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USE OF BIOLOGICALLY BASED COMPUTATIONAL MODELING IN MODE OF ACTION-BASED RISK ASSESSMENT – AN EXAMPLE OF CHLOROFORM
Citation:
CONOLLY, R. USE OF BIOLOGICALLY BASED COMPUTATIONAL MODELING IN MODE OF ACTION-BASED RISK ASSESSMENT – AN EXAMPLE OF CHLOROFORM. Presented at U.S. EPA-Health Canada Workshop , Raleigh, NC, June 02 - 03, 2005.
Impact/Purpose:
Chloroform causes hepatic and renal cancer in rodents through a mode of action characterized by chronic cytolethality and regenerative cellular proliferation. The objective of current work is to develop a new cancer dose-response assessment for chloroform using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model. The PBPK/PD model is based on a mode of action in which the cytolethality of chloroform occurs when the rate of generation of toxic metabolites exceeds the capacity of cellular repair mechanisms. The model specifies a relationship between cytolethality and cell regeneration to simulate labeling index (LI) in rodents exposed to chloroform through inhalation.
Description:
The objective of current work is to develop a new cancer dose-response assessment for chloroform using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model. The PBPK/PD model is based on a mode of action in which the cytolethality of chloroform occurs when the rate of generation of toxic metabolites exceeds the capacity of cellular repair mechanisms. The model specifies a relationship between cytolethality and cell regeneration to simulate labeling index (LI) in rodents exposed to chloroform through inhalation.