Genetic toxicology assessment of HI-6 dichloride.
The oxime HI-6 dichloride [1-(2 hydroxyiminomethyl -1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropane dichloride monohydrate] has shown to be a potent reactivator of cholinesterase activity and may have efficacy for the treatment of organophosphate intoxication [SIPRI, 1976; Schenk et al.; Arch Toxicol 36:71-81, 1976]. As part of a preclinical safety assessment program, the genetic toxicology of HI-6 dichloride was evaluated in a series of assays designed to measure induction of gene mutations and chromosomal aberrations. HI-6 dichloride gave negative responses in the Salmonella mutagenicity assay and in the CHO/HGPRT gene mutation assay. Dose-dependent increases in the frequency of chromosomal aberrations were noted when HI-6 dichloride was tested in cultured CHO cells and in cultured human peripheral blood lymphocytes. The mouse lymphoma gene mutation assay, reputed to measure both gene mutations and chromosomal deletions, was negative in the absence of metabolic activation. Depending on the criteria employed, a negative or equivocal response was seen in the presence of rat liver-derived S-9 mix. An in vivo rat bone marrow metaphase assay performed to further investigate the in vitro clastogenic responses was negative. The results from these studies indicate that HI-6 dichloride does not induce gene mutations in vitro; however, it is clastogenic in vitro but does not appear to be clastogenic in vivo.
Putman
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Division of Genetic Toxicology, Microbiological Associates, Rockville, Maryland 20850, USA.
San
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Bigger
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Levine
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Jacobson-Kram
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D000704:Analysis of Variance; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells / Q000187:drug effects; D002478:Cells, Cultured; D002801:Cholinesterase Reactivators / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000235:genetics*; D003001:Cloning, Molecular; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D008297:Male; D008677:Metaphase / Q000187:drug effects / Q000235:genetics; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D010091:Oximes; D011726:Pyridinium Compounds / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment
D002801:Cholinesterase Reactivators; D009153:Mutagens; D010091:Oximes; D011726:Pyridinium Compounds; C022870:asoxime chloride