Quantitative AOP-based predictions for two aromatase inhibitors evaluating the influence of bioaccumulation on prediction accuracy
Citation:
Poole, S., G. Ankley, B. Blackwell, J. Cavallin, W. Cheng, D. Feifarek, K. Jensen, M. Kahl, E. Randolph, R. Milsk, T. Saari, AND Dan Villeneuve. Quantitative AOP-based predictions for two aromatase inhibitors evaluating the influence of bioaccumulation on prediction accuracy. SETAC North America, Orlando, FL, November 06 - 10, 2016.
Impact/Purpose:
not applicable
Description:
The adverse outcome pathway (AOP) framework can be used to support the use of mechanistic toxicology data as a basis for risk assessment. For certain risk contexts this includes defining, quantitative linkages between the molecular initiating event (MIE) and subsequent key events (KEs) within an AOP. One AOP for which strong, quantitative linkages have been established is aromatase inhibition leading to reproductive dysfunction in fish. A series of computational models have been linked to develop a quantitative AOP (Q-AOP). A measure of aromatase inhibition is used as the model input to estimate circulating plasma estradiol (E2) concentration and resultant circulating plasma vitellogenin (VTG) concentration. To evaluate model predictions, two aromatase inhibitors, letrozole and epoxiconazole, were selected based upon their relative aromatase inhibition potency in US EPA ToxCast assays. Reproductively mature female fathead minnows (Pimephales promelas) were exposed to varying concentrations of either letrozole (0.5, 7.5, 25, 75, 250 µg/L) or epoxiconazole (8, 25, 80, 250, 800 µg/L) in 24h flow through exposures. One additional consideration for model predictions was bioaccumulation of exposure chemicals and resultant circulating plasma concentration. To identify this, plasma from exposed minnows was extracted by supported liquid extraction (SLE) and concentrations of letrozole or epoxiconazole determined by LC-MS/MS. Plasma bioaccumulation factors (BAFplasma) varied across concentration ranges with lower exposure concentrations leading to greater bioaccumulation. Letrozole (logP = 2.22) BAFplasma ranged 0.173-0.25, indicating rapid metabolism or excretion of the compound, while epoxiconazole (logP = 3.44) BAFplasma ranged 34.4-66.9. Exposure tank concentrations and calculated plasma concentrations were used as model inputs. Model estimates using both exposure water concentration and plasma concentration will be compared with experimental measurements to highlight potential refinement of Q-AOP predictions.