A Biologically Based Model of Regenerative Cell Replication Following Chloroform-Induced Cytotoxicity. P. D. Lilly, A. A. Constan, and R. B. Conolly, Chemical Industry Institute of Toxicology, 6 Davis Dr., P.O. Box 12137, Research Triangle Park, NC
Chloroform (CHCl3) is a nongenotoxic carcinogen whose mode of action has been linked to enhanced cell replication following cytotoxicity. Thus, a key aspect of human dose response assessments for CHCl3 is a quantitative model which can describe cytotoxicity and subsequent cell replication caused by CHCl3 exposure. We have developed a biologically based model describing these processes. The model is comprised of two sections. First, a physiologically based pharmacokinetic model (PBPK) is used to predict production of reactive metabolites in target tissues (based on a previously published CHCl3 PBPK model (Corley et al., (1990) TAP, 103:512-527)). Second, a pharmacodynamic (PD) component describes the relationship between rate of formation of reactive CHCl3 metabolites, the amount of tissue damage (ADAM) caused by metabolites, the fraction of cells killed, and the regeneration of killed cells. Hepatic and renal labeling indices (LI) were used as a surrogate for cell death. The fraction of tissue killed for a given ADAM was established by optimizing the model to LI data sets assuming a 1:1 correspondence between cells killed by CHCl3 and regenerative replication (ACSLOpt, MGA). The model was then used to describe several CHCl3 LI data sets from male and female F344 rats and B6C3F1 mice and 3 routes of exposure (inhalation, drinking water, and oral gavage). Evaluation of the data indicates that, except for male B6C3F1 mice, PK differences between species and routes of exposure (inhalation, drinking water, and oral gavage). Evaluation of the data indicates that, except for sections. First, a physiologically based pharmacokinetic model (PBPK) is used to predict production of reactive metabolites in target tissues (based on a previously published CHCl3 PBPK model (Corley et al., (1990) TAP, 103:512-527)). Second, a pharmacodynamic (PD) component describes the relationship between rate of formation of reactive CHCl3 metabolites, the amount of tissue damage (ADAM) caused by metabolites, the . . . . . . [RiskWorld Note: Submitted abstract incomplete]