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 (ptrend = .020) and with increasing peak formaldehyde exposure (ptrend = .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 (ptrend P trend = .020) and with increasing peak formaldehyde exposure (ptrend P 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); metaanalysis | 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.
a
Complete 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.