Quantitative carcinogenesis and dosimetry in rainbow trout for aflatoxin B1 and aflatoxicol, two aflatoxins that form the same DNA adduct

Article abstract of DOI:10.1016/0165-1161(94)90030-2

Two exposure protocols were used to establish complete dose-response relationships for the hepatic carcinogenicity and DNA adduction in vivo of aflatoxin B₁ (AFB₁) and aflatoxicol (AFL) in rainbow trout. By passive egg exposure, AFL was taken up less than AFB₁, but was more efficiently sequestered into the embryo itself, to produce an embryotic DNA binding curve that was linear with carcinogen dose and with a DNA binding index three-fold greater than AFNB₁. Both aflatoxins produced the same phenotypic respone, predominantly mixed hepatocellular/cholangiocelllular carcinoma. Tumor responses as logit vs. ln were parallel-offset, non-linear response showing a three-fold greater carcinogenic potency of AFL at all doses examined (i.e. 3 times more AFB₁ than AFL required to produce an equivalent liver tumor incidence). By molecular dosimetry analysis (logit vs. ln ), the two data sets were coincident, indicating that, per DNA adduct formed in vivo in total embryonic DNA, these two aflatoxins were equally efficient in tumor initiation. By dietary fry exposure, both carcinogens produced linear DNA binding dose response in liver, but with an AFL target organ DNA binding index only 1.14 times of that of AFB₁ by this exposure route. The tumor dose-response curves also did not exhibit the three-fold difference shown by embryo exposure, but very closely positioned non-linear curves. Since the DNA binding indices differed by only 14 percent, the resulting molecular dosimetry curves for AFL and AFB₁ by dietary exposure were similar to the tumor response curves. These results indicate that differing exposure routes produced differing relative carcinogenicity estimates based on doses applied, as a result of protocol-dependent differences in AFL and AFB₁ pharmacokinetic behaviors, but that potency comparisons based on molecular dose receiving were similar for the two protocols. By comparison with standard DNA adducts produced in vitro using the dimethyloxirane-produced 8,9-epoxides of AFB₁ and AFL, we conclude that >99 percent of AFL-DNA adducts produced in vivo were identical to those produced by AFB₁. Thus similar molecular dosimetry responses should be expected under all exposure protocols in which the two parent carcinogens do not exhibit differing toxicities to the target organ. - Keywords; Aflatoxin B₁; Aflatoxicol; Molecular dosimetry; Hepatocarcinogenesis; Rainbow trout; DNA adducts