A mechanistic evaluation of the metabolism disrupting potential of methyl tert-butyl ether

European authoritative and regulatory assessments of endocrine disruption increasingly incorporate evaluation of metabolism disrupting potential, yet there are no regulatory- or authority-validated models or guidance to identify metabolism disrupting agents (MDAs), which are agents that increase the risk of developing metabolic disorders. Methyl tert-butyl ether (MTBE), a volatile organic compound utilized as a fuel additive in many countries, was recently concluded to be a suspected endocrine disruptor based on its potential to elicit insulin resistance in rodents via an endocrine mode of action (MOA) in a Regulatory Management Option Analysis (RMOA). Therefore, a thorough mechanistic assessment was conducted to evaluate the metabolism disrupting potential of MTBE. This novel approach included review of any mechanistic data including study/endpoint relevance and study reliability. Reliable data were mapped to the twelve key characteristics (KCs) of MDAs for critical evaluation of the strength of the evidence for activity within each KC. Next, the mechanistic data were contextualized and integrated within an MOA framework. No reliable epidemiological studies of MTBE were identified. Across eight KCs, largely inconsistent activity was identified in reliable in vivo and in vitro studies related to lipid, insulin, and glucose processes. MOA analysis further demonstrated inconsistent (endocrine) activity related to metabolism disruption and a lack of biologically plausible links between MTBE and metabolism disruption. Based on the current evidence identified, MTBE does not consistently perturb insulin signaling or lipid metabolism via proposed MOAs for metabolic disorders. Overall, MTBE fails to show consistent activity and adverse effects related to metabolic disruption.