LogD-based modelling and ΔlogD as a proxy for pH-dependent action of ionizable chemicals reveal the relevance of both neutral and ionic species for fish embryotoxicity and possess great potential for practical application in the regulation of chemicals

Köhler, Heinz‐R.; Gräff, Thomas; Schweizer, Mona; Blumhardt, Jasmin; Burkhardt, Jasmin; Ehmann, Lisa; Hebel, Janine; Heid, Christoph; Kundy, Lone; Kuttler, Julia; Malusova, Miroslava; Moroff, Friederike-Marie; Schlösinger, Anne-Frida; Schulze-Berge, Pia; Panagopoulou, Evridiki; Damalas, Dimitrios Ε.; Thomaidis, Nikolaos S.; Triebskorn, Rita; Maletzki, Dirk; Kühnen, Ute; Ohe, Peter C. von der

doi:10.1016/j.watres.2023.119864

Cited by 9 publications

(7 citation statements)

References 38 publications

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“…Given the wide range of pH in natural water bodies, the fate and toxicity of ionizable chemicals vary significantly in fish, which can be denoted by the combined partition coefficient D ow . However, relatively large amounts of chemical requirement and low capacity of D ow measurement limited data availability in fish TK . A regression model which describes D ow as the best predictor of monovalent acids and bases at neutral pH and combines contribution of both neutral and ionic molecules was adopted in the fish PBTK models .…”

Section: Resultsmentioning

confidence: 99%

“…40 However, relatively large amounts of chemical requirement and low capacity of D ow measurement limited data availability in fish TK. 41 A regression model which describes D ow as the best predictor of monovalent acids and bases at neutral pH and combines contribution of both neutral and ionic molecules was adopted in the fish PBTK models. 42 The log D depends largely on the speciation, i.e., on the valency and pK a of a chemical and the external pH.…”

Section: Impacts Of External Ph For Ionizable Chemicalsmentioning

confidence: 99%

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Fish Physiologically Based Toxicokinetic Modeling Approach for In Vitro–In Vivo and Cross-Species Extrapolation of Endocrine-Disrupting Chemicals in Risk Assessment

Xie,

Xu,

et al. 2024

Environ. Sci. Technol.

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High-throughput in vitro assays combined with in vitro−in vivo extrapolation (IVIVE) leverage in vitro responses to predict the corresponding in vivo exposures and thresholds of concern. The integrated approach is also expected to offer the potential for efficient tools to provide estimates of chemical toxicity to various wildlife species instead of animal testing. However, developing fish physiologically based toxicokinetic (PBTK) models for IVIVE in ecological applications is challenging, especially for plausible estimation of an internal effective dose, such as fish equivalent concentration (FEC). Here, a fish PBTK model linked with the IVIVE approach was established, with parameter optimization of chemical unbound fraction, pH-dependent ionization and hepatic clearance, and integration of temperature effect and growth dilution. The fish PBTK−IVIVE approach provides not only a more precise estimation of tissue-specific concentrations but also a reasonable approximation of FEC targeting the estrogenic potency of endocrine-disrupting chemicals. Both predictions were compared with in vivo data and were accurate for most indissociable/dissociable chemicals. Furthermore, the model can help determine cross-species variability and sensitivity among the five fish species. Using the available IVIVE-derived FEC with target pathways is helpful to develop predicted no-effect concentration for chemicals with similar mode of action and support screening-level ecological risk assessment.

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Section: Resultsmentioning

confidence: 99%

Section: Impacts Of External Ph For Ionizable Chemicalsmentioning

confidence: 99%

Fish Physiologically Based Toxicokinetic Modeling Approach for In Vitro–In Vivo and Cross-Species Extrapolation of Endocrine-Disrupting Chemicals in Risk Assessment

Xie,

Xu,

et al. 2024

Environ. Sci. Technol.

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“…For modelling the pH-dependent action of ionisable chemicals, such as many pharmaceuticals, the relevance of log KOW-based distribution of both the neutral and the charged species (log D) has been shown [11]. Regarding acute toxicities, KOW outperformed Klipid/water as a descriptor for membrane passage.…”

Section: Difficult Substances: Pfas Siloxanes and Surfactantsmentioning

confidence: 99%

“…By definition, KOW implies that the solute under consideration has identical speciation in both the water and octanol phases, generally its neutral form. Processes such as dissociation, protonation, tautomerism and complex formation in at least one of the two phases (often in water) lead to more complex distribution phenomena [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Consolidated octanol/water partition coefficients: Combining multiple estimates from different methods to reduce uncertainties in log KOW

Nendza,

Kosfeld,

Schlechtriem

2024

Preprint

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Background: The octanol/water partition coefficient (KOW) is a key parameter for assessing the fate and effects of chemicals. It is a metric of their hydrophobicity, related to uptake and accumulation in organisms and specific tissues, and distribution in water, soil and sediments. The log KOW can be determined experimentally, more often it is calculated. Variability may be due to properties of the substances, different experimental methods, or different computational approaches with different domains of applicability. The objective of the present study is to derive coherent log KOW estimates with known variability by (1) estimating multiple log KOW values by different methods for diverse chemicals to exemplify their variabilities, (2) analysing the variabilities of log KOW estimates by underlying methods and for different chemical classes, and (3) recommending approaches to obtain reliable and robust log KOW estimates for hazard and risk assessment. Results: Comparative analyses were based on 239 case study chemicals representing diverse chemical classes, such as POPs, PCB, PAH, siloxanes, flame retardants, PFAS, pesticides, pharmaceuticals, surfactants, etc. The variability of up to 35 log KOW values per substance, determined experimentally or estimated by different computational approaches, is 1 log unit and more across the entire log KOW range from < 0 to > 8. No systematic pattern is evident. Different methods for deriving log KOW perform sometimes better and sometimes worse for different chemicals. None of the methods (experimental or computational) is consistently superior and any method can be the worst. Conclusions: For scientifically valid and reproducible log KOW estimates with known variability, we recommend a weight-of-evidence (WoE) or averaging approach combining multiple estimates. Consolidated log KOW, being the mean of at least 5 valid data obtained by different independent methods (experimental and computational), are a pragmatic way to deal with the variability and uncertainty of individual results. While this approach does not solve any of the problems about “correctly” determining log KOW, it does limit the bias due to individual erroneous estimates. Consolidated log KOW are robust and reliable measures of hydrophobicity, with variability mostly below 0.2 log units.

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“…To realistically predict occupational and environmental exposures, in silico methods to estimate and/or quantify the skin absorption of chemicals have been reported using multi-linear regression analysis to describe skin permeability in terms of logP and molecular weight (Evans et al, 2023). In a zebrafish toxicity screening model in vivo, the toxicity of chemicals was correlated with their hydrophobicity (i.e., logP) (Padilla et al, 2012), probably because neutral species of potentially toxic chemicals have been almost certainly taken up into cells according to their pHdependent distribution coefficient (logD)-based membrane permeabilities (Köhler et al, 2023). Reevaluating logP values, which constitute a crucial input parameter for PBPK models, may further enhance the accuracy of predictions for both toxicity and pharmacokinetics (Adachi et al, 2023a;Adachi et al, 2023b;Li and Jusko, 2022;Shebley et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Octanol/water partition coefficients estimated using retention times in reverse-phase liquid chromatography and calculated <i>in silico</i> as one of the determinant factors for pharmacokinetic parameter estimations of general chemical substances

Adachi,

Shimizu,

Shono

et al. 2024

J. Toxicol. Sci.

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The octanol/water partition coefficient P (logP) is a hydrophobicity index and is one of the determining factors for the pharmacokinetics of orally administered substances because it influences membrane permeability. To illustrate the wide-ranging variety of compounds in the chemical space, a two-dimensional data plot consisting of 25 blocks was previously proposed based on a substance's in silico chemical descriptors. The logP values of approximately 200 diverse chemicals (test plus reference compounds covering all 25 blocks of the chemical space) were estimated experimentally using retention times in reverse-phase liquid chromatography; these values were compared with those of authentic reference compounds with established logP values (available for 17 of 60 reference substances in the Organization for Economic Co-operation and Development Test Guideline 117). The logP values of 140 of 165 chemicals successfully estimated using four different mobile phase conditions (pH 2, 4, 7, and 10 for molecular forms) correlated significantly with those calculated using the in silico packages ChemDraw and ACD/Percepta (r > 0.72). Although substances that neighbored authentic compounds in the chemical space had precisely correlated logP values estimated experimentally and in silico, some compounds that were more distant from authentic substances showed lower logP values than those estimated in silico. These results indicate that additional authentic reference materials with wider ranging chemical diversity and their logP values from reverse-phase liquid chromatography should be included in the international test guidance to promote simple and reliable estimation of octanol/water partition coefficients, which are important determinant factors for the pharmacokinetics of general chemicals.

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LogD-based modelling and ΔlogD as a proxy for pH-dependent action of ionizable chemicals reveal the relevance of both neutral and ionic species for fish embryotoxicity and possess great potential for practical application in the regulation of chemicals

Cited by 9 publications

References 38 publications

Fish Physiologically Based Toxicokinetic Modeling Approach for In Vitro–In Vivo and Cross-Species Extrapolation of Endocrine-Disrupting Chemicals in Risk Assessment

Fish Physiologically Based Toxicokinetic Modeling Approach for In Vitro–In Vivo and Cross-Species Extrapolation of Endocrine-Disrupting Chemicals in Risk Assessment

Consolidated octanol/water partition coefficients: Combining multiple estimates from different methods to reduce uncertainties in log KOW

Octanol/water partition coefficients estimated using retention times in reverse-phase liquid chromatography and calculated <i>in silico</i> as one of the determinant factors for pharmacokinetic parameter estimations of general chemical substances

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