Improving the scientific foundation for mixtures joint toxicity and risk assessment: contributions from the SOT mixtures project--introduction.

Risk assessments are enhanced when policy and other decision-makers have access to experimental science designed to specifically inform key policy questions. Currently, our scientific understanding and science policy for environmental mixtures are based largely on extrapolating from and combining data in the observable range of single chemical toxicity to lower environmental concentrations and composition, i.e., using higher dose data to extrapolate and predict lower dose toxicity. There is a growing consensus that the default assumptions underlying those mixtures risk assessments that are conducted in the absence of actual mixtures data rest on an inadequate scientific database. Future scientific research should both build upon the current science and advance toxicology into largely uncharted territory. More precise approaches to better characterize toxicity of mixtures are needed. The Society of Toxicology (SOT) sponsored a series of panels, seminars, and workshops to help catalyze and improve the design and conduct of experimental toxicological research to better inform risk assessors and decision makers. This paper summarizes the activities of the SOT Mixtures Program and serves as the introductory paper to a series of articles in this issue, which hope to inspire innovative research and challenge the status quo.

Genotoxicity testing of methyl tertiary-butyl ether (MTBE) in the Salmonella microsuspension assay and mouse bone marrow micronucleus test.

Methyl tertiary-butyl ether (MTBE) is an oxygenated fuel additive that is present in gasoline at levels up to 15% by volume. Since the 1990 Clean Air Act amendments require the use of oxygenated gasoline in 39 areas of the USA, the use of MTBE is projected to continue to dramatically increase. As the use of MTBE increase, the potential for environmental release of MTBE from gasoline stations and automobiles will also increase. Despite its growing use as a fuel additive and its potential for increased exposure to the public, few genotoxicity data on MTBE have been published in the peer-review literature. In the present study, we tested the potential genotoxicity of MTBE in two short-term test systems, an in vitro Salmonella microsuspension assay and an in vivo mouse bone marrow micronucleus test. For the microsuspension assay, MTBE was tested at 7 dose levels of 30 to 7400 micrograms/tube in tester strain TA98, TA100, TA104, and TA1535, with and without the addition of metabolic enzymes (S9) at 4 concentration (0, 300, 600, and 1200 micrograms S9/ml final concentration). A closed system was used to minimize loss of MTBE. The response was not significant. However, a high degree of toxicity was observed at the highest doses in all tester strains. MTBE was also tested for clastogenicity i the mouse bone marrow micronucleus test using both male and female Swiss-Webster mice. Mice were administered single intraperitoneal injections of MTBE in olive oil at 5 doses ranging from 0.25 to 1.75 g/kg. There were no significant increases in micronucleus formation at any dose of MTBE when compared with the negative control animals receiving only olive oil. MTBE was not positive when tested for point mutations and clastogenicity, using respectively, a Salmonella microsuspension assay and the mouse bone marrow micronucleus test.