title: In vitro and in vivo genotoxicity assessment of HI-6 dimethanesulfonate/oxime.
abstract: Organophosphate compounds, which induce organophosphate poisoning, were originally used as pesticides. But this type of product has also been used as warfare nerve agent like sarin, soman, Russian VX, or tabun. HI-6-dimethanesulfonate is a salt of the oxime HI-6 used in the treatment of nerve-agent poisoning. It is known to be the best re-activator component of inactivated acetyl cholinesterase. HI-6-dimethanesulfonate has shown a higher level of solubility with similar potency to reactivate acetyl cholinesterase and a similar pharmacokinetics profile compared with HI-6 dichloride. HI-6 dimethanesulfonate was tested for its mutagenic and genotoxic potential by use of the standard ICH S2R (1) battery for the evaluation of pharmaceuticals. HI-6-dimethanesulfonate was mutagenic in the Ames test only in the presence of metabolic activation. In the mutation assay at the Tk locus in L5178Y mouse-lymphoma cells, HI-6-dimethanesulfonate showed mutagenic activity both with and without metabolic activation, with a significant increase in small colonies. The effects were in favour of a clastogenic activity. It was concluded that the compound was mutagenic and possibly clastogenic in vitro. In contrast, the in vivo micronucleus test in rat bone-marrow did not demonstrate any genotoxic activity and the Comet assay performed in rat liver did not show any statistically or biologically significant increases in DNA strand-breaks. The results of both in vivo studies performed on two different organs with two endpoints are sufficient to conclude the absence of a genotoxic hazard in vivo and to consider that there is no genotoxic concern in humans for HI-6-dimethanesulfonate.
authors.affiliation: Laboratoire de Toxicologie Génétique, Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019 Lille Cedex, France.
authors.forename: Lauren
authors.initials: L
authors.lastname: Nakab
authors.affiliation: Pharmacie centrale des armées, TSA 30004, 45404 Fleury les Aubrais Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bardot
authors.affiliation: Pharmacie centrale des armées, TSA 30004, 45404 Fleury les Aubrais Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bardot
authors.affiliation: Laboratoire de Toxicologie Génétique, Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019 Lille Cedex, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Simar
authors.affiliation: Laboratoire de Toxicologie Génétique, Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019 Lille Cedex, France; UDSL, EA 4483, Département Toxicologie-Santé Publique-Environnement, Faculté de Pharmacie, 1 rue du Pr. Laguesse, 59019 Lille Cedex, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Marzin
authors.affiliation: Laboratoire de Toxicologie Génétique, Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019 Lille Cedex, France; UDSL, EA 4483, Département Toxicologie-Santé Publique-Environnement, Faculté de Pharmacie, 1 rue du Pr. Laguesse, 59019 Lille Cedex, France. Electronic address: fabrice.nesslany@pasteur-lille.fr.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Nesslany
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D020552:Comet Assay; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005260:Female; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008741:Methyl Methanesulfonate / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015394:Molecular Structure; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D010091:Oximes / Q000737:chemistry / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
chemical_list: D009153:Mutagens; D010091:Oximes; D011726:Pyridinium Compounds; D008741:Methyl Methanesulfonate; C022870:asoxime chloride
keywords: Genotoxicity; Organophosphate poisoning; Oxime