amount of time involved, and the- high standard of laboratory cleanliness, IDMS is mainly of practical yalue in the development of standard reference ma terials and for the verification of other analytical methods,
|AAS Is widely used for lead measurements! in whole blood,- with sample analysis Involving analysis of venous blood with chemical degradation;, analysis of liquid samples with or without degradation, and samples applied to filter psjper. It Is thus the most flexible for samples already collected or subject to manipuljation. By means of flame or electrothermal excitation, ionic lead in a matrix is first vaporized and then converted to the atomic state, followed by resonance absorption from either a hollow cathode or electrodeless discharge lamp generating lead absorption lines at 217,0 and 283,3 nm. After monochrometer separation and photomulti plier enhancement of the differential signal, lead content is measured electronically.
The earliest methods of AAS analysis involved the aspiration of ashed blood samples into a flame, usually subsequent to extraction into an organic solvent, tp enhance sensitivity by precpncentration. Some methods did not involve digestion steps prior to solvent extraction ,,
9-8
DUPQ40G12196
(Kopito et al., 1974), Of these various flame AAS methods, Hessel1 s (1968) technique con
tinues to be used with some frequency.
Currently, lead measurement in blood by AAS employs several different methods that permit
greater sensitivity, precision/ and economy of sample and time. The flame method of Delves
(1970), called the "Delves cup" procedure, usually involves delivery of discrete small samples
. . -',
, it-
(sioo pi) of unmodified whole blood to nickel cups, with subsequent drying and peroxide decom
position of organic content befbre positioning ih the flame. The marked enhancement of sen-
sitivity over conventional flame aspiration results from immediate., total consumption of the
sample and generation of a localized population of atoms. In addition tb discrete blood vol-
ume.s, blood-containing filter paper disks have been used (Joselow andBogden, 1972; Cernik and
Sayers., 1971; HornetTi et al.y 1988). .Among the several modificatioh,s of the Delves method
qre that of Ediger and Coleman (197.2), in which dried blood samples in the cups are pre
ignited to destroy organic matter by placement near the flame- jn a precise, repeatable manner,
and the variation of Barthel et al, (1973), in which blood, samples are mixed with dilute
nitric acid i.ri the cups followed fay drying in an oven at 20tC and charring at 450C on a hot
plate, A number of laboratories eschew even these modifications .and follow dispensing and
frying with direct placement Of the cup into the flame (e. g., Mitchell et a].-, 1974). The
Delves cup procedure may require correction for background.spectral interference. This cor
rection is usually achieved using instrumentation equipped at a nonresonance absorption line.
While the 217.0-nm 1 i.ne of lead is less subject to such interference, precise work is best
done with correction. This metholi as applied to whole blood lead appears to have an oper
ational sensitivity down to 1.0 pg Pb/dl, or somewhat below when competently employed, and a
relative precision of approximately' 5 percent -in the range of levels encountered in the United
States.
!
-
| AAS methods using electrothermal (furnace) excitation in lieu Of a flame can-be approxi-
iriately tenfold more sensitive than the Delves procedure. A number of reports describing whole
bjlood lead analysis have appeared in the literature (Lawrence, 1982, 1983). Because of in-
cjreased sensitivity, the "flameless" AAS technique permits the useI of small blood volumes (1-5 pi) with samples undergoing drying and dry ashing in situ. Physicochemical and spectral
interferences are inherently severe with this approach^ requiring careful background cor
rection. In one flameless AAS configuration, background correction exploits the Zeeman ef
fect, where correction is made at the specific absorption line of the element' and not over a
band-pass region, as is the case with the deuterium are. While control of background inter
ference up to 1.5 molecular absorbance is claimed with the Zeeman system (Koizumi and Yasuda,
1976), employing charring before atomization is technically preferable. Hinderberger et al.
(1981) used dilute ammonium phosphate solution to minimize chemical interference in their fur
nace AAS method,
r I r
,
^ i
9-9
DUP040012197
Precision can be a problem in the flameless technique unless careful attention is paid to" the problem of sample diffysibiHty over and into the graphite matrix of.the receiving recep tacle (tube, cup, or rod). With the use of dilutes! samples and.larger applied volumes, the relative precision of this method can approach that of the Delves,technique. (Delves;, 1977). *
In addition to the various AAS methods noted above, electroehemi&al techniques have .been applied to blood lead analysis. Electrochemical'methods, in theory, differ from AAS methods in that the latter are "concentration" methods, regardless of sample volumes available.* while electrochemical analysis involves bulk .consumption of sample and hence would have infinite sensitivity, given an; infinite sample volume. ..This intrinsic property is of little practical advantage given usual limits of sample volume, instrgmentation. design, and blanks.
. The most widely used electrochemical method for lead measurement in whole blood and other biological media is ASV, which is also probably the moist sensitive because it involves an elec* trochemical preconcentration (deposition) step in the analysis (Matson and Roe, 1966; Matson et al., 1971). In this method, samples such as whole blood (50-100 pi) are preferably, but not commonly, wet ashed and reconstituted in dilute acid or made electro-avail able with metal exchange reagents, Using freshly prepared composite electrodes of mercury film deposited on carbon:, lepd is plated out from the solution for a specifip amount of time .and at a selected negative voltage. The plated lead is then reox-idi zed in the course of anodic sweeping, gene* rating a current peak that may be recorded on a chart or displayed on commercial instruments as units of concentration (pg/dl).
One alternative to' the time and space demands of wet ashing blood samples is the use of metal exchange reagents that displace lead from binding sites in blood by competitive binding1 (Morrell and Glridhar, .1976; Lee and Meranger, 1980). In one commercial preparation, this re-: agent consists of a solution of calcium, chromium, and mercuric ions. Use of the metal ex- : .Change reagent adds a chemical step that must be carefully controlled for full recovery of lead from the sample.
The working detection, limit of ASV for blood is comparable to that of the AAS flameless methods, while the relativfe precision is best with prior sample degradation, approximately 5 ; percent. The precision is` less when the blood samples are run directly, with the ion exchange . reagents (Morrell and Giridhar, 1976), particularly at the low end of "normal" blood lead values. While AAS methods require attention to various spectral interferences to achieve satisfactory performance, electrochemical methods such ,as ASV require consideration of such ' factors as the effects of co-reducible metals and agents that complex lead and alter its re duction-oxidation (redox) potential properties. Che!ants used in therapy, particularly peni cillamine, may interfere, as does blood copper, which may be elevated in pregnancy and during such disease states as leukemia, lymphoma, and hyperthyroidism (Berman, 1981),
9-10
DUP040012198
Correction of whole blood lead values for hematocrit, although carried out in the past,
is probably not appropriate and not commonly done at present* While the erythrocyte is the
carrier for virtually all lead in blood, the ..saturation capacity of the red blood cell (RBC)
for lead is so high that it can,still carry lead even at highly toxic levels (Kochen and
Greener, 1973), Kochen and Greener (1973) also showed that acute or chronic dosing at a given
'' 1
......
- ;
lead level in rats with a wide range of hematocrits (induced by bleeding) gave similar blood
lead values. Rosen et al, (1974), based on studies of hematocrit, plasma, and whole blood
lead in children, noted hematocrit correction was not necessary, a view supported by Chisolm
(1974).
' ; `
9.2.2.2 Lead in Plasma. While virtually all of the lead present in whole blood is bound.to
the erythrocyte (Robinson et al., 1958; Kochen and Greener, 1973), lead in plasma is trans-
ported to affected tissues. Therefore, every precaution must be taken to use nonhemolyzed
blood samples for plasma isolation. The very low levels of Mad in plasma require that mote
attention be paid to "ultra-clean" methods.
Rosen et al. (1974) used flameless AAS and microliter samples of plasma to measure plasma
lead. With background correction for the smoke signal generated'for the unmodified sample.
Cavalier! et al. (1978)1used a combination of solvent extraction of modified plasma with pre-
co.ncentrating and flameless AAS, 'these authors noted that the method used by Rosen et al.
(1974) permitted less precision and accuracy than did their technique, because a significantly
smaller amount of lead was delivered to the furnace accessory.
DeSilva (1981)., using a technique similar to that of Cavalieri et al, (1978), but col
lecting samples in heparinized tubes, claimed that the use of ethylenedianiinetetraac.etic acid
(EOTA) as anticoagulant disturbs the cel 1-plasma distribution of lead enough to yield errone
ous data. Much more cafe was given in this procedure to background contamination. In both
j
'
.,,
i
:
cases, .increasing levels} of plasma lead wefe measured with increasing whole blood lead, sug
gesting an equilibrium ratio that contradicts the data of Rosen et al, (1974). They found a
fixed level of 2-3 pg/dl plasma over a wide range of blood lead values. However, the actual
levels of lead in plasmas in the DeSilva (1081) study were much lower than those reported by
Cavalier! et al. (1978).
,
Using IDMS and sample collection/manipulation in an "ultra-clean" facility, Everson and
Patterson (1980) measured the plasma lead levels in two subjects, a control and a lead-exposed
worker. The control had a plasma lead level of D.002 pg/dl, several orders of magnitude lower
than that seen with studies using less precise analytical approaches. The lead-exposed worker
had a plasma level of 0,2 pg/dl. Several other reports in the literature using IDMS noted
somewhat higher values of plasma lead (Manton and Cook, 1979; Rabinowitz et al., 1974), which
Everson and Patterson (1980) have ascribed to problems of laboratory contamination.
1 1
4
i, "
*
9-11
DUP040012199
Using tracer lead to minimize the impact of contamination results in a value of 0.15 pg/dl
(Rabinowitz et al., 1974).
With appropriate plasma lead methodology, reported lead.levels are extremely low, the de
gree varying with the methods used to measure such concentrations. While the data of Everson 1
and Patterson (1980) were obtained from only two subjects, it seems unlikely that using..more
subjects would result in a plasma lead range extending upward to the levels seen with ordinary
methodology in ordinary laboratory surroundings. The above considerations are important when
discussing appropriate methodology for plasma analysis, and the. Everson and Patterson (198,0)
report indicates that some doubt surrounds, results oibtained with .conventional methods, *AV
though not the primary focus of their study, the. values obtained by Iverson and Patterson
(1980) for whole blood lead, unlike the data for plasma, are within the ranges for unexposed
(11 pg/dl) and exposed (80 pg/dl) subjects generally reported with other methods.i This agree
ment would suggest that, for the most part, reported values .njp actually reflect in vivo blood
lead levels rather than sampling problems or inaccurate methods.
9.2.2.3 Lead in Teeth. When analyzing shed deciduous or extracted permanent teeth, some in
vestigators have used the whole tooth after surface cleaning to remove contaminating lead
i'
*
(e.g., Moore et al., 1978; Fogsp and Justesen, 1978; Hackle et al,, 1977), while others have
measured lead ip dentine (e.g., Shapiro et al,, 1973;. Needleman et al., 1979; Al-Naimi et al.,
1980). Several reports {.GrePdjepn et al., 1979; .Shapito et al-* 1973) have also described'the
analysis of circumpulpal denjfcine, that portion Of th# tooth found to have the highest relative
fraction of lead. Needleman et al. (1979) separated dentine by embedding the tooth in wax,
followed fay thin central sagittal sectioning. The dentine was then isolated from the sawed .
sections by careful chiseling, .
Determining mineral and organic Composition of teeth and their components ;requires the
u:se of thorough chemical decomposition techniques, Including wet ashing and dry!ashing steps
and .samplp pulverizing or grinding. In the procedure of Steenhout and Pourtois (19.81), teeth
are dry ashedj at 4.50C, powdered, and dry ashed;again. The powder is then dissolved in nitric
acid. Fosse japd Justesen (1978) reduced tooth samples to a coarse powder by qr.us.hing in a
vise* followed by acid dissolution. Oehme and Lund (1978) crushed samples to a fine powder in
an agate mortar and dissolved the samples in nitric acid. Macki.e et al, (197.7) and Moore et
al. (1978) dissolved samples directly in concentrated acids. Chatman and Wilson (1975) and
Needleman et al. (1974) carried out wet ashing with nitric acid followed by dry ashing at"
450C. Oehme and Lund (1978) found that acid wet ashing of tooth samples yielded better re
sults if Carried out in a heated Teflon bomb at 200C.
With regard to methods of measuring lead in teeth, AAS and A5V have been employed most*
often. With the AAS methods, the high mineral content of teeth tends to argue for isolating
.9-12
DUP040012200
1
lead from this matrix before analysis. In the methods of Needleman et al. <1974} and Chatman
and Wilson (1975), ashed residues in.nitric acid were treated with.ammonium,nitrate and ammo--""
nium hydroxide to a pH of 2,8, followed by dilution and extraction with a methylis.obutylketone
solution of ammonium pyrrolidinecarbodithioate: Analysis was by flame AAS, using the 217.0-nm
lead-absorption line. A similar procedure was employed by Fosse and Justesen (197.8). >
!
ASV has been successfully used in tooth lead measurement (Shapiro et al., 1973; Needleman
|
et al., 1979; Oehme and Lund, 1978). As trifled by the method of Shapiro et al, (1973), sam-
,s :
pies of dentine were dissolved in a small volume of low-lead concentrated perchloric acid and
diluted (5.0 ml) with 1end-free sodium acetate solution. With deoxygenatipn, samples were
J
analyzed in a commercial ASV unit' using n plating time of 10 ,min at a plating potential of
'
-1.05 V. Anodic sweeping was at a rate .of 6f mV/seC with a variable current of 10(3-50.0 pA.`
.|
Since lead content of teeth is higher thah in most samples of biological media* the relative
precision of analysis with appropriate accommodation of the it&trix effect, such as the use of
matrixrmatched standards, in the better studies indicates a value of approximately 5-7 per-
cent. '
.
';
.,
(J
In an analysis of lead levels in permanent teeth of .Swedish subjects, Moller et al.
(1982) used particle-induced X-ray emission (FIXE). While this method permits analysis with
1j
minimal contamination risk, it measures only coronal dentine, which is. relatively less re-
<
vealing about cumulative exposure than secondary or qircump.ulpal dentine.
All of the above methods involve shed or extracted teeth and consequently provide a ret
rospective determination of lead exposure. In Bloch et al.-s (1976) procedure,;tooth lead is
;1
measured in situ using an X-ray fluorescence technique, A collimated beam of radiation from
\
57Co was allpwed to irradiate the upper central incisor teeth of the subject. Using a rela
tively safe 100-sec irradiation time and measurement .of Kai and lead lines via a germanium
diode and a piulse-height analyzer for signal processing,'lead levels of 15ppm or higher could -:
be measured. Multiple measurement by this method would be very useful in prospective studies . * f
because it wquld show the "ongoing" rate of ihcrease in body lead burden. Furthermore, when
I
combined with) serial blood sampling, -it-would provide data for blood lead-tooth Head relation
ships.
*
-
9.2-2.4 Lead in Hair, Hair constitutes a noninvasive sampling source with virtually no prob
>
lems with sample stability on extended storage. However, the advantages of accessibility and
stability are offset by the problem of assessing external contamination of the hair surface by
atmospheric fallout, hand dirt, lead in hair preparations, etc. Thus, such samples are prob
ably of less value overall than those from other media.
The various methods that have been employed fpr removal of external lead have been re
viewed (Chatt et al., 1980; Gibson, 1980; Chattopadhyay et al., 1977). Cleaning techniques
obviously should be vigorous enough to remove surface lead but not so vigorous as to remove
9-13
DUP040012201
the endogenous fraction. To date, no published cleaning procedure has been proven reliable enough to permit acceptance of reported levels of lead in hair. Such a demonstration would have to use lead isotopic studies with both surface and endogenous isotopic lead removal monitored as a function of a particular cleaning technique. 9.2.2.5 Lead in Urine. Analysis of lead in urine is complicated by its relatively low con centrations (lower than in blood in many cases) as well as by the complex mixture of mineral elements present. Lead levels are higher, of course, in cases where lead mobilization or therapy with chelants is in progress, but in these cases samples must bfi analyzed to account for lead bound to chelants such as EDTA. Such analysis requires either sample ashing or the use of standards containing the chelant. Although analytical methods have been published for the direct analysis of lead in urine, samples are probably best wet ashed before analysis, using the usual mixtures of nitric plus sulfuric and/or perchloric acids.;
Both AAS and ASV methods have been applied to urine lead analyses, the former employing either direct analysis of ashed residues or a preliminary cfWlation~extraction step. With flame AAS, ashed urine samples must invariably be extracted with a chelant such as ammonium pyrrolidineearbodithioate in methylisobutylketone to achieve reasonably satisfactory results,. Furthermore, direct analysis creates! mechanical problems with burner operation, due to the high mineral content of urine, and results in considerable maintenance problems with equip ment. The procedure of Lauwerys St al. (1975) is typical of flame AAS methods with prelimin ary lead separation. Because of the relatively greater sensitivity of graphite furnace (fThmeless) AAS,. this variation of the method has been applied to urine analysis. In scat tered reports of such analyses, adequate performance for direct sample analysis seems to require steps to minimize matrix interferencei A typical example of one of the better direct analysis methods is that of Hodges and Skelding (1981). Urine samples were mixed with iodine .solution and heated, then diluted with a .special reagent containing ammonium molybdate, phos phoric acid, and ascorbic acid. Small aliquots (5 pi) were delivered to the furnace accessory of an AAS unit containing a graphite tube pretreated with ammonium molybdate. The relative standard deviation of the method is reported to be about 6 percent. In the method of Legotte et hi. (1980), -such tube treatment and sample modifications were not employed and the average precision figure was 13 percent.
Compared with various AAS methods, ASV has been less frequently employed for urine lead analysis. From a survey of available electrochemical methods in general, such techniques * applied to urine appear to require further development. Franke and de Zeeuw (1977) used dif ferential-pulse ASV as a screening tool for lead and other elements in urine. Jagner et al, (1979) described analysis of urine lead using potentiometric stripping. In their procedure the element was preconcentrated at a thin-fi1m mercury electrode as in conventional ASV, but
9-14
DUP040012202
deoxygenated samples were reoxidized with either oxygen or mercuric ions after the circuitry
was disconnected.
As noted in Section 9.1.1,2, if collection of .24-hr samples is not possible, spot sam
pling of lead in urine can bei conducted, and results should be expressed per unit creatinine.
9.2.2.6 Lead in Other Tissues, . Bene samples of expeHmental abi.mil or: human autopsy grigin
require preliminary cleaning procedures for removal of muscle and connective tissue, with care
being taken to minimize sample s contamination. As is the case With teeth, samples must be
chemically decomposed before analysis. Satisfactory instrumental methods- for bone lead analy-
sis comprise a much smaller literature than is the case for other media,:
Wittmers at al, (19.81) have .described the measurement of lead in dry ashed (4SQflC) bone
; samples using flameless AAS. Ashed samples were weighed and dissolved in dilute nitric'.acid
j containing lanthanum ion, the latter being used to suppress interference from bone elements.
; Small volumes (20 pi) and high calcium content required that |.to,mr?atibn be done at 2400C to
; avoid condensation of calcium within the furnace. Quantification was by the method of addi
tions. Relative precision was 6-8 percent at relatively high i.ead content (60 pg/g ash) and
10-12 percent at levels of 14- pg/g ash or less.
; Ahlgren et al. (1980) described the application of X-ray fluotescenee analysis to i_n vivo
lead measurement in the human skeleton, using tibia and phaiangefe. In this technique, irra
diation is carried out with a Huai S7Co gamma ray source, thd generated Kffll and'K ^ lead
lines are detected with a lithium-drifted germanium detector. The detection limit is 20 ppm.
Soft organs differ from other biological media in the extent of anatomic heterogeneity as
well as lead distribution, e,g., brain versus kidney. Hence, sample analysis involves either
discrete regional sampling or the homogenizing of an organ. The efficiency of the latter can
vary .considerably, .depending on.the density of the homogenate, jibe efficiency of rupture of
ii the formed elements, and ..other faT-ct*ors, Glass-o.n-g' T.ass homogenizing should be avoided because
lead is liberated from the glass matrix with abrasion,
'-
AAS, in its flame or flameless variations, is the method of choice in many studies. In
`the procedure of Slavinet al* (1975), tissues were wet ashed and the residues taken up in di-
!.
i'
5
lute acid and analyzed with the furnace accessory of an AAS Unit, A large number of reports
representing slight variations of this basic technique have appeared over the years (Lawrence,
1982, 1983). Flame procedures, being less sensitive than the graphite furnace method, require
more sample than may be available or are restricted to measurement in tissues where levels are
relatively high, e.g*, kidney. In the method of Farris et al-(1978), samples of brain,
liver, lung, or spleen (as discrete segments) were lyophilized and then solubilized at room
temperature with nitric acid. Following neutralization, lead was extracted into methyliso-
butylketone with ammonium pyrrolidinecarbodithioate and aspirated into the flame of an AAS
unit. The reported relative precision was 8 percent.
? j % \ *
j
-: i ;
9-15
DUP040012203
5,2.3 Quality Assurance Procedures In Lead Analysis Regardless of technical differences among the different methodologies for lead analysis,
one can'define the quality of such techniques as ;being of certain categories: (1) poor accu racy and poor precision; (2) poor accuracy and good precision; or (3) good accuracy and good' precision. In terms of available information, the major focus in assessing quality has.been on blood lead determinations.
According to Boutwell (1376), the use of quality control testing for lead measurement rests on four assumptions: (1) that the validity of the: specific procedure for lead in some matrix has been established; (2) that the stability of the factors making up the method has been both established and manageable; (3) that the validity of the calibration process and the calibrators with respect to the media being analyzed has been established; arid (4) that surro gate quality control materials of reliably determined analyte contentcan be provided. These assumptions, when translated into practice, r.evq]vp around s|eps employed within the labora tory, using a battery of "internal checks" and a further reliance on "external checks" such as a formal, well-organized, multi"laboratory proficiency testing program.
Analytical quality protocols can be further divided into steri-up and routine procedures, the former entailing the establishment of detection limits, "wifhin-run" and "between-run" precision, and recovery of analyte. When a new method is adopted for some specific analytical advantage, the procedure is usually tested inside or outside tlhe laboratory for comparative performance, for example,. Hicks et a!. (1973) and Kubasik et al, (1972) reported that flameless techniques for measuring lead in whole blood had a satisfactory Correlation with results using conventional flame procedures. Matson et al, (1971) noted a good .agreement between ASV and both AAS and dithizone colorimetric techniques. The problem with such comparisons is that the reference method is assumed to be accurate for the particular level of lead in a given matrix. High correlations obtained in this manner may simply indicate that two inaccurate methods are simultaneously performing with the same level of precision.
Preferable approaches for assessing accuracy are the use of certified samples determined by a definitive method or direct comparison of different techniques with a definitive proce-: dure. For example, Eller and'Hartz (1977) compared the precision and accuracy of five availa ble methods for measuring lead in blood: dithizone spectrometry, extraction and tantalum boat AAS, extraction and flame aspiration AAS, direct aspiration AAS, and graphite furnace AAS techniques. Porcine whole blood certified by MBS using IDMS at 1.00 pg/g (+0,023) was tested " and all methods were found to be equally accurate. The tantalum boat technique was the least precise. The obvious limitation of data from this technique is that they relate to a high blood lead content, suitable for use in measuring the exposure of lead workers or in some * other occupational context, but less appropriate for clinical or epidemiological investi gations.
9-16
DUP040012204
Boone et al. (1979) compared the analytical performance of 113 laboratories using various
methods and 12 whole blood samples (blood from cows fed a lead salt) certified as to lead cons
tant using IDMS at the MBS. Lead content ranged from 13 to 102 pg/dl, determined by A5V and
five variations of AAS. The order of agreement with NBS values, i.e., relative accuracy, was
as follows: extraction > ASV > tantalum strip > graphite furnace > Delves cup > carbpri rod-
The AAS methods all showed bias, having positive values at less than 40 pg/dl and negative
values at levels greater than 50 pg/dl. ASV showed less of a positive bias problem, although
it was not bias free.within either of the blood lead ranges. In terms of relative precision,
the ranking was: ASV > Oelves cup > tantalum strip > graphite furnace > extraction > carbon
rod. The overall ranking in accuracy and precision indicated; ASV > Delves cup > extraction
> tantalum strip > graphite furnace > carbon rod. As the authors cautioned,, the above data
should hot be taken pi. indicate that any established laboratory using one particular technique
would not perform better; rather, it should be used as a glide for newer facilities choosing
among methods.
A number of steps in quality assurance pertinent to the routine measurement of lead are
necessary in an ongoing program! With respect to internal checks of routine performance, these steps include ial.ibration and precision and accuracy testing. With biological matrices,
the use of matrix-matched standards is quite important, as is an understanding of the range of
linearity and variation of calibration curve slopes from day to day. Analyzing a given sample
in duplicate is common practice, with further replication, carried out if the first two deter-
mi nations- vary beyond a predetermi ned range. A second desirabl e step is the analysis of Sam-
pies collected in duplicate but analyzed "blind" to avoid bias.
.'
;
Monitoring accuracy within the laboratbry is limited to the availability of control sam-
pies having a certified lead content in the same medium as the! samples being analyzed. ' Con-
trols should be.as physically close to the media being analyzed as possible. ' Standard defer.-
ence-materials (SRMs), such as orchard leaves and lybphilized bovine liver, are, of help in
some cases, but NBS-eertif1ed blood samples are needed for the general laboratory community,
Whole blood;samples, prepared and certified by the marketing facility (TOX-EL, A.R. Smith Co.,
Los Angeles, CA; Kaulson Laboratories, Caldwell, NO; Behringwerke AG, Marburg, W. Germany; and.
Health Research Institute, Albany, NY) are available commerciany. With these samples, atten
tion must be paid to the reliability of the methods used by reference laboratories. The use
of such materials, from whatever source, must minimize bias; for example, the attention given
control specimens should be the same as that given routine samples.
Finally, the most important form of quality assurance is the ongoing assessment of lab
oratory performance by proficiency testing programs using externally provided specimens for
analysis. Earlier inter!aboratory surveys of lead measurement in blood and in urine indicated
:
| | % ;5 ; J f| -?
3
; ;f 7: | f :
.
9-17
PUP040012205
1
that a number pf laboratories had performed unsatisfactorily, even when dealing with high con
centrations of lead (Keppler et a!., 1970* Donovan et al., 1971; Berlin et al., 1973), al
though some of the problems may have originated in the preparation and status of the blood
samples during and after distribution (World Health Organization, 1977). These earlier tests -
for proficiency indicated the following: (1) many laboratories were able to achieve a good
degree of precision within their own facilities; (2) the greater the number of samp!es ro.u-
tinely analyzed by a facility, the better the performance; and (3) 30 percent of the labora
tories routinely analyzing blood lead reported values differing by Wore than 1$ percent from
the true level (Pierce et al., 1976).
In the more recent, but very limited, study of PaUlev et al. (1978), five facilities par
ticipated in a survey, using samples to which known amounts of lead had been added, For lead
in both whole blood and urine, the interlaboratory coefficient of .Variation was Reported to be
satisfactory', ranging from 12.3 to 17.2 percent. Aside frof|. its limited scope, this study
used "spiked" instead of in vivo lead, so that extraction techniques used in most of the labo
ratories surveyed- would have given misleadingly better results in terms of actual recovery.
Maher e,t at. (1979) described the outcome of a proficiency study involving up to .38 lab
oratories thjat analyzed whole blood\pooled from a large number of samples submitted for blood
lead testing. The Delves cup technique was the most heavily represented, followed by the che
lation-extraction plus flame AAS method and the graphite furnace- AAS method. ASV was used by
only approximately 10 percent of the laboratories, so that the results basically portray AAS
method^. All laboratories ha<ji about the same-degree of accuracy, with no evidence of consis
tent bias, While the interlaboratory coefficient Of variation was approximately 15 percent. A
subset of .this group, certified by the American-Industrial Hygiene Association (AIHA) for air
lead, shpw.ecisa corresponding precision figure of approximately 7 percent. Over time, the sub
set of AIHAfcertified laboratories remained about the same in proficiency, while the other
facilities showed continued improvement in both accuracy and precision. This study indicates
that program participation does help the performance of a laboratory doing blood .lead determi
nations. !
! i
The most comprehensive proficiency testing program is that carried out by the Centers for
Disease Control (CDC) of the U.S, Public Health Service (USPHS). This testing program con
sists of two operationally and administratively distinct subprograms, one conducted by the
Center for Environmental Health (CEH) and the other by the Licensure and Proficiency Testing
Division, Laboratory Improvement Program Office (LIPQ). The CEH program is directed at fa
cilities involved in lead poisoning prevention and screening, while LIPQ is concerned with
laboratories seeking certification under the Clinical Laboratories Improvement Act of 1967 as "
well as under regulations of the Occupational Safety and Health Administration (OSHA). Both
9-18
DUP040012206
the CEH and LIPO protocols Involve the use of bovine whole blood certified as to content by
reference laboratories (6 in the CEH program, 20-23 in LIPO) -with an ad hoc target range of 6
pg/dl for values of 40 pg/dl or less and 15 percent-for higher levels, three samples are
provided monthly from CEH, for a total of 36 yearly, while LIPO participants receive three
samples quarterly (12 samples yearly). Use of a fixed range rather than a standard deviation
has the advantage of allowing the monitoring of overall laboratory improvement.
For fiscal year (FY) 1981, 114 facilities were in the CEH program, 92 of them participa
ting for the entire year. Of these, 57 percent each month reported all three samples within
the target range, and 85 percent on average reported two out of three samples correctly. Of
the facilities reporting throughout the year, .9.5 percent had a 50 percent or better perfor
mance,. i.e.,\18 blood samples or better. Camparing the summary data for FY 1981 with earlier
annual reports, one sees considerable improvement in the number of laboratories achieving
higher levels of proficiency. For the interval FY 1977-79, there was a 20 percent increase in
the number correctly analyzing more that! 80 percent of all samples and a 33 percent decrease
in those reporting less than 50 percent correct. In the last several years, FY 1979-81, over
all performafice has more.or less, stabilized.
With the LIPO program for 1981 (Dudley, 1982), the overall laboratory performance aver
aged across all quarters was 65 percent of the laboratories analyzing all samples correctly
and approximately 80 percent performing well with two of three samples. Over the 4 years of
this program, an increasing ability to analyze lead in blood correctly has been demonstrated.
Dudley's (1982) survey also indicates that reference laboratories in the.LIPO program are be
coming .more accurate relative to IDMS values, 1.e., bias over the blood lead range is con
tracting.
Current OSHA criteria for certification of laboratories measuring occupational blood lead
levels require that eight of nine samples, 89 percent, be within 6 pg/dl or 15 percent of re-'
ference laboratory means for samples sent over the three previous quarters (U,S. Occupational
Safety and Health Administration; 1982)^ these Criteria reflect the ability of a number of
laboratories to perform at this.level.
,
,
Note that most proficiency-programs, including the CEH and LIPO surveys, are appropriate
ly concerned with blood lead levels encountered in such cases as pediatric screening for ex
cessive exposure to lead or in occupational exposures. As a consequence, underrepresentation
of lead values in the low end of the "normal" range occurs. In the CEH distribution for FY
1981, four samples (11 percent) were below 25 pg/dl. The relative performance of the 114
facilities with these samples indicates outcomes much better than with the whole sample range.
This relative distribution of low blood lead samples appears to have continued to the present.
9-19
DUP040012207
The National Bureau of Standards has recently made available certified porcine blood lead -
standard reference material (SRM 955) at two levels of blood lead. Certified urine lead
samples are also being offered-
9.3 DETERMINATION OF ERYTHROCYTE PORPHYRIN (FREE ERYTHROCYTE PROTOPORPHYRIN, ZINC PROTOPORPHYRIN)
9.3.1 Methods of Erythrocyte Porphyrin Analysis
Lead exposure results in inhibition of the final step in heme biosynthesis, the insertion of iron into protoporphyrin IX to form heme. Inhibition of this step leads to an accumulation
of the porphyrin, with zinc (II) occupying the position normally filled by iron. Depending on
the particular method of analysis,zinc protoporphyrin (ZPP) itself or the metal-free form, free erythrocyte protoporphyrin (FEP), is measured. FEP generated as a consequence of chemi cal manipulation should be kept distinct from the metal-free form biochemically produced in
the disease, erythropoietic protoporphyria. The chemical or "wet" methods measure FEP or ZPP,
depending upon the relative acidity of the extraction medium. The hematof1uorometer in its commercially available form measures1 ZPP.
Porphyrins are labile due to photochemical decomposition; hence, samples must be protect ed from light during collection and handling and analyzed as sooh as possible. Hematocrits
must also be obtained to adjust for anemic subjects. ' In terms of methodological approaches for erythrocyte porphyrin (EP) analysis, virtually
all methods now in use exploit the ability of porphyrins to undergo intense fluorescence when
excited at the appropriate wavelength of'light. Such fluorometric techniques can be further classified as wet chemical micrometfiods or as micromethods using a recently developed instru.meht, the hematof1uorometer. The latter involves direct measurement in whole blood. Because
the mammalian erythrocyte contains all of the EP in whole blood, either packed cells or whole-
bipod may be used, although the Tatter Is more expedient.
-,
! Because of the relatively high; sensitivity of fluorometric measurement for, FEP or ZPP, laboratory methods for spectrofluorometric analysis require a relatively small, sample of blood; hence, microtechniques are currently the most popular In most laboratories. These in volve either liquid samples or blood collected on filter paper, the latter used particularly ^ in field sampling.
As noted above, chemical methods for EP analysis measure either FEP, where zinc is chemi cally removed, or ZPP, where zinc is retained. The procedures of PiomelTi and Davidow (1972), Granick et al,, (1972), and Chisholm and Brown (1975) typify "free" EP methods, while those of Lamola et al. (1975), Joselow and Flores (1977), and Chisolm and Brown (1979) involve mea surement of zinc EP.
9-20
DUP040012208
In PiomelTi and Davidow's (1972) microprocedure, small volumes of whole blood, analyzed
either directly or after collection on filter paper, were treated with a suspension of Celite
in saline followed by a 4:1 mixture of ethyl acetate to glacial acetic acid. After agitation
and centrifugation, the supernatant was extracted with 1.5N HC1. The acid layer was analyzed
fluorometrically using an excitation wavelength of 405 nm and measurement at 615 nm. Blood
collected on filter paper discs was first eluted with 0.2 ml H20. The filter paper method was
found to work just as well as liquid samples of whole blood. Protoporphyrin IX was employed
as a quantitative standard! .Grariick et al. (1972) used a similar microprocedure, but it ch'f~
fered in the concentration of acid employed and the use of a ratio of maxima. .
In Chisolm and Brown's (1975) variation, volumes, of 20 pi of whole- bipod Were, treated
with ethyl acetate/acetic acid (3:1) and briefly mixed. The acid-extraction step was done
with 3N HC1, followed by a further, dilution step with more acid if the value was beyond the
range of the calibration curve. In this procedure, protoporphyrin IX was used as the working
standard,, with copmporphyrin (a precursor to protoporphyrin) used to monitor the calibration
of the f1uorometer and any variance with the protoporphyrin standard.
. Lamola et al. (1975) arjdlyzecf the ZPP as such in their procedure. Small volumes of blood
(20 pi) were worked up iria detergent (dimethyl dodecylamine oxide) and phosphate buffer solu
tion, and fluorescence was measured .at 594 niri with excitation a| 424 nm. In the variation of
Joselcw and Flores (1977), 10 pi of whole blood was diluted 1000-jfold, along with, protoporphy
rin (Zn) standards, with the detergent-buffer solution. Note that the ZPP standard is virtu
ally impossible to obtain in pure form, Chisolm and Brown (1979) reported the use of proto
porphyrin IX plus very pure zinc salt for suet) standards.
In the single-extraction variation of Orfanos et al. (1977), liquid samples of whole
blood (40 pi) or blood on filter paper were treated with acidified ethanol. The mixtures were
agitated and centrifuged, arid the supernatants analyzed directly'in fl-uorometer .cuvettes. For
blood samples on filter paper, blood was first leached from the paper with saline by soaking
for 60 min. Coproporphyria was used as the quantitative standard. The correlation caeffiei-
i ->
ent with the Piomelli and Daviqiow (1972) procedure (see above) over the range 40-650 pg EP/dl
RBCs was r = 0.98. As in. the above methods, ZPP itself is measured.
- .
Regardless of the extraction methods used, some instrumental parameters are important,
including the variation between cut-offs in secondary emission filters and variation among
photomultiplier tubes in the red region of the spectrum. Hanna et al, (1976) compared four
micromethods for E.P analysis: double extraction with ethyl acetate/acetic acid and with HG1
(Piomelli and Davidow, 1972), single extraction with either ethanol or acetone (Chisolm et
al., 1974), and direct solubilization with detergent (Lamola et al., 1975). Of these, the
ethyl acetate and ethanol procedures were satisfactory; complete extraction occurred only with
9-21
DUP040012209
the ethyl acetate/acetic acid method. In the method of Chisholm et at. (1974), the choice of
add and its concentration appears to be more significant than the choice of organic solvent.
The levels of precision with these wet micromethods differ with the specifics of analy
sis, Piomelli (1973) reported a coefficient of variation (C.V.) of 5 percent, compared to
Herher's (1980) observation of 2-4 percent for the methods per se and 6dl percent total .y,,
which included precision of samples, standards, and day-to-day variation. The Lamoia et al,
(1975) method for ZPP measurement was found to have a C.V. of 10 percent {satne'day, presuma
bly) , whereas Herber (1980) reported a day-to-day C.V. of 9.3-44.6 percent, ' Herber (1980)
also found that the wet chemical micromethod of Piomelli (1973) had a detection limit of .20 pg
EP/dl whole blood, while that of Lamoia et al. (1975), was sensitive- to 50 pg EP/dl whole
blood,
,i
The recent development of direct Instrumental measurement of ZPP with the hematof1uoro-
meter has made it possible to use EP measurement in field screening for lead exposure in large
groups of subjects. However:, hematofluorometers were developed for and remain most useful for
lead screening programs; they were not meant to be laboratory substitutes fbr the chemical
methods of EP analysis. (See Section 9.3,2 for a comparative discussion,.) As originally de
veloped by 'Bell Laboratories (Blumberg et al,, 1977) and now produced commercially, the appa
ratus employs front-face optics, in which excitation of the fiuprophore is at ah acute angle
to the sample surface, with emitted light emerging from the same surface and thus being de
tected, Routine calibration requires a stablefluorescing material with spectra comparable to
ZPP; the triphenylmethane dye Rhpdamjne B is used for this purpose. Absolute calibration re
quires adjusting the micropiracessbr-controlled readout system to read the known concentration
of ZPP in reference blood Samples, the latter calibration performed as frequently as possible.
Hematof1 uorometers are designed for measuring EP in samples containing oxyhemagT.ob.in,
i.e,, capillary blood;. ; Venoys blood, therefore, must first be oxygenated, usually by moderate
'shaking for approximately .10 min (Blumberg et al., .1977; fir.andj.ean and Lintrup, 1978). A
second problem with .hematofluorometer use, in contrast to wet chemical methods, is interfer
ence by bilirubin (Kar^cic et al., 1980; Grandjean and Ljntrup, 1978).. This interference oc
curs with relatively low levels of EP. At levels normally encountered in'lead workers or sub
jects with anemia or nonoccupational lead exposure, the degree of such interference is not
considered significant (firandjean and Lintrup, 1978), Karacic et al. (1980) have found that
carboxybemogTobin (CDHb) may pose a potential problem, but its relevance to EP levels of sub
jects exposed to lead has not been fully elucidated. Background fluorescence in cover glass
may be a problem and should be tested in advance. Finally, the accuracy of the hematofluoro-
meter appears to be affected by hetnolyzed blood.
Competently employed, the hematofluorometer appears to be reasonably precise, but its ac
curacy may still be biased (see below). Blumberg et al. (1977) reported a C.V. of 3 percent
9-22
DUP040012210
over the entire range of ZPP values measured When using a prototype apparatus. Karacic et al.
(1980) found the relative standard deviation to vary from 1 percent (0.92 mM ZPP/M Mb) to 5
percent (0.41 mM ZPP/M Hb) depending on concentration. Grandjean and Lintrup (1978) obtained
a day-to-day C.V. of 5 percent using blood samples refrigerated for up to 9 weeks. He.rber
(1980) obtained a total C.V. of 4.1-11.5 percent.
A number of investigators have compared EP measured by the hematofluorometer with P mea
sured by the laboratory or wet chemical techniques!, ranging from a single, intralaboratory,
comparison to interlaboratory performance! testing. The latter included the EP proficiency
testing program of the USPHS' CDC. Working with prototype instrumentation, Blumberg et .al.
(1977) obtained correlation coefficients of r - 0.98 (range; 50-800 pg EP/dl RBCs) and 0.99
(range: up to 1000 pg EP/dl RBCs) for comparisons with the Gram'ck and Piomelli methods,
respectively. Grandjean and Lintrup (1978), Castoldi et al. (1979) and Karacic et al. (1980)
have achieved equally good correlation results.
1
Several reports (Culbreth et al., 1979; Scoble et al., 1981; Smith et al-, 1980) have
described the application of high-performance liquid chromatography (HPLC) to the analysis of
either FEP or ZPP in whole blood. In one'of the studies (Scoble et al., 19.81), the protopor
phyrins as well as' coproporphyrin and mesoporphyrin IX were reported to be determined on-line
fluorometrical ly in less than 6 min using 0.1 ml of bipod sample. The HPLC'appmach remains
to be tested in interlaboratory proficiency programs.
9.3,2 Interlaboratory Testing of Accuracy and Precision in EP Measurement In a relatively .early, attempt to assess interlaboratory proficiency in EP measurement,
Jackson (1978) reported results of a survey of 65 facilities that analyzed 10 whole blood sam ples by direct measurement with the hematofluorometer or by one of the wet chemical methods. In this survey, the instrumental methods had a low bias compared to the extraction' techniques but tended to show better interlaboratory correlation.
At present, COG1s ongoing EP proficiency testing program constitutes the most comprehen sive assessment of laboratory performance (U.S. Centers for Disease Control, 1981)J Every month, three, samples of who!e blood prepared at the University of Wisconsin Laboratory of Hygiene are forwarded to participants. Reference means are determined by a group of reference laboratories with a target range of i!5 percent across the whole range of EP values. For FY 1981., of the 198 laboratories participating, .139 facilities were involved for the entire year. Three of the 36 samples in the year were not included. Of the 139 year-long participants, 93.5 percent had better than half of the samples within the target range, 84.2 percent per formed satisfactorily with 70 percent or more of the samples within range, and 50.4 percent of all laboratories had 90 percent or more of the samples yielding the correct results. The par ticipants as a whole showed greater proficiency than in the previous year. Of the various
9-23
DUP040012211
methods currently used, the hematof1uorometer direct measurement technique was most heavily
represented. For example, in the January 1982 survey of the three major techniques, 154 par
ticipants used the hematof!uorometer, 30 used the; Piomelli method, and 7 used the Chisolm/
Brown method.
.\
A recent survey by Balamut et al. (1982) raises the troublesome observation that the-use
of commercially available hematofluorpmeters may yield satisfactory proficiency results but
still be inaccurate when compared to the wet chemical method using freshly drawn whole blood.
Two hematof1uorometers in wide use performed well in proficiency testing but showed an,appro
ximately 30 percent negative bias with clinical samples analyzed by both instrument and chemi
cal microtechniques. This bias leads to false negatives when used in sCr.eofitng, Periodic
testing of split samples by both fluorometer and chemical means is necessary to monitor, and
correct fpr, instrument negative bias. The basis of the bias is mush more than can be ex
plained by the difference between FEP and ZPP. This survey points out precautions noted
earlief on the restrictive use of the hematof!uorometer to screening situations.
Mitchell and Doran (1985) compared EP values measured in their laboratory by the chemical
extraction technique' with results obtained by the heiiiatofluorometer in .21 other laboratories.
These workers found: that (a) hematof!uorometer results were 11-28 percent lower than the cor
responding chemical method values, (b) hematofiuprometers demonstrated. mean error of up to 3
percent for proficiency samples, and (c) hematof1uprometers showed a negative bias of 20 per
cent at EP levels of 50 pg/dl and would miss about one third (false negatives) of children at
or somewhat above this, level.
One factor that can be important in the relative accuracy of the hematof1uorometer versus
wet chemical methods is the relative stability of ZPP levels as a proportion of total EP
across that/age range in childhood of most interest in screening. Hammond and coworkers
(1984) have 'observed that the fraction of ZPPi versus total EP was at a relative minimum`at 3
months of age in 185 children serially tested, and that it increased to 1.0 by around 33
months of age. These observations suggest that this variation of proportionality with age
should be taken into account when, screening children under approximately 30 months of age and
-*
when the hematof!uorometer is the chief means pf EP quantification,
The technical basis for this age-related change in proportionality may be spectroscopic,
i.e., changes in erythrocyte size over this age range would lead to differences in .cell
packing, which in turn would affect fluorescence yield during front-face irradiation in the
hematof!uorometer. A second factor noted by the authors may have to do with relative availa
bility of zinc. Since zinc deficiency is common at this stage of development (see Chapter
10), bioavailability of zinc for a nonessenti.a] complexing with FEP would be restricted by '
homeostatic sparing of the element for physiological needs. However, since the work of
9-24
DUP040012212
Chisolm and Brown <1979), using a chemical method, did not reveal any disparity between the two forms in subjects of the Same age range, there is probably an instrumental artifact operating here.
y
9.4 MEASUREMENT OF URINARY COPROPORPHYRIN The elevation of urinary coproporphyrin (CP-U) with lead Intoxication served as a useful
indicator of such intoxication in children and lead workers for many years. Although analysis of CP-U has declined considerably in recent times , with the development of other testing methods, such as measurement of EP, it still has the advantage of showing active intoxication (PTomelli and Qraziano, 1980).
the standard method of CP-U determination Is the fluerometric procedure described by Schwartz et al. (1951), Urine samples are treated with ac.eta.tl buffer and aqueous iodine, the latter converting coproporphyrinogen to copfoporphyrin (CP). The porphyrin is partitioned into ethyl acetate and hack'extracted (4 times) with 1.5N HC1. Coproporphyrih is employed as the quantitative standard, forking curves are linear below 5 pg CP/1 urine.
In the absorption spectrometric technique of Haeger-Aronsen (I960)., iodine is also used to convert coproporphyrinogen to `CP, The extractant is ethyl ether, from which the CP is removed with 0.1N HC1. Absorption is read at three wavelengths, 380, 430, and the Soret maximum at 402 nm, .Quantification is carried out using an equation involving the three wavelengths.
9.5 MEASUREMENT OF DELTA-AMINOLEVULINIC ACID DEHYORASE ACTIVITY
Delta-aminolevulinic acid dehydrase (5-aminolevulinate hydrolase; porphobilinogen synthe
tase; E.C. 4.2,1.24; i.e., ALA-D) is an'allosteric sulfhydryi enzyme that mediates the con
version of two units of .6-aminolevulinic acid (5-ALA) to porphobilinogen, a precursor in the
heme biosynthetic pathway to the porphyrins. Lead's inhibition of the activity of this enzyme
is the;enzymological basis ofALA-D'.s diagnostic utility in assessing lead exposure using
erythrocytes.
'
...
A number of sampling precautions are necessary when measuring this enzyme's activity.
ALA-D activity is modified by the presence of zinc as well as lead. Consequently, blood col
lection tubes that have high background zinc content, mainly in the rubber stoppers, must be
avoided completely or care must be taken to avoid stopper contact with blood, Nackowski et
al. (1977) observed that the presence of zinc in blood collection tubes is a pervasive prob
lem, and plastic-cup tubes appear the only practical means to avoid it. To guard against zinc
in the tube itself, one should determine the extent of zinc Teachability by blood and use one
9-25
DUP040012213
I
tube lot, if possible* Heparin is the anticoagulant of choice, because the lead binding"
agent, EDTA, or other chelants would affect the lead-enzyme interaction,. The relative in
stability of the enzyme in blood makes rapid determinations of activity necessary, preferably
as soon after collection as possible. Even with refrigeration, analysis of activity should be'
cone within 24 hr (Berlin and Schaller, 1974). Furthermore, porphobilinogen is light labile,
which requires that the assay be done under restricted light.
'*
Various procedures for ALA-D activity measurement are chemically .based on .measurement of
porphobilinogen generated', from the substrate. Delta-ALA porphobilinogen is condensed with p-
d'3 methyl ami nobenzaldehyde (Ehrlich's reagent) to yield a chrottiophore measured at .553 nm in a
spectrophotometer. In the European Standardized Method, for ALA-D. activity measurement (Berlin
and Schaller, 1974), developed with .the collaboration of nine laboratories for use with blood
samples having relatively low lead content, triplicate blood samples (0.2 ml) are helnolyzed,
along with a bjood blank, with water for 10 min at 37C. Sginples are then mixed with 6-ALA
solution and incubated for 60 min. The enzyme reaction is terminated by addition of a solu
tion of mercury (IT) in trichloroacetic acid, followed by centrifugation arid filtration. Fil
trates are mixed with modified Ehrlich's reagent (p-dimethylaminobenzal.ehyde in trichloro
acetic/perchloric acid mixture) and allowed to react for 5 min, followed by chromophore
measurement in a spectrophotometer at 555 nm. Activity is .quantified in terms of pM 6-ALA/
min*l erythrocytes. Note that the amount of phosphate for Solution A in Berlin & Schaller's
(.1974) report should be 1.78 g, not the 1,38 g stated. In a microscale variation, Granick et
al, (1973) used only 5 pi of blood and terminated the assay ..by trichloroacetic acid.
In comparing various reports concerning the relationship between lead exposure and ALA-D
inhibition, attention should be paid to the units of activity measurement employed with the
different techniques. Berlin and Schaller's (1974) procedure expresses activity as pH 6-ALA/
itrin*l cells, while Tomokuni1s; (1974) method expresses activity as pM porphobilinogen/hr/ml
cells. Similarly, when comparing the Bonsignore et al, (1965) procedure to that of-Berlin and
Schaller (1974), a conversion factor of 3.8 is necessary when converting from. Bonsignore to
European Standard Method units (Trevisan et al., 1981),
I
Several factors have been shown to affect ALA-D activity.- Rather than measuring enzyme
activity 'in blood once, Granick et al. (1973) measured activity before and after treatment
with dithiothreitol, an agent that reactivates the enzyme by complexing lead. The ratio of
activated to unactivated enzymes versus blood lead levels accommodates inherent differences in "
enzyme activity among individuals due to genetic factors and other reasons. Other agents for
such activation include zirjic (Finelli et al., 1975) and zinc plus glutathione (Mitchell et
al., 1977), In the Mitchell et al. (1977) study, nonphysiological levels of zinc were used.
Wigfield and Farant (1979) found that enzyme activity is related to assay pH; thus, reduced
9-26
DUP040Q12214
activity from such a pH-activity relationship could be misinterpreted as lead inhibition. These researchers find that pH shifts away from optimal;, in terms of activity, as blood lead content increases and the incubation step proceeds.
9.6 MEASUREMENT OF DELTA-AMINOLEVULINIC ACID IN URINE AND OTHER MEDIA
Delta-aminolevulinic acid (6-ALA) levels increase with elevated lead exposure, because of
the inhibitory effect of lead on the activity of ALA dehydrase and/or the increase of ALA syn
thetase activity by feedback derepression. The result.is that this intermediate in heme bio
synthesis ripes in the body and eventually results in increased urinary excretion. The meas
urement of ibis metabolite in urine provides an indication of the level of ]ead exposure.
The ALA; content of urine samples (ALA-U)is stable for approximately 2 weeks or more if
urine samples are acidified with tartaric or acetic acid afid kept refrigerated. Values of
ALA-U are adjjnsted for urine density if concentration is expressed in mg/1 or is measured per
gram creatinine. As noted in. the case of urinary lead measurement, 24-hr collection is more f
desirable than spot sampling.
i
Five mapual procedures and one automated procedure for urinary ALA measurement are most .
widely used, Mauzeral1 and Granick (1956) and Dsvis and Andelman (1967) described the most
involved procedures, requiring the Initial chromatographic separation of ALA, The approach of
GrabeCki et al. (1967) omitted chromatographic isolation, whereas the automated variation of
Lauwerys et al. (1972) omitted prechromatography but included the use of an internal standard,
Tomokuni and Ogata (1972) omitted chromatography but. employed solvent extraction to isolate
the pyrrole intermediate.
i
Mauzeral! and Granick (1956) condensed AllA with a p-dicarbonyl compound, |cetylacetone,
at pH 4,6 to iyield. a pyrrole intermediate (Kno# condensation reaction), which wds further re- ,
acted with p- dimethyl ami nobenzal dehyde in perchloric/acetic acid. The samples were then read
in a spectro>hetometer at 553 nm 15 min afterj mixing. In this method, both porphobilinogen
and ALA are separated from urine by means of h dual-column configuration of cation and anion
exchange "resins. The latter retains the porphobilinogen and the former separates ALA from
urea. The detection limit Is 3 pmol/1 urine. In the modification of this method by Davis and
Andelman (1967), disposable cation/anion resin cartridges were used, in a sequential configu
ration, to expedite chromatographic separation and increase the sample analysis rate. Commer
cial (Bio-Rad) disposable columns based on this design are now available and appear satis
factory.
In these two approaches (Mauzeral! and Granick, 195.6; Davis and Andelman, 1967), the pro
blem of interference due to anrinoaeetone, a metabolite occurring in urine, is not taken into
account. However, Marver et al. (1966) used Dowex-1 in a chromatographic step subsequent to
9-27
DUP040012215
t-'-fr
t
the condensation' reaction to form the pyrrole, This step separates the ALA derivative from
that of the amlnoacefone. Similarly., Schlenker et al, (1964) used a cation-exchanga column to retain aminoacetone.
Tomokuni and Ogata (1972) condensed ALA with ethylacetoacetate and extracted the re* suiting pyrrole with ethyl acetate. The extract was then treated with Ehrlich's reagent and the resulting chromophore measured spectrophotometridaily, lauwerys et al. (1972) developed an automated ALA analysis method for lead worker screening in which ALA, was added in known .amount as an internal standard and the preehromatography was avoided. They, reported a high correlation\(r a 0.98, no range available) with the procedure of Mauzeral] and Granick (195.6).
Roels et al. (1974) compared the relative proficiency of four Bietho4s--tho.se of Mauzeral il and Granick (1956)., Davis and Andelman (1967) , the lauwerys et ..al^ (1972) automated version,; and the Grabecki et al, (1967) method, which omits chrofliai.tographicj.separati.on and is normally1 used with occupational screening. The chromatographic: fflptjhods gave;identical results over the- range of 0-6.0 mg ALA/1 urine, while the automated method!showed a positive bias at <6 m.g/1, the Grabecki et al. (1967) technique was the least .satisfactory of the procedures com pared. jRoel.s et al. (1974) also noted that commerci-al ion-exchOnjge cdlufflnp resulted in low variability (<10 percent).
Delia Fiorentina et al. (1979) combined the Tomokuni and Ogata (1972) extraction method with a correction equation for urine density. Up to 25 mg ALA/1, the G. V. was <4 percent along wHh a good correlation (r = 0,937) with the Davis and Andelman (1967) technique. While avoiding prechromatography saves time, one must prepare a curve relating urine density to a correction factor for quantitative measurement.
Although ALA analysis is normally done'with urine as the indicator medium, Haeger-Aronsen (1960) reported a similar colorimetric method for blood and MacGee et al, (1977) described a gas-liquid chromatographic (GLC) method f.cjr ALA in plasma as well as urine,' Levels of ALA in plasma ~.5are much lower than those in urini e. In the latter method, ' A' LA w-! as isolated from plasma, !reacted with acetyl-acetone, arid partitioned into a solvent i(trimethy1phenylhydrpxidi), which also served for pyrolylic methylation in the injection 'port of. the gas-
liquid chromatograph; the methylated pyrrole was more amenable to chromatographic isolation than the' more polar precursor, , For quantification, an internal standard, 6-ammo-5-oxohexanoic acid, was used. The sample requirement is .3 ml plasma. Measured levels ranged from 6.3 to 73.5 ng ALA/ml plasma, and yielded values that were approximately tenfold lower than the colorimetric techniques (01 Flaherty et al., 1980).
In comparing the Haeger-Aronsen (I960) and MacGee et al. (1977) methods, a number of differences should be pointed out. First, the colorimetric approach of Haegar-Aronsen does not employ chromatographic steps to separate the ALA from other aminoketohes, specifically aminoacetone and porphobilinogen. While these other aminoketones are not known to be positively
9-28
V DUP040012216
i 1. 1i
correlated with blood lead) they ;would add a positive bias to the accuracy of the levels ob
tained. The GLC method of MaeGee and coworkers does not measure simultaneously these amino-
xetones in either plasma or urine, and a reading of the published methodology and its applica
tion (O'Flaherty et a!., 1980} indicates the procedure is acceptable for urinary ALA and
levels of ALA in plasma associated with fel$tively high bipod lead values, i.e., >40 $:g/dl-
The suitability of the GLC approach for relatively low levels of plasma ALA,, i. e. , at .blood
lead levels below 40 pg/dl, remains to be fully evaluated in the field.. A careful reading of
the MaeGee et al. report suggests potential interferences with low levels of ALA measurement,
while the methodology has not had wide use or multi-laboratory evaluation. Despite its added
cost, a good overall method for assessing the relationship of plasma ALA to blood lead levels
below 40 gg/dl, now an'issue pfjcontroversy (see Chapter 12.3), would be use of the MaeGee
method in tandem With computerized multiple-ion monitoring in a mass spectrometer. This
method is ah absolute means of AJiA identification as well as % sensitive means of quantifica
tion.
'
9.7 MEASUREMENT OF PYRIMIDINE-5^NUCLEOTIDASE ACTIVITY
Erythrocyte pyrimidine-5'-nucleotidase (5`-ribonucleotide phosphohydrolase, E.C. 3.1.3.5,
i.e., Py5N) catalyzes the hydrolytic dephosphorylation of the pyrimidine nucleotides uridine
monophosphate .(UMP) and cytidinemohophosphate (CMP) to uridine and qytidine (Paglia and Valen
tine, 1975). Enzyme inhibition by lead in humans and animals results in incomplete.degrad
iation of reticulocyte ribonucleic acid (RNA) fragments, accumulation of the nucleotides, and
jincreased cell hemolysis (Paglia at al., 1975; Paglia and Valentine,- 1975; Angle and Melntire,
jl.978; George and Duncan, 1982). -
'1
J Two methods are available fcjr measurement of Py5N activity.4 `One'is quite laborious in
terms of time .and manipulation, w-h-ile the other is shorter but requires the use of radioiso-
; .
;
topes and radiometric measuremenjt. in Paglia and Valentine's (jL975) method, heparinized
Venous blood was filtered throughi cotton or a commercial cellulosJe- preparation to separate
erythrocytes from platelets and leukocytes. Cells were given multiple saline washings, packed
lightly, and subjected to freeze hemolysis:. The hemolysates were dialyzed against a saline-
Tris buffer containing MgCl? and EOTft to remove nucleotides and other phosphates. The assay
system consists of dialyzed hemolysate, MgCl2, Tris buffer, at pH 8.0, and either UMP or CMP:;
incubation is for 2 hr at 37C. Activity is terminated by treatment with 20 percent trichlo
roacetic acid, followed by centrifugation. The supernatant inorganic phosphate, P-, is meas
ured by the classic method of Fiske and Subbarow (1925), and the phOsphomolybcijc acid complex
is measured spectrophotometrically at 660 nm. A unit of enzyme activity is expressed as
9-29
DUP040012217
pmo] P./hr/g hemoglobin. Hemolysates appear to be stable (90 percent) with refrigeration at'
4C for up to S days, provided that mercaptoethanol is, added at, the time of assay. Like the
other method, activity measurement requires the determination of hemoglobin.
In the simpler approach of Torrance et ,al, (1977), which can.,be feasibly applied to much7
larger numbers of samples,, erythrocytes were separated, from leukocytes and platelets with a
1:1 mixture of mierocrystanine and alphacelTulo.se,. followed by.saline washing, and hemolysis
with a solution of mercaptoethanol and EDIA. Hemolysates were incubated with a medium 'con
taining purified *4C-MP and MgCl2 for.30 min at 37C.. The,reaction was terminated by sequen-"
tial addition of barium hydroxide and zinc; sulfate solution,; Proteins and unreacted nucTeo-J
tide were precipitated, Reaving the labeled cytidine, in. the supernatant. Aliquots were;
measured fpr 14C-activity |n a liquid scintillation counter. . Enzyme activity was expressed asj
nM CMP/min/g hemoglobin, [The blank activity was determined for each sample by carrying out?
the precipitation step as I soon as the hemolysate was mixed wfh the labeled CMP, i.e., t = 0.1
This procedure shows a good correlation (r = Q.94j range; 135-189 enzyme units) with the
method of Paglia and Valentine (1975), The two methods express units of enzyme activity dif
ferently, so that one must! know which method is used when comparing enzyme activity.
-j
9.8 MEASUREMENT OF PLASMA 1,25-DIHYDROXYVITAMIN D
The active form of vitamin D in bone mineral metabolism, including absorption of calcium
and phosphorus as well as bone resorption of.these minerals, is the hormonal metabolite,
1,25-dihydroxyvitamin 0 (1,25-(0H)2.D), Given the growing interest in the adverse effects of
lead on the biosynthesis of this crucial metabolite (see Chapters 10, 12 and 13), a brief
discussion of the quantitative measurement of this metabolite is merited. Techniques for;
measurement of l,25-(0H)2Dj are all of recent vintage, are alj rather lengthy procedurally, and!
all require ;a rather high level .of laboratory expertise and proficiency,
.'
Reported methodologyd whatever the differences in specific details, can be broken down]
into three discrete steps; (1) isolation of the metabolite from plasma or serum by liquid-
liquid extraction using solvents common in lipid analysis(.2) preconcentration of the ex- .
tracts and chromatographic purification using Sephadex LH-20 or Lipidex 5.000 columns along
with, in some cases, HPLC; and (3) subsequent quantitation by either of two radiometric bind
ing techniques: the more common competitive protein binding (CPB) assay dr radioimmunoassay''
(RIA). The CPS assay normally involves the use of a receptor protein in the intestinal cyto
sol of chicks made vitamin 0-deficient.
Most illustrative of 1,25-(0H)2D measurement is the technique of Shepard et al. (1979), "
which also includes steps for the analysis of other metabolites not discussed here. Human
9-30
DUP040012218
plasma, 3-5 ml, to which tritiated metabolite is added as tracer internal standard, is ex tracted with a mixture of methanol and methylene chloride, followed by separation of the (0H)20 fraction (to include the 24,25- and 25,26.-(QH)2 metabolites) from other metabolites using a Sephadex LH-20 column. Subsequent use of HPLC (straight phase, Zorbax-SI.L) separates the l,25-(0H)g metabolite from the other two dihydroxylated products. Q.uantification As by CPB assay. In human adults, the mean metabolite level is 31 picograms/ml Limit of detection is 5 picograms/analytical tube, mean recovery is 53.4 percent, and the within-run and betweenrun coefficients of variation are 17 and 26 percent, respectively.
Two interlaboratory surveys of methodology for vitamin D metabolite analysis have recent ly been described (longer et al., 1982;-Jongen et al.1984). In the more recent and compre hensive of the two (Jongen et al., 1984), 15 1 aboratorijes carried put analyses, of eight plasma samples ana two standards for 1,25-(0H)2D. Mean interlaboratory coefficient of variation for analysis of 1,25-(OH)2D in the plasma samples was 52 percent' In this survey, nine labora tories used the CPB assay, with six using RIA for quantitation. The major reason, however, for the variance appeared to be. differences in methpc^p of purification. The upshot of this survey Is that results for a given sample will vary wjith .specifics of procedure. Thus each laboratory should establish its own reference values. 1
9.9 SUMMARY
j
j
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 col1eetlon and shipment, laboratory hand
ling, instrumental analysis, and criteria -for internal and external quality Control,
|
From a historical perspective, the definition olj "satisfactory analytical .method1! for
lead has been changing steadily as new and more sophisticated equipment has become avail able
and understanding of: the hazards: of pervasive contamination along the analytical course has increased. The best example of this change is the current use of the definitive method for lead analysis, isotope-dilution mass spectrometry (IDMS) in tandem with "ultra-clean" facili ties and sampling methods, to demonstrate conclusively not only the true extent of anthropo
genic input of lead to the environment over the years but also the relative limitations of
most of the methods used today for lead measurement.
9-31
DUP04Q012219
9.9.1 Peteminations of Lead in Biological Med
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 sam-
i -
pie should be obtained from each subject.
i
Measurements of lead in Blood. ... 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 precision, meager] adherence to criteria for accuracy and pre-
cisioft, and a limited utility across a spectruiji of analytical applications. Therefore, it is
Only useful to discuss "definitive" and, comparatively speaking, "reference" methods currently
in use-
In the case of lead in biological media, the definitive method is isotope-dilution mass
spectrometry lIDMS). 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 isotoperatios and not the absolute determinations of the Isotopes involved, which
greatly reduces instrumental corrections and'errors. Reproducible results to a {precision of
one part in 104-105 are routine with appropriately designed and competently operated instru
mentation. Although this methodology is still not recognized in many laboratories, it was the first breakthrough, in tandem with "ultra-clian" procedures and facilities, in definitive
methods for indexing the progressive increase in lead contamination of the environment over the centuries1 Given the expense, required level of operator expertise, and time and effort involved for measurements by IDMS, this method mainly serves for analyses that either require extreme accuracy and precision, e.g., geoehrOnometry, or for the establishment of analytical * reference material for general testing purposes or the validation of other methodologies.
While the term "reference method" for lead in biological media cannot be rigorously ap plied to any procedures in popular use, the technique of atomic absorption spectrometry (AA.S) * 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
.9-32
DUP040012220
metal analyses are either limited in sensitivity or are not feasible for use on theoretical grounds for lead analysis.
MS, as applied to analysis, of whole blood, generally involves flame or flameless micromethods/ One macromethod, the Hesse] procedure, still enjoys some popularity. Flame microanalysis j the Delves cup procedure, applied to blood lead appears to have an operational^.sen
sitivity of about 10 pg/dl .blood'-and a relative precision of approximately .5 percent in the range of blood lead seen in populations in industHalized areas, the flameless, or. electro
thermal ,jmethod of AAS enhances sensitivity about tenfold, but precision can be more proble
matic because of chemical and spectra] interferences:. -
r
. The I most widely used and sensitive electrochemical method for lead in biopd is AS!/, For the .most; accurate results, chemical wet ashing of samples mast be carried |.ut, although this process ;is time-consuming and requires the use of lead-free reagents. The1 use of metal ex change reagents has been employed in lieu of the ashing step1 to liberate lead from binding
sites, although this substitution is associated with less precision. For the ashing method,
relative.precision is approximately 5 percent. In terms of accuracy and sensitivity, problems appear aj: low levels, e.g., 5 pg/dl or below, particularly if samples contain elevated copper
levels, i
- Lead in Plasma. Since lead in whole blood is virtually all confined to the erythrocyte, plasma levels are quite low and extreme care must be employed to measure plasma levels relia bly. The best method for such measurement is IDMS, in tandem with ultra-clean facility use.
AAS is satisfactory for comparative analyses across a range of relatively high whole blood
values.
-;
Lead In Teeth. Lead measurement in teeth has involved either whole jtooth sampling or
analysis jof specific regions, such as dentine or circumpulpal dentine,' In leither case, sam ples-must be solubilized after careful surface cleaning to remove contamination; solubili
zation if usually accompanied by .either wet ashing directly or ashing subsequent to a dry
ashing stjep.
'1
AAS land anodic stripping have been employed more frequently for such determinations than
any other, method. With AAS,. the'.', high mineral content of teeth argues for preliminary isola
tion of lead via chelation/extraction. The relative precision of analysis for within-run mea
surement 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 in
situ measurement of lead by X-ray fluorescence spectrometry in children.. Lead measured in
this fashion allows observation of ongoing lead accumulation, rather than waiting for exfolia tion.
Lead in Hair, Hair as an exposure indicator for lead offers the advantages of being noninvasive and a medium of indefinite stability. However, the crucial problem of external
9-3.3
DUP040Q12221
surface contamination is such that it is still not possible to state that any cleaning*
protocol reliably differentiates between externally and internally .deposited lead.
Studies that demonstrate a Correlation between increasing hair lead and increasing sever
ity of a measured effect tend to support arguments for using hair as an external indicator of*
.exposure. Probably, then, such measurement Using cleaning protocols that have not been inde
pendently validated will overstate the relative accumulation of "internal" hair lead in terms
.of Some endpoint and will also underestimate the relative sensitivity of changes in internal
lead content with .exposure.- One consequence of this would be, for example, an apparent
jthreshold for a given effect in terns of hair lead which is significantly above the actual
threshold. Because of these concerns, hair is best used with the Simultaneous measurement of
;blood lead..
j
] Leacf in Urine. Analysis of- lead in urine is complicated.by the relatively low levels of
;the element in this medium as well as the complex mixture of,: mineral ..elements present. Urine
ilead levels are most useful and also somewhat easier to determine in cases of chelation mobil
ization or chelation therapy, where levels are high enough to permit good precision and dilu
tion of matrix interference.
;
Samples are probably best analyzed by prior chemical wet ashing, using the usual mixture
i*
of acids. Both ASV and AAS have been applied to urine analysis, with the latter more routine
ly used and usually with a ch.ela.tion/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 fTameless AAS is the technique of choice.
In vivo lead measurements in bone of lead workers have been reported using X-ray fluores
cence analysis, and a radioisotopic source for excitation. One problem with this approach with imoderate lead exposure is the detection limit, approximately 20 jjpm. Soft organ analysis-
poses a problem in terms of heterogeneity in lead distribution within an organ (e.g., brain and kidney). In such cases, reg'jonal sampling or homogenization niust be carried put. Both !flame and flameless AAS .appear to! be satisfactory for soft tissue ^analysis and are the most widely used.
Quality Assurance Procedures in Lead Analyses. In terms of available information, the major focus in establishing quality control protocols for lead has involved whole blood meas urements, Translated into practice, quality control revolves around steps employed.within the* laboratory, using a variety of internal checks, and the further reliance on external checks, such as a formal continuing multi-laboratory proficiency testing program.
Within the laboratory, quality assurance protocols can be divided into start-up and rou-' tine procedures, the former involving establishment of detection limits, within-run and betweeii-run precision, analytical recovery, and comparison with some reference technique
9-34
DUP040012222
within of outside the laboratory. .The reference method i:s assumed to be accurate, for the par
ticular level of lead in some matrix at a particular point in time. Correlation, with such a
method at a satisfactory levels 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.
. ..I. v
'if i!
'>'
For blood lead, the Centers for Disease Control (CDC) periodically survey overajll 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 clip and extraction varia
tions of AAS performed better than other procedures. These results do not mean that a given
laboratory cannot perform bejtter with a particular technique; rather, such data are of assist
ance for new facilities choosing among methods.
..
I; ;i
-
Of particular value to laboratories carrying out blood lead analysis are the external
quality assurance programs at both the State and Federal levels. The most comprehensive
proficiency testing program is that carried out by the CDC. This program actually consists of
two subprograms, one directed at facilities involved in lead poisoning prevention and screen
ing (Center for Environmental Health) and the other concerned with laboratories seeking certi-
fication under the Clinical .Laboratories Improvement Act of 1967 as-well as. under regulations
of the Occupational Safety and Health Administration's (OSHA) Laboratory Improvement Program
Office, Judging from the relative overall improvements, in reporting laboratories Over the
years of the programs' existence, the proficiency testing programs have served their purpose
well. - In this regard., OSHA criteria for laboratory certification require that eight of nine
samples be analyzed correctly for the previous quarter. This level of required proficiency
reflects the ability of a number of laboratories to actually perform at this level.
9.9,2 Determination of Erythrocyte Porphyrin (Free Erythrocyte Protoporphyrin, Zinc Protoporphyrin)
With lead .exposure, erythrocyte protoporphyrin IX accumulates because of impaired place-
i
merit of divalent iron to form heme. Divalent zinc occupies1 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 mani pulation. Virtually all methods now in use for EP analysis exploit the ability of the por phyrin to undergo intense fluorescence when, excited by ultraviolet light. Such fluorometric methods can be further classified as wet chemical micromethods or direct measuring fluorometry using the hematofluorometer. Because of the high sensitivity of such-measurement, relatively small blood samples are required, with liquid samples or blood collected on filter paper.
The most common laboratory or wet chemical procedures now in use represent variations of several common chemical procedures: (T) treatment of blood samples with a mixture of ethyl
9-35
DUP040012223
acetate/acetic acid followed by a repartitjoning 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 teen 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
percent, while' the direct ZPP method using buffered detergent solution is higher ancf more
variable.
. ..
The recent development of the hefflatofluorometep has made It possible to carry put EP
measurements in high numbers, thereby making population .screening feasible. Absolute calibra
tion is necessary and,requires periodic adjustment of the system using known concentrations of
EP id reference bloojd samples. Since these units are designed for oxygenated blood f,e.,
capillary blood), use! of venous blood requires an oxygenation step, usually a moderate shaking
for several minutes* I Measurement of low or moderate levels o.f. EP can be affected by inteffer-
ence with bilirubin. Competently employed, the hematpflubrprneter is reasonably precise, show
ing a total coefficient of variation of 4,11-11.5 percent. While the comparative accuracy of
the unit has been repbrted to be good relative to the reference Wet chemical technique, a]very
recent study has shojwn that commercial ' units carry with them a significant negative bias,
which may lead to false negatives in subjects having only moderate EP elevation. Such a bias
in accuracy has been difficult to detect in existing EP'proficiency testing programs. By com
parison to wet methods, the hematofluorometer should bI e restricted to field us` e 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.
9.9.3 Measurement ofi Urinary Coproporphyrin.
i
Although EP measurement has largely supplanted thk use of urinary coproporphyrin- (QP-U)
analysis tp mbnitbr 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 ah oxidant (iodine) i..s added to generate CP
from its precursor. The CP-U -is then partitioned into ethyl acetate and re-extracted with
dilute hydrochloric acid. The working curve is linear below 5 pg CP/dl urine.
9.9.4 Measurement of flel,ta-Aroinole.vuiinic Acid Dehydrase Activity
r
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 (IT) -
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
9-36
DUP040Q12224
\l
i
'
tubes. Enzyme instability necessitates that the activity measurement be carried out within 24
hr of blood collection. Porphobilinogen, 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 porphobilinogen with p-dimethylaminobenzaldehyde.
/
In the European Standardized Method for ALA-D activity determination,.blood samples are
hemolyzed with water, ALA solution added, followed by incubation at 379C, 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/percbloroacetic
acid mixture. Activity is quantified in terms of|micramol.es 6-ALA/min*l erythrocytes.
One variation in the above procedure is the initial use of a thiol agent such as dithio-
threotol, to reactivate the enzyme, giving a measure of the full native activity of the en
zyme. The ratio of activated/unactivated activity versus rtaod lead levels accommodates
genetic differences between individuals.
i
9.9.5 'Measurement of Delta-Aminolevulinic Acid irj Urine and Other. Media
Levels of delta-aminolevulipic acid (5-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 (AiA-ll) is stable for about 2 weeks
or more with sample acidification and refrigeration. : Levels of ALA-U are .adjusted for urine
density or expressed per unit creatinine. If feasible, 24~hr collection is more .desirable
than spot sampling,
.-
Virtually dll the various procedures for ALA-U measurement employ, preliminary; isolation
of ALA from the[balance of urine.constituents. Ip one method, further separation of ALA from
the metabolite aminba.eetone is done. Aminqaceto'ne can interfere with colorimetric measure
ment. ALA is recovered, condensed with a beta-dicarbonyl compound, e.g., acetyl apetone, to
yield a pyrrole jIntermediate, This intermediate is then reacted with p-dimethylam1ipobenz.al^
dehyde in perch]oric/acetic acid, followed by colorimetric reading at 553. nm.- Inone vari
ation of the basjc methodology, ALA is condensed With ethyl acetoacetate directly and the re
sulting pyrrole extracted with ethyl acetate, Ehrlich's reagent is then added as in other
procedures and the resulting chromophore is measured spectrophotometrically.
Measurement of ALA in plasma is much more difficult than in urine, since plasma ALA is at
nanogram/miHiter 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
9-37
DUP040012225
acidi is used. While the method is more involved, it is more specific than the older colon'- *
metric technique.
1
9..9.S Measurement of Pyrimidlfte-51-Nucleotidase Activity Erythrocyte pyrimidine-S1-nucleotidase (Py5|i) activity is inhibited with lead exposure.
Currently, two different methods are used for assaying the activity of this enzyme, The^oider method is quite laborious in time and effd.rt, whereas the more recent approach is shorter but uses radioisotopes and radiometric measurement.
In the older method, heparinized vencjus blood is filtered: through cellulose to separate erythrocytes from platelets and leukocytes. Cells are then frPez.e-frqcttired and the hemolysates dialyzed to remove nucleotides and-other phosphates, this dialysate is then incubated in the presence of a nucleoside, monop.hoSp.|ate and Cofactors, the enzyme reaction being termi
nated by treatment with trichloroacetic acid. The inorganic phosphate isolated from added substrate is measured colorimetricaTly as the phosphomolybdic acid complex.
In the radiometric assay, hemolysates'obtained as before are incubated with pure 14C-CMP. By addition of a barium hydrpxide/zinc sulfate .solution, proteins and unreacted nucleotide are precipitated, leaving labeled eytidine in the supernatant. Aliquots are measured for .ac tivity in a liquid scintillation .counter,. This method shows a good Correlation with the ear lier technique.
9-9-7 Measurement of Plasma 1,2.5-Pihy.droxyvitamin 0 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) preconcentratibn of the -extract and chromatographic purification using Sephadexi LH-20 or Lipidex 5000 coljjmns, as well, as high perforiDan.ee I liquid chromatography (HPLC) in s,(jme cases, and (3) quantification by either pf two radiometric binding techniques, the more common competitive protein finding (CPB) assay or radioimmgni|assay (RIA). The CPB assay uses a receptor protein in intestinal cytosol of chicks made vitamin 0-deficient.
In tone typical study, human adults had a mean level of 31 pi cograms/mi; 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 inter!aboratory survey involving 15 laboratories, the level of variance was such that it was recommended that each laboratory * should establish its own reference values.
9-38
DUP040012226
T
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DUP040012228
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Meranger, J, C.; HoTlebone, B.- R.; Blanchette, G;- A. (1981) The effects of storage times, temperatures and container.types on the accuracy of atomic absorption determinations of Cd, Cu, Hg, Pb and Zn in whole heparinized -blood, J. Anal,. Toxicol, 5: 33-41.
Mitchell, D, G.; Doran, 0, (1985) Effect of bias in hematofluoroffleter measurements of proto
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- 386-390.
`
1i . x
Mitchell, Q, G,; Ryan, ,F. J.; A)dous, K, M. (1972) The precise determination of lead in whole blood^by solvent extraction-atomic. absorption spectrometry. At. Absorpt. News). 11:
Mitchell, 0. G,; Aldous, K. M..;j Ryan,F. J. (1974) Mass screening for lead poisoning: capil lary blood sampling arid automated Delves-cup atomic-absorption analysis. N.Y. State J. Med. 74`: 1599-1603.
Mitchell, R. A.; Brake, J, E.; Wittlin, L. A. ; Regent, T, A. (1977) Erythrocyte porphobi1 inogen_ synthase (delta-aminoTaevulinate dehydratase) activity: a reliable and quanti tative indicator of lead exposure in humans, Clin. Chem. (Winston-Salem, NC) 23: 105-111.
Moller, B.; Carlsson, L.-E; Johannsson, G. I. ; Malmqvist, K, G,; Hammarstrom, L,; Berlin, M. (19.82) Lead levels determined in Swedish permanent teeth by particle-induced X-ray emmission. Scand. J. Work Environ. Health .8: 267-272-
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Moore, M. R.; Meredith, P. A. (1977) The storage of samples for blood and water lead analysis. j > Clio. CMm. Acta 75: 167-170.
Moore, M. R.; Campbell, ,B. C.:; Meredith, P. A..; Beattie, A.,. 0..; Goldberg, A. .Campbell, 0,
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:' '
Morrell, G.; Giridhar, G. (1976) Rapid mierqmethpd for blood lead;analysis by anodic strapping (voltammetry. Clin. Chem. (Winston-Salem, NC) 22: 221-223,'
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'4*
National Academy of Sciences. (1972) Lead.: airborne lead in perspective. Washington, 0C: National Academy of Sciences. (Biologic effects of atmospheric pollutants).
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.^
Needleman, H. L.; Gunnoe, C.; Leviton. A.; Reed, R.; Peresie, H,; Maher, C.; Barrett, P. (1979) Deficits in psychologic and classroom performance of children with elevated den tine lead levels. N. Engl. J, Med. 300: 689-695.
Qehme, M.; Lund, W' (1978) The determination of copper, lead, cadmium and zinc in human teeth
by anodic stripping voltammetry. Anal, Chim. Acta 100: 389-398,.
I^
O'Flaherty, ,E. 3.; Hammond, P: B.; Lerner, S. I.; Hanenson, I. B.; Roda, 5. M. B. (1980) The
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. .
1 *' r ..
!
Orfanos, A. P.; Murphey, W. H. Guthrie, R. (1977) A simple fluorometric assay of protopor
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|
.)
j.
]- , i
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Paglia, 0. .; Valentine, W. N. (1975)'Characteristics of a pyrimidine-specific 5`nucleoti-
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-`
Paglia, D. E.; Valentine, W. N.; Dahlgren, J. G. (1975) Effects of low-level lead exposure on pyrimidine 5`-nucleotidase and other erythrocyte enzymes: possible role of pyrimidine ,, -5`-nucleotidase in the pathogenesis of lead-induced anemia. ,J. Clin, Invest. 56: 1164-3169.
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9-46
DUP040012234
4 -
Patterson, C. C.; Settle, D. Mi (1976) The reduction of orders of magnitude errors in lead ana-: j
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\
. .. .
I - - ' . .
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?' j j
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`, j -i % ;f
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Piomelll, S. (1.973) A micromethod for free erythrocyte porphyrins: the FEP test. J. Lab. Clin.
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Piomelll, .5.j PaVidow, B. (1972) Free erythrocyte protoporphyrin concentration: a promising
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1!
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| | f
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Piomelli, S.; Corash, L,; Corash, M, B,; Seaman, C.; Mushak, P,; Glover, B.; Padgett, R. ' 1
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Rabinowitz, M, B.; Needleman, H, L. (1982) Temporal -trends in the lead concentrationsof umbil- ' |
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.!
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j
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Rabinowitz, M.; W^theri-ll, G, W.; Koppte, J. D. (1974) Studies of human lead metabolism by use
I
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.. j
i `-
\ .................
:1
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9-47
DUP040012235
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.' .. ... "
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!
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9-48
DUP040012236
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if DUP040G12237
10. METABOLISM OF LEAD
10.1 INTRODUCTION
:.
/
This chapter examines the absorption, distribution, retention, and excretion of lead in
humans and animals and the various factors that mediate the extent of the.toxicokinetic pro
cesses of lead. While inorganic lead- is the form of the element that has been most heavily
studied, organolead compounds are ..also emitted into tbev environment and, because they are"
quite toxic, they are also included in the discussion. Since thp preparation of the 1977 Air
Quality Criteria Document for Lead (U.S, Environmental Protection Agency, 1977), a number of
reports have appeared that have proven particularly helpful in both quantifying the various
processes to be discussed in this chapter and assessing the interactive impact of factors such
as nutritional status in determining internal exposure risk.
;
?...
10.2 LEAD ABSORPTION IN HUMANS AND ANIMALS
]
The amounts of lead entering the bloodstream from various routes of absorption are deter
mined not only by the levels of the element in the particular mediae but also by the various
physical and chemical parameters that characterize lead. Furthermore, Specific host factors
such as age and nutritional stiatus are important, as is interindividual variability. Addi
tionally, to assess absorption 'rates,' one must know whether or not the subject is in "equili
brium" with respect to a given level of lead exposure.
.>
. '
I-
10.2.1 Respiratory Absorption of Lead
i .j
The movement of lead from /ambient air to the bloodstream is a two-part process: a frac
tion of air lead is deposited jin the respiratory tract and, of ; this deposited amount, some
fraction is subsequently absorbed directly into the bloodstream or otherwise cleared from the
respiratory tract.. At present, enough.data exist to make some quantitative statements about
both of these components of respiratory absorption of lead,
The .1977 Air Quality Criteria Document for Lead described the model of the international
Radiological Protection Commission (IRPC) for the deposition and removal of lead from the
lungs and the upper respiratory tract (International Radiological Protection Commission,.
1966). Briefly, the model predicts that 35 percent of lead Inhaled from ambient air by humans
is deposited in the respiratory tract, with most of the lead going to the parenchyma and air
ways. The IRPC model predicts a total deposition of 40-50 percent for particles with a mass
median aerodynamic diameter (MMAD) of 0.5 pm and indicates that the absorption rate would vary
10-1
DUP040012238
depending on the solubility of the particular form. More recent data on lead deposition
modeling, however, provide a more precise picture (see next section).
10.2.1.1 Human Studies. Table 10-1 tabulates the various studies of human subjects thatpro
vide data on the deposition of inorganic lead in the respiratory tract. Studies of this type
have used diverse methodologies to characterize the inhaled particles in terms pf both size
(and size ranges) and fractional distribution. The Use of:radioactive or,stable lead isotopes
to .directly or indirectly measure lead deposition and^uptake into the bloodstream has been
particularly helpful in quantifying these processes; ' `s
From the studies of Kehoe (1961a,b,c) and their update by Gross (1981), as well as data
from Chamberlain et al. (1978), Morrow et al, (1980), anp Nozaki (1966), the respiratorydepo
sition of airborne lead as encountered in the general population appears to be approximately
30-50 percent, depending on particle size and veniilatijon rates. Ventilation rate is parti
cularly important with submicrometer parttclies, where Brownian.|iffusion governs deposition,
because a slower breathing rate enhances the frequency of collisions of particles with the alveolar wall.
Figure 10-1 (Chamberlain et al., 1978) compares daia, both calculated and experimentally
measured, on the relationship of percentage deposition to particle size. As particle size
increases, deposition rate decreases to a minimum over the range where Brownian diffusion pre
dominates. Subsequently, deposition increases with size (>0.5 pm MMAD) as impaction and sedi mentation become the mpin deposition factors, .
In contrast to thh ambient air or chamber data tabulated in Table 10-1, higher deposition
rates in some occupational settings are associated with, relatively large particles. However,
much of this deposition is in the upper respiratory tract, with eventual movement to the gas
trointestinal tract by.ciliary action and swallowing, Mdhani (1966) measured total deposition rates of'28-7.0 percent! in battery workers -and workers irj marine scrap yards, Chamberlain and
Heard (1981) calculated an absorption rate of approximately 47 percent for particle sizes en
countered In workplace air.
I . '!
i ,t
i
Systemic absorption of lead from the lower respiratory tract occurs directly, while much
of the absorption from the upper tract involves swallowing and some uptake in the gut. From
the'radioactive isotope data of Chamberlain et al. (1978) and Morrow et al. (1980), and the
stable isotope studies of Rab.inowitz et al. (1977), one can conclude that lead deposited in
the lower respiratory tract is totally absorbed,
Chamberlain et al. (1978) used 203Pb in engine exhaust, lead oxide, or lead nitrate
aerosols in experiments where human subjects inhaled the lead from a chamber through a mouth
piece or in wind-tunnel aerosols. By 14 days, approximately 9.0 percent of the label was re
moved from the lung. lead movement into the bloodstream could not be described by a simple
exponential function; 20 percent was absorbed within .1 hr and 70 percent within 10 hr.
10-2
'
DUP040012239
Q
4 Jt
TABLE 10-1. DEPOSITION OF LEAD IN THE HOMAN RESPIRATORY TRACT
; . M
<*s
U **
43 ^ 0 H .U 0 03 C t~ 01 0 to H *5,. -:bi w .0 H ft- v .to 0 to 05 0 0
0 'S4= C5 0'i.
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1 ! 44 }r
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> ,*a?X
; r0o 'k
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it.
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to
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rooi>*
S
o
oion*
ro
-
' /-"Xk to
r tO : 05 ? r-4 ` '*" \44 ^0 ?. O 5 SC
n. E
m :s l
o . O rH
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> r-- 0
44 0
0 p-- 0 r-- t- CO 0-rs .43 .o e rH 10 S-^ '45 O
> n 0
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e
m
tp co 0 r> 43.cn . 6 1-rl .0 W .45
mam^as sj^*xn
o . .o
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.4vjUt=oi .4j50a4- UD. I
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: *5
to CinD
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r" 0 44 0
3: O i0 2:
<u .0 13 13 *4
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/-'S
to to 01 rH ;js-/
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0 s:
US
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S8.-.`
13
>> S- .
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ao
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r*. toon 8
0b CM p
50
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. Tma3>
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O
,03 r-- JE
(A 0>4A O . -
S- . 4J 0O 0
0 rH *t t 1 ^ 43 .0 * 3 ULW 00 `i- JO 44
-.CL rr JC 0 3 44 4S.13 3U0 . :o "SL
' r--
O . V) .44
Or* U3 0 13 ' 00 ^S. 0 .*> y> U 1~ 44
00U *r- .43 0
o. n 45 0 4D 44 .43 3
3U0 0 SI
+J
'3 13 0
'.
0_ W h 4 'Ss 0 P> 0 iXH*^ . 43 OO
rH trt' 1 <Si
C3 r*.-
in L . >rr
i- .0 O to ft-- -to 44
i- O s- 0 0 0 44 *T0 44 *- 43 1-^r O r- . >Ss O
O VII r- 5L ^
i- -0 CM b 0
O
<0 rO-- >L>?
U0 <P (4 G +4 0 0 tf> U 43 Q. OI 1 O S-0 . O)
44 b) .caH* =0. O. 3 13 CO tO 0 CM <30
CO
S--M 0
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0 U) X L.
i0
e^*
G -44. 0 0 0
.0
to .0 -
0 0 rr- >
E
.0 .
*r U.W (0
f- O
13 0 3 44 0 +4 U O '5L 13 tf) 0 44
or
E 53. 0L O 44
H14
W .CM COl
n
qj
44
l .
H 44 CO J5 13 ' IL C CO 3 0 O
3 to .J
*0 rH E I0
.0 * TJOP O
>>
0 in b c 0 'ft- -in -i- ,
C*ft-
.G .
a. o u 1- tn ex .0 0 *p
.00 OO V0
O0
to
* 0e b-- 3 S-
a
0 44
5 LO .** so
44 3 *r~ CO s to *0 3 'S-TD ai ai -a .si
-P c
to
c to.0 -r- a t-
13 ft*.
01 *r- Q.
04-> 13 ft- U
'r-t*oon-- -.ie0--01 L0. c0 +<4fl cPtj JOC3id
o s~ x
4a3d. ft- 0
u1
5? 0
13 U = C0 V? f- C
0 t-
C3 . 3 *ft-
= 103 GO
13 0 f--
a> :S 4J
03 P O tn
CM O J5 5-
a. .0 03 0
O 04
-O LC GG *
0 0 53 S- U 43
T- 0 >j S- C 0 .0 0 3 *r-
.G 3 ' 44 L L. tO
G 13 O 0 0 0 0 44 .45 0 *h ai d h L G r- p 0
<
10-3 :
u 0
ci c* 0 r-* .r^*
in 0 0 04 <A wn_ .0 42 03 X.O 0 0 CM 0 O 04
i J4
13 C'
S~ 5-
0.
O *r
^ to >> x 5- S_
G00 O
-i- .0
+4
0 44 U <
13 t 4 0 0,
0 0.43 ft-
0 -4
shipbreaking operatlons
180 pg/ift3 - scrap yari
workers
DUP040012240
10-4
Source: Chamberlain et al. (1978).
DUP040012241
Rabinowitz et al. (1977) administered 304Pb tracer to adult volunteers and deterfflined (by isotope tracer and balance data) that 14 pg lead was absorbed by these subjects daily at amblent dir lead levels of 1-2 pg/m3, Assuming a daily ventilation rate of 20 m3, a deposition rate of 50 percent of ambient air (Chamberlain et al.', 1978), and a mean air lead level of 1.5 pg/m3 (2,0 pg/m3 outside the study unit!, 1.0 pg/m3 inside, as determined bji the authors), then 15 pg lead was available for absorption. Hence, better than 90 percent of deposited lead was absorbed daily.
M? orrow et al. (1980) followed the1 systemic uptake of 203Pb in. .17 adul. t ` sub/ jec.t.s..u.si.ng either lead chloride or lead hydroxide1 aerosols with an averagd site of 0,25 (0.1) pm MMA0i Half of the deposited fraction of either aerosol was absorbed in 14 hr Or less. The radiolabel data described above are consistent with the data of Hitrsh'Ibd Mercer (1970), who studied the systemic uptake of 212Pb on;a carrier aerosol.
Given the apparent Invariance of absorption rate for deposited lead in the above studies as a function of the chemical form of ;the element (Chamberlain et al> , 1978; Morrow et al.., 1980), inhaled lead lodging deep in the respiratory .'tract seems to be absorbed equally, re gardless of form. Supporting evibenc^ for total human systemic uptake of lead comes from autopsy tissue analysis for lead content, Barry (1975) found that lead was not accumulated in the lungs of lead workers. This observation is corroborated by the data of Gross et al, (1975) for nonoccupationally exposed subjects.
Dependence of the respiratory absorption rate for lead in humans on the level of lead in air has not been extensively studied, although the data of Chamberlain and coworkers (1978), using:human volunteers, show that the lung clearance rate in the adult for single lead pulses did nOt vary over a lung burden range of 0.3 to 4.50 pg. In occupational settings, a curvi linear relationship between workplace pirborne lead and blood lead results at 1 east partly from particle size changes, i.e., witl) increasing dust concentration, particle aggregation rate increases and the effective fraction of submicron particles (those penetrating to the Tung)jcompared to total particles steadjly lessens (Chamberlain, 1983). j
All of the available data for lead, deposition and uptake from the respiratory tract ir humans have been obtained with adults, and quantitative comparisons with the same exposures in children are not ppspibie. Although children 2 years of age weigh one-sixth as much as an adult, they inhale 40 percent as much air lead as adults (Baritrop, 1972). James (1978) has taken into account differences in airway dimensions in adults versus children, and has esti mated that, after controlling for weight, the ID-year-old child has a deposition rate 1.6- to 2.7-fold higher than the adult.
Recent studies support the above estimates of James (1978). Hofmann and coworkers (Hofmann, 1982; Hofmann et al., 1979) reported dose calculations for the respiratory tract as a function of age using airway length estimates from the literature and determined that intake
10-5
DUP040012242
of radioactive nuclides into both the tracheobronchial and pulmonary regions was highly agedependent, with maximal intake occurring at about age six.
10.2.1.2 Animal Studies. Experimental animal data, for quantitative assessment of lead depo
sition and absorption for the Tung and upper respiratory tract are limited. The available in- * .
formation does, however, support the finding that respired: lead^ is extensively and rapidly
absorbed.
x
Morgan and Holmes (1978). exposed adult rats, by nose-only technique, to a 2&3Pb-labeled engine exhaust aerosol generated in the same manner as by Chamberlain ,et at. {1978) over a
period of 8 days. Exposure Was at a. level, of 21,9 to 23.6 nCi label/liter chamber air. Ad-
justing for deposition on th'g animal pelt, 20-25 percent of the label wasdeposited in the j
lungs. Deposited lead was taken up extensively in blood (50 percent within 1 hr and 98 per- i
cent within 7 days). The absorption-rate kinetic profile was similar to that reported for
humans (Chamberlain et al., i|78).
:
i ;
Boudene et al, (1977) exposed rats to 210Pb-labeled aerosols at a level of 1 pg label/m3
and 10 pg label/m3, the Majority of the particles being 0-1-0.5 pm In size. At 1 hr, 30 per
cent of'the Tabel had left th| lung.; by 48 hr, 90 percent was gone.
j
Bianco et al. (1974) usbd 212Pb aerosol (0,2 pm) Inhaled briefly by dogs and found a '
clearance half-time from the lung of .approximately 14 fwv Greenhalgh et al, (1979) found that
direct instillation of 23PbH-labeled lead nitrate solution into the lungs of rats led to an
uptake of approximately 42. percent within 30 min, compared with an uptake rate of 15 percent
within 15 min ift the rabbit. These instillation data are consistent with the -report of Pott
and Brockhaus (1971), who noted that intratracheal instillation of lead- in solution (as bro
mide) or. in suspension (as oxide) serially over 8 days resulted in systemic lead levels in
tissues indistinguishabie from ..injected lead levels, Renda.11 jet al. (1975) found that the movement of lead! into blood of] baboons inhaling a lead oxide (Pb^0.4) was more, rapid and resul
ted in higher .blood lead levels when coarse (1.6 pm mean diameter) rather than fine (0.8 pm
mean diameter) particles were jised. .
]
; i
10-2.2 Gastrointestinal Absorption of Lead
-
Gastrointestinal (Gl) absorption of lead mainly involves uptake from food and beverages,
as well as lead deposited in the upper respiratory tract that is eventually swallowed. It
also includes Ingestion of nonfood material, primarily in children via normal mouthing activ
ity and pica. Two issues of concern with lead uptake from the gut are the comparative rates
of such absorption in developing versus adult organisms, including humans, and how the bio-
availability of lead affects such uptake.
10.2.2.1 Human Studies, Based on long-term metabolic studies with adult volunteers, Kehoe
(1961a,b,c) estimated that approximately .10 percent of dietary lead is absorbed from the human
10-6
DUP040012243
)
gut, According to Cross (1981), various balance parameters can vary considerably among sub jects. These studies (Kehoe, 1961a,b,c) did not take into account the contribution of biliary clearance of lead into the gut, which would have affected measurements for both absorption and total excretion. Chamberlain et al'.. (1978) determined that the level of endogenous fecal lead is approximately 50 percent of urinary lead values. They have estimated that 15 percent.of dietary lead is absorbed, if the amount of endogenous fecal lead is taken into account.
Following the Kehoe studies, a number of reports determined GI absorption using both sta ble and radioisotopic labeling of dietary lead- .Generally, these reports support the observa tion that in the adult human the absorption of lead is limited when taken with food.. Harrison et al. (19(59) determined a mean absorption r|ata of 14 percent for three adult subjects ingest ing 203Pt in diet, a figure in accord with the results of Hursh and SuomeTa (1968), 'Chamberlain et al. (1978) studied the absorption of 2?Pb 1 rj two forms (as the chloride and as the sulfide) taken with food. The .dorrespon^ihg absorption rates were 6 percent (sulfide) and 7 percent (chloride), taking into account endogenous fecal excretion. Using adult subjects who ingested the stable isotope 204Pb -in their diet, Rabinowitz et al. (1974) reported an average gut absorption of 7.7. percent. In a later study, Rabinowitz et al. (1.980) measured an ab sorption rate of 10.3 percent.
'A.number of recent studies indicate that lead.ingested under fasting conditions is absor bed to a much greater extent than lead taken with or incorporated into food- For example, Blake (1976) measured a mean absorption rate of 21 percent when 11 adult subjects ingested; 203pb-]abe'led lead chloride several hours after breakfast. Chamberlain et al. (1978) found
that lead, uptake in six subjects fed 203Pb as the chloride was 45 percent after a fasting,
period, compared to 6 percent with food. Heard and Chamberlain (1982) obtained a rate of 63.3; percent using a similar procedure -with eight subjects. Rabinowitz et .al. (1980) reported an. absorption rate of 35 percent in fiye. subjects when 204Pb was ingested after 16 hr of fasting,'
These isotope studies support the observations of Barltrop; (1975) and Garber and Wei (1974)
that lead in between-mealj beverages is absorbed to a greater extent than is lead in food,! Dependence of the lead absorption rate from the human; GI tract on the concentration of
lead in diet or water has not been.well studied. Recent data from the reports of Blake (1980),' Flanagan et al. (1982), and Heard and Chamberlain (1983), however, indicate little concentration dependency across the range of dietary lead content encountered by the general population, for example, Flanagan et al, (1982) found that human volunteers absorbed 4, 40, and 400 pc; of ingested lead at about the same rate.
The relationship of lead bioavailability in the human gut to the chemical/biochemical form of lead can be determined from available data, although interpretation is complicated by the relatively small amounts administered and the presence of various components of food
10-7
DU P040012244
already present in the gut. Harrison et al. (1969) found no difference in lead absorption
from the human gut when lead isotope was given either as the chloride or incorporated into al
ginate. Chamberlain et al, (1978) found, that labeled lead as the chloride or sulfide was ab
sorbed to the same extent when ingested with food, but the sulfide form, was absorbed at a rate
of 12 percent compared with 45 percent for the chloride under fasting.conditions. Rabinowltz
et al. (1980) obtained similar absorption rates for.the chloride, sulfide, or cysteine complex
forms when administered with food or under fasting conditions. Heard and Chamberlain (1982)
found no difference in absorption rate when.isotopic lead C203Pb).was ingested with unlabeled
meat (sheep's liver and kidney) or when the label ,iwas incorporated, into the food prior to
slaughter.
'.......
,.
The data of Moore et al. (1979) are pf interest with respect to . relative GI uptake of
lead in adult males and females. Human volunteers] (seven males, four: females) were given
203Pb in water and whole-body counting was carried out at time points. It appeared that
females absorbed somewhat more of the label than males, but the^dlfference did not reach sta
tistical significance.
:
Two reports have focused on the question of dif1 ferences in GI. absorption rates between adults and children. Alexander et al. (1973) carriejd out 11 balance studies with eight chil
dren, aged 3 months to 8 years. Daily intake averaged 10.6 pg Pb/kg body weight (range 5-17).
The mean absorption rate determined from metabolic balance studies was 53 percent- A two-part
investigation by Ziegler et .al. (1978) comprised a total of 89 metabolic balance studies with
.12 normal infants ]aged 2 weeks to 2 years. In the first part, 51 balance studies using 9
children furnished;a mean absorption rate of 42,7 percent. In the second, six children were
involved in 38 balance studies involving dietary lead intake at 3 levels. Diets were closely
controlled and lead content was measured. For all daily intakes of 5 pg Pb/kg or higher, the
mean absorption .rate was ,42 percent. , At low level j of lead intake the- data were variable,
with some childrenSapparently in negative balance, probably because of the difficulty in con
trolling low lead intake.
j
\
In contrast tb these reports, BarTtrop and Stiehlow (1978) found that the results for
children hospitalized as orthopedic or "social" admissions were highly, variable. A total of
104 balance studies were carried out in 29 children - ranging in age from 3 weeks to .14'years.
Fifteen of the subjects were in net negative balance, with an average dietary absorption of
-40 percent or, when weighted by number of balance studies, -16 percent. Closely comparing
these data with those of Ziegler et al. (1978) is difficult. Subjects were inpatients, repre
sented a much greater age range, and were not classified in terms of mineral nutrition or
weight-change status. As an urban pediatric group, the children in this study may have had
higher prior lead exposure so that the "washout" phenomenon (Kehoe, 1961a,b,c; Gross, 1981)
may have contributed to the highly variable results. The calculated mean daily lead Intake in
" *
10-8
DUP040012245
the Barltrop and Strehlow group (6.5 pg/kg) was lower than that for all but one study group
described by Ziegler et al. (1978). In the latter study, data for absorption became more
variable as the daily lead intake was lowered- Finally, in those children classified as or
thopedic admissions, whether skeletal trauma was without effect on lead equilibrium between
bone and other body compartments is-unclear.
\ /'
As typified by the results of-the second National Health Assessment and Nutritional Eval
uation Survey (NHANES II) (Mahaffey et al,, 1979), children at 2-3 years of age show a small
peak in bloojd lead. The question arises whether this peak indicates an intrinsic biological
factor, such; as increased absorption or retention when compared with older children, or whe
ther this agp group is exposed to lead in some special'way. Several studies are relevant to
the question] Zielhuis et al. (1978) reported data-for blood lead levels in 43 hospitalized
Dutch children, who ranged in age from .2 months to 5 years. Children up.to 3 years old had a
mean blood lead level of 11.9 pg/dl versus a level of 15.5 In children aged 4-6 years. A sig
nificant positive relationship between child age and blood lead was calculated (r = 0.44,
p <0.05), In the Danish survey by Nygaard et al. (1977), a subset of 126 children represent
ing various geographical areas and age groups yielded the following blood lead values by mean
age group:; cnildren (N s 8) with, a mean age of 1.8 years had a mean, blood lead level of 4.3
pg/dl.; those, with a mean age of 3.7-3,9 years had values ranging from 5.6 to 8.3 pg/dl; and
children 4.6-4,8 years of age had a range of 9.2 to 10 pg/dl. These authors note that the
youngest group was kept at a nursery., whereas !the older kindergarten children had more inter
action with the outside environment. Sartor and Rondia (1981) surveyed two population groups
in Belgium, one of which consisted of groups of children aged 1-4, 5-8, and 9-14 years.
Children under the: age of 1 year had a mean blood lead level of .10.7 pg/dl. The 1- to 4-year
and 5- bo 8-jyear age groups were comparable:, 13.9 and 13.7 pg/dl, respectively, while those
i .'
|
!'
9-14 years old had a blood lead level of 17,2i-pg/dl. All of'the children in this study-were
-hospital patients. While these ..European studies suggest that any significant restriction of 1 \\
children in ijerms of environmental interaction,] e.g,, in hospitals or nurseries, jis associated
with an .apparently different age-blood, lead feiationship than the U.$, NHANES? II subjects,
whether European children in the 2- to 3-year age group show a similar peak remains to be
demonstrated. The issue merits further study.
The normal mouthing activity of young: children, as well as the actual ingestion of non
food items (i.e,, pica), is a major concern in pediatric lead exposure, particularly in urban
areas with deteriorating housing stock and high automobile density and in nonurban areas con
tiguous to lead-production facilities. The magnitude of such potential exposures is discussed
in Chapter 7, and an integrated assessment of impact on human intake appears in Chapter 13.
Such -intake is Intensified for children with pica and would include paint,yiust, and dirt.
10-9
DUP04OG12246
Drill et al. (197.9), using data from Day et al, (1975) and Lepow et al. (1974), have at-
tempted to quantify the daily intake of soil/dust in young children from such mouthing activi
ties as thumb sucking and finger licking, A total of 10.0 mg/day was obtained for children 2-3
years old, but the amount of lead in this ingested quantity varied considerably from site to site. i In the report, a GI absorption rate of 30 percent was estimated for lead in soil arid
dust. Of relevance to this estimate are the animal data discussed in the, next section,' which
show that lead of variable chemical forms in soil or dust is as available for absorption as
lead in food. The vitro studies relating lead sol utility; in street dusts with acidity
clearly demonstrate, that the acidity of the human stomach is adequate, to- extensively solyb.ir
Hze l1ead assimilat. ed fro m soil and dus. t. \ T- o the exte nt that ingestion j,of suc. h mater' ial by children occurs other than at mealtime, the fasting factor in enhancing jlead absorption from
the
hu) man
GI
tract
(vide supra) .......
must
also
be
considered.
Hence, a factd| r of 30 percent for
lead absorption from dusts and soils is not an unreasonable value..
v-i'` ' '
A National Academy, qf Sciences (NAS) report on lead poisoning in children has estimated
that paint chip ingestion by children with pica occurs with considerable frequency (National
Academy of Sciences, 3,976), In the case of paint chips, Drill et al, (1979) estimated an ab sorption rate as high as 17 percent. This sralue may be compared with the] animal data in Sec
tion io.2.2,2ji which indicate that lead in old paint films .can undergo significant absorption
in animals.
5
10,2.2.2 Animal Studies. Lead absorption via-the gut of various adult experimental animal
species appears to resemble that for the adult human, on the order of 1-15 percent in most
eases. Kostial and her coworkers (Kostial and Kello, 1979; Kostial et al., 1978, 1971) re
portedI a value of 1 percent or less in` .adult rats maintained on commerJcial rat chow. These studies were carried out using radxoisptopic tracers. Similarly, Barltjrop and Meek (1975)
reported an absorption rate of 4 percenjt in control diets, while Aungst [et al.-, (1981) fohnd
the value to range from 0,9 to 6.9 percent, depending on the level of lead given in the diet.
In thfi.se rat studies, lead was ingested with food. Quarterman and Mo.njison (1978) admini stered, 203!Pb label in small amounts of jfood to adult rats and found an uptake rate of appro
ximately 2 percent at 4 .months of age. Pounds et al, (1978) obtained a .value of 26.4,percent
with four adult Rhesus monkeys given ?10Pb by gastric intubation. The higher rate, relative
to the rat, may reflect .various states of fasting at time of intubation or differences in
dietary composition (vide infra), two factors that affect rates of absorption.
As seen above with human subjects, fasting appears to enhance the rate of lead uptake in
experimental animals. Garber and Wei (1974) found that fasting markedly enhanced gut uptake
of lead in rats. Forbes and Reina (1972) found that lead dosing by gastric intubation of rats
yielded an absorption rate of 16 percent, which is higher than other data for the rat indi
cate. Intubation was likely done when little food was in the gut. The data of Pounds et al.
10-10
"
DUP040Q12247
(.1978), as described above, may a^so suggest a problem with administering lead by gastric in
tubation or mixed with water as opposed to food.
The bioavailability of lead in the SI tract of experimental animals has been the subject of a number of reports. The designs of these studies differ in regard to how "bioavailabi
j
lity" is defined. In some cases, .the dietary matrix was Kept constant, or nearly so, Wile - i
the chemical or physical form of the lead was varied, By contrast, other data described the * -I effect of changes in bioavailability as the basic diet matrix was changed, the latter case is - ;
complicated by the simultaneous joperation of lead-nutrient interactive relationships (de-
I
...
..
V
scribed in Section 10.5.2).
;
Altcroft {1950) observed comparable effects when calves were fed lead in the form of the
phosphate,, oxide, or basic carbonate (PbC03*.Pb(OH)?), dr incorporated into wet or dry paint.
By contrast, lead sulfide in the jform of finely ground galena ore was less toxic. Criteria
for relative toxicity Included Sidney and blood lead levels ^nd survival rate over time.
In the rat, Barltrop and Meek (1975) carried but a comparative absorption study using
lead in the form of the acetate as the reference substance. The carbonate and thallate were
ft
...
'
absorbed to. the greatest extent, while absorption of the sulfide, chromate, napthenate, and
i i
octoate was 44-67 percent of the Reference agent. Barltrop and Meek (1979) also studied the
relationship of the size of lead particles (as the metal or as lead octoate or chromate in
powdered paint films) to the .amount of gut absorption in the rat; they found an inverse rela
tionship between uptake and particle size for both forms,
^
Gage and Litchfield (1968, 1969) found that lead napthenate and;chromate can undergo con
siderable absorption from the rat gut when incorporated into dried paint films, although less
than when given with other vehicles. Ku et al. (1978) found that lead in the form of the ace
tate or as a phospholipid comp! e>j was equally absorbed from the Gj tract of both adult and
young rats at a level of- .3.00 ppm* Uptake was assessed by weight5 change, tissue levels of ,
' ead, and urinary aminolevulinic aqid (ALA) levels.'
j
in a study relevant to the problem of lead bioavailability injsoils and dusts, particu
larly in exposed-children, Dacre and Tep Ha.ar (1977) compared the effects of lead as acetate
with lead contained in roadside soil and in house paint soil, at a level of approximately 50-
ppm, in commercial rat chow. Uptake of lead was indexed by weight change, tissue lead con
tent, and inhibition of aminolevulinic acid dehydrase (ALA-O) activity. None of these para
meters differed .significantly across the three groups, suggesting that neither the geochemical
matrix in the soils nor the various chemical forms (basic carbonate in paint soil, and the
oxide, carbonate, and basic carbonate in roadside soil) affect lead uptake.
These data are consistent with the behavior of lead in dusts upon acid extraction as re
ported by Day et al. (1979), Harrison (1979), and Duggan and Williams (1977). In the Day et
al. study, street dust samples from .England and New Zealand were extracted with hydrochloric
10-11
DUPO4O012248
acid (HCT) over the pH range ,of 0-5. At an acidity, that may be equalled by gastric secre
tions, i.e., pH of 1, approximately 90 percent of the, dust, lead was solubilized, Harrison
(1979) noted that at this same acidity, up to 77 percent of Lancaster, England, street-dust
lead was soluble, while an average 60 percent solubility was seen in, London dust samples '
(Duggan and Williams, 1977). Because gastric solubilization must, occur for lead in these
media to be absorbed, the above data are useful in determining relative risk;
-. y
Kostial and Kello (1979) compared the absorption of 203Pb from the gut* of rats maintained
on commercial rat chow versus rats fed such "human" diets as baby, foods, porcine liver, bread,
and cow's milk. Absorption in the latter cases varied from 3 to ,20 percent> compared with*
<1.0 percent with rat chow* This range of uptake for the nonchow diet compares closely with,
that reported for human subjects (vide supra). Similarly, Jugo et al, (197.5a) .Observed that`
r -i :
*'
'i
rats maintained on fruit ..diets had an absorption rate of 18-20 percent. The generally ob-i
served lower absorption of lead in the adult rat compared to the adult human appears, then,:
less reflective of a species difference than of a dietary difference,
A number of studies have documented that the developing animal absorbs a relatively
.greater fraction of ingested lead than #05 the adult, thus supporting studies showing this',
age dependency in humans, j For example., the adult rat absorbs approximately 1 percent lead orj
less via diet versus a corresponding value 40-50 times greater in the rat pup (Kostial et al,,
1971, 1978; Forbes and Reina, 1972). In the rat, this difference persists through weaning
(Forbes and lleina,- 1972), at which point uptake resembles that of adults. Part of this dif
ference can be ascribed to the nature of the diet (mother's milk versus regular diet), al
though the extent of absorption enhancement with milk versus rat chow in the adult rat found
by Kello and Kostial (1973) fell short of what is seen in the. neonate. An undeveloped, less
selective Intestinal barrier may also exist in the rat neonate. In nonhuman primates, Munroi
et al, (1975) observed that infant monkeys absorbed 65-85 pefcen.t via the gut versus 4 percent;
in adults. Similarly, Pounds et al. .(1978) noted that juvenile rhesus monkeys absorbed appro-,
ximately 50 percent more Ifad than adults,
; .j
1
-
l
-I j
The question of the relationship of level of lead intake through the 61 tract and rate of;
lead absorption was addressed by Aungst et al. (1981), who exposed adult and suckling rats to'
doses of lead by intubation over the range 1-100 mg/kg or by variable concentrations in drink
ing water. With both age groups and both forms of oral exposure, lead absorption as a percent4
age. of dose decreased, suggesting a saturation phenomenon for lead transport across the gut
wall.
Similar data were obtained by Bushnell and DeLuca (1983) for weanling rats given 203Pb by
intubation along with carrier doses of 1, ID, 100, or 1000 ppm in diet. The GI absorption
rate was observed to decrease significantly between 10 .and 100 ppm carrier lead. Using iso
lated duodenal loop preparations, Conrad and Barton (1978) reported that lead uptake across
10-12
DUP040012249
the glut wall .was constant from 0.001 to 10 ppm lead, but fell off to 40 percent of the 10-ppm level at the 10Q-ppm dbsiftg.
The above concentration dependency is consistent with a saturable, active transport pro cess for lead in the mammalian gut, based on the kinetic data of Aungst and Fung (1981). MykkSneh and Wasserman (1981) also "noted that lead uptake by chick intestine occurs in two kinetic phases;, a rapid uptake is fallowed by a rate-limiting slow transfer of lead. These kinetic observations agree with an increasingly retarded\active transport process as lead con tent increases in the gut; I.es, lead affects its pwn transport, manifested aS an increasingly lower absorption rate at higher lead intake.
Of interest here .is the comparison of the kinetic behavior of blood lead as a function of oral versus parenteral dosing. With single intravenous |njections of 0.5, 1, .5, 10, and 15 mg Pb/kg lead Ip the rat, Aungst et al. (1.981) did not observe any dose dependency of the kinetic rate coefficients governing lead in blood. Integrated-exposuref i.e., area under the blood lead curves, increased linearly with dpse, On the other hand, injection of lead into rabbits at levels of 5, .10, 25, 50, and 500 jig/kg, by single daily injections for 6 days, resulted in clear curvilinearity to the dose-blood lead curve (PrpicjMajic et al., 1973). The differences ift these two reports probably reflect dosing regimen differences: Aungst et al, (1.981) used a higher dosing level as single exposures.
The implication of these experimental findings for human oral lead .exposure is not Clear, As noted earlier, lead intake orally by human subjects up to 400 pg is associated with a rather fixed absorption rate. Direct extrapolation of the animal data described above indi cates that humans would have to ingest 20 to 200 mg lead per day (assuming a 2-kg diet/day at lead contents of 10 or] 100 ppm) tp have a. lowered absorption rate. This value is up tp 4.5,00fold above the upper oral intake guideline for lead (National Academy of Sciences, 1980).
10.2.3 Percutaneous Absorption of Lead Absorption of inofganic lead compounds through the|skin appears to be considerably Tjess
significant than uptake through the. respiratory and Gil routes. This observation contrasts with observations for lead alkyls and other organic derivatives' (see Section 10.7). Rastogi and Clausen (1976) found that cutaneous or subcutaneous administration of lead napthenate in rat skin was associated with higher lead tissue levels and more severe toxic effects than was the case for lead acetate. Laug and Kunze (1948) applied lead as the acetate, orthoarsenate, oleate, and ethyl lead to rat skin and determined that the greatest levels of kidney lead were associated with the alkyl contact.
Moore et al. (1980) studied the percutaneous absorption of 203Pb-labeled lead acetate in cosmetic preparations using eight adult volunteers. Applied in wet or dry forms, absorption was indexed by blood, urine, and whole body counting. Absorption rates ranged from 0 to 0.3
10-13
i-
T
1 \
'!
V
DUP040012250
1
\
percent, with the highest values obtained when the application sites were scratched. These researchers estimated that the normal use of such preparations would result in an absorption of approxintately 0.06 percent.
*
10.2.4 Transplacental Transfer of Lead
Lead uptake by the human and animal fetus occurs readily, based on such indices as fetal tissue lead measurements and, in the human, cord blood lead levels. Baritrop (i960) and Horiuehi jet al. (1959) demonstrated by fetal tissue analysis that placental transfer in the human occurs by the 12th week of gestation, 'with fetal lead uptake increasing throughout development. The highest lead levels occur in bone, kidney, and liver,, followed by blood, brain, and heart. Cord blood contains significant amounts of lead, which generally correlate
with maternal bipod Values and are slightly bui significantly lower in concentration than the
mother's (Scanlon, 1971; Harris and Holley, 1972; Gershanik et a|., 1974; Bechet et al,, 1978;
Alexander and Delves, 1981; Rabinowitz and NeedTeman, 1982).
A cross-sectional study of maternal blood lead levels carried out by Alexander and Delves
(1981) showed that a significant decrease in maternal blood lead occurs throughout pregnancy,
a. decrease greater than the dilution effect bf the concurrent increase; in plasma volume.
Hence, during pregnancy there is either an increasing deposition of lead in placental or fetal
tissue or an increased loss of body lead via other routes. Increasing absorption by the fetus
during gestation, as demonstrated fay Barltrop (1969), implies that the former explanation is
likely. Hunter (1978) found that summer-born children showed a trend toward higher blood lead
levels than those born in the spring, suggesting increased fetal uptake in the summer result
ing from increases in circulating maternal lead, this observation was confirmed in the report
of Rabinowitz I and Needleman (1982). Ryu at alj (1978) and Singh et al. (197.8) both reported
that infants Lorn to women -having a history of [lead exposure had significantly elevated blood
lead values at birth.
10.3
Ij
II i. i DISTRIBUTION .OF LEAD IN HUMANS AND ANIMAL6
'
-
!
! i.
A quantitative understanding of the sequence of changes In lead levels in various body
pools and tissues is essential in interpreting measured lead levels with respect to past expo
sure as well as present and future risks of toxicity. This section discusses the distribution
kinetics of lead in various portions of the body (blood, soft tissues, calcified tissues, and
the "chelatable" or toxicologically active body burden) as a function of such parameters .as
exposure history and age.
4
10-14
DUP040012251
A given quantity of lead taken up from the GI tract or the respiratory tract into the
bloodstream is initially distributed according to the rate of delivery by blood to the various
organs and systems. Lead is then redistributed to organs and systems in proportion to their
respective affinities for the element. With consistent exposure for an extended period, a
near steady state of intercompartmental distribution is achieved.
/
Fluctuations in the near steady, state will occur whenever short-term lead exposures are
superimposed on .a long-term uptake pattern. Furthermore, the steady-state, description is im
perfect because, on a very short (hourly) time Seale, intake is hpt constant. Lead intake
with mealSj and changes in ambient air lead (Outside to inside and vice, versa) cause quick
changes injexposure levels that may be viewed as short-term alterations in tiie small, labile
lead pool.; Metabolic stress could remobilize and redistribute body stores, although documen
tation of jthe extent to which this happens is very limited {Chisel and Harrison, 1956).
>
"1
10.3.1 Lead in Blood Viewed from different time scales, lead in whole blood may be seen as residing in several
distinct, Interconnected pools. More than 99 percent of blood lead is associated with the erythrocytes (DeSitya, 1931; Everson and Patterson, 1980; Manton and Cook, 1979) under typical conditions, but it is the very small fraction of lead transported in plasma and extracellular fluid that provides lead to the various body organs (Baloh, 1974).
Although the toxicity of lead to the erythrocyte (Raghavan et at., 1981) is mainly asso ciated with membrane lead content, most of j the erythrocyte lead is bound within the cell. Within erythrocytes from npnexposed subjects, lead is primarily bound to hemoglobin, in par ticular HbA21 which binds approximately 50 percent of cell lead while constituting only 1-2 percent ofi total hemoglobin (Bruenger et al., 1973). A. further 5 percent j is bound to a 10,OOQ-daltOn molecular-weight-fraction, about .20 percent to'..a much heavier^ molecule, and
about 25 percent is considered "free'1 or'bound to lower-weight .molecules (Ong pnd Lee, 1980a; Raghavan anjd Gonick, 1977). Raghavan et a).j(1980) have observed that, among Workers exposed to Lead, tfiose who develop signs of toxicity!at relatively low blood lead levels seem to have a diminished binding of intracellular lead with the 10,000-dalton fraction. This reduction In binding suggests an impaired biosynthesis of a protective species, According to Ong and Lee (1980b), fetal hemoglobin has a higher affinity for lead than adult hemoglobin.
Whole blood lead in daily equilibrium with other compartments was found to have a mean life of 35 days (25-day half-life) and a total lead content of 1.9 mg, based on studies with a small number of subjects (Rabinowitz et al., 1976). Chamberlain et al. (1978) established a similar half-life for 203Pb in blood when volunteers were given the label by ingestion, inha lation, or injection. The lead inhalation studies in adults described by Griffin et al.
i"
t: . *:
:
fA'Tk
\
10-15
DUP040012252
trace amounts are bound to high-weight globulins. To state which binding form constitutes an
"active1* fraction for movement to tissues is not possible.
Although Rosen et .ah (1974); reported that plasma lead did not vary across a range of
whole blood levels, the findings of Everson and Patterson (1380), DeSilva (1981), and
Cavalleri et al, (1978) indicate that'there is an equilibrium between red blood cells (RBCs)
and plasma, such that levels in plasma rise with levels in whole blood. This observation is
consistent with the data of Clarkson and Kench (1958), who found that lead in the BBC is rela
tively labile, to exchange and a: logical prerequisite for a dose-effect relationship in various
organs. Ong and Lee (1980c), furthermore, found that plasma calcium is capable of displacing
RBC membrane lead, suggesting that plasma calcium is a factor in the cell-plasma lead equilib
rium.
j
Several studies concerning the relative distribution of lead between erythrocytes and
plasma or serum indicate that the relative percentage of blood fead in plasma versus erythro
cytes is relatively constant ;.up to a blood lead concentration of about 50-60 pg/dl, but
becomes increasingly greater above.;-.this level , i, e,, the overall blood lead/plasma lead rela
tionship is curvilinear upward.}
DeSilva (198.1) found that the relative fraction of plasma" lead versus erythrocytes in 1:0$
Australian lead workers increased at '>60 pg/dl,. Similarly, Manton and Malloy"(1983) observed
that a subject haying lead intoxication had Serum lead values ranging from 1.6 to 0.3 percent
as blood concentration changed from. 116 to 81 pg/dl. More recently, .Manton and Cook (1984)
demonstrated a curvilinear relationship between serum and whole blood lead levels. As de
picted in Figure 10-2, the curve indicates that there is a linear segment up to ^50 pg/dl,
followed by rather steep increases in'relative serum lead content?at higher levels.
Measurement of lead in plasma: by these investigators was carefully carried out, and the
Manton reports involved the definitive lead analysis technique oi isotope-dilution mass spec
trometry (IDMS, see Chapter 91. Given the increased erythrocyte fragility with increasing
blood lead content (see Section 12.3), slight hemolysis during sampling might contaminate
plasma or Serum with high erythrocyte lead and complicate such analyses; however, the reports
did not indicate that hemolysis",was considered a problem.
`
The .biological basis for higher levels of plasma versus whole blood lead with increasing
blood lead burden may be related to marked changes in the binding capacity of the erythrocyte
at high lead content. These changes may result from alterations in binding sites or in the
efficiency of lead movement from membrane to erythrocyte interior. Fukumoto et al. (.1983)
have demonstrated changes (in the form of a decrease) in lead-worker erythrocyte-membrane pro
teins that may have a role in lead transport. Perhaps more important are the long-known ef
fects of lead exposure on erythrocyte morphology and destruction rate (see Section 12.3).
10-17
DUP040012254
1
SERUM LEAD, pg/d!
Figure 10-2. The curvilinear relationship of serum lead to blood lead. Cross-hatched area represents several overlapping points. Source: Manton and Cook (1984}.
10-18
DUP040012255
Changes in cell morphology with increasing blood lead may alter accessibility to binding sites
or the relative! stability of these sites. Increased cell destruction may increase protein-
bound cell lead in plasma, which is only slowly transferred back to cell membrane.
In vitro data concerning the concentration dependency of lead partitioning between gry-
throcytes and plasma are of interest.' Keep in mind, however, that such in vitro data have dir
ployed normal erythrocytes. Clarkson and Kench (1358) showed that.the relative partitioning
between normal erythrocytes and plasiha is relatively constant up to the highest level tested,
equivalent to 100 pg Pb/dl. In the related study of jKoehen and Greener, (19733, tracer plus,-.
carrier lead was added to blood of varying hematocrit!up to a maximum addition of 1000 pg/dl. ..
At a normal hematocrit and a higher value. (0.65), t|he percent uptake of lead label by the .,
cells diminished at around 100 pg/dl, consistent with the Clarkson and Kench. (.1958) data.
Onset of eurvilinearity at a lower blood lead level in!vivo in lead-exposed subjects below the
in vitro value of ^100 pg/dl probably reflects in part altered cell morphology and stability
(DeSilva, 1981; Manton and Malloy, 198.3; Mantop and Cook, 1984).
The curvilinear relationship of plasma to' whole bldod lead pay well .be a factor in
Chamberlain's (198.3) observation that the relative rate of urinary excretion pf lead in human
adults increases with blood lead content, as determined from Various published reports provid-
ing both blood and'urinary lead data (see Section 10.4). It may piso figure in the apparently
better proportionality of tissue lead burdens to dpse than blood lead (vide infra) and,
equally important, the curvilinear relationship of-chelatabie lead to blood lead. That is, at
increasing blood lead, the higher relative rate of plasma lead movement to soft tissues and
bone is greater than, would be anticipated from simple inspection of blood lead content, the
latter rising at a slower rate relative to the increase! in plasma lead.
|
. . .
.1
10.3.2 Lead Levels ih Tissues
",
Of necessity, various relationships .of tissue l.qad to exposure and toxicity in hjumans
generally must be obtained from autopsy samples, although in some studies biopsy data! have
been described. The [inherent question then is whether* such samples adequately, represent the
behavior of lead in the living population, particularly in cases where death was preceded by
prolonged illness or disease states. Also, victims of fatal accidents are not well character
ized as to exposure status and are usually described as having no "known" lead exposure.
Finally, these studies are necessarily cross-sectional ih design, and, in the case of body ac
cumulation of lead, different age groups are assumed to have been similarly exposed. Some Im
portant aspects of the available data include the distribution of lead between soft and cal cifying tissue, the effect of age and development on lead content of soft and mineral tissue,
and the relationship between total and "active" lead burdens in the body,
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10-19
DUP040012256
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10.3,2.1 Soft Tissues. In humans over age 20 most .soft tissues do, not show age-related
Changes in lead levels, in contrast to the case with bone {Barry and Mossman, 1370; Barry,
1975, 1981" Schroeder and Tipton, 1968; Butt et al,, 1964).. Kidney, cortex also shows in
creases in lead with age that may he associated with formation of lead nuclear inclusion '
foodies (Indraprasit et al., 1974), Based on thesd rates of accumulation, the total body bur
den may ha divided into pools that behave differently. The largest and kinetically slowest
pool is the skeleton, which accumulates lead with age. The much more labile lead pool is in
Soft tissue.
;. ,.
Soft-tissue lead levels generally stabilize in early adult life and show a turnover rati .
similar to that for .blood. This turnover i| sufficient to prevent accumulation, except in the renal cortex, which may reflect formation of lead-containing nuclear inclusion bodies (Cramer
et al,, 1974; Indraprasit et al., 1974), The data.of Cross et.al. (1975) and Barry (1975)
indicate that aortic levels rise with age, although this rise fay only reflect entrapment of
lead in atherosclerotic deposits.. Biliary'and pancreatic secretions, while presumably re
flecting some of the organ levels, have tracer lead concentrations distinct from either blood
or bone pools (Rabi.nowitz et al., 1973). i
For levels of lead in soft tissue, the Reports of Barry (.1975, 19.8.1)., .Gross et al. (1975),
and Horiucihi et al. (1959) indicate that soft-tissue content generally is below 0.5 pg/g
wet weight; with higher values for aorta and kidney cortex. The higher values in aorta may or
may not reflect lead in plaque deposits, while higher kidney levels may be associated with the
presence of lead-accumulating tubular cell nuclear inclusions;. The relatively constant lead
concentration in lung tissue across age groups .suggests no accumulation of respired lead and
is consistent with data for deposition and absorption (see Section 10.2.1). Brain tissue was
generally under 0.2 ppm wet weight .and appeared to show no change with increasing age. Since
these dataj-were collected by cross-sectional study, age-related changes in trie low levels of
lead in brain would-have, been difficult to discern. Barry (1975) found that tissues in a
small group of samples from subjects with jknown or suspected occupational ^xposure showed
higher lead levels in aorta, liver, brain, skin, pancreas, and prostate, .
i
Analysis of lead levels in whole brain is less illuminating than regional analysis to the
issue of sensitivity of certain regions within the organ to toxic effects of lead. The dis
tribution of-lead across brain regions has been reported by-Various laboratories. The rele
vant data for humans and animals are set forth in Table 10-2. The data of Grandjean (1978)
and Niklowitz and Mandybur (1975) for human adults, and those of Okazaki et al. (1963) for
autopsy samples from young children who died of lead poisoning, are consistent in showing that
lead is selectively accumulated in the hippocampus. The correlation of lead level with potas
sium level suggests that uptake of lead is greater in cellulated areas, The involvement of
10-20
DUP040Q12257
TABLE 10-2. DISTRIBUTION OF LEAD IN BRAIN REGIONS OF HUMANS AND ANIMALS
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10-21
DU P040012258
the cerebellum in lead encephalopathy in children (see Section 12.4) and in adult intoxication
.from occupational exposure indicates that the sensitivity of various brain regions to lead as
well as their relative uptake characteristics are factors in lead neuropathology.
In adult rats, selective uptake of lead is shown by the hippocampus (Fjerdingslad et at.,
19H; Danscher et at., 1975) and the amygdala (Dansche.r et al, 1975), By contrast, leach
exposed neonate rats show greatest uptake of lead into cerebellum, followed by cerebral dor*
tex, then brainstem plus hippocampus. Hence, there is a developraental difference in lead dis
tribution in the rat with or without increased lead exposure (Klein and Koch, 1981),
In studies of young dogs, "unexposed" animals showed highest levels in the cerebellum.
Increased lead exposure was associated with selective uptake into gray matter, while cerebel
lar levels were relatively low. Unlike the young rat, then, the distribution Of lead In brain,
regions of dogs appears.dose-dependent (Stowe et al., 1973), -
The relationship of lead distribution to various tissues.with changes in lead exposure
has not been well researched. Available information does suggest that the nature of lead ex posure in experimental animals influences the relationship of tissue lead level to both blood
lead level and level of intake. Long-term oral exposure of experimental animals at relatively
moderate dosing would appear.to result in tissue values that show more proportionality to dose
than do blood lead values, although tissue versus blood.lead relationships still appear to be
curvilinear,. Such is the case with dogs exposed to dietary lead for 2 years (Azar et al.,
1973) and rats exposed in uterp.and postnatally up to 9 months-of age (Grant et al,, 19.80),
By contrast, short-term exposure at various dosing levels yields highly variable data
(see Section 12.4.3.5 and Table 12-8). Bull et al. (1979) have reported brain and blood lead
data for dam-exposed suckling rats that show marked deviation from linear response to dose
when lead was administered in drinking water at 0.0005 to 0.0.2 percent lead. Over this 40-
fold oral dosing range, brain 1e|d-levels increased only approximately threefold at 21 days of
age. Whether this low absorption" of lead by brain reflects tissue distribution curvilinearity
in the pups or reflects a function of nonlinear milk lead versus mdternal dosing relationships cannot be determined. Collins e|t al. (1982) reported that rats or'ally exposed to lead from 3
days of age for 4-8 weeks showed ;a two- to threefold increase in brain regions when the dosing
level was increased to 1.0 mg/kg from 0.1 mg/kg. Blood lead at these two dosing levels showed
a concentration ratio of >2.5, indicating that both brain tissue and blood showed similar non
linear response over this 10-fold change in oral exposure,
*
Barry (197.5, 1981) compared lead levels in soft tissues of children and adults, tissue
lead of infants under 1 year old was generally lower than in older children, while children
aged 1-16 years had values that were comparable to those for adult women, in Barry's (1981) -*
10-22 *
DUP040012259
study, the absolute concentration of lead in brain cortex or the ratios of brain cortex to
blood lead levels did not appear to be different in infants or older children compared to
adults. Such direct comparisons do not account for relative tissue mass changes with age, but
this factor is comparatively less with soft tissue than with the skeletal system.(see Section
10.4).
:
'
' " ` V . ... / .
.V /
Subcellular distribution of leadj-iri soft tissue is not uniform, with high amounts of lead
being sequestered in the mitochondrif and nucleus. Cramer et al, (1974) studied renal biopsy tissue in lead workers having exposures of variable duration. They observed; lead-binding
nuclear Inclusion bodies in the renal proximal tubules of subjects having short exposure, with;
all shewing mitochondrial changes, A considerable body of ..animal data (see Section 10.3.5)
documents the selective uptake; of lead into these organelles. Pounds at al, (1982) describe
these organellar pools in 'kinetic terns as hiving comparatively short half-lives in cultured
rat hepatocy^es, wtfhe MbLachlin et-al. (1980) found that ratkldhey epithelial cells form
lead-sequestering nuclear inclusions within .24 hr.
10;3.,2.2 Mineralizihg Tissue. Biopsy and autbpsy data have shown that lead becomes localized
and accumulates in human calcified tissues, t.e., bones and teeth. The accumulation begins
with fetal development (Bhrltrqp, 1969; Horiuchi et al., 19.59),'
Total lead content in bone may exceed 200 mg in men aged 60 to 70 years, but in women the
accumulation is somewhat lower. Various investigators (Barry, 1975; Horiguchi -and Utsunomiya,
1973; Schroeder and Tipton, 1968; Horiuchi et al.., 1959) have documented that approximately 35
percent of total body lead is lodged in bone. These reports not only establish the affinity
of bone for lead, but also provide evidence that lead increases in bone until 50-60 years of
age, the later fall-off reflecting some combination p.f diet and mineral metabolism changes.
Tracer data show .accumulation jin both trabecular and compact bojie (Rabinowitz et al,, 1976). ' In adults, bone lead is tjh.e most-inert pool as well as the ilarge.st, and accumulation can
serve to maintain elevated blopd lead levels years after past, particularly occupational, ex posure has ended. This fact accounts for the observation that duration of exposure correlates with the rate of reduction of blood lead-after termination of'exposure (O'Flaherty et'.al., 1982). The proportion of body lead lodged in bone is reported to be Tower in children than in adults, although concentrations of lead In bbne increase more rapidly than in soft tissue during childhood (Barry, 1975, 1981). In 23 Children, bone lead was 9 mg, or 73 percent of total body burden, versus 94 percent in adults. Expression of lead in bone in terms of con centration across age groups, however, does not accommodate the "dilution" factor, which is quite large for the skeletal system in children (see Section 10.4),
The isotope kinetic data of Rabinowitz et al. (1976) and Holtzman (1978) indicate biolog ical half-lives of lead in bone on the order of several decades, although it appears that
10-23
there are two bone compartments, one of whi.cb is a repository for relatively labile lead
(Rablnowitz et a!., 1977).
Tooth lead levels also increase with age. at a rate proportional to exposure (Steenhout
and Pourtols, 1981), and are also roughly proportional to blood lead.levelsin man (Winneke et
al., 1981;, Shapiro et al., 1978) and experimental animals (Kaplan et al., 19BQ), 'Dentine lead
is perhaps the most responsive component of teeth to lead exposure because it.is laid 'Sown
from the time of eruption until the tooth is shed. Keedleraan and Shapiro (1974) have docu
mented the usefulness of dentine lead as an indicator of the degree of subject exposure.
FreniIn and Edmonds1 (1980), using alpha-particle excitation and microautoradiography, .have
shown dentine zones' of lead enrichment related to abrupt changes in exposure. The rate of
lead deposition in teeth appears to vary with the type of tooth. Deposition is highest in the
central incisors ancj lowest in the molars, a difference that must be taken into .account when
using tooth lead data for exposure assessment, particularly for Tow levels of lead exposure
(Matkie et al., 1977; Delves et al., 1982).
"
' >
10.3.3 Chelatafale Lead
Mobile lead in organs and systems is potentially more "active." toxicologically inlterms
of being avail able to sites of action. Hence,'the presence pf diffusible, mobilizable, or ex
changeable lead may be a more .significant predictor Of imminent toxicity, or recent exposure
than total body or whole blood burdens. In. reality, however, assays for mobile lead would be
quite difficult.
|
In this regard, chelatafale urinary lead has been shown to provide an index of this mobile portion of total body burden. Note that."cbeljatable" lead refers here to the use of calcium di sodium ethyl enedi ami netetraaceti c acid (CaN.a2E.DTA) and hody compartments accessible to this chelant. Based mainly on the relationship ofjchelatable lead to, indices of hemp bio synthesis impairment, chelation challenge is now viewed as the most useful probe of undue body burden in children dnd adults (U.S. Centers for Disease Control, 1978; World Health Organiza tion, 1977; Chisolm jand Barltrop, 1979; Chisolm et a!.j, ,1976.; Saenger et al. , 1982; Hans'en et
al., 1981). In adults, chelation challenge is the most reliable diagnostic test for assess
ment of lead nephropathy., particularly when exposure is remote in time (Emerson, 1963; Wedeen et al., 1,979) of unrecognized (Batum.an et al., 1981, 1983).
A quantitative description of inputs to the fraction of body lead that is chelstable from various body compartments is difficult to define fully, but it very likely includes a sizable, fairly mobile compartment within bone as well as within soft tissues. This assertion is based on several factors. First, the amount of lead mobilized by chelation is age-dependent in nonexposed adults (Araki, 1973; Araki and Ushio, 1982), while blood and soft-tissue lead levels
-
10-24
DUP040012261
are not (Barry, 1975). This difference indicates a lead pool labile to chelation but kineti-
cally distinct from soft tissue. Second, studies of chelatable lead in animals (Hammond,
1971, 1973) suggest removal of some bone lead fraction, as does the response of ..explan.ted
fetal rat bone lead to chelants (Ro.sen and Markowitz, .198.0), Third, the tracer modeling esti
mates of Rabiriowitz et al. (1977) suggest a mobile bone: compartment, arid fourth, there is.`a
complex, nonlinear relationship of lead intake by air, food, and water (see Chapter 11) to
blood lead, and an exponential relationship of chelatable lead to blood lead (Chisolm et al.,
1976),-
` V
:
' ' ' '
The logarithmic relationship of chelatable lead to blbod lead in children (Chisolm et
al., 1976) is consistent with the studies of Saenper ei at, (1982), who reported that levels
of mobi'iizable lead in "asymptomatic" children wjith moderate elevations in blood lead were
quite similar in many cases to those Values obtained in children with signs of overt toxicity,
Hansen et al. (1981) reported that lead workers challenged with^CaNa^EDTA showed; 24-h,r urine
lead levels that in many cases exceeded the accepted limits even though blood lead was only moderately elevated in many of those workers. The action level corresponded, on the regres
sion curve, to a blood lead value of 35 pg/dl. Several reports provide insight into the behavior of labile lead pools in. children treat
ed with chef!ating agents over varying periods of time. Treatment regimens using CaNa?.EDTA or
C.aNa2f:DTA t BAIL (British anti-Lewisite, or dimercaprol) for up to 5 days have been invariably
associated with a "rebound" in blood lead, ascribed to a redistribution of lead among mobile
lead Compartments'! (Chisolm and Barltrpp, 1979). .Marcus (1982) reported that 41 childjren given
. ' .. ' i
oral .Eh-penicillamine for 3 months showed a significant drop in blood lead by 2 weeks (mean
initial value of 53.2 pg/dl), then a slight rise that was within measurement error with a peak
at 4 weeks, and ja fall at 6 weeks^, followed by rjo further change at a blood leadileve! of 36 pg/dl. Hence,! there was a nearjsteady state a| an elevated level for 10 of the*12 weeks
with continued treatment. This observation could have indicated that re-exposure was occur ring, with oral pjenici11amine and ingested lead lekding to increased lead uptake, a? seen by Jugo et al. (197Sja), However, Marcus (1982) statep that an effort was made to limit further
lead intake a;s mudh as possible. From these reports, a re-equilibration does appear to occur,
varying In characteristics with type and duration of chelation. The rebound seen in short
term treatment with CaNa2EDTA or CaNa2EDTA + 8AL, although attributed to soft tissue, could well include a shift of lead from a larger mobile bone compartment to soft tissues and blood.
The apparent steady state between the blood lead pool and other compartments that is achieved
in the face of plumburesis, induced by O-penicillamine (Marcus, 1982), suggests a rather siza
ble labile body pool which, in quantitative terms, would appear to exceed that of soft tissue alone.
r i. t
- "S';
10-25
DUP040012262
Several studies of EDTA mobilization`of lead in children (Saenger et al., 1982; Piomelli
et al.,, 1984) indicate the relative merit of assessing chelatable lead burden in children
otherwise characterized as having mild or moderate lead exposure as. indicated, by blood 1 ead
levels. Saeriger et al. (1982) noted that significant percentages of, children having mild or
moderate'lead exposure as commonly indexed were found after EDTA .challenge; to have levels of
plumburesis that would qualify them for chelation therapy under U.S. Centers for Disdass
Control (CDC) guidelines.
,
In the most comprehensive evaluation;of this issue to date (Piomelli et al., 1984), 210
children frosi four different urban lead-poisoning treatment centers were evaluated by EDTA
provocation testing.. The results showed that at a blood, lead level: of 30^39 pg/dl , 12 percent
(6/52) of children exceed the ratio of (1.6 for pg Pb excreted per mg EDTA per 8 hr. This
ratio was selected by the study clinician^ as differentiating children with mobile lead bur
dens who require further evaluation and/of treatment* Thirty-eight percent of children with
blocd lead levels of 40-49 pg/dl exceeded the action ratio of 0.6.
As indicated in Section 10.3..1, one basis for the curvilinear relationship between chela-
table lead arid blood lead may be the curvilinear relationship of plasma lead to blood lead.
The former increases at a faster rate witjh exposure increases than blood lead, permitting an
increasingly greater rate of lead transfer,to the chelatable lead compartment.
* ,,
10. 3.4 Mathematical Descriptions of Physiological lead. Kinetics
To account for observed kinetic data and make predictive statements, a:variety of mathe- .
matical (models have been suggested, including those describing "steadyrsiste" conditions;
Tracer experiments have suggested compartmental models of lead turnover based on a central
blood pobl (Holtzman, 1978; Rabinowitz etlal., 1976; Batschelet et al., 1979),. These experi
ments hajva hypothesized well-mixed,' interconnected pools and have used coupled differential
equations with linear exponential solutions to predict blood and tissue lead exchange rates.
Were lead to be retained in these pools ijn accordance with a power-law distribution of resi
dence tiAes, rather than being uniform, a semi-Markov model would be more appropriate (Marcus,,
-1
i
1979). ;
*
*
In the model proposed by Rabinowitz et al, (1976), based on the use of stable lead iso
tope tracer in adult volunteers, lead biokineti.es is envisioned in terms of three body com
partments. These compartments, consisting of a central blood compartment as well as soft-
tissue and bone compartments, differ as to biological half-lives or mean-lives (half life =
mean-life x 0,693). Blood shows the shortest biological half-life, followed by soft tissue
and then the bone compartment. Bone contains most of total body lead burden.
* *
10-26
DU P040012263
i:
A Wore recent approach has been.that of Kneip et al. (1983) for multi-organ compartmentalization of lead, based op data obtained with infant and juvenile baboons administered sin gle and chronic lead doses orally. The model proposed for infant baboons is depicted in Figure 10-3. Figure 10-3 acknowledges- differences, in certain features of lead bTokinetics that differ in the developing versus adult organism.. One of these differences is the lead transfer rate from blood to bone. Jn addition, an:.extracellular space-gut (ECS-Gut) compart ment is included in Figure 10-3. ; The emphasis Is on lead Intake through the gut, and a respirator/ intake component is not included. In common with other attempts at modeling, the blood compartment in the approach of Kneip et al. (1983) is. not further characterized kineticaljy, which is a limitation in view of. the data base concerning such relationships as the curvilinear one between'plasma-and blood lead (see Section 10.3.2). = j
i Most extant .steady-state models are deficient because they are based .on small numbers of subjects and neglect a dose dependency for some of the .Tnterpdiil transfer coefficients,. In thif case, a nonlinear dose-indicator response model would be more appropriate when consid ering changes in blood lead levels... For example, the relationship between blood lead and air lesujl (Hammond et al., 1981; Brunekreef, ,19|4) as well as that between diet (United Kingdom Central'.Directorate on Environmental Pollution, 1982) and tap.drinking water (Sherlock et al., 198.2) are .all nonlinear in mathematical form. In addition, alterations in nutritional status or the onset of metabolic stresses can complicate steady-state relationships.
In a series of papers, Marcus (1985a,b,o,d) has discussed linear and nonlinear muHicomp.artmental models of lead kinetics and has addressed in particular the relationship between plasma lead and blood lead and the relationship between blood lead and total lead intake. As shown in Figure 10-4, Marcus (1985d) differentiated four discrete pools within the blood comparijment: diffusible lead in plasma, proternrbound lead in plasma, a "shallow" red blood cell pool! (possibly the erythrocyte membrane), add a "deep" red blood cell! pool (probably .within
the erythrocyte). 1 This model was based on previously published data frjom a volunteer subject who |ingested lead under controlled experimental conditions (DeSiiva, (981). Different ver sions of the model, all assuming steddy-state conditions for lead in dll tissues, were ana lyzed in terms of three possible mechanisms that might underlie nonlinear blood kinetics: site-limited lead uptake, saturated active absorption, and Increased urinary elimination (Marcus, 1985c). The site-limited absorption model provided the best description of a non linear relationship between plasma lead and blood lead. Figure 10-5 shows the fit of the model to data from .103 subjects studied by DeSiiva (1981). At relatively high blood lead levels, the fit appears quite satisfactory, but plasma lead is underestimated below 30 pg/dl blood lead (see solid line in Figure 10-5). Adding an intercept term of 0.25 (see broken line in Figure 10-5) improves the fit at low blood lead values. The need for an intercept term can
.
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.
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!
10-27
DUP040012264
i
INTAKE----- --
GUT
0 ----fc-EXCRETION
An =0.34 (INFANT) = 0.11.(JUVENILE)
21 -3Ait = 1J3 * j bm* x. IQ
!!
A,, - 0.10
|
A,, = 0.03
A,4 = 0.03
Aa, = 0.07
[ 4
A,, = 0.08
1
Am * 0.01
!
A, = 043
'
!
Figure 10-3. Schematic model of lead metabolism in infant baboons.
Source: Kneip et ai. (1983).
'1 '1
j il
1|
ii
10-28
DUP040012265
10-2.9
Q <UJ Q OO-ix>j
Figure 10-4. A eompartmentai model for lead biokinetics with multiple pools for blood lead.
Source: Marcus (1985cl).
'.
DU P040012266
|
PLASMA LEAD C D N C E N tS A l'S Q jjg/d!
Figure 10-5. Fitting qf nonlinear blood lead model to data of DeSilva 11981). Broken line incorporates an intercept term of 0.25; solid line does not incorporate intercept term. Source; Marcus {1985c).
10-30
DUP040012267
be attributed to possible analytic."error due to contamination of the plasma samples or to
transient fluctuations in plasma lead due to lead exposure just prior to sampling (Marcus,
1985c). In any event, curvilinearity is modest below 30 pg/dl. For individuals without oc
cupational or other excessive .exposure to lead (>30 pg/dl blood lead), it is not possible to
distinguish linear .and nonlinear kinetic models-(Marcus, 198.5c).
'
.10.3.,5 Animal Studies
%.
I
......
.
the relevant questions to be asked of animal data are those that cannot be readily or
fully satisfied by data from human subjects. What .is the effect of exposure level on distri
bution wittv'n the-body at specific time points^ What' is the relationship of age or develop
mental stage on the distribution of lead In organs and systems, particularly the nervous sys
tem? What are the relationships of"physiological stress and nutritional status to the redis-
bution kinetics? Can the relationship of chelatable lead to sbch indicator lead pools as
blood be defined better?
Administration of a single dose,of lead to rats produces high initial lead concentrations
in soft tissues, which then fall rapidly as the result of excretion and transfer to bone
(Hammond, 1971), while the distribution of lead -appears to be independent of the dose.
Casteliino and Aloj (1964) reported'that single-dose exposure of rats, to lead was associated
with a fairly constant ratio of erythrocyte lead to plasma lead, a rapid distribution to
tissues, and r|e]!ati;vely higher uptake in liver, kidney, and-particularly bone. Lead loss from
'organs and tissues follows first-order kinetics except from bone. The data of Morgan et al.
(1977), Casteliino and Aloj (1864), and Keller .and Doherty (19S0a) document that the skeletal
system in ratjS and mice is the kinetlcally rate-limiting step in whole-body leajd'clearance.
SybcelTuliar distribution studies involving'.either tissue fractionation after .in vivo lead
exposure or ip -vitro data document that lead sis preferentially sequestered in- the nucleus
(CasteHip.0 ana d Aloj,' 1964; Goyer ej't-f' al., 1970i) and mitochondrial fractions (Caf steliino andAloj, 1964; Bajrltrop et al., 1974) of cells fromj lead-exposed animals. Lead enrichment in the
mitochondrion iis consistent with the high .sensiitivity of. this organelle to the toxic effects
of lead.
The neonatal animal seems to retain proportionately higher levels of tissue lead compared
with the adult (Goldstein et al., 1974; Momcilovic and Kostial, 1974; Mykkanen et al., 197.9;
Klein and Koch, 198.1) and shows slow decay of brain lead levels while other tissue levels sig
nificantly decrease over time. This decay appears to result from .enhanced entry by lead due
to a poorly developed brain barrier system in the developing animals, as well as enhanced body
retention in the young animals. The effects of such changes as metabolic stress and nutri
tional status have been noted in the literature. Keller and Doherty (1980b) have documented
10-31
that tissue redistribution of lead, specifically bone lead mobilization, occurs in
iactating female mice, with both lead and calcium transfer occurring from mother to pups
(Keller and Doherty, 1980c). Changes in lead movement from body compartments, particularly
bone, with changes in nutrition are described in Section 10.5.
In animal studies that are relevant both to the issue of Chelatable lead versus lead in
dicators in humans and to the relative lability of lead in the young versus the adult', Jugo et
al. (1975b) and Jugo (1980) studied the chelatability of lead in neonate versus adult rats and
Its lability in the erythrocyte. Challenging young rats with.metal chelants yielded propor
tionately lower levels of urinary lead than in the adult, a finding that has been ascribed to
*
'
'i
-
tighter binding of lead in the young animal (Jugo et al., 1975b). In a related observation,
the chelatable fraction of lead bound to erythrocytes of young animals given ?03Pb was approx
imately threefold greater than in the adult rat (Jugo, 1980), although the fraction, of dose in
the cells was higher in the suckling rat. The difference in the suckling rat erythrocyte re* 1 *''
garding the binding of lead and relative content compared with the adult may be compared with
JOng and Lee's (1980b) observation that human fetal hemoglobin binds lead more avidly than does
mature hemoglobin.
j
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10.4 LEAD EXCRETION AND RETENTION IN HUMANS AND ANIMALS Dietary lead that is not absorbed in humans and animals passes through the GI tract and
is eliminated with feces, as is the deposited fraction of air lead thatiis swallowed and not absorbed. Lead absorbed into the blood stream and not retained is excreted through the renal and GI tracts, the latter by biliary clearance. The amounts appearing in urine and feces appear to be a function of such factors, as species, age, and differences in dosing.
10.4.1 Human Studies looker et al. (1969) found that 2|i-2Pb injected into two adult volunteers led to initial
appearance of the label in urine (4.4 percent of dose in 24 hr), then iniboth urine and feces in approximately equal amounts. By use of the stable isotope 204Pb, Rabinowitz et al. (.197.3) reported that urinary and fecal excretion of the label amounted to 38 and 8 pg/day in adult subjects, accounting for 76 and 16 percent, respectively, of the measured recovery. Fecal ex cretion was thus approximately twice, that of all the remaining modes of excretion: hair, sweat, and nails (8 percent).
Perhaps the most detailed study of lead excretion in adult humans was done by Chamberlain et al. (1978), who administered 203Pb by injection, inhalation, and ingestion. After injec tion or oral intake, the amounts in urine (Pb-U) and feces (Pb-Fe, endogenous fecal lead) were
ID-32
DUP040012269
I
compared for the two administration routes. Endogenous fecal lead was 50 percent of that in
urine, or a 2:1 ratio of urinary to .fecal lead. (Increased transit time v/as allowed for fecal
lead to pass through the GI tract.) .
. . .. ..
Based on the metabolic balancer and isotope excretion data of Rehoe (1961a,b,c), Rabino-
witz et al. (1976), and Chamber!airt- et al. (1978), as well1 "W-oh some fecalculations ofJhe Kehoe and Rabinowitz data by Chamberlain et al. (1978), short-term lead excretion amounts to
59-60 percent of the absorbed fraction, the balance moving primarily t.d bone with some sub*
sequent fraction (approximately half) of this stored, amount eventtja] ly .being. excreted. The
irapidly excreted fraction was determined by Chamberlain et al,, (1978) to ..have an excretion half-life of about 19 days. This value is consistent with the estimates of Rabinowitz et al, (1976), who expressed clearance in terms of mean-lives. Mean-Tivjes are multiplied by In 2
(0.693) to arrive at half-lives. The similarity of the blood 23'Pb half-life with that of body excretion noted by Chamberlain et al. (1978) indicates a Steady rate of clearance from the body,
The age dependency
of
lead
excretion rates
k-
in humans ,' _
has
not
been
well
studied;
all
of
the above lead excretion data InyoWed only adults. Table 10-3 combines available data from
adults (Rcibinowitz et al.,- 1977; Thompson, 1971; Chamberlain el al.., 1978) and infants
(Ziegler et! al,, 197:8) for purposes of ..comparison. Intake, urine, fecal, and endogenous fecal lead data from two studies pn adults and one, report on infants are used. For consistency in
the adult data, 70 kg is used as ,an average adult weight, and a Pb-fe:Pb-U ratio of 0.5 is used. Daily lead intake, absorption., and excretion values are expressed as pg/kg body weight.
For the infant data, daily endogenous fecal lead excretion is calculated using the adult ratio
as well as the extrapolated value of 1.5 pg/kg, The-respiratory lead intake value for the
infants is an upper value (0.2 pglm3), since Ziegler et al, (1978)]found air lead to be <0.2 [jig/m3. .Compared to the two representative adult-groups, infants appear to have a lower total
excretion rate, although the excretion of endogenous- fecal lead may be higher than for adults.
In humans,, the dependence of lead excretion rate on level of exposure has been studied in
some detail by Chamberlain (1903)j, who used data from the published reports of Ring et al. (1979), Williams et al. (1969), "Gross (1981), Devote and Spinazzola (1973), Azar et al.
(1975), and; Chamberlain et al.'(1978). Figure 10-6 reproduces Chamberlain' s ` plots of urinary
excretion rate for lead versus blood lead as provided in the various studies. Renal clearance of lead appears to increase as blood lead increases from 25 to 80 pg/dl, the highest blood
value reported. Given the earlier discussion concerning the increased fractional partitioning
of blood lead into plasma with increasing blood lead burden (see Section 10.3.1), one would anticipate an increasing renal excretion rate for lead over a broad range of blood lead.
f -f
i, \
r \
.;?*
?
10-33
DUP040012270
i>
.1
TABLE 10-3.
DAILY LEAD EXCRETION AND RETENTION DATA FOR ADULTS AND INFANTS
v" Children*
...
; Adult . group AD
Adplt . group B
Dietary intake (pg/kg) Fraction of intake absorbed
10.76 0,46 (0,55)<1
3.63 ' 0:15
3.8,6 x . ' 0,15
Diet lead absorbed (pg/kg)
4.95 (5,92)
;
" ;o.S8
Air lead absorbed (pg/kg)
0.20
0.21
0,11
Total absorbed lead (pg/kg)
5.15 (6.12)
0.75'
0.68
Urinary lead excreted (pg/kg) Ratio: urinary/absorbed lead Endogenous fecal lead (pg/kg) ,
iM 0.19 (0-16) 0.5 (l,56)f
j 0.47 " ' .-i . 0.62
0.249
0, 34 0.50 0.179
Total excreted lead (pg/kg)
1.50,(2.56)
0.7!
P.,51
Ratio: total excreted/absorbed lepd
0.29 (0.42)
0.92
0.75 .
Fraction of intake retained
0.34 (0,33)
O.Ol
0.04
^Ziegler et al, <1978). ^Rabifiowitz et al. (1977).
cThotnpsoh (1971) and estimates of Chamberlain et al. (1978)i
%ach of the values in parentheses in this column is corrected for endogenous fecal lead at extrapolated.valine from Ziegler et al. (1978).. |
Corrected for endogenous fecal lead (Pb-Fe = 0,5 x Pb-U),
^Extrapolated value of 1.56 for endogenous fecal Pb.
i
gPb-Fe * 0.5 x Pb-U.
..
!
10-34
DUPO4O012271
1 I-
i blood lead) from (A) King et al., 1379; (B) Williams et
ai., 1969; (C) Gross, 1931; ID) DeVotd and .Spinazzola,
1973; (E) Azar et al., 1975; (Gl Chamberlain et al.,
' 1978.
!
Source: Chamberlain (19831.
;
:>
k
k 5
10-3.5
DUP040012272
i
IJ
Data in Figure 10-6 indicate increased renal excretion of lead only. How the correspon
ding biliary excretion rate changes in the face of increasing lead absorption is not known.
Hence, the overall impact of increasing exposure on total body clearance of the toxicant is
difficult to assess. In experimental animals, the relative partitioning of lead between renal
and biliary excretion routes has been shown to be dose- and species-dependent (see Section
10.4.2).
Lead accumulates in the human body with age, mainly in bone, up to approximately 60 years
of age., when a decrease.occurs with changes in intake;, as.well as in bone mineraltmetabollsm.
Total accumulation by 60 years of age .ranges up to approximately .200 mg (see review by Barry,
1978), although '.occupational exposure can raise this figure several-fold (Barry, 1975).
Holtzman (1978) has reviewed the .available literature on studies of lead retention in bone.
In normally exposed humans a biological half-life of approximately 17 years has been calcula
ted, while data for uranium miners yield a range of 1320-7000 days (4-19 years). Chamberlain
et al. (1978) have estimated lifetime averaged daily retention at 9.5 pg using data of Barry
(1975).. Within shorter time frames, however, retention can vary considerably due to such fac
tors as disruption of the individual's equilibrium with changes in level of exposure, the dif
ferences between children and adults, and, in elderly subjects, the presence of osteoporosis;
(Gross and Pfitzer, 1974).
;
Lead labeling experiments, such as those of Chamberlain et al, (1978), indicate a short
term or initial retention of approximately 40-50`percent of the fraction absorbed. Much of
this retention is by bone. Determining how mUch lead resorption from bone will eventually
occur using labeled lead is difficult, given 'the extremely small fraction of labeled to
unlabeled lead (i.e., label dilution) that would exist. Based on the estimates of :Kehoe
(1961a,b,c), the Gross (.1981) evaluation of theyKehoe studies, the Rabinowitz et; al. (1976) study, the Chajnbar.lain at al. (.1978) assessments! of the aforementioned reports, and the data
of
Thompson
(1971),
s
one
can
estimate that approxT imately 25 perc1 ent Of the
lead absJ orbed daily
undergoes long-jterm bone storage.
j
j
The above (estimates relate either to.adults lor to long-term .retention over mosit of an in
dividual 's' lifetime. Studies with children and developing animals (see Section 10,4,2) indi
cate lead retention in childhood can be higher than in adulthood. By means of metabolic
balance studies, Ziegler et al. (1978) obtained a retention figure (as percentage of total in
take) of 31.5 percent for infants, while Alexander et al. (.1973) provided an estimate of 18
percent. Corrected retention data for both total and absorbed intake for the pediatric sub
jects of Ziegler et al. (.1978) were shown in Table 10-3, using the two values for endogenous
fecal excretion as noted. Barltrop and Strehlow (1978) calculated a net negative lead reten
tion in their subjects, but problems in comparing this report with the others were noted
10-36
DUP040012273
earlier. Given the increased retention of lead in children relative to adults, as well as the greater rate of lead intake on a body-weight basis, increased uptake in soft tissues and/or bone is indicated.
Barry (1975, 1981) measured the lead Content of soft and mineral tissues in a small group of autopsy samples from children 16 years of age and under, and noted that average sofi-tissge values were comparable to thosfe in-female adults, while mean bone lead..values were lower than in adults. These results suggest that bone,in children has less retention capacity for lead than bone in adults. Note, however, that "dilution11 of bone lead will occur because of the significant growth rate of the skeletal system through childhood, Trotter and Hixon (1974) studied changes in skeletal mass, density, apd mineral content as a function of age, and noted that skeletal mass increases exponentially ijn children until the early teens, increases less up to the early 20s, levels off in adulthood, and then slowly decreases. From infancy to the late teens, bone mass increases up to 40-folid. Barry (1975) noted an approximate doubling in bone lead concentration over this interval, indicating that total skeletal lead had actually increased 80-fold. He also obtained a mean total bone lead content of approximately 8 mg for children up to 16 years old, compared with a value of approximately 18 mg estimated from both the bone concentrations in his study of children at different ages and the bone growth data of Trotter and Hixon (1974). In a later study (Barry, 1981), autopsy samples from infants, and children between 1 and 9 years old showed an approximately 3.5-fold increase in mean bone con centrations across the three bone types studied, compared with a skeletal mass increase from 0-6 months ito 3-13 years old of greater than 10-fold, for an estimated increase in total lead of approximately 35-fold. Five reports (see Barry, 1981) noted age versus tissue lead rela tionships indicating that overall bone lead ;level5 iii infants and children were, less than in adults, whefeas: four reports observed comparable levels in children and adults/
If one estimates'' total daily retention of lead in the infants studied by: Ziegler et al. (19.78), usin] g a mean body weight o-4f . approximt ately 10 kg and the corrected retention rate in Table 10-3J one obtains a total daily retention of approximately 40 pg. By[ contrast, the total reporjted or estimated skeletal lead accumulated between 2 and 14 years ijs 8-18 mg (vide supra), which averages out to a daily long-term retention of 2.0 to 4,5 pg/.day or 6-13 percentof total retention. Lead retention may be highest in infants up to about 2 years of age (the subjects of the Ziegler et al. study), then decreases in older children. The mean retention in the Alexander et al. (1973) study was 18 percent, about half that seen by Ziegler et al, (1978). This difference may result from the greater age range in the former study,
"Normal" blood lead levels in children either parallel adult male levels or are approxi mately 30 percent greater than adult female levels (Chamberlain et al., 1978), indicating (1)that the soft-tissue lead pool in very young children is not greatly elevated and thus,
1
I
10-37
DUP040012274
(2) that there is a huge labile lead pool in bone that is still kinetically quite distinct ' from soft-tissue lead or (3) that in young children, blood lead,is a much less reliable indi cator of greatly elevated soft-tissue or labile bone lead than is the case with adults, Barry (1981) found that soft-tissue lead levels were comparable in infants, 51 year old and children * 1-5 and '-9 years old.
'Given the implications of the above discusslon--that. retention of lead in young chifdren is higher than in adults and possibly older children, while at the same, time their skeletal system is less effective for long-llerm lead s,equestration'"th,e, very young child, is at greatly
elevated risk, to a toxicologically active" lead burden.. For further discussion, seeChapter. 13. : ,: ,
Rabinowi tz et al. (1916) examined the bio kinetics of a stable isotope of lead (204Pb) entering human hair after absorptiqjn, hair being a mode of lead excretion in humans and other
mammals. Feeding: adult male volunteers 204Pb daily for about 100 days.and analyzing the iso-
tope.in facial hair resulted in the observation that hair responds more gradually than blood
to changes it) uptake, with a.delay of about 35 days. Hair lead values should be interpreted
as the integral of the blood lead values over about 100 days.
'
j .
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10t4.,2 Animal Studies
In rats and other experimental animalS> both urinary and fecal excretion are. important
routes of lead removal from the organism. The relative partitioning between the two modes is
spjecies- and dose-dependent. Morgan et al, (1977) injected 333Pb into adult rats and noted
that lead initially appeared in urine, followed by equivalent elimination in both urine and.
feces. By .5 days, lead was proportionately higher in feces. Castellino and Aloj (1964),
using 2i0Pb, observed that fecal excretion was approximately twice that of urine (35.7 versus
IS.9 percent) by 14 days.' In the report of Klaassen and Shoeman (1974.1, relative excretion by -
trie tWo routes was seen to be dose-dependent up to 1.0 mg Pb/kg, Excretion was much higher by
biliary clearance into the gut. Ajt 3.0 mg Pb/kg, approximately 90 percent of the excreted
ambu.nt was detected in feces. The! relatively higher. proportion appearing in feces in the.
studies of Castellino and.Aloj (1964) and Klaassen and Shoeman (1974), compared-with the re
sults of Morgan et al. (1977), possibly results from use of carrier dosing, since Morgan
et al. (1977) used carrier-free injections. Hence, increasing dose does appear to favor bi
liary excretion, as noted by Klaassen and Shoeman (1974),
With regard to species differences, Klaassen and Shoeman (1974) found that the amount of
bill ary,.clearance in dogs was about 2 percent of that in rats, while rabbits showed 5.0 percent
of the rate of the rat at equivalent dosing. These data for the dog conflict with the results -
10-38
0UPO40O12275
!
of Lloyd et al, (1975)> who observed 75 percent of the excreted lead eliminated through bili ary clearance. Mote that the latter researchers used carrier-free label while the other in vestigators used injections with carrier at levels of 3.0-mg Pb/kg. In mice, Keller and Doherty [1980a) observed that the cumulative excretion rate of 210Pb in Urine was 25-50 percent of that in feces. In nonhuman primates, Cohen (1970) observed that baboons excreted lead > at the rate of 40 percent in feces and 60 percent in urine. Pounds et al. (1970) noted that J the rhesus monkey lost 30 percent of lead by renal excretion and 70 percent by fecal excrettpn. This discrepancy may also reflect a carrier-dosing.difference.
The extent of total lead excretion in experimental animals given labeled lead orally or ? parenterally varies, in part due to the time frames for post-exposure observation. In the adult rat, Morgan et al. (1977) found that 62 percent of injected 23Pb was excreted, by 6 days. By 8 days, 66 percent of injected 203Rb was eliminated in the adult rats studied by Momcilovic and Kostial (1974), while the 2l6Pb excretion data' of Castellino and Aloj (1964) for the adult rat showed 52 percent excreted by 14 days. Similar data were obtained by Klaassen and Shoeman (1974).- Lloyd et al. (1975) found that dogs excreted 52 percent of in- .[ jacted lead label' by 21 days, 83 percent by 1 year, and 87 percent by 2 years.. In adult mice (Keller ahd Doherty, 1980a), 62 percent of injected lead label! was eliminated by 50 days. In nonhunian primates, Pounds et; al. (1978) rheasured approximately 18 percent excretion in adult \ rhesus monkeys by 4 days.
Kinetic studies of lead* elimination in experimental animals indicate that excretion is t described by two or irtore cpiiiporients. From the elimination data of Momcilovic and Kostial (1974), Morgan et al. (1977} estimated that in the rat the excretion curve obeys a two-compo- ' ;. nent exponential expression With half-lives of .21 and 280 hr., In dogs, Lloyd et al, (1975) found that excretion could be described by three components, i. e., a sum of exponentials with [ half-lives of 12 days, 184 days, and 4951 days. Keller and Doherty (1980a) reported that the ; half-life of whole-body clearance, of injected 203Pb consisted of an initial rapid and a much , slower terminal component, tjhe latter having a half-life of 1110 days in the adult mouse. j
The dependency of excretjion rate on dose, level has been investigated in several studies. j Although Castellino and Aloj (1964) saw no difference in total excretion rate when label was injected with 7 or 100 pg of carrier, Klaassen and Shoeman (1974) did observe that the excre tion rate by biliary tract was dose-dependent at .0.1, 1,0, and 3.0 mg Pb/kg (urine values were not provided for obtaining estimates of total excretion). Momcilovic and Kostial (1974) ob served an increased rate of excretion into urine over the added carrier range of 0.1 to 2,0 pg Pb/kg with no change in fecal excretion. In the report of Aungst et al, (1981), excretion rate in the rat did not change over the injected lead dosing range of 1.0 to 15.0 mg/kg. Rat urinary excretion rates thus seem dose-dependent over a narrow range less than 7 pg, while
10-39
DUPO40O12276
\
elimination of lead through biliary clearance is dose-dependent up to an exposure level of 3
mg/kg.
lead movement from lactatfng animals to their offspring via milk constitutesboth a route
of excretion for the mother and a route of exposure for the young, investigations directed at
this phenomenon have examined both prior-plusrongoing maternal lead exposure during lactation
and the effects of immediate prior treatment, Keller and Doherty (1980b) exposed two groups
of female rats to 210Pb: one group for 105 days before matings the second before and during
gestation and nursing. During lactation, there was an overall loss of lead from the bodies of
the lactating females compared with controls, while the femur; asd weights were inversely re-;
lated to level of lead excretion, indicating that such enhancement is related to bone mineral
metabolism. Lead transfer via milk was approximately 3 percent of maternal body burden, in
creasing with continued lead exposure during lactation, j Lorenzo et al, (1977) found that
blood lead levels in nursing rabbits given injected lead p-evaske?d;. -rather rapidly (within 1 hr) , while milk lead levels showed a continuous increase for about 8 days, at which point the con
centration of lead was eightfold higher than in blood, this observation indicates that the
transfer of lead to milk can occur against a concentration gradient in blood. Morocilovic
(1978) and Kosttal and Momcilovic (1974) observed that transfer of 203Pb in the late stage of
lactation occurs readily in the rat, with higher overall -excretion of lead in nursing versus
control females. Furthermore, the fate of lead movement to milk appeared dose-dependent over
the added `lead carrier range of 0.2 to 2.0 pg.
The comparative retention of lead in developing versus adult animals has been investigate
ed in several studies using rats, mice, and nonhuman primates, MomciToyic and Kostial (1974)
compared the kinetics of lead distribution in suckling and adult rats after injection of
203Pb. Over an 8-day interval, 85 percent of the label was- retained in the suckling rat, conr-
pared with 34 percent in; the adult, Keller and Doherty. (|1980:a) compared the.levels of 210Pb
in 10-day-pld mice and adults,- noting from the. cleafance' half-lives (vide supra) that lead
retention was greater ir the suckling animals than-in. th^ adults. In both adult and young
mice, the rate of long-t;rm retention was governed by the; rate of release of lead from bone;
indicating that in the mouse, skeletal lead retention in; the young is greater than in the
adult. With infant and adult monkeys orally exposed to 210Pb, Pounds et al. (1978) observed
that at 23 days the corresponding amounts of initial dose retained were 92.7 and 81.7 percent,
respectively.
'
The studies of Rader et al, (1981a,b) are of particular interest because they demonstrate
not only that young experimental animals continue to show greater retention of lead in tissue
when exposure occurs after weaning, but also that such retention occurs in terms of either
uniform exposure (Rader at al,, 1981a) or uniform dosing (Rader et al., 1981b) when compared
with adult animals. With uniform exposure, 30-day-old rats given lead in drinking water
10-40
* '
DUP040012277
S
. ) -
!
'
i -
showed significantly higher lead levels in blood and higher percentages of dose retained in
brain, femur, and kidney, as well as higher indices of hematopoietic impairment (ALA in urine,
erythrocyte porphyrin) when compared to adult animals. As a percentage of dose retained,
levels of lead retained in the tissue of the young animals were approximately two- to three
fold higher. In part, this difference results from a higher ingestion rate of lead. However,
in the uniform dosing study where a. higher ingestion rate was not the case, an increased re*
tention of lead still prevailed, the amount of lead in brain being approximately 50 percent higher in young versus adult animals. Comparison of values in terms of percent retained is
more meaningful for such assessments, because the factor of changes in organ mass (see above)
is taken into account. Delayed excretion of lead in the young animal may reflect an immature
excretory system or a tighter binding of lead in Various faddy compartments.
j
I ..
i
I
,
'
.:
10.5 INTERACTIONS-OF LEAD WITH ESSENTIAL METALS AND OTHER FACTORS
Deleterious agents, particularly toxic metals such as lead, do not express their toxico-
kinetic or toxicological behavior in a physiological vacuum, but rather :are affected by inter
actions of the agent with a variety of biochemical factors such as nutrients. .Growing recog
nition of -this phenomenon and its; implications for lead toxicity in humans has prompted a
number of studies, many of them recent, that address both the scope and mechanistic nature of
such interactive behavior.
:
Taken collectively, the diverse human and animal data described in this section make it
clear that there is heterogeneity in pediatric populations in terms of relative risk for lead
exposure and deleterious effects depending on nutritional status. Children having multiple
.. 'nutrient deffciencijes are at greater risk.
j
;
10.5.1 Human Studies
.
In humans, the interactive behavior of lead andj various nutritional factors is appropri
ately .viewed as particularly significant for children', since this age group is not only parti
cularly sensitive t'o lead's effects,, but also experiences the greatest flux in relative nutri
ent status. Such interactions occur against a backdrop of rather widespread deficiencies in a
number of nutritional components in children. While such deficiencies are more pronounced in
lower-income groups, they exist in all socioeconomic strata. Mahaffey and Michaelson (1980)
have summarized the three national nutritional status surveys carried out in the United States
for infants and young children; the Preschool Nutrition Survey, the Ten State Nutrition Sur
vey, and the Health Assessment and Nutrition Evaluation Survey (HANES I). The most recent
body of data of this type,is the second National Health Assessment and Nutrition Evaluation
Survey (NHANE;S IT) study (Mahaffey et al., 1979), although the dietary information from it has
10-41
DUP040012278
yet to be reported. In the older surveys, iron deficiency was the most common nutritional deficit in children under 2 years of age, particularly children from low-income groups. Re duced vitamin C intake was noted in about one-third of the children, while sizable numbers of them had significantly reduced intakes of calcium. Owen and Lippman (1977) reviewed- the regional surveys of low-income groups within Hispanic, white, and black populations. In these groups, iron deficiency was a common finding, and low intakes of calcium and vitamins A and were observed regularly. Hambidge (1977) concluded that zinc intake in low-fncpms groups is generally inadequate relative to.recommended daily allowances.
Available data from a number of reports document the association of lead absorption with suboptimal 'nutritional status. Mahaffey et al. (1976) summarized their studies showing that children with blood lead levels greater than 40 pg/dl had significantly (p <0.01) lower intake of phosphorus and calcium compared with a control group, while iron intake i it the two groups was comparable. This study involved children 1-4 years old from an inner-city, low-income population, with close matching for all parameters except the blood lead level. Sorrell et al. (1977); in their nutritional assessment of 1- to 4-year-old children with a range of blood lead levels, observed that blood lead content was inversely correlated with jcalcl urn intake, while children with blood lead levels 60 pg/dl had significantly (p <0,001) lower intakes of calcium and vitamin 0.
Rosen et al. (1980, 1981) found that children with elevated blood lead (33-120 pg/dl) had significantly lower serum concentrations of:the vitamin 0 metabolite 1,25-dihydroxyvitamin D (1,25-(0H)2D) compared with age-matched controls (p <0.001), and showed a negative correlation of serum 1,25--(0H)20 with lead over the range of blood lead levels measured (see Chapter 12, Section 12,5, for further discussion). These observations and animal data. (Barton et al,, 1978a; s.e.f Section 10.5.2) mpy' suggest an increasingly adverse interactive cycle of !1,25-(QK>2Uj lead, and calcium ip which leadlreduces biosynthesis of the vitamfn 0 metaholite. This cycle leads to reduced induction of calcium binding protein (CaBP),-less absorption of Calcium frism the gut, and greater uptake pjf lead, thus further reducing metabolite levels. Barton et Jal, (1978a) isolated two mucosal!] proteins in rat intestine, one jof which bound
* *
mainly lead and was not vitamin Of stimulated!. The second bound mainly calcium and Was under vitamin control. The authors suggested direct site-binding competition between lead and cal cium in these proteins. Hunter (1978) investigated the possible interactive role of seasonal vitamin D biosynthesis in adults and children; lead poisoning occurs more often in summer than * in other seasons (see Hunter, 1977, for review). Seasonality accounts for 16 percent of ex plained variance of blood lead levels in black children, 12 percent in Hispanic children, and 4 percent in white children. More recently, it has been documented that there is no seasonal -- variation in circulating levels of 1,25-(0H)2D, the metabolite that affects the rate of lead
10-42
DUP040012279
r.i --
*
absorption from the GI tract (Chesney et al ,, 1981), These results suggest, that seasonality is related to changes in exposure.
Johnson and Tenuta (1979) determined that calcium intake was negatively correlated (r = -0,327, p <0.05) with blood lead in 43 children aged 1-6 years. The high lead group consumed less zinc than children With lower blood levels. Yip et al. (1981) found .that/43 children with elevated blood lead (f>30 pg/dl) and erythrocyte protoporphyrin (6P) (>35 pg/dl) had an increased prevalence of iron deficiency as these two parameters increased. Children classed in COC categories lb and II had M 79 percent iron deficiency rate, while those in Class III were all iron deficient. Chisolm (1981) demonstrated an inverse relationship between chelatable iron and chelatatle body lead levels as indexed by urinary ALA levels in 66 Children with elevated blood lead.- Watson et al, (1980) reported that adult subjects who were iron deficient (determined from serum fej-ritin measurement) showed a lead absorption rate 2-3
times greater than subjects who were iroh replete. In a group*f 13 children, Markowitz and
Rosen (1981) reported that the mean; serum zinc levels in children with plumbism were signifi
cantly bel'ow the values seen in normal children. Chelation therapy reduced the mean level
even further. Chisolm (1981) reported - an inverse relationship between ALA in urine (ALA-U)
and the ampunt of chelatable or systemicaTly active zinc In 66 children challenged with EOTA
and having blood lead levels ranging-from545 to 60 pg/dl. These twostudies suggest that zinc
status is probably as important an interactive modifier of lead toxicity as is either calcium
or iron.,
]
The role of nutrients in lead absorption has been reported in several metabolic balance
studies ;for both adults and children. Ziegler et al, (1978), in their investigations of lead
absorption and retention in infants, observed that lead retention Was Inversely correlated
with calcium intake, expressed either as a percentage of total Intake (r - -0,284, p <0,01) or
!!i
on a weight basis (r = -0.279, p <0,01). jInterestingly., the calcium intake*range measured was
within the range considered adequate--for infants and toddlers by the National Research Council
(National Academy of Sciences, National Research Council, 1974). These daia also support the
premise jtbat severe deficiency need not be present for an interactive relationship to occur.
Using adults, Heard and Chamberlain (.1982) monitored the uptake of 203Pb from the gut in eight
subjects as a function of the amounts of dietary calcium and phosphorus. Without supplementa
tion of these minerals in fasting subjects, the label absorption rate was approximately 60
percent, compared to 10 percent with 200 mg calcium plus 140 mg phosphorus, the amounts pres
ent in an average meal. Calcium alone reduced uptake by a factor of 1.3 and phosphorus alone
by 1.2; both together yielded a reduction factor of 6. This work suggests that insoluble cal
cium phosphate is formed and co-precipitates any lead present. This interpretation is sup
ported by animal data (see Section 10.5.2).
10-43
DUP040Q12280
10.5.2 Animal Studies
*
Reports of lead-nutrient interactions in experimental animals have generally described
such relationships in terms of a single nutrient, using relative absorption or tissue reten
tion in. the animal to index the effect. Most of the recent data are concerned with the impact
of dietary levels of calcium, iron, phosphorus, and vitamin 0> . Furthermore, some investiga
1
tors have attempted to elucidate the site(s) of interaction as,,wel1 as the mechanises)
governing the interactions. Lead's interactions involve the effect of the nutrient on lead
uptake, as well as lead's effect bn nutrients. The focus of this discussion is on the former.
These interaction studies are tabulated in Table 10-4..
,,
>I
10.5.2.1 Interactions of Lead with Calcium. The early report, of Spbel:et al. (1940) noted that variation of dietary calcium and other nutrients affected the uptake of lead by bone and
ii
blood in animals. Subsequent studies by Mahaff.ey-S.1x and Gayer (1970) in the rat have demon
strated that a considerable reduction in dietary calcium.was necessary (from 0-7 percent to
0.1 percent), at which level blood lead was increased fourfold, kidney lead content was ele vated 23-fold, and relative toxicity (Mahaffey et al., 1973).was increased. The changes in
i
calcium necessary to' alter lead's effects In the rat appear to be greater than those seen by Ziegler et al. (1978) in young children, which indicates.a species difference in terms of sen
sitivity to basic dietary differences as well as to levels of all " interactive nutrients.. , These observations in the rat have been confirmed by Xostial et .al. .(1971), Quarterman and
'! V
!: - ;;
. Morrison. (1975), Barltrop and Khoo (1975), and Barton et al. (1978a). The inverse relation-
j ship between dietary calcium and lead uptake has also been noted in the pig (Hsu et a].,
11975)., horse (Willoughby et al., 1972), lamb (Morrison et al., 1977), and domestic fowl (Berg
.; et al., 1980).
j The m:echanism(s) governing lead's interaction with "calcium operate at both the gut wall
I and within body compartments.. Barton et a). (1978a), using everted duodenal'sac preparations
in the rat, reported the following:- (1) interactions at the gut wall require the presence of
i ntubated calcium to affect l.eajd label .absorption (pre-existing I calcium deficiency in the
animal and no added calcium had|no effect on lead transport); (2) calcium-deficient animals
show increased retention of lead rather than absorption (confirmed by Quarterman et, al.,
1973); and (.3) lead transport may be mediated by two mucosal proteins, one of which has high
molecular weight and a high proportion of bound lead, and is affected in extent of lead bind
ing with changes in lead uptake. The second protein binds mainly calcium and is vitamin D-
dependent.
Smith et al. (1978) found that lead is taken up at a different site in the duodenum of
rats than is calcium, but absorption does occur at the site of phosphate uptake, suggesting a
complex interaction of phosphorus, calcium, and lead. This observation is Consistent with the
data of Barltrop and Khoo (1975) for rats and the data of Heard and Chamberlain (1982) for
10-44
DUPO4O012281
TABLE 10-4, EFFECT OF NUTRITIONAL FACTORS ON LEAD UPTAKE IN ANIMALS
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Lead retention
Iron deficiency has no' e ffe c t on lead retention
Hamittbit (1:978) """" "
DUP040012282
Factor
Species
Index.of effect
Interactive effect
Reference
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in d ie t increase lead
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B arltrop and Khoo (1975)
DUP040012283
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DUP040012284
humans. Thus, the combined action of the two mineral nutrients is greater than the sum of
their individual effects.
Mykkanen and Wassermann (1981) observed that lead uptake in the intestine of the chick
occurs in two phases: a rapid uptake (within 5 min) followed by a rate-limiting, slow transfer
of lead into blood. Conrad and Barton (1978) have observed a similar process in the rat.
Hence, either a saturation process occurs (i.e., carrier-mediated transport) or lead simply
precipitates in the lumen. In the former case, calcium interacts to saturate the carrier pro-
f
,
r'
r -
;
teins as isolated by Barton et al. (1978a) or may preeipltats lead in the 1 umen by initial
formation of calcium phosphate.
,
Quartsrman et al. (1978a) observed that calcium supplementation of the. diet above normal
also resulted in increased body retention pf lead in the rat. Because both deficiency (Barton
et al.,; 1378a) and excess in calcium intake enhance retention, two sites of influence on
retention are suggested. Goyer (1978) has suggested that body retention df lead in calcium
deficiency, i.e., reduced excretion rate, may result from renal impairment, while Quarterman
et al. (1978a) suggest that excess calcium suppresses calcium resorption froin bone, hence also
reducing lead release.
,
ID.Si.2/3 Interactions of Lead with Iron,, Mahaffey-Six and Goyer (1972) reported that iron-
deficleht rats had increased tissue levels of lead and manifested greater.toxicity compared
with control .animals. This uptake change was seen with but minor alterations In hematocrit,
indicating a primary change in lead-absorption over the time of the study. Barton et al,.
(19,78b) found that: dietary-restriction of iron, using 210Pb and everted sac preparations in
the rat, led to enhanced lead .absorption,; whereas iron loading suppressed the extent of lead
uptake, using normal intake levels of .irqh. This suppression suggests receptor-binding com-
petitiorj At a common site, consistent with the isolation by these workers of two iron-binding
mucosa fractions. While the iron level of! diet affects lead .absorption, the) effect of changes
in lead content in the gut on Iron absorption is not clear. Barton et al. (1978b).and Bobbins
et al. i(1978) observed no effect of lead in the gut on iron absorption Hn the rat, while
j I.
Flanagan, et al. (1979) reported that lead |*educed iron absorption in mice, j
In -the mouse, Hamilton (1978) found that body retention of 203 Pb-was unaffected by iron
deficiency, using intrape.ritoneal administration of the label, while gastric intubation did
lead to increased retention. Animals with adequate iron showed no changes in lead retention
at intubation levels of 0.01 to 10 nM. Cerklewskl (1980) observed that lead transfer both in
utero and in milk to nursing rats was enhanced compared with controls when dams were maintain
ed from gestation through lactation on low-iron diets.
10.5,2.3 Lead Interactions with Phosphate. The early studies of Shelling (1932), Grant et
al, (1938), and Sobel et al. (1940) documented that dietary phosphate influenced the extent of
lead toxicity and tissue retention of lead in animals. Low levels of phosphate enhanced these
.10-48
DUP040012285
parameters, while excess intake retarded the effects. More recently, Barltrop and Khoo (1975)
reported that reduced phosphate increased the uptake of 203Pb approximately 2.7-fold compared
with controls. Quarterman and Morrison (1975) found that low dietary phosphate enhanced lead
retention in rats but had no effect.on skeletal lead mobilization, nor was injected lead label
affected by such restriction. In a related study, Quarterman et al. (1978a) found that dou
bling the. nutrient over normal levels resulted in lowering lead absorption by approximately
half. Barton and Conrad (1981) found that reduced dietary phosphorus increased the retention
of labeled lead and deposition in bone, in contrast to the results of Quarterman and Morrison
(1975). Increasing the intraluminal level of phosphorus reduced lead absorption, possibly by
increasing intraluminal precipitation of lead as the mixed lead/calcium phosphate. Smith et
al. (1978) reported that lead uptake occurs at the same site as phosphate, suggesting that
lead absorption may be more related to phosphate than calcium transport.
10.5.2.4 Interactions of Lead with Vitamin 0. Several studies had earlier indicated that a
positive relationship might exist between dietary vitamin D and lead uptake, resulting in
either greater manifestations of lead toxicity or a greater extent of lead uptake (Sobel et
al., 1938, 1940). Using the everted ac technique and testing with 210Pb, Smith et al. (1978)
observed that increasing levels of intubated vitamin D iri the rat resulted in increased ab
sorption of the label, with uptake occurring at the distal end of the rat duodenum, the site
of phosphorus uptake and greatest stimulation by the vitamin. Barton et al. (1980) used 2i0Pb
to Monitor lead absorption in the rat under conditions pf normal , j deficient, .and excess
amounts of dietary vitamin D. lead, absorption is increased with either low or excess vitamin
Q. This increased absorption apparently occurs as a result of increased retention time .of
fecal mass containing the lead due to alteration of intestinal motility rather than as a re-
sulij of direct enhancement of rnucosat uptake rate.. Hart and Smith (1981) reported that vita
min ID repletion of.diet enhanced lead absorptioft (210Pb) in the rat) while also enhancing
femur and kidney lead uptake when the.'-label was injected:
10.5,.2.5 Interactions of lead .with lipids, Barltrop and Khoo (.1975) I observed that varying
theilipid (corn oil) content of rat diet'.from1 5 up`to 40 percent resulted in an increase of
lead in bipod 13.6-fold higher than-the norma! level. Concomitant increases were observed in
lead levels in kidney, femur, and carcass. Reduction of dietary lipid below'the 5 percent
control figure did not affect the lead-absorption rate. As an extension of this earlier work,
Barltrop (1982) has noted that the chemical composition of the lipid is a significant factor
in affecting lead absorption. Study of triglycerides of saturated and unsaturated fatty acids
showed that polyunsaturated trilinolein increased lead absorption by 80 percent in rats, when
given as 5- or 10-pe.rcent loadings in diet, compared with monounsaturated triolein or any of
the saturates in the series tricaproin to tristearin.
IQ-49
DUP040012286
)
.1
10,5.2-6 Lead Interaction with Protein, Quarteraan el al, (197.8b) have drawn attention to "
one of the inherent, difficulties of measuring lead-protein interactions:, i.e., the effect of
protein on both growth and the toxicokirietic parameters of lead, Oer et al, .,(1974) found that
reduction of dietary protein, from 20 to 4 percent, led fo increased uptake of lead in rat
tissues, but the approximately sixfold reduction in body weight over the interval of the study
makes it difficult to draw any firm conclusions. Sari t.rop and. Khoo (1975) found that 2^3Pb
uptake by rat tissue could be enhanced with either suboptimal or excess; levels of protein in
diet. Quarterman et al. (1978b) reported that retention of labeled lead in fats maintained on
a synthetic diet containing approximately 7 percent protein was either unaffected .or reduced
compared with controls, depending on tissues taken for study.
Not only levels of protein but also the type of protein appears to affect tissue lead
levels. Anders et al. (1982) found that rats maintained on either of two synthetic diets T "i
varying only by having casein or soybean meal as the proteip source showed significantly
higher lead levels in the casein group.
10.5.2.7 Interactions of Lead, with Milk Components, For many years, milk was recommended .as
a counteractant for lead poisoning among lead workers (Stephens and Waldron, 1975). More rec.en j
t data, however, pose a mixed picture. Kello and ((ostial (1973) found that rats maintained on
milk diets absorbed a greater amount of 203Pb than those fed commercial rat chow. This
phenomenon was ascribed to relatively lower levels of certain nutrients in milk compared with
.the rat chow. These observations were confirmed by Bell and Spickett (19.81), who also
observed that lactose-hydrolyzed milk was less effective than -the..ordinary form in promoting
lead absorption, suggesting that lactose may be the enhancing agent. Bushnell and DeLuca
(1981) demonstrated that lactose significantly increased 210Pb absorption and tissue retention
by weanling rats when given; in high doses by Intubation. However, lactose levels.close to . =
usual dietary .content actually have an inhibiting effect onjlead absorption (Bushnell and '
Deluca, 1383), In human studies, moreover, milk consumption is inversely related to blood
lead levels, suggesting a nej: protective effect (Johnson and Tpiuta, 1979; Brunekreef at al., j
1963).
j.
].
.;
10.5-2.8 Lead Interactions with Zinc and Copper. The studies 6f Cerklewski and Forbes (1976)
and El-Gazzar et al. (1,978) documented that zinc-deficient diets.promote lead absorption in
the rat, while repletion with zinc reduces lead uptake. The interaction continues within the
body, particularly with respect to ALA-D activity (see Chapter 12, Section 12.3.1,2). In a
.study of zinc-lead interactions in female rats during gestation and lactation, Cerklewski .
(1979) observed that zinc-deficient diets resulted in more transfer .of lead through milk to
the pups as well as reduced litter body weights. Bushnell and Levin (1983) have shown that '
10-50
DUP040Q12287
V
i. .
; . .; - -
1
rats fed a low-zinc diet (2,0 ppm) containing lead at levels of 10 or 100 ppm had signi
ficantly higher retention of lead In brain and calvarium compared to those fed a diet with
20 ppm zinc. Victory and coworkers (1981) evaluated the acute effects of lead Oft the behavior
of renal arid plasma zinc in the dog.. They found that lead enhanced urinary zinc, excretion and
was related to both increased ultrafilterable plasma zinc and a change in renal tubular zinc
transport.
'?
,
Klauder et al. (1973) reported.that low dietary copper enhanced lead absorption in rats
fed a hfghrlead diet (5000 ppm), these observations were confirmed by Klauder and Petering
(1975) at a level of 500 ppm lead In diet. The same researchers subsequently observed that
reduced copper enhanced the hematological effects of laid (Klauder and Petering, 1977), and
that both copper and iron deficiencies must be corrected to restore hemoglobin levels to
normal. '
I -}
; '
10.S INTERRELATIONSHIPS OF LEAD EXPOSURE, EXPOSURE INDICATORS, AND TISSUE LEAD BURDENS
Information presented so far in this chapter sets fojrth the quantitative and qualitative
aspects of lead toxicokinetics, including the cpmpartmenial modeling of lead distribution in
vivo, and leads up to the critical issue of the various interrelationships of lead toxico
kinetics to lead exposure, toxicant levels in indicators of such exposure, and exposure-target
tissue burdens of lead. }
j
Chapter 11 (Sections 11.4, 11.5, 11.6) discusses the various experimental and epidemi
ological studies relating the relative impact of various routes of lead exposure on blood lead
levels in'human subjects^ and Includes a description of mathematical models for such relation
ships. In these sections, the basic question is: what ns the mathematical, relationship pf
lead in air, food, wateri, etc., to lead in blood? This Question is descriptive'and does not
address-the biological basis of the'observed relationships. Nor does ft consider the impli
cations for adverse health risks in the sequence leading]from external lead exposure to lead
in some physiological indicator to lead intarget tissues,1
1
For purposes of discussion, this section separately considers (1) the temporal character
istics of physiological indicators of lead exposure, (2) the biological aspects' of the rela
tionship of external exposure to internal indicators of exposure, and (3) internal indicator-
tissue lead relationships, including both steady-state lead exposure and abrupt changes in
lead exposure. The relationship of internal indicators of body lead, such as blood lead, to
biological indicators such as EP or ALA-U is discussed in Chapter 13.
j.
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10.6.1 Temporal Characteristics of Internal. Indicator? of Lead Exposure
The biological half-life for blood lead dr the nonretained fraction of body lead is
generally assumed to be rather short, although it in fact depends upon the mobile lead body
burden (Cl1 Flaherty eta!., 1982; also see Sections 10.3 and 10.4). Nevertheless, ,a given -
blood or urine lead value reflects rather recent exposure compared to tooth or bone lead
values. In cases where lead exposure can be reliably assumed to have occurred at a given
level, a blood lead value is more useful than in cases.where some intermittent, high level of
expostire may have occurred. The former most often occurs with occupational exposure, while
the latter is of particular relevance tci young children.
Reports have appeared dealing with the stability of individuals' blood lead levels over
time under conditions of ambient .exposure. David et al. (1982) followed 29 children, 4-12
i, . ..
i
.
years old, with Monthly measurements arid found the stability to.be of a relatively high order
(Pearson correlation coefficients of 0.7-0.8). Rabinowitz el al, (1984) sampled more than 200
infants semiannually from birth to 2 years of age and found average changes of about 4 pg/dl,
Only 40 percent of these children tended to remain in their previous blood lead category
(quart!ie). Within this age range, however, thpre was a trend toward less fluctuation with
increasing age of the young child. Delves et ajL (1984) followed 21 adults over 7-11 months
with multiple blood lead measurements and found little fluctuation over time (about 1 pg/dl or
less, on average). Hehce, there appears to be Increasing stability with relatively constant
exposure as the individual increases in age.
Accessible mineralizing tissue, such as shed teeth, extend the time frame for assessing
lead exposure from months, to years (Section 10,3), since teeth accumulate lead up to the time .
of shedding or extraction. Levels of lead in teeth increase with age in proportion to expo
sure (Steenhout and Pourtols, 1981). Furthermore, tooth lead levels are correlate#.with blood
lead levels in humans (Shapiro et al., 1978) and-ianimals (Kaplan eial., 1980). Thk technique -
of fremliri and tdmonds (19.80), employing microautbradiography of irradiated teeth, permits the
'identification ;of dentine zones high in lead content, thus allowing the disclosure of past
periods of abrupt Increases in lead intake.
,
|
While levels of lead in shed teeth are more valuable than blood lead levels in assessing
exposure at more remote time points, such information is retrospective in nature and would not
be of use in monitoring current exposure. In this case, serial blood lead measurements must
be employed. With the development of methodology for j_n .situ measurement of tooth lead in
children (described in Chapter 9), serial in situ tooth analysis in tandem with serial blood
lead determination would provide comparative data for determining both time-concordant blood/
tooth lead relationships as well as which measure is the better indicator of ongoing exposure. *
Given the limitations of an indicator such as blood lead in reflecting lead uptake in target
organs, as discussed below, the rate of accumulation of lead in teeth measured In situ may
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DUP040012289
well be a better index of ongoing tissue lead uptake.. This aspect merits further study, espedaily since Shapiro et al, (1378) -.were able to demonstrate the feasibility of using in situ tooth lead analysis in a large group, of children screened for lead exposure., !
f | j
10.6.2 Biological Aspects of External Exposure/Internal Indicator Relationships
/
Information provided in Chapter 11 as well -as the critiques of fUtyptog et al, (1981) and
Brunekreef (1984) indicate that the relationship of lead levels in air, food, and water to
lead levels in blood is curvilinear, with the result that as "baseline" blood lead rises
(i.e., as one moves up the curve), the relative change in the dependent variable, blood lead,.
per unit change of lead in some intake medium (such as air) becomes smaller; Conversely, as
one .proceeds i down the curve with reduction in "baseline" lead, the corresponding change in
blood lead becomes larger. One assumption in this "single medium" approach is that the base-
line is not integrally related to the level of lead in the particular medium being studied.
This assumption is not necessarily appropriate fob air versus food lead, nor, in the case of
young children, for air lead versus!, total oral intake of the element. However, it'should be
noted that Hammond et al. (1911) assigned virtually all of the body compartment lead to the
blood, giving blood lead levels in their modeling scheme that were top high. The authors
recognized this and later offered a qualification (Hammond et al,, 1982).
Hammpnd et al, (1901) have also noted that the shape of the blood lead curves seen in
human subjects is similar to that discernible in certain experimental animal studies with
dogs, rats, and rabbits (Azar et al., 1973; Prpic-Majic et al., 1973).. Similarly, Kimmel et
al. (1980),, after exposing adult female rats tq lead at flpur levels in drinking water for 6-7
weeks, found s/alues of blood lead that shpwejd is curvilinear relationship to the;dose levels.
Over the riosijig range of 5. to 250 ppm in water^ the blood lead range was 8,5 to |l pg/dl, In
a related stuky (Grant et al., 1980) rats were ''exposed to 1 ead |n utero', through weaning, and
up to 9 months of age at the dosing range used in the ^immei et al. study (0,;5 to 250 ppm in
the dams' cricking water until weaning of pups,] then the same levels in the weanlings' drink
ing water), these animals showed a hlood lecid rknge of to 67 pg/dl . One may assume that in
all of the above studies the lead in the various dosing groups was near or at equilibrium
within the various body compartments.
The biological basis of the curvilinear relationship of blood lead to lead intake, .across
a broad range of blood lead values., may result from a number of factors. In lead workers, as
a specific case, increasing Workplace air lead level is associated with an Increased particle
aggregation rate leading to a lowering of the effective fraction of respirable, submicrometer
particles, as suggested by Chamberlain (1983), In studies with human volunteers, there
appears to be no change in respiratory absorption rate at lung lead burdens up to 450 pg
(Chamberlain et al., 1978). It was noted earlier that oral lead intake up to 400 pg in adults
10-53
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DUP040012290
i
is associated with unaltered absorption rate. However, animal data relevant to this question indicate that dietary levels between 10 and 100 ppm lead are associated with a decreased ab sorption rate (Bushnell and Deluca, 1S83). If these data were applied directly to humans, a daily intake rate of 20-200 rag lead would be required to produce a similar decrease.
. The curvilinear blood lead/diet lead relationship may or may not be independent of GI ab sorption rate. The experimental animal studies of Prpic-Majic et al. {1973) indicated a cur vilinear relationship of blood lead to dose of lead when the toxicant was administered by,in jection to rabbits. On the other hand, injection of higher doses into tats does show a linear relationship (Aungst et al., 1981).
The data of DeSilva (1981), Manton and Malloy (1983), and Manton and.Cook (1984) all sug gest that the increasingly greater fraction of lead in plasma as blooel lead increases may besigbificam: (see Section 10.3.1). This increase of lead in plasma would indicate a relatively greater movement of lead from plasma to tissues and a higher .gxcretibn rate, both of which serve to modulate the rate of rise of the whole blood lead with increasing circulating lead. These results are consistent with the report of Chamberlain (1983) showing an apparent in crea') sed uririapy excretion rate of lead with rising b!lood lead. They ai re also in accord with the| observations that tissue lead burdens show a better proportionality]to exposure level than does blood lead burden (see Section 10,3,1). Since an increased movement of .plasma lead to tissues with increasing blood lead butdep wquld also include deposition in bone, the curvilin ear relationship of ehelatable lead to blood lead may also be influenced by the plasma/blood relationship.
1
10.6,3 Internal Indicator/Tissue Lead Relationships i In living human subjects, to determine tissue lead burdens directly (or relate these
levels to adverse effects associatediwith target tissue) as a function ,0f. lead intake is not possible. - Instead, measurement of lead in an accessible indicator such as bipod, along with determination of some biological indicator of impairment (e.g., ALA-U oif EP), is used,
I Evidence continues to accumulate; in both the clinical and experimental animal literature
that the use of blood lead as an indicator can have limitations in reflecting both the amounts of lead in target tissues and the temporal changes in tissue lead with changes in exposure. Perhaps the best example of the problem is the relationship of blood lead to ehelatable lead (see Section 10.3,3). Currently, measurement of the plumbgresis associated with challenge by a single dose of a chelating agent such as CaNa2EDTA is considered the best measure of the mo bile, potentially toxic fraction of body lead in children and adults (Vitale et al. , 197.5; Wedeen et al., 1975; Chisolm et al,, 1976; U,5, Centers for Disease Control, 1978; Chisolm and Barltrop, 1:979; Hansen et al. , 1981).
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Chisolm et al. (1976) have documented that the relationship of blood lead to chelatabie
lead is curvilinear, such that a given incremental increase in blood lead is associated with
an increasingly larger increment of mobiSizable lead. The problems associated With this cur'-
vilinear relationship in exposure assessment are typified by the recent reports of Saenger et
al. (1982) and Piomelli et al. (1984) concerning children and Hansen et al. (1981) concerning
adult lead workers. Saenger et al.' (1982) noted that significant percentages of children
having mild to moderate lead exposure, as discernible by blood lead and-EP measurements, had
urinary outputs of lead upon challenge with CaNa2EDTA that qualified them for chelation thera
py under CDC guidelines. Similar data were obtained for 210 children evaluated in four medi
cal centers (Piomelli et al., 1984). In adult workers, Hansen et al. (1981) observed that a sizable fraction of subjects with <|nly modest elevations in blood lead levels upon EDTA chal
lenge excreted lead in amounts significantly exceeding the upper end of normal. This discrep
ancy occurred at blood lead levels if 35 pg/dl and above.
'*
The biological basis for the nonlinearity of the relationship between blood lead and che-
laiable lead appears, in major part,; tp be the existence of a sizable pool of lead in bone
that Is labile to chelation. Evidence pointing to this explanation was summarized in Section
10.3.3. The question of how long dny lead in this compartment of bone remains labile to che
lation has been addressed by several investigators, in studies of both children and adults.
The question is relevant to the issue of the-iiseful ness of EDTA challenge in assessing evi
dence for past, lead exposure,
f Chisolm et al. (1976) found that a group (N = 55) of adolescent subjects 12-22 years old,
who had a clinical history of lead poisoning a.s young children and whose mean blood lead was
22>1 pg/dl at the time of study, yielded chelatabie lead values that placed them on the same
regression, curve as a second group jof young children with current elevations of blood lead.
Thp results with the adolescent subijeots did not provide-evidence thkt they might have had a
past history of lead poisoning. According to the authors, this failure to detect prior expo
sure suggests that chelatabie lead] at the time of excessive exposure was not retained in a
pool that remained, labile to chelation years later, but underwent Subsequent excretion or
transfer to the inert compartment of, bone. One problem with drawing conclusions from this
study is that all of the adolescents apparently had one or more courses of chelation therapy
and were removed to housing where re-exposure would be minimal as part of their clinical
management after lead poisoning was diagnosed. One must assume that chelation therapy removed
a significant portion of the mobile lead burden and that placement in lead-free housing re
duced the extent of any further .exposure. The obvious question is how this group of adoles
cents would compare with subjects who had excessive chronic lead exposure as young children
but who did not require or receive chelation therapy.
?
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DUP040012292
Former lead workers challenged with EDT.A show .chelatable lead values that are signifl- '*
cantly above normal years after workplace exposure ceases (e.g., Alessio et al,, iS7J6;
Prerovska and Teisinger, 1970). In the case of former lead workers, blood lead also remains
- elevated, suggesting that the mobile lead pool in bone rem.ai.ris In equilibrium with lead in 4
. blood,
. ...
The closer correspondence of chelatable lead with actual tissue lead burdens,' compared to blood lead, is also reflected in a better correlation of this parameter with such biological
indicators of Impairment as EP, although thi| correlation is sebn only in adults. Similarly, Alessio et al, (197.6): found that EP in former lead workers was more significantly correlated with chelatable lead than with blood lead.
Consideration of 5both the intake versus blood lead and the blood lead versus chelatable
lead curves leads to the prediction that the level of lead exposure per s.e is more closely)re
lated to tissue lead burden than Is blood lead. This appe.ar| to be the case in experimental
animals, Azar et al, (1973) and Grant et al, (1980) reported.that levels of lead in brain,
kidney, and femur -followed more of a direct proportionality with the level of dosing than with
... blood lead. These observations may relate to the fact that plasma lead rises proportionately
faster than whole blood lead.
'
-i
Finally, there is the question of how adequately an internal indicator such as blood lead
reflects changes in tissue burden when exposure changes abruptly. In the study of Bjorklund
et al. (1981), lead levels in both blood and brain were monitored over a 6-week period in rats
exposed to.lead through their drinking water. Blood lead rose rapidly by day 1, during which
time brain lead content was only slightly elevated. After day 1, the rate of increase in
blood lead began to taper off, while brain lead began tb^rise in a nearly linear fashion up to
the end of the experiment.- From day 7 to 21, blood lead)increased from approximately 45 tip 55.
; pg/dl, while brain leajd increased approximately twofold.! > '
i
Abrupt reduction, in exposure similarly appears to be associated with a more rapid re
sponse in blood than! in soft tissues, particularly Brain. Goldstein and Diamond (174)
i
i ,- .
i
reported that termination of intravenous administration pf lead to 30-day-old rats resulted in
' a sevenfold drop of lead in blood by day 7, At the same time,\b.rain lead levels did not de
crease significantly, A similar difference in brain and blood response was reported by
Momcilovtc and Kostial (1974).
In all of the above studies, blood lead was of limited value in reflecting changes in the
brain, which is the significant target organ for lead exposure in children. With abrupt in
creases in exposure level, the problem concerns a much more rapid approach to steady state in
blood than in brain. Conversely, the biological half-time for lead clearance from blood in
the young rats of both the Goldstein and Diamond (1974) and Momcilovic and Kostial (1974)
studies was much less than it appeared to be for lead movement from brain.
*
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DUP040012293
: Despite the limitations in indexing tissue burden and exposure changes, blood lead .remains the one readily accessible measure that can demonstrate in a relative way the rela*tionship of various effects to increases in exposure.
i ' <* 10.7 METABOLISM OF LEAD ALKYLS -f
. `\
y
The lower alkyl lead compounds used as gasoline additives,, ;tetraethyl lead (TEL) and
tetramethyl lead (TML), are much more neurotoxic on an equivalent; dose basis than inorganic
Head. These agents are emitted in auto exhaust, and their rate of environmental degradation
depends on such factors as sunlight, temperature, and ozone levels. There is also some con-
icern that organolead compounds may result from biomethyTation in the. environment (see Chapter
1.6), Finally, a problem arises with the practice among children of sniffing leaded gasoline,
|The available information dealing with metabolism of lead alkylfe is derived mainly from ex
perimental animal studies, studies of workers exposed to the agents, and. cases of lead alkyl
poisoning.
10,7.1 Absorption of Lead Alkyls in Humans and Animals .
;
; The respiratory intake and absorption of TEL and TML in the vapor state was investigated
by Heard et al, (1973), who used human volunteers inhaling 203Pb-labeled TEL and TML, Initial
lung deposition rates were 37 and fl percent for TEL and TML, respectively. Of these amounts,
40 percent of TEL was lost by exhalation within 48 hr, while the corresponding figure for TML
within 48 hr was 20 percent. The remaining fraction was absorbed. The effect of gasoline
vapor on these parameters was not investigated. In an earlier study, Mortensen (1942) reported
that adult rats inhaling TEL labeled With 293Pb (0,07-7.00 mg TEL/1); absorbed .16-23 percent of .the fraction reaching' the alveoli). Gasol ine vapor had no effect-on. the absorption'rates.
Respiratory absorption of. organolead bound to particulate matter has not been specifi cally studied as such. According to Harrison and Laxen (1978), neither TEL nor TML adheres to particulate matter to any significant extent, but the toxicologlealTy equivalent trialkyl
derivatives, formed from photolytic dissociation or ozonolysis in the atmosphere; may do so.
-10.7..1.1 Gastrointestinal Absorption. Information on the rate of absorption of lead alkyls through the <61 tract is not available in the literature. Given the level of gastric acidity (pH 1.0) in humans, one would expect TML and TEL to be rapidly converted to the corresponding trialkyl forms, which are comparatively more stable (Bade and Huber, 1970). Given the simi larity of the chemical and biochemical behavior of trialkyl leads to their Group IV analogs, the trialkyltins, the report of Barnes and Stoner (1958) that triethyltin is quantitatively absorbed from the 61 tract indicates that triethyl and trimethyl lead would be extensively ab sorbed via this route.
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'10.7.1,2 Percutaneous Absorption of lead Alkyls. In centrist to inorganic lead salts, both TEL and TML are rapidly and extensively absorbed through the skin in rabbits and bats (Kehae ana Thamann, 1931; Laug and Kunze, 1948),. and lethal effects can be rapidly Induced in these animals by merely exposing the skin. Laug and Kunze (1348) observed that systemic uptake of TEL was still 6.5 percent even after most of the TEL had evaporated from the skin surface.. The rate of passage .of TML was somewhat slower than that of TEL in the Study of Davis eif al, (1953). Absorption of either agent was retarded somewhat When applied in gasoline,
* >
10.7.2 liotransformation and Tissue Distribution of Lead Alkyls To understand the in vivo fate of lead alkyls, one must.first discuss the bIptransf.orma-
tion processes of lead alkyls known tp occur in mammalian systems. Tetraethyl and tetramethyl lead both Undergo oxidative dealkylation in mammals to the jtri ethyl or trimethyl metabolites, which are rjow accepted as the actual toxic forms of these alkyls.
Studies of the biochemical mechanisms for these transformations, as noted by Kimmel et al. (1977), indicate a dealkylation mediated by a P-450 dependent mono-oxygenase system in liver mierddomes, with intermediate hydroxylation. In addition to rats (Cremer, 1959; Stevens et al., 1060; Eolanowska, 1968), mice (Hayakawa, 1972|, and rabbits (Bolanowska and Garczyhskii, 1968), this transformation also occurs in humans accidentally poisoned with TEL (Bolanowska et al,, 1967) or workers chronically exposed to TEL {Adamiak-Ziemba and Bolanowska, 1970).
The rate of hepatic oxidative de-ethylation of TEL in mammals appears to be rather rapid; Cremer (1959) reported a'maximum hourly conversion rate of approximately 200 pg TEL/g rat? liver. In comparison with TEL, TML may undergo transformation at either a slower rate (in rats) or more rapidly (inimice), according to Cremer and Callaway (1961) and Hayakawa (1972),;
Other transformation isteps involve conversion-of triethyl lead to the diethyl.form, the;' process appearing to be species-dependent. Bolanowska (1968) did not report the formation of diethyl lead Jo rats, whijle significant amounts of it are; present in the urine of rabbits \ (Arai et al,, 1981) and hdmans (Chiesura, 1970). Inorganic'lead is formed in various species' treated with TEL, whether the TEL arises from degradation of the diethyl lead-metabolite or from some other direct process (Bolanowska, 1968). Degradation appears to occur in rats, since little or no diethyl lead is found, whereas significant amounts of inorganic lead are present. Formation of Inorganic lead with lead alkyl exposure may account for the hematological effects seen in humans chronically exposed to the lead alkyls (see Chapter 12, Section 12.3), includ ing children who inhale leaded gasoline vapor.
Partitioning of triethyl or trimethy] lead, the corresponding neurotoxic metabolites of * TEL and TML, between the erythrocyte and plasma appears to be species-dependent. Byington et at, (1980) Studied the partitioning of triethyl lead between cells and plasma in vitro using
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DUP040012295
i
washed human and rat erythrocytes and found that human cells had a very low affinity for the alkyl lead while rat cells bound the alkyl lead in the globin moiety at a ratio of three mole cules per hemoglobin: tetramer. Similarly, injected triethy! lead wqs, found to be associated with whole blood levels approximately 10-fold greater than in rat plasma. The available lit erature on TEL poisoning in humans honours; significant plasma lead values have been routinely
reported (Boeckx et a!., 1977; Goldings and Stewart, 1982), These data indicate that the rat is a poor model for studying the adverse effects of lead alkyls in human subjects.
The biological hajf-life in blood for the lead alkyls depends on whether clearance of the tetraalkyl or trialkvi forms is being observed. Heard et al. (1979) found that 2Q3Pb-labeled
TML and TEL inhaled by human volunteers was rapidly cleared from the blood (by 10 hr), fol lowed by a reappearance of lead. The fraction of lead in plasma initially was quite ivigh, approximately 0.7, suggesting the presence of tetra/tr1alkyl 1ead. However, the subsequent
rise In blood lead showed all of it essentially, present in til cell, which would indicate
inorganic or possibly; diethyl lead. Triethyl lead in rabbits was more rapidly cleared from
the blood (3-5 days) than was the trimethyl form" 15 days) When administered as jsuch
(Hayakawa, 1972).
!.
|
Tissue distribution of lead in both humans and animals exposed to TEL and TML primarily
involves the trial kyl metabolites. Levels are highest in liver, followed by kidney,- then
brain (BolanoWska et al., 1967; Grandjean and Nielsen, 1979), Nielsen et al, (1978) observed
measurable amounts of trialkyl lead in samples of brain jns.sue from subjects with no known oc
cupational exposure.
'
The available studies on tissue retention of triethyl or trimethyl lead provide variable
findings. Bpiangwsfca .(1968) noted that tissue levels jot triethyl lead in rats were almost
constant for 16 days cjfter ,a single injection of TEL, jHayakawa (1972) found that the half-
life of.triethyl leid Ho brain was ,7-8 days for rats. "The half-time-for trimethyl lead was
much longer.- In humans, Yamamura et al. (1975) reportecf two tissue compartments for triethyl
lead having half-lives [of 35 and 100 days (Yamamura et alj., 1975).
j
10,7.3 Excretioh of Lead Alkyls
> .
<
The renal tract is the main route of lead excretion in various species exposed to lead
alkyls (Grandjean and Nielsen, 1979), The chemical forms of lead in urine suggest that the
differing amounts of the various forms are species-dependent. Arai et al. (1981) found that
rabbits given TEL parenterally excreted lead primarily in the form of diethyl lead (69 per
cent) and inorganic lead (27 percent), triethyl lead accounting for only 4 percent.
BoTa.ttQWS.ka and Garczyns.kl (1968) found that triethyl lead levels were somewhat higher in the
urine of rats than in that of rabbits. In humans, Chiesura (1970) found that tri alkyl lead
was never greater than 9 percent of total lead content in workers with heavy TEL exposure.
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DUPQ40012296
} Adamiak-Zieiiiba and Bolanowska (1970) reported' similar data; the fraction of tridthyl lead in the urine was approximately 10 percent of total lead.
The urinary rates of lead excretion in human subjects with known levels of TEl exposure were also reported by Adamiak-Ziemba and Bolanowska (1970), In workers involved with the blending and testing of leaded gasoline, workplace air levels of lead (as Til) ranged from 0.037 to 0.289 mg/m3 and the corresponding urine lead levels ranged from 14 to 49 pg/1, of which approximately 10 percent was triethyl lead.
10.$ SUMMARY;
^.
Toxicokipetic parameters of lead absorption, distribution, retention, and excretion rela
ting external environmental lead exposure to various adverse effects have been -discussed in
this chapter.) Also considered were various influences on these parameters, e.g.; nutritional
status, age, land stage of development. A number of specific issties in lead metabolism by ani
mals and humans were addressed, including:.
I!
1. HoWj does the. developing organism from gestation to maturity differ from;the adult in
toxicokinetic response to lead intake?
1
2. What do these differences in lead metabolism portend for relative risk for 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 for lead translate to' assessment of internal exposure and changes in internal exposure?
>.
10.8.1 Lead Absorption in Humans and Animals
i
1
-
}
The amoupts of lead entering the bloodstream via various routes of absorption are influ enced not only by the levels of the element in a given.medium but also by variousIphysical and
chemical.parameters and specific host factors, such as age and nutritional status..
10:8.1.1 Respiratory Absorption of Lead. The movement of lead from ambient air to the blood
stream 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
deposition 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.
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' f< '
' All of the available data for lead Uptake via the 'respiratory tractin 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. i)oe 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.
>
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 npnhuman primate support the findings that respired lead ifi 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 ievel,
i
10.8.1.2 gastrointestinal Absorption of lead. Gastrointestinal (Gl) absorption of lead
mainly involves lead uptake from-food arid 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 hates of such absorption in developing versus adult
organisms, including humans, and how the relative bioavailability of lead affects such uptake. By use of metabolic balance and Isotflpic (radioisotope or stable isotppe) 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 i absorbed to a greater degree since much beverage ingestion occurs between meals, - The], relationship of the chemieal/bioihemical 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,j 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
percent. For paint chips, a value of about 17 percent has been estimated. Experimental animal studies show that, like humans, the adult animal absorbs much less
lead from the gut than the developing animal. Adult rats maintained on ordinary rat chow ab sorb 1 percent or less of the dietary lead. Various animal species studies make it clear that
10-61
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DUPO40012298
-the newborn absorbs a much greater] amount-of lead than the adult, supporting studies showing
this age dependency in humans,. Compared to an absorption rate of about 1 percent in adult
rats, the rat pup has a rate 40-5Q times greater. Part, but not most, of the difference can
be ascribed to a difference in dietary composition. In npnh.uroan primates, infant monkeys ab-
sorb 65-85 percent of lead from the gut, compared to 4 percent for the adults.
The bioavailability of lead ih the GI tract as a factor in its absorption has beerKtbe
focus of a number of experimental studies. These data show the following! (T) lead in a
number of forms is absorbed about equally, except for lead sulfide; (2) lead in dirt and dust
and in different chemical forms is absorbed at about the same rate as pure lead salts added tp
a diet; (3) lead in paint chips undergoes significant uptake from the.gut; and (4) in some
cases, physical size of particulate lead can affect the rate of GI absorption. In humans, GI
absorption rate of lead appears to] be independent of quantity in the gilt up to a level of at
least 400 gg. In animals, dietary levels between 10 and 100 ppm result in reduced absorption.
10.8.1.3 Percutaneous Absorption of Lead. Absorption of inorgafric lead compounds through the
skin is of much less significance than absorption through respiratory and GI routes. In con
trast, absorption through skin is (far more significant than through other routes for the lead
alkyls (see Suction 10.7.1,2). One; recent study using human volunteers and 353Pb-labeled lead
acetate showed that under normal Conditions, skin absorption of lead alkyls approached 0.06
percent.
-.
10.8.1.4 Transplacental Transfer of Lead. Lead uptake by the human.and animal fetus readily
occurs, such transfer going on by the 12th week of gestation in humans, and increasing
throughout -fetal development. Cord blood contains significant amounts of lead, correlating
with, but somewhat lower than, maternal blood lead levels. Evidence for such transfer, be
sides the measured lead content of cord blood, includes fetal tissue analyses and reduction in
mjaternal blood lead during pregnancy.- There also appears to be a) seasonal effect on the
fetus, summer-born children showing a trend to higher blood lead levels than those born in the
spring.
`I
10.8.2 Distribution of Lead in Humans and Animals In this subsection, the distributional characteristics of lead in various portions of the
body (bipod, soft tissue, calcified tissue, and the "chelatable'1 or potentially toxic body burden) are discussed as a function of such variables as exposure history and age, 10,8.2.1 Lead in Blood. More than 99 percent of blood lead is associated with the erythro cytes in humans 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 (*v50 percent) erythrocyte lead is bound within the cell, primarily associated with hemoglobin (par ticularly HbA2), with approximately 5 percent bound to a 10,000-dalton fraction, 20 percent to
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DUP040012299
a heavier molecule, and .25 percent to lower-weight species. Sevierai studies.with lead-workers
and patients indicate that the fraction of lead in plasma versus whole blood increases above
'>50-60 pg/dl blood lead.
Whole blood lead in daily equilibrium with other compartments in adult humans appears to
have a biological half-life of 25-28 days and comprises about 1.9 mg in total lead content,
based on isotope studies. Other data from lead-exposed workers1 indicate that half-Wfe
depends on mobile lead burden. Human blood lead responds rather quickly to abrupt changes in
exposure. With increased lead intake, blood lead achieves a hew 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 bipod 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, females showing lower levels than males even at comparable levels of exposure.
In plasma, lead is virtually all bound to albumin and only trace amounts to.high-weight
globulins. Which binding form constitutes an "active11 fraction for movement to tissues is
impossible to state.' The most recent studies of the erythrocyte/plasma relationship 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 pg/dl, whereupon the
relationship becomes .curvilinear.
-
10,8.2,2 Lead Levels in Tissues. Of necessity, various relationships of tissue lead to expo
sure and toxicity in humans mqst generally be obtained from autopsy samples. Limitations on
these data include questions of how such samples represent lead behavior in the living popula
tion, particularly with reference to prolonged illness and disease states. The adequate char
acterization 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.
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10.8.2.2.1 Soft tissues. Aftdr 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 'ormation of nuclear inclusion bodies. Absence of lead.accumulation in
most soft tissues results from a turnover rate for lead similar to that in blood.
Based on several autopsy studies, soft-tissue lead content for individuals not occupa
tionally exposed is generally below 0.5 pg/g wet weight, with higher values for aorta and kid
ney cortex. Brain tissue lead level is generally below 0,2 pg/g wet weight with no change
with increasing age, although the cross-sectional nature of these data would make changes in
low brain lead levels difficult to discern. Autopsy data for both children and adults indi
cate that lead is selectively accumulated in the hippocampus, a finding that is also consis
tent with the regional distribution in experimental animals.
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DUP040012300
i
. Comparisons of -lead levels in soft-tissue autopsy]samples from.children with res.iiIts from
adults indicate that such values are lower in Infants than in older children, while children
aged 1"1G 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 tils,tie mass with age, although such changes
are less than for the skeletal system.
<.
'
Subcsllular distribution of lead in soft tissue is not uniform. High amounts of lead are
sequestered in the mitochondria and nucleus of the ce,l 1. Nuclear accumulation is consistent
with the existence of lead-containing nuclear .inclusions in various species, and a Targe- body
of data demonstrate the sensitivity of mitochondria to iinjury by lead.
^
10,8.2,2,2 Mineralizing tissue. Lead becomes localized and accumulates in human calcified
tissues, i.p., bones- and teeth. This accumulation in hlimans begins with fetal development and
continues tp approximately 60 years of age. The extent of lead accumulation in bone ranges up
to 200 mg in men ages 6.0-70 years, while in women lower! values hpe 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'bath the most Inert and the largest tody 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 hone lead level across childhood is modest, about
twofold if expressed as concentration, the total accumulation rate is actually 80-fold,
taking into account a 40-fold Increase in skeletal mass. To the extent that some significant -i j I
fraction of total bone lead in children, and adults isi 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.
j
i
The traditional -view that the skeletal system was; a "total" sink for body lead (and by i
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 ing, This view is now giving way to the idea that there are at least several bone compart ments for lead, with different mobility profiles. Bone lead, then, may be more of an insid ious source of long-term internal exposure than a sink for the element. This aspect of the issue is summarized more fully in the next section. Available information from studies of uranium miners and human volunteers who ingested stable isotopes indicates that there is a relatively inert bone compartment for lead, having a half-life of several decades, as well as a rather labile compartment that permits an equilibrium between bone and tissue lead,
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DUP040012301
vis* r
Topth lead also increases with age at a rate proportional to exposure and roughly propor
tional to blood lead in humans and experimental animals.,. Dentine lead is perhaps the most re
sponsive component of teeth to lead exposure since it is laid down from the time of eruption
until shedding. This characteristic underlies the usefulness of dentine lead levels in asses
sing long-term exposure.
10.8.2.2.3 Chelatable lead. Mobile lead in organs and systems is potentially more active
lexicologically in terms of being available to biological sites of action. Hence, this frac
tion of total body lead burden is a more significant predictor of imminent toxicity,In real
ity * direct measurement of such- a fraction in human subjects would net be possible.. In this
regard, chelatable lead, measured as the extent of plumburesis in response to administration
of a chelating agent, specifically CaNaaEDTA, is now viewed as the most useful probe of undue
body burden in children and adults,
'
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_1
A quantitative description of the inputs to the body lead-fraction that is chelant-mobi-
lizable is difficult to define fully, but it most likely includes a labile lead compartment
within, bore as well as within soft tissues. Support for this view includes the following:
(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) in vitfo 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 (withi out obvious external re-exposure) offer further support.
10.8.2.2.4 Animal studies. Animal studies have helped to sort out some of the relationships
Of lead exposure ito in 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 s<j>ft tissues, followed by loss of j lead from soft tissue via excretion and
transfer to bone.- Lead distribution appears to be relatively independent of dose. Other
studies have shown that lead loss from organs follows first-order kinetics except for loss
from bone, and that the skeletal system in rats and mice is the kinetically rate-limiting step
in whole-body lead clearance. ; The neonatal animal seems to retain proportionally higher levels of tissue lead compared
to the adult and manifests slow decay of brain lead levels while showing a significant decline
over time in other tissues. This decay appears to result from enhanced lead entry to the
brain because of a poorly developed brain barrier system as well as from enhanced body reten
tion of lead by young animals.
*
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DUP040012302
i . .........................
,
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 tb demonstrate tissue
redistribution of lead, specifically bane-lead resorption with .subsequent transfer of both
lead and calcium from mother to pups.
;?
.10-8-3 lead Excretion and Retention in Humans and Animals
10.8.3.1 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 SI tracts, the latter via biliary clearance. The amounts excreted
through tliase routes are a function of such factors -as species, age, and exposure charac
teristics.' i
i
>
Based1 upon the human metabolic balance data and isotope excretion finding's of various in
.vestigatoris, 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 Ithis stored amount eventually being excreted. This estimated overall retention
figure gf j25 percent necessarily assumes that isotope clearance reflects that ifor body lead in
all compartments. The rapidly excreted fraction has a biological half-life of 20-25 days,
similar to that for lead remove! from blood, based on isotope data. This similarity indicates
a steady rate of lead clearance from the body. In terms of partitioning of excreted lead
between urine end bile, one study indicates that the biliary clearance is about 50 percent
that of renal clearance.
-
Lead accumulates in the human body with age, mainly in bone, up to around 60 years of
age, when a decrease occurs with changes in!intake as well as in bone mineral:metabolism. As
noted earljier, the total amount of lead in Hong-term retention can approach 200' mg, and even
much higher in'the case of occupational exposure. This rate corresponds to a lifetime average retention irate of 9-10 pg Pb/day. Within Shorter time frames, however, retention will vary
considerably because of. such factors as development, disruption in the individuals' equilib
rium with lead intake, and the onset of such ..states as osteoporosis.
The age-dependency of lead retention/excretion in humans has not been well studied, but
most of the available information indicates that children, particularly infants, retain a sig
nificantly higher amount of lead than adults. While autopsy data indicate that pediatric sub
jects at isolated points in time actually have a lower fraction of body lead lodged in bone,
which probably relates to the less dense bones of children as well as high bone mineral turn
over, a full understanding of longer-term retention over childhood must consider the exponen
tial growth rate occurring in children's skeletal systems over the time period for which bone
lead concentrations have been gathered. This parameter itself represents a 40-fold mass
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DUP040012303
1 .-
j
Increase, 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 facb pf a
more active skeletal system, where dots 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 Jn
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adults, an assumption that remains;to be proven adequately,
10.8.3.2 Animal Studies. In rats and other experimental animals, both urinary and fecal ex
cretion appear to be important routes of lead removal from the organism. The relative parti
tioning between the two modes is species- and dose-dependent. With.regard, to species differ
ences, biliary clearance of lead in the dog is but 2 percent of that for the rat, while such
excretion 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 young, Comparative studies
of lead retention in developing versus; aduljt 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,
10.8.4 Interactions of Lead with Essential Metals and Other Factors IToxic elements] such as lead are affected in their toxicokinetlc or toxicological behavior
by interactions with a variety of biochemical factors, particularly nutrients. 10.8:4,1 Human Studies. In humans., the interactive behavior of lead and various nutritional factors is expressed most significantly in young children, with such interactions occurring against a backdrop of rather widespread deficiencies in a number of nutritio.nal components. Various surveys have indicated that iron, calcium, zinc, and vitamin deficiencies are wide spread among the pediatric population) particularly the poor. A number;of reports have docu mented the associatijon of lead absorption with suboptimal nutritional states for iron and cal cium, reduced intakei being associated with increased lead absorption. ID.8.4.2 Animal Studies. Reports of lead-nutrient Interactions in experimental animals have generally described such relationships for a single nutrient, using relative absorption or tissue retention in the animal to index the effect. Most of the recent data are for calcium, iron, phosphorus, and vitamin D. Many studies have established that diminished dietary calci um is associated with increased blood and soft-tissue lead content in such diverse species as the rat, pig, horse, sheep, and domestic fowl. The increased body burden of lead arises from both increased SI absorption and increased retention, indicating that the lead-calcium inter action operates at both the gut wall and within body compartments. Lead appears to traverse
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DUP04Q012304
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.
Iren deficiency is associated with an increase of lead in tissues and increased toxicity, effects that are expressed at the level of lead uptake by the .gut wall. In vitro studies indicate an interaction through receptor-binding competition at a common site, which probably involves iron-binding proteins. Similarly, dietary phosphate deficiency enhances the extent of lead retention and toxicity via increased uptake of lead at the gut wall, both lead and phosphate being 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-cal piUm 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, 1rony#and phosphate versus lead up take, vitamin D levels appeal* 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 suhoptimal or excess protein intake will increase lead absorption.
3. Certain milk components, particularly lactose, greatly enhance lead absorption in
the nursing animal. j
|
4. Zinc deficiency promotes lead absorption, as does reduded .dietary .copper.
Taken collectively, human (and animal data dealing with the interaction of lead and nutri ents Indicate that there are Heterogeneous subsets of the human population. In terms of. pedatric population risk for lead exposure, children having multiple nutrient deficiencies are in the highest exposure risk category.
10.8.5 Interrelationships of Lead Exposure with Exposure Indicators and Tissue Lead Burdens Three issues involving lead toxicokinetics evolve toward a full connection between lead
exposure and its adverse effects: (1) the temporal characteristics of internal indices of lead exposure; (2) the biological aspects of the relationship of lead in various media to various indicators in internal exposure; and (.3) the relationship of various internal indica tors of exposure to target tissue lead burdens.
10-68
DUP040012305
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10.8.5.1 temporal Characteristics of Internal Indicators of lead Exposure. The biological
half-life for newly absorbed lead in blood may be as short as weeks, or several months.. Or, it
may be leriger, depending on the mobile lead burden in the body.. Compared to mineral tissues,
this medium reflects relatively recent exposure. If recent exposure is fairly representative
of exposure over a considerable period of time, e.g., exposure of lead workers, then blood
lead is more useful than for cases'where exposure is intermittent or different across time, as
in the case of lead exposure of children. Accessible mineralized tissue, such as shed teeth,
extend the time frame back to years of exposure, since teeth accumulate lead with age and as a
function of the extent of exposure. Such measurements are, however, retrospective in nature,
in that identification of excessive exposure occurs aftdrj the fact and thus limits the possi
bility of timely medical intervention, exposure abatement,; pr regulatory policy concerned with
ongoing control strategies.
j*
Perhaps the most practical solution to the dilemma1 posecf by both tooth and blood lead
analyses is Tn situ .measurement of lead in teeth or bon# during the time when active accumu
lation occurs, e.g., 2- to 3-year-pld children. Available data using X-ray fluorescence anal
ysis do suggest that such approaches are feasible and cap be reconciled with such issues as
acceptable radiation hazard risk to subjects, '
!
10.8.5.2
Biological Aspects of External Exposure/lnternal Indicator Relationships,
The
literature indicates clearly that the relationship of lead in-relevant media for human expo
sure to 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 vafies across this range of exposure, with comparatively smaller blood
lead changes occurring as internal exposure increases.
;1
,
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.increas|ng]y unreliable measure of target-tissue lead burden with increasing
exposure. While the hasps of the curvilinear relationship! remains to be identified, availabjle
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 pg/dl. ;
10.8.5.3 Internal Indicator/Tissue Lead Relationships. In living human subjects, direct de
termination of tissue lead burdens or how these tel ate to adverse effects in target tissues is
not possible. Some accessible indicator (e.g., lead in a medium such as blood or a biochem
ical surrogate of lead such as erythrocyte protoporphyrin), must be employed. While blood
lead still remains the only practical measure of excessive lead exposure and health risk, evi
dence 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.
10-6:9
DUP040012306
It present, the measurement of plumbyresis associated with challenge' by a single dose of
a lead-chelating agent such as CaNa3EDTA 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'* v'f
ship may be seen in studies of children and lead workers in whom moderate elevation in blood
lead levels can disguise levels of mobile bcdy lead. In one racent .mult1-ihsti,tutioo study of
210 children, for example, 12 percent of children with blood lead 30-39 pg/dl, and 38 percent
with levels cf 40-49 pg/dl, had a positive EDTA-challenge response and required further evai--
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 jpd, 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
subsequent 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 de
crease in blood lead with reduced exposure signal a similar decrease in target tissue, parti
cularly in the brain of the developing organism.
*
10,8.0 Metabolism of Lead Alkyls
'j
The lower alkyl lead components used as gasoline additives, tetraethyl lead (TEL) and
tetramethyl lead iTML), may themselves poise a toxilc risk to humans. In particular, there is
among Children a p!roblem of sniffing leaded gasoline:'.
i
10.8.6.1 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 Si percent, respectively:,
values which are similar to those for particulate inorganic lead. Significant portions of
these deposited amounts were eventually absorbed. Respiratory absorption of organolead bound
to particulate matter has not been specifically studied as such.
While specific data for the GI absorption of lead alkyls in-humans and animals are not
available, their close similarity to organotin compounds, which are quantitatively absorbed,
would argue for extensive GI absorption. In contrast to inorganic lead salts, the lower lead
10-70
DUP040012307
alkyls are extensively absorbed through the skin and animal data show lethal effects with per
cutaneous uptake as the sole route of exposure.
10.8.6.2 Biotransformation and Tissue Distribution of Lead.Alkyls.. The lower 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. Alkyl
lead is rapidly cleared from blood and shows a higher partitioning into plasma than inorganic
lead, with triethyl lead clearance being more rapid than that of 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 tliere are detectable amounts of trial kyl lead from autopsy samples cjf human brain
even in the -absence of occupational exposure. In humans, there1 appear to be two tissue com
partments for triethyl lead, having half-times of 35 and 100 days,
1,
10.8.6.3 .(Accretion of Lead Alkyls. With alkyl lead exposure, excretion of lead through the
renal tract jis the main route of elimination. The chemical forms being excreted appear to be
spedes-depehdent. In humans; trialkyl lead in workers chronically exposed to alkyl lead is a
minor component of urine lead, approximately 9 percent.
i
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DUP040012308
10.9 REFERENCES
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Alessio, L.; Bertazzi, P. A. ; Monelli, 0.; Toffolettd., F. (1975) Free, erythrocyte protopo.rphyr-
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}. ;
Alexander, F. W.; Delves, H. T.= (1981) Blood lead levels during pregnancy. Ini. Arch, Occup.
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Alexander, F. W.; Delves, H, T.; Clayton, 8. , (197.3) The uptake and excretion by children of ; lead and other contaminants. In: Barth, D.; Berlin,, A,; Engel, R.; Recht, P..; Smeets, J.,
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'* ''
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Allcroft, % (1950.) Lead as a nutritional hazard to farm livestock.) IV: Distribution of lead
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Anders, E.; Bagnell , C. R., Jr. ; Krigman, M. R..; Mushak, P. (1982) Influence of dietary pro tein composition on lead absorption in rats.. Bull. Environ Contain.. Toxicol. 28;: 61-67.
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Aungst, B. J.; Dolce, J. A. ; Fung, H. (1981) The effect of dose on the disposition of lead in rats after intravenous and oral administration. Toxicol,. Appl. Pharmacol. 61: 48-57.
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Azar, A.; Sriee, R, D.; Habibi, K. (1975) An epidemiological approach to community air lead exposure using personal air samplers. In: Griffin, !. B. * . Kneiaon,. J. H., eds. Lead. Stuttgart, West Germany: Georg Thieme Publishers; pp. 254-290. (Coulston, F.; Korte, F., eds. Environmental quality and safety: supplement v. 2).
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Tetraorganoplumbanen und Tetraorganostannanen [Reactions of organometallic compounds. IV: Tins influence of the organic ligand and.the central atom on the speed of acidolysis of organolead compounds and ' analogous tin compounds]. J. Organometal. Cheni, 24:. 387^397,
Baloh, R. W. (1974) Laboratory diagnosis of increased lead absorption. Arch. Environ. Health
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Barltrop, 0. (1969) Transfer of lead to the human foetus. In: Barltrop, D.; Borland, W. L,,
eds. Mineral metabolism in pediatrics. Philadelphia, PA: 8'aviS Co.; pp* '135-151.
.j :
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SGbel, A.. E.; Gawron, 0.; Kramer, 8.. (1938) Influence of vitamin D in experimentallead poisoning,. Prod. Spc. Exp. Biol. Med. 38; 433-4:35.
Sdbel, A. ..; Yuska, H.; Peters, D. D.; Kramer, B. (1940) The biochemical behavior of lead: l'. i influence of calcium, phosphorus, and vitamin D on lead In blood-and bone. J. Bioi. Chem. j 132: .239-265. Reprinted (1981) in Nutr. Rev, 39.: 374-377.
Serrell, M.; Rosen, J. F.; Roginsky, M. (1977) Interactions of
calcium* vitamin 0, and
nutrition in lead-burdened children. Arch. Environ, Health 32: 160-164.
Steenhout, A.; Ppurtois, M. (1981) Lead accumulation in teeth as a function of age with different exposures. Br, J. Indj. Med. 38: 297-303.
N!
Stephens, R.; Waldron, H, A, (1975) The influence of milk and related dietary constituents on lead metabolismC Food Cosmet, Toxicol. 13; 555-563.
Stevens, C, D,.; Feldhake, G. J,; Kehoe, R. A. (I960) Isolation of triethyllead ion from liver j after inhalation of tetraethyllead. J. Pharmacol, Exp, Ther. 1204 90-94.
Stowe, y. 0.; Goyer, R, A, ; Krigman, M. M. Wilson, M.; Cates, M, (1973) Experimental oral
lead toxicity in young dogs:-clinical and morphologic effects,' Arch. Pathol, 95: 106-116. '
i_
j
!
Stliik, ,. J. (1974) Biological response of male and female volunteers; to inorganic lead. Int, Arch. Arbeitsraed. 33: .83-97. ,
Thompson, J. A. (1971) Balance between intake and output of lead in normal individuals. Br. J, Ind. Med. 28; 189-194.
Tola, S.; Hernberg, S.; Asp, S.; Nikkanen, J. (.1973) Parameters indicative of absorption and biological effect in new lead exposure: a prospective study. Br. J. Ind. Med. 30: 134-141.
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Trotter, H; Hixon, 8. B. (19743 Sequential changes in weight, density, and percentage ash weight of human skeletons from an early fetal period through old age. Anat. Rec. 179: 1*18.
U,, S. Centers for Disease Control. (1978) Preventing lead poisoning in young children.: a state ment by the Center for Disease Control, J. Pediatr. (St. Louis) 93: 709-720.
U. $. Environmental Protection Agency. (1977) Air quality criteria for lead. Research Triangle Park, NC: Health Effects Research Lab, Criteria and Special Studies Office; EPA report
no. EPA-6Q0/8-77-Q17. Available from.:.NTIS, Springfield, VA; PB-280411.
United Kingdom Central Directorate on Environmental Pollution. (1982) The Glasgow duplicate
diet study (1979/1980): a joint survey for the Department of the. Environment and the
Ministry of Agriculture, Fisheries and Food. LondonJ United Kingdom: Her Majesty's
Stationery Office; pollution report.no. 11.
.i
Victory, W,; Soifer, N. E.; Weiss, J. S. ; Vander, A, J. (1981) Acute effects of lead on the renal handling of zinc in dogs, Toxicol, Appl, Pharmacol,^ 61: 358-367.
Vitale., L. F.; Joselow, ft. M.; Wedeen, R. P.; Pawlow, M, (1975) Blood lead--an inadequate measure of occupational exposure. J, Occup. Med. 17: 155-156.
Watson, W. S.; Hume, R.; Moore, M. R. (1980) Oral absorptionjof lead and iron. Lancet 2(8188):
236-237.
!
Wedeen, R. P,; Maesaka, 0. K.; Weiner, B.; Lipat, G. A. ; Lyons, M, M.; Vitale, L. F.; Joselow, M. M.. (1975) Occupational lead nephropathy. Am. J, M.ed. 59: 630-641.
Wedeen, R. P.; Mallik, D. K.; Batuman,' V. (1979) Detection and treatment of occupational lead ` nephropathy. Arch. Intern. Med. 139: 53-57.
Williams, M. K.; King, E.;, Waiford, J. (1969) An investigation of. lead absorption in an elec- ; trie accumulator factory with the use of personal samplers. Br. J. Ind. Med. 26: 202-216.
Willoughby, R. A.; Thirapatsakun, T..; McSherry, B. J, (1972) Influence of rations low in ,
calcium and phosphorus on blood and tissue lead concentrations in the- horse. Am. j. Vet. !
Res, 33: 1165-1173.
'
Winneke, G.; Brockhaus, A, j Kramer, U,; Ewers, U.; Kujanek, G.; Lechner, H.; Janke, W. (1981)
Neuropsychological comparison of children with different tooth-lead levels: preliminary report. In: International conference: heavy'metals in-the environment; Amsterdam, The ; -Netherlands. Edinburgh, United Kingdom: CEP Consultants, Ltd.; pp. 553-556.
World Health Organization, United Nations Environmental Programme. (1977) Lead. Geneva,
Switzerland: World Health Organization. (Environmental health criteria 3).
*
Yamamura, Y.; Takakura, J.; Hifayama, F.; Yamauchi, H.; Yoshida, M. (1975) Tetraethyl lead
poisoning caused by cleaning work in the aviation fuel tank. Jpn. J. Ind. Health 17:
223-235.
Yip, R.; Norris, T. N.; Anderson, A. 5. (1981) Iron status of children with elevated blood4 lead concentrations, J. Pediatr. (St. Louis) 98: 922-925.
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Ziegler, E. E.; Edwards, 8. B.; Jensen, R. L ; Mahaffey, K, R,; Fomon, S. J. <1978) Absorption and retention of lead by infants. Pediatr. Res. 12: 28-34.
Zielhufs, R:. L.; del Castilho, Pi; Herber, R. F. M-; Wibowp, A, A. E. (1978) Levels of lead and other metals in human blood: suggestive relationships , determining factors. Environ. Health Perspect, 25: .103-109.;
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I! 11. ASSESSMENT OF LEAD EXPOSURES AND ABSORPTION IN HUMAN POPULATIONS
11.1 INTRODUCTION This chapter describes effects on internal 'body burdens of lead in human populations
resulting from exposure to lead'in their environment. Particular attention is paid to changes In indices of internal lead exposure that follow changes in external lead exposures. ^Blood lead is the main index of internal lead exposure discussed here, although other indices, such as levels of lead in teeth and bone, are also briefly discussed.
The following terms and definitions are used in this chapter. .Sources of lead are those components of the environment (a.g., gasoline'combustion,, smelters.) from which significant .quantities of lead are released into various environmental media of exposure. Environmental media are routes by Which humans become exposed to lead (elg,', air, soil; food, water, dust), External exposures are levels at which lead t$ present in..any or all of the .environmental media. Internal exposures are amounts of lead present in various body tissues and fluids.
The present chapter is structured to achieve the following four main objectives:
(1) Elucidation of patterns of internal lead exposures in U.S. populations and
identification of important demographic coyarlates,
--
(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,
.
. .
1
(4) Estimation of the relative contributions of various sources of lead in the environment to total internal 'exposure as indexed by blood lead level, :
The.existing scientific literature must be examined in light of the investigators' own objectives and,the guality of the scientific investigations performed. Although! all studies need to be evaluated in regard to their methodology, the more quantitative, studies are evalu ated here in greater depth. A discussion of the main types of methodologi.caT points con sidered in such evaluations is presented in.Section 11*. 2.
Patterns of internal exposure to lead in human populations are discussed in Section 11.3. This begins with a brief examination of the historical record of internal lead exposure in human populations. These data serve as a backdrop against which recent U.S. levels can be contrasted and define the relative magnitude of external lead exposures in the past and present. The contrast is structured as follows: historical data, recent data from popula tions thought to be isolated from urbanized cultures, and then U.S. populations showing various degrees of urbanization and industrialization.
U-l
DUPQ40012329
The statistical treatment of distributions of blood lead levels in human populations is
the next topic discussed. As part of that discussion, the empirical characteristics of blood
lead distributions in well-defined homogeneous populations are denoted.. Important issues
addressed include the proper choice of estimators of central tendencyrand dispersion, estimat
tors of percentile values and the potential influence of errors in-measurement on statistical
estimation involving blood lead data,
^
Then recent patterns of internal exposure in U,S. and other populations showing change in
blood lead levels are discussed in detail. Estimates of internal lead exposure and identifid
eation of demographic covariates ace made. Studies, examining the rfecent past for evidence of
change'in internal exposure levels are presented. Next is an examination of extensive evi
dence which points towards gasoline lead being an important determinant of changes in blood
lead level associated with exposures to airborne lead of populations. In the United States and
elsewhere.
;
Section 11,4 focuses on general relationships between ^external exposures and levels of
internal exposure. The distribution of lead in man is diagramatically depicted by the compo
nent model shown in Figure 1.1-1. Of particular importance for this document is the relation
ship between lead in air and lead in tlood. If lead in air were the only medium of exposure,
then the interpretation of a statistical relationship between lead in air and lead in blood
would be relatively simple. However, this is not the case. Lead is present in a number of
environmental media, as described in Chapter 7 and summarized in Figure 11-1. There are rela
tionships between lead levels in air and lead concentrations in food, Soil, dust, and water.
.As shown in Chapters 6, .7, and S., lead emitted into the atmosphere ultimately comes back to
contaminate the earth. However, only limited data are currently available that provide a
quantitative .estimate of the magnitude.of this secondary lead exposure^ The implication is
thatjan analysis involving estimated lead levels in ail environmental media may tend to under
estimate the relationship between lead in blood and lead in air. . .
The discussion of relationships between external exposure and internal absorption com
mences with air lead exposures. Both ^experimental and epidemiological studies are discussed.
Several studies are identified as being of greatest importance in determining the quantitative
relationship between lead in blood and lead in air. The form of the relationship between
blood lead and air lead is of particular interest and importance. After discussion of air
lead versus blood lead relationships, the chapter next discusses the relationship of blood*
lead to atmospheric lead found in other environmental media. Section 11.5 describes studies
of specific lead exposure situations useful in identifying specific environmental sources of
lead that contribute to elevated body burdens of lead. The chapter concludes with a summary*
of key information and conclusions derived from the scientific evidence reviewed.
11-2
DUP040012330
Figure 11-1. Pathways of lead from the environment to and within man.
11-3
DUP040012331
11.2 METHODOLOGICAL CONSIDERATIONS
1
11.2.1 Analytical Problems
Internal lead exposure levels in human populations have been estimated by analyses of a
variety of biological tissue matrices (e, g., blood, teeth, bone, and..hair). Lead levels in
each of these matrices have particular biological meanings with .regard to external exposure
status; these relationships are discussed in Chapter 10. The principal internal exposure
index discussed in this chapter is bipod lead concentration. Blood lead cbncentrati.pns are
most reflective of recent exposure .to ;lead and bear a consistent relationship to levels of
lead in the external environment if the latter have been stable:.1 Bipod lead levels are Vari
ously reported as pg/100 g, pg/100 ml, pg/dl, ppm, ppb, and; qmoT/lf the first four measures
are roughly equivalent, whereas ppb-values are simply divtefble by 100(1 to be equivalent.
Actually there is a small, but not meaningful, difference in blood lead levels reported on a
per volume versus per weight difference. The difference results from, the density of blood
being slightly greater than 1 g/ml, for the purposes of ^this chapter, data reported on a
weight or volume basis are considered equal. On the other hand, blood lead data reported on a
pmo.1/1 basis must be multiplied by 20.T2 to get the equivalent pg/dl Value. Data reported
originally as pmol/l in studies reviewed here are converted tp pg/dl in this chapter.
As discussed in Chapter 3, the meapurejitent of lead in blood has been accomplished via a
succession of analytical procedures over the years. The first reliable analytical methods
available were wet chemistry procedures,- succeeded by increasingly automated instrumental
procedures. With these changes in technology there has been increasing recognition of the ;
importance of control 1 tag for contamination in the sampling and analytical procedures. These
advances, as well as' institution of. external quality control programs, have resulted in
markedly improved analytical results. Data summarized in Chapter 9 show that a generalized
improvement in 'analytical l results across -many laboratories occurred during Federal Fiscal
Years 1977-1979. No further " marked improvement was sebn during . Federal Fiscal Years
1979-1981.
'
- '"
,
l i. i
Because of interest ip being able to attribute specific proportions of blood lead as \
coming from specific environmental sources., isotopic'lead determinations in blood have become ?
an Important analytic technique.- As difficult ,as it is to determine blood lead levels accu
rately, the achievement of accurate lead isotopic determinations is even more difficult.
Experience gained from the isotopic lead experiment (ILE) in Italy (reviewed in detail in.
Section 11.3.6.2.1) has indicated that extremely aggressive quality control and contamination
control programs must be implemented to achieve acceptable results. With proper procedures,
meaningful differences on the order of a single nanogram are achievable.
11-4
DUP040012332
11.2,2
t , | . . -,
ii I * Statistical Approaches
.
.. *
......
'. -
.
: -i
<
Many studies have summarized the distribution of lead levels in humans. These'studies
usually report measures of central tendency (means) and dispersion (variances). In this chap
ter, the term "mean" refers to tfie arithmetic mean unless stated otherwise. This measure is
always an estimate of the average value, but it estimates the center of the 'distribution .(Both
percentile) only for symmetric distributions. Many authors provide .geometric means, which
estimate the center of the distribution if the distribution is lognormal. Geometric means are
influenced less by unusually large values than are arithmetic means. A complete discussion of
the lognormal distribution is given by Aitchison and Brown (196$), including formulas for Con-"
verting from arithmetic to geometric means.
Most studies also gi!/e sample variances or standard deviatidns iri addition to the means.;
If geometric means are given, then the corresponding measure of dispersion Is the geometric
standard deviation. Aitchison and Brown (196.6) give formulas#for the geometric standard devi
ation and, also, explain how to estimate percentiles and construct confidence intervals. All
of the measures of dispersion actually include three sources of variation' population varia
tion, measurement variatioin, and viariatioh;due to sampling error.. Values for these components
are needed in order to Evaluate a stud^ correctly. There are also sources of variation
related to the inclusion of predictive variables in the model, dr their exclusion. .Such vari
ables include different lead uptakes attributable to exposure to lead in dust, soil, food,'
water, paint in deteriorated housing, arid other pathways! If Included in the.model, the
remaining sources of variation are due to unmeasured differences in intrinsic metabolism and
behavior. It has been the general gdaT inthis chapter to include all attributable sources of
variation, thus reducing the estimates of variability to biological differences, uncertainties
in exposure, and measurement variations that cannot be further attributed. We recognize that
if. only air lead exposure jis controlled, then there will be additional variation in blood lead
response due to imperfectly controlled covariation of lead exposure from related pathways..
This additional variation icatv be dealt with in practice by use of a larger geometric standard
deviation.
1
1~
;
A separate issue is the form of the distribution of blood lead values. Although the' nor
mal and lognormal distributions are commonly used, there are many other possible distribu
tions. The form is important for two reasons; 1) it determines which is more appropriate,
the arithmetic or geometric mean, and 2) it determines estimates of the fraction of a popula
tion exceeding given internal lead levels under various external exposures. Both of these
questions arise in the discussion of the distribution of human blood lead levels and are of
importance, ultimately, for deriving a rationale for standard-setting purposes..
11-5
DUP040012333
11-2.3 Confounding of Relevant Variables
Failure to 'include relevant variables is the most, serious difficulty in evaluating stud
ies on lead -in human populations. This usually occurs when the bipod lead response is'wholly
attributed to some observed variable, e.g., the lead concentration in air:, dust,-or water.'
Typical confounders for air lead include the following: (1) inhalation exposures not captured
by stationary air lead monitors, particularly those that o.cqpr from personal exposure to
leaded gasoline or its combustion products; (2) noninhalatibn exposures to air lead not cap
tured by stationary monitors, e.g., ingestion of food products contaminated by lead fallout,
leaded dust, and soil; <3) ingestion of lead in water and food that is iriadvertahtly associ
ated with air. lead exposure. Socioeconomic factors may be. important here sjlso. See
Brunekreef (I984p and Snee (1982b,c) for additional comments-. - .
\
.Air lead concentrations are typically highest in urban centers where the concentration of
motor vehicles is greatest. (Communities with lead! smelters^are an exception).. Suburban and
rural areas have much lower air lead concentrations. However, suburban, and rural residents
may spend more time in motor vehicles due to longer trips to work, school, and shopping.
There is some reason to believe that higher lead concentrations may be found near and inside
automobiles (seg Spengler et al., (19.84); Section .11.3.6.2.1), thus offsetting thei decreased
s'
ambient air lead concentrations measured by stationary monitors in-non-urban areas. Un
fortunately, there is no way at this time to separate the response to average ambient air lead
levels from variations in personal lead exposure patterns. )
Children are known to ingest quantities of dust and soil by normal hand-mouth contact- In
studies in which dust lead' concentrations or handi lead quantities are measured, their contri--
bution is very large -- usually much larger than the-lead intake by direct inhalation. In
smelter communities all of these variables -- ambient air lead, dust lead, soil lead;, and lead
on children's hands -- are likely to be high. It may then be difficult to separate the contri
butions .of .'each, of these components, and if any one is not measured, then its influence on
blood lead may bfe attributed to the other variables. This may cause little difficulty when in
fact there is a'single source for all exposure pathways, but positive confounding may cause
difficulty in extrapolating the relationship to situations in which air and dust lead are less
strongly coupled. Similarly, the particle size distribution may change with distance from the
source (smelter, highway, etc.) and particle size is known to affect the fraction of lead ab
sorbed by the lungs. However, air and dust lead concentrations also decrease with distance^
from the source, thus leading to potential confounding of concentration and size effects.
This may be a factor in some smelter studies, e.g., the Silver Valley, Idaho, study discussed
1 ater.
'
11-6
DUP040012334
I
5 ! i
Socioeconomic: status (SES), sex, age, and race are also confounded with air lead.
Lower
:$ES populations tend to be found in areas with high alf lead concentration such as urban cen
ters and smelter communities. There (nay also be systematic SES differences irt use of lead-
soldered food and beverage cans and in exposure: to food products with high leap content and in
personal and household cleanliness, as well. The Tatter.is important because dust control can
substantially reduce blood lead.burdens in children (Charney et SL , 19.83). Lower SES is also
associated with older housing stocks and increasing risk of encountering lead paint in poor
condition and lead pipes in water systems. Cower SES is also more likely to be associated
with inadequate dietary calcium, iron, and vitamins, all of which increase lead absorption`and
the likely toxic effects of any given level of: lead exposure. In addition, lower SES is also
more likely to imply reduced awareness Of lead! hazards .and reduced resources for .dealing with
such hazards. Other factors, such as the presence of pets in a household and the amount of
time spent, playing outside, are not obviously rblated to SES.,
Hales have higher blood lead levels than females, at least beyond ages 10-11. The most
plausible explanations suggest differential expbsure, with older boys and men typically spend
ing more time in contact with motor vehicles, jin jobs with potential lead exposure, and more
often outdoors. The risk factors have not bebn fully identified. Black children also often
have higher blood leads than do white children!, even aftpl adjusting for SES and other covar
iates; the reason for this difference has also not been clarified, but may be related to posi
tive confounding, factors.
j
For modelling purposes, the .appropriate geometric standard deviation removes; a portion of
the total variation in blood lead due to differences in air lead exposure .without removing the
variance due .to these other factors. Controlling for race, urbanization, age; income, and
location may .pvercontrol in this case, since itraiay remove variance due to environmental .expo
sure factors that will remain after air lead isjcontrolled to any-given level. It may thus be
prudent and conservative to compensate for this pvercontrol -by increasing the geometric stan
dard deviation when only air lead is used as a predictor variable.
All of the above factors make it difficult! to analyze adequately such a highly confounded,
environmental exposure variable as air lead.. However, there appear to be enough studies in
which several of the possible confounding factors were also measured that it is possible to
obtain reasonable estimated of blood lead changes in response to differences in concentrations
of lead in air, dust, soil, Water, and diet, seasonal variations, and personal risk factors
such as household quality, occupational exposure, and motor vehicle exposure. The remaining
sections of this chapter discuss studies from which such estimates are derived. Experimental
studies are much less subj'ect to confounding, and where available, are generally preferred.
Unfortunately, experimental studies do not provide information about total environmental air
11-7
DUP040012335
lead exposure, which includes multiple exposure pathways and possible time lags of many years'* due to passage of lead through the soil, the food chain, and water supplies. It is thus also necessary to obtain information about total air lead exposure from observational studies. All observational studies suffer.confounding problems. This chapter focuses mainly on those ob* servational studies in which a substantial number of the probable, important confounding.facr tors are either measured or are controlled by the .design of the study. Less importance is assigned to those studies in which too many important covariates have been omitted, or which otherwise seem critically deficient.
11.3 LEAD IN HUMAN POPULATIONS
j
.
11,3.1 Introduction
,
This descriptive section presents iInformation on dimensio-zn'i s of current internal exposures to lead for United States populations.. Several aspects of the current situation regarding
internal lead exposures are addressed, .'First, attention is focused on showing how current in*
dices of internal exposure compare with indices derived from, historical samples. Also, the
question of how contemporaneous populations compare with one another with respect to internal
exposures is addressed. The primary ..data involved in this discussion are blood lead levels
from populations showing varying degrees of urbanization. Blood lead levels are lowest in
populations living remotely from urban influences and increase as one goes from rural to urban
areas, suggesting that higher blood lead levels are linked to urban lifestyles. Following
this discussion, data hre presented on several large studies in the United States and a large
worldwide study. These data address two principal questions: 1) are there identifiable sub*
populations in the United States which exhibit higher than average blood lead levels, and
2) how do.United States blood lead leyels compare with other countries? This section next
presents studies which examine recent time trends in blood lead levels, in the United States
and elsewhere, and then concludes withja discussion of evidence which points towards gasoline
lead being an important determinant of Changes in blood lead levels associated with exposures
to airborne lead of populations in-the United States and elsewhere, -
11.3.2 Ancient and.Remote Populations One question of much interest in understanding environmental pollutants is the extent to*
which current ambient exposures exceed background levels. Because lead is a naturally occur ring element it can be surmised that some level has been and will always be present in the human body; the question of interest is what is the difference between body burdens of current* subgroups of the United States population and those."natural" levels. Information regarding
11*8
DUP040012336
i
this issue has been developed from studies of populations that lived in the past and popula
tions that currently live in .remote areas far from the.influence of. industrial and urban lead
exposures.
>
;
Man has used lead since antiquity for a variety of purposes.,; These uses have afforded
the opportunity for some segments of the human population to.be exposed to .lead and/subae-
quenily absorb it into the body.. Because lead accumulates over.a lifetime in.bones and teeth
and because bones and teeth stay intact for extremely long times,; it is possible to estimate
the extent to which populations, in the past have been exposed, to lead.; Because of the prob
lems of scarcity of samples and little knowledge of how. reRres,entatiy$; the samples are of con
ditions at the time, the data from these studies provide only rough estimates of the extent of
absorption. Further complicating the interpretation of: these,- data fare debates over proper
analytical procedures and the question of whether skeletons and teeth pick up or release lead
from or to the soil in which they are interred (Waldron et af., 1979; Waldron, 1981),
Waldron et al. (1979) have argued that, any lead found in ancient bones probably is an
accurate reflection of exposureduring life. They reported a small study which showed no cor
relation between bone and soil lead concentrations. Later, however, Waldron (1981) reported a
study in which the postmortem bone lead .levels appeared, to be. much too high to have been
developed during life., - The bones were recovered, from lead coffins. Electron microprobe
analysis on one bone from a lead coffin showed that the lead was concentrated on the surfaces
of the bone. This suggested that the lead in bones came from the lead coffin and led Waldron
(1981) to suggest that "in any further study of the-lead .content of bones from archaeological
sites, steps must be taken to assess environmental lead levels and if these are unusual!y
high, the results of the analyses should be viewed with suspicion." Barry and Connolly (1981)
es<press further concern over the usd of paleontological remains as doubtful criteria for the
in vivo assessment of lead exposure in past populations,
'
Despite these methodological difficulties, several studies provide data by which to esti-
i\
mate internal exposure, patterns among ancient populations, and some studies have included data
frpm both past and current populations for comparisons,. Data from specific studies of bone
and teeth in ancient populations are summarized below in Section 11.3.2.1. In contrast to the
study of ancient populations using bone and teeth lead levels, several studies have looked at
the issue of lead contamination from the perspective of comparing blood lead levels in current
remote and urbanized populations. These studies using blood lead levels as an indicator found
mean blood concentrations in remote populations between 1 and 5 pg/dl (an order of magnitude
below current D.S. urban population means), as discussed in Section 11.3.2.2 below.
11-9
DUP040012337
11.3.2.1 Ancient Populations. Table 11-1 summarizes several'studies that analyzed bones and*
teeth to yield approximate estimates of lead absorption in the past. Some of these studies
also analyzed contemporary current samples so that a comparison between past and present could
be made. Studies summarized in Table 11-1 show an increase of lead, levels in bone and teeth*
from older to contemporary samples.
Samples from the Sudan (ancient Nubians) were collected from several different archaeo
logical periods (Grandjean et al,, 1979), The oldest sample (3300-2900 B.C.) averaged ,0.6
pg/g for bone and 0.9 pg/g for teeth. Data from the later time of 1650-1350 B,C., show a sub
stantial increase in absorbed lead, Comparison of even the most recent ancient samples with a
current Danish sample showed a four- to eightfold increase over time.
The Shapiro et al. (1975) study compared' the tooth -lead content of ancient populations
with that of current remote populations and, also, with durrent urban populations. The
ancient Egyptian samples (1st and 2nd millenia) exhibited thd lowest tooth lead levels, with
a mean of 9.7 pg/g. The more recent Peruvian Indian samples (12tb century) had similar levels
(13.6 pg/g). The contemporary Alaskan Eskimo samples had a mean of 56.0 .pg/g, while
Philadelphia samples had a mean of 188.3 pg/g. These data suggest an increasing pattern of
lead absorption from ancient populations to current remote and; urban populations.
Data have also been obtained from ancient Peruvian and Pennsylvanian samples (Becker et
al., 1968). The Peruvian and Pennsylvanian samples for American Indian populations were from
approximately the same era (-1200-1400 A.D.). Little lead was used in these cultures as re
flected by .chemical analysis.1 of bone lead* conte.nt. The values w'ere less than 5 p'g/g for both samples. In contrast, values obtained for modern samples .from residents of Syracuse, New
York, ranged from 5 to 110: pg/g, Ericson et al, (1979) .also analyzed bone speciments from
ancient Peruvians. Samples 'from 450.0-3000 years ago to about 1400 ye.ars ago were reasonably
constant <<0.2 pg/g).
i.
i
Fosse and Wesenberg (1981) reported a study of Norwegian teeth samples from .several eras.
The older material from 1200-1800 A,Dr was significantly lower in lead (1.22 to 1.81 pg/g)
:i -I
than mddern samples (3.73 to |4.12 pg/g),
*
Aufderheide et al. (1981) report a study of 16 skeletons from colonial America. Two
social groups, identified as plantation proprietors and laborers, had distinctly different
exposures to lead as shown by the analyses of the skeletal samples. The proprietor group
averaged 185 pg/g bone ash while the laborer group averaged 35 pg/g.
*
Changes in bone and tooth lead concentrations over time (as determined by the above or
other studies) have been evaluated by Angle and Mclntire (1982), as graphically depicted in
Figure 11-2. Lead concentrations in human bones apparently markedly increased among ancient -
11-10
DUP040012338
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11-11
DUP040012339
A PERU O EGYPT NUBIA DENMARK A BRITAIN-ROMAN.
ANGLO- SAXON U.S. O BRITAIN, contemporary
\
/
/
/ / /
\S
\ \ -200
V \
-ISO
\
1
100
BONE LEAD, p g lg m
-SO
-10
5500 5000 4500 4000 BP
3500 3000 2500 2000 1500 1000 YEARS BEFORE PRESENT
500 PRESENT
Figure 11-2. Estimated lead concentrations in bones (pg/g) from 5500 years before present (BP) to the present time, from ancient Peru (Ericson et al. 1979) and Egypt, Nubia, and Denmark (Grandjean etal, 1979), Britain in the Roman and Anglo-Saxon (Waldrbn 1980) eras, contem porary British children {Barry 1981), and U.$. adults in the 1950s (Schroederand Tipton 1968).
Source: From Angle and Mclntire (1982).
Early {Britain-Roman, Anglo-Saxon) with soil possibly contaminated with lead.
Early {Britain-Roman, Anglo-Saxon) with soil believed not to be contaminated with lead.
Represents range of values.
11-12
DUP040012340
populations with the introduction of metallurgic processes and dramatic increases in produc
tion and utilization of lead. For example, bone lead concentrations, consistently below 3 pg/g
were found for prenietall.urgic societies in Peru, Egypt, Nubia, and Denmark, whereas concentra
tions of lead in bones from England during the early Soman Empire era are reported to be
10-fold higher and to hatye reached :30p to 400 pg/g by the time of the Norman invasion.- The
Danish bone lead levels also increased during medieval times and reached peak levels of about
40-50 pg/g ip the eighteenth century.. The data.aval Table for more recent contemporary popu
lations in the twentieth century appear to be widely variable, ranging from 0.1 to .5,4 pg/g
reported for contemporary adults in Denmark to 7.5 to 195 pg/g reported for U.S. adults dying
in the 1950'$, Overall, the available data (despite analytic errors.in individual studies)
collectively suggest that contemporary [Americans;, especially urban populations, absorb mani
fold higher levels of lead than did members of premetallurgic societies,
11.3.?.2 Remote Populations. Several studies have looked at/the blood lead levels in current
remote populations (Piomel1i et .al., 1980; Poole et at., 1980). These studies are important
in defining
baseline
levels
of
in'*ternal
lead
exposures
.{
found
in
the world today.
PiomeTli et al. (1980) studied blood lead levels of natives in p remote (far from indus
trialized regions) section of Nepal. Portable air samplers were used to determine air lead
concentrations in the region. The lead content of the air samples proved to be less than the
detection Timit, 0.004 pg/m3. A later study by Davidson et al. (1981) found an' average air
lead concentration of 0.00086 pg/m3 in remote areas of Nepal, thus confirming the low air lead
levels reported!by Piomelli et al, (1980).
Blood lead levels reported by PiomelTi et al, (1980) for the Nepalese natives were low;
the geometric mean blood lead for this population was 3,4 pg/dl. Adult males had a geometric
mean of 3.8 pg/dl and adult females, 2.9 pg/dl. Children had a geometric mean blood lead of
3.-5 pg/dl. Only 10 of 103 individuals tested had a blood lead level greater than 10-pg/dl.
The blood samples, which were collected oh filter paper discs, were analyzed by a modification
of the Delves ciip atomic absorption spsctrophotomjetric method. Stringent quality control pro
cedures were followed for both the blood and air samples. To put these Nepalese values in
perspective, Piomelli et al. (1980.) reported analyses of blood samples collected and analyzed
by the same methods from Manhattan, New York. New York blood leads averaged about 15 pg/dl,
fivefold higher than the Nepalese values.
Poole et al, (1980) reported another study of a remote population, using contamination-
free micro-blood sampling and chemical analysis techniques. They reported acceptable preci
sion at blood lead concentrations as low as .5 pg/dl, using spectrophotometry. One hundred
children were sampled from a remote area of Papua, New Guinea. Almost all of the children
came from families engaging in subsistence agriculture. The children ranged from 7 to 10
11-13
DUP040012341
years and included both sexes. Bipod' lead levels ranged from 1 to 13 pg/dl with a mean of 5.2. Although the data appear to be somewhat skewed to the right, they are in good agreement with those of Piomelli for Nepalese subjects.
11.3.3 Levels of Lead, and Demographic Covariates in U.S. and Other Populations Several large surveys of blood lead levels give information on the major demographic co-
variates in U.S. populations (see also sections 7.3.2.2 and 7.3.2-3.) In addition to the obvious cpvariates of age.. Sex, race, and urban-rural differences, there is a more subtle effect of seasonality. Children show a strong midsummer peak (hence the characterization of lead poisoning as "the summer disease" (Hunter, 1978}). this peak,may be attributed to many causes: 1) gasoline lead consumptioniand lead concentrations are higher in the summer; 2) many people, especially children, spend more time outside during the summer; 3) more beverages are consumed in the summer, increasing exposure from lead-soldered beverage cans; and 4) other seasonal variations in diet, climate, and health status ma^' affect blood lead levels. Thus, seasonality has an effect on all of the demographic studies, the extent to which these demo graphic studies adjust for seasonality varies. 11.3.3.1 The NHANES II Study, The National Center for Health Statistics has provided the best currently available picture 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, 19.80 (Mahaffey it al,, 1982; McDowell et al.,, 1981; Annest et al., 1982;! Annest and Mahaffey, 1984).. Ttep are the first national estimates of lead levels in whole; blood from a representative sample of the non-institutionalized U.S; civilian population aged ,6 months to 74 years.
From a total of 27,801 persons identified through a stratified, multi-stage probability cluster sample of households throughout the United States, blood lead; determinations were scheduled for 16,563 persons including all children ages 6 months to 6 years, and one-half of all persons .ages 7-74. Sampling was scheduled in 64 sampling areas over the four-year period according to a previously determined itinerary to maximize operational efficiency and response of participants. Because of the constraints of cold weather, the examination trailers traveled in the moderate climate areas during the Winter, and the more northern areas during the summer (McDowell et al,, 1981).
All reported blood lead levels were based on samples collected by venipuncture. Blood* lead levels were determined by atomic absorption spectrophotometry using a modified Delves cup micro-method. Specimens were analyzed in duplicate, with both determinations done independ ently in the same analytical run. Quality control was maintained by two systems, a benchsystem and a blind insertion of samples. If the NHANES II replicates differed by more than
11-14
DUP040012342
7 pg/dl, the analysis was repeated for the specimen (about 0.3 percent were reanalyzed). If
the average of the replicate values of either "bench" or "blind" control specimens fell out
side previously established 95 percent confidence limits, the entire run was repeated- The
estimated coefficient of variation for the "bench11 quality control ranged from 7 to .15 percent
(Mahaffey at al., 1979),
"
The reported blood lead levels were based on the average of the replicates. Blood lead
levels and related data were reported as population estimates; findings for each person were
inflated by the reciprocal of selection probabilities, adjusted, to account for persons who
were not examihed and poststratified ;by race, sex, and age,: The. final estimates closely`ap*
proximate the U.S. Bureau of Census estimates for the civilian non-institutiona 1 ized popula
tion of the United States as of March 1, 1978, aged 1/2-74 years,
!
Participation rates varied across age categories; the highest non-response rate (51
percent) was for the youngest age group, 6 months through 5 jyears. Among medically examined
persons, those with missing blood lead values were randomly distributed by race, sex, degree
of urbanization, and annual family income. These data are probably the best estimates now
available regarding the degree of lead absorption in the general United States population.
Forthofer (1983) has studied the potential effects of non-response bias in the HHANES II
survey and found no large biases in the health variables. This, was based on the excellent
agreement of the NHANES II examined data, which had a 27 percent non-response rate, with the
Matidna] Health Interview Survey data, which had a 4'percent non-response rate,
)-
The national estimates presented below are based on 9933 persons whose blood lead levels
ranged from 2.U to 66,0 pg/dl. The median -blood lead for the entire U.S. population is 13.0
pg/dl. It is- readily apparent that blacks have a higher blood lead level than whites (medians
for blacks and whites were 15,0 and 13.0.pg/dl, respectively).
Tables 11-2 through 11-4 display the observed distribution of measured blood lead levels
by race., sex, and age. The possible influence of measurement error on the percent distribu
tion estimates is discussed in Section.-11.3.4. Estimates of mean blood lead levels differ
substahtialTy with respect to race, age; and sex. Blacks have higher levels than whites, the
6-month to 5-year group is higher than the older age groups, and men.are higher than .women.
Overall, younger children show only a slight age effect, with 2- to 3-year-olds having slight
ly higher blood lead levels than older children or adults (see Figure 11-3), In the 6-17 year
grouping there is a decreasing trend in lead levels with increasing age. Holding age con
stant, there are significant race and sex differences; as age increases, the difference
between males and females in mean blood lead concentrations increases.
11-15
DUP040012343
TABLE il- 2 .
NHANES I I BLOOD LEAD LEVELS OF PERSONS 6 MONTHS-74 YEARS, WITH WEIGHTED ARITHMETIC MEAN, STANDARD ERROR OF THE
MEAN, WEIGHTED GEOMETRIC MEAN, MEDIAN, AND PERCENT DISTRIBUTION, BY RACE AND AGE, UNITED STATES, 1976-80
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11-16
/
DUP040012344
TABLE 11-3. NHANES I I BLOOD LEAD LEVELS OF HALES 6 MONTHS-74 YEARS, WITH WEIGHTED ARITHMETIC MEAN, STANDARD ERROR OF THE MEAN, WEIGHTED GEOMETRIC MEAN, MEDIAN, AND PERCENT DISTRIBUTION, BY RACE AND AGE, UNITED STATES, 1976-80
.O4
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- ocre*roo>, .ocaiMmn
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11-17
DUP040012345
TABLE 11-4. NHANES I I BLOOD LEAD LEVELS OF FEMALES 6 MQNTHS-74 YEARS, WITH WEIGHTED ARITHEMETIC MEAN,
STANDARD ERROR OF THE MEAN, WEIGHTED GEOMETRIC MEAN, MEDIAN, AND PERCENT DISTRIBUTION, BY RACE AND A 'GE, UNITED STATES, 1976-80
tSl.CO
do d
& v d .p m ^
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d dp
q3 p pm p BffO &a <n p cm d d id d dcvin d ddd'
vo <n p p
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11-18
DUP040012346
AGE, years
Figure i 1 -3, Geometric mean blood lead levels by race and age for younger children in the NHANES II study. EPA1 calculations from data furnished by the National Center for Health Statistics.
Source: An^nest and Mahaffey (1984).
|
11-19
DUP040012347
For adults 18-74 years, males have greater blood lead levels than females for both whites
and blacks. There is a significant relationship between age and blood lead, but it differs
for whites and blacks. Whites have increasing blood lead levels until 35-44 years of age and
then decline, while blacks have increasing blood lead levels until 5.5-64.
This study showed a clear relationship between blood lead level and family income group.
For both blacks and whites, increasing family income is associated with lower blood lead
level- At the highest income level the difference between blacks and whites is the smallest,
although blacks still have significantly higher blood lead levels than whites. The racial
difference was greatest for the 6-month to .5-year age range.
The NHANES II blood lead data were also examined with respect to the degree of urbaniza^
tlon at.the place of1 residence. The threejcategories used were-urban areas with population
greater than one million, urban areas with population less than one million, and rural areas.
Geometric mean blood lead' levels increased with degree of urbanization for all race-age groups
except for blacks 18-74 years of age (see Table 11-5). Most importantly, urban black children
aged 6 months - 5 years appeared to .have distinctly higher mean blood lead levels than any
other population subgroup,
;!
'
11.3,3.2 The Childhood Blood Lead Screening; Programs. In addition to the nationwide picture
presented by the NHANES II (Annest et al., 1982) study regarding important demographic corre
lates .of blood lead levels, Bi1lick et al. (1979, 1982) provide large scale analyses of blood
lead values from childhood blood lead screening programs in specific cities that also address
this issue;.
Binick et al. (1979) analyzed data from New York City blood lead screening programs from
1970 through 1976. The data include age in.months, sex, race, residence expressed ..as health
district, screening information, and blood'lead values expressed in intervals of 10 pg/dl.
0nly the venous blood lead data (178,588values), clearly identified as coming from the first
screening of a given child, were used. All blood lead determinations were done by the same
laboratory. The geometric means of the children's blood lead levels by age, race, and year of
?'
j
1
collection are presented in Table-11-6. The annual means were calculated from the four quar
terly means which were estimated by the method of Hasselblad et al, (1980).
The data obtained for New York are generally consistent with the nationwide results from
the NHANES II study. For example, all racial/ethnic 'g' roups show an increase in geometric mean* blood level with age for the first two years and a general decrease in the older age groups.
These age-related patterns are .seen in Figure .11-4, which shows the trends for all years
(1970-1976) combined. Also, the childhood screening data described by Biflick et al. (1979)
show higher geometric mean blood lead values for blacks than for Hispanics or for whitest
Table 11-6 presents these geometric means for the three racial/ethnic groups for seven years.
11-20
DU P04Q012348
TABLE 11-5. WEIGHTED GEOMETRIC MEAN BLOOD LEAQ LEVELS . FROM NHANES II SURVEY BY DEGREE OF URBANIZATION OF PLACE OF RESIDENCE IN THE' U.5. BY AGE AND RACE, UNITED STATES 1976-80
: (micrograms/deciliter) ;
Race end age
AT 1 races All ages
6 montbs-5' years 6-17 years 18-74 yearns - men:
1 women:
Whites All ages ;
6 months-5, years 6-17 years) 18-74 years - men:
women:
Blacks ATI ages
6 months-5 years 6-17 years 18-74 years - men:
women:
Urban, .>3 million'
14.0
16.8 13.1 16.9 12.2
14.0
15.6 12.6 16.9 12.4
(2,305)*
(544) (414) (677) (760)
(1,767)
' (358) (294) (531) (584)
14.4
20.8 14.6 17.4 11.8
(570)
(172) (HI) (132) (155)
Degree of urbanization
Urban; ; : . <1 million .
W <" : Rural
..
12.8
15.4 - 11.7
15.7 11.0
12.5
14.4 11.4 15.4 10.8
(3,869)-
: (944) (638)
(1,050) (1*237)
11.9
13.0 10.7 15.1
9.8
'
(3,669)
(884) (668) (1,069) (li048)
(3,144)
(699) (510) (889) (1,046)
11.8
' ' 12.1 10.5 14.8
- : 9.8
(3,458)
(819) (620) (1,011) (1,008)
14.8
: 19.2 13.6 18.6 12.4
(612)
(205) (113) (134) (160)
14.4
16.5 13.0
18.3 11.3
(150)
(42) (39) (38) (31)
aNumbe.r with lead determinations frail blood specimens drawn by venipuncture.
Source: Annest and Mahaffey, 1984; Annest et al., 1982.
11-2.1
DUP040012349
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11-22
H
1976
15.2.
18.2
17.1
16:6
16,2 ^ 15.9
8.8 15.1
DUP040012350
AGE ye.irs
Figure 11 -4, Geometric mean blood lead values by race and age
lor younger children in the New York City screening program
{1970-1976).
{
J
' Source: Adapted Irom Hasselblad et al. 1930.
11-23
DUP040012351
Using the method of Hasselbiad et al. (1980), the estimated geometric standard deviations were
I. 41, 1.42., and 1.42 for blacks, Hispanics, and whites, respectively,
II. 3.3,3 Levels of Lead and Demographic Covariates Worldwide. An international study conduc
ted under the auspices of the United Nations Environment Program and. the World Health Organir
zation provides the first analytically comparable blood lead data set available to infer the
..
y
current similarities and differences in lead absorption from country to country (Friberg and
Vahter, 1983). Extensive attention was paid to quality control issiies, with the resulting
blood lead determinations being very comparable from country to country. School teachers were
chosen as study subjects since they would be .unlikely to. have occupational exposures to lead
and also because they would have similarities in socioeconomic characteristics. A detailed
interview was administered, to the subjects to obtain background data.
Figure 11-5, derived from data in the paper., displays the variability from country to
country. Unweighted geometric mean blood lead levels ranged;from a low of 5.8 pg/dl in Japan
to 22.3 pg/dl in Mexico. Teachers in China, Israel, Japan, Sweden, and the United States all
had geometric: mean blood leads below 8.0 pg/dl.
In general, males sjiowed higher blood lead levels than females; on the average, male
teachers had blood lead levels 30 percent higher than females regardless of cigarette smoking
status, In most- Cases cigarette smokers had 10 percent higher blood lead levels than
nonsmoIters.
11.3,4 Distributional Aspects of Population Blood Lead Levels The importance of the form of the distribution.of blood lead levels was briefly discussed
in Section 11,2.2, The.distribution form determines which measure of central tendency (arith metic mean, geometric mean, median) is most appropriate. It is even more important in esti mating percentiles in the|upper tail of the-distribution, an issue of much importance In esti mating percentages (or absolute numbers) of individuals in specific population groups likely to be experiencing various: lead exposure levels,
. Distribution fitting requires large numbers of samples taken from a relatively homo geneous population. A homogeneous population is one in which the distribution of values remains constant when split into subpopulations. ' These subpopulations could be defined by demographic: factors such as race, age, sex, income, degree of urbanization; and degree of exposure. Since these factors always have some effect, a relatively homogeneous population will be defined as one with minimal effects from any factors that contribute to differences in blood lead levels.
11-24
DUP040012352
cc
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STUDY LOCATION
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Figure 11-5. Unweighted geometric mean blood lead level for male and
Source: Derived from Friberg and Vahter (1983).
11-25
DUP040012353
Several authors have suggested that the distribution of blood lead levels for any rela-*
lively homogeneous population closely follows a lognormal distribution (Yankel et al., 1977;
tepper and levin, 197:5; Azar et al., 1975), lognormality has been noted for other metals,
such as 90Sr, 144e, Pu, and Ti In various tissues of human populations (Cuddihy et al., 1979;=
Schubert et al,, 1967), Yankel et al. (1977), tepper and levin (1975), and Angle and Mclntire
(1979) all found their blood lead data to be loghormally distributed. Further analysis'))}' PA
of the Houston study of Johnson et al. (1974), the study of Azar et al, (1575), and the New
York children screening program reported by Billick et al. (1979) also demonstrated that a
lognormal distribution provided a good fit to the ciata.
I
the only nationwide survey of blood lead levels in the U.S, population is the NHANES II
survey (Annest et al., 1982). In order to obtain a relatively homogeneous subpopulation of
lower environmental exposure, the analysis was restricted to whites not living in an.SMSA
(Standard Metropolitan Statistical Area), with a family income greater than $6,000 per year,
the poverty threshold for a family of four at the midpoint of study as determined by the U.S,
Bureau of Census, this subpopulation was split'into four subgroups based on age and sex.
the summary statistics for these subgroups are in fable 11-7. ! ;i j
tABLE 11-7. SUMMARY OF UNWEIGHTED BLOOD LEAD LEVELS IN WHITES . MOT LIVING IN AN SMSA, WITH FAMILY INCOME GREATER THAN $6,000
Subgroup
Age 1/2 to 6 Age 6 to 18 Age 18+, men Ag'e 18+, women
Sample size
752 573 922 927
Unweiqhted mean
Arith. Geom,
mean,
mean,
pg/dl
pg/dl
Samp!e
99th
Arith.
median, percentile., std. dev., Geom.
pg/dl
pg/dl . pg/dl
std. dev.
13.7 11.315.7 10.7
12, 9 _ 13.0
10.6 .i io,p
14.7
15.0
10.0 , 10.0
32.0 24.0 35.8 23.0
5,03 4.34 5.95 4.14
1.43 .1.46 . 1.44 * 1.46
:ach of these four subpopulations were fitted to five different distributions.: normal, lognormal, gamma, Weibull, and Wald (Inverse Gaussian) as shown in Table 11-8. Standard* chi-square goodoess-of-fit tests were computed after collapsing the tails to obtain an expected cell size of five. The goodness-of-fit test and likelihood functions indicate that the lognormal distribution provides a better fit than the normal, gamma, or Weibull.. A, histogram and the lognormal fit for each of the four subpopulations appear in Figure 11-6.
11-26
DUP04Q012354
TABLE 11-8. SUMMARY OF FITS TO NHANES II BLOOD LEAD LEVELS OF WHITES NOT LIVING IN AN SM.SA, WITH INCOME GREATER THAN $6,000,
, ' FOR FIVE DIFFERENT TOO-PARAMETER DISTRIBUTIONS
Normal Lognormal Gamma Weibull Wald
Normal Lognormal Gamma Weibull Wald
Normal Lognormal Gamma Weibull Wald .
Normal Lognormal Gamma Weibull Wald
Chi-square
75.52 14.75 17.51 ;66.77 .15-71
Chi-square
;39.58 1 3.22 *, 4.88 24.48
2.77
Chi-square
156.98 12.22
, 34.26 132.91 14.42
Chi-square
66.31 7.70 11.28 56.70 10.26
Children <5 years
D.F.*
p-yalue
8 0.0000 10 0.1416
9 0.0413 8 0.0000 10 0.1083
Children 6 years S17
D.F.*
p-value
6 0.0000
a 0.9197
7 0.6745 6 0.0004 8 0.9480
Men 18 years
D.F.*
p-value
10 0.0000 .
13 0.5098 12 . 0.0006 11 - 0.0000 13 0.3450
Women 18 years
D.F.*
5 8 7 6 8
p-value
0.0000 0.4632 0.1267 0.0000 0.2469
loglikelihood
-2280.32 ( -2210.50 : , -2216.51 : : -2271.57 -2211.83 ' '
deviation** at 99th
perfcehtile
:V 6.61 2.57 4.68 5.51 2.76
%!>
loglikelihood
-1653.92 -1607.70 -1609.33
-1641.35 -1609.64
.
deviation** at 99th
percenti 1 e
2.58 -1,50, -0,64
1,72 -1.30
'
loglikelihood
-2952.85 -2854.04 -2864.79 -2934.14 -2855.34
deviation** at 99th
percentile
.6.24 1.51 4.00 . 4.8,8 1.72
loglikelihood
-2631.67 -2552.12 -2553.34 -2611.78 -2556.88
deviation** at 99th
percenti1e
2.68 -1,18
0.90 1.73 -1,01
*0.F. = degrees of freedom. '^observed 99th sample percentile minus predicted 99th percentile.
11-27
DUP040012355
FREQUENCY
BLOOD LEAD LEVELS, jig/dl, FOR 6-MONTH TO 6-YEAR-OLO-eHlLDREN
BLOOD LEAD LEVELS, ng/dl, FOR B-T0 17-YEAR OLD CHILDREN
FREOUENCY
0 7.5 15.5 23.5 31,5
BLOOD LEAD LEVELS. ag/.dl, FOR MEN 3= IS YEARS OLD
BLOOD LEAD LEVELS. ag/dl. FOR WOMEN 3= 18 YEARS OLD
Figure 11-6. Histograms of blood lead levels with fitted lognormal curves for the NHANES H study. All subgroups are white, non-SMSA residents, with family incomes over $6000/year.
Source: (EPA calculations from data supplied by National Center for Health Statistics.)
1.1-28
DUP040012356
The Wald distribution is quite similar to the lognormal distribution and appears to provide
almost as good a fit. Table 11-.S also indicates that the lognormal distribution estimates
the 99th percentile as well as any other distributipn.
Based, on the examination of the NHANES II data, as well :as the results of the several
other studies discussed above, it appears that the lognormal distribution is the most appro
priate for describing the distribution of blood lead levels in homogeneous populations with
relatively constant exposure levels. The lognormal distribution appears to fit well across
the entire range of the distribution, including the right tail.
The lognormal distribution describes both the mean and the. variation of the populations
under study. It is Obvious that even relatively homogeneous populations have, considerable
variation among individuals. The estimation of this variation is important for determination
of the proportion of individuals above a given bipod lead level. This variation is the result
of both analytic variation and population variation.
*
Analytic variation, which exists ip any measurement of any kind, has an impact on the
bias and precision Of statistical estimates, /For this reason, it is important to estimate the
magnitude of variation. Analytic variation! consists of both measurement variations (vari
ation between measurements run at the same time) and variation created by analyzing samples at
different times (days). This kind of variation for blood lead .determinations has been discus
sed by Lucas (1981), The measurement variation alone does not follow a lognormal distribu
tion, .as was shown by Saltzman et al, (1983)-
;'
Values for the variation within groups (or mean square error) are available from several
.studies discussed above, including the NHANES II Survey, the N.Y, Childhood .Screening Study,
the Tepper-Leven Seven City Study, and the Az.ar et al, study. Variation, including analytic
variation, ranged 'from about 1.3 to 1,4 when expressed as a geometric standard deviation.
This value! depends on the uniformness of the population's and the magnitude of the analytic
variation.
The WANES IJ study provides excellent data for the study of this variation, since it has
excellent quality control and extensive information on demographic c.ovariates. .In order to
minimize the effects of location, income, sex., and age, an analysis of variance procedure was
used to estimate the variation for several age-race groups. The variables just mentioned were
used as main effects, and the resulting mean square errors of the logarithms are shown in
Table 11-9.,. The estimated geometric standard deviations have been adjusted for sex, age, in
come, and place of residence. As a result, the values for geometric standard deviations tend
to be smaller than the unadjusted values for specific subgroups as reported by Annest and
Mahaffey (1984).
11-29
DUP040012357
TABLE 11-9. ESTIMATED MEAN SQUARE ERRORS RESULTING FROM
ANALYSIS OF VARIANCE ON VARIOUS SUBPOPULATIONS OF THE MHAMES II DATA USING UNWEIGHTED DATA '=
White,
White, SMSA,
White,
Black:,
.
Age
Non-SMSA
not central city
central city: Central city
0.5 to .6 6 to 18 18+, men 18+, women
0.0916 (1.35)* `
0.0814 (1.33)
0.1155 (1.40)
0.1083 (1.39)
0.0839 (1.34)
0.0724 (1.31)
0.0979 <1,37)
0.0.977 (1.37)
, 0,1074 (1.39)
0.0978 (1.37)
0.0790 . 0.0691
(1,33)
(1.30)
0.1127. . (1.40) .
0.1125 (1.40)
Q. 0915 (1.35)
0.0824 (1.33)
Note; Mean square errors are ba^ed on the logarithm of the blood, lead levels. ^Estimated geometric standard deviations are given in parentheses.
The .analytic variation was estimated specifically for this study by Annest et al.
(1983b), The analytical variation was estimated as the sum of components estimated from the
high and low blind pool and from the replicate measurements in the study of Griffin et al.
(1975)., The overall estimate of analytic variation for the NHANES II study was 0.02083
(estimated mean square error based on logarithms).
.
Analytic variation causes a certain amount of misclassification when estimates of the
percent of .individuals above or below a given threshold :are made,1 .This is because the true
value of a person's blood lead could be below the threshold, but the contribution from analy
tic variation may push the observed Value over the threshold. The reverse is also possible.
These two types of raise!ossifications dp not necessarily offset each other.
Annest et al. (1983b) estimated this misclassification rate for several subpopulations in
the NHANES II data using a threshold value of 30 gg/dl. In general, the percent truly greater
than this threshold was approximately 24 percent less than the prevalence of blood lead levels
equal to' or greater than 30 pg/dl, estimated from the weighted NHANES II data. This is less*
than the values predicted by Lucas (1981) which were based on some earlier studies.
The studies reviewed here provide estimates of geometric standard deviations for observed
blood lead distributions which consistently fall in the range of 1.3 to 1,4, The NHANES II,
study, thought to provide the best available data set in terms of good quality control and
11-30
DUP040012358
other features such as sample size, yields estimates of geometric standard deviations for various subgroups of young children (.0.5 to .6 years old) in the range of 1.34 to 1.39 (uncor rected for analytic error),. Variations in the site means of log(blood.lead) were calculated after controlling for race* income, and degree of urbanization, Th# remaining standard devi ation of 0.183 for site means indicates substantial variation, in baseline exposure rafter accounting for the major proxies for air lead. The geometric standard deviation attributable to the non-air lead exposure sources can be estimated by adjusting the NHANES II blood lead levels for the impact of gasoline lead by use of linear regression. Since gasoline lead during 1976-1980 accounted for 85 to 90 percent of air lead, the effect at gasoline lead 0 was reduced by an additional 15 percent tp account for/all air. le.ad.: The resulting geometric standard deviation was 1.428. If this calculation is done only fop children with blood lead < 40 gg/cll (who are more likely to be helped by an air lead standard) then the geometric stan dard deviation is 1.419. Thus, a geometric standard deviation :*for the NHANES If population of children without attribution of any source qf lead exposure except gasoline lead and indus trial air le.ad emissions may be taken as approximately 1.42.
11.3.5 Time Trends in Blood Lead levels Since 1970 In the past few years a number of reports have appeared that examined trends in blood
lead levels during the 1970's. In several of these reports some environmental exposure esti mates are available. 11.3.5.1 Time Trends in NHANES II Study Data, Blood lead data from NHANES II (see section 11.3.3.1 for full discussion of methodology)- show a significant downward trend over time for nationwide bipod; lead levels in the United States (Annest et al., 1983a). After accounting fpr the .effects of race, sex, age, region pf country, season, income:, and degree of urbaniza tion, a statistically significant negative association with date of sampling was found. Using regression model-predicted blood lead levels ,, a 37 percent drop from 14.6 to 9,2 pg/dl from the beginning to the end of the study was found. Overall nationwide mean blood lead levels from these data presented in 28-day intervals from February, .1976 to February, 1980 are dis played in Figure 11-7. Similar decreases in Overage blood lead levels were-noted for-a number of subgroups Which compose the total sample (see Figure 11-8), with the declines ranging from 31 to 42 percent for various subgroups.
A variety of possible explanations for the nationwide decline in average blood lead levels were examined. Analysis of quality control samples indicated that laboratory drift was not the Pause of the observed decline. Further statistical analyses ruled out the possibility that the decline was entirely due to season, income, geographic region, or urban-rural differ ences. Ahnest et al. (1983a) suggested that although strong correlation does not prove cause and effect, the most reasonable explanation for this trend appears to. be reduction in the
11-31
DUP040012359
11-32
DUP040012360
PERCENT REDUCTION IN BLOOD LEAD LEVELS
Figure 11-8. Reduction in mean blood lead levels, according to race, sex, and age. Data on sex and age are for whites.
Source: Annest et ak (1983a).
11-33
DUP040012361
amount of lead used in gasoline production over the same time period (as discussed in more
detail in Section 11.3.6.1).
11.3,5,2 Time Trends in the Childhood Lead Poisoning Screening Programs. Billick and col
leagues have analyzed the results of blood lead screening programs, conducted by the City or
New York (Billick et a!., 1979; Billick, 1982), Most details regarding this data set were al.>
ready described* but Table 11-10 summarizes relevant methodologic information for these analy
ses and for analyses done on a similar data base from Chicago, Illinois.- The discussion of
the New York data below is limited to an exposition of the time trend in blood lead levels
from 1970 to 1977,
......... f*1.
geometric mean blood lead levels decreased for all three racial groups and for almost all
age groups in the period 1970-76 (Table 11-6), Table 11-11 shows that the downward trend
covers the entire range'of the frequency distribution of blood lead levels. The decline in
blood lead levels showed seasonal variability, but the decrease in time was consistent for
each season. The 1977 data were supplied to EPA by Dr- Billick,
Ini addition to this time trend observed in New York City,. Billick (.1982) examined similar
data from Chicago and Louisville, The Chicago data set was much more complete than.the Louis
ville one, and was much more methodoloficaTly consistent. Therefore,- the Chicago data will
mainly be discussed-here. The lead poisoning screening program in Chicago may be, the longest
continuous program in the United States. = Data used in this report covered the years 1967-
1980. Because the data set was :s.o large, only: a 1 in 30 sample of laboratory records was
coded for statistical analysis (similar to procedures used for New York described above).
The bipod lead" data for Chicago contains samples that may be repeats, confirmatory analy
ses, or even samples collected during treatment, as well as initial screening samples. This
is a major difference from the New York City data, which had initial screening values only.
Chicago blood -lead levels were all obtained on.venous samples and were analyzed by one' labora
tory., the Division of Laboratories, Chicago Department of Health, Lead determinations were
done by atomic absorption. Racial composition was described in more detail than for New York,
but analysis showed there was no difference among the non-blacks, so. they were pooled in the
final analysis.
-
Table 11-10 displays important characteristics of the Chicago and New York screening pro
grams, including the number of observations involved in these studies. From tables in the ap
pendices of the report (Billick, 1982), specific data on geometric mean blood lead values,
race, sex, and sampling data for both cities are available. Consistency of the data across
cities is depicted in Figure 11-9. The long-term trends are quite consistent, although the
seasonal peaks are somewhat less apparent. Although the data displayed are only for blacks
aged 25 to 36 months, very similar data are available for whites and other groups covered by
the study.
11-34
DUP040012362
YEAR {Beginning Jan. 1!
Figure 11 -9, Time dependence of blood lead levels for blacks, aged 25-36 months, in New York City and Chicago.
Source: Adapted from Billick (1982).
11-35
DUP040012363
TABLE 11-10. CHARACTERISTICS OF CHILDHOOD LEAD POISONING SCREENING DATA
Time period Sampling technique Analytic technique
Laboratory Screening status Race classification
and total number of samples used in analysis*
Raw data Gasoline data
New York
1970 - 1979
Venous
AAS - ' f ' . (Basel method)
In house
Aval1abl.e/unknown
Unknown 69,658
White
5,922
Black
51,210455
Hispanic 41,3.64
Other
4,398
TOTAL 172,552
Decade grouped
Tri-state (NY, NJ, CT) . 1970 - 1979 SMSA 1974 - 1979
Chicago 1967 - ,19.80 (QTR Z) , . Venous AAS ,
(Basel method) In house Unavailable Nonblack 6,459 Black 20,353 TOTAL 26,8.12
Ungrouped . SMSA
*New York data set only includes first screens while Chicago includes also confirmatory and repeat samples.
TABLE 11-11. DISTRIBUTION OF BLOOD LEAD LEVELS FOR 13- TO 48MONTH-OLD BUCKS BY SEASON AND YEAR* FOR.NEW YORK- SCREENING DATA.
Year
1970 1971 1972 1973 1974 1975 1976 1977
January - March Percent
<15pg/di 15 - 34pg/dl >34pg/dl
(insufficient sample Size)
3.8 69.5 26.7
4.4 76.1 19.5
7.3 80,3 12,4
9,2 73.8 17,0
11,1**
77.5**
.11.4**
2i.i
74.1
4.8
28,4
66.8
4,8
July - September Percent
<lSgg/dl 15 - 34pg/dl
>34pg/dl
. 3,4 1.3
4.3 2,7 8.2 7,3**
11,9 19.9
54.7 56.0
72.2 62.4 65.4
81.3** 75.8 72.9
` 42.0 42.7 23.4
34.9 26.4 11.4**
12.3
7,2
* data provided by I.H. Billick (19.82). ^Percentages estimated using interpolation assuming a lognormal distribution.
11-36
DUP040012364
11.3.5.3 Newark. Gau.se et at* (1977) present data from Newark, New Jersey, that reinforce the findings of Billick and cpworkers. Cause et al, studied the levels of blood lead among 5and 6-year-old children tested by the Newark Board of Education during the academic years 1973-74, 1974-75, and 1975-76, All Newark schools participated, in all years. Participation rates were 34, 33, and 37 percent of the eligible children for the three years, respectively. Blood samples collected by fingerstick onto filter paper were analyzed for lead by atomic absorption spectrophotometry. The authors point out that fingerstick samples are more subject to contamination than venous samples-; and that because erythrocyte protoporphyrin confirmation of blood lead values greater than 50 pg/dl was not done until 1974, data from earlier years may contain somewhat higher proportions of false positives than later years.
Blood lead levels declined markedly during the 3-year study period. The percentage of children with bipod lead levels less than 30 pg/dl went from 42 percent for blacks in .1973-74 to 71 percent in 1975-76; similarly, the percentages went f^om 56 percent to 85 percent in whites. The percentage of high risk children (>49 pg/dl) dropped from 9 to 1 percent in blacks and from 6 to 1 percent in whites during the study period. Unfortunately, no com panion analysis was presented regarding concurrent trends in environmental exposures.
Foster et al. (1979), however, reported a study from Newark that examined the effective ness of the city's housing deleading program, using the current blood lead status of children who had earlier been identified as haying confirmed elevated blood lead levels; according to the deleading program* these children's homes should have been treated, to alleviate the lead problem. After intensive examination, the investigators found that 31 of the 100 children studied had lead-related symptoms at the time of Foster's study. Examination of the records of the program regarding the deleading activity indicated' a serious lack of compliance with the program requirements. Given the results of Foster's study, it seems unlikely that the observed trend was primarily caused by the deleading program. 11.3.5.4 Boston. Rabinowitz and Needleman (1982) studied Umbilical cord blood lead levels from 11,337 births between April, 1979 and Apri11981 in the Boston area. These represented 97 percent of the births occurring in a hospital serving a diverse population. Blood samples were analyzed for lead by anodic stripping voltammetry after stringent quality control proce dures were used. External quality control checks were done by participation in the Blood Lead Reference Program, conducted by the Centers for Disease Control. The average difference between the investigators' results and the reference lab was 1,4 pg/dl.
The overall mean blood lead concentration was 6.56 .3,19 pg/dl (standard deviation) with a range from 0.0 to 37.0 pg/dl. After regression of the individual values of blood lead against the date of birth, a significant downward trend in blood levels was observed (~0.89 pg/dl/yr), representing a decrease of .14 percent per year (Figure 11-10). Figure 11-10 also
11-37
DUP040012365
SMOOTHED AVERAGE BLOOD LEVEL, ug/dl
Figure 11-10. Modeled umbilical cord bleed lead levels by date of sample collection for infants in Boston.
11-38
DUP040012366
illustrates the complicating aspect of seasonal trends in evaluating underlying secular
trends,. The observed trend is similar to that noted in the NHAN.ES ii study described earlier.
Rabinowitz and Needleman (1982) list the following as possible causes Of the decline: (T)
modification of the water supply to decrease the lead content; (2) reduction Of the use of
lead in gasoline:; (3) reduction in contamination of food by solder; and 1) changes in prenatal /
practices, such as smoking or iron supplementation.
Rabinowitz and Needleman (1983) then sought to evaluate statistically possible reasons
for the observed two-year downward trend in umbilical cord blood lead levels. The authors
used ppirwise product moment correlations for the monthly cord lead levels (about 500 per
month) and monthly amounts of gasoline lead in Massachusetts.. A strong correlation was ob
served; with the same month's data, t,he correlation coefficient was 0.716, which increased to
a peek) correlation coefficient of 0.758 when a 1-month lag time was used- The authors indi
cate that they did not observe similar trends in maternal ^tobacco smoking, education level,
and alcohol consumption. They did observe a positive (instead of negative) trend in tap water
lead concentrations. They conclude that gasoline lead exposure changes were probably the
cause of the observed trend in blood lead levels,
1
From the ongoing .surveillance of cghsecutive births, Rabinowitz et al. (1984) also iden
tified a cohort of 249 infants who wefe enrolled in. an ongoing cohort study after meeting
certain eligibility standards, indoor air was sampled for lead from the homes of children
when each child was .6, 18, and 24 months of age, Tapwater was collected after a 4-liter flush,
at 1 and 8 months of age. Seasonal biases in indoor/outdoor air lead ratios and the amounts
of time spent indoors may have been confounding variables which may have distorted upward the
underlying inhalation slope to the observed value near nine.
For each month there was generally available a mean air lead from 12 homes, water lead
from 23 homes, and blood leads for 500 births. The study period covered, March, .13.80 to April,
1981, The blood leads were then correlated with gasoline lead sales, indoor air, and tap-
water.. A linear (although somewhat scattered) trend was found between lead in indoor air and
gasoline lead sales. Forty-eight percent of the variance in air lead could be accounted for
by the gasoline lead sales. Air lead and blood lead levels were highly correlated. The best
linear fit (r = 0.71) has a slope of 9 pg/dl/pg/m3 and an intercept of 4.9 pg/.dl. No correla
tion .was observed between water and blood lead levels. Interestingly, a higher correlation
was found between gasoline lead sales and blood lead levels than between air lead and blood
lead.
Kar.alekas et al. (1983) report additional data from the Boston metropolitan area. Re
sults of the lead screening program indicate that the percentage of screened children with
elevated blood lead levels declines over the period 1976-1981. Data on lead in water for this
11-39
DU P040012367
period are also presented. Water lead levels began to decline after the decline in blood lead levels. This relationship in this data warrants further research* 11.3.5.5 Lead Studies in the United Kingdom. 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, 19$2; Elwood, 1983a,b; Quinn, 1983). These papers cover a variety of exposure situations and populations studied. All of them obtained findings analogous to those described above fbr 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.
Oxley (1982) reported an analysis of blood lead levels found in blood samples drawn as a part of preemployment medical examinations conducted by a major U.K.-based oil company during 1967-69 bad 1978-80. Blood samples were collected by venipuncture and analyzed for lead by two different methods, Ai cornparative laboratory study also reported by Qxley suggested that the data could be adjusted from ope method to the other, geometric mean blood lead levels.de clined from 20.2 to. 16.6 pg/dl.
Elwocd (198.3a) reported a time trend analysis of blood lead levels observed in adult women studied over a 10-year period in eight surveys conducted in a variety of locations in Wales, These were analyzed and examined for trends in blood lead levels. AIT women included in this analysis came from surveys which were designed to generate representative samples of adult women in residential areas. A high response rate (90 percent or more) was obtained in each of the surveys. Venous .bipod; samples were collected and analyzed for lead. A single laboratory performed all of the analyses with an external reference laboratory performing quality control checks' in some of the suriveyjs. Overall' mean blood lead levels for the various surveys fell more than 30 percent over the period 1972-1^82, Two of the surveys were con ducted in the same area. Between 1974 and 1982, the mean blood lead concentration fell 37 percent. Surveys from mining areas showed that women there had higher blood lead levels than in non-mining areas.
Elwood acknowledges that laboratory drift may be present in the data and also that the surveys did not generate strictly comparable samples. Still, the observed decline was thought to be real. No statistical analysis of the data is presented to examine the possible reasons for the observed decline, but a number of possible environmental reasons were discussed. Re duced gasoline lead exposures as a reason werI e dismissed on the basis that while the lead concentratton in gasoline had indeed declined!, the overall use of petrol in England had in creased, therefore balancing the reduction. However, no data regarding traffic patterns or* gasoline usage in Wales were presented to verify this reasoning, A portion (amount' unspeci
11-40
DUP04Q012368
fied) of the reduction was attributed to a drop in dietary intake of lead due to the reduced use of canned foods.
El wood (1983b) also presents, data from a more homogeneous setting. In .1969 a hematologic survey of a random sample of 4070 women Was conducted in one town in Wales. Detailed studies were made of 121 of these women whose hemoglobin levels were below 10.5 g/100 ml. Samples of their whole blood were deep frozen, and'follow-up samples were obtained for some of the same women in 1982. Follow-up and Toss of original samples resulted in there being 26 women with an available blood lead at both times and who were still living at the same address. The mean fall let bipod lead levels for these women was 23 percent, representing a fall of 3.5 pg/100 ml. Again Elwood does not attribute the decline to changes in gasoline lead or water supply, but instead suggests that it may be due to changes in dietary intake although noting there are no data on which to base a judgment.
King (1983), in commenting on the results of Elwood (1983a), noted that the blood lead values before 1975 were probably falsely, elevated due to matrix problems in the chemical ana lysis. This means the magnitude of the observed decline is probably less than that quoted by Elwood (19,83b). King (1983) further examined the question of the time trend by controlling for region of Wales and reported that Elwo.od's data showed a 50 percent increase in blood lead levels from .19.81 to 1982., a most unlikely outcome.. Pirkle and Annest (1984) have also criti cized the Elwood (1983a) paper dnd concluded that various factors make reliable interpreta tions of Elwood1s data extremely difficult,
Quinn (1983) reports on the summarised findings of two large-scale survey effects in 1979 and 1981, Broad Comparisons within: the Same authority showed an overall reduction approaching 10 percent (1 pg/100 ml), Quinn himself states, however, that these two survey efforts are not. strictly comparable in that the first round focused on representative population groups while the second round focused on areas where "lead may have' presented a problem. No effort was made to attribute the decline in blood lead levels to a particular source, 11.3.5.6 Other Studies. Okubo et al, (1983) examined a total of 1933 children from 5 to 18 years of age for blood lead using the, Hesse! method over the period 1975 to 1980 in an urban area of Tokyo and in a nearby suburban area. The analysis of all blood lead was done by the same laboratory. Over the .time period of the study an apparent decrease in blood lead is shown. A part of the difference in blood lead between urban and suburban groups is related to the difference in average lead concentrations between the two areas. The difference of blood lead between urban and suburban becomes greater when the comparison of blood lead between the two areas is executed only among children who have lived in the same areas from their birth.
In an international study discussed in detail earlier, Friberg and Vahter (1983) compared data on blood lead levels obtained in 1967 with data for 1981 (see Table 11-12). For areas of
11-41
DUP040012369
TABLE 11-12. COMPARISON OF MEDIAN BLOOD LEAD LEVELS (pg/dl) IN SEVERAL COUNTRIES FROM STUDIES OF GOLDWATER AND HOOVER (1967) AND FRIBERG AND VAHTER (.1983)
Country
Japan Israel United States Yugoslavia
Median blood lead 1967
21.0 15.0 18.0 15.0
Median blood lead 1981
6..0 8.2 7.5 9.2
% change from 1967.
-- .... ' " v 71 45 58 39
14 -
the world where there were date collected by Goldwater and Hoover (.1967) as well as the UN/WHO study,, there has been 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 he thought of as providing further but limited evidence supporting a recent downward trend in blood lead levels worldwide.
11.3.6 Gasoline Lead as an Important Determinant of Trends in Blood Lead Levels
As noted in the preceding section, 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. Also noted was evidence presented by some investigators
which strongly suggests that gasoline lead usage is a major determinant of the reported down
ward trends in blood lead levels. The present section examines additional, extensive evidence
which points- towards gasoline lead being an important determinant of changes in blood lead
levels associated with exposures to airborne lead of populations in the United States and
elsewhere.
.
>'
11.3.6.1 NHANES II Study Data. Blood lead data from the second National Health and Nutrition
Examination survey (NHANES II) were described earlier in Sections 11.3,3.1 and 11.3.5.1. One
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 to 1980) of the survey. In evaluating
possible reasons, for the observed decrease in the NHANES II blood lead values, Annest et al.
(1983a) found highly significant associations between the declining blood lead concentrations
for the overall U.S. population and decreasing amounts of lead used in gasoline in the U.S. *
during the same time period (see Figure .11-11). The associations persisted after adjusting
for race, age, sex, region of the country, season, income, and degree of urbanization (see
Table 11-13). Analogous strong associations (r = 0.95; p < 0.001) were also found for blood*
lead levels for white children aged 6 months to 5 years in the NHANES II sample and gasoline
lead usage (Annest et al., 1983a).
11-42
DUP040012370
o mso Or0s>S rCsO
OS
N
s*
NO$0S 5UO| E0i 'a01H3d HiNOW-9 U3d 0350 QV311V0.OJL
11-43
110
YEAR
Figure 11-11. Parallel decreases in blood lead values observed in the NHANESII study and amounts of lead used in gasoline during 1976-1986. Source: Annest (1983).
DUP040012371
11-13. PEARSON CORRELATION COEFFICIENTS BETWEEN THE AVERAGE BLOOD LEAD LEVELS
FDR SIX-MONTH PERIODS AND THE TOTAL LEAD USED IN GASOLINE PRODUCTION PER SIX MONTHS, ACCORDING TO RACE, SEX, AND AGE3
Overall (all races) All black All whites By sex: Male
Female By age: 0.5-5 yr
6-17- yr 18-74 yr
Coefficients for 6-month periods
January-June
Apri1-September .
and July-Decemberc
and Octobef-March0
0.920
0.938
0.678
0.717
0.929
0.955
0.944 ;
0.960
0.912
0.943
0.955
0.969
0.908
0.970
0.920
0.924
y Averages 0.929 0.698 . 0.942 0-952 0.928 0.962 0.939 0.922.
aThe lead values used to compute the averages were preadjusted by regression analysis to account for the effects pf income, degree of urbanization, region of the country, season, and, when appropriate, race, sex, arid age*
L
All correlation coefficients were statistically significant (p < 0.001) except those for blacks (p < 0.05).
eAverages were based oh six-month periods, except for the first .and last time periods ,
which covered only February 1976 through June 1976 and January I960 through February 19S0,
respectively,.
"'
j
Averages were based on six-month periods, except for .the last time period, which covered
only October 1979 through February 1950.
'
6Black s could not he analyzed according to sex and age subgroups because of inadequate sample
sizes,,
Questions have been raised by some commentors regarding whether or not (1) the NHANES II survey design was adequate to allow for credible definition of time trends for nationwide average blood lead concentrations, (2) the reported significant associations between NHANES II blood lead data and U.S. gasoline usage are credible and reflect a causal relationship, and (3) the entire decline in blood lead values is attributable to decreased gasoline lead usage versus changes in other sources of lead exposure.. These issues and alternative analyses con cerning the NHANES II blood lead/gasoline lead relationships were evaluated by an expert panel (the NHANES II Time-Trend Analysis Review Group) convened by EPA.
11-44
DUPO40O12372
The NHANES II Time-Trend Analysis Review Group <1983) found the following: (1) strong
evidence that there was a substantial decline in the average level of blood lead in the U.S.
population during the NHANES II survey period; (2) after adjustment for relevant demographic
covaricbles, the magnitude of the change can be estimated for the total U.S* population and
for some major subgroups, provided careful attention is given to underlying model assumptions.
The Review Group also found a strong correlation between gasoline-lead usage and blood-lead
levels, and noted that in the absence of scientifically plausible alternative explanations,
the hypothesis that gasoline lead is an- important causal factor for .blood-lead levels' must
receive serious consideration. Nevertheless, despite the strong association between the
decline in; gasoline-lead, usage and the Recline in blood-lead levels, the survey .results- and
statistical analyses do not confirm the.causal hypothesis. Rather, this finding is based on
the qualitatively consistent results of extensive analyses done in different but complementary
ways.
*
Further support for strong, likely causative, relationships between gasoline lead usage
and blood lead levels in the U.S. is provided by analyses carried out by, Schwartz et al.
(.1384),. Those analyses not only evaluated NHANES II data, but, also, additional blood lead
data such os blood lead values from U.$. childhood lead-screening programs. Results obtained
were quite similar to those of Annest et al, (1983b), even after controlling f.pr possible
alternative contributors to the blood lead decline, e.g., deleading of lead-painted housing
units or decreased food lead intake. Large numbers (thousands) of children were also esti
mated by the analysis to have blood lead levels in excess of 30 pg/dl due.in part to exposures
to lead emitted as a consequence of leaded gasoline usage in the United States.
Still further evidence for causative relationships between ga-solrne lead usage and
changes in human blood lead levels Is provided by isotope studies of the type described next.
11,3.6.2 Isotope Studies. Two field investigations have attempted to derive estimates of the
amount of lead from gasoline that is absorbed by the blood of individuals. Both of these in
vestigations used the fact that non-radioactive isotopes of lead are stable, the varying pro
portions of the isotopes present in blood and environmental samples can indicate .the source of
the lead. The- Isotopic Lead Experiment (ILE) is an extensive study that attempted to use dif
fering1 proportions of the isotopes in geologic formations to infer the proportion of lead in
gasoline that is absorbed by the body. The other study used existing natural shifts in iso
topic proportions in an attempt to do the same thing.
11.3.6.2.1 Italy, The ILE is a large-scale community study in which the geologic source of
lead fpr antiknock compounds in gasoline was manipulated to change the isotopic composition of
the atmosphere (Garibaldi et al., 1975; Facchetti, 1979; Facchetti, 1985). Preliminary inves
tigation of the environment of Northwest Italy, and the blood of residents there, indicated
11-45
DUP040012373
that the ratio of 206Pb/207Pb in bipod was a constant, about 1.16, and the ratio in gasoline
was about 1.18. This preliminary study also suggested that it would be possible to substitute
for the .currently used geologic sources of lead for .antiknock production a geologically dis
tinct source of-lead from Australia that had an isotopic 206Pb/207Pb ratio of 1.04. It was
hypothesized that the resulting change in blood lead 20SPb/207Pb ratios (from 1.16 to a lower
!. T
' ' f.
value) would indicate the proportion of lead in the blood of exposed human populations attri
butable to 'lead in the air contributed by gasoline combustion in the study area.
Baseline sampling of both the environment and residents in the geographic areas of the
study was conducted in 1974-1975. The sampling included air, soil, plants, lead stock, gaso
line supplies, etc. Human blood sampling was done on a variety .of populations within the
area. Both environmental and human samples were analyzed for lead concentrations as well as
isotooic 206Pb/207P.b composition.
In August, 1975, the first switched (Australian lead-labeled) gasoline was introduced;
although it was originally intended to get a 10.0 percent substitution, practical .and logisti
cal problems resulted in only a 50 percent substitution being achieved by this time. By May,
1977, these problems were worked out and the substitution was practically complete. The sub
stitution was maintained until the end of 1979, when a partial return to use of the original
sources of lead began. Therefore, the project had four phases; phase zero - background;
phase one - partial switch; phase two - total switch; and phase three - switchback.
Airborne lead measurements wera collected in a number of-sites to generate estimates of
the load exposure that was experienced by residents of the area. Turin, the major city of the
region, was found to have a much greater level of atmospheric lead than the surrounding coun
tryside. There also appeared to be fairly wide seasonal fluctuations.
The isotopic lead ratios obtained in the samples analyzed are displayed in Figure 11-12.
It can easily be seen that the airborne particulate lead rapidly changed its isotope ratio in
line with expectations. Changes in the Isotope ratios of the blood samples appeared to lag
somewhajt behind. Background blood lead ratios for adults were 1.1591 + 0.0043 in rural areas
and 1.1627 i: 0.0022 in Turin in 1975. For Turin adults, a mean isotopic ratio of 1.1325 was
obtained in 1979, clearly Ipss than background. Isotopic ratios for Turin schoolchildren,
obtained starting in 1977, tended to be somewhat lower than the ratios for Turin adults.
Preliminary analysis of the isotope ratios in air lead allowed for the estimation of the
fractional contribution of gasoline in the city of Turin, in small communities within 25 km of4
Turin, and in small communities beyondj 25 km (Facchetti and Geiss, 1982). At the time of
maximal use of Australian lead isotope in gasoline (1978-1979), about 87.3 percent of the air
11-46
DUP040012374
TIME, months
RATIO
YEAR
Figure 11-12. Change in 206pjj/207pj, ratios in gasoline, blood, and airborne particulate from 1974 to 1984.
Source: Facchetti (1985).
11-47
DUP04Q012375
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 air lead con centrations, During that time, air lead averaged about 2.0 pg/m3 in Turin (from 0,88-4.54 pg/m^ depending on location of the sampling site), about 0.56 pg/m3 in the nearby .communities (0.30-0.67 pg/m3) and about 0.30 pg/m3 in more distant (> 25 km) locations. It is important to note that the contribution calculations are for local lead in gasoline, not all lead from gasoline. Large movements of air masses brought in air lead from other regions, especially for the Suburban and urban areas. In the absence of nearby lead industrial sources, this air lead was at least substantially composed of non-Australian gasoline lead and would therefore lead to an underestimate of the total contribution of gasoline lead tp blood lead,
Blood lead concentrations and isotope ratios for 63 adult subjects were determined on two or more occasions during phases 0-2 of the study, Their blood lead isotope ratios decreased over time and the fraction of lead in their blood attributable to the Australian lead-labeled gasoline could be estimated independently of blood lead concentration (see Appendix C for estimation method). The mean fraction' of blood lead attributable to the Australian leadlabeled gasoline ranged from 21.4 + 10.4 percent in Turin to 11.4 7.3 percent in the nearby (< 25 kih) countryside and 10.1 9.3 percent in the remote countryside. These likely represent minimal estimates of fractions of blood lead derived from gasoline due to the following reasons; (1) use of some non-Australian lead-labeled gasoline brought into the study area from outside; (2) probable insufficient time to have.achieved steady-state blood lead isotope ratios by the time of the switchback; and (3) probable insufficient time to fully reflect de layed movement of the Australian lead from gasoline via environmental pathways in addition to air.
These results can be combined with the actual blood lead concentrations to estimate the fraction of. gasoline uptake attributable or not attributable to direct inhalation. The results' are shown jn Table 11-14 based upon the concept outlined in Facchetti and Geiss (1982). From Section 11.4.1, we conclude that an assumed value of {=1.6 is plausible for predicting the amount of lead absorbed into blood at air lead concentrations less than 2.0 pg/m3. The predicted values for lead; from gasoline in air (in the ILE) range from 0.28 to 2.79 pg/dl in blood due to direct inhalation. The total contribution to blood lead from gasoline is much larger, from 3.21 to 4.66 pg/dl., suggesting that the non-inhalation con tribution of gasoline increases from 1.88 pg/dl in Turin to 2.33 pg/dl in the near region, and 2,93 pg/dl in the more distant region. The non-inhalation sources include ingestion of dust and soil lead, -and lead in food and drinking water. Efforts are being made to quantify the magnitude of these sources. The average direct inhalation of lead in the air from gasoline
11-48
DUP04Q012376
TABLE 11-14. ESTIMATED CONTRIBUTION OF LEADED GASOLINE TO BLOOD LEAD BY INHALATION AND NON-iNHALATION PATHWAYS.
Locatiori
Air Pb
fraction from aso? , 11oew
Turi n
<25 km >25 km
0.873
0.587 0.587
Mean air Fb Lbl Cone. } pg/m3
Blood Pb fraction
Yrom gaso? > line'-*''
2.0
0,5.6 0.30
0.214 0.114 - 0.101
Mean blood
cone.,,<vd*) pg/dl
Blood Pb
Non-
Pb
froro
inhaled
from
gaso-
Pb from
gaso-, . ltne,(e)
Pne. (f) in air, '
??so (g) line,
pg/dl pg/dl
pg/dl
Estimated fraction gas-Pb
21.77 25.06 31.78
4.66 2.86
3.21
2.79 0.53 0.28
1.88 2.33 2.93
0.60 0.19 0.09
^Fraction of air lead in Phase 2 attributable to lead in gasglline. ^Mean air lead in Phase .2, pg/m3. ^Mean fraction of blood lead in Phase 2 attributable to lead in gasoline.
Mean blood lead concentration in Phase 2., pg/dl, Lva i 'Estimated blood lead from gasoline - (c) x (d) Lv f'l'Estimated blood lead from gasoline inhalation - p x (a) x (b), p = 1.6. ^Estimated blood lead from gasoline, non-inhalation = (f)-(e)
^Fraction of blood lead uptake from gasoline .attributable to direct inhalation - (f)/(e)
Data: Facchetti and Geiss (1982); Facchetti (1985).
is 9 to 19 percent , of the total intake-attributable to gasoline in the countryside and an estimated 60 percent in the city `of Turin. Note that in this sample, the blood lead con centrations were lowest in the city and highest in the more remote areas. This is not obviously attributable to sex because the city sample was all male,. Facchetti (1985) notes that factors unaccounted for are presumably acting on the population of the ILE test area. The lead concentration in tapwater in Turin is approximately 4 pg/1, while-it ranges in >the country from 12 to 20 pg/1. Also, lead concentrations in Piedmont wines averaged ;155 67 pg/1. Daily wine consumption for rural drinkers ranges from 0,5 to 1 liter per day. Thus the importance of wine consumption becomes evident. Other differences between city and County may play a role. A more detailed statistical investigation is needed.
Spengler et al. (1984) have developed a modeling approach to try to explain these results. Their hypothesized model suggests that in-vehicle lead exposure is important and may explain part of the apparent anomaly of the blood lead levels in this study. That is, Spengler et al. (1984) hypothesized that there is a large component of personal lead exposure associated with gasoline use that is not captured by stationary ambient air lead monitors:
1.1-49
DUP040012377
personal exposure while riding in and working around motor vehicles using leaded gas. Mor? work on this problem is needed, particularly conduction of near- and in-vehicle studies.
Lead uptake may also be associated with occupation, sex, age, smoking., and drinking habits. The linear exposure model used in Section 11.4 was also used here to estimate th| fraction of labeled blood lead from gasoline attributable to exposure via direct inhalation and other pathways. EPA used the data in Facchetti and Geiss (1982) for the 35 subjedts Tor whom repeated measurements allowed estimation of the change in isotope ratios in the blood. Their blood lead concentrations in Phase 2 were also determined, allowing for estimation of the total gasoline contribution to blood lead. Possible covariates included sex, age, Cigarette smoking, drinking alcoholic beverages, occupation, residence location, and work location. In order to obtain some crude comparisons with the inhalation exposure studies of Section 11.4.1, EPA analyses assigned the air lead values listed in Table 11-15 to various locations. Lower values for air lead in Turin would increase the estimated blood lead inhala tion slope above the estimated value of 1,7.0. Since the* fraction of time subjects were exposed to workplace air was not known, this was also estimated from the data as about 41 percent (i.e,, 9.8 hours/ day). The results are shown in Figure 11-13 and Table 11-16. Df all the available variables,'only location, sex, and inhaled air lead from gasoline proved statistically .significant in predicting blood lead attributable to gasoline. The model predictability is fairly good, with.an R? value of 0,-,654. ,It should be noted that a certain amount of Confounding, of variables was unavoidable in this small, set of preliminary data, e.g., no female subjects in Turin or in occupations of traffic wardens, etc. There was a systematic increase in estimated non-inhalation contributions from gasoline use for remote areas, but the cause is unknown. The following interpretation for these results may be offered: The air lead measurements used here represent community or ambient exposures. In addition to the ambient air lead, there may have also been systematic differences in personal exposure. Nevertheless, the estimated non-inhalation contribution of gasoline to blood lead in the lLE study is significant (i.e., 1.8-3.4 gg/dT), -
TABLE 11-15, AS5UME0 AIR LEAD CONCENTRATIONS FOR MODEL
Residence or workplace code
Location Air lead concentration
1-4
outside Turin (a)
5
Turin residential 1.0 pg/m3^
6
Turin central 2.5 pg/m3^
(a) Use value for community air lead, 0,16 - 0,67 pg/m3,
(b) Intermediate between average traffic areas (1.71 pg/m3) and low traffic areas (0,88 pg/m3'? in Turin.
(c) Intermediate between average traffic areas (1.71 pg/m3) and heavy traffic areas (4.54 pg/m3) in Turin. 11-50
DUP040012378
AVERAGE AIR LEAD CONCENTRATION ATTRIBUTABLE TO GASOLINE
ng/m3
Figure 11-13. Estimated direct and indirect contributions of lead In
gasoline to blood lead in Italian men, based on EPA analysis of IU data
(Table 11-16}. .
. -'
TABLE 11-16. REGRESSION MODEL FOR BL000 LEAD ATTRIBUTABLE TO GASOLINE
Variable
Air lead from gas
Location
Tu Hr
<25 km >25 km
Sex
Coefficient standard error 1.70 1.04 yg/dl per pg/m3
1.82 2.01 pg/dl 2.56 0,59 pg/dl 3.42 0.85 pg/dl -2.03 t 0.48 pg/dl for women
11-51
DUP040012379
the preliminary linear analysis of the overall HE data set (2161 observations) found'
that total blood lead levels depended on other covariateS for which there were plausible
mechanisms of lead exposure, including location, smoking, alcoholic beverages, age, and occu
pation (Facchettf and Geiss, 1982). The difference between total blood lead uptake and blood,
lead uptake attributable to gasoline lead! has yet to be analyzed in detail, but these analyses
suggest that certain important differences may be found. Some reservations have been expres
sed about the ILE study, both by the authors themselves and, by Elwood (1983c). These include
unusual conditions of meteorology and traffic in Turin, and demographic characteristics of the
.35 subjects measured repeatedly that may restrict the generalizability of the study.
Facchetti (1985) reports additional analysis which increases the number of blood leads from 35
to 63, alleviating this concern to some extent since the new results confirm the old. How
ever, It 1$ clear that changes in air lead attributable to gasoline were tracked by changes in
blood lead in Turin residents. The airborne particulate lead isotope ratio quickly achieved
new equilibrium levels as the gasoline isotope ratio was changed, and maintained that level
during the 2k years of Phase 2, The blood lead isotope ratios fell slowly during the change
over period, and rose again afterwards as shown in Figure 11-12. Equilibrium was .not clearly
achieved for blood lead isotope ratios, possibly due to large .endogenous pools of old lead
stored in the skeleton and slowly mobilized over time. Even with such reservations, this
study provides a useful basis for relating blood lead and air lead derived from gasoline com
bustion, Colombo and Fant.echi (1983) havei presented an analysis of the ILE study using a
.dynamic model. The results of their analysis suggest that an appropriate estimate of the con
tribution of locally consumed gasoline lead; to blood lead is 26, .17, and 14 percent'for the
subject groups of Turin, and near and far countryside, respectively. These values are similar
to but somewhat larger-than those presented by Facchetti and Geiss (19.82) and Facchetti
(1985). -
"
11.3.6.2.2 United States. Manton (19770 conducted a long-term study of 10 subjects whose
blopd lead Isotopic composition 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 observed variability, estimates could then be made of the amount of
lead in air that is absorbed by the blood.
Manton took monthly blood samples from all .10 subjects from April, 1974 until June, 1975.
The blood samples were analyzed for both total lead and isotopic composition. The recruited
volunteers included a mix of males and females, and persons highly and moderately exposed to
lead. However, none of the subjects was thought to be exposed to more than 1 pg/tn3 of lead in.
air. Lead in air samples was collected by hi-vol samplers primarily from one site in Dallas.
That site, however, had been shown earlier to vary in isotopic composition paralleling another
11-52
DUP040012380
i
subjects had reduced their PbB levels insignificantly (0.7 pg/dl), Five of the control sub
jects actually had increased PbB by 6-12 pg/dl, and one by 20 jig/dl. None of the dust-
controlled subjects had any PbB increase, and most showed, a decrease of at least .6 jjg/dl.
Four experimental subjects had PbB < 30 pg/dl by the end of the experiments
Dust lead levels in experimentally cleaned homes returned to nearly the previous high
valuer within two weeks. There was no significant relation'between reduction of leaded.dust,
. initial level,of leaded dust, and the reduction in a ehildls blood lead level. This lack of
apparent correlation may have been due to failure to control or monitor hand washing, finger-
sucking and mouthing behavior, access to "hot spots," and time spent in the home. Further
more., attempts at dust control may have been more successful in some of the control homes than
-`
i
in others, resulting in blood lead reduction in at least some Individual cases. Since advice
- on dust control was .offered to caretakers of lead-burdened children visiting the Clinic, it
may be presumed that some measure of dust control would have? occurred in any event. Dust lead
values in the experimental homes were high compared to homes in other areas (13/14 had .sites
>100 j.ig/930 cm2). While many potentially important factors were not completely controlled
during the trials., the importance of pUSt Ingestion is ey1detd|. This study also points out
the difficulties in quantifying the dust-hand-mouth pathway using familiar measures of house
hold dust lead and concentration. Since the reduction in blood lead levels cannot be plausi
bly attributed to factors other than household dust control (e.g., relocation of residence or
change in diet), the experimental evidence for the importance of household dust in elevation
of blood lead levels in 0,$. Urban children is very strong, :
,
11,4.3.10 Gallacher Study. A report from England (Gallacher et a!., 1984) provides addi
tional informative data on tde importance of dust to blood lead levels. They were interested
in the effect of pica on blood lead levels. Mothers and children aged 1-3 years were recruit-
- ed .from 4 areas of Wales chosen for presumed lead exposure:, ; 1) roadside dwellings; 2) cul
de sac dwellings; 3) an old mining area; and 4) a control .area. Comprehensive environmental
sampling accompanied, the stujdy of bipod lead levels. Indoor air samples, soil from play
areas, pavement dust, house dust, and tap water, samples were collected and analyzed for lead
content. Capillary blood samples were collected from the children, while venous samples were
collected from the mothers. Blood samplies were analyzed for lead by atomic absorption spec
trophotometry, The accuracy of the capillary sampling was checked; the authors concluded that
contamination was not a problem but that the values of the capillary samples were 37 percent?
higher than venous samples. They attributed the difference as "probably owing to haemoconcen-
tration of capillary blood,"
Results from the environmental sampling indicated that for many of the environmental
media, lead exposures ware reasonably constant over a several-month period. The authors state
11-146
DUP040012381
TABLE 11-61. LEAD CONCENTRATION OF SURFACE SOIL AND CHILDREN'S BLOOD BY RESIDENTIAL AREA OF TRAIL, BRITISH COLUMBIA
.1
Residential area(.s)
1 and 2 ;5 i9
3, 4,s and 8 6 and 7
Mean soi1 1ead' ^ concentration, pg/.g, standard error (and no. of samples)
225 39 (26) 777 + 239 (12) 570 + 143- (11) 1674 i 183 (53) ,1800 + 212 (51)
Blood lead concentration,
pg/dl, mean + standard . /'
. , error (and no. of children)
1- to 3-
...
one
year olds
.children
17.2 + 1.1 (27) . 19.7 1.5 (11)
20.7 +1.6 (19)
27.7 1.8 (14) 36.2 + 3.0 (16)
18.0 1.9 (18)
18.7 2.3 (12) 19.7+1.0 (16) 23.8 + 1.3 (31) 25.6 +1.5 (26)
fatal
1320 212 (153)
22.4 1.0 (87)
21.9 + 0.7 (103)
Source: Schmitt et al., 1979.
I
I 11.4.3.9
i
. The Baltimore Charney Study.: A Controlled Trial-of Household Dust Lead Reduction.
Charriey et al. (1983) selected children'from the Lead Poisoning Clinic of-the John F, Kennedy
Institute in Baltimore. The children were all 15-72 months old at the time of enrollment and
had at least two venous blood lead levels between 30 and 49 pg/dl and FEP < 655 jjg/dl. The
children were also required to have had, the same place of residence for at least the preceding
six months. Their houses had to have been beheaded in accordance with standard procedures
used by the Baltimore City Health Department. Experimental control subjects were recruited on
the basis of attendance at routine periodic blood lead monitoring. Alternative identification
numbers were used for allocation to. experimental and control groups. Home visits were made
for children in- the experimental.group and a 930 cm2 area of the floor or windowsill was wiped
with jin alcohol-treated cloth towel and]the dust lead content analyzed. A "dust control team11 then Visited each home twice monthly add wet-mopped all. surfaces with >lb.O pg Pb per 930 cm2.
The child's caretaker was .advised to wet-mop these surfaces and.other "hot spots" more fre quently, to wash the child's hands-before meals and at bedtime, and to restrict access to highlead areas.
Both the 14 experimental subjects receiving the above treatment and the 35 control sub jects started the study with about the same moderately elevated blood lead levels, 38,6 5.2 pg/dl at the start of the experiment. These levels had remained almost stationary for six months before the experiment, increasing only 1 pg/dl on average. After a year of dust con trol, the experimental subjects had reduced their PbB levels by 6-9 pg/dl, whereas the control
11-145
DUP040012382
I
results were discarded whenever the values differed by more than S pg/dl. this procedure
probably helped control to some degree the commonly encountered positive bias in blood lead
levels observed when capillary samples are y$ed. An episode of poisoning of horses earlier
had been traced to ingestion of lead- Environmental 'monitoring at that time did not suggest
that a human health risk existed. However., tt: was later thought wise, to conduct a s^ddy of
lead absorption in the area,
"-
Trail had been the site of a smelter since the turn of the century. The smelter had
undergone numerous changes for reasons of both health and productivity. At the time of the
blood lead study, the smelter was emitting 300 pounds of lead daily, with ambient air lead
levels at about 2 pg/m3 in 1975.. Nelson, BC was chosen as the control city.. The cities are
reasonably close (~30 miles distant), similar' in population, and served by the same water
basin. The average air lead level in Nelson during the study was' 0.5 pg/m3.
Initial planning called for the sampling of 200 childre# in each of three age groups (1-3
years, 1st grade and 9th grade) from each of the two sites. A strike at the smelter at the
onset of the study caused, parts of .the Trail population to move. Hence, the recruited sample
deviated from the planned one. School chiIdrjen were sampled in May, 1975 at their schools
while the 1- to 3-year olds were sampled in September, 1975 at a clinic or home. This delayed
sampling was intentional to allow those children to be exposed to the soil and dust for the
entire summer. Blood and hair samples were collected from each child.
The children in the younger age groups living in Trail had higher blood lead levels than
those .living' in Nelson. An examination of the frequency distributions of t'hb blood lead
levels showed that the entire frequency of the distribution shifted between the residents of
the two cities. Interestingly, there was no difference in the ninth grade children.
Table 11|61 displays the results of the soil lead levels along with the blood lead levels
obtained in the earlier study. Blood lead levels were higher for 1- to 3-year olds and first
graders in the two. nearest-to-smeiter categories 'than in the far-from-smelter category.
Again, no difference was noted for the ninth graders.
j
An. EPA analysis of the Neri et al. (1978) data gives the following models for children 1-
to 3-yes.rs old
.
,
-
Blood lead (pg/dl) = 0.0.076 soil lead (pg/g) + 15.43, and
(11-21)
Blood lead (pg/dl) = 0.0046 soil lead (pg/g) + 16.37
(11-22)
for children in grade one. No confidence intervals were calculated since the analysis was based on means.
11-144
DUP040012383
the two towns, 0.60 compared with 0.29 pg/rn3. .Although this difference existed, both ,
air lead values were thought low enough not to affect the blood level values differentially. ~
Mean surface soil lead concentrations for the two communities were statistically different, >
the means for the high and low: community being 909 and 398 pg/g, respectively. Despite this 5
difference, no statistically significant differences^ in maternal blood lead levels or.-chil- ; s' i
dren's blood or hair lead levels were noted. Further statistical analysis of the data, using '
correlational analysts on either raw or log-transformed blood lead data, likewise failed to ,
show a significant relationship, of soil lead with either blood lead or hair lead.,
The second study was reported in both preliminary, and final form (Barltrop, et al., 19.74;
Barltrop, 1975). In the more detailed report (Barltrop, 1975), children's, homes were clas
sified by their, soil lead content 'into three groups: ; less than 1,000; 1,000 - 10,000; and
greater than 10,000 pg/g.. As shown in Table 11-60, children's mean blood lead levels ihcre.as.ed `
correspondingly from 20.7 to 29.0 pg/dl. Mean soil lead levels for the low and high soil ;
exposure groups were420 ahd 13,969 pg/g, respectively. Mothers' blood levels, however, did
not reflect this trend; nor were the children's fecal lead levels different across the soil ?
exposure areas.
!-
i TABLE 11-60, MEAN BLOOD AND SOIL LEAD CONCENTRATIONS IN ENGLISH STUDY
Category of soil lead
(m/0
*1000
1000-10000 -
>10000
i
; { |
Sample size
29
43
1 -10.
Chi1dren's blood lead
(pg/di)
20.7
| 23.8 | 29.0
Soil )ead (pg/g) 420
3390
13969
Source: Barltrop, 1975.
An analysis of !the data in Table 11-60 gives the following model
blood lead (pg/dl) - 0.64 soil lead (1000 pg/g) + 20.98
(11-20)
No confidence intervals were calculated since the calculations were based on means, 11.4.3.8 The British Columbia Studies. Mari et al. (1978) studied bipod lead levels in children living in Trail, British Columbia. Capillary blood samples were collected and analyzed for lead by anodic stripping voltammetry. Duplicate samples were analyzed and the
11-143
DUP040012384
cutppint :in the .chi-square contingency analysis, Fairey and Gray were the first to examine
this complex problem and, although their data support the soil lead hypothesis, the relation
ship between soil lead and blood lead levels, could not be quantified., Furthermore, because no
other Source of lead was measured, any positive association could have been confounded by
additional sources of lead, such as paint or air.,
-
P later .study by Galke at al, (1975), in Charleston,, used a hous'e-to-house survey to re
cruit 3.94 black preschoo) children. Soil, paint, and air lead exposures, as measured by traf
fic density* were established for each child. When the population was divided into two groups
based on the median soil lead value (585 pg/g), a ,5 pg/dl difference in blood lead levels was
?`
;..
obtained. Soil lead exposure for this population ranged from 9 to 7890 pg/g. Vehicle traffic
patterns were defined bjy area of recruitment as being high or low, A multiple regression
analysis of the data showed that vehicle traffic patterns, lead level in . exterior siding
paint, and lead in soil Were all independently and signifleaptly related to blood lead levels.
Using the model described in Appendix 11B, the following coefficients and standard errors were
obtained as shown in Table 11-59.
I. TABLE 11-59. COEFFICIENTS AND STANDARD ERRORS FROM MODEL OF CHARLESTON STUDY
Factor..................
Coefficient
Asymptotic .standard error
Intercept (pg/dl)
Pica (1 ~ eater, 0 =* otherwise)
Traffic pattern (1 = high, 0 - low)
Siding paint (mg/cni2)
Door paint (mg/.cm2)
Soil lead (mg/g)
j
25.92. 7.231 7.11 0`. 33 i 0.18 < 1.46:
Multiple R2 = 0;386
`
.' '
Residual standard deviation <= 0.2148 (geometric standard deviation - 1,24)
i
1.61 1.60 1,48 0.11
0.12 0.59
11
11.4.3,7 Barltrop Studies-. 8arltrop et al. (1974) described two studies in England* investi gating the soil lead to blood lead relationship. In the first study, children aged .2 and 3 and their mothers from two towns chosen for their soil lead content had their blood lead levels determined from a capillary sample. Hair samples were also collected and analyzed for* lead. Lead content of the suspended particulate matter and soil was measured. Soil samples for each home were a composite of several 2-inch core, samples taken from the yard of each home. Chemical analysis of the lead content of soil in the two towns showed a 2- to 3-fold difference, with the values in the control town about 200-300 pg/g compared with about 7001000 pg/g in the exposed town. A difference was also noted in the mean air lead content of
11-142
DUP040012385
or less than 59 pg/dl. High-level children were selected first and low-level children were
group-matched based on age, area of residence, and social class of the family. Home visits
were me.de to gain permission as well as to gather questionnaire and environmental data. Lead
analyses of the various environmental samples were done at several different laboratories.. Mo
specification was provided regarding the analytical procedures followed.
'
The matching procedure worked well for age, and mother's educational level and employment
status. There were more blacks ,in the high lead group as well as more Medicaid support.
' These factors were then controlled in the analysis; no differences were noted between the high
and low blood lead groups regarding residence on high traffic density streets (>10,050 vehi
cles/ day) or census tract of residence.
The two groups differed regarding mean house dust lead levels (1265 pg/sample for high
and 123 pg/sample for low). Median va.lues also differed, 149, versus 5.5 pg/sample. One-third
of the children in the low blood lead group had house ..dust'jead samples with more lead than
those found in any middle class hbme previously investigated.
There were considerably greater quantities of lead on the hands of the high blood lead
group compared with the low lead!group (mean values were 49 and .21 pg/sample, respectively).
Hand and house dust lead levels weife correlated (r = 0.25) but the relationship was not
linear. At the low end of the house dust lead values, hand "dust was always low but the con
verse was not true: not every child exposed to high house dust lead had high hand dust
{levels.
\
In addition to hand and house dust lead, other factors differentiated the high and low
blood lead groups. Although both groups had .access to peeling paint in their homes (~2/3),
.paint lead concentrations exceeding 1 percent were found more frequently in the high as oppo
sed to the low group. Pica (as defined ip Chapter Seven) was more {prevalent in the high lead
{group as opposed to the low--lead .group:
. Since the data suggested a ; multifactorial eontribution of lead, a multiple regression
| !i
janalysis was undertaken. The results suggest that hand lead level, house dust lead level,
.lead in outside soil,.and history of pica are very important in explaining the observed vari
ance in blood lead levels.
.
11.4.3.6 Charleston Studies. In one of the earliest investigations regarding soil lead expo
sures, Fairey and 6ray (1970) conducted a retrospective study of lead poisoning cases in
Charleston, South Carolina. Two-inch core soil samples were collected from 170 randomly
selected sites in the city and were compared with soil samples,.taken from homes where 37 cases
of lead poisoning had occurred. The soil lead values obtained ranged from 1 to 12,000 pg/g,
with 75 percent of the samples containing less than 500 pg/g. A significant relationship
between soil lead levels and lead poisoning cases was established; 500 pg/g was used as the
11-141
DUP040012386
i:
, '.
i
TABLE 11-58. RESULTS OF tEAO MEASUREMENTS REPORTED BY BRONEKREEF ET AL, (1903)
t
\ City
Concentration
Range
2 Lead deposition outdoors (arithmetic mean, pg/m /d)
Rotterdam? Rotterdam0
the Hague3.
643 220 369
394-957 144-315 317-439
Zoetermeer0
125
73-278
2 Lead on streets (geometric mean, pg/rn )
.Rotterdam? 532 .168-2304 Rotterdam0 318 113-1155-
The Hague3. Zoetermeer0
428 126
81-13.39 46-497
L4ad in garden soil (geometric mean, mg/kg)
Rotterdam? DRno4*t+teiArd/la.lmw0^
336 , 4430
6-184
jhe Hague3,
.27.8
35-527
Zoetarmee r
2.1
3-75
)2
Liiad deposition indoors (geometric mean, pg/m /d)
Rotterdam?-
2.86
0. 10-20.86
Rotterdam0
0.99
0. .10-8,40
The Hague3.
4. 32 .
1. 95-27.05
Zoetemeer0
1.51 J
0. 48-4.40
.z Lead on floors (geometric mean, pg/iri )
.Rotterdam?
81
Rotte-dam.
30
The Hague'1.
50
loetermeer0 j
3.2 i |
5-740 1-410 22-166 3-201
Lead in drinking water (geometric mean, pg/i)
Rotterdam?
, 20
Rotterdam"
2i
the- Hague3.
21 . I
Zoetevmeer0 .
1
1-126 1-50 1-85 1-4
Lead on hands (geometric mean, pg/hand)
Rotterdam?
12
Rotterdam0.
.5
Zoetermeer0
4
1-96 1-21 1-18
n
9 6 .5 10
37
is io
i 56 16 43
i
48 67 13 49
43 62 11 f
46 60 ite 53
44 65 37
t-test
/ p <0.001 p <0.001 p <0.001 p <0.001
p <0,005 p <0.005 p <0.001 p <0.00.1
p <0.001 p <0.001
p <0.001 p <0.001 p <0.001 p <0.001
p <0.001 p <0.001 p <0.025 p <0.025
p <0.001 p <0.0.01 p <0.001 p <0.001
p <0.001 p <0.001 p <0.001
aInner city.. ^Suburb.
11-140
DUP040012387
| -. i - -
TABLE 11-55. AIR LEAD LEVELS IN THE ROTTERDAM AREA (BRUNEKREEF ET AL., 1983)
Sampling location Rotterdam (center) MaassluiSj(upwind Suburb)
f'
Geometric mean air lead level in uq/m3
Janiiary-March, 1981
April -June, .1981
0 27
0,22 '
0.14
0.10
*' ... '
i 1
1 I ^i . *
City
; ,,
i
`
TABLE 11-56. BLOOD LEAD LEVELS IN pg/100 ml FOR CHILDREN WHO
PARTICIPATED IN BLOOD SURVEY .........
AND
ENVI'RONMENTAL SURVEY
-
I
Number
.Geometric mean
'i. . Range
Percentile 50 .90 "98
Rotterdam!(center) |
Rotterdam 1i (suburb)
The Hague;
54 72 16
13.1 8,2 11,5
7-31 5-15 7-21
13. 19 8 11
11 19
23 14 21
Zoeteraeer
53 7,9 4-15 8 11 14
aDiffeTence between city and suburb significant (t-test on arithmetic means; p <0.001).
TABLE 11-57. SCHOOL VARIABLES (ARITHMETIC MEANS) FOR MEASURED LEAD CONCENTRATIONS
i City |
In drinking water,
pg/i
-Deposition . indoors, pg/m2/d
On f1 o.ors, pg/m2
.On 1
schoolyard, j pg/m2 1
In sandy playground,
mg/kg
Rotterdam
6
- 11.74
100 1120
6
Rotterdam*3 Zoetermeer*3
1 1
4.29 4.59
29 364 40 .337
5 6
aIhner city. ^Suburb.
11-139
DUP040012388
Resulting blood lead levels and environmental lead measurements are shown in Tables 11-5$
to 11-58.
Multiple regression analyses were done by Brunekreef ei al, in logarithmic rather than
linear form. The equation is as follows,
4 '/
In PbS ~ 1.882 + 0,163e In (lead deposition outdoors) ~ 0.0034 (year of construc
tion - 1900) + 0.135*5 (hand dirtiness) - 0.38Q4 (milk consumption) + 0.116^
(presence
of
pets)
a + 0.106
(moui thing behavior)
-
H 0.069
(number of
rooms)'
.i '
>
ap <0.01.
bp <0.005.
cp <0.001. j 4p <0,0001, ,
(11-19)
I Multiple regression analysis for combined inner city and suburban populations give the
following: n * 193, R2 * 0.519, F-total - 28.51
' #
lead deposition outdoors was an important factor,, but only In the combined sample, so
confounding cannot be ruled out. This appeals, however, to be the single most important
environmental source, particularly in conjunction with hand 'dirtiness and with mouthing
behavior. Further analyses of these data arje proposed. The difference of about 2 yg/dl
between city and suburban children (adjusted for all other covariates) can hardly be attri
buted to. direct inhalation of ambient air lead which differs slightly from city to suburb
(0.12-0,13 Mg/m3), and hence myst be attributed to other pathways. The large coefficient for
milk reflects;the known importance of calcium in lead metabolism and is also related to mouth
ing behaviors, including pica. The presence of pets probably increases the exposure to dirt.
This study thus corroborates the importance of various non-inhalation pathways for lead in
children, .particularly the dust-hand-mputh pathway.
i
Or, Brunekreef .has (personal communicatioh, February .8, 1984) fitted his data on Dutch
children to a'linear model in logarithmic forp, as the Environmental Protection Agency has
done elsewhere in the present document. The Regression coefficients are all statistically .
significant, and variables are a$ in his 1983 paper. The logarithmic linear model had vari
ance s2 = 0.06272 and R2 =? 0,521; it thus provided an (insignificantly) better description of
the data than the original log-log model.
11.4.3;5 Charney Study. Charney et al, (1980) conducted a case control study of children
ages 1.5-6 with highly elevated and non-elevated blood lead levels. Cases and controls were*
initially identified from the lead screening programs of two Rochester, New York, health
facilities. Cases were defined as children who had at least two blood lead determinations
between 40 and 70 yg/dl and FEP values greater than 59 yg/dl during a 4-month period. Con-"'
trols were children who had blood lead levels equal to or less than 29 yg/dl and FEP equal to
11-138
DUP040012389
t
l; .
|
i :'
I960-1969 to 756 ppm for those, built in 1910-1919. Soil lead levels varied from 1.31 ppm to 1273 pptn for 1970-1977 and 1920-1929, respectively. 11.4.3.3 The Silver Valle.y/Kel-logg Idaho Study. The Silver Valley/Kellogg Idaho study was discussed in section 11.4.1.6. Yankel et al. (1977) Showed that lead in both soil and dust was independently related to b(lood lead levels. In their opinion, 1.000 pg/g soil lead exposure was cause for concern. 1 Walter et al. (I960) showed that children aged 3 through 6 showed the strongest relationship between soil lead and blood lead, but 2-year-olds and 7-yearolds also had a significant relationship (Table 11-29), The slope of 1.1 for soil lead (1000 pg/g) to1 blood lead (pg/dl) represents an average relationship for all ages.
The Silver Valley-Kellogg Idaho study also gave some information on house dust lead, al though this data was less complete than the other i.nfprmation. Regression coefficients for these data are in Tables 11-29 and' 11-30. In spite oi the correlation of these predictors, significant regression coefficients could be estimated Separately for these effects. 11.4.3.4 Blood Lead levels of Dutch City Children. Bnmekreef et al. (198:3) reported on a very extensive study on blood lead and environmental variables in native Dutch children 4-6 years old. Three hundred seventy-one children participated in the blood lead survey and 195 children in the environmental study as well. The environmental evaluation was carried out in ApriT-June 198.1 In the cities of Rotterdam, the Hague, and Zoetermeer. Blood was sampled by venipuncture. The environmental variables included:
In the home of .each child:
'
1
* lead in drinking water (one first-draw sample)
:i
lead deposition indoors, using 2 greased deposition plates per home and an averaging
time of 4 weel^s
lead in floor-dust, using a special vacuum deader to take 2 duplicate samples 4 Weeks
._ apart
j
.j
j
* lead in Q-S cm top soil...in gardens, if present !
In living area: i i i
lead deposition outdoors on 5-10 spots per arjea with an averaging time of 4 weeks
lead in street dust using the vacuum cleaner method, taking 30-40 duplicate samples
per area oh 2-occasions 4 weeks apart
In the classroom/schooi: lead in drinking water (one running sample)
lead deposition indoors, applying 2 plates in 2 classrooms per school with an averag ing time of 4 weeks
* lead in floor dust, taking 2 duplicate samples in 2 different classrooms per school, 4 weeks apalrt
* lead in playground dust, using the vacuum cleaner method to take 4 duplicate samples on two occasions 4 weeks apart
lead in 0-5 cm top soil in playground * lead on dominant hand of child, after playing outdoors for at least 30 minutes in
school playground on a dry day.
11-137
DUP040012390
TABLE 11-54, MULTIPLE REGRESSION MODELS FOR BLOOD LEAD OF CHILDREN IN NEW HAVEN,. CONNECTICUT, SEPTEMBER 1974 - FEBRUARY .1977
*
Covariate
;
Regression Coefficients and Standard Errors
Ages Ages
Ages /
0-1 yr
2-3 yr
4-7 yr
-'i
Summer - winter
j
.Dust, pg/g
Housekeeping quality
Soil near, house, pg/g j
Soil at curb, pg/g
j
Paint, child's bedroom <
Paint outside house-
Paint quality
j
Race = Black
1
6.33 2.11*
3.28 1.30*
0.00402 0,00170* * 0.00182 0.00066*
4.38 * 2.02* .
. .1, 75 1.17
0,00223 0.00091* -0.00016 0.00042
0.00230 0.00190 0.00203.^ 0.00082*
0.0189 0.0162
0,0312 0.0066*
-0.0023 0.0138
0.0200 0.0069*
0.89 1.71
3.38 0.96*
2.16 2.05
0.07 1.09
2,43 1.38*
0,00022 0.00Q77
-1.61 1,125
0,00060 + 0.03041
0.00073 0,0007.9
0.0110 0.0064*
0,0172 0.0067*
4.14
i.is4
5.81 1.00*
Residual standard deviations Multiple R2 Sample size (blood samples)
0.1299 0.289
153
f
.0,064.6 0.3.00 * 334
0.1052 0.143
439
*
Significant positive coefficient, one-tailed p <0.05,.
noted, with considerably improved predictability (R2 = 0.29, 0,30, 0.14 for ages O-l, 2-3, and 4-7). Sex was not a significant variable, bat Race = Black was significant at ages 4-7.- Ajir lead did not significantly improve the fit of the model when other covariates were available, particularly dust, soil, paint, and housekeeping quality. However, the range of air lead levels was small (CL7-1.3 pg/m3) and some of the inhalation effect may have been confounded with dust and soil ingestion. Seasonal variations were important at all ages.
EP.A analyses of data from children in New Haven (Stark et al., 1982) found substantial* evidence for dust and soil lead contributions to blood lead, as well as evidence for increased blood lead due to decreased household cleanliness. These factors are somewhat correlated with each other, but the separate roles of increased concentration and cleanliness could be distin-^ guished. Overall dust, soil, and paint lead levels were not presented in the published papers, but data presented by year of housing construction indicate that meaningful lead expo sures were present. Geometric mean dust lead levels varied from 239 ppm for houses built in
11-136
DUP040Q12391
t a b l e 11-53. c o e f f ic ie n t s a n d s t an d ar d e r r o r s f o r o ma h a s t u d y mo d e l
Factor
; Coefficient
Asymptotic Standard Error
Intercept (pg/dl) Air lead (pg/m3) Soil lead (mg/g) House dust (mg/g)
I1 15.67
1,92 6.SO 1 748
0.398 0.600 0,966
0.900
^
Multiple H2 =? 0.198
j.
Sample size = 10.75
Residual standard deviation - Oj.300 (geometric standard deviation = 1-35)
measurements fell into one of three previously defined bloodi,lead concentration categories), a
potential study population of 784 was identified, Change of residence following identifica
tion and refusal to let sanitarians make inspections resulted in 407 children being dropped; the final study population contained 377 children.
With the exception of dietary lead intake, each child's potential total external lead
exposure was assessed. Information was obtained on lead in air, house dust, interior and
exterior paint, and . soil near and far from the home. A two percent sample of homes with
children having elevated lead levels had tap water lead levels assessed. No water lead levels
above the public health service standard of 50 pg/1 were foundJ Socioeconomic variables were
also obtained.
For all children in the study, micro blood samples were taken and analyzed for lead by
AAS with Delves Cup attachment.. Blood lead values were found to follow a lognormal distri-
.|
1* .
bution. 'Study results were presented using geometric means and geometric standard deviation.
Among the various environmental measurements a number of significant correlation coefficients
were observed. However, air lead levels were independent of most of the other environmental
variables. Environmental levels of lead did not directly follow socioeconomic status. Most of the children, however, were |n the lower socioeconomic groups.
Multiple regression analyses were performed by Stark et al. (1982) and by ERA*, using all
926 blood lead measurements. Stark and coworkers derived a log-log model with ft2 ~ 0,11, and
no significant effects of race or age were found. EPA fitted--a linear exposure model in loga
rithmic form with results shown in Table 11-54. Significant differences among age groups were
*N0TE: 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.
11-135
DUP04QG12392
!
The problem: of determining the most appropriate model(s), at low water lead levels* (0-25 pg/1) is extremely difficult. Most datasets estimate a relationship that is primarily based on water lead levels of 50-2000 pg/1. and the problem becomes essentially a low-dose extrapolation problem. The only study which estimates the relationship based primarily or, lower water lead levels L0Q pg/1) is the Pdcpck et at. (1983) study. The data from this study, , as well as the authors themselves, suggest that in this lower* range of .water lead jievels, the relationship is .linear. Furthermore, the contributions to blood lead levels esti* ffnated from this study are .quite consistent with the polynomial mod"iecl;s: ' from the other first* flush water lead studies, such as Worth et al. (1.981), United Kingdom Central Directorate on Environmental Pollution (1982), and Thomas et al. (.1979), For these! reasons the Poc.ock et al. ,(19.83) slope of 0,06 is our best estimate for first-flush water lead studies. The slopes for funning water lead studies are about 1.5 to 2.0 times as large. The possibility does exist, however, that the higher initial slopes from the cube-root and logarithmic models are correct.
11.4.3 Studies Relating lead in Soil and Dust to Blood Lead
;
1 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 scientific investiga-
tion for some time (Duggan and Williams, 1977; Barltrop, 1975;.Creason et al,, 1975; Barltrop
et al., 1974; Roberts et al,, 1974; Sayre et al., 197.4; Ter Haar and Aronow, 1974; Fairey and
Gray, 1970). Duggan and Williams! (1977) published an assessment'of the risk of increased
blood lead resulting from the ingeition of lead in dust. Some of these studies have been con
cerned with the effects of such exposures (Barltrop, 1975; Creason et al., 1.975; Barltrop et
al., 1974; Roberts et al,, 1974; Fairey and Gray, 1970); others have concentrated on the means
J>y which th'e lead in soil and -dust;becomes available to the body (Sa^re et al,, 1974; Ter Haar
k'nd Aronow, 1974; Brunekreef et al., 1983), . -
* ; .
11.4.3.1 Omaha, Nebraska Studies.. 'The' Omaha studies were described in Section 11.4.1.7,
^oi 1 samples were .2-inch cores halfw.ay between the building and the lot line. Household dust
was collected from vacuum cleaner .bags. The following analysis was provided courtesy of Dr.
Angle. The .model is also described in Section 11,4.1.8, and provided the coefficients and
standard errors shown in Table 11-53.
11.4.3.2 Stark Study. Stark et al. (.1982) used a large-scale lead screening program in New
Haven, Connecticut, during 1974-77 as a means of identifying study subjects. The screening"
program had blood lead levels on 8289 children, ages .1-72 months, that represented about 80
percent of the total city population in that age group. From this initial population, a much
smaller subset of children was identified for a detailed environmental exposure -study. Using"
the classifying criteria of residential stability and repeatable blood lead levels (multiple
11-134
DUP040012393
TABLE 11-52. STt
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11-133
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Sherfotk et ah
PbB * 5.6 * 2.62 (PbW)
0.65'
study. ;
(1984)
- i ;i
*1
DUP040012394
TABLE 11-51. STUDIES RELATINS BLOOD LEAD LEVELS ( p g / d l) TO FIRST-FLUSH WATER LEAD ( iig / 1 )
t<yo *<x- -mre iu-* xixs
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11-132
Pacock e t a t. (1983) study o f 7735
Pocock e t a l. (1983) PbB = 14.48 <- 0.062 PbH
2` H .S
0 ,3 S.S 1.-6
inen aged 40-59 In G reat B r it a in .
Water leads restricted ta <100 ug/1.
Moore (19S4) study o f 568 mothers in Scotland'.
Moore <1984) '
_____________. .
PbB = 5 .5 + 2,63. (PbW)1^ 3
.............................,
0.39 2
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DUP04001239S
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11-131
DUP040012396
TABLE 11-49. STUDIES RELATING BLOOD LEAD LEVELS ( p g /d l) TO DIETARY INTAKES (p g /d a y)
. a *
ON
O
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DUP040012397
I
TABLE 11-48. BLOOD LEAD LEVELS OF 771 PERSONS IN RELATION TO LEAD CONTENT OF DRINKING WATER, BOSTON, HA
Blood lead levels, pg/dl
Persons consuming water (standing grab samples;)
<50 |ic| Pb/1 No. ' Percent
&50 OO Pfa/1 No, Percent
Total
<35
622 -' i si'
68 77.3
690 -
>35
6:1 , 9
20 22.7
81
Total
683
x* = 14:35; df = 1. p <0.01,
Source: Worth fit al. (1981).
: j 100 I J i
i
j
88 100,0 '*
'-0
771
/i Conversely, the linear equation Is probably ah underestimate. The slope from the Ryu study
was estimated directly from changes In infants and is the best estimate available. The esti
mates for adults are more accurately estimated from the experimental studies:.
The experimental studies are summarized in Table 11-50. Most of the dietary intake sup
plements were so high that many of the subjects had blo'od lead concentrations much in excess
Of ,30 pg/dl for a considerable part of the experiment. Blood lead: levels thus may not com
pletely reflect lead exposure, due to the previously noted nonlinearity of blood lead response
at high exposures. The .slope estimates fpr adult dietary intake arejabout 0.02 pg/dl increase
in blood lead per pg/day intake, but consideration of blood lead kjinetics may increase this
yalue greatly,. Such values are'.|i bit lower than those estimated jfrom the adult population
studies extrapolated to typical dietary intakes in Table 11-43, about 0,05 pg/dl per pg/day.
jhe value for infants is much larger.
j
. 1 The studies relating first flush and running water lead levels to blood lead levels are
jn Tables 11-51 and 11-52, respectively. Many of the authors chose to fit cube root models io their data, although polynomial and logarithmic models were a! so used. Unfortunately, the form of the model greatly influences the estimated contributions to blood lead levels from relatively low water lead concentrations. As indicated ih section 11.4, the models producing high estimated contributions are the cube root models and the logarithmic models. All others are polynomial models, either linear, quadratic, or cubic. The slopes of these models tend to be relatively constant at the origin.
11-129
DUP040Q12398
4.0
3.0
BLOOD LEAD, ^M liiter
2.0
f
!
1.0
0 1
1.0 2.0 F|RST FLUSH WATER LEAD mg liter
3.0
Figure 11 28. Relation of blood lead (adult female) to first flush water lead in combined estates.! (Numbers are coincidental points:] 9 * 9 or more.) Curve a, present data; curve b, data of Moore et ai, (1979).
11-128
DUP040012399
Ij j ' '
The researchers then analyzed the form of the relationship between blood lead levels and
water lead levels. They tried several different shapes for the regression line. Curvilinear
models provided better fits. Figure 11-28 depicts, the scatter diagram of blood.lead and water
lead. An ,EPA analysis of the data is in Table 11-51 in Section 11.4.2.4.
A later publication by Thomas (1980) extended his earlier analysis. Thisltiore extensive
sr .
analysis was limited to lead estate residents. Subjects who did not consume the first drawn
water from the tap had significantly lower blood lead levels than those who did (10.4 jig/dl
difference)... No gradient Was noted in blood lead levels with increasing- wat<fr consumption.
Furthermore,: no gradient, in blood lead levels was noted with total beverage consumption (tea
ingestion frequency).
'
11.4.2.3,4 jWorth study. In Boston, Massachusetts, ah, investigation.was made of water distri
bution via lead pipes, in addition to the data on lead in water, account was taken of socio
economic and demographic factors as well as other sources offfead in the environment (Worth et
al., 1981). j Participants, 771 persons from 383 households, were classified into age groups of
less than 6, 6-20, and gr.eatef than 20 years of age for analysis. A clejar association
between water lead and blood lead was apparent (Table 11-48). For children under 6 years of
age, .34,6 percent of those consuming water with lead above the U.S, standard of .50 pg/1 had a
blood lead value greater than or equal to 35 pg/dl, whereas only 17,4 percent of those con
suming water within the standard had blood lead values of greater than or equal to 3:5 pg/dl.
Worth et al. (1981) have published an extensive regression analysis of these data. Blood
lead levels were found to be significantly related to age, education of head of household, sex,
and water lead exposure. Of the two types of water samples.taken, standing grab sample and
running, grab, sample, the former was shown to be more, closely related to blood.lead levels than
the latter, j Regression equations are, given jin Tables 11-51 and .11-52 in Section 11.4.2.4.
11,4.2.4 Summary of Dietary lead Exposures, Including Water. It is difficult to obtain accu
rate dose-respon|Se .relationships between bloo| .lead levels and lead levels, in food or water.
Oietary 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 cohsumed by dif
ferent individuals add to the uncertainty of the estimated relationships.
Studies relating blood lead levels to dietary lead intake are compared in Table 11-4.9,
Two studies had subjects with relatively high dietary lead intakes. In the Sherlock et al.
(1982) study, 10 of 31 subjects had lead intake levels greater than .300 pg/day. In the United
Kingdom Central Directorate study (1982), 12 of 110 subjects had levels greater than 308
pg/day. These concentrations are high enough that the slope is clearly lower in this range
than it is in the 0-100 pg/day range. The estimates of slopes for the cube root models may
be overestimates in the low range (0-100 pg/day) for the reasons discussed in section 11.4,
11-127
DUP040012400
i
} t.
to 9 at the source., thereby maintaining the tap water at 8. At this time, more than 95 percent
of random daytime samples were less than 100 pg/1.
In the autumn and winter of 1980, 47.5 mothers from the same hospital: were studied, the
median blood lead was 6,8 pg/dl and the geometric mean was 8.1 pg/dl. Comparison of the fre*
quency distributions of blood lead between these two blood samplings show a remarkable' drop.
Ho other source of lead was thought to account firths observed change,J
Sherlock et al. (1984) report that water treatment produced a sharp fall in water lead
concentrations and a decrease in the median bipod lead concentrations from 21 to 13 pg/dl.
11.4,2.3,3 Thomas study. Thomas et al. 1979} studied women and children residing on two
adjacent housing estates. One estate was serviced by lead pipes for plumbing while the other
)'
was serviced by copper pipe- In five of the homes in the lead pipe estate, the lead pipe had
been replaced with copper pipe. The source water is. soft, acidic, and lead-free.
Water samples were collected from the coldltap in the kitchen in each house on three oc
casions at two-week intervals. The follow!ng water samples were collected: daytime - first
water out of tap at time of visit; running - collected after tap ran moderately for 5 minutes
after the daytime sample; and first flush _ first water out of tap in morning (collected by
residents). Lead was analyzed by a method (unspecified'in report) that was reportedly under
qualify control,
-.
Blood samples were collected from adu.lt females (2.5 ml venipuncture) who spent most of
the time in the home and from the youngest child (capillary sample). Blood samples were ana
lyzed for lead by a quality-controlled unspecified method. Blood lead levels were, higher in
the residents of the lead estate homes than in the residents of the copper estate homes.
Median levels for.adult females were 39 and 14,5 pg/dl for the lead and copper estate homes,
respectively, j Likewise, children's blood lead jlevels were .37 and 16.6 pg/dl, respectively. Water lead levels were substantially higher f.orl the lead estate than-for the copper, estate.
This was true for all three water samples.
.`
.
The researchers then monitored the effectiveness of replacing the lead pipe |on reducing
both exposure to lead in drinking wafer and, ultimately, blood lead levels. This monitoring
was done by examining subsamples of adult females for up to 9 months after the* change was
implemented. Water lead levels became indistinguishable from those found in the copper estate
homes. Blood lead levels declined about .30 percent after 3-4 months- and 50 percent at 6
and 9 months. At 6 months the blood lead levels reached those of women living in the copper
estates. ..A small subgroup of copper estate females was also followed during this time. .No
decline was noted among them. Therefore, it was very likely that the observed reduction in
blood lead levels among the other women Was due to the changed piping.
11-126
DUP040012401
Source: Moore 6t al. (1979), i1-125
DUP040012402
Another English study (Crawford and Crawford, 1969) showed a clear difference between thS
bone lead contents-of the populations pf Glasgow and London, the latter having a hard, .nonsol
vent water supply. In a study of 1200 blood donors in Belgium (Qe Graeve et al., 1975),
persons from homes with Tpdd piping and supplied with corrosive watef had significantly higher)
blood lead levels.
11.4.2.3..2 Moore studies.- Moore and colleagues have reported on'several studies relating,
blood lead levels to water] lead levels. Moore (1977) studied the relationship between blood;
lead level and drinking water lead irt residents of a Glasgow tenement., The tenement was
supplied with water from al lead-lined water tank carried'by lead piping, . Water samples'were {
collected during the day.; Comparative water samples were collected from, houses with copper;
pipes and from 15 lead-plumbed houses. Blood samples-were taken wherever possible from all ;
Inhabitants of these housed. The data indicated that If a house has lead-lined pipes, it is ;
almost impossible to reach] the WHO standard for lead in water (190 pg/T), Linear regression
equations relating blood lead levels to first flush and running water lead levels are in ;
Tables 11-51 and 1.1-52 in Section 11.4.2,4,
Moore (1977) also reported the analysis of blood lead and water lead data collected over
a four-year period for different sectors of the Scottish population. The combined .data showed i
consistent increases in blood lead levels as a function of first draw water lead, but the
equation was nonlinear at the higher range. The water lead values were as high as 2000 pg/1.
The fitted regression equation for the 949 subjects is in [Table 11-51 in Section 11.4.2.4.
Moore et al, (1931a,b) reported a study of the effectiveness of control measures for
plumbosolyent water supplies. In autumn and winter of 1977, they studied 236 mothers aged
17-37 in a postnatal ward of a hospital in Glasgow with no historical occupational expo
sure. Blood lead and tap [water samples from the home were analyzed for lead by AAS under a )
quality control program,; j
|
A skewed distribution of blood lead-levels was obtained with a median value of 16.6 pg/dl; 3 percent of the values exceeded 41 pg/dl, The geomeiric mean was 14,5 pg/dl. A cur- ;
vilinear relationship between blood lead level and water lead!level was found, .The log of the , maternal blood lead varied as the cube root of both first flush and running water lead concen trations, In Moore et al, (1979), further details regarding this relationship are provided. Figure 11-27 presents the observed relationship between blood lead and water lead.
In April, 1973, a closed loop lime dosing system was installed. The pH of the water was' raised from 6,3 to 7.8. Before the treatment, more than 50 percent of random daytime water samples exceeded 100 pg/1, the WHO standard. After the treatment was implemented, 80 percent of random samples were less than 100 pg/1. It was found, however, that the higher pH was notmaintained throughout the distribution system. Therefore, in August, 1980, the pH was raised
11-124
DUP040Q12403
- H H
PbB; ppb
figifcg
Figure 11-26. lead in blood (mean values and range) In volunteers. In the lower curve the average daily lead dose of the exposed group is shown.
Source: Cools et a!. (1976).
11-123
DUP040012404
W.
, .. .
i.
i;
11.4.2.2.3 Cools study. Cools et al. (197.6) extended the research of Stink (1974) by random-* ly assigning 21 male subjects to two groups.. The experimental group was to receive a 3.0 pg/kg body weight dose of oral lead acetate for a period long enough to achieve a blood lead level of 30.0 pg/g, when the lead dose would be adjusted downward to attempt; to maintain the sub jects at a blood .lead level of 40.0 pg/g. The other group received a placebo..
In the pre-exposure, phase, blood lead levels were measured three times., while during ex
posure. they were measured .once a week, except for the first three weeks,when they wete deter
mined twice a week. Blood lead was measured by flame AAS according to the Westerlund tnodifi-
catibni of Hessel's method.
'
.] Pfe-exposure blood lead values for the 21 volunteers averaged Vf ppb* The effect of
ingeistfion of lead acetate on blood lead is displayed in Figure 11-26; After 7 days, mean
blood lead levels had increased from 17.2 to 26*2 pg/g* The time t reach a blood lead
level! of 35.0 pg/g took 15 days on the average CranjSe 7-4;0 dfys).
\
11.4.. 2*2.4 Schlegel study. Schlegel and Kufner (1979) report an experiment in which two sub
jects received daily oral doses of 5 mg P,b?+ as an aqueous solution of lead nitrate for 6 and
13 wI eeks, respectivel`y. Blood ,and urine samples were taken* Blood lel}ad uptake (from 16-60 pg/dp in 6 weeks) apd washout were rapid in subject HS, but less so in subject GK. (from 12-29
pg/dl in 6 weeks). Time series data on other heme system indicators (FEP, ALA-0, ALA-U,
coproporphyrin III) were also reported.
11.4.2.2.5 Chamber!aln study.. This study (Chamberlain et a!*, 1978) was described in Section
11.4.1, and in Chapter 10. The ingestion studies on six subjects showed that the gut absorp
tion of lead was much higher when lead was ingested between meals* There were also differ
ences in absorption of lead chloride and lead sulfide. :I
11.4j.2.3 Inadvertent Lead Ingestion from Lead Plumbing.
i
.)
11.4.2*3.1 Early studies. Although ifche use of lead piping has-been flargely prohibited in
'recent .construction, occasional episodes of poisoning from this lead source still occur. Thesje cases most frequently involve isolated farms or houses in rural aieas, but a surprising
urban episode was revealed in 1972 when Beattie et al. (1972a,b) showed the seriousness of the situation in Glasgow, Scotland, whichthad very pure, but soft, drinking water as its source. The researchers demonstrated a clear association between blood lead levels and inhibition of the enzyme A.LA-0 in children living in houses with (1) lead water pipes and lead water tanks, (2) no lead water tank but with more than 60 ft of lead piping, and (3) less than 60 ft of*
lead piping. The mean lead content of the water a$ supplied by the reservoir was 17.9 pg/1;
those taken from the faucets of groups 1, 2, and 3 were 934, 239, and 108 pg/1, respectively.
11-122
DUP040012405
Figure 11-25. Average Pb8 levels, Exp. II. - Source: Stuik (1974).
11-12}
DUPO40012406
;Si IU
TABLE 11-47. DOSE-RESPONSE ANALYSIS FOR BLOOD.LEAD LEVELS IN THE KEHOE STUDY AS ANALYZED BY DROSS (1981)
Subject
SW MR EB
IF2
Added lead. pg/day
300 1000 2000
3000
Difference from control1
Diet, pg/day ;
Feces, pg/day . : . .
Urine, pg/day
308 \,
1072
|
184$ . . J
208
984 . 1547. =
.3 ' 55
_ < .. 80 :
2981' j ' 2581 7.
49 .
Blood/' pg/dl
-1 17 33
19
xEach subject servced as his own control. ^Subject did not reach equilibrium.
.1
'#
Both subjects MR and EB bad Tong exposureiperiods, during which time their blood lead
levels increased to equilibrium averages, of 53 and 60 pg/dl, respectively. The exposure for
IF was terminated early before his blood lead haU achieved equilibrium. No response in blood
lead was seen for subject SW whose supplement was 300 pg/day.
11.4.2,2.2 Stulk study. S'tuik (1974.) administered lead acetate ih two dose levels (20 and 30
pg/kg-day) to Volunteers. The study was conducted in two phases. The first phase was con
ducted for 21 days during F.ebruary-March, 1973., Five males and five females aged 18-26 were
exposed to a daily dose of 20 pg Pb2+/kg, Five males served as Controls, .In the second
phase, five females received 20 pg. Pb2+/kg and five males received 30 pg ,Pb2+/kg. Five
females served iaS controls. Pre-exposure valuei were established during the weelf preceding
.! I
j
the exposures in both phases. Blood lead levels were determined by Hesse!1s method.
The results of phase I for blood lead levels are presented in Figure 11-24. Blood lead
levels appearedj to achieve an equilibrium after jl7 days of exposure, Male blood lead levels
went from 20. 6 ;to 40.9 pg/g while females went from 12,7. to 3.0.4 pg/g. The males seemed to
respond more to.the same body weight dose,,
;
In phase II, males were exposed to a higher lead dose (30 pg/kg-day). Figure 11-25 dis
plays these results. Male blood lead rose higher than in the first study (46.2 versus 40,9
pg/g); furthermore, there was no indication of a leveling off. Females also achieved a higher
blood lead level (41.3 versus 30.4 pg/dl), which the author could not explain. The pre
exposure level, however, was higher for the second phase than the first phase (12,7 versus
17-3 pg/g).
11-120
DUP040012407
The authors cpme to the following conclusion regarding the slope of the relationship be tween blood lead and water 1ead:
:-
This study confirms that the relation is not linear at higher levels. Previous
research had suggested a power function relationship-'-for example, blood lead in- '
creases as the cube root of-water lead. Our data, based oh a large and more^
representative sample of men, do not agree with such:a curve, particularly at low
concentrations of water lead;.
-
i
i
11.4.2.1.8 Thomas study. Thomas- et al. (1981) studied blood lead levels among residents of a
hardwater area in the United Kingdom. They recruited a random sample of voters in an area
with 320 ppm calcium hardness. A tap water sample using * first draw water was requested and
was returned by 70 percent of the selected voters. Sixty women in the dwellings with the
highest water blood level and 30 randomly selected women in dwellings in the lowest water lead
levels were selected for a blood lead determination; 84 women responded. Blood lead levels
were stratified by water lead levels and-were compared to; data gathered elsewhere from soft-
water areas. Substantial differences were noted., with the residents of the hardwater areas
haying meaningfully lower blood lead levels. This is true Seven for residents in the hardwater
area with the lowest (<0.05 mg/1) water lead-level,
11.4.2.1.9 Elwood study.1 Elwood et al\ (1983) have investigated the potential of the degree
of water hardness to influence the relationship between lead concentrations in drinking water
and blood lead level. An experimental model was employed wherein two -groups pf women were
studied both before and after the water hardness of the drinking water for one group was
changed to 100 from 10 mg/1. Postconversion blood lead levels were obtained 6 months later.
Mean water lead -levels fell slightly after the change in the area where the water was
hardened, whereas it increased slightly in the central area.' Blood lead levels decreased in
the experimental areas wfvjle increasing in the central area; 'The decline in blood lead levels
was greater with increasirjg initial water lead levels.
1
j
11,4.2,2. lead Ingestion from Experimental Dietary Supplements,
1
11.4.2.2,1 Kehoe study. Experimental studies have been used to study the relationship of
food lead and blood lead levels. Gross (1981) reanalyzed the results of Keh.oe, Oral doses of
lead included 300, 1000, 2.000, and 3000 pg/day. Each subject had a control period and an ex
posure period. Some also had a post-exposure period. Blood samples were collected by veni
puncture and analyzed by spectrograph!c and dithizone methods during the study years. The
ingestion doses were in addition to the regular ingestion of lead from the diet. The results
of the dose response analysis for blood lead concentrations are summarized in Table 11-47.
11-119
DUP040012408
j-.,r
] i\:
I
!*
T
i
l
i
i M! I M
6jl 52
I
. 473|60 51 50 65' .
'1
49
--
49
Figure 11-23. Mean blood lead for men grouped by first draw water concentra
tion.
I
Source: Pocock e.t al. {1983).
U-118
DUP040012409
TABLE 11-46. RELATIONSHIP OF BLOOD LEAD AND WATER LEAD IN 310 MEN AGED 40-59 FROM 24 BRITISH TOWNS
First draw water lead,
Mg/i
<50
. 50-99
100-299
>300
Total ----------------- --
Daytime water lead,
149/1 <50
50-99
100-299
: ^300
}
Total
Number of i men - ;
J789
Mean blood lead
(jjg/dl)
15.06
69 ; 18.90 40 ] 21,65
. 12 ] 34.19 ']
910 ....... ~............... ...........-
ji
........ |
15.89
i !
845 i ' 15.31
36 19.62
23 24.78
5 39.78
909 , 15.85
Sojurce: Pocock et al. (1983.);.
Standard deviation
5.53 7.31 7.83 15.27 ;
8.57
% with blood lead
>35 (jg/dl 0.7 4.3 7. 5
41.7
1.9
5.64 7.89 . 9.68 j 15.87 ;
. 6.44
0.7 8.3 17.4 60.0
1.8
11-117
DUP040012410
Source: UnitedKingdom Central Directorate on Environmental Pollution {1982).
11-116
DUP040012411
!
.i
11 . ,, |.
J !! .
dietary intake are in Table 11-49 in Section 11.4.2.4. Models relating blood lead levels for
both mothers and infants to first flush water lead levels and .running water lead levels are in.
Tables 11-51 and 11-52 in Sectigg 11.4.2.4 respectively. In most cases, the nonlinear (cubic) -
model provided the best fit. Figure 11-22 illustrates the fit for the two modelsshowing in
fant bloodlead levels versus dietary lead-intake.
! - /"
;>
11.4.2.1.7 Ppcock study, Ppcotiik et al, (1983) haverecentlyreported animportant study examining the relationship in middle-aged men of blood lead level and water lead `levels. Men
*
aged 40-59 wpe randomly selected- from the registers of general practices located in 24
British towns) Data were obtained between January, 1978 and June, 1980,
\
Blood leiid levels were obtained on 95 percent of the 7378 men originally selected. The levels vfere determined by microatomic absorption spectrophotometry. A strict internal and ex
ternal quality control program was maintained on the blood lead determinations f.dr the entire
study period-? Tap water .samples were obtained on a small sublet of the population. About 40
men were chosdn in each of the 24 towns tof!participate in the water study. First:draw samples -
were collects^ by the subjects 'themselves, while a grab daytime and flushed sample were col
?
iso.
lected by stujjy personnel. These samples were .analyzed by several methods of AAS depending on the ednceniration range of the samples.
^
Blood lead and water lead- levels were available for a total of 910 men from 24 towns.
Table Ur-45 displays the association between' blood lead levels and water lead levels. Blood
lead levels nearly doubled from the lowest to highest water lead category.
?
The investigators analyzed their, data further by examining the form of the relationship between blood and water lead. This was done by categorizing the water lead levels into nine intervals of first draw levels.. The first group (<$ gg/1) had 4.73 men while tjhe remaining . eight intervajs had ~ 50 men each. Figure ll-j>3 presents the results of this analysis. The
authors state, "The impression:ds that mean blood lead increases linearly with first draw
water lead except for the last group with very high water, concentrations:" The regression
,!
i . ..
!
line shown inj the figure is Only for men with jwater lead levels less than 100 pg/.l, and is
given in Table 11-51 in Section 11.4.2.4. A sepiarate .regression was done for the 49 men whose
water lead exposures were greater-than 100 jjg/1. The slope for the second line was only 23' percent of the first line.
Additional analyses were done examining the possible influence of water hardness on blood lead levels. A -strong negative relationship (r = 0.67) was found between blood lead level and
water hardness. There is a possibility that the relationship between blood lead and water
hardness was due to the relationship of water hardness and water lead. It was found that a relationship with blood lead and water hardness still existed after controlling for water lead level.
11-115
DUP040012412
1i:-4;2.l.6 Central Directorate on Environmental Pollution study. The United Kingdom Central
Oirectorate on Environmental Pollution (19.82) studied the relationship between 'bipod lead
level and dietary and drinking water lead in infants." Subjects were first recruited by solic
iting, participation of all pregnant women attending tWo hospitals and residing within a single
water distribution system. Each woman gave a blood sample and a kettle water sample. The
women were then allocated to one of six potential study groups based on the concentration of
water lead.
1
. .
.
a
At the start of the second phase (duplicate -diet) a total of 155 women volunteered
(roughly 17-32 per water lead level category). Dufing the course of the study, 24 mothers
withdrew; thus a final study population of 131 mothers was achieved. When the children reached 13 weeks of age, duplicate diet for a week's duration was ob
tained for each infant. Great care was exerted to allow collection of the most accurate
sample possible. Also, at this time a variety of wafer samples were collected for subsequent
lead analysis..
i
i
Blood samples were collected by venipuncture from mothers before, birth, at delivery, and
about the time of the duplicate diet. A specimen wak also collected by venipuncture from the
infant at the time of the duplicate diet. The blood] samples were analyzed for lead by graph
ite furnace AAS with deuterium background correction..- Breast milk was analyzed analogously to
the blood sample after pretreatment for the different matrix. Water samples were analyzed by
flame atomic absorption; food samples were analyzed after ashing by flameless, atomic absorp
tion.
.1 .
j
Both mothers dnd infants exhibited increased lead absorption by EEC (European Economic
Community) directive standards. The infants generally had higher blood leads than the
mothers. However, ;in neither population was there ev idence of substantial lead absorption.
Water lead samples ranged from less than' 50 to greater than 500 pg/1, which was expected
due to the sampling procedure used. First draw samples tended to be higher than the other
samples. The composite kettle samples and the randoil daytime samples taken during the [dupli
cate diet week were! reasonably similar: 59 percent of the composite kettle samples contained
up to 150 fjg/1, as did 66 percent of the random daytime samples. Lead Intakes from breast milk were lower than !from duplicate diets. The lead intakes
estimated by duplicate diet analysis ranged from 0.04 to 3.4 mg/week; about 1/4 of- the diets had intakes less than 1.0 mg/week. The minimum intakes were truncated, as the limit of detect tion for lead was 10 pg/kg and the most common diets weighed 4 kg or more.
The central directorate data were reanalyzed by Lacey et al, (.1985). Results from both Lacey et al. (1985) and the United Kingdom Central Oirectorate on Environmental Pollution (1982) are In Tables 11-49 to 11-52 in section 11.4.2.4. The authors used both linear and cube root models to describe their data. Models relating blood lead levels of infants to
11-114
DUP040012413
TABLE 11-44. DISTRIBUTIONS OF OBSERVED BLOOD LEAD VALUES IN AYR
Groups
Adults Infants EEC directive
>2Q pg/dl
55% 100%
50%
Blood lead:-values
>30 pg/dl
16% i 55% s 10%.
>35 pg/dl, '
.2% .36%
2%
1
>
' TABLE 11-45. BLOOD LEAD AND KETTLE WATER LEAD CONCENTRATIONS FOR ADULT WOMEN LIVING IN AfR
Water lead, pg/1
Blood lead,
11- 100* 300- 500-j 1000-
pg per 100 ml <10 99
293 ' 499
999 ]
149,9
>1500
<10 1.1-15
16-20 21-2.5 26-30
31-3.5 .36-40
>40
8 .5
47
1 .3 4
3 12
9 2 2
r
33 7 5. 442 .1 2 2 .1 1 1 14 3
1
3 1 3
Total
13 19
28 ' .19
19
8
i
8
Total
13 17 22 25 12 10
4 11
114
The researchers also developed a linear model for the relationship between dietary intake ; and drinking water lead. Tfie equation indicates that, when the concentration of lead in water was about 100 pg/1, approximately equal amounts of lead would be contributed to the total : week's intake from water and diet; as water lead concentrations increase from this value, the principal contributor would be water.
A follow-up study on this same population was made from December., 1982 to March, 1983, as reported by Sherlock et al. (1984). In April 1981, the pH of the water supply was increased from pH 4.5-5.5 tp about pH 8.5 by the addition of lime. The result was ,a decrease in the median blood lead level from 21 to 13 pg/dl. The combined data set was used to give the re gression equation shown in Table 11-52 in Section 11.4.2.4.
11-113
DUP040012414
!1 i
TABLE 11-43. INFLUENCE OF l ev el o f l ead IN WATER ON BLOOD LEAD LEVEL IN BLOOD AND PLACENTA
Comparison group
Water1 level
;
.! . Mean
Age (years)
Low**
! .25.6
High*** i ; 26,3 ,
Pb-B mother (pg/dl)
Pb-B newborn (pgfdi)
Low High
LowHigh
i
C...... :
j
10.6 13,8-,
, . ..
8.8 12,1
Pb placenta (ug/lGO g)
Low High
i 9.7' j 13,3
Water Pb (pg/i)
Low High
{ i
Source: Hubermont et al. (1978)
11.8 247.4
*NS means not significant. I
**Watgr lead <50 pg/1, ***Water lead >50 pg/1,
Median
.24 25
9.9 13.1
8.5 '11.9 :
8.2 12,0 .
6.3 176,8
Range ' 18-41'
20-42 5.1-21.6 ,5.3-26.3 3,4-24.9 2.9-22.1 4.4-26.9 7.1-28 *0.2-43.4 61.5-1228.5
-
Significance NS*
<0.005 <0.001 <0.005
exposure. Venous sampleswere taken from the infants '.immediately after the duplicate diet
week. Blood lead levels were determined by AAS with a graphite furnace under good quality
control. Two other laboratories analyzed each sample by different methods. The data reported
are based on the ayerage value; of the three methods.
}
Dietary intakes for adults and children were quite different; adults had higher intakes
than children. Almost one-third'of the adults bad intakes greater than 3 mg/week while only
**
|
20 percent of the infants hadjthat level of intake. Maximum values were IT mg/week for adults
and 6; mg/week for in* fants, 'The observed blood lead value s in fthe dietary study had the dls-
.tributions shown in Table 11-44.
- ``
Table 11-45 presents the crosstabulation of drinking water lead and blood lead level for
the 1.14 adult women in the study. A strong trend of increasing blood lead levels with increa
sing drinking water lead levels is apparent. A curvilinear regression function fits the data
better than a linear one, A similar model including weekly dietary intake was fitted to the
data for adults and infants. These models are in summary Tables 11-49 and 11-52 in Section
11.4.2.4.
11-112
DUP040012415
t %
ii j,
11.4.2.1.3 Rabinowltz adult study. This study on male adults was described in Section 11.4.1 and In Chapter 10, where ingestion experiments were analyzed in more detail (Rabinowitz et al., 1980). As in other studies, the fraction of ingested stable isotope lead tracers ab sorbed into the blood was much lower when lead was consumed with meals (10.3 + 2.2 percent) than between meals (35 13 percent). [Lead nitrate, lead sulfide, and lead cysteine as car riers made little difference. The much higher absorption of lead on an empty stomach implies greater significance of lead ingestion ifrom leaded paint and from dust and soil when consumed between meals, as seems likely to be true for children, 11.4.2.1.4 Hubernont study. Hubermont let al. (1978) conducted a study of pregnant women liv
ing in rural Belgium because their dripicing water Was suspected of being lead-contaminated.
This area was known to be relatively f|eb of air pollution. Seventy pregnant women were re
cruited and asked to complete a questionnaire, information was obtained on lifetime residence
history, occupational history, smoking* and drinking habitsa First flush tap water samples
were co'lected from each home with the wkter lead level determined ,by flameless atomic absorp
tion spectrophotometry. Biological samples for lead determination were taken at delivery. A
venipuncture blood sample was collected (from the mother, as was a fragment of the placentae an
umbilical cord blood sample was used to estimate the newhorn's blood lead status.
For the entire population, first-flush tag water samples ranged from 0.2 to 1228.5 pg/1.
The mean was 109.4, while the median was 23.2. The influence of water lead on the blood lead
of the; mother and infants was examined by .categorizing the subjects-.on the basis of the lead
level 'iof the water sample, below or above 50 pg/1. Table 11-43 presents; the results of this
study. A significant differehce ip blood lead levels of mothers and newborns was found for
the water lead categories, Plapehta lead levels also differed significantly between water
lead groups. The fitted regression e^u^tion of blood lead level for pothers is given in
summary Table 11-51 in section"11,4^2,4.!
'
[
11.4.211.5 Sherlock studies, Sherlock et al. (1982) reoorte.d a studv'from Avr. Scotland,
j _ -.-' r-t -t -h-t
-i '
1-
I
Which [considered both dietary and drijiking water lead exposures for mothers and children
living, in the area. In December', 1980, water lead concentrations were determined from kettle
water from. 114 dwellings in which the mother and child lived less than'five years. The adult
women had venous blood samples taken in early 1981 as part of a European Economic Community
(EEC) survey on blood lead levels. A duplicate diet survey was conducted :on a random sample
of these 1.14 women stratified by kettle water lead levels.
A study population of 11 mothers with infants less than 4 months of age agreed to parti
cipate in the infant survey. A stratified1 sample of 31 of 47 adult volunteers was selected to
participate in the duplicate diet study.
Venous blood samples for adults were analyzed for lead immediately before the duplicate
diet study; in some instances additional samples were taken to give estimates of long-term
.11-111
DUP040012416
3
The -rends in blood lead' for the formula-fed infants are shown in Table 11-42. The re
sults up 'to day 112 are averaged for all 25 infants. The estimated average intake was 17
pg/day for this time period. After day 112, the subgroup of seven infants fed either canned
formula or heat-treated cow's milk in cans {higher lead), had average estimated lead intake of
61 pg/'day, This resulted in an increase of 7.2 pg/dl in the average blood lead level in
response to an increase of 45 pg/day in lead intake by day 195. However, singe the blood lead
levels iV1 this group had riot reach1 ed eguilibirum by this point, t'he slope calc|u lated from this
data of Pil6 should be regarded as an underestimate.
.
TABLE llj-42. BLOOD LEAD LEVELS AND LEAD INTAKE VALUES FOB INFANTS IN THE STUDY OF RYU T At.
Age, dhys 1 is
56 84 112'
.1
Blood lead of combined group, pg/dl
8.9 5.8
5.1 5.4 6.1
Lower lead
Higher lead
....
Average lead intake of combined group, pg/day
17 17 17 .17 ' 17 \
Lower lead i Higher lead
140 168 . 196
6.2 7.0 7.2
9.3 12,1 114.4
.16 61
16 61 16 61
Source: Ryu et al, (1983).
11.4.2.1.? Rabinowitz infant study. As papt of a longitudinal study of thei sources of cur rent urbah lead exposure, lead was measured in 100 breast milk samples and in 73 samples of
the infant formula used by non.-nursing mothers (Rabinowitz et al., 1985a). .Also, the blood
lead levels of the infants fed these diets Iwere determined at birth and at sijx months of age.
Among thei infants who were breast-fed, the,lead content of their milks correlated very well
wi-th their six-month blood lead levels (r 4 0.42, p- = 0.0003). The mean lead content of in-
>
3
fant formulas and breast milk were not significantly different, nor was the blood lead of
children fed one or the other. Lead levels in maternal milk correlated poorly with umbilical cord blood lead (r = 0.18, p - 0.10). Since milk represents much of the diet of young infants''
and because breast milk lead levels are stable, It is possible to relate blood lead and daily
dosage in this population.
11-110
DUP04Q012417
i - - if '
i-
j
j II
TABLE 11-41. HOUSEHOLD CONSUMPTION OF CANNED FOODS i {pounds per week)
' 1 ......... Food
i
Canned fruits* : Central city i
Suburban
i
Nonmetropo1itan
-j
Canned vegetables*
Central city j
Suburban
{
Nonmetropo!itpn
Sprihg
,
0.65 0.85 0.83
2.37 2.40 2,37
Summer
0.47 0,55 0.62
- 2, 36 2.08 1.94
Fall
0,59 0.84 0,78
2. si
2.57 , 2.46 '
Fresh fluid milk
Central city {
Suburban
;
Nonmetropol itian
1 Processed milk
Central city-i
Suburban Nonmetropo,! i tan
13.44 . 17.66
15.11
1.14 1,43 1.56
14.20 17.12 16,17
1.12 1.13 1.36
'4: 14,31 17.38 16.16
1,18 ,1.10 1.59
Canned veg, juices* Central city Suburban
Nonmetropolitan
Canned fruit juices*
Central city .
Suburban
!
Nonmetropol itian
Soft drinks (tjotal)
Central city >
Suburban
i
Noriffletropol itkn
0.39 0.42 0.56
1.34 1.16 1.29
-
5.50 6.53 5.67
0i,38 0,41 01J 3a
;
1.46 lj.26 lj.22
5i 75
6j. 88
S'. 89
0,37 0.54 0,4.6
1.39 ' 1.25
1.49
-
5,11 6.22 5.62
Winter
V
0.74 0.91 i 0.85 ;
2.83 i 2,86 i 2.89. ;
13.75 17.17 16.70
1.30' 1.14 1.90
i
i 1f ' :
. 0,35 0.47 , 0.53
1.41 1.24 1.35 j
5.35 1 5.96 i . 5.25
*Comme rcla11y canned.
supplied in quart cans and heat-treated in the same manner as the commercially available for mula. There were 10, 4, and 3 infants in each of these groups, respectively. In addition to food concentrations, data were collected oh air, dust, and water lead. Hemoglobin and f.EP
were also measured.
11-109
DUP040012418
i
The last approach is the market basket approach. This approach uses the observed lea*d
concentrations for a variety of food items coupled with estimated dietary consumption of the
particular food items. Some studies use national estimates of typical consumption patterns
upon which to base the estimated exposures. Other studies actually record the daily dietary
intakes. This approach faces similar analytic problems to those found in the duplicate diet
approach. It also faces the problem of getting accurate estimates of dietary intakes. The
most current total diet study (Pennington, 1983) is described in Section 7.3.1.2,
Exposures to lead in the diet are thought to have decreased since the 1940's, Estimates
from that period were in the range of 400-500 pg/day for U.S. papulations. Khandekar et al.
(1984) report a dietary intake of lead to be 245 pg/day. This was calculated from the lead
content in different food groups and the amount of bach food group consumed by an average
.. . '
i
resident of Bombay, India, Current estimates for U.Si populations are under 100 pg/day for
adults. Unfortunately, a good historical record regarding^the time course of dietary expo
sures is not available.- In the years 1978-1982, efforts have been made by the American food
canning industry in cooperation with the FDA to reduce the lead contamination of canned food.
Data presented in Section 7,3,1..2.5 confirm the success of this effort. Seasonal variations
in blood lead might also be partially attributable tojseasonal variations in the dietary in
take of lead. The following evidence suggests that`this does not happen. Table 11-41 is
taken from Human Nutrition Information Service (1983). The data suggest the following
pattern: . (1) Consumption of canned vegetables, and fruits is much lower in the spring and
summer, much higher iln the fall and winter, which is the opposite of the pattern of blood- lead
level variations and 'suggests that the attribution of seasonal changes to gasoline lead may be
an underestimate of its effects, (2) The pattern is similar for central city, suburban', and
nonmetropolitan households. (3) There is little seasonal variation for fruit and vegetable juices and milk, and k slight increase of soft drink consumption in the summer. The magnitude
of .such variations is too small to account for blood lead. !\
_i
The specific studies available for review regardijng dietary exposures will be organized
into three major divisions.: lead ingestion from typical diets, lead ingestion from experimen
tal dietary supplements, and inadvertent lead ingeOtion from lead plumbing.
11.4.2-jL Lead Ingestion from Typical Diets. ,
11.4.2.1.1 Ryu study on infants and toddlers. Ryu et al, (1983) reported a study of four
breast-fed infants and 25 formula-fed infants from 8-196 days of age. At 112 days of th<f
study, the formula-fed infants were separated into subgroups based upon how they were to re
ceive their milk: homogenized whole cow milk obtained in cartons from a local dairy, a com
mercially available milk-based formula supplied in quart cans, and homogenized whole cow milk
11-108
DUP040012419
dietary intakes in the United States and Canada. The report gives information on relation
ships between external lead exposures and blood lead levels. The mechanisms and absorption
rates for uptake of lead from fgod and water are described in Chapter 10, The purpose of the
present section is to establish (analogously to Section 11.4>I) the relationships between
external exposures to. lead in fpod; and drinking water and resulting internal lead exposures. ,
The establishment of these'external and internal lead exposure relationships for the en
vironmental media of food and water, however, is complicated by! the inherent relationship be
tween food and water. First, the largest component, of food {by weight is water.. Second,
drinking water is used for food preparation and, as shown in Section 7.3..Is3,^provides addi
tional quantities of lead that are appropriately included as part of external lead exposures I
ascribed to food. Third, the quantity of liquid .consumed daily by people varies greatly and
substitutions are made among different sources of liquid: soft drinks, coffee., tea, etc,, and
drinking water. Therefore, at best, any values of water lejtd jintake used in drinking water
calculations are somewhat problematic,
A further troubling fact is the influence of lead in the construction of plumbing facil
ities. Studies discussed in Section 7.3.2.1.3 have pointed out jthe .substantial lead exposures
in drinking water that can result from the use of lead pipes in the delivery of water to the
tap. This problem is thought ter occur only in limited geographic abeas in the United States,
However, where.the problem is present, substantial water lead exposures occur. In these areas
one cannot make a simplifying assumption that the lead concentration in the water component of
food is similar to that of dHnking water; rather, one is adding a potentially major addi
tional lead exposure to the equation.
Studies that have attempted to relate blood lead levels to ingested lead exposure have
used three approaches to estimate the external lead exposures involved: duplicate meals, fe cal lead determinations, and market basket surveys. In'duplicate diet studies, estimated.lead
exposures are assessed by having subjects put aside a duplicate]of what they eat at each meal for a limited period of time, (These studies probably provide a |ood, but short term, estimate
j| |
of the ingestion intake. However, the procedures available to analyze lead in foods have his- ,; \ tori cally been subject to inaccuracies. Hence, the total validity of data from this approach ' j has not been established. Studies relying on the use of fecal lead determinations face two major difficulties. First, this procedure involves the use of a mathematical estimate of the overall absorption coefficient from the gut to estimate the external exposure. Until recent ly, these estimates have not been well documented and were assumed to be relatively constant. Newer data discussed later show a much wider variability in the observed absorption coeffici ents than was thought to be true. These new observations cloud the utility of studies using this method to establish external/internal exposure relationships. Secondly, it Is difficult to collect a representative sample.
11-107.
DUP040012420
T
i
j
One can summarize the situation briefly
(1) The experimental studies at lower air lead levels, 3.2 pg/m3 or less, and lower blood levels, typically 30 pg/d1 or less, have linear blood lead inhalation rela tionships with slopes 8. of 0-3.6 for most subjects. A typical value of 1.64 + 0.22 may be assumed for'ac^ults.
(2) Population cross-sectiona^ studies at lower air lead and bipod lead levels are approximately linear witfj slopes p of 0.8-2.0 for inhalation contributions.
(3) Cross-sectional studies ip occupational exposures in which air lead levels are
higher (much above 10 pg/q3) and blood lead levels are higher (above 40 pg/dl), show a much more shallow linear blood lead inhalation relation. The slope p is in the range 0.03-0.2.
(4) Cross-sectional and experimental studies at levels of air lead somewhat above the higher ambient exposures (9-36 pg/m3) and blood leads of 30-40 pg/dl can be described either by a npnlioear relationship wii%. decreasing slope or by a linear relationship with |intermediate slope, approximately p = 0.5. Several biological mechanisms for Ithese differences have been discussed (Hammond et al,,
1981; O'Flaherty et al., 3j982; 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 an interpolation formula from low air lead to high air lead exposures. The increased steepness of the inhalation curve for the Silver Valley/ Kellogg study is inconsistent with the other studies- presented. It may be that smelter situations are unique and must be
analyzed differently, or it may be that the curvature is the result of impre cise exposure estimates.
; (5) The blood lead .inhalation slope for children is at least at steep as that for adults, with a median estimate of 1,92 from three major studies (Yankel et al.,
: 1977; Reels et al,, 1980; Angle and Mcintire, 1979).
j (6) Slopes which include both direct (Inhalation) and indirect (yia 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
j impacts) typically yield llope values' in the range 3-5* about double the-slope
>, due to inhaled air lead albne, 1 ! ..
I <
11.4..2 Dietary Lead Exposures Including Water Another major pathway by which lead enters the body is by ingestion. As noted in Chap
ters 6 and 7, the recycling of both natural and anthropogenic lead in the environment results in a certain amount of lead being found in the food we eat and the water we drink. Both of these environmental media provide external exposures to lead that ultimately increase internal exposure levels in addition to internal lead elevations caused by direct Inhalation of lead in air. The Nutrition Foundation (1982) report presents a compilation of recent estimates of
11-106
DUP040012421
- - j' - !
iS \
location as covari.ables (1.32 0.38) are not significantly different from the pooled experi
mental studies.
Snee and Pfeifer (1983) have extensively analyzed the observational studies, tested the
equivalence of slope estimates: using poqled within-study and b.etween-study variance com
ponents, and. estimated the coipibo slope, the result of five population studies on adult males
(Azar, Johnson, Nprdman, Tsuchiya, Fugas) ]was an inhalation slope estimate 95 percent confi
dence limits of 1,4 0.6* For six populations of adult females fTepper-Levin, Johnson,
Nordman, Goldsmith, Oaines (spring), Daines.(fall)], the slope was. 0.9 0.4, For four popu
lations of children [Johnson (male!, Johnson (female), Yankel, Goldsmith!], the slope estimate
was 1.3 0,4. the between-study variance component was not significant for any group so de
fined, and when these groups were pooled) and Combined with the Griffin subjects., the slope
estimate for all subjects was 1,2 0-2. j
The Azar slope estimate, was not combined with the experimental estimates because of the
lack of control on non-inhalation exposures. Similarly, the other population studies in Table
11-35 were not pooled because of the uncertainty about both inhalation .and non-inhalation lead
exposures. These studies, as a group, ha^e lower slope estimates than the individual experi
mental studies.
l:
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 kir intake and blood volume. The assumption of proportional size Hs less plausible
for - children. Slope estimates for children from population studies have been used in which
i?
some other important covariates of "lead absorption were controlled or measured, e,g.,, age,
sex, and;dust exposure in the environment.or on the hands. Inhalation slopes were estimated
for the studies of Angle and Mclntire (l.2 0,60), Reels (2.46 0.58), land Yankel et al. (1,53 4-064). The standard error of the IYankel study is extremely low and ja weighted pooled'
slope estimate for children would .reflect essentially that study alone, iln this case the small standard error estimate is attributable to the very large range of ai.rjlead exposures of children jin the Silver Valley (up to 22 pg/m3). The relationship is in fact not linear, but increases; more rapidly in the upper range ,of air lead exposures. The slope iestimate 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,
This estimate was not combined with the child population studies of Johnson or Goldsmith, The Johnson study slope estimate used air lead measured at only two sites and is sensitive to assumptions about data outliers (Snee, 1981), which adds a large non-statistical uncertainty to the slope estimate. The Goldsmith slope estimate for children (2,0 0.65) is close to the estimate derived above, but was not used due to non-statistical uncertainties about blood lead collection and storage*
11-105
DUP040012422
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1( DUP040012423
TABLE 11*39. CROSS-SECTIONAL OBSERVATIONAL STUDIES ON CHILDREN WITH ESTIMATED AIR EXPOSURES
Note: PB8 stands fo r blood lead (tig /d l.); PBA stands fo r a ir lead fpg/m3); slope means ra te o f change o f blood lead per u n it change in a ir lead a t the stated a ir lead value. The 35 percent confidence in te rv a ls fo r the slope are given in parentheses. These are approximate and should be used w ith caution. The analyses labeled EPA"" are calculated from the o rig in a l authors1 data.
*d. f.= degrees o f freedom.
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11-103
DUP040Q12424
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TABLE 11-38. CROSS-SECTIONAL OBSERVATIONAL STUDY WITH MEASURED INDIVIDUAL AIR LEAD EXPOSURE
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11-102
DUP040012425
I.
1 -Analyst s
Aslhford et al. (1977)
j Kijng et al. (1979)
i
Gajrtside et al. (1982)
)
Bishop and Hill) (1983)
1 f
1
TABLE 11-37, A SELECTION OF RECENT ANALYSES ON OCCUPATIONAL 8-HOUR- EXPOSURES TO HIGH AIR LEAD LEVELS
Study y
Williams et al,, 1`569 Globe Union Delco-Remy
Factory 1, 1975 Factory 2a, 1975 Factory 3a, 1975
Delco-Remy, 1974-1976 1
Battery plants A
1975-1981
B
C
D
E
F
Air lead*, pg/m3 50-3DD
35-1200
10-350
20-170 2-200 7-170 7-195
20-140 4-140
81ood(1ead, pg/dT
40-90
.. - .... ' - 'v l...r .... 1 25-90. .
; i. ; 22-72;
i
12-50 18-72 22-60 ' 24-78 18-60 15-53
0 slope
0.19 0.10
/'
0.03:2 0.07
0.0514
Non!inear: at 50: 0.081 0.045 0.048 0.022 0.045
- 0.101
^Assumed B-hour exposure; divide by ,3 for 24-ho.uf equivalent.
those calculated similarly for the Rabinowitz study in Table 11-24 (2.14 0.47) and the Kehoe study in Table 11-25 (1.25 0.35, jsetting subject DH ~ O')., yielding a pooled weighted slope esjtimate of 1.64 i 0.22 pg/dl per gjg/m. There are some advantages i|n using these experi.mentail studies-on adult wales, but certain deficiencies need to be acknowledged. The Kehoe study exposed subjects to a wide range of) exposure levels while they were jin the exposure chamber, bujt did not control air lead exposures outside the chamber. The Gri'iffin study provided rea-
sopable control of air lead exposurfe during the experiment; -but difficulties in defining the non-inhalation baseline-for blood lead (especially in the important, experiment at 3.2 pg/m3) add much uncertainty to the estimate. The Rabinowitz study controlled well for diet and other factors and since they used stable lead isotope tracers, they had no baseline problem. How ever, the actual air lead exposure of these subjects outside the metabolic ward was not well determined.
Among population studies, only the Azar study provides a slope estimate in which air lead exposures are known for individuals. 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
.11-101
DUP040012426
TABLE 11-36. CHARACTER!STICS OF STUDIES ON Tfe RELATIONSHIP BETWEEN AIR LEAD AND BLOOD LEAD IN CHILDREN Soiirca: from Bruhekreef (1384}.
'}
41
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11-100
DUP040012427
I
n
A comprehensive review of studies of blood lead levels in children is presented by
Brunekreef (1984). Many of the studies did not include co.variates by which air lead slopes
could be adjusted for dust or soil ingestion an^l other factors, leading to aggregate estimates
of air lead impacts (direct and indirect) on blood lead levels, the results of some of the
studies reviewed by Brunekreef i;are summarized in Table 11*36. Studies selected for/fable
11-36 are those with identified, air monitoring methods and reliable blood lead data. The range of p values that Brunekreef (1984) reports is very Targe, and typical values of 3-5 are
larger than those adjusted slopes (1.52-2.46) derived ;by PA in preceding sections. If the
aggregate approach is accepted,'then the blo.oc lead versus, total (both direct and indirect)
air lead slope for children may be approximately double the slope (~2.Q) estimated for the l
direct contribution due to inhaled air lead alofie.
There, is a great deal of information on iblpod lead responses to air lead exposures of
workers in lead-related occupations. Almost all such exposures are at air lead levels far in excess of typical non-occupational exposures. iThe blood lead versus air lead slope p is very
much smaller at high blood and air levels. Analyses of certain occupational exposure studies
are shown in Table 11-37.
j
11.4,1.TO Summary of Blood Lead versus Inhaled! Air bead Relations. Any .summary of the rela
tionship of blood lead level and air lead exposure is complicated by the need for reconciling
the results of experimental and .observational studies. Further, defining the form of the sta
tistical re!atiUnship is problematical due to the lack of consistency in the range and accu
racy of the air lead exposure measures in the various studies.
',
1
PA has chosen to emphasize the results of studies that relate lead in air- and lead in
blood under ambient conditions.. At low air lead exposures there is no statistically signifi
cant difference between curvilinear and linear]blood lea'd inhalation relationships. Colombo (1985) states! that on the basis of experimental biological evidence, theory cdn' provide a
steady-state relation of . blood Pb to air Pb wijth a curved response and that the jexi.sting P.bB
vs. PbA data iare such that they can be fitted] by several algebraically different PfoA func
tions, including a linear relationship, Colombo concludes, however, that the linear model is
preferred because it is consistent with other published models and it is much simpler in its
application. Therefore EPA has fitted linear relationships (Tables 11-38, 11-39, and 11-40)
to blood lead levels in the studies to be described next with the explicit understanding that the fitted relationships are intended only to describe changes in bipod lead due to modest
changes (of <3.0 pg/m3) in air lead among individuals whose blood lead levels do not exceed 30 pg/dl.
The blood lead inhalation slope estimates vary appreciably from one subject to another in
experimental and clinical studies, and from one study to another. The weighted slope and stan
dard error estimates from the Griffin study in Table 11-21 (1.75 0..35) were combined with
11-99
DUP040012428
and 457 jn and in which the subjects were white upper middle class women:. The air lead levels*
were trivially different at these two distances, and the blood lead levels did not differ
either. Because the residents nearest the road'were already 33 in.from.the highway, :the dif
ferences in air lead may have been insufficient to be reflected in the blood lead levels (sec
Chapter 7).
s
1;; ,` ^ .*
A`summary of linear relationships for other population; studies has been extracted from
Snee (.198 and jis shown in table 11-35. The Fugas study is described later: in. .Section
11,5.1.3. There is a large range of Slope values (-0.1 to:3,l) with most studies in the range
of 1,0-2.0> .Additional information on the more directly relevant; .studies is given in' the
Summary Section Ij..4..1.10,
'; '
.
T^BLE 11-3.5. BLOOD LEAD-AIR LEAD S.L0PE5 FOR SEVERAL POPULATION
i STUDIES AS CALCULATED BY SNEE .
________
' ''#
Study
No. i subjects
Tapper & Levin
(1975) Johnson et al.
(197*5)
|
! !
Nordman (1975)
Tsuchiya et al.()975) Goldsmith (1974)
Fugas (1977) Daines et al. (197.2)
i
Johnson et .al* (1975)
i!
1935
65
96 .536 478 537
.89 79 352 61
ss. 37a
43
Goldsmith (1974) i
.486
Sex
Female
M.al e
Female
Mai e
Female
Hale
!
Male !
Female
\
Male
Female
'
(spring) j
Female (fall)
Mai e
(children) ]
Female
1
(children) !
Male & femalje
(children) |
Slope
1.1 `
. .0.8 .
0.8 1.2 0.6 3,1 -0.1 0.7 2.2
1.6 . 2,4
1.4
l.l
2.0 ` .
95% confidence intervai l
1.81 1
0.7 :
0.6 1.0
0.9 2.2 0.7 0, 7 0.7
1.7 ; 1.2'!
" 0.6 . i
0.6 5
!,3 ,
aOutlier results for four subjects deleted. Source: Snee, 1981.
11-98
DUP040012429
1
The high school students with the highest blood lead levels did not come from the town with
the highest air lead value. However, a considerable lag time occurred between the collection
and analysis of the blood -samples.' In one of the cpmmun.ities the'blood sattipTes were reffig- .
erated rather than frozen. \ i
Another California study (Johnson et at,, 1975., 1976) examined blood lead levels in rela^ :
tion to exposure to- automojtive lead in two communities, Los Angeles and .Lancaster (a city in ; the high desert). Los Angeles residents studied were individuals living in the vicinity of j.
heavily traveled freeways thin the city. They included groups-of malesand females, aged 1 through 16, 17 through ,34,j and 34 and over. The persons selected' from Lancaster represented \
Similar age and sex distHputipns. On two Consecutive days, bipod, urine, and fecal samples
were collected. Air samples were collected from one hi-vol sampler in Los Angeles, located;
near ,a freeway, and two sujch samplers in Lancaster. The Los Angeles sampler collected for 7 :
days; the two in Lancaster' operated for 14 days. Soil .samp! e% were coll acted in each area in';
i: ^
]
the vicinity of study subjects.
Lead in ambient air along the Los Angeles freeway averaged 6.3 0.7 pg/n?3 and, in the
Lancaster area, the average was 0.6 0.2 pg/m3. The mean soil lead in Los Angeles was 3633 j pg/.g, whereas that found ijn Lancaster- was 66.:9 pg/g, Higher blood lead concentrations were 5 found in Los Angeles residents than in individuals Hying in the control area for all age.
groups studied. Differences between Los Angeles and Lancaster groups were .significant-with
the sole exception of the older males... Snee (1981) has pointed out a disparity between blood samples taken on consecutive days from the same child in the study. EPA reanalyses using other criteria for outlier detection and removal obtained different inhalation slopes. This
calls into question the validity of using this study to quantify the air lead to.blood lead .
relationship,
j
. .1 .
:!
Dairies .et al. (1972) 'Studied black' women living near al heavily traveled highway in New j
Jersey, the subjects lived in houses on streets paralleling the highway at three distances: )
3.7, 38.1, and 121.9 m. Ai]f lea d as well as blood lead levels were measured. Mean annual air j1 lead concentrations were 4-.60, 2.41, and 2.24 pg/m3, respectively, for the three distances. .;
The mean air lead concentration for the area closest to the highway was significantly differ- ,
ent from that in both the second and third, but the mean air lead concentration of the third area was not significantly different from that of the second. The results of the blood lead
determinations paralleled those of the air lead. Mean blood lead levels of the three groups
of women, in order of increasing distance, were 23,1, 17,4, and 17,6 pg/dl, respectively.
Again, the first group showed a significantly higher mean than the other two, but the second
and third groups' blood lead levels were similar to each other. Oaines et al, (1972), in the same publication, reported a second study in which the distances from the highway were 33.5
L > 1 '=
:
11-97
DUP040012430
rr
.. lit.
'
- ' - i
!
;'
i "\n.........' '
i
j ilf;
:-
'* TABLE 11-33. GEOMETRIC MEAN AI.R LEAD AND ADJUSTED BLOOD LEAD LEVELS FOR 11 COMMUNITIES
IN STUDY OF TEPPER AND LEVIN (1975) AS REPORTED BY HASSELBLAD AND NELSON (1975)
Community
Geometric mean air lead, pg/m3
Age and smoking :
adjusted geometric
mean blood lead,
pg/di
;
-- ^^....................
SainpT.e / size
Los Alamos, NM
0.17
15,1'" '1 | `
18$
OReana, OH
0,32
16.1
|
156 ' ;
Houston, TX
0,85
12.7
;
186
Port Washington, NY
1,13
15.3
196
Ardmore, PA
1.15.
17.9
v
148
Lombard, IL
1.18
14.0
:
204
Washington, DC
1.19
18.7
j
219
Philadelphia, PA
1,67
20.1
;
136
Bridgeport, IL
1.76
17.6 \ ;
146
Greenwich Village, NY
2.08
16.5
139
Pasadena, CA
3.39
17.6
194
s
j.;.
|
i
.
Multiple R3 = 0.240
..
Residual standard deviation ~ 0.2.62 (geometric standard deviation = 1.30)
TABLE 11-34. Zones
MEAN AIR AND BLOOD LEAD VALUES FOR FIVE Z!]ON..E..S....I.N....T..O..K..Y..O.....S..TUDY
Air lead pg/m3
i Blood lead. pg/100 g
l!
0.0.24
' 17.0
2
0,198
17.1
3
0.444
16.8
4
0.831
18.0
5
1.157
19.7
Source: Tsuchiya et at. 1975.
11-96
-9
DUP040012431
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
jC-
for environmental 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.,
Brunqkreef (1984) make a strong argument for the use of air lead as! the .single exjjpsura .
criterion. Their argument is that exposure to air lead is usually, of sufficient duration that 5" 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
t
, - ''
i
' - ...
other, proportional increments must be much larger than for air lead by direct inhalation
alone-
j
The following studies provide information on the relationship of blood lead to air lead
exposures using aggregate analyses that include both direct and indirect air inputs, The first;'group of studies are population studies which typically employed less accurate estimates of individual exposures. The second group .of studies represents industrial exposures at. very
:
high irair lead levels in which the response of blood lea. d appears to be su! bstantially different
than jat ambient air levels.
j
jThe Tepper and Levin (1975). study included both air and blood lead .measurements. House-*
wives were recruited from locations in the vicinity of air monitors. Table 11-33 presents the
geometric mean air lead and adjusted geometric mean blood lead values for this study. These
values were calculated by Hasselblad an1d Nelson (1975). Geometric mean air lead values ranged from 0.17 to 3.3$ pg/tn3, and geometric;,mean blood lead -values ranged from 12.7 to 20,1 pg/dl.
Mordman (1975) reported a population study from Finland in which data from five urban and
two rural areas were compared. Air Ijaad data were collected by stationary samplers. All levels were comparatively low, parti culjirly in the rural environment, whejre a concentration of
0.025! pg/m3 was seen'. Urban-suburban levels ranged -from 0.43 to 1/32 pg/m3.
-Ai study was undertaken by Tsuchiiya et al. (1975) in Tokyo. using'j male policemen who workeji, but not necessarily lived, in t|e vicinity of air samplers. In this study, five zones
were established based on degree of urbanization, ranging from1central city to suburban. Air
monitors were established: at various police stations within each zone, j^ir sampling was con
ducted from September, 1971 to September, 1972; blood and urine samples were obtained from 2283 policemen in August and September, 1971, Findings are presented in Table 11-34.
Goldsmith (1974) obtained data for elementary school (9- and 10-year-olds) and high
school students in 10 California communities. Lowest air lead exposures were 0.28 pg/m3 and
highest were 3.4 pg/m3. For boys in elementary school, blood lead levels ranged from 14.3 to
23.3 pg/dl; those for girls ranged from 13.8 to 20.4 pg/dl for the same range of air lead ex
posures. The high school student population was made up of only males from some of the 10 towns. The air lead range was 0.77-2.75 pg/m3, and the blood lead range was 9.0-12.1 pg/dl.
11-95
DUP040012432
i
1 i
Total lead content per hand is probably more directly related to ingested lead than is the lead concentration in the hand dust. The linear regression model used above was fitted by PA using lead in air (pg/m3), lead in hand dust (pg/hand),.. lead in playground dust (pg/g), and sex as covariates of blood lead. The Head variables were highly.correlated, resulting in a statistically significant regression butj not statistically significant coefficients.,1 Thus the playground dust measurement was dropped and the following model, obtained with almost as small a residual sum of squares,
In(Pb-Blood) = ln(7.37 t .2.46 Pb-Air + 0.0195 Pb-Hand + .2.10 Male)
(.45)*
(.58)*
(.0062)*
(0.56)*
*Standard error of estimatedjregression coefficients.
(11-17)
The fitted model for the 148 observations! gave an R2 of 0.4654 and a mean square error (S2) of 0.0836 (650 = 1.335). The significance of the estimated coefficient establishes that intake of lead-bearing dust from the hands! of children does play a role in childhood lead ab sorption over and above the role that canjbe assigned to inhalation of air lead. Individual
i habits of mouthing probably also affect 1dad absorption along this pathway. Note too that the estimated inhalation slope,.2.46, is somewhat larger than most estimates for adults.. However, the effect of ingestion of hand dust appears to be almost as large as the effect of air lead inhalation in children of this age (9-14 years). Reels et al. (1980), using group means, concluded that the quantitative contribution of hand lead to children's blood lead levels was far greater than that of air lead
The high mutual correlations among air, hand, and dust lead suggest jthe use of their principal; components or principal factors ias predictors. Only the first principal component (which accounted for 91 percent of the total) variance in lead exposure) proved a statistically significant covariate of blood lead. - In this form the model could be expressed as:
i 'i
In(Pb-BTocd) = ln{7.42 + l-56Pb-Air + 0. 0120Pb"Hand + 0.00212Pb-Dust + 2.29 Male) .(11-18)
The estimated standard error on the inhalation slope is 0.47. The difference between these inhalation slope and hand lead coefficients is an example of the partial attribution of the effects of measured lead exposure sources to those sources that are not measured. 11.4.1.9 Other Studies Relating Blood Lead Levels to. Air Exposure.
The present chapter has thus far evaluated 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
11-94
DUP040012433
i is .
TABLE 11-32. MEAN AIRBORNE AND BLOOD LEAD LEVELS RECORDED DURING FIVE DISTINCT SURVEYS (1974 to 1978) FOR STUDY POPULATIONS OF 11-YEAR-OLD CHILDREN LIVING LESS THAN 1 km OR 2.5 km FROM A LEAD SMELTER, OR LIVING IN A RURAL OR URBAN AREA
Study populations 1 Survey
(1974)
2 Survey (1975)
3 Survey (1976)
4 Survey (1977)
5 Survey (1978)
Setting
< 1 km 2.5 K Rural
Pb-Air, pg/m3
4.06 1.00 0.29
Bloods 1 ead concentration, uq/dl
' Total Population
. BdyS'
n.
Mean .sp .,
1i
n ' Mean SO .
D1
.37
~r
> 92
30.1 5.7 ; 14 1 14
9,4 + 2.1 j 28
31.0 5,5 21.1 3.4
9.7 1.6
23
--
64
/ Girls Mean + 50
29,6 5.9
--
9,3 .+ 2,2
<1 km 2.5 km Rural
2.94 0.74 0,31
40 29
* 45
26.4 7.3 ! 19 13.6 3.3. ] 17
9.1 3.1 j 14
27,4 -6.5 14,8 +'3,6
8.2 2.1,
21 25.4 8.1 12 11.9 1.9 31 9.5 3.4
<1 km 2.5 ton Urban Rural
<1 km 2.5 km
3,67 0.80 0,45 0.3D
3.42 0.49
.38
i 40
i-
26 44
56 . 50
24,6 8.7 l 18'
13.3 4.4 ! 24 10.4 2.0 S 17 9.0 2,0 ti 21
28.9 6.5 ! 27
14,8 4,7 1 .34
23W 8,0
15,6 : 2.9 lO j 6 * 2,0 9.2 + 2.3
31.7 9.5 15.7 4,8
20 20.8 7,6
16 9.8 + 3,8 9 9.9 2.0
23 8.7 1,7
29 26.4 + 8.7 16 13.0 4.3
< 1 km 2.5 km
-Urban Rural
2.68 0,54
0,56 0.37
43
' 36
29
42
27.8 i 9.3
16.0 + 3.8
12,7 3.1 10.7 2.8
20 29.3 9.8 26 16,6 3.5
18 13,4 2.3 17 11.9 3,0
23 26,5 8.9
10 14.3 4,2 11 11.5 '4,0
25 10,0 ;2.4
Source: Roels et a). (1980).
I
.
I`
!
i
The researchers then investigated the impb.rtancej of the various sources of lead in} deter
mining blood lead [levels. Data "were available fronj the 1976 survey on air, dust, and hand
lead levels. Boys had higher hand dust'lead than giris. . Unfortunately,, the regression! analy
ses performed on thise data were based on the group mians of four groups.
{
EPA has reanalyzed the 1976 study using original data provided by Or, Roels on the 148 children. The air[lead, playground dust lead, and band lead concentrations were all:highly correlated with each other. The hand lead measurements are used here with due regard for their limitations, because day-to-day variations in hand lead for individual children are believed to be Very large. However, even though repeated measurements were not available, this is among the most usable quantitative evidence on the role of ingested hand dust in childhood lead absorption.
11-93
DUP040012434
!i . }
I
Air lead! levels o ecreased from area A to area B, At both sites the airborne lead levels
declined over the two years of monitoring. The amount of lead produced at this smelter during
this time remained constant, about 100,-000 metric tons/year. The median air lead level at the
closer site (A) dropped from 3.2 to 1.2 pg/mf, while at the far site (B) the median went from
1,6 to 0.5-0.8 gg/m3,.. The rural area exposure levels did not vary over the study Period,
remaining rather constant at about 0.3 pg/m3.
x
Both smelter vicinity groups showed signs of increased lead absorption relative to -the
rural population. Blood lead levels for group Ik were about three times those for the rural
population (26 versus j9 pg/dl). The former blood lead levels were associated with about>4 50
percent decrease in AL1jA-D: activity and a 100 percent increase in FEP concentration, HowevI jer, FEP levels were not different for group B and rural area residents.
Later surveys of)children (Roels etal., 1980) were conducted in 1976, 1977and 1978;
the former two in autumn, the latter in spring. In total.there were five surveys conducted yearly from 1974-1978,! A group of age-matched controls from a rural area was studied each
time except 1977. In 1976 and 1978 an urban group of children was also studied. The overall age for the differentjgroups ranged from 9 to 14 years (mean 11-12). The length of residence
varied from 0.5 to 14jyears'(mean 7-10 years). The subjects were, always recruited from ithe
same five schools: one in the urban area, one in the rural area and three in the smelter area (two <1 km and:, one, 2.5 km away). In all, 661 children (328 boys and 333 girls) were studied
over the years. Two hundred fourteen children came from less than 1 km from the smelter, 169 children from 1.5 to 2.5 km from the. plant, 55 children lived in the urban area, and 223 chil dren lived in the rural area.
Air lead levels decreased from 1977 to 1978. However, the soil lead levels in the vicin ity of the. smelter wetje still elevated (<1 km, soil lead = 2000-6000 gg/g). Dustfall lead' in
the area of the near ischaols averaged 16-. 4-22.0-mg/m2* fey at 500 m from the stack, 5.817.2
mg/m2*day at 700 m, about 2 mg/m2*day at 1000 m, and fluctuated around 0,5-1 mg/m2*day at 1.5
km and beyond. The pjarticle sire was predominantly 2 jjm in diameter with a secondary peak between 4 and 9 pm, '.The particle size declined with |increasing distance from the smelter
(0.7-2,4 km).
i
-
J
The air lead and blood lead results fo'r the five years are presented as Table 11-32. The
reported air leads are not calendar year averages. The table shows that bipod lead levels (electrothermal atomic absorption spectrophotometry) are lower in the girls than the boys.1'
Within 1 km of the smelter no consistent improvement in air lead levels was noted over the
years of the study. The mean blood leads for the children- living at about 2.5 km from the
smelter never exceeded 20 pg/dl since 1975, although they were higher than for urban and ruralchildren.
11-92
DUP040012435
Angle has reanalyzed the Omaha study (Angle et al., 1984) using all of the data on chil-
dren from all years. There were 1Q75 samples from which blodd ]ead..(pg/dl),,sir:v(pg/m3), soil
(pg/g), and house dust {pg/g) 'lead were available. The linear regression model, fitted in
logarithmic form, was
K
' ...
:> '
-v c*.-..-
...
~
.
Ml Pb-Blood = 15.67 * )U92 Pb-Air + 0.00600,Pb-|gil + 0.00718 Pb-Houffi Host
(11*16)
.? } v|
S'
u-
'\
(40,40) ! (0.60)=.
(4Q 00097ji
' (0.00090)
^:
|;
(N 1= 1075, .R* W 0..-20, S2 = ol090i, 650 *llv35); ^
. ... -,'
';
Similar models fitted by age Jcategory produced.
possibly due to
small ranges pf variation in air lead within certain age categories-;,;;
11.4.1,8 Roels et al. Studies) Roels at al, (1976, 1978, llfeO) have conducted a series of
studies in the vicinity of a lead smelter in Belgium, Roels et al, (1980) report a follow-up
study in 1975 that included study populations from a rural-nonindustrialized.area as well as from the lead smelter area- Jlhe rural group consisted of 45 children (11-14 years). The
:j "i j
i \
smelter area group consisted df 69 school children from three, schools, .These chil .dren were
divided into two groups; group A (aged 10-13) lived less than 1 km from,the smelter and their
.schools were very close to the smelter; group B consisted of school children.living more than
1.5 km from the smelter and attending a school more distant frpm Ithf smelter.
In .1974 the smelter emitted 270 kg of lead-and the air lead levels were 1-2 orders of
magnitude greater than the current Belgian background concentration for air lead (0.2.3 pg/m3).
Soil and vegetation were also; contaminated with lead; within 1 km the soil lead level was
.12,250 pg/g. The eoncentratipnjof lead in drinking water was less than 5 pg/1.
.
Environmental assessment ijngluded air, soil, and .dust, Air" monitoring for lead had been
continuous since September, 19ij3 at two sites, one for .each of |"he two groups,,. In the rural
area, air monitoring was done at two sites for five days using membrane pumps. Lead was ana
lyzed by flame!ess atomic absorption spectrophotometry. Dust and soil .samples were collected
at the various school playgrounds, and Were also apalyzed by flameless atomic absorption. A.
25 ml blood sample was collected from each child and immediately divided among three tubes.
One tube was analyzed for lead content by flameless atomic absorption with background correc
tion. Another tube was analyzed for ALA-D activity while the third was analyzed for FEP. FEP
was determined by the Roels modification of the method of Sassa, ALA-D was assayed by the
European standard method.
:
11-91
DUPQ40012436
,) ! 1 . ... 1.
> TABLE 11-31, AIR, OUSTFALL AND BLOOD .LEAD CONCENTRATIONS IN OMAHA, NE STUDY, .1970-I97:7a
;Croup
Ai r ' pg/m3 (N)b
Dustfall, _ pg/ra3 - mo (N)c
i ;
All utlbarj children mixed commercial and residential site
`1970-71 i1972-73 .1974-75 : 1976-77
1.48 0.14(7;65) 0.43 0.08(8;72) 0.10 0.03(10;72) 0.52 0.07(12;47)
10.6 + 0,3(6) 6,0 0-1(4). 8,8 (7)
1 ) J
Children at school in a cp.aane.rcial site
J1970-71
11972-73 i 1974-75 1976-77
1.69 0.11(7;67) ~0,63 0.15(8;74)
0.10 0.03(10;70) 0,60 0.10(12;42)
All suburban children in a residential site
1970-71. 1972-73
11974-75 1976-77
0.79 0.06(7;65)
0.29 0.04(8;73} 0.12 0.Q5(10;73).
. .
1
-
25,9, 0.6(5)
14.3 4.1(4)
33,9
(7)
\ i i !
i
--
.4.6+ 1.1(6) 2.9 0.9(4)
j !
Blood, . pg/dl (NF
s
31.4 + 0.7(168) 23,3 0,3(211) 20.4 .+ 0.1(284) .22.8 0.7(38)
34.6 1.5(21) 21,9 0.6(54) 19.2 0.9(17) 22.8 0.7(38)
19.6 0.5(81) 14.4 + 0.6(31) 18.2 + 0.3(185)
aBlood lead 1970-71 Is by the macro technique, corrected for an established
laboratory bias of .3 pg/dl, macro-micro; all other values are by Delves micro L assay. N = Number of months; number of 24-ho.ur samples.
CN - Numberof months. H> jN = Number of blood samples.
| j
, j. '
Source: Adapted from Angle and Mcintire, 1977".
;
i || 4/ere 0, 31 and 0.29, respectively. I Air, dust, and soil lead measurements at 37 sites were im
puted to all children in the vicinity.
.
I Suburban 10- to! 12-year-olds lhad lower blood lead levels than itheir urban counterparts,
17.1 0.7 versus 21.7 0.5 pg/dl (Angle et al., 1974). Air lead exposures were higher in
the urban than in the suburban population., although the average exposure remained less than 1*
pg/ra3. Dustfall lead measurements, however, were very much higher; 32.96 mg/m2/month for ur
ban 10- to-12-year-olds versus 3.02 mg/m2/month for suburban children.
Soil lead and house dust lead exposure levels were significantly higher for the urban
black high-lead group.than for the urban low-lead group.. A significant correlation (r = 0.49)
between blood lead and soil lead levels was found.
11-90
r DUP040012437
1
t
! '; f i
1 '1
Yartkel et al. (1977), Walter et al. (1980), and Snee (1982c) make reference to a follow
up study conducted in 1975^ The second study was undertaken to determine the`effectiveness of
control and remedial measures instituted after the 1974 study. Between August, 1974 and
August, 1975, the mean annual air lead levels decreased at .all stations monitored. In order
of increasing distance from the" smelter, the annual me.anf! air' lead levels for the Ohs'year
preceding leach drawing were 18.0-10.3 pg/m3, 14.0-8.5 pg/m3,; 6.7-4.9 pg/m3, and 3.1-2.5 pg/m3
at 10-24 km. Similar reductions were noted in house dust lead concentratiend. In a separate report, v<pn Lindern and Yankel (1976) described reductions in blood lead let/els of children
for whom cjetermi nations were made in both years. A number of factors, .complicate the interpre
tation of ithe followup study, including the changes in time-varying concentrations of air lead
(Figure lij-20) from 1974 to 1975, and relocations of residence. The results demonstrated that
significanjt decreases in .blood lead concentration resulted from exposure reductions.
11.4.1.7 iOrhaha., Mebraska Studies. Exposure from both a primtfrv and secondary smelter in the
inner city area of Omaha, Mebraska, has bjeen reported in a series of publications (Angle et al., 1974;! Angle and Mclntire, 19^7, 1979; Mclntire and Angle, 1973). During 197Q-1977, chil-
dren were studied from these areas: an urban school at a site immediately adjkcent to a small battery pljarft and downwind from two other lead emission sources; from schools, in a mixed com
mercial-residential area; and from schools in a suburban setting. Children's blood lead
levels by venipuncture were obtained by macro technique for 1970 and 1971, but pelves micro
assay was used for 1972 and later. The differences for the change in techniques were taken
into account in the presentation of the data. Air lead values were obtained by hi-vol sam
plers and dustfall values were also monitored. Table 11-31 presents the authors' summary of
the entire.; data set, showing that as air lead values decrease-and then increase, dustfall and
blood lead]values follow. The authors used regression models, both log-linear land sending, to
calculate (air -lead)./(blood 'lead)-,. . .
-' '
'Specific reports present various aspeetjs of the work. Black children injthe two elemen tary. schools closest to the battery plant hid higher blood leads (34.1 pg/dlj than those in
elementary-and junior high schools farther away (2.6.3 pg/dl). Best estimates of the air ex
posures -were 1.65 and `1.48 pg/m3, respectively (Mclntire and Angie, 1973), The latter study
compared three populations: urban versus suburban high school students, ages 14-18; urban black children, ages 10-12, versus suburban whites, ages 10-12; and blacks ages 10-12 with
blood lead levels over 20 pg/dl versus schoolmates with blood lead levels below 20 pg/dl
(Angle et al., 1974). The urban versus suburban high school children did not differ signifi
cantly, 22.3 1,2 and 20.2 7,0 pg/dl, respectively, with mean values of air lead concentra
tions of 0.43 and 0.29 pg/m3. For 15 students who had environmental samples taken from their
homes, correlation coefficients between blood lead levels and soil and housedust lead levels
11-89
OUP040012438
11-88
DUP040012439
"!
TABLE 11-30. ESTIMATED COEFFICIENTS* AND STANDARD" ERRORS FOR THE IDAHO SMELTER STUDY
Factor
. Coefficifipt . ..
Asymptotic . standard .error'
Intercept (pg/dl) .
13.19 '
1.90
Air lead (pg/m3)
1.53
0,064
Soil lead (1000 pg/g)
1.10
0.14
Sex (male=l, female=0)
.1-31
. 9-59
Pica (eaters=l, noneaters=D)
2.22
0.90
Education (graduate training=0)
At least high school No high school
3.45 4.37
1.44 1.51
Cleanliness of home (clean=0) Moderately clean Dirty
3.00 6.04 ;
_
Age (1 year old=0) ,2 years old 3 years old 4 years old
5 years old 6 years old
7 years old 8 years old 0 years old
4.66 5.48 3.16
2,82 2,740,81 -0.19 -1.50 !
Work-status (no exposure^O) Lead or zinc worker
i 3.69 i
..
!.................................... ' "
4--..-..- - ...
} ' :
Residual standard devihtiotj - 0.2576 (geometric standard:deviation - 1.29),
Multiple R2 = 0.662. ;
.
|
Number of observations= 860, ^Calculations made by EPA.
0.65 i.06
1.48 1.32 1.32 1.25 1.24 1.23 1.28 1.21
0.61
, -|
2 '
11-87
DUP040012440
H, i... . '
I
blood lead level ~ 10 percent higher than .a' child in a'home with a "low" dust level, .other* `
factors being comparable.
1
The coefficients for soil lead - blood lead relationships exhibited a fairly regular pat
tern:, being highly significant (p <Q.0i) for ages 3-6 years, and significant (p <0.05} at ages. }
2-6 years. The maximum coefficient {at age 6) indicates a 4 percent increase in blood lead
per 10.30 pg/g increase in soil lead.
-
Pica (coded absent ~ 0i present ~ 1) had a significant effect at age 2 years, but was in- i
significant elsewhere; at age 2 yearSj an approximate 25 percent elevation in blood lead is
predicted in a child with!pica, compared with an otherwise equivalent child without pica.. \
Parental occupation we|s significant at ages 5, 6, and 8 years; at the other ages, how- ' ever, the sign of the coefficient was always positive, consistent with a greater lead burden ' being introduced into the hf>m.e by parents working in the smelter complex,
finally, sex (coded maile 0; female = 1) had a significant negative coefficient for ages i
8 and 9 years, indicating'ithat boys would have lead levels 15 percent .higher than girls at ;
i
'
[
this age, on the average. .This phenomenon is enhanced by similar, but nonsignificant, nega- :
tive coefficients, for ages 5-7 years-.
-\
Snee (1982c) also reanalyzed the Idaho smelter data using a log-linear model. He used !
dummy, variables for age, work status of the father, educational level of the father, and ;
household dust level (cleanliness). The resulting model had a multiple R2 of 0.67 and a resi
dual standard deviation of 0.250 (geometric standard deviation of 1.28), The model showed
that 2-year-olds bad the highest blood lead levels. The blood lead inhalation slope was es
sentially the same as that of Yankel et al. (1977) and Waiter:et al. (1980).
The above non-l inear analyses of the Idaho smelter study are the only analyses which sug
gest that the blood lead tolair lead slope increases-with increasing air lead, contrary to the ] findings of decreasing, slopes seen at high air- lead exposures in other studies. An alterna- )
tive to this would be to attempt to fit a linear model as described in Appendix ll-B. Expo- ;
sure coefficients were estimated for each of the factors shqwh in Table .11-30. The results ; for the different eovariates are similar to those of Snee (1982c) and Walter et al, (1980), '
Because the previous analyses noted above .indicated a nonlinear relationship, a similar,
model with a quadratic air'lead term added was' also fitted. The coefficients for the other
factors remained about the same, and the improvement in the model was marginally significant
(p ~ 0,05). This model gave a slope of 1,16 at an air lead of 1 pg/m3, and 1.39 at an air*
lead of 2 pg/m3. Both the linear and quadratic models, along with Snee's (1982b) model are
shown in Figure 11-21. The points represent mean blood lead levels adjusted for the factors
in Table 11-30 (except air lead) for each of the different exposure subpopulations.
3
11-86
DUP040012441
,3>....... ID
Yankel et al. (1977} fitted tlje data to the following model.
' ' .5
In (bipod lead) - 3.1 + 0 04,1 air lead + (2.1 x ID ..soil lead).-
I + 0.087 dustiness " 0.018 age
,
= i + 0.024 occupation
(1:1-15)
where air lead was in pg/m3; soil lead was in pg/g; dustiness was 1, 2, or 3; age was in
years; and occupation (parental) Was a Rollingshead index. . The -analysis included 879 sub
jects, had a multiple R2 of 0.622, and a residual standard deviation of 0.269 (geometric
standard deviation of 1.31)>
j
Valter et al. (1980) used a .^i mi Tar model toexanrine age specific differences of the re
gression coefficients for the different variables.. Those coefficients are summarized in Table
j
11-29:. The variable that was most significant overall was air lead; its coefficient was ap
proximately the same for all ages,i corresponding to a change in blood lead of about 1 pg/dl
per unit increase of air lead (in |j|g/ffl3) at an air exposure,of 1 pg/m3 and about 2.4 pg/dl per
unit increase in air at an air exposure of 22 pg/m3.
TABLE 11-29. AGE-SPECIFIC REGRESSION COEFFICIENTS FOR THE ANALYSIS OF ' LOG (BLOOD LEAD) LEVELS IN THE IDAHO SMELTER STUDY
Air Dust
l 0.0467* 0,list
b 0.0405* 0.106f
3 0.0472* 0.108t
4 Q,, 036.6* 0.lO7t
fr ' 0.. 03.88* 0.052
6 0. 0.361* 0.070
7 0.0413* 0.053
$ O.04O7* 0.051
9
i
0.0402* o.osit
*ip'-O.01
t p <0.05
Soil ;
Occupation
Pica
Sex
(xlO4)j
0.0323
0.0095
0.0252 0.0348 0.036.3t O.OBSSf 0.024b
0.042?f 0.0087
0.098 0.225*
0.077 0.117 0.048 ' 0.039 0.106
0.010 0.108
0.055 0.002
0.000 0.032 -0.081 ` -0.092 -0.061
-0.106t -0.158*
3.5 i
20.6t ` 24.2* i 32.1* j 23.4* j
38.4* i
21.3t i 16.2 ! 11.6 s
Intercept N
3.017
98 '
3.5.67
94
3,220
115
3,176
104 ,,
3.270
130
3.240 120
3.329 .113
3.076
105
3.477
104
'
The next most important variable that attained significance at a variety of ages was the household dustiness level (coded as low = 0, medium = 1, or high = 2), showing a declining effeet with age and being significant for ages 1-4 years. This suggested age-related hygiene behavior and a picture of diminishing home orientation as the child develops. For ages 1-4 years, the coefficient indicates the child in a home with a "medium11 dust level would have a
11-85
DUP040012442
I!
TABLE 11-27. GEOMETRIC MEAN BLOOD LEAD LEVELS BY AREA COMPARED WITH ESTIMATED AIR LEAD LEVELS FOR 1- TO 9-YEAR OLD CHILDREN
LIVING NEAR IDAHO SMELTER,. (GEOMETRIC, STANDARD DEVIATIONS, ' SAMPLE SIZE, AND DISTANCES FROM-SMELTER ARE ALSO GIVEN)?
l
Area 11 .
1i
21 i 3{
Geometric mean blood lead, pg/dl
55.-9
. 47,7
33.8
GSD 1,30 1.32 1.25
Sample size
170 i ;
192 ;
174 :
4j
32.2
1.29
156
5i
27,5
1.30
188
6: i
21.2 . 1.29
.90-
aEPA |nalysis of data from Yankel at al. (1977).
% blood lead
(>40 fjg/dl)
98.9
72.6
21,4
17.8 ' 8.8 r
1.1
Estimated air lead,:
(gg/m3) :j
, 18.0 j.
jj,a
8-7 3.1 ;' 1.5
t:
j
1' } j
1.2: . | .5 l .
Distance from smelter. Km
0- 1.6
1,6-'4.0
4.0-10.0
10.0-24.0
24.0-32.0
about 75
TABLE 11-28. GEOMETRIC MEAN BLOOD LEAD LEVELS BY AGE AND AREA FOR SUBJECTS LIVING NEAR THE IDAHO SMELTER
(microigrams per deciliter)
Age group:
Area > ..!
i! 2 3i 4j 5! 6j .7 i
'!
i
21 3
4
69* 72
75 75
50 51
55 46
33 . 36- .36 35
31 35
34 31
27 35
29 29
21 25
22 23
28 30 , 28 32 1
5 \6
7
68 t6 49 50
63 47
35 85 ` 31
31 85 30
29 28 25
20 22 20
30 26 37
8
60 42 32 32 27 22 30
*Error In original publication (Yankel et al., 1977),
9:
57 40 - 32' 30 24 17 20
Teenape
39;33; 28 ' j1
] 35;
Adul t
. 37 33 30 34 32
32
11*84
DUP0400'12443
11-83
DUP040012444
-- in-1974', following the hospitalization of two children from Kellogg`with suspected acute
lead poisoning, the GDC joined the State of Idaho in:a comprehensive study of children in the
Silver Valley area of Shoshone County, Idaho, near the Kellogg smelter (Yankel et al., 1977;
Landrigan et al.:j 1976).
\
The principal source of exposure was a smelter whose records showed that emissions.aver
aged ft 3 metric tons per month from 1955 to 1964 an.dill.7 metric tons`from 196.5 to September,
1973. After a September, 1973 fire extensively damaged the smelter's main emission filtration
facility; emissions averaged 35,3 metric tons from October, 1973 to September, 1974 (Landrigan
et al,,, 1976). the smelter operated during the f4l 1 and winter of 1973~74 with severely
limited air pollution control capacity; fegift.nlng ip 1971, ambient concentrations.of lead, in the vicinity of the smelter were determined from paRiculate matter collected by hi-vol air samples, fata indicated! that monthly average levels measured in. 1974 (Figure 11-20) were three to four times the levels measured in 1971 (von Lindern and Yankel, 1976). Individual exposures of study participants to lead in the air were estimated by interpolation from these data. Air lead exposures ranged from 1.5 ,pg/m3 to 30 pg/m3 monthly average (see Figure 11-20). Soil concentrations were as high as .24,000 pg/g and Averaged 7000 pg/g within one mile of the smelter. House dusts were found to contain as muchjas 140,000 pg/g and averaged 11,000 pg/g
in homes within one mile of the complex. The study was.initiated in May, 1974 and the blood samples were collected in August, 1974
from children 1-9 years old in a door-to-door survey (greater than 90 percent participation). Social, family, and medical histories were conducted by interview. Paint, -house dustl, yard ..arid garden soils, grass, and garden vegetable samples were collected. At that time, .385 of the 919 children examined (41.9 percent) had blood lead levels in excess of 40 pg/dl, 41 chil dren (4.5 percent) /had levels greater than 80 pg/dlj. All but .2 of the 17.2 children giving within 1.6 km Of thi smelter had levels greater than 4r equal to 40 pg/dl. - Those two cNildren
had moved into the area less than six months earlier and had .blood lead levels greater than.3:5 pg/dl. Both the mean blood lead concentration and thej number of children classified as exhib iting excess absorp;I tion decreased with dist*an ce from] the smelter (Table 11-27). Blood lead levels were consistently higher In 2- to 3-year-old children than they were in .other age groups"(Table 11-28J. A significant negative relationship between blood lead level and hema tocrit value was found. Seven of the 41 children (17 percent) with blood lead levels greater than 80 pg/dl were diagnosed as being anemic on the basis of hematocrit less than 33 percent,* whereas only 16 of 1006 children (1.6 percent) with blood lead levels less than 80 pg/dl were so diagnosed. Although no overt disease was observed in children with higher lead intake, differences were found in nerve conduction velocity. Details of this finding are discussed in* Chapter 12.
11-82
DUP040012445
f :
i.l i <
An important extension in the development of models for the data was the inclusion of
separate non-air contributions pr background .axposyr.es for. each separate group. The.'coeffi
cients cf tlie group variables, , in the lead exposure Diode] may be interpreted -as measures
of total exposure of that group to non-air external sources .(cigarettes. food, dust, water)
and to endogenous sources (lead'Stored in skeleton). Water and smoking variables were used to
estimate some external sources. (This required deleting.another observation for a subject
with unusually high water lead.) .The effect of endogenous lead was,estimated using subject
age as a surrogate measure of Cumulative exposure, since lead: stored in the skeleton is known
to increase approximately linearly with age,, for ages 20-60 (Gross et al. ,; !1975; Barry, ,105.;
Steenhout,! 1982) in homogeneous populations.
J
In order to facilitate comparison, with the constant p ratios calculated,from the, clinical
studies, EjPA fitted a linear exposure mode).to the Azar..data, f The model was fitted on a- loga
rithmic sgale to facilitate comparison of goodness of fit. wifsh other exposure models and to
produce an approximately normal pattern of regression resIdukl s,... Neither smoking nor water
lead provilded significantly better fits to the log (blood lead) measurements after the effect
of age was removed.
j
Age and air lead may be confounded to some extent because ;t.he regression coefficient for
age may include the effects of prior air lead exposures on skeletal lead buildup. This would
have the effect of reducing the estimated apparent slope p,
Geometric mean regressions of blood lead on air lead were..calculated by EPA for several
assumptions: (1) A linear mode) analogous to Snee's exposure model, assuming different non-
air contributions in blood lead for each of the five subgroups; (2) a linear model in which
age of the! subject is also used as a surrogate measure of the cumulative body burden of lead
that provides an endogenous isource of'blood lead; (3) a lineajr model similar to (2) , in which
the. change of blood lead with age is different in different subgroups, but it is assumed that
the non-air contribution is!the:same in all five groups (as fas assumed in the 1977 E-PA lead '1
Criteria Document); (4) a linear model in which both the non-pir background and the change in
blood lead with age may differ by group.; and (5) a*nonlinear; model similar to (4). None of
the fitted models are significantly different from each other using statistical tests of hypo
theses abopt parameter subsets in nonlinear regression (Gallant, 1975),
11.4.1.6 Silver yalley/KeTlogg, Idaho. Study. In. 197.0, EPA carried out a study of s lead
smelter in Kellogg, Idaho (Hammer et al., 1972; O.S. Environmental Protection Agency, 1972).
The study was part of a national effort to determine the effects of sulfur dioxide, total sus
pended particulate and suspended sulfates, singly and in-combination with other pollutants, on
human health. It focused on mixtures of the sulfur compounds and metals. Although it was
demonstrated that children had evidence of lead absorption, insufficient environmental data
were reported to allow further quantitative analyses.
T
11-Bl
DUP040012446
j
TABLE 11-26. GEOMETRIC MEAN AIR AND BLOOD LEAD LEVELS (pg/100 g) FOR FIVE CITY-OCCUPATION GROUPS (DATA CALCULATED: BY E.PA)
Group
Cab drivers Philadelphia, PA
Plant employees Starke, ft
Plant employeesBarksdale, WI
Cabdrive.rs Los Angeles, CA
Office workers Los Angeles, CA
Geometric mean air lead, pg/m3
2.#
GSD . 1.16
0. $9
.2,04
o.di
2,39
' 6.02
1.18
1.29
Geometric mean blood lead, pg/100 g
22.1
GSD 1.16
15.4 \ 1.41
12.8 ;
1.43
24.2
1.20
18.4
1.24
Samp!e . size
.30;
'Code Ci
29 C?
30 C.s
30 . c4
30 65
. - wJXI-i_
Source: Azar et al, (1575). s
log (blood Pb) = 2.951 Cx + 2.818 t% t
f
2.627 C3 + 2.9.10 C4 + 2.821 C + ol 153 log (air Pb) i
(11-13)
This model gave a residual sum- of squares of 9.013, .a mean square error of 0.063 (143 degrees of freedom), and a multiple R? of 0.502. The air lead coefficient had a standard error of 0.040,. The fitted model is nohlinear on air lead, and so the slope depends on both air lead and the intercept. Using, an average intercept value of 1.226, the curve has a slope ranging from 10.1 at an air lead level of 0.2 pg/m3 to 0.40 at an air lead level of 9 pg/m3,
Snee (1982b) reanalyzed t;he same data and fitted the following power function model,
log (blood Pb) = log [12.1 (air Pb + 6.00 Cj. + 1.46 C2 + 0.44 C3 + 2.23 C4 + 6.26 Cg)0*2369]
This model gave a residual sum of squares of 9.101, 3 mean square error of 0,063 (142 degrees of freedom) and a multiple R2 of 0.497. Using an average constant value of 3.28, the slops ranges from 1.29 at an air lead of 0-2 to 0.51 at an air lead of 9.
11-80
DUP040012447
QQQlfl-..
___ ;....
aiP/Sw ' v i i QOOIB
Figure 11*19. Blood level vs. air lead relationships for Kehoe inhalation studies: linear relation for low exposures, quadratic for high exposures, with 95% confidence bands.
11-79
DUP040012448
T ' -"-rr - ' '
: si
* r~* "'
I !.
...... , , - n*' \ \\
TABLE 11-25. LINEAR SLOPE FOR BLOOD LEAD VERSUS AIR LEAD AT } LOW AIR LEAD EXPOSURE IN KlSHOE'S SUBJECTS
Subject
i
Linear Slopes 8, m3/dl, s.e.
Linear Model
Quadratic Model
A1r|,: p.g/m 1
Range I
i Blood, ' pg/d y
DH 1 -0.34 t 0.28
0.70 0.46
m
i 0.67 0.07 I 0.64 + 0.11
mcr 2.60 0.32
SSC 1,31 0.20
i.
0,14 1.25 0.20 2.14 1.01 0.19 . 1,29 0.06 1. 55 1.28 1.16 0.78
. .
5.6 - 8.8 2,4 - 7,5 , 9.4 - 35.7 - -' 9:.3 - 35.9 0.6 - 4.0 0.6 - 7.2
26 - 31 21- 27
21: - 46 v: IIS - 41
20 - 30 f18' - 29
*Alsb, control - 0.
.
aNo statistically significant relationship between air and bl^od lead-
\
^Hi'gh exposures. Use linear slope from quadratic model. .
j
ct Low exposures. Use linear slope from linear model,
,' -
i *
i:
; 1
} '\
11.4.1.5 Tfle Azar et al, Study. Thirty adult male subjects were obtained froiji each of five
groups: 1). Philadelphia cab drivers; 2) DuPont employees in Starke, Florida; 3). DuPont em
ployees in Barksdale, Wisconsin; 4) Los Angeles cab drivers'; and 5) Los Angeles office workers
(Azar et al., 1975). Subjects carried air lead monitors in their automobiles and in their
breathing zones at home and work. Personal ivariables (age, smoking habits, water samples)
were obtained from all subjects, except fof water samples from Philadelphia cab drivers.
Blood lead, ALAD urine lead, and other variables were measured. From two to eight blood sam
ples were obtained from each subject during the air monitoring phase, 81ood lead determine- '
tions were done in duplicate. Table 11-26 presents the geometric means for air lead and blood
lead for the five groups. The geometric means were calculated .by EPA from the, raw data pre
sented in the authors1 report (Azar et al., 19)5).
!
The Azar study has played an important role in setting standards because ofithe care used
in measuring: air lead in the subjects' breathing zone. Blood lead levels change in response
to air lead* levels, with typicdl time constants of 20-60 days. One must assume that the
subjects' lead exposures during preceding months had been reasonably similar to those during
the study period. Models have been proposed for these data by Azar et al (1975), Snee (1981; "
1982b), and Hammond et al. (1981) including certain nonlinear models.
Azar et al, (1975) used a log-log model for their analysis of the data. The model in
cluded dummy variables, Cx, C2, C3) C4, Cs, which take on the value 1 for subjects in that *
group and 0 otherwise (see Table 11-26 for the definitions of these dummy variables). The
fitted model using natural logarithms was
11-78
f'
j
j
i
:
DUP040012449
I
MGPB/DAY
MGPB/DAY
MGPB/DAY
MGPB/100GM MdPB/OAV
Figure 11-18. Data plots for individual subjects as a function of time for iCefioe subjects, as presented by Dross (1379}.
11-77
DUP040012450
t ' j;
l\ \ . ;
.
'}
;!
'i
U
'
\
.L
11.4.1.4 the Kehoe Study. Between 1950 and 1971, Kehoe exposed 12 subjects to various levels
of air lead under a wide variety of conditions. Four earlier subjects had received oral lead
during 1937-45. The inhalation experiments were carried put in an inhalation chamber at the
University of Cincinnati, in which the subjects spent varying daily time period? over extended-
intervals. The duration was typically 112 days for each exposure /level in the inhalation
studies, and at the end of this period it was assumed the blood lead concentration had reached
a near-equilibrium level. The experiments are described by Kehoe(1961a,b,c) and the data and
their analyses by Gross (1981) and Hammond et al, (1981); The studies most,relevant to this
document are those in which .only particles of lead ses.quioXide aerosols in the submicron range
were used, so that there was at least one air lead exposure (other, than control) for which the
time-averaged air lead concentration did not exceed ID jig/m3. Only six subjects met these
criteria; ID (1960-63), JOS (1960-63), W (1963-66), SS (1963-68), HR (19|6-67), and OH
(1967-69), Subject DH had a rather high initial blood leal epncentration (30 pg/dl) that fell during the course of the experiment to 28 pg/dl; apparently daily detention in the inhalation
chamber altered OH1s normal pattern of lead exposure to one of lesser total exposure. The
Kehoe studies did not measure non-experimental airborne lead exposures, and did not measure lead exposures during "off" periods. Subject HR .received! three exposure levels from 2,4-7,5
pg/m3, subject NK seven exposure levels from 0.6-4.2 gg/m3, and subject S$ 13 exposure levels
from 0.6-7.2 pg/m3. Lb and JDS were each exposed to about 9, 19, 27, and 36 pg/m3 during
sequential periods of 109-113 days. '
:
A great de;al of data on lead content in blood, feces, urine and diet were obtained in
these studies and are ekhibited graphically in-Gross (1979) (see Figure 11-18). Apart from
the quasi-equilibrium blood lead values and balances reported in Gross (1979; 1981), there has
been little use of these data to study the uptake and distribution kinetics of lead in man.
PA analyses used only tie summary data in Gross'.(1981), -
*
- Data from Gross (1981) were fitted by,least squarps linear and quadratic regression
models. The quadratic models were not significantly better than the linear model except for
subjects LD and JOS, who!were exposed to air levels above ID pg/m3. The linear terms predomi
nate in all models for air lead concentrations below 10 pg/fm3 and are reported ,1n Table 11-25;.
These data represent most of the available experimental evidence in the higher range of
ambient exposure levels, approximately 3-10 pg/m3. Data for the four subjects with statis
tically significant relationships are shown in Figure 11-19, along with the fitted regression*
curve and its 95 percent confidence band.
11-76
DUP040012451
|H
i
!
i
i .
CTi 3 Deposition] [% Absorption] [Daily ventilation]
ft = ........... - -
.. ................
r^,7......
. [Blood volume] [0,693]
where?
' '
' Tt * biological half life
** C
'i '
'
.... ,.
-
M- *
(11-10). S
|
5. i". ' ?
! With an estimated value of = 18 days (mean residence time T^/0.693 - 26 days), with 50 per-
j cent for deposition in lung for. ordinary urban dwellers, and 55 percent of .the lung lead re-
; tained in the blood lead compartment (all based on Chamberlain's. experiments), with an assumed
| ventilation of 2D m3/day over blood volume 5400 ml (Table 10-20 in Chamberlain et al,, 1978),
i then
j.
1
- 26 day X 0.50 X 0.55 X 20 m3/day 2.llnfVdl ? p 54 dl
l.
j This value of ft could vary for the following reasons? .
:
]
(1.1-11)
1. The absorption from lung to blood used here, 0.55, refers to short-term kinetics. In the long term, little lead is lost through biliary or pancreatic secretions, nails, hair, and sweat,; so that most of the body lead is available to the blood pool even if stored in jthe skeleton from which it may be resorbed. Chamberlain suggests an empirical correction tp 0,55 X 1.3 = 0.715 absorption.
! 2. The mean residence time}, 2ft days, is shorter than in Rabinowitz's subjects, arid j the blood, volume is lesis, 54 dl. It is possible that in the Rabinfiwitz study,
the mean times "are longer and the bl.opd pool size (100 dl) is larger than here ...
j because Rabinowitz et al]. included relatively fewer 1ab i1e tissues such as kidney
i and . liver in the pool. i Assuming 40 days mean residencejtime and 100 dl blood
volume the. slope can be`recalculated,
j ...
1
,, _ 40 d X 0.50 X 0.55 X 20 m3/d _ ,, ,, P ----- -----lOQ-dl---- - 2,2 mJ/dl. 3. The breathing rate could be much less, for inactive people.
(11*12)
11-75
DUP040012452
The inhalation slopes thus calculated are the lowest that can be reasonably derived from*
this experiment, since the largest plausible air lead concentrations have been assumed. The
third-floor air monitor average of 2.1 pg/m3 is a plausible minimum exposure, leading to the
higher plausible maximum inhalation slopes in the last column of Table 11-24. These are based,
on the assumption that the time-averagpd air lead exposure is smaller by [10(4-2.1)3/24 5 0.79
p.g/m than assumed previously. It is also possible that some of this difference can be attri
buted co dust ingestionjtfhile outside Jthe metabolic ward. >
..
11,4.1.3 The Chamberlain et al. 5tud|c A series of investigaiipns were .carried out by
Chamberlain et al, (1975a,b; 1978} |at the ILK. Atomic Energy: Research Establishment in
Harwell, England, The studies included exposure of up to 10 volunteer subjects to inhaled,
ingested,, and injected lead in various physical forts. The Inhalation exposures included
laboratory inhalation of lead aerosols] generated in a wind tunnel , or box, of various particle
sizes and chemical compositions (leajj oxide and lead nitrate). Venous blood samples were
taken at several times after inhalatijon of 203Pb. Three subjects, also breathed natural high
way exhaust fumes at various locations] for times up to about 4.5 hours.:
The natural respiratory cycles ip the experiments varied from 5.7 to 17.6 seconds (4 to 11. breaths per minute) and tidal voljumes from 1,6 to 2.3 liters, lung deposition of . lead-
bearing particles depended strongly Op particle size and composition, with natural exhaust
particles being more efficiently retained by the lung (30 - 50 percent) than were the chemical
Compounds (20 - 40 percent).
.
>.
; The clearance of lead from the lungs was an extended process over] time and depended on
particle size and composition., leaving only about l percent of the fine wind tunnel aerosols
in Ihe lung after 100 hours, but about ID percent of the carbonaceous exhaust aerosols. The
203Pb isotope reached a peak blood levpl about 30 hours after inhalation] the blood level then
representing about 60 percent of the initial lung burden; `
.
j.
! A- substantial fraction of the lead deposited in the lung appears to .be unavailable to the
blood papi in the short term, possibl^ due to rapid transport to and retention in other tis
sues] including skeletal tissues. In long-term balance studies, some of/this lead in the deep
tissue compartment would return to the blood compartment. ,
`lead kinetics were also studied by use of injected and ingested tracers, which suggested
that in the short term, the mean residence time of lead in blood could be calculated from a
one-pool model analysis,
'
Chamberlain-et al. (1978) extrapolated these high-level, short-term exposures to longer
term ones. The following formula and data were used to calculate a blood-to-air level ratio
11-74
DUP040012453
T '' I !'
ii 1 .i i 1i
TABLE 11-24, ESTIMATES OF INHALATION SLOPE, p, FOR RABINOWITZ STUDIES
Changes in intake*,
Subject pg/day
Volume.,** kg
-A 17 5* 7.4 0.6
B 161 3 10.0 1 0.8
C
IS 5*
10.1 1**
D 9 2 9.9 1,2
E 12 2 11.3 1.4
. * }i Residencef
time,, days
Changes in air 1ead ,.
pg/m3
Inhalation slope, pg/d
per pg/m3
34 s!
401 5' .37 1 5' 40 1 5j 27 5j
2.5ft --. 2.98 1.06
: 2,o
3,56 1 0.93
2.2tt
2,67 1.04
2.0 2. 02 0, 60
2,0 1.591.0,47
Maximum s 1 ope -/?
4.38 1.55 5.88 1.54 4.16 1 1.62 3.34 + 0.99 2,.Gi3 1 0,78
*From Rabinowitz et al. (1977}, Table VI.. Reduced Intake by low-lead method for subjects
6, D, E, tracer method for A, balance method for C,' Standagd error for C is assumed by EPA to be same as A.
**From Rabinowitz et al- (197-6)*. Table II. EPA has assumed standard error with coefficient of variation same as that for quantity of tfacer absorbed in.Table VI, except for subject C,
^Estimates fromRabinowitz et al. (1976) Table II. Standard error estimate from combined
sample.
}
See text. For A and C, .estimated from average exposure. For B, 0, and E reduced by 0.2 gg/m3 for clean room exposure. Coefficient of variation -assumed to be 10%.
+Assumed density of blood 1.058 g/cm3.
)
Assuming butside air exposure is 2.1 pg/m3 rather than 4 pg/m3 for 10 hours, j
nominal 10 percent coefficients, of variation stated. The assumption is that for subjects B,
; .i
.
D., and E:, t.fie exposure to street level air for .10 hours per day was .twice a$ large as the mea
sured-roof level air., t.e., 4 pg/m3; and the Remaining 14 hours- per day were at: the ward level
of 0.97 pg/fi3; thus the time-averaged level' was [.(10 x 4) + (14 x 0.97)]/24 = 2123 pg/m3. The
average conjtroned exposures during the "cle^n room" part of the experiment whre 23, 22, and
.24 hours respectively for subjects B, D, E; thus averaged exposures were 0.19,; 0.28, and 0,12
pg/m3, and deductions in exposure were about- 2,0 pg/m3. This value is used tb calculate the
( - -
- 5 .
i
slope. For subject A, the total intake due to respired air is the assumed indoor average of
1.5 pg/m3 for the Sepulveda VA hospital, combining indoor and outdoor levels [(10 x 4) + (14 x
1.5)3/24 = 2.54 pg/m3. For subject C the Wadsworth average applies. Other than uncertainties
in the air lead concentration, the inhalation slope estimates for Rabinowitz's subjects have
less internal uncertainty than those calculated for subjects in Griffin's experiment.
11-73
DUP040012454
TABLE 11-23. ' AIR LEAD CONCENTRATIONS* (ug/m3) FOR TWO SUBJECTS IN THE RABJNQWITI STUDIES
r Subject A
. .
j
i J!
i
Subject B j.
} \ i
Environment
Outside (Sepulveda VA)
Inside (Sepulveda VA, air-cpnditionset without = filter)
Inside (Wadsworth VA, Open air room)
(Wadsworth VA)
Outside
In room (air conditioner with filter, no purifier)
In room (with purifiers, "clean air")
Open-air room
Organic vapor lead
Outside
"Clean air"
j
Average ...... 1,8 I
Range (1.2-2,4).
1.5 ' 2.1
2,0 0.97 0,072 1.9
(1.0-2.7)
(1.8-2.6)
' ' ''
1
(1.6-2v4)
(0.4-2.1)
(0.062-0j.-Q87) (1.8-1.9)
0.10 0,0.5
-
* 5-20 days exposure for each particulate lead filter,
! 'j
-
j
'- |
One of the" greatest .difficulties in using these experiments is that the air lead expo
sures of:the subjects were not measured directly,} .either by personal monitors or b| restric
ting the subjects to the metabolic wards. The times, when the subjects were allowed outside
the wards included possible exposures to ground f!loar and street level air, whereas the out-
- t *`
I '
%*
side air lead mdnitor was mounted outside the third-floor window of the ward. The VA hospi-
tals are not far from major streets and the subjects1 street level exposures could have been
much higher than those measured at about ID m elevation (see Section 7.2.1.3). Some estimated*
ratios between air concentrations at elevated and street level sites are given in Table 7-6.
A second complication is that the inside ward value of pg/ra3 (Rabinowitt et al., 1977)
used for subject B may be appropriate for the Wadsworth VA hospital, but not for subject A in*
the Sepulveda VA hospital (see Table 11-23). The changes in air lead values shown in Table
11-24 are thus nominal, and are likely to have systematic inaccuracies much larger than the
11-72
'
DUP040012455
.11,4,1.2 The Rabinowitz et al. Study. The use of stable lead isotopes avoids many of the
difficulties encountered'in the analysis of whole blood lead levels in experimental studies.
Five adult male volunteers were housed in the metabolic, research wards Of the Sepulveda arid Wadsworth VA hospitals in Los Angeles for. extended periods (Rabinowitz et al,, 1974; J97i;
1977). For much of the time they.were given low-lead diets with controlled lead content,^.sup
plemented by tracer leadjsalts at different times.
.. y .
Four subjects were Initially observed in the ward for several weeks. Each subject was in
the senri-controlled ward, about 14 hours per day and was.allowed outside for 10 hours per day,
allowing the blood lead concentration' to stabilize.
=> !
Subjects B, D, and then spent 22-24 hours per day for 40, 25, and 50 days, respective ly, in a low-lead room jwitb total particulate and vapor lead concentrations that were muCh
lower than in the metabolic wards or outside (see Table 11-23). The subjects were thereafter
exposed to Los Angeles air with much higher air lead concentrations than in the ward,
]
i-
^
The calculated changes in lead Intake upon entering and jeaying the low-lead chamber are
shown in Table 11-24. these were based on the assumption that the change in total blood lead
was proportional to the: change in daily lead intake. The change in calculated air lead
intakes (other than cigarettes) due to removal to the clean room were also calculated iadepeiir
dently by the lead balance and labeled tracer methods (Rabinowitz et al., 1976) and are con
sistent with these direct estimates.
Rabinowitz and .coworkers assumed that the amount of Tead in compartments within the body evolved as a coupled system of first-order linear differential equations with constant frac
tional transfer rates- This compartmental model was fitted to the data. This method of
analysis is described in Appendix 11A.
Blood lead levels dalcufated from the three compartment model adequately predicted the observed blood lead levels over periods of several' hundred days. There was no evidence to
suggest homeostasis or other mechanisms of lead metabolism not included in the model. Thetje
was some indication (RabjinoWitz et al., 1976) that gut absjorptiori may vary from time to time.
The calculated volumes of the pool with blood lead (Table 11-24) are much larger than the
body mass of blood .(about 7 percent of body,weight, estimated respectively as 4,9, 6.3, 6.3>
4.6, and 6.3 kg for subjects A-fi), The blood lead compartment must include a substantial mass of other tissue.
The mean residence time in blood in Table 11-24 includes both loss pf lead from blood to
urine and transfer of a fraction of blood lead to other tissue pools. This parameter reflects
the speed with which blood lead concentrations approach a new quasi-equilibrium level. Many
years may be needed before approaching a genuine equilibrium level that includes lead that can be mobilized from bones.
11-71
DUP04Q012456
that, "Coefficient of. variation..,, based on duplicate pairs and after logarithmic transfor
mation, was 9 percent for pavement dwellings (22 dwellings) and 10 percent for housedust
(25 dwellings). The coefficient of variation of child hand lead using the 'wet wipe' tech
nique was 19 percent (based on 17 children)." The coefficient of variation of the blood lead
sample of venous blood was around 7 percent.
In both children and mothers, the mining area differed the most from the control area.
The excess of lead in the blood of children was 30 percent for the mining area; in mothers the
excess was about 50 percent.
Pica as determined by questionnaire showed no consistent association with any area or all
areas combined. On the other hand, the analysis of the wet wipe study provided interesting
results, Within the -roadside dwell trigs,: the Cul de;sacs, and the control areas, mean lead
levels of wet wipe samples were remarkably similar for mothers' hands, children's hands, and kitchen surfaces. But the mining area had a 40 percent excels for mothers' hands, 45 percent
for children's hands,- and 35 percent for kitchen surfaces, compared to the control area.
However, the only difference Which was statistically significant Was for the children,.
Correlation analysis was performed between blood lead concentrations and hand lead:con-
centrations. In the mining area, which was the most contaminated area, the Correlation co
efficient was 0.38, which was statistically significantly different from zero. In the non-
eontami-nated areas, a statistically significant relationship was found between blood lead and
kitchen surface. No statistically significant relations were seen for the mothers. Thus
these data give additional support to thh notion of normal hand-to-mouth activity being a
pathway by which lead in dust can get into the blood of children.
11.4.3.11 Other Studies of Soil and Dusts. Rabinowitz et al. (1985c) report in a study dis
cussed in Section 11.3^.5.4 that lead levels in indoor dujst and outdoor soil were strongly pre
dictive of blood lead levels. Their.sample consisted of Boston urban and suburban infants
followed from birth to 2 years of age whose mothers had a mean age of 29 years and 15 years
mean schooling.
1
Lepow et al. (1975) studied the lead content of air, house dust, and dirt, as well as the
lead content of dirt on hands, food and water, to determine the cause of chronically elevated
blood lead lave'I s in 10 children 2 to 6 years old in Hartford, Connecticut, Lead-based paints
had been eliminated as a significant source of lead for these children. Ambient air lead con
centrations varied from 1.7 to 7.0 pg/m3. The mean lead concentration in dirt was 1,200 pg/g
and in dust, 11,000 pg/g, The mean concentration of lead in dirt on children's hands was
2,400 pg/g. The mean weight of samples of dirt from hands was 11 mg, which represented only a
small fraction of the total dirt on hands. Observation of the mouthing behavior in these
young children led to the conclusion that the hands-in-mouth exposure route was the principal
cause of excessive lead accumulation.
\
11-147
DUP0400124S7
Several studies have investigated the mechanism by which lead from soil and dust gett into the body (Sayre et al., 1974; 'Ter Hear and Aronow, 1974). . Sayre et al. (1974) in Rochester, New York, demonstrated the feasibility of house dust as a- source of lead for chil dren. Two groups of houses, one inner city and the other, suburban, were chosen for the study. Lead-^ree 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 outpoints in the chi-square contingency analysis, A statistically significant difference between the urban and suburban homes far dust levels.was noted, as was. a relation ship between; household dust levels and hand dust levels (Lepow et al.,,1975).
Ter Haar and Aronow (1974). investigated lead absorption in children that can b,e at tributed to ingestion of dust and dirt, . They reasoned that , because the .proportion of the naturally occurring isotope of 210Pb varies for paint Chips,.-airborne particulates, fallout dust, house dust, yard dirt, and street dirt, it would be passible to identify the sources of ingested lead. They collected 24-hour excreta from eight hospitalised children on the first day of hospitalization. These children, 1 to. 3 years old, were, suspected pf having elevated body burdens,- of lead, and one criterion for the suspicion Was a history of pica,;- Ten children of the same age level, who lived in good housing in Detroit and the suburbs, were selected as controls and 24-hour excreta were collected from them- The excreta were dried and stable lead as well as **opjh content determined, For seven hospitalized ;children, the stable lead mean value was 22,43 pg/g dry excreta, and the eighth child had a value of 1640 pg/g. The con trols' mean for stable lead was 4.1 pg/g dry excreta. However, the respective means for 210Pb expressed as pCt/g dry matter were 0.944 and 0.040. The authors concluded that because there Is no significant difference between these means for 21:0Pb, the hypothesis that young children with pica bat dust "is not supported. The authors further concluded" that children- with evidence of high lead-intake did not ..have dust and air suspended particulate as the sources of their lead. It is clear that air suspended particulate did not account for the lead levels in the hospitalized children. However, the 21&Pb concentrations in dust and feceS were similar for al! children, making it difficult to estimate the dust contribution.
HeyWortb et al. (1981) studied a population of children exposed to lead in mine tailings. .These tailings were used in foundations and playgrounds, and had a lead content ranging from 10,000 to 15,000 pg/g.' In December, 1979, venous blood samples and hair were collected from 181 of 346 children attending two schools in Western Australia. One of the schools was a pri*mary school; the other was a combined primary and secondary school. Parents completed ques tionnaires covering background information as well as information regarding the children's exposure to the tailings. Blood lead levels were determined by the AA5 method of Farrely and Pybos. Good quality control measures were undertaken for the study, especially for the blood
11-148
DUP040012458
lead levels. Blood lead levels were higher in boys versus girls (mean values were 14.0 and 10.4 pg/dl, respectively). This difference was statistically significant. Five percent of the children (n =.9) had blood lead levels greater than 25 pg/dl; five of these children had blood lead levels greater than 30 pg/dl. Blood lead levels decreased significantly with age and were slightly lower in children living on properties on which tailings were used. However, they were higher for children attending the school that used the tailings in the playground,
Landrigan et al. 1982) studied the impact pn soil and dust lead levels on removal of leaded paint from the Mystic River Bridge in .Masschusetts. Environmental studies, in 1977 in dicated that surface soil directly beneath the bridge had a lead content ranging from 1300 to 18.00 pg/g. Analysis of concomitant trace elements showed that the lead came from the bridge, A concurrent survey of children living in Chelsea (vicinity of bridge), found that 4,9 percent of 109 children had blood lead levels greater than or equal to .30 pg/dl. Of children living more distant from the bridge, 37 percent had that level of bldBd lead.
These findings prompted the Massachusetts Port Authority to undertake a program to delead the bridge. Paint on parts of the bridge j that extended over neighborhoods was removed by abrasive blasting and replaced by zinc primer.. Some care was undertaken to minimize both the occupational as well as environmental exposures to lead as a result of the blasting process.
Concurrently with the actual deleading work, a program of air monitoring was established to check on the environmental lead exposures being created. In dune, .1980, four air samples taken at a point 27 m from the bridge had a mean lead content of 5.32 pg/m3. As a result of these findings air pollution controls were tightened; mean .air lead concentrations 12 meters from the bridge in duly were 1.43 pg/m3.
Samples of the top 1 cm of soil were obtained in July, 1980 from within 30, 30-80, and IPO m from the bridge. Comparison samples from outside the area were also obtained. Samples taken directly under the bridge had a mean lead content of 8127 pg/g, Within 30 m of the bridge, the mean content was 3272 pg/g, dropping to 457 pg/g at 30 to SO m. At 100 m the soil lead level dropped to 197 pg/g. Comparisonisamples ranged from 83 to 165 pg/g depending on location,
Fioge.rs.tfck blood samples were obtained oh 123 children 1-5 years of age living within 0,3 km of the bridge in Charlestown, Four children (.3.3 percent) had blood lead levels greater than 30 pg/dl, with a maximum of 35 pg/dl. All four children lived within two blocks of the bridge. Two of the four had lead paint in their homes but it was intact. None of the 76 children living more than two blocks from the bridge had blood leads greater than or equal to 30 pg/dl, a statistically significant difference.
Shellshear's (1973) case report from New Zealand ascribes a medically diagnosed case of lead poisoning to high soil lead content in the child's home environment. Shellshear et al.
11-149
DUP040012459
(1975) foil owed up his case repprl of increased lead absorption resulting from exposure to
lead contaminated soil with a study carried out in Christchurch, New Zealand, two related activities comprised the study. First, from May, 1973 to November, 197.3, a random study of pediatric admissions to a local ho.spi.tai was made. Blood samples were taken and analyzed for
lead. Homes were visited and soil .samples were collected and analyzed for. lead, Lead anal
yses for both soil and blood were conducted by AAS. . Second, a soil survey of the area was
undertaken. Whenever a soil lead value greater than. 300 pg/g was found and a child aged 1-5
was present, the child was referred for blood testing..
.... .
the two methods of subject recruitment yielded a total of 170 subjects. Eight 4.7 per cent) of the children had blood lead equal to or greater than 40.pg/dl, and three of. them had a blood lead equal to or greater than BO pg/dl. No correlation with age was noted. The mean blood lead of the pediatric admissions was 17.5 pg/dl with an extremely large range (4-170 pg/dl). The mean blood lead for soil survey children was 1^5 pg/dl.
Christchurch was divided into /two sections based on the date of development of the area. The inner area had developed earlier and a higher level of lead was.used there in the house
paints.. The frequency distri.bution|of soil lead levels showed that the inner zone samples had much higher spil lead levels than] the outer zone. ' Furthermore, analysis of the soil lead
levels by type of exterior surface of the residential unit showed that painted exteriors had higher soil lead values than brick, stone, or concrete block exteriors.
; Analysis of the relationship between soil lead and blood lead was restricted to children from the sampled hospital who had lived at their current address for at least one year., table
11-62 presents the analysis- of these results.. Although the results were not statistically significant, they are suggestive of an association.
TABLE 11-62. ANALYSIS OF RELATIONSHIP BETWEEN SOIL LEAD AND BLOOD LEAD IN CHILDREN
Area of city
Inner zone Outer zone
'Soil lead (pq/q)
. - Mean
Range
h
1950 150
30-11000 - .21
30-1100
47
Blood lead (pq/dl)
Me.ah
Range
25.4 18.3
4-170 5-84
Source: Shell Ishear (1973).
Analysis of the possible effect of pica on blood lead levels showed the mean blood lead for children with pica to be 32 pg/dl while those without pica had a mean of 16,8 pg/dl. The pica blood lead mean was statistically significantly higher than the non-pica mean.
11-150
DUP040012460
Mielke et al. (19.84) reports elevated blood lead and PEP levels among Hmong children
living in Minneapolis, Minnesota. The lead .sources for these children included soil lead.,
house paint, and leaded gasoline from vehicle traffic. Fifty percent of Children with lead
poisoning (FEP > 50 pg/dl, blood lead > 80 pg/dl) inhabited homes which had soil lead levels
of 500 to 1000 pg/g,
Wedeen et al. (1978) reported a case of lead nephropathy in a black fjemale who exhibited
geophagia. The patient, who had, undergone chelation therapy, eventually reported that she had
a habit of eating soil from her garden in .East Orange, New Jersey, During spring and summer,
she continuously kept soil from her garden in her mouth while gardening. She even put a sup
ply away for winter. The soil was analyzed for lead and was found t0 contain almost 700 pg/g.
The authors .estimated that the patient consumed 100-500 mg of lead each year, 0.ne`month after
initial hospitalization her blood lead level was 70 pg/dl,
,11.4.3.12 Summary of oi 1 and Dust Lead . Studies relating soil lead to blood lead levels
ate difficult to compare. The relationship obviously depends on depth of soil lead, age of
the children, sampling method, cleanliness of the home, mouthing activities of the children,
apd possibly many other factors, Brunekreef et al, (1983) studied a population of urban and
rural children in the Netherlands. The analyses are described in detail in Section 11,4.3,4. *
Blood lead levels increased with increasing outside dustfall, with increased lead on chil
dren's hands, and with pets in the household, and decreased with increasing number of rooms
(due to dilution or confounded SES effects). Bust lead and its related transport factors sub
stantially increased blood lead, fable 11-83 gives some estimated slopes taken from several-
different studies. The range -of these values is quite Targe, ranging from 0,6 to 6.8. 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, (198.2} study and the Angle-and
'Mclntire- (1982} study. These two studies gave slope estimates of 2.2 and 6,8 pg/dl per .1000
pg/gr respectively,
1
The relationship of house dust lead to blood lead is even more difficult to obtain.
Table 11-64 contains some values for three studies that give data permitting such caculations.
The median value of 1.8 pg/dl per 1000 pg/g for children 2-3 years old in the Stark study may
also represent a reasonable value for use here,
11.4.4 Faint Lead Exposures A major source of environmental lead exposure for some in 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
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TABLE 11-63, ESTIMATES OF THE CONTRIBUTION OF SOIL LEAD TO BLOOD. LEAD
Study
Range of soil lead values
(ug/g)
Angle and Mclntire (1932) .study of
Children in' Omaha, ME
16-4792
Stark et al. (1982) study of children in New Haven, CT
30 - 7000 (age 0-1)
30 - 7600 (age.2-3)
Yanke'l et al, (1977) study of children
in Kellogg, 10
50 - 24,600
Galke et al. .(1975)
.study of children in Charleston, SC
9 - 7890
Barltrop et
al, (1975) study of children in England
420 - 13,969 (group means)
Meri et al. (1978) .study of children in British Columbia
'
225-1800 (group means,
age 1-3)
225-1800 (group means,
age 2-3)
Depth of sample
2"
. Estimated slope (X103)
6.8
Sample size
1075
V
3/4 K
2.2 153' 2.0 334 1,1 860
2" 1.5 194
2" 0, 6 82
NA 7.6
NA 4.6 *
' 87 103
.. . v8.?.......... 0.198
0,28.9 0.309 0.66Z
0.386
NA*
NA `
NA >
*NA means Not Available.
4
11-152
DUP040012462
TABLE 11-64. ESTIMATES OF THE CONTRIBUTION OF HOUSEDUST TO BLOOD LEAD IN CHILDREN
Study
Range of dust lead values (pg/g)
Angle and Mclntire (197.9] study in Omaha, NE
18-5571
Stark et al. (1982) 1 70-7600 study in New Haven, . 40-7600 CT 9-4900
Yanks1 et aT. (1977) - study in Kellogg,
ID
i 50-35,6.00
Age range . in years
1-18 6-18
0-1 2-3 4-7
0-4 5-9
Estimated
Sample
slope (X103) . si ze
7.18 3,36
1074 832
,R2;/
0.198 0,262
4,021.82 0.02
0.19 0.20
15.3 334 .. 4.3:9-
: 185 . 246
0.289' 0,300 0,143
0.721 0.623
buildings contain paint manufactured before lead content was regulated) and the physical con
dition of the paint. It is generally accepted by the public and by health professionals that
lead-based paint is ope major .source of overtly symptomatic pediatric lead poisoning in the
United States (Lin-Fu, 1973).
-
The level and distribution of lead paint in a dwelling is a complex function of history.,
geography., economics, and the decorating habits of its-residents. Lead pigments were the
first pigments produced on a large commercial scale when the paint industry began its growth
in the early 1900's. In the 1930's lead pigments were gradually replaced with zinc and other
opacifiers. By the 1940's, titanium dioxide became available and is now the most commonly
used pigment for residential Coatings, There was 'no regulation of the use of lead in house
.pafnts until.1955, when the paint industry adopted.a-voluntary standard that limited the lead
content in interior paint to no more than 1 percent by weight of the nonvolatile solids, ; At
about the same time* local jurisdictions began adopting codes and regulations that prohibited
the sale and use of interior paints containing more than .1 percent lead (Berger, 1973a,b).
In spite of the-change in paint technology and local regulations governing its use, in
terior paint with significant amounts of lead was still available in the 197D's. Studies by
Berger (197.3b) and .by the U.S, Consumer Product Safety Commission (1974) showed a continuing
decrease in the number of interior paints with lead levels greater than 1 percent. By 1974,
only Z percent of the interior paints sampled were found to have greater than 1 percent lead
in the dried, film (U,S. Consumer Product Safety Commission, 1974).
The level of lead in paint in a residence that should be considered hazardous remains in
question. Not only is the total amount of lead in paint important, but also the accessibility
11-153
DUP040012463
of the painted surface to a child, as well as the frequency of ingestion, must be considered^
Attempts to set an acceptable lead level, in situ, have been unsuccessful, and preventive con
trol measures of.lead paint hazards have been concerned with lead levels in currently manufac
tured paint.. In one of its reviews, the NAS concluded: "Since control of the lead paint
hazard is difficult to accomplish once ;mu!tiple layers have been applied in homes ovep'two to
three decades, and since control is more easily regulated at the time of manufacture, we re
commend that the lead content of paints he set and enforced at time of manufacture" (National
Academy of Sciences, 197i).
Legal control of lead paint hazards is being attempted by local, communities through
health or housing codes and regulations. At the Federal level, the Department of Housing and
Urban Uevelbpment has issued regulations for lead hazard .abatement in housing Units assisted
or supported by its programs. Generally, the lead level considered hazardous ranges.from 0.5
to 2,5 mg/cm2, but the level of lead content selected appeths to depend more on he .s.ensiti*
vity-of field measurement (using X-ray fluorescent lead detectors) than on direct biological
pose-response Relationships. Regulations also require lead hazard ahaftemant when the paint is
loose, flaking, peeling, or broken, or in some cases when it is on surfaces within reach of a
child's mouth.
Some studies have been carried out to determine the.distribution of lead levels in paint
in residences, A survey of lead levels in 2370 randomly selected,dwellings in Pittsburgh pro
vides seme Indication of the lead levels to be found (Shier and Hall, 1977), Figure 11-29
shows the distribution curves for the highest lead level found in dwellings for three age
groupings. The curves bear out the statement often made that paint with high levels of lead
is most frequently found in pre-1940 residences.- One cannot assume, however, that high lead
paint is absent in dwellings built- after 1940, in the case of the houses -surveyed in
Pittsburgh, about 20 percent of the residences built after I960 have at least- one surface with
more than 1.5 mg/cm2.
The distribution of lead within an individual dwelling varies considerably. Lead paint
is most frequently found on doors and windows where lead levels greater than 1.5 mg/cm2 were
found on .2 percent of the surfaces surveyed,'whereas only about 1 percent of the walls had
lead levels greater than 1.5 mg/cm2 (Shier and Hall, 1977).
In a review of the literature, Lin-.Fu (1973) found general acceptance that the presence of
lead in paint is necessary but not sufficient evidence of a hazard. Accessibility in terms
of peeling, flaking, or loose paint also provide evidence for the presence of a hazard. Of the
total .samples surveyed, about 14 percent of the residences had accessible paint with a lead
content greater than 1.5 mg/cm2. As discussed in Section 7.3.2.1.2, one must note that lead
oxides of painted surfaces contribute to the lead level of bouse dust.
11-154
DUP040012464
FRACTION HAVING LEAD LEVEL >
LEAD LEVEL IX}. mg/cm2
Figure 11 -29. Cumulative distribution of lead levels in dwelling units. Source: Shier and Hall (1977).
11-155
DUP040Q12465
It is not possible to extrapolate the .results of the Pittsburgh survey nationally!
However, additional data from a pilot study of .115 residences in Washington,' DC, showed
similar results (Hall 1974).
An attempt was made in the Pittsburgh study to obtain information about the correlation
between the quantity and condition of lead paint in buildings, and the blood lead of children
who resided there (Urban, 1976). Blood lead analysesand socioeconomic data for 456 children
were obtained, along with the Tnforjnsttiotj about lead levels in the dwelling. Figure 11-3D is
a plot of the blood lead levels versus the fraction of surfaces within a dwelling with lead
levels of at least 2 mg/cm2. Analysis of the data shows a low correlation between the blood
lead levels of the children and fraction of surfaces with lead levels above 2 mg/cm2, but
there is a stronger correlation between the blood lead levels and the condition of the painted
surfaces in the dwellings in which children reside. This latter correlation appeared to be
independent of the lead levels in the dwellings.
Yaffe et al. (1983) report data that suggests that soil lead possibly derived from
exterior paint was an important source for a selected group of children. They used a stable
lead isotope ratio technique.
Hammond et al. (1981, 1982) conducted a study of Cincinnati children with the dual pur
pose of determining whether inner city children with elevated blood lead levels have elevated
fecal lead and whether fecal lead correlates with lead-base paint hazard in the home or traf
fic density as compared with blood lead. Subjects with high blood lead levels were primarily
recruited. Some comparison children with low blood lead levels were also identified. The
three comparison children had to be residentially stable so that their low blood lead levels
were reflective of the lead intake of their current environment. The subjects from the inner
city were usually from' families in extremely depressed socio-economic.circumstances. Stool
samples were collected on a daily basis for up to :3 weeks, then analyzed for lead. Fecal lead
levels were expressed both as mg/kg-day and as mg/m2*day.
An environmental assessment was made at the home of each child. Paint lead exposure was
rated on a three-point scale (high, medium, and low) based on paint lead level and integrity
of the painted wall. Air lead exposure was assessed by the point scale (high, medium, and
low) based on traffic density, because there are no major point sources of lead in the
Cincinnati area.
Blood samples were collected on an irregular basis but were taken sufficiently often to
have at least one sample from a child from every house studied. The blood samples were
analyzed for lead by two laboratories that had different histories of performance in the CDC
proficiency testing program. All bipod lead levels used in the statistical analysis were ad
justed to a common base.. Because of the variable number of fecal and blood lead levels, the
data viere analyzed using a nested analysis of variance.
11-156
,r DUP040012466
G H J L D R E N 'S B L O O D L E A D LE V E LS , Aig/dl
t --i--i--r--i--i--r--r --------SURFACES IN BAD CONDITION, i.e., PEELING. 30 CHALKING, OR POOR SUBSTRATE
ALL SURFACES
.w
*
25
_^
F*..' ' "o" 20
mO n
-cr
i
1-5
0i
0
1______L
L,_____L
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
FRACTIONS OF SURFACES WITH LEAD >2 mg/cm2
1.0
Figure 11-30- Correlation of children's blood lead levels with fractions of surfaces within a dwelling having lead concentrations > 2 mg Pb/crm2.
Source: Urban (1976).
11-157
DUP040012467
The homes of the children were found to be distributed across the paint and traffic lea<j
exposure categories. Both fecal lead levels and blood levels were positively associated with
interior paint lead hazard. A marginal association between fecal lead levels and exterior
paint hazard was also obtained. Neither fecal lead nor blood lead was found to be associated
with traffic density-; the definition of the high traffic density category, however, began at a
low level of traffic flow (7500 cars/day).
V^
Examination of fecal and blood lead levels by sex and race showed that black males had
the highest fecal lead excretion rates followed by white males and black females. White
females were only represented by two subjects:, both of whom had high fecal lead excretion.
Blood lead levels were more influenced by race than by sex. The results suggested that
Children in high and medium paint hazard homes (high = at least .1 surface with >0.5 percent
Pb, peeling or loose) were probably ingesting paint in some form. This could not be con
firmed, however, by finding physical evidence in the stools.. f Long-term stool collection in a subset of 13 children allowed a more detailed examination
of the pattern of fecal lead excretion. Two patterns of elevated fecal , lead excretion were
noted. The first was a persistent elevation compared with Controls; the second was markedly
elevated occasional spikes against a normal background. One family moved from a high-hazard home to a low one during the course of the study.
This a 11 owed a detailed exa(nination of the speed of deleading.of fecal and blood lead level.
The fecal levels decreased faster than .the blood lead levels. The blood leads were still
elevated at the end of the collection.
.
Gilbert et al. (1979) studied a population of Hispanic youngsters in Springfield,
Massachusetts, in a case control study designed to compare the presence of sources of lead in
homes of lead-poisoned children and appropriately matched controls. Cases were defined as children having two consecutive blood lead levels greater than 5.0 pg/dl. Controls were chil
dren with blood lead levels less than or equal to 30 pg/dl who had no previous history of lead
intoxication and were not siblings of children with blood lead levels greater than 30 pg/dl.
Study participants had to .be residentially stable for at least 9 months and not have moved
into their current home from a lead contaminated one. All-blood lead levels were analyzed by
Delves cup method of- AAS. Cases and controls were matched by age (+3 months), sex, and neigh
borhood area. The study population consisted of 30 lead intoxication cases and 3.0 control
subjects.
*
Home visits were undertaken to gather interview information and conduct home inspection.
Painted surfaces were assessed for integrity of the surface and lead content. Lead content
was measured by X-ray fluorometry. A surface was scored as positive if the lead content
exceeded 1.2 mg/cm2. Drinking water lead was assessed for each of the cases and was found to
11-158
DUP040012468
contain less than 50 pg/1, thought by the authors to be sufficiently low sp as not to consti^ tute a hazard, tap water samples were not collected in the homes of the controls. Soil samples were collected from three sites in the yard and analyzed for lead by X-ray fluorometry.
Cases and controls were compared on environmental lead exposures and interview data^using McNemar's test for paired samples. The odds ratio was calculated as an estimator of the rela tive risk on all comparisons- Statistically significant differences between cases and con trols were noted for lead in paint and the presence of loose paint. Large odds.ratios (>"0) were obtained, suggesting a very strong association of blood lead level and paint lead expo sure. There appeared to be little influence of age of sex on the odds ratios.
Significant differences between cases and controls were obtained for both intact and loose paint by individual surfaces within specific living areas of the home. Surfaces acces sible to Children were significantly associated with lead potso.ning status while inaccessible Surfaces generally were not. Interestingly, the odds ratios tended to be larger for the in tact surface analysis than for the loose paint one.
Median paint lead levels ih the homes of cases were substantially higher than those in the homes of controls. The median paint lead for exterior surfaces in cases was about 16-20pg/cm2 and about 10 pg/cm2 for interior surfaces. Control subjects lived in houses in which the paint lead generally was less than 1.2 pg/cm2 except for some exterior surfaces. Soil lead was significantly associated with lead poisoning; the median soil lead level for homes of cases was 14-30 pg/g, while the median soil lead level for control-homes was 440 pg/g,
Rabinpwitz et al, (1985b) report that refi.nishifig activity in homes with high paint lead was associated with elevations of blood lead averaging 69 percent. Blood lead levels of 249 infants were measured semiannually. from birth to two years of age. Also, home paint was sampled and 'any recent home refinishing was recorded. Mean blood lead correlated signifi cantly with the amount of lead in the indoor paint.
Two other studies have attempted to relate blood lead levels and paint lead as determined by X-ray fluorescence, Reece et al. (1972) studied 81 children from two lower socioeconomic communities in Cincinnati. Blood leads were analyzed by the dithizone method. There was con siderable lead in the home environment, but it was not reflected in the children's blood lead. Analytical procedures used to test the hypothesis were not described; neither were the raw data presented.
Galke et al. (1975), in their study of inner-city black children, measured the paint lead, both interior and exterior, as well as soil and traffic exposure. In a multiple regression analysis, exterior siding paint lead was found to be significantly related to blood lead levels.
11-159
DUPQ40012469
Evidence indicates that a source of exposure in childhood lead poisoning is peeling lead paint and broken lead-impregnated plaster found in poorly maintained, houses,. There are also reports of exposure cases that cannot be equated with the presence of lead paint. Further, the analysis of paint in homes of children with lead poisoning has not consistently revealed a hazardous lead content (Lin-Fu, 1973). For example, one paper reported 5466 samples of paint obtained from the home environment of lead poisoning cases in Philadelphia between 1964 and 1968. Among these samples of paint, 67 percent yielded positive findings, i.e., paint with more than 1 percent lead (Tyler, 1970).
Data published or made available by the Centers for Disease Control also show that a sig nificant number of children with undue lead absorption occupy buildings that were inspected for lead-based paint hazards, but in which no hazard could be demonstrated (U.S. Centers for Disease Control, 1977a; Hopkins and Houk, 1976). Table 11-65 summarizes the data obtained frpm the HEW-funded lead-based paint poisoning control projects for Fiscal Years 1981, 1979, 1978, 1975, and 1974, These data show that in Fiscal Years 1974, .1975, and 1978, in 40-50 percent of confirmed cases of eleyated blood lead levels, a possible source of lead paint hazard was net located, in fiscal year 1.981, the U.S, Centers for Disease Control (1982a,b), screened 5.35,730 children and found 21,897 with lead toxicity. Of these, 15,472 dwellings were inspected and 10,666 or approximately 67 percent were found to have leaded paint. The implications Of these findings are not clear. The findings are presented in order to place in , proper perspective both the concept of total lead exposureand the concept that lead paint is one source of lead that contributes to the total body load. The background contribution of lead from other sources is still not known, even for those children for whom a potential lead paint hazard has been identified; nor is it known what proportion of lead came from which source.
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DU P040012470
TABLE 11-65. RESULTS OF SCREENING AND HOUSING INSPECTION IN CHILDHOOD LEAD POISONING CONTROL PROJECT BYFISEAL YEAR
Results
1981
1379;
Fiscal year 1978
= 1975
Children screened
535,730
464,751
397,963
440,650
Children with elevated lead exposure
21,897
32,537
25,801
28,5.973
Dwel1ings inspected
15,472
17,911
36,138
30,227
Dwellings with lead hazard
10,666
aConfirmed blood lead level >40 jjg/dl.
12,461
18,536
-
17,609
Source: U.5, Centers for Disease Control (1977a, 1979, 1980, 1982a,b); Hopkins and Houk, 1976.
1974 371,955
16,228 23,096 13,742
11.5 SPECIFIC SOURCE STUDIES The studies reviewed in this section all provide important Information regarding specific
environmental sources of airborne lead that play a role in population blood lead levels. These studies also illustrate several interesting approaches to this subject.
' 11.5.1 Primary Smelter Populations Some studies of nonindustry-employed populations living in the vicinity of industrial
sources of lead pollution were triggered because evidence of severe health impairment had been found.. Subsequently, extremely high exposures -and high blood lead concentrations were' found. The following studies document the excessive lead exposure that developed, as well as some of the relationships between environmental exposure and human response. '11.5.1.1 E1 Paso, Texas; In 1972, the Centers for Disease Control studied the relationships between blood lead levels and environmental factors in the vicinity of a primary smelter lo cated in El Paso, Texas emitting lead, copper, .and zinc. The smelter had been in operation since the late lSDO's (landrigan et al., 1975; U.S. Centers for Disease Control, 1973). Daily hi-vol samples collected on 86 days between February and June, 1972, averaged 6.5 pg/m3. These air lead levels fell off rapidly with distance, reaching background values approximately 5 km from the smelter. Levels were higher downwind, however. High concentrations of lead in soil and house dusts were found, with the highest levels occurring near the smelter. The geo metric means of 82 soil and 106 dust samples from the sector closest to the smelter were 1791
11-161
DUP040012471
and 4022 pg/g, respectively. Geometric means of both soil and dust lead levels near tlife
smelter were significantly higher than those in study sectors 2 or 3 km farther away.
Sixty-nine percent of children 1 to 4 years old living near the smelter had blood lead
levels greater than 40 jjg/dl, and 3,4 percent had blood lead levels that exceeded 60 pg/dl,.
Concentrations in older individuals were lower; nevertheless, 45 percent of the children 5 to 9 years old, 31 percent of the individuals 10 to 19 years old, and 16 percent of the^indivi-
duals above 19 had blood lead levels exceeding 40 pg/dl. The data presented preclude calcula
tions of means and standard deviations.
-
Oata for people aged 1-19 years of age living near the smelter showed a relationship
between blood lead levels and concentrations of lead, in soil and dust.. For individuals with
blood lead levels greater than 40 pg/dl, the geometric mean concentration of lead in soil at
their homes was 2597 pg/g, whereas for those with a blood lead concentration'less than 40 pg/dl., home soils had a geometric mean of 1419 pg/g. For hopse dust, the respective geometric
means were 6447 and 2067 pg/g. Length of residence was important only in the sector nearest
the smelter.
Additional sources of lead were also investigated. A relationship was found between
blood lead concentrations and lead release from pottery, but the number of individuals exposed
to lead-glazed pottery was very small, ho relationships were found between bipod lead levels
and hours spent out-of-dpors each day, school attendance, or employment of a parent at the
smelter. The reported prevalence of pica also was minimal.
Data `on dietary intake of lead were not obtained because there was no food available from
sources near the -smelter since the climate and proximity to the smelter prevented any farming
in the area. It was unlikely that the dietary lead intakes of the children from near the
smelter or farther away were significantly different. It was concluded that the primary factor associated with elevated blood lead levels in the children was ingestion or inhalation
of dust containing lead, .
Morse et-al. (1979) conducted a .follow-up investigation of the El Paso smelter to deter
mine whether the environmental controls instituted following the 1972 study had reduced the
lead problem described. In-November, .1977, all children 1 to 18 years old living within
1,6 km of the smelter on the U.5. side of the border were surveyed, Questionnaires were ad
ministered to the parents of each participant to gather background data. Venous blood samples were drawn and analyzed for lead by modified Delves cup spectropho-*
tometry. House dust and surface soil samples, as well as sample pottery items, were taken
from each participant's residence. Dust and soil samples were analyzed for lead.by AAS,
Pottery lead determinations were made by the extraction technique of Klein, Paint, food, and
water specimens were not collected because the earlier investigations of the problem had
demonstrated these media contributed little to the lead problem in El Paso.
11-162
DUP040012472
Fifty-five of 67 families with children (82 percent) agreed to participate in the study. There were 142 children examined in these homes. The homes were then divided Into' two groups. Three children lived in homes within 0.8 km of the smelter. Their mean blood lead level in 1977 was 17.7 gg/dl. By contrast, the mean blood lead level of 160 children who lived within 0.8 km of the smelter in 1972 hadbeen 41.4 gg/dl. In1977, 137 children lived in hgmes lo cated 0.8-1.6 "km from the smelter: Their mean blood lead level was 20.2 gg/dl. The mean blood level of 96 children who lived in that same area in 1972 had been 31:2 gg/dl.
Environmental samples showed a similar improvement. Dust lead fell from 22,191 to .1,479 pg/g while soil lead fell from 1,791 to 4:27 pg/g closest to the smelter. The mean air lead
concentration at 0,4 km from the smelter decreased from 10,0 to 5,5 gg/m3 and at 4,0 km from
2.1 to 1.7 gg/m3. Pottery was not found to. be a problem. 11.5.1.2 CDC-EPA Study. Baker et al. (1977b), in 1975, surveyed 1774 children 1-5 years old, most of whom lived within 4 miles of lead, copper, or zinc#Smelters located in various parts of the United States. Blood leadlevels were modestly elevated near 2 of the 11 copper and 2 of the 5 zinc smelters. Although blood lead levels in children were not elevated' in the vicinity of three lead .smelters, their PEP levels were somewhat higher than those found in controls. Increased levels of lead and cadmium in hair samples were found near lead and zinc smelters; this was considered evidence of external exposure. No environmehtal determinations were made for this study. 11.5.1.3 Meza Valley, Yugoslavia. A series of Yugoslavian studies investigated exposures to lead from a mine and a smelter in the Meza Valley over a period of years (Fug.as et al,, 1973; Graovae-teposavic et al. 1973; Milic et al., 1973; Ojuric et al,, 1971, 1972). In 1967, - 24-hour lead concentrations measured four on different days varied from 13 to-84 pg/ro3 in the village nearest the smelter, and concentrations of up to 60 gg/m3 were found as far as 5 km from the source, ''Mean particle size in 1968 was less, than 0.8 pm/- Analysis of some common foodstuffs showed concentrations that were 10-100 times higher than corresponding foodstuffs from the; least exposed area (Mezica) (Djuric et .al., 1971). After January, 1969, when partial control of emissions was established at the smelter, weighted average weekly exposure was cal.culatecl to be 27 gg/m3 in the village near the smelter. In contrast to'this, the city of Zagreb (Fugas et al., 197.3), which has no large stationary source of lead, had an average weekly air lead level of 1.1 gg/m3.
In 1968, the average concentration of ALA in urine samples from 912 inhabitants of 6 vil lages varied by village from 9.8-13 mg/1, A control group had a mean ALA of 5.2 mg/k Data on lead in blood and the age and sex distribution of the villagers were not given (Ojuric et al., 1971),
11-163
DUP040012473
Of the 912 examined, 559 had an ALA level greater than 10 mg/1 of urine. In 1969, a more*
extensive study of 286 individuals with ALA greater than 10 mg/1 was undertaken (Graovac-
Lepqsavic at al. 1973). ALA-IJ increased significantly from the previous year. When the pub
lished .data were examined closely, there appeared to be some discrepancies in interpretation^
The exposure from dust and from food might hate been affected by the control devices,^but no
data were collected to establish this. In one village, Zerjua, ALA-IJ dropped from 21.7 to 9.4
mg/1 in children 2-7 years of age. Corresponding ALA-U values for 8- to 15-year-olds and for
adult men and women were reduced from 18,7 tb 12,1,. from 23.9 to 9.9, and from 18.5 to 9.0
mg/1., respectively. Because lead concentrations 1ft air (Fugas et al. , 1973), .even after 1969,
indicated ah average exposure of 25 pg/m3, it is possible that some other explanation should
be sought. The author indicated in the report that the decrease in ALA-U showed "the depen
dence on meteorplogic, topographic, and technological factors" (Graovac-Leposavie et al.,
1973),
.
Fugas (1977) in a later report estimated the time-weighted average exposure of several
populations studied during-the course of this project. Stationary samplers as well as per
sonal monitors were used to estimate the exposure to airborne Tead for various parts of the
day. These values were then coupled with estimated proportions of time :at which these expo
sures held. In Table 11-66, the estimated time-weighted vaif lead values- as well as the
observed mean blood lead levels for these studied populations are presented. An .increase in
blood lead values occurs with increasing air lead exposure,
TABLE 11-66. MEAN BLOOD LEAD LEVELS IN SELECTED YUGOSLAVIAN POPULATIONS, BY ESTIMATED WEEKLY TIME-WEIGHTED AIR LEAD EXPOSURE
Population Rural I Rural II Rural III Postmen Customs officers Street car drivers Traffic policemen
N 49 47 45 44 75 43 24
Time-weighted air.lead, (pg/m3)
0.079 0,094 0.146 1.6 1.8 2,1 3.0
Blood lead level, (pg/dl)
Mean
SD
7.9 4,4
11,4
4.8
'10.5
4.0
18.3
9.3
10.4
3.3
24.3
10.5
12.2
5.1
Source: Fugas, 1977.
1
11-164
DUP040012474
11.5.1.4 Kosovo Province. Yugoslavia. Residents living in the vicinity of the Kosovo smelter were found to have elevated blood lead levels (Popovac et al., 1982). In this area of Yugoslavia, five air monitoring stations had been meas.uHng- air Iead'levelS since 1973. Mean air lead varied from 7.8 to 21.7 pg/m3 in 1973; by 1980 the air lead averages ranged from 21-3 to 29.2 pg/m3. In 1978 a pilot study suggested that there was a significant incidence of .elevated blood lead levels in children of the area. Two major surveys were than undertaken.
In August, 1978, letters were sent to randoinly Selected families from the business commu nity, hospitals or lead-related industries in the area. All family members were asked to come to a hospital for primary screening by erythropyte protqpdrphyrihi A central population of comparable socioeconomic and dietary background was collected from \a town without lead emis sions, Blood levels were determined primarily for persons.with EP greater than .8 pg/g Hgb. EP was measured by a hematof1uorimeter, while blood lead was determined by the method of Fernandez using atomic absorption with graphite furnace and background correction.
Mean EP values were higher in the 1978 survey for exposed residents compared to controls in the average age group. . EP values seemed to decline with age. Similar differences were noted for blood lead levels. The observed mean blood leads, ranging from 27,6 in the greater than 15 year age group to 50.9 pg/dl in the 5 to 10 year group, suggest substantial lead ex posure of these residents. In the control group the highest blood lead level was 19 pg/dl. In- Ddceitiber, 1980, a second survey was conducted to obtain a more representative sample of persons residing in the area. Letters were sent again, and 379 persons responded. EP levels were higher in all ages in 1980 versus 1973, although the differences were not statistically significant. The air lead levels increased from 14.3, pg/m3 in 197$ to 23.8 pg/m3 in 1980.
Comparing the i960 blood lead results with the 1978 control group shows that the 1980 levels were higher in each age group. Males older than 15 years had higher mean blood lead levels than the females (39.3 veilsus 32.4 pg/dl). 11.5.1.5 The Cava!leri- Study. Sav.alleri et al, (1981) studied children In the vicinity of a lead smelter and children from a control area (4 km from the smelter). The exposed population consisted of 85 children aged 3-6 attending a nursery school and 80 primary school children aged 8 to. 11. The control population was 2S nursery school children aged 3-6 and 64 primary school children aged 8-11. Since the smelter had installed filters 8 years before the study, the older children living in the smelter area had a much higher lifetime exposure.
Blood lead analysis was performed on venous samples using anodic stripping voltammetry by Morrell's method. Precision was checked oyer the range of 10-10.0 pg/dl. Reported reproduci bility was also good- All samples were subsequently reanalyzed by AAS using graphite furnace and background correction by the method of Volosen. The average values obtained by the second method were quite similar to those of the first (average difference 1.4 pg/dl; correla tion coefficient, 0.962).
11-165
DUP040Q12475
Air was sampled for lead for 1 month at three sampling sites. The sites were located at'
150 m, 300 m, and 4 km from the wall of the lead smelter,- The average air lead levels were
.2,32, 3.43, and 0.56 pg/m3, respectively. - f
'"
A striking difference in blood lead levels Of the exposed and control"populations was ob-u
Served; levels in the exposed population were almost twice that-in the control population.
There was no significant difference between nursery school and primary School chitdreif. The
geometric mean for nursery school children was 15.9 and 8,2 for exposed and control, respecti
vely. For primary school it was 16.1 and 7;0 pg/dl,. |n the Exposed area, 23 percent of the
subjects had blood lead levels between 21 and 30 pg/dl and 3 percent greater than 31 pg/dl.
No control children had blood lead levels greater than .20 pg/dl. The air 1dads Were between
2-3 pg/m3 in the exposed and 0.56 pg/m3 in the ..control cases,
'
11.5.1.6 Hartwell Study. Hartwell et al. (1983) report a study of 4 primary smelters: two
lead and two zinc. Study subjects were recruited in accordance with a statistical sampling
plan based on diffusion modeling. Subjects were recruited to represent a variety of ages:
1-5 years, 6-18 years, 20-40 years, and, in two sites, >60 years. Environmental samples
covering the important environmental sources of lead were obtained, as were blood samples.
Unfortunately, air sampling was only conducted for about 1 month in each of tlie study areas.
Oust, water, and soil samples were also collected and analysed for lead. Table 11-67 sum
marizes the descriptive results of this .study in terms of blood lead levels. Table 11-68
presents the Spearman correlation coefficient obtained.
11.5.2 Battery Plants
.
Studies of the effects of storage battery plants have been reported from France and Italy
(Dequidt et al., 1971; De Rosa and Gobbato, 1970), The French study found that children from
an industrialized area containing such a plant excreted more ALA than those living in-a diffe
rent area (Dequidt et al., 1971). Increased urinary excretion uf lead and coproporphyrins was
found in children living up to 100 m from a battery plant in Italy (Oe Rosa and Gobbato,
1970). Neither study gave data on plant emissions or lead in air,
11.5.3 Secondary SmeltersZielhufs et al. (1979) studied children living in the vicinity of the Arnhem secondary
lead smelter. In 1976 they recruited children to serve as subjects and controls. The chil- * dren chosen were 2 and 3 years old. Parents were asked to complete a questionnaire for back ground information, Two-ml venous samples were collected from 17 children living less than 1 km, from 54 children living 1-2 km, and from 37 children living greater than 2 km from the-' smelter (control group), 81ood samples were analyzed for lead by graphite furnace AAS and for
.11-166
DUP040012476
TABLE 11-67. LEVELS OF LEAD RECORDED IN HARTWELL ET AL, {1983) STUDY
Smelter Bartlesville
Palmerton
Ajo
Anaconda /
Distance from, smelter
3.5-24.0 1.3-3.7 0.8*4.3 0.8-1.5
11,0-26.0 5.4-14.5 3.3-9.9 0.3-2.8
3.4-68.0 1.0-6.4 0,5-2.3 0.5-1.3
10.0-26.0 3.5-21.0 2.0-li.0 2.0-3.5
Air
131 203 299 309
361 563 .128 278
94 108 191 256
141 176
91 255
Dust
241 409 386 441
263 201 198 438 .
74.2 60.0 64.7 116
235 164 210 338
Water
PbB Soil Ages l-\5 Ages 6-10
6.04
4,56
e.sr
7,63:
34.8 243
829 821
10.5 24.7 39.6 18.8
'll A
12.9 21.8 20.3
8-7 6,0 2.8 1.8
.6.9. 11,5^ 13.3
3.1
3.10 -3.52 ' 3.02 3.83
532 : 117 ' 326 . 331
- 57.8 64.5 76.5 94,8
75 115 294 424
10.3 11.3 12.6 15.9
9.9 .10,6 10.5
9,2
21.0 17.3 18.8 21.5
12,4 10,2 11.2 10.3
7.8 7.7 6.9 6,9
19.0 11.9 14.3 17.9
TABLE 11-68. SPEARMAN CORRELATIONS OF LEAD IN AIR, WATER, DUST, SOIL, AND PAINT WITH LEAD LEVELS IN BLOOD: BY SITE AND AGE GROUPS, 1978-1979
Bartlesville Palmerton
Air Water Oust ' Soil Paint
Air Water Oust Soi 1 Pai nt
` 1-5
Blood
0.40* 0.05 0.20 0.33^ -0.06
-0.12 -0.06
0.06 0.16 -0,02
^Significantly different from zero at 0.05 level.
6-18
Blood
0,22* 0.14 0.10 0.13 0.06
Age (yr) 20-40' Blood 0.27* 0.07 0.21
0.07
0.02 0.11 -0.07 0.20
0.06
-0.12 -0.01 -0.05
0,23*
Over 60 81ood 0.19 0.23 0,00.
-0.06
11-167
DU P040012477
FEP by the method of Piomelli. Air measurements for lead were made in autumn, 197$. Samples* were established about 2 km northeast and about (3.4 km north of the plant. Air lead levels ranged from 0.8 to 21.6 pg/m3 northeast and from 0.5 to 2.5 pg/m3 north of the plant.
Blood leads 'were statistically significantly higher closer to the smelter. For all chil dren the mean blood lead level was .19,7 pg/dl for the less than 1 km and 11,8 pg/dl for the controls (>2 km). Similarly, FEP levels were higher for the closer (41.9 pg/100 ml erythro cytes) children as opposed to the control (32.5 pg/100 ml BBC}. Higher blood levels were associated with lower socioeconomic status.
Farther investigation of this smelter was undertaken, by. Brunekreef et al, (1981) and Diemel et al. (1981), In May, 197$, venipuncture blood samples were collected from 95 one- to three-year~old children living within 1 km of the smelter. Blood leads were determined by graphite AAS.
Before the blood sampling, an environmental sampling program was conducted. The samples collected are listed in Table 11-69. Questionnaires were administered to collect background and further exposure information. A subset of 39 children was closely observed for 1 or 2 .days for mouthing behavior. Table 11-69 also presents the overall results of the environmen-. tal sair.pling. As cab be readily seen* there is a low exposure to airborne lead (geometric mean) 0.41 pg/m3 with a range of 0.28-0,52 pg/m3). Soil exposure was moderate, although high. Interior dust was high in lead (geometric mean of 967 pg/g with a maximum of 4741- pg/g). In a few homes, high paint lead levels were found, Diemel et al. (1981) extended the analysis of the environmental samples. They found that indoor pollution was lower than outside. In Arnhem,: it was found that lead is carried Into the homes in particulate form by sticking to shoes. Most of the lead originated from soil from gardens and street dust.
Simple correlation coefficients were calculated to investigate the relationship between log blood lead and the Independent variables. Significantly, correlations were found with quantity of house dust, quantity of deposited lead indoors, observational score of dustiness, age of child, and the average number of times an object is put in the mouth. Multiple regre ssion analyses were calculated on four separate subpopulations. Among children living in houses `with gardens, the combination of soil lead level and educational level of the parents explained 23 percent of the variations of blood lead. In children without gardens, the amount of deposited lead indoors explained 26 percent of the variance. The authors found that an in crease in soil lead level from 100-600 pg/g resulted in an increase in blood lead of 6.3 * pg/dl.
Iri a Dallas, Texas, study of two secondary lead smelters, the average blood lead level of exposed children was found to be 30 pg/dl versus an average of 22 pg/dl in control children (Johansen and Luby, 1972). For the two study populations, the air and soil lead levels were 3.5 and 1.5 pg/m3 and 727 and 255 pg/g, respectively,
11-168
DUP040012478
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11-169
A ll lead analyses were performed by atomic absorption spectrophotometry, except p a rt o f the tapwater analysis which was performed by anodic s trip p in g voltam etry. Lead in tapwater analyzed by the National In s titu te of Drinking Water Supply in Leidscherdam. S oil and s tre e t dust analyzed by the Laboratory o f S oil and P lant
Research in Oosterbeek. (Z ie lh u is , e t. a l . , 1979; Diemel, et. a l. , 1981)
DUP040012479
In Toronto, Canada, the effects of two secondary lead smelters on the blood and hair lead1
leysIs of nearby residents have been extensively studied (Ontario Ministry of the Environment,
1075;. F'oberts et al., 1974). In a preliminary report, Roberts et al, (1974),.stated that blood
and hair 'lead levels were higher iri children living near the two smelters than in children
living in an urban control area. `Biologic and environmental lead levels were reported to de
crease with increasing distance from the base of the smelter stacks,
x
A later and more detailed report identified a high rate of lead fallout around the two
secondary smelters (Ontario Ministry of the Environment, 1975). Two groups of,chiIdren living
within 300 m of each of the smelters had geometric mean blood lead levels of 27 and 28 pg/dl,
respectively; the geometric mean for 1231 controls was 17 pg/dl. Twenty-eight percent of the
sample children tested hear one smelter during the summer and 13 percent of the sample chil
dren tested.near the second smelter during the winter had blood lead levels greater than 40
pg/dl. Only 1 percent of the controls had blood lead levels greater than 40 pg/dl. For chil
dren, blood lead concentrations increased with proximity to both smelters, but this trend did
not hold for `adults, generally. The report concluded that soil lead levels were the main de
terminant of blood lead levels:; this conclusion was disputed by Horn (1976).
Blood lead levels in 293 Finnish individuals, aged 15-80, were significantly correlated
with.proximity to-a secondary lead smelter (Nordman et al. , 19731, The geometric mean .blood
lead concentration for 121 males was 18;1 pg/dl; for. 172 females, it was 14.3 pg/dl. In 59
subjects who spent their entire day at home., a positive correlation was found between blood
lead and distance from the smelter up to 5 km. Only'one of these 59 individuals had a blood
lead greater than 40 pg/dl, and none exceeded" 50 pg/dl.
11.5,4 Secondary Exposure of Children Excessive intake and absorption of lead on the part of children can result when parents
Who work in a dusty environment with a high lead content bring dust home on their clothes, shoes, or even their automobiles. Once they are home, their children are exposed to the dust.
La.ndrigan et al, (1976) reported that the 174 children of .smelter workers who lived with in 24 km of the smelter had significantly higher blood lead levels, a mean of 55.1 pg/dl, than the 511 children of persons in other occupations living in the same areas whose mean blood lead levels were 43.7 pg/dl. Analyses by EPA of the data collected in Idaho showed that employment of the father at a lead smelter, at a zinc smelter, or in a lead mine resulted in* higher blood lead levels in the children living in the same house as opposed to those children whose fathers were employed in different locations (Table 11-70). The effect associated with parental employment appears to be much more prominent in the most contaminated study areas;nearest to the smelter. This may be the effect of an intervening socioeconomic variable: the
11-170
DUP040Q12480
TABLE: 11-70. GEOMETRIC MEAN BLOOD LEAD LEVELS FOR CHILDREN BASED ON REPORTED OCCUPATION
OF FATHER, HISTORY OF PICA, AND DISTANCE OF RESIDENCE FROM SMELTER (micrograms per deciliter)
Distance from
Area smelter, km
1 1..6
2 . 1.6 to 4.0
3 4.0 to 10.0
4 10.0 to 24.0
5 .24,0 to 32.0
0 75
Lead smelter
worker No
Pica Pica
78.7 74.2
50,2 52.2
33.5 33.3
30.3
* 24.5
--
Lead/zinc mine
worker
No
Pica
Pica.
75.3
63,9
46.9
46,9
36.7
3315
38.0
32.5
31,8
27,4
--
Zinc smelter worker No
Pica Pica
69.7 59.1
62,7 50,3
36.0 29.6
-|0,9 -
36.9 -
*
OtheF occupations-
No Pica Pica
70.8 59.'9
37.2 46,3
33.3 32.6
- 39.4
28.0 26.4
17,3 21.4
Source: Landrigan et al, 1976.
lowest paid workers, employed in the highest exposure areas within the industry, might he ex pected to live in the most undesirable locations, closest to the smelter.
Lahdrigan et al. (.1976) also reported a positive history of pica for 192 of the 919 chil dren studied in Idaho- This history was obtained by physician and nurse interviews of parents. Pica was most common among 2-year-old children and only 13 percent of those with pica were above age 6. Higher blood lead levels were observed in children with pica than in those'without pica. Table 11-70 shows the mean blood lead levels in children as they were af fected by pica, occupation of the father, and distance of residence from the smelter. Among the populations living nearest to the smelter, environmental exposure appears to be sufficient
> *
at times to more than overshadow the effects of pica, but this finding may also be caused by inadequacies inherent in collecting data on pica. These data indicate that in a heavily con taminated area, blood lead levels in children may be significantly increased by the inten tional ingestion of nonfood materials having a high lead content.
Data on the parents1 occupation are, however, more reliable. It must be remembered also that the study areas were not homogeneous socioeconomically. In addition, the specific type of work an individual does in an industry is probably much more important than simply being employed in a particular industry. The presence in the home of an industrial employee exposed occupationally to lead may produce increases in the blood lead levels ranging from 10 to 30 percent.
11-171
DUP040Q12481
The Importance of the Infiltration of lead dusts onto clothing, particularly the under4' garments, of lead workers and their subsequent transportation has been demonstrated in a num ber of studies on the effects of smelters (Martin et al., 1975). It was noted in the United Kingdom that elevated blood lead levels were found in the wives and children of workers, even though they resided some considerable distance from the facility. It was most prominent in the workers themselves, who had elevated blood lead levels. Quantities of lead dust were found in workers' cars and homes. It apparently is not sufficient for a factory merely to provide outer protective clothing and shower facilities for lead workers. In another study in Bristol, 650-1400 pg/g of lead was found in the undergarments of workers as compared with'3-13 pg/g in undergarments of control subjects. Lead dust will remain on the clothing even after laundering: up to 500 mg of lead has been found to remain oh an overall garment after washing (Lead development Association, 1973).
Hiaker et al. (1977a) found blood lead levels greater.than 30 pg/dl in 38 of 91 children whose fathers were employed at a secondary lead smelter in Memphis, TN. House dust., the only source pf lead in the homls of these children, contained a mean of 2687 pg/g compared with 404 pg/g in the homes of a group of matched controls. Mean blood lead levels in the workers' children were significantly higher than those for controls and were closely correlated with the lead content of household dust. In homes with lead in dust less than 1000 pg/g, 18 chil dren had'a mean blood lead level of 21.8 7.8 pg/dl, whereas in homes where lead in dust was greater than 7000 pg/g, 6 children had mean blood lead, levels of 78.3 + 34,0 pg/dl. See Sec tion 7.3.2.1.6 for a further discussion of household dust.
Other studies have documented- increased lead absorption in children of families where at least one member was occupationally exposed to lead (Fischbein et al., 1980a). The occupa tional exposures involved battery operations (Morton et at., 1982; U.S. Centers for Disease Control, 1977b; Dolcourt et al., 1978, 1981; Watson et .al, , 1978; Fergusson et al.1981) as well as other occupations (Snee, 1932b; Rice et al,,. 1978),
In late summer of 1976, a battery plaht in southern Vermont provided the setting for the first documented instance of increased'lead absorption in children of employees in the battery industry. The data were first reported by the U.S. Centers- for Disease Control (1977b) and more completely by Watson et al. (1978). Reports of plant workers exposed to high levels of lead stimulated a study of plant employees and their children in August and September, 1975. In the plant, lead oxide powder is used to coat plates in the construction of batteries-* Before the study, the work setting of all 230 employees of the plant had been examined and 62 workers (22 percent) were identified as being at risk for high lead exposure. All of the high-risk workers interviewed reported changing clothes before leaving work and 90 percent of them reported showering. However, 87 percent of them stated that their work clothes were washed at home.
11-172
DUP040012482
Of the high-risk employees* 24 had children between the ages of 1 and 6 years, A case-
control study was conducted in the households of 22 of these employees. Twenty-seven children
were.identified, The households were matched with neighborhood controls, including 32 control
children. None of the control family members worked in a lead industry. Capillary blood
specimens vrere collected from all children and the 22 battery plant employees had venpus/Spec-
imens taken. All blood samples were analyzed for lead by AA& Interviewers obtained back
ground data, including an assessment of potential lead exposures.
About 56 percent of the employees' children had blood leads greater than 30 pg/dl com
pared v/ith about 13 percent Of the conttrol children. Mean blood lead levels were signifi
cantly different, 31.8 pg/dl and 21.4 pg/dl, respectively. Blood lead levels in children were
significantly correlated with employee blood lead levels.
House dust lead levels were measured in all children's homes. Mean values were .2239.1
pg/g and 718,2 pg/g for employee arid control homes, respectively; this was a statistically
significant difference. Examination of the correlation Coefficient between soil lead and
blood lead levels in the two sets of homes showed a marginally significant coefficient in the
employee households but no correlation in the Control homes. Tap water and paint lead levels
did not account for the observed .difference in blood leads between children of workers and
neighborhood controls. It is significant that these findings were obtained despite the. chang
ing of clothes at the plant.
Morton ei at, (1982) conducted their study of children of battery plant workers and con
trols during February-Mar.ch, 1978, Children were included in the study if one parent had at
least 1 year of occupational exposure, if they had lived at the same residence for at least 6
months, and if- they were from 12-83 months of age. Children for the control group had to have
no parental occupational exposure to lead for 5 years, and had to have lived at the same ad
dress at least 6 months.
'
Thirty-four children were control-matched to the exposed group by neighborhoods and age
(1 year). No matching was thought necessary for sex because in this age group blood lead
levels are unaffected by sex, The selection of the control population attempted to adjust for
both socioeconomic status as well as exposure to automotive lead.
Capillary blood specimens were collected concurrently for each matched pair. Blood lead
levels were measured by the CB.C lab using a modified Delves cup AA5 procedure. Blood lead
levels for the employees for the previous year were obtained from company records. Question
naires were administered at the same time as the blood sampling to obtain background informa
tion. The homemaker was asked to complete the interview to try to get a more accurate picture
of the hygiene practices followed by the employees.
11-173
DU P040012483
Children's blood lead levels differed significantly between the exposed and control
groups. Fifty-three percent of the employees1 children had blood, lead levels greater than 30
pg/dl, while no child in the control population had. a value greater than 30 pg/dl. The mean
blood lead For the children of the employees was 49.2 pg/dl with a standard deviation of 8.J
pg/dl.. These data represent the population average for yearly individual average levels. The
employees had an average greater than 60 pg/dl. Still, this is lower than the industry
average. Of the eight children with blood levels greater than 40 pg/dl, seven had fathers
with blood lead greater -than SO pg/dl. Yet there was not;a significant correlation between
children's blood lead level and father's blood lead level.
Investigations were made into the possibility that other lead .exposures could account for
the observed difference in blood lead levels between children of employees and control chil
dren. In 11 of the 33 pairs finally included in the study, potential lead exposures other
than fathers' occupations were found in the employee chi 1^ of the matched pair. These in
cluded a variety of lead sources such as automobile body painting, casting of lead, and
playing with spent shell casings. The control and exposed populations were again compared
after removing these 11 pairs from consideration. There was still a statistically significant
difference in blood lead level between the two groups of children.
An examination of personal Hygiene practices of the workers showed that within high-ex
posure category jobs, greater compliance with recommended lead containment practices resulted
in lower mean blood lead levels in children. Mean blood leads were 17.3, 36.0, and 41.9 pg/dl
for good, moderately good, and poor compliance groups, respectively. In fact, there was only
a small difference between the good hygiene group within the high-exposure category and the
mean of the control group .(17.3 pg/dl versus 15.9 pg/dl). Insufficient sample sizes were
available to evaluate the effect of compliance on medium and low lead exposures for fathers,
Doi.court et ai. (1978) investigated lead absorption in children of workers in a plant
that manufactures lead-acid storage batteries. The-plant became .known to these researchers as
a result of finding an elevated blood lead level in a 20-month-old child during routine
screening. Although the child was asymptomatic, his mother proved not to be. Two siblings
were also found to have elevated blood lead levels. The mother was employed by the plant; her
work involved much hard labor and brought her into continual contact with powdery lead oxide.
No uniforms or garment covers were provided by the company. As a result of these findings,
screening was offered to all children of plant employees,
4
During February to May, 1977, 92 percent of 63 eligible children appeared for screening.
Age ranged from 10 months to 15 years. About equal numbers of girls and boys underwent
screening. Fingerstick blood samples were collected oh filter paper and were analyzed fo?
lead by AAS. Children with blood lead levels equal to or greater than 40 pg/dl were referred
U-174
DUP040012484
for more detailed medical evaluation including an analysis of a venous blood specimen for
lead. Oust samples were collected from carpeting in each home and analyzed for lead by gra
ph'll e furnace AAg. Home tap water was analyzed for lead by.AA,>and house paint was analyzed
for lead by XRF.
Of the .58 children who had the initial f:lngerstick blood' lead elevation, 69 percyent had blood lead levels equal to or greater than 30 gg/dl. Ten children from six families had blood
lead levels equal to or greater than 40 pg/dl, and. blood lead levels were found to vary
markedly with age, the 0- to O^year-ojd category exhibited the highest mean (48.6 pg/dl) with
the 3- to 6-year-olds the next highest (38.2 pg/dl). Lowest mean values were found in the
equal to or greater than lO-year-old group; :2$,7 pg/dl).
More detailed investigation of the six families with the highest blood lead levels in
their children revealed the following: five of the six lived in rural communities, with no
pre-existing source of lead from water supply, house paig, industrial emissions, or heavy
automobile traffic. However, dust samples from the carpets exhibited excessively high lead
concentrations. These ranged from 1700 to 84,050 pg/g.
Fergusson et al, (1981) sampled three population groups.: general population, employees
of a battery plant, and children of battery plant employees, using hair lead levels as indices
of lead. ' Hair lead .levels ranged from 1.2 to 110.9 pg/g in the 203 samples from the general
population. The distribution of hair lead levels was nearly lognormal. Employees of the bat
tery factory had the highest hair lead levels (median ~250 pg/g), while family members (median
~40 pg/g) had a lesser degree of contamination and the general population (median ~5 pg/g)
still less,
,
.
Analysis of variance results indicated a highly significant difference between mean lead
-levels of the general survey and family members of the employees, and a significant difference
between the mean lead levels in the hair of the employees and their families. No significant
differences were found comparing mean hair lead- levels among family members in terms of`age
and sex. The analyses of the house dust suggested that the mechanism of exposure of family
members is via the lead in dust that is carried home. Mean dust lead level among the homes of
factory employees was 5580 pg/g .while the dust inside of houses along a busy road was only
1620 pg/g. Both of these concentrations are for particles less than 0.1 mm,
Delcourt et al, 1981) reported two interesting cases of familial exposure to lead caused
by recycling of automobile storage batteries. The first case was of a 22-member, four-
generation family living in a three-bedroom house in rural eastern North Carolina. The great
grandfather pf the index case worked at a battery recycling plant. He had two truckloads of
spent casings delivered to the home to serve as fuel for the wood stove; the casings were burned over a 3-month period.
11-175
DUP040012485
The index case presented with classic signs of acute lead encephalopathy, the most severe and potentially fatal form of acute lead poisoning, The bipod lead level was found to be 220 pg/dl. Three months after initial diagnosis and after chelation therapy, she continued to have seizures and was profoundly mentally retarded. Oust samples were obtained by vacuto cleaner and analyzed for lead by flameless AAS. Oust from a sofa near the wood stpve c.ontained 13,283 pg/g lead, while the kitchen floor dust had.41,<283 pg/g, There was ho paint lead.. All other members of the family had elevated blood lead levels ranging from 27-256 pg/dl.
The other case involved a truck driver working in a low-exposure area of a battery recycling operation in rural western North Carolina. He was operating an illegal battery re cycling operation in his home by melting down reclaimed lead on the kitchen stove. No family member was symptomatic for lead symptoms but blood lead levels ranged from 24 to 72 pg/dl. Soil samples taken from the driveway, which was paved with'^fragments of the discarded battery casings, contained 12-13 percent lead by weight.
In 'addition to families being exposed as a result of employment at battery plants, stu dies have been reported recently for smelter worker families (Sice et al., .1978; Snee, 1982c).. Rice et al. studied lead contamination in the homes of secondary lead smelters. Homes of em ployees of secondary smelters in two separate geographic areas of the country were examined to determine whether those homes had a greater degree of lead contamination than homes of workers in the same area not exposed to lead. Both sets of homes (area I and,IT) were examined at the same time of the year.
Thirty-three homes of -secondary smelter employees were studied; 19 homes in the same or similar neighborhoods were studied as controls. Homes studied were In good condition and were one- or two-family dwellings. Blood lead levels were not obtained for children in these homes. In the homes of controls, a detailed, occupational history was obtained for each employed person. Homes where one or more residents were employed' in a lead-contaminated environment were excluded from the analysis.
House dust samples were collected by Vostal1s method and were analyzed for lead by AAS. In one of the areas,-samples of settled dust were collected from the homes of employees and controls. Oust was collected over the doorways, in homes where the settled dust was collec ted, zinc protoporphyrin (ZPP) determinations were made in family members of the lead workers and in the controls.
In -both areas, the wipe samples were statistically significantly higher in the homes of employees compared to controls (geometric mean 79,3 61.8 pg/g versus 28.8 7.4 pg/g Area I; 112.0 2.8 pg/g versus 9.7 + 3.9 pg Area II). No significant differences were found between workers1 homes or controls between Area I and Area IT, Settled dust lead was significantly
11-176
DU P040G12486
higher in the homes of employees compared to .controls (3300 versus 1200 pg/g). Lead contents of particulate matter collected at the curb and of paint chips collected in the home were not significantly different between employee homes and controls. Zinc protoporphyrin determina tions were done on 15 children., 0 years or younger, ZPP levels were higher in employee chil dren than in control children. Mean levels were 61,4 pg/ml and 37.6 pg/ml, respectively.
s'
It should be noted again that the wipe samples were not different between employes homesin the two areas. Interviews with employees indicated that work practices were quite similar in the two areas.. Most workers showered and changed before going home. Work clothes were washed by the company. Obviously, much closer attention needs to be paid to other potential sources of lead introduction into the home (e.g., automobile surfaces).
From Mexico (Molina-Ballesteros et al., 1983) comes a report.of yet another Occupation which can contribute to the lead burden of children whose parents work ih settings contami nated by lead. One hundred and fifty-three children belongit^i to pottery-making families with home workshops were studied, as well as 30 randomly selected Children serying as controls. Venipuncture blood samples were collected arid analyzed by atomic absorption spectrophotometry. Mean blood lead levels were 15 pg/dl higher1 for .children whose parents had the home pottery workshops than for control children. The mean bipod lead level in the exposed children was
39.5 pg/dl, which indicates a high degree of lead absorption in these children.
11.5.5 Miseelianeous Studies
\
11.5.5.1 Studies Using Indirect Measures of Air Exposure,
.
11.5.5.1.1 Studies in the United States:. A 19.73 Houston study examined the blood lead levels
of parking garage attendants, traffic policemen, and adult females living near freeways
(Johnson et al., 1974), A control group 'for each of the three exposed populations was selec
ted by matching for age, education, and race. Unfortunately, the matching was not altogether
.successful; traffic policemen had less education than their controls, and the garage employees
were younger than their controls. Females were matched adequately, however. It should be
noted that the mean blood lead values for traffic policemen and parking garage attendants, two
groups regularly exposed to higher concentrations of automotive exhausts, were significantly
higher than the means for their relevant control groups, Statistically significant differ
ences in mean values were not found, however, between women living near a freeway, and control
women living at greater distances from the freeway.
A study of the effects of lower-level urban traffic densities on blood lead levels was
undertaken in Dallas, Texas, in 1976 (Johnson et al., 1978). The study consisted of two
phases. One phase measured air lead values for selected traffic densities and conditions,
ranging from equal to or less than .1,000 to about 37,000 cars/day. The second phase consisted
11-177
DUP040Q12487
of an epidemiological study of traffic density and blood lead levels among residents. 11-31 shows the relationship between arithmetic means of air lead.and traffic density. be seen from the graph, a reasonable fit was obtained.;
Figure As can
Figure 11-31. Arithmetic mean of air lead levels by traffic volume. Dallas, 1976. Source: Johnson et al. {1978).
In addition, for all distances measured (1.5-30.5 m from the road), air lead concentra tions declined rapidly with distance from the street. At 15 m, concentrations were about 55 percent of the street concentrations. In air lead collections from 1.5 to 30.5 m from the street, approximately 50 percent of the airborne lead was in the respirable range (<1 pm), and the proportions in each size class remained approximately the'same as the distance from the street increased.
Soil lead concentrations were, higher in areas with greater traffic density, ranging from. 73.6 pg/g at less than 1,000 cars per day to a mean of 105.9 at greater than 19,500 cars per day. The maximum soil level obtained was 730 pg/g, Dustfal 1 samples for 28 days from nine locations showed no relationship to traffic densities, but outdoor levels were at least 10 times the indoor concentration in nearby residences.
11-.17,8
DUP040012488
In the second phase, three groups of subjects, 1 to 6 years old, .1$ to 49 years old, and .50 years and older, were selected in each of four study areas. Traffic densities selected were less than 1,000, 8,000-14,000, 14,000-20,000, and 20,000-25,000 cars/day. The study groups averaged about 35 subjects, although the number varied from.21 to 50. The smallest groups were from the highest traffic density area. No relationship: between traffic density and blood lead levels in any of the age groups was found .(.Figure .11-32). Blood lead levels were significantly higher in children, 12-18 pg/dl, than in adults, 9-14 pg/dl,
Caprip et al. (1974) compared blood lead levels and proximity to major traffic arteries in a study reported in 1971 that included 5226 children in Newark, New Jersey, Over 57 per cent Of the .children living within 30.5 a of roadways had blood lead levels greater than 40 pg/dl, For those living between 30.5 and 61 "m from' the roadways, more than .27 percent had such levels, and at distances greater than 61 m, 31 percent exceeded 40 pg/dl. The effect of automobile traffic was seen only in the group that Hived wiihiji 30.5 m of the road.
No other sources of lead were considered in this study. However, data from other studies on mobile sources indicate. that it is unlikely that the blood lead levels observed in this study resulted entirely from automotive exhaust emissions..
In 1964, Thpmas et al. (1967) investigated blood lead levels in 50 adults who had lived for at least 3 years within 76 m. of a freeway (Us Angeles) and those of 50 others who had lived for a similar period,near the ocean or at least 1.6 km from a freeway. Mean blood lead levels for those near the freeway were 22.7 + 5.6 for men and .16.7 .+ 7,0 pg/dl for women. These concentrations were higher than for control subjects living near the ocean: 16.0 8.4 pg/dl for men and .9.9 4.9 pg/dl for women, The higher values, however, were similar to those of other Us Angeles populations. Measured mean air concentrations of lead in LosAngeles for October, 1964, were as follows: 12,25 2.70 pg/m3 at a location 9 m from the San Bernardino freeway; 13.25 1.90. pg/m3 at a fourth-floor location 91.5 m from the freeway; and 4,60 1.92 pg/m3 1.6 km from the nearest freeway. The investigators concluded that the dif ferences observed were consistent with coastal inland atmospheric and blood lead gradients in the Los Angeles basin and that the effect of residential proximity to a freeway (7.6-76 m) was not demonstrated.
Ter Hajar and Chadzynski report a study of blood lead levels of children living near three heavily travelled streets in Detroit (Ter Haar, 19.81; Ter Haar and Chadzynski, 1979). Blood' lead levels! were not found to be related to distance from the road but were related to condi tions of housing and age of the child after multiple regression analyses, 11.5,5.1.2 British studies. In a Birmingham, England, study, mean blood lead levels in 41 males and S8 females living within 800 m of a highway interchange were 14.41 and 10.93 pg/dl, respectively, just before the opening of the interchange in May, 1972 (Waldron, 1975). From
. 11-179
DUP040012489
*
BLOOD LEAD CONCENTRATION, jjg/dl
Figure 11-32. Blood lead concentration and traffic density by sex and age, Dallas, 1976.
Source; Johnson et ai. (1978).
11-180
DUP040012490
October, 1:972, to February, 1973, the respective values for the Same individuals were 18.95 and 14.93 pg/dl. In October, 1973, they were 23.73 and 19.21 gg/cii. The Investigators noted difficulties in the blood collection method during the baseline period and changed from capil lary to venous blood collection for the remaining two sets of samples. To interpret the significance of the change in blood collection method, some individuals gave both cagJilary and venous blood at the second collection. The means for both capillary and venous bloods were calculated for the 10 males add 23 females who gave both types of bldod samples (Barry,' 1975), The venous blood mean values for both these males and females were lower by 0.8 and 0.7 pg/dl, respectively. If these differences were applied to the .means of the third series, the mean for males would be reduced to 24,8 pg/dl and that fof the'fe'males to 18.7 pg/dl. These adjusted means still show an increase over the means obtained fdr the first series. Comparing only the means for venous bloods, namely series two andthree, again shows an in crease for both groups. The increase in blood lead values w#s larger than expected following the model of Knelson et al. (1973), because air lead values near the road were approximately 1 pg/rn3, The investigators concluded that either the lead aerosol of very small particles behaved more like a gas so that considerably more than 37 percent of inhaled material was absorbed, or that ingestion of lead-contaminated dust might be responsible.
Studies of taxicab drivers have employed different variables to represent the drivers' lead exposure (Flindt et al., 1976;' Jones et al., 1972): one variable was night versus dayshift drivers (Jones et al,, 1972); the other was mileage driven (Flindt et al;, 1976): No difference was observed, in either case.
The studies reviewed show that automobiles produce sufficient emissions to increase air and nearby'soil concentrations of lead as well, and to increase blood lead concentrations in children and adults. The problem is of greater importance when houses are located within 100 ft (30 m) of the roadway-, 11.5.5.2 Miscellaneous Sources of. Lead, The habit of cigarette smoking is a source of lead exposure. Shaper et al. (1982) report that blood lead concentration is higher for smokers than no.nsmokers and ..that cigarette smoking makes a significant independent contribution to blood lead concentration in middle-aged men in British towns. A direct increase in lead in take from cigarettes is thought to be responsible. Hopper and Mathews (1983) comment that current smoking has a significant effect on blood lead level, with an average increase of 5.8 percent In blood lead levels for every 10 cigarettes smoked per day. They also report that past smcking history had no measurable effect on blood lead levels. Hasselblad and Nelson (1975) report an average increase in women's blood lead levels of 1.3 pg/dl for "smokers com pared to nonsmokers in the study of Tapper and Levin .(1975).
11-181
DUP040012491-
Although no studies are available, it is conceivable that destruction of lead-containihg plastics (to recover copper), which has caused cattle poisoning, also could become a source of lead exposure for humans. Waste disposal is a more general problem.because lead-containing materials may be incinerated and may thus contribute to increased air lead levels-. This source of lead has not been studied in detail, Tyrer (1977) cautions of the lead hazard in the recycling of waste.
The consumption of illicitly distilled liquor has been shown to produce clinical cases of lead poisoning. Domestic and imported earthenware (Oe Rosa et a!,, 1980) with improperly fired glazes have also been related to clinical lead poisoning. This source becomes important when foods or beverages high in acid are stored in.earthenware containers, because the acid releases lead from the walls of the containers,.
Particular cosmetics, popular among some Oriental and Indian ethnic groups, contain high percentages of lead that sometimes are absorbed by users i {^.quantities sufficient to be toxic, Ali et al. (1978) and Attenburrow et al. (1980) discuss the practice of surma and lead poison ing, In addition to lead-containing cosmetics causing lead poisoning, folk remedies have also been linked to lead poisoning (0. 5. Centers for Disease Control., 1983a,b). Two Mexican folk remedies, Azarcon and greta, have been implicated as causing lead poisoning In children (U.S, Centers for Disease Control, 1983a). These products have a high lead content (70-90 percent) and are primarily lead tetroxide and lead oxide for. Azarcon and greta, respectively. There haye been a minimum of 15 reported cases of lead poisoning associated with, these products. A survey of Mexican-Hispanics living in Los Angeles estimated that 7.1-21.1 percent of MexicanHispanic households had at some time used these products,
A folk medicine used by Hmong .refugees from Northern Laos has also been implicated in lead poisoning of children (U.S, Centers for Disease Control, 1983b). The product, "pay-looah," has a variable composition and texture, making control more difficult. Other sources of lead are presented in Table 11-71.
Source
Gasoline sniffing
Colored gift wrapping Gunshot wound Drinking glass decorations Electric kettles Hair dye Snuff use Firing ranges Glazed pottery
TABLE 11-71. SOURCES OF LEAD
References
11-182
Kaufman and Wiese (1978) Coodin and Boeckx (1978) Hansen and Sharp (1978) Bertagnolli and Katz (1979)
Diliman et al, (1979) Anonymous (1979) Wigle and Chariebois (1978) Searle and Harnden (1979) Filippini and Simmler (1980) Fischb.ein et al. (1979, 1980b)
Acra et al. (1981)
DUP040012492
11.6 SUMMARY AND CONCLUSIONS Using the bones and teeth of ancient populations, studies show that levels of internal
.exposures of lead today are substantially elevated over past levels. Studies of current populations living in remote areas far from urbanized cultures show blood lead levels in the range of 1-5 pg/dl. In' 1con. trast to1 the b:lood lead l. evels found'in remo. te populations, X" data from current U.S, populations have geometric means ranging from <10 to 20 pg/dl depending on age, race, sex, and degree of urbanization. These higher current exposure levels appear to be associated with industrialization and widespread commercial use of lead, e,g., in gasoline .combustion.
Age appears to be one of the single .most important demographic covariates of blood .lead levels. Blood lead levels in children up to six years of age are generally higher than those in non-occupationally exposed adult?. Children aged two to three years tend to have the high est levels, as shown in Figure 11-33. Blood lead levels in ngp-oceupationally exposed adults may increase slightly with age due to skeletal lead accumulation.
Sex has a differential impact op blood lead levels depending on age. No significant dif ferences exist 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 months-5 years) have markedly higher blood lead concentrations than any other racial or age group.. Possible genetic factors associated with race have yet to be fully untangled from differential exposure levels and other factors as important determinants of blood lead levels.
Blood lead levels also generally increase with degree of urbanization. Data from NHANE.S II show blood lead levels in the United States, averaged over 1976^-1980, increasing from a geometric mean of 11.9rpg/dl in rural populations'to 12.8 p.g/dl - in urban populations .of less than one million, and increasing again to 14.0 pg/dl in urban populations of one million or more.
Blood lead levels, examined on a population basis, have similarly skewed distributions. Blood lead levels, from a- populatioh thought to be homogeneous in terms of demographic and lead exposure characteristics, approximately follow a lognormal distribution. The geometric standard deviations, an estimation of dispersion, for four different studies are shown in Table 11-72. The values, including [analytic error, are about 1.4 for children and possibly somewhat smaller for adults. This ajlows 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 may be derived from the NHANEjS II study when only gasoline and industrial air lead emission exposures are assumed to be controllable sources of variation.
11-183
DUP040012493
40 T
-- NEW YORK SCREENING - BLACKS -- NEW Yb#K SCREENING - WHITES .... NEW YORK SCREENING - HISPANiCS
-- NHANES II STUDY - BLACKS -- NHANES II STUDY - WHITES
15
1__
01-
1 -1
I
I
1
0 2 34 5 6
AGE, yr
9 10
Figure 11-33. Geometric mean blood lead levels by race and age for younger children in the NHANES 11 study, and the Kcllogg/Silver Valley and New York Childhood Screening Studies.
11-134
DUP040012494
TABLE 11-72. SUMMARY Of BLOOD LEAD POOLED GEOMETRIC STANDARD DEVIATIONS AND ESTIMATED ANALYTIC ERRORS.
Study
Pooled geometric standard deviations
Inner city ..;
Innef city
black children
white children
Adult females
Adult males
.Estimated analytic
error
NHANES II
N.Y, Childhood Screening Study
1.37* i>4l
lv39a 1^42
: . 1.36b 1.40b
0.021 _c
Tapper-.Laven Azar et al.
*
i'
1.30
- 0.056*
! i
~ -.
1.29
CL042b
Note: To calculate an estimated person-to-person GSD, compute'lxp [((In(GSQ))2 -
Analytic Error)1//2-*
\
aA geometric .standard deviation of 1.42 may be derived when only gasoline and industrial air lead emission exposures are assumed to he Control Table Sources of variability.
"Pooled across areas of differing urbanization
cNot known, assumed to be .similar to NHANES Jl
j * .*
Taken from Lucas (1981).
j
Recent U.S. blood lead levels show a downward temporal trend occurring consistently across race, age, and geographic location. The downward pattern commenced in the early part of the 19701s and has continued into 1980, The downward trend has occurred from a shift in the entire distribution and not through a truncation in the high blood lead levels. This con sistency suggests a general "causative factor, and attempts- have .been made to identify the
causative element. Reduction in lead emitted jfrom the combustion of leaded gasoline is a prime candidate.. ! i ;
Studies of data from bipod lead screening programs (i.e., New York City) spggest that the downward trend in blood lead levels noted earlier is due to the reduction in air lead levels, which has been attributed to the reduction of lead in gasoline:. The NHANES I.I analysis found a highly significant association between the declining blood lead concentrations for the over all U.S. population and decreasing amounts of lead used in gasoline in the United States during the same time period. Two studies used isotope ratios of lead to estimate the relative proportion of lead in the blood coming from airborne lead. From one study, by Manton, it can be estimated that between 7 and 41 percent of the blood lead in study subjects in Dallas
11-185
DUP040Q12495
resulted from airborne lead. Additionally, these data provide a means of estimating the in*
direct contribution of air lead to blood lead. By one estimate, Only 10 - 20 percent of the
total airborne contribution in Dallas is from direct inhalation.
From the ILE data in Faccbetti! and Gei.ss (1982) and Facchetti (1985), as shown in Table
11-73, the direct inhalation of ain lead may account for 60 percent of the total adult-blood
lead uptake from leaded gasoline in ja large urban Center, but inhalation i:s a much less impor
tant pathway in suburban parts of the region (19 percent of the total gasoline lead contribu
tion) and in the rural parts of tije region (9 percent of the total gasoline lead contribu
tion), f:PA analyses of the preliminary results from the ILE study separated the inhalation
and non-inhalation contributions oij leaded gasoline to blood lead into the following three
parts; (1) an increase of about l; 7 pg/dl in blood lead per pg/m3 of air lead, attributable
to direct inhalation of the combustion products of leaded gasoline; (2) a sex difference of
about 2 pg/dl attributable to lower exposure of women to ^idir.ect (non-inhalation) pathways
for gasoline lead; and (3) a non-inhalation background attributable to indirect gasoline lead
pathways, such as ingestion of dust and food, increasing from about 2 pg/dl in Turin to 3
I
'
pg/dl in remote rural areas. The ncjn-inhalation'background represents only two to three years
of environmental accumulation at the new experimental lead isotope ratio. It is not clear how
to numerically extrapolate these estimates to U.S, subpopulations; but it is evident that even
in rural and suburban parts of a metropolitan area, the indirect (non-inhalation) pathways for
exposure to leaded gasoline make a significant contribution to blood lead. This can be seen in
Table 11-73. It should also be noted that the blood lead isotope' ratio responded fairly
rapidly when the lead isotope ratio returned to its pre-experimental value, but it is not yet
possible to estimate the long-term change in blood lead attributable to persistent exposures
tg accumulated environmental lead, ]
The strongest kind of scientific evidence about causal-relationships Is based on an ex
periment in which all possible extraneous factors are controlled. The eyideh.ce derived from
the Isotopic Lead Experiment (ILE)' comes very close to this ideal.1 The experimental inter
ygntion consisted of replacing the normal 206Pb/207Pb isotope ratio by a very different ratio.
There is no plausible mechanism by which other concurrent lead exposure variables .(food, water
and beverages, paint, and 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, our analy
ses (Section 11.3.6.2.X) show that consideration of inhalation of community air lead alone
will substantially under estimate the total effect of gasoline lead, at least in the 35 sub
jects whose blood leads were tracked in the ILE Preliminary Study. This may be partially
explained by the differences in the lead concentration measured by stationary monitors
11-186
DUP040Q12496
TABLE 11-73. ESTIMATED CONTRIBUTION OF LEADED- GASOLINE TO BLOOD LEAD BY INHALATION AND NON-INHALATION PATHWAYS
Location
Air lead fraction from
gasoline
.V; Blood
lead fraction . from
gasoline*1
Blood lead from gasoline in airc
(pg/dl)
Blood lead hot inhaled from^gaso-
j-(Ma/6T)J
/
Estimated fraction gas-lead
inhalation6
Turin <25 km. >25 km
0.873
0.587 0.587
0.214 0.114 0.101
2,79 0.53 0.28
; 1.88 ... : 2.33, ! 2.93 .
. 0,60 0.19 0,09
fFraction of air lead in Phase 2 attributable jto lead in gasol|h.e> Mean fraction of blood lead in Phase 2 attributable to lead ini gasoline. ^Estimated blood lead from gasoline inhalation = p x a x b, p 1.0. "Estimated blood lead from gasoline, non-inhalation = f-e.
Fraction of blood lead uptake from gasoline attributable to direct inhalation = f/e. 1
Source.: Facchetti and Geiss (1982), pp, 52-56; Facehotti (1965),
compared to those that would be measured by personal monitors, exp.ecially if higher .exposures
occur in certain microenvironments, Diet lead is also an explanation for the large excess of
gasoline lead isotope ratio ig blood beyond that expected from inhalation of ambient air lead,
both from gasoline lead entering the food chain and added by 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 caiji be extended to U.S, populations! Turin's unusual meteorology,
high lead levels, and "reversed1' urban-rural- gradient of the subjects .in the ILE study indi
cate the need for future research. But 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,
j
Because the main purpose! of this chapter is to examine relationships of lead in air and
lead in blood under ambient conditions, the results of studies most appropriate to this area
have been emphasized. A summary of the most appropriate studies appears in Table 11-74. At
air lead exposures of 3.2 Mg/m3 or less, there is no statistically significant difference be
tween curvilinear and linear blood lead inhalation relationships.' At air lead exposures of 10
Mg/m3 or more, either nonlinear or linear relationships can be fitted. Thus, a reasonably
consistent picture emerges in which the blood lead to air lead relationship by direct inhala
tion was approximately linear in the range of normal ambient exposures of 0.1-2.0 pg/m3 (as
discussed in Chapter 7). Differences among individuals in a given study (and among several
11-187
DUP040012497
-.'5
i
t- -
i
........................
;.
'
! ! - } > i* 6
TABLE 11-74. . SUMMARY OF BLOOD INHALATION SLOPES,; (0) jjg/dl per pg/m3 f
Population Children Children Children
Adult :males Adult males Adult males Adult males
Study
Study type
Angle and
Population
MeIntire, 1979
Omaha, ME
Roels et al. (.1980) Belgium
Population
Yankel et al. Population (1977); Walter
et al. (1980) Idaho
Azar et al. (1975). Five groups
Population
Griffin et al. (1975), MY prisoners
Experiment
Gross i (1979)
Experiment
Rabinowitz et Experiment al. (1973,1976, 1977) ;
; (0) Slope,
N pg/dl per pg/m3
1074 ' ' 1.92
i 1
148 1i 2.46
Model sensitivity G f slope*
(1.40 - 4.40)a,b,c
(1.55 - 2.46)a,b
879 : 1.52 '
(1.07 - 1.52)a>b'e
t
149 i 1.32 . j
43 1.75
(1.08 * 2.39)b,C (1,52 - 3.38)d
6- 1.25 5 : 2.14
(1.25 - i.55)b ; (3.14 - 3.51)e ,
^Selected from among the most plausible statistically equivalent models. For nonlinear
models, slope at 1.0 pg/m3.
i
Sensitive 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 covan ate. ^Sensitive to baseline changes in controls. 6Sensitive to assumed air lead exposure.
11-188
DUP040012498
- i. -
studies) are large, so that pooled"estimates of the blood lead inhalation slope depend upon
the -weight given to various studies. Several studies were selected for analysis,'based upon
factors described earlier. EPA analyses* of experimental and. clinical studies (Griffin et
at.., 1975] Rabinowitz et al,, 1974, 1976, 1977; Ketone 19U,b,e-; Gross, 198.1; Hammqnd et a].,
1981) suggest that blood lead in adults increases by 1.64 0.22 pg/dl from direct-inhalation
f .':
'
S'
of each additional pg/nr of air lead, EPA analysis of Azar's population study (Azar et al..,
1975) yields a slope of 1.32 0,38 for adult males, EPA analyses of population studies
(Yankel et al., 1977; Reels et al., 1980; Angle and Melntir.e, 1979.) suggest that,; for chil dren, the fltediarj blood lead increase is. 1.97 pg/dl per pg/m3 for inhaled air lead. -!
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 leig-term inhalation slopes should be about 30 percent larger than these estima
tes. Inhalation slopes quoted here are associated with a half-life of blood lead ip adults of
about 30 days, { 0`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 ai., 19,83).
One possible approach would be to regard all inhalation slope studies as equally infor
mative and to calculate an average slope using reciprocal squared standard error estimates as
weights. This approach hap been rejected for two reasons. First, the standard error estima
tes characterize only the internal precision of an estimated slope, not its representativeness
(i.e., bias) or predictive validity. Secondly, experimental and clinical studies obtain more
information from a single individual than do population studies. Thus, it may not be appro
priate to combine the two types of studies.
. Estimates of the inhalation slope for children are only' available from population
studies. The importance of dust ingestion as a non-inhalation pathway for children is estab
lished by many studies. A pooled slope estimate,: 1.97 + 0.39, has been derived for air lead
inhalation base4 on those studies (Angle .and Mclritire, 1979; RoeIs et al., 1980; Vankel et
al., 1977) from:which th.e 'air inhalation and dusp ingestion contributions can both be esti
mated. Aggregate analyses of data from these and'several other studies typically yield slope
estimates in the range of 3-5 for the combined impact of both direct (inhaled.) and indirect
(via dust, etc.) contributions of air lead to blood lead in children.
*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.
11-189
DUP040012499
While direct inhalation of air lead is stressed, this is not the only air lead contribu*-
ticn that needs to be considered. Smelter studies allow partial assessment of the air lead
contributions to soil, dust, and finger lead.. Conceptual models allow preliminary estimation
of the propagation of lead through the total food chain as shown in Chapter;7. Useful mathe
matical models tp quantify the propagation of lead through the food chain need to be devel-
oped. The direct inhalation relationship does provide Useful information op changes in blood
lead as responses to changes in air lead on a time scale of several months. The indirect
pathways; through dust and soil and through the food chain may thus delay the total blood lead
response; to changes in air lead, perhaps by one dr mpfe years.. Thd italiah'TLE study facili
tates partial assessment of this delayed response from leaded gasoline as a .puree.
Dietary absorption of lead varies greatly from one person to another and depends on the
physicall 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 loy jctiildren of leaded paint, dust, and Soil. Typical Values of 10 percent absorption of
, ingested lead into blood have been ..assumed for adults and 25 to 50 p.erdent for children.
It Hs 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 add to the uncertainty of the esti
mated relationships.
;
Quantitative analyses relating blood lead levels and dietary lead exposures have been re
ported., Studies on infants provide estimates that are in close agreement. Only one indi
vidual study is available for adults (Sherlock et al. 1982); another estimate from a number of
pooled studies is also available. These! two estimates are in good agreement. Most of the
t!
;
subjects in the Sherlock et al, (1982) and'United Kingdom Central Directorate on Environmental
Pollution .(19.82.) studies received quite high dietary lead levels (>300 pg/day). The fitted
cube root equations give high slopes at-lower dietary lead levels. Oh the other hand, 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. 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. Estimates for adults
should be taken from the experimental ..studies or calculated from assumed absorption and half*
life values. Most of the dietary intake supplements were so high that many of the subjects
had blood lead concentrations much in excess of 30 pg/dl for a considerable part of the ex
periment, Blood lead levels thus may not completely reflect lead exposure, due to the
previously noted nonlinearity of blood lead response at high exposures. The slope estimates
11-190
DUP04Q012500
for adult dietary intake are about Di02 pg/dl increase in blood lead per pg/day intake, but
consideration of blood lead kinetics &py increase this value to about 0.04.' Such values are a
bit lower than slopes of about 6.,05 gf/dl per pg/day estimated from the population studies ex-
trapolated. to typical dietary intakes] The value for infants is larger.1
\i
_
The relation between blood -dead 5a.nd water lead is not clearly defined and is often;-de*
scribed as nonlinear. Water lead intake varies greatly from; one person to another. It has
been assumed that children pan 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 jgreatly influences the estimated contributions to blood
leads from relatively low water lead concentration.
Although there is close agreement in the quantitative analyses of the relationship bet
ween blood lead level and dietary leqd, there is a larger degree of variability in results of I'
the various water lead studies. The relationship is curvilinear, but its exact form is yet to
be determined. At typical levels for? U.S. populations, the relationship appears linear. The
only study that determines the relationship based on lower water lead values (<1Q0 pg/1) is
the Pocock et al, (1983) study. The Idata from this study, as well as the authors themselves,
suggest that, in this lower range of Water lead levels., the relationship is linear. Further
more, 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 a-1. (1983)
slope of 0.06 is considered to represent the best estimate. The possibility still exists,
however, that the higher estimates of the other studies may be correct-in certain situations,
especially at higher water lead levels (>100 pg/1).
'
Studies relating soil lead to blood lead levels are difficult to compare. The relation
ship; obviously depends on depth of sen 1 lead, age of the children, sampling method, cleanli
ness! of the home, mouthing activities! of the children, and possibly many other factors, Var
ious; soil sampling methods and sampling depths have been used over timel, and as such they may
not be directly comparable and may pfc-duce a dilution effect of the major lead concentration
contribution from dust which is located primarily in the top 2 cm of the soil. Increases in
soil: dost lead significantly increase blood lead in children. From several'studies (Yankel et
al., 1977; Angle and Mclntire, 1979) EPA estimates an increase of 0,6-6,8 pg/dl in blood lead
for each increase of 1000 gg/g in soil lead concentration. Values of about 2.8 pg/dl per
1,000 pg/g soil lead from the Stark et al. (1982) study may represent a reasonable median
estimate. The relationship of housedust lead to blood lead is difficult to obtain. House
hold dust also increases blood lead, as children from the cleanest homes in the Silver Valley/
Kellogg Study had 6 pg/dl less lead in blood, on average, than those from the households with
the most dust.
I
*
!'
11-191
DUP040012501
A number of specific environmental sources of airborne lead have been identified as haying a direct influence on blood lead levels. Primary lead smelters, secondary lead smelters, and battery plants jemit lead directly into the air bftd 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, Blbod lead levels in these residents have been shown to be related to air, as well as to soil or dust exposures. The habit of cigarette smok,ing is a source of lead exposure.' Other sources include the following; lead based cosmetics, lead-based folk remedies, and glared pottery.
1 I
11-192
0-
DUP040012502
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Ontario Ministry of the Environment. (1975) Report of the Head data analysis task force. Toronto, ON, Canada: Ontario Ministry of .the Environment.
Oxley, G. R, (1982) Blood lead concentrations: apparent reduction over approximately one decade, Int, Arch. Qccup. Environ. Health 49: 341-343.
Pennington, J. A. T. (1983) Revision of the total diet study food list and diets, J, Am. Diet. Assoc. 82: 166-173,
Plomelli, S.; Corash, L.; Corash, M, B.; Seaman, C.; Mushak, P,; Glover, B,; Padgett, R. (1980) Blood lead concentrations in a remote Himalayan population. Science (Washington, DC) 210: 1135-1137.
11-205
DUP040012515
1
for subjects follow-up in Castagnettp (4 subjects).
Figure 11C-3. Individual values pf blood ?Q6Pb/207Pb ratio for subjects follow-up in Druento and Fiano {6 subjects!.
Source: Faechetti and Geiss (1982).
X 1C--3
DUP040012517
2 0 6 p J j/2 0 7 p K
j Figure 11C-4. individual values of blood 2<?6Pb/207Pb ratio for subjects follow-up in Nole and Santena (9 subjects)-
2 0 6 p jv /2 0 7 p k
Figure 11C-5. Individual values of blood 206Pb/2f>7Pb ratio for subjects follow-up in Viu (4 subjects).
Source: Facchetti and Geiss (1982).
11C-4
irU.S. GOVERNMENT PRINTING OFFICII 9 8 6- 6 4 6 - 1 1 6 " 4 0 .6 4 3
DUP040012518
sits stuns 16 miles away. All analyses were carried out under clean conditions with care and
caution being exercised to avoid lead contamination;
The isotope ratio of 206Pb/204Pb increased linearly with time from about 18.45 to 19.35,
approximately a 6 percent increase. At least one of the two isotopic lead ratios increased
linearly in 4 of the 10 subjects. In one other, they increased, but erratically, fn the
remainder of the subjects,- the isotopic ratios followed \smooth curves showing'inflection
points. The curves obtained for the two subject's -born in South Africa Were 6 months out of
phase with the curves of the native-born Americans; The fact that the isdioge ratios in 9s of
the 10 subjects varied regularly was thought to indicate, that the nop-airborne sources of lead
varied in isotopic composition very slowly.
!
The blood lead levels exhibited a variety of patterns, although" hone of the subjects
showed more than a 25 percent change from initial ljevels, th#i: s su"g gests a reasonably steady-
state external environment.
Man ton carried his analyses further to estimate the percentage ,o.f lead in blood that
comes from air. He estimated that the percentage jvaried from 7 to 41 percent, assuming that
dietary sources of lead had a constant isotopic ratio while air varied. He calculated the
percent contribution according to the following equation,
- =5=
," where
i 100+q -a
(11-1)
b, ! = rate of change of an isotope ratio in blood,
a =*
rate of change of the same ratio in the air, and
q ] ==
constant defined as the number of atoms of the isotope in the! denominator of the airborne ilead ratio mixed with 1GD atoms of the same isotope of lead from non-aifbprne sources,-
tI The results are shown .in Table 11-17, Slopes were obtained by least squares regression.
Percentages of airborne lead in blood varied between 7 3 and 41 + 3.-
Stephens (1981) extended the analysis of data in Manton's study (Table 11-18). He used
the observed air lead concentrations based on actual 24-hour air lead exposures in three adults. He assumed values for breathing rate, lung deposition, and absorption into blood to estimate the blood lead uptake attributable to 204Pb by the direct inhalation pathway. Sub
jects 5, 6, and 9 absorbed far more air lead in fact than was calculated using the values in
Table 11-17, The total air lead contribution for those subjects was 8.4, 4,4, and 7,9 times, respectively, larger than the direct inhalation. These estimates are sensitive to the assumed parameter values.
11-53
DUP040012519
TABLE 11-17. RATE OF CHANGE OF 206pb/204pb ANj, 206Pb/207Pb IN AIR AND BLOOD, AND PERCENTAGE OF AIRBORNE LEAD IN BLOOD OF SUBJECTS 1, 3, 5, 6, AND 9
Subject
Rate of change per day
206pb/204pb
206pb/2Q7pb
X .10
X 10"
' ;
Percentage of airborne lead in blood*
From 26Pb/27Pb
From 206Pb/207pb
(Air) 1` 3 5 6 9*
Note:
17.60 0.77 .
5.52 0.55 .*
5.53 st 0.49
3.25
9.97 0:42 0.70 + 0.30
3.13 0.34 4.10 0,25 2.01
...... .
/ i '
-ii
Errors quoted are one standard deviation
31.4 + 3.4 ,: ; . . .
' 37,1 2.8 18.5
73
. 31.4 3.7 41,1 + 3.0 20.0
*From slope of tangent drawn to the minima'of subject's blood curves.. Errors cannot .realistically be assigned.
TABLE 11-18. CALCULATED BLOOD LEAD UPTAKE FROM AIR LEAD USING MANTON ISOTOPE STUDY
Sub Concen ject tration
Expo sure*
Deposi tion*
:5 Q.22 pg/m3 15 m3/day 37% 6 1.09 pg/m3 .15 m3/day 37% 9 0.45 pg/m3 15 m3/day 37%
Absorpti on*
Blood uptake from air
Calcu-
lated
inhala
tion
Observed
Fraction of ,lead uptake /from gasoline
by direct inhalation
50% 0.61 pg/d 5.1 pg/d ia% 3.0 pg/d '13.2 pg/d 50% 1:2 pg/d ' 9.9 pg/d
; 0.120 I 0.229
0.126
^assumed rather than measured exposure, deposition and absorption. Source: Stephens, 1981, based on Manton, 1977; Table III,
In Manton (19851 the earlier isotope studies were greatly extended and the results were reinterpreted. The recent study emphasized time changes in blood lead and in 26pb/207pb isotope ratios in three subjects in Dallas, Texas, from 1974 to 1983. Two of the subjects.described earlier (Manton, 1977) were included here, a husband (subject 8) and his first wife (subject 9). The more recent subject was the husband's second wife. The husband
11-54
DUP04001252Q
had grown up in South Africa and in England; thus ha had deep bone pools of lead that reflec ted the Australian lead isotope ratio. As noted earlier, the husband1? seasonal minima in isotope ratio appeared to be the opposite of the two women with whom he shared a very .similar pattern of environmental exposures. Manton (1985) now attributes this to a large efflux.of lead from the skeletal pool. The husband's estimated dietary intake was 55 pg/day. If 10 percent of this is absorbed into blood (5.5 pg/day), mean residence time of 40 days and volume of distr ibution of 75 dl imply a dietary contribution to blood lead of 'about 8 pg/dl, much less than his observed average of 17 pg/dl. There was little indication of large changes in diet lead Isotope ratio during this period, hence the changes in blood 1Sad isotope ratio may be attributed to changes in the air lead particulate isqtbpe ratio, and to changes in isotope ratio Ifor endogenous sources. Manton attributes the large changes in isotope ratio in the husband to changes in isotope ratio from lead resorbed from bone Into the blood. His estimate
I' is that approximately 70 percent of the daily blood input is due to the; endogenous skeletal pool pf this subject. The subject's wife also exhibited a variety of fluctuations in blood lead ijevel and isotope ratio due to childbirth and to short-term fluctuatijons in dietary lead. The apparent effect of childbirth was to increase resorption of both skeletal calcium and skeletal lead into bipod. The contribution of airborne lead to blood lead isotope ratios thus did not require correction fob long-term secular changes in dietary lead isotope ratios. On this basis the direct inhalation contribution was again calculated as about 20 to 60 percent of the total uptake of atmospheric lead using 8 *= 4.1. Manton's calculations are shown in Table 11-19. The cumulative effects of long-telrm lead absorption on the mobilizable lead pool in the skeleton have been ignored, but are apparently not negligible.
In summary, the .direct inhalation pathway accounts for only a fraction of the total air lead contribution to blood, the direct, inhalation contribution being on .the order of 12-23 percent of-the total uptake of lead attributable to gasoline, using Stephen's assumptions, and 20-60 percent based qn Manton's analysis. This is consistent with estimates from the ILE study,'taking into account the much higher air lead levels in Turin. 11.3.6.3 Studies of Childhood Blood Lead. Poisoning Control Programs. Billick et al. (1979) presented several possible .explanations -for the observed decline (described in Section 11.3.5,2) in blood lead levels in New York City children as well as evidence supporting and refuting each. The suggested contributing factors include -the active educational and screen ing program of the New York City Bureau of Lead Poisoning .Control, the decrease in the amount of lead-based paint exposure as a result of rehabilitation or removal of older housing, and changes in environmental lead exposure.
11-55
DUP040G12521
TABLE 11-19. -RESPIRED AND OTHER INPUTS OF AIRBORNE Pb TO BLOOD FOR SOME DALLAS RESIDENTS IN 19751
-G
+O > 3
sj ,
-S? oo> ><a
.o ^
a-
0
JtPs
4JN.
C C o
xSoi- oeOJ .3-
s- o
a. >, C .0# <0 - C T3
O -C3) nMs XsI. a.
.0*1*
7 1=CL XI Jj *
Q- t>
40 "C* "O fcO
O 'N. -Q Ol
11-56
u '-+5X
C
.0) .fc .
cu . o u
o .
+* a. La-i o
X3 T3 O '
L 0)
c cu , <0 jB o O *3 -a
**.j<k0
2u O g
to&s>. +<010
7 -i*
mV) lSxU
.g M
W>
o. . -v- *a
<*- U Q>
a> &.
tJX o
. m coi
ns 6-
*"? * 3ec
o>- ai
r* g OJ
<0 .
oo
UOJ
00 S(0- U(0)
2 -ga -*oT3 ^ ai +* ** "i .p . X* 3 A3 'a*"0 w ai c a x f- ft. 4-
W0.10^
(A *2 O* fiS
(0 r-t tH
*o 6. *x:
at `f - * .o io
Ho--f-.ipxj ,<A .Coui ..C*0--J
13 01 -F-1.wi 'W3.U+fil*^i O
CO. U(L_o OUju .-5fa-l
DUP040012522
Information was only available to partially evaluate the last source of lead exposure and particularly only for ambient air lead levels. Air lead measurements were available during the entire study period for only one station which was located on the west .side of Manhattan at a height of 56 m. Superposition of the air lead and blood lead levels indicated a simi larity fn seasonal cycle arid long-term decline. The authors cautioned against overinterpre tation because of the necessary assumptions in this analysis and because one air monitoring site was used to be representative of the air lead exposure of New York City residents. With this in mind, the investigators fitted a multiple regression model to the data to try- to j define the important determinants of blood! lead levels for this population. Age, ethnic . group, and air lead level were all found tp be significant determinants of blood lead levels. The authors further point Out the possibility of a change in the nature of the population ' 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 varied.
.Bil.lick et a!. (1980) extended their previous analysis of the data from the single moni- , taring site mentioned above. The investigators examined the possible relationship between : blood lead level and the amount of lead in gasoline used in the area. Figures 11-14 and 11-15 present illustrative trend Tines.in blood leads for blacks and Hispanies versus air lead and gasoline lead, respectively. Gasoline lead was estimated by multiplying the sales of gasoline by the estimated concentrations of lead in gasoline;. Semiannual concentrations of lead for the Mid-Atlantic Coast were interpolated to get quarterly values. Sales were computed using figures for New York, New York plus New Jersey, New York plus Connecticut, or New York plus New Jersey plus Connecticut*, all gave similar results. The 1 ead in gasoline trend line ap pears to fit the blood lead trend line better than the air. lead trend, especially in the summer of 1973.
Multiple regression analyses were calculated using six separate models. The best fitting model had an R:i = 0,745. Gasoline lead content was included rather than air lead. The gaso line lead content coefficient was significant for all three racial groups. Partial correla tions with gasoline alone were not provided.. The authors state a number of reasons for gaso line lead providing a better fit than air lead, including the fact that the single monitoring site might not be representative.
Nathanson and Nudelman (1980) provide more detail regarding air lead levels in New York City. In 1971, New York City began to regulate the lead content of gasoline sold. Lead in gasoline was to be totally banned by 1974, but supply and distribution problems delayed the effect of the ban. Ultimately, regulation of lead in gasoline was taken over by the U..S. Environmental Protection Agency,
11-57
DUP040012523
Figure 11-14. Geometric mean blood lead levels of Neyv York City children (aged 25-36 months) by ethnic group, and ambient air lead concentration versus quarterly sampling period, 1970-1976.
Source: Billick et al. (1980).
11-58
DUP040012524
sn
%
a <
tit
ui
Z
oOl
Figure 11-15. 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 versus quarterly sampling period, 1970-1975.
Source: Billiek et al. {1980).
-
n-53
DUP040012525
)
5
New York City measured air lead levels during the periods dune 1969 to September 1973 arid
during 1978 at multiple sites. The earlier monitoring was done by 40 rooftop samplers using
cellulose filters analyzed by AAS. The latter sampling was done by 27 rooftop samplers using
glass fiber filters analyzed by X-ray -fluorescence (XRF). There was excellent agreement
between the XRF and atomic absorption analyses for lead (f - 0.985). Furthermore, the XRF
analyses were checked against EPA AAS and again excellent agreement was found. The authors
did, however, point out that cellulose filters are not as efficient as glass fiber filters.
Therefore, the earlier results tend to be; underestimates of air lead levels.
Quarterly citywide air lead averages generally declined during the years 1969-1978,' The
maximum quarterly cityw.ide average obtained was about 2.5 gg/rn3 for the third quarter of 1970.
The citywide trend corresponds to the results obtained frolti the single monitoring site used in
Billick et al.'s (19791 analysis. The ditywi.de date suggest that the single monitoring site
in Manhattan is a responsible indicator of air lead level trends. The graph in figure 11-16
reinforces this assertion by displaying-the geometric mean blood lead levels for blacks and
Hispanics in the 25- to 36-month age groups and the quarterly citywide air lead levels for the
periods of interest. A good correspondence was noted-
As part of a detailed investigation; of the relationship of blood lead levels and lead in
gasoline covering three cities, Billick (1982) extended the time trend analyses of New York
City blood lead data. Figure 11-17 presents the time trend line for geometric mean blood
leads for blacks aged 25-36 months extended to 1979. Similar results held for other ages.
The downward trend noted earlier was still continuing, although the slopes for both the blood
and gasoline lead seem to be somewhat shallower toward the most recent data, A similar
picture is presented by the percentage ..of'.children with blood lead levels greater than 30
pg/dl, ; In the early 7Q's, about 60 percept of the screened children had these levels; by 1979
the percentage had dropped between 10 and 15 percent.
11.3,6.4 Frankfurt, West Germany. Sinn (1980; 1981) conducted a study specifically examining
the environmental and biological impact- of the gasoline lead phasedown implemented in West
Germany on January 1, 1976. Frankfurt am Main provided a good setting for such a study
because of its physical character,
'
-
Air and dustfall lead levels at several sites in and about the city were determined be
fore and after the phasedown was implemented. The mean air lead concentrations obtained
during the study are presented in Table 11-20. A substantial decrease in air lead levels wa%
noted for the low-level high traffic site (3.18 pg/m3 in 1975-76 to 0,68 pg/m3 in 1978-1979).
No change was noted for the background site while only minor changes were observed for the
other locations. Dustfall levels fell markedly (218 mg/cm2*day for 1972-1973 to 128
mg/cm2-day for 1977-1978). Traffic counts were essentially unchanged in the area during the course of study.
11-60
DUP040012526
v
09 3.-'
Ui U-IJ Q <: i-lJl .
<' UJ '
<3 ce:^
UJ ` >' <
>P
ft UJ H -J ft
< ' 3 0 :
UJ
0
o
Figure 11-16. Geometric mean blood levels for blacks and H'ispanics in the 2S-to-36-month-age group and rooftop quarterly averages for ambient citywide lead levels.
Source: Nathanson and lMudelman (1980).
l
11-61
DUP040012527
YEAR
Figure 11-17- Time-dependence of blood lead and gas lead for blacks,
aged 25 to 36 months, in New York.
.'
Source: Billick (1982).
11-62
DUP040012528
TABLE 11-20. MEAN AIR LEAD CONCENTRATIONS DURING THE VARIOUS BLOOD SAMPLING PERIODS AT THE MEASUREMENT SITES DESCRIBED IN THE TEXT (pg/m3)
1975-1976 1976-1977 1977-1978
1978-1979
Residential low traffic
0.57 0.39 0.32 0.39
High traffic (>2Qm)
0.59 0.38 0.31 0.31
High traffic (3m)
3:18 1.04 0.66 : 0.68
Background site
0.12 .0.09 0.10 0,.,12
.
Source: Sinn (1980, 1981)
A number of population groups wore Included In the stud^ of the blood lead levels; they were selected for having-either occupational or residential exposure to high density automo bile traffic. Blood samples were taken serially throughout the study (three phases in December-Jarfuary 1975-1976, Oecember-January 1976-1977, and December-January 1977-1978). Blood samples were collected by venipuncture and analyzed by three different laboratories. All the labs used AAS although sample preparation procedures. varied. A quality control program across the laboratories was conducted. Due to differences in laboratory analyses, attrition, and loss of sample, the number of subjects who could be examined throughout the study was considerably reduced from the initial number recruited (124 out of 80D).
Preliminary analyses indicated that the various Categories of subjects had different blood lead levels, and that males .and females within the same category differed. A very com plicated series of analyses then ensued that made it difficult to draw conclusions because the various years' results were displayed separately by each laboratory performing the-chemical analysis and by different groupings by sex and category. In Sinn's later report (1981); a downward trend was shown to exist for males and females who were in all years of the study arid whose blood levels were analyzed by the same laboratory.
11.4 STUDIES RELATING EXTERNAL DOSE TO INTERNAL EXPOSURE The purpose of this section is to assess the importance of environmental exposures in
determining the level of lead in human populations. Of prime interest are those studies that yield quantitative estimates of the relationship .between air lead exposures and blood lead levels. Related to this question is the evaluation of which environmental sources of airborne lead play a significant role in determining the overall impact of air lead exposures on blood lead levels.
11-63
DUP040012529
A factor that complicates the analysis presented here is that lead does not remain sus-* pended in the atmosphere but rather falls to the ground, is incorporated into soil, dust, and water, and enters the food chain over time (see Figure 11-1).. Since man is exposed to lead from all of these media, as will be demonstrated below, studies that relate air lead levels to*, blood lead levels (especially experimental exposure studies) may underestimate the overall impact of airborne lead on blood, lead levels. In observational studies., on the other hand, the effects of air lead will thus be confounded with lead exposures from Other pathways. The simultaneous presence of lead in multiple environmental media requires the use of multiple variable analysis techniques or surrogate assessment of all other external exposures. Virtu ally no assessments of simultaneous exposures to all media have been done*
There are several key features that characterize good studies relating external exposure to internal exposure of lead:
; (!) The study population is well-defined. (2) There is a good measure of the exposure of each individual. .(.3) The response variable (blood lead) is measured with adequate quality control,
preferably with replicates. (4) The statistical analysis model is biologically plausible and is consistent with
the data. : (5) The important covariates are either controlled for or measured.
Some studies of considerable importance do not address all of these factors adequately. Key studies selected for discussion here are those which address enough of these factors suffi ciently well to establish meaningful relationships. .
The choice of. the statistical analysis model is important in determining these relation ships (for a more detailed discussion .see Appendix 11B), The model used is especially criti cal 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 blood lead from various environmental media. For simplicity, let FbB - blood lead, . environmen tal exposure from source j, and b^ ^ the regression coefficient for source j. Using this notation, the more common models can be written as follows:
Linear Model: PbB - b0 + bx t +
+ bg Eg + "error"
> (.11-2)
Linear Model (log form): log(PbB) = log(b0 + bx + ... + b Eg) + 'error11
(11-3)
Log-log Model: log(PbB) - l0g(bo) + bx 1og(Ei) + ... + bg log(s) + 'error11
(11-4)
Log Total Exposure Model: log(PbB) - b log(b0 + b, E, + ... + b'tS E^S. + "error" (11-5)
11-64
DUP040012530
Rower-Function Model: PbB = bQ + (bt Et + ... + b E )c + "error" ss
1/3 Cube-root Model: PbB = b + bt (E^ 7 + "error"
(11-6) (11-7)
There is no question that the relationship between blood lead and environmental exposure
is nonlinear across the entire range of potential exposures, from very low to high levels. At
lower levels of exposure, however, the various models all provide adequate descriptions of the
observed data. The choice of a model must be based at least in part on the biological mecha
nisms.. At the very least, no model should be adopted which is inconsistent with biological
reality,
;
The compartment-type metabolic models described in Section 10.3.4 predict a linear
response to total lead intake. Compartment models are described by a.system of coupled first-
order linear differential equations for the quantity of lead Jn various kinetically distinct
body pools, (see Appendix 11-A). These compartments or kinetic pools may or may not corres
pond to distinct physiological systems. It is well known that if the kinetic rate coeffi
cients arid absorption coefficients in such a model! are constant, then the equilibrium blood
lead in a steady-intake environment is
a. c _ (lead absorbed into blood, pg/d) (Pb mean residence time in blood, d) (PbB volume of distribution, dl)
(11-8)
The only allowable places for nonlinearity in intake are either in the absorption process, or "in the kinetics of lead distribution affecting the residence time. Non! linearities affecting distribution volume are less plausible. Some of the evidence relating to these mechanisms was reviewed in Chapter 10- Chamberlain (1983) and U.$. ERA (1983) have concluded that after several months of steady exposure to environmental lead, blood lead levels achieve a nearequilibrium concentration that increases linearly with the ambient concentration no matter what the exposure pathway (directly by air inhalation, or by ingestion of food, water, dust, soil-, or'paint), provided the total exposure does not cause blood lead to exceed 30-40 pg/dl. However, when total lead exposure by any pathway becomes so great that blood lead levels greatly exceed 60-80 pg/dl, then the blood lead concentrations increase much more slowly with increasing exposure concentration than they did at lower levels.
On the other hand, the log-log and cube root models have slopes which approach infinity as the exposure approaches zero. The curves are so highly nonlinear at low doses that the models attribute nearly all of the increase of blood lead levels to the lowest exposures, and attribute relatively little increase to any additional exposures. However, the data of
11-65
DUPQ40012531
Piomelli et al, (1980) on a population of Nepalese exposed to an air lead of 0.00086 pg/m3 hacl a geometric mean blood lead level of 3.4 pg/dl. This is similar to the value predicted by the log-log model of Goldsmith-Hexter.
The following sections give the models as presented by the original authors. In many cases, EPA has fitted other models in order to show the sensitivity of analysis to the.model selected,
11,4,1 Air Studies The studies emphasized in this section are those most relevant to answering the following
question: If there is moderate change- in average ambient air lead concentrations due to changes in environmental exposure (at or, near existing EPA air lead standards), what changes .are expected in blood lead levels of individual adults and children in the population? Longi tudinal studies in which changes in blood lead can be measured in single individuals aS re sponses to changes in air lead are discussed first. The cross-sectional relationship between blood `,ead and air lead levels in an exposed population provides a useful but different kind of information, since the population "snapshot" at some point'in time does not directly mea sure changes in blood lead levels or responses to changes in air lead exposure. In this chapter consideration is also restricted to those individuals without known excessive occupa tional or personal exposures (except,, perhaps, for some children in the Kellogg/SiTver Valley study).
The previously published analyses of relevant studies have not agreed.on a single form for the relationship between air lead and blood lead. All of the experimental studies have at least partial individual air lead exposure measures, as does the cross-sectional observational study of Azar et al. (1975). The 1974 Kello.g;g/$ilver Valley study (Yankel et al., 1977) has also been analyzed using several models.*' Other population - .cross-sectional studies have been analyzed by Snee (1981). The-most convenient method for summarizing these diverse studies and their several analyses is by use of the blood lead - air lead slope (p), where p measures the change in blood lead that is expected for a unit change in air lead. If determined for indi vidual jsgbjects in a study population, this slope is denoted ft.. If the fitted equation is linear, then p or p, is the slope of the straight line relationship at any air lead level. If the fitted relationship is nonlinear, then the slope of the relationship measures the expected effect on blood lead of a small change in air lead at some given air lead value and thus will4 be somewhat different at different air lead levels.
A basic assumption here is that the distribution of blood lead in human populations with homogeneous exposure (same geometric mean blood lead) is lognormal; a second assumption is" that all such lognormal distributions have the same geometric standard deviation (g.s.d.) or
11-66
DUP040012532
is, 1g c [10 blood lead =5 1,265 + 6.2433 log10 atmospheric air lead. The average diet content of
lead Was measured and blood lead levels were observed at 1- or 2-week interyals for several
months. Eight subjects received the maximum 4~month exposure to 10,9 pg/m3; nine.subjects
were exposed for 1-3 months. Six subjects had the maximum 4-month exposure to 3.2 pg/m3,''
and ejcht others had shorter exposures,
Ccmpartmental models have been fitted to these data by O' Flaherty et al. {1982) and by
EPA. The basis of these models is that the mass of lead in each of several distinct pools or
compartments within the body changes according to a system of coupled first-order linear dif
ferential equations with constant fractional transfer rates (BatscheTet et al., 1979; Rabino-
witz et al., 1976). Such a model predicts that when the lead intake changes from one constant
level:to another, then the relationship between the mass of lead in each ..compartment and time
with constant intake has a single exponential term,
-
The subjects at 3.2 pg/m3 exhibited a smaller increase^in blood lead, with correspond
ingly: less accurate estimates of the parameters. Several of the lead-exposed subjects failed
to show an increase. ! EPA has reanalyzed these data using a two-fcompartment model for two reasons;
(1) Semilogarithmic plots of blood lead versus time for most subjects showed a twocomponent exponential decrease of blood lead during the postexposure Or washout phase of the'experiments, Rabinpwitz et al, {1977} show that at least two pools are necessary to model blood lead kinetics accurately. The first pool is tenta tively .identified with blood and the most labile soft tissues. The second pool probably includes soft tissues and labile bone pools.
(2) Kinetic models .are needed to account for the subjects1 lead burdens not being in equilibrium at any phase of the experiments.
Previously published analyses have not used data for all 43 subjects, particularly for the same six subjects (labeled 15-20 in both experiments) who served as controls both years. These subjects establish a baseline for non-inhalation exposures to lead, e.g.s in diet and water, and allow an'independent assessment of within-subject variability over time. EPA ana lyzed data for these subjects as well as others who received lead exposures of shorter dura tion.
The estimated blood lead inhalation slope, .{5, was calculated for each individual subject,, according to the formula
_ (Change in intake, pg/day) x (mean residence time in blood, day) (11-9) (Change in air exposure, pg/m3) x (Volume of distribution, dl)
11-68
DUP040012533
coefficient of variation (c.v.) It is then possible to calculate the fraction of the popu lation in excess of any specific level of bipod lead. Most subpopulations not occupationally exposed to lead have geometric mean blood lead < 20 pg/dl, at which level the effects of a few pg/dl change in blood lead can be well approximated by a linear function. On the other hand, many important experimental studies involve subjects with much higher blood lead. We re sponse relationships derived from lead-exposed subjects (blood lead > 30 pg/dl) usually show much lower slopes b. when blood lead exceeds 40 pg/dl. These two uses of blood lead versus intake models -- to predict the fraction of an exposed population at risk and to predict,the change in blood lead of subjects exceeding a criterion bipod lead level when blood lead expo sure changes -- may require different blood lead slopes b.. These Wo uses are not neces-
J
sarily inconsistent, e. g., if there was a corresponding increase in biological variability of response to high levels of intake offsetting the decreased slope; For this reason we sepa rately analyte the single-subject and population studies. 11.4.1.1 The griffin et al. Study. The study of Griffin et al, (1975) has the largest number of human subjects exposed to atmospheric particulate lead at near-ambient conditions, under conditions of long-term controlled exposure. In two separate experiments conducted at the Clinton Correctional Facility in 1971 and 1972, adult male prisoner volunteers were sequest ered in a prison hospital unit and exposed to .approximately constant levels of lead oxide (ayerage 10.9 pg/m3 in the first study and 3.2 pg/m3 in the second)-. Volunteers were exposed in an exposure chamber "to an aerosol of submicron-sized particles of lead oxide, which was prepared by burning tetra-ethyl lead in a propane flame.. There was an approximate additional 10-15 percent exposure to ambient organic lead vapor. All volunteers were introduced into the chamber 2 weeks before the initiation of the exposure; the lead exposures were scheduled to last 16 weeks, although the volunteers could drop out whenever they wished. Twenty-four vol unteers', including 6 controls, participated in the 10.9 pg/m3 exposure study. Mot all volun teers completed the exposure regimen. Blood lead levels were found to stabilize after appro ximately 12 weeks. Among 8 men exposed to 10.9 pg/m3 for :at least 60 days, a stabilized mean level of 34.5 5.1 pg/dl blood.was obtained, as compared with an initial level of 19.4 3.3 pg/dl. All but two_ of the' 13 men exposed at 3.2 pg/m3 for at least 60 days showed increases and an overall stabilized level of 25.6 3.9 pg/dl was found, compared with an initial level of 20.5 4.4 pg/dl. This represented an increase of about 25 percent above the base level.
The aerosols used in this experiment were somewhat less complex chemically., as well as somewhat smaller, than those found in the ambient environment,. The particle size obtained was 0.05-0.16 pm, which is smaller than true urban aerosol of 0.3 pm. Griffin et al, (1975), how ever, pointed out that good agreement was achieved on the basis of the comparison of their ob served blood lead levels with those predicted by Goldsmith and Hexter's (1967) equation; that
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The changes in alp exposure were 10.9-0.15 = 10,75 pg/m3 for 1970-71 and 3,2-0,15 - 3.05 pg/m5 in 1971-72. Paired sample t-tests of equal means were carried out for the six controls and five subjects with exposure both years, and independent sample t-tests were carried out com paring the remaining 12 subjects the first year and nine different subjects the next year. All standard error estimates include within-subject parameter estimation uncertainties a^ well as between subject differences. The following are observations:
(1; Non-inhalation lead, intake of the control subjects varied, substantially during the second experiment at 3.2 pg/m3, with clear indication of low intake during the 14day pre-exposure period (resulting in a net decrease of blood lead). There was an increase in lead intake (resulting in either equilibrium or net increase of blood lead) during the exposure period. Subjects 16 and 20 had substantial increases, subjects 15 and 19 had moderate increases, and subject .18 had no increase in blood lead during exposure. Subject 17 had a marked decline in blood lead, but the rate of decrease was much faster in the pre-exposure period, suggesting an apparent in crease of intake during exposure periods even for this subject. These subjects had not apparently achieved equilibrium in either blood or tissue compartments. Even though these subjects were not exposed to air lead, the estimated difference between blood lead intake before and during exposure of the other subjects was used to cal culate the apparent inhalation slope at that exposure. The pooled inhalation slope estimated for all six controls (1.48 0.82 s,e.) was significantly positive (2 = 1.76, one-tailed p <0.05), as shown in Table 11-21. ' No explanation for the in creased lead intake during the winter of 1071-72 can be advanced at this time, but factors such as charges in diet :or changes in resorption of bone lead are likely to have had an equal effect on the lead-.expo.sed subjects. No statistically significant changes in the controls were found during the first experiment at 10.9 pg/m3.
(2) Among the controls,; the estimated mean residence time in blood was slightly longer for the first year than the second year, 41.8 9.2 days versus 34.6 6.5 days, but a paired sample Z-test found that the mean difference for the controls (7.2 11,2 days) was not significantly different from zero (see Table 11-22).
(3) Among the five subjects exposed to 10.9 pg/m3 the first year and 3.2, pg/m3 the second year, the mean residence time in blood was almost identical (43.9 9.4 versus 44.7 8.7 days).
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TABLE 11-21. GRIFFIN ET AU (1975) EXPERIMENT INHALATION SLOPE ESTIMATES
Group
... At 3.2 pg/m3
At iO.R pg/m3
Controls A11 exposed
1.48 0.82 (n = 6)* 3.00 0.76 (n = 14)
4-0.20 + 0.27 (n - )
1.57 0.26 (n = 17)
Difference (Exposed, control s)
Pooled: (all subjects) (without subjects 1,6)**
' 1.52 1.12 .*
1.77- 0,37
1,75 0, 35 .1,78 ,0.35
*n number of subjects. **Subjects 1 and 6; were "non-responders.11
**
.
TABLE Ilf22. GRIFFIN ET AL,, (1975) EXPERIMENT MEAN RESIDENCE TIME IN BLOOD :
Control Exposed
3.2 pg/m3 experiment
34,,6 6.5 days
40. 8 4.4 days
10.9 pg/m3 experiment
41.8 9,2 days
40,6 3.6 days
(4) The average inhalation slope for all 17 subjects exposed to 10,9 pg/m3 is 1.77 0.37 when the slope for the controls is subtracted. The corrected inhalation slope for all 14 subjects exposed.to 3.2 pg/m3 is -1.52 1.12, or 1.90 1.14 without subjects 1 and .6 who were 11 non-responders.These are not significantly different.. The pooled slope estimate for all subjects is 1.75 0-35. The pooled mean resi dence time for all subjects is 39.9 2.5 days.
Thus, in spite of the large estimation variability at the lower exposure level, the aver
age inhalation slope estimate and blood lead half-life are not significantly different at the
#- -
*
two exposure levels. This suggests that blood lead response to small changes in air lead in
halation is approximately linear at typical ambient levels.
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