title: Mixture toxicity of S(N)2-reactive soft electrophiles: 2-evaluation of mixtures containing ethyl α-halogenated acetates.
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 EC(50) 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.
authors: Department of Biology/Toxicology, Ashland University, OH 44805, USA. ddawson2@ashland.edu
authors: D A
authors: DA
authors: Dawson
authors: T
authors: T
authors: Mooneyham
authors: J
authors: J
authors: Jeyaratnam
authors: T W
authors: TW
authors: Schultz
authors: G
authors: G
authors: Pöch
mesh_terms: D000085:Acetates / Q000633:toxicity*; D048908:Aliivibrio fischeri / Q000187:drug effects / Q000378:metabolism; D045424:Complex Mixtures / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004583:Electrons; D005463:Fluoroacetates / Q000633:toxicity; D054879:Halogenation; D006842:Hydrocarbons, Brominated / Q000633:toxicity; D007461:Iodoacetates / Q000633:toxicity; D049449:Luminescence; D008826:Microbial Sensitivity Tests; D018675:Toxicity Tests
chemical_list: D000085:Acetates; D045424:Complex Mixtures; D005463:Fluoroacetates; D006842:Hydrocarbons, Brominated; D007461:Iodoacetates; C006972:chloroacetic acid; C010144:ethyl bromoacetate