Significance of DNA adducts at low dose: shortening the time to spontaneous tumor occurrence.
Formation and repair of adducts from DNA-reactive carcinogens as well as induction of genetic changes is expected to be proportional to dose as long as the rates of the enzymatic reactions are proportional to the substrate concentration and as long as the kinetics of cell division are not affected. Deviations from linearity are expected in situations of saturated or induced kinetics and whenever toxicity stimulates regenerative processes and accelerates the fixation and accumulation of mutations resulting from primary DNA lesions. Background DNA damage is postulated to drive the process of carcinogenesis resulting in what is called "spontaneous" tumor formation. Exposure to a low dose of a DNA-reactive carcinogen can result in a dose-dependent acceleration of the spontaneous process but it cannot induce cancer "out of the blue." The shortening of the time to occurrence of a tumor is estimated for different situations using the multistage model. For a tumor which has a high background rate and a large number of steps, life shortening is small, while at a low background incidence rate and a small number of stages, life shortening can be larger. For the majority of tumors, therefore, the approach presented should be able to relieve from the idea that a low dose of a carcinogen could induce cancer early in the life of an individual who without exposure would have lived a much longer, tumor-free life.
Lutz
W K
WK
Department of Toxicology, University of Würzburg, Germany.
Gaylor
D
D
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015994:Incidence; D008962:Models, Theoretical; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*; D012307:Risk Factors
D002273:Carcinogens; D018736:DNA Adducts