Experimental reactivity parameters for toxicity modeling: application to the acute aquatic toxicity of SN2 electrophiles to Tetrahymena pyriformis

Chemical Research in Toxicology
David W RobertsAynur O Aptula

Abstract

A diverse set of 60 haloaliphatic compounds were evaluated for reactivity with cysteine thiol groups in the previously described RC(50) assay using glutathione (GSH) as a model nucleophile. Reactivity was quantified by the RC(50) value, the concentration of test compound that produced 50% reaction of the GSH thiol groups in 120 min. Under standard conditions, RC(50) values are mathematically proportional to reciprocal rate constants. Quantitative structure-activity relationship (QSAR) analysis correlating acute aquatic toxicity (IGC(50)) to Tetrahymena pyriformis with RC(50) values was carried out. It was found that subdivision of the compounds into subdomains according to their reaction mechanism characteristics enabled toxicity-reactivity relationships to be identified. The largest subdomain consisting of 22 compounds in which a primary halogen is alpha to a carbonyl or other electronegative unsaturated group and which can be confidently assigned as S(N)2 electrophiles fits the equation pIGC(50) (mM) = 0.94 (+/-0.07) pRC(50) (mM) + 1.34 (+/-0.07), n = 22, r(2) = 0.889, r(2)(adj) = 0.884, s = 0.27, and F = 161. Compounds in which the halogen is not alpha to an unsaturated group are not reactive in the GSH assay and do not exhi...Continue Reading

References

Sep 20, 2005·Chemical Research in Toxicology·Aynur O AptulaDavid W Roberts
Jul 18, 2006·Cell Biology and Toxicology·T W SchultzS K Koss
Aug 22, 2006·SAR and QSAR in Environmental Research·T W SchultzG D Veith
Aug 4, 2007·Chemical Research in Toxicology·T Wayne SchultzAynur O Aptula
Jan 15, 2008·Chemical Research in Toxicology·Grace PatlewiczE Uriarte
Dec 9, 2008·SAR and QSAR in Environmental Research·C M EllisonT W Schultz
Jan 8, 2009·Contact Dermatitis·Terry Wayne SchultzAynur Osman Aptula

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Citations

Apr 21, 2010·Archives of Environmental Contamination and Toxicology·D A DawsonT W Schultz
Apr 1, 2011·Archives of Environmental Contamination and Toxicology·D A DawsonG Pöch
Mar 11, 2011·SAR and QSAR in Environmental Research·F BajotT W Schultz
Apr 23, 2013·SAR and QSAR in Environmental Research·M P Payne, W G Button
Jul 26, 2011·Journal of Allergy·Itai ChipindaPaul D Siegel
Dec 26, 2013·Archives of Environmental Contamination and Toxicology·D A DawsonT W Schultz
Jun 15, 2014·Journal of Pharmacological and Toxicological Methods·Masaharu FujitaTakanori Hioki
May 3, 2011·Archives of Toxicology·Sarah AdlerJosé-Manuel Zaldivar
Aug 21, 2010·Critical Reviews in Toxicology·S J Enoch, M T D Cronin
Mar 6, 2012·Environmental Toxicology and Pharmacology·Tian ZhangPeng Liu
Mar 16, 2011·Chemical Reviews·Johannes A H SchwöbelMark T D Cronin
Jun 15, 2011·Environmental Science & Technology·Franziska SchrammGerrit Schüürmann
Oct 7, 2010·Chemical Research in Toxicology·Alexander BöhmeGerrit Schüürmann
Jan 15, 2014·Chemical Research in Toxicology·Malinee PromkatkaewM Paul Gleeson

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