Mutagenicity of chloroacetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophosphamide.

Abstract

We have previously described a very sensitive and efficient bacteria] test designed to detect chemical carcinogens as mutagens. Chloroacetaldehyde is mutagenic in this system and is of interest because it is a possible metabolite in mammals of the large volume industrial chemicals 1,2dichloroethane (ethylene dichloride)(3.5 billion kg/ yr, U.S.) and vinyl chloride (2.5 billion kg/yr, U.S.), and of the antineoplastic agent cyclophosphamide. Chloroacetaldehyde reverts a new Salmoneira bacterial tester strain (TAlOO). Chloroacetaldehyde is shown to be hundreds of times more effective in reversion of TA100 than is chloroethanol (ethylene chlorohydrin), a known metabolic precursor of chloroacetaldehyde and a possible metabolite of dichloroethane and vinyl chloride, or than vinyl chloride, which is itself mutagenic for TAIOO. Chloroethanol is shown to be activated by rat (or human) liver homogenates to a more highly mutagenic form with reversion properties similar to chloroacetaldehyde. Reversion jwperties of cyclophosphamide after in vitro metabolic activation suggest that chloroacetaldehyde is not the active mutagenic form of this antineoplastic drug. We have previously described a rapid, sensitive bacterial test designed to detect chemical carcinogens as mutagens (1-7). The test utilizes a special set of histidine mutants of Salmonella typhimurium for reversion, and a rat (or human) microsomal system for metabolic conversion of carcinogens to their active forms. The standard bacterial tester strains have been described in detail (1, 3, 5) and contain histidine missense (TA1535) or frameshift (TA1537, TA1538) mutations. The strains also contain uvrB and rfa (deep rough) mutations which greatly increase their sensitivity to reversion by a variety of carcinogens: uvrB causes loss of the excision repair system and rfa causes loss of the lipopolysaccharide permeability barrier. The compound to be tested, the bacterial tester strain, and when required rat (or human) liver microsomal enzymes, are combined on a petri dish and after incubation at 370 for 2 days histidine revertants are scored.Hundreds of carcinogens and noncarcinogens have been tested using the Salmonella/mammalian-microsome bacterial test system in this laboratory (1-13) and in many laboratories throughout the world. We (J.M. and B.N.A.) are currently preparing a compilation of these results, and so far about 85% of the known carcinogens tested have been detected as mutagens in the test, and very few (<10%) noncarcinogens (many close relatives of carcinogens have been tested) are positive. This and other evidence showing that a high percentage of carcinogens are mutagens is most easily explained if carcinogens cause cancer by somatic mutation (4). We believe there is a high probability that chemicals found to be mutagens in the Salmonella test will turn out to be carcinogens.We have recently introduced two new tester strains (TA100 and TA98) which were constructed by transferring to our standard tester strains TA1535 and TA1538 respectively, a res...

Comparison of high and low dose cyclophosphamide therapy in rheumatoid arthritis

“…Sterility as a result of cyclophosphamide therapy is well documented (12,13) but was not evaluated in this study. Delayed toxicity such as mutogenesis (14) and oncogenesis (15,16) cannot be effectively evaluated in a short term project, but there exists a potential advantage for lower dose medication in this important area.…”

8-(Hydroxymethyl)-3,N4-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

“…The compound has produced base-pair mutations in two strains of Salmonella typhimurium (TA1535 and TA1000) (2,3) as well as reverse base-pair mutations in Saccharomyces cerevisiae strain S211 (4,5). Glycidaldehyde is classified as an animal carcinogen by International Agency on Research in Cancer (IARC) based on long-term rodent experiments (3,5).…”

Mechanisms of vinyl chloride carcinogenicity/mutagenicity

“…Induction of (dA-dT)-(dC-dG) and (dCdG)-(dA-dT) transversions from etheno-dA and etheno-dC are consistent with the fact that chloroethylene oxide, chloroacetaldehyde and metabolically activated vinyl chloride induce base-pair-substitution mutations (Rannug et al, 1974;Malaveille et al, 1975;McCann et al, 1975;Phillips et al, 1980), but not frame-shift mutations, in Salmonella typhimurium strains. It follows that the mechanism of vinyl chloride carcinogenicity/ mutagenicity has been studied more intensively than that of any other human carcinogen.…”