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© 1994 Oxford University Press

research-article

The Impact of Exercise and Intersubject Variability on Dose Estimates for Dichloromethane Derived from a Physiologically Based Pharmacokinetic Model

DAVID A. DANKOVIC*,1 and A. JOHN BAILER*,{dagger}

*Risk Assessment Program, MS C15, Division of Standards Development and Technology Transfer, National Inst it ute for Occupational Safety and Health 4676 Columbia Parkway, Cincinnati. Ohio 45226-1998 {dagger}Department of Mathematics and Statistics, Miami University Oxford, Ohio 45056

Received January 19, 1993; accepted July 28, 1993

Andersen et al. and Reitz et al. have developed physiologically based pharmacokinetic models for the human metabolism of methylene chloride (dichloromethane; DCM) and have advanced the hypothesis that the carcinogenicity of DCM is related to target organ metabolism of DCM by glutathione S transferase (GST). The models included physiological parameters appropriate for humans at rest and metabolic parameters based on average rates of DCM metabolism. Increasing the model parameters describing cardiac output, alveolar ventilation, and blood flows to tissues from resting values to values consistent with light work conditions, and assuming a 25 ppm exposure for an 8-hr work day, increases the estimated GST metabolized dose for human liver by a factor of 2.9 compared to the GST-metabolized dose estimate of Reitz et at These modifications also increase the GST-metabolized dose to the lung by 2.4-fold. If the model is also modified to reflect individual variation in DCM metabolism (in addition to the modifications for light work conditions), the estimated GST-metabolized dose for human liver ranges from 0 to as much as 5.4-fold greater than the dose estimated by Reitz et al. The GST-metabolized dose to the lung ranges from 0 to as much as 3.6-fold greater than the dose estimated by Reitz et al. These results indicate that some occupationally-exposed individuals may receive GST-metabolized doses several-fold greater than the Reitz et al. human dose estimates.


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