Identifying an indoor air exposure limit for formaldehyde considering both irritation and cancer hazards

Figures & data

Table 1.  Summary of authoritative or comprehensive evaluations and other relevant data on formaldehyde exposure concentrations associated with or protective from symptoms of sensory irritation or other adverse effects.

Formaldehyde air concentration (ppm)	Source	Comment/observation
6−15	Monticello et al. 1996; Kerns et al. 1983a, b;	Chronic inhalation dose range required for the sustained cytotoxicity and regenerative proliferation leading to development of nasal tumors.
1.0	TNO, 2003; Arts et al., 2006	“..… minimal/mild/slight eye irritation starts at levels of 1.0 ppm formaldehyde and higher.”
0.9	EPA, 2004; Acute exposure guideline level (AEGL)	“At 0.35 to 0.9 ppm, the subject’s subjective eye irritation responses ranged from none to slight, the same as their responses to clean air.”
0.75	OSHA, 2006; (Occupational exposure standard) Noisel et al. 2007	In effect for many years with no evidence of significant worker complaints of sensory irritation. “The level of 0.75 ppm can be considered as a safe level that allows protecting virtually all workers.” Noisel et al. (2007)
	Noisel et al., 2007	“The level of 0.75 ppm can be considered as a safe level that allows protecting virtually all workers.”
0.7	Andersen et al., 2008, 2010	Inhaled concentration in rats that produces no significant toxicogenomic changes in nasal epithelial cells following 21 or 90 days of exposure.
0.5	Lang et al., 2008 (most recent controlled human study) EPA/NCEA 2005	““… the no-observed-effect level for subjective and objective eye irritation due to formaldehyde exposure was 0.5 ppm in case of constant exposure level and 0.3 ppm with peaks of 0.6 ppm in terms of short term peak exposures.”Clear threshold at 0.5 ppm for any effects (including odor) with an effective concentration at 1.5 ppm for moderate effects.
	US EPA/NCEA, 2005	Clear threshold at 0.5 ppm for any effects (including odor) with an effective concentration at 1.5 ppm for moderate effects.
0.3	ATSDR, 1999, 2007 NAS, 2007 WHO, 2010 ACGIH, 2001 MAK, 2006 OECD/SIDS, 2002 NICNAS, 2005	Most weight of evidence–based reviews conclude that 0.3 ppm is a reasonable and appropriate level below which symptoms of sensory irritation are unlikely to occur, e.g., “…symptoms of eye and mucous membrane irritation at that concentration were not increased above control conditions in controlled chamber studies.” (NAS, 2007) and “Studies in the literature have reported a variety of responses induced by exposure to gaseous formaldehyde, generally beginning in the range of 0.3 to 0.5 ppm for eye irritation, the most sensitive endpoint. However, the severity of response at these levels is generally mild, and only a small portion of the population may respond.” (OECD/SIDS, 2002).
0.2	SCOEL, 2008	“This especially considers possible interindividual differences in susceptibility to irritation by formaldehyde, which may be expected based on the entire body of data.”
0.1	BfR, 2006; Health Canada, 2001, 2005; ASHRAE NASA/NAS, 2008	Partially derived from animal data, i.e., “The proposed level of 0.1 ppm is 2 fold lower than the level derived from animal data by applying appropriate safety factors.” [emphasis in original]. 0.1 ppm (1 hour) = 1/5th of NOAEL (i.e., 0.5 ppm) for eye irritation.
0.08	WHO, (2010); Wolkoff and Nielsen, 2010	“An air quality guideline of 0.1mg/m^3 (0.08 ppm) is considered protective against both acute and chronic sensory irritation in the airways in the general population assuming a log normal distribution of nasal sensory irritation.” “Thus, prevention of nasal cancer is considered to prevent lymphohematopoietic malignancies…. the guideline value of the WHO [of]…0.08 ppm FA, is considered preventive of carcinogenic effects in compliance with epidemiological findings.”
	WHO, 2010; Nielsen and Wolkoff, 2010	“Thus, prevention of nasal cancer is considered to prevent lymphohematopoietic malignancies…the guideline value of the WHO [of]…0.08 ppm FA, is considered preventive of carcinogenic effects in compliance with epidemiological findings.”

Table 2.  Correction of NCI 1994 data and additional follow-up for leukemia and resulting attenuated exposure-response relationships.

Highest peak(ppm)	NCI study						Marsh et al. (2004) re-analysis^e
	1994 follow-up original^a,b		1994 follow-up revised^c		2004 follow-up^d
	No. deaths	RR (95% CI)	No. deaths	RR (95% CI)	No. deaths	RR (95% CI)	SMR (95% CI)
Unexposed	4	0.78 (0.25–2.43)	4	0.52 (0.17–1.57)	7	0.59 (0.25–1.36)	0.38* (0.10–0.97)
>0–1.9 (base)	16	1.00 (—)	23	1.00 (—)	41	1.00 (—)	0.50* (0.28–0.81)
2.0− 3.9	20	2.04 (1.0–4.01)	20	1.36 (0.73–2.51)	27	0.98 (0.60–1.62)	1.04 (0.63–1.60)
>4.0	29	2.46 (1.31–4.62)	29	1.60 (0.90–2.82)	48	1.42 (0.92–2.18)	1.31 (0.88–1.89)

^aUsed by IARC in 2004;. ^b p_trend = .001 (all groups), p_trend = .004 (exp. only); ^ccp_trend = .021 (all groups), p_trend = .094 (exp. only); ^dp_trend = .02 (all groups), p_trend = .12 (exp. only); ^ep < 0.05.

Table 3.  Comparison of IARC, NTP, and US EPA use of or reliance on data from key studies addressed in present review.

Study/issue/findings	IARC (2009)^a	NTP (2010)	US EPA/IRIS (2010a)
Lu et al. (2009)/)—Lack of exogenous FA-DNA adducts at any sites distant to nasal epithelium	Study not available for most recent assessment; acknowledged as key issue by Smith and Goldstein (2010)^b	Background document: Acknowledged finding of no exogenous FA-DNA adducts at any sites distal to nasal epithelium.Expert panel report: Not mentioned.	Cited only for finding of endogenous FA-DNA adducts; failed to mention key finding of no exogenous FA-DNA adducts detected at any sites distal to nasal epithelium.
Meng et al. (2010))—No increase in p53 mutations in nasal epithelium following 13 13-wk exposure to FA at up to 15 ppm	Not available	Background document: Not cited Expert panel report: Not mentioned	Cited only for findings on cell proliferation (used with permission of authors); did not mention that p53 mutations not increased after 13 wks exposure to FA at 15 ppm
Marsh et al. (2004, 2005, 2007) —Re-analyses of NCI cohort data on NPC and leukemia; alternative explanation for increased NPC in Plant 1 and implications of significant mortality deficits on RR calculations.	Not available	Background document: Marsh et al. (2007): Misrepresents key findings on previous exposure to metals and acids as plausible explanation for increased NPC in Plant #1 in NCI cohort Expert panel report: Ignored all Marsh et al. re-analyses of NCI data	Marsh 2004: Failed to cite reanalysis of NCI cohort data on leukemia;Marsh 2007: Inaccurately characterizes key findings, e.g., previous exposure to metals and acids as plausible explanation for increased NPC in NCI cohort
Beane Freeman et al. (2009);)—Update of NCI cohort; reveals >1000 missing deaths in previous studies (Hauptmann et al., 2003, 2004)	Not available	Background document: Findings accurately characterized Expert panel report: Incorrectly implied study as reporting significant increased mortality from AML	Inappropriately relied on to support conclusion of FA-induced increased risks of all forms of leukemia (AML, CML, ALL, CLL) and Hodgkin’s lymphoma; relied on statistically insignificant cumulative exposure findings for cancer risk projections
Bachand et al. (2009)—Meta-analysis of leukemia and NPC epidemiology data, only meta-analysis to include Beane Freeman et al. (2009)	Not available	Background document: Findings accurately characterized for NPL and leukemia. Expert panel report: Not mentioned or cited.	Not cited or discussed even though available; sole reliance on Zhang et al. (2009) cited 44 times as primary support for interpreting Beane Freeman et al. (2009) findings that all forms of leukemia and Hodgkin’s lymphoma causally associated with exposure to formaldehyde
Conolly et al. (2003, 2004)—Biologically based dose response (BBDR) model for FA-induced nasal tumors	Not available	Background document: Both studies discussed Expert panel report: Neither study mentioned	Appendices D, E, and F devoted to questioning/critiquing basis for and conclusions from BBDR model
Andersen et al. (2008, 2010)—3 and 13- wk FA inhalation dose-response toxicogenomic studies; Thomas et al. (2007); benchmark dose analysis	Not available	Background document: 2008 study mentioned. Expert panel report: Neither study mentioned.	Appendices G and H devoted to questioning/critiquing conclusions of dose-response toxicogenomic data and benchmark dose analysis; primary emphasis on Hester et al. (2003, 2005) single dose nasal instillation studies
Fox et al. (1985) and Matubayasi et al. (2007)—Basis for explaining FA toxicity at distant sites due to methanediol dissociation to free FA	Fox: Summarizes FA use at 4% (40,000 ppm) for tissue fixation; no explanation for relevance in living systems (2 ppm)^c	Fox: Summarizes FA use at 4% (40,000 ppm) for tissue fixation; no explanation for relevance in living systems (2 ppm) Matubayasi: Article on FA−-methanediol equilibrium in boiling water	Neither study cited.

FA = formaldehyde.

^a: Complete report on 2009 meeting not yet available.

^{b: b}Goldstein, B.D. and, Smith, M.T. (2010). Formaldehyde. Identification of research needs to resolve the carcinogenicity of high priority IARC carcinogens. IARC Technical Publication No. 42. Lyon, France: IARC.

^{c: c}Preliminary IARC report.

Table 4.  Comparison of the basis for IARC, NTP, and US EPA conclusions on formaldehyde-induced cancers.

Study/issue/findings	IARC (2009)^a	NTP (2010)	US EPA/IRIS (2010a)	Comment
How conclusions reached	Vote of working group: 11 to 9 for leukemia	Vote of Expert Panel: Single 11 to 0 vote for AML, NPC, and SNC	Key selected studies with little if any critical assessment of methodological issues.	Single NTP vote for all endpoints presumes same strength of evidence for all endpoints.
Major conclusions and key studies relied on as primary support	Leukemia and NPC	AML, NPC, and sinonasal cancer AML: Beane Freeman (2009), Hauptmann (2009), Coggin (2003), and Pinkerton (2004); 3 of 4 studies found elevated risks of AML in individuals with high exposure to FA, as well as positive exposure-response relationships. NPC: Hauptmann 2004; the only cohort study that is individually informative for NPC	AML, CML, ALL, CLL, Hodgkin’s lymphoma, and NPC Beane Freeman (2009), Zhang (2009, 2010), Hauptmann (2004)	Only NTP concluded that sinonasal cancer an endpoint associated with FA exposure; US EPA/IRIS uses statistically insignificant cumulative exposure data from Beane Freeman as basis for yearly incidence projections for all leukemia, Hodgkin’s lymphoma and NPC
Beane Freeman et al. (2009); most recent update of NCI cohort	Primary support for leukemia	AML not significantly elevated based on peak, no. of peaks, cumulative, duration, or average intensity of exposure; no significant trends	Does not support conclusion of FA-induced increased risks of all forms of leukemia (AML, CML, ALL, CLL) and Hodgkin’s lymphoma; insignificant cumulative exposure findings used for cancer incidence risk projections	No consideration of numerous issues with study; no mention of implications of >1000 missed deaths
Coggin et al. (2003)	No significant increase in NPC or all forms of leukemia; myeloid leukemia not separately evaluated	No significant increase in all forms of leukemia; myeloid leukemia not separately evaluated	No significant increase in all forms of leukemia; myeloid leukemia not separately evaluated;	Little, if any, emphasis on study findings as basis for conclusions
Pinkerton et al. (2004)	Myeloid leukemia significantly elevated 20+ years after first exposure; test for trend not positive; no NPC cases.	Myeloid leukemia significantly elevated 20+ years after first exposure; test for trend not positive; no NPC cases	Myeloid leukemia significantly elevated 20+ years after first exposure; test for trend not positive; no NPC cases.	Little, if any, emphasis on study findings as basis for conclusions
Hauptmann et al. (2009)	Not cited in IARC (2009). Formaldehyde 4. Mechanistic and other relevant data. Vol. 100F, Monograph No. 09-Formaldehyde,	Duration of embalming practice associated with significantly increased risk for mortality from myeloid leukemia; myeloid leukemia significantly associated with increasing number of years of embalming (p trend = .020) and with increasing peak formaldehyde exposure (p trend = .036).	Duration of embalming practice associated with significantly increased risk for mortality from myeloid leukemia; myeloid leukemia significantly associated with increasing number of years of embalming (ptrendP trend = .020) and with increasing peak formaldehyde exposure (ptrendP trend = .036).	Formaldehyde exposure not measured; number of embalming a surrogate for exposure; major issue concerns failure to test key results for statistical significance
Hauptmann et al. (2004)	Primary support for NPC	Primary support for NPC	Primary support for NPC	Most reviews dismiss or ignore analysis by Marsh et al. (2007) showing previous exposure to known NPC risk factors a likely explanation for reported results
Hauptmann et al. (2003)	Reported leukemia findings not accurate due to failure to account for >1000 missing deaths	Reported leukemia findings not accurate due to failure to account for >1000 missing deaths	Reported leukemia findings not accurate due to failure to account for >1000 missing deaths	Analyses by Marsh et al. (2004, 2007) demonstrate substantial attenuation of risks after accounting for >1000 missing deaths
Zhang et al. (2009); meta-analysis	Cited in bibliography; no indication how used to reach conclusions.	“...more informative because it used data for individuals with the highest exposure to formaldehyde to calculate the summary relative risks.”	Cited 44 times to support reliance on Beane Freeman (2009) results for all leukemia and Hodgkin’s lymphoma	Findings at odds with 2 other meta-analyses including Bachand et al. (2009), which is only one to include the Beane Freeman results.
Zhang et al. (2010); Chinese worker study	Support for biological plausibility of epidemiology results; no critical assessment of methods or assertion that FA equivalent to benzene in leukemogenic potential	Support for biological plausibility of epidemiology results; no critical assessment of methods or assertion that FA equivalent to benzene in leukemogenic potential	Support for biological plausibility of epidemiology results; no critical assessment of methods or assertion that FA equivalent to benzene in leukemogenic potential	Numerous methodological and interpretive issues undermine study; no critical assessment of reported conclusions.
Tang et al. (2009); review of studies purporting to demonstrate FA-induced hematotoxicity	Support for FA-induced hematotoxicity; reported results uncritically accepted.	Support for FA-induced hematotoxicity; reported results uncritically accepted.	Support for FA-induced hematotoxicity; reported results uncritically accepted.	All but one study in Chinese; only study in English does not support FA-induced hematotoxicity
Fox et al. (1985); basis for claiming FA toxicity at distant sites due to methanediol dissociation to free FA	Cited to explain how methanediol could dissociate at distant sites to release free FA as explanation for leukemia	Cited to explain how methanediol could dissociate at distant sites to release free FA as explanation for leukemia	Not cited; still implies that FA or methanediol may reach sites distal to portal of entry	Article on use of 4% formalin for tissue fixation (40,000 ppm); not relevant for living systems (2 ppm)
Matubayasi et al. (2007); basis for claiming FA toxicity at distant sites due to methanediol dissociation to free FA	Cited to explain how methanediol could dissociate at distant sites to release free FA as explanation for leukemia	Cited to explain how methanediol could dissociate at distant sites to release free FA as explanation for leukemia	Not cited; still implies that FA or methanediol may reach sites distal to portal of entry	Article about methanediol dissociation in boiling water; no relevance for living systems.

FA = formaldehyde.

^aComplete report on 2009 meeting not yet available.

^bGoldstein BD, Smith MT. (2010). Formaldehyde. Identification of research needs to resolve the carcinogenicity of high priority IARC carcinogens. IARC Technical Publication No. 42. Lyon: IARC.

^cPreliminary IARC report.

Table 5.  Possible contributors leading to false positive results in NCI cohort studies.

Generic issue	Suggested examples
Chance	Statistically significant deficits in leukemia mortality in internal non- and low-exposed comparison groups that substantially influence RR calculations. This single issue alone, if properly addressed and accounted for, would appear to undermine any conclusion about a causal association between formaldehyde exposure and leukemia.
Systematic errors in design of study	Questionable reliance on an unconventional measure of exposure, (i.e., peak); all significant associations with leukemia mortality disappeared when assessed using cumulative number of peaks ≥4 ppm as a more appropriate metric of potential exposure.
Analysis of study	Failure to consider using an external comparison group in light of significant mortality deficits in internal groups; as shown by the Marsh et al. (2004) analysis, significant effects disappeared when this was done. In addition, the implications of >1000 deaths missed in the 1994 follow-up, and the substantial effects of these missed deaths on the RRs as shown in Table 2, should have been addressed.
Inadequate accounting for confounding variables	Previous employment in occupations with exposure to known risk factors for NPC.

Table 6.  Projected number of cases/year of leukemia, Hodgkin’s lymphoma, and NPC attributable to formaldehyde at various exposure levels.

Endpoint	Incident number cases/year in US	Projected cases at various formaldehyde exposures
		5 ppb	20 ppb	300 ppb	750 ppb
Leukemia	44,800	1900	7580	Everyone?	Everyone?
Hodgkin’s lymphoma	8500	564	1360	Everyone?	Everyone?
NPC	2100	220	880	Everyone?	Everyone?

Table 7.  Comparison of observed and expected leukemia and NPC mortality in formaldehyde-exposed workers.

Cohort	No. of Workers	Leukemia		NPC
		Observed	Expected^b	Observed	Expected
NCI^a	25,600	116	≈116	8	2
Coggin	14,000	12	13	1	2
Pinkerton	11,000	24	≈24	0	1
Total	50,600	152	153	9	5

^a: Beane Freeman et al. (2009) for leukemia and Hauptmann et al. (2004) for NPC.

^b: When only observed mortality was reported, the expected mortality was calculated by dividing the observed mortality by the SMR.

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