Reassessment of MTBE cancer potency considering modes of action for MTBE and its metabolites

<div><p></p><p>A 1999 California state agency cancer potency (CP) evaluation of methyl <i>tert</i>-butyl ether (MTBE) assumed linear risk extrapolations from tumor data were plausible because of limited evidence that MTBE or its metabolites could damage DNA, and based such extrapolations on data from rat gavage and rat and mouse inhalation studies indicating elevated tumor rates in male rat kidney, male rat Leydig interstitial cells, and female rat leukemia/lymphomas. More recent data bearing on MTBE cancer potency include a rodent cancer bioassay of MTBE in drinking water; several new studies of MTBE genotoxicity; several similar evaluations of MTBE metabolites, formaldehyde, and <i>tert</i>-butyl alcohol or TBA; and updated evaluations of carcinogenic mode(s) of action (MOAs) of MTBE and MTBE metabolite's. The lymphoma/leukemia data used in the California assessment were recently declared unreliable by the U.S. Environmental Protection Agency (EPA). Updated characterizations of MTBE CP, and its uncertainty, are currently needed to address a variety of decision goals concerning historical and current MTBE contamination. To this end, an extensive review of data sets bearing on MTBE and metabolite genotoxicity, cytotoxicity, and tumorigenicity was applied to reassess MTBE CP and related uncertainty in view of MOA considerations. Adopting the traditional approach that cytotoxicity-driven cancer MOAs are inoperative at very low, non-cytotoxic dose levels, it was determined that MTBE most likely does not increase cancer risk unless chronic exposures induce target-tissue toxicity, including in sensitive individuals. However, the corresponding expected (or plausible upper bound) CP for MTBE conditional on a hypothetical linear (e.g., genotoxic) MOA was estimated to be ∼2 × 10^–5 (or 0.003) per mg MTBE per kg body weight per day for adults exposed chronically over a lifetime. Based on this conservative estimate of CP, if MTBE is carcinogenic to humans, it is among the weakest 10% of chemical carcinogens evaluated by EPA.</p></div

Data_Sheet_1_Approaches to risk–benefit assessment of seafood consumption: lessons learned from an evidence scan.docx

Qualitative and quantitative risk–benefit assessments (RBA) can be used to support public health decisions in food safety. We conducted an evidence scan to understand the state of the science regarding RBA in seafood to help inform seafood dietary advice in the United States. We collected published RBA studies assessing seafood consumption, designed inclusion and exclusion criteria to screen these studies, and conducted systematic data extraction for the relevant studies published since 2019. Our findings indicate the selection of health risks and benefits does not generally follow a systematic approach. Uncertainty and variability in RBAs is often not addressed, and quantitative RBAs making use of a single health metric generally have not been leveraged to directly support published regulatory decisions or dietary guidance. To elevate the role of RBA in supporting regulatory decision-making, risk assessors and risk managers must work together to set expectations and goals. We identified the need for a prioritization phase (e.g., multicriteria decision analysis model) to determine the risks and benefits of greatest public health impact to inform the RBA design. This prioritization would consider not only the degree of public health impact of each risk and benefit, but also the potential for risks and benefits to converge on common health outcomes and their importance to subpopulations. Including a prioritization could improve the utility of the RBAs to better inform risk management decisions and advance public health. Our work serves to guide the United States Food and Drug Administration’s approaches to RBA in foods.</p