Recommendations for Improving Methods and Models for Aquatic Hazard Assessment of Ionizable Organic Chemicals.

Thomas F Parkerton,Ruben Abagyan,Aaron D Redman,Christiane Zarfl,Nils Klüver,Beate I Escher,Michelle Embry

doi:10.1002/etc.4602

Abstract

Ionizable organic chemicals (IOCs) such as organic acids and bases are an important substance class requiring aquatic hazard evaluation. Although the aquatic toxicity of IOCs is highly dependent on the water pH, many toxicity studies in the literature cannot be interpreted because pH was not reported or not kept constant during the experiment, calling for an adaptation and improvement of testing guidelines. The modulating influence of pH on toxicity is mainly caused by pH-dependent uptake and bioaccumulation of IOCs, which can be described by ion-trapping and toxicokinetic models. The internal effect concentrations of IOCs were found to be independent of the external pH because of organisms' and cells' ability to maintain a stable internal pH milieu. If the external pH is close to the internal pH, existing quantitative structure-activity relationships (QSARs) for neutral organics can be adapted by substituting the octanol-water partition coefficient by the ionization-corrected liposome-water distribution ratio as the hydrophobicity descriptor, demonstrated by modification of the target lipid model. Charged, zwitterionic and neutral species of an IOC can all contribute to observed toxicity, either through concentration-additive mixture effects or by interaction of different species, as is the case for uncoupling of mitochondrial respiration. For specifically acting IOCs, we recommend a 2-step screening procedure with ion-trapping/QSAR models used to predict the baseline toxicity, followed by adjustment using the toxic ratio derived from in vitro systems. Receptor- or plasma-binding models also show promise for elucidating IOC toxicity. The present review is intended to help demystify the ecotoxicity of IOCs and provide recommendations for their hazard and risk assessment. Environ Toxicol Chem 2020;39:269-286. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Highlights

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record
Since both bioaccumulation and toxicity typically increase with increasing fraction of neutral species, we argue that the pH-dependence of toxicity is a result of the differences in bioaccumulation and toxicokinetics
Many of the approaches and principles developed for assessing neutral chemicals can be applied to Ionizable organic chemicals (IOCs) if the role of speciation is correctly included in toxicokinetic (TK) models

Summary

INTRODUCTION

The full ion-trapping model is delineated for acids by eq (Escher et al 2004a) and for bases by eq (Neuwoehner et al 2011) If the both species can be taken up but the uptake of the neutral species is faster than that of the charged species, we can apply the kinetic ion-trapping model (eq 24), which was based on earlier models for the uptake of ions into human cells (Trapp et al 2005) or bacteria (Zarfl et al 2008) and applied previously to predict internal lethal concentrations ILC50w in zebrafish embryos (Bittner et al 2019b) in relation to a given pair of external and internal pH (Table 4). The first step is to translate the Dplasma/w(pH) from humans to fish and the second step is to back-calculate from internal aqueous to external exposure concentrations using an inverse form of the simple ion-trapping models described above or more complex TK models (Nichols et al 2015)

CONCLUSION

Findings

Negatively