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.

Factors affecting the formation of nitrogenous disinfection by-products during chlorination of aspartic acid in drinking water

“…However, the formation of hazardous disinfection by-products (DBPs), such as trihalomethanes, haloacetic acids, nitrosamines, cyanogen halides, haloacetonitriles (HANs), haloacetamides, halonitromethanes and so on, through reactions between precursor materials and chlorine has been reported (Ma et al, 2014;Muellner et al, 2007;Stalter et al, 2016;West et al, 2016).…”

Reducing disinfection byproduct formation potential using ozonation and biological drinking water treatment

“…That study also compared 26 carbon-based DBPs and 29 nitrogenous DBPs (N-DBPs) and found that N-DBPs are the most toxic among all DBPs investigated. These trends were also consistent with the recent study by Stalter et al (2016a) wherein a set of cell-based in vitro bioassays was used to assess molecular mechanisms of reactive toxicity of 50 different DBP species.…”

“…Although N-DBP concentrations are lower than C-DBPs, increasing concerns on N-DBP formation arise because of its higher toxicity compared to C-DBPs (Plewa et al 2008, Stalter et al 2016a). Halonitromethanes (HNMs), haloacetonitriles (HANs), and haloacetamides (HAMs) are among the most frequently detected N-DBPs in drinking water.…”

“…These bioassays were based on the specific modes of actions in presence of DBPs including various molecular events (e.g., interactions with DNA, proteins/peptides, and membrane lipids) initiating a series of effects like gene damage, disruption of redox balance, and enzyme inhibition (Stalter et al 2016a). These effects can then activate a multitude of subsequent adaptive stress responses such as oxidative stress response, p53-mediated response (DNA repair), and inflammation, among others (Stalter et al 2016a).…”

“…These effects can then activate a multitude of subsequent adaptive stress responses such as oxidative stress response, p53-mediated response (DNA repair), and inflammation, among others (Stalter et al 2016a). The results of these effect-driven bioassays suggest that the genotoxic effect of DBPs could occur indirectly through oxidative stress induction and/or enzyme inhibition than direct DNA damage.…”