Implication of nonlinear kinetics on risk estimation in carcinogenesis. Science 1983 Mar 04;219(4588):1032-7
Date
03/04/1983Pubmed ID
6823565DOI
10.1126/science.6823565Scopus ID
2-s2.0-0020683689 (requires institutional sign-in at Scopus site) 181 CitationsAbstract
Efforts in estimating carcinogenic risk in humans from long-term exposure to chemical carcinogens have centered on the problem of low-dose extrapolation. For chemicals with metabolites that interact with DNA, it may be more meaningful to relate tumor response to the concentration of the DNA adducts in the target organ rather than to the applied dose. Many data suggest that the relation between tumor response and concentration of DNA adducts in the target organ may be linear. This implies that the nonlinearities of the dose-response curve for tumor induction may be due to the kinetic processes involved in the formation of carcinogen metabolite--DNA adducts. Of particular importance is the possibility that the kinetic processes may show a nonlinear "hockey-stick" like behavior which results from saturation of detoxification or DNA repair processes. The mathematical models typically used for low-dose extrapolation are shown potentially to overestimate risk by several orders of magnitude when nonlinear kinetics are present.
Author List
Hoel DG, Kaplan NL, Anderson MWMESH terms used to index this publication - Major topics in bold
AnimalsCarcinogens
Cell Transformation, Neoplastic
DNA, Neoplasm
Dose-Response Relationship, Drug
Humans
Kinetics
Models, Biological
Neoplasms
Risk
