title: Potentiation of 2,6-dinitrotoluene genotoxicity in Fischer 344 rats by pretreatment with coal tar creosote.
abstract: Pretreatment of male Fischer 344 rats for 5 wk with coal tar creosote, a coal distillation product that is widely used as a wood preservative, potentiated the excretion of urinary mutagens in 2,6-dinitrotoluene (DNT) treated rats. Creosote increased the bioactivation of DNT to significantly greater levels of urinary genotoxic metabolites and/or formed DNA adducts in the liver. A significant increase in the excretion of mutagenic DNT metabolites was observed after the first week of creosote treatment, peaked at wk 3, and then decreased by 33% after 5 wk of treatment. Nevertheless, there was a significant increase (66%) in the formation of DNT-derived DNA adducts in the livers of rats treated with DNT plus creosote at wk 5. Increased cecal beta-glucuronidase activity and reduced small intestinal nitroreductase activity may play roles in the bioactivation of DNT. The excretion of mutagenic DNT metabolites supplies useful information about the bioactivation of DNT; it does not provide a useful index of DNT-derived hepatic DNA adduct formation. Such interactions could be important to predictive risk assessment because the overall cancer risk of such chemical mixtures may exceed the sum of the component risks.
authors.affiliation: Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
authors.forename: R W
authors.initials: RW
authors.lastname: Chadwick
authors.forename: S E
authors.initials: SE
authors.lastname: George
authors.forename: M J
authors.initials: MJ
authors.lastname: Kohan
authors.forename: R W
authors.initials: RW
authors.lastname: Williams
authors.forename: J C
authors.initials: JC
authors.lastname: Allison
authors.forename: D L
authors.initials: DL
authors.lastname: Talley
authors.forename: Y O
authors.initials: YO
authors.lastname: Hayes
authors.forename: J
authors.initials: J
authors.lastname: Chang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001420:Bacteria, Aerobic / Q000187:drug effects; D001421:Bacteria, Anaerobic / Q000187:drug effects; D002432:Cecum / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D003033:Coal Tar / Q000737:chemistry; D003407:Creosote / Q000633:toxicity*; D018736:DNA Adducts / Q000235:genetics / Q000378:metabolism; D004136:Dinitrobenzenes / Q000633:toxicity*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005966:Glucuronidase / Q000378:metabolism; D007420:Intestine, Large / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology / Q000382:microbiology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009601:Nitroreductases / Q000378:metabolism; D016273:Occupational Exposure; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D018736:DNA Adducts; D004136:Dinitrobenzenes; D003033:Coal Tar; D003407:Creosote; D009601:Nitroreductases; D005966:Glucuronidase; C023514:2,6-dinitrotoluene