DOC

DRAFT- FOR INTERNAL POLICY DELIBERATIONS ONLY

By Luis Butler,2014-11-25 10:14
10 views 0
DRAFT- FOR INTERNAL POLICY DELIBERATIONS ONLY

    Revised MassDEP Cancer Unit Risk for

    Tetrachloroethylene

    Office of Research and Standards

    MassDEP

    September, 2008

    Contributing Authors:

    Tsedash Zewdie Ph.D.

    Sandra Baird D.Sc.

    C. Mark Smith Ph.D., M.S.

    Carol Rowan-West, MSPH

    Advisory Committee:

    DEP/DPH Advisory Committee on Health Effects

DEP is very appreciative of the participation of the members of the Health Effects

    Advisory Committee in the scientific peer review of DEP’s draft toxicity assessment.

    Their generous commitment of time and tremendous expertise have been extremely

    helpful to our efforts on this important issue. The participation of independent public

    health scientists is a critical component of our state’s efforts to protect public health and

    the environment in MA. Participants included:

    David Brown, ScD

    Public Health Toxicologist

    Northeast States for Coordinated Air Use Management

    Boston, MA

    Barbara Callahan, PhD.

    Toxicology and Adjunct Professor

    University of Massachusetts

    Amherst, MA

    Suzanne Condon, MPH

    Assistant Commissioner

    Bureau of Environmental Health Assessment

    Massachusetts Department of Public Health

    Boston, MA

    Ann Marie Desmaris, PhD.

    Toxicologist

    Professor, Civil and Environmental Engineering

    Tufts University

    Medford, MA

     Page ii

    Gary Ginsberg, PhD

    Toxicologist, Department of Public Health, Division of Environmental Epidemiology

    and Occupational Health

    Hartford, CT

    Dale Hattis, PhD

    Toxicologist, Center for Environment and Technology

    Clark University

    Worcester, MA

    David Naparstek

    Commissioner of Health

    City of Newton

    Newton, MA

    Martha Steele, MPH

    Deputy Director

    Bureau of Environmental Health Assessment Massachusetts Department of Public Health

    Boston, MA

    William Sweet, PhD

    Toxicologist, Agency for Toxic Substances and Disease Registry

    U. S. Center for Disease Control

    Boston, MA

     Page iii

    Table of Contents

EXECUTIVE SUMMARY ....................................................................................... VII

    1.0 INTRODUCTION ............................................................................................. 1

    2.0 SUMMARY OF CARCINOGENICITY INFORMATION ............................. 2

    2.1 CANCER STUDIES IN HUMANS ........................................................................... 2 2.2 CANCER STUDIES IN ANIMALS........................................................................... 2

    2.2.1 Mouse Oral Study (NCI, 1977) ................................................................. 3

    2.2.2 Rat Oral Study (NCI, 1977) ...................................................................... 3

    2.2.3 Mouse Inhalation Study (NTP, 1986) ........................................................ 3

    2.2.4 Rat Inhalation Study (NTP, 1986) ............................................................ 4

    2.2.5 Mouse Inhalation Study (JISA, 1993) ....................................................... 4

    2.2.6 Rat Inhalation Study (JISA, 1993) ............................................................ 4

    3.0 MODES OF ACTION, METABOLISM AND BASIS OF

    EXTRAPOLATION TO HUMANS ............................................................................. 5

    3.1 MODES OF ACTION ........................................................................................... 5 3.2 METABOLISM ................................................................................................... 5

    3.2.1 Metabolic pathways.................................................................................. 5

    3.2.2 Human Metabolism at Low Exposure Concentrations............................... 6

    3.3 DOSE METRIC FOR CROSS-SPECIES EXTRAPOLATION ....................................... 10

    3.4 METHODS APPLIED FOR CROSS-SPECIES EXTRAPOLATION ............................... 12

    3.4.1 Metabolized Dose Method ...................................................................... 12

    3.4.2 Duration Adjusted Applied Concentration Method ................................. 13

    4.0 SUMMARY OF PAST PCE CARCINOGENIC RISK ASSESSMENTS BY

    MASSDEP (1990); CAEPA (1992; 2001) AND WHO (2006) .................................... 13

    4.1 MASSDEP (1990) ........................................................................................... 13

    4.1.1 Unit Risk Derivation in MassDEP 1990 Assessment ............................... 14

    4.2 CAEPA (1992) ............................................................................................... 16 4.3 CAEPA (2001) ............................................................................................... 18 4.4 WORLD HEALTH ORGANIZATION (2006) ......................................................... 19 5.0 BASIS OF REVISED MASSDEP UNIT RISK VALUE ................................ 21

    5.1 HAZARD IDENTIFICATION AND CARCINOGENIC CLASSIFICATION ...................... 21

    5.2 MECHANISM OF ACTION ................................................................................. 21 5.3 CHOICE OF CRITICAL STUDIES AND ENDPOINTS TO DERIVE UNIT RISK VALUE . 21

    5.3.1 Exposure Route ...................................................................................... 21

    5.3.2 Study Choice .......................................................................................... 22

    5.3.3 Response Endpoints................................................................................ 22

    5.4 ESTIMATING THE FRACTION OF PCE METABOLIZED BY HUMANS AT LOW

    EXPOSURE CONCENTRATIONS ..................................................................................... 23 5.5 CHOICE OF DOSE METRICS TO DERIVE UNIT RISK VALUE ................................ 23

    6.0 CONCLUSIONS .............................................................................................. 23

     Page iv

7.0 REFERENCES ................................................................................................ 28

    TABLE LIST

    Table 1. Studies Evaluating Metabolism of Tetrachloroethylene in 7

     Humans

    Table 2. Comparison of Potency Factors and Unit Risk Values 16

     Calculated by MassDEP Based on the NCI (1977) and NTP

    (1986) Studies (MassDEP, 1990)

    Table 3. Comparison of Cancer Potency Factors and Unit Risks 17

     Calculated by CAEPA Based on the NCI (1977) and NTP

    (1986) Studies (CAEPA, 1992)

    Table 4. Cancer Potency Factors and Unit Risks Calculated by 18

     CAEPA Based on the NTP (1986) Studies (CAEPA, 2001)

    Table 5. Summary of Potency Factors and Unit Risk Values Derived 20

     by Various Groups Based on Cancer Bioassays

    Table 6. Proposed Interim Unit Risk Value Derived by MassDEP 24

    FIGURE LIST

    Figure 1. Tetrachloroethylene Carcinogenicity: Hepatocellular 25

     Carcinomas and Adenomas Combined in Mice

    Figure 2. Tetrachloroethylene Carcinogenicity: Mononuclear Cell 25

     Leukemia in Rats

    Figure 3. Oxidative biotransformation pathway of tetrachloroethylene 26

     (de Raat, 2003, as cited in WHO, 2006)

    Figure 4. Conjugative biotransformation pathway of 27

     tetrachloroethylene (de Raat, 2003, as cited in WHO, 2006).

    APPENDICES

    Appendix A Summary of Epidemiology Literature from WHO (2006)

    Appendix B Individual Subject and Occasion Data from Chui et al.

     (2007)

     Page v

    Appendix C MassDEP (1990) Derivation of Unit Risk for PCE from

     the NCI (1977) Oral Gavage Study

    Appendix D MassDEP (1990) Derivation of Unit Risk for PCE from

     the NTP (1986) Inhalation Study

    Appendix E CAEPA (1992) Derivation of Unit Risk Values for PCE

     Using the NTP (1986) Inhalation Study

    Appendix F CAEPA: 1992 and 2001 Comparison of Methods Used for

     Derivation of Unit Risk for PCE Using the NTP (1986)

    Inhalation Study

    Appendix G MassDEP (2007) Derivation of Unit Risk for PCE Using

     the Japan Industrial Safety Association (JISA, 1993)

    Inhalation Study

    Appendix H Brief Critique of Covington et al. 2007 Paper

    Appendix I Benchmark Dose Analysis Modeling Summaries

     Page vi

Executive Summary

     -5 3-1An interim unit risk value of 1 x 10(g/m) is recommended for tetrachloroethylene

    (PCE, also known as perchloroethylene) in air. The unit risk value is based on statistically significant incidence of leukemia in rats, supported by liver tumor data in mice (NTP, 1986; JISA, 1993). Statistically significant increases in the incidence of tumors at several sites have also been observed in certain studies of workers in the dry-cleaning industry (WHO, 2006 and citations there in).

    For the calculation of the cancer potency estimates, used as a basis for the unit risk value, the United States Environmental Protection Agency (USEPA, 2005) Guidelines for

    Carcinogenic Risk Assessment were used. Although the mode of action is uncertain for

    PCE, several lines of evidence suggest that the linear low-dose extrapolation assumption is reasonable. The multistage model (USEPA Benchmark Dose Software, version 1.4.1) was fit to the experimental data in order to estimate the lower 95 percent confidence bound on the dose associated with a 10 percent increased risk of cancer (BMDL), and 10

    the slope (potency factor) was calculated using the result (0.1/BMDL). 10

    The dose metric chosen to perform the dose-response assessment was the metabolized dose calculated using Michaelis-Menton steady-state kinetics. Chui and Bois (2006) estimated an upper limit of the fraction metabolized at an environmentally relevant concentration in a human population to be 61%. This calculation was performed using population toxicokinetics, Bayesian statistics and physiological modeling. MassDEP selected this value as a conservative, health protective estimate of the low dose metabolism of PCE in humans.

    Proposed Interim Unit Risk Value Derived by MassDEP

    MassDEP Proposed Interim Bioassay and Species, Strain Unit Risk Values Unit Risk Value 3-13-1exposure route Sex, Tumor type (ug/m) (ug/m)

     -5 NTP, 1986 F344 rat 1.7 x 10

    inhalation male, leukemia -5 a 1 x 10

     -6JISA, 1993 F344 rat 9.3 x 10

    inhalation male, leukemia

     -5 -5NTP, 1986 B6C3F1 mice male 1.30 x 10 1 x 10

    inhalation liver tumors

     a Mean of the unit risk values based on leukemia in rats incidence observed in the NTP (1986) and

    JISA (1993) studies. The values were averaged because the tumor bioassays were conducted in the -53-1-53-1same species. The geometric mean, 1.26 x 10 (ug/m), and arithmetic mean 1.32 x 10 (ug/m) are -53-1both equivalent to 1 x 10 (ug/m) when rounded to one significant figure. The male mice liver tumor

    data yields the same value.

     Page vii

1.0 Introduction

    Tetrachloroethylene (PCE, also known as PERC) is a frequent soil and groundwater contaminant. Because it is volatile, indoor air can be contaminated to potentially significant levels in buildings situated over soil or groundwater containing PCE. To reflect new scientific information, the MassDEP Bureau of Waste Site Cleanup (BWSC) recently updated various chemical-specific factors that are used in fate and transport modeling to assess potential exposures and risks from groundwater and soil contaminants. 1As a result of these updates, the Groundwater 2 (GW-2) standard for PCE decreased

    from 3000 ppb to 50 ppb leading to more sites of concern for indoor air contamination and the need for further quantitative, site-specific assessments to address PCE inhalation cancer risk. The degree of cancer risk posed by PCE is a matter of considerable national debate and ongoing scientific research. The cancer risk value previously derived and adopted by MassDEP in 1990 has been questioned as being overly health-protective and out-of-date.

    To address these issues, BWSC requested the Office of Research and Standards (ORS) to review and update, as necessary, the MassDEP inhalation cancer value for PCE. ORS had planned to revise the MassDEP PCE cancer risk value in light of a pending report by USEPA and scheduled review by the National Academy of Sciences. USEPA has worked for several years to complete an updated toxicity assessment of PCE and was scheduled to release a draft of its report in November 2006 and then again this past summer. In light of the controversy regarding PCE toxicity, a National Academy of Science panel was also selected to review the USEPA report when it is completed.

    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.

The purpose of this brief report is to review and update MassDEP’s carcinogenic 2assessment and inhalation unit risk value for PCE in light of more recent assessments by

    the California Environmental Protection Agency (CAEPA); the Northeast States for Coordinated Air Use Management (NESCAUM); and the World Health organization (WHO). The reassessment addresses new inhalation data from a second series of cancer bioassays by the Japan Industrial Safety Association (JISA, 1993) not available when MassDEP completed its 1990 assessment; new information on the extent of PCE

     1 GW-2 values apply to groundwater that is not protected as drinking water but which may impact buildings. Values are set at levels to prevent significant indoor risk attributable to vapor intrusion. 2 For more comprehensive review of the overall toxicity of this chemical, readers are referred to documents completed by the groups noted above as well as by the Agency for Toxic Substances and Disease Registry (ATSDR, 1997).

     Page 1

    metabolism in humans (e.g. Chui et al. (2007), Chui and Bois (2006), Bois et al. (1996); Covington et al. (2007)); and the adoption by USEPA of a revised interspecies scaling factor for dose extrapolation and new cancer risk assessment guidelines.

2.0 Summary of Carcinogenicity Information

    Based on compelling positive data from multiple animal bioassays and equivocal epidemiological data, many groups have classified PCE as a known animal carcinogen and possible to probable human carcinogen. The International Agency for Research on Cancer (IARC) has classified PCE as a category 2A carcinogen (probable human carcinogen, indicating sufficient evidence of carcinogenicity in animals and inadequate evidence in humans) (IARC, 1995b). PCE was previously classified as a possible human carcinogen by the USEPA Integrated Risk Information System (IRIS) program but is currently being reassessed by USEPA. CAEPA (1992, 2001) considers PCE to be an animal carcinogen and a possible human carcinogen.

    Brief summaries of the human and animal carcinogenicity information on PCE are presented below.

2.1 Cancer Studies in Humans

    The cancer epidemiology data in humans exposed to PCE have been extensively reviewed by ATSDR (1997), IARC (1995a, b), CAEPA (1992), USEPA (1985). Twenty-five epidemiological studies published between 1981 and 2003 were also reviewed by WHO (2006) (see Appendix A for a summary table of the studies including relative risk values). Epidemiological studies have reported possible associations between exposures to PCE and cancer of esophagus, kidney, bladder and urinary tract, cervix, non-Hodgkin’s lymphoma, multiple myeloma, liver, pancreas, larynx and lung. The cancer studies showed fairly consistent positive, although typically not statistically significant, associations between exposure to PCE and esophageal and cervical cancer and non-Hodgkin’s lymphoma. IARC noted that, “These associations appear unlikely to be due to chance, although confounding cannot be excluded and the total cohort studies combined are relatively small” (IARC (1995b), as cited in WHO (2006)).

    None of the epidemiological studies provide data adequate for quantitative risk assessment. As in many epidemiological studies they are confounded by exposure to other chemicals, limited individual exposure data, and other factors that preclude the derivation of quantitative potency estimates.

2.2 Cancer Studies in Animals

    The carcinogenicity of PCE has been evaluated in several animal bioassays. The three studies that provide good dose-response data for carcinogenic potency assessment of PCE are summarized briefly below. These include bioassays by the US National Cancer Institute (NCI, 1977), the US National Toxicology Program (NTP, 1986), and the Japan Bioassay Research Centre (JISA, 1993). In these studies, ingestion and inhalation

     Page 2

    exposure pathways were assessed using 2 or 3 dose groups (in addition to concurrent controls) in males and females of two strains of mice and one strain of rats. Statistically positive results were observed in each study with the predominant and consistent responses being tumors of the liver in mice and mononuclear cell leukemia (MCL) in rats. Less significant elevations of tumor rates at other sites were also observed in one or more of the bioassays. These studies are briefly discussed in the following paragraphs.

2.2.1 Mouse Oral Study (NCI, 1977)

     In the National Cancer Institute study (NCI, 1977), B6C3Fmice were administered PCE 1

    in corn oil by gavage, 5 days/week for 78 weeks with an additional 12 week observation period. Mice were 25 days old at initial treatment. The administered doses of PCE were 536 and 1,072 mg/kg for male mice and 386 and 722 mg/kg for female mice. A

    statistically significant increase (P<0.001, Fisher Exact test) in hepatocellular carcinoma was observed in both males and females (See Appendix C, Table C-1). The

    NCI concluded that under the conditions of this study, PCE was a liver carcinogen to B6C3F mice of both sexes. Interpretation of this data is complicated by the fact that 1

    epichlorohydrin (ECH), which itself is a direct acting alkylating agent and mutagen that has been demonstrated to be weakly tumorigenic in mice, was apparently used as a stabilizer. However, an analysis by the NCI concluded that ECH at the concentrations likely to have been present was unlikely to have contributed significantly to the observed tumor responses (NCI, 1977).

2.2.2 Rat Oral Study (NCI, 1977)

    Male and female Osborne-Mendel rats were treated with 471mg/kg-d or 941mg/kg-d, and 474 mg/kg-d or 949 mg/kg-d PCE, respectively, by gavage in corn oil (78 weeks with an additional 32 week observation period). Early mortality occurred in all groups of rats dosed with PCE. Half of the high-dose males had died by week 44 and half of the high-dose females died by week 66. The survival time of control animals ranged from 88 to 102 weeks. The NCI determined that there was a statistically significant association (p<0.001) between increased dosage of PCE and increased mortality. The early mortality observed in rats, and its statistical association with PCE dose, indicate that the maximum tolerated dose was exceeded in this experiment. Because optimum dosages were not used and because significant early mortality occurred, firm conclusions regarding the carcinogenicity of PCE in rats are not possible from this study.

2.2.3 Mouse Inhalation Study (NTP, 1986)

B6C3F mice were exposed to 99.9 percent pure PCE by inhalation, 6 hours/day, 5 l

    days/week for 103 weeks at concentrations of 0, 100, or 200 ppm (NTP, 1986). Hepatocellular adenoma and hepatocellular carcinoma in males and hepatocellular carcinomas in females were observed. The incidences of hepatocellular carcinoma

    compared to controls were significantly increased (P<0.01, Fisher Exact test) for mid- and high-dose males and females (See Figure 1 and Appendix D, Table D-1). The NTP determined that there was “clear evidence of carcinogenicity” of PCE for both sexes of B6C3F mice in this study. 1

     Page 3

Report this document

For any questions or suggestions please email
cust-service@docsford.com