Comparison of a simple and a complex model for BCF prediction using in vitro biotransformation data

Krause, Sophia; Goss, Kai‐Uwe

doi:10.1016/j.chemosphere.2020.127048

Cited by 15 publications

(19 citation statements)

References 19 publications

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“…A total of 225 freshwater fish species that are members of 32 families have been described in Canada. 10 The families with the highest number of species (in parentheses) within this list are Cyprinidae (57), Salmonidae (37), Catostomidae (18), Percidae (16), Centrarchidae (13), Petromyzontidae (11), Ictaluridae (10), and Cottidae (10). The final physiological database contains 2815 parameter values from 69 different fish species (31% of total) representing 23 families (72% of total).…”

Section: Resultsmentioning

confidence: 99%

“…These predictive methods can be applied to explain differences in the chemical concentration time-course at the target site (also referred to as toxicokinetics) or differences in the interaction of a chemical with molecular structures of the organism (also referred to as toxicodynamics). , Toxicokinetics and dynamics are mutually dependent, and a detailed understanding of chemical concentration at the target site is often considered a prerequisite to quantitatively study toxicodynamics. Thus, various toxicokinetic models, including physiologically based toxicokinetic (PBTK) models, have received much attention in recent years. − By predicting toxicokinetic processes mechanistically over time and specific to various tissues and organs, PBTK models facilitate extrapolation between levels of biological organization, exposure conditions, and among species . The first PBTK models for fish were used to predict the uptake and accumulation of neutral organic chemicals in rainbow trout (Oncorhynchus mykiss). , Several other single-species PBTK models were since developed, encompassing species such as channel catfish (Ictalurus punctatus), lake trout (Salvelinus namaycush), fathead minnow (Pimephales promelas), roach (Rutilus rutilus), European eel (Anguilla anguilla), and zebrafish (Danio rerio). , All these previous models require full sets of model parameters to describe the specific physiology of individual species.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Multispecies Toxicokinetic Modeling Approach in Support of Chemical Risk Assessment

Mangold-Döring

Grimard

Green

et al. 2021

Environ. Sci. Technol.

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Standardized laboratory tests with a limited number of model species are a key component of chemical risk assessments. These surrogate species cannot represent the entire diversity of native species, but there are practical and ethical objections against testing chemicals in a large variety of species. In previous research, we have developed a multispecies toxicokinetic model to extrapolate chemical bioconcentration across species by combining single-species physiologically based toxicokinetic (PBTK) models. This "top-down" approach was limited, however, by the availability of fully parameterized single-species models. Here, we present a "bottom-up" multispecies PBTK model based on available data from 69 freshwater fishes found in Canada. Monte Carlo-like simulations were performed using statistical distributions of model parameters derived from these data to predict steady-state bioconcentration factors (BCFs) for a set of wellstudied chemicals. The distributions of predicted BCFs for 1,4-dichlorobenzene and dichlorodiphenyltrichloroethane largely overlapped those of empirical data, although a tendency existed toward overestimation of measured values. When expressed as means, predicted BCFs for 26 of 34 chemicals (82%) deviated by less than 10-fold from measured data, indicating an accuracy similar to that of previously published single-species models. This new model potentially enables more environmentally relevant predictions of bioconcentration in support of chemical risk assessments.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Multispecies Toxicokinetic Modeling Approach in Support of Chemical Risk Assessment

Mangold-Döring

Grimard

Green

et al. 2021

Environ. Sci. Technol.

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“…Both one-(assuming whole organism as a single well-mixed compartment) and multicompartment (e.g., the PBK model) can predict wholebody chemical concentrations and thus BCFs. Previous studies 29,43,75,76 have indicated that the accuracy of simple one-compartment models appeared to be comparable or only marginally lower compared to that of complex PBK models. However, PBK models are essential to estimate time-course chemical concentrations in potentially targeted tissues, especially relevant to pharmaceuticals acting on specific tissues.…”

Section: Discussionmentioning

confidence: 97%

A Generalized Physiologically Based Kinetic Model for Fish for Environmental Risk Assessment of Pharmaceuticals

Wang

Nolte

Owen

et al. 2022

Environ. Sci. Technol.

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An increasing number of pharmaceuticals found in the environment potentially impose adverse effects on organisms such as fish. Physiologically based kinetic (PBK) models are essential risk assessment tools, allowing a mechanistic approach to understanding chemical effects within organisms. However, fish PBK models have been restricted to a few species, limiting the overall applicability given the countless species. Moreover, many pharmaceuticals are ionizable, and fish PBK models accounting for ionization are rare. Here, we developed a generalized PBK model, estimating required parameters as functions of fish and chemical properties. We assessed the model performance for five pharmaceuticals (covering neutral and ionic structures). With biotransformation half-lives (HLs) from EPI Suite, 73 and 41% of the time-course estimations were within a 10-fold and a 3-fold difference from measurements, respectively. The performance improved using experimental biotransformation HLs (87 and 59%, respectively). Estimations for ionizable substances were more accurate than any of the existing species-specific PBK models. The present study is the first to develop a generalized fish PBK model focusing on mechanism-based parameterization and explicitly accounting for ionization. Our generalized model facilitates its application across chemicals and species, improving efficiency for environmental risk assessment and supporting an animal-free toxicity testing paradigm.

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“…These ratios were then combined with composition information for each phase to estimate K S9W , K BW , and K FW (Equations 12−14 in Table 1). The ppLFER approach for partition ratio estimation is employed in the IVIVE model given by Krause and Goss (2020).…”

Section: Methodsmentioning

confidence: 99%

Models Used to Predict Chemical Bioaccumulation in Fish from in Vitro Biotransformation Rates Require Accurate Estimates of Blood–Water Partitioning and Chemical Volume of Distribution

Saunders

Nichols

2022

Enviro Toxic and Chemistry

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Methods for extrapolating measured in vitro intrinsic clearance to a whole-body biotransformation rate constant (k B ) have been developed to support modeled bioaccumulation assessments for fish. The inclusion of extrapolated k B values into existing bioaccumulation models improves the prediction of chemical bioconcentration factors (BCFs), but there remains a tendency for these methods to overestimate BCFs relative to measured values. Therefore, a need exists to evaluate the extrapolation procedure to assess potential sources of error in predicted k B values. We examined how three different approaches (empirically based, composition based, and polyparameter linear free energy relationships [ppLFERs]) used to predict chemical partitioning in vitro (liver S9 system; K S9W ), in blood (K BW ), and in whole fish tissues (K FW ) impact the prediction of a chemical's hepatic clearance binding term (f U ) and apparent volume of distribution (V D ), both of which factor into the calculation of k B and the BCF. Each approach yielded different K S9W , K BW , and K FW values, but resulted in f U values that were of similar magnitude and remained relatively constant at log octanol-water partition ratios (K OW ) greater than 4. This is because K BW and K S9W values predicted by any given approach exhibit a similar dependence on log K OW (i.e., regression slope), which results in a cancelation of "errors" when f U is calculated. In contrast, differences in K BW values predicted by the three approaches translate to differences in V D , and by extension k B and the BCF, which become most apparent at log K OW greater than 6. There is a need to collect K BW and V D data for hydrophobic chemicals in fish that can be used to evaluate and improve existing partitioning prediction approaches in extrapolation models for fish.

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Comparison of a simple and a complex model for BCF prediction using in vitro biotransformation data

Cited by 15 publications

References 19 publications

A Novel Multispecies Toxicokinetic Modeling Approach in Support of Chemical Risk Assessment

A Novel Multispecies Toxicokinetic Modeling Approach in Support of Chemical Risk Assessment

A Generalized Physiologically Based Kinetic Model for Fish for Environmental Risk Assessment of Pharmaceuticals

Models Used to Predict Chemical Bioaccumulation in Fish from in Vitro Biotransformation Rates Require Accurate Estimates of Blood–Water Partitioning and Chemical Volume of Distribution

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