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dc.contributor.authorDavid, Raymond M.
dc.contributor.authorClewell, Harvey J.
dc.contributor.authorGentry, P. Robinan
dc.contributor.authorCovington, Tammie R.
dc.contributor.authorMorgott, David A.
dc.contributor.authorMarino, Dale J.
dc.date.accessioned2009-05-20T10:24:31Z
dc.date.available2009-05-20T10:24:31Z
dc.date.issued2006-06
dc.identifier.citationRegul. Toxicol. Pharmacol. 2006, 45 (1):55-65en
dc.identifier.issn0273-2300
dc.identifier.pmid16439044
dc.identifier.doi10.1016/j.yrtph.2005.12.003
dc.identifier.urihttp://hdl.handle.net/10146/68636
dc.descriptionKEYWORDS - CLASSIFICATION: analysis;chemically induced;Carcinogens;Dose-Response Relationship,Drug;Environment;genetics;Glutathione;Glutathione Transferase;Humans;Inhalation Exposure;Laboratories;metabolism;methods;Markov Chains;mechanisms of carcinogenesis;Methylene Chloride;Models,Biological;Monte Carlo Method;Neoplasms;pharmacokinetics;Polymorphism,Genetic;Risk Assessment;toxicity.en
dc.description.abstractAn updated PBPK model of methylene chloride (DCM, dichloromethane) carcinogenicity in mice was recently published using Bayesian statistical methods (Marino et al., 2006). In this work, this model was applied to humans, as recommended by Sweeney et al.(2004). Physiological parameters for input into the MCMC analysis were selected from multiple sources reflecting, in each case, the source that was considered to represent the most current scientific evidence for each parameter. Metabolic data for individual subjects from five human studies were combined into a single data set and population values derived using MCSim. These population values were used for calibration of the human model. The PBPK model using the calibrated metabolic parameters was used to perform a cancer risk assessment for DCM, using the same tumor incidence and exposure concentration data relied upon in the current IRIS entry. Unit risks, i.e., the risk of cancer from exposure to 1 microg/m3 over a lifetime, for DCM were estimated using the calibrated human model. The results indicate skewed distributions for liver and lung tumor risks, alone or in combination, with a mean unit risk (per microg/m3) of 1.05 x 10(-9), considering both liver and lung tumors. Adding the distribution of genetic polymorphisms for metabolism to the ultimate carcinogen, the unit risks range from 0 (which is expected given that approximately 20% of the US population is estimated to be nonconjugators) up to a unit risk of 2.70 x 10(-9) at the 95th percentile. The median, or 50th percentile, is 9.33 x 10(-10), which is approximately a factor of 500 lower than the current EPA unit risk of 4.7 x 10(-7) using a previous PBPK model. These values represent the best estimates to date for DCM cancer risk because all available human data sets were used, and a probabilistic methodology was followed.
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WPT-4J3WSK2-2&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=d898c2cb33cb4a8051bc27025a9d6366en
dc.subjectMethylene chlorideen
dc.subjectDichloromethaneen
dc.subjectRisk assessmenten
dc.subjectPBPK modelingen
dc.subjectBayesian analysisen
dc.subjectMonte Carlo analysisen
dc.subjectGST polymorphismen
dc.subject.meshCarcinogens
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshGlutathione Transferase
dc.subject.meshHumans
dc.subject.meshInhalation Exposure
dc.subject.meshMarkov Chains
dc.subject.meshMethylene Chloride
dc.subject.meshModels, Biological
dc.subject.meshMonte Carlo Method
dc.subject.meshNeoplasms
dc.subject.meshPolymorphism, Genetic
dc.subject.meshRisk Assessment
dc.titleRevised assessment of cancer risk to dichloromethane II. Application of probabilistic methods to cancer risk determinations.en
dc.typeArticleen
dc.identifier.journalRegulatory toxicology and pharmacology : RTPen
html.description.abstractAn updated PBPK model of methylene chloride (DCM, dichloromethane) carcinogenicity in mice was recently published using Bayesian statistical methods (Marino et al., 2006). In this work, this model was applied to humans, as recommended by Sweeney et al.(2004). Physiological parameters for input into the MCMC analysis were selected from multiple sources reflecting, in each case, the source that was considered to represent the most current scientific evidence for each parameter. Metabolic data for individual subjects from five human studies were combined into a single data set and population values derived using MCSim. These population values were used for calibration of the human model. The PBPK model using the calibrated metabolic parameters was used to perform a cancer risk assessment for DCM, using the same tumor incidence and exposure concentration data relied upon in the current IRIS entry. Unit risks, i.e., the risk of cancer from exposure to 1 microg/m3 over a lifetime, for DCM were estimated using the calibrated human model. The results indicate skewed distributions for liver and lung tumor risks, alone or in combination, with a mean unit risk (per microg/m3) of 1.05 x 10(-9), considering both liver and lung tumors. Adding the distribution of genetic polymorphisms for metabolism to the ultimate carcinogen, the unit risks range from 0 (which is expected given that approximately 20% of the US population is estimated to be nonconjugators) up to a unit risk of 2.70 x 10(-9) at the 95th percentile. The median, or 50th percentile, is 9.33 x 10(-10), which is approximately a factor of 500 lower than the current EPA unit risk of 4.7 x 10(-7) using a previous PBPK model. These values represent the best estimates to date for DCM cancer risk because all available human data sets were used, and a probabilistic methodology was followed.


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