GENETIC TOXICOLOGY ASSESSMENT OF HI-6 DICHLORIDE

The oxime HI-6 dichloride [1-(2 -pyridino)-3-(4-carbamoyl-1-pyridino)- 2-oxapropane dichloride monohydrate] has shown to be a potent reactiva tor of cholinesterase activity and may have efficacy for the treatment of organophosphate intoxication [SIPRI, 1976; Schenk et al.; Arch Tox icol 36:71-81, 1976]. As part of a preclinical safety assessment progr am, the genetic toxicology of HI-6 dichloride was evaluated in a serie s of assays designed to measure induction of gene mutations and chromo somal aberrations. HI-6 dichloride gave negative responses in the Salm onella mutagenicity assay and in the CHO/HGPRT gene mutation assay. Do se-dependent increases in the frequency of chromosomal aberrations wer e noted when HI-6 dichloride was tested in cultured CHO cells and in c ultured human peripheral blood lymphocytes. The mouse lymphoma gene mu tation assay, reputed to measure both gene mutations and chromosomal d eletions, was negative in the absence of metabolic activation. Dependi ng on the criteria employed, a negative or equivocal response was seen in the presence of mt liver-derived S-9 mix. An in vivo rat bone marr ow metaphase assay performed to further investigate the in vitro clast ogenic 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. (C) 1996 Wiley-Liss, Inc.