Implications of the carcinogenic hazard of low doses of three hepatocarcinogenic N-nitrosamines.
The data of a large-scale experiment on single and combination effects of very low doses of the hepatocarcinogenic N-nitrosamines N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR), and N-nitrosodiethanolamine (NDElA) were modeled by new statistical methods to derive implications of the carcinogenic hazard of dose ranges so low as to result in long-term toxic effects only slightly different from the background. According to this model a linear relationship was found to exist between daily exposure to low N-nitrosamine levels and time to death with liver tumor. Extrapolation of these data to zero exposure suggested the occurrence of one to ten percent of spontaneous liver tumors in animals surviving more than 1000 days. At this advanced age a further reduction of carcinogen-induced liver tumor incidence does not contribute to a longer overall survival due to competitive, probably independent, causes of death. A quasi-threshold in terms of a "no-observed-effect level" can thus be derived from the data. The observed combination effect indicates a mere additivity in liver tumor occurrence, even at very low doses which alone cause no significant carcinogenic effect during the animal's lifetime. Within the combination of NDEA, NPYR and NDElA, N-nitrosodiethylamine was found to be the most carcinogenic agent: it contributes by at least 17 orders of magnitude more to the relative risk of dying with liver tumor than the other two compounds, if the daily dose is increased by one unit (0.1 mg/kg). Likewise, NDEA shows the steepest slope when assessing the relationship between daily carcinogen doses and time to liver tumor occurrence; relative to NDElA--the least potent carcinogen on a weight basis--and NPYR a 40-fold and 9-fold quicker appearance of liver tumors has to be expected, if the daily doses are increased by an equivalent amount.
Berger
M R
MR
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Schmähl
D
D
Edler
L
L
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D003043:Cocarcinogenesis; D004052:Diethylnitrosamine / Q000633:toxicity / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D015233:Models, Statistical; D009242:N-Nitrosopyrrolidine / Q000633:toxicity; D009602:Nitrosamines / Q000633:toxicity*; D051381:Rats; D012044:Regression Analysis; D016019:Survival Analysis
D002273:Carcinogens; D009602:Nitrosamines; C014129:N-nitrosodiethanolamine; D004052:Diethylnitrosamine; D009242:N-Nitrosopyrrolidine