A 1999 California state agency
cancer potency (CP) evaluation of
methyl tert-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
tert-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.