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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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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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.</description><identifier>ISSN: 0272-4332</identifier><identifier>EISSN: 1539-6924</identifier><identifier>DOI: 10.1111/j.1539-6924.2007.00987.x</identifier><identifier>PMID: 18093051</identifier><language>eng</language><publisher>Malden, USA: Blackwell Publishing Inc</publisher><subject>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</subject><ispartof>Risk analysis, 2007-12, Vol.27 (6), p.1535-1551</ispartof><rights>2007 Society for Risk Analysis</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5187-20beeab0b3be42e3ab871eed4f0a08bb62c5a5dea11fb68af711586228042ffc3</citedby><cites>FETCH-LOGICAL-c5187-20beeab0b3be42e3ab871eed4f0a08bb62c5a5dea11fb68af711586228042ffc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1539-6924.2007.00987.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1539-6924.2007.00987.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18093051$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liao, Kai H</creatorcontrib><creatorcontrib>Tan, Yu-Mei</creatorcontrib><creatorcontrib>Conolly, Rory B</creatorcontrib><creatorcontrib>Borghoff, Susan J</creatorcontrib><creatorcontrib>Gargas, Michael L</creatorcontrib><creatorcontrib>Andersen, Melvin E</creatorcontrib><creatorcontrib>Clewell, Harvey J. 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. 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.</description><subject>Animals</subject><subject>Bayes Theorem</subject><subject>Bayesian analysis</subject><subject>Bayesian method</subject><subject>Biological Transport, Active</subject><subject>Cancer</subject><subject>Carcinogens</subject><subject>Carcinogens - pharmacokinetics</subject><subject>Carcinogens - pharmacology</subject><subject>Carcinogens - toxicity</subject><subject>Cells</subject><subject>Chloroform</subject><subject>Chloroform - pharmacokinetics</subject><subject>Chloroform - pharmacology</subject><subject>Chloroform - toxicity</subject><subject>Drugs</subject><subject>Environmental Exposure</subject><subject>Female</subject><subject>Humans</subject><subject>Illness</subject><subject>Kidney - metabolism</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Markov analysis</subject><subject>Markov Chain Monte Carlo (MCMC) analysis</subject><subject>Markov Chains</subject><subject>Mathematical models</subject><subject>Medical research</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Monte Carlo Method</subject><subject>Monte Carlo simulation</subject><subject>Neoplasms - chemically induced</subject><subject>Neoplasms, Experimental - chemically induced</subject><subject>Neoplasms, Experimental - metabolism</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Risk</subject><subject>Risk Assessment</subject><subject>Risk management</subject><subject>Studies</subject><issn>0272-4332</issn><issn>1539-6924</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcGO0zAURSMEYsrAL4DFgl3Ks53YzoJFW4YyaIBRhwF21kvywqRt4sFORfsB_DcuHRWJDXhj6_ncK9knSRiHMY_r5XLMc1mkqhDZWADoMUBh9Hh7LxkdL-4nIxBapJmU4iR5FMISgAPk-mFywg0UEnI-Sn5OcUehxZ6dhaHtcGhdz1zDLm_Qd1i5VdvT0FYM-_o4q3c9dnF2iR47GsgH1vYM2XtXU-qadFLtW9IpBqrZDPuKPFu0YcUmIVAIHfUDa5xns5u18y6eusfJgwbXgZ7c7afJ9ZuzT7O36cXH-flscpFWOTc6FVASYQmlLCkTJLE0mhPVWQMIpiyVqHLMa0LOm1IZbDTnuVFCGMhE01TyNHlx6L317vuGwmC7NlS0XmNPbhOsVIXKVQ7_BAVkyhRGRfD5X-DSbXwfHxEZrbTOIYuQOUCVdyF4auytj3_td5aD3Qu1S7v3Zvfe7F6o_S3UbmP06V3_puyo_hO8MxiBVwfgR7um3X8X28X51SSeYj495Nsw0PaYR7-ySkud2y8f5nbxeT4t3r2e2q-Rf3bgG3QWv_k22OsrAVwCGKmUKOQvnu7I2w</recordid><startdate>200712</startdate><enddate>200712</enddate><creator>Liao, Kai H</creator><creator>Tan, Yu-Mei</creator><creator>Conolly, Rory B</creator><creator>Borghoff, Susan J</creator><creator>Gargas, Michael L</creator><creator>Andersen, Melvin E</creator><creator>Clewell, Harvey J. III</creator><general>Blackwell Publishing Inc</general><general>Blackwell Publishing Ltd</general><scope>FBQ</scope><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7ST</scope><scope>7U7</scope><scope>7U9</scope><scope>8BJ</scope><scope>8FD</scope><scope>C1K</scope><scope>FQK</scope><scope>FR3</scope><scope>H94</scope><scope>JBE</scope><scope>JQ2</scope><scope>KR7</scope><scope>M7N</scope><scope>SOI</scope><scope>7U1</scope><scope>7U2</scope></search><sort><creationdate>200712</creationdate><title>Bayesian Estimation of Pharmacokinetic and Pharmacodynamic Parameters in a Mode-of-Action-Based Cancer Risk Assessment for Chloroform</title><author>Liao, Kai H ; Tan, Yu-Mei ; Conolly, Rory B ; Borghoff, Susan J ; Gargas, Michael L ; Andersen, Melvin E ; Clewell, Harvey J. 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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. 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.</abstract><cop>Malden, USA</cop><pub>Blackwell Publishing Inc</pub><pmid>18093051</pmid><doi>10.1111/j.1539-6924.2007.00987.x</doi><tpages>17</tpages></addata></record> |
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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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