PROMOTION OF AFLATOXIN-B1 CARCINOGENESIS BY THE NATURAL TUMOR MODULATOR INDOLE-3-CARBINOL - INFLUENCE OF DOSE, DURATION, AND INTERMITTENT EXPOSURE ON INDOLE-3-CARBINOL PROMOTIONAL POTENCY

Indole-3-carbinol (I3C), a secondary metabolite from cruciferous vegetables, inhibits aflatoxin B1 (AFB1) hepatocarcinogenesis in trout (Bailey et al., J. Natl. Cancer Inst., 78:931-934, 1987) and rats (Selivonchick et al., unpublished results) when given prior to and with carcinogen but promotes carcinogenesis in both species when given continuously following AFB1 initiation. Since human I3C intake may not be continuous, and the promotional stimulation may be reversible, we have assessed I3C promotion using delayed and discontinuous exposure protocols. Following initiation with AFB1, I3C was fed to trout for varying periods of time, with varying lengths of delay after initiation and continuous or intermittent patterns of I3C treatment. Promotional enhancement of tumor incidence if I3C was found to be significant when I3C treatment was delayed for several weeks or months after the initial AFB1 challenge. Promotion also was found to increase with length of exposure to I3C treatment and to be decreased but still evident when I3C was given in alternating months or weeks, or twice per week only. These results do not support the idea that promotional stimulation in hepatocarcinogenesis is a reversible phenomenon. To quantify I3C promotional potency in terms of its dietary concentration, a series of AFB1 tumor dose-response curves was established, each with a different level of I3C fed continuously following AFB1 initiation. The resultant tumor dose-response curves, plotted as logit percentage of incidence versus log AFB1 dose, were displaced parallel toward lower AFB1 50% tumor take (TD50) values with increasing I3C concentration. The level of I3C that halves the AFB1 dose for 50% tumor incidence was calculated to be approximately 1000 ppm I3C, fed continuously, with no substantial threshold for promotion. By comparison, I3C, when fed before and with AFB1, shows a 50% inhibitory value (I3C concentration that doubles the dose of AFB1 for 50% tumor incidence) in trout of 1400 ppm I3C [Dashwood et al., Carcinogenesis (Lond.), 10:175-181, 1989]. Thus the potential for I3C as a dietary additive to promote prior hepatic initiation events when fed continuously is approximately as great as its potential to inhibit concurrent AFB1 initiation.