title: Autoxidative activation of the nematocide 1,3-dichloropropene to highly genotoxic and mutagenic derivatives: consideration of genotoxic/carcinogenic mechanisms.
abstract: 1,3-Dichloropropene (1,3-DCP) is used as a soil nematocide worldwide. Technical grade 1,3-DCP is genotoxic/mutagenic and carcinogenic. Talcott and King reported that mutagenic activity is lost after purification of 1,3-DCP samples via silica gel column chromatography. We found that mutagenicity and SOS repair in Escherichia coli, strain PM 21, are strongly reduced after purification via silica gel and that mutagenicity and induction of SOS repair depend on oxidative impurities and secondary products. Both isomers (E and Z) of 1,3-DCP are oxidized to 1,3-dichloropropene epoxide (1,3-DCP-Ox). The epoxide is subjected to rapid internal rearrangement to 2,3-dichloropropanal (2,3-DCPA), which spontaneously eliminates HCl and forms the extremely mutagenic, genotoxic, and carcinogenic 2-chloroacrolein (alpha-chloroacrolein) alpha-ClA. Thus, the genotoxic/mutagenic effects of unpurified 1,3-DCP samples mainly depend on alpha-ClA. The underlying genotoxic and mutagenic mechanism is formation of promutagenic exocyclic 1,N(2)-propanodeoxyguanosine adducts of alpha-ClA. Pure 1,3-DCP samples have only a very low S(N)1 reactivity as measured in trifluoroacetic acid solvolysis reactions, hydrolysis, and computed reactivities but possess a moderate S(N)2 reactivity as determined in alkylation tests with the nucleophiles 4-(p-nitrobenzyl)pyridine (NBP) and N-methyl-mercaptoimidazole (MMI). Evidently, the low S(N)1 reactivity is not sufficient to form necessary amounts of O(6)-alkylguanine DNA adducts required for back-mutation in Salmonella typhimurium strain TA1535. The S(N)2 reactivity may, however, lead to other DNA adducts, e.g., N7-guanine adducts, which can induce error prone repair in S. typhimurium strain TA100 and thus lead to back-mutation in this strain. Application of 1,3-DCP samples in agriculture must be considered as a mutagenic risk because the samples can be oxidized and form the extremely mutagenic alpha-ClA. As a consequence, it is questionable whether any stabilizers can prevent oxidation during application.
authors.affiliation: Department of Toxicology, University of Würzburg, Germany. eder@toxi.uni-wuerzburg.de
authors.forename: Erwin
authors.initials: E
authors.lastname: Eder
authors.forename: Jaime
authors.initials: J
authors.lastname: Espinosa-Gonzalez
authors.forename: Andreas
authors.initials: A
authors.lastname: Mayer
authors.forename: Karin
authors.initials: K
authors.lastname: Reichenberger
authors.forename: Donald
authors.initials: D
authors.lastname: Boerth
mesh_terms: D000498:Allyl Compounds / Q000737:chemistry* / Q000378:metabolism; D000969:Antinematodal Agents / Q000737:chemistry* / Q000378:metabolism; D002273:Carcinogens / Q000737:chemistry* / Q000633:toxicity; D004249:DNA Damage; D006843:Hydrocarbons, Chlorinated; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity; D010084:Oxidation-Reduction
chemical_list: D000498:Allyl Compounds; D000969:Antinematodal Agents; D002273:Carcinogens; D006843:Hydrocarbons, Chlorinated; D009153:Mutagens; C023891:1,3-dichloro-1-propene