Toward improved models for predicting bioconcentration of well‐metabolized compounds by rainbow trout using measured rates of in vitro intrinsic clearance

Nichols, John W.; Huggett, Duane B.; Arnot, Jon A.; Fitzsimmons, Patrick N.; Cowan-Ellsberry, Christina

doi:10.1002/etc.2219

Cited by 112 publications

(268 citation statements)

References 54 publications

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“…PBTK model development in ecotoxicology has thus far largely been focused on fish, e.g. (Nichols et al, 1990;Nichols and Fitzsimmons, 2004;Murphy et al, 2005Murphy et al, , 2009Watanabe et al, 2009;Li et al, 2011a;Stadnicka et al, 2012), with incorporation of biotransformation being an area of active research (Nichols et al, 2006(Nichols et al, , 2007(Nichols et al, , 2013Fay et al, 2014). The same concepts can certainly be applied to other organisms, such as invertebrates, e.g.…”

Section: Integration With Computational Modelsmentioning

confidence: 96%

Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology

et al. 2015

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To elucidate the effects of chemicals on populations of different species in the environment, efficient testing and modeling approaches are needed that consider multiple stressors and allow reliable extrapolation of responses across species. An adverse outcome pathway (AOP) is a concept that provides a framework for organizing knowledge about the progression of toxicity events across scales of biological organization that lead to adverse outcomes relevant for risk assessment. In this paper, we focus on exploring how the AOP concept can be used to guide research aimed at improving both our understanding of chronic toxicity, including delayed toxicity as well as epigenetic and transgenerational effects of chemicals, and our ability to predict adverse outcomes. A better understanding of the influence of subtle toxicity on individual and population fitness would support a broader integration of sublethal endpoints into risk assessment frameworks. Detailed mechanistic knowledge would facilitate the development of alternative testing methods as well as help prioritize higher tier toxicity testing. We argue that targeted development of AOPs supports both of these aspects by promoting the elucidation of molecular mechanisms and their contribution to relevant toxicity outcomes across biological scales. We further discuss information requirements and challenges in application of AOPs for chemical- and site-specific risk assessment and for extrapolation across species. We provide recommendations for potential extension of the AOP framework to incorporate information on exposure, toxicokinetics and situation-specific ecological contexts, and discuss common interfaces that can be employed to couple AOPs with computational modeling approaches and with evolutionary life history theory. The extended AOP framework can serve as a venue for integration of knowledge derived from various sources, including empirical data as well as molecular, quantitative and evolutionary-based models describing species responses to toxicants. This will allow a more efficient application of AOP knowledge for quantitative chemical- and site-specific risk assessment as well as for extrapolation across species in the future.

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Section: Integration With Computational Modelsmentioning

confidence: 96%

Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology

et al. 2015

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“…Moreover, as standardised methods to measure metabolic products and the kinetics of biotransformation currently do not exist, it is difficult to assess the influence of biotransformation in accumulation (Cowan-Ellsberry et al., 2008). Several authors have applied in vitro intrinsic clearance rates to extrapolate to whole body biotransformation rates for predictive BCF modelling (Arnot et al., 2008, Nichols et al., 2013). However, these extrapolations measure only the loss of parent compound to predict whole body biotransformation.…”

Section: Introductionmentioning

confidence: 99%

Uptake, biotransformation and elimination of selected pharmaceuticals in a freshwater invertebrate measured using liquid chromatography tandem mass spectrometry

et al. 2017

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Methods were developed to assess uptake and elimination kinetics in Gammarus pulex of nine pharmaceuticals (sulfamethazine, carbamazepine, diazepam, temazepam, trimethoprim, warfarin, metoprolol, nifedipine and propranolol) using targeted LC-MS/MS to determine bioconcentration factors (BCFs) using a 96 h toxicokinetic exposure and depuration period. The derived BCFs for these pharmaceuticals did not trigger any regulatory thresholds and ranged from 0 to 73 L kg−1 (sulfamethazine showed no bioconcentration). Metabolism of chemicals can affect accurate BCF determination through parameterisation of the kinetic models. The added selectivity of LC-MS/MS allowed us to develop confirmatory methods to monitor the biotransformation of propranolol, carbamazepine and diazepam in G. pulex. Varying concentrations of the biotransformed products; 4-hydroxypropranolol sulphate, carbamazepine-10,11-epoxide, nordiazepam, oxazepam and temazepam were measured following exposure of the precursor compounds. For diazepam, the biotransformation product nordiazepam was present at higher concentrations than the parent compound at 94 ng g−1 dw. Overall, the results indicate that pharmaceutical accumulation is low in these freshwater amphipods, which can potentially be explained by the rapid biotransformation and excretion.

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“…However, the lack of a priori consideration of biotransformation rates is a major limitation in current bioaccumulation assessments. The other approach is the application of experimental in vitro biotransformation tests [3][4][5][6][7][8]. Empirical BCFs and BAFs do not exist for the vast majority of commercial chemicals.…”

Section: Introductionmentioning

confidence: 99%

In vitro biotransformation rates in fish liver S9: Effect of dosing techniques

Lee

Delafoulhouze

et al. 2014

Enviro Toxic and Chemistry

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In vitro biotransformation assays are currently being explored to improve estimates of bioconcentration factors of potentially bioaccumulative organic chemicals in fish. The present study compares thin-film and solvent-delivery dosing techniques as well as single versus multiple chemical dosing for measuring biotransformation rates of selected polycyclic aromatic hydrocarbons in rainbow trout (Oncorhynchus mykiss) liver S9. The findings show that biotransformation rates of very hydrophobic substances can be accurately measured in thin-film sorbent-dosing assays from concentration-time profiles in the incubation medium but not from those in the sorbent phase because of low chemical film-to-incubation-medium mass-transfer rates at the incubation temperature of 13.5 °C required for trout liver assays. Biotransformation rates determined by thin-film dosing were greater than those determined by solvent-delivery dosing for chrysene (octanol-water partition coefficient [KOW ] =10(5.60) ) and benzo[a]pyrene (KOW =10(6.04) ), whereas there were no statistical differences in pyrene (KOW =10(5.18) ) biotransformation rates between the 2 methods. In sorbent delivery-based assays, simultaneous multiple-chemical dosing produced biotransformation rates that were not statistically different from those measured in single-chemical dosing experiments for pyrene and benzo[a]pyrene but not for chrysene. In solvent-delivery experiments, multiple-chemical dosing produced biotransformation rates that were much smaller than those in single-chemical dosing experiments for all test chemicals. While thin-film sorbent-phase and solvent delivery-based dosing methods are both suitable methods for measuring biotransformation rates of substances of intermediate hydrophobicity, thin-film sorbent-phase dosing may be more suitable for superhydrophobic chemicals.

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Toward improved models for predicting bioconcentration of well‐metabolized compounds by rainbow trout using measured rates of in vitro intrinsic clearance

Cited by 112 publications

References 54 publications

Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology

Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology

Uptake, biotransformation and elimination of selected pharmaceuticals in a freshwater invertebrate measured using liquid chromatography tandem mass spectrometry

In vitro biotransformation rates in fish liver S9: Effect of dosing techniques

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