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DRAFT-DO NOT CITE OR QUOTE 

NCEA Proposed Draft SAB Peer Review Charge for EPA’s Response to “Health 

Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment 

(2006)” Published by the National Research Council of the National Academies

 

May, 2010 

EPA has been preparing an assessment of the potential 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 Related 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 Academy 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: Evaluation of 

the EPA Reassessment (NRC, 2006). 

The current draft document EPA's Reanalysis of Key Issues Related to Dioxin Toxicity 

and Response to NAS Comments (“Response to Comments”) before the SAB is a response 

to the review by the NRC, and includes new analyses completed 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. However, the draft Response to Comments provides a noncancer 

reference dose and updated cancer values. Detailed discussions of many of the issues 

addressed 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 they believed would result in 

substantial improvement to the EPA 2003 Reassessment and thus support a scientifically 

robust characterization of human responses to exposures to TCDD. These three key areas 

are (1) improved transparency and clarity in the selection of key data sets for doseresponse analysis, (2) further justification of approaches to dose-response modeling for 

cancer and noncancer endpoints, and (3) improved transparency, thoroughness, and 

clarity in quantitative uncertainty analysis. The NRC Report also encouraged EPA to 

calculate a reference dose (RfD), which had not been derived in the 2003 Reassessment. 

The draft Response to Comments document addresses each of these issues. Please 

consider the accuracy, objectivity, and transparency of EPA’s reanalysis and responses in 

your review. 

General Charge Questions 

1. Is the draft Response to Comments clear and logical? Has EPA objectively and clearly 

presented the three key NRC recommendations? 
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2. Are there other critical studies that would make a significant impact on the 

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

noncancer and cancer health effects of TCDD?

Specific Charge Questions

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

1. Is this Section responsive to the NAS concern about 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 bioassay study criteria/considerations 

in a scientifically sound manner? If not, please identify 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 metric. In the 

draft Response to Comments document, EPA used a physiologically-based 

pharmacokinetic (PBPK) model (Emond et al., 2004, 2005, 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 biological description of the dose-dependent 

elimination rate of TCDD. EPA made specific modifications 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 literature, EPA chose whole blood 

TCDD concentrations as the relevant dose metric because 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 justification of applying a PBPK model with whole blood TCDD 

concentration as a surrogate for tissue TCDD exposure in lieu of using first-order 

body burden for the dose-response assessment of TCDD. 

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

 other available TCDD kinetic models. 

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

 

 d. Whether EPA adequately characterized the uncertainty in the kinetic models. 
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2. Several of the critical studies for both noncancer and cancer dose-response assessment 

were conducted in mice. A mouse PBPK model was developed from an existing rat 

model in order to estimate TCDD concentrations in mouse tissues, including whole 

blood. 

Please comment on: 

a. The scientific rationale for the development of EPA’s mouse model based on 

the published rat model (Emond et al., 2004, 2005, 2006). 

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

 c. Whether EPA adequately characterized the uncertainty in the mouse and rat 

 kinetic models. Please comment specifically on the scientific justification of the 

 kinetic extrapolation factor from rodents to humans. 

3. Please comment on the use of the Emond et al. PBPK model to estimate human 

intakes based on internal exposure measures. 

4. Please comment on the sensitivity analysis of the kinetic modeling (see section 3.3.5). 

5. Both EPA’s noncancer and cancer dose-response assessments 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. Reference Dose

1. The Mocarelli et al. (2008) and Baccarelli et al. (2008) studies were selected as cocritical studies for the derivation of the RfD. Is the rationale for this selection 

scientifically justified and clearly described? Please identify and provide the rationale for 

any other studies that should be selected, including the rationale for why the study would 

be considered a superior candidate for the derivation of the RfD. In addition, male 

reproductive effects and changes in neonatal thyroid hormone levels, respectively, were 

selected as the co-critical effects for the RfD. Please comment on whether the selection of 

these critical effects is scientifically justified and clearly described. Please identify and 

provide the rationale for any other endpoints that should be selected as the critical effect. 

2. In the Seveso cohort, the pattern of exposure to TCDD is different from the average 

daily exposure experienced by the general population. The 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 pulse of TCDD was slowly 

eliminated from body tissues over time. There is uncertainty regarding the influence of 

the high-dose pulse exposure on the effects observed later in life. 

 a. Mocarelli et al. (2008), reported male reproductive effects observed later in 

 life for boys exposed to the high dose pulse of TCDD between the ages of 1 and 
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 10. EPA identified a 10 year critical exposure window. In the development of 

 the candidate RfD, EPA used an exposure averaging approach that differs from 

 the typical approach utilized for animal bioassays. EPA determined that the 

 relevant exposure should be calculated as the mean of the pulse exposure and the 

 10-year critical exposure window average. Please comment on the following: 

 i. EPA’s approach for identifying the exposure window and calculating 

 average exposure for this study. 

 ii. EPA’s designation of a 20% decrease in sperm count (and an 11% 

 decrease in sperm motility) as a LOAEL for Mocarelli et al. (2008). 

 b. 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 of 

 the relevant effective dose as opposed to extrapolating from the measured infant 

 TCDD concentrations 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: 

 

 i. EPA’s decision to use the reported maternal levels and the 

 appropriateness of this exposure estimate for the Baccarelli et al. study. 

 

 ii. EPA’s designation of 5 μ-units TSH per ml blood as a LOAEL for 

 Baccarelli et al. (2008). 

3. Please comment on the rationale for the selection of the uncertainty factors (UFs) for 

the RfD. If changes to the selected UFs are proposed, please identify and provide a 

rationale. 

4. EPA did not consider biochemical endpoints (such 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 adversity associated with such endpoints 

and quantitative determination of appropriate response levels for these types of endpoints 

in relation to TCDD exposure. Please comment on whether this decision is scientifically 

justified and clearly described 

5. In using the animal bioassays, EPA averaged internal blood TCDD concentrations over 

the entire dosing period, including the 24 hours following the last exposure. Please 

comment on EPA’s approach for averaging exposures including intermittent and one day 

gestation exposure protocols. 
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6. Please comment on the benchmark dose (BMD) modeling conducted by EPA to 

analyze the animal bioassay data and EPA’s choice of points of departure (PODs) from 

these studies. 

7. For the animal bioassay modeling, EPA applied the kinetic extrapolation at the level 

of the POD prior to applying the uncertainty factors 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. 

8. Please comment as to whether EPA’s qualitative discussion of uncertainty in the RfD 

is justified and clearly described. 

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 Guidelines for Carcinogen Risk 

Assessment (U.S. EPA, 2005) TCDD is “carcinogenic to humans.” Is the weight-ofevidence characterization scientifically justified and clearly 

described? 

2. Mode of Action: The mode of action of a carcinogen can inform identification of 

hazards and approaches used for a dose-response assessment. The mode of carcinogenic 

action for TCDD has not been elucidated for any tumor 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 downstream events involved are unknown. 

 a. Are the available data related to mode(s) of action for the carcinogenicity of 

 TCDD appropriately characterized and clearly presented? 

 

 b. Do the available data support EPA’s conclusion that the overall mode(s) of 

action for TCDD-induced carcinogenesis is largely unknown? Please comment 

on whether this evaluation is clearly described. 

3. Is EPA’s approach for selecting data sets from the key epidemiologic studies and 

animal bioassays identified for cancer dose response 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 approach) from the 

point of departure (POD). EPA also estimated the composite risk of the occurrence of 

several tumor types from the animal cancer bioassay data. 

a. Please comment on whether the approach for estimating cancer risk, including 

the use of tumor modeling of the TCDD animal cancer bioassay data, is 

scientifically justified and clearly described. 
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5. EPA selected Cheng et al. (2006) -- an analysis of the NIOSH occupational cohort-- as 

the critical study for oral slope factor (OSF) development. 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 this selection is scientifically 

 justified and clearly described. Please identify and provide the rationale for any 

other studies that should be considered and provide a critical evaluation of the 

study and of its suitability for meeting the goals of a quantitative cancer 

assessment. 

 b. Cheng et al. (2006) analyzed all-cancer mortality. Please comment on the use 

 of all-cancer mortality as the basis of the OSF. 

 c. Please comment on whether the use of the Emond PBPK model in the 

 derivation of the (dose-dependent) OSF using the Cheng et al. dose-response 

 modeling results is scientifically justified and clearly described. 

 d. Due to nonlinearities in the Emond PBPK model (specifically pertaining to the 

 relationship between exposure and internal dose), EPA calculated a series of 

 risk-specific oral slope factors. Please comment on EPA’s rationale for and 

 presentation of these slope factors. 

e. The slope factor derived from Cheng et al. (2006) was extrapolated below the 

background TCDD exposure levels experienced by the NIOSH cohort. Please 

comment on this extrapolation. 

6. Please comment on whether EPA has clearly described the major qualitative 

uncertainties in the derivation of the OSF. 

7. EPA did not consider dioxin-like compounds (DLCs) in the cancer dose-response 

modeling because the occupational exposures in the available cohorts were primarily to 

TCDD. Background DLC exposures were not incorporated in the dose-response 

modeling because EPA judged that it was not possible to disaggregate the responses from 

background exposure to DLCs and occupational exposure to TCDD. Please comment on 

whether this approach is scientifically justified and clearly described. 

8. 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. 

 a. Please comment on EPA’s conclusions regarding the limitations of these 

 approaches. 
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 b. Are there other nonlinear approaches that could be readily developed based on 

 existing data for the assessment of TCDD carcinogenicity? If so, please suggest 

 alternative approaches and describe their utility and suitability for meeting the 

 goals of a quantitative cancer assessment. 

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

the 2003 Reassessment

1. Please comment on the discussion in this Section. Is the response clearly presented 

and scientifically justified? 

2. Please comment on EPA’s overall conclusion that a comprehensive quantitative 

uncertainty analysis is not feasible. 

 

 a. Please comment on the discussion in Section 6 regarding volitional uncertainty 

 and how this type of uncertainty limits the ability to conduct a quantitative 

 uncertainty analysis. 

3. Throughout the document (including the Appendices), EPA presents a number of 

limited sensitivity analyses (e.g., toxicokinetic modeling, RfD ranges, cancer OSF ranges, 

cancer RfD development). Please comment on the approaches used, and the utility of 

these sensitivity analyses in clarifying potential significant uncertainties.