Post-initiation dose-dependent effects of the chemopreventive
antioxidant 1-O-hexyl-2, 3, 5-trimethylhydroquinone (HTHQ), a potent inhibitor of heterocyclic
amine-induced mutagenesis and
carcinogenesis, on the development of forestomach and tongue
tumors were investigated in male F344 rats. Groups of 22 rats were treated with 0.01% ethylnitrosourethane (
ENUR) as an initiator in the
drinking water for 4 weeks, then placed on diet containing 1.0%, 0.5%, 0.25% or 0.125% HTHQ, or basal diet alone for 36 weeks. Further group of 12 rats each were similarly treated with the different doses of HTHQ or given basal diet alone for 36 weeks without prior
ENUR treatment. All animals were killed at week 40. Tongue papillary
hyperplasia and
papillomas tended to be increased in the groups treated with
ENUR followed by 0.5-0.125% HTHQ, though there was no effect at the highest dose, in line with increased
bromodeoxyuridine labeling indices. In the forestomach, the incidences of
papillomas and
carcinomas were also significantly elevated only in the group treated with
ENUR followed by 0.125% HTHQ. Without
ENUR pretreatment, papillary
hyperplasia was found in the 1-0.125% HTHQ groups and the labeling index was also increased, though without clear dose dependence. The results indicate that HTHQ may have very weak or weak promotion potential for tongue and forestomach
carcinogenesis, but that both minimum and maximum thresholds for active dose levels may exist.