The mutagenic potential of chronic treatments of male CF-1 mice with ethanol and delta 9-tetrahydrocannibinol (THC), and their comutagenic potential with a known mutagenic agent, Trenimon, were examined. This was accomplished by measuring the frequency of dominant lethal mutations arising from mating of treated males with nontreated females. Adult male mice were treated with 5% (v/v) ethanol as part of a liquid diet (28% ethanol-derived calories) for five weeks; 10 mg/kg body weight (p.o.) THC every two days for five weeks; a single injection of Trenimon (0.125 mg/kg, i.p.) on day 28 of diet treatment; and all combinations of treatments. The control group was pair-fed a liquid diet in which isocaloric sucrose replaced ethanol; these males were also given sesame oil (vehicle for THC) and saline (vehicle for Trenimon) on the same schedule as that for the treated males. Neither body weights nor hematocrits were adversely affected by any treatment. Both ethanol and Trenimon treatments resulted in a small (8-9%; p less than 0.05) decrease in testicular weight. The effect of combined treatment with ethanol and Trenimon was roughly additive. Treatment with THC had no effect on testicular weight. Seminal vesicle weights were not affected by any treatment. Treatments were without significant effect on fertility, as measured by the frequency of males producing pregnancies. Ethanol and Trenimon treatments produced approximately 3- and 7-fold increases, respectively in the frequencies of preimplantational loss over that seen for the control group (7.3%), resulting in significant ethanol and Trenimon effects (p less than 0.001). No interactive effects of ethanol and Trenimon treatments were noted. Frequencies of dead fetuses per pregnancy in the ethanol- and Trenimon-treated groups were increased approximately 2.5- and 4-fold, respectively, over the control value of approximately 16%. However, the effect of combined treatments was not greater than that due to Trenimon alone, resulting in Trenimon and ethanol effects (p less than 0.001) and ethanol-Trenimon interaction (p less than 0.001). The calculated mutation index resulting from each treatment yielded significant (p less than 0.001) ethanol- and Trenimon-induced effects. In contrast to effects of ethanol and Trenimon treatments, THC, given alone, or in combination with ethanol and/or Trenimon, had no effect on either preimplantational loss, fetal mortality or the resulting mutation index. The data suggest that chronic ethanol treatment, at levels resulting in minimal fertility impairment, increases the frequency of dominant lethal mutations. In contrast, chronic treatment with THC, as administered in the present study, appears to be without effect.(ABSTRACT TRUNCATED AT 400 WORDS)