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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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9118555 | PMC |
| http://dx.doi.org/10.1021/acs.est.1c08068 | DOI Listing |
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