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LARGE SCALE CARCINOGEN DOSE RESPONSE STUDIES WITH JAPANESE MEDAKA (ORYZIAS LATIPES)
Citation:
Hawkins, W. E., W W. Walker, J W. Fournie, AND Y. Zhu. LARGE SCALE CARCINOGEN DOSE RESPONSE STUDIES WITH JAPANESE MEDAKA (ORYZIAS LATIPES). Presented at Aquaria Fish Models of Human Disease, Southwest Texas State University, San Marcos, TX, September 21-24, 2000.
Description:
To investigate the responses to low carcinogen doses in animal models, large sample sizes are needed and it is an advantage if the model has a low spontaneous tumor rate. Three large scale dose response studies were conducted using Japanese medaka and the carcinogen diethylnitrosamine (DEN). In the first two studies, 3,000 6-day-old medaka and 3,000 52-day-old medaka were exposed to DEN concentrations of 0, 2.5, 5.0, 10, or 20 mg/l (ppm) for 28 days and held in clean water for up to 9 months following initiation of exposure. Fish were sampled for histological examination at 0.5, 2, 4, 6, and 9 months. For the most part, neoplasms were limited to the liver. The 6-day-old fish group was more sensitive to the carcinogenic effects of DEN than was the 52-day-old group, developing neoplasms earlier and in higher percentages. Statistical analyses showed that increased DEN dose generally led to increases in hepatocellular adenomas and carcinomas, biliary neoplasms, and hemangiopericytomas. The dose response curves for combined adenomas and carcinomas appeared to be nonlinear, particularly in the 6-day-old group sampled at 9 months. Data from these tests were used to establish diagnostic criteria for neoplastic lesions and estimate parameters for a larger study designed to explore the carcinogen dose response curve around the 1% incidence level (ED01). That study utilized 36,000 medaka conducted as four 9,000-animal replicates. Fish aged 14-16 days old were exposed to 0.0, 0.075, 0.15, 0.3, 0.6, 1.5, or 3.0 ppm DEN for 28 days and sacrificed at 9 months. The ED01 for DEN in medaka occurred between the dose levels of 0.3 ppm and 0.6 ppm DEN. Further analyses of the dose response relationships are underway. Overall, the studies show the utility of small aquarium fish such as the medaka in large scale dose response studies. Such studies take advantage of the facts that the fish have low spontaneous tumor rates and high carcinogen sensitivity, can be produced in large numbers so