DIALKYLQUINONEIMINE METABOLITES OF CHLOROACETANILIDE HERBICIDES INDUCE SISTER-CHROMATID EXCHANGES IN CULTURED HUMAN-LYMPHOCYTES

Some of the most widely-used herbicides are the chloroacetanilides exe mplified by alachlor and butachlor (derived from 2,6-diethylaniline) a nd metolachlor and acetochlor (synthesized from 2-ethyl-6-methyIanilin e). This investigation tests the hypothesis that the previously-observ ed oncogenicity of these herbicides is due to genotoxic intermediates such as diethylbenzoquinoneimine, a purported alachlor metabolite. Syn theses are reported here for the corresponding 2,6-dialkylbenzoquinone imines, selected chloroacetyldialkylbenzoquinoneimines and several oth er candidate or known metabolites. The possible mutagenicity of diethy lbenzoquinoneimine was tested in Salmonella typhimurium strains TA98 a nd TA100 with a weakly-positive response in the TA100 strain indicatin g induction of base-pair substitution mutations. The frequency of sist er chromatid exchange (SCE) in Chinese hamster ovary cells was increas ed by alachlor at 10 mu M and diethylaniline but not ethylmethylanilin e at 30 and 3 mu M Isolated and cultured peripheral lymphocytes (mostl y T cells) were used from two human donors to study the effects of the chloroacetanilides and their metabolites on primary human cells. In t ests at 10 mu M, the SCE frequency was increased by alachlor and possi bly acetochlor but not by butachlor, metolachlor, dimethachlor (a 2,6- dimethyl analog) and dimethenamid (an analog based on 2,4-dimethyl-3 - thienylamine). At 0.3 mu M in cultured human lymphocytes, alachlor, th e corresponding chloroacetanilide( N-dealkyl-alachlor) and aniline met abolites (and their 4-hydroxy derivatives), and diethylbenzoquinone we re inactive or active in only one of the two donors whereas at 0.1-0.3 mu M the SCE ratio for treated cells divided by the controls was alwa ys higher for diethylbenzoquinoneimine than for ethylmethyl- and dimet hylbenzoquinoneimines. All the tested compounds were toxic to lymphocy tes, but the depression of the mitotic index and increased duration of the cell cycle were not directly linked with SCE induction. Previous investigations have suggested that chloroacetanilide herbicides such a s alachlor derived from 2,6-dialkylanilines are metabolized to 2,6-dia lkylbenzoquinoneimines and the present study provides the first direct evidence that these metabolites are genotoxic in human lymphocytes. ( C) 1997 Elsevier Science B.V.