Early detection of carcinogenic substances and modifiers in rats

Over the past 20 years, we have been developing in vivo medium-term bioassa y systems in rats for detecting carcinogenic and modifying effects of test compounds. The systems are based on the two-step hypothesis of carcinogenes is. Ln a liver model, male F344 rats are initially given a single dose of d iethylnitrosamine (DEN, 200 mg/kg, i.p.) and starting 2 weeks Inter are tre ated with test compounds for 6 weeks and then killed, all rats being subjec ted to two-thirds partial hepatectomy at week 3. Carcinogenic potential is scored by comparing the numbers and areas per cm(2) of induced glutathione S-transferase placental form (GST-P) positive foci in the livers of groups of about 15 rats with those of corresponding control groups given DEN alone . A positive response is defined as a significant increase in the quantitat ive values of GST-P-positive foci, such a negative response as no change or a decrease. The results obtained have been compared with reported Salmonel la/microsome and long-term carcinogenicity test findings for the same compo unds. Of the Liver carcinogens, 30 out of 31 (97%) mutagenic and 29 out of 33 (88%) non-mutagenic compounds gave positive results. Carcinogens other t han hepatocarcinogens gave a lower proportion of positive results (9 out of 42, 21%). This bioassay also provides information concerning inhibitory po tential. The practical utility and benefits of a multi-organ medium-term ex perimental protocol for early detection of carcinogenic agents and modifier s acting at sites other than the liver are also discussed, (C) 2000 Elsevie r Science B.V. All rights reserved.