Long-term Carcinogenesis Studies Research Articles

Optimal Designs for the Analysis of Interactive Effects of Two Carcinogens or Other Toxicants

In this paper we consider the design of animal experiments conducted to test for interaction between two carcinogens or other toxicants. We examine 2 x 2 designs which contain an untreated control group, two groups treated with a single dose of each toxic agent alone, and one group treated with both agents together. Optimal rules for allocating animals to the experimental groups are derived on the basis of expected response rates for acute toxicity studies and these rules are then extended to long-term carcinogenesis studies by considering times-to-tumor under an assumption of proportional hazards. Unbalanced designs with more animals in the combination group than in the control group are shown to provide a gain in efficacy of about 20% over balanced designs.

Synergistic effects of N-nitroso compounds in experimental long-term carcinogenesis studies.

Combination effects in chemical carcinogenesis can be described either as syncarcinogenesis action of two or more carcinogens or as modified effects of noncarcinogenic substances on the action of carcinogens. Combination experiments in which one or more carcinogenic N-nitroso compounds are administered to experimental animals together with other cancer-inducing or noncarcinogenic xenobiotics show that in animal experimental animals together with other cancer-inducing or noncarcinogenic xenobiotics show that in animal experiments independent activities, additive effects, and synergistic actions as well as inhibitions may occur. After the administration of several carcinogenic substances predominantly additive effects were observed so far. A large number of experiments demonstrate the influence of different modifying xenobiotics on the action of chemical carcinogens. It is shown that in animal experiments there are real synergistic and inhibitory effects of noncarcinogenic compounds of different chemical structure on the action of chemical carcinogens. As far as the mechanism of action can be made plausible, these are either enzyme-inducing or enzyme-inhibiting effects, competitive or noncompetitive inhibitions of substrates on the enzymes, or alterations of the rate of cell division and correspondingly of the cell-specific protein synthesis. Before establishing acceptable risk values for individual chemical carcinogens it should be taken into account that as a rule interactions are to be expected in man.

DNA phosphotriesters as indicators of cumulative carcinogen-induced damage.

RECENT studies on phosphotriesters induced in DNA in vivo by several potent chemical carcinogens have suggested that these lesions are chemically stable and that they are not eliminated by cellular DNA-repair systems2–3. It seemed possible therefore that in long-term carcinogenesis studies the accumulation of phosphotriesters might be used as a measure of the extent of damage to DNA. In a preliminary study rats have been fed continuously with either dimethylnitrosamine or diethylnitrosamine in the drinking water (0.1–5 p.p.m., w/v) and significant concentrations of methyl or ethyl phosphotriesters have been detected in tissue DNA even at the lowest dose.