In vitro-in vivo and cross-life stage extrapolation of uptake and biotransformation of benzo[a]pyrene in the fathead minnow (Pimephales promelas)

Toxicokinetic Models for Bioconcentration of Organic Contaminants in Two Life Stages of White Sturgeon (Acipenser transmontanus)

“…Whole-body biotransformation was calibrated using the measured whole-body B­[ a ]P metabolite concentrations. While this was not the preferred method, it was not possible to accurately scale embryo-larval k MET from the measurements of subadult biotransformation (0.219 ± 0.070 mL h –1 mg protein –1 , SI Section 5; Figure S6), as done in previous studies . The reason why allometric scaling from subadult biotransformation was not possible in this case is because the embryo-larval white sturgeon showed unexpectedly very low biotransformation activity.…”

“…The subadult PBTK model is a reparameterization of the PBTK model originally designed for rainbow trout (Oncorhynchus mykiss) and subsequently reparameterized for a multitude of other species. ,, This model was modified to include stochasticity, allowing for Monte Carlo-like simulations to be performed. , Model performance was assessed by comparing predictions to a subset of experimental values obtained from the literature, as due to the size of subadult white sturgeon and their endangered status, an in vivo exposure was impractical.…”

“…The major B­[ a ]P metabolites, OH-B­[ a ]P and gluc-B­[ a ]­P, were quantified in the whole-body tissue of embryo-larval white sturgeon to generate a validation data set for the one-compartment embryo-larval model. Both metabolites were quantified with ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS) in whole-body embryos using the method described by Grimard et al Briefly, whole-body embryo samples ( n = 3; one larva per treatment/sample day) were homogenized in HPLC-grade acetonitrile (ACN, Fisher Scientific Co., Ottawa, ON, Canada) at a ratio of 1:10 (w/v) for 20 s. Samples were centrifuged at 1700 g for 15 min, and the supernatant subsequently sampled for quantification of metabolites. Metabolites were analyzed using a Vanquish UHPLC and Q-Exactive HF Quadrupole-Orbitrap mass spectrometer (Thermo-Fisher, Waltham, MA), followed by ionization in negative mode heated electrospray ionization and a full MS/parallel reaction monitoring (PRM) method.…”

“…Furthermore, there are ethical limitations when conducting research with endangered species, since the contribution of the research to species conservation must justify the environmental impact, i.e ., disruption to habitat and population. , The use of toxicokinetic (TK) models, an in silico approach, can be a powerful alternative to in vivo studies with endangered species to relate internal chemical concentrations to external exposure scenarios . For early-life stages (ELSs), empirically based one-compartment models are useful to obtain estimates of whole-body internal concentrations in the egg, yolk, and free-feeding stages. , For the subadult and adult life stages, a more complex mechanistic model, i.e ., a physiologically based toxicokinetic (PBTK) model, can be used to obtain estimates of internal concentrations in the whole fish and specific tissues during the time course of an exposure. , PBTK models use the physiological parameters cardiac output, oxygen consumption rate, and effective respiratory volume and characterize individual tissues by volume, total lipid content, total water content, and tissue perfusion rates . Both model types can be integrated with parameters specific to biotransformation of an organic contaminant when applicable. ,, Additionally, the TK model framework allows for interpolation and extrapolation in relation to life stage, intraspecies, and interspecies differences in bioconcentration, and, thus, a better understanding of these differences can be obtained.…”

Identification of Cytochrome P450 Isozymes Involved in Enantioselective Metabolism of Fipronil in Fish Liver: In Vitro Metabolic Kinetics and Molecular Modeling

“…In addition, it is difficult to further identify the principal enzymes involved in metabolizing target compounds using in vivo bioaccumulation information alone (Heijnen & Verheijen, 2013). Recently, in vitro models have become increasingly attractive in toxicological and toxicokinetic experiments to supplement the above‐mentioned limitations of in vivo tests, providing a mechanistic understanding in ADME processes (Grimard et al, 2020). The liver is the main metabolic organ and contains the majority of the metabolic enzymes, for example, cytochrome P450 (CYP) and glutathione S ‐transferases (Ardeshir et al, 2018).…”