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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

___________________________________________________________________

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 .................................