Acceptable levels for ingestion of dimethylsilanediol in water on the International Space Station.

INTRODUCTION: Water is recovered aboard the International Space Station (ISS) from humidity condensate and treated urine. The product water is monitored for total organic carbon (TOC). In 2010 the TOC readings indicated that a new contaminant had entered the potable water and was steadily increasing toward the TOC screening limit of 3 mg x L(-1). In a ground-based laboratory, chemists discovered that dimethylsilanediol (DMSD) was the principal new contaminant. As no standard existed for safe levels of DMSD in water, the Toxicology Office at Johnson Space Center was asked to set such a standard. METHODS: The Toxicology Office used methods developed over the past decade, in collaboration with the National Research Council Committee on Toxicology, for setting Spacecraft Water Exposure Guidelines (SWEGs). These methods require a thorough literature search and development of an acceptable concentration (AC) for each potential toxic effect, keeping in mind that the adverse effects that accompany spaceflight could increase toxicity for certain end points. Benchmark dose modeling was encouraged if sufficient data were available. The most sensitive AC becomes the driver for the SWEG. RESULTS: Hematotoxicity, hepatotoxicity, and possibly neurotoxicity were the most sensitive toxicological endpoints for DMSD. CONCLUSIONS: The SWEG for DMSD for 100 d of ingestion was set at 35 mg x L(-1), which is equivalent to 9 mg x L(-1) as TOC. This is well above the TOC SWEG of 3 mg x L(-1) and the peak DMSD level of processed water observed on orbit, which was 2.2 mg x L(-1) asTOC (8.5 mg x L(-10 of DMSD).

Mechanisms of circadian rhythmicity of carbon tetrachloride hepatotoxicity.

The toxicity of carbon tetrachloride (CCl(4)) and certain other chemicals varies over a 24-h period. Because the metabolism of some drugs follows a diurnal rhythm, it was decided to investigate whether the hepatic metabolic activation of CCl(4) was rhythmic and coincided in time with maximum susceptibility to CCl(4) hepatotoxicity. A related objective was to test the hypothesis that abstinence from food during the sleep cycle results in lipolysis and formation of acetone, which participates in induction of liver microsomal cytochrome P450IIE1 (CYP2E1), resulting in a diurnal increase in CCl(4) metabolic activation and acute liver injury. Groups of fed and fasted male Sprague-Dawley rats were given a single oral dose of 800 mg of CCl(4)/kg at 2- to 4-h intervals over a 24-h period. Serum enzyme activities, measured 24 h post dosing as indices of acute liver injury, exhibited distinct maxima in both fed and fasted animals dosed with CCl(4) near the beginning of their dark/active cycle. Blood acetone, hepatic CYP2E1 activity, and covalent binding of (14)CCl(4)/metabolites to hepatic microsomal proteins in untreated rats fed ad libitum followed circadian rhythms similar to that of susceptibility to CCl(4). Parallel fluctuations of greater amplitude were seen in rats fasted for 24 h. Hepatic glutathione levels were lowest at the time of greatest susceptibility to CCl(4). Acetone dose-response experiments showed high correlations between blood acetone levels, CYP2E1 induction, and CCl(4)-induced liver injury. Pretreatment with diallyl sulfide suppressed CYP2E1 and abolished the circadian rhythmicity of susceptibility to CCl(4). These findings provide additional support for acetone's physiological role in CYP2E1 induction and for CYP2E1's role in modulating CCl(4) chronotoxicity in rats.