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Mixture Toxicity of SN2-Reactive Soft Electrophiles: 2—Evaluation of Mixtures Containing Ethyl α-Halogenated Acetates

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Abstract

Four ethyl α-halogenated acetates were tested in (1) sham and (2) nonsham combinations and (3) with a nonreactive nonpolar narcotic. Ethyl iodoacetate (EIAC), ethyl bromoacetate (EBAC), ethyl chloroacetate (ECAC), and ethyl fluoroacetate (EFAC), each considered to be an SN2-H-polar soft electrophile, were selected for testing based on their differences in electro(nucleo)philic reactivity and time-dependent toxicity (TDT). Agent reactivity was assessed using the model nucleophile glutathione, with EIAC and EBAC showing rapid reactivity, ECAC being less reactive, and EFAC lacking reactivity at ≤250 mM. The model nonpolar narcotic, 3-methyl-2-butanone (3M2B), was not reactive. Toxicity of the agents alone and in mixture was assessed using the Microtox acute toxicity test at three exposure durations: 15, 30 and 45 min. Two of the agents alone (EIAC and EBAC) had TDT values >100%. In contrast, ECAC (74 to 99%) and EFAC (9 to 12%) had partial TDT, whereas 3M2B completely lacked TDT (<0%). In mixture testing, sham combinations of each agent showed a combined effect consistent with predicted effects for dose-addition at each time point, as judged by EC50 dose-addition quotient values. Mixture toxicity results for nonsham ethyl acetate combinations were variable, with some mixtures being inconsistent with the predicted effects for dose-addition and/or independence. The ethyl acetate–3M2B combinations were somewhat more toxic than predicted for dose-addition, a finding differing from that observed previously for α-halogenated acetonitriles with 3M2B.

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Acknowledgments

This study was made possible by Grants No. 2 R15 ES08019-03 and -04 from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). Its contents are solely the responsibility of the investigators and do not represent the official views of the NIEHS, NIH. Two undergraduate students (T. M. and J. J.) were supported by the NIH AREA Grant program.

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Authors and Affiliations

  1. Department of Biology/Toxicology, Ashland University, Ashland, OH, 44805, USA

    D. A. Dawson, T. Mooneyham & J. Jeyaratnam

  2. Department of Comparative Medicine, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, 37996-4543, USA

    T. W. Schultz

  3. Department of Pharmacology and Toxicology, University of Graz, 8010, Graz, Austria

    G. Pöch

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  1. D. A. Dawson
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  2. T. Mooneyham
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  3. J. Jeyaratnam
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  4. T. W. Schultz
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  5. G. Pöch
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Correspondence to D. A. Dawson.

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Dawson, D.A., Mooneyham, T., Jeyaratnam, J. et al. Mixture Toxicity of SN2-Reactive Soft Electrophiles: 2—Evaluation of Mixtures Containing Ethyl α-Halogenated Acetates. Arch Environ Contam Toxicol 61, 547–557 (2011). https://doi.org/10.1007/s00244-011-9663-1

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  • DOI: https://doi.org/10.1007/s00244-011-9663-1

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