UNITED STATES 

CONSUMER PRODUCT SAFETY COMMISSION 

WASHINGTON, DC 20207 

Date: April 21, 2010 

Dear Sirs, 

 The following memo provides the U.S. Consumer Product Safety Commission’s 

(CPSC’s) Health Sciences’ staff assessment of the U.S. EPA IRIS program’s draft 

“Toxicological Review of Formaldehyde Inhalation Toxicity” (FA IRIS). This document was 

forwarded electronically to CPSC for review on March 22nd, 2010. EPA has set a deadline for 

interagency replies by April 19th, 2010. CPSC has been granted an extension for review until 

April 21st, 2010 COB. 

These comments are those of the CPSC staff, have not been reviewed or approved 

by, and may not necessarily reflect the views of, the Commission. 

Overview

 Formaldehyde is an environmentally ubiquitous chemical that is present naturally in 

outdoor air and is a metabolic byproduct and carbon source in mammalian respiration. 

Formaldehyde is also used in a variety of manufacturing processes as a component in resins, a 

lubricant, a finish, and a preservative/antimicrobial. Currently it is in the top 25 of highest 

volume chemicals produced in the United States. Formaldehyde is also a byproduct of 

combustion processes from motor vehicles, power plants, refineries, wood burning stoves, and 

cigarettes. 

 The CPSC staff has been involved in the assessment of toxicity, exposure and risk due to 

the use of formaldehyde in consumer products for decades. Historically, CPSC has been 

involved in the assessment of formaldehyde-related toxicity for consumer products such as Urea 

Formaldehyde Foam Insulation (UFFI) pressed wood products, and its use in imparting 

permanent press characteristics in textiles. In the 1980s, CPSC funded exposure studies by way 

of outside contracts, interagency agreements, and work in its own laboratory that were critical to 

the development of voluntary standards for formaldehyde in pressed wood products. In 1982, 

after a conducting a large toxicological review including exposure and risk assessments, the 

Commission voted to ban UFFI because of concerns regarding its carcinogenic and acute 

(irritation and sensitization) effects. This ban was ultimately overturned by the U.S. Court of 
Appeals, 5th Circuit, in New Orleans. However, the publicity surrounding CPSC’s efforts to ban 

UFFI, and its assessment of the potential harm due to formaldehyde off gassing from this 

product, led to a severe reduction of the residential use of UFFI at the time. Subsequent efforts 

such as the creation of an informational brochure for consumers (1997) have attempted to further 

reduce exposure to exogenous formaldehyde. 

The FA IRIS document is comprised of 4 volumes; 1) Introduction, Background, and 

Toxicokinetics, 2) Hazard Characterization, 3) Quantitative Assessment: Inhalation Exposure 

and Major Conclusions and 4) Appendices A-H. Approximately 900+ pages of documentation 

describe the stages for estimation of multiple inhalation reference concentrations (RfCs) and unit 

cancer risks based on different toxicological pathologies. 

CPSC staff is pleased to have had the opportunity to review and provide comments on the 

FA IRIS document. Review of the FA IRIS document will take place in order of discussion in 

the document. Scientific commentary will be provided for many areas. Commentary on policy 

may also be noted, since science and policy is sometimes blurred (i.e. selection of uncertainty 

factors), even though EPA has remarked that these comments will not be considered in 

stakeholder response reports. Finally, a lack of commentary on issues presented in the FA IRIS 

document does not necessarily indicate agreement with what has been written. The substantial 

size of the document and the need for accelerated review (< 30 days) has precluded in-depth 

review for a significant portion of the document. 

Overall Commentary 

This document has done a remarkable job of summarizing and evaluating an immense 

amount of data on the potential toxicity and risks following exposure to formaldehyde. In 

general, the text is well written and understandable throughout. There are, however, a few issues 

that detract from the overall conclusions presented. These are presented below. 

1) A primary issue with the FA IRIS document is that the discussion of study limitations 

(i.e. small number of test subjects, confounding-related issues, methodological/statistical issues) 

seems inconsistent in many cases. Some studies receive substantial criticism and others receive 

little or none without qualifying statements as to why. Inconsistent application of study criticisms 

gives the appearance of partiality. 

2) The FA IRIS document is also very difficult to read in its current form. Document 

readability can be improved substantially by considering the following: 

A) Merge the 4 volumes in to 1 volume. This will eliminate the repetitious nature 

of seeing the same Contents, List of Tables, List of Figures, and List of Abbreviations and 

Acronyms for each volume (removing approximately 90 pages of repetition). 

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B) For the main document, use a consecutive numbering scheme not based on 

Chapters (i.e. use 1, 2, 3 instead of 1-1, 1-2, 1-3) 

C) Convert measures of atmospheric concentration to a standard unit such as ppb, 

ppm, or μg/m3

. 

D) Italicize et al. to et al. 

 E) Data for some studies seems to be segregated into a variety of places in the 

document (i.e. Malek et al. 2003a; 4-256, 257; 5-23). The FA IRIS document would be easier to 

read and understand if all of the pertinent data or methods were contained in one place and then 

referred back to by other sections when needed. 

3) At least one internal referral (i.e. to section 4.2.1.4, Page 5-18) is inaccurate (should be 

to 4.2.1.6). The authors should check other internal referrals to ensure that these are correct. 

4) In Point of Departure Tables (i.e. Table 5.1, 5-3, etc), it is important to note additional 

data such as the number of test and control subjects (or litters, i.e. “n”), the statistical 

significance of the response (i.e. P<0.05), and/or the biological significance of the response (i.e. 

10% decrease). 

5) It is unclear to the reviewer what the selection criteria were for studies included in 

Point of Departure Tables. For example, in the case of neurological and behavioral POD tables, 

some species (mice) were excluded on the basis of reflex bradypnea, while studies with similar 

exposures to rats were included. The Table also included results from a human study with 

numerous confounders and other deficiencies, which were seemingly substantial enough to 

warrant exclusion from the Table. Clarifying the criteria for inclusion in the POD tables (i.e. 

using only “acceptable” studies) would go a long way to resolving confusion associated with 

their subsequent interpretation. Note that disqualification from the POD Tables could be based 

on study deficiencies. Subsequent exclusion from RfC derivation (i.e. the Pitten et al (2000) 

study, Page 5-22) should be based on other criteria (i.e. inability to extrapolate exposure 

durations). 

6) On some of the study summaries (i.e. page 4-255, line 14, etc); the exposure duration 

is left out of the description. This is an important piece of methodological information that 

should be provided in order to judge durational effects. 

7) In the portions of the FA IRIS document reviewed by CPSC staff, there were no 

incidences in which a review of publications resulted in the conclusion that there were not 

enough consistent information/data to conclude with any certainty that the effect occurred. EPA 

should consider the addition of this possibility to discussions related to adverse effects. 

8) Overall, unrelated pathologies should not serve as mutual support for the conclusion 

that an effect on a particular organ system is occurring. If discrete pathologies (i.e. change in 

Page 3 of 11 KRC
fecundity) are not consistent among studies, effects should be discounted or caveated in 

discussion material. 

9) Overall, a variety of study endpoints (i.e. pathologies) have been subjectively deemed 

significant, either in disregard for the statistics that demonstrate otherwise, or using the argument 

of biological plausibility. A lack of statistical association generally means either 1) there is no 

association, or 2) there are study confounders (i.e. group size) that preclude the generation of an 

association. Making the jump to biological plausibility from non-significant data should be 

discouraged except in special circumstances in which these specific pathologies are also 

demonstrated in other studies at similar doses. 

Volume I discusses the properties, uses, environmental concentrations, human 

exposures, protein binding, endogenous and exogenous sources, metabolites, absorption, 

metabolism, distribution, excretion, and the toxicokinetics of formaldehyde and DNAprotein crosslinks. 

No comments on this section. 

Volume II is a hazard characterization and reviews data on human and animal noncancer effects (i.e. sensory irritation, lung function, asthma, neurological, developmental 

and reproductive) and cancer effects (respiratory, gastrointestinal, lymphohematopoetic) 

effects. It also covers genotoxicity (i.e. formaldehyde-DNA reactions, in vitro clastogenicity, 

in vitro mutagenicity, in vivo mammalian genotoxicity), potentially susceptible populations, 

co-exposures, and database uncertainties. 

General Commentary 

1) Review of many of the inhalation studies did not include a description of the physical 

characteristics of the experimental dose (i.e. mass median aerodynamic diameter, MMAD; 

particle droplet size distribution). Without this information, it is impossible to determine where 

the dose is being deposited (i.e. nasopharyngeal area, bronchi, bronchioles, alveoli), and hence 

determine the relevance or lack of pathologies. Inhalation studies should include a physical 

characterization of the exposure aerosol or discuss potential complications with not having this 

information (in terms of pathologies seen or not seen). Grading the studies (as to their 

confidence; low, medium, high) should also consider the lack of this information. 

Specific Commentary 

Page 4-44, line 1-17 – Were the dose levels (atmospheric concentrations) measured or 

inferred for these various chemicals? If this study is to be used as primary support for suggesting 

neurological impairment (“...and the epidemiology study by Weisskopf et al. (2009) provide 

strong support for an association between increasing neurotoxicity and increasing duration of 

exposure”), more study details should be provided. 

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Page 4-45, line 18-19 – Suggest deleting “There is....needed.” because the “serious 

concern” generated by epidemiological and controlled exposure human studies assessing 

neurobehavioral endpoints may be overstated. As stated on Page 4-42, line 31, “some suggestion 

of neurological impairment” is probably a better descriptor, since the studies are really a mixed 

bag of possibly positive, equivocal, and negative results. Perhaps this sentence could be worded 

something like “Additional research is needed to address these limitations”. 

Page 4-257, Figure 4-21 – There are no significance or error bars assigned to any of the 

treatment groups in this Figure. Are any of these results significant? 

Volume III covers the quantitative assessment of RfCs from inhalation exposures. 

Included in this section are candidate RfCs for: 1) sensory irritation of the eyes, nose, and 

throat; 2) upper respiratory tract pathology; 3) pulmonary function effects; 4) asthma and 

allergic sensitization; 5) immune function; 6) neurological and behavioral toxicity, and; 7) 

developmental and reproductive toxicity. A quantitative cancer assessment (based on the 

NCI cohort study) is also provided for 1) nasopharyngeal cancer, 2) lymphohematopoetic 

cancer (Hodgkin lymphoma and Leukemia). The cancer assessment is supported by doseresponse modeling of animal squamous cell carcinoma in the respiratory tract. Inhalation 

unit risk estimates are estimated for both human and animal data. 

General Commentary 

1) The broad application of a database uncertainty factor to account for reproductive 

and/or developmental effects is unwarranted when assessing RfCs (or RfDs) for various target 

organs. A database uncertainty factor should be applied to a particular target organ endpoint only

if data are lacking for, or are not able to be extrapolated to, that endpoint. For example, if a 

hypothetical RfC was based on coronary effects, an extra database uncertainty factor for 

reproductive data deficiencies might not be applied. If, however, developmental data were 

lacking and developmental processes in the heart could potentially be affected, then a database 

uncertainty factor for developmental affects might be applied. 

Specific Commentary 

Page 5-2, line 10 – Two commas after category 

Page 5-3, line 30 – This sentence makes the process of evaluating whether the study 

might have been influenced by reflex bradypnea sound very subjective. How is it possible to 

differentiate whether there is 1) no effect on an organ system because it is not affected by 

formaldehyde or 2) no effect on an organ system because reflex bradypnea decreased the overall 

systemic dose? 

Page 5-6, line 19 – The sentence starting with “The mean score” is awkward. Also, 

should the statistical measure be the geometric mean instead of the mean? 

Page 5 of 11 KRC
Page 5-6, line 24 – The lack of correlation between duration of exposure and histologic 

changes decreases the confidence one has in using this study for RfC derivation. 

Page 5-7, line 21 – How many students and is the difference in PEF biologically or 

statistically significant? What is the variation of these measures? 

Page 5-8, line 5 – “chrinic” after “and” 

Page 5-9, line 28 – Is the difference statistically significant? Can it be distinguished from 

normal variation? 

Page 5-10, line 14-21 – What relevance do dermal studies have in a discussion of 

inhalation-induced pathologies? Either qualify why it is OK to evaluate dermal studies (i.e. 

because the immune pathways for hypersensitization are the same in dermal and respiratory 

systems) or support this section with examples of hypersensitization derived from inhalation 

studies. 

Page 5-11, line 17 – How does the reported question compare to a medical diagnosis of 

asthma? What other diseases have the same reportable symptoms (“attack”, “wheezing”, “short 

of breath”), and in what comparative frequency? 

Page 5-11, line 21 – Indoor air concentrations of formaldehyde (2.3 μg/m3

) are less than 

outdoor air concentrations (5.8 μg/m3)? Is this correct? Indoor air concentrations in this study are 

substantially below all levels cited in other review documents (i.e. NTP ROC, 2010, page 60-63). 

Page 5-11, line 22-24 – Cumulative asthma and daytime attacks of breathlessness were 

associated with outdoor exposure levels (4.7 ppb), but not with indoor exposure levels (1.9 ppb)? 

Were these values distinguishable statistically or biologically? 

Page 5-13, line 15-17 – Please explain why a “no effect” determination is “consistent 

with two-fold increase in risk” 

Page 5-13, line 30-33 – This sentence is unclear. Is the author using peak measurements 

as exposure estimates for each group? 

Page 5-14, line 3-4 – OR’s of 1.34 and 1.42 are very weak positive associations. 

Page 5-14, line 9-12 – As with line 30-33 of the previous page, the meaning of this 

sentence is unclear. 

Page 5-14, line 25-26 – An OR of 1.39 is a very weak positive association. 

Page 5-14, line 30-33 – What is the citation? How were the other confounders in cigarette 

smoke controlled for? Why are the concentration cutoffs 40 and 60 ppb? What is the variation 

around the percentages of asthma? A dose-response is not evident for this study (<40 ppb = 

Page 6 of 11 KRC
15.1%, 40-60 ppb = 0%, >60 ppb = 45.5% asthma). Trends with non-smokers (range 4.3-14.0 

ppb) seem to refute positive asthma findings at lower concentrations (page 5-11, line 22-24). 

Page 5-14, line 34 – Delete blank line 

Page 5-15, line 2 – What was the geometric mean for formaldehyde concentrations? and 

were the average concentrations significantly different? 

Page 5-16, line 9, line 21 – Use of the word “potentiation” implies a synergistic response 

rather than just an additive one. Is this what the author meant? 

Page 5-16, line 19-20 – Data exists to support a neurogenically-mediated 

hypersensitization response rather than an immunological response. Should these two different 

types of responses be separated into different categories since their mode of actions are different? 

Page 5-17, line 14 – Is there any supporting animal information for decrements in 

immune function? The small size of the supporting human study (line 7) precludes the use of this 

as a sole support for RfC derivation. 

Page 5-17, line 9-10 – Addition of the erythrocyte count and hematocrit discussion does 

not add support to decrements in immune function, since these are not functionally related to the 

immune system. 

Page 5-17, line 23 – What does “inform the formaldehyde RfC” mean? 

Page 5-17, line 35 – Mice were not considered for RfC development because of potential 

reflex bradypnea? The doses used in mouse studies (Table 4-57) are substantially similar or 

lower than doses used in similar rat studies. Using this argument, why aren’t the high dose rat 

studies also eliminated. Is this criteria considered in the evaluation of other pathological 

endpoints (i.e. are all studies with potential reflex bradypnea discounted in POD tables?). 

Page 5-18, line 1 – reference to Section 4.2.1.4 refers to “Immune Function” section, and 

should refer to “Neurological and Neurobehavioral Function” section (4.2.1.6). 

Page 5-19, Table 5-1 – As commented upon on page 4-44 and 4-45, Bach et al. 

considered their results preliminary until confirmed. Other issues such as a small number of test 

subjects, no observable symptoms of respiratory irritation following doses up to 1.1 ppm, nondose related effects, and no adjustment for numerous confounders, suggests that this study 

should not be selected for consideration in the POD table (under “Human neurobehavioral 

outcomes”). Other issues with this study are noted on Page 5-22, line 1-13. 

Page 5-19, Table 5-1 – There seems to be a discrepancy in the reporting of exposure 

duration and other factors for Bach et al. (1990; as described in 4.1.1.6.2, page 4-44) in the Table 

(Table 5.1) and text (page 5-21, line 5). 

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Page 5-21, Figure 5-1 – The Figure contains the unit (mg/m3

)

1

/3. Is this correct? Also, 

calculated concentrations appear to be 260, 471, 634, and 813 ppb, rather than the 32, 170, 390, 

or 890 ppb displayed in the title. 

Page 5-23, Table 5-2 – Swimming times are significantly different than controls at a 

LOAEL of 0.5 ppm for male and female rats (Day 6 and 10). When the data is normalized to 

control values the same dose-dependent relation is seen. Overall, the effect is mitigated 

substantially as time following dose increases. Significant increases in the swimming time error 

rate are also observed at a LOAEL of 0.1 ppm. Both the raw and normalized data do not display 

a dose-response relationship. As with swimming time, the error rate is mitigated over time when 

comparing Day 6 to Day 10 exposures. Mitigation of the higher swim times and error rates in a 

short amount of time (with continued dosing) suggest that adaptation, accommodation, or 

compensation is occurring. Since the observed effects are substantially reversible in a short 

amount of time, and the effects are not dose related, choice of this data set to use in RfC 

calculation is not warranted, in our view. 

Page 5-23, line 9-16 – Methodologies for the swim time/water maze testing in Malek 

(2003a,c) are not provided in sufficient detail to facilitate a rigorous review of these studies (or 

in 4-255-4-258). 

Page 5-24, Figure 5-2 – Normalization to Day 1 results may remove the bias inherent in 

displaying raw data. 

Page 5-24, line 11 – Concentration related effects were seen for swimming time and 

normalized swimming time, not mean error rates. 

Page 5-25, line 3-24 – Behavioral studies are not supported by neural pathology 

endpoints. Issues associated with selection of the Malek studies as an RfC have been discussed 

above. 

Page 5-26, line 28 – extra space prior to “Of”. 

Page 5-27, line 1 – Was cumulative exposure reported for this study, and if so, was it 

significant? 

Page 5-27, line 6 – Increased ORs do not appear to be dose related among the low, 

medium, and high exposure groups, weakening effect arguments for this study. Further, the 

range of ORs for the high exposure group (1.2-8.3) is twice as high as that for the low (1.2-4.8) 

and medium (0.8-4) groups. Was the increased OR in the high dose group caused by a high 

outlier? 

Page 5-27, line 8 – The use of “lost statistical significance” implies that the gloved 

workers were significantly different than controls. If this is accurate, please state this. From Page 

5-30, line 5, this may not be accurate? 

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Page 5-27, Figure 5-3 – The 95% CIs in this figure appear to be asymmetrically 

distributed around each Fecundity Density Ratio center point. 

Page 5-28, line 18-21 – The lack of additional doses and repeatability in other studies 

should preclude the use of the Senichenkova studies in POD tables. As with that defined above, 

criteria used to define POD tables for developmental and reproductive effects have not been 

defined. Studies with significant deficiencies (large uncertainties) should not be presented in 

POD tables. 

Page 5-30, line 5 – “Although this FDR is not statistically significant, it can reasonably 

be assumed to be part of a trend of decreased FDR with increasing inhalation exposure”. The 

jump from non-significance to biological plausibility should only be considered in circumstances 

in which these discrete pathologies are repeated in other studies at similar dose levels. 

Page 5-44, line 30 - Choice of the NOAEL for the asthma POD (40 μg/m3

) was based on 

a “biologically significant” trend of increasing asthma risk. This exposure dose had a nonsignificant Odds Ratio (OR) of less than one. The next highest exposure dose (50-59 μg/m3

) was 

also had a non-significant OR of approximately 1.2 (estimated LOAEL). The high dose (60+ 

μg/m3

) was significantly different from controls and had an OR of 1.39 (weak association). 

Choice of a non-significant exposure dose with a weak association to asthma (low OR) to 

represent a LOAEL is unwarranted, in our view (see comment #9 above). Further, the use of the 

exposure group 60+ μg/m3

 as a LOAEL is problematic because the grouping does not identify 

the range or average of exposures included. Because of this, the NOAEL can’t be used as a point 

of departure with confidence (i.e. is the LOAEL 60, 600, 6000 μg/m3

 and if it’s 6000, is a 

NOAEL of 54 μg/m3 a good POD to use?). Another option EPA should consider is to use the 

dose-response data and perform a benchmark dose-type of approach to estimate a nominal POD. 

 Page 5-74, line 29 and on - Most of the evidence used to support an association between 

formaldehyde and non-respiratory tract cancers (specifically all LHP, myeloid leukemia, all 

leukemia, multiple myeloma and Hodgkin lymphoma) comes from the NCI cohort. EPA’s 

statements that “Epidemiologic studies involving formaldehyde-exposed workers provide 

sufficient evidence of a causal association between formaldehyde exposure and all LHP 

malignancies” (4.5.2.2), “The associations between myeloid leukemia and formaldehyde 

exposure are strong and 14 consistent” (4.5.2.5), and “There is evidence for an exposure 

response relationship for both Hodgkin lymphoma and multiple myeloma in the NCI industrial 

cohort among exposed workers” (4.5.2.6) would be much more difficult to make without the 

consideration of the many analyses of that cohort. EPA chooses this cohort as a basis for risk 

estimates for these endpoints for this reason and many others (including the strength of the 

exposure data) (5.2.1), and it is agreed that if a study had to be chosen for this purpose, the NCI 

cohort would be most relevant. 

Page 9 of 11 KRC
 However, with one exception (Hodgkin lymphoma), all of the conclusions from the latest 

analysis of the NCI cohort (Beane-Freeman et al 2009) are based on peak exposure only. The 

evidence from average exposure, and the most important determinant, cumulative exposure, 

show no significant associations, either at any given exposure range or overall exposure-related 

trend, between exposure and any of the endpoints except for Hodgkin lymphoma. And for 

Hodgkin lymphoma, this only applies for average exposure, and not, again, for the most 

important determinant, cumulative exposure. 

 EPA chose to provide estimates of risk based on all leukemia and Hodgkin lymphoma. 

For all leukemia, there is nothing significant at all based on cumulative or average exposure. For 

peak exposure, there is a significant exposure-related trend when considering both unexposed 

and exposed person-years. 

 The problem, in our view, is the usefulness of “peak exposure”. The authors themselves 

state “Peak exposures could be related to either routine or non-routine high-exposure tasks or 

could result from non-routine unusual events, such as spills. Peak frequency was estimated on 

the basis of knowledge of the job and the likelihood that a high-exposure task or event would 

occur. Because there was no direct information on frequency of peaks, a higher degree of 

uncertainty is associated with the frequency than the level of peak exposure”; peak exposures 

were also defined as short-term exposures, generally less than 15 minutes. Given this large 

uncertainty, and the lack of significance with any other metric, it seems premature at this time to 

use this as a basis of cause and effect, and then to take the non-significant exposure trend for 

cumulative exposure and base an estimate of risk on it. 

 For Hodgkin lymphoma, there are significantly elevated relative risks at the two highest 

peak exposure ranges, and the overall trend is significant compared to the referent (low) 

exposure level. The same is true for average exposure, but the RR at the highest level is lower 

than that at the second highest level. Again, for cumulative exposure, the RR at the highest level 

is lower than that at the second highest level, but nothing is significant. 

 The problems with peak exposure are the same as described for all leukemia. The 

average exposure suffers from two uncertainties: first, it does not consider number of years of 

exposure (a critically important parameter – which is why cumulative exposure is used) and 

second, the relative risk at the higher dose is lower than that at the second highest exposure, 

which is worrisome. 

 Again, it seems premature at this time to use this as a basis of cause and effect, and then 

to take the non-significant exposure trend for cumulative exposure and base an estimate of risk 

on it. 

Page 6-2, line 4-5 – formaldehyde what? Decreased and where was this measured? 

Page 6-6, line 23 – add “allergic” before rhinitis? 

Page 10 of 11 KRC
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Volume IV contains the Appendices. These Appendices cover external peer review 

and public comments, modeling simulations, a lifetable analysis, sensitivity analyses, and 

an expert panel consultation (on the use of animal data for estimating quantitative cancer 

risk). 

No comments 

Thank you for the opportunity to review and comment on this draft document. If you have any 

questions, please feel free to contact me ( kcarlson@cpsc.gov ). 

 Sincerely, 

 Kent Carlson, Ph.D. 

 Toxicologist, Health Sciences Directorate