Evaluation and updates to the Leggett model for pharmacokinetic modeling of exposure to lead in the workplace – Part I adjustments to the adult systemic model

Abstract

California’s Division of Occupational Safety and Health has initiated a process to update its standards for exposure to lead in workplaces. In support of this effort, the state’s Office of Environmental Health Hazard Assessment evaluated the age-specific, bio-kinetic model of lead metabolism in humans, originally published by R.W. Leggett in 1993. This model was ultimately chosen for its physiologic realism and practicality in characterizing the relationship between air lead concentrations and blood lead levels in chronically exposed worker and its practicality in making necessary adjustments. Leggett’s original model systematically under-predicts bone and blood levels in workers such that several adjustments to the parameters are needed to improve predictions for occupational exposure scenarios. The aim of this work is to incorporate new information about the bio-kinetics of lead in workers and to adjust the Leggett model to improve its predictions.

The Leggett model was evaluated by comparing its predictions with information on lead concentrations in bone, blood, and urine from workers and other chronically exposed adults. Key model parameters were identified based upon a review of the relevant exposure assessment and modeling literature. Adjustments to the model parameters were made based on empirical evidence. They included reducing the level of lead in blood (BLL) where the rate of decrease in red blood cell binding begins and ends, lead accumulation rate in cortical bone, the rate of lead elimination in trabecular bone, and rate of lead transferred from diffusible plasma to urine. Regression methods and visual inspection of plotted data were used to assess the effect of adjustments on model predictions. When compared with the original, the adjusted Leggett model more accurately predicted lead concentrations observed in active and retired workers. Also, the adjusted Leggett model required less lead uptake to reach the same BLLs for BLLs less than 25 µg/dL and more time for BLLs to decline than the original Leggett model. These findings are important for defining an adequately protective occupational standard for lead exposure.

Keywords:

• Leggett lead model
• occupational lead exposure
• PBPK model

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Acknowledgments

The analyses presented in this article were based on work funded through an inter-agency agreement with the California Department of Public Health, Occupational Lead Poisoning Prevention Program and later by an inter-agency with the California Department of Industrial Relations, Division of Occupational Safety and Health. This article reflects the professional views of the authors and not those of the funding agencies or the California Office of Environmental Health Hazard Assessment, Cal EPA. The authors thank the original reviewers of this work, Drs. John Froines, Dale Hattis, Richard W. Leggett, Michael Kosnett and Gary Ginsberg and the helpful comments made by Drs. Ken Kloc, David M. Siegel, John Budroe, and two anonymous journal reviewers.