VALIDATION IN RATS OF 2 BIOMARKERS OF EXPOSURE TO THE FOOD-BORNE CARCINOGEN 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE (PHIP) - PHIP-DNA ADDUCTS AND URINARY PHIP

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in white blood cells and tissues and unmetabolized PhIP in urine were val idated as biomarkers of exposure in male Fischer-344 rats treated with daily PhIP doses ranging from 1 to 0.0001 mg/kg, At the end of the 23 day treatment period all rats were killed and their blood and 10 tiss ues were collected for isolation of DNA and analysis of PhIP-DNA adduc ts by P-32-postlabeling and alkaline hydrolysis with GC/MS, PhIP-DNA a dducts could be detected only in animals receiving 1 or 0.1 mg/kg/day, with highest adduct levels in the pancreas, heart and kidneys, There was a good correlation (r = 0.77, P < 0.005) between the two methods o f analysis, with average adduct levels determined by P-32-postlabeling similar to 1.4 times higher than those determined by alkaline hydroly sis with GC/MS, PhIP-DNA adducts accumulated in most tissues, especial ly in the liver, kidneys, heart and pancreas, with lower levels in the white blood cells, small intestine, stomach, colon and cecum, Using G C/MS levels of unmetabolized PhIP were measurable in four weekly 24 h urine samples even at 0.0001 mg/kg/day, a dose comparable with reporte d human dietary exposure. A linear dose-response was obtained for excr etion of unmetabolized PhIP across the range of doses, with similar to 1.8% of the dose excreted daily, largely independent of the number of doses, No PhIP was detected in the urine of untreated rats, If it can be shown that a constant percentage of PhIP is excreted unchanged in human urine, irrespective of dose, as has been found with the rat, mea surement of urinary PhIP could be used as an accurate measure of dieta ry exposure to this amine in man.