Estimating the risk of liver cancer associated with human exposures to chloroform using physiologically based pharmacokinetic modeling

Reitz, Richard H.; Mendrala, Alan L.; Corley, Richard A.; Quast, J.F.; Gargas, Michael L.; Andersen, Melvin E.; Staats, D.A.; Conolly, Rory B.

doi:10.1016/0041-008x(90)90148-n

Cited by 122 publications

(36 citation statements)

References 14 publications

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“…Cell death was more closely associated with high rates of metabolism over relatively short times then to persistence of macromolecular adducts (105,107). An empirical approach was taken to describe the relationship between the rate of death of normal hepatocytes (-4JNhlat) and the rate of metabolism per unit volume of tissue (aAmetlat)/V).…”

Section: Dna Reactive Chemicalsmentioning

confidence: 99%

“…(97,98). In other cases, the chemical is converted to reactive metabolites in the target tissues: chloroform, carbon tetrachloride, and vinylidene chloride kill hepatocytes only after metabolism to phosgene, trichloromethyl free radical, and chloroacetylchloride, respectively (99)(100)(101) (105). CHC13 is metabolized to short-lived intermediates, phosgene and hydrochloric acid, which are highly irritant, but whose adducts are not persistent (106).…”

Section: Dna Reactive Chemicalsmentioning

confidence: 99%

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Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment.

Krewski

Withey

et al. 1994

Environ Health Perspect

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The use of physiologically based pharmacokinetic (PBPK) models has been proposed as a means of estimating the dose of the reactive metabolites of carcinogenic xenobiotics reaching target tissues, thereby affording an opportunity to base estimates of potential cancer risk on tissue dose rather than external levels of exposure. In this article, we demonstrate how a PBPK model can be constructed by specifying mass-balance equations for each physiological compartment included in the model. In general, this leads to a system of nonlinear partial differential equations with which to characterize the compartmental system. These equations then can be solved numerically to determine the concentration of metabolites in each compartment as functions of time. In the special case of a linear pharmacokinetic system, we present simple closed-form expressions for the area under the concentration-time curves (AUC) in individual tissue compartments. A general relationship between the AUC in blood and other tissue compartments is also established. These results are of use in identifying those parameters in the models that characterize the integrated tissue dose, and which should therefore be the primary focus of sensitivity analyses. Applications of PBPK modeling for purposes of tissue dosimetry are reviewed, including models developed for methylene chloride, ethylene oxide, 1,4-dioxane, 1-nitropyrene, as well as polychlorinated biphenyls, dioxins, and furans. Special considerations in PBPK modeling related to aging, topical absorption, pregnancy, and mixed exposures are discussed. The linkage between pharmacokinetic models used for tissue dosimetry and pharmacodynamic models for neoplastic transformation of stem cells in the target tissue is explored. Environ Health Perspect 1 02(Suppl 1 1): 37-50 (1994)

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Section: Dna Reactive Chemicalsmentioning

confidence: 99%

Section: Dna Reactive Chemicalsmentioning

confidence: 99%

Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment.

Krewski

Withey

et al. 1994

Environ Health Perspect

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“…If the kidney and lung carcinogenicity of TCE is considered to result primarily from enhanced cell proliferation secondary to recurrent toxicity, possible dose metrics would include measures of cytotoxicity, cell death, or cell division, as has been proposed for the liver carcinogenicity of chloroform (35,166). In the case of chloroform, fairly complicated metrics involving the instantaneous rates of metabolism and distributions of cellular sensitivity have been suggested (5,35). To apply these approaches to (100).…”

Section: Dose Metric Sdection Uncertaintymentioning

confidence: 99%

“…Risk assessments using PBPK models have also been proposed for many other chemicals, including not only TCE (23)(24)(25)(26), but also perchloroethylene (PERC) (24,27,28), ethylene dichloride (29), vinyl chloride (26,(30)(31)(32), dioxane (33,34), chloroform (35), benzene (36), and ethyl acrylate (37). However, apart from the case with methylene chloride described above, there still have been no risk assessments published by a regulatory agency in which a PBPK model was used for estimating target tissue dose.…”

Section: Introductionmentioning

confidence: 99%

Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

Covington¹,

Clewell²,

Fisher³

2004

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A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA), in the mouse, rat, and human for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Cancer dose metrics provided in the model include the area under the concentration curve (AUC) for TCA and DCA in the plasma, the peak concentration and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Additional dose metrics provided for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TCE divided by the body weight. Sensitivity and uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, and TCOH concentrations in rodents and humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating crossspecies differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung and kidney should be used with caution.

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“…We are beginning to see more examples of application of these models for the assessment of tumorigenic risk associated with human exposure to chemicals (25)(26)(27). The PBPK modeling addresses only the tissue dose aspect of the exposure-dose-response continuum.…”

Section: Issues Surrounding the Use Of Pbpk Models In Risk Assessmentmentioning

confidence: 99%

Physiologically based pharmacokinetics and cancer risk assessment.

Andersen

Krishnan

1994

Environ Health Perspect

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Physiologically based pharmacokinetic (PBPK) modeling involves mathematically describing the complex interplay of the critical physicochemical and biological determinants involved in the disposition of chemicals. In this approach, the body is divided into a number ofbiologically relevant tissue compartments, arranged in an anatomically accurate manner, anddefined with appropriae physiologicalcharacteristic The extapolation ofpharmaconeicbehavior ofeas from high dose to low dose for various exposure routes and species is possible with this approach because these models are developed by integrating quantitative information on the critical determinnts ofcemi disposition undera biological modeling framework. The principal application of PBPK models is in the prediction of tissue dosimetry of toxic moiety (e.g., parent chemical, reactive metabolite, macromolecular adduct) of a chemical. Such an application has been demonstrated with dichloromethane, a liver and lung carcinogen in the B6C3F~mouse. The PBPK model-based risk assessment approach estimated a cancer risk to people of3.7x10-8 for a lifetime inhalation exposure of 1 Ag/m3, which is lower by more than two orders of magnitude than that calculated by the U.S. Environmental Protection Agency using the linearized multistage model (for low-dose extrapolation) and body surface correction factor (for interspecies scaling).The capability of predicting the target tissue exposure to toxic moiety in people with PBPK models should help reduce the uncertainty associated with the extrapolation procedures adopted in conventional dose-response assessment.

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Estimating the risk of liver cancer associated with human exposures to chloroform using physiologically based pharmacokinetic modeling

Cited by 122 publications

References 14 publications

Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment.

Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment.

Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

Physiologically based pharmacokinetics and cancer risk assessment.

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