Relationship between dose and risk reduction: statistical evaluation of a combination experiment with three hepatocarcinogenic N-nitrosamines in rats.
Data from an experiment on the single and combination effects of very low doses of N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR) and N-nitrosodiethanolamine (NDELA) in 1800 male Sprague-Dawley rats were analysed for age-specific incidence (time to death with liver tumour) by Cox's proportional hazards model. The model revealed a linear relationship between daily exposure to low levels of N-nitrosamine and time to death with liver tumour within the dose range investigated: an increase in individual dose resulted in a proportional decrease in liver tumour-free survival. The finding was established for the three individual carcinogens as well as for their combination. NDEA was 40 times more active than NDELA. Extrapolation to N-nitrosamine exposure levels lower than those used in the experiment revealed only a minor reduction in age-specific liver tumour incidence compared to that achieved by an equivalent reduction within the experimental dose range. In rats at advanced age a further reduction in carcinogen-induced liver tumour incidence did not contribute to longer overall survival, due to competitive, probably independent causes of death. The data thus support the idea of a quasi-threshold in terms of a 'no observed effect level'.
Berger
M R
MR
Institute of Toxicology and Chemotherapy, German Cancer Research Centre, Heidelberg.
Schmähl
D
D
Edler
L
L
D000367:Age Factors; D000818:Animals; D002273:Carcinogens; D004052:Diethylnitrosamine / Q000633:toxicity* / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D009242:N-Nitrosopyrrolidine / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012306:Risk
D002273:Carcinogens; D004338:Drug Combinations; C014129:N-nitrosodiethanolamine; D004052:Diethylnitrosamine; D009242:N-Nitrosopyrrolidine