title: Mixture toxicity of SN2-reactive soft electrophiles: 1. Evaluation of mixtures containing α-halogenated acetonitriles.
abstract: The concept of multiple modes of toxic action denotes that an individual chemical can induce two or more toxic effects within the same series of concentrations, for example, reactive toxicity and narcosis. It appears that such toxicity confounds the ability to develop precise predictions of mixture toxicity and makes it more difficult to clearly link a dose-additive combined effect to agents in the mixture having a single common mechanism of toxic action. This initial study of a three-part series begins to examine this issue in greater detail by testing three α-halogenated acetonitriles: (1) in sham combinations, (2) in true combinations, and (3) with a nonreactive nonpolar narcotic. Iodo-, bromo-, and chloro-derivatives of acetonitrile were selected for testing based on their electro(nucleo)philic reactivity, via the S(N)2 mechanism, and their time-dependent toxicity individually. Reactivity of each agent was assessed in tests with the model nucleophile glutathione (GSH). Each acetonitrile was reactive with GSH, but the nonpolar narcotic 3-methyl-2-butanone was not. In addition, toxicity of the agents alone and in mixtures was assessed using the Microtox(®) acute toxicity test at three time points: 15, 30, and 45 min of exposure. Each of the three agents alone had time-dependent toxicity values of about 100%, making it likely that most of the toxicity of these agents, at these times, was due to reactivity. In contrast, the nonpolar narcotic agent lacked time-dependent toxicity. In mixture testing, sham combinations of each acetonitrile showed a combined effect consistent with predicted effects for dose-addition at each time point, as did the sham combination of the nonpolar narcotic. Mixture toxicity results for true acetonitrile combinations were also consistent with dose-addition, but the acetonitrile-nonpolar narcotic combinations were generally not consistent with either the dose-addition or independence models of combined effect. Based on current understanding of mixture toxicity, these results were expected and provide a foundation for the second and third studies in the series.
authors.affiliation: Department of Biology/Toxicology, Ashland University, Ashland, OH 44805, USA. ddawson2@ashland.edu
authors.forename: D A
authors.initials: DA
authors.lastname: Dawson
authors.forename: J
authors.initials: J
authors.lastname: Jeyaratnam
authors.forename: T
authors.initials: T
authors.lastname: Mooneyham
authors.forename: G
authors.initials: G
authors.lastname: Pöch
authors.forename: T W
authors.initials: TW
authors.lastname: Schultz
mesh_terms: D000097:Acetonitriles / Q000633:toxicity*; D048908:Aliivibrio fischeri / Q000187:drug effects; D001463:Barbiturates / Q000633:toxicity; D055598:Chemical Phenomena; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004583:Electrons; D054879:Halogenation; D009294:Narcotics / Q000633:toxicity; D018675:Toxicity Tests
chemical_list: D000097:Acetonitriles; D001463:Barbiturates; D009294:Narcotics; C020322:5-ethyl-5-(3'-methylbut-2'-enyl)barbituric acid; C069277:chloroacetonitrile
references.citation: Toxicol Appl Pharmacol. 2004 Dec 1;201(2):85-96
references.pmid: 15541748
references.citation: Toxicology. 2000 Jul 5;147(3):193-207
references.pmid: 10924801
references.citation: Cell Biol Toxicol. 2006 Sep;22(5):339-49
references.pmid: 16845611
references.citation: Chem Res Toxicol. 2010 Jan;23(1):228-34
references.pmid: 19928804
references.citation: Environ Toxicol Chem. 2005 Dec;24(12):3117-27
references.pmid: 16445094
references.citation: J Pharmacol Methods. 1990 Dec;24(4):311-25
references.pmid: 2292882
references.citation: Environ Sci Technol. 2002 Oct 15;36(20):4201-17
references.pmid: 12387389
references.citation: Chemosphere. 2006 Jun;64(1):17-25
references.pmid: 16457872
references.citation: SAR QSAR Environ Res. 2005 Aug;16(4):313-22
references.pmid: 16234173
references.citation: Regul Toxicol Pharmacol. 2001 Aug;34(1):35-41
references.pmid: 11502154
references.citation: Ecotoxicol Environ Saf. 1995 Jun;31(1):23-8
references.pmid: 7544261
references.citation: Arch Environ Contam Toxicol. 2007 Apr;52(3):283-93
references.pmid: 17253098
references.citation: Toxicology. 2002 Aug 15;177(2-3):267-84
references.pmid: 12135629
references.citation: Environ Toxicol Pharmacol. 2004 Mar;16(1-2):13-23
references.pmid: 21782690
references.citation: J Environ Sci Health A Tox Hazard Subst Environ Eng. 2008 Jan;43(1):43-52
references.pmid: 18161557
references.citation: Chem Res Toxicol. 2007 Jan;20(1):44-60
references.pmid: 17226926
references.citation: Ecotoxicol Environ Saf. 2006 Oct;65(2):171-80
references.pmid: 16139365
references.citation: SAR QSAR Environ Res. 2007 Jan-Mar;18(1-2):21-9
references.pmid: 17365956