Environmental risk assessment is essential but often relies on ethically controversial and expensive methods. One of the biggest current challenges in ecotoxicology is to replace animal testing with in vitro methods, for example based on cell cultures. However, evaluating whether a cell line is a suitable replacement involves testing many substances in animals and cell cultures in biologically similar conditions, i.e. the same amount of the chemical needs to be available to the cells in the culture and in animal tissues to expect the effect to be comparable. We develop physiologically based toxicokinetic (PBTK) models in fish and toxicokinetic models in cell cultures to computationally determine the chemical concentrations needed for a comparable test. Our PBTK models include physiological uptake of the chemical via breathing or food, stratification of the chemicals into vital organs and metabolization of the chemical therein. We have recently shown that, for some chemicals, exposure tests performed on the rainbow trout RTgill-W1 cell line and combined with the modeling approach can replace growth tests with juvenile fish.
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title => protected'In vitro-in vivo extrapolation to predict bioaccumulation and toxicity of ch emicals in fish using physiologically based toxicokinetic models' (140 chars)
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categories => protected'PBTK model; fish growth; lethality; integrated testing design; predictive mo deling; chemical risk assessment; fish cell lines; toxicokinetics and toxico dynamics' (160 chars)
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title => protected'Biotransformation of benzo [<i>a</i>] pyrene by three rainbow trout (<i>Onch orhynchus mykiss</i>) cell lines and extrapolation to derive a fish bioconce ntration factor' (167 chars)
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description => protected'Permanent fish cell lines constitute a promising complement or substitute fo r fish in the environmental risk assessment of chemicals. We demonstrate the potential of a set of cell lines originating from rainbow trout (<i>Oncorhy nchus mykiss</i>) to aid in the prediction of chemical bioaccumulation in fi sh, using benzo[<i>a</i>]pyrene (BaP) as a model chemical. We selected three cell lines from different tissues to more fully account for whole-body biot ransformation in vivo: the RTL-W1 cell line, representing the liver as major site of biotransformation, and the RTgill-W1 (gill) and RTgutGC (intestine) cell lines, as important environment-organism interfaces, which likely infl uence chemical uptake. All three cell lines were found to effectively biotra nsform BaP. However, rates of in vitro clearance differed, with the RTL-W1 c ell line being most efficient, followed by RTgutGC. Co-exposures with α-nap hthoflavone as potent inhibitor of biotransformation, assessment of CYP1A ca talytic activity, and the progression of cellular toxicity upon prolonged Ba P exposure revealed that BaP is handled differently in the RTgill-W1 compare d to the other two cell lines. Application of the cell-line-derived in vitro clearance rates into a physiology-based toxicokinetic model predicted a BaP bioconcentration factor (BCF) of 909-1057 compared to 920 reported for rain bow trout in vivo.' (1386 chars)
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authors => protected'Stadnicka-Michalak, J.; Schirmer, K.; Ashauer, R.' (64 chars)
title => protected'Toxicology across scales: cell population growth in vitro predicts reduced f ish growth' (86 chars)
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description => protected'Environmental risk assessment of chemicals is essential but often relies on ethically controversial and expensive methods. We show that tests using cell cultures, combined with modeling of toxicological effects, can replace test s with juvenile fish. Hundreds of thousands of fish at this developmental st age are annually used to assess the influence of chemicals on growth. Juveni les are more sensitive than adult fish, and their growth can affect their ch ances to survive and reproduce. Thus, to reduce the number of fish used for such tests, we propose a method that can quantitatively predict chemical imp act on fish growth based on in vitro data. Our model predicts reduced fish g rowth in two fish species in excellent agreement with measured in vivo data of two pesticides. This promising step toward alternatives to fish toxicity testing is simple, inexpensive, and fast and only requires in vitro data for model calibration.' (931 chars)
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description => protected'Effect concentrations in the toxicity assessment of chemicals with fish and fish cells are generally based on external exposure concentrations. External concentrations as dose metrics, may, however, hamper interpretation and ext rapolation of toxicological effects because it is the internal concentration that gives rise to the biological effective dose. Thus, we need to understa nd the relationship between the external and internal concentrations of chem icals. The objectives of this study were to: (i) elucidate the time-course o f the concentration of chemicals with a wide range of physicochemical proper ties in the compartments of an <I>in vitro</I> test system, (ii) derive a pr edictive model for toxicokinetics in the <I>in vitro</I> test system, (iii) test the hypothesis that internal effect concentrations in fish (<I>in vivo< /I>) and fish cell lines (<I>in vitro</I>) correlate, and (iv) develop a qua ntitative <I>in vitro</I> to <I>in vivo</I> toxicity extrapolation method fo r fish acute toxicity. To achieve these goals, time-dependent amounts of org anic chemicals were measured in medium, cells (RTgill-W1) and the plastic of exposure wells. Then, the relation between uptake, elimination rate constan ts, and log K<SUB>OW</SUB> was investigated for cells in order to develop a toxicokinetic model. This model was used to predict internal effect concentr ations in cells, which were compared with internal effect concentrations in fish gills predicted by a Physiologically Based Toxicokinetic model. Our mod el could predict concentrations of non-volatile organic chemicals with log K <SUB>OW</SUB> between 0.5 and 7 in cells. The correlation of the log ratio o f internal effect concentrations in fish gills and the fish gill cell line w ith the log K<SUB>OW</SUB> was significant (r>0.85, p = 0.0008, F-test). Thi s ratio can be predicted from the log K<SUB>OW</SUB> of the chemical (77% of variance explained), comprising a promising model to predict lethal effects on fish based on <I>in ...' (2015 chars)
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description => protected'Quantification of chemical toxicity continues to be generally based on measu red external concentrations. Yet, internal chemical concentrations have been suggested to be a more suitable parameter. To better understand the relatio nship between the external and internal concentrations of chemicals in fish, and to quantify internal concentrations, we compared three toxicokinetic (T K) models with each other and with literature data of measured concentration s of 39 chemicals. Two one-compartment models, together with the physiologic ally based toxicokinetic (PBTK) model, in which we improved the treatment of lipids, were used to predict concentrations of organic chemicals in two fis h species: rainbow trout (<em>Oncorhynchus mykiss</em>) and fathead minnow ( <em>Pimephales promelas</em>). All models predicted the measured internal co ncentrations in fish within 1 order of magnitude for at least 68% of the che micals. Furthermore, the PBTK model outperformed the one-compartment models with respect to simulating chemical concentrations in the whole body (at lea st 88% of internal concentrations were predicted within 1 order of magnitude using the PBTK model). All the models can be used to predict concentrations in different fish species without additional experiments. However, further development of TK models is required for polar, ionizable, and easily biotra nsformed compounds.' (1387 chars)
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In vitro-in vivo extrapolation to predict bioaccumulation and toxicity of chemicals in fish using physiologically based toxicokinetic models
Out of the >107 million chemicals already registered with the Chemical Abstracts Services, less than 0.5% are being regulated, and even fewer are evaluated for their safety. Consequently, a new paradigm in risk assessment is urgently needed. It should encompass faster and less costly methods and reduce the number of animals needed for testing. One proposal is to combine computational modeling with small-scale bioassay methods. This chapter describes the methods that link in vitro bioassays using fish cells with physiologically based toxicokinetic (PBTK) modeling in order to predict the acute toxicity, bioaccumulation, and impact of chemicals on fish growth. The main focus is on PBTK modeling; thus all the model equations and parameters available for eight fish species as well as suggestions for possible software implementation will be provided. The PBTK model described here can account for respiratory and dietary uptake routes and for chemical biotransformation processes.
Stadnicka-Michalak, J.; Schirmer, K. (2022) In vitro-in vivo extrapolation to predict bioaccumulation and toxicity of chemicals in fish using physiologically based toxicokinetic models, In: Seiler, T.-B.; Brinkmann, M. (Eds.), In situ bioavailability and toxicity of organic chemicals in aquatic systems, 229-258, doi:10.1007/7653_2019_34, Institutional Repository
Biotransformation of benzo [a] pyrene by three rainbow trout (Onchorhynchus mykiss) cell lines and extrapolation to derive a fish bioconcentration factor
Permanent fish cell lines constitute a promising complement or substitute for fish in the environmental risk assessment of chemicals. We demonstrate the potential of a set of cell lines originating from rainbow trout (Oncorhynchus mykiss) to aid in the prediction of chemical bioaccumulation in fish, using benzo[a]pyrene (BaP) as a model chemical. We selected three cell lines from different tissues to more fully account for whole-body biotransformation in vivo: the RTL-W1 cell line, representing the liver as major site of biotransformation, and the RTgill-W1 (gill) and RTgutGC (intestine) cell lines, as important environment-organism interfaces, which likely influence chemical uptake. All three cell lines were found to effectively biotransform BaP. However, rates of in vitro clearance differed, with the RTL-W1 cell line being most efficient, followed by RTgutGC. Co-exposures with α-naphthoflavone as potent inhibitor of biotransformation, assessment of CYP1A catalytic activity, and the progression of cellular toxicity upon prolonged BaP exposure revealed that BaP is handled differently in the RTgill-W1 compared to the other two cell lines. Application of the cell-line-derived in vitro clearance rates into a physiology-based toxicokinetic model predicted a BaP bioconcentration factor (BCF) of 909-1057 compared to 920 reported for rainbow trout in vivo.
Stadnicka-Michalak, J.; Weiss, F. T.; Fischer, M.; Tanneberger, K.; Schirmer, K. (2018) Biotransformation of benzo [a] pyrene by three rainbow trout (Onchorhynchus mykiss) cell lines and extrapolation to derive a fish bioconcentration factor, Environmental Science and Technology, 52(5), 3091-3100, doi:10.1021/acs.est.7b04548, Institutional Repository
Toxicology across scales: cell population growth in vitro predicts reduced fish growth
Environmental risk assessment of chemicals is essential but often relies on ethically controversial and expensive methods. We show that tests using cell cultures, combined with modeling of toxicological effects, can replace tests with juvenile fish. Hundreds of thousands of fish at this developmental stage are annually used to assess the influence of chemicals on growth. Juveniles are more sensitive than adult fish, and their growth can affect their chances to survive and reproduce. Thus, to reduce the number of fish used for such tests, we propose a method that can quantitatively predict chemical impact on fish growth based on in vitro data. Our model predicts reduced fish growth in two fish species in excellent agreement with measured in vivo data of two pesticides. This promising step toward alternatives to fish toxicity testing is simple, inexpensive, and fast and only requires in vitro data for model calibration.
Stadnicka-Michalak, J.; Schirmer, K.; Ashauer, R. (2015) Toxicology across scales: cell population growth in vitro predicts reduced fish growth, Science Advances, 1(7), 1-8, doi:10.1126/sciadv.1500302, Institutional Repository
Measured and modeled toxicokinetics in cultured fish cells and application to in vitro - in vivo toxicity extrapolation
Effect concentrations in the toxicity assessment of chemicals with fish and fish cells are generally based on external exposure concentrations. External concentrations as dose metrics, may, however, hamper interpretation and extrapolation of toxicological effects because it is the internal concentration that gives rise to the biological effective dose. Thus, we need to understand the relationship between the external and internal concentrations of chemicals. The objectives of this study were to: (i) elucidate the time-course of the concentration of chemicals with a wide range of physicochemical properties in the compartments of an in vitro test system, (ii) derive a predictive model for toxicokinetics in the in vitro test system, (iii) test the hypothesis that internal effect concentrations in fish (in vivo) and fish cell lines (in vitro) correlate, and (iv) develop a quantitative in vitro to in vivo toxicity extrapolation method for fish acute toxicity. To achieve these goals, time-dependent amounts of organic chemicals were measured in medium, cells (RTgill-W1) and the plastic of exposure wells. Then, the relation between uptake, elimination rate constants, and log KOW was investigated for cells in order to develop a toxicokinetic model. This model was used to predict internal effect concentrations in cells, which were compared with internal effect concentrations in fish gills predicted by a Physiologically Based Toxicokinetic model. Our model could predict concentrations of non-volatile organic chemicals with log KOW between 0.5 and 7 in cells. The correlation of the log ratio of internal effect concentrations in fish gills and the fish gill cell line with the log KOW was significant (r>0.85, p = 0.0008, F-test). This ratio can be predicted from the log KOW of the chemical (77% of variance explained), comprising a promising model to predict lethal effects on fish based on in vitro data.
Stadnicka-Michalak, J.; Tanneberger, K.; Schirmer, K.; Ashauer, R. (2014) Measured and modeled toxicokinetics in cultured fish cells and application to in vitro - in vivo toxicity extrapolation, PLoS One, 9(3), e92303 (10 pp.), doi:10.1371/journal.pone.0092303, Institutional Repository
Predicting concentrations of organic chemicals in fish by using toxicokinetic models
Quantification of chemical toxicity continues to be generally based on measured external concentrations. Yet, internal chemical concentrations have been suggested to be a more suitable parameter. To better understand the relationship between the external and internal concentrations of chemicals in fish, and to quantify internal concentrations, we compared three toxicokinetic (TK) models with each other and with literature data of measured concentrations of 39 chemicals. Two one-compartment models, together with the physiologically based toxicokinetic (PBTK) model, in which we improved the treatment of lipids, were used to predict concentrations of organic chemicals in two fish species: rainbow trout (Oncorhynchus mykiss) and fathead minnow (Pimephales promelas). All models predicted the measured internal concentrations in fish within 1 order of magnitude for at least 68% of the chemicals. Furthermore, the PBTK model outperformed the one-compartment models with respect to simulating chemical concentrations in the whole body (at least 88% of internal concentrations were predicted within 1 order of magnitude using the PBTK model). All the models can be used to predict concentrations in different fish species without additional experiments. However, further development of TK models is required for polar, ionizable, and easily biotransformed compounds.
Stadnicka, J.; Schirmer, K.; Ashauer, R. (2012) Predicting concentrations of organic chemicals in fish by using toxicokinetic models, Environmental Science and Technology, 46(6), 3273-3280, doi:10.1021/es2043728, Institutional Repository
