Pharmacokinetics, biochemical mechanism and mutation accumulation: a comprehensive model of chemical carcinogenesis.

Chemical carcinogenesis is a process beginning with carcinogen absorption and ending with development of a malignant tumor. Individual elements of this process have been studied intensively but no comprehensive model has been developed. This report describes a comprehensive model which incorporates carcinogen pharmacokinetics, biochemical mechanism of action, and the resultant mutation of normal cells to malignancy. Model parameters correspond to specific physiological and biochemical structures and processes. The model was encoded in a simulation language and used to examined biochemical and cellular effects of exposure to an initiator and a promoter. With laboratory validation, the model should be useful for interpretation and design of studies on carcinogenic mechanisms and for risk assessment.

[1]  S H Moolgavkar,et al.  A stochastic two-stage model for cancer risk assessment. I. The hazard function and the probability of tumor. , 1988, Risk analysis : an official publication of the Society for Risk Analysis.

[2]  P. Emmelot,et al.  The first relevant cell stage in rat liver carcinogenesis. A quantitative approach. , 1980, Biochimica et biophysica acta.

[3]  S H Moolgavkar,et al.  Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. , 1980, Journal of the National Cancer Institute.

[4]  J. Barrett,et al.  Comparison of spontaneous mutation rates of normal and chemically transformed human skin fibroblasts. , 1983, Cancer research.

[5]  J. Barrett,et al.  Comparison between mutagenesis in normal and transformed Syrian hamster fibroblasts: difference in the temporal order of HPRT gene replication. , 1981, Mutation research.

[6]  B. Carnes,et al.  Evidence for growth heterogeneity among foci with different phenotypes in the population of altered hepatocyte foci induced by a single neonatal treatment with carcinogen. , 1986, Carcinogenesis.

[7]  T. Gasiewicz,et al.  Cytosolic receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Evidence for a homologous nature among various mammalian species. , 1984, Molecular pharmacology.

[8]  I. Weinstein,et al.  Current concepts and controversies in chemical carcinogenesis. , 1981, Journal of supramolecular structure and cellular biochemistry.

[9]  E. McGuire,et al.  Coumarin and 4-methylcoumarin induced changes in the hepatic endoplasmic reticulum studied by quantitiative sterelogy. , 1975, Toxicology.

[10]  B. Ames,et al.  Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S H Moolgavkar,et al.  Mutation and cancer: a model for human carcinogenesis. , 1981, Journal of the National Cancer Institute.

[12]  J. Barrett,et al.  Neoplastic transformation induced by a direct perturbation of DNA , 1978, Nature.

[13]  R. S. Yang,et al.  Age-dependent pharmacokinetic changes of ethylenediamine in Fischer 344 rats parallel to a two-year chronic toxicity study. , 1984, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[14]  F. A. Smith,et al.  Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. , 1987, Toxicology and applied pharmacology.

[15]  S. Moolgavkar.  Carcinogenesis modeling: from molecular biology to epidemiology. , 1986, Annual review of public health.

[16]  M E Andersen,et al.  A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans. , 1984, Toxicology and applied pharmacology.

[17]  S. Moolgavkar.  Model for human carcinogenesis: action of environmental agents. , 1983, Environmental health perspectives.

[18]  V. Digernes.  Chemical liver carcinogenesis: monitoring of the process by flow cytometric DNA measurements. , 1983, Environmental health perspectives.

[19]  H. Lodish.  Molecular Cell Biology , 1986 .

[20]  S. Moolgavkar,et al.  Two-event models for carcinogenesis: incidence curves for childhood and adult tumors☆ , 1979 .

[21]  T. Rushmore,et al.  Identification of a characteristic cytosolic polypeptide of rat preneoplastic hepatocyte nodules as placental glutathione S-transferase. , 1987, Biochemical and biophysical research communications.

[22]  H. Matthews,et al.  Pharmacokinetics of PCBs , 1984 .

[23]  E. Reddy,et al.  Nucleotide sequence analysis of the T24 human bladder carcinoma oncogene. , 1983, Science.

[24]  R. Lutz,et al.  A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. , 1977, Drug metabolism and disposition: the biological fate of chemicals.