Internal and Deliberative Draft 3 16 2010

1 NCEA Proposed Draft SAB Peer Review Charge for EPA’ s Response to “Health Risks from Dioxin and Related Compounds: Evaluatio n of the EPA Reassessment” Published by the National Research Council of the N ational Academies

March, 2010

EPA has been preparing an assessment of the potenti al health impacts of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) for many years. In 2003, EPA released an external review draft report entitled, Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Rela ted Compounds (U.S. EPA, 2003) (herein referred to as “ 2003 Reassessment ”) that was reviewed by the EPA Science Advisory Board (SAB), and then by the National Acad emy of Sciences (NAS). In 2006, the National Research Council (NRC) of the National Academies published their report of EPA’s reassessment, Health Risks from Dioxin and Related Compounds Eval uation of

the EPA Reassessment

(NRC, 2006).

The current draft document (“ Response to Comments ”) before the SAB is a response to the review by the NRC, and includes new analyses co mpleted in response to the NRC recommendations and recently published literature, as well as a discussion of topics

where our views differed. The draft Response to Comments document is not an assessment per se; it is designed to supplement the information provided in the 2003

Reassessment . Detailed discussions of many of the issues addre ssed in the draft Response to Comments are available in the 2003 Reassessment and have not been reproduced in the current draft document– whenever appropriate; the reader is directed to the pertinent chapters of the 2003 Reassessment

.

The NRC identified three key recommendations that t hey believed would result in substantial improvement to the EPA 2003 Reassessment and thus support a scientifically robust characterization of human responses to expos ures to TCDD. These three key areas are (1) improved transparency and clarity in the se lection of key data sets for doseresponse analysis, (2) further justification of app roaches to dose-response modeling for cancer and noncancer endpoints, and (3) improved tr ansparency, thoroughness, and clarity in quantitative uncertainty analysis. The N RC Report also encouraged the EPA to calculate a Reference Dose (RfD), which had not bee n derived in the 2003 Reassessment

sent to them for review. The draft Response to Comments document addresses each of

these issues.

General Charge Questions

1. Is the draft Response to Comments clear and logical? Has EPA objectively and clearl y presented the three key NRC recommendations?

2. Are there other critical studies that would mak e a significant impact on the

conclusions of the hazard characterization or dose- response assessment of the chronic

noncancer and cancer health effects of TCDD?Internal and Deliberative Draft 3 16 2010

2 Specific Charge Questions

Section 2. Transparency and Clarity in the Selecti on of Key Data Sets for DoseResponse Analysis

1. Is this Section responsive to the NAS concern a bout transparency and clarity in dataset selection for dose-response analysis?

2. Are the epidemiology and animal bioassay study criteria/considerations scientifically justified and clearly described?

3. Has EPA applied the epidemiology and animal bio assay study criteria/considerations in a scientifically sound manner? If not, please i dentify and provide a rationale for alternative approaches.

Section 3. The Use of Toxicokinetics in the Dose- Response Modeling for Cancer and Noncancer Endpoints

1. The 2003 Reassessment utilized first-order body burden as the dose metri c. In the

draft Response to Comments document, EPA used a physiologically-based pharmacokinetic (PBPK) model (Emond et al., 2004, 2 005, 2006) with whole blood

concentration as the dose metric rather than first- order body burden. This PBPK model was chosen, in part, because it includes a biologic al description of the dose-dependent elimination rate of TCDD. EPA made specific modifi cations to the published model based on more recent data. Although lipid-adjusted serum concentrations (LASC) for TCDD are commonly used as a dose metric in the lite rature, EPA chose whole blood

TCDD concentrations as the relevant dose metric bec ause serum and serum lipid are not true compartments in the Emond PBPK models (LASC is a side calculation proportional to blood concentration).

Please comment on: a. The appropriateness of applying a PBPK model wi th whole blood TCDD concentration as a surrogate for tissue TCDD exposu re in lieu of using first-order body burden for the dose-response assessment of TCD D.

b. The scientific justification for using the Emo nd et al. model as opposed to

other available TCDD kinetic models.

c. The modifications implemented by EPA to the pu blished Emond et al. model.

d. Whether EPA adequately characterized the uncer tainty in the kinetic models.

2. Several of the critical studies for both noncan cer and cancer dose-response assessment

were conducted in mice. A mouse PBPK model was dev eloped from an existing ratInternal and Deliberative Draft 3 16 2010

3 model in order to estimate TCDD concentrations in m ouse tissues, including whole

blood.

Please comment on: a. The scientific rationale for the development o f EPA’s mouse model based on the published rat model (Emond et al., 2004, 2005, 2006).

b. The performance of the mouse model in referenc e to the available data.

c. Whether EPA adequately characterized the uncer tainty in the mouse and rat kinetic models. Please comment specifically on th e scientific justification of the kinetic extrapolation factor from rodents to huma ns.

3. Please comment on the sensitivity analysis of t he kinetic modeling (see section 3.3.5).

4. Both EPA’s noncancer and cancer dose-response a ssessments are based on a lifetime average daily dose. Did EPA appropriately estimate lifetime average daily dose? If not, please suggest alternative approaches that could be readily developed based on existing

data.

Section 4. Chronic Reference Dose

1. EPA did not consider biochemical endpoints (suc h as CYP induction, oxidative stress, etc.) as potential critical effects for derivation of the RfD for TCDD due to the uncertainties in the qualitative determination of a dversity associated with such endpoints and quantitative determination of appropriate respo nse levels for these types of endpoints in relation to TCDD exposure. Please comment on wh ether this decision is scientifically justified and appropriate.

2. EPA selected two epidemiological studies from t he Seveso cohort as the co-critical studies to use in deriving the RfD (Mocarelli et al ., 2008; Bacarelli et al., 2008). In the Seveso cohort, the pattern of exposure to TCDD is d ifferent from the average daily exposure experienced by the general population. Th e explosion in Seveso created a high dose pulse of TCDD followed by low level background dietary exposure in the exposed population. In the population, this high dose puls e of TCDD was slowly eliminated from body tissues over time. There is uncertainty regar ding the influence of the high-dose pulse exposure on the effects observed later in lif e.

Mocarelli et al. (2008), reported male reproductiv e effects observed later in life for boys exposed to the high dose pulse of TCDD between the ages of 1 and 10. EPA identified a 10 year critical exposure window. In the developme nt of the candidate RfD, EPA used an exposure averaging approach that differs from th e typical approach utilized for animal bioassays. EPA determined that the relevant exposu re should be calculated as the mean of the pulse exposure and the 10-year critical expo sure window average. Please commentInternal and Deliberative Draft 3 16 2010

4 on EPA’s approach for identifying the exposure wind ow and calculating average exposure for this study.

For Baccarelli et al. (2008), the critical exposure window occurs long after the high-dose pulse exposure. Therefore, the variability in the exposure over the critical exposure window is likely to be less than the variability in the Mocarelli et al. subjects. EPA concluded that the reported maternal exposures from the regression model developed by Baccarelli et al. provide an appropriate estimate o f the relevant effective dose as opposed to extrapolating from the measured infant TCDD conc entrations to maternal exposures. Additionally, EPA selected a LOAEL of 5 μ-units TSH per ml blood in neonates; as this was established by World Health Organization (WHO) as a level above which there was concern about abnormal thyroid development later in life. Please comment on the following:

a. EPA’s decision to use the reported maternal levels and the appropriateness of this exposure estimate for the Baccarelli et al. study.

b. EPA’s designation of 5 μ-units TSH per ml blood as a LOAEL for the Baccarelli et al. study.

3. In using the animal bioassays, EPA averaged inte rnal blood TCDD concentrations over the entire dosing period, including the 24 hours fo llowing the last exposure. Please comment on EPA’s approach for averaging exposures i ncluding intermittent and one day gestation exposure protocols.

4. Please comment on the benchmark dose (BMD) model ing conducted by EPA to analyze the animal bioassay data and EPA’s choice o f points of departure (PODs) from

these studies.

5. For the animal bioassay modeling, EPA applied t he kinetic extrapolation at the level of the POD prior to applying the uncertainty factor s because EPA has less confidence in the kinetic model output at lower doses reflective of the RfD. Please comment on whether this approach was scientifically justified and clearly described.

6. The Mocarelli et al. (2008) and Baccarelli et a l. (2008) studies were selected as cocritical studies for the derivation of the RfD. Is the rationale for this selection scientifically justified and clearly described? Pl ease identify and provide the rationale for any other studies that should be selected, includin g the rationale for why the study would be considered a superior candidate for the derivati on of the RfD.

7. Please comment on the rationale for the selecti on of the uncertainty factors (UFs) for the RfD. If changes to the selected UFs are propos ed, please identify and provide a

rationale.Internal and Deliberative Draft 3 16 2010

5 8. Please comment as to whether EPA’s qualitative discussion of uncertainty in the RfD is justified and appropriate.

Section 5. Cancer Assessment

1. Weight of Evidence Cancer Descriptor: The 2003 Reassessment concluded that TCDD is a “known human carcinogen.” In the current draft Response to Comments document, EPA concluded that under the 2005 Guideli nes for Carcinogen Risk Assessment (“ 2005 Cancer Guidelines ”; U.S. EPA, 2005) TCDD is “carcinogenic to humans.” Is the weight-of-evidence characterizatio n scientifically justified and clearly

described?

2. Mode of Action: The mode of action of a carcin ogen can inform identification of hazards and approaches used for a dose-response ass essment. The mode of carcinogenic action for TCDD has not been elucidated for any tum or type. EPA concluded that, while interaction with the Ah receptor is likely to be a necessary early event in TCDD carcinogenicity in experimental animals, the downst ream events involved are unknown.

a. Are the available data related to mode(s) of a ction for the carcinogenicity of TCDD appropriately characterized and clearly prese nted?

b. Do the available data support EPA’s conclusion that the overall mode(s) of action for TCDD-induced carcinogenesis is unknown? Please comment on whether this evaluation is clearly described and c onsistent with the 2005 Cancer

Guidelines ?

3. Is EPA’s approach for selecting data sets from the key epidemiologic studies and animal bioassays identified for cancer dose respons e modeling scientifically justified and clearly described?

4. For the animal bioassay data, potential cancer oral slope factors (OSFs) were calculated by linear extrapolation (using a linear, nonthreshold cancer model) from the point of departure (POD). EPA also modeled the com posite risk of several tumor types from the animal cancer bioassay data.

a. Has the modeling approach been appropriately c onducted and clearly

described?

b. Is the use of multiple tumor modeling of the TC DD animal cancer bioassay data scientifically justified and appropriate?

7. EPA selected Cheng et al. (2006) -- an analysis of the NIOSH occupational cohort-- as the critical study for oral slope factor (OSF) deve lopment. This study was chosen because it considers dose-dependent elimination of TCDD rather than first-order kinetics.

a. Please comment on whether the rationale for thi s selection is scientificallyInternal and Deliberative Draft 3 16 2010

6 justified and appropriate. Please identify and pr ovide the rationale for any other studies that should be considered and provide a cr itical evaluation of the study and of its suitability for meeting the goals of a quantitative cancer assessment as outlined by the 2005 Cancer Guidelines

.

b. Please comment on whether the use of the Emond PBPK model in the derivation of the (dose-dependent) OSF using the C heng et al. dose-response modeling results is scientifically justified and a ppropriate.

8. Did EPA appropriately and clearly describe the qualitative uncertainties in the

derivation of the OSF?

9. EPA did not consider dioxin-like compounds (DLC s) in the cancer dose-response modeling because the occupational exposures in the available cohorts were primarily to TCDD. Background DLC exposures were not incorporat ed in the dose-response modeling because EPA judged that it was not possibl e to disaggregate the responses from background exposure to DLCs and occupational exposu re to TCDD. Please comment on whether this approach is scientifically justified a nd appropriate.

10. The NRC suggested that EPA consider nonlinear approaches for the assessment of TCDD carcinogenicity. In the Response to Comments , EPA presents two illustrative nonlinear approaches for cancer, but considers both inappropriate to use because of the

lack of MOA information. Are there other nonlinear approaches that could be readily developed based on existing data for the assessmen t of TCDD carcinogenicity? If so, please suggest alternative approaches and describe their utility and suitability for meeting the goals of a quantitative cancer assessment as ou tlined by the 2005 Cancer Guidelines

.

Section 6. Feasibility of Quantitative Uncertainty Analysis from NAS Evaluation of

the 2003 Reassessment

1. Please comment on the discussion in this Sectio n. Is the response cogently presented and scientifically justified?

2. EPA presents a number of limited sensitivity an alyses (e.g., toxicokinetic modeling, RfD ranges, cancer OSF ranges, cancer dose-response curve shape analyses, cancer RfD development). Please comment on the approaches use d, and the utility of these sensitivity analyses in clarifying potential signif icant uncertainties.