Assessing the Human Health Risks of Trichloroethylene Key Scientific Issues (2006) / Chapter Skim
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Vapor intrusion through walls and floors can be a source of indoor exposure in buildings near contaminated groundwater. To help protect the public from potential health effects caused by exposure to trichloroethylene, government agencies conduct risk assessments to develop exposure guidelines intended to restrict human contact with the chemical.
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To accomplish its task, the committee held public data-gathering sessions to hear from the sponsoring agencies, other invited speakers, representatives from citizens' groups, and the public. The committee reviewed a large body of technical material on trichloroethylene, including relevant scientific literature, a draft risk assessment by EPA released in 2001, scientific and technical review comments on that draft assessment, and additional information provided by the sponsoring agencies and other interested parties.
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Thus, the committee recommends that federal agencies finalize their risk assessment with currently available data so that risk management decisions can be made expeditiously. Hazard Characterization Synthesizing Epidemiologic Data A large body of epidemiologic data is available on trichloroethylene and possible cancer outcomes, and quantitative analysis of the collective evidence will be the most informative for characterizing cancer hazards.
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Key scientific issues for characterizing these hazards include identifying the metabolites responsible for the effects, elucidating the mode of action, and understanding the relevance of animal data for humans. Kidney Toxicity and Cancer Trichloroethylene and some of its metabolites in the glutathione-conjugation pathway have been shown to be nephrotoxic and nephrocarcinogenic.
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The genotoxic effect of trichloroethylene metabolites likely results from bioactivation pathways in the kidney leading to renal VHL gene damage and renal cell carcinomas. However, there remains a lack of direct evidence that alterations in the VHL gene initiate renal tumors, but the alterations, especially in protein expression, might contribute to tumor progression.
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Trichloroethylene, chloral hydrate, and trichloroacetic acid induce liver cancer in mice when blood concentrations achieve millimolar concentrations. In contrast, dichloroacetic acid is active in rats as well and requires a much lower concentration to produce liver tumors.
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Evidence that trichloroacetic acid and dichloroacetic acid are as potent as trichloroethylene suggests that CYP2E1 metabolic activation, as well as the fractional formation of trichloroacetic acid from chloral, is important in trichloroethylene cardiac teratogenesis. Neurotoxicity Past evidence showed that inhalation of trichloroethylene causes neurotoxic effects in laboratory animals and humans that are similar in nature (e.g., massiter reflex latency, motor incoordination, changes in heart rate)
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Results of most epidemiologic studies of occupational exposure to trichloroethylene do not show a strong association between trichloroethylene exposure and increased incidence of lung tumors. Thus, pulmonary cancer does not appear to be a critical end point in assessing human health risks to trichloroethylene.
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Mixtures The available data indicate that toxic effects of trichloroethylene are likely to change in the presence of exposure to other chemicals, including its metabolites and similar metabolites of other toxicants. Clear understanding of whether and which of the toxic effects might be increased, decreased, or unchanged is lacking, but it appears that the major potential mechanisms of such interactions at the biophase include altered xenobiotic metabolizing enzymes, toxicokinetic factors (absorption, distribution, and elimination)
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Thus, it is appropriate to consider dose metrics generated from PBPK modeling along with other dose metrics that have been used in the past. PBPK models do not resolve the uncertainty about the mode of action of trichloroethylene, but they can inform experimental designs for studying it.
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However, the committee notes that information on response variability among humans is required in addition to mode-of-action information to clarify the shape of the low dose-response curve in humans. The mode of action for trichloroethylene as a kidney carcinogen remains unclear and likely involves multiple pathways.
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-l-cysteine S-conjugate sulfoxidation products. · Evaluation of the potential of missense specific mutations in the VHL gene contributing to tumor initiation and progression.
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· Evaluation of the relevant dose ranges and mode of action for trichloroethylene-induced developmental effects to determine the most appropriate species for human modeling. More information on metabolic activation in the avian model to evaluate interspecies differences, tissue-specific concentrations of trichloroethylene and its metabolites, and human data with better ascertainment of congenital heart disease and improved quantitative assessment of trichloroethylene exposures.
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PBPK Modeling: · Future PBPK models for trichloroethylene risk assessment should include a description of dermal absorption. · Studies to evaluate how well alternative dose metrics predict toxic response.
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