PCE Toxicity Value Review

On February 10, 2012, U.S. EPA published a final Health Assessment for Tetrachloroethylene (Perchloroethylene, or “Perc” or PCE) on the IRIS database (http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showQuickView&substance_nmbr=0106). In the new Health Assessment, EPA provides revised toxicity values for oral exposures (a reference dose [RfD] for non-cancer and a cancer slope factor [CSF] for cancer risk) and for inhalation exposures (a reference concentration [RfC]for non-cancer and an inhalation unit risk factor [URF] for cancer).

Several years ago, while EPA’s Health Assessment was still in progress, assessment of tetracholorethylene in indoor air arose as a critical issue for a number of MCP sites.  The Bureau of Waste Site Cleanup (BWSC) requested that the Office of Research and Standards (ORS) review the inhalation unit risk factor (URF, for evaluating cancer risk from exposure to air contaminants) in use at the time.  ORS toxicologists conducted the review of the scientific literature available at the time, obtained a peer-review of the ORS assessment, and published a revised inhalation unit risk value in 2008 (http://www.mass.gov/dep/toxics/chemrs.htm).

In addition to the URF published in 2008, ORS has recently reviewed and updated the RfC used to calculate MassDEP’s Threshold Effects Limits (non-cancer) for tetrachloroethylene (http://www.mass.gov/dep/toxics/stypes/telaal.htm).  This review considered all of the toxicological data currently available.

Some of the toxicity values published in EPA’s Health Assessment differ significantly from those developed by MassDEP.  ORS plans to review the basis for the values provided by EPA before adopting final values.  MassDEP expects to complete the review by the end of March. Until then, MassDEP recommends the continued use of the MassDEP cancer slope factor of 5 x 10-2 (mg/kg/day)-1 and the inhalation unit risk of 1 x 10-5 (µg/m3)-1 for site-specific risk assessments conducted under the Massachusetts Contingency Plan (310 CMR 40.0000).

Any questions may be directed to BWSC.Information@state.ma.us.


2 Responses

  1. Ben Ericson
    Assistant Commissioner
    Bureau of Waste Site Cleanup
    Massachusetts Department of Environmental Protection
    One Winter Street
    Boston, MA 02108

    Reconsideration of Risk Factors for Tetrachloroethylene
    Based on USEPA’s Final Health Assessment

    Dear Mr. Ericson:

    On February 23, 2010 the Bureau of Waste Site Cleanup (BWSC) posted a notice entitled PCE Toxicity Value Review on its Indoor Air Guidance Project Blog (http://indoorairproject.wordpress.com/). That notice was prompted by the release on February 10, 2012 of the U.S. Environmental Protection Agency’s (USEPA’s) final Health Assessment for tetrachloroethylene (PCE). According to the notice, the Office of Research and Standards (ORS) plans to review the Department’s current interim inhalation unit risk factor (IUR) and cancer slope factor (CSF) for PCE because “some of the toxicity values published in EPA’s Health Assessment differ significantly from those developed by MassDEP.”

    When ORS announced its current IUR of 1 x 10^-5 (μg/m3)^-1 and CSF of 5 x 10^-2 (mg/kg/day)^-1 for PCE, it stated that it was adopting these values solely on an interim basis because of delays in USEPA’s Integrated Risk Information System (IRIS) process (MassDEP, 2008). Specifically, ORS stated:

    As the USEPA report and NAS review have been repeatedly delayed, and because BWSC response decisions are needed in the short-term regarding a number of MA contamination sites, ORS has completed a review of recent information and assessments on PCE carcinogenicity by other groups. Based on this review and as an interim step, pending the completion of the USEPA and NAS work, ORS is proposing a revised inhalation unit risk value for PCE. ORS will reevaluate PCE carcinogenicity after the USEPA and NAS work is published.

    Notably, the MCP requires that MassDEP use unit risk factors published by USEPA: “Unit Risk means the cancer risk (proportion affected) per concentration unit of an oil or hazardous material, as published by EPA” (emphasis added) (310 CMR 40.0006).

    The purpose of this letter is to summarize key differences between the MassDEP’s interim IUR and USEPA’s final IUR, and to highlight scientific data on which USEPA based its final IUR that were not considered by ORS when it adopted its interim IUR. A copy of this letter will be posted on the Indoor Air Guidance Project Blog.

    Reliance on Mononuclear Cell Leukemia Carcinogenic Endpoint

    The interim Unit Risk Factor of 1 x 10^-5 (μg/m3)^-1 is the average of two Unit Risk Factors derived using the results of mononuclear cell leukemia (MCL) in F344 male rats in two carcinogenesis bioassay studies (NTP, 1986; JISA, 1993). When it adopted its interim IUR in 2008, ORS acknowledged that questions already existed as to the significance of this toxicological endpoint in F344 rats to human risk assessment (MassDEP, 2008):

    The MCL data has been questioned in the past because of: (1) the high background rate of MCL in F344 rat; and (2) concerns about the relevance of this tumor type to humans (Ishmael and Dugard, 2006).

    MassDEP discounted the concerns expressed by toxicologists about this endpoint in 2008 and based the interim IUR on the MCL endpoint.

    When USEPA released its draft Health Assessment in 2008, it, too, relied on the MCL endpoint in F344 rats. Specifically, USEPA proposed a range from 2×10^-6 to 2×10^-5 (μg/m3)^-1 based on the results of three physiologically based pharmacokinetic (PBPK) models (Rao & Brown, 1993; Reitz et al. 1996; Bois et al. 1996). However, in 2010, the NRC criticized EPA for basing its proposed IUR on MCL in F344 rats. Specifically, NRC stated:
    An increased incidence of MCL in F344 rats has been reported in two bioassays. The biologic significance of the increases was debated by the committee because increases were observed in only one strain of rat, which is known to have a high background incidence of MCL, and because MCL’s relevance to humans and the mode of action of tetrachloroethylene causing it are not understood. In considering the high background of MCL, the committee found a published assessment by Thomas et al. (2007) that applied statistical approaches (life-table analyses) to bioassays of the National Toxicology Program (NTP) to interpret dose response relationships. Tetrachloroethylene was one of five chemicals of 500 tested by NTP that showed statistically significant increases in MCL in both male and female rats despite the high background rates. (NRC, 2010)
    NTP has decided to stop using its F344/N rat colony in its bioassays for reasons that include the high background rate of MCL (King-Herbert and Thayer 2006). (NRC, 2010)

    Given the high background rate and other uncertainties with respect to MCL in F344 rats, the majority of the NRC committee recommended that USEPA abandon its reliance on the MCL endpoint and instead focus on the hepatic cancer endpoint:
    The committee was unable to reach consensus on the selection of the critical cancer end point. The majority of the members judged that the uncertainties associated with MCL (particularly the high background incidence, uncertainty about the dose-response relationship, and poor understanding of mode of action) were too great to support using MCL data rather than data on hepatic or renal cancer for determining quantitative estimates of risk. Those members judged that the use of the MCL data could be justified only if it is EPA’s policy to choose the most conservative unit risk when considering options but that such justification should be distinguished as a policy decision, not a scientific one. They believed that a more scientifically defensible approach would be to use the dataset that has the least uncertainty rather than the dataset that yields the highest estimate of risk. In their judgment, the hepatic-cancer data would have the least uncertainty, followed by the data on renal cancer and MCL. (NRC, 2010)

    In its response to comments, USEPA (2012) accepted the NRC’s recommendations and issued a final IUR based on hepatic cancer in the mouse:
    In accordance with the majority of the NRC peer review panel, the oral slope factor and inhalation unit risk are now based on the male mouse hepatocellular tumor data from the JISA (1993) bioassay as shown in Sections and EPA also presents what the cancer risk estimates would be if they were based on the male and female rat MCL data from the JISA (1993) bioassay. (USEPA, 2012)
    In short, the MCL endpoint in F344 rats on which ORS derived its interim IUR has been criticized by the NRC and rejected by USEPA. Based on current scientific data and standards, the more appropriate endpoint is the hepatic cancer endpoint in the mouse.

    Reliance on Metabolized Dose Approach versus Physiologically Based Pharmacokinetic Models for Cross-Species Extrapolation

    ORS considered two approaches for extrapolating the data from the PCE animal toxicology studies to humans when deriving the interim IUR. These include use of physiologically based pharmacokinetic (PBPK) models and estimation of total metabolized dose of PCE using simple scaling methods. (MassDEP, 2008). ORS rejected the use of any of the then available PBPK models (such as Rao & Brown, 1993; Reitz et al. 1996; Bois et al. 1996; Chiu and Bois, 2006; and Hattis, et al. 1990, 1993), finding that all of them had high uncertainties:
    Many PBPK models have been developed with the intent of reducing the uncertainties inherent in cross-species and high dose to low dose extrapolations. At this time these models for PCE are limited by uncertainties: 1) regarding mechanism of action; 2) about the carcinogenic activities and potencies of the various metabolite(s) potentially responsible for PCE’s ultimate carcinogenic activity; 3) over the relative quantitative significance of various metabolic pathways across species and between high and low
    dose exposures; and, 4) in the variability in metabolism between individuals and life stages. (MassDEP, 2008)

    ORS said, “Although the mode of action for PCE tumorigenicity in animals and humans is not well known, there is consensus that the active moiety is not PCE, but one of its metabolites.” ORS acknowledged that the specific metabolite or metabolites that lead to the carcinogenic response had not been determined. It therefore opted for an estimated total metabolized dose approach. ORS said its approach “makes no assumptions regarding the active metabolite while acknowledging the likely involvement of metabolism in activating PCE.” This lack of specificity was stated to be an “advantage” of the estimated total metabolized dose approach.

    In 2007, when ORS was reviewing the available scientific data on PCE and deriving the interim IUR, there was considerable uncertainty about PCE’s mode of action and there was considerable uncertainty associated with the available PBPK models for PCE. In 2008, when USEPA issued its draft Toxicological Review of Tetrachloroethylene, it performed interspecies extrapolation of PCE doses by using several PBPK models (Rao & Brown, 1993; Reitz et al. 1996; Bois et al. 1996). USEPA proposed a range of IURs based on the different PBPK model results.

    In 2010, when the NRC issued its Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene, the NRC also noted the uncertainties in the pre-2000 PBPK models for PCE and requested that USEPA develop a single “harmonized” PBPK model for the IUR derivation. Specifically, NRC stated:

    Tetrachloroethylene can be viewed as being metabolized by three pathways. The predominant pathway is the cytochrome P-450 (CYP) pathway that produces metabolites that have been associated with hepatic cancer. Two other pathways involve the GSH conjugation pathway that produces metabolites that are further metabolized by the β-lyase pathway or the β-lyase-independent pathway, each of which produce metabolites that have been associated with renal cancer. To take those metabolic factors into account, EPA used three PBPK models to estimate human equivalent doses from animal studies and to perform route-to-route extrapolations. Each of the models used total metabolism of tetrachloroethylene as the dose metric. In some instances, EPA used a single model; in others, it used all three. The justification for using single or multiple models is not always clear. The committee observed that the models could yield different results because they were calibrated with different datasets, so comparisons among them were not straightforward. For consistency and to allow for better comparisons among end points, the committee recommends that EPA use a single PBPK model for its assessment. Ideally, the model would be a “harmonized” version of the three models used by EPA or of other relevant models (that is, a single model that integrates multiple exposure routes and tissue compartments). (NRC, 2010)

    USEPA (2012) agreed with the NRC and developed a “harmonized” PBPK model that was published as Development and Evaluation of a Harmonized Physiologically Based Pharmacokinetic (PBPK) Model For Perchloroethylene Toxicokinetics In Mice, Rats, and Humans (Chiu & Ginsberg, 2011).

    USEPA’s direct response to the NRC comment was:

    EPA accepts these NRC recommendations, agrees that a “harmonized” PBPK model that includes data regarding the GSH pathway would be beneficial, and has developed such a model that integrates multiple exposure routes and tissue compartments (Section 3.5). Additionally, EPA followed the NRC advice of separating metabolism into three pathways (oxidation, GSH-conjugation with further β-lyase metabolism, and GSH-conjugation with further β-lyase-independent metabolism). (USEPA, 2012)

    USEPA’s dose response modeling relied on the Chiu and Ginsberg (2011) PBPK model to estimate the total rate of oxidative metabolism in the liver, which was determined to be the most relevant dose-metric for tetrachloroethylene-induced adenomas and carcinomas.

    In conclusion, the NRC in 2010 had similar criticisms about the existing PBPK models for PCE as ORS did in 2008. Subsequently, USEPA took NRC’s recommendations into account and developed a robust “harmonized” PBPK model, which it used to derive the final IUR. USEPA’s harmonized model comprehensively incorporates all metabolic pathways known for PCE and uses a dose metric that reflects scientific advances in the understanding of PCE’s mode of action that have occurred during the five years since ORS last reviewed the toxicological literature on PCE.

    Superiority of the JISA (1993) Study Versus the NTP (1986) Study

    USEPA (2012) derived an IUR for PCE based on benchmark dose modeling of the combined incidence of hepatic adenomas and carcinomas from JISA (1993) using the one-degree multi-stage model. USEPA relied on JISA (1993) versus NTP (1986) because JISA (1993) was a superior study for dose response modeling. According to USEPA:

    The lower exposure of both mice and rats in the JISA bioassay and the use of three—rather than two—exposure groups provides a stronger basis for deriving dose-response relationships for risk assessment purposes, insofar as all other aspects of these studies can be considered comparable. For mice, the lowest and mid-dose exposure concentrations in the JISA (1993) study were 10- and twofold lower, respectively, than the lower exposure concentration (100 ppm) in the NTP (1986) inhalation study. (USEPA, 2012)

    Specifically, NTP (1986) had two dose groups, 100 ppm and 200 ppm. JISA (1993) had three dose groups, 10 ppm, 50 ppm, and 250 ppm.

    Despite the fact that the interim IUR was based on the MCL endpoint, MassDEP (2008) also derived candidate IURs for the combined incidences of hepatic adenomas and carcinomas in male mice using data from both the NTP (1986) and the JISA (1993) studies. ORS gave equal weight to both studies: “Data from both inhalation studies were deemed to be adequate for dose response analysis.” (MassDEP, 2008) ORS found that the candidate IURs based on male mouse hepatic cancer were identical using both data sets.

    Given that ORS concluded that both studies were adequate for dose-response analysis and lead to the same results, ORS should have no disagreement with USEPA’s reliance on the JISA (1993) study for purposes of deriving its IUR.


    In 2008, MassDEP (2008) derived an interim IUR for PCE based on an assessment of the toxicological database for PCE as it existed in 2007. Since 2007, there has been significant progress on the hazard assessment of PCE. USEPA (2008) issued its Draft IRIS Assessment of Tetrachloroethylene in 2008. The NRC (2010) issued its Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene in 2010, in which it provided USEPA with several criticisms of its draft report. When USEPA (2012) issued its Final IRIS Assessment of Tetrachloroethylene, it performed significant additional work to address the NRC’s comments. Given the massive investment in PCE risk assessment made by USEPA and NRC, the improvement in our understanding of PCE’s mode of action, the development of a robust “harmonized” PBPK model for PCE, and the MCP’s stated reliance on USEPA as a source of Unit Risk factors, ORS should withdraw the interim IUR for PCE and adopt USEPA’s final IUR.


    USEPA. 2008. (United States Environmental Protection Agency). Toxicological ReviewOfTetrachloroethylene. (Perchloroethylene)
    (CAS No. 127-18-4). In Support of Summary Information on the
    Integrated Risk Information System (IRIS). June 2008. EPA/635/R-08/011A.

    USEPA. 2012. (United States Environmental Protection Agency). Toxicological Review Of Tetrachloroethylene. (Perchloroethylene)
    (CAS No. 127-18-4). In Support of Summary Information on the
    Integrated Risk Information System (IRIS). February 2012. EPA/635/R-08/011F.

    MassDEP. 2008. Revised MassDEP Cancer Unit Risk for Tetrachloroethylene. Office of Research and Standards. September 2008

    NRC. 2010. (National Research Council). Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene. Committee to Review EPA’s Toxicological Assessment of Tetrachloroethylene. National Research Council.

    ARCADIS U.S., Inc.

    Brian Magee, Ph.D.
    Vice President
    Principal Toxicologist

    cc: Sandra Baird, ORS
    Gregory A. Bibler, Esq.

  2. NAIOP Supports EPA’s PCE Toxicity Values

    Letter from Tamara C. Small
    Director of Government Affairs
    NAIOP Massachusetts

    download: https://mcpregreform.files.wordpress.com/2012/04/final_march_2012_pce_naiop_ericson_memo.pdf

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