A number of N-
nitroso compounds and an azoxyalkane have been labeled with
deuterium in various positions and have been administered to rats, hamsters, or mice in parallel with the unlabeled compounds. The treatments with the labeled and analogous unlabeled compounds were equimolar and for the same time. Mortality rates from
tumors and
tumor incidences were compared between
deuterium-labeled and the unlabeled analogs. In many cases more than one dose level was used for the comparisons. An increased rate of mortality from
tumors or an increased incidence of induced
tumors was considered an index of increased potency of one treatment compared with the other. Using these criteria
deuterium in the alpha positions of
nitrosodimethylamine, nitrosomorpholine, nitrosoheptamethyleneimine, and
nitrosoazetidine reduced carcinogenic potency compared with the unlabeled compounds. This indicated that cleavage of a
carbon-hydrogen bond in the alpha position was a rate-limiting step in
carcinogenesis by these
nitrosamines. In both
nitrosomethylethylamine and nitroso-2,6-dimethylmorpholine, the presence of
deuterium at different positions increased or decreased carcinogenic potency, suggesting that competition for oxidation between these sites might be the determining factor in activation of the molecule. This also applied to
nitrosomethyl-n-butylamine and nitrosomethyl-phenylethylamine with
deuterium at the methyl group or at the alpha
carbon of the butyl or phenylethyl groups, and to
azoxymethane with
deuterium in the 1-methyl or 4-methyl group. In
nitrosomethylcyclohexylamine,
nitrosomethyl-n-dodecylamine, and dinitroso-2,6-dimethylpiperazine there was no detectable effect of
deuterium on carcinogenic potency, suggesting that the conditions did not provide sufficient sensitivity for detection of an
isotope effect, or that oxidation at the alpha
carbon was not a rate-limiting step in
carcinogenesis by these molecules.