AFLATOXIN ALBUMIN ADDUCTS - A BASIS FOR COMPARATIVE CARCINOGENESIS BETWEEN ANIMALS AND HUMANS

The study objectives were (a) to correlate AFB(1) serum albumin adduct levels with AFB(1)-DNA adduct levels in liver in different rodent spe cies to determine whether the former could serve as a marker of hepati c DNA adduct levels irrespective of species, and (b) to relate the lev els of both adducts to differences in susceptibility to tumor inductio n by AFB(1) in the different species. Finally, an attempt was made to compare the dose response for AFB(1)-albumin adduct formation in the r odent species with that in human populations exposed environmentally t o AFB(1). Three strains of rat (Fischer 344, Wistar, and Sprague-Dawle y), and one strain each of guinea pig (Hartley), hamster (Syrian golde n), and mouse (C57BL) were treated by gavage with up to 14 daily doses of between 1 and 80 mu g AFB(1)/kg body weight. Animals were killed 2 4 h after 1, 3, 7, or 14 days treatment, A dose response in both AFB(1 )-albumin and AFB(1)-DNA adducts was seen for all species and strains with steady-state adduct levels at 14 days, In rat strains at 14 days after treatment with 20 mu g/kg, the mean AFB(1)-albumin levels were b etween 24 and 26 pg AFB(1)-lysine equivalent/mg albumin, and the mean AFB(1)-DNA adduct levels were between 1.5 and 2.5 pmol -oxo-3,4-dihydr o-pyrimid-5-ylforamido-)-9-hydroxy) AFB(1)/mg DNA, The level of both a dducts was in the following order: rat > guinea pig > hamster > mouse. In the case of AFB(1)-albumin, the mean adduct level at 14 days in th e three rat strains was approximately 1.5, 3.0, and 8-fold higher than in the guinea pig, hamster, and mouse, respectively, When the levels of the albumin and DNA adducts at 14 days were plotted against each ot her for all species and strains, a correlation was observed (r = 0.83; P = < 0.0001; n = 57; two-tailed test) suggesting a constant relation ship between the level of binding of AFB(1) to serum albumin and liver DNA, The levels of AFB(1)-albumin adduct also reflect at least qualit atively the relative susceptibility of the different species to AFB(1) carcinogenesis; the rat is sensitive and the hamster and mouse are re sistant, The level of AFB(1)-albumin adduct formed as a function of a single dose of AFB(1) in rodents was compared to data from humans expo sed environmentally to AFB(1). This comparison yielded a value for the three rat strains of between 0.3 and 0.51 pg AFB(1)-lysine equivalent /mg albumin/1 mu g AFB(1)/kg body weight and a value for the mouse of < 0.025, The best estimate for people from The Gambia and southern Chi na was 1.56 pg/mg albumin for the same exposure, These data suggest th at humans exposed to AFB(1) form amounts of albumin adducts, and by ex trapolation amounts of DNA adducts, closer to those observed in AFB(1) -sensitive species and 1-2 orders of magnitude higher levels than the AFB(1)-resistant species.