Effect‐Based Trigger Values for Mixtures of Chemicals in Surface Water Detected with In Vitro Bioassays

Abstract

Effect-based trigger (EBT) values for in vitro bioassays are important for surface water quality monitoring because they define the threshold between acceptable and poor water quality. EBTs have been derived for highly specific This article is protected by copyright. All rights reserved. Accepted Article bioassays, such as hormone-receptor activation in reporter gene bioassays, by reading across from existing chemical guideline values. This read-across method is not easily applicable to bioassays indicative of adaptive stress responses, which are triggered by many different chemicals, and activation of nuclear receptors for xenobiotic metabolism, to which many chemicals bind with rather low specificity. We propose an alternative approach to define the EBT from the distribution of specificity ratios of all active chemicals. Specificity ratios are the ratio between the predicted baseline toxicity of a chemical in a given bioassay and its measured specific endpoint. Unlike many previous read-across methods to derive EBTs, the proposed method accounts for mixture effects and includes all chemicals, not only high-potency chemicals. The EBTs were derived from a cytotoxicity EBT that was defined as equivalent to 1% of cytotoxicity in a native surface water sample. The cytotoxicity EBT was scaled by the median of the log-normal distribution of specificity ratios to derive the EBT for effects specific for each bioassay. We illustrate the new approach using the example of the AREc32 assay indicative of the oxidative stress response and two nuclear receptor assays targeting the peroxisome proliferator activated receptor PPAR and the arylhydrocarbon receptor AhR. The EBTs were less conservative than previously proposed but were able to differentiate untreated and insufficiently treated wastewater from wastewater treatment plant effluent with secondary or tertiary treatment and surface water.

Bioanalytical Tools in Water Quality Assessment

“…SR baseline is a quantitative measure of how much more potent the activation of a specific response is in comparison with the baseline cytotoxicity of the same compound (Figure 13.8a). Baseline toxicants have an SR baseline of 1 and the data are logarithmically distributed around log SR baseline of 0 (Escher and Neale, 2021). Chemicals activating category 1 bioassays have high log SR baseline values, often in the range of 4-8, while category 2 chemicals have log SR baseline with medium values and often very broad distributions (Figure 13.8b).…”

“…Recognising the subjectivity associated with an MF correction based mainly on expert knowledge, Escher and Neale (2021) recently proposed a method to derive the EBT for category 2 assays from experimental data specific for each bioassay (approach 6 in Figure 13.12), starting with the constant critical membrane concentration for baseline toxicity (minimum toxicity caused by narcosis, see Chapter 4) common to all cells (Escher et al, 2019). By definition, mixtures of baseline toxicants will have very similar cytotoxicity IC 10 irrespective of the cell line used.…”

“…For specific endpoints, the generic EBT-IC 10 of REF 10 was then divided by the median of the distributions of the specificity ratios log SR baseline of the given bioassay (Escher and Neale, 2021). The resulting effect concentration can then be translated to an EBT-BEQ for mixtures in category 2 bioassays by applying the bioassays-specific EC 10 of the associated reference compound (Figure 13.13).…”

AI for predicting chemical-effect associations at the chemical universe level – deepFPlearn

“…Recently, Escher et al [39, 40] classified the association between selected compounds in six of the high through-put Tox21 assays, including AR and ER. The aim has been to evaluate whether the observed effect was likely due to specific action via the mode of action (MoA) under consideration or rather due to unspecific consequences of cytotoxicity.…”

Critical Membrane Concentration and Mass-Balance Model to Identify Baseline Cytotoxicity of Hydrophobic and Ionizable Organic Chemicals in Mammalian Cell Lines

“…The concentration causing 10% cytotoxicity (IC 10 , eq ) was derived from the slope of the linear portion of the concentration response curve (eq ), which was typically linear up to a 30 to 40% effect The majority of IC 10 values listed in Table S2 was already published earlier, ,− but to expand the MBM also to more hydrophobic chemicals, we measured 75 additional hydrophobic neutral chemicals in AREc32, AhR-CALUX, and PPARγ-BLA; the resulting IC 10 values are given in Table S4. For SH-SY5Y, cytotoxicity was determined within this study and the resulting IC 10 values are listed in Table S2.…”