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. 2022 May 17;56(10):6500-6510.
doi: 10.1021/acs.est.1c08068. Epub 2022 Apr 26.

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

Jiaqi Wang  1 , Tom M Nolte  1 , Stewart F Owen  2 , Rémy Beaudouin  3 , A Jan Hendriks  1 , Ad M J Ragas  1   4
Affiliations

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

Jiaqi Wang et al. Environ Sci Technol. .

Abstract

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.

Keywords: fish; internal concentrations; ionization; pharmaceuticals; physiologically based kinetic model.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Scheme of the generalized fish PBK model. Boxes represent fish compartments. Black arrows represent blood flow. Red and blue arrows represent exposure and excretion routes in respective tissues, respectively. The green arrow represents hepatic metabolism.
Figure 2
Figure 2
Relative tissue volume (fraction of whole-body mass) versus body mass (g). Muscle volume was assumed to be the difference between the total volume and the summed volumes of other compartments. Open circles are the measured relative muscle volume.,− Derived regressions are listed in Table S2.
Figure 3
Figure 3
Mass-normalized (A) cardiac output and (B) oxygen consumption rate versus inverse temperature (1/T, K–1) based on the Boltzmann–Arrhenius equation.
Figure 4
Figure 4
Comparison of modeled concentrations (μg/g) with measured concentrations (μg/g) for (A) carbamazepine, (B) diclofenac, (C) ibuprofen, (D) diphenhydramine, and (E) fluoxetine. Modeled concentrations were based on the biotransformation half-life derived from EPI Suite v4.11. Organs are classified by colors. Means and standard errors are shown. Dotted and dashed lines represent the 3-fold and 10-fold differences, respectively.
Figure 5
Figure 5
Comparison of modeled concentrations (μg/g) with measured concentrations (μg/g) for (A) diclofenac and (B) diphenhydramine. Modeled concentrations were based on the measured biotransformation half-life from the literature. Organs are classified by colors. Means and standard errors are shown. Dotted and dashed lines represent the 3-fold and 10-fold differences, respectively.
See this image and copyright information in PMC

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