A critique of the use of the maximum tolerated dose in bioassays to assess cancer risks from chemicals.
The maximum tolerated dose (MTD) regimen for testing substances for their ability to induce cancer and other chronic diseases in laboratory rodents has been required by governmental authorities for several decades. Cancer researchers originally suggested the MTD approach and it was then adopted by the FDA and EPA. The intention was to detect the ability of any substance under any circumstances, including the most extreme, to induce cancer in laboratory rodents. We question the validity of using the MTD in animal bioassays to evaluate risk for human cancer. The paradox is that the safer the chemical, the higher the MTD, but the higher the MTD, the more likely that biochemical distortions will result and cause cellular injury, abnormal cell replication, toxic hyperplasia, and toxicity-induced cancer. All chemicals are toxic at some dose, whether relevant to anticipated human exposure or vastly exceeding it. New approaches to cancer-testing lifetime bioassays are needed. A minimally toxic dose is defined and suggested to avoid specific tissue toxicity detected by clinical or pathology examination in animals subchronically exposed to the test compound for 90 days. The highest subtoxic dose that can be tolerated by test animals over a long period of time is suggested as being more appropriate for carcinogenicity bioassays.
Carr
C J
CJ
Scientific Information Associates, Columbia, Maryland 21046.
Kolbye
A C
AC
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans
D002273:Carcinogens