Development of a Quantitative Model Incorporating Key Events in a Hepatotoxic Mode of Action to Predict Tumor Incidence
Biologically based dose-response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically labeled as either genotoxic or nongenotoxic. Though both the genotoxic and the...
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description | Biologically based dose-response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically labeled as either genotoxic or nongenotoxic. Though both the genotoxic and the nongenotoxic MOA may be operative as a function of dose, it is important to note that the label informs but does not define a MOA. One commonly proposed MOA for nongenotoxic carcinogens is characterized by the key events cytotoxicity and regenerative proliferation. The increased division rate associated with such proliferation can cause an increase in the probability of mutations, which may result in tumor formation. We included these steps in a generalized computational pharmacodynamic (PD) model incorporating cytotoxicity as a MOA for three carcinogens (chloroform, CHCl3; carbon tetrachloride, CCL4; and N,N-dimethylformamide, DMF). For each compound, the BBDR model is composed of a chemical-specific physiologically based pharmacokinetic model linked to a PD model of cytotoxicity and cellular proliferation. The rate of proliferation is then linked to a clonal growth model to predict tumor incidences. Comparisons of the BBDR simulations and parameterizations across chemicals suggested that significant variation among the models for the three chemicals arises in a few parameters expected to be chemical specific (such as metabolism and cellular injury rate constants). Optimization of model parameters to tumor data for CCL4 and DMF resulted in similar estimates for all parameters related to cytotoxicity and tumor incidences. However, optimization of the CHCl3 data resulted in a higher estimate for one parameter (BD) related to death of initiated cells. This implies that additional steps beyond cytotoxicity leading to induced cellular proliferation can be quantitatively different among chemicals that share cytotoxicity as a hypothesized carcinogenic MOA. |
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Chemicals that produce tumors are typically labeled as either genotoxic or nongenotoxic. Though both the genotoxic and the nongenotoxic MOA may be operative as a function of dose, it is important to note that the label informs but does not define a MOA. One commonly proposed MOA for nongenotoxic carcinogens is characterized by the key events cytotoxicity and regenerative proliferation. The increased division rate associated with such proliferation can cause an increase in the probability of mutations, which may result in tumor formation. We included these steps in a generalized computational pharmacodynamic (PD) model incorporating cytotoxicity as a MOA for three carcinogens (chloroform, CHCl3; carbon tetrachloride, CCL4; and N,N-dimethylformamide, DMF). For each compound, the BBDR model is composed of a chemical-specific physiologically based pharmacokinetic model linked to a PD model of cytotoxicity and cellular proliferation. The rate of proliferation is then linked to a clonal growth model to predict tumor incidences. Comparisons of the BBDR simulations and parameterizations across chemicals suggested that significant variation among the models for the three chemicals arises in a few parameters expected to be chemical specific (such as metabolism and cellular injury rate constants). Optimization of model parameters to tumor data for CCL4 and DMF resulted in similar estimates for all parameters related to cytotoxicity and tumor incidences. However, optimization of the CHCl3 data resulted in a higher estimate for one parameter (BD) related to death of initiated cells. This implies that additional steps beyond cytotoxicity leading to induced cellular proliferation can be quantitatively different among chemicals that share cytotoxicity as a hypothesized carcinogenic MOA.</description><identifier>ISSN: 1096-6080</identifier><identifier>EISSN: 1096-0929</identifier><identifier>DOI: 10.1093/toxsci/kfq021</identifier><identifier>PMID: 20106946</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Animals ; Carbon Tetrachloride - pharmacokinetics ; Carbon Tetrachloride - toxicity ; Carcinogens - pharmacokinetics ; Carcinogens - toxicity ; Cell Death - drug effects ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Chemical and Drug Induced Liver Injury, Chronic - etiology ; Chemical and Drug Induced Liver Injury, Chronic - metabolism ; Chemical and Drug Induced Liver Injury, Chronic - pathology ; Chloroform - pharmacokinetics ; Chloroform - toxicity ; Computational Biology ; Computers ; Dimethylformamide - pharmacokinetics ; Dimethylformamide - toxicity ; Female ; Humans ; Liver Neoplasms - chemically induced ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Male ; Mice ; mode of action ; Models, Biological ; quantitative modeling ; Regeneration - drug effects ; Risk Assessment</subject><ispartof>Toxicological sciences, 2010-05, Vol.115 (1), p.253-266</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c369t-255765e6649c94749dcb4cd89038c5ba61299d5c81c6b293a154478145ce297c3</citedby><cites>FETCH-LOGICAL-c369t-255765e6649c94749dcb4cd89038c5ba61299d5c81c6b293a154478145ce297c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20106946$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Luke, Nicholas S.</creatorcontrib><creatorcontrib>Sams, Reeder</creatorcontrib><creatorcontrib>DeVito, Michael J.</creatorcontrib><creatorcontrib>Conolly, Rory B.</creatorcontrib><creatorcontrib>El-Masri, Hisham A.</creatorcontrib><title>Development of a Quantitative Model Incorporating Key Events in a Hepatotoxic Mode of Action to Predict Tumor Incidence</title><title>Toxicological sciences</title><addtitle>Toxicol Sci</addtitle><description>Biologically based dose-response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically labeled as either genotoxic or nongenotoxic. Though both the genotoxic and the nongenotoxic MOA may be operative as a function of dose, it is important to note that the label informs but does not define a MOA. One commonly proposed MOA for nongenotoxic carcinogens is characterized by the key events cytotoxicity and regenerative proliferation. The increased division rate associated with such proliferation can cause an increase in the probability of mutations, which may result in tumor formation. We included these steps in a generalized computational pharmacodynamic (PD) model incorporating cytotoxicity as a MOA for three carcinogens (chloroform, CHCl3; carbon tetrachloride, CCL4; and N,N-dimethylformamide, DMF). For each compound, the BBDR model is composed of a chemical-specific physiologically based pharmacokinetic model linked to a PD model of cytotoxicity and cellular proliferation. The rate of proliferation is then linked to a clonal growth model to predict tumor incidences. Comparisons of the BBDR simulations and parameterizations across chemicals suggested that significant variation among the models for the three chemicals arises in a few parameters expected to be chemical specific (such as metabolism and cellular injury rate constants). Optimization of model parameters to tumor data for CCL4 and DMF resulted in similar estimates for all parameters related to cytotoxicity and tumor incidences. However, optimization of the CHCl3 data resulted in a higher estimate for one parameter (BD) related to death of initiated cells. This implies that additional steps beyond cytotoxicity leading to induced cellular proliferation can be quantitatively different among chemicals that share cytotoxicity as a hypothesized carcinogenic MOA.</description><subject>Animals</subject><subject>Carbon Tetrachloride - pharmacokinetics</subject><subject>Carbon Tetrachloride - toxicity</subject><subject>Carcinogens - pharmacokinetics</subject><subject>Carcinogens - toxicity</subject><subject>Cell Death - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Chemical and Drug Induced Liver Injury, Chronic - etiology</subject><subject>Chemical and Drug Induced Liver Injury, Chronic - metabolism</subject><subject>Chemical and Drug Induced Liver Injury, Chronic - pathology</subject><subject>Chloroform - pharmacokinetics</subject><subject>Chloroform - toxicity</subject><subject>Computational Biology</subject><subject>Computers</subject><subject>Dimethylformamide - pharmacokinetics</subject><subject>Dimethylformamide - toxicity</subject><subject>Female</subject><subject>Humans</subject><subject>Liver Neoplasms - chemically induced</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>mode of action</subject><subject>Models, Biological</subject><subject>quantitative modeling</subject><subject>Regeneration - drug effects</subject><subject>Risk Assessment</subject><issn>1096-6080</issn><issn>1096-0929</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkFFPwjAQxxujEUQffTX9ApN2W7v1kQAKESImiMSXpus6U2Hr7ArCt3c4xKe73P3un8sPgFuM7jFiQdeZXSV1d5V9IR-fgXY9pB5iPjs_9hTFqAWuquoTIYwpYpeg5SOMKAtpG3wP1FatTZmrwkGTQQFfNqJw2gmntwpOTarWcFxIY0tj61nxAZ_UHg63NV9BXdQHI1UKZ-o_tPzlDzE96bQpoDNwZlWqpYPzTW7sIUmnqpDqGlxkYl2pm2PtgNeH4bw_8ibPj-N-b-LJgDLn-YRElChKQyZZGIUslUko05ihIJYkERT7jKVExljSxGeBwCQMoxiHRCqfRTLoAK_JldZUlVUZL63Ohd1zjPhBIG8E8kZgzd81fLlJcpWe6D9j_4G6cmp32gu74jQKIsJHy3e-WE7JYvY24H7wAwhJfic</recordid><startdate>20100501</startdate><enddate>20100501</enddate><creator>Luke, Nicholas S.</creator><creator>Sams, Reeder</creator><creator>DeVito, Michael J.</creator><creator>Conolly, Rory B.</creator><creator>El-Masri, Hisham A.</creator><general>Oxford University Press</general><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></search><sort><creationdate>20100501</creationdate><title>Development of a Quantitative Model Incorporating Key Events in a Hepatotoxic Mode of Action to Predict Tumor Incidence</title><author>Luke, Nicholas S. ; Sams, Reeder ; DeVito, Michael J. ; Conolly, Rory B. ; El-Masri, Hisham A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c369t-255765e6649c94749dcb4cd89038c5ba61299d5c81c6b293a154478145ce297c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Carbon Tetrachloride - pharmacokinetics</topic><topic>Carbon Tetrachloride - toxicity</topic><topic>Carcinogens - pharmacokinetics</topic><topic>Carcinogens - toxicity</topic><topic>Cell Death - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Chemical and Drug Induced Liver Injury, Chronic - etiology</topic><topic>Chemical and Drug Induced Liver Injury, Chronic - metabolism</topic><topic>Chemical and Drug Induced Liver Injury, Chronic - pathology</topic><topic>Chloroform - pharmacokinetics</topic><topic>Chloroform - toxicity</topic><topic>Computational Biology</topic><topic>Computers</topic><topic>Dimethylformamide - pharmacokinetics</topic><topic>Dimethylformamide - toxicity</topic><topic>Female</topic><topic>Humans</topic><topic>Liver Neoplasms - chemically induced</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>mode of action</topic><topic>Models, Biological</topic><topic>quantitative modeling</topic><topic>Regeneration - drug effects</topic><topic>Risk Assessment</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Luke, Nicholas S.</creatorcontrib><creatorcontrib>Sams, Reeder</creatorcontrib><creatorcontrib>DeVito, Michael J.</creatorcontrib><creatorcontrib>Conolly, Rory B.</creatorcontrib><creatorcontrib>El-Masri, Hisham A.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Toxicological sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Luke, Nicholas S.</au><au>Sams, Reeder</au><au>DeVito, Michael J.</au><au>Conolly, Rory B.</au><au>El-Masri, Hisham A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of a Quantitative Model Incorporating Key Events in a Hepatotoxic Mode of Action to Predict Tumor Incidence</atitle><jtitle>Toxicological sciences</jtitle><addtitle>Toxicol Sci</addtitle><date>2010-05-01</date><risdate>2010</risdate><volume>115</volume><issue>1</issue><spage>253</spage><epage>266</epage><pages>253-266</pages><issn>1096-6080</issn><eissn>1096-0929</eissn><abstract>Biologically based dose-response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically labeled as either genotoxic or nongenotoxic. Though both the genotoxic and the nongenotoxic MOA may be operative as a function of dose, it is important to note that the label informs but does not define a MOA. One commonly proposed MOA for nongenotoxic carcinogens is characterized by the key events cytotoxicity and regenerative proliferation. The increased division rate associated with such proliferation can cause an increase in the probability of mutations, which may result in tumor formation. We included these steps in a generalized computational pharmacodynamic (PD) model incorporating cytotoxicity as a MOA for three carcinogens (chloroform, CHCl3; carbon tetrachloride, CCL4; and N,N-dimethylformamide, DMF). For each compound, the BBDR model is composed of a chemical-specific physiologically based pharmacokinetic model linked to a PD model of cytotoxicity and cellular proliferation. The rate of proliferation is then linked to a clonal growth model to predict tumor incidences. Comparisons of the BBDR simulations and parameterizations across chemicals suggested that significant variation among the models for the three chemicals arises in a few parameters expected to be chemical specific (such as metabolism and cellular injury rate constants). Optimization of model parameters to tumor data for CCL4 and DMF resulted in similar estimates for all parameters related to cytotoxicity and tumor incidences. However, optimization of the CHCl3 data resulted in a higher estimate for one parameter (BD) related to death of initiated cells. This implies that additional steps beyond cytotoxicity leading to induced cellular proliferation can be quantitatively different among chemicals that share cytotoxicity as a hypothesized carcinogenic MOA.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>20106946</pmid><doi>10.1093/toxsci/kfq021</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Carbon Tetrachloride - pharmacokinetics Carbon Tetrachloride - toxicity Carcinogens - pharmacokinetics Carcinogens - toxicity Cell Death - drug effects Cell Proliferation - drug effects Cell Survival - drug effects Chemical and Drug Induced Liver Injury, Chronic - etiology Chemical and Drug Induced Liver Injury, Chronic - metabolism Chemical and Drug Induced Liver Injury, Chronic - pathology Chloroform - pharmacokinetics Chloroform - toxicity Computational Biology Computers Dimethylformamide - pharmacokinetics Dimethylformamide - toxicity Female Humans Liver Neoplasms - chemically induced Liver Neoplasms - metabolism Liver Neoplasms - pathology Male Mice mode of action Models, Biological quantitative modeling Regeneration - drug effects Risk Assessment |
title | Development of a Quantitative Model Incorporating Key Events in a Hepatotoxic Mode of Action to Predict Tumor Incidence |
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