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Mutagenicity of Chloroacetaldehyde, a Possible Metabolic Product of 1,2

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Mutagenicity of Chloroacetaldehyde, a Possible Metabolic Product of 1,2 Proc. Nat. Acad. Scd. USA Vol. 72, No. 8, pp. 3190-3193, August 1975 Genetics Mutagenicity of chloroacetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophosphamide (environmental carcinogens/alkyl halides) JOYCE MCCANN, VINCENT SIMMON,* DAVID STREITWIESER, AND BRUCE N. AMES Biochemistry Department, University of California, Berkeley, Calif. 94720; and *Department of Toxicology, Stanford Research Institute, Menlo Park, California 94025 Contributed by Bruce N. Ames, June 2,1975 ABSTRACT We have previously described a very sensi- We have recently introduced two new tester strains tive and efficient bacteria] test designed to detect chemical (TA100 and TA98) which were constructed by transferring carcinogens as mutagens. Chloroacetaldehyde is mutagenic in this system and is of interest because it is a possible me- to our standard tester strains TA1535 and TA1538 respec- tabolite in mammals of the large volume industrial chemi- tively, a resistance transfer factor (R factor), pKM101 (7). cals 1,2dichloroethane (ethylene dichloride)(3.5 billion kg/ The new tester strains are greatly enhanced in sensitivity to yr, U.S.) and vinyl chloride (2.5 billion kg/yr, U.S.), and of the reversion with a variety of potent carcinogens such as the antineoplastic agent cyclophosphamide. Chloroacetaldehyde fungal toxin aflatoxin, 7,12-dimethylbenz(a)anthracene, reverts a new Salmoneira bacterial tester strain (TAlOO). benzo(a)pyrene, and others, and also can be used to detect Chloroacetaldehyde is shown to be hundreds of times more a effective in reversion of TA100 than is chloroethanol (ethyl- variety of carcinogens and mutagens not detected by our ene chlorohydrin), a known metabolic precursor of chloro- standard tester strains. acetaldehyde and a possible metabolite of dichloroethane and vinyl chloride, or than vinyl chloride, which is itself mu- tagenic for TAIOO. Chloroethanol is shown to be activated by RESULTS AND DISCUSSION rat (or human) liver homogenates to a more highly mutagenic form with reversion properties similar to chloroacetal- Chloroacetaldehyde. A compound of unusual interest dehyde. Reversion jwperties of cyclophosphamide after in that was positive on the new strain TA100 was chloroacetal- vitro metabolic activation suggest that chloroacetaldehyde is dehyde. Fig. 1A shows that, at the levels tested, chloroacetal- not the active mutagenic form of this antineoplastic drug. dehyde is quite effective in reverting TA100, but does not revert TA1535. [We find at higher concentrations a slight We have previously described a rapid, sensitive bacterial test activity of chloroacetaldehyde in reverting TA1535; weak designed to detect chemical carcinogens as mutagens (1-7). activity has been found independently (14-17).] Chloroacet- The test utilizes a special set of histidine mutants of Salmo- aldehyde is relatively specific for TA100, and does not sig- nella typhimurium for reversion, and a rat (or human) mi- nificantly revert the other R factor tester strain, TA98 crosomal system for metabolic conversion of carcinogens to (TA1538 containing the pKM101 plasmid), or our other their active forms. The standard bacterial tester strains have standard tester strains. been described in detail (1, 3, 5) and contain histidine mis- We originally tested chloroacetaldehyde because of its sense (TA1535) or frameshift (TA1537, TA1538) mutations. known unique reactions with nucleotides, which have been The strains also contain uvrB and rfa (deep rough) muta- extensively studied in connection with its use as a fluorescent tions which greatly increase their sensitivity to reversion by label (18-21). It is known to react specifically with the N-1 a variety of carcinogens: uvrB causes loss of the excision re- and N6 nitrogens of adenosine and the N-3 and N4 nitrogens pair system and rfa causes loss of the lipopolysaccharide of cytidine to form a highly fluorescent cyclic derivative. It permeability barrier. The compound to be tested, the bacte- has been used extensively for fluorescent labeling of a vari- rial tester strain, and when required rat (or human) liver mi- ety of adenine and cytosine containing compounds, includ- crosomal enzymes, are combined on a petri dish and after ing single-stranded DNA. The mutagenic activity of chlo- incubation at 370 for 2 days histidine revertants are scored. roacetaldehyde reported here strongly suggests it can also Hundreds of carcinogens and noncarcinogens have been react with chromosomal DNA, possibly at exposed single- tested using the Salmonella/mammalian-microsome bacte- stranded regions such as the replication fork, or in regions of rial test system in this laboratory (1-13) and in many labora- the DNA undergoing recombinational repair. tories throughout the world. We (J.M. and B.N.A.) are cur- Chloroacetaldehyde has also become of interest recently rently preparing a compilation of these results, and so far as a possible metabolic product of the large volume indus- about 85% of the known carcinogens tested have been de- trial chemical, and human carcinogen vinyl chloride (15-17, tected as mutagens in the test, and very few (<10%) noncar- 22-25). It is also a possible active metabolite of several wide- cinogens (many close relatives of carcinogens have been test- ly used chemicals and we discuss this in relation to its muta- ed) are positive. This and other evidence showing that a high genicity. percentage of carcinogens are mutagens is most easily ex- 1,2-Dichloroethane (ethylene dichloride) is metabolized plained if carcinogens cause cancer by somatic mutation (4). in mammals to chloroacetic acid, probably through chlo- We believe there is a high probability that chemicals found roethanol and chloroacetaldehyde (26, 27). It is an extremely to be mutagens in the Salmonella test will turn out to be car- toxic chemical produced industrially in enormous quantities cinogens. [about 3.5 X 109 kg in 1974 in the U.S. (28) and about 20 X 3190 Downloaded by guest on October 1, 2021 Genetics: McCann et al. Proc. Nat. Acad. Sci. USA 72 (1975) 3191 o00 Table 1. Reversion of TA100 with 1,2-dichloroethane, A Chloroacetaldehyde vinyl chloride, and several possible metabolites 2!00 TA100 Revertant colonies ,ug per plate per pmol 1'00 Dichloroethane* 1.3 X 104 25 0.19 Chloroacetaldehyde 30 285 746 0 / 0 10 20 3C0 Chloroethanol 2.1 x 104 159 0.6 Micrograms Chloroacetic acid 1.0 X 103 0 Vinyl chloride 7.4 X 103 128 1.0 B Chloroethanol 100 Results are from linear dose-response curves after subtracting spon- taneous background revertants (approximately 150 per plate). Re- version was determined on petri plates by incorporating mutagen and bacteria directly into an agar overlay as previously described 0 (3); no microsomes were used. For vinyl chloride, TA100 was ex- 0 1 2 3 4 5 posed on petri plates in desiccators for various times to a vinyl Milligrams 0- chloride atmosphere (20% v/v) (15). Revertant colonies were scored after incubation of the petri plates for 48 hr at 370. All chemicals were of the highest purity available: vinyl chloride (99.9% pure) was .c 0 from Union Carbide; vacuum distilled chloroacetaldehyde was a 0 cJ gift of Nelson Leonard; 1,2-dichloroethane and chloroethanol were z 2 from Aldrich. * Dichloroethane is an extremely weak mutagen, and reproducible dose-response curves were not obtained; results reported are averages from several experiments. tive. The metabolites were also tested on the complete set of tester strains (TA1535, TA1537, TA1538, TA98) and except for the expected weak reversion of TA1535 with chloroetha- nol and chloroacetaldehyde, the other strains were not re- D Cyclophosphamide 2000 verted. Attempts to activate dichloroethane to a more muta- genic form using the standard rat liver S-9 Mix (4, 12) for activation were unsuccessful. This could be related to the relatively inefficient conversion of chloroethanol to chloro- 1000i acetaldehyde in the in vitro system (Fig. 1B), or to other un- determined factors. We are currently optimizing our rat liver activation system for the metabolic conversion of this and a variety of other alkyl halides such as carbon tetrachlo- A ride and the results of these experiments will be published O 100 200 500 elsewhere. Micrograms Chloroethanol, itself an industrial chemical, is a likely FIG. 1. Reversion of TA100 and TA1535 with (A) chloroacet- metabolic product of dichloroethane and precursor of chlo- aldehyde, (B) chloroethanol, (C) vinyl chloride, and (D) cyclophos- roacetaldehyde. It is known to be metabolized in vtvo (38) phamide. Procedures were as described previously (ref. 3 and Table 1). S-9 (150 Al per plate) obtained from phenobarbital-in- and in vitro to chloroacetaldehyde by rat (38) or human (39) duced rats (4) was added for vinyl chloride activation; S-9 ob- liver alcohol dehydrogenase. We have examined the rever- tained from Aroclor-induced rats (12) was added for chloroethanol sion of TA100 and TA1535 with chloroethanol, and Fig. 1B (150 Al S-9 per plate) and cyclophosphamide (300 Al S-9 per plate) shows that in the presence of rat liver microsomes, chlo- activation. 0, TA1535; A, TA1538; 0, TA100; 0, TA100 + S-9; *, roethanol is activated to a form which shows clear activity TA1535 + S-9. on TA100 and a very slight activity for TA1535f. Similar re- 106 tons worldwide (29)]. It is used primarily in the manu- sults were obtained for TA100 using human liver extracts. facture of vinyl chloride and other industrial chemicals, but Fig. 1B also
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