title: Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products.
abstract: A set of nine in vitro cellular bioassays indicative of different stages of the cellular toxicity pathway was applied to 50 disinfection by-products (DBPs) to obtain a better understanding of the commonalities and differences in the molecular mechanisms of reactive toxicity of DBPs. An Eschericia coli test battery revealed reactivity towards proteins/peptides for 64% of the compounds. 98% activated the NRf2-mediated oxidative stress response and 68% induced an adaptive stress response to genotoxic effects as indicated by the activation of the tumor suppressor protein p53. All DBPs reactive towards DNA in the E. coli assay and activating p53 also induced oxidative stress, confirming earlier studies that the latter could trigger DBP's carcinogenicity. The energy of the lowest unoccupied molecular orbital ELUMO as reactivity descriptor was linearly correlated with oxidative stress induction for trihalomethanes (r(2)=0.98) and haloacetamides (r(2)=0.58), indicating that potency of these DBPs is connected to electrophilicity. However, the descriptive power was poor for haloacetic acids (HAAs) and haloacetonitriles (r(2) (<) 0.06). For HAAs, we additionally accounted for speciation by including the acidity constant with ELUMO in a two-parameter multiple linear regression model. This increased r(2) to >0.80, indicating that HAAs' potency is connected to both, electrophilicity and speciation. Based on the activation of oxidative stress response and the soft electrophilic character of most tested DBPs we hypothesize that indirect genotoxicity-e.g., through oxidative stress induction and/or enzyme inhibition-is more plausible than direct DNA damage for most investigated DBPs. The results provide not only a mechanistic understanding of the cellular effects of DBPs but the effect concentrations may also serve to evaluate mixture effects of DBPs in water samples.
authors.affiliation: National Research Centre for Environmental Toxicology, Entox, The University of Queensland, Brisbane, Australia; Eawag, Swiss Federal Institute of Aquatic Science and Technology, Duebendorf, Switzerland. Electronic address: daniel.stalter@eawag.ch.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stalter
authors.affiliation: National Research Centre for Environmental Toxicology, Entox, The University of Queensland, Brisbane, Australia.
authors.forename: Elissa
authors.initials: E
authors.lastname: O'Malley
authors.affiliation: Eawag, Swiss Federal Institute of Aquatic Science and Technology, Duebendorf, Switzerland; School of Architecture, Civil and Environmental Engineering (ENAC), Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: von Gunten
authors.affiliation: National Research Centre for Environmental Toxicology, Entox, The University of Queensland, Brisbane, Australia; Department of Cell Toxicology, UFZ - Helmholtz Centre for Environmental Research, Leipzig, Germany; Department of Environmental Toxicology, Center for Applied Geosciences, Eberhard Karls University, Tübingen, Germany.
authors.forename: Beate I
authors.initials: BI
authors.lastname: Escher
mesh_terms: D004202:Disinfectants / Q000633:toxicity*; D004203:Disinfection; D060766:Drinking Water; D004926:Escherichia coli / Q000187:drug effects*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D004202:Disinfectants; D060766:Drinking Water; D014874:Water Pollutants, Chemical
keywords: Disinfection byproduct; Electrophilicity; Mutagenicity; Oxidative stress; QSAR; p53 activation