A Pharmacokinetic/Mechanism-Based Analysis of the Carcinogenic Risk of Perchloroethylene.
Hattis-D; Tuler-S; Finkelstein-L; Luo-Q
Center for Technology, Policy and Industrial Development, Massachusetts Institute of Technology, Cambridge, MA, CTPID 86-7, 1986 Sep:197 pages
The implications of existing pharmacokinetic information for the human carcinogenic risk of perchloroethylene were explored using physiologically based pharmacokinetic modeling. The models used were easily implemented on the Apple MacIntosh microcomputer based systems dynamics modeling system (STELLA) and could be used by relatively inexperienced people, facilitating understanding of effects of changes in model structure and parameters. Human models incorporated a realistic diurnal pattern of change in breathing rates and blood flows to tissues allowing different assumptions for activity during waking hours and timing of exposure relative to activity and sleep. Regression analysis of data from other compounds was used to determine human tissue partition coefficients for perchloroethylene (127184). The models reproduced human, rat, and mouse data on metabolite output. Comparison with published human data on breath concentrations indicated possible loss from an unknown route, perhaps skin. Data from gavage studies were integrated with inhalation data. Best estimate and plausible upper limit calculations were presented. The largest contributor to spread between these values was uncertainty in human metabolic rate for perchloroethylene. Conclusions were presented on interspecies comparison of overall efficiency of production of active perchloroethylene metabolites and implications for human risk. Expected best estimate risk for human occupational lifetime exposure of 100 parts per million per workday was an increase of 4 percent in cancer incidence.
NIOSH-Cooperative-Agreement; Cooperative-Agreement-U60-CCU-100929; Metabolic-study; Kinetics; Pharmacodynamics; Computer-models; Laboratory-animals; Risk-analysis; Chlorinated-ethylenes; Risk-factors; Carcinogenesis; Humans;
NTIS Accession No.
Center for Technology, Policy and Industrial Development, Massachusetts Institute of Technology, Cambridge, MA, CTPID 86-7, 197 pages, 70 references