The case for an upper dose limit of 1000 mg/kg in rodent carcinogenicity tests

We examined two rodent carcinogenicity data bases comprising 301 chemicals from the US National Toxicology Program (NTP) and 241 pharmaceuticals from the US Physicians' Desk Reference (PDR) to determine the nature of the tumors produced at dose levels > 1000 mg/kg (or equivalent dietary concentrations). Ten chemicals increased tumors only at dose levels greater than 1000 mg/kg. For six of these, the lowest dose tested was > 1000 mg/kg, so they may be active at dose levels below 1000 mg/kg. One chemical was active in rats and mice, 2 in rats only and 7 in mice only. Four of the chemicals were mutagenic to Salmonella. The tumor types produced by the other six putatively non-genotoxic chemicals suggest that a high dose limit of 1000 mg/kg is appropriate for rodent bioassays. Overtly genotoxic chemicals are no longer routinely subjected to bioassays.