401 

### 1 Exposure Data

1.1 Identification of the agent

From ( IARC, 2006 ).

Chem. Abstr. Serv. Reg. No. : 50-00-0
Chem. Abstr. Name : Formaldehyde IUPAC Systematic Name : Methanal Synonyms : Formaldehyde gas; formic aldehyde; methaldehyde; methyl alde

hyde; methylene oxide; oxomethane; oxymethylene

C O

H H

CH

2 O

Relative molecular mass: 30.03 Description : Colourless gas with a pungent

odour Conversion factor : mg/m 3 = 1.23 × ppm; calculated from: mg/m 3 = (relative molecular mass/24.45) × ppm, assuming standard temperature (25 °C) and pressure (103.5 kPa). 

### 1.2 Use

Formaldehyde is produced worldwide on a large scale by catalytic, vapour-phase oxidation of methanol. Formaldehyde is used mainly in the production of various types of resin. Phenolic,
urea, and melamine resins have wide uses as adhesives and binders in the wood-production,pulp-and-paper, and the synthetic vitreousfibre industries, in the production of plastics and coatings, and in textile finishing. Polyacetal resins are widely used in the production of plas

tics. Formaldehyde is also used extensively as an

intermediate in the manufacture of industrial
chemicals, such as 1,4-butanediol, 4,4 ′ -methyl

enediphenyl diisocyanate, penta-erythritol, and hexamethylenetetramine. Formaldehyde is used directly in aqueous solution (known as formalin) as a disinfectant and preservative in many appli

cations ( IARC, 2006 ). 

# FORMALDEHYDE

Formaldehyde was considered by previous IARC Working Groups in 1981, 1987, 1994, and
2004 ( IARC, 1982

, 1987

, 1995

, 2006 ). Since that time new data have become available, which have been incorporated in this Monograph , and taken into consideration in the present

evaluation.IARC MONOGRAPHS – 100F



### 1.3 Occurrence and exposure

1.3.1 Environmental occurrence and

exposure

Formaldehyde is found as a natural product in most living systems and in the environment. It occurs naturally in fruits and some foods, and it is formed endogenously in mammals, including humans, as a consequence of oxida

tive metabolism. In addition to these natural sources, common non-occupational sources of exposure to formaldehyde include combus

tion processes, e.g. through emissions from motor vehicles, power plants, incinerators,
refineries, wood stoves, and kerosene heaters. Formaldehyde may be released from particle boards and similar building materials, carpets, paints and varnishes, during cooking of some foods, and during its use as a disinfectant. It is also present in tobacco smoke. An indirect source of exposure to formaldehyde is its formation via photochemical oxidation of hydrocarbons, such as methane, and other precursors emitted from combustion processes ( NTP, 2005 ; IARC, 2006 ). Formaldehyde has a short half-life in the envi

ronment, because it is removed from the air by photochemical processes and by precipitation and biodegradation ( NTP, 2005 ). Concentrations of formaldehyde in outdoor air are generally below 0.001 mg/m 3 in remote areas and below 0.02 mg/m 3 in urban settings. The levels of formaldehyde in indoor air of houses are typically 0.02–0.06 mg/m 3 ; indoor combustion sources can significantly increase these levels. Cigarettes may contribute as much as 10–25% of the indoor exposure. Average concentrations of 0.5 mg/m 3 or more have been
measured in ‘mobile homes’, but these have

declined since the late 1980s as a result of stand

ards that require that building materials – e.g. particle boards – emit lower concentrations of formaldehyde. A recent study of emissions from mosquito coils found the average concentration of formaldehyde exceeded 100 μg/m 3 ( IARC, 2006

, 2010 ; Lee & Wang, 2006 ). Data on formaldehyde

concentrations in outdoor air in residential and public settings, and information on exposure to formaldehyde associated with household use of solid fuels and high-temperature frying, have

been reviewed in IARC Monograph Volumes 88 and 95 ( IARC, 2006

, 2010 ). Automobile exhaust is a major source of formaldehyde in ambient air. Recent reports suggest that formaldehyde emissions may be higher from vehicles powered by compressed natural gas compared with those running on ethanol or gasohol ( Corrêa & Arbilla, 2005 ), and that these emissions may be decreased by substi

tution of an ethanol-biodiesel-diesel blend for diesel fuel ( Shi et al

. , 2006 ). In addition, formal

dehyde can be absorbed through the skin from

cosmetics or via contact with other consumer products containing formaldehyde, such as unwashed permanent-press fabrics treated with formaldehyde-releasing resins ( NTP, 2005 ).



### 1.3.2 Occupational exposure

Occupational exposure to formaldehyde occurs in a wide variety of occupations and industries. CAREX (CARcinogen EXposure) is an international information system on occupational exposure to known and suspected carcinogens based on data collected in the European Union (EU) from 1990 to 1993. The CAREX database provides selected exposure

data and documented estimates of the number of exposed workers by country, carcinogen, and industry ( Kauppinen et al

. , 2000 ). Table 1.1 presents the results for formaldehyde in the EU by industry ( CAREX, 1999 ).

In IARC Monograph Volume 88 ( IARC, 2006 ) data were reviewed on occupational exposure to formaldehyde by type of industry. The highest continuous exposures (2–5 ppm; 2.5–6.1 mg/m 3 ) were measured in the past during varnishing of furniture and wooden floors, in the finishing of

402Formaldehyde

403 Table 1.1 Estimated numbers of workers exposed to formaldehyde above background levels in the European Union

Industry, occupational activity

Manufacture of furniture and fixtures, except primarily of metal 179000 Medical, dental, and other health and veterinary services 174000 Manufacture of wearing apparel, except footwear 94000 Manufacture of wood and wood and cork products, except furniture 70000

Personal and household services 62000

Construction 60000

Manufacture of textiles 37000

Iron and steel basic industries 29000 Manufacture of fabricated metal products, except machinery 29000 Manufacture of other non-metallic mineral products 23000 Manufacture of machinery, except electrical 20000

Manufacture of industrial chemicals 17000 Manufacture of other chemical products 17000 Manufacture of plastic products not classified elsewhere 16000 Agriculture and hunting 16000 Manufacture of paper and paper products 13000 Printing, publishing and allied industries 13000

Wholesale and retail trade and restaurants and hotels 13000 Manufacture of transport equipment 11000 Manufacture of electrical machinery, apparatus and appliances 10000

Manufacture of footwear 9000 Manufacture of glass and glass products 8000

Research and scientific institutes 7000

Non-ferrous metal basic industries 6000 Manufacture of leather and products of leather or of its substitutes 6000 Beverage industries 4000 Manufacture of instruments, photographic and optical 4000 Other manufacturing industries 3000 Food manufacturing 3000 Crude petroleum and natural gas production 2000 Manufacture of rubber products 4000 Financing, insurance, real estate and business services 3000

Education services 2000 Sanitary and similar services 2000 Services allied to transport 2000 Manufacture of miscellaneous products of petroleum and coal 1000

Other industries 2000
Total (all industries) 971000

From Kauppinen et al . (2000)

, CAREX (1999)IARC MONOGRAPHS – 100F

textiles, in the garment industry, in the treatment of fur, and in certain jobs within manufactured board mills and foundries. Short-term exposures to high levels (3 ppm and higher; ≥ 3.7 mg/m 3 ) have been reported for embalmers, pathologists, and paper workers. Lower concentrations have usually been encountered during the manufac

ture of man-made vitreous fibres, abrasives and rubber, and in formaldehyde-production indus

tries. A very wide range of exposure levels has been observed in the production of resins and plastic products. The development of resins that release less formaldehyde, and improved venti

lation have resulted in lower exposure levels in many industrial settings in recent decades ( IARC, 2006 ).



### 2. Cancer in Humans

2.1 Cancer of the nasopharynx

In IARC Monograph Volume 88 ( IARC, 2006 )

it was concluded that there was sufficient evidence for the carcinogenicity of formaldehyde, based primarily on its association with nasopharyn

geal cancer. There have been relatively few new studies published on this association since that time, although there have been several re-evalu

ations and meta-analyses.



### 2.1.1 Cohort studies

In the most recent follow-up of the largest cohort study from the USA of industrial workers exposed to formaldehyde, a statistically signifi

cant excess of deaths from nasopharyngeal cancer was observed in comparison with the US national population, with statistically significant exposure–response relationships for peak expo

sure and cumulative exposure ( Hauptmann et al

. , 2004 ; see Table 2.1 available at http://monographs. iarc.fr/ENG/Monographs/vol100F/100F-24- Table2.1.pdf ). Based on eight cases, a significant excess mortality from nasopharyngeal cancer was observed among formaldehyde-exposed workers (SMR, 2.10; 95%CI: 1.05–4.21). A highly statistically significant ( P trend < 0.001) exposure– response relationship was observed between peak-exposure to formaldehyde and risk fornasopharyngeal cancer in a Poisson regressionanalysis. All exposed cases were in the highest category of peak-exposure, and the relative risk was 1.83. This analysis excluded one case which, according to cancer registry data, had been misclassified as nasopharyngeal cancer. Weaker exposure–response relationships were observed between nasopharyngeal cancer and average or cumulative exposure, and duration of exposure ( P trend = 0.07, 0.03 and 0.15, respectively). In the two other large cohort studies of indus

trial workers, cases of nasopharyngeal cancer were fewer than expected, but the power of these studies to detect an effect on nasopharyngeal

cancer was low and the deficits were small. In the first study, of British chemical workers, one death was observed when 2.0 were expected ( Coggon

et al

. , 2003 ); in the second study, no deaths were observed among US garment-manufacturers, where 0.96 were expected ( Pinkerton et al

. , 2004 ). An excess of deaths from nasopharyngeal cancer was observed in a proportionate mortality analysis of the largest US cohort of embalmers ( Hayes et al

. , 1990 ) and in a Danish study of proportionate cancer incidence among workers at companies that used or manufactured formal

dehyde ( Hansen & Olsen, 1995 ; see Table  2.2

available at http://monographs.iarc.fr/ENG/ Monographs/vol100F/100F-24-Table2.2.pdf ).

Marsh et al

. (1996) conducted a cohort study in one of the plants considered in the NCI study (where five of the nine cases of nasopharyngeal cancer occurred). The cohort included earlier year of entry and was enumerated independently. Significantly increased mortality due to naso

pharyngeal cancer was observed among formal

dehyde-exposed workers compared with US and regional populations (Connecticut State and

404Formaldehyde

local county). In a recent follow-up through 2003,

Marsh et al

. (2007a) showed elevated SMRs when both national and local county rates were used. In addition, when conducting a case–control study nested within the cohort and including seven deaths from nasopharyngeal cancer, the authors obtained information on employment outside the formaldehyde industry and showed that five of these workers had been employed as a silver

smith. However, while there was some evidence of effect modification by activities as a silver

smith (based on small numbers), confounding alone did not explain the relatively high number of deaths from nasopharyngeal cancer in this plant ( Marsh et al

. , 2007a ). Two analyses have been conducted to re-analyse the data from the most recent update
of the NCI cohort, with a focus on solid tumours ( Hauptmann et al

. , 2004 ). The first included an analysis of exposure category and SMR, as well as an analysis of Plant 1, where five of nine deaths from nasopharyngeal cancer occurred, compared with all other plants in the cohort ( Marsh & Youk, 2005 ). Using their own cutpoints of exposure, the authors concluded that their analysis lent uncertainty to the findings from the NCI cohort. In another re-analysis, the authors further controlled for the effect of plant for the peak-exposure metric and performed sensitivity analyses by imputing additional cases, which showed instability in the risk estimates ( Marsh et al

. , 2007b ). The authors concluded that an interaction between plant group and exposure makes generalization beyond Plant 1 difficult.



### 2.1.2 Case–control studies

The relationship between nasopharyngeal cancer and exposure to formaldehyde has also been investigated in seven case–control studies,

five of which found elevated risks for overall exposure to formaldehyde or in higher expo

sure categories, although not all were statis

tically significant (see Table  2.3 available at http://monographs.iarc.fr/ENG/Monographs/ vol100F/100F-24-Table2.3.pdf ; Vaughan

et al

. , 1986b ; Roush et al

. , 1987 ; West et al

. , 1993 ; Vaughan et al

. , 2000 ; Hildesheim et al

. , 2001 ). One study found an elevation among women, but not men ( Olsen et al

. , 1984 ) and one found no evidence of an association ( Armstrong et al

. , 2000 ). Two case–control studies were consid

ered as the most informative because of their size, their exposure assessment, and the evalua

tion of potential confounders. The first, a popu

lation-based case–control study in the USA, showed a significant association for the workers whose exposure duration had been the longest (OR = 2.1; 95%CI: 1.0–4.5, P trend = 0.07), but not for maximum exposure ( P trend = 0.57) ( Vaughan

et al

. , 2000 ). When the analysis was limited to differentiated squamous-cell and epithelial NOS, there was a significant association in the highest exposure category for both duration and cumula

tive exposure with significant exposure-response trends ( P trend = 0.014 and 0.033, respectively). In the other study, conducted in Taiwan, China, an OR of 1.6 (95%CI: 0.91–2.9, P trend = 0.08) was found in the category with the longest dura

tion of exposure ( Hildesheim et al

. , 2001 ). For cumulative exposure, there was a non-significant elevation in the highest exposure category and the trend test was not significant ( P = 0.10). In

sub analyses that were restricted to cases and controls who were seropositive for antibodies against Epstein-Barr virus, the association between exposure to formaldehyde and naso

pharyngeal cancer appeared to be stronger, with an OR for ever exposure of 2.7 (95%CI: 1.2–6.2). However, no clear dose–response pattern was observed with increasing duration of exposure, or with estimated cumulative exposure.



### 2.1.3 Meta-analyses

A meta-analysis published in 1997 included
some but not all of the above studies, and found an overall meta-relative risk for nasopharyngeal

405IARC MONOGRAPHS – 100F

cancer of 1.3 (95%CI: 1.2–1.5) ( Collins et al

. , 1997 ). From a pooled analysis including the three recently updated industrial cohorts ( Coggon

et al

. , 2003 ; Hauptmann et al

. , 2004 ; Pinkerton

et al

. , 2004 ), Bosetti et al

. (2008) reported an overall SMR of 1.33 (95%CI: 0.61–2.53). A recently published meta-analysis included both case–control studies ( n = 6) and cohort studies ( n = 7) ( Bachand et al

. , 2010 ). For the case–control studies, the overall OR was 1.22 (95%CI: 1.00– 1.50), with the meta-regression OR no longer significant when limited to studies that included adjustment for socioeconomic status, smoking or

location. The risk estimate for cohort studies was 0.72 (95%CI: 0.40–1.29), including seven studies ( Bachand et al

. , 2010 ). For the cohort studies, the authors used a re-analysis of the NCI cohort study from which Plant 1 was left out ( Marsh &
Youk, 2005 ).



### 2.2 Leukaemia

In IARC Monograph Volume 88 ( IARC,

2006 ) it was concluded that there was strong,

but not sufficient evidence for the leukaemo

genic effects of formaldehyde. Since that time, an update to the NCI cohort and a nested case–control study of workers in the funeral industry have been published ( Beane Freeman

et al

. , 2009 ; Hauptmann et al

. , 2009 ), as well as three meta-analyses ( Bosetti et al

. , 2008 ; Zhang et al

. , 2009 ; Bachand et al

. , 2010 ; see Table  2.1 online, and Table  2.5 available at http://monographs.iarc.fr/ENG/Monographs/ vol100F/100F-24-Table2.5.pdf ).



### 2.2.1 Cohort studies

Excess mortality from leukaemia has been observed relatively consistently in studies of professional workers (i.e. embalmers, funeral parlour workers, pathologists and anatomists), with six mortality studies showing positive asso

ciations ( Walrath & Fraumeni, 1983

, 1984 ; Levine et al

. , 1984 ; Stroup et al

. , 1986 ; Hayes et al

. , 1990 ; Hall et al

. , 1991 ) and one not ( Logue et al

. , 1986 ; see Table 2.2 online). A weakness of the proportionate mortality studies among professionals has been the lack of exposure assessment. A recently published nested case–control study conducted among professionals in the funeral industry examined lifetime work practices and exposure in the funeral industry to develop metrics of expo

sure among this group, which included dura

tion of jobs held while embalming, number of embalmings, average intensity of embalming and peak exposure ( Hauptmann et al

. , 2009 ). Details of work practices were obtained by interviews

with next of kin and co-workers. Positive associ

ations were seen – at many levels of exposure and for multiple exposure metrics – for deaths fromlymphohaematopoietic malignancies of nonlymphoid origin ( n = 48). For myeloid leukaemia ( n =  34) the OR was 13.6 (95%CI: 1.6–119.7;

P trend = 0.020) for the longest duration of work in jobs with embalming. Because only one case was reported to have never embalmed, additional analyses were conducted in which those who reported to have embalmed ≤  500 times were taken as the referent group, to provide a more
stable estimate. Results were attenuated, but still significant (OR  =  3.9; 95%CI: 1.2–12.5). [There was a considerable amount of missing data that required imputation for analyses.] The findings for leukaemia in studies of profes

sional workers appeared to be contradicted by the lack of such findings among industrial workers.
However, some evidence for an excess of deaths from leukaemia has been reported in the recent updates of two of the three major cohort studies of industrial workers. Since the previous evalua

tion ( IARC, 2006 ), the NCI cohort of industrial workers in the USA has been updated with an additional ten years of mortality data resulting in 123 deaths from leukaemia, including 48 from myeloid leukaemia ( Beane Freeman et al

. , 2009 ). This update extended the mortality follow-up

406Formaldehyde

through 2004 and included additional deaths before 1994 that had not been previously consid

ered. Risk estimates from follow-up through

2004 were diminished for leukaemia and myeloid leukaemia compared with the follow-up through 1994 ( Hauptmann et al

. , 2003 ), when both conditions had been significantly associ

ated with increasing peak-exposure and average intensity of exposure to formaldehyde. As in the previous analysis of leukaemia, the associa

tion in the most recent update was stronger for myeloid leukaemia and peak exposure than for lymphatic leukaemia and for other metrics of exposure ( Beane Freeman et al

. , 2009 ). However, because the last known exposure occurred in 1980 and median follow-up was over 40 years, the authors not only examined risks at the end of follow-up in 2004, but also assessed associa

tions over time by extending follow-up in yearly increments. Risks appeared to be highest before 1980, but only achieved statistical significance
in the mid-1990s, when a sufficient number of deaths had accrued. Additional analyses with time since first exposure and time since first high peak-exposure indicated that risks were highest during the first twenty-five years. Patterns were similar, but attenuated, for average intensity of exposure; no association was observed with cumulative exposure. Mortality from leukaemia was also found to be in excess in an update of the study of US garment workers exposed to formaldehyde ( Pinkerton et al

. , 2004 ). A small and statisti

cally non-significant excess was observed for the entire cohort in comparison with rates among the general population (SMR  =  1.09; 95%CI: 0.7–1.63). This excess was somewhat stronger for myeloid leukaemia (SMR  =  1.44; 95%CI: 0.80– 2.37), which is consistent with the findings from the study of industrial workers in the USA and several of the studies of medical professionals and embalmers. The excess was also stronger among workers with a longer duration of expo

sure and longer follow-up, and among those who had been employed early in the study period when exposures to formaldehyde were believed to be highest. The positive associations observed in the subgroup analyses presented in the study of US garment workers were based on a relatively
small number of deaths, and were thus not statis

tically stable. The updated study of British industrial workers found no excess mortality for leukaemia among all workers exposed to formaldehyde (SMR = 0.91; 95%CI: 0.62–1.29) or among those with the highest exposure (SMR = 0.71; 95%CI: 0.31–1.39) ( Coggon et al

. , 2003 ). The lack of posi

tive findings in this study is difficult to reconcile with the findings from the studies of garment
workers and industrial workers in the USA, and with the results of studies on professionals exposed to formaldehyde. This British study is a relatively large, high-quality study with suffi

ciently long follow-up to have had a reason

able chance to detect an excess of deaths from leukaemia. It did not examine specifically the risk for myeloid leukaemia, which represented the strongest finding in the studies of garment

workers and industrial workers in the USA and in several of the studies of medical professionals

and funeral workers.



### 2.2.2 Case–control studies

Three case–control studies evaluated expo

sure to formaldehyde and risk for leukaemia ( Linos et al

. , 1990 ; Partanen et al

. , 1993 ; Blair et al

. , 2001 ; Table 2.5 online). However, the numbers of exposed cases were few, and no significant eleva

tions of risk were found.



### 2.2.3 Meta-analyses

A meta-analysis published in 2004 for ‘ever exposure’ to formaldehyde and leukaemia included eighteen studies and presented sepa

rate analyses by type of job: for industrial workers, the mRR was 0.9 (95%CI: 0.8–1.0); for

407IARC MONOGRAPHS – 100F

embalmers 1.6 (95%CI: 1.2–2.0); and for patholo

gists and anatomists 1.4 (95%CI: 1.0–1.9), with an overall mRR of 1.1 (95%CI: 1.0–1.2) ( Collins &
Lineker, 2004 ). In another meta-analysis, anal

ysis was restricted to 13 cohort or proportionate mortality studies and similar results were found, with a pooled RR based on the weighted average of the SMRs for leukaemia among industrial workers of 0.9 (95%CI: 0.75–1.07), based on 122 deaths, and of 1.39 (95%CI: 1.15–1.68) among professionals, based on 106 deaths ( Bosetti et al

. , 2008 ). A further meta-analysis differed from these two previous ones by excluding all propor

tionate mortality studies and including the most recent update of the NCI cohort ( Bachand et al

. , 2010 ). For leukaemia overall, a risk estimate of 1.05 (95%CI: 0.93–1.20) was calculated for ‘ever exposure’, based on 15 studies with the use of a fixed-effects model. For myeloid leukaemia, the calculated mRR was  1.09 (95%CI: 0.84– 1.40, based on three studies) and for lymphatic leukaemia the mRR was 1.11 (95%CI: 0.81–1.52, based on two studies). Zhang et al

. (2009) published a meta-anal

ysis that included 15 cohort or case–control studies. The authors selected only studies where it was clear that the workers had been exposedto formaldehyde. In contrast to the other metaanalyses, this one used one exposure metric from each study and considered the highest exposure category for calculating the mRR. For leukaemia, the mRR was 1.54 (95%CI: 1.18–2.00). In addi

tion, a separate analysis of myeloid leukaemia – for the six studies that reported it – found an mRR of 1.90 (95%CI: 1.31–2.76).



### 2.3 Cancer of the nasal sinuses

2.3.1 Cohort studies

An analysis of proportionate cancer inci

dence among industrial workers in Denmark showed an increased risk for squamous-cell carcinomas ( Hansen & Olsen, 1995

, 1996 ). No excess of mortality from sinonasal cancer was observed in the three recently updated studies of industrial and garment workers in the USA, and of chemical workers in the United Kingdom (see
Table 2.1 online; Coggon et al

. , 2003 ; Hauptmann

et al

. , 2004 ; Pinkerton et al

. , 2004 ).



### 2.3.2 Case–control studies

The association between exposure to formal

dehyde and the risk for sinonasal cancer has been evaluated in six case–control studies that prima

rily focused on formaldehyde (see Table  2.4

available at http://monographs.iarc.fr/ENG/ Monographs/vol100F/100F-24-Table2.4.pdf ; Olsen et al

. , 1984 ; Hayes et al

. , 1986 ; Olsen &

Asnaes, 1986 ; Vaughan et al

. , 1986a ; Roush et al

. , 1987 ; Luce et al

. , 1993 ; Pesch et al

. , 2008 ). Four of these six studies reported an increased risk ( Olsen et al

. , 1984 ; Hayes et al

. , 1986 ; Vaughan

et al

. , 1986a ; Luce et al

. , 1993 ).



### 2.3.3 Pooled analysis

Four of the cohort studies contributed to a pooled analysis that collated occupational data from 12 case–control investigations ( Luce et al

. , 2002 ). After adjustment for known occupational confounders, this analysis showed an increased risk for adenocarcinoma associated with high exposure (> 1 ppm) to formaldehyde in both men (OR, 3.0; 95%CI: 1.5–5.7) and women (OR, 6.3; 95%CI: 2.0–19.7). An exposure–response trend

was observed in relation to an index of cumu

lative exposure. There was some evidence of an association with squamous-cell carcinoma. [Most epidemiological studies of sinonasal cancer have not distinguished between tumours that arise in the nose and those that develop in the nasal sinuses. Thus, any effect on the risk for nasal cancer specifically would tend to be diluted if there were no corresponding effect on

the risk for cancer in the sinuses and could mask its detection, particularly in cohort studies that

408Formaldehyde

have relatively low statistical power. However, the apparent discrepancy between the results of the case–control as compared with the cohort studies might also reflect residual confounding by wood dust in the former. Almost all of the formaldehyde-exposed cases in the case–control studies were also exposed to wood dust, which resulted in a high relative risk, particularly for adenocarcinomas.]



### 2.4 Other cancers

Several studies have identified statisti

cally significant positive associations between exposure to formaldehyde and cancer at othersites, including the oral cavity, oro-and hypopharynx, larynx, lung, brain, pancreas, Hodgkin lymphoma, and multiple myeloma. However, the results are inconsistent (see Tables  2.4 and  2.5
online; Table  2.6 available at http://mono

graphs.iarc.fr/ENG/Monographs/vol100F/100F24-Table2.6.pdf , and Table  2.7 available at http://monographs.iarc.fr/ENG/Monographs/ vol100F/100F-24-Table2.7.pdf ).



### 2.5 Synthesis

The Working Group noted one industrial cohort study with both a strong overall asso

ciation between exposure to formaldehyde and nasopharyngeal cancer, and the most elevated risks in the highest exposure category. Positive associations were also observed in many of the case–control studies, in particular those of larger size and higher-quality exposure assessment.

While there was no association observed in the two other large industrial cohort studies, the expected number of cases in those studies was quite small. It is concluded that occupational exposure to formaldehyde causes nasopharyn

geal cancer in humans. The Working Group noted that it was unlikely that confounding or bias could explain the observed association. Elevated risks of leukaemia have been consistently observed in proportionate mortality studies of professionals exposed to formalde

hyde (i.e. embalmers, workers in the funeral industry, pathologists and anatomists). Results from a nested case–control study of workers in the funeral industry show elevated risks for many measures of exposure, which are strongest for myeloid leukaemia. In two of the three large industrial cohort studies positive associations
were observed for leukaemia, which were some

what stronger for myeloid leukaemia. It is diffi

cult to reconcile the lack of association observed in the third industrial cohort study with the overall positive associations in the others. However, there seems to be no strong evidence that confounding or bias explains the posi

tive associations seen in multiple settings. On balance, the Working Group concluded that the epidemiologic evidence shows that occupational exposure to formaldehyde causes leukaemia. Many case–control studies show positive associations for exposure to formaldehyde and
sinonasal cancer, some with evidence of an exposure–response pattern. However, many of these cases were also exposed to wood dust, which was strongly associated with sinonasal

cancer in these studies. The industrial cohort studies show no such association, which may be due to lack of statistical power, or could indicate that uncontrolled confounding to wood dust partially explains the observed associations in the case–control studies. The Working Group could not rule out the possibility of residual confounding in the case–control studies and

noted the discordant results between the cohort

and case–control studies.

409IARC MONOGRAPHS – 100F



### 3. Cancer in Experimental Animals

Carcinogenicity studies with mice, rats and hamsters exposed to formaldehyde by inhalation, via the drinking-water, or through the skin were

reviewed in IARC Monograph Volume 88 ( IARC,

2006 ). Results of adequately conducted carcino

genicity studies are summarized in Table  3.1

. There have been no additional carcinogenicity studies in experimental animals reported since the previous review.



### 3.1 Inhalation

In one inhalation study in B6C3F1 mice, formaldehyde marginally increased the inci

dence of squamous cell carcinomas of the nasal cavity in males. The incidence of lymphoma in females exposed to 14.3 ppm (27/121) was also marginally increased ( P = 0.06) when compared (pair-wise) with controls (19/121) ( CIIT, 1981 ;
Kerns et al

. , 1983a

, b ; Gibson, 1984 ). In six studies ( Swenberg et al

. , 1980 ; CIIT,

1981 ; Albert et al

. , 1982 ; Kerns et al

. , 1983a

, b ; Gibson, 1984 ; Sellakumar et al

. , 1985 ; Feron,

et al

. , 1988 ; Woutersen et al

. , 1989 ; Monticello

et al

. , 1996 ; Kamata et al

. , 1997 ) in differentstrains of rats (F344, Wistar, and SpragueDawley), there were treatment-related increases in tumours of the nasal cavity (primarily squa

mous-cell carcinomas but also squamous-cell papillomas, polypoid adenomas, carcinomas, rhabdomyo sarcomas, adenocarcinomas, and mixed/combined tumours). In one study ( CIIT, 1981 ), the incidences of undifferentiated leukaemia [Fischer rat leukaemia, as indicated in the report] were 12/120 (control), 17/120 (2 ppm), 16/120 (5.6 ppm) and 7/120 (14.3 ppm) in
females; there was a marked decrease in survival in the animals exposed to the high dose. Based on a survival-adjusted analysis, the incidence of leukaemia in females exposed to 14.3 ppm was increased compared with controls ( P =  0.0056; Tarone-extension of the Cox test; level of signifi

cance, P < 0.0167). [The Working Group noted that this type of leukaemia is a very common, spontaneously occurring neoplasm in the F344 rat strain].



### 3.2 Oral administration (drinkingwater)

In one drinking-water study in male Wistar
rats, there was a treatment-related increase in fore-stomach squamous-cell papillomas ( Takahashi et al

. , 1986 ). Another study in male and female Wistar rats did not report any increase in tumours ( Til et al

. , 1989 ). In a study with life-long exposure to formalde

hyde, beginning in utero (transplacentally), there

was an increased incidence of smooth-muscle

tumours of the small intestine (leiomyosarcoma) in female offspring ( Soffritti et al

. , 1989 ). In another study in male and female rats, increased incidences of total malignant tumours, haemat

opoietic tumours, and interstitial-cell adenomas were observed in males ( Soffritti et al

. , 1989

, 2002 ). [The Working Group reaffirmed the concerns of the previous Working Group ( IARC, 2006 ) regarding the pooling of all ‘leukaemias’ diag

nosed as lymphoblastic leukaemias and lympho

sarcomas, immunoblastic lymphosarcomas, and “other types” of leukaemia and haemolympho

reticular sarcomas. Also noted were the lack of reporting of non-neoplastic lesions and historical control data, and the numerous discrepancies in tumour incidence between the first ( Soffritti

et al

. , 1989 ) and second report ( Soffritti et al

. , 2002 ) of the results of this study].



### 3.3 Skin application

In one study in male and female hairless Oslo mice, topical application of 10% formaldehyde in water reduced the latency of 7,12-dimethylbenz[ a ] anthracene-induced skin tumours ( Iversen,

1986 ).

410Formaldehyde

411Table 3.1 Carcinogenicity studies in experimental animals exposed to formaldehydeSpecies, strain (sex)DurationReferenceDosing regimen,Animals/group at startIncidence of tumoursSignificanceCommentsInhalation studiesC3H mouse (unspecified)35 wk (some for 64 wk)Hortonet al. (1963)0, 50, 100, 200 mg/m31 h/d, 3 d/wk42–60/groupNo pulmonary tumoursNSUSP gradeDue to severe toxicity, exposure to 200mg/m3was discontinued after the 11thexposure. Thirty-six mice exposed to 50mg/m3were exposed to 150 mg/m3for29 additional wk. Basal-cell hyperplasia,squamous metaplasia and atypicalhyperplasia were observed in trachea andbronchi of many exposed mice. Nasaltissues were not examined.Short period of exposure and shortduration of study.B6C3F1 mouse (M)30 moKernset al. (1983a,b),Gibson (1984)0, 2, 5.6, 14.3 ppm (0, 2.5,6.9, 17.6 mg/m3)6 h/d, 5 d/wk for 24 mo119–120/groupNo increased tumour incidence> 97.5% purityInterim sacrifices (10/group) at 6 and12 mo; 0–1 at 18 mo; 17–21 at 24 mo.Squamous-cell hyperplasia, metaplasia anddysplasia were commonly present in nasalpassages of mice exposed to 14.3 ppm.Nasal cavity (malignant)a: 2/17 (14.3ppm) vs 0/21 (controls) at 24 moNSB6C3F1 mouse (F)30 moKernset al. (1983a,b),Gibson (1984),CIIT(1981)0, 2, 5.6, 14.3 ppm (0, 2.5,6.9, 17.6 mg/m3)6 h/d, 5 d/wk for 24 mo120–121/groupNo increased tumour incidence> 97.5% purityInterim sacrifices (10/group) at 6 and 12mo; 19–20 at 18 mo; 26–41 at 24 mo; 9–16at 27 mo. Squamous-cell hyperplasia,metaplasia and dysplasia were commonlypresent in nasal passages of mice exposedto 14.3 ppm.Lymphoma: 27/121 (14.3 ppm) vs19/121 (controls)NS (P= 0.06)IARC MONOGRAPHS – 100F

412Species, strain (sex)DurationReferenceDosing regimen,Animals/group at startIncidence of tumoursSignificanceCommentsF344 rat (M)30 moSwenberget al. (1980),Kernset al. (1983a,b),Gibson (1984)0, 2, 5.6, 14.3 ppm (0, 2.5,6.9, 17.6 mg/m3)6 h/d, 5 d/wk for 24 mo119–120/groupNasal cavity (malignant)a: 0/118, 0/118,1/119, 51/117**P< 0.001> 97.5% purityInterim sacrifices (10/group) at 6 and 12mo; 20 at 18 mo; 13–54 at 24 mo; 5–10at 27 mo; 0–6 at 30 mo. Squamous-cellhyperplasia, metaplasia and dysplasia werecommonly present in nasal passages of ratsexposed to 14.3 ppm.Nasal cavity (malignant)b: 0/118, 0/118,0/119, 4/117NSNasal cavity (benign)c: 1/118, 4/118,6/119, 4/117NSF344 rat (F)30 moSwenberget al. (1980),Kernset al. (1983a,b),Gibson (1984),CIIT(1981)0, 2, 5.6, 14.3 ppm (0, 2.5,6.9, 17.6 mg/m3)6 h/d, 5 d/wk for 24 mo120/groupNasal cavity (malignant)a: 0/114, 0/118,1/116, 52/115**P< 0.001> 97.5% purityInterim sacrifices (10/group) at 6 and 12mo; 19–20 at 18 mo; 14–47 at 24 mo; 0–10at 27 mo; 0–5 at 30 mo. Squamous-cellhyperplasia, metaplasia and dysplasia werecommonly present in nasal passages of ratsexposed to 14.3 ppm.Nasal cavity (malignant)b: 0/114, 0/118,0/116, 1/115NSNasal cavity (benign)c: 0/114, 4/118,0/116, 1/115NSHaematopoietic tissue (spleen,F344 rat leukaemia diagnosed asundifferentiated leukaemia): 12/120,17/120, 16/120, 7/120P= 0.0056;Tarone-extensionof the Cox test(adjustment formortality), levelof significance isP< 0.0167Sprague-Dawley rat (M)LifetimeAlbertet al. (1982);Sellakumaret al. (1985)0, 14.3 ppm (0, 17.6 mg/m3)6 h/d, 5 d/wk99–100/groupNasal cavity (malignant)a: 0/99, 38/100P≤ 0.001A mixed carcinoma and fibrosarcoma ofthe nasal cavity was also present in theformaldehyde-treated group.Nasal cavity (benign): 0/99, 10/100P≤ 0.001Table 3.1 (continued)Formaldehyde

413Species, strain (sex)DurationReferenceDosing regimen,Animals/group at startIncidence of tumoursSignificanceCommentsWistar rat (M)126 wkFeronet al. (1988)0, 10, 20 ppm (0, 12.3 or25 mg/m3)6 h/d, 5 d/wk for 4, 8 or13 wk45/group/intervalNasal cavity: 2/134, 2/132, 10/132(denominator combines all intervalsof exposure for control and treatedgroups); the authors considered 6/10tumoursdin the high-dose group astreatment-related.NRPurity NRHyperplasia and metaplasia of nasalepithelium were observed in all ratsexposed to formaldehyde. Authorsconsidered most nasal-cavity tumours inthe high-dose group to be related to thetreatment.Wistar rat (M)28 moWoutersenet al. (1989)0, 0.1, 1, 10 ppm (0, 0.123,1.23, and 12.3 mg/m3)6 h/d, 5 d/wk for 3 or 28mo30/group (U: undamaged)or 60/group (D: damaged)Nasal cavity (malignant)e:28 mo exposureU: 0/26, 1/26, 1/26, 1/26D: 1/54, 1/58, 0/56, 17/58*3 mo exposureU: 0/26, 0/30, 0/29 2/26D: 0/57, 2/57, 2/53, 2/54*[P< 0.001; Fisher’sexact test]Purity NRMucosa severely damaged by electrocoagulation during the first wk.Eight squamous-cell carcinomas from thenasolacrimal duct were excluded by theauthors.Sprague Dawley rat (F)104 wkHolmströmet al. (1989)0, 12.4 ppm (0, 15.3 mg/m3)6 h/d, 5 d/wk16/groupNasal cavity: 0/16, 1/16aNSPurity NRPronounced squamous-cell metaplasiaand/or dysplasia in 10/16 rats exposedto formaldehyde vs 0/15 controls. Smallgroup-size noted.F344 rat (M)24 moMonticelloet al. (1996)0, 0.69, 2.05, 6.01, 9.93,14.96 ppm (0, 0.84, 2.4,7.2, 12, 19 mg/m3)6 h/d, 5 d/wk90 or 147 (high dose grouponly)/groupNasal cavity (malignant)a:0/90, 0/90,0/90, 1/90, 20/90, 69/147*NR,*[P< 0.001]Formaldehyde vapour of paraformaldehydeInterim sacrifices at 3, 6, 12 and 18 mo (6/group).Nasal cavity (benign)c: 0/90, 0/90, 0/90,0/90, 5/90, 14/147$One nasal rhabdomyosarcoma andnasal adenocarcinoma each present ingroups given 9.93 and 14.96 ppmNR,$[P< 0.02]Table 3.1 (continued)IARC MONOGRAPHS – 100F

414Species, strain (sex)DurationReferenceDosing regimen,Animals/group at startIncidence of tumoursSignificanceCommentsF344 rat (M)28 moKamataet al. (1997)0, 0, 0.3, 2.17, 14.85 ppm(0, 0, 0.36, 2.6, 17.8 mg/m3)6 h/d, 5 d/wk32/group (one roomair control and onemethanol-exposed controlgroup)Nasal cavity (malignant)a:0/32, 0/32,0/32, 0/32, 13/32**P< 0.01Formaldehyde vapour of 37% aqueousformaldehyde solution with 10% methanol(4.2 ppm)Interim sacrifices at 12, 18 and 24 mo (5/group).Nasal cavity (benign)f:0/32, 0/32, 0/32,0/32, 3/32NRRat (strain not specified)(F)LifetimeYanyshevaet al. (1998)0, 0.003, 0.03, 0.3 mg/m3,7 h/d, 5 d/wk for 12 moIntratracheal injection ofa total dose of 0, 0.02, 0.1or 5.0 mg B[a]P/animalover 20 wk50/groupLung tumours:24/35 (68.6%, 5.0 mg B[a]P + 0.3 mg/m3formaldehyde) vs 8/28 (28.1%, 5.0mg B[a]P)P< 0.01Purity NRPromotion effectHamster, Syrian golden(M)LifetimeDalbey (1982)0, 10 ppm (0, 12.3 mg/m3)5 h/d, 5 d/wk88/group (132 controls)No tumours-Purity NRHyper- and metaplastic areas were eachobserved in the nasal epithelium of 5% ofexposed animalsHamster, Syrian golden(M)LifetimeDalbey (1982)0, 30 ppm (0, 36.9 mg/m3)5 h/d, 5 d/wk50/groupNo tumours-Purity NRHamster, Syrian golden(M)LifetimeDalbey (1982)0, 30 ppm (0, 36.9 mg/m3)5 h/d, 5 d/wkBoth groupssubcutaneously injectedwkly with 0.5 mg NDEAfor 10 wk50/groupTracheal tumours:[~2.8 tumours/tumour-bearinganimal (NDEA + formaldehyde) vs~1.7 tumours/tumour-bearing animal(NDEA)]P< 0.05Purity NRPromotion effectDrinking-water studiesWistar rat (M)40 wkTakahashiet al. (1986)Experiment #10 or 0.5% formaldehyde10/groupFore-stomach squamous-cellpapillomas:8/10 vs 0/10P< 0.01Purity NRTable 3.1 (continued)Formaldehyde

415Species, strain (sex)DurationReferenceDosing regimen,Animals/group at startIncidence of tumoursSignificanceCommentsWistar rat (M)40 wkTakahashiet al. (1986)Experiment #20 and 0.5% formaldehyde.MNNG administered inthe drinking-water toboth groups for first 8 wkwith a diet containing10% NaCl30 (control) and 17/groupAdenocarcinoma of the pylorus:4/17 vs 1/30P< 0.05Purity NRWeak promotion of tumour incidence inthe glandular stomach. Incidence of forestomach papillomas was also increasedvs controls, but was similar to that in thegroup treated with formaldehyde only(experiment #1)Wistar rat (M)105 wkTilet al. (1989)0, 1.2, 15, 82 mg/kg bw/d70/groupNo increase in tumour incidenceNSFormaldehyde generated from 95% pureparaformaldehyde.Interim sacrifices of 10 rats after 53 and 79wk.Wistar rat (F)105 wkTilet al. (1989)0, 1.8, 21, 109 mg/kg bw/d70/groupNo increase in tumour incidenceNSFormaldehyde generated from 95% pureparaformaldehyde. Interim sacrifices of 10rats after 53 and 79 wk.Sprague Dawley (M, F)LifetimeSoffrittiet al. (1989)0 and 2 500 ppmExposure of breeders(18–20/group/sex) andoffspring (36–59/group/sex) for 104 wk. Exposureof offspring began on d 13of gestation.Leukaemias:Previous and current Working Groupand other authors (Feronet al., 1990;IARC, 2006) noted concern about studydesign, significance of tumour findingsand laboratory-control incidences.The Working Group also noted thatleukaemias included three types,diagnosed as lymphoblastic leukaemiasand lymphosarcomas, immunoblasticlymphosarcomas, and other types ofleukaemias and haemolymphoreticularsarcomas.Increased incidence of a variety of benignand malignant stomach and intestinaltumours was also reported. The stomachtumours in treated groups representedsingle occurrences of neoplasm of differentsites/cell type fore-stomach/squamous,smooth muscle and glandular stomachepithelium.Breeders (M): 2/18 (11.1%) vs 0/20 (0%)NSBreeders (F): 2/18 (11.1%) vs 1/20 (5%)NSOffspring (M): 4/36 (11.1%) vs 3/59(5.1%)NSOffspring (F): 0/37 (0%) vs 3/49 (6.1%)NSSmall intestine leiomyosarcoma:Offspring (F): 6/37 (16.2%) vs 0/49 (0%)P< 0.01Table 3.1 (continued)IARC MONOGRAPHS – 100F

416Species, strain (sex)DurationReferenceDosing regimen,Animals/group at startIncidence of tumoursSignificanceCommentsSprague Dawley (M, F)LifetimeSoffrittiet al. (1989,2002)0 (control), 0 (15 mg/Lmethanol control), 10,50, 100, 500, 1 000, 1 500mg/L for 104 wk50/group/sex (100/controlgroup)Testicular interstitial-cell adenomas:24/50 (1 000 mg/L) vs 6/50 (methanolcontrol)[P< 0.01]Purity of 99% with 0.3% methanol asstabilizer.Concerns by the Working Groupabout pooling of several types oflymphohaematopoietic tumours. Concernalso about interpretation of the results forlymphohaematopoietic tumours due tothe numerous and extensive discrepanciesin tumour incidences between the first(Soffrittiet al., 1989) and second report(Soffrittiet al., 2002) on results forthis study. Increased incidence of totalmalignant tumours in males treated with1 500 mg/L [P< 0.01].Lymphohaematopoietic tumours:Males8/100, 20/50, 8/50, 20/50, 26/50, 24/50,22/50, 46/50*[P< 0.01, trend],*[P< 0.01, vsmethanol control]aNasal cavity tumours were squamous-cell carcinomas.bNasal cavity tumours (combined) included carcinomas (2), undifferentiated carcinomas or sarcomas (2) or carcinosarcomas (1).cNasal cavity tumours were polypoid adenomas.dThree squamous-cell carcinomas, 2 polypoid adenomas, and 1 carcinoma in situ.eNasal cavity tumours were squamous-cell carcinomas except for one adenosquamous carcinoma and one adenocarcinoma at 10 ppm (D) with 28 months of exposure and onecarcinoma in situ at 10 ppm (D) and one polypoid adenoma at 10 ppm (U) with 3 mo of exposure.fNasal cavity tumours were squamous-cell papillomas.B[a]P, benzo[a]pyrene; d, day or days; h, hour or hours; F, female; M, male; mo, month or months; MNNG,N-methylN′-nitroN-nitrosoguanidine; NDEA,N-nitrosodiethylamine; NR,not reported; NS, not significant; vs, versus; wk, week or weeksTable 3.1 (continued)Formaldehyde



### 4. Other Relevant Data

In IARC Monograph Volume 88 ( IARC,

2006 ) mechanistic considerations supported a role for cytotoxicity and genotoxicity in formal

dehyde-induced nasal tissue carcinogenesis. With regards to leukaemia, it was unclear to the Working Group at the time how this reactive compound could penetrate to the bone marrow, and no animal model of formaldehyde-induced

leukaemia was available.

The discussion below focuses on mechanistic issues related to the potential causal association between formaldehyde inhalation and hema

tological cancers, and includes considerations on the mechanism underlying nasal carcino

genesis in laboratory animals and humans. A

more detailed review can be found in Volume 88 ( IARC, 2006 ).



### 4.1 Absorption, distribution, metabolism, and excretion

One-carbon metabolism is central to many biological processes, including the biosynthesis of purines and thymidine – essential compo

nents of nucleic acids –, the biosynthesis of certain amino acids, and the demethylation of a variety of important biological compounds

that are central to cell function and survival.Formaldehyde is an intermediate in the onecarbon pool and is present in measurable concentrations in all metabolically active cells and tissues ( Heck et al

. , 1982

, 1985 ; Casanova

et al

. , 1988 ). In aqueous solution, formaldehyde is rapidly converted to its diol form, methanediol (formaldehyde hydrate, CH

2 (OH)

2, methylene glycol), which enters in a dynamic equilibrium with formaldehyde. The concentration of the diol and that of formaldehyde depend on the precise conditions (temperature, pH, formaldehyde concentration) under which the reaction occurs ( Walker, 1964 ). Importantly, methanediol, with a molecular weight of only 48, can readily pene

trate into tissue ( Fox et al

. , 1985 ). Thus, formal

dehyde may reach the bone-marrow through the blood as methanediol, where it equilibrates again to reactive formaldehyde. Further investigation of this equilibrium in living biological systems

is warranted. The absorption of formaldehyde occurs readily in the upper respiratory tract ( Casanova

et al

. , 1991 ; Kimbell et al

. , 2001a

, b ). Once inhaled, formaldehyde can react directly with mucus or with macromolecular cellular compo

nents including proteins and nucleic acids; it can be incorporated into biological molecules through folate-dependent enzymatic processes;

it can be oxidized to formic acid or to carbon dioxide through enzymatic processes dependent on formaldehyde dehydrogenase, aldehyde dehy

drogenase and, in limited situations, catalase ( Hedberg et al

. , 2002 ), or itcan be exhaled. It

has been estimated that as much as 22–42% of inhaled formaldehyde may be removed by mucus flow ( Schlosser, 1999 ). Formaldehyde reacts readily and reversibly with amino groups to form Schiff bases, and with sulfhydryl groups resulting in the forma

tion of S -hydroxymethylglutathione, which is oxidized by alcohol dehydrogenase-3 (ADH3)

to S -formylgluthahione. The latter is further metabolized by S -formylgluthione hydrolase to generate formate and gluthione. The formate can also be formed non-enzymatically ( Hedberg

et al

. , 2002 ). Incubation of 0.1–5.0 mM formal

dehyde with reduced glutathione in solutionfollowed by addition to deoxyguanosine or to calfthymus DNA leads to the formation of the rela

tively stable adduct S- [1-( N 2 -deoxyguanosinyl) methyl]glutathione ( Lu et al

. , 2009 ). This adduct may form endogenously, as both formaldehyde and reduced glutathione are present in reason

ably high concentrations within cells. It may also serve as a biomarker to study the penetra

tion of inhaled radio-labelled formaldehyde, to distinguish endogenous from exogenous

417IARC MONOGRAPHS – 100F

formaldehyde-derived adducts. Whether this could also be a mechanism by which inhaled formaldehyde could lead to bone-marrow toxicity

has not been studied. Red blood cells have relatively high levels of enzymes that rapidly metabolize formaldehyde. The concentration of formaldehyde in the blood of six human volunteers did not change imme

diately after exposure to 1.9 ppm [2.34 mg/m 3 ] formaldehyde for 40 minute ( Heck et al

. , 1985 ), and no change in formic acid concentration

was observed in the urine of medical students over a three-week period during which they were exposed to air concentrations <  0.5 ppm [0.62 mg/m 3 ] ( Gottschling et al

. , 1984 ). No statis

tically significant change in the concentration of formaldehyde in blood was found after inhala

tion of this substance at 1.9 ppm [2.34 mg/m 3 ] for 40 minute by six human volunteers; at 14.4 ppm [17.8 mg/m 3 ] for two hours in rats ( Heck et al

. , 1985 ); and at 6 ppm [7.4 mg/m 3 ] for six hours/ day, five days per week, for four weeks in Rhesus monkeys ( Casanova et al

. , 1988 ). Blood was drawn approximately 7 min and 45 hours after the end of the exposure period, from monkeys whose blood levels were 1.84  ±  0.15 μg/g and 2.04 ± 0.40 μg/g, respectively. However, there are methodological concerns with these studies. In the monkey study three animals were used to

determine control levels and three others were exposed to formaldehyde. The mean levels were then compared. It would have been better if the monkeys had served as their own control. A similar lack of change in formaldehyde levels was reported in rats (2.25 ± 0.07 vs 2.24 ± 0.07 μg/g blood) and humans (2.77 ± 0.28 vs 2.61 ± 0.14 μg/g blood; approximately 0.1 mM) exposed for short periods to 14.4 and 1.9 ppm, respectively ( Heck

et al

. , 1985 ; Casanova et al

. , 1988 ; IARC, 2006 ). [The Working Group noted that, given the short half-life for formaldehyde observed in rodents, the time from end-of-exposure to sampling in monkeys and in humans was likely too long; this could not be evaluated for rats]. Studies of the uptake of radio-labelled formal

dehyde by inhalation, ingestion and through the skin do not provide information that would help to determine whether unreacted formaldehyde reaches the bone marrow, because it is rapidly taken up in the one-carbon pool and incorpo

rated in macromolecules. There was no evidence of the formation of formaldehyde-specific DNA– protein crosslinks in the bone marrow of Rhesus monkeys exposed for six hours to 0.7, 2.0 and 6.0 ppm formaldehyde ( Heck & Casanova, 2004 ), or in rats, including glutathione (GSH)-depleted rats, exposed to concentrations of formalde

hyde up to 10 ppm ( Casanova-Schmitz et al

. , 1984 ; Casanova & Heck, 1987 ). The formation of formaldehyde-DNA adducts was demonstrated in lymphocytes of smokers ( Wang et al

. , 2009 ). In this study, liquid chromatography-electro

spray ionization-tandem mass spectrometry was used to quantify the adduct N 6 -hydroxymethyldeoxyadenosine ( N 6 -HOMe-dAdo) in leukocyteDNA samples from 32 smokers (≥ 10 cigarettes per day) and 30 non-smokers. This adduct would be expected to be formed upon exposure to formaldehyde. N 6 -HOMe-dAdo was detected in 29 of the 32 samples from smokers, but in only 7 of the 30 samples from non-smokers ( P

< 0.001). These findings would support a role for inhaled formaldehyde in causing the DNAadducts that may ultimately lead to smokingassociated leukaemia. The authors caution thatthe observed adducts may result from cigarettesmoke components other than formaldehyde – such as 4-(methylnitrosamino)-1-(3-pyridyl)- 1-butanone (NNK) or nicotine, which may be metabolized to formaldehyde within the cell – or from other sources, rather than reflecting the actual penetration of inhaled formaldehyde to lymphocytes. Rietbrock (1965) reported that the half-life in plasma of formaldehyde injected intravenously in the rat was about one minute. [Assuming a similar half-life of formaldehyde in humans, this would be sufficient time for inhaled formaldehyde

418Formaldehyde

to reach the blood and circulate to the bone marrow in humans].



### 4.2 Toxic effects

Formaldehyde produces irritation of the nose and pharynx in humans and laboratory animals under a variety of circumstances. There appears to be a large inter-individual variation in the human response to the irritating effects of formaldehyde. Under controlled exposure conditions, symptoms of irritation were noted by healthy individuals exposed to formaldehyde concentrations of 2–3 ppm during periods that varied between 40 minute and three hours (for
details, see Table 30 in IARC Monograph Volume 88 ( IARC, 2006 )). Formaldehyde is a known cause of allergic
contact dermatitis and, somewhat more contro

versial, of occupational asthma. Nasal biopsies of workers chronically exposed to formaldehyde
showed chronic inflammation, loss of cilia, mild dysplasia, hyperplasia and squamous metaplasia, although the latter finding has been inconsistent and may have been confounded by other expo

sures, such as to wood dust ( IARC, 2006 ). The cytotoxicity of formaldehyde has been confirmed in numerous in-vitro systems. Irritation of the nasal and upper respiratory tract is also noted in animal studies. Dose-dependent pathological findings include inflammation, hyperplasia, degenerative changes, necrosis and squamous metaplasia. Recently, a finding relevant to the possible involvement of formaldehyde in leukaemo

genesis was reported by Zhang et al

. (2010)

. Their study showed that colony formation by colony-forming unit-granulocyte-macrophage (CFU-GM) progenitor cells is inhibited in cell cultures exposed to formaldehyde at toxico

logically relevant concentrations. Furthermore, colony formation by the more primitiveCFU-granulocyte- erythrocyte-monocytemegakaryocyte (CFU-GEMM) progenitors, which give rise to formation of all myeloid cells, showed a linear negative dose–response when treated with formaldehyde. These effects were observed at formaldehyde concentrations of 100–200 μM [3–6 μg/mL], which are toxicologi

cally relevant since background levels of formal

dehyde in human blood have been reported to be 50–100 μM [1.5–3 μg/mL] ( Heck et al

. , 1985 ; Casanova et al

. , 1988 ). Because the CFU-GEMM multipotent myeloid progenitor cells and the pluripotent stem cells are the target cells for leukaemogenesis and are converted to leukaemic stem cells in acute myeloid leukaemia, the finding that formaldehyde damages these cells in vitro adds some weight to the notion that it may be associated with myeloid leukaemia.



### 4.3 Genetic and related effects

The genotoxicity of formaldehyde was thor

oughly reviewed in IARC Monograph Volume 88 ( IARC, 2006 ). Genotoxicity has been observed in

vitro in many systems with multiple endpoints.



### 4.3.1 Humans

Micronucleus formation has been repeat

edly reported to occur in cells of the nasal and oral mucosa of formaldehyde-exposed humans.

The outcome of studies on induction of micro

nuclei, sister chromatid exchange and chromo

somal aberrations in the lymphocytes of exposed humans – which is pertinent to the question concerning the potential of formaldehyde to cause lympho-haematopoietic cancer – has been less consistent (see Table 4.1 ). DNA–protein crosslinks in circulating white blood cells were found to be higher in 12 workers exposed to formaldehyde in an anatomy department and a pathology institute than in eight controls ( P =  0.03) ( Shaham et al

. , 1996 ). The number of crosslinks tended to be higher in workers who had been exposed longer (exposure duration, 2–31 years). Smoking had no effect. In a

419IARC MONOGRAPHS – 100F

420Table 4.1 Cytogenetic studies on formaldehyde–exposed humansReferenceDescription of exposedand controlsExposure levelsCytogenetic/genotoxic endpointResponse inexposedResponse incontrolsCommentsCostaetal. (2008),PortugalWorkers in an anatomypathology laboratory(n= 30)Controls non-exposed(n= 30)0.44 ± 0.08 ppm(range 0.04–1.58)Micronucleus formation inlymphocytes (MN/1000 cells)5.47 ± 0.763.27 ± 0.69P= 0.003Sister-chromatid exchange(SCE)6.13 ± 0.294.49 ± 0.16P< 0.05DNA-breakage (comet taillength, μm) in lymphocytes60.00 ± 2.3141.85 ± 1.97P< 0.05Palaet al.(2008), ItalyLaboratory workers(n= 36) in a cancerresearch instituteExposure range:4.9–268.7 μg/m3Low: < 26 μg/m3High: ≥ 26 μg/m3High:Low:Micronucleus formation (MN)MN: 0.31 ± 0.17MN: 0.26 ± 0.24Chromosomal aberrations (CA)CA: 2.22 ± 1.27CA: 2.95 ± 1.79SCE in lymphocytesSCE: 5.06 ± 0.76SCE: 6.57 ± 1.38Iarmarcovaiet al. (2007),FrancePathologists/anatomists(n= 18)Controls (n= 18)2.3 ppm(range 0.4–7 ppm)MN in lymphocytes (MN/1000cells)21.0 ± 12.614.4 ± 8.1P< 0.01Yuet al. (2005),the People’sRepublic ofChinaWorkers (n= 151;low-exposed, 62; highexposed, 89) in twoplywood factories; 112non-exposed controls.TWA: 0.10–7.88 mg/m3(< 0.01 mg/m3incontrols)MN in lymphocytes (MN/1000cells)High exp. 6.5 ± 3.6Low exp. 4.1 ± 2.52.7 ± 1.3P< 0.05DNA-breakage (comet taillength, μm) in lymphocytesHigh exp., 12.6(95% CI: 11.8–13.4)Low exp., 11.3(95% CI: 10.1–12.5)6.8 (95%CI:6.1–7.6)P< 0.05Yeet al. (2005),the People’sRepublic ofChinaWorkers (n= 18; allnon-smokers) in aformaldehyde factory(mean exposure duration,8.5 yrs), and waiters(n= 16; all non-smokers)exposed to formaldehydefor 12 wk in a newly fittedballroom. Controls were23 students (non-smokers)Factory: 8-h TWA,0.99 ± 0.29 mg/m3,with peak exposure1.69 mg/m3.Ballroom: 5-h TWA0.11 ± 0.07 mg/m3,with peak exposure0.3 mg/m3Control:0.01 ± 0.003 mg/m3, with peak 0.015mg/m3MN in nasal mucosa (MN/1000cells) of factory workers2.70 ± 1.501.25 ± 0.65P< 0.05SCE in lymphocytes of factoryworkers8.24 ± 0.896.38 ± 0.41P< 0.05No effects in ballroom waitersFormaldehyde

421ReferenceDescription of exposedand controlsExposure levelsCytogenetic/genotoxic endpointResponse inexposedResponse incontrolsCommentsShahamet al.(2002), IsraelWorkers (n= 90) inhospital pathologydepartments; controlswere 52 unexposedworkers from the samehospitals. Averageduration of exposure 15.4yrs (range, 1–39)Low:0.4 ppm (0.04–1.7)High:2.24 ppm (0.72–5.6)SCE in lymphocytes(mean number of SCE perchromosome)0.27 ± 0.0030.19 ± 0.002P< 0.01Burgazet al.(2002), Turkeya) Workers (n= 22) in ashoe factoryn-hexane, toluene,methyl ethyl ketoneMN in buccal cells (MN/1000cells)a) 0.62 ± 0.45P< 0.05b) Pathologists (n= 28),anatomy laboratories2–4 ppmformaldehydeb) 0.71 ± 0.56P< 0.05c) Controls (n= 18):university staffnonec) 0.33 ± 0.30Burgazet al.(2001), TurkeyWorkers (n= 23) inpathology and anatomylaboratories, and 25 nonexposed controlsAir concentration offormaldehyde in thebreathing zone 2–4ppm.MN in nasal mucosa (MN/1000cells; mean ± SD).1.01 ± 0.620.61 ± 0.27P< 0.01Surudaet al.(1993), USAStudents (n= 29)taking 85-d course inembalming; averagenumber of embalmings,6.9; total number 144.Average airconcentration offormaldehyde: 1.4ppm, range 0.15–4.3mean duration ofembalming 125minute with peakexposures > 4 ppm.MN per 1 000 cells:MN after courseMN before course- buccal cells0.60 ± 1.270.046±0.17P< 0.05- nasal cavity0.50 ± 0.670.41±0.52NS- lymphocytes6.36 ± 2.034.95 ± 1.72P< 0.05SCE in lymphocytes7.14 ± 0.897.72 ± 1.26P= 0.01(decrease inSCE)Yinget al.(1999), ChinaStudents (n= 23; nonsmokers) in 8-wk (3h x 3times weekly) anatomyclass.TWA 0.51 ± 0.30mg/m3, with peakexposure 1.28Background levelin dormitories0.012 ± 0.0025 mg/m3SCE after courseSCE before courseSCE in lymphocytes6.61 ± 0.796.38±0.41NSTable 4.1 (continued)IARC MONOGRAPHS – 100F

422ReferenceDescription of exposedand controlsExposure levelsCytogenetic/genotoxic endpointResponse inexposedResponse incontrolsCommentsHeet al. (1998),ChinaStudents (n= 13; nonsmokers) in 12-wk (10hper wk) anatomy class.Ten other students (nonsmokers) served as nonexposed controls.Average airconcentration offormaldehyde: 2.37ppm (3.17 mg/m3)MN per 1 000 cells inlymphocytes6.38 ± 2.503.15 ± 1.46P< 0.01CA in lymphocytes5.92 ± 2.403.40 ± 1.57P< 0.01SCE in lymphocytes5.91 ± 0.715.26 ± 0.51P< 0.05Yinget al.(1997), ChinaStudents (n= 25; nonsmokers) in 8-wk (3h x 3times weekly) anatomyclass.TWA0.51 ± 0.30 mg/m3,with peak exposure1.28Background levelin dormitories0.012 ± 0.0025 mg/m3MN per 1 000 cells in- nasal exfoliated cells3.84 ± 1.481.20 ± 0.67P< 0.001- oral mucosa cells0.86 ± 0.560.57 ± 0.32P< 0.01- lymphocytes1.11 ± 0.540.91 ± 0.39n.s.TitenkoHollandet al.(1996), USAStudents (n= 28) takinga 90-d embalming class;average number ofembalmings, 6.9; totalnumber 144.Accumulated doseover 90 d: 4.3–26.4ppmMaximum peakexposure: 2.86 ppmMN per 1 000 cells withcentromere-specific probes(FISH) in:MN after classMN before class[betweenparentheses:values forcentromerenegative MN]- buccal cells2.0 ± 2.0 (0.9 ± 1.1)0.6±0.5 (0.1 ± 0.2)P= 0.007(P= 0.005)- nasal cells2.5 ± 1.3 (1.0 ± 0.6)2.0 ± 1.3 (0.5 ± 0.5)P= 0.20(P= 0.03)Table 4.1 (continued)Formaldehyde

423ReferenceDescription of exposedand controlsExposure levelsCytogenetic/genotoxic endpointResponse inexposedResponse incontrolsCommentsDobiásetal. (1988),Czechoslovakia- Schoolchildren (n= 20children) in schoolbuilding constructed withwood-particle boards- Control group (n= 17children) in brick schoolbuilding in the same area- Control group in brickschool building elsewhereFormaldehydeconcentration in air:1984: 317.0 μg/m31985: 130.0 μg/m31986: 36.5 μg/m3CA in lymphocytes (per 100cells) in lymphocytes1984: 71984: 4.21985: 4.2NR1986: NRNRThe frequencyof chromosomalaberrations isstated ‘normal’ in1986 but the valueis not givenBuilding wascleaned in ‘85, ‘86Percentage of aberrant cells1984: 4.71 ± 2.091984: 1.37 ± 0.87P= 0.0051985: 2.82 ± 1.641985: 1.4 ± 0.791986: 2.06 ± 1.51NRBauchinger &Schmid (1985),GermanyWorkers (n= 20;6 smokers) in apaper factory, whereformaldehyde wasused for impregnatingthe paper. Durationof exposure 2–30 yrs,average 14.5 ± 7.2 yrs.Controls were 20 nonexposed workers (13smokers) elsewhere in thefactoryFormaldehydeexposure, < 0.2 ppmPeak during repairand cleaning, 3 ppmCA in lymphocytes (dicentrics,rings) per 100 cellsSCE/cell ± SE0.13 ± 0.050.05 ± 0.028.87 ± 0.249.53 ± 0.35NSCA, chromosomal abberations; d, day or days; h, hour or hours; min, minute or minutes; MN, micronuclei; NR, not reported; NS, not significant; SCE, sister chromatid exchange; TWA,time-weighted average concentrationTable 4.1 (continued)IARC MONOGRAPHS – 100F

subsequent study, Shaham et al

. (2003) reported an increase in the number of DNA–protein crosslinks in lymphocytes and in serum concen

trations of the p53 protein in hospital pathologydepartment workers. The exposed subjects were assigned to a high-exposure subgroup (mean formaldehyde concentration in air, 2.24 ppm) and a low-exposure subgroup (mean, 0.4 ppm), based on personal sampling and field sampling for 15-minute periods on typical working days. The control group consisted of personnel of the administrative sections in the hospital. The amount of protein–cross-linked DNA was statis

tically significantly higher in the exposed group than in the controls (0.20 vs 0.14; these values are the ratios between protein-bound DNA – precipitable with sodium dodecyl sulfate – and total DNA) after controlling for age, smoking and other factors. Very little difference in DNA– protein crosslink levels was observed between the high- and low-exposure groups (0.20 vs 0.19); or between workers with > 16 years or < 16 years of exposure (0.20 vs 0.19). The percentage of formaldehyde-exposed male workers who had pantropic p53-protein (wild-type plus mutant p53) concentrations in serum higher than 150 pg/ml was statistically significantly greater than in the control group (54.8% vs 36.5%,

P

< 0.05; this difference was not seen in female workers). Formaldehyde-exposed workers with DNA–protein crosslink levels above the median had a significantly greater likelihood of having p53 concentrations in serum above 150 pg/ml. [The Working Group noted that the rationale for using a p53-protein level of 150 pg/ml as a cut-point was based upon previous experience with this assay; no reason is given for using 16 years as the cut-point between longer/shorter exposure. Questions have also been raised about the persistence of DNA–protein crosslinks, which are thought to be rapidly repaired within the cell ( Schmid & Speit, 2007 )]. In an earlier study, Casanova-Schmitz et al

. (1984) failed to observe DNA–protein crosslinks in bone marrow of Fischer-344 rats exposed to [ 14 C]- and [ 3 H]-formaldehyde. Compared with matched controls, pathology/ anatomy workers from five hospitals, who were exposed to mean formaldehyde concen

trations of 2.0 ppm (range, <  0.1 to 20.4 ppm) during 15 minute, or to 0.1 ppm (range < 0.1 to 0.7 ppm) during 8 hours, showed a statistically significant increase in bi-nucleated cells and

in mono-centromeric micronucleus formation in a cytokinesis-blocked micronucleus assay combined with fluorescence in situ hybridization (FISH) ( Orsière et al

. , 2006 ). A higher frequency of micronuclei was found

in exfoliated nasal and oral cells of students with short-term exposure (3  hours per day; 3  days per week, for 8 weeks) to an average of 0.508  ±  0.299 mg/m 3 formaldehyde, compared with controls ( Ying et al

. , 1997

, 1999 ). No increase

in micronucleus formation or in the level of sister chromatid exchange (SCE) was observed in lymphocytes. Ye et al

. (2005) reported a comparative analysis of 18 workers involved for various periods (mean, 8.5  years; range, 1–15 years) in a formaldehyde-manufacturing process, 16 waiters exposed for 12 weeks to an indoor source of formaldehyde during interior renovations, and a control group of 23 students; all were non-smokers. Average formaldehyde exposure-concentrations were 0.011 mg/m 3 for the student controls; 0.107 mg/m 3 for the waiters; and 0.99 mg/m 3 for the formaldehyde-plant workers. There was a statistically significantly higher frequency of micronuclei in nasal mucosal cells and of SCE in peripheral lymphocytes in the workers at the formaldehyde-manufacturing plant, but not in the waiters, although both groups were exposed to formaldehyde at comparable concentrations ( Table  4.1 ). The result is in line with the much longer exposure duration for the plant workers. The same authors ( Ye et al

. , 2005 ) reported an increase in B-cells and changes in the ratios between lymphocyte subsets, similar to those reported by Madison et al

. (1991) in an

424Formaldehyde

Alaskan community subject to acute formal

dehyde exposure (estimated at 2–5 ppm) for a few days. Blood analyses were done three years

after the accident. Total white blood cell counts and total lymphocyte counts did not differ from those in the control community in Alaska, also measured three years later ( Madison et al

. , 1991 ). An increase in SCE and other genotoxic effects were observed in the lymphocytes of workers with long-term exposure to formalde

hyde ( Costa et al

. , 2008 ). Thirty workers from four pathology/anatomy hospital units and 30 matched controls were included in the study. Compared with the control group, statistically significant effects were seen in SCE (6.13 ± 0.29

vs 4.49 ± 0.16 SCE/cell, P < 0.05), micronucleus frequency (in 1000 bi-nucleated cells: 5.47 ± 0.76

‰ vs 3.27 ± 0.69 ‰, P = 0.003) and tail length in the comet assay (60.0 ± 2.31 μm vs 41.85 ± 1.97

μm, P < 0.05). A statistically significant positive correlation was found between formaldehyde exposure levels and micronucleus frequency and tail length. The mean formaldehyde exposure was 0.44 ppm (range, 0.04–1.58 ppm). None of

the observed effects were related to the duration of exposure. No genotoxic effects were observed in a study of 36 laboratory workers at a cancer-research institute who were exposed to 4.9–268.7 μg/m 3 formaldehyde. There was a direct relationship between formaldehyde exposure levels andthe presence of a formaldehyde human serumalbumin (FA-HSA) conjugate. The genotoxic endpoints measured were SCE, micronuclei and
chromosome aberrations, but these did not show significantly elevated levels ( Pala et al

. , 2008 ). Although a small study, its strength is its linkage to a biological marker of formaldehyde exposure. Hayes et al

. (1997) evaluated O 6 -Alkylguanine-DNA–alkyltransferase (AGT) activity as a measure of DNA-repair capacity in blood lymphocytes of 23 science students in a mortuary, before and after a nine-week period of classroom exposure to approximately 1.5 ppm formaldehyde. A statistically significant finding

was that more students had a reduction in AGT activity than an increase. There was no clear link between the extent of exposure to formaldehyde and AGT activity. Zhang et al

. (2010) cultured myeloid progen

itor cells from the peripheral blood of formalde

hyde-exposed workers and controls and measured leukaemia-specific chromosomal changes. In a subset of ten of the most highly exposed subjects in their study, monosomy (loss) of chromosome 7 and trisomy (gain) of chromosome 8 were signif

icantly elevated in the myeloid progenitor cells of formaldehyde-exposed workers compared with the same phenomena in 12 unexposed controls. The loss of chromosome 7 and gain of chromo

some 8 were examined because they are among the most frequent cytogenetic changes observed in myeloid leukaemia and myelodysplastic syndromes; these events have been shown to be affected by exposure to the established human leukemogen, benzene. [The Working Group noted that the study is small and needs to be replicated].



### 4.3.2 Experimental systems

(a) In-vivo studies (laboratory animals)

Studies on a variety of genotoxic endpoints in laboratory animals inhaling formaldehyde have generally shown effects in the nasal tissues of these animals ( IARC, 2006 ). Much less consistent have been the findings of genotoxic effects in the blood lymphocytes from exposed animals. Among the recent studies, Im et al

. (2006) reported genotoxicity based on a positive result in the comet assay in the lymphocytes of rats inhaling 5 or 10 ppm formaldehyde for two weeks, six hours/day, five days/week. In contrast,

in a review of their own work and of the litera

ture, Speit et al

. (2009) concluded that there was no evidence of systemic genotoxic effects in labo

ratory animals inhaling formaldehyde. Their own negative studies in this review focused on

425IARC MONOGRAPHS – 100F

lymphocyte genotoxicity, measured as micronu

clei, SCE, and DNA-breakage – the latter deter

mined with a sensitive form of the comet assay – in rats exposed for four weeks (six hours/day, five days/week) to formaldehyde concentrations of 0.5, 1, 2, 6, 10 and 15 ppm. More recently, DNA strand-breaks were induced by formaldehyde in vivo , in mouse liver (maternal and fetal), and in lung cells in the rat ( Wang & Liu, 2006 ; Sul et al

. , 2007 ).

(b) In-vitro studies

The spectrum of mutations related to exposure to formaldehyde in vitro and in vivo was presented

and discussed in IARC Monograph Volume 88 ( IARC, 2006 ). In-vitro studies since then have expanded the wide range of potential mutagenic mechanisms, to include the hydroxymethyla

tion of DNA and DNA-microsatellite instability ( Zhong & Que Hee, 2004 ; Wang et al

. , 2007 ). The evidence of formaldehyde-induced mutations in various experimental systems is consistent, encompassing both clastogenic effects and direct DNA mutation. Formaldehyde showed mutagenic potential in several bacterial systems, both with and without S9 activation. Formaldehyde induced deletions, point muta

tions, insertions, and cell transformation in in-vitro assays with mammalian cells ( IARC,

2006 ). Formaldehyde-induced DNA strand-breaks (SSB) have been demonstrated in several mammalian cell systems, including hepato

cytes, lymphosarcoma cells, and epithelial cells
from the rat, leukaemia L1210 cells from the mouse, and lung/bronchial epithelial cells, skin fibroblasts, keratinocytes, and peripheral blood lymphocytes from humans ( IARC, 2006 ).
Chromosomal aberrations, micronuclei and

SCE were all increased in vitro in numerous rodent and human primary cells and cell lines treated with formaldehyde ( IARC, 2006 ). Consistent with these findings, more recent

data show increased numbers of chromosomal aberrations in Syrian hamster embryo cells, and

chromosomal aberrations and SCE in Chinese hamster ovary and embryo cells ( Hikiba et al

. , 2005

, Hagiwara et al

. , 2006 ; Lorenti Garcia et al

. , 2009 ). Further evidence of formaldehyde-induced

micronucleus formation was obtained in studieswith human lymphocytes isolated from wholeblood cultures exposed in vitro to formaldehyde, 44 hours after the start of the culture ( Schmid & Speit, 2007 ). Both micronuclei and SCE were induced upon in-vitro treatment of Chinese hamster V79 lung epithelial cells with formal

dehyde ( Speit et al

. , 2007 ). In a recent study, SCE was induced in A549 human lung cells and V79 Chinese hamster cells following incubation with 0.1 mM [3 μg/mL] or higher concentra

tions of formaldehyde. One hour after the addi

tion of the agent to the A549 cells, the culture medium still retained the capacity to produce SCE in non-exposed V79 cells, suggesting that genotoxicity persists despite the high reactivity of formaldehyde with macromolecules in the culture medium ( Neuss & Speit, 2008 ). When the formaldehyde-exposed A549 cells were washed and then suspended in fresh culture medium containing the V79 cells, SCE formation was not observed in the latter. [The authors present no evidence that it is formaldehyde itself that persists, rather than a formaldehyde product that is responsible for genotoxicity. The Working Group noted that there is no reason to preclude the transfer of formaldehyde from cell to cell]. Formaldehyde has also been reported to interfere with DNA repair. A recent finding that

chicken DT40 cells deficient in the FANC/BRCA (Fanconi’s anaemia complementation groups/ breast cancer A) pathway are hypersensitive to formaldehyde in plasma, is consistent with a role for this pathway in repairing DNA–protein cross-links caused by formaldehyde. The DT40 mutants were also more sensitive to acetaldehyde, but not to acrolein and other aldehydes ( Ridpath

et al

. , 2007 ). Endogenous formaldehyde may be

426Formaldehyde

important in producing leukaemia in patients with Fanconi’s anaemia, a genetic disorder that is characterized by progressive pancytopenia. DT40 cells with deficient repair mechanisms

have also been shown to be more sensitive to other cross-linking agents such as cisplatin, a myelotoxic chemotherapeutic agent that leads to pancytopenia and acute myelogenous leukaemia (AML) ( Nojima et al

. , 2005 ).



### 4.4 Mechanistic considerations

4.4.1 Cancer of the nasopharynx and nasal

sinuses

Mechanistic evidence supporting a causal relation between inhalation of formaldehyde and induction of cancer of the nasopharynx and nasal sinuses is based on the chemical reactivity offormaldehyde in producing DNA–protein crosslinks, and its genotoxicity in vitro and in vivo

, including in the nasal cells of exposed humans. Computational fluid-dynamic models of formal

dehyde in the nasal passages of rats, monkeys and humans have generally been accurate in predicting the area in the nose with the highest number of DNA–protein crosslinks ( Georgieva

et al

. , 2003 ). Local effects in the nasal passages, genotoxicity, and cell-proliferation rate appear to be the major determinants of nasal carcino

genicity after exposure to formaldehyde.



### 4.4.2 Leukaemia

The findings reviewed in IARC Monograph Volume 88 ( IARC, 2006 ) pertaining to a poten

tial mechanism for formaldehyde-induced leukaemogenesis were summarized as follows:
“Based on the data available at this time, it was not possible to identify a mechanism for the induction of myeloid leukaemia in humans.” The Working Group further stated that “It is possible that formaldehyde itself can reach the bone marrow following inhalation, although the evidence is inconsistent.” Since that time, Zhang

et al

. (2009) , reviewed potential pathways by which formaldehyde could act as a leukaemogen. Three mechanisms were suggested:

• by damaging stem cells in the bone mar

row directly, as most other leukaemogens
do;

• by damaging haematopoietic stem/pro

genitor cells circulating in the peripheral

blood and

• by damaging the primitive pluri-potent stem cells present within the nasal tur

binates and/or olfactory mucosa. This subject was reviewed by Heck & Casanova (2004)

, Pyatt et al

. (2008) , and Goldstein (2011)

.

(a) Studies in animals

Studies of bone marrow cells in formalde

hyde-exposed animals have been inconsistent.

Kitaeva et al

. (1990) described clastogenic and cytogenetic effects in the bone marrow of rats inhaling 0.5 mg/m 3 or 1.5 mg/m 3 of formalde

hyde during four hours/day for four months. In

contrast, Dallas et al

. (1992) found no evidence of cytogenetic abnormalities in the bone marrow of rats exposed to 0.5, 3 or 15 ppm [0.62, 3.7 or 18.45 mg/m 3 ] formaldehyde for six hours/ day, five days per week, for one or eight weeks. Mice that received up to 25 mg/kg bw formal

dehyde in two intra-peritoneal injections within

24 hours showed no increase in chromosomal

aberrations or micronuclei in the femoral bone marrow ( Natarajan et al

. , 1983 ). As described insection 4.1 above, no increase in formaldehydespecific DNA–protein cross-links was observed in the bone marrow of Rhesus monkeys or rats under various experimental conditions ( Heck &

Casanova, 2004 ).

427IARC MONOGRAPHS – 100F

(b) Considerations of formaldehyde as a leukaemogen in relation to other known myeloleukaemogens

Known myeloid leukaemogens in humans include benzene, ionizing radiation and a variety of chemotherapeutic anti-neoplastic agents, all of which give rise to pancytopenia. There is evidence that for each of these myeloleukaemogens, pancy

topenia is caused by genotoxic damage leading to destruction of primitive progenitor cells in the bone marrow. These cells are responsible for the
formation of red blood cells, white blood cells and platelets, and they are the same progenitor cells in which mutations and clonal expansion leads to myeloid leukaemia. In view of the wide variety of genotoxic mechanisms shown by the diverse agents that have pancytopenia and myeloleukaemogenesis in common, it could be anticipated that genotoxic effects of formaldehyde on myeloid progenitor cells would also result in pancytopenia. Pancytopenia has not been among the haema

tological findings in experiments with labora

tory animals exposed to relatively high doses of formaldehyde, including classic long-term safety assessment studies. An increase in haemoglobin and monocytes and a decrease in lymphocytes were observed in rats receiving 0, 20, 40, or 80 mg/kg bw formaldehyde by gastric intubation on five days/week for four weeks. Lymph-nodeweights were increased but no change in lymphnode cellularity was observed ( Vargová et al

. , 1993 ). In one long-term study there was actually a statistically significant increase in bone-marrow hyperplasia in rats exposed to formaldehyde at 15 ppm ( Batelle, 1981 ), the opposite of what would be expected for an agent that has effects similar to those of other known myeloleukaemogens. In contrast to the findings in laboratory animals, there has been some evidence suggesting a mild pancytopenic effect in humans. A study of 50 haemodialysis nurses exposed to formalde

hyde compared with 71 non-exposed ward nurses from five different hospitals comprised measure

ments of formaldehyde and two different blood counts recorded one a year apart. Both personal and ambient measurements of formaldehyde varied widely, from non-detectable up to 2.8 ppm. Average duration of employment was three years for both groups. Symptoms attributable to formaldehyde were reported in the exposed group. For the second blood count, but not the first, there was a statistically significant inverse correlation ( P < 0.05) between white blood-cell count and formaldehyde concentration, as well as between white blood-cell count and symptom score. No statistically significant correlation was observed between formaldehyde concentrations or symptoms and platelet or red blood-cell counts. The exposed group had a lower white blood-cell count than the control group ( Kuo et al

. , 1997 ). [The Working Group noted that absolute data for blood counts were not given, nor was the statis

tical methodology described] An increase in B-lymphocytes and changes in ratios of lymphocyte subsets were noted in formaldehyde-plant workers exposed to an average of 0.99 mg/m 3 formaldehyde for a mean duration of 8.5 years ( Ye et al

. , 2005 ). Differences in the ratios of lymphocyte subsets were also observed in an Alaskan community with an acute formaldehyde exposure (2–5 ppm for a few days), but no differences with the control community were seen in total white blood-cell counts or lymphocyte counts ( Madison et al

. , 1991 ). Likewise, no significant differences in blood counts were found in a comparative study
of students of two schools, in one of which there were elevated concentrations of formaldehyde and toluene ( Vozenílková et al

. , 1991 ). In a review of formaldehyde exposure in the People’s Republic of China, Tang et al

. (2009)mentioned eight studies on formaldehydeexposed individuals. Lower white blood-cell

counts were observed in the six studies that provided information on this point, four of which were statistically significant; platelet

428Formaldehyde

counts were decreased in all three studies where
this was measured, two of which were statisti

cally significant; and haemoglobin was lower

in one of the three studies for which data were reported. The one study that found lower than

normal values for each blood count – consistent with a pancytopenic effect – was specifically the study with the lowest exposure to formalde

hyde (0.022–0.044 mg/m 3 ), although the largest cohort. [From the Table in the Tang et al

. (2009) paper, it is not clear whether these are the same individuals or separate individuals who have each of the lower counts, i.e. how many were pancy

topenic. There also is no information about the usual confounders, including gender and age]. The finding of statistically significant, moderately lower blood counts in formalde

hyde-exposed Chinese workers as compared to a matched control group would be consistent with formaldehyde-induced damage to either circu

lating haematopoietic precursor cells, or with a

direct effect on such cells within the bone marrow ( Zhang et al

. , 2010 ). In this study the 43 exposed workers at a formaldehyde-melamine producing factory or a factory in which formaldehyde-mela

mine resins were used to produce utensils, were exposed to a median of 1.28 ppm formaldehyde(10–90%, range 0.63–2.51 ppm; 8-hour timeweighted average), compared with a median level, in a matched control group of 51 individuals, of 0.026 ppm (10–90%, range 0.0085–0.026 ppm). Absolute blood counts were only given for total white blood-cell counts: in controls, mean (SD) 6269 (1452) cells per μl blood; and in exposed: mean 5422 (1529) cells per μl blood, P = 0.0016. Data for the other blood counts are presented in a bar chart, and for red blood cells, platelets, granulocytes and lymphocytes there are small but statistically significant decreases that appear to fall within the clinical range of normal. Also of note is a statistically significant increase in the mean corpuscular volume (MCV) of red

blood cells. The MCV tends to be increased in myelodysplastic conditions. The study appeared to have adequately taken into account possible

confounders such as alcoholism and nutritional issues that might cause pancytopenia and an

increased MCV.

(c) Leukaemogenesis on the basis of reactions with myeloid stem cells within the nose

As indicated above, Zhang et al

. (2009) havesuggested that one mechanism of formaldehydeinduced leukaemogenesis might involve reac

tion of formaldehyde or a reactive formaldehyde derivative with myeloid precursors present within the nose. This has been questioned on two indirect grounds ( Goldstein, 2011 ). Nasal tissue does not seem to have been reported as
a location for chloromas, which are isolated collections of myeloid leukaemia cells, despite the presence of chloromas in virtually all other tissues. Second, known nasal carcinogens, including cross-linking agents such as nickel and chromium, are not reported to cause an increase in acute myelogenous leukaemia. The one possible exception is sulfur mustard, a nasal carcinogen for which an increase in leukaemia (13 deaths observed; 8.51 expected; not statisti

cally significant) was reported by Easton et al

. (1988) in workers producing sulfur mustard gas during World War II. However, this agent also produces pancytopenia, an outcome that led to the development of nitrogen mustard as a chemo

therapeutic compound. None of the other known human nasal carcinogens has been reported to
cause pancytopenia.

(d) Formaldehyde and lymphoid cancers

Genotoxicity studies on blood lymphocytes from laboratory animals that inhaled formal

dehyde have tended to be negative, although not consistently so. In comparison, somewhat more studies with the lymphocytes of humans exposed to formaldehyde have reported geno

toxicity, although the findings are also incon

sistent. Genotoxicity in circulating lymphocytes would be consistent with the possibility that

429IARC MONOGRAPHS – 100F

formaldehyde is a cause of lymphatic tumours. Particularly at risk would be mucosa-associated lymphatic tissue in the nasal area. The evolution of our understanding of lymphohaematopoitetic cancers has led to ongoing reclassification of these tumours. There is also recognition of their inter-relatedness through a common stem cell, and the fact that there is a risk for malignant transformation during various stages of the differentiation and maturation process of the precursor cells. Recent evidence suggests that an underlying cytoge

netic abnormality in an early precursor cell predisposes to subsequent mutations leading to a specific haematological cancer. The possibility of a mutagenic effect of formaldehyde on circu

lating lymphocytes or local lymphatic tissue

cannot be excluded.



### 4.5 Synthesis

The current data strongly indicate that geno

toxicity plays an important role in the carci

nogenicity of formaldehyde in nasal tissues in humans, and that cellular replication in response to formaldehyde-induced cytotoxicity promotes the carcinogenic response. Three possible mech

anisms, all focused around genotoxicity, are moderately supported as the underlying mecha

nism for induction of haematological malig

nancies in humans. Further research is needed

to decide which of the mechanisms is the most
important.



### 5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of formaldehyde. Formaldehyde causes cancer of the nasopharynx and leukaemia. Also, a positive association has been observed between exposure to formaldehyde and sinonasal

cancer. There is sufficient evidence in experimental animals for the carcinogenicity of formaldehyde. The Working Group was not in full agree

ment on the evaluation of formaldehyde causing leukaemias in humans, with a small majority viewing the evidence as sufficient of carcino

genicity and the minority viewing the evidence as limited. Particularly relevant to the discus

sions regarding sufficient evidence was a recent study accepted for publication which, for the first time, reported aneuploidy in blood of exposed workers characteristic of myeloid leukaemia and myelodysplastic syndromes, with supporting information suggesting a decrease in the major circulating blood-cell types and in circulating haematological precursor cells. The authors and Working Group felt that this study needed to be replicated. Formaldehyde is carcinogenic to humans (Group 1)

.



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