External Peer Review Charge Questions for the IRIS
Toxicological Review of Formaldehyde—Inhalation

June 2022

Introduction

The U.S. Environmental Protection Agency (EPA) is seeking a scientific peer review of a draft IRIS
Toxicological Review of Formaldehyde—Inhalation developed in support of the Agency's online database,
the Integrated Risk Information System (IRIS). IRIS is prepared and maintained by EPA's Center for Public
Health and Environmental Assessment within the Office of Research and Development

IRIS is a human health assessment program that evaluates scientific information on effects that could
result from exposure to specific chemicals or pollutants in the environment. Through IRIS, EPA provides
high-quality science-based human health assessments to support the Agency's regulatory activities and
decisions to protect public health. IRIS assessments contain information that can be used to support
hazard identification and dose-response assessment, two of the four steps in the human health risk
assessment process. When supported by available data, IRIS provides health effects information and
toxicity values for health effects (including cancer and effects other than cancer) resulting from lifetime
exposure. When used by risk managers in combination with information on human exposure and other
considerations, IRIS assessments support the Agency's regulatory activities and decisions to protect
public health.

An existing IRIS assessment for formaldehyde includes an oral reference dose (RfD) from 1990, and a
cancer weight of evidence descriptor and inhalation unit risk (IUR) for cancer from 1991. A draft IRIS
formaldehyde assessment was reviewed by the National Academy of Sciences (NAS) in 2011 (NRC.
20111. The IRIS Program decided to conduct a reassessment of formaldehyde inhalation from scratch on
the basis of that review, using transparent and predefined systematic review methods. The 2022 draft
Toxicological Review of Formaldehyde—Inhalation is based on a comprehensive review of the available
scientific literature informing the noncancer and cancer health effects in humans exposed to
formaldehyde via inhalation, including human and animal health effect studies, as well as extensive
mechanistic analyses. Two other documents provide supporting information, the Supplemental
Information to the Toxicological Review of Formaldehyde—Inhalation (i.e., Appendices) and the
Assessment Overview for the Toxicological Review of Formaldehyde—Inhalation. The draft assessment
was developed according to EPA guidelines and technical reports and contains conclusions on the
noncancer human health hazards and carcinogenicity potential posed by formaldehyde inhalation,
including a standardized cancer descriptor to express formaldehyde's human carcinogenic potential.
The assessment also derives noncancer toxicity values, including a reference concentration (RfC) for
lifetime inhalation, and a cancer IUR estimate.

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Charge Questions on the Draft Toxicological Review of Formaldehyde—Inhalation

In response to the numbered charge questions below, the advice provided as part of this peer review
would be most useful when prioritized to indicate its relative importance as follows:

•	Tier 1: Necessary Revisions - Please use this category for any revisions you believe are
necessary to adequately support and substantiate the assessment conclusions in the
formaldehyde (inhalation) assessment For Tier 1 recommendations, please clearly describe and
justify each necessary revision.

•	Tier 2: Suggested Revisions - Please use this category for any revisions you encourage EPA to
implement to strengthen the analyses or scientific basis for the assessment conclusions, or to
improve the clarity of the presentation in the formaldehyde (inhalation) assessment

•	Tier 3: Future Considerations - Please use this category for any advice you have for
scientific exploration that might inform future work. While these recommendations are
generally outside the immediate scope or needs of the formaldehyde (inhalation)
assessment, they could inform future assessments or research efforts.

1. Assessment Development Methods and Organization. The Toxicological Review describes and
applies a systematic review process for identifying, screening, and evaluating pertinent studies,
and then for prioritizing the evidence to inform hazard and dose-response decisions. This process
is described in the Toxicological Review's Preface on Assessment Methods and Organization, with
documentation primarily in Appendix A.5. Please answer parts (a) and (b).

a.	Please comment on whether the methods for assessment development (Preface on
Assessment Methods and Organization) and the organization of the assessment are clear and
transparent.

b.	Please comment on whether there is sufficient documentation on methods and criteria for
the following:

o Identification of epidemiologic, experimental, and mechanistic studies (please identify
any additional peer-reviewed studies that would significantly alter key assessment
conclusions and thus should be incorporated prior to finalization).1

o Critical evaluation of individual studies or sets of studies.

o Assessment of the weight of evidence (i.e., evidence integration).

o Selection of studies and data sets for deriving toxicity values

1 If newly identified studies that meet the assessment PECO criteria are found by, or brought to the attention of, the
panel during the peer review, EPA asks the panel to judge whether the studies would significantly alter key
conclusions (e.g., the draft RfC or IUR) and, if so, how. For any studies judged to significantly alter key conclusions,
please recommend where and how such studies should be incorporated in the final assessment.

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2.	Toxicokinetics. Several assumptions and interpretations were applied in the Toxicological Review
that were based on current research (although the draft acknowledges that uncertainties remain).
Please answer parts (a), (b), and (c) considering the extent to which the available science on the
toxicokinetics of inhaled formaldehyde is clearly presented and appropriately applied in the
assessment of potential respiratory and systemic (i.e., nonrespiratory) health hazards.

a.	Please comment on the Toxicological Review conclusion that inhaled formaldehyde is not
likely to be distributed in appreciable amounts beyond the respiratory tract to distal tissues.
This conclusion underpins the organization of the assessment and several key assumptions.

b.	Please comment on the Toxicological Review assumptions (based on [a]) that:

o Inhaled formaldehyde is not directly interacting with tissues distal to the portal-of-
entry (POE) to elicit systemic effects.

o Formaldehyde levels in the blood or at systemic sites are not appreciably changed as a
result of formaldehyde from exogenous sources (inhalation).

o Inhaled formaldehyde does not cause appreciable changes in normal metabolic

processes associated with formaldehyde in distal tissues. Therefore, studies examining
potential associations between levels of formaldehyde or formaldehyde byproducts in
tissues distal to the POE (e.g., formate in blood or urine; brain formaldehyde levels) and
health outcomes are not considered relevant to interpreting the human health hazards
of inhaled formaldehyde.

c.	Please comment on the Toxicological Review evaluation of considerations regarding
endogenous formaldehyde in assessing the health risk due to inhaled formaldehyde.

3.	Respiratory System Health Effects (Noncancer). For each noncancer POE health effect considered
in the assessment and outlined in (a) to (e), below, please comment on whether the evidence
integration decisions for hazard identification are clearly described and scientifically justified
(considering the extent to which the available data have been appropriately synthesized to describe
the strengths and limitations). In addition, please separately comment on whether the dose-
response decisions are transparent and scientifically justified, including study selection for dose-
response analyses; point of departure (POD) estimates, including modeling choices and assumptions,
and dosimetric adjustments; selection of uncertainty factors and derivation of candidate values;
selection of organ- or system-specific RfCs (osRfCs); and confidence in the calculated values. For
these well-studied health effects, confidence was consistently judged as either medium or high.

a. Sensory irritation

o The assessment concludes that the evidence demonstrates that inhalation of

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formaldehyde causes increased sensory irritation in humans, given appropriate
exposure circumstances.2 Well-conducted studies in humans and animals support this
hazard conclusion, and strong mechanistic evidence provides a plausible mode of action
(MOA) for the identified outcome.

o A POD from Hanrahan et al. (19841. a human study, was ultimately selected to calculate
an osRfC of 0.009 mg/m3 for eye irritation. A composite uncertainty factor (UFc) of 10
was applied to address intraspecies uncertainty (UFh). The assessment also considers
PODs from controlled human exposure studies and discusses their utility for developing
an RfC for lifetime exposure as well as their potential increased utility for purposes
outside the scope of the current assessment (e.g., derivation of an acute RfC).

b.	Pulmonary function

o The assessment concludes that the available evidence indicates that long-term

formaldehyde inhalation likely causes decreased pulmonary function in humans given
appropriate exposure circumstances. This conclusion was supported primarily by
evidence in exposed humans, with supportive mechanistic evidence indicating that
formaldehyde inhalation results in biological changes related to this outcome.

o The assessment concludes that the available evidence is inadequate to determine
whether acute or short-term (hours to weeks) formaldehyde inhalation might cause
decreased pulmonary function in humans.

o A POD from Krzyzanowski et al. (19901. a human study, was ultimately selected to
calculate an osRfC of 0.007 mg/m3 for pulmonary function. A UFcomposite of 3 was
applied to address UFh. This UFh value was selected using available evidence on
potential susceptibility including consideration of children's health.

c.	Allergy-related conditions

o The assessment concludes that the available evidence indicates that formaldehyde
inhalation likely causes increased allergic responses in humans, given appropriate
exposure circumstances. This conclusion was supported primarily by evidence in
exposed humans, with supportive mechanistic evidence indicating that formaldehyde
inhalation results in biological changes related to this outcome.

o A POD from Annesi-Maesano et al. f20121. a human study, was ultimately selected to
calculate an osRfC of 0.008 mg/m3 for allergy-related conditions. A UFcomposite of 3 was
applied to address UFh. This UFh value was selected using available evidence on potential

2 For all non-cancer health effects for which the evidence demonstrates or indicates an effect is caused (or likely to
be caused) in humans by formaldehyde inhalation, the exposure circumstances that may be necessary for this to occur
are estimated through subsequent dose-response analysis. This phrase is included to signify the linkage between
hazard identification and dose-response analysis.

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susceptibility including consideration of children's health.

d.	Prevalence of current asthma and degree of asthma control

o The assessment concludes that the available evidence indicates that formaldehyde

inhalation likely causes an increased frequency of current asthma symptoms or difficulty
controlling asthma, given appropriate exposure circumstances. This conclusion was
supported primarily by evidence in exposed humans, with supportive mechanistic
evidence indicating that formaldehyde inhalation results in biological changes related to
these outcomes.

o PODs from the Annesi-Maesano et al. (2012). Krzyzanowski et al. (1990). and Venn et al.
(2003) human studies were ultimately selected to calculate an osRfC of 0.006 mg/m3 for
current asthma or degree of asthma control. A UFcomposite of 3 or 10 was applied to
address UFh. The UFh value applied to the POD from Annesi-Maesano et al. (2012) was
selected using available evidence on potential susceptibility including consideration of
children's health.

e.	Respiratory tract pathology

o The assessment concludes the evidence demonstrates that inhalation of

formaldehyde causes respiratory tract pathology in humans, exposure circumstances.
Well-conducted studies in humans and animals support this hazard conclusion, and
strong mechanistic evidence in animals provides a plausible MOA for the identified
outcomes.

o PODs from the Kerns et al. (1983) and Woutersen et al. (1989) rat studies were

ultimately selected to calculate an osRfC of 0.003 mg/m3 for squamous metaplasia. The
PODs were estimated using dosimetric simulations of formaldehyde flux to the nasal
lining using a computational fluid dynamics model to extrapolate from results in rats to
humans. A UFcomposite of 30 or 100 was applied to address UFh, subchronic (UFs) and
interspecies (UFa) uncertainties.

4. Systemic (i.e., nonrespiratory) Health Effects (Noncancer). For each noncancer systemic health
effect considered in the assessment and outlined in (a) to (c), below, please comment on whether the
evidence integration decisions for hazard identification are clearly described and scientifically
justified (considering the extent to which the available data have been appropriately synthesized to
describe the strengths and limitations). In addition, please separately comment on whether the dose-
response decisions are transparent and scientifically justified, including study selection for dose-
response analyses; POD estimates, including modeling choices and assumptions, and dosimetric
adjustments; selection of uncertainty factors and derivation of candidate values; selection of osRfCs;
and confidence in the calculated values. Confidence was consistently lower for these effects as
compared with POE effects.

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a.	Female reproductive or developmental toxicity:

o The assessment concludes that the evidence indicates that inhalation of formaldehyde
likely causes female reproductive or developmental toxicity, given appropriate exposure
circumstances. The conclusion for female reproductive or developmental toxicity is
supported by evidence in humans, specifically, increases in time-to-pregnancy (TTP) and
spontaneous abortion risk; mechanistic evidence explaining such effects without
systemic distribution of formaldehyde is lacking.

o A POD from Taskinen et al. (1999), a human study, was ultimately selected to calculate
an osRfC of 0.01 mg/m3 for TTP. A UFcomposite of 10 was applied to address UFh and UFs.

b.	Male reproductive toxicity

o The assessment concludes that the evidence indicates that inhalation of formaldehyde
likely causes reproductive toxicity in men, given appropriate exposure circumstances.
The conclusion for male reproductive toxicity is supported primarily by coherent
evidence of several alterations to the male reproductive system in animals exposed to
very high levels of formaldehyde (>6 mg/m3), with some corroborative changes in an
occupational epidemiological study; although no MOA is available, some relevant
mechanistic changes have been observed in well- conducted studies.

o A POD from Ozen et al. (2002). a rat study, was ultimately selected to calculate an
osRfC of 0.01 mg/m3 for testis weight. A UFcomposite of 3,000 was applied to address
UFh, LOAEL (UFl), UFs, and UFA.

c.	Nervous system toxicity

o While many studies reporting evidence of potential neurotoxic effects were available,
due to limitations identified in the database (e.g., poor methodology, lack of
consistency), it was ultimately determined that the evidence suggests, but is not
sufficient to infer, that formaldehyde inhalation might pose a human nervous system
hazard. This judgment was separately arrived at for three different manifestations of
potential neurotoxicity, namely developmental neurotoxicity, altered neurobehavior,
and an increased incidence of, or mortality from, the motor neuron disease amyotrophic
lateral sclerosis. The evidence integration narrative emphasizes that additional study is
warranted.

o The available data on potential nervous system effects were considered insufficient for
developing quantitative toxicity estimates.

Noncancer RfC. An RfC was selected based on the grouping of osRfCs for sensory irritation,
decreased pulmonary function, allergy-related conditions, and increased prevalence of current
asthma or decreased degree of asthma control. Please comment on whether the approach and
selection of the proposed RfC was clear and scientifically justified, including consideration of other

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potentially sensitive health effects.

6. Cancer. The assessment concludes that formaldehyde is Carcinogenic to Humans by the

Inhalation Route of Exposure. Please comment on whether the judgments in (a) to (f), below, are
clearly described and scientifically justified. Note that the three judgments in (a), (b), and
(c) outline the primary evidentiary support, and that each of these judgments would independently
substantiate the carcinogenicity conclusion.

a.	The evidence demonstrates that formaldehyde inhalation causes nasopharyngeal cancer
(NPC) in humans, based primarily on observations of increased risk of NPC in groups
exposed to occupational formaldehyde levels and evidence of nasal cancers in animals, with
strong, reliable, and consistent mechanistic evidence in both animals and humans,
including support for a mutagenic MOA.

b.	The evidence demonstrates that formaldehyde inhalation causes sinonasal cancer
(SNC) in humans, based primarily on observations of increased risk of SNC in groups
exposed to occupational formaldehyde levels and supported by the evidence of nasal
cancers in animals, with consistent mechanistic evidence and support for a mutagenic
MOA.

c.	The evidence demonstrates that formaldehyde inhalation causes an increased risk of
myeloid leukemia in humans, based primarily on observations of increased risk in groups
exposed to occupational formaldehyde levels. This judgment is supported by other studies
of human occupational exposure that provide strong and coherent mechanistic evidence
identifying clear associations with additional endpoints relevant to lymphohematopoietic
(LHP) cancers, including an increased prevalence of multiple markers of mutagenicity and
genotoxicity in peripheral blood cells of exposed workers, other perturbations to immune
cell populations in blood (primarily from human studies). Generally, evidence supporting
the development of LHP cancers after formaldehyde inhalation has not been observed in
experimental animals (i.e., rodents), including a well-conducted, chronic cancer bioassay in
two species, a similar lack of increased leukemias in a second rat bioassay, and multiple
mechanistic evaluations of relevant biological changes such as genotoxicity in systemic
tissues of exposed rodents. The lack of findings in animals does not detract from the strong
human evidence.

d.	The overall conclusion on the carcinogenicity of inhaled formaldehyde was independently
supported by the three sets of evidence outlined in 6a-6c above. This carcinogenicity
conclusion was not influenced by the judgments for several other cancer types. Specifically,
the evidence suggests, but is not sufficient to infer, that formaldehyde inhalation might
cause oropharyngeal/hypopharyngeal cancer, Hodgkin lymphoma, or multiple myeloma in
humans; there is inadequate evidence to determine whether formaldehyde inhalation may

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be capable of causing laryngeal cancer or lymphatic leukemia in humans.

e.	Formaldehyde is genotoxic in several test systems and operates, at least in part, through a
mutagenic MOA. Specifically, a mutagenic MOA was identified in association with the
development of nasal (i.e., nasopharyngeal and sinonasal) cancers, while no MOA was
identified for other cancer types. The mechanistic evidence was sufficient to conclude that
both mutations and cellular proliferation play a role in nasal carcinogenesis.

f.	The MOA(s) leading to cancer formation outside of the respiratory tract are unknown.

7. Inhalation unit risk for cancer. An IUR for cancer is derived on the basis of nasal cancers using
data on nasopharyngeal cancers (NPCs) in a human study from the National Cancer Institute (NCI),
specifically the results reported in fBeane Freeman et al. 20131. In addition, comparative estimates
are provided on the basis of modeling of nasal tumors in exposed rodents. Finally, although not
included in the draft IUR, an estimate for myeloid leukemia is presented. Please comment on the
clarity and scientific justification for each specific decision in the draft cancer dose-response analyses
outlined in (a) to (d), below, including study selection; POD estimates; and confidence in the
calculated values. Part (e) includes a specific, additional question on myeloid leukemia.

a.	The NCI study results on NPCs were ultimately selected and used to develop the draft IUR
estimate. A lifetable analysis was used to develop a POD and, given the mutagenic MOA for
this cancer type, a linear extrapolation was applied. Age-dependent adjustment factors
(ADAFs) were applied to this estimate, in accordance with EPA guidelines when a
mutagenic MOA is supported. Confidence in the IUR is medium.

b.	As a comparison for the modeling of the human data, data from two chronic rat bioassays
were used to develop an estimate of nasal cancer risk. Multiple models, including a
biologically-based dose-response model, were evaluated and used to extrapolate the
results in rats to a POD in humans. A linear extrapolation was applied based on a
mutagenic MOA for formaldehyde. Furthermore, a candidate RfC based on cell
proliferation was also developed for comparison.

c.	For sinonasal cancer, the draft draws an evidence integration judgment of evidence
demonstrates. Given the lack of quantifiable data to allow the use of dose-response
information to identify a POD, the IUR does not incorporate potential contributions to risk
for sinonasal cancer. Please comment on this decision and, if this is not supported, include a
recommended method to account for this cancer risk.

d.	For myeloid leukemia, a unit risk estimate is presented using the NCI study results (Beane-
Freeman et al., 2009). The derivation of a unit risk estimate for myeloid leukemia from these
data is not straightforward, and several quantitative risk assessment approaches were
considered. The selected data set used to derive the myeloid leukemia unit risk estimate

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combined the results from myeloid leukemia with results for other/unspecified leukemias
based on other NCI studies showing that one third to one half of other/unspecified leukemias
on death certificates were diagnosed as myeloid leukemias in the hospital. ADAFs were not
applied to this estimate, as the assessment concludes that the MOA is unknown.

e. Although the draft concludes that the evidence demonstrates that formaldehyde

inhalation causes myeloid leukemia, the only data available to develop a unit risk estimate
for myeloid leukemia are uncertain. The draft Toxicological Review discusses the strengths
and limitations of the myeloid leukemia estimate in detail. Please comment specifically on
how the unit risk estimate for myeloid leukemia should inform the IUR for cancer, if at all.

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References

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Denis. C. (2012). Poor air quality in classrooms related to asthma and rhinitis in primary
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Beane Freeman. LEi Blair. A: Lubin, THi Stewart. PA: Haves. RB: Hoover. RN: Hauptmami, M. (2013).
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Kerns. WD: Pavkov. KL: Donofrio. Df: Gratia. ET: Swenberg. TA. (1983). Carcinogenicity of

formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res 43: 4382-
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Krzvzanowski. M: Ouackenboss. II: Lebowitz. MP. (1990). Chronic respiratory effects of indoor
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NRC (National Research Council). (2011). Review of the Environmental Protection Agency's draft
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Ozen. OA: Yaman. M: Sarsilmaz. M: Songur, A: Kus. I. (2002). Testicular zinc, copper and iron
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672Xf02180038~4

Taskinen. HK: Kyvronen. P: Sallmen. M: Virtanen. SV: Liukkonen, TA: Huida, 0: Lindbohm. ML:

Anttila. A. (1999). Reduced fertility among female wood workers exposed to formaldehyde.
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0274f199907136:1 <206: :aid-aiim29>3.0.co:2-d
Venn. AT: Cooper. M: Antoniak. M: Laughlin, C: Britton. I: Lewis. SA. (2003). Effects of volatile

organic compounds, damp, and other environmental exposures in the home on wheezing
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Woutersen. RA: van Garderen-Hoetmer. A: Bruijnties. TP: Zwart. A: Feron. VI (1989). Nasal tumours
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