The toxicokinetics of bisphenol A and its metabolites in fish elucidated by a PBTK model

Mit, Corentin; Bado‐Nilles, Anne; Danièle, Gaëlle; Giroud, Barbara; Vulliet, Emmanuelle; Beaudouin, Rémy

doi:10.1016/j.aquatox.2022.106174

Cited by 20 publications

(17 citation statements)

References 62 publications

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“… 27 , 28 A recent PBTK study modeled BPA and its two major metabolites in stickleback, zebrafish, and trout. 86 This model showed improved performance as compared to the previous generic model 27 and showed performance comparable to our model. The predictions of BPA glucuronic acid metabolite are of similar accuracies (mostly 2–5-fold error) to the present study despite different methodologies being employed for model calibration.…”

Section: Resultssupporting

confidence: 56%

“…Nevertheless, the majority of predicted concentrations were within a 2-fold error, which is considered adequate for the purpose of risk assessment . For more generic fish models used for organic pollutants, a 10-fold error has been considered acceptable. , A recent PBTK study modeled BPA and its two major metabolites in stickleback, zebrafish, and trout . This model showed improved performance as compared to the previous generic model and showed performance comparable to our model.…”

Section: Resultsmentioning

confidence: 79%

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Physiologically Based Toxicokinetic Modeling of Bisphenols in Zebrafish (Danio rerio) Accounting for Variations in Metabolic Rates, Brain Distribution, and Liver Accumulation

Chelcea

Örn

Hamers

et al. 2022

Environ. Sci. Technol.

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Bisphenol A (BPA) is an industrial chemical, which has raised human health and environmental concerns due to its endocrine-disrupting properties. BPA analogues are less well-studied despite their wide use in consumer products. These analogues have been detected in water and aquatic organisms around the world, with some analogues showing toxic effects in various species including fish. Here, we present novel organ-specific time-course distribution data of bisphenol Z (BPZ) in female zebrafish ( Danio rerio ), including concentrations in the ovaries, liver, and brain, a rarely sampled organ with high toxicological relevance. Furthermore, fish-specific in vitro biotransformation rates were determined for 11 selected bisphenols. A physiologically based toxicokinetic (PBTK) model was adapted for four of these bisphenols, which was able to predict levels in the gonads, liver, and brain as well as the whole body within a 2–5-fold error with respect to experimental data, covering several important target organs of toxicity. In particular, predicted liver concentrations improved compared to currently available PBTK models. Predicted data indicate that studied bisphenols mainly distribute to the carcass and gonads and less to the brain. Our model provides a tool to increase our understanding on the distribution and kinetics of a group of emerging pollutants.

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Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 79%

Physiologically Based Toxicokinetic Modeling of Bisphenols in Zebrafish (Danio rerio) Accounting for Variations in Metabolic Rates, Brain Distribution, and Liver Accumulation

Chelcea

Örn

Hamers

et al. 2022

Environ. Sci. Technol.

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“…Physiologically-Based Kinetic (PBK) models encompass both pharmaco- (PBPK) and toxico-kinetic (PBTK) models depending on the context referring either to toxicity risk assessment [14, 19] or therapeutic drug development [35]. All PBK models are compartment models employing ordinary differential equations (ODE) to quantify chemical absorption, distribution, metabolism ( i.e .,biotransformation) and excretion (ADME) processes within living organisms when exposed to chemical substances [33].…”

Section: Introductionmentioning

confidence: 99%

“…Physiologically-Based Kinetic (PBK) models encompass both Physiologically-Based Pharmaco-Kinetic (PBPK) and Physiologically-Based (eco-)Toxico-Kinetic (PBTK) models depending on the context referring either to therapeutic drug development (Zhang et al, 2006) or environmental risk assessment (Grech et al, 2017; Mit et al, 2022). All PBK models are compartment models employing ordinary differential equations (ODE) to quantify chemical absorption, distribution, metabolism (i.e., biotransformation) and excretion (ADME) processes within living organisms when exposed to chemical substances (Wang and Rainbow, 2008).…”

Section: Introductionmentioning

confidence: 99%

Generic solving of physiologically-based kinetic models in support of next generation risk assessment due to chemicals

Charles

Gestin

Bruset

et al. 2022

Preprint

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FigureIncrease the confidence in using in vitro and in silico data to aid the chemical risk assessment process is one, if not the most, important challenge currently facing regulatory authorities. A particularly crucial concern is to fully take advantage of scientifically valid physiologically-based kinetic (PBK) models. Nevertheless, risk assessors remain still unwilling in employing PBK models within their daily work. Indeed, PBK models are not often included in current official guidance documents. In addition, most users have limited a limited experience in using modelling in general. So, the complexity of PBK models, together with a lack to evaluation methods of their performances, certainly contributes to their under-use.This paper proposes an innovative and unified modelling framework, in both the writing of PBK equations as matrix ordinary differential equations (ODE), and in its exact solving simply expressed with matrix products. This generic PBK solution allows to consider as many as state-variables as needed to quantify chemical absorption, distribution, metabolism and excretion processes within living organisms when exposed to chemical substances. This generic PBK model makes possible any compartmentalisation of the model to be considered, as well as all appropriate inter-connections between compartments and with the external medium.We first introduce our PBK modelling framework, with all intermediate steps from the matrix ODE until the exact solution. Then we apply this framework to bioaccumulation testing, before illustrating its concrete use through complementary case studies in terms of species, compound and model complexity. Upon our findings, we finally propose to consider this approach to eventually be part of a future revision of the current regulation.

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“…1,2 Hence, PBK models can refer either to therapeutic drug development 3 or environmental risk assessment. [4][5][6] All PBK models are compartment models employing ordinary differential equations (ODE) to quantify chemical absorption, distribution, metabolism (i.e., biotransformation), and excretion processes within living organisms when exposed to chemical substances. 7, 8 One fundamental aspect of PBK model complexity is the degree of compartmentalization (i.e., differentiation of an organism into various tissues or organs).…”

Section: Introductionmentioning

confidence: 99%

Generic Solving of Physiologically-based Kinetic Models in Support of Next Generation Risk Assessment Due to Chemicals

Charles¹,

Gestin²,

Bruset³

et al. 2022

J Explor Res Pharmacol

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Increasing confidence in using in vitro and in silico model-based data to aid the chemical risk assessment process is one of the most significant challenges faced by regulatory authorities. A crucial concern is taking full advantage of scientifically valid physiologically-based kinetic (PBK) models. Nevertheless, risk assessors remain unwilling to employ PBK models in their daily work. Indeed, PBK models are not often included in current official guidance documents. In addition, most users have limited experience with modeling in general. So, the complexity of PBK models and a lack of evaluation methods for their performance certainly contribute to their limited use in practical risk assessment. This paper proposes an innovative and unified modeling framework for writing PBK equations as matrix ordinary differential equations (ODE) and their solutions, expressed with matrix products. This generic PBK solution considers as many state variables as needed to quantify chemical absorption, distribution, metabolism, and excretion processes within living organisms when exposed to chemical substances. This generic PBK model makes possible any compartmentalization to be considered, as well as all appropriate interconnections between compartments and with the external medium. We first introduce our PBK modeling framework, with all the intermediate steps from the matrix ODE to the exact solution. Then we apply this framework to bioaccumulation testing before illustrating its concrete use through complementary case studies regarding species, compounds, and model complexity.

show abstract

The toxicokinetics of bisphenol A and its metabolites in fish elucidated by a PBTK model

Cited by 20 publications

References 62 publications

Physiologically Based Toxicokinetic Modeling of Bisphenols in Zebrafish (Danio rerio) Accounting for Variations in Metabolic Rates, Brain Distribution, and Liver Accumulation

Physiologically Based Toxicokinetic Modeling of Bisphenols in Zebrafish (Danio rerio) Accounting for Variations in Metabolic Rates, Brain Distribution, and Liver Accumulation

Generic solving of physiologically-based kinetic models in support of next generation risk assessment due to chemicals

Generic Solving of Physiologically-based Kinetic Models in Support of Next Generation Risk Assessment Due to Chemicals

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