MODULATION OF 2,6-DINITROTOLUENE GENOTOXICITY BY ALACHLOR TREATMENT OF FISCHER-344 RATS

Due to its widespread use as a preemergent herbicide, alachlor has bee n detected as a groundwater contaminant. The procarcinogen, 2,6-dinitr otoluene (DNT), a by-product of the munitions industry and a precursor to polyurethane production, is found in the manufacturing waste strea m. This study explores the effect of alachlor treatment on the bioacti vation of DNT by examining urine mutagenicity, intestinal enzymes, and hepatic DNA adducts to detect changes in metabolism. Five-week-old ma le rats were treated daily by gavage with 50 mg/kg of alachlor for up to 5 weeks while control animals received an equal volume of peanut oi l. At 1, 3, and 5 weeks following the initial alachlor dose, animals w ere administered p.o. 75 mg/kg DNT or DMSO. Urine was collected for 24 hr in metabolism cages. Following incubation with sulfatase and beta- glucuronidase, urines were individually concentrated by C-18 solid pha se extraction, dried under N-2, and prepared for bioassay in Salmonell a typhimurium strain TA98 with and without metabolic activation. Urine From peanut oil- and alachlor-treated rots was not mutagenic. Even th ough calf thymus DNA-alachlor adducts formed in vitro, no hepatic DNA adducts were detected in vivo in these two treatment groups. Interesti ngly, a significant increase in excretion of mutagenic urine from DNT- treated rats was observed following 3 weeks of alachlor treatment in t he absence of S9 (690 +/- 130 vs. 339 +/- 28 revertants/ml) which corr esponded to increased DNT-related hepatic DNA adduct formation (5.90 /- 0.88 adducts/10(8) nucleotides vs. 10.56 x +/- 0.59 adducts/10(8) n ucleotides [relative adduct level (RAL)]). Elevation in the production of mutagenic urine from control and treated animals was linked to inc reases in intestinal nitroreductase and beta-glucuronidase activities; however, the only significant alachlor-related effects were an increa se in small intestinal 1-week beta-glucuronidase and 5-week dehydrochl orinase activities. The increased urine mutagenicity and hepatic DNA a dduct formation indicates that alachlor has a transient effect on DNT bioactivation that apparently is unrelated to intestinal bioactivation . (C) 1998 Wiley-Liss, Inc.