In vitro to in vivo extrapolation of biotransformation rates for assessing bioaccumulation of hydrophobic organic chemicals in mammals

Abstract

Incorporating biotransformation in bioaccumulation assessments of hydrophobic chemicals in both aquatic and terrestrial organisms in a simple, rapid, and cost-effective manner is urgently needed to improve bioaccumulation assessments of potentially bioaccumulative substances. One approach to estimate whole-animal biotransformation rate constants is to combine in vitro measurements of hepatic biotransformation kinetics with in vitro to in vivo extrapolation (IVIVE) and bioaccumulation modeling. An established IVIVE modeling approach exists for pharmaceuticals (referred to in the present study as IVIVE-Ph) and has recently been adapted for chemical bioaccumulation assessments in fish. The present study proposes and tests an alternative IVIVE-B technique to support bioaccumulation assessment of hydrophobic chemicals with a log octanol-water partition coefficient (K ) ≥ 4 in mammals. The IVIVE-B approach requires fewer physiological and physiochemical parameters than the IVIVE-Ph approach and does not involve interconversions between clearance and rate constants in the extrapolation. Using in vitro depletion rates, the results show that the IVIVE-B and IVIVE-Ph models yield similar estimates of rat whole-organism biotransformation rate constants for hypothetical chemicals with log K ≥ 4. The IVIVE-B approach generated in vivo biotransformation rate constants and biomagnification factors (BMFs) for benzo[a]pyrene that are within the range of empirical observations. The proposed IVIVE-B technique may be a useful tool for assessing BMFs of hydrophobic organic chemicals in mammals. Environ Toxicol Chem 2017;36:1934-1946. © 2016 SETAC.

Concentration dependence of in vitro biotransformation rates of hydrophobic organic sunscreen agents in rainbow trout S9 fractions: Implications for bioaccumulation assessment

“…The ϕ S9 was estimated using algorithms given by Han et al (), Nichols et al (), and Lee et al (). The empirical relationship given by Han et al () was originally developed using binding data for rat liver microsomes, but has been incorporated in current IVIVE approaches (Nichols et al ) to describe the unbound chemical fraction in trout liver S9 as a function of chemical log K OW and S9 protein content ( C S9 ; mg mL −1 ): …”

“…It was shown previously that Equation 6 provides reasonable estimates of f P compared with blood-binding data for chemicals covering a range in log K OW from 1 to 8 (Nichols et al 2013b). The f S9 was estimated using algorithms given by Han et al (2009), Nichols et al (2018a, and Lee et al (2017). The empirical relationship given by Han et al (2009) was originally developed using binding data for rat liver microsomes, but has been incorporated in current IVIVE approaches (Nichols et al 2013b) to describe the unbound chemical fraction in trout liver S9 as a function of chemical log K OW and S9 protein content (C S9 ; mg mL À1 ):…”

“…The tissue-composition-based algorithm given by Lee et al (2017) estimates f S9 based on fractional amounts of lipid and nonlipid organic matter (protein) in the incubation medium:…”

“…The different BCFs calculated at each initial concentration reflect the use of different binding models to estimate f S9 . The models evaluated were those given by Han et al (2009;solid squares), Lee et al (2017;gray diamonds), and Nichols et al (2018a;open circles). Additional BCFs were generated assuming that f U ¼ 1.0 (gray triangles).…”

“…The red shaded areas represent modeled BCFs that exceed regulatory bioaccumulation criteria (BCF > 2000 L kg À1 ), and the blue shaded areas show the range of empirical BCFs for each UVF. Lee et al (2017) 0.004997 0.000709 0.000366 Nichols et al (2018a) 0.002355 0.000175 0.000028 Fraction unbound in plasma (f P ) Fitzsimmons et al (2001) 0.001277 0.000306 0.000050 Hepatic clearance binding correction factor (f U ) Han et al (2009) 0.11 0.10 0.02 Lee et al (2017) 0.25 0.43 0.14 Nichols et al (2018a) 0.54 1.75 1.77 f U ¼ 1.0 1.00 1.00 1.00…”