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Estimating Workplace Air and Worker Blood Lead Concentration using an Updated Physiologically-based Pharmacokinetic (PBPK) Model
October 2013
Air, Community and Environmental Research Branch
Office of Environmental Health Hazard Assessment
California Environmental Protection Agency
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Estimating Workplace Air and Worker Blood Lead Concentration using an Updated
Physiologically-based Pharmacokinetic (PBPK)
Model
October 2013 Office of Environmental Health Hazard Assessment (OEHHA)
California Environmental Protection Agency
Authors Kathleen Vork, Ph.D., Research Scientist
Jim Carlisle, D.V.M., M.Sc., Staff Toxicologist Joseph P. Brown, Ph.D., Staff Toxicologist
Air, Community and Environmental Research Branch
OEHHA Scientific Reviewers Robert Blaisdell, Ph.D., Chief (Retired), Exposure Modeling Section,
Air Toxicology and Epidemiology Branch
Melanie Marty, Ph.D. Assistant Deputy Director for Scientific Affairs
Andrew G. Salmon, M.A., D.Phil., Chief, Air Toxicology and Risk Assessment Section, Air, Community and Environmental Research Branch
David Siegel, Ph.D., Chief, Air, Community and Environmental Research Branch
Lauren Zeise, Ph.D. Deputy Director for Scientific Affairs
George Alexeeff, Ph.D., Director
Allan Hirsch, Chief Deputy Director
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External Scientific Reviewers
Earlier versions of this document were reviewed by five independent peer reviewers
selected for their expertise in the fields of toxicology, occupational medicine, industrial
hygiene, mathematics, pharmacokinetics, and physiologically-based pharmacokinetic
(PBPK) modeling. Their invaluable expertise contributed to the development of the final
document. The peer reviewers are listed below.
John R. Froines, Ph.D., University of California, Los Angeles, Department of
Environmental Health Sciences, Los Angeles, CA
Gary L. Ginsberg, Ph.D., University of Connecticut, School of Community Medicine,
Farmington, CT
Dale B. Hattis, Ph.D., Clark University, The George Perkins Marsh Institute,
Worcester, MA
Michael J. Kosnett, M.D., M.P.H., University of Colorado, Department of Medicine and
Department of Environmental and Occupational Health, Denver, CO
Richard W. Leggett, Ph.D., Oak Ridge National Laboratory, Environmental Sciences
Division, Oak Ridge, TN
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Table of Contents
Summary.................................................................................................................. 1
1 Introduction............................................................................................................... 5
2 Methods and Results ................................................................................................ 6
2.1 Selection and modification of lead model........................................................... 6
2.2 Predicting blood lead from workplace air and vice versa (Task 1) ..................... 7
2.2.1 Model adjustments and assumptions .......................................................... 7
2.2.2 Inhalation transfer coefficient....................................................................... 8
2.2.3 Validation of the Leggett+ Model ................................................................. 9
2.2.4 Simulating Workers Blood Lead using Leggett+ ....................................... 10
2.3 Time to decline to target BLL following removal from workplace exposure
(Task 2) .............................................................................................................. 13
2.3.1 Scenario one: Constant PbA resulting in identified blood lead levels ........ 14
2.3.2 Scenario two: Declining workplace air concentrations sustaining over
40 years a BLL reached in one year .......................................................... 18
3 Discussion .............................................................................................................. 19
3.1 Updates to approach taken by Center for Policy Alternatives to predict air
lead/blood lead relationships .............................................................................. 20
3.2 Limitations and uncertainty............................................................................... 21
3.2.1 Population BLL variability .......................................................................... 21
3.2.2 Breathing rate ............................................................................................ 22
3.2.3 Erythrocyte saturation................................................................................ 22
3.2.4 Leads toxic effects could alter the kinetics of lead in the body.................. 23
3.2.5 Particle size distribution............................................................................. 23
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3.2.6 Gastrointestinal absorption ........................................................................ 25
3.2.7 Lead in bone.............................................................................................. 25
Summary and Conclusions..................................................................................... 25
A Appendix: Review, Selection, Modification, and Testing of Lead Models ............... 27
A.1 Lead biokinetics ............................................................................................... 27
A.1.1 Pulmonary deposition and clearance......................................................... 27
A.1.2 Gastrointestinal absorption ........................................................................ 28
A.1.3 Erythrocyte uptake and saturation ............................................................. 29
A.1.4 Uptake and elimination from blood and soft tissue .................................... 29
A.1.5 Uptake and elimination from bone ............................................................. 29
A.2 Model screening............................................................................................... 30
A.2.1 Bert model ................................................................................................. 32
A.2.2 Leggett model............................................................................................ 33
A.2.3 OFlaherty model ....................................................................................... 37
A.3 Model selection ................................................................................................ 40
A.4 Further evaluation and adjustment of the nonlinear Leggett model.................. 42
A.4.1 Coding integrity.......................................................................................... 42
A.4.2 Assessing model performance .................................................................. 44
A.5 Conclusion ....................................................................................................... 65
B Appendix: OEHHA Modifications to the Adjusted core Model to Accommodate
Workplace Exposure in Leggett+ Model ................................................................. 67
B.1 Description of exposure features added to the nonlinear Leggett model ......... 67
B.1.1 Breathing rate ............................................................................................ 67
B.1.2 Inhalation transfer coefficient..................................................................... 68
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B.2 Methods for deriving a coefficient for the transfer of inhaled lead to blood in
workers............................................................................................................... 71
B.2.1 Studies selected for analysis ..................................................................... 71
B.2.2 Lead particle dosimetry using the MPPD2 model ...................................... 72
B.3 Results ............................................................................................................. 74
B.3.1 Dosimetry results from MPPD2 ................................................................. 74
B.3.2 Dosimetry results from ICRP Human Lung Model publication 66 lookup
tables ......................................................................................................... 80
B.3.3 Default inhalation transfer coefficient (ITC)................................................ 82
B.4 Methods for assessing the performance of the Leggett+ model....................... 85
B.4.1 Study and subject selection criteria ........................................................... 86
B.4.2 Data extraction .......................................................................................... 87
B.5 Results ............................................................................................................. 90
B.5.1 Test 1: Goodness of fit .............................................................................. 92
B.5.2 Test 2: Model performance versus exposure duration............................... 94
B.6 Conclusion ....................................................................................................... 95
C Appendix: Acronyms, symbols and special terms................................................... 97
D References .................................