Revised assessment of cancer risk to dichloromethane II. Application of probabilistic methods to cancer risk determinations.
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AuthorsDavid, Raymond M.
Clewell, Harvey J.
Gentry, P. Robinan
Covington, Tammie R.
Morgott, David A.
Marino, Dale J.
MetadataShow full item record
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.
CitationRegul. Toxicol. Pharmacol. 2006, 45 (1):55-65
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.
- Revised assessment of cancer risk to dichloromethane: part I Bayesian PBPK and dose-response modeling in mice.
- Authors: Marino DJ, Clewell HJ, Gentry PR, Covington TR, Hack CE, David RM, Morgott DA
- Issue date: 2006 Jun
- Probabilistic dose-response modeling: case study using dichloromethane PBPK model results.
- Authors: Marino DJ, Starr TB
- Issue date: 2007 Dec
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- Issue date: 1999 Aug 1
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- Authors: Jonsson F, Johanson G
- Issue date: 2001 Jul 15
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- Issue date: 1996 May