複製DNA合成(RDS)試験法を応用した非変異・肝癌原性物質の検出系確立 : 第28回大会受賞講演
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To better establish an in vivo-in vitro rodent hepatocyte replicative DNA synthesis (RDS) test for screening nongenotoxic (Ames-negative) rodent hepatocarcinogens, experimental conditions and judgement criteria were assessed. After single-gavage of three model compounds, isolated hepatocytes showed the highest labeling index (L.I., %) when plated at density of 2.5 × 10^4 cells/ cm^2. Spontaneous RDS incidences showed constant values in hepatocytes from male F344 rats aged 9 weeks or older and from male B6C3F1 mice aged 6 weeks or older, respectively. Based on the distribution of spontaneous L.I., in 9-week-old rats, L.I. of 2% or more induced by a test compound should be judged as positive and that of less than 1% as negative using the maximum tolerated dose in the time-course experiment at 24, 39 and 48 hr. In the case of L.I. between 1 and 2%, the finding clear dose-dependence was considered to justify the conclusion of a positive effect. In 8-week-old mice, 0.4% or more of L.I. was judged as a positive response. Under the above experimental conditions, 18 of 22 rat hepatocarcinogens and 32 of 41 mouse ones gave positive responses (positive sensitivity : 82% and 78%, respectively) and 20 of 25 noncarcinogens and 25 of 31 ones gave negative responses (negative specificity : 80% and 81%, respectively) in the rat and mouse RDS test, respectively. These findings suggest that the RDS test is a useful method for early detection of nongenotoxic hepatocarcinogens. A collaborative study was conducted to evaluate whether an RDS test in rat livers using a continuous 5-bromo-2'-deoxyuridine-labeling method can detect nongenotoxic hepatocarcinogens with three daily administration at dose-levels effective in long-term bioassays. Six of seven nongenotoxic hepatocarcinogens tested gave positive or equivocal results. It is considered that the RDS test can detect many nongenotoxic rat hepatocarcinogens with short-term administration at dose-levels used in long-term bioassays.
- 日本環境変異原学会の論文
- 2000-07-31
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