Potentiation of 2,6-dinitrotoluene genotoxicity in Fischer-344 rats by pretreatment with Aroclor 1254.
Pretreatment of Fischer 344 rats for 5 weeks with Aroclor 1254, a commercial mixture of polychlorinated biphenyls, potentiated the genotoxicity of 2,6-dinitrotoluene (DNT), a component of an industrial chemical used in the production of polyurethane foams. This interaction resulted from Aroclor 1254-mediated bioactivation of DNT to markedly greater levels of the genotoxic metabolites, that were excreted in urine and formed DNA adducts in the liver. A significant increase in the excretion of mutagenic urinary DNT metabolites was observed after the first week of Aroclor 1254 treatment, peaked at week 2 and then declined by nearly 25% at week 4. Nevertheless, by week 5, there was almost a 4-fold increase in the formation of hepatic DNA adducts. Significantly elevated hepatic metabolism and increased beta-glucuronidase in the small intestine and cecum, at 4 weeks, may account for the increased adducts and decreased urinary mutagens. Altered nitroreductase activity, reduced pH, and changes in the microfloral population may also play a role in the effect of Aroclor 1254 on the bioactivation of DNT. Such chemical interactions could be important to predictive risk assessment because the overall cancer risk of the mixture would exceed that determined by the current guidelines for chemical mixtures.
Chadwick
R W
RW
Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
George
S E
SE
Kohan
M J
MJ
Williams
R W
RW
Allison
J C
JC
Hayes
Y O
YO
Chang
J
J
D000818:Animals; D001140:Aroclors / Q000633:toxicity*; D001439:Bacteroides / Q000302:isolation & purification; D001644:Bifidobacterium / Q000302:isolation & purification; D001711:Biotransformation; D002432:Cecum / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D020111:Chlorodiphenyl (54% Chlorine); D004247:DNA / Q000187:drug effects; D004136:Dinitrobenzenes / Q000493:pharmacokinetics / Q000633:toxicity*; D004357:Drug Synergism; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D007778:Lactobacillus / Q000302:isolation & purification; D008297:Male; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013291:Streptococcus / Q000302:isolation & purification
D001140:Aroclors; D004136:Dinitrobenzenes; D009153:Mutagens; D020111:Chlorodiphenyl (54% Chlorine); D004247:DNA; C023514:2,6-dinitrotoluene