QUANTITATIVE CARCINOGENESIS AND DOSIMETRY IN RAINBOW-TROUT FOR AFLATOXIN-B-1 AND AFLATOXICOL, 2 AFLATOXINS THAT FORM THE SAME DNA ADDUCT

Two exposure protocols were used to establish complete dose-response r elationships for the hepatic carcinogenicity and DNA adduction in vivo of aflatoxin B-1 (AFB(1)) and aflatoxicol (AFL) in rainbow trout. By passive egg exposure, AFL was taken up less well than AFB(1), but was more efficiently sequestered into the embryo itself, to produce an emb ryonic DNA binding curve that was linear with carcinogen dose and with a DNA binding index three-fold greater than AFB(1). Both aflatoxins p roduced the same phenotypic response, predominantly mixed hepatocellul ar/cholangiocellular carcinoma. Tumor responses as legit [incidence] v s. In [dose] were parallel-offset, non-linear responses showing a thre e-fold greater carcinogenic potency for AFL at all doses examined (i.e . 3 times more AFB, than AFL required to produce an equivalent liver t umor incidence). By molecular dosimetry analysis (logit [incidence] vs . In [DNA adducts]), the two data sets were coincident, indicating tha t, per DNA adduct formed in vivo in total embryonic DNA, these two afl atoxins were equally efficient in tumor initiation. By dietary fry exp osure, both carcinogens produced linear DNA binding dose responses in liver, but with an AFL target organ DNA binding index only 1.14 times that of AFB(1) by this exposure route. The tumor dose-response curves also did not exhibit the three-fold difference shown by embryo exposur e, but were closely positioned non-linear curves. Since the DNA bindin g indices differed by only 14%, the resulting molecular dosimetry curv es for AFL and AFB(1) by dietary exposure were similar to the tumor re sponse curves. These results indicate that differing exposure routes p roduced differing relative carcinogenicity estimates based on doses ap plied, as a result of protocol-dependent differences in AFL and AFB(1) pharmacokinetic behaviors, but that potency comparisons based on mole cular dose received were similar for the two protocols. By comparison with standard DNA adducts produced in vitro using the dimethyloxirane- produced 8,9-epoxides of AFB(1) and AFL, we conclude that > 99% of AFL -DNA adducts produced in vivo were identical to those produced by AFB, . Thus similar molecular dosimetry responses should be expected under all exposure protocols in which the two parent carcinogens do not exhi bit differing toxicities to the target organ.