S. Hussain

Estimation of genetic risks of alkylating agents: VI. Exposure of mice and bacteria to methyl bromide

Methyl bromide was studied in a forward mutation system of E. coli to evaluate the relationship between dose and mutagenic response. The compound had a high toxicity and a low mutagenic efficiency, as expected from the high s value. The mutagenic effectiveness was estimated to be 1 mutation per 10(8) surviving bacteria per mM . h, in reasonable agreement with expectation from reaction kinetic data. To study the possibilities of using hemoglobin alkylation for an estimation of DNA alkylation in vivo, mice were treated with 14C-labeled methyl bromide. The degree of alkylation of DNA, determined in liver and spleen, was considerably lower than expected (200 and 20 times, respectively) from the degree of alkylation of hemoglobin and from the relative reactivities of DNA and hemoglobin towards methyl bromide in vitro. when hemoglobin alkylation is used for quantitative risk estimations, a correction factor has to be applied by taking into account the difference between the dose in red blood cells and the dose in the compartments of DNA.

Comment on the mutagenic effectiveness of vinyl chloride metabolites.

Abstract The dose—response curve for mutation induced by alkylating agents is indicated to exhibit a linear component in the region of low doses [1]. In this region, the mutagenic effectiveness per unit dose, determined as the time integral of concentration (dimension mM · h) [2] was found for several alkylating agents to be approximately proportional to the calculated rate of reaction at a certain low nucleophilic strength, n ≈ 2 [3,4]. This proportionality appears, by and large, to be independent of the nature of the alkyl introduced, and for this reason the computed degree of alkylation at n = 2, and at a given tissue dose, may be used tentatively to estimate genetic risk [2]. Comparing the slopes of the dose—response curves (number of mutants per 10 8 survivors per mM · h) with the rates of reaction at n = 2 of chloroacetaldehyde and chloroethylene oxide, using ethylene oxide and methyl methanesulfonate as standards, the values in Table I are obtained.

Prophage Inductive Efficiency of Alkylating Agents and Radiations

The prophage inducing efficiency in E. coli K-12 (lambda) of a number of agents--alkylating agents and radiations--has been compared at a high survival of bacteria. The inducing effectiveness (per alkylation in DNA) and efficiency (compared with mutation frequency in E. coli Sd-4) was found to decrease in the order 2-hydroxyethylating agents (2-hydroxyethyl methanesulphonate and ethylene oxide) greater than isopropyl methanesulphonate approximately equal to methyl methanesulphonate greater than ethylating agents (diethyl sulphate, ethyl methanesulphonate). The low inducing activity of the ethylating agents could not be explained with respect to their reactivity towards targets of differing nucleophilicity, nor could the effectiveness in mutagenicity or the ability to break the chromosomes in the presence of metal ions be invoked. The high inducing efficiency of hydroxyalkylating agents may be related to their ability to break DNA strands.

Chemical reactivity and mutagenicity of some dihalomethanes.

Four dihalomethanes; dichloromethane, bromochloromethane, dibromomethane and diiodomethane, have been studied with respect to their reactivities towards nucleophilic compounds of different strengths in water solution and with respect to their toxicities and mutagenic effectiveness in bacterial test systems. The correlation between biological activity (toxicity and mutagenic effectiveness in Salmonella TA100) and reactivity towards strong nucleophiles indicates that reactions with nucleophilic groups of high reactivity in the biological material, possibly SH or amino groups in proteins, are involved in their mechanism of action.

Mutagenicity of primary amines combined with nitrate

Summary The mutagenicity of methyl-, ethyl- and isopropylamines was studied alone and in combination with nitrite. Methyl- and ethylamine in combination with nitrite were significantly mutagenic. The combination of isopropylamine with nitrite did not yield a detectable increase in mutation frequency over that due to nitrite alone.