Hepatotumorigenicity of ethyl tertiary-butyl ether with 2-year inhalation exposure in F344 rats

Abstract

Carcinogenicity of ethyl tertiary-butyl ether (ETBE) was examined with inhalation exposure using F344/DuCrlCrlj rats. Groups of 50 male and 50 female rats, 6 week old at commencement, were exposed to ETBE at 0, 500, 1,500 or 5,000 ppm (v/v) in whole-body inhalation chambers for 6 h/day, 5 days/week for 104 weeks. A significant increase in the incidence of hepatocellular adenomas was indicated in males exposed at 5,000 ppm, but not in females at any concentration. In addition, significantly increased incidences of eosinophilic and basophilic cell foci were observed in male rats at 5,000 ppm. Regarding non-neoplastic lesions, rat-specific changes were observed in kidney, with an increase in the severity of chronic progressive nephropathy in both sexes at 5,000 ppm. Increased incidences of urothelial hyperplasia of the pelvis were observed at 1,500 ppm and above, and mineral deposition was apparent in the renal papilla at 5,000 ppm in males. There were no treatment-related histopathological changes observed in any other organs or tissues in either sex. The present 2-year inhalation study demonstrated hepatotumorigenicity of ETBE in male, but not in female rats.

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

“…To determine exposure concentrations above which the kinetics of ETBE and TBA become nonlinear, the model was used to simulate ETBE blood AUC 0–∞ following either single oral gavage administration or 6 h inhalation exposure to ETBE at the concentrations used in two separate cancer bioassays (Saito et al ., 2013; Suzuki et al ., 2012); the results are presented in Fig. 11.…”

“…Saito et al . (2013) estimated that an exposure concentration of 5000 ppm corresponded to a dose level of 4442 mg kg −1 bw day −1 , assuming 100% absorption. However, as noted in Fig.…”

“…It was also negative in two in vivo micronucleus assays, with one assay finding no micronucleus formation in the bone marrow following ETBE exposure of rats and mice via drinking water (Noguchi et al ., 2013). However, two reliable ETBE cancer bioassays were conducted in male and female F344 rats via different routes of administration – inhalation (ETBE at 0, 400, 1500 and 5000 ppm, 6 h day −1 , 5 days week −1 for 104 weeks) (Saito et al ., 2013) and drinking‐water exposure (at estimated daily dose levels up to 560 mg kg −1 bodyweight (bw) day −1 ) (Suzuki et al ., 2012). At the highest inhalation exposure concentration of 5000 ppm, male rats exhibited an increased incidence of hepatocellular adenomas (only one rat had a hepatocellular carcinoma), as well as an increased incidence of eosinophilic and basophilic cell foci, both of which are considered pre‐neoplastic lesions.…”

Lack of micronucleus induction activity of ethyl <i>tertiary</i>-butyl ether in the bone marrow of F344 rats by sub-chronic drinking-water treatment, inhalation exposure, or acute intraperitoneal injection

“…However, in a review of the health hazards of MTBE, McGregor (2006) notes that the results of the carcinogenicity studies of MTBE are generally not consistent and replication of results was observed in only three cases, none of which had human relevance. In a more recent study, Saito et al (2013) reported that inha--cant increase in hepatocellular adenomas in male, but not in female, rats. When administered by gavage, ETBE is reported to have carcinogenesis activity.…”

In vitro systems: current limitations and future perspectives

“…Moreover, zebrafish-based test systems have been studied as an alternative method to identify hepatotoxic compounds (Driessen et al 2013;Scholz 2013). Compared to the high number of studies based on in vitro systems the fraction of in vivo studies published in the Archives of Toxicology has become relatively small (Rossato et al 2013;Yu et al 2013;Early et al 2013;Cordova et al 2013;Saito et al 2013;Hammad et al 2014). Moreover, studies systematically comparing the functions of in vitro systems to the in vivo situation are rare Heise et al 2012).…”