IRIS STEP 3 INTERAGENCY COMMENTS

OMB Staff Working Comments on EPA’s Toxicological Review of Formaldehyde Inhalation 

Toxicity [dated March 17, 2010] and Draft Charge to External Reviewers 

April 27, 2010

General Science Comments:

Throughout section 4, the hazard characterization, EPA takes the approach, particularly in sections 

4.1 and 4.2, of setting up each section, focused on a specific endpoint, with an overall summary 

followed by the details of each study evaluated. In many cases, EPA provides a concluding 

summary, similar to the overall summary in the beginning of the subsection. The overall summary 

appears to present the weight of evidence conclusions regarding the endpoints. It would be useful if 

EPA were to clarify for readers the parameters EPA used to reach their weight of evidence

conclusions for each endpoint. Specifically, it would be helpful for EPA to:

o Provide an overall perspective on how negative results were considered as well as how 

determinations of clinical and statistical significance were made. 

o Provide in the opening of Section 4 a discussion of the parameters and framework EPA used 

to reach their overall conclusions regarding formaldehyde‟s impact on individual endpoints.

o Provide in the overall summaries the citations of the specific studies EPA relied on to reach 

the conclusion as well as information regarding the level at which EPA concludes that 

clinically significant effects and/or statistically significant effects have been documented. 

This information is provided in some subsections, but not all.

o Provide for each of the endpoint discussions in section 4.1, a table that describes the studies 

discussed, presents information on exposure levels and levels at which effects of interest 

were seen, their statistical significance, and perhaps includes information on the key 

strengths and limitations of each study. Seeing the information presented this way may be 

helpful in understanding how EPA reached their overall conclusion regarding 

formaldehyde‟s impact on the endpoint. This would be particularly helpful for endpoints for 

which EPA developed candidate RfCs. Presenting such a table in section 4.4 would also be 

very helpful to readers as this is where EPA once again synthesizes the major conclusions 

regarding noncancer impacts.

o Provide information regarding whether or not the critical effect is considered to be adverse or 

perhaps a precursor to an adverse effect. Whether or not the endpoint is reversible upon 

cessation of exposure should also be helpful information. EPA may also want to consider a 

charge question to expert reviewers asking them to comment on the specific non-cancer 

endpoints EPA has chosen and if reviewers agree with EPA‟s characterization of their health 

significance.

We applaud EPA for making chapter 5.1 so easy to read. The flow, the writing, and the presentation 

of information made the section very accessible. We are very supportive of EPA‟s approach to so 

clearly present many alternative derivations and candidate RfC values. [minor point: we note that 

when a non-color printer is used, the text boxes showing the alternate RfC derivations are a bit hard 

to read. EPA may want to consider a background that does not have a pattern in it.]

In the discussion of cancer slope factor derivations, EPA provides a „reality check‟ type of 

discussion where a calculation of crude incidence rates that would be expected from the proposed 

risk values are compared to current incidence rates. This discussion is very informative and useful.
IRIS STEP 3 INTERAGENCY COMMENTS

2

As we saw at the recent SAB review examining how EPA implemented the 2007 SAB Arsenic panel

recommendations, this is exactly the type of evaluation expert reviewers were seeking. It would be 

very useful to have a similar type of „reality check‟ discussion in section 5.1.4, or elsewhere, in 

regards to the RfC derivations. EPA is proposing candidate values in the range of 4-9ppb. From 

Section 2 of the draft toxicological review we know that levels in homes average from 17-33 ppb 

(see Salthammer study cited in Section 2) under normal living conditions indoors. Similarly, as per 

Figure 2-3 and Table 2-2, mean outdoor levels range from about 2.5 to 8ppb. As typical outdoor 

levels are about equal to the proposed RfC values and the typical indoor levels are about four times 

greater, one could ask whether or not we are seeing the effects described in the candidate RfC 

studies, in particular are we seeing the effects predicted in the Rumchev, Garrett and Krzyzanowksi

studies? And are we seeing the eye irritation in indoor environments that is predicted by the three 

studies evaluating this endpoint. This type of reality check is worth exploring and it might help to 

inform the discussion to ask public commenters and expert reviewers to weigh in on this discussion. 

Discussion of other ambient or background exposures that may cause these same effects could also 

be part of the dialogue. 

o In addition we note that other federal, state and government agencies have also proposed or 

finalized non cancer exposure values for formaldehyde. For example, in addition to the 

ATSDR chronic MRL at 8ppb, Health Canada in 2005 proposed a guideline of 40ppb to 

protect against both noncancer and negligible cancer risk (http://www.hc-sc.gc.ca/ewhsemt/pubs/air/formaldehyde-eng.php), CalEPA suggested an acute value of 27ppb 

(http://www.arb.ca.gov/research/indoor/formaldGL08-04.pdf ), WHO suggested a value of 

83pppb (http://www.inchem.org/documents/ehc/ehc/ehc89.htm#PartNumber:10 ) and the 

state of Wisconsin set a value at 100ppb for irritant effects, although they noted that sensitive 

individuals may see effects at lower levels 

(http://www.dhfs.state.wi.us/eh/Air/pdf/Frmldhyde.pdf). It may be helpful, perhaps in an 

appendix, to provide a summary of these other values and discuss how the EPA proposed 

RfC‟s are similar and different to the approaches that other agencies have suggested. This 

type of discussion may be very informative for public commenters and peer reviewers who 

may be grappling with how to handle risk levels that are in the same range as background 

exposure levels.

In section 5.2 EPA states that “the weight of evidence suggests that formaldehyde carcinogenicity 

can be attributed, at least in part, to a mutagenic MOA” and thus EPA uses only linear low dose 

extrapolation. EPA refers readers to the EPA cancer guidelines to support this approach. We note 

that the EPA cancer guidelines also state: “Nonlinear approaches generally should not be used in

cases where the mode of action has not been ascertained. Where alternative approaches with 

significant biological support are available for the same tumor response and no scientific consensus 

favors a single approach, an assessment may present results based on more than one approach.” As 

the mode of action section clearly describes an integrated mode of action where multiple key events 

may be acting (see 4-446, and page 6-21, lines 11-13), and Section 4.5.3 clearly and transparently 

lays out multiple plausible modes of action with significant biological support, it would be helpful 

for EPA to present alternative approaches to linear modeling for the tumor endpoints, informed by 

the alternate plausible modes of action discussed in Section 4.5.3. Even if presented only as a 

sensitivity analysis, by which to compare the results of the linear extrapolation, this information 

would be useful and informative. In addition, if the peer reviewers have concerns about EPA‟s MOA 

conclusion, or would like to be informed by evaluating the results of a non-linear modeling 
IRIS STEP 3 INTERAGENCY COMMENTS

3

approach, having the alternative cancer quantification derivations available for consideration will 

also speed the peer review process.

Specific Science Comments:

Specific examples of where understanding how clinical significance, statistical significance, and 

negative findings were treated would improve public understanding of how the data were evaluated 

are listed below. For instance when evaluating an individual study if the confidence interval shows 

that the effect is not statistically significant, EPA may want to simply characterize the findings as 

suggestive of an association. In some cases, it may be helpful for EPA to present the confidence 

intervals surrounding the risk values.

o Page 4-21/22, in discussing 

Fransman et al.

o Page 4-24, line 3-6 and page 5-

13, line 15-17 in discussing 

Tavernier et al 2006

o Page 4-25, in discussing 

Rumchev 2002

o Page 4-49, line 18-25

o Page 4-56 line 18-20, in the 

context of Page 4-50, line 28-29

o Page 5-7, line 20-22

o Page 5-11, line 10-11

o Page 5-61, lines 18-21

o Page 4-76, line 26

o Page 4-88, line 29-30

o Page 4-92, line 3 and line 5

o Page 4-92, line 21

o Page 4-93, line 15

o Page 4-421, line 13

o Page 4-15, in discussing Herbert 

et al 1994

Specific examples where EPA may want to characterize which studies in particular where 

relied upon to reach the conclusion:

o Page 4-36, line 14

o Page 4-42, line 12

o Page 4-45, line 18-19

o Page 4-68, line 27

o Page 4-70, line 26

o Page 4-83, line 14

o Page 4-417, line 23-32

o Page 4-419, line 16

o Page 4-390, line 24

o Page 4-393, line 17

o Page 4-426, line 24-34

o Page 5-70, line 7

Page 2-3, lines 25-31, discusses how formaldehyde is formed naturally in the atmosphere. If 

data are available regarding the levels of formaldehyde produced, adding this information 

would be helpful. 

Section 2, perhaps addition to section 2.3, the National Cancer Institute (NCI) notes 

(http://www.cancer.gov/cancertopics/factsheet/Risk/formaldehyde) that formaldehyde is 

produced in small amounts by most living organisms as part of normal metabolic processes. 

EPA may want to provide further details regarding the levels normally produced in the 

human body on a daily basis in section 2. Understanding how these levels relate to the 

proposed RfC levels will be helpful information and could be added to sections which 

provide the “reality check” type discussion in section 6. Section 3.1.2.1 discusses this a bit 

and provides background levels for methanol, but not formaldehyde levels. In section 3.1.2.6, 

EPA does provide further helpful information from the Heck and Casanova studies. These 
IRIS STEP 3 INTERAGENCY COMMENTS

4

studies suggest levels around 2.5 ug/g in blood, giving an average of 2.5 ppm (2.5 mg/L). 

Using Hillman (1984) as discussed on page 3-8, EPA derives a value of 210-810 ug as an 

endogenous level in humans. Section 3.5.2 discusses levels in exhaled human breath (mean 

about 4.3ppb in Moser 2005) in subjects breathing ambient air. Are there data available that 

would allow EPA to put the proposed RfC exposure levels (4-9ppb in air) and proposed 

cancer risk levels in a context that could compare the internal dose to the endogenous levels 

in humans? It may also be helpful to ask the expert reviewers to comment on how the 

production of endogenous formaldehyde in the body should be considered as EPA proposes 

an RfC and cancer risk values.

Page 2-4, line 1-3, in discussing atmospheric residence time, EPA provides a value which 

assumes no reaction with hydroperoxyl radicals. It may be helpful to describe how this 

assumption relates to typical atmospheric condition.

Page 3-53, line35, it may be helpful to clarify EPA‟s conclusion here. The text seems to be 

saying that although the extent of mechanistic data available is more than most cases, EPA is 

still concerned that using rat and monkey data to inform allometric scaling to humans is still 

weak. Is this the correct interpretation? It may also be helpful to clarify what EPA means by 

“the empirical strength of a power law...”.

Page 4-1, line 27-35. (note: for most comments made on Section 4, any conforming changes 

should also be considered for Section 6)

o Line 27, it may be helpful to provide the level at which direct sensory responses are seen. 

Citations to the particular critical studies EPA is relying upon may also be helpful.

o Line 31, it may be helpful for EPA to provide the levels at which irritations are seen after 

acute and chronic exposures.

o Line 33, please provide citation for this statement regarding lifelong health effects from 

short-term or transient exposures.

o Page 4-2, line 1-10, discusses conclusions from Doty, 2004. However a more thorough 

description of this study, including doses evaluated, does not appear to be provided in the 

subsections of 4.1.1.1.

Page 4-3, line 4-17, EPA states that a clear dose response was seen in residential occupants,

in the Ritchie and Lehnen (1987) study, however it seems that smokers also reported similar

effects. EPA states that confounding cannot be an alternative explanation, since the authors 

reported that formaldehyde was the most important explanatory variable. Can further 

information on the importance of smoking be provided? We note that section 5 provides a 

NOAEL of 50 ppb for this study. As exposures here are cited as ranging from 100-300 ppb, it 

is unclear how the NOAEL was determined. Perhaps more information on doses examined 

could be provided.

Page 4-6, in discussing Kriebel et al 1993, can EPA say anything about whether or not the 

nose and throat irritation differences were statistically significant? It is not clear that they 

were, but considering the exposure level (730ppb), it is surprising that they would not be. 

Similarly this study saw no differences in asthmatics irritation levels.

Section 4.1.1.2, discusses many endpoints including FEV, PEF, PEFR, FVC. As many 

studies are negative for some of these endpoints and some studies are positive for others, it 

may be useful to have a discussion regarding the physiological differences behind what each 
IRIS STEP 3 INTERAGENCY COMMENTS

5

of these endpoints measures and why we may expect formaldehyde to impact some of these 

measures of pulmonary function but not others. A table arraying the results of all the studies 

discussed in this section might be helpful as this endpoint (pulmonary function) is used for 

candidate RfC determinations.

Page 4-45, line 22, it may be helpful to clarify which studies suggest a „convincing 

relationship‟ as the sentence which follows clarifies that not all studies reported significant 

associations and line 29 refers to „mixed results‟ in studies looking at congenital 

malformations.

Page 4-56 lines 23-27 refer to support from studies by Gray and Wu, 2005, Hakim et al 1995, 

and Correa et al 1996. We could not find any discussion of these supporting studies in this 

section. Is it correct that the only statistically significant study in this section on 

developmental and reproductive is the Taskinen et al 1999 study? More discussion on how 

EPA derived their overall weight of evidence conclusion regarding this endpoint may be 

helpful.

Page 4-56/ 4-57, section 4.1.1.9, for a summary section, this write-up could be more detailed. 

For each of the summary sentences it would be helpful to cite the specific studies that lead 

EPA to their overall summary regarding the specific non-cancer endpoints evaluated. 

Similarly, for each sentence where it appears that EPA‟s support is coming from specific 

studies, it would be most helpful to clarify for readers and reviewers which studies these are. 

Perhaps a summary table for the non-cancer effects would be most helpful, this way EPA 

could also array the exposure levels associated with each of the associations.

Page 4-57, section 4.1.2.1.1, in discussing NPC (nasopharyngeal cancer), EPA mentions that 

it is rare and may be associated with EBV and other risk factors. When we look at 

http://www.cancer.gov/cancertopics/pdq/treatment/nasopharyngeal/Patient, there seems to be 

a focus on two risk factors only: “ethnic background and exposure to the Epstein-Barr virus 

can affect the risk of developing nasopharyngeal cancer.” The cite then refers to Chinese or 

Asian ancestry. It may be helpful to have some summary discussion regarding how the 

critical studies considered these two main risk factors. If this is not addressed in any of the 

studies, it may be helpful to discuss the implications of this and how it relates to (or perhaps 

has no impact on) findings from the epidemiological literature.

Page 4-59, table 4-1, this table is extremely helpful, in particular because it shows the 

confidence intervals around the risk values. Would there be a way to easily add the exposure 

levels at which the effects were seen? In many cases, the 95% confidence interval includes a 

range of 1.0 and thus the findings are not technically statistical significant, though we 

understand that multiple findings that are close to statistically significant may still carry some 

weight-of-evidence value. In other cases, EPA simply says NS, instead of providing the 95% 

confidence interval. It is not clear why the confidence range is provided sometimes but not 

all the time. We would suggest providing the detailed information whenever it is available, 

regardless of whether or not the result was statistically significant. (similar comment for table 

4-4 where some of the confidence interval ranges are not provided)

Page 4-67, EPA has a good discussion around Marsh 2007a and the impact of silversmithing 

as an artifactual confounder. It may be helpful to have a specific charge question asking the 

expert panel to comment on this as it appears to be a controversial aspect of the analysis and 

likely plays a role in the weight of evidence determination regarding NPC and formaldehyde. 
IRIS STEP 3 INTERAGENCY COMMENTS

6

It may also be helpful to add this study and its revised OR‟s to table 4-1. Similarly, it may be 

helpful to add and discuss Marsh and Youk 2005 as well as the other Marsh analyses. It is 

not clear why all the studies are not presented in table 4-1.

Page 4-68, line 32-35, EPA refers to the theoretical possibility of coexposures at the plant as 

confounders, however the study itself seems to refer to other non-occupational exposures. 

What evaluation is EPA referring to regarding coexposures at the plant? 

Page 4-69, line16-23, refers to Hayes 1990 and other supporting evidence. The Hayes study 

is presented in the table but is not discussed elsewhere. Does EPA have data regarding the 

confidence intervals around the PMR estimate? Further discussion may help readers to 

understand how this study and the Hansen and Olsen, 1995 study provide modest support. An 

expanded discussion regarding which statistics EPA is relying upon and what parameters 

were used to inform the weight of evidence conclusion regarding the associations may be 

helpful.

Page 4-83, line 26-28, EPA refers to the Hildesheim study. It may be helpful to provide 

further detail on the exposure response relationship that was seen. The only finding of 

statistical significance was when people were classified as „ever exposed‟ but when the 

groups were broken into duration of exposure, the results were not statistically significant.

Page 4-366, for the human studies discussed in 4.3.4.2.2, it may be helpful for EPA to clarify 

which studies took into account differences in smoking habits between the control and 

exposed cohorts.

Page 4-378, line 13, in discussing Ritchie and Lehnen 1987, EPA refers to a LOAEL of 200

ppb. Should this also mention the NOAEL (50ppb) EPA presents in table 5-6?

Page 4-378, EPA is proposing a possible MOA related to stimulation of the trigeminal nerve. 

As sensory irritation is used to derive the candidate RfCs, EPA may want to consider a 

charge question for the expert reviewers regarding plausible modes of action.

Page 4-381, line 27-29, as EPA discusses how many of the studies examining pulmonary 

function show only slight deficits or are transient and did not show statistical significance, it 

is unclear why EPA finds pulmonary function alterations to be an “important symptom often 

associated with formaldehyde exposure”. More discussion of this finding might be useful. In 

the MOA discussion which follows, EPA may want to provide some citations and may want 

to consider a charge question as this endpoint is also used for candidate RfC development.

Page 4-391, in discussing behavioral effects and human data EPA seems to suggest that the 

human data provide support for the animal data. It may be helpful to clarify what studies 

EPA is basing this on. 

Page 4-393, line 28-30, EPA seems to be implying that because the co-exposures in each 

occupational study were different, these should not negate the findings linking the 

associations to formaldehyde exposure. Is this what is intended? If so, it is not clear that this 

conclusion necessarily follows. Plausibly confounding co-exposures would be an issue of 

concern even if the specific substances were different in different studies, wouldn‟t they? 

Page 4-401, as the discussion of MOA for developmental and reproductive effects ranges 

from possible endocrine effects to genotoxicity of the gametes, EPA may want to consider a 
IRIS STEP 3 INTERAGENCY COMMENTS

7

specific charge question taking comment on the MOA determinations for this endpoint and 

other endpoints which are used for RfC and cancer slope determinations.

Page 402, section 4.4.9.8, as part of the data gaps discussion, EPA may want to include 

discussion of the data gap related to the lack of information to inform the MOA.

Page 4-430, lines 2-7, in discussing MOA can EPA provide more information regarding the 

dose levels at which regenerative cell proliferation and clastogenic effects are seen?

Page 5-2, line 7, EPA lists the identified effect categories. It may be helpful for EPA to 

explain how these categories were chosen from all the non-cancer endpoints identified in 

Section 4. It may also be helpful to have a discussion regarding how strong the weight of 

evidence is for effects in each category and the general level at which formaldehyde exposure 

is statistically related to each of these effects. A summary table might be very helpful here. 

This weight of evidence determination could include discussion of the mode of action and

how the available information increases or decreases the likelihood of these effects being 

related to formaldehyde exposure.

Page 5-5, line 6-18, it appears that for sensory irritation the effect is eye irritation (as per line 

13). It would be helpful for EPA to replace “sensory irritation” with “eye irritation” moving 

forward in the rest of the document and in summaries as this is a more specific descriptor. 

Page 5-6, line 7, refers readers to table 5-1 to see the candidate RfC studies for the URT 

pathology endpoint. This table appears to be missing as table 5-1 shows POD‟s for nervous 

system toxicity only. It would be helpful for EPA to add this table to help readers understand 

the weight of evidence, including an array of studies considered for quantifying an RfC for 

this endpoint. Similarly, it would be very useful to have a table describing the studies 

considered for the endpoint of pulmonary function effects. It would also be helpful if these 

tables included information on whether or not the effects found were statistically significant.

Page 5-9, line 17-35, in discussing the choice of the Kryzanowski et al study, it may be 

helpful to have some discussion regarding the lack of linearity in the adult results and what 

this may mean for mode of action. Some discussion of this, and discussion of whether or not 

PEFR measurements are related to adverse effects or are measurements of a precursor to an 

adverse effect would be helpful. It may also be helpful to discuss whether or not changes to 

this measurement are expected to be reversible upon cessation of exposure. It may be helpful 

to ensure that there are some clinical pulmonologists on the expert panel to help comment on 

the use of this endpoint as a candidate RfC.

Page 5-10, line 30-33, refers to NOAEL and LOAEL values from the Rumchev and Garrett 

studies. However in Section 4, how EPA determined these values was never described, the 

values are simply stated in summary sentences. It may be helpful to add this information to 

both sections. For the Rumchev study, page 4-25 states that effects in asthmatics were 

statistically significant at exposures > 48 ppb. Was 30ppb the next lower exposure group? 

Was it the average of a range of exposures? When discussing the Garrett study, page 4-24, it 

is not clear whether or not the effects seen were statistically significant as the text states that 

the odds ratios did not remain statistically significant after controlling for parental allergy 

and asthma. More clarity on the details of these candidate RfC studies would be helpful to 

readers and reviewers.
IRIS STEP 3 INTERAGENCY COMMENTS

8

Page 5-22, line 1, in discussing Bach, EPA discusses the inability to perform BMD modeling. 

This discussion is very informative, and in discussing the other candidate RfC values, it

would be helpful to have a similar discussion.

Page 5-30, line 3-8, in discussing the FDR for the candidate RfC, EPA indicates that the 

findings in the highest exposure group were not statistically significant. It is not clear how 

this was considered in determining if this exposure group should be treated as a LOAEL or 

NOAEL. More clarity regarding this discussion would be helpful.

Page 5-35, lines 3-17, for sensory irritation (eye irritation), EPA selects three studies as 

candidate studies. As EPA was able to conduct BMD modeling on only the Hanrahan et al 

study, and EPA has always stated that BMD modeling is preferred to a NOAEL/LOAEL 

approach, it is not clear why EPA isn‟t showing a preference for the Hanrahan et al study. 

We suggest that EPA propose using this study alone, based on the robustness of the available 

data in that it allows for BMD modeling, as a candidate RfD in addition to approaches which 

average or present a range of findings. Similarly, for the studies which look at the respiratory 

effects endpoint (as per table 5-6), only the Krzyankowski study used a BMD approach. It 

would be helpful for EPA to specifically ask reviewers to comment on the proposed 

approaches.

Page 5-36, in table 5-4, it is unclear how EPA determined that the NOAEL for the Ritchie 

and Lehnen study was 50 ppb. Similarly, for other studies that present a NOAEL, it is 

difficult to determine from previous text how these values were derived. More clarity on this, 

as well as a clear presentation of BMD modeling results for endpoints which rely on the 

BMD approach would be helpful.

Page 5-39, lines 25-30, in discussing the narrowed list of best studies evaluated, it would be 

useful for EPA to include discussion of whether or not these effects are considered adverse 

and also irreversible. 

Page 5-40, in discussing the ATS statements regarding pulmonary function tests, it may be 

helpful to note whether or not ATS specifically mentions PEFR measurements. 

Page 5-41, in discussing Krzyzanowki, the details of the BMD modeling (including 

discussion of model fit) should be provided as is typically done in these sections of the 

toxicological reviews. EPA may also want to consider a charge question which takes 

comment on the details of the BMD modeling approach for the cases where it is used.

Page 5-44, in determining the Rumchev NOAEL, from figure 5-5, it appears that the 50-59 

ug/m3exposure group was the NOAEL. EPA describes this in text as being 30-49 ug/m3. 

Please clarify which is correct as this impacts the NOAEL value. From the figure, it appears 

that the value should be 55 ug/m3(46 ppb rather than 33 ppb). In addition, on page 5-45, as 

EPA states that it is unclear whether a study of children under 3 yrs of age is adequate and 

thus is unclear as to whether or not the subchronic to chronic 3x uncertainty factor (UF) is 

needed, EPA may want to present a derivation without the UF as another alternate derivation. 

This could results in a candidate RfC equal to the NOAEL (46 or 33 ppb). EPA may want to 

also ask the expert panel to comment specifically on the appropriateness of such a derivation.

Page 5-50, in describing Garrett, EPA states it is unknown whether the findings in the lowexposure group are comparable to the responses that would be observed in an unexposed 

population. It would seem that this argument is relevant to whether or not an UF for human 
IRIS STEP 3 INTERAGENCY COMMENTS

9

variability is needed. It would also be helpful for EPA to explain why this group is treated as 

a LOAEL rather than NOAEL, given that it did not show statistically significant effects. In 

addition, EPA may want to present the derivation using the low exposure group as a 

NOAEL, thus not applying an UF for LOAEL to NOAEL extrapolation, as an alternate 

derivation and take comment on it. 

Page 5-56, for the eye irritation studies, EPA may want to explicitly take comment on their 

determination of the POD for each of these studies as some decisions appear to be based on 

professional judgment, rather than explicit data. In addition, this section should provide the 

modeling details for the Hanrahan BMCL calculation.

Page 5-62, line 21, states “It is preferable that the critical effect be the most sensitive of the 

effects which is well supported by the given study.” We assume this means that once the 

critical (most sensitive) effect is identified, a weight of evidence evaluation of the entire 

database regarding exposure levels at which the effect is seen should be considered, not just 

the study with the lowest value. It would be helpful for EPA to clarify this point. Page 5-65, 

line 5, more clarity on why the mid-exposure level was considered the NOAEL in the 

Taskinen study would be helpful. Perhaps EPA can provide a table describing dose levels 

and effects, including statistical significance. 

Page 5-74, in discussing the POD determination, EPA may want to include discussion of how 

BMD modeling is typically preferred by the agency. 

Page 5-82, line 23-24, EPA refers to the “preferred estimated” as being 1.1x 10-2for NPC. It 

is unclear what is meant by “preferred”. Isn‟t this the plausible upper bound value? As EPA 

is using human data, it may be helpful to also clearly provide central or „best estimates‟ for 

the cancer risk values as well, particularly since these are often needed for regulatory impact 

assessments associated with regulatory determinations. Similar presentation would be helpful 

for all tumor types and for the combined cancer incidence and risk estimate values.

Page 5-83, EPA provides a very helpful discussion which compares the unit risk estimate to 

actual case numbers. In one case, EPA assumes 20ppb exposure (a value within the range of 

human indoor exposures, but not a necessarily a high-end exposure value) and estimates 880 

cases of NPC per year. Is this plausible, since it represents just over 40% of estimated NPC 

cases? It would be useful to see how the levels would compare if EPA used the best estimate 

cancer risk value, rather than the upper bound risk value. A similar discussion would be 

useful on page 5-95, where EPA calculates that a 20 ppb exposure results in about 16% of all 

Hodgkin lymphomas per year. EPA may want to specifically ask the expert reviewers to 

comment on the comparative analyses provided and their implications for derived risk 

values. 

Page 5-95, footnote 12, EPA presents values using the ADAF calculations and estimates that 

if EPA were to assume lifetime exposure, a 20ppb exposure would account for about 27% of 

incident Hodgkin lymphomas per year. We suggest EPA have a charge question regarding 

whether or not the ADAF should be applied to formaldehyde, and if this application, based 

on the MOA discussions, should perhaps be dependent on exposure levels. In addition, EPA 

should ask reviewers to comment on whether it would be appropriate to apply this factor to 

all tumors or perhaps just specific cancer endpoints.
IRIS STEP 3 INTERAGENCY COMMENTS

10

Section 5.4.4, as the ADAF guidance recommends that information specific to the exposure 

scenarios of concern be used in the evaluations, we recommend that EPA refer readers to the 

guidance for examples on how to apply the factors, rather than creating a full life time 

exposure value in this assessment. If the life-time exposure value is retained, EPA should 

remind risk managers to apply case specific exposure values that are appropriate to the 

particular risk management scenario under consideration. 

Page 5-137, line18, it is unclear why EPA considers the impacts of the partial risk to be 

negligible. As there seem to be questions about whether or not the factors should be applied 

to Hodgkin lymphoma and leukemia values, EPA may want to consider a specific charge 

question asking the expert reviewers to comment on this as well as EPA‟s determination that 

the ADAF‟s should be applied to all cancer endpoints.

Editorial Comments (with Scientific Impacts):

In addition to the list of abbreviations and acronyms it may be helpful to define each 

acronym and abbreviation in the text of the document the first time it is used. We also note 

that some acronyms are not defined in the preface list (eg FA, SI).

Page1-2, line 20-21, EPA states that relevant literature was reviewed through April 2009, but 

some critical literature after this date has been considered. As some 2010 literature, and late 

2009 literature is cited, it may be helpful to explain the process EPA used to determine which 

studies were considered “critical literature” for inclusion.

Page 2-3, line 3-6, EPA lists consumer products that formaldehyde is used in. It may be 

helpful to clarify whether it may be in some brands of some of these products or whether it is 

known to be in all of these products, regardless of brand/source. Currently the language says 

“ is present in”, which leads readers to assume it is in all of these products regardless of 

brand/source. Clarification on page 2-11 will also be helpful.

Page 2-7, cites NLM 2001. We could not find this citation in the references

Page 2-10, EPA discusses mobile homes and trailers. EPA may want to clarify for readers if 

these are the same types of units or are different. Are all trailers considered mobile homes? It 

is our understanding that HUD regulates mobile homes but not trailers, so the distinction may 

be important.

Page 3-29, table 3-5, please clarify units in the table.

Page 3-26, line 22, was the omission truly „explicit‟?

Page 3-51, line 4-6, in discussing Conolly 2000, EPA mentions possible errors in the paper. 

As Connolly now works within EPA, perhaps he could be asked directly about the issue and 

it can be clarified in the document.

Page 4-12, line 1-2, please provide citation for this statement.

Page 4-12, in describing ATS 2000 (cited in references as ATC 2000) it may be helpful to 

put the ATS statement in quotations. Also, while this is an important part of a discussion 

regarding what constitutes an adverse effect, perhaps it belongs elsewhere in the document 

where there is a broader discussion of this topic. It is unclear why this discussion is in the 
IRIS STEP 3 INTERAGENCY COMMENTS

11

section describing eye, nose, and throat irritation as the specific example given discusses 

lung function.

Page 4-15, in discussing, Holness & Nethercott, 1989, and Horvath et al 1988, it may be 

helpful to provide information on exposure levels.

Page 4-20, line 3, EPA describes the Stenton and Hendrick study as reporting on 

formaldehyde and asthma. However Figure 4-1 from the same study states that the exposure 

was to formalin. 

Page 4-25, line 33-35, please provide citations for this statement. Similarly on page 4-26, line 

1-2, it may be helpful to specifically cite the studies EPA found to be limited.

Page 4-26, in section 4.1.1.4, EPA begins to apply NOAEL and LOAEL values, where 

possible, to specific studies described. This is very helpful. EPA may want to consider doing 

this in the earlier sections of 4.1.1 (4.1.1.1, 4.1.1.2, and 4.1.1.3).

Page 4-26, line 5-7, please provide citations for this statement. On line 13 in describing 

protective and defensive mechanisms, it may be useful to provide information on the levels 

of exposure that are expected to cause these responses.

Page 4-28, line 23 and 25 (and elsewhere throughout the section), it may be helpful to clarify 

that the LOAEL is for increased eosinophils (rather than simply stating „nasal 

histopathology‟). Line 29- please define SI.

Page 4-28, section 4.1.1.4.2, EPA refers to this section as mucociliary clearance, however 

many of the studies did not examine clearance, but instead examined mucociliary activity. 

(eg Holmstrom and Wilhelmsson). EPA may want to discuss the relationship between 

activity and clearance or perhaps clarify exactly what was examined throughout the 

document.

Page 4-29, line 17, the sentence begins „thus‟ however it is not clear what previously 

discussed studies reported epithelial lesions. Do you mean to refer to mild nasal swelling? 

On line 27, it may be helpful to clarify why the Holmstrom and Wilhelmsson study is the 

most robust. Describing how total exposure was carefully calculated and averaged may be 

helpful (line 31).

Page 4-30, line 16, EPA refers to studies in section 4.1.1.2 which showed exacerbation of 

asthma. It may be helpful to specifically cite the studies EPA is referring to.

Page 4-30, line 31, suggest replacing “diverse studies” with “three studies”

Page 4-31, line 29, please clarify that the studies reported on the incidence of self reported 

chronic bronchitis.

Page 4-31, line34, is the citation to Ohtani 2004 correct? We note that this was an in vitro

experiment using human cells. Thus it is not clear that systemic effects were examined.

Page 4-32, line 1, please clarify that the associations with formaldehyde exposure in Erdei et 

al, were likely due to a mix of air pollutants, including formaldehyde (as per line 26-27). It 
IRIS STEP 3 INTERAGENCY COMMENTS

12

may also be helpful to clarify in this summary sentence, on line 1, that the children were 

immunologically compromised (as per line 11). 

Page 4-34, line16, it may be helpful to clarify how EPA, or study authors, defined 

“formaldehyde-sensitive subjects.” Similarly, on page 4-37, line 20, it may be helpful to 

define what is meant by “formaldehyde specific IgE.”

Page 4-35, line 34, it may be helpful to explain the implications of having elevations in the 

“binucleated micronucleated cell rate”

Page 4-42, line 7-9, please provide citation. For lines 26-28, please provide citation or clarify 

if this is a hypothesis.

Page 4-46, line 1-2, can EPA provide the confidence intervals surrounding the relative risk 

values? Line 5-15, in describing Axelsson et al 1984, is there any information available 

regarding other exposures in the laboratories (including non-solvent exposures that may be 

associated with spontaneous abortions)?

Page 4-48, line 33, EPA refers to the John et al 1994 study as also supporting an association. 

It may be helpful for EPA to clarify which previously discussed studies did show a 

relationship. Many of the previously discussed studies had confounding exposures or were 

not statistically significant.

Page 4-52, line 15-18, in EPA‟s discussion that this negative report does not “temper the 

conclusion” that formaldehyde exposure has been shown to increase the risk of spontaneous 

abortion, it may be helpful for EPA to clarify the dose levels at which the increased risk is 

seen and also which studies specifically support the overall conclusion. Similar comment for 

line 31-34, where EPA refers to the results of this second study as not appearing to be 

“exculpatory of a true casual relationship.” This is a section where a table arraying all the 

studies and their outcomes (including statistical significance) may be particularly helpful to 

readers.

Page 4-54, line 12-14, it would be helpful to clarify which studies EPA is referring to as 

providing the collective evidence. Similarly on line 19-20, EPA may want to clarify which 

studies specifically looked at diminished fertility (it is unclear how EPA is defining this).

Page 4-56, line 6-8, it may be helpful to clarify, or perhaps show in a table, those studies that 

cannot be dismissed in regards to showing a positive relationship with formaldehyde 

exposure.

Page 4-68, line 8-10. It is unclear why EPA is citing IARC 1995. As they updated their 

findings in 2006, shouldn‟t EPA be citing the most recent review? 

Page 4-69, line 2, please provide a citation for the analysis regarding particulates.

Page 4-69, line 4-8, EPA may want to soften these sentences or provide citations to support 

the arguments. Does the medical literature provide no basis for the supposition or is the 

medical literature silent on any possible association? Similarly, if there are data regarding 

how common the activity is in Wallingford, please cite these data. A charge question on this 

may be helpful.
IRIS STEP 3 INTERAGENCY COMMENTS

13

Page 4-83, line 15, EPA may want to replace “in some studies” with “in one study”. 

Additionally, when EPA states that some studies have “suggested a dose-response” it would 

be helpful to clarify what “suggested” means in this context.

Page 4-84, line 26, it may be helpful to specifically cite the studies from table 4-4 that EPA 

finds to show support for an increased risk. 

Page 4-89, line 35, it may be helpful to show the confidence intervals surrounding these 

SMR values. We could not find all this information in Table 4-4. Similar comment for page 

4-90, line 22-23.

Page 4-91, line 11, suggest deleting “representing the formaldehyde industry”, unless this is 

relevant to the discussion and EPA provides similar information for all commenters. On line 

14, EPA may want to provide a specific cite to the discussions that are referred to. In 

addition, as the assignment of peak exposures in the Hauptmann 2003 study appears to be an 

area of disagreement, perhaps a charge question specifically addressing this would be 

helpful.

Page 4-97, line 1-35, please provide citations for the discussion here regarding mode of 

action. EPA may also want to consider moving this discussion to the section of the 

toxicological review which discusses mode of action and biological plausibility. Please also 

provide citations on page 4-109, lines 19-24.

Page 4-368, line 7-11, it may be helpful to provide information on the formaldehyde 

exposure levels in these studies. 

Page 4-386, line 1, please clarify the 2009 citation

Page 4-386, line 5-14, EPA‟s policy guidance suggests a case by case consideration of 

genomics data in the weight of evidence determinations. Is it true that genomic data may 

only be applied to discussion of MOA. 

Page 4-387, line 15-17, EPA may want to clarify the exposure.

Page 4-388, line 1, it may be helpful for EPA to clarify exactly what changes they consider to 

be adverse effects

Page 4-388, line 14, suggest replacing “these data indicate” with “these data suggest”. 

Page 4-388, line 23, EPA may want to clarify exactly which “omics” changes are being 

referred to here.

Page 4-390, line 32, instead of saying “exquisitely sensitive”, it would be helpful to provide 

the specific exposure level at which effects are seen.

Page 4-393, section 4.4.8.5 provides a very brief discussion of data gaps. Is this intended to 

be the full discussion of data gaps for all non-cancer effects? We don‟t recall seeing this 

discussion in other sections of the non-cancer discussion. A broader discussion of noncancer endpoint data gaps would be helpful. 
IRIS STEP 3 INTERAGENCY COMMENTS

14

Page 4-394, line 9, is it appropriate to imply that FDR (fecundability density ratio) is a 

measure of “risk of pregnancy loss”? Is it possible that FDR also measures inability to 

conceive? Page 4-395, line 3, refers to the study as a finding of reduced fertility and 

increased risk of spontaneous abortion. It may be helpful to clarify exactly what the FDR is a 

surrogate for.

Page 4-410, line 1-3, can a citation be provided?

Page 4-412, table 4-90. It is unclear why some risk values are bolded and others are not.

Page 4-424, table 4-94, EPA may want to provide information on statistical significance in 

the results column.

Page 4-434, line 7, it may be helpful for EPA to define what is meant by “level 3”and “level 

2”

Page 5-8, line 5, “chrinic” should be “chronic”

Page 5-25, line 30 (and elsewhere in section 5), EPA states “where adversity is characterized 

as per EPA risk assessment guidelines”. Although a citation is provided, it would be helpful 

for EPA to provide a footnote describing how these guidelines define adversity. Page 5-31, 

table 5-3, it may be helpful to provide information in the table regarding whether or not the 

effects seen in each study were statistically significant.

Page 5-36, table 5-4, it may be helpful to provide information in the table regarding whether 

or not the effects seen in each candidate study were statistically significant.

Page 5-39, section 5.1.1.2.2, thus far the document has had a consistent flow in the order by 

which non-cancer effects are discussed. It may be helpful to simply reorganize this so that the 

studies are presented consistent with the order provided in the summary on page 5-39, line 

26-29.

Page 5-70, for the general discussion of other endpoints not considered, it may be most 

helpful to have a summary table comparing the PODs from some of the studies EPA 

considers to be key studies for the candidate PODs and RfC values.

Page 5-101, line 11 and 24, please clarify what is meant by a “reasonable estimate”. Aren‟t 

these upper bound estimates?

Page 5-138, line 1-19, as per comments above, suggest deletion of this text. Similar deletion 

is suggested for page 6-42, line 19-21 and in section 6.2.2.8 (page 6-45 and 6-46).

Chapter 6 as per discussion on Page I-xxxii, in 6.2.1.5 EPA should include a clear discussion 

of EPA‟s confidence in the candidate RfC values, and a confidence descriptor (eg high, low, 

medium) as EPA typically does for RfC and RfD values. Taking into account typical 

background exposures, expert reviewers could be asked to comment on EPA‟s determination 

of their confidence in the overall values.

Comments on the Draft Charge:

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

and have not been reiterated here but should be considered as equally important .)
IRIS STEP 3 INTERAGENCY COMMENTS

15

General Comments:

o EPA‟s charge asks the panel to consider, among other things, “theory and experience”. It 

may be helpful to also emphasize the value of having the committee provide, when possible, 

peer reviewed citations to support their findings.

It may be helpful to broaden the charge to also take comment on EPA‟s conclusion regarding 

the following topics:

o findings regarding metabolism

o conclusions regarding the potential modes of action for each non-cancer and cancer 

endpoint discussed

o conclusions regarding the weight of evidence supporting the findings related to 

formaldehyde exposures and each non-cancer endpoint.

o conclusions regarding susceptible populations and the ALDH2 and ALDH3 

polymorphism and how EPA might use this information

o conclusions regarding animal data which support the cancer MOA (in particular the 

Soffriti studies)

o EPA‟s evaluation of the rodent modeling relating to toxicokinetics, dosimetry 

modeling and the evaluation of dose response models of DPX, cell replication and 

genomics data, and BBDR models for risk estimations using animal models

o EPA‟s decision to rely upon the re-implemented Subramanian 2007 model

o EPA‟s characterization and presentation of the information related to the uncertainty 

in the non-cancer and cancer estimates

o EPA‟s characterization of data gaps

In addition, EPA may also want to ask the peer reviewers to comment on the significant of 

risk values that are at or below background. This may have impacts for how EPA may 

recommend the values be used and considered by risk managers.

Since the development of Agency Information Quality (IQ) guidelines required by statute, 

many agencies have been using charge language that tracks with the standards of their own 

IQ guidelines. For example, such language often focuses on whether or not the information in 

question is accurate, clear, complete, transparently and objectively described, and 

scientifically justified. We believe it may be useful for EPA to follow a similar approach and 

incorporate some of the language from your IQ guidelines into the formulation of the charge 

questions. It will also be helpful for EPA to ask reviewers to comment on both the objectivity 

of the presentation and the objectivity of the substantive results and underlying assumptions.

Section A:

o EPA may want to consider asking the expert reviewers to specifically comment on which 

alternate values are most scientifically supported. The panel should be explicitly asked to 

comment on EPA‟s final recommendations, including the application of uncertainty factors 

for each alternate derivation.

Section B:

o EPA may want to consider charge questions which ask the NAS to comment on the 

conclusions related to each specific cancer endpoint.
IRIS STEP 3 INTERAGENCY COMMENTS

16

o EPA may want to consider a charge question asking about EPA‟s choice to use the NCI 

cohort over other studies. In addition, this could include taking comment on the choice of 

exposure metric (peak vs cumulative), as well as the derivation of the extra risk level (EPA 

used 0.05% for determination of the POD for NPC and LHP). 

o EPA may want to consider a question to reviewers regarding the uncertainties in the cancer 

derivations (for NPC, EPA states that the major uncertainty is “the appropriate 

model/exposure metric for extrapolation to environmental exposures”) and how these 

uncertainties may affect the interpretation of the results and use of the results.

o EPA may want to consider a specific question regarding how EPA grouped and treated 

leukemia subtypes.

o EPA may want to consider a charge question regarding EPA‟s approach to combining cancer 

risks for all sites.