Mutagenicity of halogenated aliphatic hydrocarbons in Salmonella typhimurium, Streptomyces coelicolor and Aspergillus nidulans

doi:10.1016/0009-2797(80)90110-6

Chemico-Biological Interactions

Volume 30, Issue 1, April 1980, Pages 9-23

https://doi.org/10.1016/0009-2797(80)90110-6 Get rights and content

Abstract

Eight structurally related halogenated aliphatic hydrocarbons mono-, di- and trichloroacetaldehyde (the last in the anhydrous and hydrate form), mono-, di- and trichloroethanol and allyl chloride, were tested for their ability to induce gene mutations in prokaryotic and eukaryotic microorganisms. The genetic systems employed were the Salmonella reversion test with strain TA1535 and TA100, with and without metabolic activation, a forward and a back-mutation system in S. coelicolor and two forward mutation systems in A. nidulans. Each compound was tested with the spot and plate incorporation assay techniques.

Mono-, di- and trichloroacetaldehyde were mutagenic in all the microorganisms employed; all the halogenated ethanols were positive in A. nidulans, while in S. typhimurium and in S. coelicolor the only active forms were respectively the mono- and dichloroderivatives. Allyl chloride was active in S. typhimurium and S. coelicolor and negative in A. nidulans.

The technical approach as well as the complex influence of different factors (toxicity, volatility and stability) on the genetic response of each of the compounds under test did not allow to obtain more than a qualitative relationship between mutagenic potency and chemical structure.

References (41)

G.W. Fischer et al.
Zur mutagenität von dichloroacetaldehyd und 2,2-dichlor-1,1 dihydroxy-Athanphosphon säure-methylester, möglichen metaboliten des phosphororganischen pestizides trichlorphon
Chem.-Biol. Interact.
(1977)
H. Greim et al.
Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxirane formation
Biochem. Pharmacol.
(1975)
A. Carere et al.
Microbiological mutagenicity studies of pesticides in vitro
Mutat. Res.
(1978)
A. Carere et al.
Mutagenicity of Dichlorvos and other structurally related pesticides in Salmonella and Streptomyces
Chem.-Biol. Interact.
(1978)
M. Bignami et al.
Mutagenic and recombinogenic action of pesticides in Aspergillus nidulans
Mutat. Res.
(1977)
F.J. De Serres
The utility of short-term tests for mutagenicity
Mutat. Res.
(1976)
M. Bignami et al.
A simplified method for the induction of 8-Azaguanine resistance in S. typhimurium
Toxicol., Lett.
(1979)
D.A. Hopwood et al.
Genetics of S. coelicolor
Adv. Genet.
(1962)
L.J. Lilly
An investigation on the suitability of suppressors of meth A1 for the study of induced and spontaneous mutations
Mutat. Res.
(1965)
J.D. Elmore et al.
Vinyl chloride mutagenicity via the metabolites chlorooxirane and chloroacetaldehyde monomer hydrate
Biochim. Biophys. Acta
(1976)

C. Malaveille et al.

Mutagenicity of vinyl chloride, chlorethylene oxide, chloroacetaldehyde and chloroethanol

Biochem. Biophys. Res. Commun.

(1975)

U. Rannug et al.

Mutagenicity of chloroethylene oxide, chloroacetaldehyde, chloroethanol and chloroacetic acid, conceivable metabolites of vinyl chloride

Chem.-Biol. Interact.

(1976)

S. Rosenkranz et al.

2-Haloethanols: mutagenicity and reactivity with DNA

Mutat. Res.

(1974)

C.E. Voogd et al.

On the mutagenic action of dichlorvos

Mutat. Res.

(1972)

L. Waskell

The study on the mutagenicity of anesthetics and their metabolites

Mutat. Res.

(1978)

E. McCoy et al.

Genetic activity of allyl chloride

Mutat. Res.

(1978)

M. Hollstein et al.

Short-term tests for carcinogens and metagens

Mutat. Res.

(1979)

R.E. Hefner et al.

Preliminary studies on the fate of inhaled vinyl chloride monomer in rats

Ann. N.Y. Acad. Sci.

(1975)

G. Bonse et al.

Chemical reactivity, biotransformation and toxicity of polychlorinated haliphatic compounds

CRC Crit. Rev. Toxicol.

(1976)

C. Maltoni et al.

Carcinogenicity bioassay of vinyl chloride

Environ. Res.

(1974)

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The CPDB (Gold et al., 2010) indicates a TD50 for chloroacetaldehyde of 36.1 mg/kg day, based upon the study of Daniel et al. (1992). The genotoxicity of other saturated (Loforth, 1978; Bignami et al., 1980) and unsaturated haloaldehydes (Rosen et al., 1980; Meier et al., 1985; Segall et al., 1985) has been studied extensively and have been found positive as mutagens. However, the in vivo toxicological studies of the haloaldehydes found in drinking water appear to be limited to chloroacetaldehyde and chloral hydrate.
Drinking water disinfectants react with natural organic material (NOM) present in source waters used for drinking water to produce a wide variety of by-products. Several hundred disinfections by-products (DBPs) have been identified, but none have been identified with sufficient carcinogenic potency to account for the cancer risks projected from epidemiological studies. In a search for DBPs that might fill this risk gap, the present study projected reactions of chlorine and chloramine that could occur with substructures present in NOM to produce novel by-products. A review of toxicological data on related compounds, supplemented by use of a quantitative structure toxicity relationship (QSTR) program TOPKAT^® identified chemicals with a high probability of being chronically toxic and/or carcinogenic among 489 established and novel DBPs. Classes of DBPs that were specifically examined were haloquinones (HQs), related halo-cyclopentene and cyclohexene (HCP&H) derivatives, halonitriles (HNs), organic N-chloramines (NCls), haloacetamides (HAMs), and nitrosamines (NAs). A review of toxicological data available for quinones suggested that HQs and HCP&H derivatives appeared likely to be of health concern and were predicted to have chronic lowest observed adverse effect levels (LOAELs) in the low μg/kg day range. Several HQs were predicted to be carcinogenic. Some have now been identified in drinking water. The broader class of HNs was explored by considering current toxicological data on haloacetonitriles and extending this to halopropionitriles. 2,2-dichloropropionitrile has been identified in drinking water at low concentrations, as well as the more widely recognized haloacetonitriles. The occurrence of HAMs has been previously documented. The very limited toxicological data on HAMs suggests that this class would have toxicological potencies similar to the dihaloacetic acids. Organic N-halamines are also known to be produced in drinking water treatment and have biological properties of concern, but no member has ever been characterized toxicologically beyond bacterial or in vitro studies of genotoxicity. The documented formation of several nitrosamines from secondary amines from both natural and industrial sources prompted exploration of the formation of additional nitrosamines. N-diphenylnitrosamine was identified in drinking waters. Of more interest, however, was the formation of phenazine (and subsequently N-chorophenazine) in a competing reaction. These are the first heterocyclic amines that have been identified as chlorination by-products. Consideration of the amounts detected of members of these by-product classes and their probable toxicological potency suggest a prioritization for obtaining more detailed toxicological data of HQs > HCP&H derivatives > NCls > HNs. Based upon a ubiquitous occurrence and virtual lack of in vivo toxicological data, NCls are the most difficult group to assign a priority as potential carcinogenic risks. This analysis indicates that research on the general problem of DBPs requires a more systematic approach than has been pursued in the past. Utilization of predictive chemical tools to guide further research can help bring resolution to the DBP issue by identifying likely DBPs with high toxicological potency.
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The extensive metabolic competence of the transformed strain is underlined by results showing strong mutagenicity between 10 and 500 μg N-nitrosopyrrolidine per plate. Unexpectedly, 2-aminoanthracene was mutagenic at a concentration range between 25 and 250 μg per plate using YG7108pin3ERb₅. Moreover, we demonstrate for the first time a clear response of sufficiently characterised allyl chloride in the Ames test at a reasonably low concentration range between 300 and 1500 μg per plate. We achieved similar results in the parent strain YG7108 with conventional metabolic activation. Without metabolic activation less pronounced mutagenicity occurred, suggesting a contribution of a direct alkylating effect. Propylene oxide is usually contained in allyl chloride as stabilizer at amounts up to 0.09%. Though YG7108 revealed to be very sensitive towards propylene oxide, allyl chloride dissolved in water was not mutagenic, showing that no water soluble compounds contribute to its mutagenicity. None of the remaining compounds showed mutagenic effects using YG7108pin3ERb₅.
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Mutagenicity of halogenated aliphatic hydrocarbons in Salmonella typhimurium, Streptomyces coelicolor and Aspergillus nidulans

Abstract

Chem.-Biol. Interact.

Biochem. Pharmacol.

Mutat. Res.

Chem.-Biol. Interact.

Mutat. Res.

Mutat. Res.

Toxicol., Lett.

Adv. Genet.

Mutat. Res.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Chem.-Biol. Interact.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Preliminary studies on the fate of inhaled vinyl chloride monomer in rats

Ann. N.Y. Acad. Sci.

Chemical reactivity, biotransformation and toxicity of polychlorinated haliphatic compounds

CRC Crit. Rev. Toxicol.

Carcinogenicity bioassay of vinyl chloride

Environ. Res.