Abstract
The standard procedure for evaluating carcinogen risk is the rodent bioassay coupled with statistically-based risk extrapolation. Extrapolation serves to bridge the physiological differences between the experimental species and man and between the experimental exposure scenario and that occurring in the “real world”. Little of what is known, however, about carcinogen pharmacokinetics, biochemical mechanisms of action, and cancer biology in either the experimental species or in man is used in risk assessment because no paradigm has been available to guide the incorporation of this information. Moolgavkar and Venzon (1979), and Moolgavkar and Knudson (1981), have described a biologically structured model of carcinogenesis (M-V-K model) that provides quantitative insights into the relationship between cellular proliferation, mutation, and tumor development. This is not, however, (and was not intended to be) a fully integrated model of chemical carcinogenesis as it lacks a biologically-based description of carcinogen pharmacokinetics, nor does it explicitly define biochemical mechanisms linking target tissue dose with tumorigenesis.
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References
Andersen, M.E., Clewell, H.J., III, Gargas, M.J., Smith, F.A. and Reitz, R.H. (1987). Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol. Appl. Pharmacol. 87: 185–205.
Andersen,M.E. (1987). Tissue dosimetry in risk assessment, or What’s the Problem Here Anyway? In: Drinking Water and Health, Volume 8: Pharmacokinetics in Risk Assessment, National Academy Press, Washington, D.C., pp. 8–23.
Barrett, J.C., Tsutsui, T. and Tso, P.O.P. (1978). Neoplastic transformation induced by a direct perturbation of DNA. Nature 274: 229–232.
Bischoff, K.B. and Brown, R.G. (1966). Drug Distribution in Mammals. Chemical Engineering Progress Symposium Series 62: 33–45.
Darnell, J., Lodish, H. and Baltimore, D. (1986). Molecular Cell Biology, Scientific American Books, p. 138.
de la Iglesia, F.A., McGuire, H.J. and Feuer, G. (1975). Coumarin and 4methylcoumarin induced changes in the hepatic endoplasmic réticulum studied by quantitative stereology. Toxicology 4: 305–314.
Digernes, V. (1983). Chemical liver carcinogenesis: Monitoring of the process by flow cytometric DNA measurements. Environ. Hlth. Perspect. 50: 195–200.
Elmore, E., Kakunaga, T. and Barrett, J.C. (1983). Comparison of spontaneous mutation rates of normal and chemically transformed human akin fibroblasts. Cancer Research 43: 1650–1655.
Emmelot. P. and Scherer, E. (1980). The first relevant cell stage in rat liver carcinogenesis. A quantitative approach. Biochimica Biophysica Acta 605: 247–304.
Freidberg, E.C. (1985). DNA Repair, W.H. Freeman and Co., New York, pp. 2340.
Gasiewicz, T.A. and Rucci, G. (1984). Cytosolic receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Evidence for a homologous nature among various mammalian species. Molec. Pharmacol. 26: 90–98.
Lutz, R.J., Dedrick, R.L., Matthews, H.B., Eling, T.E. and Anderson, Y.W. (1977). A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. Drug Metal. Diet. 5: 386–396.
Matthews, H.B. and Dedrick, R.L. (1984). Pharmacokinetice of PCBs. Ann. Rev. Pharmacol. Toxicol. 24: 85–103.
McCann, J., Choi, E., Yamasaki, E. and Ames, B.N. (1975). Detection of carcinogens as mutagena in the salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. 72: 5135–5139.
Moolgavkar, S.H. (1983). Model for human carcinogenesis: action of environmental agents. Environ. Hlth. Perspect., 50: 285–291.
Moolgavkar, S.H. (1988). Carcinogenesis modeling: From molecular biology to epidemiology. Ann. Rev. Public Health 7: 151–189.
Moolgavkar, S.H., Day, N.H. and Stevens, R.G. (1980). Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. J.N.C.I. 65: 559–569.
Moolgavkar, S.H., Dewanii, A., and Venzon, D.J. (1988). A stochastic two-stage model for cancer risk assessment I: The hazard function and the probability of tumor. To be published in Risk Analysis.
Moolgavkar, S.H. and Knudson, A.G., Jr. (1981). Mutation and cancer: A model for human carcinogenesis. J.N.C.I. 66: 1037–1052.
Moolgavkar, S.H. and Venzon, D.J. (1979). Two-event models for carcinogenesis: Incidence curves for childhood and adult tumors. Mathematical Biosciences 47: 55–77.
Peraino, C., Carnes, B.A. and Stevens, F.J. (1986). Evidence for growth among foci with different phenotypes in the population of altered hepatocyte foci induced by a single neonatal treatment with carcinogen. Carcinogenesis 7: 191–192.
Quinn, D.W. Calculating the hazard function and probability of tumor for cancer risk assessment when the parameters are time dependent. Submitted to Risk Analysis.
Ramsey, J.R. and Andersen, Y.E. (1984). A physiological model for the inhalation pharmacokinetics of inhaled styrene in rats and humans. Toxicol. Appt. Pharmacol. 73: 159–175.
Reddy, E.P. (1983). Nucleotide sequence analysis of the T24 human bladder carcinoma oncogene. Science 220: 1061–1063.
Rushmore, T.H., Sharma, R.N.S., Roomi, Y.W., Harris, L., Satoh, K., Sato, K., Murray R.K. and Farber, E. (1987). Identification of a characteristic cytosolic polypeptide of rat neoplastic hepatocyte nodules as placental glutathione S-transferase. Biochem. Biophys. Res. Commun. 143: 98–103.
Tsutsui, T., Crawford, B.D. and Ts’o, P.O.P. (1981). Comparison between mutagenesis in normal and transformed Syrian hamster fibroblasts. Difference in the temporal order of HPRT gene replication. Mutation Research 80: 357–371.
Weinstein, I.B. (1981). Current concepts and controversies in chemical carcinogenesis. J. Suptamolecular Structure and Cellular Biochemistry 17: 99–120.
Yang, R.S., Tallant, Y.J. and McKelvy, J.A. (1984). Age-dependent pharmacokinetic changes of ethylenediamine in Fisher-344 rats parallel to a two-year chronic toxicity study. Fund. Appl. Toxicol. 4: 663–670.
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© 1989 Plenum Press, New York
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Conolly, R.B., Reitz, R.H., Clewell, H.J., Andersen, M.E. (1989). Computer Simulation of Chemical Carcinogenesis. In: Travis, C.C. (eds) Biologically Based Methods for Cancer Risk Assessment. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5625-7_22
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DOI: https://doi.org/10.1007/978-1-4684-5625-7_22
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