Bayesian Estimation of Pharmacokinetic and Pharmacodynamic Parameters in a Mode-of-Action-Based Cancer Risk Assessment for Chloroform

Chloroform is a carcinogen in rodents and its carcinogenicity is secondary to events associated with cytotoxicity and regenerative cell proliferation. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that links the processes of chloroform metabolism, reparable c...

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Veröffentlicht in:Risk analysis 2007-12, Vol.27 (6), p.1535-1551
Hauptverfasser: Liao, Kai H, Tan, Yu-Mei, Conolly, Rory B, Borghoff, Susan J, Gargas, Michael L, Andersen, Melvin E, Clewell, Harvey J. III
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container_end_page 1551
container_issue 6
container_start_page 1535
container_title Risk analysis
container_volume 27
creator Liao, Kai H
Tan, Yu-Mei
Conolly, Rory B
Borghoff, Susan J
Gargas, Michael L
Andersen, Melvin E
Clewell, Harvey J. III
description Chloroform is a carcinogen in rodents and its carcinogenicity is secondary to events associated with cytotoxicity and regenerative cell proliferation. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that links the processes of chloroform metabolism, reparable cell damage, cell death, and regenerative cellular proliferation was developed to support a new cancer dose-response assessment for chloroform. Model parameters were estimated using Markov Chain Monte Carlo (MCMC) analysis in a two-step approach: (1) metabolism parameters for male and female mice and rats were estimated against available closed chamber gas uptake data; and (2) PD parameters for each of the four rodent groups were estimated from hepatic and renal labeling index data following inhalation exposures. Subsequently, the resulting rodent PD parameters together with literature values for human age-dependent physiological and metabolism parameters were used to scale up the rodent model to a human model. The human model was used to predict exposure conditions under which chloroform-mediated cytolethality is expected to occur in liver and kidney of adults and children. Using the human model, inhalation Reference Concentrations (RfCs) and oral Reference Doses (RfDs) were derived using an uncertainty factor of 10. Based on liver and kidney dose metrics, the respective RfCs were 0.9 and 0.09 ppm; and the respective RfDs were 0.4 and 3 mg/kg/day.
doi_str_mv 10.1111/j.1539-6924.2007.00987.x
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III</creatorcontrib><title>Bayesian Estimation of Pharmacokinetic and Pharmacodynamic Parameters in a Mode-of-Action-Based Cancer Risk Assessment for Chloroform</title><title>Risk analysis</title><addtitle>Risk Anal</addtitle><description>Chloroform is a carcinogen in rodents and its carcinogenicity is secondary to events associated with cytotoxicity and regenerative cell proliferation. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that links the processes of chloroform metabolism, reparable cell damage, cell death, and regenerative cellular proliferation was developed to support a new cancer dose-response assessment for chloroform. 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III</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bayesian Estimation of Pharmacokinetic and Pharmacodynamic Parameters in a Mode-of-Action-Based Cancer Risk Assessment for Chloroform</atitle><jtitle>Risk analysis</jtitle><addtitle>Risk Anal</addtitle><date>2007-12</date><risdate>2007</risdate><volume>27</volume><issue>6</issue><spage>1535</spage><epage>1551</epage><pages>1535-1551</pages><issn>0272-4332</issn><eissn>1539-6924</eissn><abstract>Chloroform is a carcinogen in rodents and its carcinogenicity is secondary to events associated with cytotoxicity and regenerative cell proliferation. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that links the processes of chloroform metabolism, reparable cell damage, cell death, and regenerative cellular proliferation was developed to support a new cancer dose-response assessment for chloroform. 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subjects Animals
Bayes Theorem
Bayesian analysis
Bayesian method
Biological Transport, Active
Cancer
Carcinogens
Carcinogens - pharmacokinetics
Carcinogens - pharmacology
Carcinogens - toxicity
Cells
Chloroform
Chloroform - pharmacokinetics
Chloroform - pharmacology
Chloroform - toxicity
Drugs
Environmental Exposure
Female
Humans
Illness
Kidney - metabolism
Liver - metabolism
Male
Markov analysis
Markov Chain Monte Carlo (MCMC) analysis
Markov Chains
Mathematical models
Medical research
Metabolism
Mice
Models, Biological
Monte Carlo Method
Monte Carlo simulation
Neoplasms - chemically induced
Neoplasms, Experimental - chemically induced
Neoplasms, Experimental - metabolism
Pharmacodynamics
Pharmacokinetics
Pharmacology
physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling
Rats
Rats, Inbred F344
Risk
Risk Assessment
Risk management
Studies
title Bayesian Estimation of Pharmacokinetic and Pharmacodynamic Parameters in a Mode-of-Action-Based Cancer Risk Assessment for Chloroform
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