Anticarcinogenesis in fish

Rainbow trout respond to a range of natural and synthetic dietary tumor modulators. Observed modulations of final tumor incidence include inhibition, promotion and cocarcinogenesis, depending on modulator, carcinogen, target organ, and relative order of carcinogen and modulator exposure. Despite several obvious limitations (e.g. lung, colon, mammary gland, bladder are not available as target organs), the trout model possesses several important features that have made it valuable for tumor modulation studies. (1) The comparative advantage. Since rodents are not perfect human surrogates, studies with alternative vertebrates such as trout have provided important comparative mechanism information for confident extrapolation of animal studies to humans. For example, beta-naphthoflavone appears to inhibit aflatoxin B1 hepatocarcinogenicity by species-independent mechanisms that readily extrapolate to humans. By contrast other modulators, including butylated hydroxyanisole, inhibit aflatoxin B1 hepatocarcinogenesis in rats by an enabling mechanism shown to be absent in trout, namely the induction of an aflatoxin B1-specific glutathione S-transferase isozyme. Interestingly, evidence is presently lacking that this determinant mechanism would be operative in humans. (2) The sensitivity advantage. Trout sensitivity and small body size at exposure have permitted tumor studies with carcinogens and HPLC-purified anticarcinogen intermediates too scarce to study in rodents. (3) The low cost advantage. The very low cost of trout tumor studies has enabled statistically challenging issues in molecular dosimetry, dose-response, and risk-benefit analysis to be addressed using as many as 9600 animals per tumor study at modest budget. In particular, these designs provide modulator-mediated alterations in precisely determined carcinogen TD50 values, rather than changes in simple tumor incidence, to quantify more rigorously modulator potencies for tumor inhibition or promotion as a function of dietary concentrations.