Molecular dosimetry in fish: quantitative target organ DNA adduction and hepatocarcinogenicity for four aflatoxins by two exposure routes in rainbow trout

Abstract

Rainbow trout, a species highly sensitive to aflatoxins, was used to investigate the relative carcinogenicities of four structurally related aflatoxins in terms of their target organ DNA binding characteristics. Tritiated syntheses were carried out, DNA binding dose-response curves were established, and liver DNA binding indices were calculated for the four aflatoxins following a 2-week dietary fry exposure protocol. The results indicated that adduct levels increased linearly with dietary dose concentration, with relative DNA binding indices of 20.7, 20.3, 2.35, and 2.22 x 10(3) (pmoles aflatoxin mg-1 DNA)/(pmoles aflatoxin g-1 diet) for aflatoxin B1 (AFB1), aflatoxicol (AFL), aflatoxin M1 (AFM1), and aflatoxicol M1 (AFLM1), respectively. A similar protocol used over 7200 trout fry averaging 1.2 g initial body weight to establish full carcinogen dose-response curves for each aflatoxin, along with a single-dose estimate of DNA binding index within the tumor study animals. Owing to trout sensitivity a total of 180 micrograms or less of each aflatoxin was required. Data analyzed on logit incidence vs. Ln dose coordinates generated four curves which were modeled as parallel in slope over most or all dose ranges studied. By this analysis, relative tumorigenic potencies were: AFB1 1.00; AFL 0.936; AFM1 0.086; and AFLM1 0.041. When data were plotted as logit incidence vs. Ln adducts (effective dose received), all aflatoxin adducts described the same dose-response curve; that is, they were equally tumorigenic, except those from AFLM1, which were 2-3 fold less potent. Therefore, by these molecular dose studies, differences in tumorigenicity among the four dietary aflatoxins are largely or entirely accounted for by differences in uptake and metabolism leading to DNA adduction, rather than any inherent differences in tumor initiating potency per DNA adduct.