Maximum dosage level in testing low-toxicity chemicals for carcinogenicity in rodents

Owing to the lack of sufficient theoretical and empirical information, the initial guidelines regarding animal carcinogenicity testing of chemicals adopted the most conservative approach possible. One of the recommendations was that non-toxic chemicals be tested at a level as high as 5% of the diet. Since then, a wealth of information has been accumulated, which indicates that such highly exaggerated dosage levels are not only unnecessary but produce scientifically misleading and regulatorily detrimental results that impede the development and evaluation of useful chemicals, including human drugs. This paper presents the rationale supporting the necessity of revision of the outdated maximum level of dietary exposure from 5% to 1% or 1000 mg kg-1 day-1 when the test chemical is administered in drinking water or by gavage.