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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