MEDIUM-TERM BIOASSAYS AS ALTERNATIVE CARCINOGENICITY TEST

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A medium-term liver bioassay system for rapid detection of carcinogenic agents using male F344 rats has been developed, in order to bridge the gap between long-term carcinogenity tests and short-term screening assays. The system is fundamentally based on the two-stage hypothesis of oarcinogenesis : intiation with diethylnitrosamine (200 mg/kg bw, ip) is follwed by test chemical administration during the second, in combination with 2/3 partial hepatectomy. It requires only 8 weeks for animal experimental treatment and a further few weeks for quantitative analysis of immunohistochemically-demonstrated glutathione S-transferase placental from positive hepatic foci. A total of 291 chemicals/substances have already been analyzed in this laboratory and the efficacy of the system for hepatocarcinogens has thereby been well established. This bioassay is particularly useful for dose-response and chemical mixture studies, usually requiring large0scale experiments and also for evaluation of chemoperventive agents. Another bioassay, a medium-term multiorgan bioassay system, using 5 different chemical carcinogens, diethylnitrosamine (DEN), N-methylnitrosourea (MNU), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), 1, 2-dimethylhydrazine (DMH) and 2, 2-dihydroxy-di-n-propylnitrosamine (DHPN), has also been established for rapid detection of not only hepaticatcinogens, but also other organ-target carcinogens. Rats were initially treated with a single ip administration of 100 mg/kg DEN, 4ip administrations of 20 mg/kg MNU, 4 sc doses of 40 mg/kg DMH for 2 weeks and then 0.1% DHPN for 2 weeks. Test chemicals are administered after the carcinogens exposure. Animals were sacrificed at the end of week 36, and major organs were examined histologically. Carcinogenic activities of test chemicals were compared between the test chemical treated group and carcinogen exposures group (control froup). It is increasingly becoming regarded that these bioassays are useful methods and are appropriate alternative tests systems for carcinogencity risk assessment. Therefore, 'the International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use' has proposed that these two bioassays can be used as "additional tests for cercinogenic activity in vivo."
日本トキシコロジー学会の論文
1998-07-24

MEDIUM-TERM BIOASSAYS AS ALTERNATIVE CARCINOGENICITY TEST

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