Toxicology Studies on Lewisite and Sulfur Mustard Agents: Mutagenicity of Lewisite in the Salmonella Histidine Reversion Assay Final Report

The mutagenic potential of lewisite was evaluated in the standard plate incorporation method and by the preincubation modification of the Ames Salmonella/microsomal assay with tester strains TA97, TA98, TAlOO and TA102. All strains were tested with activation (20 and 50 {micro}l/ plate) and without activation. The lewisite was screened initially for toxicity with TA98 over a range of concentrations from 0.01 to 250 {micro}g of material per plate. However, concentrations selected for mutagenicity testing were adjusted to a range of 0.001 to 5 {micro}g/plate because of the sensitivity of tester strain TA102, which exhibited cytotoxicity at 0.01 ug/plate. No mutagenic response was exhibited by any of the strains in either method used. All other tester strains showed evidence of cytoxicity (reduction in mutagen response or sparse background lawn) at 5.0 {micro}g/plate or lower

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Mutagenicity of Lewisite in the Salmonella Histidine Reversion Assay Final Report

The mutagenic potential of lewisite was evaluated in the standard plate incorporation method and by the preincubation modification of the Ames Salmonella/microsomal assay with tester strains TA97, TA98, TAlOO and TA102. All strains were tested with activation (20 and 50 {micro}l/ plate) and without activation. The lewisite was screened initially for toxicity with TA98 over a range of concentrations from 0.01 to 250 {micro}g of material per plate. However, concentrations selected for mutagenicity testing were adjusted to a range of 0.001 to 5 {micro}g/plate because of the sensitivity of tester strain TA102, which exhibited cytotoxicity at 0.01 ug/plate. No mutagenic response was exhibited by any of the strains in either method used. All other tester strains showed evidence of cytoxicity (reduction in mutagen response or sparse background lawn) at 5.0 {micro}g/plate or lower

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Mutagenicity of Sulfur Mustard in the Salmonella Histidine Reversion Assay Final Report

The mutagenic potential of bis 2-chloroethyl sulfide (HD} a bifunctional sulfur mustard was evaluated in the standard plate incorporation version and the preincubation modification of the Salmonella/microsomal assay with tester strains TA97, TA98, TA100 and TA102, with and without 59 activation. HD-induced point mutations in strain TA102 and frameshift mutations in TA97 but showed little or no mutagenicity against strains TA98 and TA100. Extensive HD-induced cell killing was observed with the excision repair deficient strains (TA100, TA98 and TA97) but not with strain TA102, which is wild-activation by Aroc1or induced rat liver microsomes (S9)

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Mutagenicity of Sulfur Mustard in the Salmonella Histidine Reversion Assay Final Report

The mutagenic potential of bis 2-chloroethyl sulfide (HD} a bifunctional sulfur mustard was evaluated in the standard plate incorporation version and the preincubation modification of the Salmonella/microsomal assay with tester strains TA97, TA98, TA100 and TA102, with and without 59 activation. HD-induced point mutations in strain TA102 and frameshift mutations in TA97 but showed little or no mutagenicity against strains TA98 and TA100. Extensive HD-induced cell killing was observed with the excision repair deficient strains (TA100, TA98 and TA97) but not with strain TA102, which is wild-activation by Aroc1or induced rat liver microsomes (S9)

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Genetic Toxicity of Sulfur Mustard (HD) in Chinese Hamster Ovary Cells Final Report

The cytotoxic, clastogenic and mutagenic effects of sulfur nustard in Chinese hamster ovary cells are described in this reoort. The cytotoxicity data indicate that micromolar amounts of HC are highly toxic in microrolar amounts. Chromosone aberration frequencies increased in a dose-dependent manner over a dose range of 0. 5 to 1.0 {micro}m and SCE increased in a dose-dependent fashion in the dose range of 0.0625 to 0.25 {micro}M. Mutation induction at the HGPRT locus was sporadic, but the majority of the exoosures resulted in mutation frequencies which were 1.2 to 4.3 fold higher than the spontaneous frequencies

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Genetic Toxicity of Sulfur Mustard (HD) in Chinese Hamster Ovary Cells Final Report

The cytotoxic, clastogenic and mutagenic effects of sulfur nustard in Chinese hamster ovary cells are described in this reoort. The cytotoxicity data indicate that micromolar amounts of HC are highly toxic in microrolar amounts. Chromosone aberration frequencies increased in a dose-dependent manner over a dose range of 0. 5 to 1.0 {micro}m and SCE increased in a dose-dependent fashion in the dose range of 0.0625 to 0.25 {micro}M. Mutation induction at the HGPRT locus was sporadic, but the majority of the exoosures resulted in mutation frequencies which were 1.2 to 4.3 fold higher than the spontaneous frequencies

Toxicology Studies of Lewisite and Sulfur Mustard Agents: Genetic Toxicity of Lewisite (L) In Chinese Hamster Ovary Cells

The cytotoxic clastogenic and mutagenic effects of the arsenic containing vesicant, Lewisite (L) [dichloro(2-chlorovinyl) arsine], have been investigated using Chinese hamster ovary cells. One hour exposures to Lewisite were cytotoxic in uM amounts. The cell survival response yields a D37 of 0.6 uM and an extrapolation number of 2.5. The mutagenic response at the hypoxantnine-guanine phosporibosyl transferase (HGPRT) locus was sporadic and not significantly greater than control values when cells were exposed over a range of 0.125 to2.0 uM. Sister chromatid exchange (SCE) induction, a measure of chromosomal rearrangement, was weakly positive over a range of 0.25 to 1.0 uM but the values were not significantly greater than the control response. Chromosomal aberrations were induced at 0.75 and 1.0 UMin one experiment and 0.5 and 0.75 uM in another experiment. The Induced values were significantly greater than the control values. Lewisite appears to be cytotoxic and clastogenic in our investigations but SCE and mutation at the HGPRT locus are not significantly greater than control values. Lewisita toxicity was in some ways similar to radiomimetic chemicals such as bleomycin

Teratology Studies on Lewisite and Sulfur Mustard Agents: Effects of Sulfur Mustard in Rats and Rabbits

Sulfur mustard (HD) was administered to rats and rabbits by intragastric intubation. Rats were dosed daily from 6 through 15 days of gestation (dg) with 0. 0.5, 1.0 or 2.0 mg of HD/kg; rabbits were dosed with 0, 0.4, 0.6 or 0.8 mg/kg on 6 through 19 dg. Maternal animals were weighed periodically and, at necropsy, were examined for gross lesions of major organs and reproductive performance; live fetuses were weighed and examined for external, internal and skeletal defects. In rats, reductions in body weights were observed in maternal animals and their female fetuses at the lowest administered dose (0.5 mg/kg), but the incidence of fetal malformations was not increased. In rabbits the highest administered dose (0.8 mg/kg) induced maternal mortality and depressed body weight measures but did not affect fetal development. These results suggest that orally administered HD is not teratogenic in rats and rabbits since fetal effects were observed only at dose levels that induced frank maternal toxicity. Estimations of dose ranges for "no observable effects levels" in rats and rabbits, respectively, were: 0.8 mg/kg in their fetuses

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Subchronic Toxicity of Sulfur Mustard (HD) In Rats Final Report

Occupational health standards have not been established for sulfur mustard [bis(2- chlorethyl)-sulfide], a strong alkylating agent with known mutagenic properties. Seventytwo Sprague-Dawley rats of each sex, 6-7 weeks old, were divided into six groups (12/group/ sex) and gavaged with either 0, 0.003 , 0.01 , 0.03 , 0.1 or 0.3 mg/kg of sulfur mustard in sesame oil 5 days/week for 13 weeks. No dose-related mortality was observed. A significant decrease (P ( 0.05) in body weight was observed in both sexes of rats only in the 0.3 mg/kg group. Hematological evaluations and clinical chemistry measurements found no consistent treatment-related effects at the doses studied. The only treatment-related lesion associated with gavage exposure upon histopathologic evaluation was epithelial hyperplasia of the forestomach of both sexes at 0.3 mg/kg and males at 0.1 mg/kg. The hyperplastic change was minimal and characterized by cellular disorganization of the basilar layer, an apparent increase in mitotic activity of the basilar epithelial cells, and thickening of the epithelial layer due to the apparent increase in cellularity. The estimated NOEL for HD in this 90-day study is 0.1 mg/kg/day when administered orally