caused a significant increase in liver weight (not corrected for body weight) in mice. The study also reported an increase in plasma butyrylcholinesterase (BuChE) in mice exposed to tetrachloroethylene at over 9 ppm for 30 days. Although the importance of the change in BuChE is not clear, the exposure in the study was so much lower than those in the other studies cited by EPA that it is important in considering the noncarcinogenic liver end points. EPA does not note that the increase in BuChE at 9 ppm was not significant (it was significant only at 37 ppm and above). It would be valuable for EPA to discuss this study critically in comparison with others in which much higher lowest observed-adverse-effect levels were found. In particular, it should be mentioned that increased BuChE in the Kjellstrand et al. study occurred at 37 ppm only when the exposure was continuous for the entire period, not when exposure at this concentration was intermittent, whereas other studies have involved intermittent exposure (usually 3-6 hours/day). Therefore, the total dose per mouse in the Kjellstrand et al. study must have been several times higher than that in other studies, and the information given in the draft (p. 4-12 and Table 4-2 on p. 4-14) is misleading. It would also be useful for EPA to discuss the quality of studies (for example, deficiencies in reporting by Kjellstrand et al.) and the toxicologic meaning, if any, of the reported effects. Furthermore, the increase in BuChE as a toxic effect does not appear to have been considered important by other investigators, on the basis of citations of the Kjellstrand et al. paper, nor does the effect seem to have been reported by others. Thus, a more critical analysis of the study is necessary to determine the significance of its findings in comparison with other reports of hepatotoxicity that required higher exposure concentrations.

The National Toxicology Program (NTP 1986) and Japan Industrial Safety Association (JISA 1993) studies lend some support to the possibility of hepatotoxicity associated with exposure to tetrachloroethylene. In the NTP 13-week study in rats, hepatotoxicity was evidenced as congestion in the liver. In the 13-week study in mice, there was leukocytic infiltration, centrolobular necrosis, and bile stasis in animals exposed to tetrachloroethylene at 400, 800, or 1,600 ppm. Liver degeneration was observed to occur in a dose-dependent fashion in the 2-year study in mice. In the JISA study, there was an increase in spongiosis hepatitis in Crj:BDF1 mice, but it is a common finding in these mice and is likely to be unrelated to chemical exposure. Hyperplasia was not statistically significantly increased; there were increases in angiectasis and central degeneration.

In updating and revising the draft IRIS assessment, EPA should include a new 30-day gavage study in Swiss Webster mice given tetrachloroethylene at 150, 500, and 1,000 mg/kg/day (Philip et al. 2007). The metabolism of tetrachloroethylene and its toxicity were examined. That is one of the few studies that were conducted with oral administration and repeated dosing. The investigators found that hepatic injury peaked at 7 days but then was repaired. That suggests that single-dose studies demonstrating hepatic damage on the basis of measurements made after short periods might not mimic the effects of repeated dosing.



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