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OMB Staff Working Comments on EPA’s Response to “Health Risks from Dioxin and 

Related Compounds Evaluation of the EPA Reassessment” Published by the National 

Research Council (NRC) of the National Academies (NAS), [dated January 10, 2010] and

Draft Charge to External Reviewers [dated March, 2010].

April 22, 2010

General Science Comments:

• So as to not confuse readers, EPA may want to consider revising the name of this document. 

NAS provided many recommendations to EPA and this document is not a full response, but 

is only a response to comments regarding three key areas (we note that on page xxxiii, line 

16, EPA states that this document only addresses issues related to dose-response. 

Clarification of this in the title would thus be helpful). For instance, EPA does not address 

recommendations related to assessing human exposures. In addition, EPA does much more 

than simply respond to the NAS comments, as EPA provides detailed discussion and analysis 

of new studies, published since 2003 (see Sections 3 and 6). As these new analyses will 

likely be of great interest to EPA’s stakeholder community, a change in title to reflect these 

new evaluations would be helpful. 

o The current title does not accurately reflect all the work EPA has put into updating 

the dioxin reassessment. A suggested title might be along the lines of: “2010 Updated 

Dose Response Analysis of Dioxin and Related Compounds” A subtitle could say: 

“Including a Response to key NRC Recommendations Relating to These Analyses.” 

• We would like to thank EPA to deciding to conduct this interagency review under the IRIS

process, as that serves to clarify for the public how EPA intends to proceed with the review. 

As this document is somewhat unique, and includes much new information and analysis that 

will be undergoing peer review, it may be helpful for EPA to clarify for the public that EPA 

equates this document as being in the new IRIS process at Step 3. As the new IRIS process 

is becoming well-known to the public, this would likely facilitate their participation in the 

document review. 

• One of the important NAS comments, related to the cancer risk, a topic discussed in the 

response to comments, has to do with the classification of Dioxin Like Compounds (DLC). 

NAS stated (page 4): “The committee agrees with EPA in classifying other dioxins and 

DLCs as “likely to be carcinogenic to humans.” However, because mixtures of DLCs may 

also contain dioxins, including TCDD, EPA should reconsider its classification of such 

mixtures as “likely to be carcinogenic to humans” if it continues to classify TCDD as 

“carcinogenic to humans.”” We did not see where this comment was mentioned and 

discussed in the EPA response. Discussion of this may be helpful (for instance on page xlv 

where EPA discusses the weight of evidence statement for carcinogenicity, and elsewhere 

throughout the document).

• In the 3rd paragraph of the charge and elsewhere, EPA states that NRC encouraged EPA to 

calculate an RfD. While this is true, it is important to note that NAS encouraged this in the 

context of providing appropriate margin of exposure (MOE) information. NAS stated on 

page 187 & 197, in the conclusions and recommendations section of the review of the risk 
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characterization: “The committee encourages EPA to calculate RfDs as part of its effort to 

develop appropriate margins of exposure for different end points and risk scenarios, 

including the proportions of the general population and of any identified groups that might be 

at increased risk.” In addition, on page 180, NAS discusses concerns with the EPA use of the 

ED01 and appears more interested in having EPA use traditional point of departure measures 

(such as the NOAEL, LOAEL or BMD). NAS then continues to stress the importance of the 

MOE (page 181: “Because the exposures of a proportion of the U.S. population would be 

above any RfD, it would have been useful for EPA to define the nature and magnitude of the 

risks at different levels of intake, the groups of the population most at risk, and the major 

sources of exposure for any at risk groups. Alternatively, if MOEs were calculated for 

noncancer effects, then the risk characterization should describe the nature of the adverse 

effect and the uncertainties and variability inherent in both the BMD (ED) estimate and the

relevant exposure estimate. It would have been useful if MOE values had been calculated and 

discussed for different exposure scenarios.”). 

o Considering this recommendation, we were disappointed to see that EPA has not 

calculated MOEs as NAS suggested. While following the NAS recommendation is a 

preferred approach, at a minimum EPA should add language discussing this context 

for the NAS recommendation and provide a response. It may also be helpful to have a 

charge question addressing this particular NAS recommendation. 

• As a point of departure (POD) for non-cancer effects, EPA uses a LOAEL which 

corresponds to thyroid stimulating hormone (TSH) values above 5 uU/ml (page xliv and 

elsewhere). It would be helpful for EPA to provide further discussion as to whether or not 

this is an adverse effect or a precursor effect. In Section 4, EPA mentions that the 5uU/ml 

standard “was established by the World Health Organization (WHO, 1994) as an indicator of 

potential iodine deficiency (and potential thyroid problems) in neonates.” What exactly did 

WHO intend when saying it was an indicator of potential thyroid problems? What is the 

rationale of using this as a LOAEL? As WHO mentions iodine deficiency, an evaluation of 

iodine sufficiency in the control and exposed populations would be extremely helpful.

• In flow charts and text throughout the document describing EPAs inclusion criteria for the 

epidemiologic studies and the animal bioassays, criteria include for epidemiology studies 

“dose-response is apparent between TCDD and adverse health effects” “with some 

suggestion of an exposure-response relationship” and for animal studies “magnitude of 

animal response is outside range of normal variability.” Both these criteria lead to the 

exclusion of well-designed studies which did not show adverse effects at the dose levels 

evaluated (which could include the low dose range EPA is interested in). On page 6-15, 

when discussing quantitative uncertainty analysis, EPA states: “If the analysis is restricted to 

experiments showing a positive response, the results will be biased.” 

o While we understand the problems of quantitatively evaluating studies which have no 

dose-response, how does EPA’s weight of evidence approach consider these studies 

which may provide informative information in the low-dose range? Are the studies 

simply excluded? It may be helpful to categorize these studies and perhaps present 

them in a table such that when discussing the weight of evidence for cancer and noncancer effects, EPA could include discussion of the well-designed studies (such as the 

Eskanzi study, for example) which did not show adverse effects when certain key 
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endpoints were evaluated. A charge question on EPA’s approach to handling these 

studies may be helpful.

• Page 4-2 states: “In this document, EPA has developed a strategy for identifying the 

noncancer data sets and PODs that represent the most sensitive and biologically relevant 

endpoints for derivation of an RfD for TCDD.” The layout of the response to comments 

document discusses the selections of animal and epidemiology data showing the lowest 

TCDD doses associated with noncancer effects, then discusses kinetic modeling and 

estimation of human equivalent doses and then in Section 4 EPA presents the dose response 

modeling and then derives the RfD (as described on page 4-1). It may be helpful for EPA to 

have a section discussing the mode of action and scientific plausibility, as well as biological 

relevance of the potential non-cancer effects. This aspect does not appear to be part of EPAs 

inclusion criteria and thus an explicit discussion connecting the potential PODs to the 

potential RfD derivations (including scientific plausibility) may be useful. Page 4-3 cites the 

NAS stating: “The committee recommends that the Reassessment use levels of change that 

represent clinical adverse effects to define the BMR level for noncancer continuous end 

points as the basis for an appropriate POD in the assessment of noncancer effects.” 

o Based on the NAS recommendation, it is not clear that the EPA response is rigorous 

in discussing the clinical adversity of the individual adverse effects that have been 

modeled. If EPA is unable to determine levels of change that represent adversity, this 

limitation should be brought forward for those endpoints. It may be helpful to have a 

charge question addressing this issue.

• Page 5-57, line 3-6, EPA states: “The linear approach is used if the mode of action is not 

understood (U.S. EPA, 2005)”. EPA relies on this, and other information, to support linear 

low dose extrapolation.This seems like an oversimplification as the Cancer Guidelines state 

(see page 1-15 and elsewhere): “Where alternative approaches have significant biological 

support, and no scientific consensus favors a single approach, an assessment may present 

results using alternative approaches.” 

o Page 3-23 of the EPA Cancer Guidelines further states “Nonlinear extrapolation 

having a significant biological support may be presented in addition to a linear 

approach when the available data and a weight of evidence evaluation support a

nonlinear approach, but the data are not strong enough to ascertain the mode of action 

applying the Agency’s mode of action framework.” 

o In the introduction of the Cancer Guidelines EPA states, at page 1-8: “When there are 

alternative procedures having significant biological support, the Agency encourages 

assessments to be performed using these alternative procedures, if feasible, in order to 

shed light on the uncertainties in the assessment, recognizing that the Agency may decide 

to give greater weight to one set of procedures than another in a specific assessment or 

management decision.

o Considering this, it appears that the Cancer Guidelines do not require a full 

understanding of mode of action to support a nonlinear approach. In light of the NAS 

evaluation and their recommendations for a nonlinear approach, it would seem that in 

this case, the nonlinear approach has significant biological support and thus it may 

make sense to present results using both approaches. As the health assessments are 

risk analyses (or really hazard assessments) it would seem that EPA should be 

presenting both approaches and then the risk managers can make the decision 
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regarding which approach may be most appropriate for their intended use as the EPA 

Cancer Guidelines suggest. EPA however discounts the nonlinear approach and thus 

only presents some illustrative examples. 

o It may be useful for EPA to present both approaches and to ask the reviewers to 

comment on whether or not there is significant biological support in their minds for a 

nonlinear approach. If the reviewers then disagree, EPA can move forward with that 

recommendation. However, if the reviewers, consistent with NAS, think that a 

nonlinear approach is supported, then it may be helpful to also provide the reviewers 

with a rigorous set of questions seeking their comments on all aspects of the nonlinear 

approach as EPA has presented it in the illustrative examples.

Specific Science Comments:

• Page xlvii, and elsewhere, EPA states that for the Oral Slope Factor (OSF) calculations using 

Cheng et al., the upper 5% of the exposure range was excluded in estimating the slope. EPA 

further states: “Because this exclusion reduces the upper portion of the response where the 

slope is shallow, this likely better represents the slope in the region of the curve where the 

fatal cancer risk is increasing with dose, which is the equivalent of dropping the highest dose 

in an animal bioassay.” As expert reviewers have commented on previous assessments (see 

Dale Hattis and Bruce Allen comments on 1,1,2,2 Tetrachloroethane available at: 

http://cfpub.epa.gov/ncea/iris_drafts/recordisplay.cfm?deid=56732 ), we are unclear why 

EPA is dropping dose groups that may be very informative to the shape of the dose-response 

curve in the low dose region. As Dr. Hattis stated, in the context of BMD modeling, “In the 

light of Dr. Allen’s premeeting comments I would recommend that EPA at least show earlier 

results with the highest doses and show the lack of fit that led the analyst to make the dose 

exclusions that were made. I agree that it is probably not correct to exclude the higher doses 

for all endpoints in summary fashion without analyzing the specific fits for different 

endpoints, if that is what was done in this case.”

• Page 2-13, line 28-31, in discussing the Fingerhut study, EPA states that there was only a 

modest correlation between duration of employment and cumulative TCDD exposures. EPA 

also states that duration of employment is a surrogate measure of exposure to other chemicals 

and that the lack of correlation between employment and TCDD exposure suggests that 

confounding due to coexposures was unlikely to have biased results. It would be helpful if 

EPA could clarify why duration of employment is an appropriate surrogate for exposure to 

other chemicals and how a lack of relationship between TCDD exposure and employment 

suggests that coexposures were unlikely to have biased the results.

• Page 2-14, line 27-30, EPA states that when the authors adjusted for smoking, there were 

only small changes in the SMR for lung cancer in the overall cohort and in the higher 

exposure cohort. EPA should also note, looking at the confidence intervals (CI) for the 

SMRs both before and after smoking adjustment, that none of the SMRs were statistically 

significant. As the CI’s spanned one it appears that all these relationships could be due to 

chance. 
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• Page 2-16, line 9 states that the study is not subject to important sources of bias, however, 

line 25 states that the study did not allow for the accounting of other possible confounders. 

Wouldn’t the presence of confounders create a bias that could materially alter the findings of 

the analysis?

• Page 2-18, line 19, EPA refers to the results as “borderline statistically significant.” It is 

unclear what this term means. As the CI’s include one for all cancer sites combined, 

shouldn’t EPA be clearly stating that the results were not statistically significant?

• Page 2-31, line 11, EPA states that statistically significant excesses were found for leukemia. 

As the CI’s included one, shouldn’t EPA be stating that the leukemia’s were not statistically 

significant?

• Page 2-32, line 27-29, EPA states that no dose-response effects were detected and thus the 

study was inadequate for further analysis. We note that page 2-31 states that there was a 

statistically significant exposure-response trend for soft tissue sarcomas. Thus shouldn’t this 

study have been included since it met EPA’s criteria?

• Page 2-41, line 29, EPA states that for breast cancer mortality, the SMR was of “borderline 

statistical significance.” As the CI spans one, shouldn’t EPA be stating that the SMR was not 

statistically significant?

• Page 2-43, line 1-5, in discussing the Manz study, EPA states that since there were no 

changes in the production process after 1954, the exposures to other carcinogens (benzene 

etc) would be comparable for both time frames and thus confounding due to coexposures is 

unlikely to explain the dose-response relationship between all cancer mortality and TCDD 

exposure. The rationale for this statement could be clarified as its unclear why a consistent 

level of coexposures between exposure periods would negate the impact of confounding.

• Page 2-46, line 3-7, please clarify EPA’s rationale for determining that other exposures were 

unlikely to have biased the results. As there were known coexposures to benzene and other 

compounds it is unclear why EPA is excluding them from having an impact.

• Page 2-59, line 26, EPA states that since the average age was 45.2, most women have not 

reached the age when breast cancer is typically diagnosed. It would be helpful for EPA to 

provide a citation here to the source of information regarding typical diagnosis. While NCI 

web pages state that the majority of cases occur in women over 50, it is not clear that the risk 

of developing breast cancer at age 45 is trivial. The follow-up period may have been long 

enough to detect some of these cancers and thus it is not clear that EPA should so quickly 

discount these findings.

• Page 2-86, lines 1-8, states: “Although the risk estimates produced for all cancer sites have 

important limitations and uncertainties, the data are far more consistent in terms of the 

magnitude of an association and latency intervals. The IARC evaluation has put forth the 

possibility of a pleuripotential mode of action between TCDD and the occurrence of cancer. 

Despite the criticism of this assertion by some (Cole et al., 2003), the general consistency of 
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an increased risk for all-cancer mortality across the occupational cohorts when latency 

intervals have been incorporated, provides adequate justification for dose-response

quantification of all cancer sites combined.” As this is an area where EPA acknowledges a 

divergence of opinions as well as limitations and uncertainties, it may be helpful for EPA to 

have a specific charge question asking the experts to comment on EPAs chosen approach.

• Page 2-89, lines 11-13, EPA seems to discount the Collins study because no increased risks 

were seen for non-cancer outcomes. Consistent with previous text in this section, wouldn’t a 

better rationale for discounting this study be because it only looked at mortality effects which 

EPA does not consider appropriate for RfD development?

• Page 2-94, line 13, as the CI spans one, shouldn’t the effect be characterized as not 

statistically significant (rather than as having marginal statistical significance)? A similar edit 

is suggested on page 2-95, line 2. As such, in discussions on page 2-94, line 24, it seems as 

though the Eskanazi study does not suggest that exposures impact menstrual cycle 

characteristics in women exposures before menarche.

• Page 2-96, line 16-18, as the study discusses coexposures to other DLC’s, please clarify why 

EPA (or perhaps the authors) thought that most TEQ exposures were attributable to TCDD.

• Page 2-103, line 30-31, it appears that EPA is not conducting further evaluation of the uterine 

leiomyoma endpoint because an inverse dose response relationship was seen. We note that 

for many of the Eskenazi endpoints an inverse or U shaped relationship is seen. While this is 

a dose response relationship, and thus should meet EPA’s criteria, it is unclear why EPA is 

not evaluating this study further. Leaving out all endpoints or evaluations which do not show 

a dose-response relationship in the direction EPA expects, may be discounting valuable 

information, in particular, information that could inform mode of action as well as doseresponse. It may be helpful if EPA were to provide discussion and perhaps a table of studies 

which meet the criteria, but are not amenable to further analysis due to odd shaped doseresponse curves (for instance EPA could also include the findings of Baccarelli 2004 on 

immunologic effects which showed an inverse dose-response relationship). This information, 

when evaluated as a whole, may be useful. It may also be helpful for EPA to have a specific 

charge question asking the expert reviewers to comment on how EPA is handling these 

studies.

• Page 2-104, lines 23-27, EPA discusses statistically significant changes in sperm count, 

progressive sperm motility and total number of motile sperm relative to the comparison 

group. 

o As EPA relies on these endpoints for the RfD, it would be helpful to have a 

discussion regarding how the measured values in the exposed group compare to 

national averages and how they relate to clinical effects (for instance, were the 

number of sperm in a range that today would lead a man to be deemed infertile?). 

o We also note that EPA finds that men aged 10-17 at the time of exposure (rather than 

1-9 at time of exposure) showed opposite effects. It may be helpful for EPA to 

discuss whether or not these “opposite effects” were statistically significant. If they 
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are statistically significant, it may be helpful for EPA to have an expanded discussion 

of the clinical significance of all the findings.

o It is not clear which exposure groups showed the changes in serum E2 levels and FSH 

concentrations. In addition, EPA may want to clarify if these changes were 

statistically significant and of clinical relevance. 

o It would be helpful to ensure that the expert panel includes some reviewers who have 

clinical expertise in diagnosing and understanding male infertility. In addition, these 

and other experts may be able to inform a discussion of the mode of action on these 

effects to understand whether or not causation is plausible and would be expected.

o As these effects have been measured 40 years post exposure, and since the lifespan of 

a sperm is quite short (65-90 days) and they are created throughout a males life, it 

would be helpful to examine the population for any confounders (eg smoking, 

occupational exposures, medications such as those that treat blood pressure, obesity, 

alcohol use, etc ) that are known to have impacts on male fertility. EPA should 

present a discussion of confounders and it would likely be very helpful for EPA to 

have a specific charge question asking reviewers to comment on EPA’s choice of 

relying on this endpoint.

o Page 2-105, line 4, EPA states that the findings “could contribute to reported decrease 

in sperm quality in young men in the industrialized world.” Its not clear that enough 

information has been presented for EPA to make this statement. In particular, the 

men examined here were over 40 yrs of age and its not clear that any possible 

confounders have been examined. 

o As the exposure scenario in this study is quite different than the exposures of US 

women today, it may be helpful to specifically ask the peer reviewers to comment on 

this aspect of the exposure differences. Charge queston 2 in section 4 mentions this as 

background. It may also be helpful to ask the peer reviewers to comment on the 

implications of this for the development of a POD an RfD for todays exposures. 

Interestingly, when discussing the Alaluusua study, which also used the Seveso 

cohort, on page 2-112 EPA states: “For example, it is difficult to discern whether 

these health effects are a consequence of the initial high exposure during childhood or 

a function of the cumulative exposure for this entire exposure window beginning at 

the early age. If the latter is true, averaging exposure over the critical window would 

add considerable uncertainty to effective dose estimates given the large difference 

between initial TCDD body burden and body burden at the end of the critical

exposure window.”

• Page 2-108, lines 14-through page 2-109, throughout this section (including in its header) 

EPA refers to an examination of “neonatal thyroid function.” It is important for EPA to be 

clear about what is a change in a hormone level verses a change in function. As the thyroid 

responds to positive and negative feedback of hormones, fluctuations in hormone levels are 

not always equated with a change in function that is physiologically or clinically significant. 

It may be more accurate to characterize this study as evaluating hormone levels rather than 

evaluating thyroid function. If EPA agrees, editorial changes are suggested throughout the 

document.

o As the NAS ensured when they evaluated perchlorate, it would be very helpful for 

EPA’s review to include clinical endocrinologists and developmental biologists who 
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can comment and provide insights as to the clinical significance of the changes EPA 

is relying upon for the RfD derivation. 

o EPA states that “Apart from iodine deficiency, no other environmental exposure has 

been associated consistently with reduced neonatal thyroid functioning.” What about 

compounds like thiocyanates, perchlorate or cigarette smoke? Aren’t these 

compounds which can impact thyroid function? We note that table 2-5, page 2-213, 

states that there was limited evidence of confounding. It would be helpful for EPA to 

clarify which relevant confounders were adjusted for.

o Page 2-109, line 11, it would be helpful for EPA to explain why a cutpoint of 5 uU/ml 

was used to assess associations. Is this level associated with clinical adversity? 

o EPA should provide discussion of potential coexposures that could act as confounders 

(eg smoking) and how they were addressed.

o EPA states that the mean TSH levels were positively correlated with average soil 

TCDD levels in the three zones. It would be helpful to clarify if these correlations 

were statistically significant.

o It looks like the odds ratio’s were only statistically elevated in the highest exposure 

zone (zone A) compared to the reference population.

o As the exposure scenario in this study is quite different than the exposures of US 

women today, it may be helpful to specifically ask the peer reviewers to comment on 

this aspect of the exposure differences. Charge question 2 in section 4 mentions this 

as background. It may also be helpful to ask the peer reviewers to comment on the 

implications of this for the development of a POD an RfD for todays exposures.

• Section 2.4.2, it seems that many of the studies discussed are more informative as mode of 

action studies rather than studies that help determine the non-cancer endpoint of concern. For 

instance, Devito 1994 evaluates TCDD impacts on EROD induction and phosphotyrosyl 

protein, Hassoun 1998 evaluated impacts on lipid peroxidation and oxidative stress, Slezak 

2000 looked at GSH levels as well as oxidative stress, Crouch 2005 evaluated IGF signaling, 

and Rier 2001 evaluated TNFalpha. In many of these studies, it is not clear that the 

magnitude of response is outside the range of normal variability, thus it is not clear how the 

studies met EPA’s criteria for inclusion in the evaluation. While the EPA document does not 

have a section addressing mechanism of action, has EPA considered a separate section that 

would include studies that inform mode of action?

• Page 3-52, line 8-12 for the human equivalent dose (HED) in the gestational exposure 

scenario, EPA assumed that pregnancy begins at 45 yrs of age. EPA acknowledges that this 

is health protective as the daily exposure achieving the target blood concentration is smaller 

than for earlier pregnancies. As studies show that the birth rate for women ages 25-29 is 116 

births per 1000 women and 0.6 births per 1000 women for women aged 45-49, with the 

average age of pregnancy being between 25-27, it would be helpful for EPA to also provide 

the calculations that use the average aged woman. EPAs cancer modeling approach is 

typically health protective and in the RfD calculations EPA adds an uncertainty factor to 

protect sensitive individuals, thus it would be very helpful for EPA to provide the impacts of 

having the gestational exposure scenario use the average aged woman. While understanding 

the impacts of the most sensitive populations is critically important, it is also important that 

risk managers understand the impacts to the average (or more average) individual. EPA 
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should provide a clear discussion of the impacts in overall values when EPA uses the average 

verses older woman model. It may also be very helpful for EPA to have a specific charge 

question asking the experts to comment on this parameter. It may also be very helpful for 

EPA to have a specific charge question asking EPA to comment on the approach of 

determining the HED based upon the continuous daily intake that would result in the target 

concentration over peak 5- year period (as per lines 12-31). EPA states that this is health 

protective. It would be helpful for EPA to provide information to the reviewers so that they 

can see the impacts of this choice compared to other choices.

• Page 4-8 , line 30-32, states in discussing the epidemiological studies: “EPA did not conduct 

Benchmark Dose modeling because the covariates identified by the study authors could not 

be incorporated by modeling the grouped response data.” As a BMD approach is always 

preferred over a NOAEL/LOAEL approach, we are wondering if EPA did any outreach to 

the study authors (as has been done for other assessments) to try to gather the data points that 

would allow for BMD modeling. Would such data be informative and helpful?

• Page 4-9, line 24, in discussing Mocarelli EPA states that men who were 10-17 were not 

affected. However, according to the previous discussion and the Mocarelli publication it 

looks like this age group showed statistically significant increases in sperm count, motile 

sperm counts, FSH and also reduced estradiol. Shouldn’t EPA be discussing these impacts 

and their potential clinical significance as well? For both age groups, an enhanced discussion 

of potential mode of action and clinical and physiological significance would be helpful. We 

suggest that EPA ensures that there are fertility experts on the review panel. A specific 

charge question relating to the opposing effects (depending on age of exposure) would be 

helpful. EPA assumes this is due to the need for a 10 yr critical exposure window, but the 

discussion for the scientific justification for this, considering the lifespan of a sperm, is not 

provided. Such a discussion would be useful and would give the expert reviewers something 

to react to during their review. Similar comments apply to the discussion on page 4-22, line 

1-3.

• Page 4-15, line 3-18, EPA describes the BMD modeling approach. While this information is 

all in Appendix E, it may be helpful for EPA to create a table which arrays the potential 

BMD/ BMDL values as well as their AIC values so that readers can easily see the 

implication of the choices EPA made. In previous assessments we have seen that the choice 

of the lowest AIC, which may differ by only 0.5 from a non-chosen AIC value can have big 

implications for the chosen BMD/BMDL value. EPA states that if the BMDL values were 

within a factor of 3, EPA chose the model with the lowest AIC value, otherwise EPA chose 

the model with the lowest BMDL. Does this mean that the lowest BMDL value, rather than 

the AIC value drove the model choice? More clarification on what this looks like and its 

implications for the chosen BMDL values would be helpful. A specific charge question on 

this aspect of EPAs approach may be very helpful as this could end up being a key driver in 

choosing the BMDL value.

• Page 4-15, line 23 states: “On occasion, high doses were dropped and the models were refit.” 

As per comments above (see comments regarding page xlvii), it would be helpful for EPA, at 

a very minimum, to provide information, perhaps in the BMDL summary tables, that makes 
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it clear when dose groups were dropped to improve model fit. A charge question on the 

impacts of this approach may also be useful.

• Page 4-18, line 24-30, EPA states: “Baccarelli et al. (2008) reported increased levels of TSH 

in newborns exposed to TCDD in utero, indicating a possible dysregulation of thyroid 

hormone metabolism.” This appears to be the first sentence EPA has put out describing 

potential impacts. More detail here, and whether or not the changes put the hormone levels in 

a range that is clinically or physiologically believed to be associated with dysregulation 

would be helpful. What is the citation that Baccarelli provides for their statement? More 

discussion of the science regarding the impacts associated with the changes seen would be 

extremely helpful. Similarly, EPA notes the findings for men who were 1-9 yrs old in the 

Mocarelli study, but does not discuss the findings of the older group or the clinical or 

physiological implications of the changes.

• Page 4-21, line 14-19, as per comments above, please provide more scientific information to 

support the statement regarding dysregulation of thyroid hormone metabolism. EPA 

mentions that the 5uU/ml standard “was established by the World Health Organization 

(WHO, 1994) as an indicator of potential iodine deficiency (and potential thyroid problems) 

in neonates.” What exactly did WHO intend when saying it was an indicator of potential 

thyroid problems? What is the rationale of using this as a cutpoint for adverse effects? Or 

does EPA believe this is a precursor to adverse effects. As WHO mentions, iodine 

deficiency, did the study authors also looks at iodine levels in the children? Including this 

information would be extremely helpful.

• On page 4-22, line 1-18, EPA further describes the Mocarrelli studies. As per comments 

above (page 4-9, line 24), edits to the discussion of the men in the older age group are 

suggested. EPA states: “Although a decrease in sperm production of 20% would not have

clinical significance for an individual, EPA considers a 20% shift in the population mean to 

be of biological significance.” What is the scientific rationale behind this statement and 

supporting the determination that a 20% shift in the population mean is of biological 

significance. EPA has previously mentioned that RfD’s are based on endpoints that are 

adverse or precursors to an adverse effect. Is this referring to an individual response or a 

population based response? More clarity would be helpful as it seems as though using a POD 

that is known to not be of clinical significance to an individual seems like a novel approach. 

A charge question on this specific aspect of choosing the Mocarrelli study for the RfD 

derivation would be helpful.

• Page 5-5, line 4-6, please clarify that the relative risk for all cancer mortality could be due to 

chance since the CI includes 1.0. Similarly, in lines 12-15, please clarify if the increases were 

statistically significant. It would be helpful to clarify this for risks presented throughout 

section 5.1.2.1.1

• Section 5.2.3.1.2, as NAS recommended that “EPA should compare cancer risks by using 

nonlinear models consistent with a receptor mediated mechanism of action and by using 

epidemiological data and the new National Toxicology Program (NTP) animal bioassay data 

(NTP, 2006),” it is not clear why EPA has not provided an updated nonlinear evaluation of 
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the epidemiology studies presented in the 2003 assessment. It is clear that EPA has 

conducted a robust evaluation of two newer studies, however providing the modeling that 

NAS recommended for these older datasets may be very informative and it is not clear why 

EPA has not provided these evaluations as part of their update.

• Page 5-43, line 30-31, EPA states: “The bioassay-based cancer dose-response assessment in 

this section has used the multistage model which is the standard model choice for such 

assessments and has been the basis for most of EPA’s cancer risk assessments. In that sense, 

there is no associated uncertainty for model choice.” Please explain the scientific rationale 

for this statement.

• In section 5.2.3.4.1.3, EPA in discussing receptor theory modeling, states that TCDD will 

show linear dose response binding in the 1-10% receptor occupancy region. It may be helpful 

if EPA were to discuss what the expectations are for receptor occupancy at current 

background US exposure levels.

• Page 5-67, line 30, EPA recommends and OSF when the target risk range is 10-5 to 10-7

. It is 

unclear why EPA has chosen this target risk range. As most environmental statutes refer to 

the 10-4 to 10-6 risk range, it would be extremely helpful for EPA to provide a 

recommendation for this risk range.

• Page 6-3, lines 1-4, instead of misrepresenting the OMB efforts (for example draft proposals 

are not retracted) it would be more helpful to readers if EPA were to cite the current state of 

the OMB and OSTP recommendations regarding risk assessment (similar to how EPA 

describes the NRC reports). The following language is suggested: In 2007, the US Office of 

Science and Technology Policy (OSTP) and the Office of Management and Budget (OMB) 

released a Memorandum on Updated Principles for Risk Analysis. These principles provide 

Federal Agencies with recent guidance from the scientific community, the Congress, and the 

Executive Branch concerning generally-accepted principles for risk analysis. Of particular 

interest, the principles state that: “When something more than a superficial analysis can be 

conducted, quantitative uncertainty analysis, sensitivity analysis, and a discussion of model 

uncertainty can greatly inform risk management decisions.” (memorandum available at: 

http://www.whitehouse.gov/omb/assets/omb/memoranda/fy2007/m07-24.pdf )

• Section 6.1.3, it may be helpful for EPA to provide a citation to the source that led EPA to 

discuss the specific basic requirements that are presented in this section. If one looks at the 

section headers in this section, it is not clear how these aspects were determined to be the 

basic requirements.

• Page 6-10, line 25-28, EPA interprets the cancer guidelines to imply that to use a nonlinear 

model,” it must have a preponderance of evidence” to override the default choice. This 

language is not in the Cancer Guidelines and appears to be an over-interpretation. As per our 

general comment above, EPA may wish to revise this (perhaps using quotes from the cancer 

guidelines) to reflect that when alternative approaches have significant biological support, 

they may be presented.

• In section 6.4 EPA spends a great deal of time discussing the lack of feasibility of conducting 

a quantitative uncertainty analysis. This is done in the context of responding to the NAS. It 
IRIS STEP 3 INTERAGENCY COMMENTS

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seems that what could be much improved is EPA’s discussion and presentation of qualitative 

uncertainties. It would greatly benefit this updated dose-response assessment if EPA 

provided further discussion on these qualitative uncertainties. 

• Page 6-34, line 19-24, EPA states: “The NAS committee explicitly requested that the 

uncertainty attending the choice of a BMR be quantified. First of all, simply plugging other 

values in for the BMR does not constitute a quantitative analysis of uncertainty. The 

plugged-in values must be sampled from some uncertainty distribution. Since this concerns 

volitional uncertainty, there is no underlying distribution from which to sample, unless the 

choice of BMR is related to some claim about the state of the world.” While EPA may argue 

about what constitutes an uncertainty analysis, a more useful discussion might be one that 

focuses around what EPA has done to address the NAS request. Perhaps a similar approach 

would be more useful throughout section 6.4 and 6.5. We note that the NAS stated: “When 

selecting a BMD as a POD, EPA should provide justification for selecting a response level 

(e.g., at the 10%, 5% or 1% level). In either case, the effects of this choice on the final risk 

assessment values should be illustrated by comparing point estimates and lower bounds 

derived from selected PODs.”

• Section 6.5, as per comments above, it may be more useful for EPA to present what they 

have done in response to NAS, rather than to simply argue against the NAS 

recommendations. In addition, on page 6-37, line 22, EPA makes the argument that rationale 

does not exist to choose between options. While this may be true, perhaps the point of the 

NAS comments were to inform the risk managers by providing them with a range of 

information. 

• Page 6-39, lines 7-14, contains a pure policy determination that any pushes forward in the 

uncertainty arena must be nondisruptive to the traditional process. Is this the official agency 

position? Considering the number of assessments that EPA is working on that are proposing 

safe levels of exposure below our natural background exposures, perhaps some out of the box 

thinking that improves the traditional process, and may be disruptive, could be of use in 

moving the risk analysis field forward.

Editorial Comments (with Scientific Impacts):

• When quoting the NAS we suggest that EPA provide full sentences without deletions of text 

from the NAS. For instance (and this is just one example), on page 2-1, lines 30-33, EPA 

quotes the NAS from page 27 of their report. However this quote does not include the full 

sentence and this is not clear to the reader. If EPA is going to delete text or end sentences 

early, at a minimum EPA should note this and include the full sentence in the footnote.

• Page xvii, section 6.5 is entitled “Conclusions” yet it is only responding to some comments 

addressed in chapter 6. It may be helpful for EPA to provide some overall conclusions and/or 

recommendations stemming from their updated analysis and response to NAS.

• Page xxxiii, EPA reiterates parts of the dioxin science plan. As EPA has not met their 

deadlines for some of these items, we suggest deleting the details provided and simply 

referring readers to the webpage (which hopefully explains and provides updates as to how 

EPA is doing in meeting the established timelines and provides revised dates).
IRIS STEP 3 INTERAGENCY COMMENTS

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• Page xxxviii, lines 12 and 28, in discussing the epidemiology and bioassay inclusion criteria 

and evaluation process, EPA states that “only studies meeting these criteria were included...” 

Please clarify if studies had to meet all the criteria or just some of the criteria.

• Page xliii, line 20, please provide citation for the dioxin workshop recommendations. 

Similarly please provide citation for statement on line 26.

• Page li, its not clear that the discussion of Bussard et al, is appropriately presented on line 27. 

This book chapter presents a summary from a workshop that evaluated the approaches EPA 

then describes. However, EPA presents these as possible methodologies. It may be helpful to 

clarify that these approaches do not represent the complete universe of methodologies but 

only the four evaluated at the workshop.

• Page 2-5, line 10, in citing the draft BMD guidance, EPA has it cited as US EPA 2008. 

Please note that this document is from 2000. In the references, it is cited both ways and thus 

some edits are needed here and in the references. In the text it would be helpful for EPA to 

clarify that they are referring to a draft guidance that does not represent official agency 

position, nor has the approach been codified as EPA states. We encourage EPA to work 

towards updating and finalizing this document in the near future.

• Page 2-21, line 10, refers to “the IARC recommendation”. As this is the first time this 

recommendation is mentioned, it would be helpful to provide a citation and clarify exactly 

what recommendation EPA is referring to.

• Page 2-25, lines 20-25, EPA states that “although the serum-based measures did not fit the 

data as well as the exposure scores, the authors regarded them as providing reasonable fit.” Is 

there any further information from the authors that may help clarify what was meant by 

“reasonable fit”?

• Page 2-44, line 2-4, please clarify whether or not this dataset is further analyzed.

• Page 2-49, line 25, as the p= 0.06, please replace “marginally statistically significant” with 

“not statistically significant”. Similar comment for line 27 and on page 2-50, line 2 where 

EPA states “borderline statistically significant”.

• Page 2-81, line 3-4, please clarify whether or not this dataset is further analyzed.

• Page 2-112, line 3, EPA refers to “developmental defects”, does EPA mean to say “dental 

defects”?

• Page 2-116, line 1-2, it would be helpful for EPA to provide specific citations back to the 

specific studies, with positive findings to which they are referring here.

• Section 2.4.2, throughout this section, when discussing the animal bioassays, EPA does not 

always provide a clear statement as to whether or not the study was considered further for 

dose-response modeling. As this summary statement was very helpful in the discussion of the 

epidemiology data, a similar statement for each animal bioassay would be quite useful. 

Similarly throughout this section, it would be helpful for EPA to clarify who identified the 
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LOAEL in each study. Many times it is not clear if the LOAEL is determined by EPA or by 

the study authors.

• Section 2.4.2.6, in the epidemiology section, EPA evaluates cancer studies first and then noncancer studies. EPA may want to use a similar approach in the animal bioassay section, 

rather than presenting the animal cancer endpoint studies after presenting the majority of the 

animal bioassay data.

• Section 3.3.3.3, as this section only addresses smoking, EPA may want to consider renaming 

the title of this section.

• Page 3-44, line 21, EPA states that the re-estimation of urinary clearance did not result in any 

significant changes in the fit and performance of the original model. It may be helpful for 

EPA to numerically present the changes so that readers can better understand what EPA 

means.

• Page 3-49, line 31, EPA states that absorption and excretion parameters were among the 

sensitive parameters in the rat. Does this mean that they were the most uncertain? Please 

clarify.

• Table 4-6 lays out the strengths and limitations/uncertainties associated with the animal 

bioassays that provided candidate PODs for the RfD. A similar table describing the strengths 

and limitations/uncertainties associated the epidemiology studies would also be helpful.

• Page 4-11, line 24, mentions the menstrual effects reported in Eskenazi. It may be helpful to 

clarify what effects in particular EPA is referring to and if the effects were statistically 

significant and have clinical relevance.

• Page 4-15, line 6, please clarify that the current guidance is only a draft and has not been 

finalized by the agency.

• Table 4-4, please provide units for the NOAEL/LOAEL and BMD/BMDL values

• Table 4-5, page 4-18 describes the table as presenting a wide area of toxicological endpoints. 

It may be helpful if for each of the endpoints, EPA defines the effect seen as adverse or as a 

precursor effect.

• Section 4.4, in the past in addition to having a discussion of the uncertainties and limitations 

in the RfD derivation, EPA has also provide a table that visually and succinctly shows the 

impact of the major assumptions and uncertainties. This table has always been very useful to 

readers and reviewers. EPA may want to consider such a table for this document. For 

instance EPA could expand table 6-1 to show the impacts that their determinations have on 

each of the uncertainties presented.

• Page 5-4, line 18-20, as so many studies were reviewed in section 2.4, it may be helpful to 

specifically cite the recent ones that do address the concerns for potential confounders. Age 

5-6, line 3-5 states: “Despite these uncertainties, many of the more recent studies have 

greatly improved exposure assessments compared to earlier studies of the same cohorts and 

have addressed the potential for confounding and other types of biases.” Perhaps we missed 
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this discussion in section 2.4, but it may be useful to clarify exactly what these improvements 

in exposure were.

• Page 5-6, line 17, is it true that strength of association, is considered “irrespective of 

statistical significance”? If this is true, its not clear why the statistical community exists if not 

to inform the determinations regarding strength of association.

• Page 5-6, line 26-30, EPA states that the consistent results are not likely due to chance. As 

many of the CI include 1.0, isn’t this statement inconsistent with the statistical evaluations?

• Page 5-15, section 5.1.2.3.3 includes a section for the hypothesized more of action of TCDD 

in rodents and then has specific subsections for each type of tumor. It might be helpful to 

have a similar section for the mode of action of the particular human cancers that have been 

detected in the epidemiological studies.

• Page 5-22, section 5.2.2 could be improved by clearly listing each of the NAS key 

recommendations and then giving a short summary of the EPA response with reference to the 

section of the response document that addresses the comment. For instance it is unclear in 

this overview section what EPA did to address the NAS key finding that EPA should 

compare cancer risks by using nonlinear modeling.

• Section 5.2.3.6, in discussing the quantitative uncertainties in the slope factor estimates, EPA 

may want to include a section which summaries the uncertainties and limitations associated 

with use of the Emond PBPK model.

• Page 5-44, line 28, to defend EPA’s choice of POD, it seems as though EPA should replace 

the word “fact” with “policy determination”.

• Page 6-9, line 23-24 EPA states that the reference values “suggest a biological population 

threshold beneath which no harm is anticipated.” This is an oversimplification as the 

complete definition of an RfD states that it is: “An estimate (with uncertainty spanning 

perhaps an order of magnitude) of a daily oral exposure to the human population (including 

sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects 

during a lifetime.” It is important that EPA be clear to readers that reference values are 

estimates that may contain a wide range of uncertainty and also don’t claim to provide no 

harm but instead use a standard below which there is no “appreciable risk of deleterious 

effects.”

• Page 6-34, line 28-29, it is unclear where EPA presents the suggested research agenda that is 

referred to.

Comments on the Draft Charge:

(Note: some suggestions for charge questions are provided in comments in the above sections. 

Many of those comments have not been reiterated here, but should be considered as equally 

important in ensuring a rigorous peer review of this highly technical document.)

• It may be helpful to clarify to reviewers, as well as the public, what steps EPA will take after 

this review is complete. For instance, if EPA plans to finalize the dioxin reassessment after 
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this review, it may be helpful to state that. Alternatively, if EPA plans to take these 

comments into account, and subsequently produce a revised draft assessment that will go 

through a review process before being finalized, EPA may want to state that as well. As the 

2009 dioxin plan is a bit outdated, it may be helpful to be very clear about exactly what this 

review will be informing.

• In the 2nd paragraph EPA states that the draft document is not an assessment per se and that it 

is designed to supplement the 2003 reassessment. While this is correct, in supplementing the 

2003 reassessment, EPA now provides updated recommended non-cancer and cancer values. 

If EPA is going to continue to provide these recommendations, we suggest that EPA be 

clearer in characterizing this as an updated assessment of the cancer and non-cancer health 

effects and their impacts.

General Charge Questions:

• Q1, since this is a response to the NAS comments, EPA may additionally want to ask the 

experts to comment on whether or not the document adequately captures the predominant 

NAS concerns related to dose-response assessment.

Section 2:

• It may be helpful to add a charge question to explicitly take comment on the inclusion criteria 

EPA has developed for both the epidemiology data and the animal bioassays. While it should 

be helpful to have the experts comment on each element of the criteria, in particular EPA 

should ask the reviewers to comment on the inclusion of only those studies showing effects. 

We note that there are differences in the two criteria (epi and animal) in that the 

epidemiology criteria includes only studies that show “adverse effects” and yet the animal 

bioassays include studies which show “responses outside the range of normal variability.” It 

may additionally be helpful if EPA defines, and then takes comment on their definition of an 

adverse effect for the purposes of this document.

Section 3:

• In Section 3 of the document, EPA includes a lengthy discussion of the CADM model, 

including discussion of its structure, mathematical representation, parameter estimation, 

model performance and confidence. In charge question 3(1), EPA simply asks the reviewers 

to comment on the justification of using the Edmond model as opposed to other models. As 

EPA spends so much time on the CADM model, it may be useful to have a specific charge 

question in this section which asks the PBPK experts to comment on EPAs review of the 

CADM model and its utility.

• While question 3(1) asks for comment on EPAs justification for using the Emond model, 

there are a few areas of EPA’s approach where EPA may want to ask for specific comments. 

These include:

o Taking comment on EPA approach to addressing concerns that the dose-dependency 

of metabolic elimination in the model was not calibrated to human data and the 
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conclusion (as stated on page 3-39) that it is not unreasonable to use the model as it 

stands.

o Taking comment on EPAs conclusions regarding the reliability of the model for 

simulating liver concentrations in the rat and human

o Taking comment on EPAs conclusions regarding the confidence in the model for 

different important aspects as described by EPA in 3.3.4.5

• In Q4, in addition to asking the reviewers to comment on EPAs estimation, it may be helpful 

to specifically ask reviewers to comment on EPA’s use of lifetime average daily dose.

Section 4:

• In Q2, EPA mentions that there is uncertainty due to the influence of the high-dose pulse 

exposure and the fact that the Seveso cohort exposure pattern is different than the exposures 

experienced by the general population. It would be helpful to ask the expert reviewers to 

comment on the implications of this and what it may mean for the relevance of the 

determined POD’s and RfDs. If EPA could say anything about the direction of the 

uncertainty (eg leads to an underestimate or overestimate of risk) this would also be helpful.

• In Q2, it may be helpful to have an expanded charge question that asks reviewers to 

specifically comment on EPA’s approach for estimating the TCDD intake associated with the 

LOAEL in the Mocarelli study (as described by EPA on page 4-10). Considering the 

endpoint of concern, a question regarding the use of peak blood concentrations may also be 

helpful.

• In Q2, EPA states that for the Baccarelli study EPA used reported maternal levels and asks 

for comment on this. However page 4-9 states: “Therefore, EPA determined the maternal 

intake at the LOAEL from the maternal serum-TCDD/TSH regression model by finding the 

maternal TCDD LASC at which neonatal TSH exceeded 5 μU/mL. EPA then used the 

Emond PBPK model under the human gestational scenario (see Section 4.2.1) to estimate the 

continuous daily TCDD intake that would result in a TCDD LASC corresponding to a 

neonatal TSH of 5 μU/mL at the end of gestation, with the resulting maternal intake 

established as the LOAEL (0.024 ng/kg-day), shown in Table 4-1 as a candidate POD for 

derivation of candidate RfDs.” It may be helpful for EPA to explicitly ask the expert 

reviewers to comment on this entire approach.

• In Q3, EPA takes comment on the approach of averaging TCDD blood concentrations over 

the entire dosing period. Page 4-13, line 8, mentions that EPA started by using the initial 

peak TCDD blood concentration as this was considered to be the most relevant exposure 

metric. It may be helpful for EPA to also take comment on the use of peak blood 

concentration. Additionally page 4-14, line 16-19, discusses some critical choices made 

during EPA’s model fitting approach, including the exclusion of supralinear fits and 

saturated models. EPA may also want to specifically ask the expert reviewers to comment on 

EPAs approach.
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• Q4, it may be helpful to expand this question as EPA typically does to inquire about the 

reviewers opinions on the chosen response levels.

• Q6, EPA may want to explicitly ask reviewers to comment on EPA’s determination of the 

critical effect, and the use of the NOAEL/LOAEL approach for quantify the POD for the 

epidemiology studies. 

• Q7, as EPA is also taking comment on other studies that reviewers may recommend, EPA 

may want to expand this question to include asking for recommendations related to the 

uncertainty factors applied to other potential studies that reviewers may think are more 

appropriate for an RfD determination.

• Q8, as section 4.4 also discusses the key limitations of the epidemiologic studies, it may also 

be helpful to ask the expert reviewers to comment on these limitations and any implications 

they may have for the utility of the RfD EPA has derived using these studies.

Section 5:

• Section 5.2.3.4.1.2, EPA spends some time interpreting the cancer guidelines and applying 

new terminology to define threshold/nonthreshold responses as well as nonlinear models and 

defines them in an individual and population sense. It may be helpful if EPA were to ask the 

reviewers to comment on these definitions. In particular, it may also be helpful for EPA to 

seek confirmation of interpretations of the “zero slope at zero” model for the population and 

the impacts that receptor kinetics may have on the ultimate population response. This is a 

critical point that EPA makes and seems to underlie the EPA response to the NAS as EPA 

argues against the NAS conclusion which favored a nonlinear model that would include a 

threshold response.

• In section 5.2.3.4.1.3, EPA concludes that linear low dose extrapolation should be the 

preferred modeling approach. It would be helpful to have a specific charge question that asks 

the expert reviewers to comment on this conclusion and its scientific justification. In 

particular, EPA, on page 5-72, states that this choice was made because EPA determined that 

the Agency lacked sufficient evidence to support an assumption of nonlinearity. In addition, 

EPA also states that there was insufficient evidence to support an assumption of a threshold 

Taking comment on these determinations seems to be of critical importance for establishing 

consensus for EPA’s preferred modeling approach..

• It may be helpful to ask the reviewers to specifically comment on EPAs decision to use 

cumulative serum concentrations as the primary metric for carcinogenicity (as described on 

page 5-69). 

• In Q1, it may be helpful to clarify what routes of exposure EPA is referring to when 

providing the weight of evidence cancer descriptor. We presume this is only related to oral 

exposure but if EPA is going to broaden thisa discussion of the rationale should be added to 

the document.
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• In Q4, it might be very helpful to ask the reviewers to comment on EPAs choice of using a 

BMDL01 (1% excess risk) as the POD for the development of candidate oral slope factors. 

Similarly, as NAS recommended that EPA consider nonlinear models (“Because the 

committee concludes that the data support the hypothesis that the dose-response relationship 

for dioxin and cancer is sublinear, it recommends that EPA include a nonlinear model for 

cancer risk estimates but that EPA also use the current linear models for comparative 

purposes.”), EPA may want to specifically ask a charge question about their choice of relying 

on the linear model rather than the nonlinear models. 

• In Q10, EPA states that they considered nonlinear approaches and asks the expert reviewers 

to comment on other approaches that could be developed. It may also be helpful if EPA asks 

the expert reviewers to provide scientific comments on the two illustrative approaches EPA 

has provided. It may also be helpful to ask the reviewers to comment on EPA’s conclusions 

regarding the limitations and utility of these approaches.

• EPA may want to consider a charge question that takes comment on EPA’s determination to 

not conduct a meta-analysis.

Section 6:

• Q1 describes the discussion as a response, however much of the discussion reads as a white 

paper regarding quantitative uncertainty analysis. Thus EPA may want to reframe this 

question and ask for comments on all aspects of the discussion provided. In particular, EPA 

may want to ask the reviewers to comment on each of EPA’s feasibility determinations as 

well as the EPA responses to NAS in section 6.5. EPA may also want to ask about whether or 

not the reviewers find that the aspects of discussion are useful in addressing the concerns 

articulated by NAS. In particular, EPA could also take comment on the utility of their 

discussion framed around volitional uncertainty and how this type of uncertainty limits the 

ability to conduct a quantitative uncertainty analysis.