THE SENSITIVITY OF THE NTP BIOASSAY FOR CARCINOGEN HAZARD EVALUATION CAN BE MODULATED BY DIETARY RESTRICTION

Studies were undertaken to compare outcomes when four chemicals were e valuated under typical NTP bioassay conditions as well as by protocols employing dietary restriction. Four Chemicals, using three different routes of exposure (in utero [accomplished by feeding the dam dosed fe ed], dosed feed, and gavage) were used to 1) evaluate the effect of di et restriction on the sensitivity of the bioassay toward chemically-in duced chronic toxicity and carcinogenicity; and 2) evaluate the effect of weight-matched control groups on the sensitivity of the bioassays. Control and chemical exposed F344 rats and B6C3F1 mice (50-60/group) were fed NIH-07 diet either ad libitum or at restricted levels such th at body weights were similar to 80 % of ad libitum control weights. Th e dietary restricted groups were either sacrificed at the end of two o r 3-years. Results consistently show that feed restriction decreased t he incidence of neoplastic and non-neoplastic lesions at a variety of anatomic sites in both control and chemical exposed animals. Furthermo re, the sensitivity of the bioassay to detect chemical carcinogenic re sponse were altered by dietary restriction: three of the four chemical s were found to increase the incidence of neoplastic lesions at four s ites when evaluated under standard ad libitum conditions for 104 weeks . When unexposed and exposed groups were both subjected to dietary res triction, none of these 4 sites were detected as a target for carcinog enesis after two or three years. Rather, two different sites of carcin ogenesis were detected. When the top dosed ad libitum fed animals were compared against their weight-matched control groups, a total of 10 s ites were identified as targets for carcinogenesis. These included all four sites identified under the ad libitum protocol, both sites ident ified unter the feed restricted protocol, and an additional four sites that were not identified under the other two protocols. These studies show that dietary restriction of all animals can be expected of decre ase the sensitivity of carcinogenesis bioassays. However, restricting only unexposed groups (weight matching) of control for non-specific we ight loss in chemical exposed groups yielded the most sensitivity amon g our comparisons.