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Toward a Molecular Equivalent Dose: Use of the Medaka Model in Comparative Risk Assessment.
Citation:
Hobbie, K. R., A. B. DEANGELO, L. C. KING, R. N. Winn, AND J. M. Law. Toward a Molecular Equivalent Dose: Use of the Medaka Model in Comparative Risk Assessment. Presented at Environmental Mutagenesis Society Meeting, St. Louis, MO, October 24 - 29, 2009.
Impact/Purpose:
We compared the dose response in F344/N rat with a fish model, Japanese medaka (Oryzias latipes) to parallel exposures to the alkylating hepatocarcinogen, dimethylnitrosamine (DMN).
Description:
Recent challenges in risk assessment underscore the need to compare the results of toxicity and dose-response testing among a growing list of animal models and, possibly, an array of in vitro screening assays. Assays that quantify types of DNA damage that are directly relevant to carcinogenesis integrate the factors such as chemical exposure, uptake, distribution, and metabolism that tend to vary widely at different phyletic levels. We compared the dose response in F344/N rat with a fish model, Japanese medaka (Oryzias latipes) to parallel exposures to the alkylating hepatocarcinogen, dimethylnitrosamine (DMN). The DNA adducts N7-methylguanine 8-hydroxyguanine, and 06-methylguanine in the liver and the mutation frequency using A cll transgenic medaka and Big Blue® rats were measured. In addition, morphologic changes in the livers of both models using histopathology and immunohistochemistry were examined. Pulse dose levels in fish were 0, 10, 25, 50, or 100 ppm DMN in the ambient water for 14 days; rats received 0, 0.1, 1\ 5, 10, or 25 ppm DMN in the drinking water for the same period. Similar magnitudes of liver DNA adduct concentrations in both species were found, 1 -2 fmoles 06Mdg/10ASdG. However, the mutant frequencies in the DMN-exposed medaka were up to 20 times higher than in the Big Blue rats, 91 -308 vs. S -20 MF respectively. These data begin the development of a complete picture of comparative dose response between different phyletic levels and will help guide risk assessors using "alternative" models. (This abstract does not necessarily reflect the views of the USEPA).