Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

Abstract

In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary‐butyl ether (ETBE), caused liver tumors in male rats, while tertiary‐butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary‐butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat‐specific protein α2u–globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0–∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male‐rat‐specific mode of action for TBA‐induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0–∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd

A physiologically based kinetic modeling of ethyl <i>tert</i>-butyl ether in humans–An illustrative application of quantitative structure-property relationship and Monte Carlo simulation

“…The expected values for V maxc and K m for ETBE were 1.11 mg/ hr/kg (29.6 μmol/hr/kg) and 0.09 mg/L (10.7 μM), respectively. The results had a large logarithmic standard deviation and were significantly lower than V maxc (499 μmol/ hr/kg) and K m (1248 μM) used in the rat PBK model of Borghoff et al (2017).…”

“…These metabolites are detected in rat and human urine (Amberg et al, 2000). Salazar et al (2015) and Borghoff et al (2017) independently developed rat ETBE PBK models, in which the mechanism of ETBE-induced tumorigenesis in the kidney and liver was elucidated by estimating the levels of its metabolite, TBA. The model of Salazar et al proposed two metabolism pathways from ETBE to TBA, whereas the model of Borghoff et al proposed a single oxidative metabolic pathway from ETBE to TBA.…”

SIRT1 exhibits antioxidative effects in HT22 cells induced by tert‐butyl alcohol

“…And the result showed that cell viability decreased statistically after HT22 cells exposed to different concentrations of TBA compared to the control ( P < 0.05) (Figure ), which indicated that TBA had a direct cytotoxic effect on HT22 cells. As with MTBE, TBA also triggered oxidative stress in the kidney by forming adducts with DNA or α2u‐globulin . So, it is presumed that oxidative stress may contribute to the neurotoxicity mechanism of TBA.…”

“…TBA, an important intermediate of MTBE biodegradation, has also been shown to form adducts with DNA and α2u‐globulin in rats . It is known that protein adduct and DNA adduct are the biomarkers of oxidative stress or lipid peroxidation.…”

Heading Towards a Possible Rebirth of the Induced Renal Cell Carcinoma Models?

“…In a study published in 2019 by Hartmann and al., for example, the renal oncogenic effects of angiotensin II were investigated in Big Blue rats [79]. In a study published by Borghoff et al in 2017, the development of kidney tumors following exposure of rats to ethyl tertiary-butyl ether and tertiary-butyl alcohol was studied as well [80]. In a study by Balansky and al.…”