DNA ADDUCT FORMATION IN SALMONELLA-TYPHIMURIUM, CULTURED LIVER-CELLS AND IN FISCHER 344 RATS TREATED WITH O-TOLYL PHOSPHATES AND THEIR METABOLITES

2-Phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide is an electrophilic an d a neurotoxic metabolite of o-tolyl phosphates. In a previous paper w e reported that 2-phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide is mut agenic in Salmonella typhimurium TA100 and forms DNA adducts in incuba tions with nucleotides, nucleosides and isolated DNA. In the present s tudy we compare DNA adduct formation using P-32-post-labelling assays in 2-phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide-treated bacteria (S .typhimurium TA100) and hepatoma cells with DNA adducts formed in live r, kidney, lung and heart of tri-o-tolyl phosphate-exposed Fischer 344 male rats. In both bacteria and hepatoma cells two DNA adducts could be detected after treatment with 2-phenoxy-4H-1,3,2-benzodioxaphosphor in 2-oxide. The minor adduct co-chromatographed with synthetic N3-(o-h ydroxy-benzyl)deoxyuridine 3' monophosphate after postlabelling. The m ajor DNA adduct was a cytidine adduct, most likely N3-(o-hydroxybenzyl )deoxycytidine 3' monophosphate. Male Fischer 344 rats were treated or ally for 10 days with tri-o-tolyl phosphate (50 mg/kg/day) and DNA was isolated from liver, kidney, lung, heart, brain and testes 1, 4, 7 an d 28 days after giving the last dose. Analysis by P-32-postlabelling r evealed that two adducts were present in the DNA isolated from liver, kidney, lung and heart on the first day after giving the last dose; DN A adducts were not detected in the brain and testes. The adduct patter n after in vivo treatment with tri-o-tolyl phosphate was identical wit h that found in bacteria and hepatoma cells treated with 2-phenoxy-4H- 1,3,2-benzodioxaphosphorin 2-oxide, the major adduct being N3-(o-hydro xybenzyl)deoxycytidine 3' monophosphate and the minor N3-(o-hydroxyben zyl)deoxyuridine 3' monophosphate. Both DNA adducts persisted in the l ungs for the entire observation period, whereas in the kidney only the cytidine adduct could be detected 28 days after the last dose of tri- o-tolyl phosphate. In liver and heart the adducts were detectable only on the first day after completion of the treatment. The results indic ate that in addition to the well established neurotoxicity, some o-tol yl phosphates may have a carcinogenic potential.