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Review of the Environmental Protection Agency's Draft IRIS Assessment of Tetrachloroethylene (2010) / Chapter Skim
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6 Hepatic Toxicity and Cancer
Pages 59-67

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From page 59...
... A number of studies have been conducted with acute administration, but the draft correctly focuses on subchronic and chronic exposures, particularly those involving inhalation as a route of administration. Most of the toxicologic findings focus on increased liver weight, hypertrophy, and histologic lesions, including necrosis.
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From page 60...
... 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.
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From page 61...
... The draft IRIS assessment's section on hepatic carcinogenicity is written reasonably well in a descriptive sense, with regard to the style of the presentation of the cancer-relevant results of long-term studies with tetrachloroethylene. However, the presentation would benefit if the table on page 5-37, which now gives cumulative tumor incidence, were expanded to include information on species; strain; dose; duration; incidence and multiplicity of adenomas, carcinomas, and other hepatic tumors (such as hemangiosarcomas)
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From page 62...
... Such tumors have been commonly encountered after exposure to other halogenated solvents, such as dichloromethane, trichloroethylene, tetrachloroethane, carbon tetrachloride, and 1,1,2-trichloroethane. The curious observation of hepatic and splenic hemangiosarcomas reported in male mice in one of the tetrachloroethylene mouse bioassays (JISA 1993)
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From page 63...
... Some evidence is suggestive of an association between solvent exposure and laundry work and hepatic cancer in women, but the exposure models for these studies are crude, and methods of control selection raise questions about the validity of the results. The draft IRIS assessment does not use that limited evidence of an association between tetrachloroethylene and hepatic cancer as supportive of classifying tetrachloroethylene as a carcinogen.
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From page 64...
... Although the discussion of the PPARα-mediated events and their possible roles in species differences with regard to the hepatocarcinogenic potency of tetrachloroethylene is extensive, other important potential MOAs or key events are largely overlooked. For example, the possible role of epigenetic changes caused by TCA and DCA is mentioned, but there is little discussion of the studies that have been conducted on this subject.
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From page 65...
... the relevance of this MOA to mouse hepatic tumors induced by tetrachloroethylene or to human risk. As presented, the draft IRIS assessment seems to be more concerned with critiquing the current dominant view in the field that the peroxisome-proliferator MOA may not be relevant to human hepatocarcinogenesis than with providing evidence of links between tetrachloroethylene and this MOA.
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From page 66...
... And it is possible that activation of PPARα and consequent peroxisomal proliferation; genotoxic events induced by tetrachloroethylene metabolites, including chromosomal aberrations; and other nongenotoxic events -- such as promotion of growth of previously initiated foci, changes in epigenetic status, and oxidative stress -- may all contribute to the overall MOA through several simultaneous mechanisms. The hypothesis that the mutagenic metabolites of tetrachloroethylene (tetrachloroethylene-epoxide, TCA, DCA, chloral hydrate [if it is formed]
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From page 67...
... . Further studies are needed to define the MOAs for tetrachloroethyleneinduced liver tumors, with particular emphasis on the importance of PPARα and whether species difference might exist.
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Key Terms

  • draft iris
  • iris assessment
  • hepatic toxicity
  • hepatic tumors
  • key events

  • species differences
  • hepatocellular carcinomas
  • initiated foci
  • cause hepatic
  • hepatic carcinogenicity

  • mouse hepatic
  • key metabolites
  • aerospace workers
  • oxidative metabolites
  • previously initiated

  • epigenetic status
  • chloral hydrate
  • halogenated solvents
  • quantitative differences
  • human risk

  • male mice
  • oxidative stress
  • inhalation exposure
  • hepatic effects
  • causes hepatic

  • rodent hepatic
  • malignant hepatic
  • demonstrating hepatic
  • hepatic damage
  • hepatic tumor


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