A EPA
EPA/635/R-22/039C
www.epa.gov/iris
ASSESSMENT OVERVIEW
for the
TOXI CO LOGICAL REVIEW OF FORMALDEHYDE -
INHALATION
[CASRN 50-00-0]
April 2022
Integrated Risk Information System
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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Toxicological Review of Formaldehyde - Inhalation (Overview)
DISCLAIMER
This document is a public comment draft for review purposes only. This information is distributed
solely for the purpose of public comment. It has not been formally disseminated by EPA. It does not
represent and should not be construed to represent any Agency determination or policy. Mention of
trade names or commercial products does not constitute endorsement or recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review of Formaldehyde - Inhalation (Overview)
CONTENTS
AUTHORS xii
1. SUMMARY AND ASSESSMENT METHODS 1
1.1. ASSESSMENT METHODS 5
1.1.1. Literature Search and Screening 6
1.1.2. Study Evaluation 7
1.1.3. Results Display and Evidence Synthesis 11
1.1.4. Evidence Integration 14
1.1.5. Dose-response Analysis 25
2. SUMMARY OF TOXICOKINETICS 26
3. NONCANCER HEALTH EFFECTS 28
3.1. SENSORY IRRITATION 29
3.1.1. Literature Identification 29
3.1.2. Study Evaluation 30
3.1.3. Synthesis of Human Health Effect Studies 30
3.1.4. Mode-of-action Information 32
3.1.5. Overall Evidence Integration Judgment and Susceptibility for Sensory Irritation 33
3.1.6. Dose-response Analysis 34
3.2. PULMONARY FUNCTION 38
3.2.1. Literature Identification 39
3.2.2. Study Evaluation 39
3.2.3. Synthesis of Human Health Effect Studies 40
3.2.4. Mode-of-action Information 43
3.2.5. Overall Evidence Integration Judgment and Susceptibility for Pulmonary Function 44
3.2.6. Dose-response Analysis 45
3.3. IMMUNE-MEDIATED CONDITIONS, FOCUSING ON ALLERGIES AND ASTHMA 47
3.3.1. Literature Identification 48
3.3.2. Study Evaluation 48
3.3.3. Synthesis of Human Health Effect Studies 49
3.3.4. Mode-of-action Information 53
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3.3.5. Overall Evidence Integration Judgments and Susceptibility for Immune-mediated
Conditions including Allergies and Asthma 56
3.3.6. Dose-response Analysis 58
3.4. RESPIRATORY TRACT PATHOLOGY 64
3.4.1. Literature Identification 64
3.4.2. Study Evaluation 65
3.4.3. Synthesis of the Human Health Effect Studies 66
3.4.4. Synthesis of the Animal Health Effect Studies 66
3.4.5. Mode-of-action Information 70
3.4.6. Overall Evidence Integration Judgment and Susceptibility for Respiratory Tract
Pathology 71
3.4.7. Dose-response Analysis 72
3.5. NERVOUS SYSTEM EFFECTS 75
3.5.1. Literature Identification and Study Evaluation 76
3.5.2. Evidence Synthesis and Overall Evidence Integration Judgement for Nervous
System Effects 76
3.6. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY 77
3.6.1. Literature Identification 78
3.6.2. Study Evaluation 78
3.6.3. Developmental and Female Reproductive Toxicity 78
3.6.4. Male Reproductive Toxicity 82
3.6.5. Dose-response Analysis 84
3.7. REFERENCE CONCENTRATION (Rfc) FOR NONCANCER HEALTH EFFECTS 89
3.7.1. Summary of cRfCs and osRfCs across Noncancer Health Effects 89
3.7.2. Selection of the RfC and Discussion of Confidence 91
3.7.3. Basis and Interpretation of the RfC 93
3.7.4. Previous IRIS Assessment: Reference value 95
4. CARCINOGENICITY 95
4.1. METHODS FOR IDENTIFYING AND EVALUATING STUDIES 96
4.1.1. Literature Identification 96
4.1.2. Study Evaluation 96
4.2. UPPER RESPIRATORY TRACT CANCERS 97
4.2.1. Synthesis of Human Health Effect Studies 98
4.2.2. Synthesis of Animal Health Effect Studies 104
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4.2.3. Mode-of-action Information 107
4.2.4. Overall Evidence Integration Judgments and Susceptibility for Upper Respiratory
Tract Cancers 110
4.3. LYMPHOHEMATOPOIETIC (LHP) CANCERS 114
4.3.1. Synthesis of Human Health Effect Studies 114
4.3.2. Synthesis of Animal Health Effect Studies 122
4.3.3. Mode-of-action Information 123
4.3.4. Overall Evidence Integration Judgments and Susceptibility for LHP Cancers 126
4.4. WEIGHT-OF-EVIDENCE SUMMARY FOR CARCINOGENICITY 129
4.4.1. Weight-of-evidence Narrative Summary 129
4.5. INHALATION UNIT RISK (IUR) FOR CARCINOGENICITY 130
4.5.1. Derivation of Cancer Unit Risk Estimates for Nasal Cancers 131
4.5.2. Derivation of Cancer Unit Risk Estimates for Myeloid Leukemia 146
4.5.3. Estimates of Cancer Risk based on "Bottom-up" Approach 154
4.5.4. Summary of Unit Risk Estimates and the Preferred Estimate for Inhalation Unit
Risk 155
4.5.5. Previous IRIS Assessment: Inhalation Unit Risk 159
5. REFERENCES 161
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TABLES
Table 1. Evidence integration judgments for noncancer health effects and the reference
concentration (RfC) 2
Table 2. Cancer evidence integration judgments, carcinogenicity descriptor and inhalation unit
risk (IUR) for cancer incidence 3
Table 3. General approach to literature search strategies 6
Table 4. Synthesized information most relevant to drawing evidence integration judgments 12
Table 5. Considerations that inform judgments regarding the strength of the human and animal
evidence3 16
Table 6. Framework for strength of evidence judgments (human evidence) 19
Table 7. Framework for strength of evidence judgments (animal evidence) 20
Table 8. Overall evidence integration judgments for characterizing the integrated evidence for
noncancer health effects and cancer outcomes 23
Table 9. Criteria for applying cancer descriptors to evidence integration judgments for cancer
types 24
Table 10. Evidence integration summary for effects on sensory irritation 33
Table 11. Eligible studies for POD derivation and rationale for decisions to not select specific
studies 35
Table 12. Summary of derivation of PODs for sensory irritation 36
Table 13. Derivation of cRfCs for sensory irritation 37
Table 14. Evidence integration summary for effects on pulmonary function 44
Table 15. Eligible studies for POD derivation and rationale for decisions to not select specific
studies 45
Table 16. Summary of derivation of PODs for pulmonary function 46
Table 17. Derivation of the cRfCfor pulmonary function 47
Table 18. Evidence integration summary for effects on immune-mediated conditions, including
allergies and asthma 56
Table 19. Eligible studies for POD derivation and rationale for decisions to not select specific
studies 58
Table 20. Summary of derivation of PODs for allergies and current asthma based on
observational epidemiological studies 60
Table 21. Derivation of the cRfC for allergy-related conditions and asthma 63
Table 22. Evidence Integration Summary for Effects of Formaldehyde Inhalation on Respiratory
Pathology 71
Table 23. Eligible studies for POD derivation and rationale for decisions to not select specific
studies 73
Table 24. Summary of derivation of PODs for squamous metaplasia 74
Table 25. Derivation of cRfCs for respiratory tract pathology 75
Table 26. Evidence integration summary for effects of formaldehyde inhalation on
developmental or female reproductive toxicity in humans 81
Table 27. Evidence integration summary for effects of formaldehyde inhalation on reproductive
toxicity in males 83
Table 28. Eligible studies for POD derivation and rationale for decisions to not select specific
analyses 85
Table 29. Summary of derivation of PODs for developmental and reproductive toxicity in
females 86
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Table 30. Summary of derivation of PODs for reproductive toxicity in males 87
Table 31. Derivation of cRfCs for female reproductive or developmental toxicity and male
reproductive toxicity 88
Table 32. Organ/System-specific RfCs (osRfCs) for formaldehyde inhalation 91
Table 33. Proposed RfC for formaldehyde-inhalation 93
Table 34. Summary considerations for upper respiratory tract (URT) carcinogenesis (the primary
support for genotoxicity or mutagenicity is noted; see Toxicological Review for
additional details) 108
Table 35. Evidence integration summary for effects of formaldehyde inhalation on URT cancers Ill
Table 36. Incidence of hematopoietic cancers in B6C3F1 mice and F344 rats [source: (Kerns et
al., 1983; Battelle, 1982)] 123
Table 37. Summary conclusions regarding plausible mechanistic events associated with
formaldehyde induction of lymphohematopoietic cancers 124
Table 38. Evidence integration summary for effects of formaldehyde inhalation on LHP cancers 127
Table 39. Relative risk estimates for mortality from NPC (based on ICD code) and regression
coefficients from NCI log-linear trend test models3 by level of cumulative
formaldehyde exposure (ppm x years). Source: Beane Freeman et al. (2013) 133
Table 40. ECooos, LECooos, and unit risk estimates for nasopharyngeal cancer mortality based on
the Beane Freeman et al. (2013) log-linear trend analyses for cumulative
formaldehyde exposure 134
Table 41. ECooos, LECooos, and unit risk estimates for nasopharyngeal cancer incidence based on
the Beane Freeman et al. (2013) log-linear trend analyses for cumulative
formaldehyde exposure 135
Table 42. F344 rat nasal cancer data 137
Table 43. Benchmark concentrations and human equivalents using formaldehyde flux to nasal
tissue as a dose-metric 137
Table 44. BBDR model estimated extra risk of SCC in human respiratory tract compared with
EPA's modeling of extra risk of NPC from the human occupational data 142
Table 45. Unit risk estimates derived from benchmark estimates using animal data and
formaldehyde flux as dose-metric 144
Table 46. Comparison and basis of unit risk estimates for NPC in humans and nasal SCCs in rats 144
Table 47. Strengths and uncertainties in the cancer type-specific unit risk estimate for NPC 146
Table 48. Relative risk estimates for mortality from leukemia (based on ICD codes) and
regression coefficients from NCI log-linear trend test models3 by level of
cumulative formaldehyde exposure (ppm x years). Source: Beane Freeman et
al. (2009) 148
Table 49. ECoos, LECoos, and unit risk estimates for myeloid plus other/unspecified leukemia
mortality based on log-linear trend analyses of cumulative formaldehyde
exposure data from the Beane Freeman et al (2009) study 150
Table 50. ECoos, LECoos, and unit risk estimates for myeloid plus other/unspecified leukemia
incidence based on Beane Freeman et al. (2009) log-linear trend analyses for
cumulative formaldehyde exposure 151
Table 51. ECoos and LECoos estimates for mortality and incidence and unit risk estimates for all
leukemia and myeloid leukemia using alternate approaches (all person-years) -
shaded estimate is preferred 151
Table 52. Dose-response modeling (all person-years) and (incidence) unit risk estimate
derivation results for different leukemia groupings - shaded estimate is
preferred 152
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Table 53. Strengths and uncertainties in the cancer type-specific unit risk estimate for myeloid
leukemia 153
Table 54. Summary of inhalation unit risk estimates from occupational epidemiological
studies3*5 155
Table 55. Inhalation unit riska b 158
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FIGURES
Figure 1. Overview of assessment methods for hazard identification 5
Figure 2. Process for evidence integration 15
Figure 3. Schematic of the rat upper respiratory tract depicting the gradient of formaldehyde
concentration formed following inhalation exposure 27
Figure 4. Prevalence of eye irritation among study groups exposed to formaldehyde in
residential settings and controlled human exposure studies 32
Figure 5. Likely mechanistic association between formaldehyde exposure and sensory irritation 33
Figure 6. Association of PEFR measured at bedtime and in the morning with household mean
formaldehyde concentration among children less than 15 years of age
(Krzyzanowski et al., 1990) 42
Figure 7. Possible mechanistic associations between formaldehyde exposure and decreased
pulmonary function 43
Figure 8. Relative risk estimates for prevalence of allergy-related conditions in children and
adults in relation to formaldehyde in residential and school settings 50
Figure 9. Relative risk estimates for prevalence of asthma in children and adults in relation to
formaldehyde by exposure level in general population and occupational studies 52
Figure 10. Possible mechanistic associations between formaldehyde exposure and immune-
mediated conditions, including allergic conditions and asthma 55
Figure 11. Squamous metaplasia incidence in chronic pathology studies of rats 68
Figure 12. Possible mechanistic associations between formaldehyde exposure and respiratory
tract pathology 71
Figure 13. Candidate RfCs (cRfCs) with corresponding POD and composite UF 90
Figure 14. Organ or system-specific RfC (osRfC) scatterplot 92
Figure 15. Illustration of noncancer toxicity value estimations 94
Figure 16. All epidemiological studies reporting nasopharyngeal cancer risk estimates 99
Figure 17. Highest (medium) confidence epidemiological studies reporting sinonasal cancer risk
estimates 102
Figure 18. All epidemiological studies reporting oropharyngeal/hypopharyngeal cancer risk
estimates 104
Figure 19. Incidence of nasal squamous cell carcinomas in rats exposed to formaldehyde for at
least 2 years 106
Figure 20. All epidemiological studies reporting myeloid leukemia risk estimates 117
Figure 21. High and medium confidence epidemiological studies reporting myeloid leukemia risk
estimates 118
Figure 22. Epidemiological studies reporting acute myeloid leukemia risk estimates 119
Figure 23. All epidemiological studies reporting multiple myeloma risk estimates 121
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ABBREVIATIONS
Acronym
Definition
ADAF
age-dependent adjustment factors
ADME
absorption, distribution, metabolism, excretion
ALS
amyotrophic lateral sclerosis
AML
acute myeloid leukemia
ATS
American Thoracic Society
BAL
bronchoalveolar lavage
BBDR
biologically based dose-response
BMC
benchmark concentration
BMR
benchmark response
CASRN
Chemical Abstracts Service Registry Number
CFD
computational fluid dynamics
CFU
colony-forming unit
CML
chronic myeloid leukemia
cRfC
candidate reference concentration
DPX
DNA-protein cross-link(s)
ETS
environmental tobacco smoke
FDR
fecundability density ratio
FEF
forced expiratory flow
FVC
forced vital capacity
GLP
good laboratory practice
GM
granulocyte, monocyte
HEC
human equivalent concentration
HERO
Health and Environmental Research Online
HSPC
hematopoietic stem or progenitor cell
IARC
International Agency for Research on Cancer
ICD
International Classification of Disease
IUR
inhalation unit risk
LEC
lowest effective concentration
LH
luteinizing hormone
LHP
lymphohematopoietic
LOAEL
lowest-observed-adverse-effect level
LOD
limit of detection
LRT
lower respiratory tract
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Acronym
Definition
MDA
malondialdehyde
MDS
myelodysplastic syndrome
MLE
maximum likelihood estimate
MOA
mode of action
MOR
mortality odds ratio
NALT
nasal associated lymphoid tissues
NCHS
National Center for Health Statistics
NCI
National Cancer Institute
NOAEL
no-observed-adverse-effect level
NPC
nasopharyngeal cancer
NRC
National Research Council
NTP
National Toxicology Program
OR
odds ratio
osRfC
organ/system-specific reference concentration
PBL
peripheral blood lymphocyte
PBPK
physiologically based pharmacokinetic
PECO
Populations, Exposures, Comparisons, Outcomes
PEFR
peak expiratory flow rate
PMR
proportionate mortality ratio
POD
point of departure
POE
portal of entry
RfC
reference concentration
ROS
reactive oxygen species
RR
relative risk
see
squamous cell carcinoma
SES
socioeconomic status
SMR
standardized mortality ratio
TSCE
two-stage clonal expansion
TSFE
time since first exposure
TTP
time-to-pregnancy
TWA
time-weighted average
UF
uncertainty factor
URT
upper respiratory tract
WBC
white blood cell
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AUTHORS
Assessment Team*
Barbara Glenn (Chemical Manager)
Andrew Kraft (Chemical Manager)
Thomas F. Bateson
Susan Makris
Deborah Segal
Ravi Subramaniam
Suryanarayana Vulimiri
Glinda Cooper
Jason Fritz
Jennifer Jinot
John Whalan
U.S. EPA/ORD/CPHEA
U.S. EPA/ORD/CPHEA
U.S. EPA/ORD/CPHEA
U.S. EPA/ORD/CPHEA
U.S. EPA/ORD/CPHEA
U.S. EPA/ORD/CPHEA
U.S. EPA/ORD/CPHEA
Separated from U.S. EPA
U.S. EPA/Region 8
Retired from U.S. EPA
Retired from U.S. EPA
*Please see the Toxicological Review for a full list of contributors,
production team, contractor support, executive direction, and reviewers.
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Toxicological Review of Formaldehyde - Inhalation (Overview)
1. SUMMARY AND ASSESSMENT METHODS
This IRIS health assessment presents a systematic evaluation of the publicly available studies
relevant to inhalation exposure to formaldehyde and potential adverse health outcomes. The purpose
of the review was to identify hazards that may result from formaldehyde inhalation and describe the
level of confidence in the supporting evidence (see EPA cancer guidelines and standard IRIS procedures
(U.S. EPA. 2020, 2005a). When there was sufficient confidence in the evidence supporting a hazard and
appropriate studies and data were available, toxicity values were derived using either analyses of dose-
response or selected no-adverse-effect or lowest-adverse-effect levels (NOAEL or LOAEL). The results of
the assessment are summarized in Tables 1 and 2.
The evidence identification, evaluation, and integration framework depicted in Figure 1 was
used to conduct the assessment. Potential health hazards were evaluated, including sensory irritation;
reduced pulmonary function; immune system effects, focusing on allergic conditions and asthma;
respiratory tract pathology; nervous system effects; reproductive and developmental toxicity; and
cancer. Several well-studied cancer sites were specifically evaluated, including cancers of the upper
respiratory tract (i.e., nasopharyngeal cancer, sinonasal cancer, cancers of the oropharynx/hypopharynx,
and laryngeal cancer) and of the lymphohematopoietic system (i.e., Hodgkin lymphoma, multiple
myeloma, myeloid leukemia, and lymphatic leukemia).
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Table 1. Evidence integration judgments for noncancer health effects and the
reference concentration (RfC)
Noncancer health effect
Confidence in
health effect
POD basis
Confidence in
POD
UFC
osRfC
(mg/m3)
Decreased pulmonary function
Allergic conditions
Current asthma symptoms or
degree of asthma control
Sensory irritation
evidence
indicates [likely]c
evidence
indicates [likely]
evidence
indicates [likely]
evidence
demonstrates
Human
Human
Human
Human
high
high
medium
medium
3
3
10
10
0.007
0.008
0.006:
0.009
Female reproductive or
developmental toxicity
evidence
indicates [likely]
Human
low
10
0.01
Respiratory tract pathology
evidence
demonstrates
Rat
medium
30a
0.003d
Male reproductive toxicity
evidence
indicates [likely]
Rat
low
3,000
0.001
Nervous system effects3
evidence
suggests
Not Derived
-
-
-
Confidence in
health effects
PODs basis
Confidence in
PODs
UFC
Confidence in
database
RfC
(mg/m3)
Overall
confidence
RfC:
Medium or High
Human
Medium or High
3 or 10:
High
0.007
High
Abbreviations and definitions: RfC, reference concentration: an estimate (with uncertainty spanning perhaps an
order of magnitude) of a continuous inhalation exposure of a chemical to the human population (including
sensitive subpopulations), that is likely to be without risk of deleterious noncancer effects during a lifetime.
osRfC, organ-or system-specific RfC: an RfC based on the evidence for effects on that particular organ or system.
UFC: composite (total) uncertainty factor; POD: point-of-departure.
aThree separate judgments were drawn for nervous system effects, all evidence suggests; specifically, the
evidence suggests, but is not sufficient to infer, that formaldehyde inhalation might cause increases in
amyotrophic lateral sclerosis incidence or mortality, developmental neurotoxicity, and behavioral toxicity.
bBasis for RfC—sensory irritation, decreased pulmonary function, current asthma symptoms or degree of asthma
control, and allergic conditions. The corresponding osRfCs (i.e., based on human studies with medium or high
confidence in the health effects and PODs) are highlighted in gray, which also have the lowest UFC values.
Tor decreased pulmonary function, the judgment evidence indicates [likely] was drawn for long-term exposure
durations. For acute or intermediate durations (hrs to wks), the evidence is inadequate to draw judgments.
dThese two osRFCs and the RfC are based on multiple studies and candidate values, sometimes with different UFcs
applied. The UFC values shown in this table reflect the candidate values selected to represent each osRfC [i.e., the
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UFc applied to the POD from Krzyzanowski et al. (1990) for asthma and from Woutersen et al. (1989) for
respiratory pathology].
Table 2. Cancer evidence integration judgments, carcinogenicity descriptor and
inhalation unit risk (IUR) for cancer incidence
Cancer type investigated
Evidence
integration
judgment for
cancer type risk
Unit risk
estimate basis
Unit risk
estimate
(perng/m3)
ADAF-adjusted
unit risk estimate
(per |ig/m3)a
Confidence in
the unit risk
estimate
Nasopharyngeal cancer
evidence
Human
6.4 x 10
1.1 X 10
medium
(NPC) (nasal cancer in
animals)
demonstrates13
Animal0
8.9 x 10"6 to
1.8 x 10"5
NAd
medium
Myeloid leukemia
evidence
demonstratese
Human
3.4 x 10"5
NAf
low
Sinonasal cancer
evidence
demonstratesg
No usable
data
-
-
Oropharyngeal/
Hypopharyngeal cancer
evidence
suggests
Not derived
-
-
Multiple myeloma
evidence
suggests
Not derived
-
-
Hodgkin lymphoma
evidence
suggests
Not derived
-
-
Laryngeal cancer
evidence
inadequate
Not derived
-
-
Lymphatic leukemia
evidence
inadequate
Not derived
-
-
Cancer descriptor:
Carcinogenic to humans
Total cancer risk (IUR) :
1.1 x 10 5 per |ig/m3; Confidence in the IUR is Medium
Abbreviations and definitions: IUR, inhalation unit risk: the upper-bound excess lifetime cancer risk estimated to
result from continuous exposure to an agent at a concentration of 1 ng/m3 in air. ADAF: age-dependent
adjustment factor.
aADAF adjustments are recommended for cancers for which there is sufficient evidence that formaldehyde has, at
least in part, a mutagenic mode of action (MOA) (see Section 2.2.4).
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bThe judgment of evidence demonstrates for NPC cancer is based on robust human evidence of increased risk in
groups exposed to occupational formaldehyde levels, and robust animal evidence of nasal cancers in rats and
mice that exhibits steeply increasing incidence at high formaldehyde levels. Strong mechanistic support is
provided across species (primarily rats, but also mice, monkeys, and humans), including genotoxicity, epithelial
damage or remodeling, and cellular proliferation that are consistent with neoplastic development in a regional,
temporal, and dose-related fashion.
cWhile the preferred unit risk estimate for NPC is based on a cancer mortality study in humans, several estimates in
general agreement with each other were also derived based on animal nasal tumor incidence. These estimates
used multiple mechanistic and statistical models, including biologically based dose-response (BBDR) modeling
(see Section 2.2.1). In addition, cRfCs for one mechanism contributing to nasal cancer development, specifically
cytotoxicity-induced regenerative cell proliferation, were estimated to be between 0.006 and 0.018 mg/m3 based
on calculations using animal data. Specifically, this narrow range of cRfCs was estimated based on PODs from a
pathology study of hyperplasia, labeling studies of proliferating cells, and BBDR modeling results (see Section
2.2.1).
dNA= not applicable; an ADAF-adjusted value was not calculated for the unit risk estimates based on the animal
data on nasal cancer, as the human unit risk estimate for NPC was the preferred estimate.
eThe judgment of evidence demonstrates for myeloid leukemia is based on robust human evidence of increased
risk in groups exposed to occupational formaldehyde levels. Supporting mechanistic evidence consistent with
leukemia development is provided across numerous studies of peripheral blood isolated from exposed workers,
including evidence of mutagenicity and other genotoxic damage in lymphocytes and myeloid progenitors, and
perturbations to immune cell populations. The animal evidence is inadequate and the findings to date suggest
that there may be a lack of concordance across species for leukemia, as leukemia was not increased in two well-
conducted chronic bioassays of rats or mice, and the available animal data provide weak mechanistic support for
LHP cancers. No MOA has been established to explain how formaldehyde inhalation can cause myeloid leukemia
without systemic distribution (inhaled formaldehyde does not appear to be distributed to an appreciable extent
beyond the respiratory tract to distal tissues).
fNA = not applicable; no ADAF adjustment is recommended for myeloid leukemia because the MOA is unknown
(see Section 1.3.3).
gThe judgment of evidence demonstrates for sinonasal cancer is based on robust human evidence of increased risk in groups
exposed to occupational formaldehyde levels. The strong animal and mechanistic evidence for nasal cancers across species is
interpreted to provide moderate evidence supportive of sinonasal cancer (a judgment of moderate rather than robust reflects
some uncertainty in interpreting the nasal cavity findings in animals as fully applicable to the specific human disease of
sinonasal cancer).
hThe full lifetime (ADAF-adjusted) IUR estimate is based on the ADAF-adjusted estimate for nasopharyngeal cancer
(which includes a mutagenic MOA; see Section 1.2.5). Less-than-lifetime exposure scenarios with a very large
fraction of exposure during adulthood may not warrant ADAF adjustment, and one may choose to use the
unadjusted unit risk estimate of 6.4 x 10"6 per ng/m3.
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Literature Searches (Hazard-specific)
1
Reference retrieval
Reference lists
Inclusion/ exclusion criteria
(based on PECO)
Reference screening by hazard domain
o Excluded references grouped by PECO category
o Included references grouped by lines of
evidence (human, animal, mechanistic)
o Literature search diagrams by hazard domain
~
Evaluation of study methods (Outcome/ endpoint specific)
Outcome-specific
evaluation criteria
for health effects
studies in humans
and animals;
informed by ADME
research
Study evaluation tables
o By outcome and study
o Study confidence by outcome
Medium
iT
Syntheses of results
Low
Unlnformative
Interpretation of
results from health
effect studies in
humans and animals
(consistency,
magnitude of effect,
dose-response,
coherence, etc.)
Evaluation and
interpretation of
mechanistic evidence
Judgments on health effects
separately for human or animal
studies
based on health effects and biological
plausibility from mechanistic studies
Overall evidence judgments
regarding potential of chemical to
cause health effects in humans, using
judgments on human and animal
evidence and mechanistic inference3
Evidence demonstrates
Evidence indicates (likely)
Evidence suggests
Evidence inadequate
1 Figure 1. Overview of assessment methods for hazard identification.
This figure illustrates the flow of evidence through the assessment, sequentially focusing on the most
useful information, as well as the decision-making processes for arriving at evidence integration
judgments regarding the potential for noncancer health effects and for developing specific types of
cancer. * Mechanistic inference considered during evidence integration included biological plausibility,
relevance of animal study results to humans, and, in consideration with the available health effect data,
identification of susceptible groups. Notes: for this assessment, "compelling evidence of no effect" was
not reached for any evidence and, as such, is not discussed further. Importantly, hazard identification for
carcinogenicity includes an additional step of assigning a descriptor regarding the potential for
formaldehyde to cause cancer (this step is not shown but is discussed in Section 1.1 below).
Abbreviations: HERO, Health and Environmental Research Online; PECO, Populations, Exposures,
Comparisons, Outcomes; ADME, absorption, distribution, metabolism, excretion; MOA, mode-of-action.
2 1.1. ASSESSMENT METHODS
3 Assessment development was based on EPA guidelines as well as standard IRIS procedures (U.S.
4 EPA. 2020) that were reviewed by the National Academy of Sciences, Engineering, and Medicine
5 (NASEM) (NASEM, 2021). The approaches implemented can be grouped into (1) those used to identify
6 and evaluate individual studies; (2) those used to synthesize the evidence, including interpreting the
7 degree of support for particular human health hazards by integrating different evidence streams (i.e.,
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human, animal, and mechanistic studies) and coming to summary conclusions; and (3) selecting and
analyzing studies and data to derive quantitative (dose-response) toxicity values. The process involves a
successive focusing on the more informative outcomes within each hazard domain as well as the most
methodologically robust studies to judge and integrate the evidence within, and across, the human,
animal, and mechanistic evidence.
1.1.1. Literature Search and Screening
The literature search strategy used to identify primary research was conducted using the
databases and approaches listed in Table 3. A separate, systematic literature search strategy was
developed for each health effect considered in the assessment. These strategies are described in detail
in Appendix Section A.5, with populations, exposures, comparators, and outcomes (PECO) criteria, and
diagrams depicting the search and sorting process. Health effects and search terms were selected after
reviewing the draft Toxicological Review for Formaldehyde (U.S. EPA. 2010) and other relevant health
assessments or reviews of formaldehyde toxicity. A series of comprehensive literature searches was
conducted annually beginning in 2012 through 2016, after which the completed 2017 Step 1 draft IRIS
formaldehyde-inhalation assessment was suspended at the request of senior EPA management. When
the IRIS assessment was unsuspended in March 2021 (http://www.epa.gov/sites/production/files/2021-
03/documents/iris program outlook mar2021.pdf). systematic evidence mapping (SEM) methods were
employed to survey the newer literature and expedite updating the unsuspended draft (see Appendix F
for the methods and results of the formaldehyde SEM update). In all searches, electronic database
queries for published and unpublished studies were supplemented using various approaches to identify
additional papers, including review of reference lists in identified publications and national-level health
assessments.
Table 3. General approach to literature search strategies
Databases
Health effect-specific searches'5
Web of Science
ToxNet3
PubMed
TSCATS2
[formaldehyde, formalin, paraformaldehyde, OR CASN 50-00-0] AND:
Sensory Irritation0
Pulmonary Function0
Immune-Mediated Conditions, focusing on Allergies and Asthma
Respiratory Tract Pathology
Developmental and Reproductive Toxicity
Nervous System Effects
Cancer
Inflammation and Immune Effects (mechanistic information01)
aToxicology information previously contained in ToxNet were integrated into other NLM products (see
https://www.nlm.nih.gov/toxnet/index.html for where to access).
Specific parameters and keywords for each hazard-specific database search strategy are included in Appendix A.5.
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CA systematic search strategy was not applied to the database of animal studies on this health outcome. Sensory
irritation in animals is a well-described phenomenon. For pulmonary function, there was an extensive set of
research studies in humans, and therefore, the few studies on this outcome in animals were not reviewed.
dThis separate, systematic literature search was performed to augment the analyses of mechanisms relevant to
other health effect-specific searches. Details are not included in this Overview (see Appendix A.5.6).
The citations for primary health effects studies were screened using inclusion and exclusion
criteria based on health effect-specific Populations, Exposures, Comparisons, Outcomes (PECO)
considerations. In general, although studies of other routes of exposure might inform the mechanistic
understanding of potential health effects, the formaldehyde database is large and the toxicokinetics
following inhalation exposure differ significantly from those observed after exposure via other routes
(see Section 2 of this Overview); thus, mechanistic descriptions were focused on inhalation exposure
studies (an exception includes studies of genotoxicity). Ambient levels of formaldehyde in outdoor air
are significantly lower than those measured in the indoor air of workplaces or residences, and the
narrow range of exposures (encompassing 0.005 mg/m3 or less) evaluated in the few epidemiological
studies of outdoor exposure limited their sensitivity to find any associations with health outcomes even
if they existed. Therefore, the few studies examining health effects in relation to outdoor formaldehyde
concentrations were excluded. Other exclusions were based on specific outcome-specific criteria
relating to each health hazard, which are summarized in each of the respective health effect-specific
PECO tables (see Appendix A.5).
In addition to the health effects listed in Table 3, relevant literature on additional topics (e.g.,
formaldehyde exposure, toxicokinetics) was identified. The references identified and selected through
the literature search process (i.e., all included and excluded studies), including bibliographic information
and abstracts, can be found on the Health and Environmental Research Online (HERO) web site:
http://hero.epa.gov/hero/index.cfm/proiect/page/proiect id/4051.
For the literature update from 2016-2021 using SEM approaches (overlapping with the searches
conducted for the 2017 draft), while the aforementioned description of the search and screening
process was largely identical (see Appendix F) a few differences are important to note. Most notably,
after screening the studies for PECO relevance, only those studies meeting the PECO criteria and judged
as likely to have a potential impact on the conclusions or toxicity values described in the suspended
2017 draft are synthesized in this assessment. Studies meeting PECO criteria that were judged to have
no impact on those conclusions or toxicity values are summarized in Appendix F, along with explanations
for these decisions. These latter studies are not further discussed or synthesized in the assessment.
1.1.2. Study Evaluation
All human and experimental animal health effect studies identified in the search and included by
the screening process described above, without regard to study results, were considered for use in
assessing the evidence for health effects potentially associated with inhalation exposure to
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formaldehyde. Study methods were evaluated to assign a level of confidence in the results of the study
with respect to the health outcome under consideration. These evaluations were performed on a health
outcome-specific basis, rather than a study-specific basis; thus, a single study was sometimes evaluated
multiple times for different outcomes, sometimes involving slightly different considerations. The
evaluations focused on potential sources of bias or other limitations (including reduced sensitivity) that
can affect the validity or interpretation of study results. The general procedure involved evaluating
specific methodological features, which differed somewhat between observational epidemiology,
animal toxicology, and human controlled exposure studies. Sets of studies for each hazard-specific
outcome were evaluated by a primary reviewer. The results of the evaluations were then commented
on by a second reviewer who also evaluated each study; the evaluation decisions were discussed, and
any differences were resolved. A study confidence level was drawn and the evaluation, including
relevant study characteristics and an indication of the expected impact of any identified limitations on
the results (when possible), was documented in tables (see Appendix A.5).
Systematic evaluations of individual mechanistic studies were also conducted in relation to
several important health hazards where a reasonable number of studies were available, but the
mechanistic interpretations were not well established. Specifically, this included: biomarkers of
genotoxicity in exposed humans, and mechanistic data related to potential nervous system effects or
potential respiratory health effects. For these studies, the literature identification methods and study
confidence conclusions were similarly documented (see Appendices A.4 and A.5).
The study confidence levels were high, medium, and low confidence, and not informative, and
are presented as italicized text in the various assessment documents. High confidence studies generally
had no significant methodological limitations for an outcome, while medium confidence studies were
considered well conducted but had specific issues that might introduce some uncertainty about
attribution of the results solely to formaldehyde exposure on the health outcome in question.
Methodological limitations of low confidence studies are considered significant, but the outcome-
specific results might still be of limited use (e.g., as support for observations from other studies; to
identify potential data gaps). The results of studies identified as not informative are not discussed in the
Toxicological Review or this Overview.
In some situations, study author(s) were contacted to obtain key study details or results that
were not presented. A decision to contact an author was based on whether the missing information
might result in the reevaluation of methodological features and possibly change the study confidence
level, or if it was useful for dose-response analyses. Any additional study details obtained from the
authors are noted.
Evaluation of observational epidemiological studies
For each type of health outcome examined, the studies were evaluated for each of the
categories of information relevant to internal validity (bias) that could lead to an under- or overestimate
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of risk, and sensitivity, features that could affect the interpretation of the results or limit the ability to
detect a true association (e.g., narrow exposure range). The categories used for the epidemiological
studies included: population selection, exposure (measurement and levels/range), outcome
ascertainment, consideration of confounding, and analytic approach. The potential for selection bias,
information bias (relating to exposure and to outcome), and confounding were evaluated. The expected
direction of bias was explicitly considered and the impact of a potential bias on effect estimates was
incorporated in the determination of overall confidence. Emphasis was placed on discerning a bias that
would be expected to produce a substantive change in the estimated effect estimate, which would
result in a categorization of low confidence. If a study or individual analysis was judged to have multiple
severe limitations, or if reporting deficiencies precluded the ability to conduct an evaluation for multiple
categories, a study or individual analysis was concluded to be not informative.
Evaluation of controlled exposure studies in humans
A process incorporating aspects of the evaluation approaches used for epidemiological studies
and experimental animal studies (see below) was used to evaluate controlled exposure studies in
humans. The evaluation categories included: exposure generation, outcome classification,
consideration of possible bias (i.e., randomization and blinding), consideration of confounding (i.e.,
adequacy of randomization), and details of analysis and presentation of results. The primary reason that
some of these studies were judged to be low confidence was if the exposure generation method was
interpreted to result in significant exposure to substances other than formaldehyde.
Evaluation of animal toxicological studies
In general, toxicology study evaluations considered categories related to those evaluated for
epidemiological studies. The categories were based on the design of a toxicology study, and included
test animals, experimental design (e.g., duration of exposure, timing of endpoint evaluations, allocation
procedures), exposure conduct, endpoint evaluation procedures, and data presentation and analysis.
Since experimental studies should attempt to control all variables, any study limitation interpreted as
capable of influencing the data was considered to have negatively affected the quality (e.g., validity,
accuracy) of the results. Thus, these "confounding factors" differ from what would be deemed a
potential "confounder" in epidemiological studies. Observations in low confidence experimental animal
studies were determined to have a high likelihood of being influenced by factors other than
formaldehyde exposure alone, or there were significant concerns that the observations were
attributable to non-specific effects (e.g., toxicity; irritation).
Evaluation of mechanistic studies
For the datasets described previously, evaluations of individual mechanistic studies involving
formaldehyde inhalation in experimental animals or in vitro models of gaseous formaldehyde exposure
considered the same general features evaluated for more apical measures of toxicity (i.e., evaluations of
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exposure quality and study design were emphasized). The specific criteria, however, were simplified to
accommodate the increased heterogeneity of the available mechanistic studies, as compared to the
data available for apical measures of toxicity. Similarly, study evaluations of individual mechanistic
studies involving exposed humans emphasized consideration of exposure assessment, study design,
outcome ascertainment, and comparison groups for potential sources of bias and their potential impact.
For the mechanistic studies related to potential noncancer respiratory effects, given the large number of
studies identified, individual studies were characterized as high or medium confidence, low confidence,
or not informative. Subsequent to this, groupings of studies or related endpoints were evaluated to
assess the strength of the evidence for different "mechanistic events" as robust, moderate, slight, or
indeterminate. Robust evidence required multiple, consistent high or medium confidence studies, while
moderate evidence required at least one high or medium confidence study and some supporting
information (see Appendix A.5.6 for additional details). For studies of genotoxicity biomarkers in
exposed humans, a confidence level of high, medium, low, or not informative was assigned to each
study, consistent with evaluations of human health effect studies.
Exposure-specific considerations in experimental studies
Experimental exposure to formaldehyde by inhalation is typically achieved through volatilization
of formalin or depolymerization of paraformaldehyde. Methanol, present in aqueous formaldehyde
solutions to inhibit polymerization, is a potential confounder of associations between observed effects
and formaldehyde exposure and, because methanol can be converted to formaldehyde in the body, it
can also introduce quantitative uncertainty. Thus, a critical evaluation of exposure quality (with an
emphasis on the test article used to generate formaldehyde) was applied to experimental studies,
although conclusions about the level of concern varied by health outcome. Specifically, far greater
concern was raised for potential impacts of methanol coexposure on nonrespiratory health effects (i.e.,
nervous system effects, developmental and reproductive system effects, LHP cancers), as compared to
respiratory health effects. This disproportionate level of concern was primarily based on two factors: (1)
as compared to formaldehyde, which does not appear to be distributed to systemic sites in appreciable
amounts, inhaled methanol would be readily transported beyond the URT and could elicit direct effects
at distal target tissues; and (2) certain, systemic effects evaluated in this assessment (i.e., nervous
system effects; reproductive and developmental toxicity) are known to be a target of methanol toxicity,
while other health effects, although they are generally less well studied, have not been clearly
associated with methanol exposure. Separately, for some endpoints (e.g., nervous system effects), the
study evaluations also considered the potential impact of the irritant and odorant nature of
formaldehyde gas, and the inescapable nature of these exposures (animals cannot terminate exposure
at irritating levels), which can complicate interpretations of causality. Similarly, uncertainties introduced
by phenomena such as reflex bradypnea, an irritant response to formaldehyde that can occur in rodents
but not humans, are discussed in the evidence syntheses. Thus, during study evaluation, care was taken
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to consider the exposure protocols in detail, including the duration between exposure and testing and
whether the tested exposure levels were likely to introduce variables such as reflex bradypnea.
1.1.3. Results Display and Evidence Synthesis
For each hazard category, or specific hazard outcome, and depending on the data available,
separate syntheses were developed for each of the three streams of evidence: namely, human and
animal health effect studies, and mechanistic studies. One notable exception is the mechanistic
evidence related to potential respiratory health effects. Given the abundant data available and the
assumed interdependence of the mechanisms involved across these health effects, the data were
identified and evaluated in a single overarching analysis (see Appendix A.5.6). For brevity, while
detailed discussions and analyses are included in the Appendix, the mechanistic syntheses in the
Toxicological Review focus on the primary conclusions that could be drawn from the analysis and any
outstanding issues, uncertainties, or data gaps that might remain. The evidence syntheses, which
incorporate the evaluations of the strengths and limitations of the available studies, are narrative
summaries analyzing the information provided by each stream of evidence regarding the potential for
exposure to formaldehyde via inhalation to result in specific health effects. All informative human and
animal health effect studies (see above), or mechanistic studies (i.e., when individual studies were
evaluated) were considered in assessing the evidence; however, the focus of the synthesis was on the
high and medium confidence studies, when available. Low confidence studies supported the evaluation
of consistency, or if no or few higher confidence studies were available, low confidence studies were
considered in greater depth. Descriptive information about study methods and detailed results were
generally presented in tabular or graphical displays, with supportive text in the Toxicological Review.
The evidence syntheses discuss the nature and breadth of the available literature, highlighting details
that contribute to the analysis of the strength of the evidence within and across the three streams of
evidence, as described in the next section.
The synthesis of the separate streams of evidence, human health effect studies, animal health
effect studies, and mechanistic studies, involved related considerations that differed due to the nature
of the study designs and applicability of the data considered within each stream of evidence (Table 4).
Consistency, magnitude of effects, and dose-response gradients were emphasized in the synthesis of
results of epidemiological and controlled human exposure studies. While the precision of effect
estimates could add to the strength of evidence for a health effect, results were summarized, regardless
of precision. Consistency between studies was examined by comparing study results by confidence
level, specific methodological features that contributed to potential bias, exposure setting, and level of
exposure. The primary considerations for synthesizing the results of animal studies were consistency
(e.g., across species and across research groups, with consideration of study confidence), magnitude and
severity of the effects, dose-response, and coherence of findings for related effects. The information
from mechanistic studies in humans or animals relevant to each apical outcome was synthesized,
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1 highlighting information that could inform either biological plausibility, relevance to humans,
2 susceptibility (considering both apical and mechanistic data), or an improved understanding of dose-
3 response. Given the exposure-related issues specific to formaldehyde, and the abundance of data
4 available, the mechanistic evaluations in this assessment focused almost exclusively on in vivo studies of
5 inhalation exposures, with rare exception (e.g., evaluation of in vitro genotoxicity studies).
6 Table 4. Synthesized information most relevant to drawing evidence integration
7 judgments
Consideration
Description and synthesis methods
Consistency
• Examines the similarity of results (e.g., direction; magnitude) across studies.
When inconsistencies exist, the synthesis considers whether results were "conflicting"
(i.e., unexplained positive and negative results in similarly exposed human populations
or in similar animal models) or "differing" (i.e., mixed results explained by differences
between human populations, animal models, exposure conditions, or study methods)
(U.S. EPA, 2005a) based on analyses of potentially important explanatory factors
such as:
- Confidence in studies' results, including study sensitivity (e.g., some study
results that appear to be inconsistent may be explained by potential biases or
other attributes that affect sensitivity, resulting in variations in the degree of
confidence accorded to the study results)
- Exposure, including route (if applicable), levels, duration, etc.
- Populations or species, including consideration of potential susceptible groups
or differences across lifestage at exposure or endpoint assessment
- Toxicokinetic information as an explanation for any observed differences in
responses across route of exposure, other aspects of exposure, species, or
lifestages
The interpretation of the consistency of the evidence and the magnitude of the
reported effects will emphasize biological significance as more relevant to the
assessment than statistical significance. Statistical significance (as reported by
p-values, etc.) provides no evidence about effect size or biological significance, and a
lack of statistical significance will not be automatically interpreted as evidence of no
effect.
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Consideration
Description and synthesis methods
Strength (effect
magnitude) and
precision
Biological
gradient/dose-response
Coherence
• Examines the effect magnitude or relative risk, based on what is known about the
assessed endpoint(s), and considers the precision of the reported results based on
analyses of variability (e.g., confidence intervals; standard error). In some cases,
this may include consideration of the rarity or severity of the findings (in the context
of the health effect being examined).
Syntheses will analyze results both within and across studies and may consider the
utility of combined analyses (e.g., meta-analysis). While larger effect magnitudes and
precision (e.g., p < 0.05) help reduce concerns about chance, bias or other factors as
explanatory, syntheses should also consider the biological or population-level
significance of small effect sizes. Thus, a lack of statistical significance should not be
automatically interpreted as evidence of no effect.
• Examines whether the results (e.g., response magnitude; incidence; severity)
change in a manner consistent with changes in exposure (e.g., level; duration),
including consideration of changes in response after cessation of exposure.
Syntheses will consider relationships both within and across studies, acknowledging
that the dose-response (e.g., shape) can vary depending on other aspects of the
experiment, including the outcome and the toxicokinetics of the chemical. Thus,
when dose-response is lacking or unclear, the synthesis will also consider the potential
influence of such factors on the response pattern.
• Examines the extent to which findings are cohesive across different endpoints that
are known/expected to be related to, or dependent on, one another (e.g., based on
known biology of the organ system or disease, or mechanistic understanding such
as toxicokinetic/dynamic understanding of the chemical or related chemicals). In
some instances, additional analyses of mechanistic evidence from research on the
chemical under review or related chemicals that evaluate linkages between
endpoints or organ-specific effects may be needed to interpret the evidence. These
analyses may require additional literature search strategies.
Syntheses will consider potentially related findings, both within and across studies,
particularly when relationships are observed within a cohort or within a narrowly
defined category (e.g., occupation; strain or sex; lifestage of exposure). Syntheses will
emphasize evidence indicative of a progression of effects, such as temporal- or dose-
dependent increases in the severity of the type of endpoint observed.
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Consideration
Description and synthesis methods
Mechanistic evidence
related to biological
plausibility
Natural experiments
• There are multiple uses for mechanistic information and this consideration
overlaps with 'coherence.' This examines the biological support (or lack thereof)
for findings from the human and animal health effect studies and becomes more
impactful on the hazard conclusions when notable uncertainties in the strength
of those sets of studies exist. These analyses can also improve understanding of
dose- or duration-related development of the health effect. In the absence of
human or animal evidence of apical health endpoints, the synthesis of
mechanistic information will drive evidence integration conclusions (when such
information is available).
Syntheses can evaluate evidence on precursors, biomarkers, or other molecular or
cellular changes related to the health effect(s) of interest to describe the likelihood
that the observed effects result from exposure. This will be an analysis of existing
evidence, and not simply whether a theoretical pathway can be postulated. This
analysis may not be limited to evidence relevant to the PECO, but may also include
evaluations of biological pathways (e.g., for the health effect; established for other,
possibly related, chemicals). The synthesis will consider the sensitivity of the
mechanistic changes and the potential contribution of alternative or previously
unidentified mechanisms of toxicity.
• Specific to epidemiological studies and rarely available, this examines effects in
populations that have experienced well-described, pronounced changes in exposure
to the chemical of interest (e.g., blood lead levels before and after banning lead in
gasoline).
1.1.4. Evidence Integration
For transparency in the sequential decision steps taken to draw overall evidence integration
judgments, a two-step, sequential process was used (see Figure 2). First, judgments regarding the
strength of the evidence from the available human and animal studies were made. These judgments
incorporated mechanistic evidence (or MOA understanding) in exposed humans and animals,
respectively, that informed the biological plausibility and coherence of the available human or animal
health effect studies. Second, the animal and human evidence judgments were combined to draw an
overall conclusion(s) that incorporated inferences drawn based on information on the human relevance
of the animal evidence (i.e., based on default assumptions or empirical evidence), coherence across the
human and animal evidence streams, and susceptibility.
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Human and animal evidence judgments from Step 1 and the overall evidence integration
conclusion from Step 2 were reached using decision frameworks based on considerations originally
described by Austin Bradford Hill (Hill. 1965).
STEP 1: INTEGRATION OF HEALTH EFFECT
AND MECHANISTIC EVIDENCE IN HUMANS
OR ANIMALS
HUMAN EVIDENCE JUDGMENT
The synthesis of evidence about health
effects and mechanisms from human studies
is combined (integrated) to make a
judgment about health effects in human
studies
ANIMAL EVIDENCE JUDGMENT
The synthesis of evidence about health
effects and mechanisms from animal studies
is combined (integrated) to make a
judgment about health effects in animal
studies.
Figure 2. Process for evidence integration.
In the first step, the strength of the human and, separately, the animal evidence for each
noncancer health effect (or groups of related effects) and specific cancer type (or groups of related
cancer types) was summarized using the following terms: robust, moderate, slight, and indeterminate,
which are presented as italicized text in the various assessment documents. The strength of the human
and animal evidence was determined starting from the evidence syntheses that summarized the
evidence from the available human and animal health effects studies, respectively, and then considering
coherent effects from mechanistic evidence, which could add to or detract from the strength of
evidence. Note, however, that the lack of mechanistic data explaining an association did not discount
results from human or animal health effect studies. To draw these judgments, a modified set of
considerations was applied to evidence from studies in humans and animals (see Table 5).
STEP 2: OVERALL INTEGRATION OF EVIDENCE
FOR HAZARD ID
EVIDENCE INTEGRATION CONCLUSION
The judgments regarding the human and
animal evidence are integrated in light of
evidence on the human relevance of the
findings in animals, susceptibility, and the
coherence of the findings across evidence
streams to draw a conclusion about the
evidence for health effects in humans.
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1 Table 5. Considerations that inform judgments regarding the strength of the human and animal evidence3
Consideration
Increased evidence strength
(of the human or animal evidence)
Decreased evidence strength
(of the human or animal evidence)
The structured categories and criteria in Tables 6 and 7 will guide the application of strength of evidence judgments for an outcome or health effect. Evidence synthesis
scenarios that do not warrant an increase or decrease in evidence strength will be considered "neutral." These ideas build upon the discussion for assessing causality of
disease in Hill (1965), although there are some differences in the use or interpretations of the terms (see Toxicological Review).
Risk of bias;
sensitivity (across
studies)
• An evidence base of high or medium confidence studies increases
strength.
• An evidence base of mostly low confidence studies decreases strength. An
exception to this is an evidence base of studies where the primary issues
resulting in low confidence are related to insensitivity. This may increase
evidence strength in cases where an association is identified because the
expected impact of study insensitivity is toward the null.
• Decisions to increase strength for other considerations in this table should
generally not be made if there are serious concerns for risk of bias.
Consistency
• Similarity of findings for a given outcome (e.g., of a similar
magnitude, direction) across independent studies or experiments
increases strength, particularly when consistency is observed across
populations (e.g., location) or exposure scenarios in human studies,
and across laboratories, populations (e.g., species), or exposure
scenarios (e.g., duration; route; timing) in animal studies.
• Unexplained inconsistency (conflicting evidence) decreases strength.
Generally, strength should not be decreased if discrepant findings can be
reasonably explained by study confidence conclusions, variation in
population or species, sex, or lifestage, exposure patterns (e.g., intermittent
or continuous), levels (low or high), duration or intensity. However, any
decisions about decreased strength will be determined by the extent to
which residual questions about the evidence may persist.
Strength (effect
magnitude) and
precision
• Evidence of a large magnitude effect (considered either within or
across studies), can increase strength. Effects of a concerning rarity
or severity can also increase strength, even if they are of a small
magnitude.
• Precise results from individual studies or across the set of studies
increases strength, noting that biological significance is prioritized
over statistical significance.
• The presence of small effects is not typically used to decrease confidence in
a body of studies. However, if effect sizes that are small in magnitude are
concluded not to be biologically significant, or if there are only a few
studies with imprecise results, then strength is decreased.
• In animal studies, an example of evidence that can decrease strength
involves an effect for which there is a lesser level of concern under some
conditions (e.g., rapid reversibility after removal of exposure). Note that
many reversible effects are of high concern. Such a decision is informed by
factors such as the toxicokinetics of the chemical and the conditions of
exposure [see U.S. EPA (1998)1, judgments regarding the potential for
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Consideration
Increased evidence strength
(of the human or animal evidence)
Decreased evidence strength
(of the human or animal evidence)
delayed or secondary effects, as well as the exposure context focus of the
assessment (e.g., addressing intermittent or short-term exposures).
Biological
gradient/dose-
response
• Evidence of dose-response increases strength. Dose-response may
be demonstrated across studies or within studies and it can be dose-
or duration-dependent. It may also not be a monotonic dose-
response (monotonicity should not necessarily be expected), and the
analysis will consider the extent to which this might be explained by
the available evidence (e.g., different outcomes may be expected at
low versus high doses due to activation of different mechanistic
pathways or induction of systemic toxicity at very high doses).
• Decreases in a response after cessation of exposure (e.g., symptoms
of current asthma) also may increase strength by increasing certainty
in a relationship between exposure and outcome (this is applicable
to human observational studies, but not experimental studies).
• A lack of dose-response when expected based on biological understanding
and having a wide-range of doses/exposures evaluated in the evidence
base can decrease strength.
• In rare cases, and typically only in toxicology studies, the duration of
exposure might reveal an inverse association with effect magnitude (e.g.,
due to tolerance or acclimation). Similar to the discussion of reversibility
above, a decision about whether this decreases strength depends on the
exposure context focus of the assessment and other factors.
• If the data are not adequate to evaluate a dose-response pattern, then
strength is neither increased nor decreased.
Coherence
• Biologically related findings within an organ system, or across
populations (e.g., sex) increase strength, particularly when a
temporal- or dose-dependent progression of related effects is
observed within or across studies, or when related findings of
increasing severity are observed with increasing exposure.
• An observed lack of expected coherent changes (e.g., well-established
biological relationships), particularly when observed for multiple related
endpoints, will typically decrease evidence strength. The decision to
decrease depends on the strength of the expected relationship(s), and
considers factors (e.g., dose and duration of exposure) across studies of
related changes.
Mechanistic
evidence related
to biological
plausibility
• Mechanistic evidence of precursors or health effect biomarkers in
well-conducted studies of exposed humans or animals, in
appropriately exposed human or animal cells, or other relevant
human or animal models (for the human or animal evidence stream,
respectively) increases strength, particularly when this evidence is
observed in the same cohort/population exhibiting the health
outcome.
• Evidence of changes in biological pathways or providing support for
a proposed mode-of-action (MOA) in models also increases
strength, particularly when support is provided for rate-limiting or
• Mechanistic understanding is not a prerequisite for judging the evidence,
and thus absence of knowledge should not be used a basis for decreasing
strength NTP (2015); NRC (2014a). The human relevance of animal
findings is assumed unless there is sufficient evidence to the contrary [see
U.S. EPA (2005a); IARC (2006)1.
• Mechanistic evidence in well-conducted studies that demonstrates that the
health effect(s) are unlikely to occur, or only likely to occur under certain
scenarios (e.g., above certain exposure levels), can decrease evidence
strength. A decision to decrease depends on an evaluation of the strength
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Consideration
Increased evidence strength
(of the human or animal evidence)
Decreased evidence strength
(of the human or animal evidence)
key events, or conserved across multiple components of the
pathway or MOA.
of the mechanistic evidence supporting vs. opposing biological plausibility,
as well as the strength of the health effect-specific findings (e.g., stronger
health effect data require more certainty in mechanistic evidence opposing
plausibility).
1
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1 Decision frameworks, with criteria described in Tables 6 and 7 were used to develop the
2 judgments concerning the strength of evidence for a health effect within each of the human and animal
3 evidence bases, weighing the strengths and weaknesses of both positive and null studies. These
4 frameworks, which add clarity, consistency, and transparency to the evidence evaluations and
5 conclusions, are consistent with generally accepted principles in epidemiology and toxicology and are
6 meant to convey a distribution of confidence in each body of evidence pertaining to a hazard, a process
7 that relies on expert judgment.
8 Table 6. Framework for strength of evidence judgments (human evidence)
Strength of
Evidence Judgment
Description
Robust
... evidence in human
studies
A set of high or medium confidence independent studies reporting an association
between the exposure and the health outcome, with reasonable confidence that
alternative explanations, including chance, bias, and confounding, can be ruled out across
studies. The set of studies is primarily consistent, with reasonable explanations when
results differ; an exposure-response gradient is demonstrated; and the set of studies
includes varied populations. Additional supporting evidence, such as associations with
biologically related endpoints in human studies (coherence) or large estimates of risk or
severity of the response, may increase confidence but are not required.
In exceptional circumstances, a finding in one study may be considered to be robust, even
when other studies are not available (e.g., analogous to the finding of angiosarcoma, an
exceedingly rare liver cancer, in the vinyl chloride industry).
Mechanistic evidence from exposed humans or human cells, if available, may add
support, informing considerations such as exposure-response, temporality, coherence,
and MOA, thus raising the level of certainty to robust for a set of studies that otherwise
would be described as moderate.
Moderate
... evidence in human
studies
A smaller number of studies (at least one high or medium confidence study with
supporting evidence), or with some heterogeneous results, that do not reach the degree
of confidence required for robust. For multiple studies, there is primarily consistent
evidence of an association, but there may be lingering uncertainty due to potential
chance, bias or confounding.
For a single study, there is a large magnitude or severity of the effect, or a dose-response
gradient, or other supporting evidence, and there are not serious residual methodological
uncertainties. Supporting evidence could include associations with related endpoints,
including mechanistic evidence from exposed humans or human cells, if available, based
on considerations such as exposure-response, temporality, coherence, and MOA, thus
raising the level of certainty to moderate for a set of studies that otherwise would be
described as slight.
Slight
One or more studies reporting an association between exposure and the health outcome,
where considerable uncertainty exists. In general, only low confidence studies may be
available, or considerable heterogeneity across studies may exist. Supporting coherent
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Strength of
Evidence Judgment
Description
... evidence in human
studies
evidence is sparse. Strong biological support from mechanistic evidence in exposed
humans or human cells may also be independently interpreted as slight. This also
includes scenarios where there are serious residual uncertainties across studies (these
uncertainties typically relate to exposure characterization or outcome ascertainment,
including temporality) in a set of largely consistent medium or high confidence studies.
This category serves primarily to encourage additional study where evidence does exist
that might provide some support for an association, but for which the evidence does not
reach the degree of confidence required for moderate.
Indeterminate
... evidence in human
studies
No studies were available in humans or situations when the evidence is inconsistent or
primarily of low confidence.
Compelling evidence
of no effect
... in human studies
Several high confidence studies showing null results (for example, an odds ratio of 1.0),
ruling out alternative explanations including chance, bias, and confounding with
reasonable confidence. Each of the studies should have used an optimal outcome and
exposure assessment and adequate sample size (specifically for higher exposure groups
and for susceptible populations). The set as a whole should include the full range of levels
of exposures that human beings are known to encounter, an evaluation of an exposure-
response gradient, and an examination of at-risk populations and lifestages.
1 Table 7. Framework for strength of evidence judgments (animal evidence)
Strength of evidence
judgment
Description
Robust
... animal evidence
A set of high or medium confidence experiments includes consistent findings of
adverse or toxicologically significant effects across multiple laboratories, exposure
routes, experimental designs (e.g., a subchronic study and a two-generation study), or
species, and the experiments can reasonably rule out the potential for nonspecific
effects (e.g., resulting from toxicity) to have resulted in the findings. Any inconsistent
evidence (evidence that cannot be reasonably explained by the respective study design
or differences in animal model) is from a set of experiments of lower confidence. At
least two of the following additional factors in the set of experiments increases
certainty in the evidence for the health outcome(s): coherent effects across multiple
related endpoints (may include mechanistic evidence); an unusual magnitude of effect,
rarity, age at onset, or severity; a strong dose-response relationship; or consistent
observations across animal lifestages, sexes, or strains. Alternatively, mechanistic data
in animals or animal cells that address the above considerations or that provide
experimental support for a MOA that supports causality with reasonable confidence
may raise the level of certainty to robust for evidence that otherwise would be
described as moderate or, exceptionally, slight or indeterminate.
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Strength of evidence
judgment
Description
Moderate
... animal evidence
A set of evidence that does not reach the degree of certainty required for robust, but
which includes at least one high or medium confidence study and information
strengthening the certainty in the evidence for the health outcome(s). Although the
results are largely consistent, notable uncertainties remain. However, while
inconsistent evidence or evidence indicating nonspecific effects (e.g., toxicity) may
exist, it is not sufficient to reduce or discount the level of concern regarding the
positive findings from the supportive experiments or it is from a set of experiments of
lower confidence. The set of experiments supporting the effect provide additional
information supporting causality, such as consistent effects across laboratories or
species; coherent effects across multiple related endpoints (may include mechanistic
evidence); an unusual magnitude of effect, rarity, age at onset, or severity; a strong
dose-response relationship; or consistent observations across exposure scenarios (e.g.,
route, timing, duration), sexes, or animal strains. Mechanistic data in animals or
animal cells that address the above considerations or that provide information
supporting causality with reasonable confidence may raise the level of certainty to
moderate for evidence that otherwise would be described as slight.
Slight
... animal evidence
Scenarios in which there is a signal of a possible effect, but the evidence is conflicting
or weak. Most commonly, this includes situations where only low confidence
experiments are available and supporting coherent evidence is sparse. It also applies
when one medium or high confidence experiment is available without additional
information increasing the certainty in the evidence (e.g., corroboration within the
same study or from other studies). Lastly, this includes scenarios in which there is
evidence that would typically be characterized as moderate, but inconsistent evidence
(evidence that cannot be reasonably explained by the respective study design or
differences in animal model) from a set of experiments of higher confidence (may
include mechanistic evidence) exists. Strong biological support from mechanistic
studies in exposed animals or animal cells may also be independently interpreted as
slight. Notably, to encourage additional research, it is important to describe situations
where evidence exists that might provide some support for an association but is
insufficient for a conclusion of moderate.
Indeterminate
... animal evidence
No animal studies were available, or a set of low confidence animal studies exist that
are not reasonably consistent or are not informative to the hazard question under
evaluation.
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Strength of evidence
judgment
Description
Compelling evidence of
no effect
... in animal studies
A set of high confidence experiments examining a reasonable spectrum of endpoints
relevant to a type of toxicity that demonstrate a lack of biologically significant effects
across multiple species, both sexes, and a broad range of exposure levels. The data are
compelling in that the experiments have examined the range of scenarios across which
health effects in animals could be observed, and an alternative explanation (e.g.,
inadequately controlled features of the studies' experimental designs; inadequate
sample sizes) for the observed lack of effects is not available. The experiments were
designed to specifically test for effects of interest, including suitable exposure timing
and duration, postexposure latency, and endpoint evaluation procedures, and to
address potentially susceptible populations and lifestages.
The second stage of evidence integration combined the animal and human evidence judgments,
while also considering mechanistic information on the human relevance of the animal evidence,
relevance of the mechanistic evidence to humans (especially in cases where animal evidence was
lacking), coherence across streams of evidence, and information on susceptible populations, to arrive at
an overall evidence integration judgment regarding the evidence for causation (see Table 8). This
evidence integration framework interprets the instructions and examples provided in the cancer
guidelines (U.S. EPA. 2005a) to allow clarity and consistency in the evaluation of each hazard. The
evidence integration framework illustrates the principle that evidence in humans generally has greater
weight than evidence in animals. In the absence of sufficiently justifiable MOA information, effects in
animal models are assumed to be relevant to humans. In this assessment, for potential health hazards
where the evidence from animal models influenced the overall evidence integration judgment, the
available mechanistic evidence was considered in light of human relevance.
For each potential health effect evaluated, a narrative summary and evidence integration
judgment regarding the available evidence were developed. The overall evidence integration
judgments: evidence demonstrates, evidence indicates [likely], evidence suggests, and evidence
inadequate (to judge hazard) are presented as bolded text throughout the assessment and are
accompanied by a description of the conditions of expression (e.g., exposure levels, exposure patterns)
in the studies that served as the basis for the judgment. For each credible hazard identified (in this
assessment, judgments of evidence demonstrates or evidence indicates [likely]), the "appropriate
exposure circumstances" alluded to during hazard identification are more fully evaluated and defined
through dose-response analysis (including, when possible, the derivation of toxicity values).
Importantly, for the purposes of this assessment, the same evidence integration approach was
used to draw evidence integration judgments for both noncancer health effects and specific cancer
types. This approach uses the methods and considerations and described in the EPA cancer guidelines
(U.S. EPA. 2005a). Consistent with these guidelines, for carcinogenicity, a final step of categorizing the
totality of the evidence using a "descriptor" was performed, as described below.
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1 Table 8. Overall evidence integration judgments for characterizing the integrated
2 evidence for noncancer health effects and cancer outcomes
Overall
evidence
integration
judgment in
narrative
Explanation and example scenarios
Evidence
demonstrates
This signifies a very high level of certainty that formaldehyde exposure caused the health effect.
For this assessment, if the data were amenable, a toxicity value was estimated.
• This category was3 used if there was robust human evidence supporting an effect.
• This category could also be used with moderate human evidence and robust animal evidence
if there was strong mechanistic evidence that MOAs and key precursors identified in animals
were anticipated to occur and progress in humans.
Evidence
indicates
[likely]b
This reflects a reasonable certainty that the relationship between formaldehyde exposure and
the health outcome was causal, although there may be some outstanding questions that remain.
For this assessment, if the data were amenable, a toxicity value was estimated.
• This category was used if there is robust animal evidence supporting an effect and moderate-
to-indeterminate human evidence when strong mechanistic evidence was lacking.
• This category was also used with moderate human or animal evidence supporting an effect
and slight or indeterminate evidence from the opposite evidence stream. In these scenarios,
any uncertainties in the moderate evidence were not sufficient to reduce or discount the
level of concern, or mechanistic evidence in the opposite evidence stream (e.g., precursors)
existed to increase confidence in the moderate evidence.
Evidence
suggests (but is
not sufficient to
infer)c
This conveys some concern that formaldehyde may cause a particular health outcome, but there
were very few studies that contributed to the evaluation, the evidence was very weak or
conflicting, or the methodological conduct of the studies was poor. Given the substantial degree
of uncertainty, additional research would provide valuable information for future evaluations.
Although it may sometimes be possible to develop toxicity values for evidence in this category,
given the particulars of the available data in this assessment, toxicity values were not estimated.
• This category was used if there was slight human or animal evidence.
• This category could also be used with moderate human or animal evidence and sliaht or
indeterminate evidence in the opposite evidence stream. In these scenarios, there were
outstanding issues regarding the moderate evidence that reduced the level of concern or
confidence in the reliability of the findings, or mechanistic evidence from the opposite
evidence stream (e.g., null results in well-conducted evaluations of precursors) existed to
decrease confidence in the moderate evidence.
• Exceptionally, when there is general scientific understanding of mechanistic events that result
in a hazard, this category could also be used if there was strong mechanistic evidence that is
sufficient to identify a cause for concern—in the absence of adequate conventional studies in
humans or in animals (i.e., indeterminate evidence in both).
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Overall
evidence
integration
judgment in
narrative
Explanation and example scenarios
Evidence
inadequated
This conveys either a lack of information or an inability to interpret the available evidence. A
toxicity value was not estimated.
• This category was used if there was indeterminate human and animal evidence.
• This category could also be used with sliaht-to-robust animal evidence and indeterminate
human evidence if strong mechanistic information indicated that the animal evidence was
unlikely to be relevant to humans.
A conclusion of inadequate is not a determination that the agent does not cause adverse health
outcomes or is safe. It generally indicates that further research is needed.
Note: This table does not supersede or alter any EPA guidelines. It is meant only to provide added transparency
for conclusions drawn regarding the level of evidence from human, animal, and mechanistic studies.
aTerminology of "was" refers to the default option; terminology of "could also be" refers to alternative options.
bFor some applications, such as benefit-cost analysis, to better differentiate the categories of evidence
demonstrates and evidence indicates (likely), the latter category should be interpreted as evidence that supports
an exposure-effect linkage that is likely to be causal.
cHealth effects characterized as having evidence demonstrates and evidence indicates (likely) (and, in some cases,
evidence suggests) are evaluated for use in dose-response assessment. When the database includes at least one
well-conducted study and a judgment of evidence suggests is drawn, quantitative analyses may still be useful for
some purposes (e.g., providing a sense of the magnitude and uncertainty of estimates for health effects of
potential concern, ranking potential hazards, or setting research priorities), but not for others [see related
discussions in (U.S. EPA, 2005a)l. It is critical to transparently convey the extreme uncertainty in any such
estimates.
dSpecific narratives for each of the health effects with an evidence integration judgment of evidence inadequate
may be deemed unnecessary.
1 For carcinogenesis only, the weight of evidence as to whether formaldehyde inhalation
2 exposure is carcinogenic to humans is summarized using descriptors, consistent with EPA guidelines
3 (U.S. EPA. 2005a) (see Table 9). For this assessment, the descriptors build upon the overall evidence
4 integration judgments for individual cancer types, as described in Table 8; however, this does not alter
5 or supersede any EPA guidelines.
6 Table 9. Criteria for applying cancer descriptors to evidence integration judgments for
7 cancer types
Cancer descriptor
Criteria
Carcinogenic to humans
• This descriptor was used if the evidence demonstrates that, for at least one
cancer type, formaldehyde inhalation exposure caused the increase in cancer
incidence or mortality.
• This descriptor could also be used in rare instances if for the evidence indicates
that formaldehyde inhalation exposure likely causes different cancer types across
evidence bases (e.g., when one type of cancer is based on human evidence and
tumors at another site is supported by animal evidence, consistent with EPA
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Cancer descriptor
Criteria
guidelines (U.S. EPA, 2005a) that site-concordance is not required). Such a
decision would depend on mechanistic understanding (i.e., in this example, the
decision would consider differences in tumor types or ADME across species).
Likely to be carcinogenic to
humans
• This descriptor was used if the evidence indicates that, for at least one cancer
type, formaldehyde inhalation exposure likely caused the increase in cancer
incidence or mortality.
• Similar to the rationale provided above, this descriptor could also be used in rare
instances when the evidence suggests formaldehyde inhalation exposure may
cause multiple tumor types, depending on mechanistic inference.
Suggestive evidence of
carcinogenic potential
This descriptor was used if, for the evidence relating to carcinogenicity, the evidence
was only suggestive that formaldehyde inhalation exposure may cause any of the
observed increases in cancer incidence or mortality for any cancer type. This would
reflect a substantial degree of uncertainty in any potential causal inference.
Inadequate evidence to
assess carcinogenic potential
This descriptor was used if the evidence was inadequate to draw a conclusion
regarding cancers of any type with any confidence. This might reflect a lack of
information or highly conflicting information.
Not Likely to be carcinogenic
to humans
This descriptor conveys a high degree of certainty that there is negligible concern for
carcinogenic effects. A substantial amount of evidence would be required to support
this descriptor [see (U.S. EPA, 2005a)l.
1.1.5. Dose-response Analysis
The Toxicological Review includes an inhalation reference concentration (RfC). The RfC is
defined as an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous daily
inhalation exposure of formaldehyde to the human population (including sensitive subgroups) that is
likely to be without an appreciable risk of deleterious effects during a lifetime. A carcinogenicity
assessment was also performed, including derivation of an inhalation unit risk value (IUR), which is an
upper-bound excess cancer risk estimated to result from continuous exposure to an agent at a
concentration of 1 ng/m3 in air for a lifetime. In addition, organ/system-specific RfCs (osRfCs) were
derived for the various noncancer health endpoints, when supported by the available evidence, which
may be useful when considering cumulative risk scenarios. Multiple candidate RfCs (cRfCs) were
sometimes compared before choosing a representative osRfC. Where relevant, mechanistic
understanding regarding the development of specific health effects (e.g., temporal progression;
potential thresholds in dose-response), as well as knowledge of susceptibility, was used to inform
approaches to derive points of departure (PODs), uncertainty factors, or confidence levels for the
quantitative estimates (e.g., osRfCs; RfC; IUR). A confidence level of high, medium, or low was assigned
to each osRfC and the RfC based on the reliability of the associated POD and cRfC calculation(s).
Confidence in the completeness of the database for each osRfC and the overall RfC was also assigned.
These decisions were used to draw an overall level of confidence in the RfC. Likewise, an overall level of
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confidence was assigned to the IUR. Where possible, the assessment attempts to describe the level of
response observed across different exposure levels within the range of the data and transparently
discusses the uncertainties and assumptions when deriving and applying the different toxicity value
estimates (e.g., cRfCs, IUR).
2. SUMMARY OF TOXICOKINETICS
Several detoxification and removal processes exist for inhaled formaldehyde, including at the
site(s) of first contact (e.g., human nasal passages). Much of what is known regarding the uptake and
distribution of inhaled formaldehyde is based on experiments using monkeys and rats. Species
differences in the structure of the airways and breathing patterns, as well as the composition of the
surface epithelium at various nasal locations, are important considerations when interpreting results in
experimental animals and extrapolating observations to humans. While the nasal passages in humans
are generally similar to other mammalian species, one key difference is that humans and non-human
primates have nasal passages adapted for both oral and nasal (oronasal) breathing, as opposed to
obligate nasal breathing in rodents. A second key difference regards the shape and complexity of the
nasal turbinates, with relatively simple shapes in humans, and complex, folded patterns in rodents. In
general, these differences provide better protection of the rodent lower respiratory tract (LRT) against
inhaled toxicants than is provided to the human LRT (Harkema et al.. 2006).
Uptake of inhaled formaldehyde is based on rough estimates determined from the amount of
formaldehyde removed from the air and indicates that the vast majority of formaldehyde is removed
from inhaled air by the upper respiratory tract (URT) in monkeys (Casanova et al.. 1991; Monticello et
al.. 1989), dogs (Egle, 1972), and rats (Kimbell et al.. 2001b; Chang et al.. 1983; Heck et al.. 1983; Kerns
et al.. 1983). Further, dosimetric modeling studies in humans have shown close agreement with
observations of exposed rodents. Overall, a concentration gradient of inhaled formaldehyde follows an
anterior to posterior distribution, with high concentrations of formaldehyde distributed to nasal
squamous, transitional and respiratory epithelium, and less uptake by olfactory epithelium, and very
little formaldehyde reaching more distal sites such as the larynx or lung. The possibility that more
extensive distribution to the LRT may occur when people are breathing through the mouth during
exercise or when they have an upper respiratory tract infection has not been investigated.
As inhaled formaldehyde enters the URT, it interacts with the mucociliary apparatus, the first
line of defense against inhaled materials in the nose. In nasal mucus, most of the formaldehyde is
rapidly converted to methanediol (~99.9%) and a minor fraction remains as free formaldehyde (~0.1%)
(Bogdanffy et al.. 1986; Fox et al.. 1985). Formaldehyde levels are reduced through interactions with
components of the mucus and through mucociliary clearance; through reactions with cellular materials
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at the plasma membrane of the respiratory epithelium; via interactions with glutathione (GSH) and
other macromolecules in the intracellular and extracellular space; through localized metabolism and
conjugation reactions; and through reversible interactions with intracellular materials. This results in
the formation of a gradient of formaldehyde across the tissue space, with the greatest formaldehyde
concentration at the apical surface of the mucosa, and the lowest levels of formaldehyde at deeper
components of the tissue, such as the nasal associated lymphoid tissues (NALT) and blood vessels.
Models developed by Schroeter et ai, (2014) and Campbell et al. (2020) demonstrate that at sufficiently
low levels of exogenous formaldehyde, the uptake of exogenous formaldehyde is reduced due to the
presence of endogenous formaldehyde. These results add to the characterization of the uncertainty in
formaldehyde dose-response at low exposure concentrations (discussed in further detail in Section 1.1.3
and 2.2.1 of the Toxicological Review).
Several of the key considerations for evaluating the distribution of inhaled formaldehyde to the
portal-of-entry (the rat nose is depicted) and systemic sites are represented in Figure 3.
Inspired air and
formaldehyde (red)
Mucus
Cilia
Epithelium
[epithelial cells
(EC) and goblet
cells (GC)]
1 Basement membrane
Lamina propria
[systemic circulation
(SC) and lymphoid
tissue (NALT)]
Gradient
formaldehyde
concentration
Rat nose [formaldehyde
(in red), squamous
epithelium (se),
respiratory epithelium
(re), nasal turbinates with
olfactory epithelium (NT-
oe) or with re (NT-re),
cribiform plate (CP), and
olfactory bulb (OB)]
Vialt*
••V*
Nasopharynx (to lower
respiratory tract)
Figure 3. Schematic of the rat upper respiratory tract depicting the gradient of
formaldehyde concentration formed following inhalation exposure.
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The gradient both from anterior to posterior locations, as well as across the tissue depth is depicted.
Modeling based on observations in rodents predicts a similar pattern of distribution in humans. Drawn
based in part on images by NRC (2011) and Harkema et al. (2006).
In the respiratory tissue, formaldehyde can be metabolized to formate, which can either enter
the one-carbon pool leading to protein and nucleic acid synthesis, or be further metabolized to C02 and
eliminated in expired air or excreted in urine unchanged. Alternatively, upon interactions with cellular
macromolecules, it can form DNA-protein cross-links (DPX), protein adducts (Edrissi et al.. 2013b; Edrissi
et al.. 2013a), or other products, as demonstrated by concentration-dependent increases in DPX
formation in rat and monkey nasal passages. Recently, analytical methods have been developed that
can distinguish between N2-hm-dG adducts from exogenous (inhaled) formaldehyde and N2-hm-dG
adducts from endogenous formaldehyde (Lu et al.. 2012; Lu et al.. 2011; Moeller et al.. 2011; Lu et al..
2010). DNA monoadducts (Leng et al.. 2019; Yu et al.. 2015; Lu et al.. 2011; Moeller et al.. 2011; Lu et
al.. 2010) and DPX (Leng et al.. 2019; Lai et al.. 2016) derived from exogenous formaldehyde were
detectable in nasal tissues, but not in distal tissues (including the bone marrow) of experimental animals
exposed by inhalation, supporting that exogenous formaldehyde is not systemically distributed. Also,
toxicokinetic studies demonstrate that labeled carbon from inhaled formaldehyde measured in bone
marrow of rats was the result of metabolic incorporation from the 1-Carbon (1C) pool, not covalent
binding, further supporting the lack of transport of formaldehyde or metabolites of formaldehyde to the
distal tissues (Casanova-Schmitz et al.. 1984). Finally, inhalation exposure to formaldehyde does not
appear to alter blood formaldehyde levels (approximately 0.1 mM across different species), suggesting
that inhaled formaldehyde is not significantly absorbed into blood (Kleinnijenhuis et al.. 2013; Casanova
et al.. 1988; Heck et al.. 1985).
The toxicokinetics of formaldehyde may be influenced by certain formaldehyde-related effects,
such as altered mucociliary clearance [e.g., (Morgan. 1983)1, reflex bradypnea in rodents (Chang et al..
1983; Chang et al.. 1981). and dynamic changes in tissue structure (Kamata et al.. 1997). which have the
potential to modulate formaldehyde uptake and clearance. For example, during repeated inhalation
exposure to formaldehyde, mice, and to a lesser extent rats, lower their minute volume thereby
restricting the intake of the gas (Chang et al.. 1983; Chang et al.. 1981), which may impact dosimetric
adjustment if the dose-response results from these studies are extrapolated to humans.
3. NONCANCER HEALTH EFFECTS
Based on the current understanding of the toxicokinetics of formaldehyde inhalation exposure,
several practical working assumptions were applied to this assessment. Although some uncertainties
remain, the organization and analyses in the assessment assume that inhaled formaldehyde is not
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distributed to an appreciable extent beyond the respiratory tract to systemic sites; thus, it is assumed
that inhaled formaldehyde is not directly interacting with tissues distal to the portal-of-entry to elicit
effects. Similarly, it is assumed that formaldehyde does not cause appreciable changes in normal
metabolic processes associated with formaldehyde in distal tissues. Thus, for the purposes of this
assessment, studies examining potential associations between levels of formaldehyde or formaldehyde
byproducts measured in distal tissues and health outcomes are not considered relevant to inhaled
formaldehyde.
Research on several noncancer respiratory health effects was evaluated: sensory irritation;
pulmonary function; immune-mediated conditions, focusing on allergic conditions and asthma; and
respiratory tract pathology. An overarching evaluation of the mechanistic information pertinent to any
or all potential noncancer respiratory system health effects was performed (see Appendix A.5.6), with
the most pertinent results summarized within each section. Evaluations were also performed for
noncancer systemic (i.e., non-respiratory) health effects: nervous system effects; reproductive or
developmental toxicity.
3.1. SENSORY IRRITATION
Individuals exposed to formaldehyde in indoor air reported symptoms of irritation in the eyes,
nose, and throat; eye irritation is the most sensitive effect. Controlled human exposure studies
evaluated frequency and severity of symptoms during brief periods of exposure, and a few studies also
evaluated objective measures, such as conjunctival redness or frequency of eye blinking.
Epidemiological studies of exposure to indoor formaldehyde among residential populations evaluated
symptoms of irritation, including burning and watering eyes, sneezing and rhinitis, sore throat, and
coughing. This review of sensory irritation focused on symptoms and other measures of eye irritation,
which is an immediate response to formaldehyde exposure (Andersen and Molhave. 1983: Andersen.
1979).
3.1.1. Literature Identification
While the review focused on the more informative controlled human exposure studies and
observational studies in residential populations, occupational studies and studies of students exposed to
embalming fluid during dissection labs were also reviewed. The bibliographic databases, search terms,
and specific strategies used to search them are provided in Appendix A.5.2, as are the specific PECO
criteria and the methods for identifying literature from 2016-2021 are described in Appendix F.
Mechanistic studies relevant to sensory irritation were separately identified (and evaluated) as part of
the overarching review of mechanistic data informing respiratory effects (see Appendix A.5.6 for
additional details and supporting analyses).
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3.1.2. Study Evaluation
The controlled human exposure studies were able to evaluate symptoms in a controlled
environment; therefore, the dose-response relationship was more precise and potential confounders
were less of a concern. However, the study groups were selected for age (younger adults) and were
healthy enough to conform to study protocols. These studies evaluated formaldehyde concentrations
above 0.1 mg/m3, while exposure levels in the residential studies ranged between 0.01 (LOD) to
approximately 1 mg/m3, with a large proportion of residences less than 0.1 mg/m3. The studies of
residential formaldehyde exposure included a wider range of ages (adults and children) and potentially
susceptible individuals; some had existing respiratory and other health conditions.
3.1.3. Synthesis of Human Health Effect Studies
The controlled human exposure studies showed that the irritant response to formaldehyde is an
immediate phenomenon apparent at concentrations of 0.1 mg/m3, the lowest concentration evaluated,
and higher, and resolves when exposure is removed (Sauder et al.. 1986; Andersen and Molhave, 1983).
Both prevalence and severity of symptoms were associated with concentration. In addition, a large
variability in sensitivity to the irritant properties of formaldehyde at specific concentrations was
observed (Mueller et al.. 2013; Berglund et al.. 2012). Because of the wide variability in responses, it has
been difficult for experimental studies to characterize the exposure-response relationship in the lower
range of concentrations experienced by the general population.
Only a few studies evaluated whether symptom prevalence or severity changed over the course
of the exposure period. Controlled exposure studies by one research group indicate that irritant
responses to 2.46 mg/m3 do not differ across groups as a result of previous, routine formaldehyde
exposure (Schachter et al.. 1987; Schachter et al.. 1986). Studies that examined change in response
during exposures at relatively high levels (>1 mg/m3) reported higher symptom scores initially with
subsequent declines suggestive of acclimation during exposure (Green et al.. 1987; Schachter et al..
1986; Andersen and Molhave. 1983). However, at lower concentrations (0.3 and 0.5 mg/m3), the
initiation of symptoms was delayed and symptom severity continued to increase during the exposure
period (Andersen and Molhave. 1983). Overall, these few studies suggest that some acclimatization
may occur over a few hours at higher concentrations, however this phenomenon may not be apparent
when concentrations are lower (<1 mg/m3).
Two studies investigating the prevalence of symptoms of irritation in relation to residential
formaldehyde exposure observed a statistically significant relationship between increasing
formaldehyde concentration (from approximately 0.01 to >0.60 mg/m3) and symptoms of irritation
using logistic regression models with adjustment for age, gender, smoking behavior and other potential
confounders (Liu et al.. 1991; Hanrahan et al.. 1984). Data were collected on symptoms occurring since
participants had moved into their homes (Hanrahan et al.. 1984) or those that occurred during the two
weeks prior to the end of the one-week formaldehyde sampling period (Liu et al.. 1991). Although the
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sampling period used by Hanrahan et al. (1984) was short (1 hour), the study ruled out several exposure
sources that might contribute to variability in concentrations. Other emissions released from the same
sources as formaldehyde that also may contribute to eye irritation, including phenols, pinene, and
terpenes, were not adjusted for in the analysis, but were present at lower levels compared to
formaldehyde. A strong dose-response relationship with formaldehyde, as a cumulative measure (ppm-
hour) or a one-hour concentration, was reported by these two medium confidence studies, indicating
that the associations are unlikely to be entirely explained by unmeasured confounding from
coexposures. Although the studies were limited by low participation rates, a potential source of
selection bias if related to formaldehyde concentrations, participants were randomly selected for
recruitment and the investigators noted that the characteristics of respondents and non-respondents,
such as age of housing stock, demographics, and formaldehyde concentrations, were comparable.
Figure 4 graphs prevalence of eye irritation (or burning eyes) by formaldehyde concentration
reported by controlled human exposure studies and residential studies that evaluated concentrations
below 1 mg/m3. These results are complementary for the most part and indicate a consistent pattern in
response to formaldehyde concentrations between 0 and 1 mg/m3. The study by Bender et al. (1983)
used a protocol that involved exposure to the eyes only, although the concentration-response pattern
was similar to the studies that evaluated exposure via inhalation. Two controlled human exposure
studies that also evaluated concentrations below 1 mg/m3 reported results using a different metric, a
subjective symptom score rather than symptom prevalence (Mueller et al.. 2013; Lang et al.. 2008). The
results of the two studies differed. Lang et al. (2008) reported an increase in symptom scores for eye
irritation at 0.3 mg/m3, whereas Mueller et al. (2013) reported no effect related to formaldehyde
exposure.
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{T
I
t5
Formaldehyde {mg/m"
•
Anderson 1983
¦
Kulle 1987
~
Bender 1983
T
Main & Hogan 1983
~
Olsen & Dossing 1982
O
Hanrahan 1984
~
Liu 1991
Figure 4. Prevalence of eye irritation among study groups exposed to formaldehyde in
residential settings and controlled human exposure studies.
Exposure in these studies was either in mobile trailer offices or residential mobile homes. Prevalence at
formaldehyde concentrations measured among comparison groups is graphed if reported (Holness and
Nethercott, 1989; Holmstrom and Wilhelmsson, 1988; Horvath et al., 1988; Olsen and Dossing, 1982).
Error bars are standard error (SE) calculated by EPA. Average weekly concentrations in three categories
for Liu et al. (1991) were estimated from the midpoint of each category of reported weekly cumulative
exposure (ppm-hour) and an assumption that individuals spent 60% of a 24-hour period at home.
3.1.4. Mode-of-action Information
Sensory irritation is understood to occur as a result of direct interactions of formaldehyde with
cellular macromolecules in the nasal mucosa leading directly or indirectly to stimulation of trigeminal
nerve endings located in the respiratory epithelium (see Figure 5; see Appendix A.5.6 for additional
details, related analyses, and discussion). This potential mechanism is most directly supported by
studies demonstrating increases in afferent nerve activity after acute exposure to approximately
0.5 mg/m3 formaldehyde or lower (Tsubone and Kawata, 1991; Kulle and Cooper. 1975), although
several related findings provide additional confirmation. While other mechanistic changes (e.g.,
oxidative stress; airway inflammation; damage or dysfunction of the respiratory epithelium, not shown)
and biological differences (e.g., nasal morphology; underlying allergy, infection, or other respiratory
conditions) are expected to be strong modifiers of this sequence of events, this pathway is interpreted
as likely to be the dominant mechanism by which formaldehyde exposure causes sensory irritation. All
of the mechanistic events in this pathway are supported by robust or moderate evidence, and the
relationships described are largely well-understood biological phenomena or have been demonstrated
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following formaldehyde exposure. This mechanistic understanding provides strong support for the
biological plausibility of this effect. Although the primary support for an MOA reliant on stimulation of
receptors on nasal trigeminal nerve endings is from studies in experimental animal models, the
mechanistic events presumed to be driving sensory irritation after formaldehyde exposure are expected
to be conserved in humans.
Possible Initial Alterations Secondary Alterations
Effector-Level Changes
Key Hazard Feature
0 <*>
1s oxidative
stress in URT
URTTRPA1
binding
Trigeminal nerve
stimulation in URT
Centrally mediated
sensory irritation
Legend
^ Plausibly an initial
effect of exposu re
~ Key feature of sensory
irritation
EVIDENCE
(fjfi Robust
( ) Moderate
{_; Slight
RELATIONSHIP
—> Robust
--> Moderate
Slight
Figure 5. Likely mechanistic association between formaldehyde exposure and sensory
irritation.
An evaluation of the formaldehyde exposure-specific mechanistic evidence informing the potential for
formaldehyde exposure to cause respiratory health effects identified this sequence of mechanistic events
as likely to be the dominant mechanism by which formaldehyde inhalation could cause sensory irritation.
3.1.5. Overall Evidence Integration Judgment and Susceptibility for Sensory Irritation
Studies in humans provide robust evidence of sensory irritation based on the controlled human
exposure studies and observational epidemiological studies, and this effect also is well described and
accepted across a range of experimental animal species (robust), as well as in an established MOA based
on mechanistic evidence in animals (this MOA is interpreted to be operant in humans). Overall, the
evidence demonstrates that inhalation of formaldehyde causes sensory irritation in humans, given
appropriate exposure circumstances (see Table 10). The primary basis for this conclusion is based on
residential studies with mean formaldehyde concentrations >0.05 mg/m3 (range 0.01->1.0 mg/m3) and
controlled human exposure studies testing responses to concentrations 0.1 mg/m3 and above.
Table 10. Evidence integration summary for effects on sensory irritation
Evidence
Evidence judgment
Hazard determination
Human
Robust, based on:
Human health effect studies:
The evidence demonstrates that
formaldehyde inhalation causes
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• Four high and medium confidence studies of symptom prevalence (eye,
nose, throat) among adults and children in residential settings (mean
>0.05 mg/m3 formaldehyde, range 0.01 to approximately 1.0 mg/m3)
• Numerous high and medium confidence studies involving acute exposure
(controlled human exposure studies)
• Numerous high and medium confidence studies with longitudinal designs
(occupational, panel studies of medical school pathology/ anatomy lab
courses)
• Consistent observations of irritation symptoms in all studies; clear
exposure-response trends
Biological Plausibility.
No directly relevant human mechanistic studies were found
sensory irritation in humans
given appropriate exposure
circumstances3
Primarily based on well-
conducted residential studies
with mean formaldehyde
concentrations >0.05 mg/m3
and controlled human exposure
studies testing >0.1 mg/m3
Animal
Robust, based on:
Animal health effect studies:
Although animal studies were not formally evaluated, formaldehyde
inhalation-induced sensory irritation in rodents is a well-documented
phenomenon (e.g., reflex bradypnea in mice and rats; see Appendix A.3).
Biological Plausibility.
Robust and moderate evidence for mechanistic events from animal studies
identifies stimulation of the trigeminal nerve as the dominant MOA
Potential susceptibilities:
Potentially large variations in
sensitivity are expected,
depending primarily on
differences in nasal health
(including allergy or
inflammatory status) and
physiology
Other
inferences
• Relevance to humans: Assumed, based on similarities in systems
mediating the identified MOA across species
• MOA: Trigeminal nerve stimulation is likely to be the dominant
mechanism
• Other: This effect does not appear to worsen with longer exposure
durations, although uncertainties remain
aThe "appropriate exposure circumstances" are more fully evaluated and defined through dose-response analysis (see below).
1 3.1.6. Dose-response Analysis
2 Because of the rapid nature of the irritant response generated by inhalation of formaldehyde,
3 the studies considered to be the most informative for derivation of a cRfC were those where the
4 exposure assessment was concurrent with the outcome assessment. Data from studies in humans
5 involving residential populations with continuous exposure, as well as controlled human exposure
6 studies evaluating acute effects, were determined to be pertinent to the derivation of a cRfC.
7 Study selection
8 The high and medium confidence studies that included information about dose-response
9 relationships for sensory irritation are presented in Table 11, which indicates for each study whether the
10 study was used to develop a POD or the rationale for why the study was not suitable.
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Table 11. Eligible studies for POD derivation and rationale for decisions to not select
specific studies
POD
Rationale for decision
Reference
Endpoint
derived?
not to advance
(Hanrahan et al.. 1984)
Eye irritation: Prevalence
Yes
(Liu et al.. 1991)
Eye irritation: Prevalence
No
Incomplete reporting of modeling
results; provided support for
analyses using Hanrahan et al.
(Kulle et al.. 1987)
Eye irritation: Prevalence
Yes
(Andersen and
Eye irritation: Prevalence
Yes
Molhave. 1983)
(Mueller et al.. 2013)
Eye irritation: Tear film break-up time,
symptom score using visual analogue
scale (VAS)
No
An exposure-response trend was not
observed for either endpoint.
Difficult to define an adverse
response level cutoff for these
endpoints
(Lang et al.. 2008)
Eye irritation: Conjunctival redness,
blinking frequency, symptom score
No
Difficult to define an adverse
response level cutoff for these
endpoints and appeared to less
sensitive than symptom score
Derivation of PODs
The PODs and supporting information from the studies are presented in Table 12. Two studies
involving adults and children in a residential exposure setting, for which there was medium confidence,
presented results based on responses at multiple exposure levels, although only the study by Hanrahan
et al. (1984) provided the quantitative results of statistical analyses necessary for dose-response analysis
(Liu et al.. 1991; Hanrahan et al.. 1984). Hanrahan et al. (1984) used one-hour average formaldehyde
measurements taken in two rooms in the mobile homes of a group including teenagers and adults, and
presented the predicted concentration-response for prevalence of "burning eyes" experienced by the
participants since moving into the homes from a logistic regression model that adjusted for age, gender,
and smoking. The mathematical expression for the dose-response pattern and a BMCLio was
determined from a graph of the predicted prevalence and upper and lower 95% confidence bounds for
several concentrations between 100 and 800 ppb (0.12-0.98 mg/m3).1 The concentration
corresponding to a 13% prevalence of "burning eyes" was calculated from the model based on a 10%
increase in irritation as a result of formaldehyde exposure in addition to an assumed background
prevalence of 3%. The background prevalence of 3% was considered to be a reasonable estimate, but
the impact of using alternative estimates (1% and 2%) was evaluated and was found to be minimal.
PODs also were determined using two controlled human exposure studies of formaldehyde for
which there was medium confidence that evaluated multiple levels of exposure (Kulle et al.. 1987;
1EPA estimates that 44% of the average measured concentrations were below 100 ppb (see Appendix B.1.2 for modeling details
and supporting rationale).
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1 Andersen and Molhave. 1983). Kulle et al. (1987) evaluated results for participants exposed for 3 hours
2 once a week to five concentration levels (including a clean air exposure), while Andersen and Molhave
3 (1983) exposed subjects for 5-hour periods to four concentration levels with a 2-hour clean air exposure
4 prior to each trial. The occurrence of irritation symptoms during the clean air exposure was not
5 reported. Two sets of models were evaluated using the data from (Andersen and Molhave. 1983) and
6 estimates of 0% and 3% for prevalence of irritation during the clean air exposure. The BMC of 0.37
7 mg/m3 derived from the model using a baseline prevalence of 3% was selected.
8 Table 12. Summary of derivation of PODs for sensory irritation
Endpoint and
reference
Population
Observed effects by exposure level3
POD (mg/m3)
Residential exposure
Symptom prevalence
fHanrahan et al.,
1984;
Teenage and
adult (M and F),
n = 61
Third degree polynomial model fit to In prevalence odds
using presented results of logistic regression analysis: upper
95% confidence bound for predicted prevalence between
<0.123-0.98 mg/m3, BMCi0%: concentration where an
increased prevalence of 10% over a 3% background
prevalence is anticipated.
BMCiob 0.19
BMCLio 0.09c
Controlled human exposure
Symptom prevalence
CKulleetal., 1987)
Nonsmoking,
healthy, n = 10-
19, Mean age
26.3 yr,
(M and F)
Exposure
mg/m3
nd proportion responding
0 0.62 1.2 2.5 3.7
BMCio 0.85c
BMC/2d 0.42
%
trend, p <
Probit moc
5 0 26 53 100
0.05
el BMC = 0.69 ppm
Symptom prevalence
f Andersen and
Molhave, 1983]
Healthy students,
n = 16, age 30-33
years, 31.2%
smokers (M and
F)
Exposure
end of exp
mg/m3
nd percentage responding (prevalence at the
osure)
0.3 0.5 1.0 2.0
BMCio 0.37c
BMC/2d 0.19
%
Assuming
0% LogLog
3% LogLog
19 31 94 94
jrevalence for clean air dose
stic model BMC = 0.26 mg/m3
stic model BMC = 0.37 mg/m3
Concentrations reported in publication converted to mg/m3
bBMCio benchmark concentration at 10% increase in prevalence over estimated 3% background prevalence. An
increase of 10% was selected consistent with EPA guidelines (U.S. EPA, 2012) because the endpoint, burning eyes
with mild to moderate severity, was considered a minimally adverse outcome.
cThe POD was not adjusted for a 24-hour equivalent concentration because the timing of formaldehyde
measurements was concluded to be appropriate to the timeframe of reported symptoms.
dThe BMD models did not account for the correlated measures between concentration levels (each participant was
exposed to each concentration). Therefore the 95% confidence limit for the BMC estimated by the model is too
narrow to use as the POD. A factor of 2 was used to adjust the BMC to identify a lower estimate that
approximates the BMDL
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Derivation of cRfCs
Table 13 describes the uncertainty factors used to adjust the POD to derive the cRfC for each of
the three studies. For the cRfC for sensory irritation in adult (and teenage) populations (residential
exposures) in Hanrahan et al. (1984), a UFH of 10 was used. Although the study population in Hanrahan
et al. (1984) comprised randomly selected households in mobile homes with individuals representing a
range of age, gender, health behavior, occupational status, and health status, the identified PODs were
not based on evaluation of differential susceptibility among subgroups with conditions or characteristics
that may contribute to variation in response. For the controlled human exposure studies (Kulle et al..
1987; Andersen and Molhave, 1983), a factor of 10 was applied to account for variation in the broader
human population not represented by participants in controlled human exposure studies. No other
uncertainty factors greater than one were applied.
Table 13. Derivation of cRfCs for sensory irritation
Endpoint (reference; population)
POD
POD basis
UFa
UFh
UFl
UFS
UFd
UFcomposite
cRfC (mg/m3)
SENSORY IRRITATION
Eve irritation symptoms fHanrahan et
al., 1984); adult M+F, n = 61, residential,
prevalence at POD 13%)
0.09
BMCLio
1
10
1
1
1
10
0.009
Eve irritation symptoms fKulle et al.,
1987); adult M+F, n = 10, controlled
exposure)
0.42
BMC/2
1
10
1
1
1
10
0.04
Eve irritation symptoms f Andersen and
Molhave, 1983): adult M+F, n = 16,
controlled exposure)
0.19
BMC/2
1
10
1
1
1
10
0.02
Organ system-specific RfC (osRfC)
The POD was derived using the dose-response model using prevalence data from the residential
population in Hanrahan et al. (1984) is 0.09 mg/m3. The study by Hanrahan et al. (1984) is pertinent to
the U.S. general population because (1) the population was randomly selected from the general
population in the study area; (2) the exposure levels were concluded to reflect the usual, relatively
constant formaldehyde concentrations in the residences; and (3) exposed individuals included a range of
ages (teenagers and adults), men and women, some with chronic disease. Moreover, a significant
proportion of the study population was estimated to be exposed to average formaldehyde
concentrations below 0.05 mg/m3.
The PODs based on the two controlled human exposure studies were 0.19 and 0.42 mg/m3
(Kulle et al.. 1987; Andersen and Molhave. 1983), less than an order of magnitude greater than the
BMCL estimated from residential exposure. There is less confidence in the PODs based on these studies
because (1) the study participants were young, healthy volunteers, not representative of the age
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distribution and health status in the general population; (2) the PODs are based on small sample size,
more subject to random variation; and (3) formaldehyde concentrations were high, imposing substantial
uncertainty regarding responses at the low tail of the exposure distribution.
Therefore, the cRfC of 0.009 mg/m3 based on Hanrahan et al. (1984) was chosen as the osRfC for
sensory irritation. Confidence in the POD is medium because of uncertainties in the concentration
measurements relative to the study period for which the symptoms were being assessed. There is
extensive literature on this response to formaldehyde and the completeness of the database is high.
Because sensory irritation is an immediate response to exposure, the osRfC is applicable to short-term
as well as long-term exposure scenarios.
3.2. PULMONARY FUNCTION
Several studies in humans examined the effect of formaldehyde inhalation on pulmonary
function in various populations using different study designs. The systematic review process assigned
controlled human exposure studies of acute exposure involving healthy individuals to the review of
pulmonary function and the studies involving asthmatic volunteers to the review of effects on immune-
mediated conditions and their results are summarized there (see Section 1.2.3 of the Toxicological
Review). However, since all of these studies involved measurements of pulmonary function, the results
of the studies involving participants with asthma have been integrated with the evidence from studies of
acute exposure in healthy individuals in this section. The few animal studies of analogous endpoints (all
acute exposure) were not included in the hazard evaluation. Changes in pulmonary function measures
involving acute or intermediate-duration exposures have been evaluated using experimental study
designs (controlled human exposure studies), panel studies of medical school anatomy students, and
occupationally exposed populations. In addition, occupational groups with long-term exposures are
available, which compared effects in exposed groups to effects in referents using different exposure
metrics, such as time-weighted average (TWA) or cumulative measures. Population-based studies of
adults and children that analyzed cross-sectional associations with average indoor formaldehyde
concentrations also have been conducted. Generally, groups exposed to formaldehyde at work
experienced TWA concentrations above 0.2 mg/m3 with intermittent peaks above 1 mg/m3. Students
meeting once or twice a week in anatomy labs experienced fluctuating concentrations during dissections
averaging between 0.1 and >1.0 mg/m3. Formaldehyde concentrations in residential or primary school
settings are much lower and less variable (<0.1 mg/m3). EPA included both the higher exposure and the
lower exposure studies in its evaluation of pulmonary function effects.
Poor pulmonary function as well as a decrease in pulmonary function is an important health
endpoint, associated with the development of chronic respiratory disease, coronary heart disease, and
mortality (Clayton et al.. 2014; Menezes et al.. 2014; Young et al.. 2007; Sin et al.. 2005; Schroeder et al..
2003; Schunemann et al.. 2000; Sorlie et al.. 1989). Spirometric measures (the focus of this section) are
commonly used diagnostic criteria. EPA considered a decrease in mean values to suggest a shift toward
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a decline in the respiratory health status of the population. Consistent with this, the American Thoracic
Society (ATS) evaluated the clinical significance of small average declines in pulmonary function
observed in a population in response to air pollutants and concluded that although the magnitude of the
observed declines may not be clinically relevant to an individual, a shift in the population distribution
toward lower pulmonary function, assuming the association is causal, may have a large impact on public
health (ATS. 2000).
3.2.1. Literature Identification
This review focused on standard quantitative measures of pulmonary function (i.e., spirometry;
peak flow measurements). The bibliographic databases, search terms, and specific strategies used to
search them are provided in Appendix A.5.3, as are the specific PECO criteria and the methods for
identifying literature from 2016-2021 are described in Appendix F. Mechanistic studies relevant to
pulmonary function were separately identified (and evaluated) as part of the overarching review of
mechanistic data informing respiratory effects (see Appendix A.5.6 for additional details and supporting
analyses).
3.2.2. Study Evaluation
Forty-two observational epidemiological studies and eleven controlled human exposure studies
were evaluated for sources of bias and sensitivity. Pulmonary function is assessed using spirometry,
which measures the volume and speed of air that is exhaled or inhaled. Several parameters can be
measured during spirometric testing to characterize an individual's respiratory health. The
measurement of pulmonary function outcomes used by the studies in this section was considered to be
adequate if they followed the guidelines published by the American Thoracic Society (Tepper et al..
2012; Miller et al.. 2005a; Miller et al.. 2005b; Pellegrino et al.. 2005). or provided a description of the
protocols and reference equations that were used. In addition to the use of conventional spirometric
equipment to measure forced expiratory volume (FEVi), forced vital capacity (FVC), and forced
expiratory flow (FEF), peak expiratory flow (PEF) has been measured in research settings using portable
flow meters operated by study participants trained in their use. Although it requires careful training and
monitoring, this method has the advantage that it can be used in large epidemiological studies and
multiple measurements can be obtained over time. Studies of residential exposure to formaldehyde
were conducted in this way (Krzvzanowski et al.. 1990).
Lung function varies by race or ethnic origin, gender, age, and height, and is best compared
when normalized to the expected lung function based on these variables (Pellegrino et al.. 2005;
Hankinson et al.. 1999). Analyses were considered to be limited if they did not adjust or otherwise
account for these variables. Smoking status also was considered as a potential confounder. FEVi and
peak expiratory flow rate (PEFR) exhibit diurnal variation and this complicates the interpretation of
changes across a work shift or during a laboratory session if no comparisons were made with an
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unexposed group (Tepper et al.. 2012; Lebowitz et al.. 1997). Studies with no comparison group were
given less weight in evaluating the results of studies that measured short-term changes.
The healthy worker effect and survivor (lead time) bias was a concern for several cross-sectional
occupational studies, some of which had no other major limitations. Removal of individuals more
sensitive to the irritant effects of formaldehyde from jobs or tasks with formaldehyde exposure likely
occurred in industries with high formaldehyde exposures, and this type of selection bias might result in
an attenuation of risk estimates or a null finding if these individuals also experienced effects on
pulmonary function.
3.2.3. Synthesis of Human Health Effect Studies
While studies involving acute exposure either observed no change or inconsistent responses,
studies of occupational populations exposed over long periods and children exposed in residential
settings reported declines in pulmonary function. The controlled human exposure studies of healthy or
asthmatic volunteers consistently did not observe changes even at high concentrations, although two
studies by one research team observed small decrements (<5%) when longer exercise components (15
minutes) were included. Studies using shorter exercise components (8-10 minutes) reported no
changes. One exception among asthmatic participants was a heightened response to a dust mite
challenge in the formaldehyde inhalation arm compared to the clean air exposure in one study that used
nose clips, although a different study did not observe an increased response in a study with a similar
design but using a pollen challenge and no nose clip. Many of the studies of occupational groups or
anatomy students observed pulmonary function declines over the course of the work day or lab;
however, most did not account for diurnal changes, limiting the interpretation of these results. The few
studies of exposure during dissection labs that included an unexposed comparison group generally
reported that referent groups also experienced a change (increase or decrease) in pulmonary function.
A panel study using repeated peak expiratory flow measures taken by students trained in the procedure
at multiple points during dissection lab sessions found that PEF declined during the labs, and these
declines became attenuated over successive weeks (Kriebel et al.. 2001).
The review of the epidemiological literature provides evidence that long-term formaldehyde
exposure is associated with declines in pulmonary function, including FEVi, FVC, FEF, and PEF. Although
precision was low for most studies, pulmonary function was generally lower in highly exposed
occupational groups employed at exposed jobs for long durations compared to their nonexposed or
lesser-exposed comparison groups. The occupational groups under study were exposed to high average
formaldehyde concentrations (>0.2 mg/m3) in a variety of industries with different formaldehyde
sources. Employees had worked at these jobs for at least 5 years, and in a few studies, for more than 10
years. While a few studies conducted longitudinal analyses, most of the occupational studies were
cross-sectional in design, recruiting only current employees, and likely were limited by lead time bias, a
selection bias that results in attenuated effect estimates.
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Three studies conducted longitudinal analyses of small groups of workers with continued
exposure over 4-6 years (Lofstedt et al.. 2011; Nunn et al.. 1990; Alexandersson and Hedenstierna,
1989). For FEVi (only one study tested multiple parameters), all the longitudinal studies reported no
change in the full cohorts over the study period; however, one (Nunn et al.. 1990) reported that among
exposed nonsmokers, the annual decline was -45 mL/year (95% CI: -28, -62 mL/year), which is 50%
greater than the expected rate of decline in FEVi in nonsmokers [29 mL/year; (Redlich et al.. 2014; Lee
and Fry, 2010)1. In addition, Alexandersson and Hedenstierna (1989) reported a decline in FEF25-75 at a
TWA concentration of 0.42-0.5 mg/m3, with FEF25-75 percentage declining by -168 ± 46 mL/second
(10.1 L/minute) for each year of exposure over a 5-year period (p < 0.001). The annual decrease was
corrected for normal aging and reference pulmonary function spirometry values. Consistent with the
results for FEVi, there was a larger decrease among nonsmokers compared to smokers, likely reflecting
the already reduced FEVi in smokers (-212 mL/sec/yr and -60 mL/sec/yr, respectively).
The longitudinal studies were limited with respect to duration of follow-up and sample size.
Given the large amount of within-person variability in these measures when assessed over time, these
studies would have had limited sensitivity to detect a small longitudinal change. Loss to follow-up of
exposed participants with symptoms also was evident. This type of selection bias also could result in an
attenuated effect estimate. Overall, the longitudinal analyses appear to be inconsistent, but while
hindered by a lack of sensitivity, seem to support a conclusion that occupational exposure may result in
declines in FEVi and FEF overtime.
Most of the occupational studies adjusted for smoking in statistical analyses or otherwise
addressed potential confounding by smoking, and two studies found no correlation between pulmonary
function measures and cigarette smoking indicating that smoking was not a confounder in the cohorts
(Malaka and Kodama, 1990; Holmstrom and Wilhelmsson, 1988). Potential confounding by coexposures
is an uncertainty for this review. However, many independent associations with formaldehyde for one
or more pulmonary function measures were found using statistical models that addressed potential
confounding (e.g., dust), and, since a pattern of reduction in pulmonary function was observed across
several different exposure settings (all involving high formaldehyde exposure), confounding by a
coexposure becomes less compelling as an alternative explanation for the observed associations.
Results among four studies of residential exposure among adults are difficult to compare
because different methods were used to assess pulmonary function and two of the studies did not
report results quantitatively (Norback et al.. 1995; Broder et al.. 1988). A cross-sectional study of
residential formaldehyde exposure in a large, randomly selected sample in Arizona observed an
association with declines in PEFR among adult smokers at formaldehyde concentrations between 0.049
and 0.172 mg/m3, but not among the group as a whole (Krzyzanowski et al.. 1990). Another study
among elderly nursing home residents observed an elevated risk of low pulmonary function defined as
values falling in the lower 20% of the distribution associated with formaldehyde concentrations above
the median level measured in each nursing home [overall median and range: 0.007 mg/m3 and
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0.001-0.021 mg/m3; (Bentaveb et al.. 2015)1. Two additional studies in primarily adult residential
populations exposed to concentrations between 0.009 and 0.279 mg/m3 reported no associations,
although the outcomes evaluated by each study were not equivalent (Norback et al.. 1995; Broder et al..
1988).
There are few studies of residential exposure among children; however, Krzyzanowski et al.
(1990) found a clear dose-response relationship among the children in their Arizona study where most
household concentrations were less than 0.045 mg/m3. A linear relationship between increased
formaldehyde exposure and decreased PEFR among children exposed to average concentrations of
0.032 mg/m3 was reported by this large, population-based, cross-sectional study of residential
formaldehyde exposure. The investigators reported a statistically significant decrease of
-1.28 ± 0.46 L/minute in PEFR per ppb household mean formaldehyde for all children. Figure 6 shows
the incremental decrement in PEFR measured at bedtime versus morning and shows differences in the
morning among asthmatics and nonasthmatics. Asthmatic children (15.8% of the total) showed a
steeper decline in PEFR in the morning at formaldehyde concentrations less than 0.049 mg/m3 (40 ppb).
The analysis of multiple PEFR measurements for each individual resulted in an increased statistical
power to detect an association at the lower formaldehyde levels present in the homes. The statistical
model adjusted for potential confounders including asthma status, smoking status, SES, N02 levels,
episodes of acute respiratory illness, and the time of day. Two other studies among children exposed to
similar levels of formaldehyde, but with limitations that reduced their sensitivity, did not find an
association for either FVC or FEVi (Wallner et al.. 2012; Franklin et al.. 2000).
HCHO (ppb)
Figure 6. Association of PEFR measured at bedtime and in the morning with
household mean formaldehyde concentration among children less than 15 years of
age (Krzyzanowski et al.. 1990).
Reproduced with permission.
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3.2.4. Mode-of-action Information
There is mechanistic support, primarily from studies in animals, although a definitive MOA(s) has
not been fully defined (see Figure 7; see Appendix A.5.6 for additional details, related analyses, and
discussion). Overall, the most relevant mechanistic events included inflammatory structural alterations
and eosinophil increases in the lower airways that appear to be at least partially related to indirect
activation of sensory nerve endings. Inflammatory changes in the lower airways are supported most
directly by evidence from short-term studies of rodents at 0.3-2.5 mg/m3 formaldehyde (Fujimaki et al..
2004; Riedel et al., 1996), although indirect effects (e.g., biomarkers of airway oxidative stress) at lower
levels have been suggested in human studies (Flamant-Hulin et al.. 2010; Franklin et al., 2000).
However, the initial cellular or tissue modifications that ultimately lead to these later events are not
understood, and it is unclear whether and to what extent certain events would be triggered with
chronic, low-level exposure. Although other important mechanistic events would likely be identified
with additional study, the available data provide reasonable support for the biological plausibility of the
observed associations and identify what is likely to be an incomplete mechanism by which formaldehyde
inhalation could cause decreased pulmonary function. Variation in sensitivity is likely to be affected by
underlying respiratory health status.
o-
->!
O O O
^oxidative Sensorynerve 'f'LRT neuro- "f* LRT micro- 1s Eosinophils ^ airway edema/ Decreased pulmonary
stress in LRT stimulation in LRT peptides vascular leakage in LRT* inflammatory function
structural change*
h ¦& o
URT protein/ DNA oxidative "t1 URT URT mucociliary URT epithelial
modification stressinURT neuropeptides dysfunction damage
Mucus membrane Decreased pulmonary
change in URT function
Legend
^ Plausibly an initial
effect of exposure
EVIDENCE
Q Robust
( ) Moderate
Key feature of decreased
pulmonary function { J Slight
RELATIONSHIP
Robust
Moderate
Slight
*effects are amplified
with allergen exposure
Figure 7. Possible mechanistic associations between formaldehyde exposure and
decreased pulmonary function.
An evaluation of the formaldehyde exposure-specific mechanistic data informing the potential for
formaldehyde exposure to cause respiratory health effects identified these sequences of mechanistic
events as those most directly relevant to interpreting effects on pulmonary function. Evidence of airway
inflammatory changes, including eosinophil recruitment to both the upper and lower respiratory tract
(URT and LRT; upper pathway), is considered as likely to represent an incomplete mechanism by which
formaldehyde inhalation could cause decreased pulmonary function, although whether certain events
occur at lower exposure levels is unclear, and other unexplored mechanistic events are expected to
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contribute. URT modifications, primarily structural changes (bottom pathway), may also contribute;
however, this is not interpreted as likely to be a significant contributing mechanism.
1 3.2.5. Overall Evidence Integration Judgment and Susceptibility for Pulmonary Function
2 Overall, based on the moderate human evidence from observational epidemiological studies, as
3 well as slight animal evidence from mechanistic studies supporting biological plausibility, the evidence
4 indicates that long-term inhalation of formaldehyde likely causes decreases in pulmonary function in
5 humans given appropriate exposure circumstances (see Table 14). The primary basis for this conclusion
6 includes a study of children and adults in a residential setting (mean, 0.03 mg/m3, maximum 0.17
7 mg/m3) and several studies of workers with long-term exposure to >0.2 mg/m3. The evidence is
8 inadequate to interpret whether acute or intermediate-term (hour to weeks) formaldehyde exposure
9 might cause this effect.
10 Table 14. Evidence integration summary for effects on pulmonary function
Evidence
Evidence judgment
Hazard determination
Long-term Exposure (years)
Human
Moderate for Lona-Term Exposure (years), based on:
Human health effect studies:
• 1 high and two medium confidence studies in residential and school
populations indicating that susceptible individuals may experience
reduced pulmonary function at lower average concentrations
(<0.05 mg/m3).
• Numerous high and medium confidence studies showing a pattern of
reduced mean pulmonary function in formaldehyde-exposed occupational
groups across a variety of exposure settings and countries. However,
some inconsistencies were noted for specific measures; possible
explanations may be random variation and low study sensitivity.
• Concentration-related associations from four high and medium
confidence adjusted analyses indicate an independent association for
formaldehyde exposure suggesting confounding is not an alternative
explanation.
• Longitudinal declines were reported for one occupational population and
a panel study of medical students, but null or equivocal associations were
identified from other studies, all with possible differential loss to follow-
up and low sensitivity.
Biological Plausibility:
Some indirectly supportive mechanistic information from well-conducted
human studies exists related to increased lower airway oxidative stress
following exposures likely to span months to years.
The evidence indicates that
long-term inhalation of
formaldehyde likely causes
decreased pulmonary function
in humans given appropriate
exposure circumstances3
Primarily based on a study of
children and adults in a
residential setting (mean,
0.03 mg/m3, maximum
0.17mg/m3) and several studies
of workers with long-term
exposure to >0.2 mg/m3
Potential Susceptibilities:
Variation in sensitivity is
anticipated to depend on age
and respiratory health, with the
potential for children to be
more sensitive.
Animal
Slight, based on:
Biological Plausibility:
Robust and moderate evidence for several mechanistic events, primarily
from experimental animal studies, provides support for inflammatory
changes in the lower airways, including eosinophil increases, which appear
to be at least partially dependent on indirect stimulation of sensory nerve
endings. While evidence exists for some changes in the range of
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0.3-0.5 mg/m3 with exposure for several weeks, some potential associations
in the identified, incomplete MOA pathway have only been tested at higher
(i.e., >1 mg/m3) levels and with shorter-term exposures.
Animal health effect studies: Not formally evaluated.
Other
inferences
Relevance to humans: The observed mechanistic changes are expected to
occur in humans, given similarities across species in the systems that appear
to be involved, and some support is based on studies in both humans and
animals (e.g., lower airway oxidative stress).
MOA: Not established, but likely to involve airway eosinophil increases and
stimulation of airway sensory nerve endings.
Acute or Intermediate-Term Exposure (hours to weeks)
Humans
Indeterminate for Acute or Intermediate-Term Exposure (hours to weeks),
based on:
Human health effect studies:
Small reductions in two controlled human exposure studies of healthy
volunteers (1 lab) with longer exercise periods (15 min), but no associations
with other exposure protocols (including those with <10 min exercise
periods) in studies involving healthy subjects or asthmatics (see discussion
above and Section 1.2.3 for pulmonary function results in asthmatics);
inconsistent results among studies of medical school dissection labs and
cross-shift measurements in occupational studies.
Biological Plausibility: Increases in lower airway eosinophils were not
observed in the few low confidence acute studies in humans available.
The evidence is inadequate to
draw judgments regarding acute
or intermediate-term exposure
(hours to weeks)
Animals
Indeterminate, based on:
Biological Plausibility: Although some mechanistic changes relevant to
pulmonary function, including most of the immunogenic effects, were
altered after short-term exposure in animals, given the dependence of some
of the key mechanistic events (e.g., URT damage or dysfunction; LRT
oxidataive stress) on exposure duration, it remains unclear whether the
potential mechanistic pathways would be relevant to interpreting acute or
short-term exposure scenarios.
Animal health effect studies: Not formally evaluated.
aThe "appropriate exposure circumstances" are more fully evaluated and defined through dose-response analysis (see below).
1 3.2.6. Dose-response Analysis
2 Study selection
3 The high and medium confidence studies that included information about dose-response
4 relationships for decreased pulmonary function are presented in Table 15, which indicates for each
5 study whether the study was used to develop a POD or the rationale for why the study was not suitable.
6 Table 15. Eligible studies for POD derivation and rationale for decisions to not select
7 specific studies
Reference
Endpoint
POD derived?
Rationale for decisions to not select
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Krzyzanowski et al.
(1990)
PEFR
Yes
Malaka and Kodama
(1990)
FEVi, FEF25-75
No
Incomplete reporting of modeling results
Kriebel et al. (2001)
PEFR
No
Difficult to use modeling results because of
covariance in model coefficients
Wallner et al. (2012)
FEF25-75
No
Incomplete reporting of modeling results
Derivation of PODs
Declines in PEFR were associated with increases in 2-week average indoor residential
formaldehyde concentrations, with greater declines observed in children (5-15 years of age) compared
to adults (Krzyzanowski et al.. 1990). This study of effects in a residential population used the most
thorough exposure assessment protocol and repeated measurements of PEFR, thus enhancing the
ability to detect an association at lower concentrations. Mean formaldehyde levels were 26 ppb
(0.032 mg/m3), and more than 84% of the homes had concentrations 40 ppb (0.049 mg/m3) and lower.
A BMCio of 0.033 mg/m3 and a BMCLio of 0.021 mg/m3 were determined from the regression coefficient
from a random effects model of PEFR among children with and without asthma reported by the study
authors. Table 16 summarizes the study and the derivation of the POD for pulmonary function.
Table 16. Summary of derivation of PODs for pulmonary function
Endpoint and
reference
Population
Results by exposure level3
BMC and BMCL
(mg/m3)
PODADJb
(mg/m3)
PEFR
fKrzvzanow
ski et al.,
1990;
Residential,
prevalence
202 households, 298 children
aged 5-15 yrs, current asthma
prevalence 15.8%;
613 adults and adolescents >15
yr, 24.4% current smokers,
current asthma prevalence
12.9%
Random effects model; decreased PEFR,
children
-1.28 ± 0.46 L/min-ppb (95% upper bound
-2.04 L/min-ppb)
Formaldehyde concentrations: Mean
0.032 mg/m3, maximum 0.172 mg/m3
BMCioc 0.033
BMCLio 0.021
0.021
Concentrations reported in publication converted to mg/m3.
bThe POD was not adjusted for a 24-hour equivalent concentration because formaldehyde is present in all indoor
environments and time-activity information for participants was not reported.
cBMCio benchmark concentration at 10% increase in prevalence over background prevalence. A BMR of 10%
reduction in PEFR was selected as a cut-off point for adversity, based on rationales articulated by the American
Thoracic Society (see Appendix B.1.2 for details on the rationale).
Derivation ofcRfCs
Table 17 describes the uncertainty factors used to adjust the POD and the resulting cRfC. For
the POD for decreased PEFR among children from Krzyzanowski et al. (1990). a UFH of 3 was used with
support from the model results reported by the authors. While the BMC was defined as the
concentration where a 10% decrease in PEFR among all the children in the study was predicted to occur,
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the model results also predicted the degree of response among asthmatic and healthy children.
Multiple observations in the study indicate that a UFH of 3 applied to the endpoint can be expected to be
protective of asthmatic children and other susceptible individuals. EPA used the published regression
coefficients from the random effects model to calculate the predicted decrease in PEFR from the
baseline level (i.e., formaldehyde concentration equal to zero) for each group. At the BMC
corresponding to a 10% decrease overall (0.033 mg/m3), the asthmatic children experienced a
decrement in PEFR that was 1.5-fold greater than that of the nonasthmatic children. Further, at the
BMCL selected as the POD (0.021 mg/m3), the decrease in PEFR among asthmatic children was 10.5%
while that in nonasthmatic children was 7.2%, a 1.5-fold difference. The authors stated that other
characteristics affecting variability, such as acute respiratory illness episodes during the observation
period, environmental tobacco smoke in the home, or socioeconomic status, did not increase sensitivity.
These observations indicate that a UFH of 1 is not appropriate since the asthmatic children experienced a
larger decline in PEFR compared to the healthy children. However, a UFH of 3 can be expected to be
protective of asthmatic children and other susceptible individuals.
Table 17. Derivation of the cRfC for pulmonary function
Endpoint (reference; population)
POD
POD basis
UFa
UFh
UFL
UFS
UFD
UFcomposite
cRfC (mg/m3)
PULMONARY FUNCTION
Peak expiratory flow rate
^Krzvzanowski et al., 1990];
Children M + F, n = 298, residential)
0.021
BMCLio
1
3
1
1
1
3
0.007
Selection of osRfCs
The cRfC for pulmonary function of 0.007 mg/m3 (Krzvzanowski etal.. 1990) was chosen as the
osRfC. This population-based study used a thorough exposure assessment based on two-week average
measurements in multiple rooms and two different seasons. Hence, confidence in the POD value is
high. The hazard conclusion is based on several studies in diverse exposure settings, and the
completeness of the database is considered high.
3.3. IMMUNE-MEDIATED CONDITIONS, FOCUSING ON ALLERGIES AND ASTHMA
This section examines the evidence pertaining to the effect of formaldehyde exposure on
immune-mediated responses, primarily in the respiratory system, including allergy-related conditions
(e.g., rhinitis; rhinoconjunctivitis) and asthma; sensitization related to dermal exposure is not a focus of
this review. Epidemiological studies have investigated potential associations between formaldehyde
and outcomes relevant to various exposure durations and time windows in children and in adults using
formaldehyde measurements conducted in occupational, residential, and school-based settings. A few
studies described other respiratory conditions in infants and toddlers, but these outcomes were not the
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focus of the review. Controlled human exposure studies also are available that evaluated pulmonary
function responses to formaldehyde among subjects with asthma, but their results are most informative
to the pulmonary function outcome and are included in the integration of evidence in that section (see
Section 1.2.2). Only two of these studies are relevant to the evaluation of effects on immune-related
endpoints; these studies assessed responses to an allergen challenge during formaldehyde exposures:
dust mite in Casset et al. (2006) and grass pollen in Ezratty et al. (2007). While exposures were high in
occupational settings (>0.1 mg/m3), formaldehyde concentrations measured in schools and homes
averaged between 0.03 and <0.1 mg/m3.
Experimental animal studies were ultimately concluded to be unsuitable models (indeterminate)
for evaluating allergy-related conditions and asthma as apical endpoints. However, in the context of the
health effects data available, these findings, as well as a few studies that indirectly suggest that
respiratory immune function could be affected by formaldehyde exposure, are discussed within the
wider context of potential mechanistic changes that might explain respiratory health hazards.
3.3.1. Literature Identification
The focus of this search was on studies with a direct measure of formaldehyde exposure in
relation to measures of allergic respiratory conditions, eczema, or current asthma, reflecting the
question of whether formaldehyde exposure influences the sensitization response to respiratory
allergens. The bibliographic databases, search terms, and specific strategies used to search them are
provided in Appendix A.5.4, as are the specific PECO criteria and the methods for identifying literature
from 2016-2021 are described in Appendix F. Additionally, mechanistic studies relevant to immune-
mediated conditions, including potential immunological changes in distal tissues and blood, were
separately identified (and evaluated) as part of the overarching review of mechanistic data informing
respiratory effects (see Appendix A.5.6 for additional details and supporting analyses). Ultimately (see
Section 1.2.3 of the Toxicological Review for details), the animal hypersensitivity studies were included
as part of the overarching review of respiratory system-related mechanistic information (see Appendix
A.5.6) rather than as apical health effect studies; thus, they provided information about potential
mechanisms for the reviewed outcomes in the human studies.
3.3.2. Study Evaluation
The category of allergic sensitization and allergies includes allergic sensitization based on skin
prick tests and history of allergy-related symptoms. Because the time windows for exposure
assessments used in the studies had uncertain relevance to when sensitization may have occurred,
lower confidence was placed in the results of skin prick tests for studies in adults than in children (these
studies are not discussed in this Overview). For symptoms, International Study of Arthritis and Allergies
in Children (ISAAC) questionnaires for rhinitis or rhinoconjunctivitis were considered to provide an
adequate basis for case ascertainment in studies in Europe and the United States; in studies in other
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areas (i.e., areas that have not been included in ISAAC), specific mention of validation of the
questionnaire was needed to receive a high confidence rating.
Studies that ascertained asthma outcomes using American Thoracic Society (ATS)-based
questionnaires or subsequent variations [ISAAC, European Community Respiratory Health Survey
(ECHRS)] for prevalence of current asthma that include questions on medication use and symptoms
were considered to provide an adequate basis for case ascertainment in studies in Europe and the
United States; in studies in other areas (i.e., areas that have not been included in ISAAC), specific
mention of validation of the questionnaire was needed to receive this level of confidence. Some studies
included results for more than one asthma measure; in this assessment, outcomes that were defined
over a recent period were included (e.g., symptoms in the past 12 months), but outcomes defined over
a lifetime (e.g., ever had asthma) were not, as the formaldehyde measures available do not reflect
cumulative exposures that could be related to cumulative risk. Studies that did not clearly delineate the
period of ascertainment were included, but lower confidence was placed in these studies.
The age of study participants is an important consideration in the interpretation of various
measures. Specificity of symptom questions is reduced in the very young (<5 years) because wheezing
can occur with respiratory infections in infants and young children, and specificity is reduced at older
ages (e.g., >75 years) because of the similarities in symptoms and medication use for chronic obstructive
pulmonary disease and asthma (Abramson et al.. 2014; Taffet et al.. 2014). Rumchev et al. (2002), a
study of emergency room visits for asthma in children ages 6 months to 3 years, and two other studies
that examined wheezing episodes among infants (Roda et al.. 2011; Raaschou-Nielsen et al.. 2010). were
thus classified as not informative with respect to asthma.
The evaluation of controlled exposure studies of responses among asthmatic subjects examined
four primary elements: the type of exposure (paraformaldehyde preferred over formalin or undefined
test articles), use of randomization procedures to allocate exposure, blinding of the participant and of
the assessor to exposure, and the details regarding the analysis and presentation of results.
3.3.3. Synthesis of Human Health Effect Studies
Allergic conditions and sensitization
The general population studies in children and adults provide evidence of an association
between formaldehyde exposure and prevalence of rhinitis or rhinoconjunctivitis (Figure 8). The
exposure range was similar in these studies (0.04-0.06 mg/m3) and estimated RRs were comparable for
rhinitis endoints ranging from 1.14 to 1.21 for comparisons of the higher exposed to the referent
groups. These studies were conducted in school children in France (Annesi-Maesano et al.. 2012),
Romania (Neamtiu et al.. 2019). and Korea (Yon et al.. 2019). and in adults in France (Billionnet et al..
2011) and Japan (Matsunaga et al.. 2008). The classification of rhinoconjunctivitis by Annesi-Maesano et
al. (2012) is the most sensitive and specific of the measures, and the narrower confidence intervals in
this study reflect the larger sample size. No other pollutants (e.g., NOx, PM2.5, acetaldehyde, acrolein,
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and environmental tobacco smoke) analyzed by this study were associated with rhinoconjunctivitis.
Although the effect size is small, these are relatively common conditions and could result in a large
impact in the population. A stronger association with formaldehyde inhalation (2-fold risk) was seen in
the only study of atopic eczema (Matsunaga et al.. 2008). Eczema, while not indicative of an allergic
respiratory response, is often associated with other allergic disorders, including those affecting the
respiratory system. Consistent results are seen in studies in both children and adults in school and
residential settings (see Figure 8). Two of the studies had sufficient sample size and range of exposure
to examine dose-response patterns and observed the highest relative risk estimates in the highest
exposure groups. Further, an analysis by categories of rhinitis severity in children observed a statistically
significant increasing trend in risk (Yon et al.. 2019). Two population-based studies evaluated atopy
based on skin prick tests (Garrett et al.. 1999; Palczynski et al.. 1999), but confidence in these analyses
was lower than for the studies of allergy symptoms. It was not certain that the time frame represented
by the exposure measurements were relevant to the development of sensitization as measured by skin
prick tests. Overall, the evidence indicates that formaldehyde exposure at levels seen in the general
population studies can enhance the immune hypersensitivity response to allergens.
A, Highest Exposure Group per Study
Children
Norback et al. 2017 -|
O
Formaldehyde Levels (mg/m3)
Total Approximate Referent RR
Norback et al. 2017-
(rhinitis)-
Neamtiu et al. 2019-
(eye, nose and skin symptoms) -
Yon et al. 2019-
(rhinitis)-
Arincsi Marsano et al, 2012 -
(rhinoconjunctivitis) -
Adults
BHHonnet et al. 2001 -
(rhinitis)-
Matsunaga et al* 2008 -
(rhinitis) -
(eczema) -
No quantitative results reported;
Reported no association
N
Midpoint
462
0.004
Per unit mg/m3
280
0.045
<0.035
3.23
246
0.027
Per 0.01
1.21
mg/m3
6,683
0.044
<0.019
1.19
916
0.06
<0.028
1.14
998
0.07
<0.058
1.22
998
0.07
<0.058
2.25
0.4
4 5
10
Figure 8. Relative risk estimates for prevalence of allergy-related conditions in
children and adults in relation to formaldehyde in residential and school settings.
High and medium confidence studies are depicted for rhinitis (diamond) and eczema (circle) and symptom
combinations (square). Open symbols are for studies in children; closed symbols are for studies in adults.
Results from the highest exposure group in each study are depicted.
Asthma
The available general population studies also provide evidence of an association between
formaldehyde exposure and prevalence of current asthma, as determined by symptoms or medication
use in the past 12 months in studies with higher exposures (e.g., above 0.05 mg/m3), but associations
are not seen in settings with a lower exposure range (see Figure 9). The six medium or high confidence
studies in homes or schools with relatively low exposures (<0.05 mg/m3, most from approximately
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0.02-0.04 mg/m3) report relative risks around 1.0. This set of studies includes a variety of designs and
populations; the school-based studies are relatively large (from 1,014 to 6,683 total participants). Six
medium confidence general population studies in children or adults where a proportion of the study
sample had exposures of 0.05-0.1 mg/m3 were available. Two of these included both children and
adults (Zhai et al.. 2013; Krzvzanowski etal.. 1990). and each provides evidence of a greater
susceptibility in children. A limitation of the Krzyzanowski et al. (1990) analysis is the relatively small
number in the highest exposure group (n = 21). The summary RR in children calculated for this review
combining these two studies was 4.5 (95% CI: 0.76, 27). One other study of children (mean age 10
years) was a hospital-based case-control study that calculated an OR of 2.74 per quartile increase in
formaldehyde concentration (95% CI: 1.098, 5.516) using a more specific diagnosis for prevalent asthma
including symptoms over the previous 3 or more months, and an FEVi increase of 15% in response to IB-
agonist inhalation (Liu et al.. 2018). Exposure levels in the highest quartile ranged from 0.05 to 0.14
mg/m3. Of note, a Canadian intervention study of impacts on symptom exacerbation among asthmatic
children from increasing ventilation rates in homes reported that a 50% reduction in formaldehyde
concentrations in the bedroom was associated with a 14 to 20% decrease in the annual change in some
symptoms or medical care in the intervention group (Laioie et al.. 2014). However, other coexposures
also were reduced by the intervention resulting in uncertainty in the independent effect of
formaldehyde, although the reductions were to a lesser extent and separate effects of the other factors
were not analyzed. Two other medium confidence studies with exposures above 0.05 mg/m3 were
conducted only in adults (Billionnet et al.. 2011: Matsunaga et al.. 2008): EPA has lower confidence in
the results of Matsunaga et al. (2008) because of the lower sensitivity and specificity of the asthma
ascertainment (self-report of medication use for asthma). The pattern of results is indicative of an
elevated risk, as none of the point estimates are below 1.0; however, the confidence intervals around
each of the estimates is relatively wide.
Relatively strong associations were seen in three studies examining prevalence of current
asthma in relation to formaldehyde exposure in occupational settings (i.e., >0.10 mg/m3). A greater
than 3-fold increased risk of asthma was seen in each of these studies; the summary RR calculated for
this review was 3.79 (95% CI: 1.98, 7.28). One of the wood worker studies addressed potential
confounding by dust exposure by the inclusion of this variable in the analysis (Malaka and Kodama,
1990), and another study specifically noted that the measured dust levels were not related to high
formaldehyde exposure and that the asthma symptoms were not strongly related to other exposures
(Fransman et al.. 2003). The results from these studies may represent underestimates of risk, primarily
because these were prevalent cohorts with 2 or more years of work duration who would have lost
affected individuals prior to the study. In addition, in two of the studies, the comparison group included
workers who may have also been exposed to formaldehyde or other respiratory irritants, resulting in an
underestimate of the relative risks (Fransman et al.. 2003; Herbert et al.. 1994). Overall, given the
strength of the relative risks, the consistency of the associations seen in the three different workplaces
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1
2
3
and populations, and the likelihood that the observed associations were underestimates of the true
associations, these studies collectively support a strong association between formaldehyde
concentrations above 0.10 mg/m3 in occupational settings and increased prevalence of current asthma.
A. General Population, Low Exposures (< 0.050 mg/m )
Children
Palczynski et al., 1999-
Venn et al,, 2003-
Annesi-Maesano et al., 2012-
Mi et al., 2006-
Kim et al., 2011-
Adults
Palczynski et al., 1999-
Matsunaga et al., 2008-
0.5 1
10
B. General Population, High Exposures (> 0.050 mg/m )
Children
tiu et al, 2018-
Zhaietal., 201 J-
Krzyzanowski et al., 1990-
Adults
Zhai et al., 2013 -
Krzyzanowski et at., 1990-
Billionnet et al. 2001 -
Matsunaga et at., 2008-
Formaldehyde Levels (mg/m3)
Total Approximate
N Midpoint Referent
Not calculated <0% in referent)
Reported as "not significantly related" but
rate of wheeze "somewhat higher" with
higher exposure
187
0.037
<0.025
0.98
190
0.019
<0.016
1.14
0.027
1.08
0.041
1.04
6,683
0.025
<0.019
1.10
0.044
0.90
1,414
0.010
per 0.010 mg/m3
1.30
1,028
0.030
per 0.010 mg/m3
1.04
278
0.037
<0.025
0.72
998
0.028
<0.022
0.80
0.046
0.72
Formaldehyde Levels (mg/m3)
Total
Approximate
N
Midpoint
Referent
RR
360
0.05
per q uartile
2.74J
82
0.115
<0.08
12
298
0.09
<0.049
2
186
0.115
<0.08
613
0.09
<0.049
916
0.046
<0.028
1.43
998
0.07
<0.058
2.65
4
5
6
C. Occupational Settings (> 0.01 mg/m3)
Herbert et al., 1394-
Fransman et al. 2003 (all)-
(duration > 6.5 years)-
(>0.080 mg/m3)-
Malaka and Kodama, 1990-
0.5 1 2 5 10
Relative Risk
50
Total
N
Formaldehyde Levels (mg/m3)
Approximate
Midpoint Referent
RR
99
0.20
<0.08
12
112
0.08
<0.049
1.5
0.08
<0.08
3.1
0.16
<0.049
4.3
93
0.12
<0.058
2.65
Figure 9. Relative risk estimates for prevalence of asthma in children and adults in
relation to formaldehyde by exposure level in general population and occupational
studies.
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High and medium confidence studies in the general population with highest exposure categories at
midpoints of <0.05 mg/m3 (Panel A) and >0.05 mg/m3 (Panel B), and occupational populations with
exposures >0.1 mg/m3 (Panel C). Lajoie et al. (2014) was not included in the figure because the study
assessed percent change in current asthma symptoms over 12 months, not relative effect.
Levels for most of the participants in the study groups in Panel A, low exposure, were < 0.05 mg/m3. The
exposure value for Liu et al. (2018) is the 75% percentile concentration, which resulted in classifying the
study as high exposure. Exposure levels in Billionnet et al. (2011) ranged to a maximum of 0.09 mg/m3,
which resulted in classifying the study as high exposure. Effect estimates are RR or OR.
Two studies examined symptom frequency and medication use in the past 4 weeks, a measure
of asthma control among children with asthma. This population could represent a group with greater
susceptibility or vulnerability than the general population. Venn et al. (2003) reported a 2- to 3-fold
increased risk of frequent symptoms associated with the highest quartile of exposure (>0.032 mg/m3)
compared with <0.016 mg/m3, with some evidence of an increased risk at even lower exposures. For
nighttime symptoms, which may be most relevant with respect to measurements taken in the bedroom,
the relative risk estimate was 3.33 (95% CI: 1.23, 9.02). The case definition of wheezing during the past
year is interpreted as relevant to the definition of current asthma as used in this assessment, since 88%
of the cases also reported using a reliever inhaler in the past year. These results were not impacted by
inclusion of measures of room dampness in the models. In a smaller study of 37 low-income children in
Boston, Dannemiller (2013) observed higher formaldehyde levels in homes of children with poor asthma
control compared to those with better asthma control (geometric mean 0.066 and 0.042 mg/m3,
p = 0.078).
Most of the acute formaldehyde exposure studies among adults with asthma provide little or no
evidence of short-term effects; no controlled exposure studies have been conducted in children with
asthma. Only two of these studies included an assessment of the response to an allergen challenge,
with effects on FEVi observed in one study (Casset et al.. 2006) but not the other (Ezratty et al.. 2007).
One difference in these studies is that the Casset et al. (2006) protocol used a nose clip, thus resulting in
inhalation solely by mouth.
3.3.4. Mode-of-action Information
The mechanistic information that may inform the potential for formaldehyde to affect allergic
conditions or asthma includes animal models using ovalbumin as an experimental allergen, which can
provide insight into some of the mechanistic changes that are relevant to these human conditions, while
not fully capturing the phenotype of human asthma or allergy-related conditions (see Section 1.2.3 of
the Toxicological Review for details on the decision to use animal hypersensitivity studies as mechanistic
support). The mechanistic evidence that provides the most direct information regarding the potential
role of formaldehyde in respiratory hypersensitivity responses consists of a set of high or medium
confidence studies (Larsen et al.. 2013; Fujimaki et al.. 2004; Ito et al.. 1996; Riedel et al.. 1996;
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Swiecichowski et al.. 1993).2 These studies differed in the conditions under which formaldehyde
affected the relevant endpoints, specifically increased bronchoconstriction and airway
hyperresponsiveness, using short-term and acute exposures in sensitized and nonsensitized animals.
The data do not indicate that formaldehyde is itself immunogenic, but instead suggest that
formaldehyde may augment immune responses to other allergens.
As shown in Figure 10, the analysis identified several pathways describing potential associations
between the most relevant mechanistic data available, with several of the initial or early events in these
hypothesized pathways (e.g., oxidative stress and inflammatory changes) generally observed to occur at
lower formaldehyde levels than other downstream changes (see Appendix A.5.6 for additional details,
related analyses, and discussion). The mechanistic evidence indicates that formaldehyde exposure can
induce bronchoconstriction and lead to the development of hyperresponsive airways,3 particularly with
allergen sensitization. These heightened responses may be due to a combination of potentially
progressive changes, including neurogenic increases in tachykinins and eosinophil recruitment and
activation in the lung; however, there was an absence of reliable data supporting mechanistic changes
that are typically thought to be essential for sensitization (e.g., IgE). The mechanistic studies also
provide consistent evidence that formaldehyde may stimulate a number of immunological and
neurological processes related to asthmatic responses; however, a molecular understanding of how
formaldehyde exposure favors asthmatic Th2 responses has not been experimentally established.
2Note: Swiecichowski et al. (1993) and Leikauf (1992) are considered to involve the same cohort of animals.
3Hyperresponsive airways (or hyperresponsiveness) represents a mechanistic event (supported by robust evidence) and a
potential key feature of respiratory health hazards that is defined to encompass any of a range of relevant airway features,
including hyperreactivity (exaggerated response) and hypersensitivity (lower dose to elicit response).
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Initial Alterations
o-
Secondary Alterations
Effector-Level Changes
Key Hazard Feature
¦^oxidative Sensory nerve "T1 LRT neuro- LRT micro- ^Eosinophils -j1 airway edema/
stressinLRT stimulation in LRT peptides vascular leakage in LRT* inflammatory
structural change*
Airway hyper-
responsiveness*
• O o o o
stress I* oxidative ^ CDS* T cells IL-4, -i- IFNy Altered B
hormone stressin blood in blood in blood cells
o
IV
V
Altered antibody Allergic Airway hyper-
responses* sensitization responsiveness*
0---CF-
-X
O"
URT epithelial ^ URT ¦f'airway 't'CD^ T cells & Eosinophils Sustained airway Allergic Airway hyper-
damage inflammatory neuropeptides Th2-related jn LRT* inflammation* sensitization responsiveness*
cells & factors cytokines in LRT
Legend
*
Plausibly an initial
effect of exposure
Key feature of
respiratory immune-
mediated conditions
EVIDENCE
iQ) Robust
( ) Moderate
( ; Slight
RELATIONSHIP
Robust
•-> Moderate
Slight
*effectsare amplified
with allergen exposure
Figure 10. Possible mechanistic associations between formaldehyde exposure and
immune-mediated conditions, including allergic conditions and asthma.
An evaluation of the formaldehyde exposure-specific mechanistic evidence informing the
potential for formaldehyde exposure to cause respiratory health effects identified these mechanistic
pathways. Similar to effects on pulmonary function, events related to indirect stimulation of lower
respiratory tract (LRT) sensory nerve endings (top pathway) were considered as likely to represent an
incomplete mechanism by which formaldehyde inhalation could cause airway hyperresponsiveness,
although whether certain events occur with chronic, low-level exposure remains unclear. While the
observed alterations to circulating antibodies (i.e., primarily IgG, not IgE) after formaldehyde exposure
might contribute to the development of both allergic sensitization and airway hyperresponsiveness
(middle pathway), in the absence of additional clarifying data, this was not identified as a likely
mechanism for these effects. Likewise, the slight evidence of altered T cell-related airway responses
and, secondarily, inflammatory eosinophil responses might be useful for explaining allergic sensitization
(bottom pathway) if additional data were available to better explain the pattern and strength of these
associations. Conversely, sustained airway inflammation, at least in animals previously sensitized to an
allergen, was considered likely to be an incomplete explanatory mechanism for airway hyper-
responsiveness. It is expected that there would be overlap between the top and bottom pathways for
airway hyperresponsiveness.
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3.3.5. Overall Evidence Integration Judgments and Susceptibility for Immune-mediated Conditions
including Allergies and Asthma
Overall, based primarily on moderate human evidence as well as slight animal evidence from
mechanistic studies supporting biological plausibility (including molecular and cellular inflammatory
changes and evidence of hypersensitivity), the evidence indicates that inhalation of formaldehyde likely
causes increased risk of prevalent allergic conditions and prevalent asthma symptoms, as well as
decreased control of asthma symptoms given appropriate exposure circumstances (see Table 18). The
primary basis for this conclusion includes studies of occupational settings (>0.1 mg/m3) and population
studies where formaldehyde concentrations measured in schools and homes averaged between 0.03
and <0.1 mg/m3.
Table 18. Evidence integration summary for effects on immune-mediated conditions,
including allergies and asthma
Evidence
Evidence judgment
Hazard determination
Allergic Conditions
Human
Moderate for Allergic Conditions, based on:
Human health effect studies:
Small elevated risks in five out of six high and medium confidence studies of
prevalence of rhinitis, conjunctivitis, and eczema among adults and children
in residential and school settings with exposures in the range of
0.04-0.06 mg/m3 formaldehyde. Very low formaldehyde concentrations
were measured in the one insensitive null study.
Biological Plausibility (both conditions)\
Studies in humans do not provide robust or moderate evidence for
mechanistic events that clearly support the development of asthma,
although effects in the blood, such as cytokine, cell, and antibody changes,
might contribute
The evidence indicates that
inhalation of formaldehyde
likely increases the prevalence
of allergic conditions in humans,
given the appropriate exposure
circumstances3
This judgments is primarily
based on studies of occupational
settings (>0.1 mg/m3) and
population studies where mean
formaldehyde concentrations
Animal
Sliaht for Immune-Mediated Resoiratorv Effects based on:
Biological Plausibility.
Robust evidence for mechanistic events exists in relation to
formaldehyde-induced augmentation of responses to allergens and airway
bronchoconstrictor effects in animal models. Although several events
typically associated with asthma were not corroborated (i.e., slight or
inadequate evidence exists for these events), moderate evidence for
mechanistic events exists for stimulation by formaldehyde of important
immunological and neurological processes. These include airway eosinophil
increases and other inflammatory changes in the airways and systemic
circulation that can be reasonably associated with effects on airway
hyperreactivity or other responses relevant to the development of allergic
conditions and, potentially, asthma.
Animal health effect studies:
Experimental animal models are generally considered to be unable to
reproduce the overt manifestations of allergic conditions and are not
interpreted to provide direct support.
measured in schools and homes
were between 0.03 and
0.1 mg/m3
Potential Susceptibilities:
Variation in sensitivity is
anticipated depending on
respiratory health, physiologic
changes during pregnancy, age,
and exposure to tobacco smoke
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Other
inferences
• Relevance to humans: The most relevant mechanistic findings in animals
involve neurological and immunological constituents present in both
human and rodent airways.
• MOA: Several incomplete MOAs involving airway inflammatory changes
are considered likely to be involved.
Prevalence of Current Asthma
Humans
Moderate for Asthma, based on:
Human health effect studies:
• Elevated risks in eight medium confidence studies of prevalence of
current asthma in adults and children, change after an intervention to
reduce exposure, or reduced symptom control in children in residential
settings including homes with >0.05 mg/m3 formaldehyde; greater
susceptibility among children
• Inconsistencies in study results appear to be explained by exposure levels.
No elevated risk of current asthma in six high and medium confidence
studies with relatively low exposures (<0.05 mg/m3), but associations with
adequacy of asthma control were observed in one study at this lower
exposure level
• Strongly elevated risks in three medium confidence studies in
occupational settings with exposures from 0.100 to >0.500 mg/m3
Biological Plausibility (both conditions):
Studies in humans do not provide robust or moderate evidence for
mechanistic events that clearly support the development of asthma,
although effects in the blood, such as cytokine, cell, and antibody changes,
might contribute
The evidence indicates that
inhalation of formaldehyde
likely increases the prevalence
of asthma symptoms in humans,
as well as decreased control of
asthma symptoms, given
appropriate exposure
circumstances3
This judgment is primarily based
on studies of occupational
settings (>0.1 mg/m3) and
population studies where mean
formaldehyde concentrations
measured in schools and homes
were between 0.03 and
0.1 mg/m3
Animals
Sliaht for Immune-Mediated Respiratory Effects based on:
Biological Plausibility.
In the same way the available mechanistic data are interpreted to provide
slight animal evidence supporting the development of allergic conditions in
humans, this evidence provides slight evidence supportive of asthma.
Animal health effect studies:
Experimental animal models are generally considered to be unable to
reproduce the overt manifestations of asthma and are not interpreted to
provide direct support.
Potential Susceptibilities:
Variation in sensitivity is
anticipated depending on
respiratory health, physiologic
changes during pregnancy, age,
and exposure to tobacco smoke
Other
Inferences
• Relevance to humans: For the animal mechanistic data, while several
events (e.g., amplified bronchoconstriction; eosinophil increases) have an
unclear direct linkage to complex human diseases like asthma, these
findings inform the potential for exposure to result in changes to relevant
neurological and immunological constituents present in both human and
rodent airways.
• MOA: Several incomplete MOAs involving airway inflammatory changes
are considered likely to be involved.
aThe "appropriate exposure circumstances" are more fully evaluated and defined through dose-response analysis (see below)
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1 3.3.6. Dose-response Analysis
2 Study selection
3 The high and medium confidence studies that included information about dose-response
4 relationships for allergic conditions and current asthma are presented in Table 19, which indicates for
5 each study whether a POD was developed or the rationale for why the study was not suitable.
6 Table 19. Eligible studies for POD derivation and rationale for decisions to not select
7 specific studies
POD
Rationale for decisions to
Reference
Endpoint
derived?
not select
Respiratory immune-mediated conditions: Allergic conditions
Annesi-Maesano et
Rhinoconjunctivitis prevalence:
Yes
al. (2012)
Children
Matsunaga et al.
Atopic eczema
Yes
(2008)
Yon et al. (2019)
Rhinitis prevalence
No
Minimal details provided on
formaldehyde distribution
Neamtiu et al. (2019)
Allergy-like symptoms (eyes, nose
and skin)
No
Provided support for use of Annesi-
Maesano et al. (2012)
Garrett et al. (1999)
Atopy prevalence (skin prick tests):
No
Uncertain window of exposure with
Children
respect to skin prick test results
Palczvnski et al.
Atopy prevalence (skin prick tests):
No
Uncertain window of exposure with
(1999)
Children
respect to skin prick test results; too few
individuals in third tertile
Respiratory immune-mediated conditions: Current asthma
Krzvzanowski et al.
Current asthma prevalence:
Yes
(1990)
Children
Annesi-Maesano et
Current asthma prevalence:
Yes
al. (2012)
Children
Matsunaga et al.
Current asthma prevalence: Adults
No
Definition of current asthma was narrow
(2008)
and resulted in ascertainment of fewer
cases than would be expected
Palczvnski et al.
Current asthma prevalence:
No
Uncertainty regarding asthma definition
(1999)
Children and adults
(current, ever?); few cases in third tertile
(n<5)
Kim et al. (2011)
Current asthma prevalence:
Children
No
Provided support for use of Annesi-
Maesano et al. (2012)
Mi et al. (2006)
Current asthma prevalence
No
Provided support for use of Annesi-
Maesano et al. (2012)
Respiratory immune-related conditions: Asthma control
Venn et al. (2003)
Asthma control: Children
Yes
Dannemiller et al.
Asthma control: Children
Yes
(2013)
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Derivation of PODs
Allergic conditions and sensitization
The selected high confidence studies presented a dose-response analysis using formaldehyde as
three (Annesi-Maesano et al.. 2012) or four groups (Matsunaga et al.. 2008). NOAELs and LOAELs were
identified in each of these studies based on the pattern of risk seen across the exposure groups; the
PODs were based on NOAELs. The study by Annesi-Maesano et al. (2012) used a relatively long
exposure period (5 days) and was a very large study in a school-based sample of children in France
(n = 6,683) with analysis presented by tertile. Matsunaga et al. (2008) used 24-hour personal samples in
a study of 998 pregnant women in Japan. The primary limitation of the Matsunaga (2008) study was
that it was conducted only among adults, and so was less able to address the variability in susceptibility
that would be anticipated within a population. However, it is a study of pregnant women, a sensitive
population for eczema prevalence.
For allergy-related conditions (rhinoconjunctivitis), EPA selected NOAEL and LOAEL values of
0.024 and 0.040 mg/m3, respectively, in the Annesi-Maesano et al. (2012) study. Higher values
(NOAEL = 0.046, LOAEL = 0.062) were selected based on the study in adults by Matsunaga et al. (2008).
Current asthma
Several residential and school-based exposure studies examined prevalence of current asthma
in relation to formaldehyde exposure in adults and children in relatively low exposure settings. The six
medium or high confidence studies at exposures of <0.050 mg/m3 do not indicate risk at these lower
exposure levels. Several of the relative risk estimates from the individual studies at these exposure
levels were limited by low statistical power. However, the consistency of the results, and the absence of
an increased risk in the study by Annesi-Maesano et al. (2012), a large school-based study (n = 6,683)
that used a 5-day sampling period for formaldehyde measurement, strengthens the basis for
interpreting this set of studies as indicating an absence of risk of current asthma below 0.05 mg/m3.
Based on the study by Annesi-Maesano et al. (2012) and this collection of studies, EPA selected a NOAEL
of 0.042 mg/m3for risk of current asthma.
Krzyzanowski et al. (1990) examined prevalence of current asthma in children (5-15 years of
age) in higher exposure residential settings (>0.05 mg/m3). These results are based on a relatively large
sample size, with a comprehensive exposure assessment protocol. An increased prevalence of current
asthma was seen in the highest exposure group in a categorical analysis. The exposure range in this
group was 0.075-0.172 mg/m3, but the study notes that few values were above 0.11 mg/m3. Based on
this information, EPA selected a LOAEL based on the midpoint of the range estimated as 0.075 to 0.11
mg/m3 (midpoint of 0.092 mg/m3). The middle exposure category was selected as a NOAEL, although
confidence in this NOAEL is less, given the imprecision of the estimate (n with asthma = 1).
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EPA identified two studies that examined degree of asthma control in children with asthma in
relation to formaldehyde measures in the home (Dannemiller et al.. 2013; Venn et al.. 2003). The larger
sample size, longer sampling period, and more detailed dose-response analysis makes Venn et al. (2003)
a stronger basis for providing a POD. EPA selected a NOAEL of 0.027 mg/m3 (no or weak relative risks
seen below this value) and a LOAEL of 0.041 mg/m3 (2- to 3-fold increased risk of symptoms was seen).
The Venn et al. (2003) analysis also evaluated dose-response trends using logistic regression, and EPA
used the reported odds ratio per quartile exposure for frequent nighttime symptoms indicating poor
asthma control and the median exposure values for each quartile to estimate the concentration
associated with a 5% increase in prevalence of symptoms above that observed in the referent group (for
modeling details, see Appendix B.1.2). A BMR of 5% was selected because asthma attacks are overt
effects, generally requiring the use of drugs to control symptoms (i.e., a frank or adverse effect) (U.S.
EPA. 2012).
Table 20 presents the studies with the epidemiology data and sequence of calculations leading
to the derivation of a point of departure for each data set with effects relating to allergies and asthma.
Table 20. Summary of derivation of PODs for allergies and current asthma based on
observational epidemiological studies
Endpoint and
Reference
Population
Observed Effects by Exposure Level
PODadj
(mg/m3)
Allergic conditions
Rhinoconjunctivitis
(prevalence); school-
based exposure (5 d)
Annesi-Maesano
et al. (2012)
Children
(M and F)
n = 6,683
Prevalence 12.1%,
OR (95% CI) (adjusted)
<0.0191 mg/m3 1.0 (referent)
>0.0191-0.0284 1.11 (0.94,1.37)
>0.0284- ~0.055 1.19 (1.03, 1.39)
NOAEL selection: 0.024 mg/m3, midpoint of second exposure category
LOAEL selection: 0.040 mg/m3, midpoint of third exposure category
NOAEL: 0.024
LOAEL: 0.040
Atopic eczema
(prevalence); personal
monitor-based
exposure (24 hrs)
Matsunaga et al.
(2008)
Adult women
(pregnancy
cohort)
n = 998
Atopic eczema
(5.7% prevalence)
mg/m3
n
OR
(95% CI)
<0.022
298
1.0
(referent)
0.023-0.033
299
1.03
(0.47, 2.29)
0.034-0.057
301
1.11
(0.50, 2.42)
0.058-0.161
100
2.36
(0.92, 6.09)
(trend p-value)
(0.08)
0.058 to 0.161 vs. <0.058
2.25
(1.01, 5.01)
per 0.0123 mg/m3
1.16
(0.99, 1.35)
Atopic
eczema
NOAEL: 0.046
LOAEL: 0.062
[Stronger associations in women with no family history of atopy]
For atopic eczema NOAEL selection: 0.046 mg/m3, midpoint for third
category; LOAEL selection: 0.062 mg/m3, estimated median of fourth
category (based on correspondence with Dr. Matsunaga)
For rhinitis NOAEL selection: 0.062 mg/m3, median of fourth category
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Endpoint and
PODadj
Reference
Population
Observed Effects by Exposure Level
(mg/m3)
Current asthma/degree of asthma control
Current asthma
Children
Exposure (mg/m3) na OR (95% CI)
NOAEL: 0.042
(prevalence);
school-based
(M and F)
n = 6,683
<0.0191 2,200 1.0 (referent)
exposure (5 d)
>0.0191-0.0284 2,200 1.10 (0.85,1.39)
Annesi-Maesano
>0.0284-~0.055 2,200 0.90 (0.78,1.07)
etal. (2012)
Approximation, based on tertiles, with total n = 6,590
NOAEL selection: 0.042 mg/m3, midpoint of third exposure category
Current asthma
Children
Exposure (mg/m3) N Proportion with asthma
NOAEL: 0.062
(prevalence);
(M and F)
<0.049 248 0.12
LOAEL: 0.092
residence-based
n = 298
0.049-0.074 24 0.04
exposure (two 1-wk
0.075-0.172 21 0.24
periods)
(trend p-value) (0.03)
Krzvzanowski et
Only a few values were reported to be above 0.11 mg/m3.
al. (1990)
NOAEL selection: 0.062 mg/m3, midpoint of second category
LOAEL selection: 0.092 mg/m3, estimated midpoint of third category
Asthma control among
Children
Exposure (mg/m3) N Proportion OR (95% CI)
NOAEL: 0.027
children with asthma,
residence-based
exposure (3 d)
(M and F)
n = 194
LOAEL: 0.041
From
Frequent nighttime symptoms
<0.016 39 0.41 1.0 (referent)
Venn et al. (2003)
0.016-0.022 35 0.49 1.40 (0.54,3.62)
0.022-0.032 36 0.53 1.61 (0.62,4.19
regression
results:
0.032-0.083 33 0.67 3.33 (1.23,9.01)
BMCL5:
0.0133
(trend p-value) (0.02)
per quartile increase 1.45 (1.06,1.98)
Frequent daytime symptoms
<0.016 37 0.62 1.0 (referent)
0.020-0.022 34 0.47 0.47 (0.47,1.25)
0.022-0.032 37 0.73 2.00 (0.71,5.65)
0.032-0.083 32 0.73 2.08 (0.71,6.11)
(trend p-value) (0.05)
per quartile increase 1.40 (1.00,1.94)
NOAEL selection: 0.027 mg/m3, median of third category
LOAEL selection: 0.041 mg/m3, median of fourth category (based
on correspondence with Dr. Venn)
Asthma control among
Children
Geometric mean formaldehyde (mg/m3)
NOAEL: 0.042
people with asthma,
(M and F)
Very poor control (score <12, n = 6) 0.066 mg/m3
residence-based
n = 37
All others (score >12, n = 31) 0.042 mg/m3 p = 0.078
exposure
(30 min)
Dannemiller et al.
(2013)
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Derivation ofcRfCs
Table 21 describes the uncertainty factors used to adjust the PODs and the resulting cRfCs for
allergy-related conditions and asthma. For rhinoconjunctivitis among children from Annesi-Maesano et
al. (2012), a UFH of 3 was used for the POD. Childhood is a susceptible lifestage for asthma and allergy,
and the sample size of 6,600 children was large enough to have characterized an adequate spectrum of
human variability. However, a UFH of 1 was not used because susceptibility among subsets of the study
population was not specifically assessed. For the cRfC for atopic eczema in women by Matsunaga et al.
(2008), a UFh of 3 was used. Matsunaga et al. (2008) was a study of pregnant women, a sensitive
population for eczema prevalence, however no information was available for other sensitive lifestages,
including children, a subgroup with a higher prevalence of eczema compared to adults.
A UFh of 3 was used for the POD for current asthma prevalence among children from Annesi-
Maesano et al. (2012) using the same rationale as described above for rhinoconjunctivitis. For current
asthma prevalence among children with residential exposure (Krzvzanowski et al.. 1990). a UFH of 10
was used because susceptibility among subsets of the population was not specifically assessed, and the
precision of the NOAEL was lower compared to that in Annesi-Maesano et al. (2012). For Venn et al.
(2003), a UFh of 3 was used because the POD was based on the degree of asthma control in children
with asthma, a highly sensitive group. (A UFH of 1 was considered but the number of individuals in the
two higher exposure groups was relatively low [n = 31-35], and likely did not characterize a wide range
of human variability).
The PODs for all studies were based on the NOAEL; therefore, a UFL of 1 was applied. Further, a
UFS of 1 was used, based on the following rationale: (1) The definitions of prevalence of
rhinoconjunctivitis, current asthma, or atopic eczema involved symptoms occurring during the past 12
months, while asthma control included symptoms during the past 4 weeks. These time frames are
components of validated definitions for these conditions and are expected to capture the occurrence of
symptoms that tend to be intermittent. (2) The evaluation of children using residential or school-based
exposures is presumed to represent several years of exposure. This reflects a large portion of what is
expected to be a vulnerable lifestage for these effects (particularly for asthma-related measures).
Consistent with the rationale for developmental effects, this would not require the application of a UFS.
The study of the occurrence of atopic eczema during the past 12 months in a group of pregnant women
was an exception where a subchronic UF of 3 was applied to the POD. In Matsunaga et al. (2008), the
exposure assessment corresponded to the time during pregnancy, which is a less-than-lifetime window
of vulnerability. However, this outcome may have been pre-existing in a portion of the study sample
and the window of susceptibility may not have been sufficiently represented by the shorter exposure
period (Cho et al.. 2010). Therefore, a UF of 1 was not applied.
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Table 21. Derivation of the cRfC for allergy-related conditions and asthma
Endpoint (reference; population)
POD
POD basis
ufa
UFh
ufl
UFS
UFd
UFcomposite
cRfC
(mg/m3)
ALLERGY-RELATED CONDITIONS
Rhinoconiunctivitis prevalence [Annesi-
Maesano et al. (2012)
children M+F, n = 2,200 at POD, school-
based exposure]
0.024
NOAEL
1
3
1
1
1
3
0.008
Atopic eczema prevalence [Matsunaga
et al. (2008) adult F (pregnant) n = 301
at POD, personal monitor-based exposure]
0.046
NOAEL
1
3
1
3
1
10
0.005
ASTHMA
Current asthma prevalence [Annesi-
Maesano et al. (2012) children M+F,
n = 2200 at POD, school-based exposure]
0.042
NOAEL
1
3
1
1
1
3
0.01
Current asthma prevalence
[Krzvzanowski et al. (1990) children
M+F, n = 24 at POD, residential]
0.06
NOAEL
1
10
1
1
1
10
0.006
Degree of asthma control [Venn et al.
(2003) with asthma M+F, n = 35 at POD,
residential]
0.013
BMCLs
1
3
1
1
1
3
0.004
Selection ofosRfC
The osRfCfor allergy-related conditions is based on one study in children (Annesi-Maesano et
al.. 2012) and one study in adults (Matsunaga et al.. 2008). Both PODs were based on NOAELs and are
interpreted with high confidence. In particular, the large study of children (n = 6,683) by Annesi-
Maesano et al. (2012) was better able to address the variability in susceptibility that would be
anticipated within a population. EPA selected an osRfC of 0.008 mg/m3, based on the overall greater
strength of Annesi-Maesano et al. (2012). The completeness of the database relating formaldehyde
exposure to allergic sensitization is considered to be high, based on the variety of endpoints,
populations, and exposure scenarios considered in these studies.
There were three cRfCs developed for asthma based on current asthma and degree of asthma
control (Annesi-Maesano et al.. 2012; Venn et al.. 2003; Krzyzanowski et al.. 1990). The POD based on
Annesi-Maesano et al. (2012) was derived from a NOAEL using a large study with a relatively long
exposure measurement period, supported by a collection of several other smaller studies. Although the
effect estimates derived by Venn et al. (2003) were less precise because of relatively small group sizes,
the POD derived from Venn et al. (2003) reflects the response among a susceptible population,
asthmatic children. To account for the different uncertainties in the PODs from the three studies, the
median of the three PODs, 0.006 mg/m3, was selected for the osRfC. The confidence in the PODs was
medium. As there was a relatively small number of limited studies (e.g., low statistical power,
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incomplete reporting of study results and exposure measures) examining asthma risk in relation to
exposures between 0.05 and 0.1 mg/m3 and a scarcity of data pertaining to asthma control among
people with asthma, the database for asthma was considered to be medium.
3.4. RESPIRATORY TRACT PATHOLOGY
This section describes research on formaldehyde inhalation and pathology endpoints in the
respiratory system in experimental animal studies and observational studies in humans. Numerous well-
conducted experimental animal studies, while testing relatively high formaldehyde concentrations,
provide consistent support for concentration- and, to a lesser extent, duration-dependent upper
respiratory tract hyperplasia and metaplasia after formaldehyde exposure. These data are supported by
a set of four studies in formaldehyde-exposed workers that demonstrate consistent findings of an
elevated prevalence of nasal lesions such as hyperplasia and metaplasia. The evidence for metaplasia, in
particular, is considered to be the best representation of a potential health hazard.
In the URT, both hyperplasia and metaplasia often reflect adaptive tissue responses. These
cellular responses help reduce the impact of stressors by changing the structure or function of the
locally affected tissue (Harkema et al.. 2013). Hyperplasia, generally a response to cell injury, involves
an increase in the population of resident cells that results in additional cell layers noticeable by
histology, whereas metaplasia, which typically occurs following prolonged or repeated insults, results in
the replacement of one differentiated cell type with another, more resilient cell type (Harkema et al..
2013). Importantly, squamous metaplasia results in a hardened, drier, and non-ciliated skin-like layer
(Tomashefski, 2008). Along with the acquisition of a protective, barrier-type phenotype, this
metaplastic change causes a loss of normal tissue function, including reduced mucous secretion and
ciliary clearance (Harkema et al.. 2013). Thus, this loss of normal function is judged to be an adverse
outcome in and of itself (i.e., independent from its potential role in progression to cancer). As an
interpretation regarding adversity is less clear for hyperplasia, this discussion emphasizes the data on
squamous metaplasia.
3.4.1. Literature Identification
This review focused on histopathological endpoints and signs of pathology in respiratory
(including nasal) tissues. The bibliographic databases, search terms, and specific strategies used to
search them are provided in Appendix A.5.5, as are the specific PECO criteria and the methods for
identifying literature from 2016-2021 are described in Appendix F. The mechanistic studies related to
pathology endpoints were considered in the overarching mechanistic evaluation informing all potential
respiratory health effects (see Appendix A.5.6 for additional details and supporting analyses), the most
relevant results of which are summarized herein.
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3.4.2. Study Evaluation
Hyperplasia can be precipitated by damage to the nasal epithelium, which is evaluated
histologically by measures of, for example, cell loss or necrosis, epithelial degeneration, and erosions.
Relatedly, squamous metaplasia is an adaptive response to continued toxic insult that involves cellular
substitution. Thus, it is useful to consider these cellular damage-related endpoints in the context of
hyperplasia and metaplasia. While evaluations of necrosis- and cytotoxicity-related pathology can be
informative, these endpoints were generally inconsistently measured or poorly reported across the
available studies and are therefore only summarily discussed, whereas the potential development of
hyperplasia and metaplasia was documented in nearly all the long-term histopathological studies.
Studies that evaluated related outcomes, such as mucociliary flow rates, cellular proliferation counts
based on DNA labeling, and mucosal swelling (which generally only investigated acute or short-term
exposure), were included and summarized as part of the respiratory system MOA evaluation.
Given the large number of long-term exposure studies with information on URT pathology and
the focus of the assessment on the effects of lifetime formaldehyde exposure, this section focuses on
animal studies of subchronic or chronic exposure, and on human studies of occupational exposure
where exposed employees were generally employed for longer than 5 years. Exceptions include
discussion of shorter-term studies that might inform the potential for relationships between lesion types
and studies specifically considering differences in exposure paradigm for lesion induction.
For human studies that evaluated histopathological lesions in nasal biopsies, the evaluation
emphasized either a detailed explanation of how tissues were evaluated and scored, or a citation for a
standard method. Cross-sectional studies among occupational cohorts likely were influenced by the
selection of the workforce toward individuals less responsive to the irritant properties of formaldehyde,
with a reduction in sensitivity. Confidence in these studies was downgraded because of this limitation.
Age, gender, and smoking were considered to be important confounders to evaluate for effects on
pathological endpoints. Confounding by other coexposures in the workplace specific to the
occupational setting also was considered. Higher confidence was placed in studies with the ability to
differentiate between exposed and unexposed, or between low and high formaldehyde exposure.
In addition to general factors considered for all toxicology studies of formaldehyde inhalation
exposure (see Appendix A.5.1), factors specific to the interpretation of respiratory tract pathology were
considered to give greater weight to results from the large database of well-conducted studies. These
factors included: (1) the use of too few test subjects; (2) a failure to report lesion incidence or severity;
(3) the lumping of multiple lesions (e.g., squamous metaplasia and hyperplasia); (4) a failure to report
quantitative incidences or statistical analyses; (5) the use of insensitive sampling procedures (multiple
sections across multiple levels of the respiratory tract were preferred); and (6) use of an exposure
duration or follow-up that is likely insensitive for detecting slow-developing lesions (a duration of >1
year was preferred). Most studies of respiratory pathology used paraformaldehyde or freshly prepared
formalin, which yield high purity formaldehyde gas. In studies that tested commercial formalin,
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coexposure to methanol was less of a concern for investigations of URT respiratory pathology because
most inhaled methanol bypasses the nose and is readily absorbed in the lungs for systemic distribution.
3.4.3. Synthesis of the Human Health Effect Studies
The epidemiological studies that evaluated pathological endpoints in the nasal epithelium
indicated that formaldehyde exposure is associated with higher scores indicating a higher prevalence of
cells with morphological changes including squamous metaplasia. There was no evidence of a time-
dependent relationship with formaldehyde. Additionally, there was no indication that coexposure with
wood-dust or smoking modifies the pathological effects of formaldehyde.
Cross-sectional studies among occupational cohorts likely were influenced by the selection of
the workforce in favor of individuals less responsive to the irritant properties of formaldehyde, with
resulting bias toward null results. Despite this methodological limitation and subsequent reduction in
sensitivity, most of the studies observed increases in histopathological outcomes among exposed
workers, which increased confidence in the reported exposure-related associations. Nasal biopsies were
taken in four occupational studies, and tissues were subsequently stained and cell structure examined
according to variations of the Torjussen et al. (1979) method. The original Torjussen method scored
morphological characteristics of the nasal epithelium using a whole number between 0 and 8, with 0
indicating normal epithelium, 8 indicating carcinoma, and the midpoint of 4 signifying stratified
squamous epithelium with a horny layer. Despite the variations of this scale, in each study the lowest
numbers (0 or 1) always indicated normal cell structure while increasingly higher numbers indicated
more disruptive cellular changes. Although the focus of this section is nonneoplastic histopathological
lesions, the studies compared the means of the total score between exposed and referent groups.
Although more equivocal in one study (Boysen et al.. 1990), the four studies examining
histopathology found that participants exposed to average formaldehyde levels between 0.05 and 0.6
mg/m3 had a higher average histopathology score than their respective comparison group (Ballarin et al..
1992; Holmstrom et al.. 1989b; Edling et al.. 1988). While the studies were limited by probable survival
bias and, in some cases, other limitations resulting in a bias toward the null, a consistent association
with histopathological endpoints, including squamous metaplasia, was observed. Therefore, the
observational human data provide moderate evidence that inhaled formaldehyde induces
histopathological lesions in the URT, including squamous metaplasia.
3.4.4. Synthesis of the Animal Health Effect Studies
A large database of well-designed studies has characterized formaldehyde-induced respiratory
tract pathology in mice, hamsters, and monkeys, but primarily in rats. The durations of these studies
ranged from a few hours to longer than 2 years, and several studies having included recovery periods
that explored the reversibility of lesions. Because of the abundance of studies of respiratory pathology,
this section focuses on longer duration (i.e., chronic and subchronic) studies interpreted with high or
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medium confidence, primarily studies in rats (see Section 1.2.4 in the Toxicological Review for an
expanded discussion of pathology in other species). Finally, although other nasal lesions have been
observed to develop after formaldehyde exposure (e.g., necrosis), this summary focuses on the more
reliably evaluated and more consistently reported information on hyperplasia and metaplasia.
Only a few studies evaluated sections of the respiratory tract distal to the nasal cavity, and these
evaluations were generally less rigorous (e.g., examining only a single tissue section). Pathological
findings in the lower respiratory tract were generally not identified in higher confidence studies, and are
not discussed in detail in the assessment. However, the limited evidence for lesions beyond the nasal
cavity in rats suggests that concentration is an important variable in long-term studies. Laryngeal or
tracheal lesions, including hyperplasia and squamous metaplasia, were only observed at high
concentrations, with no evidence for effects across multiple rat strains at levels <12 mg/m3. Findings in
a single study of rhesus monkeys observed changes in URT regions proximal to the nasal cavity (but not
the lungs) at lower concentrations (i.e., exposure for <6 weeks to 7.4 mg/m3 formaldehyde in Monticello
et al. (1989), which might suggest that the monkey nose is less efficient than the rodent nose at
scrubbing formaldehyde from inhaled air.
Hyperplasia and metaplasia have been consistently reported in multiple rodent species/strains,
and in monkeys, with consistent and clear indications of concentration-dependence. These studies also
identify a clear relationship between formaldehyde exposure duration and the development of
squamous metaplasia, with somewhat weaker data indicating a duration-dependency for hyperplasia.
Both squamous metaplasia and hyperplasia appear to be at least partially reversible after exposure
ceases. Due to the high reactivity and water solubility of formaldehyde, nasal metaplasia and
hyperplasia have primarily been assessed (and subsequently observed) in the epithelium lining the
anterior regions of rodent nasal passages (typically levels I, II, and III: level I refers to the area posterior
to the nostrils, with higher levels indicating more posterior sites) following formaldehyde inhalation
exposure, mostly in regions containing respiratory epithelium.
Squamous metaplasia, in particular (which, as previously mentioned, is considered adverse), has
been observed after chronic, subchronic, and short-term exposure to inhaled formaldehyde. Overall,
the most robust responses (i.e., higher incidence or severity at lower formaldehyde concentrations)
occur following chronic exposure, particularly in rats. As compared to rats, other laboratory rodents
appear to require higher levels (i.e., mice) or exhibit a reduced response (i.e., hamsters), suggesting that
there may be differences in species sensitivity to formaldehyde-induced squamous metaplasia. These
differences in sensitivity are likely at least partially due to differences in the magnitude of reflex
bradypnea across species. Multiple chronic rat studies have reported clear increases in squamous
metaplasia following exposures of approximately 2.5-2.7 mg/m3 (Kamata et al.. 1997; Kerns et al.. 1983;
Battelle. 1982) or 11.3-11.6 mg/m3 (Woutersen et al.. 1989; Appelman et al.. 1988). although some data
suggest that slight increases might be present at lower levels (i.e., 0.4-1.2 mg/m3; (Kamata et al.. 1997;
Woutersen et al.. 1989). With subchronic exposure, squamous metaplasia is observed in rat noses at
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higher concentrations (i.e., >11.3 mg/m3) in high confidence studies by Appelman et al. (1988).
Woutersen et al. (1987), and Feron et al. (1988), the results of which are supported by consistent
observations in two medium confidence studies (Andersen et al.. 2010; Zwart et al.. 1988), although
these latter studies observed increases at lower exposure levels (i.e., 2.5-3.7 mg/m3). The rat data from
medium or high confidence studies of chronic formaldehyde exposure are summarized in Figure 11.
10°-| ~ ~ ¦ *
90- O
80-
a. 70"
S 60H O
•G 50
c
30-
20-
10|
0<
0 3 6 9 12 15 18
Formaldehyde concentration (mg/m3)
High confidence
Medium confidence
~
Kerns, 1983 (F344; 2yr; n=27-100)
o
Sellakumar, 1985 (SD; life; n=99-100j
¦
Woutersen, 1989 (Wistar; 2.5yr; n=26-28)
o
Kamata, 1997 (F344; 2.5yr; n=32)
~
Appelman, 1998 (Wistar; lyr; n=10)
Figure 11. Squamous metaplasia incidence in chronic pathology studies of rats.
Smaller symbols reflect smaller sample sizes. High confidence studies are outlined in black.
The duration-dependency of these lesions in rat studies represents an important consideration.
For squamous metaplasia, the duration of exposure affects the locations at which lesions develop, as
well as their severity, probably in parallel with increases resulting from increasing formaldehyde
concentration. The association with lesion location is demonstrated by the results of Kerns et al. in the
supporting Battelle report (1983; 1982) who observed that, in anterior nasal regions (i.e., level I and II)
of F344 rats exposed to >2.5 mg/m3, the incidence of squamous metaplasia increased from <20% to
100% with increasing duration (i.e., 6-24 months); however, in posterior nasal regions (i.e., levels 111—V),
a duration-dependent increase in incidence was only observed at 17.6 mg/m3. In some instances, noted
by Kerns et al. (1983; 1982), more posterior lesions were entirely unique to longer exposure durations as
compared to shorter exposures (e.g., level III at 6.9 mg/m3 only with 24 months of exposure). Regarding
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severity, squamous metaplasia was observed to increase (i.e., from slight focal lesions to metaplasia
with keratinization) with exposure duration increases from 13 to 52 weeks of exposure to 11.6 mg/m3 in
Wistar rats (Appelman et al.. 1988). Similarly, at >11.6 mg/m3 in Wistar rats, an increase in the severity
of squamous metaplasia in respiratory epithelium occurred as exposure duration increased from 4 to 8
to 13 weeks (Feron et al.. 1988). Several studies in rats, which compared longer-term exposure to
shorter-term exposure, confirm the important role for exposure duration in lesion development by
demonstrating that the increases in lesions were not attributable to longer latencies after the
formaldehyde exposures were begun (Woutersen et al.. 1989; Feron et al.. 1988). When animal ages at
evaluation and formaldehyde exposure levels were matched, comparisons of subchronic exposure to
chronic exposure (Woutersen et al.. 1989) and of short-term exposure to subchronic exposure (Feron et
al.. 1988) revealed greater incidences or severity of these lesions with the longer exposure durations.
Comparisons of the formaldehyde concentrations at which significant increases in hyperplasia
are observed across studies of differing exposure duration do not provide as clear a picture regarding
the potential duration-dependence of formaldehyde-exposure induced hyperplasia. However, like the
results for metaplasia, several rat studies comparing exposures of differing exposure duration (e.g.,
chronic versus subchronic) demonstrate that increasing exposure duration results in increases in the
incidence or severity of hyperplasia in the respiratory epithelium when testing the same formaldehyde
concentrations and anatomical levels (Woutersen et al.. 1989; Appelman et al.. 1988; Feron et al.. 1988;
Kerns et al.. 1983; Battelle, 1982). Considering the notable influence of exposure duration on
metaplasia at formaldehyde levels ranging from 2.5 to 2.7 mg/m3 in rat studies (Kamata et al.. 1997;
Kerns et al.. 1983; Battelle. 1982), the easier reversibility of hyperplasia, and the generally more robust
effects of duration on the incidence of metaplasia as compared to hyperplasia across species, exposure
duration appears to be more important to the development of metaplasia in laboratory animals than to
the development of hyperplasia. Rat studies by Wilmer et al. (1989. 1987) indicate that formaldehyde,
perhaps similar to mortality responses following acute exposure to some other local irritants (see
below), does not appear to adhere strictly to Haber's rule for the induction of nasal pathology. Although
duration of exposure has a clear and substantial role for the development of these nasal lesions (see
discussion above), the experiments by Wilmer et al. (1989. 1987) suggest that a powers equation (Cn x t
= K) where n is >1 may better represent formaldehyde exposure-induced nasal lesions than C x t = K, at
least when interpreting short-term or subchronic exposure [the exposure scenarios examined by Wilmer
et al. (1989. 1987)1. Although a value for n was not identified for formaldehyde, or specifically for
exposure-induced nasal pathology, studies of acute exposure to other local irritants and the
concentration-duration dependence for mortality suggest that the value for n, on average, is
approximately 1.8-1.9 (ranging from 0.5 to 4.0)4. It is difficult to speculate where within this range a
4Values of n for 11 local irritants as estimated by Berge et al. (1986) averaged 1.9 (range: 1.0-3.5), while 21 local irritants relying
on data in rats or mice, as summarized by California EPA (2008). averaged 1.8 (range: 0.5-4.0). Of potential interest to this
assessment, the chemicals included ammonia (n = 2.0) and acrolein (n = 1.2).
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value for n might be most applicable to formaldehyde, particularly within the context of respiratory
pathology and long-term exposures (i.e., since these n values are for mortality after acute exposure);
however, based on the data discussed in previous sections, it might be reasonable to expect that an n
defined for associations with hyperplasia should be higher than one defined for metaplasia.
Overall, a number of well-conducted studies across multiple species (i.e., rats, mice, and
monkeys) demonstrate a clear association between formaldehyde exposure and the development of
respiratory tract pathology, primarily in the nasal cavity.
3.4.5. Mode-of-action Information
Histopathological lesions in the respiratory tract following formaldehyde exposure appears to
result, at least in part, from a series of increasingly severe effects including altered mucociliary function,
damage to the nasal epithelium (e.g., sustained cytotoxicity), and sustained reparative cell proliferation
culminating in a hyperplastic epithelium, or transitioning to an adaptive, metaplastic tissue (see
Figure 12; see Appendix A.5.6 for additional details, related analyses, and discussion). Consistent with
observations of metaplasia without hyperplasia in some of the rodent health effect studies, this
pathway illustrates that metaplasia can develop following damage (noting that damage does not need
to be overt) to the epithelium in the absence of hyperplasia (i.e., hyperplasia may not be an essential
precursor). All the mechanistic events and relationships between events in the proposed pathway are
based on robust or moderate evidence, indicating that this is likely a mechanism by which formaldehyde
exposure causes squamous metaplasia. Specifically regarding the well-established alterations to mucus
flow and proliferation, mucociliary function appears to be affected at relatively low concentrations (e.g.,
0.25-0.3 mg/m3) in humans (Holmstrom and Wilhelmsson. 1988; Andersen and Molhave. 1983).
whereas multiple high and medium confidence rodent studies do not see notable changes in either
mucociliary function or proliferation below 1.23 mg/m3 (increases generally occur above 2.5 or
sometimes 3.5 mg/m3) [e.g., (Monticello et al.. 1996; Monticello et al.. 1991; Morgan et al.. 1986a;
Morgan et al.. 1986c)1. Overall, consistent with some of the animal health effect studies, these data
suggest that concentration is likely to be more of a driver of these mechanistic effects than duration
(noting that duration still contributes). Because modification of epithelial cell health and function in the
URT can occur via multiple direct and indirect mechanisms following formaldehyde inhalation, which are
expected to vary due to differences in both exposure duration and intensity, there are likely to be other
plausible mechanisms by which formaldehyde exposure could cause this health effect. The current
understanding provides strong biological support for an association between formaldehyde exposure
and respiratory tract pathology. Additionally, as many of the mechanistic events in this pathway have
been observed in both humans (sometimes indirectly) and experimental animals, including effects on
mucociliary function and cell proliferation as well as evidence of elevated oxidative stress, findings from
experimental animals are considered relevant to humans.
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Possible Initial Alterations Secondary Alterations
Effector-Level Changes
Key Hazard Feature
1* oxidative URT protein/ DNA
stressiriURT modification
URT mucociliary
dysfunction
URT epithelial
damage
URT epithelial
proliferation
Squamous
metaplasia
Legend
EVIDENCE
J Robust
^ Plausibly an initial
effect of exposure
( j Moderate
~ Key feature of respiratory
tract pathology Slight
RELATIONSHIP
—> Robust
--> Moderate
Slight
Figure 12. Possible mechanistic associations between formaldehyde exposure and
respiratory tract pathology.
Ari evaluation of the formaldehyde exposure-specific mechanistic evidence informing the potential for
formaldehyde exposure to cause respiratory health effects identified this sequence of mechanistic events
as likely to be a mechanism by which formaldehyde inhalation could cause respiratory tract pathology,
specifically squamous metaplasia, although it is assumed that other plausible pathways explaining this
association have yet to be defined.
3.4.6. Overall Evidence Integration Judgment and Susceptibility for Respiratory Tract Pathology
Overall, the strength of the evidence for hyperplasia and squamous metaplasia include robust
evidence of an effect in animals and moderate human evidence from observational epidemiological
studies, supported by more limited findings in mechanistic studies of exposed humans and strong
support for a plausible MOA based largely on mechanistic evidence in animals (with coherent findings in
human studies). Therefore, the evidence demonstrates that inhalation of formaldehyde causes
respiratory tract pathology in humans given appropriate exposure circumstances (see Table 22). The
primary basis for this conclusion is based on rat bioassays of chronic exposure which consistently
observed squamous metaplasia at formaldehyde exposure levels >2.5 mg/m3.
Table 22. Evidence Integration Summary for Effects of Formaldehyde Inhalation on
Respiratory Pathology
Evidence
Evidence judgment
Hazard determination
Human
Moderate based on:
Human health effect studies:
Of the four occupational studies interpreted with medium confidence (less
sensitive due to healthy survival bias), 3 observed a higher prevalence of
abnormal nasal histopathology, including loss of ciliated cells, hyperplasia,
and squamous metaplasia at concentrations ranging from 0.1-2 mg/m3,
while the remaining (1) study had more equivocal findings.
Biological plausibility:
The evidence demonstrates that
inhalation of formaldehyde
causes respiratory tract
pathology in humans given
appropriate exposure
circumstances3
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Mechanistic changes in two studies (one interpreted with medium
confidence) in humans provides evidence of changes in mucociliary
clearance and mucus flow beginning at formaldehyde concentrations of
0.25-0.3 mg/m3.
Primarily based on rat bioassays
of chronic exposure which
consistently observed squamous
metaplasia at formaldehyde
exposure levels >2.5 mg/m3.
Potential Susceptibilities:
Variation in sensitivity may
depend on differences in URT
immunity, allergen sensitivity,
and nasal structure or past
injury (e.g., studies support
increased sensitivity of rodents
with intentionally damaged
nasal cavities), and males may
be more sensitive than females.
Animal
Robust, based on:
Animal health effect studies:
• Consistent evidence of squamous metaplasia and hyperplasia in the nasal
respiratory epithelium across numerous independent studies interpreted
with high or medium confidence, with generally the most sensitive effects
being metaplasia observed after chronic exposure to >2.5 mg/m3
formaldehyde.
• Evidence of both metaplasia and hyperplasia in monkeys, rats, mice, and
hamsters; the data were more limited for monkeys; mice and hamsters
exhibited less sensitivity.
• Multiple studies provided clear evidence of a concentration dependence
for lesion development, as demonstrated by increases in the incidence,
severity, and anatomical location of the observed lesions with increasing
exposure.
Biological plausibility:
Robust or moderate evidence for mechanistic events based predominantly
on experimental animal studies supports a biological progression of changes
that appears to include mucociliary dysfunction, epithelial damage, and
often cellular proliferation, leading to the eventual development of nasal
lesions, including squamous metaplasia.
Other
inferences
• Relevance to humans: Similarities in the function and properties of the
nasal epithelium across species, as well as similar mechanistic and apical
effects observed in both humans and animals, provide strong support for
the relevance of the findings in experimental animals to humans.
• MOA\ Although it may be incomplete, a MOA involving effects on
mucociliary function and epithelial cell health is well supported and
considered to be a major contributor to these effects.
• Other: Data from animal studies suggest that lesion development may be
driven more by concentration than duration, particularly for hyperplasia.
While estimates for formaldehyde were not identified, estimates for other
irritants indicate that concentration is ~1.8- to 1.9-fold (on average) more
influential than duration regarding exposure-induced mortality after acute
exposure.
aThe "appropriate exposure circumstances" are more fully evaluated and defined through dose-response analysis (see below)
1 3.4.7. Dose-response Analysis
2 Study selection
3 Of the medium and high confidence studies that exposed rodents to formaldehyde for at least
4 one year, the chronic rat bioassays by Kerns et al. (1983; 1982) and Woutersen et al. (1989) were
5 considered to be the most informative for dose-response analysis (see Table 23 for the rationale
6 supporting this decision). As an interpretation regarding adversity was less clear for hyperplasia, dose-
7 response analysis relied on the data on squamous metaplasia.
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Table 23. Eligible studies for POD derivation and rationale for decisions to not select
specific studies
Respiratory Pathology (Animal Exposure Duration >52 Weeks; Humans All Employed >5 Yrs)
POD
Rationale for
Reference
Endpoint
derived?
decisions to not select
Kerns et al. (1983);
Squamous metaplasia: nasal
Yes
Battelle (1982)
turbinates, Fischer 344 rats
Kerns et al. (1983);
Squamous metaplasia: nasal
No
Mice are less susceptible for this
Battelle (1982)
turbinates, B6C3F1 mice
endpoint
Woutersen et al.
Squamous metaplasia: nasal
Yes
(1989)
turbinates, Wistar rats
Appelman et al.
Squamous metaplasia: nasal
No
Limited sample size (n = 10/group) and
(1988)
turbinates, Wistar rats
exposure duration (1 yr), as compared to
Kerns et al. (1983; 1982) (n = up to
~100/group; 24 mos) and Woutersen et
al. (1989) (n = 30/group; 28 mos)
Kamata et al. (1997)
Squamous metaplasia: nose and
No
Some quantitative uncertainty
trachea, Fisher 344 rats
associated with methanol coexposure;
small sample size at 28 months;
metaplasia results pooled across
scheduled sacrifices
Derivation of PODs
There was high confidence in both studies selected for POD derivation, as both studies were
well designed and executed with adequate reporting of data [notably, Kerns et al. (1983; 1982) was
conducted under GLP conditions]. Table 24 summarizes the derivation of PODs using data from these
studies. In determining the BMR level for the POD from Kerns et al. (1983; 1982), the average severity
score was in the range of minimal-to-mild at the lowest dose for both the 18-month and 24-month
durations for Level 1. This finding supports a BMR of 0.1 extra risk, representing a minimal level of
adversity. Due to difficulties modeling the 24-month data, the 18-month data, for which incidence rises
more gradually, were chosen even though these data would be less preferred (see Toxicological Review
Section 2.2.1). Interspecies extrapolation of the rat BMCL level to humans was carried out in two steps.
First, average flux values in the Level 1 region of the rat corresponding to the rat BMCL derived from the
incidence of squamous metaplasia were estimated. Next, the exposure concentration at which any
region in the human nose is exposed to this same level of formaldehyde flux at the inspiratory rate of 15
L/min was estimated.
For the POD from Woutersen et al. (1989) the same minimal adversity was assumed and a BMR
of 0.10 extra risk was used; however, a dosimetry model for flux to the nasal lining of the Wistar rat was
not available. U.S. EPA (2012) concluded that internal dose equivalency in the extrathoracic region for
rats and humans is in general achieved through similar external exposure concentrations; that is, even
for highly soluble and reactive gases ppm equivalence is a more appropriate default method for
extrapolation than an approach based on adjustment by the ratio of surface area to minute volume.
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Confidence in the POD calculation based on Woutersen et al. (1989) was medium, while
confidence based on Battelle (1982) and Kerns et al. (1983) was low. Confidence is lower in the latter
due to extrapolation well below the tested formaldehyde concentrations, a BMCL was based on the 18-
month exposure although the response was greater in magnitude after 24 months, and modeling of the
incidence at Level 1 in the nose, although concentrations in Level 2 were lower.
Table 24. Summary of derivation of PODs for squamous metaplasia
Endpoint and
reference
Model
BMR
Rat BMC
(mg/m3)
Rat BMCLa
(mg/m3)
Flux3
(pmol/mm2-
hr)
Human
Exposure
(mg/m3)
Human PODVij
(mg/m3)
Squamous metaplasia
Kerns et al. (1983);
Battelle (1982) F344
rat, M & F, 18 mos,
Level 1
Log-probit
0.10
0.587
0.456
685
0.484
0.086c
Squamous metaplasia
Woutersen et al.
(1989) Wistar Rats,
M, 28 mos, Level 1
Log-logistic
0.10b
1.00
0.526
N/A
N/A
0.094d
Approximate average flux over nasal lining at this level corresponding to the BMCL.
bPODADj is the human equivalent of the rat BMCL duration adjusted (6/24) x (5/7) for continuous daily exposure.
cHuman extrapolation was based on modeled estimates of regional formaldehyde tissue flux. If extrapolation is based on ppm
equivalence instead, value increases by 1.14-fold.
dHuman extrapolation was based on ppm equivalence derived from pharmacokinetic principles.
Derivation of cRfC
Table 25 describes the uncertainty factors used to adjust the POD to the resulting cRfCs for each
of the two selected studies. For both PODs, a UFA of 3 was applied to address residual uncertainties in
interspecies extrapolation after dosimetry modeling (Kerns et al.. 1983; Battelle. 1982) or an assumption
of ppm equivalence (Woutersen et al.. 1989) was used to estimate a human equivalent concentration
and account for toxicokinetic differences between animals and humans. A UFH of 10 was applied to
both PODs to address the limited variability in susceptibility factors encompassed by these typical
studies of inbred laboratory animal populations. Finally, a UFS of 3 was applied for the Battelle (1982)
and Kerns et al. (1983) study because it was based on 18-month exposure data in lieu of the 24-month
exposure data available in the same study. Specifically, the lesion incidence data were higher with
longer exposure duration (i.e., 24 months versus 18 months), and thus a lower POD would be expected
if the 24-month data could have been modeled. Although the 18-month exposure duration reduced the
uncertainty associated with extrapolating to lifetime exposure compared with a shorter duration, this
reduction was considered incomplete, and a factor of 3 was applied.
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Table 25. Derivation of cRfCs for respiratory tract pathology
Endpoint (reference; population)
RESPIRATORY TRACT PATHOLOGY
POD
POD basis
UFa
UFh
ufl
UFs
UFd
UFcomposite
cRfC (mg/m3)
Squamous metaplasia: [Kerns et al.
(1983); Battelle (1982) F344 rat, M &
F, 18 mos, Level 1]
0.088
BMCLio
3
10
1
3
1
100
0.0009
Squamous metaplasia: [Woutersen et
al. (1989) Wistar Rat, M, 28 months,
Level 1]
0.094
BMCL10
3
10
1
1
1
30
0.003
Selection of the osRfC
The osRfC for respiratory tract pathology is based on squamous metaplasia observed in anterior
rodent nasal passages in two studies of long-term exposure. EPA could discern no particular basis to
select either the Woutersen et al. (1989) study or the Battelle (1982) and Kerns et al. (1983) study over
the other on grounds of confidence in the study methods, or known differences in sensitivity between
Wistar and F344 rats. In addition, the PODs were nearly identical and the cRfCs were very similar for the
two datasets (i.e., cRfCs of 0.0009 for Kerns et al. (Kerns et al.. 1983; Battelle. 1982) and 0.003 for
Woutersen et al. (1989) which are comparable given the limited precision of the calculations). However,
there was lower confidence in the derivation of the POD from Battelle (1982) and Kerns et al. (1983),
which involved an extrapolation well below the tested formaldehyde concentrations. In addition, the
cRfC for Battelle (1982) and Kerns et al. (1983) involved the application of an uncertainty factor for
exposure duration. While exposure duration is important to the development of this lesion, such effects
appear to be more dependent on exposure concentration. Thus, if a factor describing the
concentration-duration relationship5 were available for formaldehyde (and interpretable in the context
of metaplasia), a data-defined UFs could have been applied. Considering these uncertainties and the
comparability of the cRfCs, to represent the results of both studies, the cRfC from Woutersen et al.
(1989) was used to derive an osRfC of 0.003 mg/m3 for the respiratory pathology endpoint. Since the
POD basis for this value is from Woutersen et al. (1989) the confidence in the POD is considered
medium. Completeness of the database for respiratory tract pathology is high, based primarily on
numerous well-conducted long-term studies in experimental animals.
3.5. NERVOUS SYSTEM EFFECTS
Numerous studies reported data suggesting that formaldehyde inhalation might result in
noncancer nervous system effects; however, few studies in humans were available and the animal data
5Studies of other irritants have, on average, identified a factor of ~1.8-1.9 for relationships between acute exposure and
mortality (i.e., the observed mortality is more attributable to concentration, by 1.8- to 1.9-fold, than duration; see Toxicological
Review Section 1.2.4). A value for formaldehyde was not identified, nor were values for long-term exposure.
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were often compromised by significant methodological limitations. In addition, there was generally
weak consistency in the evidence across well-conducted studies, a potential mode-of-action for nervous
system effects without systemic distribution of inhaled formaldehyde has not been established, and the
database is considered incomplete. Overall, conclusive evidence of a nervous system health hazard in
humans exposed to formaldehyde was not identified (i.e., suggestive evidence). Thus, this Overview
provides only a brief synopsis. However, given the potential for nervous system effects reported across
a variety of study types, and the general lack of comprehensive and rigorous experiments, a need for
additional studies, particularly well-conducted studies relevant to childhood exposure, was identified.
3.5.1. Literature Identification and Study Evaluation
Literature identification and study evaluations were conducted in a manner similar to the other
noncancer health effect sections (see Appendix A.5.7 and Appendix F for details). The study evaluations
emphasized an analysis of potential issues relating to exposure (e.g., for these systemic effects, known
or presumed coexposure to methanol represented a serious study deficiency) and the irritant effects of
formaldehyde.
3.5.2. Evidence Synthesis and Overall Evidence Integration Judgement for Nervous System Effects
Data were available and analyzed relating to the following outcomes:
• Amyotrophic lateral sclerosis (ALS): several medium and high confidence observational
epidemiological studies were available, generally without quantified exposure levels and with
outstanding questions of consistency.
• Developmental neurotoxicity: the evidence primarily consisted of a medium confidence animal
study and some studies reporting potentially relevant mechanistic findings. Given the potential
for effects in children exposed to formaldehyde, this represents a notable data gap.
• Neurobehavioral effects:
o Neural sensitization (i.e., an exposure-induced increased responsiveness of the nervous
system to other stimuli): several animal studies were available, with questions of human
relevance.
o Motor-related behaviors: numerous human and animal studies of low confidence and
some studies reporting potentially relevant mechanistic findings were available,
o Learning and memory: numerous human and animal studies of low confidence and
some studies reporting potentially relevant mechanistic findings.
Among these outcomes, the studies of ALS are of particular note. An association between
formaldehyde exposure and ALS was suggested across four studies in the United States, Sweden and
Denmark by two separate groups of researchers (Peters et al.. 2017; Seals et al.. 2017; Roberts et a I..
2016; Weisskopf et al.. 2009). Positive associations observed in a large prospective study (Weisskopf et
al.. 2009) were somewhat corroborated by a few (but not most) comparisons in the other studies,
noting that some associations were based on a very small number of cases or secondary analyses.
However, two of the studies had uncertainties in the assignment of individual exposure to formaldehyde
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(Roberts et al.. 2016; Fang et al.. 2009). and the third did not observe a dose-response relationship when
the data were stratified by estimated formaldehyde levels (Peters et al.. 2017). The observed
association reported by the study in Denmark was not corroborated by a second study that examined
joint effects by multiple health and chemical risk factors (Bellavia et al.. 2021). In addition, the results
were not verified in another study in a different population, which had greater certainty in individual
exposure assessments (Pinkerton et al.. 2013). Thus, the currently available human evidence was not
considered sufficient to identify a clear hazard. However, the unexpected nature of the observed
associations between formaldehyde exposure and this rare and fatal disease across a growing number
of studies (the first association was reported in 2009, with corroborating evidence in 2015 and 2016)
identifies an urgent need for additional research.
Overall, while a number of studies reporting evidence of potential neurotoxic effects were
available, due to limitations identified in the database (e.g., poor methodology, lack of consistency), the
integration of the evidence ultimately resulted in a determination (for each of the bulleted
manifestations of potential neurotoxicity noted above) that the evidence suggests, but is not sufficient
to infer, that formaldehyde inhalation might cause nervous system effects in humans given appropriate
exposure circumstances.
The data were considered insufficient for developing quantitative estimates.
3.6. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
Studies in humans, and a number of animal studies have analyzed effects of inhaled
formaldehyde on pre- and post-natal development and on the female and male reproductive systems.
The health effects studies of human exposure included studies of residential exposure during pregnancy
and fetal and infant growth measures, as well as occupational epidemiological studies conducted in
different industries and countries that evaluated decreased fecundity,6 spontaneous abortion, and
adverse birth outcomes associated with formaldehyde exposure among men and women. A few studies
also analyzed sperm quality parameters. Exposure levels in the occupational settings were high (>0.1
mg/m3) with intermittent peaks depending on specific uses. Animal studies investigated manifestations
of developmental toxicity (i.e., decreased survival, decreased growth, or increased evidence of structural
anomalies), female reproductive toxicity (ovarian and uterine pathology, ovarian weight, and hormonal
changes), and effects on the male reproductive system. However, all of the available medium and high
confidence studies exposed animals to high formaldehyde concentrations (>5 mg/m3), and exposure
protocols for the remaining studies were limited (i.e., the use of formalin, or an uncharacterized test
substance). This review assesses health effects of exposure for females and males separately.
6The capacity to conceive and deliver a baby.
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3.6.1. Literature Identification
The literature searches focused on reproductive and developmental outcomes in
epidemiological studies and animal studies, as well as mechanistic studies. The bibliographic databases,
search terms, and specific strategies used to search them are provided in Appendix A.5.8, as are the
specific PECO criteria and the methods for identifying literature from 2016-2021 are described in
Appendix F.
3.6.2. Study Evaluation
The epidemiological analyses that assigned individual-level exposures based on formaldehyde-
specific quantitative information, such as formaldehyde measurements or reported frequency of
product use, were considered to have greater accuracy than studies that defined participants as
exposed or nonexposed. Several studies classified individuals based on work processes, an informed
source, or occupation/industry codes from census data; there was less certainty about whether these
exposure classifications successfully distinguished high exposure from low or no exposure. Exposure
misclassification and the inclusion of individuals with probable low or infrequent exposure as exposed
reduced the sensitivity of analyses; these analyses were considered to be of low confidence.
For studies in experimental animals, a key consideration for the interpretation of developmental
and reproductive outcomes associated with inhalation exposures to formaldehyde was the potential for
coexposure to methanol, a known developmental and reproductive toxicant, when the test article was
an aqueous solution of formaldehyde. Studies that used formalin but did not control for methanol and
studies that did not characterize the formaldehyde source were assigned a low confidence rating and
contributed little to the synthesis of evidence regarding formaldehyde effects on development or the
reproductive system.
3.6.3. Developmental and Female Reproductive Toxicity
Synthesis of human health effect studies
The observational studies of reproductive toxicity or pregnancy outcomes evaluated
associations with exposure during pregnancy in three studies and with occupational exposure among
cosmetologists, woodworkers, laboratory workers, and hospital staff. The evidence regarding
fecundability7 (e.g. time to pregnancy or TTP), spontaneous abortion, pre- and post-natal growth and
other birth outcomes, and male reproductive toxicity was synthesized Time-to-pregnancy is a measure
of fertility and has been characterized in terms of number of menstrual cycles that occurred prior to
conception.8 Increased TTP reflects potential effects on gametogenesis, transport, fertilization,
migration, implantation, or survival of the embryo (Baird et al.. 1986). Thus, the measure encompasses
7 A couple's probability of conception in one menstrual cycle.
sTime-to-pregnancy of greater than 12 months of unprotected intercourse is indicative of reduced fertility. Time-to-pregnancy
is not a measure of infertility, as these studies only include women who became pregnant and had a live birth.
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both developmental and reproductive toxicity, reflects an impact on multiple biological processes in
both partners, and is sensitive to the detection of early events before a pregnancy is clinically
recognized. One medium confidence retrospective cohort study evaluated effects on TTP in relation to
maternal occupational exposure to formaldehyde (Taskinen et al.. 1999). The fecundability density ratio
(FDR) for individuals in the highest formaldehyde exposure category (mean 8-hour TWA exposure of
0.27 mg/m3) compared to nonexposed individuals was 0.57 (95% CI: 0.37, 0.85) in a model that adjusted
for potential confounders and phenol exposure. Other coexposures in the workplace were ruled out as
potential confounders. An ancillary analysis suggested that dermal exposure may have contributed to
risk of increased TTP in this cohort; this is an uncertainty with regard to the TWA concentrations
associated with this outcome.
Two medium confidence studies provided evidence that formaldehyde exposure to female
workers is associated with an increased risk of spontaneous abortion (Taskinen et al.. 1999; John et al..
1994). Of the six studies included in this review, three were determined to be low confidence, primarily
because of concerns about exposure misclassification, with probable decreased study sensitivity (Steele
and Wilkins, 1996; Hemminki et al.. 1985; Hemminki et al.. 1982). A fourth low confidence study
evaluated dose-response patterns, an important consideration for the synthesis of formaldehyde
associations, and, despite potential confounding by another exposure, found associations similar in
magnitude to the medium confidence studies (Taskinen et al.. 1994).
These studies examined diverse occupational groups exposed to different combinations of
chemical exposures and products containing formaldehyde (wood working, cosmetology, research
laboratories). Relatively high odds ratios were associated with formaldehyde exposure; odds ratios
reported by the medium confidence studies were 2.1 (95% CI: 1.0, 4.3) and 3.2 (95% CI: 1.2, 8.3)
(Taskinen et al.. 1999; John et al.. 1994). The studies addressed potential confounders, including other
workplace exposures, and found that formaldehyde was independently associated with spontaneous
abortion. Studies of hospital, nursing, or medical employees generally did not report an association,
although these low confidence studies tended to use less precise exposure assessment methods,
reducing their sensitivity.
The epidemiology literature is limited regarding formaldehyde exposure and birth outcomes.
One medium confidence birth cohort study reported decreases in birth weight and head circumference,
respectively, with each 1 ng/m3 unit increase in formaldehyde concentration measured in the mother's
homes at 34 weeks gestation (Franklin et al.. 2019). Gestational age was not associated with exposure.
The median concentration in the homes was 0.0028 mg/m3 and 23.3% of samples were below the LOD
in this relatively small study. Another medium confidence pregnancy cohort study in South Korea
observed lower birth weights associated with increasing formaldehyde concentration measured at mid
to late pregnancy (mean concentrations were 0.08 mg/m3), although there was evidence of confounding
in the positive direction by volatile organic compounds (Chang et al.. 2017). An elevated association
with congenital malformations and maternal exposure was reported by a set of low confidence studies
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among female hospital or laboratory workers (Zhu et al.. 2006; Saurel-Cubizolles et al.. 1994; Stucker et
al.. 1990; Hemminki et al.. 1985; Ericson et al.. 1984), although the precision of the odds ratios was low
(wide confidence intervals overlapping 1.0).
Synthesis of animal health effect studies
Several studies in experimental animals evaluated developmental toxicity (survival, growth, and
morphological alterations), and a few evaluated reproductive toxicity in females, however they all were
weak (low confidence) studies with methodological limitations. Notably, for most of the studies, lack of
information about the test substance or the described use of formalin, with known or presumed
methanol coexposures limited interpretation of their results. Effects on fetal survival, pre- or post-natal
growth, or morphological alterations were observed in several studies and sometimes more than one
rodent species, and maternal toxicity did not appear to be a confounding influence. However,
inconsistencies in response were also observed, and clear dose-response relationships were not
discernable. The studies tested concentrations ranging from 0.5 to 49 mg/mg3.
Mode of action information
No experimentally established MOA exists, and any potential mechanisms have not been well-
studied for any effects on development or the female reproductive system. However, evidence of
elevated oxidative stress in the blood of occupationally exposed adults might provide a potential
indirect linkage (Bono et al.. 2010). Evidence of elevated oxidative stress and hormonal alterations in
the blood and other tissues of adult rodents also might provide indirect evidence, as it is recognized that
both oxidative stress and the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal
(HPA) axes have potential roles in developmental toxicity as well as female reproductive function (Sari et
al.. 2004; Sore et al.. 2001; Kitaev et al.. 1984).
Overall evidence integration judgments and susceptibility for developmental or female reproductive
toxicity
Overall, the evidence indicates that inhalation of formaldehyde likely causes increased risk of
developmental or female reproductive toxicity in humans given appropriate exposure circumstances.
This conclusion is based on moderate evidence in observational studies finding increases in TTP and
spontaneous abortion risk among occupationally exposed women; the evidence in animals is
indeterminate, and a plausible, experimentally verified MOA explaining such effects without systemic
distribution of formaldehyde is lacking (see Table 26). The primary basis for this conclusion is from
studies of women with occupational exposures involving periodic peaks.
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1 Table 26. Evidence integration summary for effects of formaldehyde inhalation on
2 developmental or female reproductive toxicity in humans
Evidence
Evidence judgment
Hazard determination
Human
Moderate for female reproductive or developmental toxicity, based on:
Human health effect studies:
• Two medium confidence studies in two independent populations
(woodworkers, cosmetologists): decreased fecundability and increased
spontaneous abortion risk. Supporting evidence of association with
spontaneous abortion from one low confidence study among laboratory
workers. All studies evaluated multiple exposure categories with highest
risk at highest exposure level.
• Two low confidence studies of maternal exposure among health workers
with low precision: small increased risk of malformations (all combined).
• Two medium confidence studies of pregnancy cohorts indicating
decreased birth weight and head circumference.
• Null evidence from five low confidence studies with low sensitivity:
fecundability, spontaneous abortion.
Biological plausibility:
No direct evidence. However, evidence of elevated oxidative stress in the
blood of exposed adults (see Section 1.2.3) might provide a potential indirect
linkage (see explanation at right).
The evidence indicates that
inhalation of formaldehyde
likely causes increased risk of
developmental or female
reproductive toxicity in humans,
given the appropriate exposure
circumstances3
Primarily based on studies of
women with occupational
exposures to formaldehyde
concentrations as high as 1.2
mg/m3.
Potential susceptibilities: no
specific data were available to
inform potential differences in
susceptibility.
Animal
Indeterminate for developmental toxicity, based on:
Animal health effect studies:
• Mixed findings for evidence of decreased fetal survival (pre- or
postimplantation loss) across multiple low confidence studies
• Mixed findings for evidence of altered fetal or postnatal growth across
multiple low confidence studies. Variations in study design and reporting
deficiencies inhibit interpretation.
• Mixed findings for evidence of structural anomalies across multiple low
confidence studies.
Biological plausibility:
No direct evidence. However, evidence of elevated oxidative stress and
hormonal alterations in the blood of adult rodents (see Section 1.2.3) might
provide a potential indirect linkage, as it is recognized that both oxidative
stress and the HPG axis have potential roles in developmental toxicity.
Indeterminate for female reproductive toxicity, based on:
Animal health effect studies:
• Two low confidence studies in rats: decreased ovarian weight, ovarian
histopathology, and hormonal alterations
• One low confidence study in mice: Ovarian and uterine histopathology
(hypoplasia)
Biological plausibility:
Neuroendocrine-mediated mechanisms, particularly involving disruption of
the hypothalamic-pituitary-gonadal axis, are consistent with alterations of
female reproductive hormones observed in low confidence rodent studies
following formaldehyde exposures.
Other
inferences
• Relevance to humans: Relevant health effects observed in humans are the
primary basis for the hazard determination.
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• MOA\ No experimentally established MOA exists, and any potential
mechanisms have not been well studied.
a The "appropriate exposure circumstances" are more fully evaluated and defined through dose-response analysis (see below).
3.6.4. Male Reproductive Toxicity
Synthesis of human health effect studies
Two medium confidence studies from one research group reported associations with lower
sperm motility (total and progressive), delayed fertility, and spontaneous abortion (Wang et al.. 2015;
Wang et al.. 2012). A quantitative, individual-level exposure assessment was conducted; average
exposures in the workplace were 0.2-3 mg/m3. Progressive motility and total motility were inversely
associated with the formaldehyde exposure index, a cumulative measure of exposure based on a job
exposure matrix, and a strong association was observed in logistic models of below-normal values of
these motility measures (Wang et al.. 2015). For example, odds ratios of 2.58 (95% CI: 1.11, 5.97) and
3.41 (95% CI: 1.45, 7.92) were found for progressive motility less than 32% in the low and high exposure
groups, respectively, compared to the community-based referent group. TTP and spontaneous abortion
also were associated with paternal exposure to formaldehyde in this cohort (Wang et al.. 2012). Two
low confidence studies with low sensitivity found no association (Lindbohm et al.. 1991; Ward et al..
1984).
Synthesis of animal health effect studies
Fourteen studies in rodents assessed effects on the male reproductive system following
inhalation formaldehyde exposure, although eight of the studies had substantial methodological
limitations and were categorized as low confidence. The six remaining medium or high confidence
studies (examining five cohorts of rats or mice) were conducted by three research teams and only tested
high formaldehyde concentrations (>5 mg/m3). In all of these studies paraformaldehyde was
administered to the test animals and study methods provided adequate characterization of the
exposure paradigm (Sapmaz et al.. 2018; Vosoughi et al.. 2013; Vosoughi et al.. 2012; Ozen et al.. 2005;
Ozen et al.. 2002; Sarsilmaz et al.. 1999). Their studies reported that formaldehyde inhalation resulted
in adverse testes and epididymides histopathological changes in mice (Vosoughi et al.. 2013) and rats
(Sapmaz et al.. 2018; Ozen et al.. 2005; Sarsilmaz et al.. 1999), and decreased sperm count, motility, and
morphology in mice (Vosoughi et al.. 2013). The decreases in sperm count (44-49%), sperm motility
(40-46%) and abnormal sperm morphology were observed at 35 days posttreatment involving
concentrations >12.2 mg/m3 to paraformaldehyde for 10 days (Vosoughi et al.. 2013). The delayed
response suggests that the effects may have resulted from a disruption of spermatogenesis. Decreases
in serum testosterone in mice (32-49% at 24 hours postexposure) and rats (6-9% with 91 days
exposure) also were observed with exposure levels ranging from 6-25 mg/m3 (Vosoughi et al.. 2013;
Ozen et al.. 2005), a response that is biologically consistent with the Leydig cell pathology also
associated with these exposure levels (Vosoughi et al.. 2013; Sarsilmaz et al.. 1999). Results from the
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low confidence studies were largely consistent (Han et al.. 2015);(Zhou et al.. 2011a);(Zhou et al..
2011b);(Zhou et al.. 2006);(Golalipour et al.. 2007);(Appelman et al.. 1988);(Maronpot et al.. 1986);(Xing
Sy. 2007). Since the available studies only tested very high formaldehyde levels (i.e., the lowest levels
tested were often >12 mg/m3, with only a few studies testing 6.15 mg/m3 as the lowest exposure level),
significant uncertainties remain. Taken together, however, these studies provide coherent evidence of
toxicity to the male reproductive system spanning biochemical, cellular, tissue, and functional levels.
Mode of action information
No experimentally established MOA exists, and any potential mechanisms have not been well-
studied for any effects on the male reproductive system. However, mechanistic data provide some
support for indirect effects, including multiple biomarkers of oxidative stress, as well as heat shock
protein induction, that have been observed in the testes or epididymides of exposed rats in well
conducted studies (Sapmaz et al.. 2018; Zhou et al.. 2011b; Ozen et al.. 2008; Zhou et al.. 2006; Ozen et
al.. 2005; Ozen et al.. 2002). Heat shock protein (Hsp) immunoreactivity and oxidative stress resulting in
hypomethylated sperm (no studies were identified that evaluated sperm methylation changes) have
been linked to human male infertility (Werner et al.. 1997).
Overall evidence integration judgments and susceptibility for male reproductive toxicity
Overall, the evidence indicates that inhalation of formaldehyde likely causes increased risk of
reproductive toxicity in men given appropriate exposure circumstances, based on robust evidence in
animals that presents a coherent array of adverse effects in two species, and slight evidence from
observational studies of occupational exposure levels, and no plausible, experimentally verified MOA
explaining such effects without systemic distribution of formaldehyde. However, some support for
indirect effects in rodents is provided by relevant mechanistic changes in male reproductive organs (see
Table 27). The primary basis for this conclusion is based on bioassays in rodents testing formaldehyde
concentrations >6 mg/mg3.
Table 27. Evidence integration summary for effects of formaldehyde inhalation on
reproductive toxicity in males
Evidence
Evidence judgment
Hazard determination
Humans
Sliaht for male reproductive toxicity, based on:
Human health effect studies:
• One medium confidence study of exposure among male woodworkers:
inverse association with sperm motility measures, increased prevalence of
time to pregnancy, spontaneous abortion and birth defects.
• Null evidence for effects on sperm counts and morphology in one low
confidence study (because of low power).
Biological plausibility: No directly relevant studies were identified.
The evidence indicates that
inhalation of formaldehyde
likely causes increased risk of
reproductive toxicity in men,
given appropriate exposure
circumstances3
Primarily based on bioassays in
rats and mice testing
formaldehyde concentrations
above 6 mg/mg3 (no medium or
Animals
Robust for male reproductive toxicity, based on:
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Animal health effect studies:
• One high confidence study in mice, three high or medium confidence
studies in rats, and five low confidence studies in rats: dose-related
qualitative or quantitative histopathological lesions of the testes or
epididymides.
• Null evidence for testes histopathology in one low confidence study in
mice.
• One high confidence study in mice and four low confidence studies in rats:
dose-related effects on epididymal sperm.
• One high confidence study in mice, one high confidence study in rats, and
one low confidence study in rats: dose-related decreased serum
testosterone (and decreased serum luteinizing hormone in the high
confidence study in mice).
• Mixed results for organ weight changes (i.e., testes; epididymis) across
multiple high, medium, and low confidence studies.
• One low confidence study in mice with evidence of male-mediated
decreases in fetal survival.
• Note: No multigeneration study was conducted.
Biological plausibility:
Multiple biomarkers of oxidative stress, as well as heat shock protein
induction, have been observed in the testes or epididymides of exposed rats
in well-conducted studies. Heat shock protein immunoreactivity and
oxidative stress resulting in hypomethylated sperm (no studies on this
endpoint were identified) were linked to human male infertility.
high confidence studies tested
lower exposure levels).
Potential susceptibilities: No
specific data were available to
inform potential differences in
susceptibility.
Other
inferences
• Relevance to humans: Some uncertainty regarding the relevance of the
animal evidence exists, as the studies only tested extremely high
concentrations expected to cause strong irritant effects that may not
occur in humans; however, in light of the concordant findings in a well-
conducted study of humans and an absence of other evidence to the
contrary, the relevance of animal male reproductive toxicity outcomes to
humans is presumed.
• MOA: No experimentally established MOA exists, and any potential
mechanisms have not been well-studied; however, mechanistic data
provide some support for indirect effects on the male reproductive
system.
aThe "appropriate exposure circumstances" are more fully evaluated and defined through dose-response analysis (see below).
1 3.6.5. Dose-response Analysis
2 Study selection
3 The dose-response analysis for developmental and female reproductive toxicity used data from
4 one medium confidence epidemiological study that assessed dose-response relationships for the
5 outcomes, TTP and spontaneous abortion, although the timing of exposure measurements had
6 uncertain relevance to responses during the pregnancies that ended in spontaneous abortion. For male
7 reproductive toxicity, two studies of rats exposed for 13 weeks, that assessed relatively sensitive
8 endpoints, were considered appropriate for the derivation of toxicity values (see Table 28 for study
9 selection rationales).
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1 Table 28. Eligible studies for POD derivation and rationale for decisions to not select
2 specific analyses
Reference
Endpoint
POD
derived?
Rationale for
decisions to not select
Taskinen et al. (1999)
Time-to-pregnancy
Yes
Taskinen et al. (1999)
Spontaneous abortion
No
Uncertain temporal applicability of
exposure data for evaluating 1st
trimester effects
Franklin et al. (2019)
Birth weight, head circumference
No
Uncertainties in exposure distribution
due to large % < LOD and impact on
quantitative results
Chang et al. (2017)
Birth weight
No
Evidence of confounding by co-exposure;
Log transformed formaldehyde
concentration
Ozen et al. (2002)
Relative testes weight, 13-wk
exposure
Yes
Ozen et al. (2005)
Serum testosterone, Wistar rat,
13-wk exposure
Yes
Ozen et al. (2005)
Seminiferous tubule diameter,
Wistar rat, 13-wk exposure
No
Analysis of pooled tissues;
interpretability to individual rats
uncertain
(2013); Vosoughi et
al. (2012)
Seminiferous tubule diameter,
NMRI mice, 10-d exposure
No
Short exposure duration
(2013); Vosoughi et
al. (2012)
Sperm abnormalities, NMRI mice,
10-d exposure
No
Short exposure duration
(2013): Vosoughi et
al. (2012)
Serum testosterone, NMRI mice,
10-d exposure
No
Short exposure duration
Vosoughi et al.
(2013)
Testes weight, NMRI mice, 10-d
exposure
No
Short exposure duration
Sarsilmaz et al.
(1999)
Leydig cell quantity or nuclear
damage, Wistar rat, 4-wk exposure
No
Short exposure duration
Sarsilmaz et al.
(1999)
Testes weight (relative), Wistar rats,
4-wk exposure
No
Short exposure duration; non-preferred
metric (absolute testes weight preferred)
Sapmaz et al. (2018)
Seminiferous tubule measures,
Sprague-Dawley rats, 4- and 13-wk
exposure
No
Short exposure duration (for 4-wk
experiment); single exposure level
3 Derivation of PODs
4 Developmental and female reproductive toxicity
5 Taskinen et al. (1999) presented fecundability density ratios (FDR) for increased time to
6 pregnancy for index pregnancies of women in three exposure categories for jobs held beginning at least
7 6 months prior to the index pregnancy. TTP was elevated in the high exposure group relative to the
8 unexposed group and the middle 8-hour TWA exposure level was selected as a NOAEL (see Table 29).
9 The mean 8-hour TWA concentrations reported for each exposure category were adjusted for
10 likely background formaldehyde exposures experienced by the employees when they were not
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conducting work tasks involving formaldehyde exposure. Normally, exposures from occupational
studies are adjusted to account for the daily breathing volume appropriate to an environmental (versus
occupational) setting and for exposure every day of the year (U.S. EPA. 1993). However, with
formaldehyde, there is potential for exposure outside of work from in-home and environmental sources
of formaldehyde. Therefore, the POD represents exposure during an 8-hour workday.
Table 29. Summary of derivation of PODs for developmental and reproductive toxicity
in females
Endpoint and reference
Population
Observed effects by exposure level
POD (mg/m3)
Time to pregnancy in females
Occupational prevalence
studyTaskinen et al.
(1999)
Adult
women,
n = 602
Time to Pregnancy by Formaldehyde Category;
Fecundability density ratio (FDR)a
Mean 8-hr # FDRb 95% CI
TWA (mg/m3)
NOAEL = 0.106
LOAEL = 0.278
Not exposed 367 1.00
0.042 119 1.09 0.86-1.37
0.106 77 0.96 0.72-1.26
0.278 39 0.64 0.43-0.92
Fecundability density ratio = ratio of average incidence
densities of pregnancies in exposed compared to employed
unexposed women
Discrete proportional hazards regression; adjusted for
employment, smoking, alcohol consumption, irregular
menstrual cycles and # children
Comparison: index pregnancies that occurred when
participants were not employed in exposed workplace
Concentrations converted to mg/m3.
b8-hr TWA reported by authors were recalculated by EPA to account for background formaldehyde exposure while working in
"nonexposed" work areas.
Male reproductive toxicity
Both studies selected for candidate reference value derivation exposed the animals to
paraformaldehyde via inhalation (Ozen et al.. 2002) (Table 30). In Ozen et al. (2002), statistically
significant duration- and dose-dependent decreases in testis weight (relative to body weight) were
observed after 4 and 13 weeks of formaldehyde exposure. Although absolute organ weights are
preferred for this measure, because testes weights are generally conserved when body weight is
decreased, mean body weights were also significantly decreased with exposure; thus, this response
pattern suggests that the organ weight decreases were likely due to a direct effect on the testis (note: in
this case, decreased relative testis weight is likely an underestimate of the more appropriate decrease in
absolute testis weight). For the decreased testis weight at week 13 (Ozen et al.. 2002), a LOAEL of 12.3
mg/m3 was adjusted for continuous exposure based upon the experimental paradigm to yield a PODadj
of 2.93 mg/m3 (POD adj — 12.3 mg/m3 x 8 hr exposed per day/24 hours per day x 5 days exposed per
week/7 days per week).
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In Ozen et al. (2005). statistically significant dose-dependent decreases in serum testosterone
levels (6 to 9% decreases from control values) were observed following 91 days of inhalation exposure.
At the same exposure levels, significant decreases of 23 to 26% from control were noted in mean
seminiferous tubule diameters, an effect that could have been directly related to testosterone
decreases. A BMCLisd of 0.208 mg/m3 was calculated. U.S. EPA (2012) indicates that for highly soluble
and reactive gases that interact with tissue at the point of entry or for gases with systemic penetration
ppm equivalence is an appropriate default method for extrapolation.
Table 30. Summary of derivation of PODs for reproductive toxicity in males
Endpoint and reference
Species/
sex
Model
BMR
(mg/m3)
BMC
(mg/m3)
BMCL
(mg/m3)
PODADja
(mg/m3)
Ozen et al. (2005)
Decreased relative
testes weight (13 wk)
Rat/M
LOAEL
N/A
N/A
N/A
2.93
Ozen et al. (2005)
Decreased serum
testosterone (13 wk)
Rat/M
Exponential
(M2)
1SD
0.284
0.208
0.050
aPODADj is the human equivalent of the rat BMCL duration adjusted (6/24) x (5/7) for continuous daily exposure.
Derivation ofcRfCs
A UFh of 10 was applied to the developmental toxicity POD based on reduced fecundity in
reproductive age women in an occupational cohort studied by Taskinen et al. (1999) to account for
variation in the broader human population not represented by occupationally exposed groups. No other
adjustments were made to this cRfC (see Table 31).
For interspecies uncertainty for results in the animal studies, an assumption of ppm equivalence
(which is derived from pharmacokinetic principles) (Ozen et al.. 2005; Ozen et al.. 2002). male
reproductive toxicity was used to estimate a human equivalent concentration. Then a UFA of 3 was
applied to account for residual uncertainties in interspecies extrapolation from the two cRfCs for
reproductive toxicity in males derived from rat studies. A UFS of 10 was applied to both PODs to
approximate the potential effect of lifetime exposure, as these effects are not necessarily dependent on
a specific exposure window and they are expected to worsen with continued exposure. In addition, a
UFl of 10 was applied to the POD for relative testis weight, which was based on a LOAEL (Ozen et al..
2002). Finally, a UFH of 10 was applied to both PODs to account for the limited variability in
susceptibility factors encompassed by these typical studies of inbred laboratory animal populations.
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Table 31. Derivation of cRfCs for female reproductive or developmental toxicity and
male reproductive toxicity
Endpoint (reference; population)
POD
POD basis
UFa
UFh
UFl
UFs
UFd
UFcomposite
cRfC (mg/m')
FEMALE REPRODUCTIVE OR DEVELOPMENTAL TOXICITY
Delayed pregnancy Taskinen et al.
(1999); pregnant F, n = 11 at POD)
0.106
NOAEL
1
10
1
1
1
10
0.01
MALE REPRODUCTIVE TOXICITY
Relative testes weight Ozen et al.
(2005); adult rat M, 13-wk exposure)
2.93
LOAEL
3
10
10
10
1
3,000
0.001
Serum testosterone Ozen et al. (2005):
adult rat M, 13-wk exposure)
0.05
BMCLisd
3
10
1
10
1
300
0.0002
Derivation of the osRfC
The cRfC for effects on delayed pregnancy (Taskinen et al.. 1999) was chosen as the osRfC.
Although TTP is a sensitive measure of effects on the reproductive system, confidence in the POD is
judged to be low because the outcome was evaluated in a healthy working population with relatively
high exposure, which raises uncertainty about its applicability to more diverse populations. More
complete assessments of developmental endpoints by epidemiology or toxicology studies were not
available. Thus, the completeness of the database is considered low. As a mechanistic understanding is
lacking, the relevant time period for exposure effects on TTP through unrecognized fetal losses or
factors controlling the ability to conceive could range from the weeks just prior and after conception, to
the entire period of prior exposure during the life of the individual. Thus, the osRfC is 0.01 mg/m3.
The cRfC derived from Ozen et al. (2002) was considered the stronger of the two candidates for
male reproductive toxicity, and thus was chosen to represent the osRfC. The magnitude of the testes
weight response in Ozen et al. (2002) was greater than the testosterone decreases observed in Ozen et
al. (2005). and a number of other rodent studies in the formaldehyde database demonstrated similar
testis (and epididymal) weight deficits, while specific evidence of treatment-related serum testosterone
decreases was quite limited. The osRfC is 0.001 mg/m3 using the cRFC from Ozen et al. (2002). The
confidence in the POD derived from its results is low, given that the lowest formaldehyde concentration
tested in this study was 12 mg/m3. Confidence in the database is also considered low because, while a
number of published studies evaluated reproductive toxicity in males, the interpretation of study results
is complicated by their methodological limitations and exclusive use of formaldehyde concentrations
above 6 mg/m3, and data are lacking regarding functional endpoints.
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1 3.7. REFERENCE CONCENTRATION (Rfc) FOR NONCANCER HEALTH EFFECTS
2 3.7.1. Summary of cRfCs and osRfCs across Noncancer Health Effects
3 The RfC was chosen to reflect an estimate of continuous inhalation exposure to the human
4 population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious
5 effects during a lifetime. The RfC was determined from the group of osRfCs, which in turn were selected
6 from the cRfCs in each health effect system. Figure 13 presents the cRfCs derived for each health effect
7 system, the points of departure from each study, and the uncertainty factors that were applied to them.
8 As summarized in Figure 13 and Table 32, the osRfCs for each health effect system were either selected
9 from among the cRfCs or the values were combined. The rationales for osRfC selection were described
10 previously in the hazard evaluations for each health effect system.
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Eye irritation symptoms (humans)
Hanrahan et al., 1984
Eve irritation symptoms (humans)
Ku lie et a I., 1987
Eye irritation symptoms (humans)
Andersen, 1983
QJ
>- -O
5? §
u
<
Peak expiratory flow rate (humans)
Krzyzanowski et al,, 1990
Rhirioconjunctivltis prevalence (children)
Annesi-Maesana et al., 2012
Atopic excema prevalence (preganant women)
Matsunaga et al., 2008
Asthma control (children with asthma)
Venn et al.H 2003
Current asthma prevalence (children)
Annesi-Maesano et al., 2012
Current asthma prevalence (children)
Krzyzanowski et al., 1990
Squamous metaplasia (male Wistarrats)
Woutersen et al,, 1989
™ Squamous metaplasia (F344 rats of both sexes)
Kerns et al., 1983
i A
ro 2
E °-
QJ £ -J
LL CC T3
¦
> o B ¦-
Vi k "S3 c .y
* £
P n
Delayed pregnancy (pregnant women)
(Taskinen et al,, 1999)
Relative testes weight (male Wistar rats)
(Ozen et al., 2002)
Serum testosterone (male Wistar rats)
(Ozen et al., 200S)
Composite UF
A Candidate RfC
• POD(HEC)
^ *
~ •
~ •
A •
A
A
0.0001 0.0010 0.0100 0.1000
log formaldehyde concentration (mg/ m3)
Figure 13. Candidate RfCs (cRfCs) with corresponding POD and composite UF.
Note: as PODs reflect exact values, and cRfCs are rounded to 1 significant figure, the extrapolation is not
exact.
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1 Table 32. Organ/System-specific RfCs (osRfCs) for formaldehyde inhalation
Health effect
Basis
reference(s) [species]
UFC
osRfC
(mg/m3)
Integrated
hazard judgment
Confidence in
POD
estimate(s)a
Database
completeness*1
Sensory Irritation
Hanrahan et al. (1984)
[human]
10
0.009
Evidence
demonstrates
medium
high
Pulmonary Function
Krzvzanowski et al. (1990)
[human]
3
0.007
Evidence
indicates (likely)
high
high
Allergy-related
Conditions
Annesi-Maesano et al.
(2012) [humanl
3
0.008
Evidence
indicates (likely)
high
high
Asthma (prevalence of
current asthma/degree
of asthma control)
Annesi-Maesano et al.
(2012); Venn et al. (2003);
Krzvzanowski et al. (1990)
[human]
10c
0.006
Evidence
indicates (likely)
medium
medium
Respiratory Pathology
Kerns et al. (1983); Battelle
(1982); Woutersen et al.
(1989) [rati
30c
0.003
Evidence
demonstrates
medium
high
Female Developmental
Toxicity
Taskinen et al. (1999)
[human]
10
0.01
Evidence
indicates (likely)
low
low
Male Reproductive
Toxicity
Ozen et al. (2002) [rati
3,000
0.001
Evidence
indicates (likely)
low
low
This table presents the osRfCs, the studies and uncertainty factors used to derive them, and the level of confidence in the
evidence integration, the PODs, and the completeness of the database.
aThis reflects a judgment regarding how well the study-specific data are able to estimate a no-effect or minimal-effect level of
response (e.g., a lower level of confidence would be applied to high concentration studies which required extrapolation far
below the lowest tested concentration to estimate a POD). A low confidence level means that the POD derived is expected to
be less accurate.
bAlthough no UFD was applied to any cRfC, it is recognized that the evidence databases for the various health effects are not
equal. This level of confidence was added to emphasize the health areas where additional research could reduce existing
uncertainties. A low confidence level means the degree of certainty regarding the RfC is lower.
cThese two osRFCs are based on multiple studies and candidate values, sometimes with different UFcs applied. The UFC values
shown in this table and Figure 13 reflect the candidate values selected to represent each osRfC [i.e., the UFC applied to the
POD from Krzyzanowski et al. (1990) for asthma and from Woutersen et al., (1989) for respiratory pathology].
2 3.7.2. Selection of the RfC and Discussion of Confidence
3 Choice of the RfC involved consideration of both the level of certainty in the estimated osRfCs,
4 as well as the level of certainty in the evidence for the observed health effect(s). Thus, the collection of
5 studies and results used to characterize the hazard(s) and derive the osRfCs, as well as the cRfC
6 calculations themselves (including derivation of the PODs and the application of UFs), were considered
7 when choosing the RfC. These considerations are illustrated separately in Table 32, and as a composite
8 depiction of certainty in Figure 14 to support selection of the RfC (see Table 33). Based on this analysis,
9 an RfC for formaldehyde of 0.007 mg/m3 was selected. This value is within the narrow range (0.006-
10 0.009 mg/m3) of the group of respiratory system-related osRfCs derived from PODs that are the lowest
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of those identified in human population studies for formaldehyde hazards (i.e., sensory irritation,
pulmonary function, allergy-related conditions and current asthma prevalence or degree of control).
These osRfCs are each interpreted with high or medium confidence in the hazard conclusion and in the
POD estimate, and very low composite uncertainty factors were applied.
An overall confidence level of high, medium, or low is assigned to reflect the level of confidence
in the study(ies) and hazard(s) used to derive the RfC, the completeness of the database, and the RfC
itself, as described in EPA guidelines (U.S. EPA, 1994). Overall confidence in the RfC is high; the RfC is
based on a spectrum of adverse effects reported in multiple well-conducted studies of exposed humans.
Most of the study populations were exposed to formaldehyde levels in a residential or school setting,
and some of the studies focused on sensitive individuals. Finally, the hazard conclusions are supported
by an extensive literature database.
osRfCs and RfC (formaldehyde mg/ m3)
| Pulmonary function (Krzyzanowski et al., 1990)
i! A Allergy-related Conditions (Annesi-Maesano et al., 2012)
-g # Sensory Irritation (Hanrahan et al., 1984)
O Respiratory Tract Pathology (Kerns et al., 1983; Woutersen et al., 1989)
" ~ Asthma (Venn et al., 2003; Annesi-Maesano et al., 2012; Kryzanowski et al., 1990)
0>
-gj ~ Female Reproductive and/ or Developmental Toxicity (Taskinen et al., 1999)
1 o Male Reproductive Toxicity (Ozen et al., 2002)
Figure 14, Organ or system-specific RfC (osRfC) scatterplot.
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Organ/system RfCs (osRfCs) that are represented by larger shapes and that are closer to the top of the
graph are interpreted with higher confidence regarding the basis from which the value was derived (see
Table 32), and with less uncertainty (i.e., lower UFs were applied). Size of the shape represents
confidence in the study(ies) and health hazard (i.e., hazards with evidence demonstrates judgments are
larger than those with evidence indicates [likely] judgments), POD estimate(s) (for the purposes of this
graphic, confidence in the POD was given slightly greater weight than the others), and completeness of
the available evidence database for each health outcome: larger shapes indicate higher confidence; solid
shapes indicate studies in humans; hollow shapes indicate animal studies. For composite UF, if multiple
studies served as the basis for an osRfC, the composite UF associated with the candidate value selected to
represent the osRfC was used (see Table 32). The dashed line represents the proposed overall RfC of
0.007 mg/m3; the circled osRfCs indicate the cluster of effects selected as the basis for this value.
Table 33. Proposed RfC for formaldehyde-inhalation
Health effect(s) basis
RfC (mg/m3)
Overall confidence
Sensory irritation, pulmonary function, allergy-related conditions,
and degree of asthma control/prevalence of current asthma in
humans3
0.007
High
aBased on the following studies: (Annesi-Maesano et al., 2012: Matsunaga et al., 2008: Venn et al., 2003: Krzvzanowski
et al., 1990: Hanrahan et al., 1984)
3.7.3. Basis and Interpretation of the RfC
The RfC is an estimate of exposure that is likely to be without an appreciable risk of adverse
health effects over a lifetime. As illustrated in Figure 15, the selected RfC is at the upper end of the
range of outdoor formaldehyde levels recorded in some locations, and it would be expected that levels
in indoor air would exceed this concentration in most situations. However, it is important to reiterate
that this level is interpreted to be without appreciable risk. It is also important to note that the RfC does
not provide information about the magnitude of the risk of respiratory-related effects that might occur
at different concentrations above the RfC (e.g., at 0.02 or 0.03 mg/m3). As illustrated in Figure 15, nearly
all the study-specific findings of effects (e.g., LOAELs, BMCs) were not observed until formaldehyde
levels were in the upper end of the range of average indoor air concentrations, with effects generally
being observed at or above ~35-40 ng/m3. As an example comparison, a fairly large study of 398 homes
in Los Angeles, CA, Houston, TX, and Elizabeth, NJ, between 1999 and 2001 reported formaldehyde
levels of 22 ± 7.1 ng/m3 (Weisel et al.. 2005). One study that contributed to the RfC derivation involved
an analysis of the degree of asthma control in children with current asthma, and the RfC is expected to
apply to this susceptible subgroup in the population. Although current asthma symptoms and allergic
conditions were not observed in studies of children with exposures less than the range of 0.02-0.05
mg/m3, at 0.021 mg/m3, a 10.5% decrease in peak expiratory flow rate among asthmatic children could
be estimated (the regression model included a term for asthma status), based on a model using results
of Krzyzanowski et al. (1990). Thus, attributes that increase susceptibility in individuals are expected to
play a role in increasing the advent of adverse responses to formaldehyde levels above the RfC (e.g.,
somewhere between 0.007 and 0.04 mg/m3).
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Although the RfC is designed to apply to exposures over a lifetime, the relevant window of
exposure for some of the effects observed in the contributing studies may be less than lifetime. Sensory
irritation is an immediate response to reactive compounds such as formaldehyde. The relevant window
of exposure for effects on asthma outcomes also is less than lifetime, although the time frame for the
control of asthma symptoms (i.e., a few weeks) is expected to differ from that for the prevalence of
current asthma symptoms or a decrease in pulmonary function (i.e., the past 12 months). In addition,
the relevant window of exposure for the osRfC for female reproductive or developmental outcomes is
from conception to the end of the pregnancy. Thus, while the RfC is a concentration associated with
minimal risk over a lifetime of exposure, a few of the hazards or outcomes supporting the RfC could be
relevant to a shorter exposure time frame. Such interpretations might be informed by the information
presented in Figure 13 (POD to cRfC calculations) and Figure 15 (below).
Outdoor Indoor Air (normal conditions) Indoor Air (atypical; e.g., some sealed mobile homes)
Hanrahan (19S4);
Burning eyes
Krzyzanowski (1990);
PEFR measures
Annesi-Maesano (2012);
Rhinoconjunctivitis
Krzyzanowski (1990);
asthma prevalence
Annesi-Maesano (2012);
asthma prevalence
Venn (2003);
asthma control
Woutersen (1989);
squamous metaplasia
Kerns (1983);
squamous metaplasia
Taskinen (1999);
time-to-pregnancy
Ozen (2002);
testes weight
55-
ffi Q —
H
B-
Gh
Eh r
a- - i-
5h
5^
-Q-
¦O
I
-O
o-
G—
-Q
-o
Effects continue
at higher levels
Effects not observed
until higher levels
lb 15 20 4i0 60 80 100 2(50 400 600 8t)0 lOtlO
Formaldehyde Concentration [\xgj m3)
2000 4000 6000
; RfC; [x] cRfC: No appreciable risk O NO ALL, POD, N/C: No adverse change (study) 9 LOAEL or above: adverse effect in study (size = effect magnitude} — - UFs
<^> POD^,: Negligible risk (adjusted study data) ~ BMCL POD: Negligible risk in study ¦ BMC: 5-10% change (study data) — ROD adjustment — - BMC to BMCL
Figure 15, Illustration of noncancer toxicity value estimations.
This figure provides a representation of the estimates from studies supporting the osRfCs, including a
summary of formaldehyde exposure data. Formaldehyde exposure estimates reflect approximates of the
range (boxes), medians or means (black vertical bars), and more commonly reported estimates
(gradations), based on the data discussed in Appendix A.1.2. Horizontal lines in the figure reflect the
extrapolation process for arriving at points of departure (PODs) and toxicity values (unfilled symbols) in
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the context of the study-specific evidence for effects (filled symbols; effect magnitude estimated based on
study figures, tables, or reported regressions; see previous sections). Note: The x-axis is intentionally not
on a linear or log scale so as not to convey a false level of precision. Abbreviations: cRfC (candidate RfC);
N/LOAEL (no/lowest-observed-adverse-effect level); UFs (uncertainty factors); BMCL (benchmark
concentration, lower confidence bound).
3.7.4. Previous IRIS Assessment: Reference value
An inhalation RfC for formaldehyde has not previously been derived. In 1990, an oral RfD of
0.2 mg/kg-day was developed. This value was based on reduced weight gain and histopathology
(primarily of the gastrointestinal system) in Wistar rats during a 2-year bioassay in which formaldehyde
was administered in the drinking water (Til et al.. 1989). A UFC of 100 was applied to the NOAEL to
account for inter- and intraspecies differences. This RfD was interpreted with medium confidence,
based on high confidence in the principal study and medium confidence in the database.
4. CARCINOGENICITY
Multiple review articles and meta-analyses have examined the epidemiological evidence
informing potential associations between formaldehyde and cancer endpoints (e.g., Checkoway et al..
2012; Bachand et al.. 2010; Zhang et al.. 2009; Bosetti et al.. 2008; Collins and Lineker, 2004; Collins et
al.. 2001; Oiaiarvi et al.. 2000; Collins et al.. 1997; Blair et al.. 1990). The vast majority of studies focused
on cancers of the upper respiratory tract (URT) and lymphohematopoietic (LHP) system. Other cancer
types studied include bladder, brain, colon, lung, pancreas, prostate, and skin. However, aside from
lung and brain cancer, few studies showed evidence of increased risks; a cursory review of the studies of
lung and brain cancer did not provide any indication of an association with formaldehyde exposure (see
Appendix A.5.9). Given the large number of studies available on URT and LHP cancers, other cancer
types were not systematically evaluated.
The occurrences of URT cancers in humans have been described and grouped according to the
International Classification of Disease (ICD) codes. The specific cancers of the URT that are commonly
reported are sinonasal cancers (nose and nasal sinuses), cancers of the pharynx (nasopharynx,
oropharynx, and hypopharynx), and laryngeal cancer. Rarely, cancers of the buccal cavity are reported,
but as this grouping includes lip, tongue, salivary glands, gums, and the floor of the mouth, which
combine cancers of potentially different etiology and cell origin, cancers of the buccal cavity were not
reviewed. Thus, the above groupings were used for literature identification and hazard analyses.
In human studies, the specific LHP cancers that were formally reviewed were Hodgkin
lymphoma, multiple myeloma, myeloid leukemia, and lymphatic leukemia. Non-Hodgkin lymphoma is a
non-specific grouping of dozens of different lymphomas and classification systems for specific subtypes
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that have changed over time, complicating the evidence synthesis for this cancer type. As a cursory
review of the available studies did not suggest an association between formaldehyde exposure and non-
Hodgkin lymphoma, this endpoint was not formally reviewed.
4.1. METHODS FOR IDENTIFYING AND EVALUATING STUDIES
4.1.1. Literature Identification
The primary focus of this review was whether exposure to inhaled formaldehyde is associated
with specific URT or LHP cancers in humans or, in separate searches (i.e., nasal and LHP cancer studies
were searched separately), in animals. The bibliographic databases, search terms, and specific
strategies used to search them are provided in Appendix A.5.9, as are the specific PECO criteria and the
methods for identifying literature from 2016-2021 are described in Appendix F.
4.1.2. Study Evaluation
Human studies
The epidemiological studies generally examined occupational exposure to formaldehyde either
in specific work settings (e.g., cohort studies) or in case-control studies. The overwhelming majority of
information bias in epidemiological studies of formaldehyde stems from the use of occupational records
to gauge exposures with some degree of exposure misclassification or exposure measurement error
considered to be commonplace. Thus, a primary consideration in the evaluation of these studies was
the ability of the exposure assessment to reliably distinguish between levels of exposure within the
study population, or between the study population and the referent population. A large variety of
occupations were included within the studies; some represent work settings with a high likelihood of
exposure to high levels of formaldehyde, and some represent work settings with variable exposures and
in which the proportion of people exposed is quite small. In the latter case, the potential effect of
formaldehyde would be "diluted" within the larger study population, limiting the sensitivity of the study.
EPA categorized the exposure assessment methods of the identified studies into four groups (A through
D), reflecting greater or lesser degree of reliability and sensitivity of the measures. Outcome-specific
associations based on Group A exposures were considered without appreciable information bias due to
exposure measurement error, while other groups were considered increasingly biased towards the null.
Studies with small case counts may have little statistical power to detect divergences from the
null but are not necessarily expected to be biased, and no study was excluded solely on the basis of case
counts as this methodology would exclude any study which saw no effect of exposure. Therefore,
cohort studies with extensive follow-up that reported outcome-specific results on a number of different
cancers, including very rare cancers such as nasopharyngeal cancer (NPC) and sinonasal cancer, were
evaluated even when few or even no cases were observed, if information on the expected number of
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cases in the study population was provided so that confidence intervals could be presented for the
effect estimate. Studies with five or fewer exposed cases were considered to have low confidence.
Other considerations included an evaluation of limitations in effect estimates that may have
been confounded by exposure to other substances in the workplace that were known risk factors for
URT or LHP cancers and were likely to have been highly correlated with formaldehyde, as well as strong
healthy worker effects, and other selection biases.
Animal studies
Studies of cancer development in experimental animals exposed for at least subchronic duration
(shorter exposure durations were not prioritized for review, given the robust database), and which
performed histopathological evaluations of respiratory tract or hematopoietic tissues, were evaluated
(with preference given to studies that included a reasonable latency for cancers to develop, such as
conducting histopathological evaluations at >1 year of age). As these evaluations consider many of the
same studies previously evaluated for inclusion in the noncancer respiratory tract pathology section,
many parallels exist between both sets of evaluations, although several notable differences exist. For
example, duration of exposure was more important for evaluations of dysplasia and neoplasms, as
compared with evaluations of noncancer respiratory tract lesions. In addition, whereas a substantial
emphasis was placed on the characterization of the severity of the lesion for noncancer respiratory tract
changes, severity was not considered integral to the identification of cancers and dysplasia. Generally,
the study authors did not provide statistical comparisons for reported respiratory tract tumors; given
the rarity of these neoplasms in unexposed animals, any observations of malignant tumors were
considered to be biologically relevant, abnormal changes. Finally, although most studies used
paraformaldehyde or freshly prepared formalin as the test article, some studies tested commercial
formalin. Coexposure to methanol was considered to be a major concern for LHP cancers; it was
considered to be less of a concern when identifying effects of inhaled formaldehyde on respiratory
cancers. A final minor difference involved the preference for microscopic examination of several tissues
applicable to assessing potential LHP cancers, and a preference for blinded assessment of the slides.
4.2. UPPER RESPIRATORY TRACT CANCERS
This section examines the evidence pertaining to the carcinogenic effect of formaldehyde
exposure on the URT of humans and animals. The specific endpoints considered included diagnoses of
nasopharyngeal cancer, sinonasal cancer, cancers of the oropharynx and hypopharynx, and laryngeal
cancer; however, as it was ultimately judged that there was inadequate evidence on laryngeal cancer,
these data are not discussed in this Overview (see Section 1.2.5 in the Toxicological Review). This
section describes experimental animal studies examining the potential for cancers of the nasal cavity
and proximal regions of the URT, and mechanistic studies relevant to interpreting potential carcinogenic
effects on the URT.
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4.2.1. Synthesis of Human Health Effect Studies
Nasopharyngeal Cancer
The evidence for formaldehyde exposure and the risk of nasopharyngeal cancer presents
consistent findings of increased risk in exposed groups across several studies, including results classified
with high, medium, and low confidence. These studies examined different populations, in different
geographical locations, under different exposure settings and employing different study designs.
Fourteen of 17 studies reported increased risks of nasopharyngeal cancer with at least one metric of
formaldehyde exposure—often with both clear statistical significance and dose-response relationships
(see Figure 16). These included the results of a large cohort study of 25,619 U.S. workers (Beane
Freeman et al.. 2013) classified with high confidence, and all four sets of results classified with medium
confidence. Nine studies in eight independent populations reported relative effect estimates greater
than three-fold. The study results exhibited a biologically coherent temporal relationship consistent
with a pattern of exposure to formaldehyde and subsequent death from nasopharyngeal cancer,
allowing time for cancer induction, latency, and mortality.
The reported dose-response relationships showing that multiple measures of increased
exposure to formaldehyde were repeatedly associated with increased risk of mortality from
nasopharyngeal cancer were especially strong among studies primarily focused on squamous cell
carcinomas. Excluding nasopharyngeal cancer cases with undifferentiated or nonkeratinizing histology,
Vaughan et al. (2000) reported a clear dose-response with increased probability of exposure. Among
those subjects considered to be "definitely exposed," there were increasing risks of nasopharyngeal
cancer with increasing duration of formaldehyde exposure (p < 0.001) and with increased cumulative
formaldehyde exposure (p < 0.001). Further evidence of dose-response relationships was reported by
Beane Freeman et al. (2009) for peak formaldehyde exposures (p = 0.005, model including exposed and
unexposed person-years), and, to a lesser degree, for cumulative exposures (p = 0.06, model including
exposed and unexposed person-years) and with average intensity of formaldehyde exposure (p = 0.09,
model including exposed and unexposed person-years).
The evaluation of potential biases resulted in reasonable confidence that alternative
explanations have been ruled out, including chance, bias, and confounding within individual studies or
across studies. There are reasonable explanations for the lack of findings in the three studies with very
low background rates of nasopharyngeal cancer. The NPC results from the Coggon et al. (2014), Meyers
et al. (2013), and Siew et al. (2012) studies were all considered to lack sensitivity to detect any true
effect because there was a very low number of expected cases in study populations, which contributed
to their classifications of low confidence.
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medium and low confidence. Seventeen informative studies evaluated sinonasal cancer among study
subjects with formaldehyde exposure based on occupational history, including 4 sets of results classified
with medium confidence—one of which represents a large, pooled analysis of 12 case-control studies
(see Figure 17). These studies examined different populations, in different locations, under different
exposure settings, and used different study designs.
For sinonasal cancer, it is important to consider the histological subtype or types in each report
(squamous cell carcinoma, adenocarcinoma, or mixed). Sinonasal cancer is exceedingly rare; eight
cohort studies reported zero cases in their study populations. With expected rates for sinonasal cancer
as low as 0.6 cases per 100,000 people each year, these studies lacked the statistical sensitivity to detect
an association with formaldehyde and were classified with low confidence. Of the nine studies that did
observe cases of sinonasal cancer, results from six reported increased risks of sinonasal cancer that
appeared to be associated with exposure to formaldehyde—four of six sets of results had been classified
with medium confidence (Beane Freeman et al.. 2013; Luce et al.. 2002; Roush et al.. 1987; Olsen and
Asnaes, 1986) and two with low confidence (Teschke et al.. 1997; Hansen and Olsen. 1995).
Associations were stronger for adenocarcinomas than for squamous cell carcinomas. However, both
histological cell type groupings, and a mixed type group, yielded results that were consistently
elevated—with a clear demonstration of statistical significance for the adenocarcinomas. Two medium
confidence studies reported at least a 3-fold increase in risk for adenocarcinoma. Potential confounding
by wood dust was addressed and ruled out by the authors. Each of the other three sets of results that
did not report some increase in risk associated with formaldehyde exposure had been in the group
classified with low confidence, in part due to their lack of sensitivity to detect a true effect (Coggon et
al.. 2014; Siew et al.. 2012; Pesch et al.. 2008).
A dose-response relationship was observed in a large, pooled analysis of 12 case-control studies.
Luce et al. (2002)9 pooled 196 cases of sinonasal adenocarcinoma and 432 cases of squamous cell
carcinoma and were able to contrast risks in three levels of exposure probability with the risk in the
unexposed. An exposure-response relationship for adenocarcinoma, controlling for coexposure to wood
dust, was observed for both men and women with the highest risks among those with the highest
probability of exposure. The odds ratio (OR) among men with the highest cumulative exposure was 3.0
(95% CI: 1.5, 5.7), while it was 5.8 (95% CI: 1.7, 19.4) among women. No dose-response pattern was
observed for squamous cell carcinoma. Analyses by Luce et al. (2002) allowing for a 20-year induction
period showed only minimal impacts on the magnitude of relative risk; longer latency periods were not
evaluated, which leaves some uncertainty.
The evaluation of chance, bias, and confounding within individual studies or across studies
resulted in the conclusion that these alternative explanations for the observed associations could be
reasonably ruled out. While smoking and alcohol may be independent risk factors for sinonasal cancer
9Note the pooled study by Luce et al. (2002) includes data from 12 publications and thus represents substantially more
information than a single result (see Toxicological Review for additional details).
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they are unlikely to be related to formaldehyde exposure and therefore unlikely to be across-the-board
confounders. Wood dust, however, is a potential confounder as many wood-related jobs also have
exposures to formaldehyde and the association between wood dust exposure and sinonasal cancer is
extremely strong, with relative risks greater than 30-fold (Olsen and Asnaes, 1986). Wood dust may be
an independent risk factor for sinonasal cancer; however, the majority of investigators presented
analytic results for formaldehyde among workers who were either not exposed to wood dust (Hansen
and Olsen. 1995; Olsen and Asnaes. 1986), or else controlled for the potential confounding of the effects
of wood dust on the risk of sinonasal cancer and did not find wood dust to be a confounder (Luce et al..
2002). Although many of the analyses lacked precision due to the rarity of sinonasal cancer, the
observations of multiple instances of very strong associations in different settings reduces the likelihood
that chance, confounding, or other biases can explain the observed associations.
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Figure 17. Highest (medium) confidence epidemiological studies reporting sinonasal
cancer risk estimates.
Results are grouped by histological type as squamous cell carcinomas, mixed cell types, or
adenocarcinoma. SMR: standardized mortality ratio. SPIR: Standardized Proportional Incidence Ratio.
RR: relative risk. OR: odds ratio. TSFE: time since first exposure. For each measure of association, the
number of exposed cases is provided in brackets. For studies with multiple metrics of exposure, only the
highest category of each exposure metric is presented. Note that two studies (Luce et al., 2002; Olsen
and Asnaes, 1986) reported separate results for squamous cell carcinoma and adenocarcinoma and
appear twice in the figure. Also note that the pooled analysis by Luce et al. (2002) includes data from 12
publications and thus represents substantially more information than a single set of results.
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Oropharyngeal/Hypopharyngeal cancer
Evidence describing an association between formaldehyde exposure and the risk of
oropharyngeal/hypopharyngeal cancer was available from nine reports on six distinct study
populations—four reports on three cohort studies (Coggon et al.. 2014; Meyers et al.. 2013; Marsh et
al.. 2007; Marsh et al.. 2002) and five reports on three case-control studies (Laforest et al.. 2000;
Gustavsson et al.. 1998; Vaughan. 1989; Vaughan et al.. 1986a. b).
Overall, the findings were heterogeneous. Increased risks of oropharyngeal/hypopharyngeal
cancer were reported by two medium confidence studies associated with multiple metrics of
formaldehyde exposure, but little other evidence of increases in risk across one other medium and two
low confidence was observed (see Figure 18). The strength of the association was variable with several
studies reporting results near the null, and two medium confidence studies reporting 3- to 5-fold
increases in risk among groups with the highest exposure probability or duration. One study observed
dose-response relationships using multiple metrics of exposure.
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rats (see Figure 19). Following exposure of rats to formaldehyde for 2 years, an increase in SCCs was
observed in five of six studies interpreted with medium or high confidence. SCCs were not reproducibly
detected below 6 mg/m3 formaldehyde; however, none of the available rat studies tested exposure
between 3 and 6 mg/m3, introducing some uncertainty.
Specifically regarding SCCs, these exposure-induced tumors were restricted to the nasal cavity,
were not observed in other respiratory tract regions, such as the larynx and lung, and generally
developed in animals that were observed for longer than 12 months. The locations of the induced SCCs
were consistent with both the distribution of inhaled formaldehyde and locations of other
formaldehyde-induced nasal pathologies. There were clear species differences in the severity of SCCs,
with hamsters displaying little evidence of toxicity and rats exhibiting amplified responses as compared
to mice (likely attributable to a lower inhaled dose of formaldehyde). While these tumors were
detected in exposed male and female Fischer 344 (F344) and Sprague Dawley (SD) rats, findings in
Wistar rats were less clear. The rat studies are summarized in Figure 19.
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4.2.3. Mode-of-action Information
In F344 rats chronically exposed to formaldehyde, there is a clear temporal, dose-responsive
and biological relationship in the appearance of exposure-related genotoxicity, sustained epithelial
damage, cellular proliferation, and eventual development of SCC or polypoid adenoma (PA; a benign
lesion independent from, and not a precursor to, SCC), consistent with similar relationships evident in
analogous URT tissues from both the monkey and human databases. Furthermore, the chronic
formaldehyde exposure concentrations reported to elicit nasal cytotoxic pathology appear to be higher
in the rats and monkeys evaluated experimentally, compared with the results from human
epidemiological cohorts, whereas formaldehyde-associated genotoxicity has been induced in analogous
portal-of-entry tissues from rats, monkeys, and humans exposed to similar formaldehyde concentrations
(see Toxicological Review for details). Together, genotoxicity, cellular proliferation, and cytotoxicity-
induced tissue regenerative proliferation exhibit multiple layers of coherence as a function of species
and anatomy, temporality, concentration, and duration of exposure. When integrated, this evidence
forms a biologically relevant MOA for formaldehyde-induced URT carcinogenesis (U.S. EPA. 2005a). A
summary and evaluation of the mechanistic evidence is presented in Table 34.
Strong, consistent evidence from rodents and monkeys supports the role for both direct (i.e.,
potentially DNA-protein crosslinks, DPX, or hmDNA adduct associated) mutagenicity as well as indirect
genotoxicity, mutagenicity, and regenerative proliferation resulting from respiratory tissue pathology, in
rodent URT carcinogenesis (see Toxicological Review Section 1.2.5 Upper Respiratory Tract Cancer
Mode-of-Action Analysis for details). DNA labeling studies in rodent nasal epithelium suggest that cell
division may also accelerate in response to marginally cytotoxic tissue concentrations resulting from
short-term, lower level, or discontinuous exposure scenarios, although this evidence was neither strong
nor consistent across similar studies and model systems. Observations of mutagenicity, cytotoxic
epithelial pathology, and proliferation correspond histologically, anatomically, temporally, and dose-
responsively with subsequent SCC and PA formation, consistent with contribution of both mutagenesis
and regenerative proliferation to rodent URT carcinogenesis following formaldehyde exposure.
Mutagenicity is presumed to be a relevant component of URT carcinogenesis in humans,
supported by strong evidence of direct genotoxicity in both rodents and monkeys and consistent
observations of direct genotoxicity and mutagenicity from human epidemiological studies. Increased
nasal epithelial cell proliferation (in rats and monkeys) coincides anatomically with dysplastic lesions
found in tissues from similar species as well as with progressive, proliferative lesions in the nasal/buccal
epithelium and nasopharynx of chronically exposed humans. This cross-species concordance, combined
with the observation that cellular proliferation may be induced at lower exposures or following shorter
durations of exposure than those eliciting tissue metaplasia, suggests that cellular proliferation in the
presence of marginal tissue toxicity may also be potentially relevant to human URT carcinogenesis, as
this episodic exposure scenario may be more frequently encountered in human populations than the
continuous, chronic high-level exposures traditionally employed in rodent cancer bioassays. Increasing
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incidence or severity of nasal dysfunction and progressive pathology is associated with escalating
formaldehyde exposure concentration or duration in humans, monkeys, and rats. While POE tissue
sensitivity to formaldehyde toxicity may quantitatively differ from humans to rats and other rodents,
qualitatively similar nasal dysfunction and pathology consistent with pre-neoplastic stages of cancer
progression are observed across analogous tissues from all affected species, and therefore conclusions
derived from these model systems are presumed relevant to human URT carcinogenesis. Given this
presumed relevance, the potential for an increased susceptibility of specific human populations to
developing URT cancers can be informed by both the human data and relevant mechanistic evidence
from experimental model systems.
Table 34. Summary considerations for upper respiratory tract (URT) carcinogenesis
(the primary support for genotoxicity or mutagenicity is noted; see Toxicological Review
for additional details)
Hypothesized
mechanistic
event
Experimental evidence
pertinent to mechanistic event
Human relevance
Weight-of-evidence and
biological plausibility
Direct, or
presumed direct,
genotoxicity and
mutagenicity
(and indirectly
supporting
information)
• 'T* MN in URT tissue from human students
and workers at average concentrations as
low as 0.1 mg/m3 (subchronic-to-chronic
exposure) (Aglan and Mansour, 2018);
(Ballarin et al., 1992); (Burgaz et al..
2001); (Burgaz et al., 2002); (Costa et
al., 2019); (Costa et al., 2008);
(Ladeira et al., 2013); (Peteffi et al.,
2015); (Viegas et al., 2013); (Viegas et
al., 2010); (Ye et al., 2005)
• 'T* DNA monoadducts in nasal tissues of
exposed rats and monkeys using highly
sensitive methods (short-term or subchronic
exposure) (Yu et al., 2015; Lu et al.,
2011; Moeller et al., 2011; Lu et al.,
2010)
• 'T* DPX in URT tissues of monkeys (acute
exposure) and F344 rats (acute-to-
subchronic exposure) (e.g., (Lai et al.,
2016; Georgieva et al., 1999;
Casanova et al., 1994)) [note: not
observed in 2 short- term controlled
exposure studies]
• No effect on MN incidence nasal tissue
(Speit et al., 2011) or in BAL cells (Neuss
et al., 2010) in single studies in rats (28d
exposure)
Yes. Markers of direct
genotoxicity correspond
anatomically and temporally
with subsequent URT
neoplasia in experimental
animal models, are consistent
with increased MN induction
following exposure in
humans and are presumed
relevant to human
carcinogenesis.
Strong and consistent
evidence for formaldehyde-
induced direct genotoxicity
and mutagenicity exists
from both experimental
animal models and human
molecular epidemiology to
support a significant role
for mutagenicity in URT
carcinogenesis.
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Hypothesized
mechanistic
event
Experimental evidence
pertinent to mechanistic event
Human relevance
Weight-of-evidence and
biological plausibility
• While several studies suggest a role for
exposure-induced modifications to the
tumor suppressor, p53, in SCC development
(see Appendix A.4.5), a short-term study in
mice deficient for Trp53 (encodes p53) failed
to observe increases in tumors (Morgan et
al., 2017)
• Indirect support: strong and consistent
evidence of mutagenicity (increased
incidence of MN, CA, and chromosome
aneuploidies) in PBLs of human workers (see
Section 4.3)
• Indirect support: strong and consistent
evidence of genotoxicity and mutagenicity in
numerous in vitro mammalian and non-
mammalian systems (see Appendix A.4)
Cytotoxicity-
induced
regenerative
proliferation
• \1/ Nasal mucociliary function, 'T* nasal
hyperplasia, keratinization or squamous
metaplasia, URT rhinitis, irritation, and
inflammation in humans (acute-to-chronic
exposure)
• \1/ Nasal cilia content, 'T* hyperplasia and
squamous metaplasia in URT tissues from
monkeys (acute-to-subchronic exposure)
• Associated with 'T* URT cell proliferation in
rhesus monkeys
• \1/ Nasal mucociliary function, 'T* nasal
rhinitis, hyperplasia and squamous
metaplasia dysplasia in various rat strains
and B6C3F1 mice (acute-to-chronic
exposure)
• Associated with 'T* URT proliferation (rats;
mice)
Yes. Increasing incidence or
severity of URT dysfunction
or pathology is positively
associated with
formaldehyde exposure in
humans, monkeys, and rats.
A continuum of similar
epithelial pathology is
observed across affected
species at POE tissues, and
therefore the resulting
increased cellular turnover
observed in experimental
models is presumed relevant
to human carcinogenesis.
Strong and consistent
evidence exists which
associates the nasal
epithelial pathology-driven
proliferation with SCC
abundance following
formaldehyde exposure in
rodent experimental
models to support a
significant role for
regenerative proliferation
in URT carcinogenesis.
Cellular
mitogenesis in
the absence of
cytotoxic tissue
pathology
• Clear evidence of 'T* URT cell proliferation
under conditions also resulting in tissue
pathology in rhesus monkeys
• Exposure to subcytotoxic concentrations not
evaluated
• Clear evidence of 'T* URT cell proliferation
under conditions also resulting in tissue
pathology in Wistar and F344 rats
(>4 mg/m3)
• Suggestive evidence of 'T* URT cell
proliferation under conditions not clearly
causing tissue pathology (<4 mg/m3)
Yes. Cellular proliferation
may be increased at lower
exposures or following
shorter durations of exposure
than that eliciting tissue
pathology, which suggests
that mitogenesis may be
directly stimulated by
formaldehyde exposure.
Proliferation is expected to
accelerate and enhance
carcinogenesis in both
humans and animals and is
presumed relevant to human
carcinogenesis.
Limited and inconsistent
evidence associates cellular
proliferation with
formaldehyde exposures
below those eliciting
cytotoxic pathology in the
rat nasal epithelium, which
precludes a determination
as to the importance of this
phenomenon in URT
carcinogenesis.
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Hypothesized
mechanistic
event
Experimental evidence
pertinent to mechanistic event
Human relevance
Weight-of-evidence and
biological plausibility
Oxidative stress,
immune disease
and dysfunction
in the URT
• 'T* LRT infection frequency, inflammation,
allergic outcomes in children; 'T* leukocyte
activation, allergy symptoms, chronic URT
inflammation and \|/ infection resistance in
adult workers (subchronic-to-chronic
exposure)
• 'T* LRT oxidative stress, markers of
inflammation and leukocyte recruitment in
rats and mice; 'T* airway wall thickening or
remodeling in mice and rats following
ovalbumin sensitization
• 'T* Malignancy and neutrophil involvement of
lung metastases, \|/ lung natural killer (NK)
cell numbers and activity in C57BL/6 mice
Yes. Nasal infection, markers
of persistent inflammation or
immune dysfunction are
positively associated with a
range of formaldehyde
exposure in both humans and
rodents. Oxidative stress and
chronic inflammatory
diseases
(immunosuppression) are
presumed relevant to human
carcinogenesis. The
relevance of other immune
system dysfunctions to
human carcinogenesis, such
as allergy, is less clear.
While evidence exists
supporting oxidative stress,
chronic inflammation and
various immune
dysfunctions following
formaldehyde exposure in
humans and experimental
animal models, the
evidence supporting
associations between these
effects and URT
carcinogenesis is
insufficient to evaluate the
contribution of these
effects independently in
either humans or
experimental animals.
4.2.4. Overall Evidence Integration Judgments and Susceptibility for Upper Respiratory Tract Cancers
Table 35 summarizes the evidence integration judgments and supporting rationale for the
individual URT cancers.
Epidemiological findings provide robust evidence for nasopharyngeal cancers (NPCs), based on
groups with occupational exposure. Consistent increases in NPC risk were reported by numerous high
and medium confidence studies involving occupational exposure to formaldehyde among diverse
populations in different geographic locations and exposure settings that accounted for expected
temporal relationships for cancer induction and progression, with several reporting a large magnitude of
relative risk (RR >3). A dose-response gradient was reported for various measures of exposure, including
cumulative exposure, duration of exposure, and peak exposure. Robust evidence for nasal cancers is
provided from studies in experimental animals (rats and mice). In animals, the incidence of lesions, as
well as the tumor invasiveness and latency, was reproducibly shown to worsen with increasing
formaldehyde exposure level. The distribution of tumors was dependent on duration of exposure as
well as formaldehyde concentration. Mechanistic changes associated with the development of cancer in
the nasal cavity were consistently observed in humans and experimental systems, including
genotoxicity, epithelial damage and proliferation, and eventual cancer development in relevant URT
tissues. The mechanistic changes and URT lesions exhibited a temporal and dose-response relationship
coherent with carcinogenesis and supportive of a mutagenic MOA. The observed formaldehyde
exposure-induced nasal tumors and mechanistic changes in animals are considered directly relevant to
changes in the human nasopharynx (the nasopharynx is part of the nasal cavity and a recognized target
of inhaled nasal toxicants). Thus, based on robust human evidence, robust animal evidence, and
mechanistic evidence supporting a mutagenic MOA for NPC, the evidence demonstrates that
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formaldehyde inhalation causes nasopharyngeal cancer in humans, given appropriate exposure
circumstances. This conclusion is primarily based on studies of groups exposed to occupational
formaldehyde levels and coherent findings in animals, with tumors in rodents generally only observed at
formaldehyde concentrations above 6 mg/m3.
Epidemiological findings also provide robust evidence for sinonasal cancer (SNC), based on
groups with occupational exposure. The robust judgment for SNC is supported by a smaller set of
epidemiological studies than for NPC, although a large, pooled analysis of 12 casecontrol studies
included a large number of cases and greater detail on formaldehyde exposures, which increased
confidence. This study observed an increasing trend in risk for adenocarcinoma with higher cumulative
exposure among men and women in analyses that controlled for key confounders including exposure to
wood dust. The studies were conducted in different geographic locations and exposure settings that
accounted for expected temporal relationships for cancer induction and progression. Rodent nasal
cancers and related mechanistic changes in the nasal cavity are considered relevant to human SNC,
although some uncertainty in their applicability to SNC, as compared to NPC remains, and thus
judgments of both robust and moderate animal evidence were considered. Ultimately, given this
uncertainty in applicability, while the animal and mechanistic evidence cited for NPC is judged as
informative and supportive for interpreting SNC, including providing sufficient support for a mutagenic
MOA for this cancer type, the animal evidence overall is interpreted as moderate rather than robust.
Based on robust human evidence, moderate animal evidence, and mechanistic evidence supporting a
mutagenic MOA for SNC, the evidence demonstrates that formaldehyde inhalation causes sinonasal
cancer in humans, given appropriate exposure circumstances. This conclusion is primarily based on
studies of groups exposed to occupational formaldehyde levels.
For oropharyngeal/hypopharyngeal cancers, the human evidence is slight, based on data from
highly exposed workers, and slight animal evidence is provided from relevant observations of
preneoplastic lesions and mechanistic changes. Taken together, the evidence suggests, but is not
sufficient to infer, that formaldehyde inhalation might cause oropharyngeal/hypopharyngeal cancers
given appropriate exposure circumstances.
Table 35. Evidence integration summary for effects of formaldehyde inhalation on
URT cancers
Evidence
Evidence judgment
Hazard determination
Nasopharyngeal cancer (NPC)
Human
evidence
Robust, based on:
Human health effect studies:
•Consistent increases in risk across numerous high, medium and low
confidence studies
•Very strong associations (eight studies reported at least a threefold increase
in risk for some exposure categories, three of the eight were of high or
The evidence demonstrates
that formaldehyde inhalation
causes nasopharyngeal cancer
in humans, given appropriate
exposure circumstances3
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medium confidence, direction of potential bias toward the null)
• Evidence of exposure-response relationships across multiple measures of
increased exposure
• A temporal relationship consistent with causality (i.e., allowing for cancer
induction, latency and mortality)
Biological Plausibility:
Although not as strong as the animal database of mechanistic studies,
mechanistic evidence from human studies indicates a clear biological
relationship with genotoxicity, epithelial damage and proliferation, and
eventual cancer development in relevant URT tissues
Primarily based on studies of
groups of workers exposed to
occupational formaldehyde
levels, coherent findings in
animals (with tumors in rodents
generally only at formaldehyde
levels above 6 mg/m3), and a
well-supported MOA for nasal
tumor development
Animal
evidence
Robust, based on:
Animal health effect studies:
• Tumors of the respiratory tract (predominantly nasal squamous cell
carcinomas, SCCs, but including other epithelial and nonepithelial tumors)
were consistently observed in mice and in several strains of rats in
numerous high and medium confidence studies, but not in hamsters,
generally at formaldehyde levels above 6 mg/m3.
• The lesions progressed to more posterior locations with increasing duration
and concentration of formaldehyde exposure
• The development of these lesions, particularly the SCCs, depended on the
duration of observation and, based on an increasing incidence and severity
of lesions in animals exposed for longer periods of time, the formaldehyde
exposure duration. Most notably, the lesion incidence, as well as the tumor
invasiveness and latency, was reproducibly shown to worsen with increasing
formaldehyde exposure level.
Biological Plausibility:
Mechanistic changes consistent with cancer development in nasal tissues were
observed across species, including rats, mice, and monkeys. In rats chronically
exposed to formaldehyde, a clear temporal, dose-responsive, and biological
relationship was observed in the appearance of genotoxicity, sustained
epithelial damage, cellular proliferation, and eventual tumor development.
Potential Susceptibilities: There
is very little evidence to
evaluate the potential risk to
sensitive populations and/or
lifestages. However, several
animal studies suggest that
prior damage to the nasal
epithelium might increase the
development of cancer in these
damaged regions.
Other
Inferences
• Relevance of the animal evidence to human NPC. The types of findings were
consistent and coherent across species (including humans). Although site
concordance is not essential (U.S. EPA, 2005a), considering the anatomy
of the rodent and human URT and the importance of the distribution of
inhaled formaldehyde, the observed formaldehyde exposure-induced nasal
tumors and mechanistic changes in animals are considered directly relevant
to changes in the human nasopharynx.
• /WO/4: Together, genotoxicity, cellular proliferation, and cytotoxicity-
induced regenerative proliferation exhibit multiple layers of coherence as a
function of species, anatomy, temporality, concentration, and duration of
exposure, and when integrated, form a biologically relevant MOA for
formaldehyde-induced URT carcinogenesis (U.S. EPA, 2005a). While the
chronic formaldehyde exposure concentrations reported to elicit nasal
cytotoxic pathology appear to be higher in the rats and nonhuman
primates evaluated experimentally (>4 mg/m3), compared with the results
from human epidemiological cohorts (>0.3 mg/m3), formaldehyde-
associated genotoxicity has been induced in analogous POE tissues from
rats, nonhuman primates and humans exposed similarly (<0.9 mg/m3).
Sinonasal cancer (SNC)
Human
evidence
Robust, based primarily on:
Human health effect studies:
The evidence demonstrates
that formaldehyde inhalation
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• Consistent increases in risk across a set of medium and low confidence
studies; four (2 medium and 2 low confidence) studies reporting at least a
threefold increase in risk, primarily for adenocarcinoma, including the
largest study, a pooled analysis of 12 case-control studies, demonstrating a
clear exposure-response relationship.
• Increased risk of lower magnitude reported by two other medium
confidence studies.
• Null results in 3 insensitive low confidence studies.
Biological Plausibility:
The human mechanistic evidence cited for NPC is informative and supportive
for interpreting the biological plausibility of SNC.
causes sinonasal cancer in
humans, given appropriate
exposure circumstances3
Primarily based on studies of
groups of workers exposed to
occupational formaldehyde
levels. Although less certain
than the support provided for
NPCs, animal and MOA
evidence provide support for
the human evidence.
Potential Susceptibilities: There
is very little evidence to
evaluate the potential risk to
sensitive populations and/or
lifestages. However, several
animal studies suggest that
prior damage to the nasal
epithelium might increase the
development of cancer in these
damaged regions.
Animal
evidence
Moderate, based on:
Animal health effect studies:
(Same evidence base as for NPC above)
• Note: tumors were not reported in the maxillary sinus of exposed animals
Biological Plausibility:
(Same mechanistic evidence base as for NPC above)
• Although infrequently examined, studies that measured noncancer lesions
in the maxillary sinus did not detect treatment-related respiratory tract
pathology, although cell proliferation was observed (see Section 1.2.4).
• Although also poorly studied, some mechanistic changes consistent with
the MOA for nasal cancers, including increased DPX in the monkey maxillary
sinus, have been observed.
Other
Inferences
• Relevance of the animal evidence to human SNC. The types of findings were
consistent and coherent across species (including humans). The strong
animal and mechanistic evidence for nasal cancers across species is
interpreted to provide moderate evidence supportive of sinonasal cancer (a
judgment of moderate rather than robust reflects some uncertainty in
interpreting the nasal cavity findings in animals as fully applicable to human
sinonasal cancer specifically).
• MOA\ Similar to the inference above, although there is uncertainty in the
application of the identified MOA to SNC, the evidence overall is interpreted
to provide reasonable support for the mutagenic MOA asapplicable to SNC.
Oropharyngeal/ Hypopharyngeal cancer (OHPC)
Human
evidence
Slight, based on:
Human health effect studies:
• Increased risks in two of three medium confidence studies that evaluated
multiple metrics of exposure and reported three- to fivefold increases in
those highly exposed, including one which demonstrated clear exposure-
response relationships across several metrics
• However, little evidence of increases in risk (near the null) across one
medium and two low confidence results
Biological Plausibility:
Although cells from exposed humans in tissues closely apposed to the
oropharynx and, more indirectly, the hypopharynx (e.g., buccal cells)
demonstrate mechanistic changes consistent with the development of cancer,
including genotoxicity, these data were not interpreted as sufficient to further
strengthen the human evidence judgment beyond slight.
The evidence suggests, but is
not sufficient to infer, that
formaldehyde inhalation might
cause oropharyngeal
/hypopharyngeal cancer, given
appropriate exposure
circumstances'5
Animal
evidence
Slight, based on:
Animal health effect studies:
• While most findings in animals were localized to the nasal cavity, some data
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suggest that changes in more caudal (e.g., in the trachea) regions, including
evidence of dysplasia (a dedicated pre-neoplastic lesion) in one study, can
occur with very high formaldehyde exposures and/or different breathing
patterns (e.g., oronasal breathing in monkeys).
• Changes in the more caudal URT tissues most relevant to OHPC were
generally less direct indicators of cancer development, were less severe, or
occurred only at very high exposure levels.
Biological Plausibility:
Mechanistic changes within caudal portions of the rodent and monkey URT
have been observed, and oronasal breathing in humans (contrasting nasal-
only breathing in rodents) infers an increased potential relevance of
mechanistic changes in rostral (anterior) regions of the rodent to human
OHPC. However, this was not interpreted as sufficient to further strengthen
the evidence judgment beyond slight.
Other
inferences
• Relevance of the animal evidence to human OHPC. While cancer site
concordance is not reauired for hazard determination (U.S. EPA, 2005a),
given the known reactivity and distribution of inhaled formaldehyde, a
lesser level of confidence in the applicability of the animal nasal findings is
inferred for OHPC as compared to NPC or SNC.
• /WO/4: While aspects of the MOA for nasal cancers, including NPC and SNC,
may be operant for OHPC, the evidence overall is not interpreted to
provide reasonable support for a MOA that is relevant to OHPC.
Note: Laryngeal cancer evidence is not presented in this Overview (see Section 1.2.5 of the Toxicological Review).
aThe "appropriate exposure circumstances" are more fully evaluated and defined through dose-response analysis (Section 4.5).
bGiven the uncertainty in this judgment and the available evidence, this assessment does not attempt to define what might be
the "appropriate exposure circumstances" for developing this outcome.
4.3. LYMPHOHEMATOPOIETIC (LHP) CANCERS
This section examines the evidence pertaining to the carcinogenic effect of formaldehyde
exposure on lymphohematopoietic (LHP) cancer in humans and animals. The specific endpoints
included: Hodgkin lymphoma, multiple myeloma, myeloid leukemia, and lymphatic leukemia; however,
as it was ultimately judged that there was inadequate evidence on lymphatic leukemia, these data are
not discussed in this Overview (see Section 1.3.3 of the Toxicological Review). This section discusses
experimental animal studies examining histopathological lesions associated with leukemia or lymphoma,
and mechanistic studies relevant to interpreting potential carcinogenic effects on these tissues.
4.3.1. Synthesis of Human Health Effect Studies
Myeloid Leukemia
Evidence describing the association between formaldehyde exposure and the risk of myeloid
leukemia was available from 13 epidemiological papers reporting on 10 different study populations:
three case-control studies (Talibov et al.. 2014; Hauptmann et al.. 2009; Blair et al.. 2001) and nine
cohort studies (Coggon et al.. 2014; Pira et al.. 2014; Meyers et al.. 2013; Saberi Hosnijeh et al.. 2013;
Beane Freeman et al.. 2009; Hayes et al.. 1990; Ott et al.. 1989; Stroup et al.. 1986; Walrath and
Fraumeni. 1984. 1983). Hauptmann et al. (2009) combined the study populations from Hayes et al.
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(1990) with those from Walrath and Fraumeni (1984. 1983) and reconstructed individual exposure
estimates. Checkoway et al. (2015) reanalyzed Beane Freeman et al. (2009) with different definition of
the exposure categories and presented results for specific sub-types of myeloid leukemia. For the
purposes of this evaluation, cancer cases reported as monocytic leukemia or nonlymphocytic leukemia
were included as myeloid leukemia.
The majority of the studies of the 10 populations reported increased risks of myeloid leukemia
associated with exposure to formaldehyde for at least one metric of exposure, although four low
confidence studies reported results based on fewer than 10 cases and two other low confidence studies
reported relative effect estimates of RR = 1.02 and OR = 1.17. These studies examined different
populations in different locations and exposure settings and using different study designs. Consistent
reports of elevated risks were provided by the five studies with population-level exposure assignments
(Pira et al.. 2014; Hayes et al.. 1990; Stroup et al.. 1986; Walrath and Fraumeni. 1984, 1983). The results
from Walrath and Fraumeni (1984. 1983) and Hayes et al. (1990) were classified with medium
confidence, while the results from the other two studies were classified with low confidence. Although
the exposure settings in studies of anatomists and embalmers involved coexposure to methanol,
whether there is an association of methanol exposure with leukemia is not known, and elevations in
leukemia risk also were observed in studies involving other exposure settings. Four high and medium
confidence studies with individual-level exposure assignments (Coggon et al.. 2014; Meyers et al.. 2013;
Beane Freeman et al.. 2009; Hauptmann et al.. 2009) also showed elevated risks; three of the studies
allowed for the evaluation of dose-response relationships with increased formaldehyde exposures using
multiple metrics of exposure (see Figures 20 and 21 for all myeloid leukemia studies and high or medium
confidence studies only, respectively). A pattern of increasing dose-response was indicated in analyses
of exposure duration (Meyers et al.. 2013; Hauptmann et al.. 2009), cumulative exposure (Meyers et al..
2013). and with peak exposure metrics (Meyers et al.. 2013; Beane Freeman et al.. 2009; Hauptmann et
al.. 2009). These three studies with high confidence results also observed some indication of an
increase in mortality risk at about 15-20 years since the initial exposure consistent with a biologically
relevant induction/latency period; Hauptmann et al. (2009) showed a clear increase in risk at 20+ years
since first exposure.
Studies with higher quality exposure data based on individual-level exposure assessment
generally reported stronger associations. The results at the highest levels of formaldehyde showed an
approximately 2-to 3-fold relative increase in risk of mortality (Meyers et al.. 2013; Beane Freeman et
al.. 2009; Hauptmann et al.. 2009; Blair et al.. 2001). One study's results that were classified with
medium confidence due to exposure measurement error (Coggon et al.. 2014) showed no increase in
risk among those who had ever had a job in the highest category of exposure. However, this high
exposure category included workers with a broad range of duration, resulting in low sensitivity to detect
an association. Alternative explanations for the associations observed by the high and medium
confidence studies can be reasonably ruled out, reinforced across studies by the consistency in results
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and dose-response patterns. Four other studies with results classified as low confidence were less
consistent, possibly because these studies were limited by low case numbers and missing or imprecise
exposure information (Talibov et al.. 2014; Saberi Hosnijeh et al.. 2013; Blair et al.. 2001; Ott et al..
1989).
Different measures of exposure reflected different risks both within and among studies,
although most provided some evidence of increased mortality from myeloid leukemia associated with
formaldehyde exposure. One study showed the strongest relationship of myeloid leukemia mortality
with duration of formaldehyde exposure (Hauptmann et al.. 2009). Another showed increased risks for
peak exposure and average exposure but not for cumulative exposure or "any" exposure (Beane
Freeman et al.. 2009). A third study showed increased risk in the study population as a whole that was
stronger among workers with the longest duration of exposure and workers with the greatest length of
time since first exposure to formaldehyde (Meyers et al.. 2013). As the different measures of exposure
are likely to be correlated, it may not be possible to single out one exposure metric as most biologically
meaningful.
The pattern of increased risk of myeloid leukemia reflects the associations seen within two
subtypes, acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). However, among the
studies with separate estimates by subtype, risks were elevated for both AML and CML, with the
associations for CML appearing to be as strong as or stronger than the associations with AML
(Checkoway et al.. 2015; Saberi Hosnijeh et al.. 2013; Blair et al.. 2001; Stroup et al.. 1986). Six studies
reported specific results for AML; two were classified with high confidence (Meyers et al.. 2013;
Hauptmann et al.. 2009), and four with low confidence (Checkoway et al.. 2015; Talibov et al.. 2014;
Saberi Hosnijeh et al.. 2013; Blair et al.. 2001). Both of the high confidence results showed non-
significantly elevated risks of AML associated with formaldehyde, as did three out of four of the low
confidence results—although substantially higher risks were reported in the high confidence results.
The precision of these more specific analyses was very low (a total of 0 to 6 exposed cases were
observed in these studies). The Checkoway et al. (2015) reanalysis of Beane Freeman et al. (2009)
reported non-significant increased risks of AML and CML with a redefinition of peak exposure that
shifted nine cases of myeloid leukemia from the highest category of peak exposure in Beane Freeman et
al. (2009) to the lowest category (referent group) in Checkoway et al. (2015).10 Checkoway et al. (2015)
also reported stronger effects of peak exposure with CML compared to AML but the number of cases in
each exposure category was small. Results specific to AML are plotted in Figure 22.
10ln Beane Freeman et al. (2009). for peak exposure there were 4 cases of ML who were unexposed, 14 cases with peak
exposure from >0 to <2 ppm, 11 cases with peak exposure from 2 to <4 ppm and 19 cases with peak exposure >4 ppm. In
Checkoway et al. (2015) the new definition of peak exposure and the recategorization results in 27 cases of ML with peak
exposures from 0 to <2 ppm, 11 cases with peak exposure from 2 to <4 ppm, and 10 cases with peak exposure >4 ppm. The
Checkoway et al. (2015) results were classified with low confidence due to information bias and low sensitivity.
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results on multiple metrics of exposure, each metric is included; however, only the highest category of
each exposure metric is presented in the figure.
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1 Multiple Myeloma
2 Evidence describing the association between formaldehyde exposure and the risk of multiple
3 myeloma was available from 14 epidemiological studies: 5 case-control studies (Hauptmann et al.. 2009;
4 Heinernan et al.. 1992; Pottern et al.. 1992; Boffetta et al.. 1989; Ott et al.. 1989) and 9 cohort studies
5 (Coggon et al.. 2014: Pira et al.. 2014: Meyers et al.. 2013: Beane Freeman et al.. 2009: Stellman et al..
6 1998; Band et al.. "1997; Dell and Teta. 1995; Hayes et al.. 1990; Edling et al.. 1987).
7 The results of these studies appear to be mixed with some showing non-significant increases in
8 risk and other showing non-significant decreases in risk. Nine of the 14 studies were low confidence
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(Pira et al.. 2014; Stellman et al.. 1998; Dell and Teta. 1995; Pottern et al.. 1992; Boffetta et a I.. 1989; Ott
et al.. 1989; Edling et al.. 1987) with many results based on fewer than five cases, (see Figure 23).
Among all the studies that used individual-level exposure assessment, the study with the highest quality
exposure assessment methodology was the National Cancer Institute study (Beane Freeman et al.. 2009)
among industrial workers. The most pronounced effects in this high confidence study showed a two-
fold increased risk of mortality from multiple myeloma associated with the highest level of peak
exposure to formaldehyde (RR = 2.04; 95% CI: 1.01, 4.12). The evaluation of the study for this review
produced reasonable confidence that alternative explanations were ruled out, including chance, bias,
and confounding.
The findings by Beane Freeman et al. (2009) are supported by the results of one medium
confidence study (Hayes et al.. 1990) and two low confidence studies (Dell and Teta. 1995; Edling et al..
1987), all with population-level exposure assessments. The occupational exposures in the three studies
involved very high peaks and were consistent with Beane Freeman et al. (2009) in showing an elevated
risk, although none was able to rule out chance. Hauptmann et al. (2009) and Ott et al. (1989) assessed
individual-level exposure but only presented results specific to formaldehyde exposures for the study
population as a whole. Similarly, the study of garment workers, a medium confidence study, Meyers et
al. (2013) relied on individual measures of the timing of exposure but did not have formaldehyde
concentration data beyond the industrial hygiene data used to plan the study (Stayner et al.. 1988).
Continuous area monitoring showed that formaldehyde levels were relatively constant with no
substantial peak levels over the work shift (Stayner et al.. 1988). a possible explanation for differences in
results. A set of four studies that assessed individual-level exposure gathered minimal information (e.g.,
questionnaire data on "ever" exposure to formaldehyde) on formaldehyde exposure and were
considered to be low confidence (Stellman et al.. 1998; Heineman et al.. 1992; Pottern et al.. 1992;
Boffetta et al.. 1989). The weaknesses of their relatively imprecise exposure assessment may have
precluded their ability to detect an association, thus explaining their generally null results. Overall, the
collection of studies with analyses of multiple myeloma found an association with formaldehyde
exposure limited to groups of people who experienced high peak exposures.
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2009) reported an elevated mortality risk from Hodgkin lymphoma for the cohort as a whole
(SMR = 1.42; 95% CI: 0.96, 2.1; 27 cases) and a pronounced increase in risk among those workers with
the highest peak formaldehyde exposures (RR = 3.96; 95% CI: 1.31, 12.02; 11 cases)—results that were
classified with medium confidence. However, the other medium confidence result from Gerin et al.
(1989) was an OR = 0.5 (95% CI: 0.2, 1.2; 8 cases). The results of the other 10 studies (all low
confidence) were largely null, based on small numbers of cases and wide confidence intervals. The high
survival rate for Hodgkin lymphomas (86%) indicates that mortality data may not be a good proxy for
incidence data for this LHP cancer subtype. Given the relatively weak evidence, these data are not
illustrated in this Overview.
4.3.2. Synthesis of Animal Health Effect Studies
This section considers incidence data for histopathological lesions associated with leukemia or
lymphoma; other evidence supportive of the development of these cancers (e.g., hematological
changes) is discussed in the mode-of-action section. Two medium or high confidence animal bioassays
(in addition, two low confidence studies are briefly discussed in the Toxicological Review) evaluated the
carcinogenic potential of inhaled formaldehyde with respect to lymphohematopoietic (LHP)
malignancies (Kamata et al.. 1997; Kerns et al.. 1983; Battelle, 1982). The majority of formaldehyde
exposure studies in animals focused primarily on the respiratory tract and did not provide routine
examination of other tissues, preventing their ability to inform leukemia and lymphoma.
The largest and most comprehensive cancer bioassay evaluating formaldehyde inhalation
exposure in animals is the chronic study in B6C3F1 mice and F344 rats conducted by Kerns et al., with
documentation in the supporting Battelle report (1983: 1982). The cumulative incidence of lymphoma
(in B6C3F1 mice) and leukemia (in F344 rats) as indicated in the summary tables of this report are shown
in Table 36. The p-values reported by the authors were based on a Cox-Tarone test for the comparison
that adjusts for reduced survival (Battelle. 1982). There was a suggestion of a possible slightly increased
incidence in lymphoma (p-value, 0.06) in female mice, and a slightly decreased incidence in leukemia in
female rats (p-value, 0.006) at the high dose. Taken together with the exposure-induced increases in
bone marrow hyperplasia in rats, this represents an area of uncertainty warranting additional study. A
separate study in male F344 rats also did not report any significant intergroup differences in non-nasal
neoplasms using histopathological evaluations that included tissues relevant to leukemia or lymphoma
(Kamata et al.. 1997), although specific incidence data were not provided to compare with the results of
the more comprehensive bioassay. In addition, high mortality at 18.5 mg/m3 (the next lower group was
2.43 mg/m3) limited this study's ability to detect long-term effects (e.g., surviving rats: 0/32 at 28
months; ~3/32 at 24 months). Given the findings in the well-reported bioassay by Kerns et al. (1983;
1982), there is a need for additional animal studies specifically designed to target LHP cancers as the
main endpoint.
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Table 36. Incidence of hematopoietic cancers in B6C3F1 mice and F344 rats [source:
(Kerns et al.. 1983; Battelle, 1982)1
Endpoint, species
Sex
Incidence (% incidence)
p-valuesa
0 ppm
18.5 mg/m3
Lymphoma, B6C3F1 Mice
Male
0/119 (0%)
0/115 (0%)
Female
19/121 (16%)
27/121 (22%)
0.062
Leukemia, F344 Rats
Male
11/120 (9%)
5/120 (4%)
0.690
Female
11/120 (9%)
7/120 (6%)
0.006
aThe authors' p-values were based on a Cox-Tarone test that adjusts for reduced survival.
While the results of both Kerns et al. (1983; 1982) and Kamata et al. (1997) suggest that LHP
cancers do not appear to develop in F344 rats, given the identified limitations of the available studies
and the few suggestive changes that were reported (i.e., bone marrow hyperplasia in rats and slight but
uncertain increases in lymphomas in mice), it is difficult to draw definitive conclusions (i.e.,
indeterminate evidence) as to whether formaldehyde exposure might be capable of causing leukemia or
lymphoma in animals based on the currently available evidence.
4.3.3. Mode-of-action Information
The mechanistic database pertinent to leukemogenesis was evaluated based upon the
fundamental assumption that exogenous formaldehyde is not distributed appreciably beyond the
portal-of-entry. The available evidence supports some events that could contribute to plausible
mechanistic pathways relating formaldehyde exposure to LHP carcinogenesis (summarized in Table 37).
However, the database was insufficient to support the evaluation or development of any specific MOA.
There is largely consistent and strong evidence linking genotoxicity and mutagenicity in circulating blood
cells with formaldehyde exposure in studies of humans. Both temporal and dose-response relationships
have been demonstrated in these studies, and mechanistic pathways exist that support a biologically
plausible relationship between formaldehyde exposure and cancer, even though the mechanistic
pathways explaining such systemic effects are unclear (NRC. 2014b). In addition, the evidence
supporting noncancer systemic effects following formaldehyde exposure (e.g., reproductive or
developmental toxicity) provides additional plausibility for cancers at systemic sites. It is important to
note that systemic delivery of formaldehyde is not a prerequisite for the observed mechanistic changes,
as some of the reported systemic effects might result from direct interactions with formaldehyde in the
URT, while others could plausibly result indirectly from events such as URT irritation, cytotoxicity,
oxidative stress, and inflammation locally initiated at the POE.
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1 Table 37. Summary conclusions regarding plausible mechanistic events associated
2 with formaldehyde induction of lymphohematopoietic cancers
Hypothesized
mechanistic event
Experimental support for mechanistic event
Human
relevance
Evidence integration
considering biological
plausibility
Formaldehyde-
induced DNA
damage to
peripheral blood
leukocytes
• HSPC aneuploidy and structural chromosome damage in
myeloid progenitors (CFU-GMs) from one population of
human workers occupationally-exposed to median levels
of 1.6 mg/m3 (Lan et al.. 2015: Zhang et al., 2010):
'T* Monosomy and polysomy in multiple chromosomes
(especially monosomy 1, 5, 7) consistent with damage
observed in patients with MDS or AML (Bassig et al.,
2016; Lan et al., 2015); and /T breaks, deletions, and
translocations in chromosome #5. Assay methodology
could not distinguish whether formaldehyde exposure is
associated with a potential tendency toward cytotoxicity
in CFU-GM cells either in vivo or during the in vitro cell
culture period. Inconsistencies in assay protocol reported
by Gentry et al. (2013), which were addressed by
Rothman et al. (2017).
• Deficiencies in progenitor cells (CFU-GM and BFU-E) in
exposed mice (Zhao et al., 2020), although results
may be confounded by methanol coexposure (low
confidence)
• 'T* genotoxicity or mutagenicity in circulating PBLs from
exposed humans, including increases in strand breaks,
MN, CA (Costa et al., 2019: Wang et al., 2019:
Aglan and Mansour, 2018: Zendehdel et al.,
2018: Costa et al., 2015: Peteffi et al., 2015:
Kirsch-Volders et al., 2014), NBUDs, orSCE
induction at >0.14 mg/m3 (Jiang et al., 2010), and
DPX at higher exposures (Lin et al., 2013; Shaham
et al., 2003)
• -T DPX in PBLs from mice (Ye et al., 2013), although
results may be confounded by methanol coexposure (low
confidence)
• 'T* MN in human PBLs and buccal cells from exposed
humans, and associations with years of exposure, in
studies evaluating both tissues (Ladeira et al., 2011;
Viegas et al., 2010)
Yes. Evidence
comes
primarily
from exposed
humans.
Strong and consistent human
data exist associating
formaldehyde exposure with
various genotoxic outcomes
in myeloid progenitors and
PBLs, and dose-response
relationships demonstrated.
Genotoxicity in circulating
leukocytes shows
concordance with similar
endpoints in POE tissues.
Aneugenic damage observed
in CFU-GMs from
formaldehyde-exposed
human workers is associated
with MDS or AML in humans.
Together this evidence
constitutes the strongest
support for the biological
plausibility for LHP cancer
induction by formaldehyde.
Evidence of
formaldehyde-
induced impacts
other than
genotoxicity on
circulating blood
cell populations,
including
inflammatory
changes or immune
system dysfunction
• \1/ CFU-GM colony formation in human workers
occupationally-exposed to median levels of 1.6 mg/m3
(Zhang et al., 2010), which may reflect not only
altered bone marrow progenitor cell viability, but also
immune dysfunction or altered activation
• Numerous published studies reporting divergent changes
in various peripheral blood cell populations from
formaldehyde exposed humans, including: 'T*
pancytopenia in a few studies and reasonably consistent
decreases in total WBCs; \1/ or ^ in some lymphocyte
populations, with decreased CD8 T cells likely at
Yes. Most of
the available
data come
from human
studies.
The evidence supporting
changes in populations or
function of circulating blood
leukocytes following human
exposure to formaldehyde is
strong in terms of a
frequency of alterations, but
different patterns in changes
are reported (e.g., specific
direction of changes in
various lymphocyte
subpopulations, or in blood
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Hypothesized
mechanistic event
Experimental support for mechanistic event
Human
relevance
Evidence integration
considering biological
plausibility
concentration >0.5 mg/m3; and fluctuations in immune
cell numbers and immune/inflammation markers show a
complex pattern with concentration, with decreases in
blood cell number and decreased cytotoxic response
generally at higher concentrations, some of which are
consistent with observations in AML patients (Kim et
al., 2015). Other studies indicate immune cell
activation generally observed at lower concentrations
<0.36 mg/m3.
levels of soluble signaling
mediators). LHP cancer risk
increases with loss of normal
immune function.
Formaldehyde-
induced systemic
oxidative stress
• 'T* Malondialdehyde-dG adducts in whole blood DNA
from pathologists, compared to workers and students in
other science labs (Bono et al., 2010), elevated
plasma malondialdehyde (MDA) and plasma p53
associated with each other and with urinary formate
concentrations (imprecise marker of formaldehyde
exposure) among cosmetics workers (Attia et al.,
2014), and 'T 15-F2t isoprostane levels in the urine of
formaldehyde-exposed workers (Romanazzi et al.,
2013)
• Inconclusive evidence for and against involvement by
genes that regulate oxidative stress in formaldehyde
associations with DNA damage risk in PBL in humans
• \1/ GSH, 'T* ROS, 'T* MDA in bone marrow, peripheral
blood mononuclear cells, liver, spleen and testes (Ye et
al., 2013), although markers of oxidative stress were
not correlated with changes in DPX
Yes. Some
human data
available, and
results from
experimental
models are
presumed
relevant to
humans
without
evidence to
the contrary.
Limited human and rodent
evidence supports the
association between
formaldehyde exposure and
induction of oxidative stress
beyond the POE. While
biologically plausible, the
available evidence is
inadequate to determine
what role such oxidative
stress may play in LHP
carcinogenesis.
Formaldehyde-
induced changes in
the bone marrow
niche
• DNA adducts linked to inhaled (exogenous)
formaldehyde were not found in the bone marrow of
monkeys or rats in studies using highly sensitive
detection methods
• 'T* Bone marrow hyperplasia in rats from one study
(Kerns et al., 1983; Battelle, 1982), unclear if
other results were negative or null (Sellakumar et al.,
1985); (Kamata et al., 1997) due to imprecise
reporting
• Dose-related 'T* DPX in the bone marrow of formalin-
exposed mice (Ye et al., 2013), although results may
be confounded by methanol coexposure
• HSPC mobilization and the BM-MSC niche is regulated by
cytokines, hormones and signals, which may be
distributed through circulation as a result of
inflammation; however, these effects have not been
directly evaluated following formaldehyde exposure
Yes.
Available data
are from
experimental
models
presumed
relevant to
humans.
The limited evidence
available is currently
inadequate to evaluate any
effect on bone marrow or
stromal cells following
formaldehyde exposure,
although such an effect
appears consistent with
current understanding of
hematopoiesis.
Evidence of
formaldehyde-
induced changes in
gene expression or
post-transcriptional
regulation in
peripheral blood
• Limited study reported some statistically significant
differences in mRNA expression in either nasal or whole
blood samples from human volunteers associated with 5
day exposures up to 1 mg/m3 formaldehyde, however
study limitations prevent interpretation that results were
related to formaldehyde exposure (Zeller et al.,
Yes.
Available data
are from
experimental
models
presumed
Limited rodent evidence
supports the association
between formaldehyde
exposure and epigenetic
effects in circulating
leukocytes; the available
human evidence is
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Hypothesized
mechanistic event
Experimental support for mechanistic event
Human
relevance
Evidence integration
considering biological
plausibility
leukocytes or bone
marrow
2011) In F344 rats, significant changes in both miRNA
and mRNA expression were reported in the nasal
epithelium and circulating white blood cells following
inhalation exposure to 2.5 mg/m3 formaldehyde for 1 or
4 wks; no changes were observed in miRNA expression in
the bone marrow, and mRNA was not evaluated (Rager
et al., 2014): "Immune system/inflammation" markers
were enriched in both nasal tissue and WBCs at both
time points; and 'T* WBC miR-326 expression, associated
with bone marrow metastasis in other models
(Valencia et al., 2013)
relevant to
humans.
inadequate. Insufficient
evidence is available to
determine what role
epigenetics may play in LHP
carcinogenesis.
4.3.4. Overall Evidence Integration Judgments and Susceptibility for LHP Cancers
Table 38 summarizes the evidence integration judgments and supporting rationale for the
individual LHP cancers.
The strength of the evidence from human studies is robust for myeloid leukemia. The
assessment of LHP cancers was based on epidemiological studies of groups with occupational
formaldehyde levels either in specific work settings (e.g., cohort studies) or in case-control studies.
Aneuploidy in chromosomes 1, 5, and 7 in circulating myeloid progenitor cells, considered a potential
primary target for LHP carcinogenesis, was associated with occupational formaldehyde exposure. The
type of aneuploidies observed in the formaldehyde-exposed asymptomatic human workers are also
found in patients with leukemia, specifically MDS and AML, as well as other worker cohorts at increased
risk of developing leukemias, which provides support for the plausibility of an association between
chronic formaldehyde exposure and leukemogenesis. Moreover, the strong and consistent evidence
from a large set of studies that observed mutagenicity in circulating leukocytes of formaldehyde-
exposed humans, specifically chromosomal aberrations (CA) and micronucleus (MN) formation, provides
additional evidence of biological plausibility for these cancer types. Further support is provided by
studies that observed perturbations to immune cell populations in peripheral blood associated with
formaldehyde exposure. In particular, decreases in RBCs, WBCs, and platelets, along with a 20%
decrease in CFU-GM colony formation in vitro were observed in the same exposed group (Zhang et al..
2010), suggesting both a decrease in the circulating numbers of mature RBCs and WBCs as well as
possible decreases in the replicative capacity of myeloblasts.
Increased LHP cancers have not been observed in a well-reported chronic rodent bioassay
involving inhalation exposure of both rats and mice to formaldehyde, nor in another rat bioassay that
failed to report the incidence of non-nasal neoplastic lesions. Further, positive associations with
leukemia have not been reported in rodent studies, although there are notable uncertainties in the
available data (i.e., increased bone marrow hyperplasia in rats; slight but uncertain increases in
lymphoma in mice; and a general lack of rigorous evaluation of non-respiratory tissues). Thus, there
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appears to be a lack of support for the human epidemiological evidence from rodent bioassays, although
concordance across species is not necessarily expected (U.S. EPA. 2005a). The apparent lack of
consistency in results raises uncertainties about the currently available research results on these
diseases, including both how formaldehyde-induced LHP cancers might arise without substantial
distribution to target sites. Notably, the available animal evidence was judged as indeterminate and not
compelling evidence of no effect (see assessment Preface), as there are important uncertainties that
prevent such an interpretation. Thus, the animal evidence does not detract from the strength of the
association between formaldehyde exposure and myeloid leukemia (and related mechanistic changes)
in epidemiological studies (NRC. 2014b). Differences in physiology between humans and rodents, as
well as the relative insensitivity of rodent models to reflect the human pathogenesis of myeloid
leukemia, in particular, may together contribute to the potential lack of concordance between the
abundant human epidemiological data and the limited results available from rodent bioassay data.
Taken together, based on the robust human evidence, the evidence demonstrates that
formaldehyde inhalation causes myeloid leukemia in humans given appropriate exposure circumstances.
Separately, based on a limited number of epidemiological studies and potentially relevant mechanistic
evidence in exposed humans, the evidence integration results in a judgment that the evidence suggests,
but is not sufficient to infer, that formaldehyde inhalation might cause Hodgkin lymphoma and multiple
myeloma, given appropriate exposure circumstances. While mechanisms for the induction of myeloid
leukemia are yet to be elucidated, they do not appear to require direct interactions between
formaldehyde and bone marrow constituents, and either are different in animals or the existing animal
models tested thus far do not characterize the complex process leading to cancers in exposed humans.
These conclusions were primarily based on epidemiological studies of groups with occupational
formaldehyde exposure. Notably, evidence exists to suggest a lack of concordance between chronic
rodent bioassays and human epidemiological evidence.
Table 38. Evidence integration summary for effects of formaldehyde inhalation on
LHP cancers
Evidence
Evidence judgment
Hazard determination
Myeloid Leukemia
Human
evidence
Robust for myeloid leukemia based on:
Human health effect studies:
• Consistent increases in risk across a set of high and medium confidence,
independent studies with varied study designs and populations
• Several of these studies demonstrated strong associations (1.5- to 3-fold
increase in risk) and clear exposure-response relationships across multiple
measures of increasing exposure
• The studies possessed a temporal relationship consistent with causality
(e.g., allowing time for induction, latency, mortality)
Biological plausibility (also of potential relevance to LHP cancer types below):
Evidence from high and medium confidence studies of exposed humans
The evidence demonstrates
that formaldehyde inhalation
causes myeloid leukemia in
humans, given appropriate
exposure circumstances3
This conclusion was primarily
based on epidemiology studies
of groups with occupational
formaldehyde exposure.
While evidence exists to
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identifies relevant mechanistic changes for cancers of the blood such as myeloid
leukemia, including impacts on peripheral immune cell populations (which seem
to be affected in a complex manner), and elevated levels or severity of DNA or
chromosomal damage in circulating myeloblasts and mature lymphocyte
populations. The DNA damage exhibits aneugenic characteristics similar to that
found in humans with, or at increased risk for, AML.
suggest a lack of concordance
between chronic rodent
bioassays and human
epidemiological evidence,
notable uncertainties prevent
an animal evidence judgment
of compelling evidence of no
effect
Po ten ti al suscep tibili ties:
There is no evidence to
evaluate the potential risk to
sensitive populations or
lifestages
Animal
evidence
Indeterminate for any LHP cancer type, based on:
Animal health effect studies:
Overall, the available data do not provide evidence supporting the development
of LHP cancers in a high confidence chronic bioassay of rats and mice, a second
medium confidence rat bioassay, and two other low confidence, long-term
exposure studies.
Biological plausibility:
Although some potentially relevant changes have been observed in mechanistic
studies of exposed animals (e.g., inflammatory and immune changes in systemic
tissues and bone marrow hyperplasia in rats), the evidence related to
genotoxicity (i.e., in systemic tissues) or other more directly relevant changes
were weak (e.g., only in low confidence studies) or not observed and, overall,
the mechanistic data do not suggest a judgment other than indeterminate for
LHP cancers in animals.
Other
Inferences
• Relevance to humans: The evidence is from studies in humans.
• MOA: No MOA exists to explain how formaldehyde might cause LHP cancers
without systemic distribution (i.e., without direct interactions of inhaled
formaldehyde with constituents in bone marrow tissue); however, given the
mechanistic changes in exposed humans, it is reasonable to infer that an
undefined MOA is likely to involve modulatory effects on circulating immune
cells.
Multiple myeloma
Human
evidence
Sliaht for multiple myeloma, based on:
Human health effect studies:
• Increases in risk associated with peak exposure metrics across one high, one
medium, and two low confidence studies; no associations with other
exposure metrics
• Increases spanned an approximate 1.2- to 4-fold increase in risk, with the
highest confidence evidence showing a 2-fold increase
• Very limited evidence of an exposure-response relationship in one high
confidence study
• However, risks may have been driven by peak exposures as increases were
limited to groups of people who experienced high peak exposures, and two
low confidence studies reported inverse relationships with duration of
exposure
The evidence suggests, but is
not sufficient to infer, that
formaldehyde inhalation
might cause multiple myeloma
given appropriate exposure
circumstances'5
Animal
evidence
Indeterminate (for any LHP cancer type):
See explanation for myeloid leukemia
Other
Inferences
• Relevance to humans: The evidence is from studies in humans.
• MOA: No MOA exists to explain how formaldehyde might cause LHP
cancers without systemic distribution
Hodgkin lymphoma
Human
evidence
Sliaht for Hodgkin lymphoma, based on:
Human health effect studies:
The evidence suggests, but is
not sufficient to infer, that
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• Significantly increased risk in the highest peak exposure group alongside an
exposure-response relationship in one medium confidence study of
industrial workers
• An inconsistent pattern of risks across 1 medium and the low confidence
studies, many with <5 exposed cases
• The high survival rate for Hodgkin lymphoma may indicate that mortality
data are not a good proxy for incidence.
formaldehyde inhalation
might cause Hodgkin
lymphoma given appropriate
exposure circumstances'5
Animal
evidence
Indeterminate (for any LHP cancer type):
See explanation for myeloid leukemia
Other
inferences
• Relevance to humans: The evidence is from studies in humans.
• MOA: No MOA exists to explain how formaldehyde might cause LHP
cancers without systemic distribution
Note: Lymphatic leukemia evidence is not presented in this Overview (see Section 1.3.3 of the Toxicological Review).
aThe "appropriate exposure circumstances" are more fully evaluated and defined through dose-response analysis (Section 4.5).
bGiven the uncertainty in this judgment and the available evidence, this assessment does not attempt to define what might be
the "appropriate exposure circumstances" for developing this outcome.
1 4.4. WEIGHT-OF-EVIDENCE SUMMARY FOR CARCINOGENICITY
2 "Formaldehyde is Carcinogenic to Humans by the Inhalation Route of Exposure"
3 This conclusion is independently supported by three evidence integration judgments, namely
4 that the evidence demonstrates that formaldehyde inhalation causes nasopharyngeal cancer, sinonasal
5 cancer, and myeloid leukemia in exposed humans given appropriate exposure circumstances.
6 These overall evidence integration judgments, as well as the strength of the human and animal
7 evidence (i.e., robust, moderate, slight, indeterminate), were based on the currently available evidence
8 using the approaches presented in the description of methods in the Introduction to this Overview
9 (Section 1), which included a consideration of mechanistic evidence when drawing each conclusion.
10 4.4.1. Weight-of-evidence Narrative Summary
11 The carcinogenicity conclusion is independently supported by three evidence integration judgments:
12 • The evidence demonstrates that formaldehyde inhalation causes nasopharyngeal cancer (NPC)
13 in humans. This is based primarily on observations of increased risk of NPC in groups exposed to
14 occupational formaldehyde levels and nasal cancers in mice and several strains of rats, with
15 strong, reliable, and consistent mechanistic evidence in both animals and humans (i.e., robust
16 evidence for both the human and animal evidence, and strong mechanistic support for the
17 human relevance of the animal data). The nasopharynx, although not typically specified in
18 animal studies, is the region adjacent to the nasal cavity, where the animal evidence was
19 predominantly observed (thus, the animal evidence is judged as robust). In addition, the
20 evidence is sufficient to conclude that a mutagenic MOA of formaldehyde is operative in
21 formaldehyde-induced nasopharyngeal carcinogenicity.
22 • The evidence demonstrates that formaldehyde inhalation causes sinonasal cancer (SNC) in
23 humans. This is based primarily on observations of increased risk of SNC in groups exposed to
24 occupational formaldehyde levels (i.e., robust human evidence) and supported by apical and
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mechanistic evidence for nasal cancers across multiple animal species. Some uncertainties
remain in the interpretation of the animal nasal cavity data as wholly applicable to interpreting
human sinonasal cancer (thus, the animal evidence is judged as moderate). In addition, while
uncertainties remain, the evidence is sufficient to conclude that a mutagenic MOA of
formaldehyde is operative in formaldehyde-induced sinonasal carcinogenicity.
• The evidence demonstrates that formaldehyde inhalation causes myeloid leukemia in humans.
This is based primarily on observations of increased risk in groups exposed to occupational
formaldehyde levels. This evidence integration judgment is further supported by other studies
of human occupational exposure that provide strong and coherent mechanistic evidence
identifying clear associations with additional endpoints relevant to LHP cancers, including an
increased prevalence of multiple markers of mutagenicity and other genotoxicity in peripheral
blood cells of exposed workers, other perturbations to immune cell populations in blood
(primarily from human studies), and evidence of other systemic effects (i.e., developmental or
reproductive toxicity). 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, including genotoxicity (i.e., inadequate evidence). The exact mechanism(s) leading to
cancer formation outside of the respiratory tract are unknown.
Other information
The remaining evidence relevant to evaluating the potential for formaldehyde inhalation to
cause cancer (see Sections 4.2 and 4.3) did not contribute to the carcinogenicity conclusion above,
including evaluations of oropharyngeal/hypopharyngeal cancer, Hodgkin lymphoma, and multiple
myeloma (the evidence suggests, but is not sufficient to infer, that formaldehyde inhalation might cause
these types of cancers given appropriate exposure circumstances), and of laryngeal cancer and
lymphatic leukemia (there is inadequate evidence to determine whether formaldehyde inhalation may
be capable of causing these types of cancers in humans; evidence not presented in this Overview).
4.5. INHALATION UNIT RISK (IUR) FOR CARCINOGENICITY
Unit risk estimates for cancer were derived from different data sets available from both
epidemiological and experimental animal studies. In addition, an approach to bound low-dose cancer
risks from formaldehyde exposure using DNA adduct concentrations in nasal epithelium and bone
marrow from animal experiments and U.S. cancer incidence statistics (a "bottom-up" approach) is
summarized to provide some perspective on the uncertainty in extrapolating from high-dose animal
toxicology or human occupational data (Starr and Swenberg, 2016, 2013). Unit risk estimates could be
derived for two cancer types for which the evidence supporting a human health hazard was sufficiently
strong: nasal cancers (i.e., nasopharyngeal cancer in human studies; nasal squamous cell carcinoma in
experimental animal studies) and myeloid leukemia.
Specifically, unit risk estimates were derived based on dose-response modeling of mortality and
cumulative formaldehyde exposure for nasopharyngeal cancer (NPC) and myeloid leukemia in a human
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occupational cohort. Cumulative exposure, which incorporates both average concentration and the
duration of time over which exposure occurred, is generally the preferred metric for quantitative
estimates of lifetime risk from environmental exposure to carcinogens, and thus cumulative exposure
was chosen as the exposure metric for calculations in this assessment. The "true" exposure metric best
describing the biologically relevant delivered dose of formaldehyde is unknown. Few epidemiological
studies presented dose-response analyses based on cumulative measures of formaldehyde
concentration that could support the derivation of unit risk estimates; estimates were derived only for
NPC and myeloid leukemia.
In experimental animals, multiple approaches, including biologically based dose-response
(BBDR) modeling, and statistical time-to-tumor modeling, were used to derive unit risk estimates based
on data in rats. Results from the different approaches were evaluated and compared. In addition, other
approaches based on mechanistic hypotheses, including derivation of cRfCs based solely on cell
proliferation (one mechanism that contributes to cancer risk) and assessing the potential impacts of
endogenous formaldehyde concentration on dosimetric estimates, were explored quantitatively and
compared.
The unit risk estimates from the well-conducted human occupational study were preferred.
However, while the estimates for nasopharyngeal cancer and myeloid leukemia could be combined to
derive an IUR for formaldehyde, there is considerable scientific uncertainty in the data used to estimate
a unit risk for myeloid leukemia. Therefore, the unit risk estimate for myeloid leukemia is not included
in the IUR calculation in this draft assessment. The following sections outline the best supported
approaches for each cancer subtype based on the data currently available. The strengths and
weaknesses of the statistical approaches, as well as the rationale supporting each estimate, are
presented, including scientific judgments of confidence in the estimates for each cancer type.
4.5.1. Derivation of Cancer Unit Risk Estimates for Nasal Cancers
Derivation of a nasal cancer unit risk estimate based on human data
The quantitative analysis of nasal cancer from epidemiological studies is based on the NPC
results from the latest follow-up of the NCI cohort of industrial workers exposed to formaldehyde
(Beane Freeman et al.. 2013). While the evidence supporting a human health hazard from sinonasal
cancer from studies in occupational cohorts and experimental animals also was sufficiently strong, it was
not possible to derive a unit risk estimate for this cancer types. Out of almost 14,000 deaths observed in
the NCI cohort, there were 10 deaths from NPC and 5 deaths from cancers of the nose and nasal sinus.
Only the data for NPC could be modeled with adequate precision. The NCI cohort study is the largest of
the three independent industrial worker cohort studies [the other two being Meyers et al. (2013) and
Coggon et al. (2014)1 and, more importantly, it is the only one with sufficient individual exposure data
for dose-response modeling. In addition, the NCI study is the only one that used internal comparisons
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rather than standardized mortality ratios (SMRs), thus minimizing the potential impact of the healthy
worker effect by addressing unmeasured confounding, which can bias effect estimates.
The NCI cohort consists of 25,619 workers (88% male) employed prior to 1966 in any of the 10
plants in the study. The most recent follow-up, based on 998,239 person-years of observation (through
2004) reported a total of 13,951 deaths (Beane Freeman et al.. 2013). Beane Freeman et al. (2013)
analyzed 10 deaths from NPC as well as deaths from other solid tumors. A detailed exposure
assessment was conducted for each worker in the NCI cohort, based on exposure estimates for different
jobs held and tasks performed (Stewart et al.. 1986). Exposure estimates were made using several
different metrics—peak exposure,11 average intensity, cumulative exposure, and duration of exposure.
Respirator use and exposures to formaldehyde-containing particulates and other chemicals were also
considered.
Dose-response modeling of data from the NCI cohort
The results of the internal analyses (i.e., comparing exposed workers to an internal referent
group of other workers in the cohort) of Beane Freeman et al. (2013) for NPC using the cumulative
exposure metric are presented in Table 39. The relative risks (RRs) were estimated using log-linear
Poisson regression models stratified by calendar year, age, sex, and race and adjusted for pay category.
Beane Freeman et al. (2013) used a 15-year lag interval in estimating exposures to account for a latency
period for the development of solid cancers, including NPCs. Models with alternative lag intervals (2-20
years) produced similar results. The NCI investigators used the low-exposure category as the reference
category to "minimize the impact of any unmeasured confounding variables since nonexposed workers
may differ from exposed workers with respect to socioeconomic characteristics" (Hauptmann et al..
2004). In this review, the nonexposed person-years were included in the primary cancer risk analyses to
be more inclusive of all the dose-response data. The analyses adjusted for pay category, a measure of
socioeconomic status, thus possible SES differences between exposed and nonexposed were at least
partially addressed. Final results for the exposed person-years only are also presented for comparison.
Cumulative exposure was included as a continuous variable in the log-linear models analyzed by
Beane Freeman et al. (2013) (general model form: RR = e(BX, where (B represents the regression
coefficient and X is exposure). The regression coefficients are presented in Table 39.
nSome of the strongest exposure-response relationships in the NCI cohort (Beane Freeman et al.. 2013) (e.g., for NPC) were
observed for the peak exposure metric. It is not clear how to extrapolate RR estimates based on peak exposure estimates to
meaningful estimates of lifetime extra risk of cancer from continuous exposure to low environmental levels. If a short-term
(<15 minute) excursion above the 8-hour TWA concentration for a job was observed, or expected based on industrial hygiene
expertise, then that job was assigned to a peak exposure category, namely none, >0 to <0.5 ppm, 0.5 to <2.0 ppm, 2.0 to <4.0
ppm, or >4.0 ppm. Individual workers may have experienced these peak concentrations rarely, intermittently, or routinely, and
in jobs they held for a long time or only briefly. At a given time point, a worker's peak exposure estimate is the highest peak
exposure category ever attained by the worker. As such, this exposure metric is not interpretable in terms of a lifetime
exposure risk.
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Table 39. Relative risk estimates for mortality from NPC (based on ICD code) and
regression coefficients from NCI log-linear trend test models3 by level of cumulative
formaldehyde exposure (ppm x years). Source: Beane Freeman et al. (2013)
Relative risk estimates
for nasopharyngeal
cancer
Rate ratio (number of deaths)
p-trend, all
person-years'5
p-trend,
exposed
person-years0
0
>0 to <1.5d
1.5 to <5.5
>5.5
1.87 (2)
1.0 (4)
0.86 (1)
2.94 (3)
0.07
0.06
Regression coefficients
for nasopharyngeal
cancer
Person-years
P (per ppm x year)®
Standard error (per ppm x year)®
All
0.04311
0.01865
Exposed only
0.0439
0.01852
aModels stratified by calendar year, age, sex, and race and adjusted for pay category; cumulative exposures
calculated using a 15-year lag interval for NPC and a 2-year lag interval for LHP cancer types.
bLikelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (as a continuous variable)
among all (nonexposed and exposed) person-years.
likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (as a continuous variable)
among exposed person-years only.
Reference category for all categories.
eSource: Personal communications from Laura Beane Freeman to Jennifer Jinot (February 22, 2013 and February
21, 2014) and to John Whalan (August 26, 2009).
Prediction of lifetime extra risk of nasopharyngeal cancer mortality
To predict the extra risk of NPC mortality from environmental exposure to formaldehyde:
Extra risk = (Rx - Ro) 4- (1 - Ro)
where Rx is the lifetime risk in the exposed population and Ro is the lifetime risk in an
unexposed population (i.e., the background risk). Extra risk estimates were calculated using the p
regression coefficients and a life table program that accounts for competing causes of death.12 U.S. age-
specific 2010 all-cause mortality rates and 2000-201013 NPC mortality rates for all race and sex groups
combined were used to specify the all-cause and cause-specific background mortality rates in the life
table program. Risks were computed up to age 85 years because cause-specific mortality (and
incidence) rates for ages above that are less reliable. Conversions between occupational formaldehyde
exposures and continuous environmental exposures were made to account for differences in the
number of days exposed per year (240 versus 365) and in the amount of air inhaled per day (10 versus
20 m3). An adjustment was also made for the 15-year lag period. The reported standard errors for the
regression coefficients were used to compute the one-sided 95% upper confidence limits (UCLs) for the
extra risks based on a normal approximation.
12
This program is an adaptation of the approach that was previously used in BEIR IV, "Health Risks of Radon and Other Internally
Deposited Alpha Emitters." National Academy Press, Washington, DC, 1988, pp. 131-134.
13Typically, 5-year ranges are used as the basis for population cause-specific disease and mortality rates; a larger range is used
here to get better stability in the rates because NPC is a rare cancer.
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Consistent with EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA. 2005a). the life table
program was used to estimate the exposure level (effective concentration [ECX]) and the associated
(one-sided) 95% lower confidence limit (LECX) corresponding to an extra risk of 0.05% (x = 0.0005).
Although EPA guidelines emphasize the use of exposure levels associated with a 10% extra risk level for
the POD for low-dose extrapolation, for epidemiological studies, this can result in the need to
extrapolate upward to risks well above those that were observed in the study populations. Thus, a 1%
extra risk level is typically used for epidemiological data. However, NPC has a very low background
mortality rate (e.g., lifetime background risk is about 0.00019); therefore, even a 1% extra risk (i.e., 0.01)
would be a large increase relative to the background risk. This is consistent with the fact that, even with
a large cohort followed for a long time, only 10 NPC deaths were observed in the NCI follow-up through
2004.14 Based on the life table program, the 1% level of risk for NPC mortality is associated with an RR
estimate of 53, a level substantially higher than was observed in the epidemiological study. A 0.05%
extra risk level yields an RR estimate of 3.6, which better reflects the RRs in the range of the data. Thus,
0.05% extra risk was selected for determination of the POD, and the LEC value corresponding to that risk
level was used as the POD.
Because formaldehyde is a mutagenic carcinogen and the weight of evidence supports the
conclusion that formaldehyde carcinogenicity for URT cancers can be attributed, at least in part, to a
mutagenic MOA, a linear low-dose extrapolation was performed in accordance with EPA's cancer
guidelines (U.S. EPA. 2005a). The ECooos, LECooos, and inhalation unit risk estimates for NPC mortality are
presented in Table 40.
Table 40. ECooos, LECooos, and unit risk estimates for nasopharyngeal cancer mortality
based on the Beane Freeman et al. (2013) log-linear trend analyses for cumulative
formaldehyde exposure
ECooos
LECooos
Unit risk3
Unit risk
Person-years
(ppm)
(ppm)
(per ppm)
(per mg/m3)
All
0.191
0.112
4.5 x 10"3
3.7 x 10"3
Exposed only
0.187
0.111
4.5 x 10"3
3.7 x 10"3
aUnit risk = 0.0005/LECooos.
Prediction of lifetime extra risk of nasopharyngeal cancer incidence
EPA cancer risk estimates are typically derived to represent a plausible upper bound on
increased risk of cancer incidence, as from experimental animal incidence data. Cancer data from
epidemiological studies are more often mortality data, as is the case in the NCI study. For cancers with
low survival rates, mortality-based estimates are reasonable approximations of cancer incidence risk.
14Eleven NPCs were reported on death certificates and included in NCI's SMR analyses, but one of these cases was apparently
misclassified on the death certificate, so only 10 cases were used to estimate the RRs in the internal comparison analyses
(Beane Freeman et al.. 2013).
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However, for NPC, the survival rate is substantial [51% at 5 years in the 1990s in the United States,
according to Lee and Ko (2005)1, and incidence-based risks are preferred because EPA is concerned with
cancer occurrence, not just cancer mortality.
Therefore, an additional calculation was done using the same regression coefficients provided
by Dr. Beane Freeman but with age-specific NPC incidence rates for 2000-2010 from NCI's Surveillance,
Epidemiology, and End Results (SEER) Program in place of the NPC mortality rates in the life table
program (www.seer.cancer.gov). The incidence-based calculation relies on the reasonable assumptions
that NPC incidence and mortality have the same dose-response relationship for formaldehyde exposure
and that the incidence data are for first occurrences of NPC or that relapses provide a negligible
contribution. The calculation also takes advantage of the fact that NPC incidence rates are negligible
compared with the all-cause mortality rates and thus no special adjustment to the population at risk to
account for live individuals who have been diagnosed with NPC is necessary.
The resulting ECooos, LECooos, and inhalation unit risk estimates for NPC incidence are presented
in Table 41. The unit risk estimate for cancer incidence is two-fold higher than the corresponding
mortality-based estimate, for all person-years, reflecting the high survival rates for NPC.
Table 41. ECooos, LECooos, and unit risk estimates for nasopharyngeal cancer incidence
based on the Beane Freeman et al. (2013) log-linear trend analyses for cumulative
formaldehyde exposure
Person-years
ECooos (ppm)
LECooos (ppm)
Unit risk3 (per ppm)
Unit risk (per mg/m3)
All
0.0942
0.0550
9.1 x 10"3
7.4 x 10"3
Exposed only
0.0925
0.0546
9.2 x 10"3
7.5 x 10"3
aUnit risk = 0.0005/LEC0oos-
The preferred estimate for the inhalation cancer unit risk for NPC is the estimate of 9.1 x 10"3
per ppm derived using incidence rates for the cause-specific background rates, for all person-years. The
results from the exposed person-years are essentially identical.
Because NPC is a rare cancer in the United States, with a relatively low number of cases
occurring per year, a rough calculation was done to ensure that the unit risk estimate derived for NPC
incidence is not implausible in comparison to actual case numbers. For example, assuming an average
constant lifetime formaldehyde exposure level of 5 ppb for the U.S. population (probably at the very low
end of potential lifetime averages) the inhalation unit risk estimate for NPC equates to a lifetime extra
risk estimate of 4.6 x 10"5. Assuming an average lifetime of 75 years (this is not EPA's default average
lifetime of 70 years but rather a value more representative of actual demographic data) and a U.S.
population of 300,000,000, this lifetime extra risk estimate suggests a crude upper-bound estimate of
180 incident cases of NPC attributable to formaldehyde exposure per year. Alternatively, for 20 ppb
(probably toward the upper end of potential lifetime averages), the calculation suggests a crude upper-
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bound estimate of 730 incident cases of NPC per year. Both upper-bound estimates, using different
assumed lifetime exposure levels, are well below the estimated 2,300 total incident NPC cases per year
calculated from the SEER NPC incidence rate of 0.75/100,000.15,16
Dose-response modeling of nasal SCC tumor incidence in the F344 rat
Dose-response analyses of cancer risk were calculated using conventional multistage-Weibull
time-to-tumor modeling and a biologically based clonal expansion model of cancer, both based on nasal
squamous cell carcinoma (SCC) incidence data from laboratory bioassays using F344 rats. The
biologically based modeling was informed by a large body of mechanistic data on cell replication, DNA
protein cross-link (DPX) and DNA monoadduct formation, and dosimetry modeling of formaldehyde flux
to local tissue, and was therefore considered useful to provide potential information on the shape of the
dose-response curve as well as the interpretation and extrapolation of results from the rat bioassays to
humans.
These models were employed to derive multiple PODs and corresponding human equivalent
concentrations. Unit risks derived by straight line extrapolation from a point of departure as well as a
candidate RfC (cRfC) derived from these human equivalent concentrations were presented, with the
cRfC interpreted as the concentration below which nasal cancers arising from increased cell proliferation
due to cytotoxicity are unlikely to occur (some researchers have argued that protection against this
putative precursor event is sufficient to prevent a cancer response). cRfCs for this mechanism
contributing to cancer were also derived from modeling of data on cell proliferation and basal
hyperplasia in F344 rats and Wistar rats, respectively.
Approaches to modeling the animal nasal tumor incidence
An increased incidence of nasal SCCs was seen in two long-term bioassays using F344 rats
(Monticello et al.. 1996; Kerns et al.. 1983; Battelle, 1982), with similar incidences between the two
studies even though they were conducted 13 years apart (and similar incidences between males and
females in Kerns et al. (1983; 1982). which tested both sexes). Therefore, for greater power in dose-
response analysis, these data were combined (see Table 42).
15This crude NPC incidence rate is similar to a published NPC incidence rate for the United States of 0.7/100,000 person-years
(Lee and Ko. 2005). The age-adjusted NPC incidence rate from SEER was also 0.75/100,000.
16With the application of age-dependent adjustment factors, the lifetime unit risk estimate for NPC would increase by a factor
of 1.42, and the crude upper-bound estimates of the incident cases per year attributable to formaldehyde exposure would
similarly increase by a factor of 1.42. The resulting adjusted upper-bound estimates of 260 and 1,030 for 5- and 20-ppb
exposure levels, respectively, are still well below the estimated total number of 2,300 incident cases per year in the United
States.
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Table 42. F344 rat nasal cancer data
Formaldehyde exposure levels
Incidence of SCC tumors
References
0, 0.7, 2.0, 6.01, 9.93, and 14.96 ppm
(0, 0.86, 2.5, 7.4,12.2, and 18.4 mg/mB)
0/341, 0/107, 0/353, 3/343, 22/103,162/386
(Kerns et al., 1983;
Battelle, 1982) &
(Monticello et al.,
1996) (combined
bioassays)
Several models (described below) were used to calculate BMCs and the corresponding BMCLs
(95% lower confidence bounds on dose) at a benchmark response (BMR) level at the lowest end of the
range of the observed data [(U.S. EPA. 2012); see Table 43], Benchmark concentrations at the 0.005 as
well as 0.01 extra risk levels were determined with the BBDR models. The BMCs and corresponding
BMCLs were then converted to their human equivalent concentrations (HECs) based on formaldehyde
flux to the nasal tissue obtained using computational fluid dynamic (CFD) modeling in the rat and human
(Kimbell et al.. 2001b). The HEC corresponding to a particular benchmark level in the rat was then
calculated by assuming that continuous lifetime exposure to a given steady-state flux of formaldehyde
leads to equivalent risk of nasal cancer across species. This extrapolation included an adjustment to the
laboratory exposure regimen for continuous exposure (multiplication by 6/24 x 5/7).
Table 43. Benchmark concentrations and human equivalents using formaldehyde flux
to nasal tissue as a dose-metric
Models
Rat benchmark conc. (ppm)
Human equivalent conc. (ppm)a
Extra riskb
Extra riskb
0.005
0.01
0.05
0.1
Dose
metric3
0.005
0.01
0.05
0.1
Multistage Weibull time-to-
tumor
EC
LEC
4.28
3.57
5.93
5.52
6.84
6.41
Flux
EC
LEC
0.35
0.30
0.49
0.46
0.57
0.53
Weibull with threshold
Schlosser et al. (2003)
EC
LEC
5.91
5.58
6.12
5.94
6.40
6.22
Flux
EC
LEC
0.75
0.71
0.78
0.76
0.82
0.79
Rat BBDR "model l"c
EC
LEC
4.99d
4.95
5.37d
5.19
Flux
EC
LEC
0.42
0.41
0.45
0.43
Rat BBDR "model 2"c
EC
LEC
5.41
5.25
5.75
5.59
Flux
EC
LEC
0.45
0.44
0.48
0.46
EC=BMC and LEC=BMCL at the specified extra risk; these abbreviations are used here to facilitate comparisons to the modeling
of the human data.
aThe human equivalent benchmark concentrations decrease by a factor of 1.4 if flux estimates based on Schroeter et al. (2014)
are used instead of Kimbell et al. (2001b).
bThe BMR of 0.005 is lower than the value of 0.0085 corresponding to the lowest observed tumor response, corrected for
survival, and was used only with the BBDR modeling because these models incorporate precursor response data related to
cellular proliferation. Because benchmark concentrations at 0.005 and 0.010 extra risk levels were reported, they were not
calculated at the higher levels when BBDR modeling was used.
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cSee text for a description of models 1 and 2.
dBenchmark concentrations corresponding to the hockey-stick model in Conolly et al. (2003) as discerned from Figure 5 of their
paper were ECoos = 4.84 ppm and EC0i = 5.48 ppm. LEC levels could not be estimated since confidence bounds were not
reported by these authors.
Weibull time-to-tumor modeling
Because higher exposures were associated with both earlier tumor occurrence and increased
mortality in the rats, methods that can reflect the influence of competing risks and intercurrent
mortality on site-specific tumor incidence rates were preferred. For this reason, EPA used the
multistage Weibull time-to-tumor model (Portierand Bailer. 1989; Krewski et al.. 1983), which (a)
modeled the replicate animal data, (b) included the exact time of observation of the tumors and
therefore gave appropriate weight to the amount of time each animal was on study without a tumor,
and (c) acknowledged earlier tumor incidence with increasing dose level.
Weibull modeling of the grouped incidence data assuming a threshold in dose
This assessment also presents results from statistical modeling of the same data by Schlosser et
al. (2003) in Table 43. These authors did not carry out a time-to-tumor analysis of the individual animal
data but applied a Kaplan-Meier survival adjustment of the grouped incidence data. The best fit in
Schlosser et al. (2003) was obtained with the polynomial and Weibull (shown) models for the tumor
incidence data with a nonzero intercept (threshold) on the dose axis.
Biologically based dose-response modeling
A biologically based dose-response (BBDR) time-to-tumor model for the formaldehyde-induced
rat nasal tumors was available (Conolly et al.. 2003; CUT, 1999). This model consisted of interfacing
dosimetry models for formaldehyde and formaldehyde-induced DPX in the rat nasal passages (Kimbell et
al.. 2001a; Kimbell et al.. 2001b; Conolly et al.. 2000) with two-stage clonal expansion (TSCE) models for
predicting the probability of occurrence of nasal SCC (Conolly et al.. 2003). Formaldehyde-induced
changes in cell replication and DPX concentrations were considered a function of local formaldehyde
flux to each region of nasal tissue as predicted by computational fluid dynamics (CFD) modeling on
anatomically accurate representations of the nasal passages of a single F344 rat. DPX tissue
concentrations were calculated in Conolly et al. (2003) using a physiologically based pharmacokinetic
model developed in Conolly et al. (2000). In addition to the data from the two tumor bioassays, these
authors included all historical control data on 7,684 animals obtained from National Toxicology Program
F344 rat inhalation and oral bioassays. Conolly et al. (2003) characterized the dose-response for cell
replication rates as a J-shaped curve, indicating that at low exposure concentrations cell division rates
decreased below that determined for the unexposed case. In addition, these authors used a hockey
stick shaped curve such that the dose-response for cell division rates remained changed from the
baseline only at 6 ppm and higher exposure concentrations. This resulted in more conservative
estimates of risk when used in the clonal expansion model for cancer. The BBDR models for the rat used
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here for the purpose of calculating benchmark concentrations were based on Conolly et al. (2003) with
the following modifications.
"Model 1" presented in Table 43 was based on the more conservative, "hockey stick", model in
Conolly et al. (2003), with one critical modification. Conolly et al. (2003) added historical control data
from all NTP studies to the concurrent controls, whereas the model used here included historical data
from only the inhalation route of exposure.17
"Model 2" presented in Table 43 made major modifications to Conolly et al. (2003) in regard to
model structure as well as values for input parameters: (1) the shape of the dose-response for the
division rates of normal cells as a function of formaldehyde flux, aN(flux), was monotone increasing
without a threshold in dose, and obtained by fitting the cell replication data for 13-week exposure
duration in Monticello et al. (1996); (2) the dose-response for the division rates of initiated cells was
assumed to be a sigmoid-shaped curve, increasing monotonically with flux; (3) the death rate of an
initiated cell was assumed to be proportional to its division rate at all formaldehyde flux values and
given by Pi(flux) = K-ai(flux), where k is an unknown estimated constant of proportionality; and (4) as in
model 1, only historical controls from NTP inhalation studies were added to the concurrent controls.
Estimated impact of a revised dosimetry model incorporating endogenous formaldehyde
Schroeter et al. (2014) revised the dosimetry model of Kimbell et al., used for the flux estimates
in the table above, to include endogenous formaldehyde production and to explicitly model
formaldehyde pharmacokinetics in the respiratory mucosa. EPA estimated the extent to which the
results in the above table change if flux estimates from Schroeter et al. (2014) were used. The average
flux over non-squamous regions of the rat nose was roughly one-third18 of that in the human based on
the dosimetry in Schroeter et al. (2014) in which endogenous formaldehyde was taken into account,
compared to a ratio of roughly one-half based on the dosimetry in Kimbell et al. (2001b). As a result, the
benchmark concentrations calculated in the above table were not appreciably altered (decreasing by
roughly a factor of 1.419) if the revised dosimetry model by Schroeter et al. (2014) was applied.
Threshold-based RfC approach for precursor lesion data in the rat: cell proliferation and hyperplasia
The highly curvilinear and steeply increasing dose-responses for DPX formation and cell
proliferation, concomitant with the highly nonlinear observed tumor incidence in the F344 rat, have led
to mechanistic arguments that formaldehyde's nasal carcinogenicity arises only in response to
significant cytotoxicity-induced regenerative cell proliferation (Conolly et al.. 2002; Morgan. 1997). In
particular, Conolly et al. (2003) and Conolly et al. (2004) inferred from BBDR modeling results that the
17ln accordance with generally accepted practice when using historical controls (Peddada et al.. 2007: Haseman. 1995).
ls0.33 at 0.1 ppm, 0.32 at 1 ppm.
19This is only approximate because the various components of the BBDR modeling were not recalibrated or rerun in light of the
revised flux estimates for both species. Furthermore, the above estimate is for resting inspiration, whereas the human flux
values in this assessment pertain to an equal apportionment of sleeping, sitting, and light activity levels.
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direct mutagenicity of formaldehyde is not an important contributor compared to the importance of
cytotoxicity-induced cell proliferation in explaining the rat tumor response. Thus, candidate RfCs (cRfCs)
derived from available experimental data relevant to this mechanism were presented and discussed.
The interpretation of these cRfCs was that they may help identify formaldehyde concentrations
below which it is unlikely that hyperplastic lesions develop or that cancers arising from cytotoxicity-
induced regenerative cell proliferation occur. Cytotoxicity-induced regenerative cell proliferation and
the subsequent development of hyperplastic lesions were considered precursor events that, if protected
against, would prevent these mechanisms from contributing to the cancer response. Below these cRfCs,
formaldehyde may still increase the risk of nasal or upper-respiratory cancer through direct
mutagenicity or other mechanisms, but the magnitude of cancer risk may be significantly lower due to
the absence of increased cellular proliferation or hyperplasia.
Significantly increased cell proliferation and hyperplasia (increased cellular proliferation that is
identified to be pathologically "abnormal" in tissues) have been observed in response to exposure to
formaldehyde, and these data were used to estimate benchmark PODs to calculate cRfCs. Schlosser et
al. (2003) modeled the dose-response for cellular proliferation using labeling index data reported by
Monticello et al. (1996) and calculated a value of 0.44 ppm for the HEC corresponding to the BMCLoi (rat
BMC and BMCL of 4.79 and 3.57 ppm, respectively) using dose-response functions that allowed for a
threshold in dose.20
Although Monticello et al. (1996) represented the longest duration cell proliferation study
available that included a range of exposure durations and nasal regions, five other medium or high
confidence cellular proliferation studies testing formaldehyde exposure durations of 12-13 weeks were
also available. Based on the findings from these studies, reasonable alternatives or adjustments to the
Schlosser et al. (2003) estimate were presented in the assessment. The range of results from the
various cell labeling data attempt to represent some key uncertainties; these include the single-day time
frame (the last day of exposure) over which cell labeling was carried out (a methodological constraint
intrinsic to all available cellular labeling studies) and the specific averaging approach employed in
Schlosser et al. (2003), where the labeling index was weighted by exposure durations and averaged over
several locations on the F344 rat nose. Such a time-weighted averaging underweights early exposures
that may have contributed significantly to carcinogenesis (note: the few studies that investigated latent
effects in rats did observe an increased tumor incidence at 1-2+ years following high-level formaldehyde
exposure lasting only ~13 weeks (Woutersen et al.. 1989; Feron et al.. 1988). It was estimated that the
data from these additional studies would result in benchmark levels that were roughly 2- to 3-fold
lower.
Separately, EPA developed a benchmark POD based on modeling the incidence of basal
hyperplasia reported by Woutersen et al. (1989) in a 28-month bioassay using Wistar rats. The BMC and
20They also modeled with functions that were constrained to pass through the origin, but BMCL values are not reported.
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BMCL at the benchmark response of 0.1 extra risk21 were 1.68 and 1.108 ppm, respectively. The HEC
corresponding to the BMCL was 0.1609 ppm when adjusted for continuous human lifetime exposure,
which was roughly three times lower than the HEC derived from the time-weighted averaged labeling
index by Schlosser et al. (2003). As a point of comparison, this value is roughly similar to the LECooos
derived from EPA's modeling of the NPC risk from the NCI epidemiology data.
Based on these estimates, proliferation-based cRfCs were estimated as follows:
1) The HEC derived from Schlosser et al. (2003) was 0.44 ppm (0.54 mg/m3); the other cell-labeling
studies indicated a 2-fold or 3-fold lower adjustment to this value, i.e., values of 0.27 and 0.18
mg/m3, respectively. Applying a UF = 3 to reflect other uncertainties in extrapolating from
animals to humans and a UF = 10 to account for human variability (total UF = 30) resulted in
cRfCs based on cell proliferation data that ranged from 0.006 mg/m3 to 0.018 mg/m3.
2) The hyperplasia data from Woutersen et al. (1989) resulted in an HEC of 0.1609 ppm (0.1979
mg/m3); applying the UFs described above (total UF=30), the cRfC = 0.007 mg/m3.
As noted earlier, it has been argued that the rat nasal tumors can be quantitatively explained
based solely on formaldehyde's cytotoxic potential. In accordance with this point of view, a cRfC
estimated from benchmark concentrations derived using the two rat BBDR models in Table 43 may be a
reasonable approximation for the dose at which there is no regenerative cell proliferative contribution
to the nasal or upper-respiratory cancer response. A cRfC of 0.017 mg/m3 may be obtained in this
manner corresponding to the average HEC estimated using the two models at a benchmark response of
0.005 extra risk and reduced by an uncertainty factor of 30. This value is encompassed by the range of
0.006-0.018 mg/m3 obtained for the proliferation-based cRfCs above.
However, the direct mutagenicity of formaldehyde plays a key role in its carcinogenicity.
Cytogenetic effects in occupational studies and the formation of DPX in experimental animals have been
reported at exposures well below those considered to be cytotoxic (e.g., approximately 0.7-2 ppm in
rats). In addition, genotoxicity is itself thought to be one of the mechanisms by which formaldehyde
exerts its cytotoxic action, arguing against a demarcation of one MOA over the other along the
concentration axis. Overall, because formaldehyde-induced tumors are not fully explained only by
indirect mutagenicity (i.e., due to regenerative cell proliferation) at any exposure, and since other
modes of action also contribute to the tumor response, the use of an RfC approach was not preferred.
Human Extrapolation of Rat BBDR Model
Subsequent to their model for predicting the risk of rat nasal cancer, Conolly et al. (2004)
developed a corresponding model for humans for the purpose of extrapolating the observed risk in the
rat to human exposures. This human extrapolation model was conceptually very similar to the rat two-
stage clonal expansion model in Conolly et al. (2003) but did not incorporate any data on human
21A 10% BMR was chosen to reflect "minimal adversity," consistent with the noncancer respiratory pathology modeling.
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responses to formaldehyde exposure. Specifically, it used DPX concentrations and values of local
formaldehyde flux to the tissue obtained from the PBPK and CFD models and incorporated a more
detailed biological hypothesis and mechanistic data than are normally employed in modeling cancer risk.
For perspective, Table 44 presents continuous human lifetime extra risk estimates from the
Conolly et al. (2004) model following inhalation exposure to formaldehyde concentrations of 1.0 ppb-
1.0 ppm, in comparison to human risk estimates derived from EPA's modeling of the NPC mortality in
the NCI occupational data. Conolly et al. (2004) developed two models: the "optimal model" in Table 44
refers to derivations using the best fit, a J-shaped curve, to the dose-response for the time-weighted
averaged cell-labeling data in rats such that values at 0.7 ppm and 2.0 ppm were below the control
value; the "conservative model" was derived using a hockey stick-, rather than J-, shape in the low dose
portion (i.e., values at 0.7 and 2.0 ppm were the same as the control). In calculating risk estimates,
Conolly et al. (2004) used a statistical upper bound of the model parameter (kmu)22 (which related DPX
to the probability of mutation per cell generation) and used maximum likelihood (MLE) values for all
other model parameters. Since there is uncertainty inherent to using any statistical model to
extrapolate outside the range of observed data, the relevant question in the context of using the BBDR
modeling for such extrapolation is whether it decreased uncertainty in extrapolating risk (i.e., as
compared to default approaches) or if, by explicitly identifying the sources of uncertainty, the BBDR
modeling pointed to approaches and data needs that may have helped reduce the uncertainty.
Table 44. BBDR model estimated extra risk of SCC in human respiratory tract
compared with EPA's modeling of extra risk of NPC from the human occupational data
Formaldehyde levels:
0.001 ppm
0.01 ppm
0.10 ppma
1.0 ppm
Conollv et al.
(2004) "J-shape
optimal model"
-1.0 x 10"5
-1.0 x 10"4
-9.1 x 10"4
-5.0 x 10"3
Conollv et al.
(2004) "hockey stick
conservative model"
+3.1 x 10"s
+3.2 x 10"7
+3.5 x 10"6
+2.7 x 10"4
EPA analysis of NCI
NPC, MLE (UCL)b
+1.2 x 10"6 (+2.1 x 10"6)
+1.3 x 10"5 (+2.3 x 10"5)
+1.8 x 10"4 (+4.1 x 10"4)
+2.7 xlO1 (+8.7 xlO1)
aThe mortality-based ECooos (LECooos) from the NCI epidemiology data correspond roughly to 0.2 (0.1) ppm.
bMLE = maximum likelihood estimate; UCL=95% upper confidence limit.
22The model estimated MLE value for kmu was found to be zero, leading to the inference by the authors that formaldehyde's
direct mutagenic action is not relevant to carcinogenicity in the rat or human, and that the observed tumor response in the rat
can be explained on the basis of regenerative cellular proliferation to cell injury.
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The assessment included a careful evaluation of the level of confidence and sources of
uncertainties in different components of the rat BBDR and the corresponding human extrapolation
models. Of the potential issues identified, those related to replication rates of normal and initiated
cells, and the use of historical control animals were found to have major impacts on qualitative and
quantitative conclusions from the modeling. In particular, modeling results were unstable in response
to slight perturbations in the assumed values for the division rates for initiated cells, and there are
currently no data of any kind even in rats to inform the effect of formaldehyde on the kinetics of
initiated cells. The model was also extremely sensitive to the inclusion of historical control animals.
Because SCC in the nose is a rare tumor, Conolly et al. (2004. 2003) included in their model control rats
from all NTP cancer bioassays. When the NTP control data were restricted to those animals from NTP
inhalation studies, the upper bound human risk estimate obtained by Conolly et al. (2004) (i.e., with
everything else in their modeling retained unchanged) was increased by 50-fold (Crump et al.. 2008). If
only concurrent controls were used, the model for extrapolation of risk to humans became numerically
unstable (i.e., the MLE and upper-bound estimates of risk became infinite). Subramaniam et al. (2007)
and Crump et al. (2008) provide details. The human extrapolation model exhibited extreme uncertainty
at all exposure concentrations, above as well as below the human equivalent concentrations that were
calculated in Table 43 [see (2009; Crump et al.. 2008)1.
Unit risk estimates based on animal data, considering confidence in the available models
Overall, use of biologically based modeling allowed utilization of various data, including
mechanistic information, in an integrated manner for modeling the incidence of nasal SCCs in F344 rats
and for deriving benchmark levels for extrapolation. In this way, the rat BBDR modeling improved the
dose-response modeling of the observed nasal cancers in the F344 rat, and multiple BBDR model
implementations provided similar estimates of risk and confidence bounds in the general range of the
observed rat tumor incidence data. Therefore, the rat BBDR models were used to calculate benchmark
concentrations for points of departure (PODs). In addition, given the reasonable confidence in flux
estimates derived from the rat and human CFD models, model-derived formaldehyde flux values were
used in deriving human equivalent concentrations corresponding to these PODs and candidate unit risk
estimates using these values were calculated.
However, it was determined that the human extrapolation modeling in Conolly et al. (2004) was
extremely uncertain and did not provide robust measures of human nasal SCC risk at any exposure
concentration. Therefore, this human extrapolation model was not used to directly calculate risk at
human exposure scenarios.
The assessment presents strong arguments in support of a low dose linear extrapolation from
the POD. Given formaldehyde's direct mutagenic potential, following the procedures in EPA's cancer
guidelines (U.S. EPA. 2005a) for when the knowledge of the MOA does not support an alternative
approach, a low dose linear approach was used to predict low-dose formaldehyde cancer risk from the
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1 rat data. Extrapolation was carried out as a straight line drawn to the origin from the HEC corresponding
2 to the BMDL. Unit risks were calculated using several modeling approaches, including modifications to
3 the rat BBDR model, as shown in Table 45 below. The unit risks corresponding to BMRs at the 0.005 or
4 0.01 extra risk levels spanned a remarkably tight range of 0.01-0.03 per ppm.
5 Table 45. Unit risk estimates derived from benchmark estimates using animal data
6 and formaldehyde flux as dose-metric
Models
Unit risk estimates (1/ppm)
LEC005
LECoi
LECos
LEC10
Weibull with threshold3 Schlosser et
al. (2003)
0.014
0.066
0.127
Multistage Weibull time-to-tumor
0.033
0.109
0.189
Rat BBDR "model 1"
0.012
0.023
Rat BBDR "model 2"
0.011
0.022
Estimates using steady-state DPX as a dose metric were identical.
Note = values were not estimated for vacant cells.
7 Selection of a unit risk estimate for nasal cancers
8 The unit risk estimates derived using the available human and animal data on nasal cancers are
9 similar (see Table 46), with the human estimate being only slightly lower than those values estimated
10 using rat bioassay and mechanistic data.
11 Table 46. Comparison and basis of unit risk estimates for NPC in humans and nasal
12 SCCs in rats
Human NPC estimate
Animal nasal cancer estimate
Study/Endpoint
Beane Freeman et al. (2013s)
(NCI industrial cohort): NPC mortality
Kerns et al. (1983s); Monticello et al. < 1996):
Incidence of nasal squamous cell carcinoma
in rats
Model features
Estimation of inhalation unit risk using
Poisson regression model and life table
analysis:
• U.S national incidence data
• Regression coefficients from log-linear
models of nasopharyngeal (NPC)
mortality (exposed and unexposed
workers)
• Linear low-dose extrapolation from
LEC
Multiple mechanistic and statistical models,
including BBDR modeling, used for modeling
tumor incidence. Mechanistic information
included:
• Dosimetric (CFD) modelling of
formaldehyde flux to rat, monkey and
human airway lining
• PBPK model for rats incorporating dose-
response data on DNA-protein crosslinks
• Site-specific cell labeling measurements in
nose
Linear low-dose extrapolation was carried
out from human equivalent dose at BMCL
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Human NPC estimate
Animal nasal cancer estimate
POD
95% lower bound on concentration at
0.05% incidence (approx. 0.05 ppm)
95% lower bound on concentration at 0.5%
incidence (approx. 0.2 ppm)
Unit risk estimate3
7.4 x 10"3 per mg/m3
(9.1 x 10"3 per ppm)
8.9 x 10"3 to 1.8 x 10 2 per mg/m3
(1.1 x 10"2 to 2.2 x 10"2 per ppm)
aNote that these estimates are provided for comparison purposes and do not represent ADAF-adjusted values.
Ultimately, it was determined that the human data provided a more appropriate basis for
estimating human nasal cancer risk than did the rodent data, given that a well-conducted
epidemiological study was available with appropriate quantitative analyses. However, candidate unit
risks in Table 46 at 0.005 extra risk were comparable to that derived using the occupational data on
nasopharyngeal cancers (see Section 2.2.1 in the Toxicological Review). Because the unit risk estimates
from the human data were preferred, the rodent-based estimates were not adjusted for the assumed
increased early-life susceptibility arising from the determination of a mutagenic MOA for URT cancers;
however, if the rodent-based estimates were to be used, ADAFs should be applied (U.S. EPA. 2005b).
As previously described, using the human NPC data, a plausible upper bound lifetime extra
cancer mortality unit risk of 4.5 x 10"3 per ppm (3.6 x 10"6 per ng/m3) of continuous formaldehyde
exposure was estimated using a life table program and linear low-dose extrapolation of the excess NPC
mortality and log-linear modeling results (for cumulative exposure) reported in a high confidence
occupational epidemiological study (based on 10 NPC deaths). Applying the same regression coefficient
and life table program to background NPC incidence rates yielded a lifetime extra cancer (incidence) unit
risk estimate of 9.1 x 10"3 per ppm (7.4 x 10"6 per ng/m3).
The weight of evidence supports the conclusion that formaldehyde carcinogenicity for URT
cancers such as NPC can be attributed, at least in part, to a mutagenic MOA. Therefore, because there
were no chemical-specific data to evaluate susceptibility of different lifestages, increased early-life
susceptibility was assumed for NPC and age-dependent adjustment factors (ADAFs) were applied,
consistent with EPA guidelines (U.S. EPA. 2005b).
The application of ADAFs resulted in a lifetime unit risk estimate of 1.1 x 10"5 per ng/m3 (1.3 x
10"2 per ppm) for NPC incidence, adjusted for postulated increased early-life susceptibility, assuming a
70-year lifetime and constant exposure across age groups.
Uncertainties and confidence in the selected unit risk estimate for nasal cancers
The strengths and uncertainties in the unit risk estimate for NPC incidence are summarized in
Table 47. One of the largest sources of uncertainty in the NPC estimate has to do with the rarity of the
cancer and, thus, the small number of exposed cases (n = 8) that informed the dose-response analysis.
It is important to note that, although a unit risk estimate could only be calculated for NPC (for which an
evidence integration judgment of evidence demonstrates was drawn), the systematic evaluation of
evidence on URT cancers also resulted in a judgment that the evidence demonstrates (based on studies
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1 in occupational cohorts and animals) that inhalation of formaldehyde causes sinonasal cancer, given
2 appropriate exposure circumstances.
3 Table 47. Strengths and uncertainties in the cancer type-specific unit risk estimate for
4 NPC
Strengths
Uncertainties
• IIIR estimated from data that
are directly relevant to
humans.
• Based on the results of a
large, high confidence
epidemiological study
involving multiple industries
with detailed, individual
cumulative exposure
estimates and allowance for
cancer latency.
• Low-dose linear extrapolation
is supported by a mutagenic
MOA (i.e., not a default).
• Similar unit risk estimates
derived using rat bioassay
and mechanistic data on
nasal cancers.
• NPC is a very rare cancer. This study followed more than 25,000 workers
for over 40 years and observed a statistically significant increase in relative
risk associated with the highest category of average exposure intensity,
however, only 10 cases occurred. The small number of deaths creates
uncertainties for the dose-response modeling (borderline model fit for
cumulative exposure including exposed and unexposed person-years,
p = 0.07).
• Uncertainty about optimal exposure metric(s). Cumulative exposure is the
standard metric used for unit risk estimates. Use of cumulative exposure
assumes equal importance of concentration and duration on cancer
incidence; yet, associations with peak exposure in epidemiological studies
and the nonlinear shape of the dose-response from animal bioassays
suggest greater influence of concentration.
• Although statistically significant increases in risk for NPC were reported by
multiple studies for several metrics of exposure (duration, cumulative, time
since first exposure, peak), the relationship with cumulative exposure in
the study used for IUR derivation was less precise (p-trend = 0.07 based on
the regression coefficient for the continuous model).
• Some uncertainty in the low-dose extrapolation is introduced based on the
potential for endogenous formaldehyde to reduce the uptake of the
inhaled gas at low doses, as demonstrated in modeling efforts by Schroeter
et al. (2014) and Campbell et al. (2020).
5 Based on the attendant strengths and uncertainties outlined above, there is medium confidence
6 in the unit risk estimate for NPC incidence. The greatest uncertainty was related to the small number of
7 cases that contributed to the statistical analysis and resulting imprecision in modeling the shape of the
8 dose-response curve.
9 4.5.2. Derivation of Cancer Unit Risk Estimates for Myeloid Leukemia
10 The quantitative analyses of myeloid leukemia are based on results from the latest follow-up of
11 the NCI cohort of industrial workers exposed to formaldehyde (Beane Freeman et al.. 2009). Although
12 no association was indicated for cumulative exposure and myeloid leukemia in this study, the
13 combination of myeloid leukemia and other/unspecified leukemia was marginally associated (p = 0.1)
14 with cumulative formaldehyde exposure. The evaluation of this combined group is supported by
15 analyses by NCI during the 1980s and 90s that compared diagnoses on death certificates to original
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hospital diagnoses and found that as many as 50% of deaths classified as other or unspecified leukemia
were originally diagnosed as myeloid leukemia (Percy et al.. 1990; Percy et al.. 1981).23
Derivation of a myeloid leukemia unit risk estimate based on human data
Choice of epidemiology study
Similar to the unit risk estimate for NPC, the estimate for myeloid leukemia is based on results
from the latest follow-up of the NCI cohort of industrial workers exposed to formaldehyde (Beane
Freeman et al.. 2009). the largest (25,619 workers) of the three independent industrial worker cohort
studies and the only one with sufficient individual exposure data for dose-response modeling. Beane
Freeman et al. (2009) conducted dose-response analyses of 123 deaths attributed to leukemia and
leukemia subtypes, as well as deaths from other LHP malignancies. As previously described, this well-
conducted study is the only one that used internal comparisons rather than standardized mortality
ratios (reducing the impact of potential unmeasured confounding), and it included a detailed exposure
assessment conducted for each worker based on exposure estimates for different jobs held and tasks
performed (Stewart et al.. 1986). and exposure estimates were made using several different metrics-
peak exposure, average intensity, cumulative exposure, and duration of exposure.
Dose-response modeling of data from the NCI cohort
The results of the internal analyses (i.e., comparing exposed workers to an internal referent
group of other workers in the cohort) of Beane Freeman et al. (2009) for LHP cancer types using the
cumulative exposure metric are presented in Table 48. The relative risks (RRs) were estimated using log-
linear Poisson regression models stratified by calendar year, age, sex, and race and adjusted for pay
category. A two-year lag interval was used to determine exposures to account for a latency period for
LHP cancers. For all cancer types, the NCI investigators used the low-exposure category as the reference
category to "minimize the impact of any unmeasured confounding variables since nonexposed workers
may differ from exposed workers with respect to socioeconomic characteristics" (Hauptmann et al..
2004). In this review, the nonexposed person-years were included in the primary cancer risk analyses to
be more inclusive of all the dose-response data. The analyses adjusted for pay category, a measure of
socioeconomic status, thus possible SES differences between exposed and nonexposed were at least
partially addressed. Final results for the exposed person-years only are also presented for comparison.
23ln the Percy et al. (1990; 1981) studies, only about 10% of leukemia deaths were classified as "other or unspecified" based on
hospital diagnoses (versus 29% from death certificates in the Beane Freeman et al. (2009) study), and 51% (Percy et al.. 1981)
and 53% (Percy et al.. 1990) of leukemia deaths were myeloid leukemias based on hospital diagnoses (versus 39% from death
certificates in the Beane Freeman et al. (2009) study), suggesting that about a third or more of the "other or unspecified"
leukemia deaths in the Beane Freeman et al. (2009) study were probably myeloid leukemias. Percy et al. (1990) reported in
their study that "Of the nearly 600 deaths from leukemia NOS [other or unspecified] nearly 50% were originally diagnosed as
myeloid... Obviously myeloid leukemia is grossly underreported on death certificates."
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1 Cumulative exposure was included as a continuous variable in the log-linear models (general
2 model form: RR = e|3X, where (B represents the regression coefficient and X is exposure). The regression
3 coefficients are presented in Table 48.
4 Table 48. Relative risk estimates for mortality from leukemia (based on ICD codes)
5 and regression coefficients from NCI log-linear trend test models3 by level of
6 cumulative formaldehyde exposure (ppm x years). Source: Beane Freeman et al. (2009)
Relative risk estimates
cancer type
Rate ratio (number of deaths)
p-trend, all
person-years'3
p-trend, exposed
person-yearsc
0
>0 to <1.5d
1.5 to <5.5
>5.5
Leukemia
0.53 (7)
1.0(63)
0.96 (24)
1.11 (29)
0.08
0.12
Myeloid leukemia
0.61(4)
1.0(26)
0.82 (8)
1.02 (10)
0.44
>0.50
Other/unspecified
leukemia
0.77 (2)
1.0(15)
1.65 (10)
1.44 (9)
0.13
0.15
Regression coefficients
cancer type
Person-years
p (per ppm x year)'
Standard error (per ppm x year)'
Leukemia
All
0.01246
0.006421
Exposed only
0.01131
0.00661
Myeloid leukemia
All
0.009908
0.01191
Exposed only
0.008182
0.01249
Myeloid leukemia plus
other/unspecified leukemia6
All
0.01408
0.007706
Exposed only
0.01315
0.007914
aModels stratified by calendar year, age, sex, and race and adjusted for pay category; cumulative exposures
calculated using a 15-year lag interval for NPC and a 2-year lag interval for LHP cancer types.
bLikelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (as a continuous variable)
among all (nonexposed and exposed) person-years.
likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (as a continuous variable)
among exposed person-years only.
Reference category for all categories.
ep-trend values for the myeloid and other/unspecified leukemia categories combined are 0.10 for all person-years
and 0.13 for exposed person-years only.
'Source: Personal communications from Laura Beane Freeman to Jennifer Jinot (February 22, 2013 and February
21, 2014) and to John Whalan (August 26, 2009).
7 Approaches used for quantitative risk assessment of myeloid leukemia
8 EPA explored several approaches for deriving a unit risk estimate for myeloid leukemia based on
9 cumulative exposure. A standard approach for deriving the unit risk estimate was considered using the
10 regression coefficient for myeloid leukemia and cumulative exposure; however, the p-value (0.44) for
11 that regression coefficient was far from 0.05, indicating a poor model fit. The poor model fit could be
12 due, at least in part, to inadequate statistical power, likely exacerbated by the underreporting of
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myeloid leukemia deaths. The regression coefficient for all person-years for myeloid leukemia is only
slightly lower than that for all leukemia (0.0099 and 0.0125 per ppm-years, respectively). The
association with all leukemia cancer had a lower p-value of 0.08 and should include all the myeloid
leukemia deaths, both specified and unspecified. The "other/unspecified" leukemias comprise a
sizeable portion of all leukemia deaths (almost 30%) in the cohort and presumably include a good
proportion of unclassified myeloid leukemias (Percy et al.. 1990; Percy et al.. 1981). To address this
underreporting, two additional approaches for deriving a unit risk estimate for myeloid leukemia were
considered.
One approach involved using the all leukemia grouping.24 Use of the all leukemia background
rates in the life table calculations (described in more detail below) might inflate the unit risk estimate for
myeloid leukemia by increasing the background risk relative to which the formaldehyde-related risks are
calculated. However, the inclusion of any leukemia subtypes not related to formaldehyde exposure
should theoretically dampen the dose-response relationship (lowering the regression coefficient)
relative to that for all the myeloid leukemias alone; thus, this should mitigate at least some of the effect
of using the all leukemia background rates.
The preferred approach involved using a combined grouping of the myeloid leukemia and
other/unspecified leukemias subcategories. The myeloid and other/unspecified leukemias grouping had
a stronger association with cumulative exposure (p-trend = 0.10 for all person-years) in the Beane
Freeman et al. (2009) study than did myeloid leukemia alone and it captures the unclassified myeloid
leukemias with the least inclusion of nonmyeloid leukemias. There is likely more uncertainty associated
with the background rates for the other/unspecified leukemias than for the specified myeloid and
lymphocytic leukemia subtypes; however, the benefits of focusing on the myeloid plus
other/unspecified leukemias rather than the broader "all leukemias" grouping in attempting to be more
inclusive of all the myeloid leukemias were deemed to outweigh any additional uncertainty associated
with the background rates. Although the unit risk estimate based on the preferred approach of using
myeloid plus other/unspecified leukemias inevitably includes some nonmyeloid leukemias, it is
considered the best approach for deriving a unit risk estimate for myeloid leukemia specifically.25
24The all leukemia category includes all 123 leukemias observed in the cohort. Of these, 48 (39.0%) were myeloid, 37 (30.1%)
were lymphoid, and 36 (29.3%) were other/unspecified; the remaining 2 (1.6%) were monocytic leukemias (ICD-8 code 206).
25Although the inclusion of cancer subtypes not necessarily causally associated with the chemical exposure in the grouping of
cancers represented in the regression coefficient and the corresponding background rates for the life table analysis is overt
here, it is not uncommon that, due to data limitations, unit risk estimates based on human data reflect cancer groupings
broader than what might be strictly causally associated with the chemical exposure (e.g., all leukemias or all lung cancers). As
noted in the text, any inclusion of unassociated cancer subtypes in the derivation of the regression coefficient should
theoretically attenuate the coefficient in a manner that would offset the use of the unassociated subtypes in the background
rates in the life table analysis.
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Prediction of lifetime extra risk of myeloid leukemia mortality and incidence
Unit risk estimates for myeloid leukemia mortality (and incidence) were calculated from the
regression results using the different approaches discussed above and the same general methodology
described for the NPC mortality estimates with the exception of the use of a 2-year lag period, as
selected by Beane Freeman et al. (2009). Mortality (and incidence) rates from the time frame 2006-
2010 were used in the life table program. Although the background mortality rates of leukemia are
higher (lifetime risk of 0.0062 according to the life table analysis) than those of NPC, the 1% extra risk
level typically used as the basis for the POD for epidemiological data still corresponds to an RR estimate
(2.5) that would be above the highest categorical result reported, even after adjusting the RR estimates
upward relative to the 0-exposure group (because our primary analyses include the nonexposed
workers). A 0.5% extra risk level yields an RR estimate of 1.8, which better corresponds to the RRs in the
range of the data. Thus, the LEC value corresponding to 0.5% extra risk (LECoos) was selected for the
POD for all leukemia and for myeloid leukemia and myeloid plus other/unspecified leukemias, which
have lower background rates than all leukemia (lifetime risks of 0.0031 and 0.0046, respectively).
There are insufficient data to establish the MOA for formaldehyde-induced myeloid leukemia;
thus, linear low-dose extrapolation was performed as the default approach, in accordance with EPA's
cancer guidelines (U.S. EPA. 2005a). The ECoos, LECoos, and inhalation unit risk estimates for myeloid plus
other/unspecified leukemia mortality are presented in Table 49.
Table 49. ECoos, LECoos, and unit risk estimates for myeloid plus other/unspecified
leukemia mortality based on log-linear trend analyses of cumulative formaldehyde
exposure data from the Beane Freeman et al (2009) study
Person-years
ECoos (ppm)
LECoos (ppm)
Unit riska(per ppm)
Unit risk(per mg/m3)
All
0.253
0.133
1
o
1
X
00
ro
3.1 x 10~2
Exposed only
0.269
0.135
3.7 x 10"2
3.0 x 10"2
aUnit risk = 0.005/LECoos-
All leukemia and myeloid leukemia have substantial survival rates;26 thus, it is preferable to
derive incidence estimates. Unit risk estimates for leukemia incidences were calculated as described
above for the NPC incidence estimates. The incidence-based calculation relies on the assumptions that
incidence and mortality for these leukemia subtype groupings have the same dose-response relationship
for formaldehyde exposure and that the incidence data are for first occurrences of the cancers or that
relapses provide a negligible contribution. The first assumption is more uncertain for all leukemia,
myeloid leukemia, and myeloid plus other/unspecified leukemias than it was for NPC because these are
26Survival rates were 55.0% at 5 years for all leukemia [http://seer.cancer.gov/statfacts/html/leuks.htmll. 23.4% at 5 years for
acute myeloid leukemia [http://seer.cancer.gov/statfacts/html/amvl.htmll. and 59.1% at 5 years for chronic myeloid leukemia
[http://seer.cancer.gov/statfacts/html/cmvl.htmll based on 2002-2009 SEER data.
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1 groupings of subtypes with quite different survival rates (e.g., see footnote 26). The incidence-based
2 calculation also takes advantage of the fact that incidence rates for these cancer types are negligible
3 compared with the all-cause mortality rates and thus no special adjustment to the population at risk to
4 account for live individuals who have been diagnosed with these cancers is necessary.
5 The ECoos, LECoos, and inhalation unit risk estimates for myeloid plus other/unspecified leukemia
6 incidence are presented in Table 50. The incidence unit risk estimate is about 10% higher than the
7 mortality estimate. This difference is lower than the ~24% increase that would have been seen for
8 specified myeloid leukemias alone (see the LECoosS in Table 51). This is because the difference between
9 age-specific mortality and incidence rates for the other/unspecified leukemias is not very large, and for
10 some age groups the mortality rates are actually larger than the incidence rates. This irregularity is to
11 be expected for "other/unspecified" classifications because greater attention is given to diagnosing
12 incident leukemia cases than to accounting for causes of death, so one would anticipate less
13 underreporting of myeloid leukemias as incident cases than as causes of death on death certificates.
14 Table 50. ECoos, LECoos, and unit risk estimates for myeloid plus other/unspecified
15 leukemia incidence based on Beane Freeman et al. (2009) log-linear trend analyses for
16 cumulative formaldehyde exposure
Person-years
ECoos (ppm)
LECoos (ppm)
Unit risk3 (per ppm)
Unit risk (per mg/m3)
All
0.224
0.118
4.2 x 10~2
3.4 x 10~2
Exposed only
0.239
0.120
4.2 x 10"2
3.4 x 10"2
aUnit risk = 0.005/LECoos-
17 The ECoos and LECoos estimates for mortality and incidence and incidence unit risk estimates for
18 all leukemia and for myeloid leukemia using the alternate approaches discussed above are presented in
19 Table 51. The same underlying life table methodology was used for each approach—only the regression
20 coefficients and background cancer rates differed. As discussed above, and consistent with the results
21 just presented, the preferred approach (shaded in Table 51) is the life table analysis using the regression
22 coefficient and background rates for myeloid plus other/unspecified leukemias because this grouping
23 captures the unclassified myeloid leukemias with the least inclusion of non-myeloid leukemias.
24 Table 51. ECoos and LECoos estimates for mortality and incidence and unit risk
25 estimates for all leukemia and myeloid leukemia using alternate approaches (all
26 person-years) - shaded estimate is preferred
Approach (by cancer type used as
basis for regression coefficient and
cause-specific background rates)
ECoos (|
LECoos (
>pm)
ppm)
Unit risk estimate
(per ppm)a
Unit risk estimate
(per mg/m3)
Incidence
Mortality
(Incidence)
(Incidence)
Myeloid leukemia
0.378
0.127
0.468
0.157
3.9 x 10"2
3.2 x 10"2
All leukemia
0.156
0.229
5.9 x 10"2
4.8 x 10"2
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0.0846
0.124
Myeloid + Other/Unspecified
0.224
0.118
0.253
0.133
4.2 x 10"2
3.4 x 10"2
aUnit risk estimate = 0.005/(LEC0os for incidence).
incidence background rates also include monocytic leukemia, but that contribution is negligible.
1 Thus, the preferred unit risk estimate for myeloid leukemia is the estimate of 4.2 x 10"2 per
2 ppm.27 The unit risk estimate calculated using the exposed person-years only is essentially
3 indistinguishable from the preferred estimate using all person-years (see Table 50). The unit risk
4 estimates from the other approaches considered are fairly close, with the unit risk estimate based on
5 the myeloid leukemia category's being virtually identical to the preferred estimate based on myeloid
6 plus other/unspecified leukemias, and the estimate based on all leukemia being somewhat greater (see
7 Table 52).
8 Table 52 summarizes some of the key information comparing the different approaches
9 considered for the derivation of the unit risk estimate for myeloid leukemia.
10 Table 52. Dose-response modeling (all person-years) and (incidence) unit risk
11 estimate derivation results for different leukemia groupings - shaded estimate is
12 preferred
Deaths
Regression
SE
Unit risk
Unit risk
in NCI
coefficient
(per ppm
estimate
estimate
Cancer grouping
cohort
(per ppm x year)
x year)
p-value
(per ppm)
(per mg/m3)
Myeloid leukemia
48
0.009908
0.01191
0.44
3.9 x 10"2
3.2 x 10"2
All leukemia
123
0.01246
0.006421
0.08
5.9 x 10"2
4.8 x 10"2
Myeloid +
Other/Unspecified
84a
0.01408
0.007706
0.10
4.2 x 10"2
3.4 x lO"2
leukemias
aThis is the sum of the leukemias classified as myeloid and those classified as "other/unspecified." At least 70-80%
of this number are expected to be myeloid leukemias, assuming that a third to a half of leukemias not otherwise
specified on death certificates are myeloid leukemias, as discussed above.
13 Selection of a unit risk estimate for myeloid leukemia
14 The best estimate that can be derived for myeloid leukemia was calculated using human
15 occupational data from the NCI industrial cohort (Beane Freeman et al.. 2009). As previously described,
16 a plausible upper bound lifetime extra cancer mortality unit risk of 3.8 x 10"2 per ppm (3.1 x 10"5 per
17 Hg/m3) of continuous formaldehyde exposure was estimated using a life table program and linear low-
27Comparable to calculations done for NPC, a rough calculation was done to ensure that the unit risk estimate derived for
myeloid leukemia incidence is not implausible in comparison to actual case numbers. For example, assuming an average
constant lifetime formaldehyde exposure level of 20 ppb for the U.S. population, the inhalation unit risk estimate for myeloid
(and other/unspecified) leukemia equates to a lifetime extra risk estimate of 8.4 x 10~4. Assuming an average lifetime of 75
years (this is not EPA's default average lifetime of 70 years but rather a value more representative of actual demographic data)
and a U.S. population of 300,000,000, this lifetime extra risk estimate suggests a crude upper-bound estimate of 3,400 incident
cases of myeloid leukemia attributable to formaldehyde exposure per year. This upper-bound estimate is well below the
estimated 17,100 total incident myeloid leukemia (not including other/unspecified leukemias) cases per year.
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dose extrapolation of the excess myeloid plus other/unspecified leukemia mortality and log-linear
modeling results (for cumulative exposure) reported in a well-conducted occupational epidemiological
study (based on 84 deaths). Applying the same regression coefficient and life table program to
background myeloid leukemia incidence rates yielded a lifetime extra cancer (incidence) unit risk
estimate of 4.2 x 10"2 per ppm (3.4 x 10"5 per ng/m3).
Since there is no knowledge as to whether a mutagenic MOA might be operative for
formaldehyde-induced myeloid leukemia, no adjustments for increased early-life susceptibility (i.e.,
application of age-dependent adjustment factors) were made for myeloid leukemia, consistent with EPA
guidelines (U.S. EPA. 2005b).
Uncertainties and confidence in the selected unit risk estimate for myeloid leukemia
The strengths and uncertainties in the unit risk estimate for myeloid leukemia incidence are
summarized in Table 53. The primary uncertainty in this estimate relates to the complexities in the
study-specific data for cumulative formaldehyde exposure and mortality from myeloid leukemia.
Table 53. Strengths and uncertainties in the cancer type-specific unit risk estimate for
myeloid leukemia
Strengths
Uncertainties
• IIIR estimated from data that are
directly relevant to humans.
• Based on the results of a large,
high confidence epidemiological
study involving multiple
industries with detailed,
individual cumulative exposure
estimates and allowance for
cancer latency.
• Moderate number of deaths to
model (n = 84).
Uncertainties with a potentially greater impact:
• Although the dose-response relationship with peak exposure was
marginally significant (p = 0.07), and statistically significant associations
were reported for several metrics of exposure in other studies, the
reported relationship with cumulative exposure showed a non-
significant, small increase in risk for myeloid leukemia (based on the
regression coefficient for the continuous model), potentially due in part
to misclassification of myeloid leukemia cases.
• The association with cumulative exposure was stronger for the other/
unspecified grouping of leukemia diagnoses (n = 36) than for myeloid
leukemia alone (n = 48). Although a sizable proportion of this category
is assumed to include myeloid leukemia cases, the stronger association
is surprising given the more heterogeneous set of leukemia cases in this
category, some presumably not associated with formaldehyde
exposure. Hence, the association would be expected to be attenuated.
• Uncertainty about optimal exposure metric(s). Use of cumulative
exposure assumes equal importance of concentration and duration on
cancer incidence. The specific metrics analyzed differed across studies,
and the results of the NCI study were not completely consistent with
those of other studies (associated only with peak exposure).
Uncertainties likely to have a minor impact:
• Grouping of myeloid leukemias used for exposure-response modeling
includes non-myeloid leukemias.
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Strengths
Uncertainties
• Borderline model fit for myeloid plus other/unspecified leukemias
(p = 0.1) and uncertain shape of exposure-response function.
Based on the attendant strengths and uncertainties outlined above, there is low confidence in
the unit risk estimate for myeloid leukemia incidence. This uncertainty is discussed further in the
summary section below. However, given the judgment that the available evidence demonstrates that
formaldehyde inhalation causes myeloid leukemia in humans given appropriate exposure circumstances,
and the associated public health burden that it poses (e.g., myeloid leukemia is far more prevalent than
NPC), EPA thoroughly considered the complexity in the data and used an innovative approach to derive
and present potential unit risk estimates for myeloid leukemia. A charge question will be provided for
the peer-review panel regarding the development of a unit risk estimate for myeloid leukemia and
asking for advice about how, if at all, the unit risk estimate might inform the quantification of risk for
cancer.
4.5.3. Estimates of Cancer Risk based on "Bottom-up" Approach
Swenberg et al. (2011) and (Starr and Swenberg. 2013), followed by an update of results in Starr
and Swenberg (2016), developed an approach to bound low-dose human cancer dose-response from
formaldehyde exposure in a manner that only uses information regarding: (1) background incidence of
the target tumors (nasopharyngeal cancers, leukemia, and Hodgkin lymphoma) in the U.S. population,
(2) assumptions as to the target tissue for a key event interaction with formaldehyde for each type of
tumor, and (3) measures of internal formaldehyde tissue dose in laboratory animals derived from either
endogenously produced formaldehyde or from exogenous exposure to formaldehyde. The tissue dose
measures are based on highly sensitive measurements in rats and monkeys of formaldehyde-induced
DNA adducts (Yu et al.. 2015; Lu et al.. 2011; Moeller et al.. 2011; Lu et al.. 2010).
To develop these bounding estimates, the authors attributed the background tumor incidences
to endogenous formaldehyde in the presumed target tissues (as measured by endogenous adducts).
The approach assumed extra cancer incidence to be linearly related to exogenous adduct levels, with a
slope equal to the ratio of background tumor incidence to background tissue dose of endogenous
formaldehyde.
Risk estimates from this approach are claimed by the authors to produce conservative upper
bounds, primarily because (a) the method attributes all the background risks of specific cancers to
endogenous formaldehyde although other environmental factors might also contribute to these
cancers, (b) lower confidence bounds on measured adduct levels are used, and (c) the above linear
relationship is assumed.
Swenberg et al. (2011) and Starr and Swenberg (2016) then compared these values with the risk
estimates in EPA's 2010 draft Toxicological Review, which were obtained by linearly extrapolating to
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lower doses from a point of departure (a lower bound on the concentration associated with the
benchmark response) derived by dose-response modeling of the epidemiological data. When adduct
data from rats were used, the estimates Swenberg and Starr derived at 1 ppm exposure concentration
were 2.67 x 10"4 for nasal cancer (based on Yu et al.. 2015) and were at most 12.6 xlO4 for leukemia
(based on the limit of detection, LOD, from Lu et al. (2010). since no exogenous adducts were detected
in bone marrow). In monkeys (Yu et al.. 2015), the Swenberg and Starr bottom-up estimates were
2.69 x 10"4 for NPC and were less than 1.24 x 10 s for leukemia. In comparison, the EPA upper-bound
risk estimates were higher than the adduct-based upper-bound estimates by 40-fold for NPC and at least
45-fold (rat adduct data) or over 45,000-fold (monkey adduct data) for leukemia.
EPA concludes that the bottom-up approach does not necessarily provide an upper bound on
the slope of the dose-response at low exogenous exposures, primarily because the ratio of background
tumor incidence to internal endogenous concentration at the true target tissue may underpredict the
slope of the dose-response above that endogenous concentration. This is further discussed in Crump et
al. (2014). Furthermore, the approach assumes direct interaction of inhaled formaldehyde with a
particular target tissue; if other sites of interaction and mechanisms are involved, the measures of DNA
adducts in a specific tissue could lead to underestimates of the cancer potency when utilizing the
"bottom-up" approach. Nonetheless, the bottom-up approach, which uses cancer incidence in the
general population and is independent of the tumor dose-response data, can potentially provide some
perspective on the likely contribution of a specific mode-of-action and the uncertainty in risk estimates
derived from occupational exposures or derived by extrapolating downward from higher dose animal
data where other phenomena may be occurring.
4.5.4. Summary of Unit Risk Estimates and the Preferred Estimate for Inhalation Unit Risk
As discussed previously, the NPC unit risk estimate based on data from the human occupational
epidemiology study of the NCI updated by Beane Freeman et al. (2013) was preferred over estimates
based on rodent cancer bioassay data. The best estimate for myeloid leukemia was also derived from
the human occupational epidemiology study of the NCI updated by Beane Freeman et al. (2009). These
estimates are presented in Table 54.
Table 54. Summary of inhalation unit risk estimates from occupational
epidemiological studies3'13
Cancer type
Preferred unit risk
estimate
(ppm"1)
ADAF-adjusted
unit risk estimate
(ppm"1)
Preferred unit risk
estimate
((Hg/m3)"1)
ADAF-adjusted unit
risk estimate
((Hg/m3)"1)
Nasopharyngeal
0.0079°
0.013
6.4 x 10^c
1.1 X 10"5
Myeloid leukemia
0.042
NAd
3.4 x 10"5
NAd
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aThe inhalation unit risk estimate is typically expressed as the (upper-bound) increase in cancer risk estimated for
an exposure increase of 1 ng/m3.
bThe unit risk estimates are all for cancer incidence.
cAdult-based (rescaled) unit risk estimate for NPC intended for the application of ADAFs.
dNA = not applicable; no ADAF adjustment is recommended for myeloid leukemia.
However, the data reported for myeloid leukemia (Beane Freeman et al.. 2009) are complex and
there are reasons for and against the use of these data in the derivation of the inhalation unit risk (IUR).
Given the judgment that the available evidence demonstrates that formaldehyde inhalation causes
myeloid leukemia in humans given appropriate exposure circumstances, and the associated public
health burden that it poses (e.g., myeloid leukemia is far more prevalent than NPC), EPA thoroughly
considered the complexity in the data and used an innovative approach to derive and present potential
unit risk estimates for myeloid leukemia. Some important uncertainties are discussed in greater detail
below.
• Despite the quality of the literature base for the formaldehyde assessment and the judgment that
the available evidence demonstrates that formaldehyde inhalation causes myeloid leukemia in
humans given appropriate exposure circumstances, the only study suitable for dose-response
quantification for myeloid leukemia may be viewed as insufficient for developing a quantitative
estimate of risk with an acceptable level of confidence.
o The Beane Freeman study failed to observe an association between cumulative formaldehyde
exposure and myeloid leukemia (p = 0.44), despite a reasonable number of cases (n = 48) and
adequate follow up. The peak exposure metric was marginally associated (p = 0.07). This result
raises questions about the relative importance of the intensity of exposure and duration in the
association of myeloid leukemia mortality. On the other hand, myeloid leukemia mortality
increased with time since first exposure, cumulative exposure, and exposure duration in two
other occupational cohorts (garment workers and embalmers).
o The available animal studies do not provide any compelling evidence for an association between
formaldehyde inhalation and myeloid leukemia. Thus, there are no other data that can be used
to support the POD estimate that can be derived from the only suitable human study.
• Analyses from NCI comparing causes of death recorded on death certificates with original diagnoses
in hospital records suggest a misclassification of myeloid leukemia cases (n = 48), with a significant
proportion reported as "other/unspecified" (n = 36).
o In the Percy et al. (1990; 1981) studies, only about 10% of leukemia deaths were classified as
"other or unspecified" based on hospital diagnoses (versus 29% from death certificates in the
Beane Freeman et al. (2009) study), and 51% (Percy et al.. 1981) and 53% (Percy et al.. 1990) of
leukemia deaths were myeloid leukemias based on hospital diagnoses (versus 39% from death
certificates in the Beane Freeman et al. (2009) study), suggesting that about a third or more of
the "other or unspecified" leukemia deaths in the Beane Freeman et al. (2009) study were
probably myeloid leukemias. Percy et al. (1990) reported in their study that "Of the nearly 600
deaths from leukemia NOS [other or unspecified] nearly 50% were originally diagnosed as
myeloid... Obviously myeloid leukemia is grossly underreported on death certificates."
o Because it is likely that a proportion of myeloid leukemia cases were reported as
"other/unspecified," a more complete estimate of the association of cumulative formaldehyde
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exposure with myeloid leukemia might be obtained using the regression results for a
combination of myeloid leukemia and other/unspecified leukemia,
o Although a unit risk estimate that combines myeloid leukemia and other/unspecified leukemia
overtly includes cancer subtypes not necessarily causally associated with the chemical exposure,
it is sometimes the case that, due to data limitations, unit risk estimates are based on human
data that reflect cancer groupings broader than what might be strictly causally associated with
the chemical exposure (e.g., all leukemias or all lung cancers). The inclusion of unassociated
cancer subtypes in the derivation of the regression coefficient should theoretically attenuate the
association.
o A comparison of the unit risk estimates for all leukemia, myeloid leukemia plus other
unspecified leukemia, and myeloid leukemia (ICD-8/9: 205) indicates that all of the estimates
are within a factor of 1.5. Unit risk estimates were 3.9 x 10 "2, 4.2 x 10"2, and 5.9 x 10"2 for all
leukemia, myeloid leukemia plus other unspecified leukemia, and myeloid leukemia (ICD-8/9:
205), respectively.
• The approach for combining myeloid leukemia and other/unspecified leukemia to estimate risk,
while arguably consistent with the identified misclassification of myeloid leukemia on death
certificates (Percy et al.. 1990; Percy et al.. 1981) is uncommon, and retains significant quantitative
uncertainties, including some inconsistencies in statistical results. To a limited extent, it might also
be viewed as combining cancer types that differ in terms of the cell of origin and other
characteristics of cancer development (e.g., latency; MOA).
o The combination of myeloid leukemia and other/unspecified leukemia in the regression model
yields a p-value of 0.1. While the number of cases is increased by n = 36, cancers in this
category, with the exception of the myeloid leukemia cases, were not identified to be causally
associated with formaldehyde exposure during the hazard evaluation. The inclusion of cancers
not causally associated with formaldehyde exposure would be expected to attenuate the
association, but in contrast to this expectation, there was a stronger association for the
regression model of other/unspecified leukemia alone (p = 0.13) compared to the model of
myeloid leukemia alone (p = 0.44). There is not a clear explanation for why the association
would be stronger for the more heterogeneous leukemia category,
o There is likely more uncertainty associated with the background cancer rates in the U.S.
population for the other/unspecified leukemias than for the specified myeloid and lymphocytic
leukemia subtypes. The survival rates of the other/unspecified cancers had to be estimated by
subtracting myeloid and lymphocytic leukemia rates from the rates for all leukemia,
o As the Beane Freeman et al. (2009) study did evaluate myeloid leukemia, the use of either
myeloid leukemia plus other/unspecified leukemias or the even broader category of all
leukemias would represent deviations from using the most specific diagnoses possible.
Depending on the extent to which the combined cancer types differ (e.g., in terms of cancer
development), this could introduce significant quantitative uncertainties. However, such a
decision to group or focus on individual cancer types must also consider the number and power
of the available studies to be capable of detecting changes with reasonable confidence.
• Given the completely unknown MOA for myeloid leukemia, it is possible and perhaps likely that
there are dose and duration effects for the development of myeloid leukemia following
formaldehyde inhalation that are not fully understood.
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1 o Acknowledging the complexity of the different dose metrics available in the observational
2 studies, as well as the lack of an association between cumulative exposure and myeloid
3 leukemia in the Beane Freeman et al. (2009) study, it is possible that the specific, individual
4 exposure metrics in this study failed to fully capture the patterns of exposure most relevant to
5 the development of myeloid leukemia. Importantly, this concern is independent of the
6 identified hazard for myeloid leukemia, as myeloid leukemia mortality was increased in
7 association with the peak exposure metric in this study (industrial workers) and others, as well
8 as with duration-dependent metrics including time since first exposure, cumulative exposure,
9 and exposure duration in two other occupational cohorts (garment workers and embalmers).
10 o As information supporting a nonlinear extrapolation from the identified POD is not available for
11 myeloid leukemia, the current approach uses a default linear extrapolation. It is possible that
12 additional study on the development of this cancer after formaldehyde exposure could provide
13 support for the linear extrapolation or, alternatively, support a nonlinear approach.
14 Considering these uncertainties in the myeloid leukemia unit risk estimate, the selected IUR,
15 summarized in Table 55, reflects the estimate for NPC incidence alone. For benefits analyses and certain
16 other situations, "central" estimates of risk per unit dose may be preferred over (upper bound) unit risk
17 estimates. Therefore, the assessment also provides estimates of risk per unit dose resulting from linear
18 extrapolations of risk from the central estimate (here, the EC, or effective concentration associated with
19 the benchmark response level of risk).
20 Table 55. Inhalation unit riska'b
Cancer type
Preferred unit risk
estimate
(ppirr1)
ADAF-adjusted
unit risk estimate
(ppm"1)
Selected unit risk
estimate
((Hg/m3)"1)
ADAF-adjusted unit
risk estimate
((Hg/m3)"1)
Nasopharyngeal
0.0079°
0.013
6.4 x 10"6 c
1.1 X 10"5
aThe inhalation unit risk estimate is typically expressed as the (upper-bound) increase in cancer risk estimated for
an exposure increase of 1 ng/m3.
bThe unit risk estimate is for cancer incidence.
cAdult-based (rescaled) unit risk estimate for NPC intended for the application of ADAFs.
21 Sources of uncertainty associated with the selected inhalation unit risk
22 The availability of suitable human data from which to derive unit risk estimates eliminates one
23 of the major sources of uncertainty inherent in most unit risk estimates—the uncertainty associated
24 with interspecies extrapolation. The NCI study used as the basis for the selected unit risk estimate was
25 considered a high-quality study for the purposes of deriving unit risk estimates. The NCI study is a large
26 longitudinal cohort study that developed individual-worker exposure estimates using detailed
27 employment histories and formaldehyde concentration measurements. In addition to the detailed
28 exposure assessment, the study used internal analyses and gave careful consideration to potential
29 confounding or modifying variables. Moreover, the NCI study comprises a large cohort that has been
30 followed for a long time. Nonetheless, uncertainties in the derived unit risk estimates are inevitable.
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The primary uncertainty in the selected inhalation unit risk is the lack of inclusion of an estimate
for the prevalent cancer, myeloid leukemia, due to complexities in the quantitative data, the strengths
and limitations of which are outlined above. Other important sources of uncertainty in the selected unit
risk estimate are the retrospective estimation of individual worker exposures, the dose-response
modeling of the NCI data, the exposure metric, and the high-to-low exposure extrapolation. These
factors, particularly the latter two, could have a large impact on the unit risk estimate. The former two
factors could result in either overprediction or underprediction of the true risk, although regarding the
retrospective estimation of exposures, comparisons with the Marsh et al. (1996) exposure estimates
suggest that the NCI exposure estimates might be overestimates, which would tend to underpredict the
true risk. The latter two factors, the use of cumulative exposure as the exposure metric and the use of
linear high-to-low exposure extrapolation, which are related, would tend to overpredict the true risk.
Additional sources of uncertainty include the use of a single study for the derivation of the unit
risk estimate and the derivation of unit risk estimates for the general population from an occupational
study. The first factor could result in either overprediction or underprediction of the true risk. The
second factor would tend to underpredict the true risks.
While the proven genotoxicity and mutagenicity of formaldehyde and the observation of human
cytogenetic effects in human occupational exposures provide strong support for preferring the linear
extrapolation, an uncertainty in the low dose-response comes from the potential for endogenous
formaldehyde levels in respiratory tissue to reduce the uptake of the inhaled gas at low doses, as
demonstrated in modeling efforts by Schroeter et al. (2014) and Campbell et al. (2020). This would be
expected to result in an overprediction of the true risk.
Sources of uncertainty expected to have minimal quantitative impact include the inability to
derive unit risk estimates for potential cancer sites other than NPC and myeloid leukemia, the derivation
of incidence estimates from mortality data, the influence of confounding and modifying factors (with the
possible exception of particulates, where a modifying effect cannot be ruled out; if particulates are
modifying the NPC risk, the NCI data would tend to overestimate the risk from formaldehyde alone,
possibly to a more considerable extent), and the application of the ADAFs used to address assumed
increased early life susceptibility.
Although substantial uncertainty exists with respect to the low-exposure extrapolation, the
estimate is based on human data from a large, high-quality epidemiological study and mutagenic and
cytogenic modes-of-action are well documented. Furthermore, the estimate is similar to estimates
derived from rodent data. Based on these considerations, overall confidence in the selected inhalation
unit risk is medium.
4.5.5. Previous IRIS Assessment: Inhalation Unit Risk
In the previous assessment (last updated in 1991), an inhalation unit risk of 1.3 x 10"5 per ng/m3
was developed based on nasal SCCs in F344 rats from Kerns et al. (1983). The data were modeled from
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the estimates of the probability of death with tumor and its variance using a linearized multistage
procedure.
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This document is a draft for review purposes only and does not constitute Agency policy.
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