FORMALDEHYDE

This substance was considered by previous working groups in October 1981 (IARC,

1982), March 1987 (IARC, 1987a) and October 1994 (IARC, 1995). Since that time, new

data have become available, and these have been incorporated in the monograph and taken

into consideration in the evaluation.

1. Exposure Data

1.1 Chemical and physical data

1.1.1 Nomenclature

Chem. Abstr. Serv. Reg. No.: 50-00-0 

Deleted CAS Reg. Nos.: 8005-38-7; 8006-07-3; 8013-13-6; 112068-71-0

Chem. Abstr. Name: Formaldehyde 

IUPAC Systematic Name: Methanal

Synonyms: Formaldehyde, gas; formic aldehyde; methaldehyde; methyl aldehyde;

methylene oxide; oxomethane; oxymethylene

1.1.2 Structural and molecular formulae and relative molecular mass

CH2O Relative molecular mass: 30.03

1.1.3 Chemical and physical properties of the pure substance

From Lide (2003), unless otherwise specified

(a) Description: Colourless gas with a pungent odour (Reuss et al., 2003)

(b) Boiling-point: –19.1 °C

(c) Melting-point: –92 °C

(d) Density: 0.815 at –20 °C

–39–

C O

H

H
(e) Spectroscopy data: Infrared [prism, 2538], ultraviolet [3.1] and mass spectral

data have been reported (Weast & Astle, 1985; Sadtler Research Laboratories,

1991).

(f) Solubility: Soluble in water, ethanol and chloroform; miscible with acetone,

benzene and diethyl ether

(g) Stability: Commercial formaldehyde–alcohol solutions are stable; the gas is stable

in the absence of water; incompatible with oxidizers, alkalis, acids, phenols and

urea (IARC, 1995; Reuss et al., 2003; Gerberich & Seaman, 2004).

(h) Reactivity: Reacts explosively with peroxide, nitrogen oxide and performic acid;

can react with hydrogen chloride or other inorganic chlorides to form bis(chloromethyl) ether (see IARC, 1987b) (IARC, 1995; Reuss et al., 2003; Gerberich &

Seaman, 2004).

(i) Octanol/water partition coefficient (P): log P = 0.35 (Hansch et al., 1995)

(j) Conversion factor: mg/m3 = 1.23 × ppm1

1.1.4 Technical products and impurities 

Trade names: BFV; FA; Fannoform; Floguard 1015; FM 282; Formalin; Formalin 40;

Formalith; Formol; FYDE; Hoch; Ivalon; Karsan; Lysoform; Morbicid; Paraform; Superlysoform

Formaldehyde is most commonly available commercially as a 30–50% (by weight)

aqueous solution, commonly referred to as ‘formalin’. In dilute aqueous solution, the predominant form of formaldehyde is its monomeric hydrate, methylene glycol. In more concentrated aqueous solutions, oligomers and polymers that are mainly polyoxymethylene

glycols are formed and may predominate. Methanol and other substances (e.g. various

amine derivatives) are usually added to the solutions as stabilizers, in order to reduce

intrinsic polymerization. The concentration of methanol can be as high as 15%, while that

of other stabilizers is of the order of several hundred milligrams per litre. Concentrated

liquid formaldehyde–water systems that contain up to 95% formaldehyde are also

available, but the temperature necessary to maintain the solution and prevent separation

of the polymer increases from room temperature to 120 °C as the concentration in solution increases. Impurities include formic acid, iron and copper (Cosmetic Ingredient

Review Expert Panel, 1984).

Formaldehyde is marketed in solid form as its cyclic trimer, trioxane ((CH2O)3), and

its polymer, paraformaldehyde, with 8–100 units of formaldehyde (WHO, 1991; IARC,

1995; Reuss et al., 2003).

40 IARC MONOGRAPHS VOLUME 88

1Calculated from: mg/m3 = (relative molecular mass/24.45) × ppm, assuming normal temperature (25 °C) and

pressure (103.5 kPa)
1.1.5 Analysis

Selected methods for the determination of formaldehyde in various matrices are

presented in Table 1.

The most widely used methods for the determination of the concentration of formaldehyde in air are based on spectrophotometry, with which sensitivities of 0.01–0.03 mg/m3

can be achieved. Other methods include colorimetry, fluorimetry, high-performance liquid

chromatography (HPLC), polarography, gas chromatography (GC), infrared detection and

gas detector tubes. Most methods require the formation of a derivative for separation and

detection. 

HPLC is the most sensitive method (limit of detection, 2 μg/m3 or less). Gas detector

tubes (Draeger Safety, undated; Sensidyne, undated; WHO, 1989; MSA, 1998; Matheson

Tri-Gas®, 2004; Sensidyne, 2004; SKC®, 2005) that have sensitivities of about 0.05–

0.12 mg/m3 [0.04–0.1 ppm] and infrared analysers (Interscan Corporation, undated; Environmental Protection Agency, 1999a,b; MKS Instruments, 2004a,b; Thermo Electron

Corporation, 2005) that have sensitivities of about 1.2–230 μg/m3 [1–110 ppb] are often

used to monitor workplace atmospheres.

Based on these methods, several standards have been established to determine levels of

formaldehyde emissions from wood products (European Commission, 1989; ASTM International, 1990; Groah et al., 1991; Jann, 1991; Deutsche Norm, 1992, 1994, 1996; Standardiseringen i Sverige, 1996; Composite Panel Association, 1999; ASTM International,

2000; Japanese Standards Association, 2001; ASTM International, 2002a,b; Composite

Panel Association, 2002).

Sandner et al. (2001) reported a modification of the existing method 1 of the Deutsche

Forschungsgemeinschaft (1993) to monitor formaldehyde in the workplace that uses

adsorption to 2,4-dinitrophenylhydrazine-coated sorbents followed by HPLC with ultraviolet (UV)/diode array detection. The detection limit decreased from approximately

15 μg/m3 for the original method to 0.07 μg/m3 for the modified method.

In the development of new methods to monitor formaldehyde in air, emphasis has been

on direct optical sensors and on increased sensitivity (Friedfeld et al., 2000; Lancaster

et al., 2000; Chan et al., 2001; Mathew et al., 2001; Alves Pereira et al., 2002; Werle et al.,

2002).

Methods for the analysis of formaldehyde in biological matrices (e.g. blood and

urine) have been reviewed (ATSDR, 1999), and new methods continue to be reported

(Carraro et al., 1999; Spanel et al., 1999; Luo et al., 2001; Kato et al., 2001). Formaldehyde has been measured in blood by gas chromatography–mass spectrometry (GC–MS)

after derivatization to pentafluorophenylhydrazone (Heck et al., 1982, 1985). Formic acid

or formate is produced from formaldehyde and can be measured in blood and urine

(Baumann & Angerer, 1979). However, biological monitoring of exposure to formaldehyde is not common practice.

FORMALDEHYDE 41
42 IARC MONOGRAPHS VOLUME 88

Table 1. Methods for the analysis of formaldehyde in air and food 

Sample 

matrix 

Sample preparation Assay 

procedure 

Limit of 

detection 

Reference 

Air Draw air through impinger 

containing aqueous pararosaniline; 

treat with acidic pararosaniline and 

sodium sulfite 

Spectrometry 10 μg/m3 Georghiou et al. 

(1993) 

Draw air through PTFE filter and 

impingers, each treated with sodium 

bisulfite solution; develop colour 

with chromotropic acid and sulfuric 

acid; read absorbance at 580 nm 

Spectrometry 0.5 μg/sample NIOSH (1994a) 

[Method 3500] 

Draw air through solid sorbent tube 

treated with 10% 2-(hydroxymethyl) 

piperidine on XAD-2; desorb with 

toluene 

GC/FID 

GC/FID & 

GC/MS 

GC/NSD 

1 μg/sample 

2 μg/sample 

20 μg/m3

NIOSH (1994b) 

[Method 2541] 

NIOSH (1994c) 

[Method 2539] 

Occupational 

Safety and Health 

Administration 

(1990a) [Method 52] 

Draw air through impinger 

containing hydrochloric acid/2,4-dinitrophenylhydrazine reagent and 

isooctane; extract with hexane/dichloromethane 

HPLC/UV 2 μg/m3 Environmental 

Protection Agency 

(1988) [Method TO5] 

Draw air through a glassfibre filter 

impregnated with 2,4-dinitrophenylhydrazine; extract with acetonitrile 

HPLC/UV 15 μg/m3 Deutsche 

Forschungsgemeinschaft (1993) 

[Method 1] 

Draw air through silica gel coated 

with acidified 2,4-dinitrophenylhydrazine reagent 

HPLC/UV 2 μg/m3

(0.6–123 

μg/m3

) 

Environmental 

Protection Agency 

(1999c); INRS (2003) 

[Method TO11A] 

Draw air through a cartridge 

containing silica gel coated with 

2,4-dinitrophenylhydrazine; extract 

with acetonitrile 

HPLC/UV 0.07 μg/m3 Sandner et al. (2001) 

Draw air through a cartridge 

containing silica gel coated with 

2,4-dinitrophenylhydrazine; extract 

with acetonitrile 

HPLC/UV 0.07 μg/ 

sample 

NIOSH (2003a) 

[Method 2016] 
1.2 Production and use

1.2.1 Production 

Formaldehyde has been produced commercially since 1889 by the catalytic oxidation

of methanol. Various specific methods were used in the past, but only two are widely used

currently: the silver catalyst process and the metal oxide catalyst process (Bizzari, 2000;

Reuss et al., 2003; Gerberich & Seaman, 2004). 

The silver catalyst process is conducted in one of two ways: (i) partial oxidation and dehydrogenation with air in the presence of silver crystals, steam and excess methanol at

680–720 °C and at atmospheric pressure (also called the BASF process; methanol conversion, 97–98%); and (ii) partial oxidation and dehydrogenation with air in the presence of

crystalline silver or silver gauze, steam and excess methanol at 600–650 °C (primary conversion of methanol, 77–87%); the conversion is completed by distilling the product and

FORMALDEHYDE 43

Table 1 (contd) 

Sample 

matrix 

Sample preparation Assay 

procedure 

Limit of 

detection 

Reference 

Expose passive monitor containing 

bisulfite-impregnated paper; desorb 

with deionized water; acidify; add 

chromotropic acid; read absorbance 

at 580 nm 

Chromotropic acid 

test 

0.14 μg/m3 Occupational 

Safety and Health 

Administration 

(1990b) 

[Method ID-205] 

Collect gases with portable directreading instrument; compare spectra 

with references 

FTIRS 0.49 μg/m3 NIOSH (2003b) 

[Method 3800] 

Dust 

(textile 

or 

wood) 

Draw air through inhalable dust 

sampler containing a PVC filter; 

extract with distilled water and 2,4-

dinitrophenylhydrazine/acetonitrile 

HPLC/UV 0.08 μg/ 

sample 

NIOSH (1994d) 

[Method 5700] 

Food Distil sample; add 1,8-dihydroxynaphthalene-3,6-disulfonic acid in 

sulfuric acid; purple colour indicates 

presence of formaldehyde 

Chromotropic acid 

test 

NR AOAC (2003) 

[Method 931.08] 

Distil sample; add to cold sulfuric 

acid; add aldehyde-free milk; add 

bromine hydrate solution; purplishpink colour indicates presence of 

formaldehyde 

HehnerFulton test NR AOAC (2003) 

[Method 931.08] 

FTIRS, Fourier transform infrared spectrometry; GC/FID, gas chromatography/flame ionization detection; 

GC/MS, gas chromatography/mass spectrometry; GC/NSD, gas chromatography/nitrogen selective detection; HPLC/UV, high-performance liquid chromatography/ultraviolet detection; NR, not reported; PTFE, 

polytetrafluoroethylene; PVC, polyvinyl chloride 
recycling the unreacted methanol. Carbon monoxide, carbon dioxide, methyl formate and

formic acid are by-products (Bizzari, 2000; Reuss et al., 2003; Gerberich & Seaman, 2004).

In the metal oxide (Formox) process, methanol is oxidized with excess air in the

presence of a modified iron–molybdenum–vanadium oxide catalyst at 250–400 °C and

atmospheric pressure (methanol conversion, 98–99%). By-products are carbon monoxide,

dimethyl ether and small amounts of carbon dioxide and formic acid (Bizzari, 2000; Reuss

et al., 2003; Gerberich & Seaman, 2004).

Paraformaldehyde, a solid polymer of formaldehyde, consists of a mixture of poly-

(oxymethylene) glycols [HO–(CH2O)n–H; n = 8–100]. The formaldehyde content is

90–99%, depending on the degree of polymerization, the value of n and product specifications; the remainder is bound or free water. As a convenient source of formaldehyde for

certain applications, paraformaldehyde is prepared commercially by the concentration of

aqueous formaldehyde solutions under vacuum in the presence of small amounts of

formic acid and metal formates. An alternative solid source of formaldehyde is the cyclic

trimer of formaldehyde, 1,3,5-trioxane, which is prepared commercially by strong acidcatalysed condensation of formaldehyde in a continuous process (Bizzari, 2000; Reuss

et al., 2003; Gerberich & Seaman, 2004).

Available information indicates that formaldehyde was produced by 104 companies in

China, 19 companies in India, 18 companies in the USA, 15 companies each in Italy and

Mexico, 14 companies in Russia, 11 companies each in Brazil and Japan, eight companies

each in Canada and Germany, seven companies each in China (Province of Taiwan),

Malaysia and the United Kingdom, six companies each in Argentina and Spain, five companies in Belgium, four companies each in Colombia, France, Iran, the Netherlands and

Thailand, three companies each in Chile, Israel, Poland, Portugal, the Republic of Korea,

Sweden, Turkey and the Ukraine, two companies each in Australia, Austria, Ecuador,

Egypt, Pakistan, Peru, Romania and Serbia and Montenegro, and one company each in

Algeria, Azerbaijan, Bulgaria, Denmark, Estonia, Finland, Greece, Hungary, Indonesia,

Ireland, Lithuania, Norway, Saudi Arabia, Singapore, Slovakia, Slovenia, South Africa,

Switzerland, Uzbekistan and Venezuela (Chemical Information Services, 2004).

Available information indicates that paraformaldehyde was produced by eight companies in China, four companies each in Germany and India, three companies each in

Russia and the USA, two companies each in China (Province of Taiwan), Iran, Mexico

and Spain and one company each in Canada, Egypt, Israel, Italy, Japan, the Netherlands,

the Republic of Korea, Romania, Saudi Arabia and the United Kingdom (Chemical Information Services, 2004).

Available information indicates that 1,3,5-trioxane was produced by three companies

in Germany, two companies each in China, India and the USA and one company in Poland

(Chemical Information Services, 2004).

Production of formaldehyde in selected years from 1983 to 2000 and in selected

countries is shown in Table 2. Worldwide capacity, production and consumption of formaldehyde in 2000 are shown in Table 3. 

44 IARC MONOGRAPHS VOLUME 88
1.2.2 Use

Worldwide patterns of use for formaldehyde in 2000 are shown in Table 4. The most

extensive use of formaldehyde is in the production of resins with urea, phenol and melamine, and of polyacetal resins. Formaldehyde-based resins are used as adhesives and

impregnating resins in the manufacture of particle-board, plywood, furniture and other

wood products; for the production of curable moulding materials (appliances, electric

controls, telephones, wiring services); and as raw materials for surface coatings and

controlled-release nitrogen fertilizers. They are also used in the textile, leather, rubber and

cement industries. Further uses are as binders for foundry sand, stonewool and glasswool

mats in insulating materials, abrasive paper and brake linings (WHO, 1989; IARC, 1995;

Reuss et al., 2003; Gerberich & Seaman, 2004).

Another major use of formaldehyde is as an intermediate in the synthesis of other

industrial chemical compounds, such as 1,4-butanediol, trimethylolpropane and neopentyl

glycol, that are used in the manufacture of polyurethane and polyester plastics, synthetic

resin coatings, synthetic lubricating oils and plasticizers. Other compounds produced from

formaldehyde include pentaerythritol, which is used primarily in raw materials for surface

coatings and explosives, and hexamethylenetetramine, which is used as a cross-linking

agent for phenol–formaldehyde resins and explosives. The complexing agents, nitrilotriacetic acid (see IARC, 1990a) and ethylenediaminetetraacetic acid, are derived from formaldehyde and are components of some detergents. Formaldehyde is used for the production

of 4,4′-methylenediphenyl diisocyanate (see IARC, 1979), which is a constituent of polyurethanes that are used in the production of soft and rigid foams, as adhesives and to bond

particle-board (WHO, 1989; IARC, 1995; Reuss et al., 2003; Gerberich & Seaman, 2004).

Polyacetal plastics produced by the polymerization of formaldehyde are incorporated

into automobiles to reduce weight and fuel consumption, and are used to make functional

FORMALDEHYDE 45

Table 2. Production of 37% formaldehyde in selected 

regions (thousand tonnes) 

Country or region 1983 1985 1990 1995 2000 

North America 

 Canada 

 Mexico 

 USA 

 256 

 79 

2520a

 288 

 106 

2663 

 288 

 118 

3402 

 521 

 139 

3946 

 675 

 136 

4650 

Western Europeb 3757 3991 4899 5596 6846c

Japan 1089 1202 1444 1351 1396 

From Bizzari (2000) a

 Data for 1980 

b

 Includes Austria, Belgium, Denmark, Finland, France, Germany, 

Greece, Ireland, Italy, the Netherlands, Norway, Portugal, Spain, 

Sweden, Switzerland and the United Kingdom 

c

 Data for 1999 
components of audio and video electronic equipment. Formaldehyde is also the basis for

products that are used to manufacture dyes, tanning agents, precursors of dispersion and

plastics, extraction agents, crop protection agents, animal feeds, perfumes, vitamins,

flavourings and drugs (WHO, 1989; Reuss et al., 2003).

Formaldehyde itself is used to preserve and disinfect, for example, human and veterinary drugs and biological materials (viral vaccines contain 0.05% formalin as an inactivating agent), to disinfect hospital wards and to preserve and embalm biological specimens.

Formaldehyde and medications that contain formaldehyde are also used in dentistry (Lewis,

1998). Formaldehyde is used as an antimicrobial agent in many cosmetics products,

46 IARC MONOGRAPHS VOLUME 88

Table 3. World supply and demand for 37% formaldehyde 

in 2000 (thousand tonnes) 

Country/region Production Consumption 

North America 

 Canada 675 620 

 Mexico 136 137 

 USA 4 650 4 459 

South and Central Americaa 638 636 

Western Europeb 7 100 7 054 

Eastern Europec 1 582 1 577 

Middle Eastd 454 438 

Japan 1 396 1 395 

Africae 102 102 

Asia 

 China 1 750 1 752 

 Indonesia 891 892 

 Malaysia 350 350 

 Republic of Korea 580 580 

 Otherf 789 795 

Australia and New Zealand 304 304 

Total 21 547 21 091 

From Bizzari (2000) a

 Includes Argentina, Brazil, Chile, Colombia, Ecuador, Peru, Uruguay and 

Venezuela 

b

 Includes Austria, Belgium, Denmark, Finland, France, Germany, Greece, 

Ireland, Italy, the Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and the United Kingdom 

c

 Includes Bulgaria, the Czech Republic, Hungary, Lithuania, Poland, 

Romania, Russia, Slovakia, Slovenia, the Ukraine and Yugoslavia

d

 Includes Iran, Israel, Saudi Arabia and Turkey 

e

 Includes Algeria, Nigeria, South Africa and Tunisia

f

 Includes Bangladesh, Cambodia, China (Province of Taiwan), Democratic 

People’s Republic of Korea, India, Laos, Myanmar, Pakistan, the Philippines, Singapore, Sri Lanka, Thailand and Viet Nam 
Table 4. Worldwide use patterns (%) of formaldehyde in 2000Region or country Use 

(million tonnes) 

UFR PFR PAR MFR BDO MDI PE 

USA 4.5 24.2 16.6 12.7 3.1 11.2 6.8 5.0 Canada 0.62 51.3 32.3 3.2 12.9 Mexico 0.14 70.8 11.7 5.1 South and Central  Americac

0.64 55.8 18.9 7.9 1.6 10.8 

Western Europed 7.1 44.4 8.6 7.1 7.5 6.7 5.4 5.4 Eastern Europee 1.6 71.5 5.1 3.2 4.4 Africaf 0.10 70.6 14.7 7.8 Middle Eastg 0.43 75.1 4.6 14.8 Japan 1.4 12.3 7.7 32.9 4.8 2.1 8.4 6.7 Asiai 4.4 54.2 9.8 8.4 8.7 5.8 Oceaniaj 0.30 67.4 12.2 20.4 From Bizzari (2000) UFR, urea–formaldehyde resins; PFR, phenol–formaldehyde resins; PAR, polyacetal resins; MFR, melamine–formadiol; MDI, 4,4′-diphenylmethane diisocyanate; PE, pentaerythritol; HMTA, hexamethylenetetramine; TMP, trimethya Not defined b Including chelating agents, trimethylolpropane, trimethylolethane, paraformaldehyde, herbicides, neopentyl glycol

derivatives, textile treating and controlled-release fertilizer 

c Includes Argentina, Brazil, Chile, Colombia, Ecuador, Peru, Uruguay and Venezuela d Includes Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, N

Switzerland and the United Kingdom 

e Includes Bulgaria, the Czech Republic, Hungary, Lithuania, Poland, Romania, Russia, Slovakia, Slovenia, the Ukraif Includes Algeria, Nigeria, South Africa and Tunisia g Includes Iran, Israel, Saudi Arabia and Turkey

h Including 6.4% for paraformaldehyde

i Includes Bangladesh, Cambodia, China, China (Province of Taiwan), Democratic People’s Republic of Korea, 

Myanmar, Pakistan, the Philippines, Republic of Korea, Singapore, Sri Lanka, Thailand and Viet Nam

j Includes Australia and New Zealand
including soaps, shampoos, hair preparations, deodorants, lotions, make-up, mouthwashes

and nail products (Cosmetic Ingredient Review Expert Panel, 1984; Reuss et al., 2003).

Formaldehyde is also used directly to inhibit corrosion, in mirror finishing and electroplating, in the electrodeposition of printed circuits and in the development of photographic

films (Reuss et al., 2003). 

Paraformaldehyde is used in place of aqueous solutions of formaldehyde, especially

when the presence of water interferes, e.g. in the plastics industry for the preparation of

phenol, urea and melamine resins, varnish resins, thermosets and foundry resins. Other

uses include the synthesis of chemical and pharmaceutical products (e.g. Prins reaction,

chloromethylation, Mannich reaction), the production of textile products (e.g. for creaseresistant finishes), the preparation of disinfectants and deodorants (Reuss et al., 2003) and

in selected pesticide applications (Environmental Protection Agency, 1993).

1.3 Occurrence

Formaldehyde is a gaseous pollutant from many outdoor and indoor sources. Outdoors, major sources of formaldehyde include power plants, manufacturing facilities, incinerators and automobile exhaust emissions. Forest fires and other natural sources of combustion also introduce formaldehyde into the ambient air. Other than in occupational

settings, the highest levels of airborne formaldehyde have been detected indoors where it

is released from various building materials, consumer products and tobacco smoke. Formaldehyde may be present in food, either naturally or as a result of contamination (Suh

et al., 2000).

Natural and anthropogenic sources of formaldehyde in the environment, and environmental levels in indoor and outdoor air, water, soil and food have been reviewed (WHO,

1989; IARC, 1995; ATSDR, 1999).

1.3.1 Natural occurrence 

Formaldehyde is ubiquitous in the environment; it is an endogenous chemical that

occurs in most life forms, including humans. It is formed naturally in the troposphere

during the oxidation of hydrocarbons, which react with hydroxyl radicals and ozone to

form formaldehyde and other aldehydes as intermediates in a series of reactions that

ultimately lead to the formation of carbon monoxide and dioxide, hydrogen and water. Of

the hydrocarbons found in the troposphere, methane is the single most important source

of formaldehyde. Terpenes and isoprene that are emitted by foliage react with hydroxyl

radicals to form formaldehyde as an intermediate product. Because of their short half-life,

these sources of formaldehyde are important only in the vicinity of vegetation. Formaldehyde is one of the volatile compounds that are formed in the early stages of decomposition of plant residues in the soil, and occurs naturally in fruit and other foods (WHO,

1989; IARC, 1995). 

48 IARC MONOGRAPHS VOLUME 88
An overview of the formation and occurrence of formaldehyde in living organisms

has been reported (Kalász, 2003). The reader is referred to Section 4.1 for a discussion of

blood levels of endogenously formed formaldehyde in humans.

1.3.2 Occupational exposure

Estimates of the number of persons who are occupationally exposed to formaldehyde

worldwide are not available. However, an estimate of the number of people who were

exposed in the European Union in the early 1990s is available from the International Information System on Occupational Exposure to Carcinogens (more commonly referred to as

CAREX) (Kauppinen et al., 2000). Approximate numbers of persons who were exposed to

levels of formaldehyde above 0.1 ppm [0.12 mg/m3] are presented by major industry sector

in Table 5. While these are not precise estimates, they do indicate that exposure to formaldehyde, at least at low levels, may occur in a wide variety of industries.

Three main sets of circumstances may lead to occupational exposure to formaldehyde.

The first is related to the production of aqueous solutions of formaldehyde (formalin) and

their use in the chemical industry, e.g. for the synthesis of various resins, as a preservative

in medical laboratories and embalming fluids and as a disinfectant. A second set is related

to its release from formaldehyde-based resins in which it is present as a residue and/or

through their hydrolysis and decomposition by heat, e.g. during the manufacture of wood

products, textiles, synthetic vitreous insulation products and plastics. In general, the use of

phenol–formaldehyde resins results in much lower emissions of formaldehyde than that of

urea- and melamine-based resins. A third set of circumstances is related to the pyrolysis or

combustion of organic matter, e.g. in engine exhaust gases or during firefighting.

(a) Manufacture of formaldehyde, formaldehyde-based resins and

other chemical products

Concentrations of formaldehyde measured in the 1980s during the manufacture of

formaldehyde and formaldehyde-based resins are summarized in Table 6. More recent

data were not available to the Working Group.

Mean levels during the manufacture of formaldehyde were below 1 ppm [1.2 mg/m3].

These workers may also be exposed to methanol (starting material), carbon monoxide,

carbon dioxide and hydrogen (process gases) (Stewart et al., 1987).

The reported mean concentrations in the air of factories that produce formaldehydebased resins vary from < 1 to > 10 ppm [< 1.2 to > 12.3 mg/m3]. There are obvious differences between factories (the earliest measurements date from 1979) but no consistent

seasonal variation. Chemicals other than formaldehyde to which exposure may occur

depend on the types of resin manufactured: urea, phenol, melamine and furfural alcohol

are the chemicals most commonly reacted with liquid formaldehyde (formalin). Some

processes require the addition of ammonia, and alcohols are used as solvents in the production of liquid resins (Stewart et al., 1987).

FORMALDEHYDE 49
50 IARC MONOGRAPHS VOLUME 88

Table 5. Approximate number of workers exposed to formaldehyde 

above background levels (0.1 ppm) in the European Union, 1990–93 

Industry Estimate

Manufacture of furniture and fixtures, except primarily of metal 179 000 

Medical, dental, other health and veterinary services 174 000 

Manufacture of wearing apparel, except footwear 94 000 

Manufacture of wood and wood and cork products, except furniture 70 000 

Personal and household services 62 000 

Construction 60 000 

Manufacture of textiles 37 000 

Iron and steel basic industries 29 000 

Manufacture of fabricated metal products, except machinery 29 000 

Manufacture of other non-metallic mineral products 23 000 

Manufacture of machinery, except electrical 20 000 

Manufacture of industrial chemicals 17 000 

Manufacture of other chemical products 17 000 

Manufacture of plastic products not classified elsewhere 16 000 

Agriculture and hunting 16 000 

Manufacture of paper and paper products 13 000 

Printing, publishing and allied industries 13 000 

Wholesale and retail trade and restaurants and hotels 13 000 

Manufacture of transport equipment 11 000 

Manufacture of electrical machinery, apparatus and appliances 10 000 

Manufacture of footwear 9 000 

Manufacture of glass and glass products 8 000 

Research and scientific institutes 7 000 

Non-ferrous metal basic industries 6 000 

Manufacture of leather and products of leather or of its substitutes 6 000 

Beverage industries 4 000 

Manufacture of instruments, photographic and optical 4 000 

Other manufacturing industries 3 000 

Food manufacturing 3 000 

Crude petroleum and natural gas production 2 000 

Manufacture of rubber products 4 000 

Financing, insurance, real estate and business services 3 000 

Education services 2 000 

Sanitary and similar services 2 000 

Services allied to transport 2 000 

Manufacture of miscellaneous products of petroleum and coal 1 000 

Other industries 2 000 

Total (all industries) 971 000 

From Kauppinen et al. (2000); CAREX (2003)
Table 6. Concentrations of formaldehyde in the workroom air in formaldehyde and resin Industry and operation No. of 

measurements

Meana(ppm [mg/m3])

Range(ppm [mg/m3])

Year 

Special chemical manufacturing plant (USA) 8 NR < 0.03

–1.6 [0.04

–2.0] NR 

Production of formaldehyde (Sweden) 9 0.3 [0.3] NR 1980s Resin manufacture (Sweden) 22 0.5 [0.6] NR 1980s Formaldehyde manufacture (USA) 1983 

Plant no. 2, summer 15 0.6b [0.7] 0.03

–1.9 [0.04

–2.3]

Plant no. 10, summer 9 0.7b [0.9] 0.6

–0.8 [0.7

–1.0]

Resin manufacture (USA) 1983

–

Plant no. 1, summer 24 3.4b [4.2] 0.2

–13.2 [0.3

–16.2]

Plant no. 6, summerc 6 0.2b [0.3] 0.1

–0.2 [0.1

–0.3]

Plant no. 7, summer 9 0.2b [0.3] 0.1

–0.3 [0.1

–0.4]

Plant no. 7, winter 9 0.6b [0.7] 0.4

–0.9 [0.5

–1.1]

Plant no. 8, summerc,d 13 0.4b [0.7] 0.2

–0.8 [0.3

–1.0]

Plant no. 8, winterc,d 9 0.1b [0.1] 0.1

–0.2 [0.1

–0.3]

Plant no. 9, summerc,d 8 14.2b [17.5] 4.1

–30.5 [5.0

–37.5]

Plant no. 9, winter 9 1.7b [2.1] 1.1

–2.5 [1.4

–3.1]

Plant no. 10, summerd 23 0.7b [0.9] 0.3

–1.2 [0.4

–1.5]

Chemical factory producing formaldehyde

and formaldehyde resins (Sweden)

62 0.2 [0.3] 0.04

–0.4 [0.05

–0.5] 1979

–

Resin plant (Finland) 

Furan resin production 3 2.3 [2.9] 1.0

–3.4 [1.3

–4.2] 1982

Maintenance 4 2.9 [3.6] 1.4

–5.5 [1.8

–6.9] 1981

Urea–formaldehyde resin production 7 0.7 [0.9] 0.6

–0.8 [0.7

–1.1] 1981

NR, not reporteda Arithmetic mean unless otherwise specifiedb Mean and range of geometric meansSome of the results were affected by the simultaneous occurrence in the samples (Stewart et al., 1987) of: c phenol (leading to low values) d particulates that contained nascent formaldehyde (leading to high values).
No measurements of exposure to formaldehyde in other chemical plants where it is

used, e.g. in the production of pentaerythritol, hexamethylenetetramine or ethylene glycol,

were available to the Working Group.

(b) Histopathology and disinfection in hospitals 

Formalin is commonly used to preserve tissue samples in histopathology laboratories.

Concentrations of formaldehyde are sometimes high, e.g. during tissue disposal, preparation of formalin and changing of tissue processor solutions (Belanger & Kilburn, 1981).

The usual mean concentration during exposure is approximately 0.5 ppm [0.6 mg/m3].

Other agents to which pathologists and histology technicians may be exposed include

xylene (see IARC, 1989a), toluene (see IARC, 1989b), chloroform (see IARC, 1987c) and

methyl methacrylate (see IARC, 1994a) (Belanger & Kilburn, 1981). Concentrations of

airborne formaldehyde in histopathology laboratories and during disinfection in hospitals

are presented in Table 7.

Levels of formaldehyde were measured in 10 histology laboratories using area

samplers for 1–4 h for a study of neurobehavioural and respiratory symptoms. Concentrations of formaldehyde in areas where tissue specimens were prepared and sampled were

0.25–2.3 mg/m3 (Kilburn et al., 1985). In two studies in Israel, pathology staff were divided

into two groups: those who had low exposure (mean, 0.5 mg/m3), which included laboratory assistants and technicians, and those who had high exposure (mean, 2.8 mg/m3),

which included physicians and hospital orderlies, based on 15-min samples (Shaham et al.,

2002, 2003). Another study by the same group [it is not clear whether these are the same

data or not] reported 15-min area measurements of 1.7–2.0 mg/m3 and personal measurements of 3.4–3.8 mg/m3 during exposure (Shaham et al., 1996a,b). 

Formaldehyde has also been used extensively in hospitals for disinfection (IARC,

1995; see Table 7).

(c) Embalming and anatomy laboratories 

Formaldehyde is used as a tissue preservative and disinfectant in embalming fluids

(Table 7). Some parts of bodies that are to be embalmed are also cauterized and sealed

with a hardening compound that contains paraformaldehyde powder. The concentration of

formaldehyde in the air during embalming depends on its content in the embalming fluid,

the type of body, ventilation and work practices; mean levels are approximately 1 ppm

[1.2 mg/m3]. Embalming of a normal intact body usually takes approximately 1 h. Disinfectant sprays are occasionally used, and these may release small amounts of solvent, such

as isopropanol (Williams et al., 1984). Methanol is used as a stabilizer in embalming

fluids, and concentrations of 0.5–22 ppm [0.7–28.4 mg/m3] have been measured during

embalming. Low levels of phenol have also been detected in embalming rooms (Stewart

et al., 1992).

Skisak (1983) measured levels of formaldehyde in the breathing zone at dissecting

tables and in the ambient air in a medical school in the USA for 12 weeks. Concentrations

of > 1.2 mg/m3 formaldehyde were found in 44% of the breathing zone samples and

52 IARC MONOGRAPHS VOLUME 88
Table 7. Concentrations of formaldehyde in the workroom air of mortuaries, hospitals anIndustry and operation (location)

Type of sample 

No. of measurements 

Meana

(ppm [mg/m3]) 

Range (ppm [mg/m3]) Ye

Histopathology laboratories Pathology laboratory (Sweden) 13 0.5 [0.7] NR 198Histology laboratory, tissue specimen  preparation and sampling (USA) 

NR NR 0.2–1.9 [0.25–2.3] NR 

Pathology laboratories (Germany) 21 0.5b [0.6] < 0.01–1.2 [< 0.01–1.6] 198Hospital laboratories (Finland) 80 0.5 [0.6] 0.01–7.3 [0.01–9.1] 198Histology laboratory (Israel)  Area samples  Personal samples 

NR NR 

NR NR 

1.4–1.6 [1.7–2.0] 2.8–3.1 [3.4–3.8] 

NR 

Teaching laboratory (USA) 16 0.3 [0.4] NR Pathology laboratories (Turkey) 10 NR max., < 2 [< 2.5] NR Histology laboratory (Israel)  Laboratory assistants/technicians (15 min)  Physicians and orderlies (15 min) 

NR 

0.4 [0.5] 2.2 [2.8] 

0.04–0.7 [0.05–0.9] 0.7–5.6 [0.9–7.0] 

NR 

Disinfection in hospitals Cleaning hospital floors with detergent  containing formaldehyde (Italy)  Personal samples (38–74 min) 

 4 0.18 [0.22] 0.15–0.21 [0.18–0.26] NR 

Disinfection of dialysis clinic (USA)  Personal samples (37–63 min) 

 7 0.6 [0.8] 0.09–1.8 [0.12–2.2] 198

Disinfecting operating theatres (Germany) 43 0.4c [0.5] 0.04–1.4 [0.05–1.7] NR Bedrooms in hospital (Germany) 14 0.05 [0.06] < 0.01–0.7 [< 0.01–0.9] 198Disinfecting operating theatres (Germany)d  3% cleaning solution 43 0.8 [1.1] 0.01–5.1 [0.01–6.3] 

NR 

 0.5 % cleaning solution 26 0.2 [0.2] 0.01–0.4 [0.01–0.5] Disinfection in hospitals (Finland) 18 0.1 [0.1] 0.03–0.2 [0.04–0.3] 198
Table 7 (contd) Industry and operation (location) Type of sample No. of measurements Meana (ppm [mg/m3]) Range (ppm [mg/m3]) YeaEmbalming Embalming, six funeral homes (USA) NR 0.7 [0.9] 0.09–5.3 [0.1–6.5] NR Autopsy service (USA)d Personal samples 27 1.3c [1.7] 0.4–3.3 [0.5–4.0] NR 

Area samples 23 4.2 [5] 0.1–13.6 [0.1–16.7] Museum, taxidermy (Sweden) 8 0.2 [0.3] NR 198

Embalming, seven funeral homes Intact bodies (personal samples) Autopsied bodies (personal samples) 8 15 0.3 [0.4] 0.9 [1.1] 0.18–0.3 [0.2–0.4] 0–2.1 [0–2.6] 198Embalming, 23 mortuaries (USA) 8-h TWA NR 1.1 [1.4] 0.2 [0.2] 0.03–3.2 [0.04–3.9] 0.01–0.5 [0.01–0.6] NR Autopsy (Finland) 5 0.7 [0.8] < 0.1–1.4 [< 0.1–1.7] 198Embalming (USA) Personal samples Area 1 Area 2 25 25 25 2.6 [3.2] 2.0 [3.0] 2.2 [2.7] 0.3–8.7 [0.4–10.7] 0.2–7.5 [0.3–9.2] 0.3–8.2 [0.3–10.0] NR Embalming (Canada) Intact bodies (personal samples)  Autopsied bodies (personal samples)  Area samples 

24 24 72 

0.6 [0.8] 0.6 [0.8] 0.5 [0.6] 

0.1–4.6 [0.1–5.6] 0.09–3.3 [0.1–4.1] 0.04–6.8 [0.05–8.4] 

NR 

Funeral home, embalming (USA)  Area samples  Personal samples 

 4  4 

NR 0.16 [0.19] 

< 0.1–0.15 [< 0.1–0.19] NR 

NR 

Anatomy laboratories Anatomy laboratory, dissecting (USA)  Personal samples 

54 NR 0.3–2.6 [0.4–3.2] NR 
Table 7 (contd)Industry and operation (location) Type of sample 

No. of measurements 

Meana

(ppm [mg/m3]) 

Range (ppm [mg/m3]) Ye

Anatomy laboratory, dissecting (USA)  Laboratory  Stock room  Public hallway 

NR NR NR 

NR NR NR 

7–16.5 [8.6–20.3] 2.0–2.6 [2.4–3.2] max., < 1 [< 1.2] 

198

Anatomical theatre (Germany) 29 1.1b [1.4] 0.7–1.7 [0.9–2.2] 198Anatomy laboratory, dissecting (USA)  Personal samples (1.2–3.1 h)  Personal samples (TWA)  Area samples (2.5 min)  Area samples (TWA) 

32 NR 13  2 

1.2 [1.5] 0.4 [0.5] 1.4 [1.7] 1.7 [2.0] 

0.07–2.9 [0.09–3.6] 0.09–0.95 [0.11–1.17] 0.9–1.8 [1.1–2.2] 1.0–2.3 [1.2–2.8] 

NR 

Anatomy laboratory, dissecting (USA)  Personal samples  Area samples 

44 76 

1.9 [2.3] 1.0 [1.2] 

0.3–4.5 [0.4–5.5] 0.6–1.7 [0.7–2.1] 

NR 

Anatomy laboratory, dissecting (China) 25 0.4 [0.5] 0.06–1.04 [0.07–1.28] NR Anatomy laboratory, dissecting (China) NR 2.4 [2.9] NR NR Anatomy/histology laboratory, dissecting 48 3.0 [3.7] 0.2–9.1 [0.2–11.2] NR Anatomy laboratory, dissecting (Austria)  Two locations in a room over 4 weeks 

NR NR 

0.22 [0.27] 0.12 [0.15] 

0.11–0.33 [0.13–0.41] 0.06–0.22 [0.07–0.27] 

NR NR 

Anatomy laboratory, dissecting (Turkey) NR NR max., < 4 [< 5] NR Anatomy laboratory, dissecting (USA) 15 0.9 [1.1] 0.3–2.6 [0.3–3.1] NR Biology laboratory, dissecting (Canada)  Laboratory 1  Laboratory 2 

18 18 

0.20 [0.25] 0.51 [0.63] 

0.08–0.62 [0.11–0.76] 0.3–1.2 [0.3–1.5] 

NR 

Anatomy laboratory, dissecting (Japan) NR NR 0.11–0.62 [0.14–0.76] NR NR, not reported; TWA, time-weighted average a Arithmetic means unless otherwise specified b Median c Mean of arithmetic means d 8-h TWA 
11 ambient air samples; the levels in breathing zone samples were in the range of

0.4–3.2 mg/m3, and 50% of the samples contained 0.7–1.2 mg/m3.

Korky et al. (1987) studied the dissecting facilities at a university in the USA during

the 1982–83 academic year. Airborne concentrations of formaldehyde were 7–16.5 ppm

[8.6–20.3 mg/m3] in the laboratory, 1.97–2.62 ppm [2.4–3.2 mg/m3] in the stockroom and

< 1 ppm [< 1.2 mg/m3] in the public hallway. 

Concentrations of formaldehyde in the breathing zone of two embalmers in the USA

were measured during the embalming of an autopsied body, which generally results in

higher exposures than that of non-autopsied bodies. The average was 0.19 mg/m3 [duration of measurement not provided] (Korczynski, 1996). 

Samples (1–2-h) taken in an anatomy/histology laboratory in the Republic of Korea

for a cross-sectional study of serum antibodies showed concentrations of formaldehyde

that ranged from 0.19 to 11.25 mg/m3 with a mean of 3.74 mg/m3 (Kim et al., 1999). 

In a cross-sectional study of immunoglobulin (Ig)E sensitization in Austria, concentrations of formaldehyde were measured in two locations in a dissection room for the full

period that students were present. The mean level was 0.15 mg/m3 (Wantke et al., 1996a,b).

The windows were open and the ventilation was working continuously. In a second study in

the same laboratories, medical students were exposed to an average indoor concentration of

0.27 mg/m3 formaldehyde (Wantke et al., 2000).

Levels of formaldehyde measured in anatomy laboratories in China for a cytogenetic

study averaged 0.51 mg/m3 over a 3-h period; the peak occurred while cadavers were being

dissected (Ying et al., 1997, 1999). 

A cross-sectional study on the cytogenetic effects of formaldehyde on anatomy students

in China found personal exposures of 2.92 mg/m3 (He et al., 1998). 

In a study of respiratory function, 34 personal samples and short-term area samples were

collected in a gross anatomy laboratory in the USA. The mean concentration of formaldehyde in the room was 1.53 mg/m3 during the 1.2–3.1-h dissecting period. The direct-reading

short-term area samples (2.5-min) averaged 1.68 mg/m3. Eight-hour time-weighted average

(TWA) personal exposures ranged from 0.11 to 1.17 mg/m3, with a mean of 0.52 mg/m3

(96% of subjects were exposed to levels of formaldehyde above the 0.38 mg/m3 ceiling, and

the 8-h TWA exposure of 3% of them was above 0.94 mg/m3) (Akbar-Khanzadeh et al.,

1994). A subsequent study of respiratory function was conducted in the same laboratory

because, among other reasons, the concentration of formaldehyde in the embalming solution

was increased. The mean concentration of formaldehyde in the personal samples was

2.31 mg/m3 (duration, 2.5 h) (Akbar-Khanzadeh & Mlynek, 1997). In the same laboratory,

area measurements were taken in the centre of and at various locations in the room over a

16-week period; each measurement lasted for the time the students were active during a

session (3–4 h per day). The average concentration in the centre of the room was 1.13 mg/m3

(15 measurements) (Keil et al., 2001). Breathing zone concentrations were expected to be

higher because of the proximity of the students to the cadaver during dissection. Although

the room had mechanical air supply and exhaust systems, the ventilation system served the

entire building and intake air was contaminated with formaldehyde.

56 IARC MONOGRAPHS VOLUME 88
The concentration of formaldehyde in the air in pathology and anatomy laboratories

in Turkey did not exceed 2 and 4 mg/m3, respectively [no other information available],

when measured in a study of cytogenetic responses (Burgaz et al., 2001).

In a study of two biological laboratories in Canada where dissection of animal specimens was performed, 3-h personal samples showed mean concentrations of 0.25 mg/m3

and 0.63 mg/m3 formaldehyde, respectively (Dufresne et al., 2002). The first laboratory

had a general mechanical ventilation system, whereas the second had no ventilation

system. 

Measurements in an anatomy class in Japan rose to 0.76 mg/m3 after 10 min of class;

30 min later, the formaldehyde concentration had decreased to 0.14 mg/m3 (Tanaka et al.,

2003). 

(d) Manufacture of wood products and paper

Exposure to formaldehyde may occur in several sectors of the wood-related industries

because of the use of formaldehyde-based resins. Table 8 summarizes the concentrations

of formaldehyde observed in the wood product and pulp and paper industries. 

Exposure to formaldehyde is typically monitored by measuring its gaseous form; slight

additional exposure may occur through the inhalation of formaldehyde bound to wood

dust, although this was considered to be negligible in one study (Gosselin et al., 2003). For

example, at a plant in the USA that constructed products made of particle-board, measurements were taken for 4.5 h at the sawing operation. A back-up impinger was positioned

behind an inhalable dust sampler or a closed-face cassette to capture both dust-bound and

gaseous formaldehyde. Levels of formaldehyde gas behind the inhalable dust sampler averaged [132 μg/m3 (standard deviation [SD], 14 μg/m3; four samples)] and those of bound

formaldehyde from inhalable dust averaged [11 μg/m3 (SD, 4 μg/m3; 12 samples)]. Respective measurements for the closed cassettes averaged [147 μg/m3 (SD, 9 μg/m3; four

samples)] and [8 μg/m3 (SD, 2 μg/m3; 12 samples)] (Kennedy et al., 1992). 

(i) Veneer and plywood mills

Plywood consists of three or more veneers glued together or a core of solid wood

strips or particle-board with veneered top and bottom surfaces. The dried panels may also

be patched or spliced by applying a liquid formaldehyde-based adhesive to the edges,

pressing the edges together and applying heat to cure the resin. To produce panels,

veneers are roller- or spray-coated with formaldehyde-based resins, then placed between

unglued veneers. The plywood industry has used formaldehyde-based glues in assembling

of plywood for over 50 years. Before the introduction of formaldehyde-based resins in the

1940s, soya bean and blood–albumen adhesives were used, and cold pressing of panels

was common. Exposure to formaldehyde from resins may occur among workers during

the preparation of glue, during splicing, patching, sanding and hot-pressing operations

and among nearby workers. Urea-based resins release formaldehyde more readily during

curing than phenol-based resins; however, improvements in the formulation of resins

have reduced exposures.

FORMALDEHYDE 57
Table 8. Concentrations of formaldehyde in the workroom air of plywood milfurniture factories, other wood product plants, paper mills and the construction indusIndustry and operation (location) Type of sample No. of measurements Meana (ppm [mg/m3]) Range (ppm [mg/m3]) Year Plywood mills Plywood production (Sweden) 47 0.3 [0.4] NR 1980s Plywood mills (Finland) Glue preparation, short-term 15 2.2 [2.7] 0.6

–5.0 [0.7

–6.2] 1965

–

Glue preparation, short-term 19 0.7 [0.9] 0.1

–2.3 [0.1

–2.8] 1975

–

Assembling 32 1.5 [1.9] < 0.1

–4.4 [< 0.1

–5.4] 1965

–

Assembling 55 0.6 [0.7] 0.02

–6.8 [0.03

–8.3] 1975

–

Hot pressing 41 2.0 [2.5] < 0.1

–7.7 [< 0.1

–9.5] 1965

–

Hot pressing 43 0.5 [0.6] 0.06

–2.1 [0.07

–2.6] 1975

–

Sawing of plywood 5 0.5 [0.6] 0.3

–0.8 [0.4

–1.0] 1965

–

Sawing of plywood 12 0.1 [0.1] 0.02

–0.2 [0.03

–0.3] 1975

–

Coating of plywood 7 1.0 [1.2] 0.5

–1.8 [0.6

–2.2] 1965

–

Coating of plywood 28 0.3 [0.4] 0.02

–0.6 [0.03

–0.7] 1975

–

Plywood panelling manufacture (USA)

Plant no. 3, winterPlant no. 3, summer

2726

0.2b [0.3]0.1b [0.1]

0.08

–0.4 [1.0

–0.5]

0.01

–0.5 [0.01

–0.6]

1983

–

Plywood mill (Indonesia) 40 0.6 [0.8] 0.2

–2.3 [0.3

–2.8] NR 

Plywood factory (Italy)

Warehouse 3 0.3 [0.4] 0.1

–0.5 [0.2

–0.6]

NR 

Shearing press 8 0.08 [0.1] 0.06

–0.11 [0.08

–0.14]

Plywood mill (Finland)

Personal samples

1996

–

Patching 6 0.06 [0.07] 0.02

–0.08 [0.03

–0.10]

Feeding of drying machine 6 0.05 [0.06] 0.01

–0.12 [0.01

–0.15]

Forklift driving 6 0.06 [0.07] 0.02

–0.16 [0.02

–0.20]

Scaring 6 0.11 [0.14] 0.06

–0.20 [0.07

–0.24]

Assembly (machine I) 4 0.24 [0.30] 0.08

–0.66 [0.10

–0.81]

Assembly (machine II) 6 0.12 [0.15] 0.08

–0.22 [0.10

–0.27]

Hot pressing (machine I) 5 0.11 [0.13] 0.07

–0.19 [0.08

–0.23]
Table 8 (contd)Industry and operation (location)

Type of sample

No. of measurements

Meana(ppm [mg/m3])

Range (ppm [mg/m3]) Year 

Glue preparation 2 0.12 [0.15] 0.06–0.19 [0.07–0.23]Finishing (puttying) 4 0.07 [0.09] 0.06–0.11 [0.07–0.14]Carrying plywood piles 2 0.05 [0.06] 0.04–0.06 [0.05–0.07]Finishing (sanding) 2 0.04 [0.05] 0.01–0.06 [0.01–0.07]

Plywood mill (New Zealand) [2000] 

Dryers 14 0.06b [0.07] GSD, [3.2]Composers 2 0.02b [0.03] GSD, [1.0]Pressing 5 0.13b [0.16] GSD, [2.7]Finishing end 1 0.03b [0.04] NA

Particle- and other board millsParticle-board production (Sweden) 21 0.3 [0.4] NR 1980s Medium-density fibre board (Sweden) 19 0.2 [0.3] NR 1980s Particle-board mills (Finland)

Glue preparation 10 2.2 [2.7] 0.3–4.9 [0.4–6.0] 1975–Blending 10 1.0 [1.2] 0.1–2.0 [0.1–2.5] 1965–Blending 8 0.7 [0.9] < 0.1–1.4 [< 0.1–1.7] 1975–Forming 26 1.7 [2.1] < 0.5–4.6 [< 0.6–5.7] 1965–Forming 32 1.4 [1.7] 0.1–4.8 [0.1–5.9] 1975–Hot pressing 35 3.4 [4.2] 1.1–9.5 [1.4–11.7] 1965–Hot pressing 61 1.7 [2.1] 0.2–4.6 [0.25–5.7] 1975–Sawing 17 4.8 [5.9] 0.7–9.2 [0.9–11.3] 1965–Sawing 36 1.0 [1.2] < 0.1–3.3 [< 0.1–4.1] 1975–Coating 7 1.0 [1.2] 0.5–1.8 [0.6–2.2] 1965–Coating 12 0.4 [0.5] 0.1–1.2 [0.1–1.5] 1975–

Chip-board production (Germany) 24 1.5 [1.9] < 0.01–8.4 [< 0.01–10] 1980–Particle-board mill (Indonesia) 9 2.4 [3.0] 1.2–3.5 [1.5–4.3] NR Block-board mill (Indonesia) 6 0.5 [0.6] 0.4–0.6 [0.5–0.7] NR 
Table 8 (contd) Industry and operation (location) Type of sample No. of measurements Meana (ppm [mg/m3]) Range (ppm [mg/m3]) Year Oriented strand board plant (Canada) 1990s 

Debarking 5 ≤ 0.05 [0.06] NR Pre-heat conveyor 5 ≤ 0.05 [0.06] NR Post-heat press conveyor 5 ≤ 0.05 [0.06] NR Packaging/storage 5 ≤ 0.05 [0.06] NR Fibreboard, sawing and sanding (United Kingdom) 1990s 

Standard MDF (Caberwood) Gaseous form Extracted from dust 56 0.06 [0.07] 0.08 [0.10] 0.04–0.07 [0.05–0.09] 0.06–0.11 [0.07–0.13] Moisture resistant (Medite MR) Gaseous form Extracted from dust 56 0.05 [0.06] 0.10 [0.13] 0.01–0.10 [0.01–0.12] 0.04–0.14 [0.05–0.17] Zero added formaldehyde (Medite ZF) Gaseous form Extracted from dust 66 0.04 [0.04] 0.03 [0.04] 0.02–0.06 [0.03–0.07] 0.02–0.06 [0.03–0.07] Medite exterior grade (Medex) Gaseous form Extracted from dust 66 0.03 [0.04] 0.04 [0.05] 0.01–0.07 [0.01–0.08] 0.04–0.06 [0.05–0.07]

Furniture factoriesFurniture factories (Sweden)

Varnishing with acid-cured varnishes 32 0.7 [0.9] NR

1980s 

Furniture factories (Finland)

Feeding painting machine 14 1.1 [1.4] 0.3–2.7 [0.4–3.3] 1975–Spray painting 60 1.0 [1.2] 0.2–4.0 [0.3–5.0]Spray painting assistance 10 1.0 [1.2] 0.2–1.6 [0.3–2.0]Curtain painting 18 1.1 [1.4] 0.2–6.1 [0.3–7.5]Before drying of varnished furniture 34 1.5 [1.8] 0.1–4.2 [0.1–5.2]After drying of varnished furniture 14 1.4 [1.7] 0.2–5.4 [0.3–6.6]
Table 8 (contd)Industry and operation (location)

Type of sample

No. of measurements

Meana(ppm [mg/m3])

Range (ppm [mg/m3]) Year 

Cabinet-making (Canada) 48 NR max., < 0.1 [< 0.1] NR Furniture factories, surface finishing with

acid curing paints (Sweden)

NR 

Paint mixer/supervisor 6 0.2 [0.3] 0.1–0.4 [0.2–0.5]Mixed duties on the line 5 0.4 [0.5] 0.3–0.5 [0.3–0.6]Assistant painters 3 0.5 [0.6] 0.2–0.7 [0.2–0.9]Spray painters 10 0.4 [0.5] 0.1–1.1 [0.2–1.3]Feeder/receiver 13 0.2 [0.3] 0.1–0.8 [0.1–0.9]

Furniture factories (Finland)

Glueing 73 0.3 [0.4] 0.07–1.0 [0.09–1.2]

1981–

Machining in finishing department 9 0.3 [0.4] 0.1–0.9 [0.1–1.1]Varnishing 150 1.1 [1.4] 0.1–6.3 [0.1–7.9]

Manufacture of furniture (Denmark)

Painting 43 0.16 [0.20]b GSD, [2.25]

NR 

Glueing 68 0.12 [0.15]b GSD, [2.87]

Wood-working shops (Egypt) 1990s

Ventilated workshop 14 0.42 [0.52] 0.28–0.54 [0.34–0.66]Unventilated workshop 14 0.64 [0.79] 0.48–0.84 [0.59–1.03]

Other wood product plantsGlueing in wood industry (Sweden) 65 0.2 [0.3] NR 1980s Parquet plant (Finland)

Machining 3 0.3 [0.4] 0.16–0.5 [0.2–0.6]

1981 

Varnishing 5 0.8 [1.0] 0.2–1.4 [0.3–1.7]

Production of wooden structures (Finland) 1981–

Glueing 36 0.7 [0.8] 0.07–1.8 [0.1–2.2]Machining 19 0.4 [0.4] 0.1–0.8 [0.1–0.9]

Manufacture of wooden bars (Finland) 1983 

Glueing 33 0.6 [0.7] 0.2–1.9 [0.2–2.4]Machining 7 1.2 [1.5] 0.2–2.2 [0.3–2.7]
Table 8 (contd) Industry and operation (location) Type of sample No. of measurements Meana (ppm [mg/m3]) Range (ppm [mg/m3]) Year Match mill, impregnation of matchbox parts (Finland) Short-term 2 2.0 [2.5] 1.9–2.1 [2.3–2.6] 1963 Wooden container mill, glueing and sawing (Finland) 6 0.3 [0.4] 0.2–0.4 [0.3–0.5] 1961 Paper mills Laminated paper production (Sweden) 23 0.3 [0.4] NR 1980s Manufacture of offset paper (Sweden) 8 0.2 [0.2] NR 1980s Lamination and impregnation of paper with melamine and phenol resins (USA) Plant no. 6, summerc,d 53 0.7b [0.9] < 0.01–7.4 [< 0.01–9.1] 1983 

Plant no. 6, winterd 39 0.3b [0.4] 0.05–0.7 [0.06–0.9] Paper mill (Finland) Coating of paper 30 0.7 [0.9] 0.4–31 [0.5–39] 1975–8

Gum paper production 4 0.4 [0.5] 0.3–0.6 [0.3–0.8] Impregnation of paper with amino resin 6 3.1 [3.9] 0.5–13 [0.6–16] Impregnation of paper with phenol resin 20 0.1 [0.1] 0.05–0.3 [0.06–0.4] Paper mill (Finland)Glueing, hardening, lamination and

rolling of special paper

12 0.9 [1.1] 0.3–2.5 [0.4–3.1] 1971–7

Impregnation of paper with phenol resin,

partly short-term

38 7.4 [9.1] < 1.0–33.0 [< 1.1–40.6] 1968–6

Paper storage, diesel truck traffic 5 0.3 [0.4] 0.2–0.4 [0.25–0.5] 1969

Pulp and paper industries (12 countries) 1950–9

Pulping, refining of stock (8 mills) 25 0.5 [0.6] 0–3.1 [0–3.8]Newsprint and uncoated paper machine

(2 mills)

7 0.15 [0.18] 0.04–0.46 [0.05–0.57]

Fine and coated paper machine (6 mills) 51 1.1 [1.4] 0.01–9.9 [0.01–12.2]
Table 8 (contd)Industry and operation (location)

Type of sample

No. of measurements

Meana(ppm [mg/m3])

Range (ppm [mg/m3]) Year 

Paperboard machine (1 mill) 8 0.5 [0.6] 0.2–2.2 [0.2–2.7]Paper/paperboard machine from more

than one of above categories (24 mills)

228 0.4 [0.5] 0–6.6 [0–8.1]

Calendering or on-machine coating

(10 mills)

166 4.2 [5.2] 0–50 [0–61.5]

Winding, cutting and grading (17 mills) 111 0.2 [0.3] 0–1.1 [0–1.4]

Recycled paper industry (12 countries)

Re-pulping of waste paper (2 mills) 8 0.2 [0.3] 0.05–0.4 [0.06–0.5]

Construction industryInsulating buildings with urea–formaldehyde

foam (Sweden)

6 0.1 [0.2] NR 1980s 

Insulating buildings with urea–formaldehyde

foam (USA)

66 1.3e [1.6] 0.3–3.1 [0.4–3.8] NR 

Varnishing parquet with urea–formaldehyde

varnish (Finland)

10 2.9 [3.6] 0.3–6.6 [0.4–8.1] 1976 

Varnishing parquet with urea–formaldehyde

varnish (Finland)

6 4.3 [5.3] 2.6–6.1 [3.2–7.5] 1987 

Sawing particle-board at construction site

(Finland)

5 < 0.5 [< 0.6] NR 1967 

GSD, geometric standard deviation; NA, not applicable; NR, not reporteda Arithmetic mean unless otherwise specifiedb Geometric meanSome of the results in the Stewart et al. (1987) study were affected by the simultaneous occurrence in the sampc phenol (leading to low values)d particulates that contained nascent formaldehyde (leading to high values).e Mean of arithmetic means
Recent studies conducted in these industries in Finland and New Zealand (Mäkinen

et al., 1999; Fransman et al., 2003) found mean concentrations of formaldehyde to be less

than 0.5 mg/m3. In contrast, mean levels of 2 ppm [2.5 mg/m3] have been observed historically in some operations in the Finnish industry (Kauppinen, 1986).

(ii) Manufactured board mills

Both phenol–formaldehyde and urea–formaldehyde resins are used in mills that

produce particle- and other manufactured boards, including oriented strand boards and

medium-density fibre boards. Phenolic resins are more liable to be used for panels that are

destined for applications that require durability under adverse conditions, while ureabased resins are used for less demanding, interior applications. Melamine–formaldehyde

resins may also be used to increase durability, but rarely are because they are more expensive. Exposure to formaldehyde and other resin constituents is possible during the mixing

of glues, the laying of mat and hot-pressing operations.

Herbert et al. (1995) and Chung et al. (2000) found levels of formaldehyde below

0.2 mg/m3 in recent studies in Canada and the United Kingdom, respectively, in oriented

strand-board and fibre-board plants. Mean exposures greater than 1 ppm [1.2 mg/m3] have

been observed in the past in particle- and chip-board mills (Kauppinen & Niemelä, 1985;

Triebig et al., 1989; Malaka & Kodama, 1990). 

(iii) Furniture factories

Furniture varnishes may contain acid-cured urea–formaldehyde resins dissolved in

organic solvents. In Finland, workers were exposed to an average level of about 1 ppm

[1.23 mg/m3] formaldehyde in most facilities (Priha et al., 1986; Heikkilä et al., 1991). 

In a recent study in wood-working shops in Egypt, the levels of formaldehyde were

found to average 0.42 and 0.64 ppm [0.52 and 0.79 mg/m3] in ventilated and unventilated

workplaces, respectively (Abdel Hameed et al., 2000). [The origin of the formaldehyde

was not stated.]

(iv) Paper mills

Some paper mills produce special products that are coated with formaldehyde-based

phenol, urea or melamine resins. Coating agents and other chemicals used in paper mills

may also contain formaldehyde as a bactericide.

As part of an IARC international epidemiological study of workers in the pulp and

paper industry, measurements were carried out in the production departments of paper and

paperboard mills and recycling plants in 12 countries. The highest exposures were

observed during calendering or on-machine coating (Korhonen et al., 2004). 

(e) Building and construction industry 

Exposure to formaldehyde may also occur in the construction industry (Table 8).

Specialized construction workers who varnish wooden parquet floors may have relatively

high exposure. The mean levels of formaldehyde in the air during varnishing with urea–

formaldehyde varnishes ranged between 2 and 5 ppm [2.5–6.2 mg/m3]. One coat of varnish

64 IARC MONOGRAPHS VOLUME 88
takes only about 30 min to apply (Riala & Riihimäki, 1991), but the same worker may

apply five or even 10 coats per day. Other chemical agents to which parquetry workers are

usually exposed include wood dust from sanding (see IARC, 1995) and solvent vapours

from varnishes, putties and adhesives. Operations that may have resulted in exposure to

formaldehyde in the building trades are insulation with urea–formaldehyde foam and

machining of particle-board, but these have now largely been discontinued. Various levels

of formaldehyde have been measured during insulation with urea–formaldehyde foam, but

exposure during handling and sawing of particle-board seems to be consistently low.

Formaldehyde may be released when synthetic vitreous fibre-based insulation is applied to

hot surfaces, i.e. high-temperature insulation in power plants, due to decomposition of the

phenol–formaldehyde binder at temperatures > 150 °C (International Labour Office, 2001)

(see also under (f)).

(f) Manufacture of textiles and garments 

The use of formaldehyde-based resins to produce crease-resistant fabrics began in the

1950s. The early resins contained substantial amounts of extractable formaldehyde: over

0.4% by weight of fabric. The introduction of dimethyloldihydroxyethyleneurea resins in

1970 reduced the levels of free formaldehyde in fabrics to 0.15–0.2%. Since then,

methylation of dimethyloldihydroxyethyleneurea and other modifications of the resin have

decreased the level of formaldehyde gradually to 0.01–0.02% (Elliott et al., 1987). Some

flame-retardants contain agents that release formaldehyde (Heikkilä et al., 1991). The

cutting and sewing of fabrics release low levels of textile dust, and small amounts of chlorinated organic solvents are used to clean spots. Pattern copying machines may emit

ammonia and dimethylthiourea in some plants (Elliott et al., 1987). Finishing workers in

textile mills may also be exposed to textile dyes, flame-retardants, carrier agents, textilefinishing agents and solvents (see IARC, 1990b).

Measurements of formaldehyde in the air of textile mills are summarized in Table 9.

In the late 1970s and 1980s, levels of formaldehyde in the garment industry averaged

0.2–2 ppm [0.25–2.5 mg/m3]. However, exposures in the past were generally higher,

probably because of the higher content of free formaldehyde in fabrics. For example, the

concentrations of formaldehyde were reported to have been 0.9–2.7 ppm [1.1–3.3 mg/m3]

in a post-cure garment manufacturing plant and 0.3–2.7 ppm [0.4–3.3 mg/m3] in eight

other garment manufacturing plants in the USA in 1966 (Elliott et al., 1987). Goldstein

(1973) reported that concentrations of formaldehyde in cutting rooms decreased from over

10 ppm [12 mg/m3] in 1968 to less than 2 ppm [2.4 mg/m3] in 1973 as a result of improvements in the processes of resin treatment. The mean formaldehyde concentration in air

increased from 0.1 to 1.0 ppm [0.12 to 1.23 mg/m3] in a study in the USA when the

formaldehyde content of the fabric increased from 0.015 to 0.04% (Luker & Van Houten,

1990). Measurements from the late 1980s onwards indicate lower levels, usually averaging

0.1–0.2 ppm [0.12–0.25 mg/m3]. 

Full-shift personal (for 5.7–6.4 h; eight samples) and area (for 6.3–7.3 h; 12 samples)

measurements were taken at a pre-cured permanent-press garment manufacturing plant in

FORMALDEHYDE 65
Table 9. Concentrations of formaldehyde in the workroom air of textile mills and garmIndustry and operation (location) Type of sample No. of measurements Meana (ppm [mg/m3]) Range or SD in ppm [mg/m3

]

Textile millsTextile plants (Finland)

Finishing department, mixing 8 0.8 [1.1] < 0.2

–>5 [< 0.2

–> 6]

Crease-resistant treatment 52 0.4 [0.5] < 0.2

–>3 [< 0.2

–> 4]

Finishing department (excluding creaseresistant and flame-retardant treatment) 17 0.3 [0.4] max., 1.3 [1.5]Flame-retardant treatment 67 1.9 [2.5] < 0.2

–>10 [< 0.2

–> 11]

Fabric store 6 0.8 [1.1] 0.1

–1.3 [0.1

–1.6]

Textile mills (Sweden)

Crease-resistant treatment 29 0.2 [0.2] NRFlame-retardant treatment 2 1.2 [1.5] NR

Garment factoriesManufacture from crease-resistant cloth (USA) 181 NR < 0.1

–0.9 [< 0.1

–1.1] 

Manufacture of shirts from fabric treated with

formaldehyde-based resins (USA)

326 ~0.2 [~0.25] < 0.1

–0.4 [< 0.1

–0.5] 

Garment industry (Finland)

Handling of leather 3 0.1 [0.1] 0.02

–0.1 [0.03

–0.1]

Pressing 32 0.2 [0.3] 0.02

–0.7 [0.03

–0.9]

Sewing 15 0.1 [0.1] 0.02

–0.3 [0.03

–0.3]

Sewing plant (USA)

Processing of 0.04% formaldehyde fabricProcessing of 0.015% formaldehyde fabric 

99

1.0 [1.2]0.1 [0.1]

0.5

–1.1 [0.6

–1.4]

< 0.1

–0.2 [< 0.1

–0.3]

Garment manufacturing (USA)

Sewers, cutters and bundlers

Personal samples

8-h TWA

Area samples

8-h TWA

8888

0.21 [0.26]0.16 [0.19]0.24 [0.30]0.21 [0.26]

0.18

–0.23 [0.22

–0.28]

0.14

–0.17 [0.17

–0.21]

0.17

–0.30 [0.21

–0.37]

0.16

–0.25 [0.20

–0.31]
Table 9 (contd)Industry and operation (location)

Type of sample

No. ofmeasurements

Meana(ppm [mg/m3])

Range or SD in ppm [mg/m3]

Cut and spread

Formaldehyde gas (inhalable dust) 6 0.03 SD, 0.01Bound formaldehyde (inhalable dust) 6 < 0.01 SD, < 0.01Formaldehyde gas (total dust) 6 0.04 SD, 0.01Bound formaldehyde (total dust) 6 < 0.01b SD, < 0.01

Turn and ticket

Formaldehyde gas (inhalable dust) 6 < 0.01 SD, < 0.01Bound formaldehyde (inhalable dust) 6 < 0.01 SD, < 0.01Formaldehyde gas (total dust) 6 0.03 SD, 0.01Bound formaldehyde (total dust) 6 < 0.01 SD, < 0.01

Retail dress shops (USA) NR NR 0.1–0.5 [0.1–0.6] Fabric shops (Finland) 3 0.17 [0.21] 0.12–0.24 [0.15–0.30] Fabric stores (USA)

24-h area samples

Independent storesChain stores

773344

0.14 [0.17]0.10 [0.13]0.19 [0.24]

0.03–0.28 [0.04–0.34]0.03–0.28 [0.04–0.34]0.09–0.27 [0.11–0.33]

NR, not reported; SD, standard deviationa Arithmetic meanb Five samples with non-detectable levels
the USA. Levels of exposure to formaldehyde for sewers, cutters and bundlers ranged from

0.22 to 0.28 mg/m3 (8-h TWA, 0.17–0.21 mg/m3). Area measurements of formaldehyde at

cutting, sewing, pressing, spreading and receiving (storage) locations ranged from 0.21 to

0.37 mg/m3 (8-h TWA; 0.20–0.31 mg/m3). Full-shift (for 5.8–6.4 h; eight samples) personal measurements of formaldehyde in inhalable dust showed levels of up to 29 μg/mg

dust; settled dust samples showed concentrations of 0.7 and 0.8 μg/mg dust (Echt & Burr,

1997). In another garment production facility in the USA, formaldehyde gas and formaldehyde bound to dust were detected at levels of 26–36 μg/m3 and 0.2–0.7 μg/m3, respectively

(Kennedy et al., 1992).

The use of formaldehyde-based resin to finish textiles and some garments may also

result in exposure in retail shops. Measurements in dress shops in the USA in the 1950s

showed levels up to 0.5 ppm [0.62 mg/m3] (Elliott et al., 1987). The air in three Finnish

fabric shops in the 1980s contained 0.15–0.3 mg/m3 formaldehyde (Priha et al., 1988). In

fabric stores in the USA that were monitored by placing samplers on a shelf in the store

for 24 h, the average concentration of formaldehyde was 0.17 mg/m3 (McGuire et al.,

1992). 

(g) Foundries 

Formaldehyde-based resins are commonly used as core binders in foundries (Table 10).

Urea–formaldehyde resin is usually blended with oleoresin or phenol–formaldehyde resin

and mixed with sand to form a core, which is then cured by baking in an oven or by heating

from inside the core box (hot-box method). The original hot-box binder was a mixture of

urea–formaldehyde resin and furfuryl alcohol (commonly referred to as furan resin). Furan

resins were then modified with phenol to produce urea–formaldehyde/furfuryl alcohol,

phenol–formaldehyde/furfuryl alcohol and phenol–formaldehyde/urea–formaldehyde

resins.

The mean concentrations of formaldehyde measured during core-making and operations following core-making in the 1980s in Sweden and Finland were usually below

1 ppm [1.2 mg/m3]; however, measurements made before 1975 suggest that past exposures may have been considerably higher (Heikkilä et al., 1991). Many other chemicals

occur in foundries, e.g. silica (see IARC, 1987d) and other mineral dusts, polycyclic aromatic hydrocarbons (see IARC, 1983), asbestos (see IARC, 1987e), metal fumes and

dusts, carbon monoxide, isocyanates (see IARC, 1986), phenols (see IARC, 1989c),

organic solvents and amines (see IARC, 1999). These exposures have been described in a

previous monograph (IARC, 1984).

(h) Synthetic vitreous fibre production

Formaldehyde resins are commonly used to bind man-made vitreous fibre products.

Measurements of formaldehyde in the air of plants manufacturing synthetic vitreous fibres

are summarized in Table 10. 

Measurements in glasswool and stonewool plants in the 1980s showed mean concentrations of 0.1–0.2 ppm [0.12–0.25 mg/m3] formaldehyde. Very high levels were measured

68 IARC MONOGRAPHS VOLUME 88
Table 10. Concentrations of formaldehyde in the workroom air of foundries and durisynthetic vitreous fibres and plastics Industry and operation (location)  Type of sample 

No. of measurements 

Meana

(ppm [mg/m3]) 

Range (ppm [mg/m3]) Ye

Foundries Foundry (Sweden)  Hot-box method 5 1.5 [1.9] NR 

198

 Moulding 17 0.1 [0.1] NR Foundries (Sweden)  Moulders and core-maker handling furan  resin sand  8-h TWA 

36 0.1 [0.1] 0.02–0.22 [0.02–0.27] NR 

Foundries (Finland)  Core-making 43 2.8 [3.4] < 0.1–> 10 [< 0.1–> 11] 

Be

 Core-making 17 0.3 [0.4] 0.02–1.4 [0.03–1.8] 198 Casting 10 0.2 [0.2] 0.02–0.2 [0.03–0.8] 198 Moulding 25 0.3 [0.4] 0.04–2.0 [0.05–2.5] 198Synthetic vitreous fibre plants(Sweden)  Production 16 0.15 [0.19] NR 

198

 Form pressing 4 0.16 [0.20] NR (Finland)  Production  Form pressing 

36 24 

0.20 [0.25] 0.09 [0.11] 

0.02–1.5 [0.03–1.7] 0.01–0.3 [0.01–0.4] 

198

Fibrous glass manufacturing plant (USA) NR  Fixed location workers (n = 17) 97 0.07; 0.05b GSD, 4.0  Forming attendant (n = 2) 11 0.07; 0.03b GSD, 8.2  Forming attendant leader (n = 3) 18 0.09; 0.07b GSD, 1.9  Binder water leader (n = 1) 4 0.05; 0.01b GSD, 10.9  Binder water operator (n = 1) 6 0.06; 0.05b GSD, 2.1  Pipefitter (n = 1) 5 0.05; 0.05b GSD, 1.4  Forehearth operator (n = 6) 35 0.07; 0.05b GSD, 4.4  Curing oven machine operator (n = 3) 18 0.08; 0.07b GSD, 1.7 
Table 10 (contd) Industry and operation (location) Type of sample No. of measurements Meana (ppm [mg/m3]) Range (ppm [mg/m3]) Ye

Mobile workers (n = 20) < 100 0.03; 0.02b GSD, 3.1 Crew (packaging) (n = 2) 12 0.02; 0.01b GSD, 4.1 Washwater tender (n = 1) 3 0.04; 0.04b GSD, 1.5 Mechanical repair (n = 7) 35 0.02; 0.01b GSD, 3.4 Electrician (n = 5) 25 0.03; 0.02b GSD, 3.1 Sheet metal worker (n = 2) 10 0.03; 0.02b GSD, 2.7 Welder (n = 2) 10 0.04; 0.03b GSD, 2.6 Pipefitter (n = 1) 5 0.03; 0.02b GSD, 1.9 Plastics production Production of moulded plastic products (USA) Plant no. 8, phenol resin, summer Plant no. 9, melamine resin, summer 10 13 0.5b [0.6] 9.2b [11.3] 0.1–0.9 [0.1–1.1] < 0.01–26.5 [< 0.01–32.6] 19

Moulding compound manufacture (USA) Plant no. 9, winter 9 2.8b [3.4] 0.04–6.7 [0.05–8.2] Plant no. 9, summerc 18 38.2b [47.0] 9.5–60.8 [11.7–74.8] Plant no. 1, winter 12 1.5b [1.8] 0.9–2.0 [1.1–2.1] Plant no. 1, summer 24 9.7b [11.9] 3.8–14.4 [4.7–17.7] Plant no. 8, winter 13 0.3b [0.4] 0.07–0.7 [0.09–0.9] Plant no. 7, summer 43 0.3b [0.4] 0.05–0.6 [0.06–0.8] Plant no. 2, summer 15 6.5b [8.0] 0.3–20.6 [0.4–25.3] Plastics production (Finland)  Casting of polyacetal resin 10 0.3 [0.4] 0.06–0.7 [0.08–0.8] 

19

 Casting of urea–formaldehyde resin 4 0.4 [0.5] 0.2–0.5 [0.3–0.6]  Casting of other plastics 29 < 0.1 [< 0.1] < 0.1–0.2 [< 0.1–0.3] Plastics manufacturing (Canada)  Polyethylene extrusion 9 NR max., [< 0.12] NR GSD, geometric standard deviation; NR, not reported; TWA, time-weighted average a Arithmetic mean unless otherwise specified b Geometric mean c Some of the results were affected by the simultaneous occurrence in the samples of particulates that contained 

values). 
occasionally in factories close to cupola ovens and hardening chambers (Heikkilä et al.,

1991). Other exposures in man-made vitreous fibre production have been described in a

previous monograph (IARC, 2002).

Personal measurements of maintenance and production workers were taken in a

fibreglass insulation manufacturing plant. The average level of exposure to formaldehyde

for all fixed location workers (basement workers, forehearth operators and curing oven

operators; 17 samples) was 0.07 mg/m3. The mean of the measurements for all mobile

workers (packaging crew, washwater tender, mechanical repairer, electrician, sheet metal

workers, welder and pipefitter; 20 samples) was 0.03 mg/m3. No measurement was below

the limit of detection (Milton et al., 1996). 

(i) Plastics production

Formaldehyde-based plastics are used in the production of electrical parts, dishware

and various other plastic products (Table 10).

The concentrations of formaldehyde measured in such industries have usually been

< 1 ppm [1.2 mg/m3], but much higher exposures may occur. Plastic dust and fumes may

be present in the atmospheres of moulded plastic product plants, and exposures in these

facilities are usually considerably higher than those in facilities where the products are

used. The mean concentration of formaldehyde was > 1 ppm in many plants in the USA

where moulding compounds were used. Some workers may have been exposed to

pigments, lubricants and fillers (e.g. historically, asbestos and wood flour) that were used

as constituents of moulding compounds (Stewart et al., 1987).

An experimental scenario was created in Canada to evaluate thermal decomposition

products that are emitted from the extrusion of polyethylene into a variety of products.

Eight-hour area samples, collected at worst-case locations at typical operator locations,

and 8-h personal samples were collected. All levels of formaldehyde were below

0.12 mg/m3 (Tikuisis et al., 1995). 

(j) Firefighters

Measurements of the exposure of firefighters to formaldehyde are given in Table 11.

One study measured personal exposures to formaldehyde outside a self-contained

breathing apparatus (if worn) while fighting fires in two cities in the USA. Formaldehyde

was detected in six of 24 samples. Concentrations ranged from 0.1 to 8.3 ppm

[0.12–10.2 mg/m3], with a second highest concentration of 3.3 ppm [4.1 mg/m3] (BrandtRauf et al., 1988). In another study in the USA, levels of formaldehyde ranged from the

limit of detection (0.13 mg/m3) to 9.8 mg/m3 during knockdown (when the main body of

the fire is brought under control), and formaldehyde was detected in 73% of the samples,

from the limit of detection to 0.5 mg/m3, during overhaul (searching for and extinguishing

hidden fires) for 22 fires (Jankovic et al., 1991). Exposure levels inside the self-contained

breathing masks ranged from the limit of detection to 0.4 mg/m3. Two of the

measurements during knockdown exceeded the 15-min short-term exposure limit (STEL)

of 2.5 mg/m3. 

FORMALDEHYDE 71
Table 11. Concentrations of formaldehyde during firefighting and exposure to engine Industry and operation (location) Type of sample No. of measurements Meana (ppm [mg/m3]) Range (ppm [mg/m3]) Year Firefighting City fire (USA) 24 0.55 [0.68]b 0.1

–8.3 [0.1

–10.2]b 1986 

City fire (USA) 22 fires NR 

Knockdownc NR ND

–8 [ND

–9.8]

Overhaulc NR ND

–0.4 [ND

–0.5]

Inside mask NR ND

–0.3 [ND

–0.4]

Wildland fire (USA) 5 0.05 [0.06] 0.02

–0.07 [0.02

–0.09] 1990 

Wildland fire (USA) 30 0.13 [0.16] 0.04

–0.3 [0.05

–0.4] 1989 

City fire (USA) 96 0.25 [0.31] 0.02

–1.2 [0.02

–1.5] 1998 

Engine exhaustChain-sawing (Sweden) NR 0.05 [0.06] 0.02

–0.11 [0.03

–0.13] NR 

Chain-sawing (Finland)

8-h TWA

NR < 0.1 [< 0.1] < 0.1

–0.5 [< 0.1

–0.6] NR 

Automobile garage

Personal samples

53 0.03 [0.04] NR NR 

ND, not detected; NR, not reported; TWA, time-weighted average a Arithmetic meanb Excluding 18 values noted as 0 c See text for definitions
A comprehensive study that monitored air was conducted to characterize exposures

of firefighters during 25 structure fires. Exposures of firefighters during overhaul, when

they look for hidden fire inside attics, ceilings and walls often without respiratory protection, were measured. Ceiling values for formaldehyde (National Institute for Occupational Safety and Health [NIOSH]; 0.1 ppm [0.12 mg/m3]) were exceeded at 22 fires

(Bolstad-Johnson et al., 2000).

Limited studies of exposure to aldehydes that is related to forest and wildland fires

indicate lower exposures. Formaldehyde was detected in all 30 samples collected during

a study of wildland fires. Concentrations ranged from 0.048 to 0.42 mg/m3; the mean was

0.16 mg/m3 (Materna et al., 1992). A smaller study by NIOSH also detected formaldehyde in each of five samples collected during wildfire. Concentrations ranged from

0.02 to 0.07 ppm [0.02–0.09 mg/m3] and the mean was 0.05 ppm [0.06 mg/m3] (Reh

et al., 1994).

(k) Automobile and engine exhausts

Engine exhausts are a source of exposure to formaldehyde (see Section 1.3.3;

Table 11).

Maître et al. (2002) evaluated individual airborne exposures to gaseous and particulate

pollutants of a group of policemen who worked close to traffic in the centre of Grenoble,

France. Personal active air samples were collected during the workshifts of eight policemen

in summer and winter during the occurrence of a thermal inversion phenomenon for 4 days

at each period. Stationary air samples were taken in the policemen’s work area during the

same period. The median concentration of the personal samples for formaldehyde was

14 μg/m3 in the summer and 21 μg/m3 in the winter.

Zhang et al. (2003) examined whether work in an automobile garage and tobacco

smoke can significantly affect personal exposure to a number of important carbonyl compounds, including formaldehyde. The study was carried out on 22 garage workers (nine

smokers and 13 nonsmokers) and 15 non-garage workers (four smokers and 11 nonsmokers). Daily exposure was estimated using 48-h integrated measurements of breathing

zone concentrations. The mean formaldehyde concentrations were: 40.6 μg/m3 for smoking

garage workers, 41.1 μg/m3 for nonsmoking garage workers, 34.6 μg/m3 for smoking nongarage workers and 30.2 μg/m3 for nonsmoking non-garage workers (total range,

14.1–80.1 μg/m3). 

(l) Offices and public buildings

Concentrations of formaldehyde in offices and public buildings (museums, geriatric

homes) are given in Table 12.

In Australia, measurements of formaldehyde over 3–4 days were found to average

0.03 mg/m3 in conventional offices and 1.4 mg/m3 in portable office buildings (Dingle

et al., 2000).

Exposure measurements were taken for an epidemiological study of nasal symptoms

in a Swedish office building that had recently been painted with low-emitting products [the

FORMALDEHYDE 73
Table 12. Concentrations of formaldehyde in offices and miscellaneous other workplaces Industry and operation (location) Type of sample No. of measurements Mean (ppm [mg/m3])a Range (ppm [mg/m3])a Offices Offices (USA) 25 80.0b μg/m3 NR Non-industrial office workplaces and restaurants

(Brazil) 

12 20.4 μg/m3 4.7

–60.7 μg/m3 

Four offices on several floors of an office

building (Brazil)

11 40 μg/m3 12.2

–99.7 μg/m3 

Offices (Sweden)

Recently painted with low-emitting paintThree months laterControl (at the time and 3 months later)

NRNRNR

18 μg/m38 μg/m38 μg/m3

16

–20 μg/m3

7–10 μg/m38–9 μg/m3

Offices (Australia)

Conventional offices (18 sites)Portable office buildings (20 sites)

NR40

27 μg/m31400 μg/m3

12

–96 μg/m3

516

–2595 μg/m3

Six office buildings (USA) [72] 1.7

–13.3 μg/m3 c NR 

Five office buildings (Taiwan, China)

8-h average during working time frommeasurements conducted continuously ≥ 24 h 

54 140

–1190 μg/m3 d NR 

MiscellaneousCoal coking plant (former Czechoslovakia) NR 0.05e [0.06] < 0.01

–0.25 [< 0.01

–0.3] 

Pitch coking plant (former Czechoslovakia) NR 0.4e [0.5] 0.05

–1.6 [0.07

–2.0] 

Electrical machinery manufacture (Finland)

Soldering 47 < 0.1 [< 0.1] NRLacquering and treatment of melamine plastics 8 0.35 [0.4] NR

Rubber processing (USA) NR NR 0.4

–0.8 [0.5

–0.98] 

Painting with bake-drying paints (Sweden) 13 < 0.1 [< 0.1] NR Abrasive production (Sweden) 20 0.2 [0.3] NR 
Table 12 (contd)Industry and operation (location)

Type of sample

No. ofmeasurements

Mean(ppm [mg/m3])a

Range (ppm [mg/m3])a 

Sugar mill (Sweden)

Preservation of sugar beets 26 0.4 [0.5] NR

Fur processing

8-h TWA

16 NR 0.8–1.6 [1.0–2.0] 

Photographic film manufacture (USA)

Plants no. 4 and 5, summer 49 0.1e [0.1] < 0.01–0.4 [< 0.01–0.5]Plants no. 4 and 5, winter 29 0.3e [0.4] 0.02–0.9 [0.03–1.1]

Agriculture (Finland)

Handling of fodder NR NR 0.02–0.4 [0.03–0.5] Disinfection of eggs 11 2.6 [3.2] 0.2–7.8 [0.3–9.6] 

Metalware plant, bake painting (Finland) 18 0.3 [0.4] 0.03–0.7 [0.04–0.9] Print (Finland)

Development of photographs 11 0.04 [0.05] 0.02–0.1 [0.03–0.13]

Malt barley production (Finland)

Preservation of malt barley 6 0.7 [0.9] 0.4–1.5 [0.5–1.8]

Photographic laboratories (Finland) 10 0.07 [0.09] 0.02–0.3 [0.03–0.40] Fish hatchery (USA)

Treating fish eggs (6 sites)

8-h TWA

6 0.02 [0.02] 0.006–0.038 [0.007–0.05]

NR, not reported; TWA, time-weighted averagea Arithmetic mean unless otherwise specified; values in ppm [mg/m3], unless stated otherwiseb Medianc Range of geometric meansd Range of arithmetic meanse Mean of arithmetic means
recency was not identified but appeared to be within a few months]. The measurements

taken at that time showed average levels of formaldehyde of 18 μg/m3 (range, 16–

20 μg/m3); those taken 3 months later averaged 8 μg/m3 (range, 7–10 μg/m3) (Wieslander

et al., 1999a). The latter were equivalent to the levels found in the same office complex in

an area that had not been redecorated (mean, 8–9 μg/m3).

Laser-jet printers have been found to be a source of formaldehyde, as a result of the

ozonolysis reactions of volatile organic compounds emitted from the toner powder (Wolkoff

et al., 1992; Tuomi et al., 2000). In a study in an office environment in Finland (Tuomi et al.,

2000), the emission rate of formaldehyde of three printers that used traditional coronadischarge technology (dating from approximately 1990) ranged from 9 to 46 μg/m3,

whereas a newer technology printer did not produce detectable levels of formaldehyde.

In another study in Sweden, average levels of formaldehyde in four geriatric homes

ranged from 2 to 7 μg/m3 (Wieslander et al., 1999b). 

(m) Miscellaneous

Formaldehyde is used in agriculture as a preservative for fodder and as a disinfectant

(Table 12). For example, fodder was preserved with a 2% formalin solution several times

per year from the late 1960s until the early 1980s on farms in Finland. As the air concentration during preservation was < 0.5 ppm [0.6 mg/m3], the annual mean exposure was

probably very low. Formaldehyde gas is also used 5–10 times a year to disinfect eggs in

brooding houses. The concentration of formaldehyde in front of the disinfection chamber

immediately after disinfection was as high as 7–8 ppm [8.6–9.8 mg/m3], but annual exposure from this source probably remains very low (Heikkilä et al., 1991).

One worker in each of six different fish hatcheries in the USA was monitored once

over the 15–90-min period it took to treat fish eggs with a formalin solution to control

infection. Concentrations ranged from not quantifiable to 1 mg/m3. Area measurements

during treatment were < 0.062–0.84 mg/m3, and 8-h TWAs were reported to be < 0.01–

0.05 mg/m3 (mean, 0.02 mg/m3) (Lee & Radtke, 1998). 

Formaldehyde is also used or formed during many other industrial operations, such as

treatment of fur and leather, preservation of barley and sugar beets, coal and pitch coking,

rubber processing and production of abrasives (Table 12). Some of these activities may

entail heavy exposure. For example, treatment of furs with formaldehyde resulted in the

highest exposure to formaldehyde of all jobs and industries studied in a large Swedish

survey in the early 1980s. The 8-h TWA concentration of formaldehyde was assessed to

be 0.8–1.6 ppm [1.0–2.0 mg/m3] and high peak exposures occurred many times per day

(Rosén et al., 1984).

Heating of bake-drying paints and soldering may release some formaldehyde in plants

where metalware and electrical equipment are produced, but the measured concentrations

are usually well below 1 ppm [1.2 mg/m3] (Rosén et al., 1984).

The mean concentrations of formaldehyde measured during the coating of photographic

films and during development of photographs are usually well below 1 ppm [1.2 mg/m3]

76 IARC MONOGRAPHS VOLUME 88
(Table 12). Methanol, ethanol, acetone and ammonia are other volatile agents that may

occur in film manufacturing facilities (Stewart et al., 1987). 

Formaldehyde has been found consistently in spacecraft atmospheres at concentrations that exceed the 180-day spacecraft maximum allowable concentration of

0.05 mg/m3. The source is thought to be hardware off-gassing and possibly leakage from

experiments that involve fixatives. Small amounts could also be present from human

metabolism and exhalation (James, 1997).

1.3.3 Ambient (outdoor) air

Measurements of indoor and outdoor levels of formaldehyde have been generated in

many countries for several decades. Standard sampling and analytical methodologies are

sufficiently sensitive to detect formaldehyde in most samples of ambient (outdoor) air.

Concentrations of formaldehyde in urban, suburban and rural areas are presented in

Table 13.

Although formaldehyde is a natural component of ambient air, anthropogenic sources

usually contribute most to the levels of formaldehyde in populated regions, since ambient

levels are generally < 1 μg/m3 in remote areas. For example, in the unpopulated Eniwetok

Atoll in the Pacific Ocean, a mean of 0.5 μg/m3 and a maximum of 1.0 μg/m3 formaldehyde

were measured in outdoor air (Preuss et al., 1985). Other authors have reported similar

levels in remote, unpopulated areas (De Serves, 1994; IARC, 1995; Environment Canada/

Health Canada, 2001). 

Outdoor air concentrations of formaldehyde in urban environments are more variable

and depend on local conditions. They are usually in the range of 1–20 μg/m3 (Preuss et al.,

1985; IARC, 1995; Jurvelin, 2001). Urban air concentrations in heavy traffic or during

severe inversions can range up to 100 μg/m3 (Báez et al., 1995; IARC, 1995; Williams

et al., 1996; de Andrade et al., 1998). 

A major source of formaldehyde in urban air is incomplete combustion of hydrocarbon

fuels, especially from vehicle emissions (Vaught, 1991; Pohanish, 2002). Combustion

processes account directly or indirectly for most of the formaldehyde that enters the

atmosphere, particularly from engines that are not equipped with catalytic converters

(WHO, 1989; Pohanish, 2002). In the USA, emissions of formaldehyde from automobiles

were estimated to be about 277 million kg each year just prior to the introduction of the

catalytic converter in 1975 (Environmental Protection Agency, 1976) and to have decreased

since (Zweidinger et al., 1988). In Mexico, a comparison of exhaust emissions from lightduty vehicles in the early 1990s showed a 10–30-fold decrease in emissions of

formaldehyde from vehicles that were equipped with a catalytic converter compared with

those with no catalyst (Schifter et al., 2001). In contrast, emissions of formaldehyde from

automobile exhaust have been reported to have risen again with the introduction of oxygenated fuels (Kirchstetter et al., 1996). Gaffney et al. (1997) found that, in Albuquerque (NM,

USA), the introduction of oxygenated fuels was associated with higher ambient air levels of

formaldehyde during the winter, the season during which these fuels were used. Levels of

FORMALDEHYDE 77
Table 13. Occurrence of formaldehyde in outdoor (ambient) air Country Location/region Settings Sampling period No. of samples Mean concen- tration or range of means (μg/m3)a Range (μg/m3)a Comments Algeria Algiers Ouargla Algiers Urban Urban Suburban 2000–01 10 4 14 12.7 4.0 11.9 5.2–27.1 2.6–5.2 6.0–21.2 Austria Exelberg Raasdorf Schoeneben Semi-rural Semi-rural Rural 1986–87 21 18 20 6.4–13.4 ppb 6.6–11.1 ppb 4.0–8.9 ppb NR NR NR Measured in July 

Measured in July Measured in Sep

Brazil São Paulo and Rio de Janeiro Urban 1993 12 10.7 4.0–27.7 Measured outsid

industrial office wand restaurants 

Salvador, Bahia Urban NR 68 2.9–80 ppb 1.3–88 ppb Collected at six s

city 

Rio de Janeiro Rural Urban 1995 37 11 1.2–1.5 ppb 14.5 ppb 0.2–4.6 ppb 7.1–21.0 ppb Collected at two 

area Measured outsidbuilding 

São Paulo Urban 1999 37 16.4–18.0 ppb 10.7–13.1 ppb 9.8–10.7 ppb 1.1–46.3 ppb 1.2–28.3 ppb 2.7–38.1 ppb Collected in wint

Morning Midday Evening 

São Paulo Urban 1997 11 5.0 ppb 1.4–9.7 ppb Measured in Feb

use of alcohol fu

Theobroma Rural 1995 15 12.8 ppb 

daytime, 16.5 ppb nighttime, 8.6 ppb 

5–25 ppb Measured during 

open agricultural cultural biomass 

Rio de Janeiro Urban 2000 13 10.8 NR Collected from M

November during commute 

Rio de Janeiro Urban 1998–2001 28 13.7 ppb 1.5–54.3 ppb Measured on a h

street in the dow
Table 13 (contd) Country Location/region Settings Sampling 

period 

No. of samples 

Mean concentration or range of means (μg/m3)a

Range (μg/m3)a

Comments 

Canada Ontario Rural 1988 49 

 47 

1.6 ppb 1.8 ppb 

0.6–4.4 ppb 0.7–4.2 ppb 

Dorset site Egbert site 

Alert, Nunavut Remote 1992 NR 0.48 

NR 

0.04–0.74 0.12–0.86 

Polar night Sunlit period 

Nova Scotia Remote 1993 108 NR < 0.6–4.2 Summer measureSix provinces Various 1989–98 NR 

 NR  NR 

NR NR NR 

ND–27.5 ND–12.0 ND–9.9 

Measured at eighMeasured at two Measured at six r

Rural 1995–96 

Spring Summer Winter 

 NR NR 

max., 3.0 max., 1.7 max., 4.4 

Near a forest pro

Prince Rupert, BC 

Urban, residential, and industrial areas 

1994–95 96 0.7–3.9 0.08–14.7 Collected from th

sites 

Various Urban and 

suburban 

1990–98 2819 3.3 (2.8)b Four urban and f

sites from the NaPollution Survey 
Table 13 (contd) Country Location/region Settings Sampling period No. of samples Mean concen- tration or range of means (μg/m3)a Range (μg/m3)a Comments China Hong Kong Urban 1997–2000 182 3.6–4.2 4.8–5.1 0.6–10 1.9–11 Residential and c

Residential, comlight industrial 

Hong Kong Urban 1999–2000 41 4.1 5.9 2.6 1.0–11.3 NR NR Overall average (

Summer average Winter average (February) 

Guangzhou Urban 2002 25 12.4 6.4–29.0 Measured outsid

evening on 7 con

Denmark Copenhagen Urban 1994 37 2.6 ppb 0.2–6.4 ppb Winter measurem

(February) 

Lille Valby Semi-rural 18 28 0.9 ppb 0.8 ppb 0.1–2.8 ppb 0.3–1.8 ppb Winter measurem

(February) Spring measurem

Lille Valby Semi-rural 1995 244 1.2 ppb 0.1–4.7 ppb Measured in May

Egypt Cairo Urban 1999 98 

 49  49 

33 ppb 29 ppb 37 ppb 

SD, 8.6 SD, 7.1 SD, 9.5 

Residential area  Spring  Summer 

France Grenoble Urban 1995 NR NR 2–18 ppb Measured during 

May 

Paris Urban and 

semi-urban 

1985 NR 2–32 ppb NR Measured at one 

three rural sites wurban influence 
Table 13 (contd) Country Location/region Settings Sampling 

period 

No. of samples 

Mean concentration or range of means (μg/m3)a

Range (μg/m3)a

Comments 

Germany Mainz-Finthen Semi-rural 1979 14 1.9 ppb 0.7–5.1 ppb Measured during 

Deuselbach Rural 14 1.7 ppb 0.4–3.8 ppb Measured during The Alps Rural 1991 NR 1.3 ppb 0.4–3.3 ppb Measurement at 

Wank mountain i

Schauinsland Rural 1992 22 1.0 ppb 0.4–2.3 ppb Measured continu

11 days 

Hungary Budapest Urban 1987–89 185 14.9 ppb 

34.6 ppb 

ND–58 ppb 7–176 ppb 

Measured at dowMeasured at the bdowntown with a emission source 

Italy Rome Urban 1994–95 56 

 57 

17.0 ppb 11.2 ppb 

8.8–27.7 ppb 8.2–17.0 ppb 

Measured in sumMeasured in win

Milan Urban 1998–99 NR NR 

5.9 8.0–15.7 

4.1–53.4 NR NR 

Winter measuremRural-industrial (Urban (five sites) 

Japan Takasaki Urban 1984 38 NR 2.5–11.4 ppb Measured during 

August 

Osaka Urban 1997 NR 1.9 ppb 0.1–4.3 ppb Measured in Octo

December 

Nagoya NR 1998 37 5.8c GSD, 1.5 Measured in Feb

Lithuania Kaunas NR 1998 NR 3.1 1.4–5.3 Measured at 12 m

monitoring sites 

Mexico Mexico City Urban 1993 48 35.5 ppb 5.9–110 ppb Measured at the U

Mexico campus 

Mexico City and Xalapa 

Urban 1996–98 145d 4–32 2–63 Measured outside 

three museums a
Table 13 (contd) Country Location/region Settings Sampling period No. of samples Mean concen- tration or range of means (μg/m3)a Range (μg/m3)a Comments Norway Drammen Urban 1994–97 1998–2000 974 973 8.9 2.9 NR NR Reduction of me

attributed to incrvehicles with cat

South Africa Cape Point Semi-rural 1979 5 0.5 ppb 0.2–1.0 ppb Measured during Spain Madrid Urban 1996 NR 9.0 4.7–20 Air sampling in S

October from 8 h 

Sweden Uppsala Urban 1998 27 1.3c GSD, 1.8 Measured in Feb

near 22 houses anapartments 

Taiwan, China Taipei Urban 1999 NR 7.2–9.8 ppb range of max., 20.6– 34.8 ppb Measured from F

at five locations 

United Kingdom London Urban 1991–92 9 7 19.2 ppb 7.4 ppb ND–98 ppb 0.8–13.5 ppb West London, re

North London, re

USA Country-wide Various 1975–85 629 8.3 ppb (4.1 ppb)b NR All sites combine

Urban 332 6.5 ppbb NR Suburban 281 2.7 ppbb NR Rural 12 2.7 ppbvb NR 

Atlanta, GA Urban 1992 217 2.7–3.0 ppb max., 8.3 ppb Measured at four 

during July and A

Albany, NY Semi-urban 1991 NR NR 0.6–3.7 ppb Measured during Boston, MA Residential 1993 8 

 18 

3.1 ppb 2.6 ppb 

0–3.1 ppb 1.2–5.9 ppb 

Winter measuremfour residences Summer measurenine residences 
Table 13 (contd) Country Location/region Settings Sampling 

period 

No. of samples 

Mean concentration or range of means (μg/m3)a

Range (μg/m3)a

Comments 

USA (contd) 

Denver, CO Urban 1987–91 NR 3.9 ppb 

2.3 ppb 2.7 ppb 

NR NR NR 

Measured in winMeasured in spriMeasured in sum

Los Angeles, CA 

Urban Rural 

1993 32 5.3 ppb 

0.8 ppb 

1.4–10.6 ppb 0.7–1.0 ppb 

Measured during season (SeptembBackground loca

Eniwetok Atoll Remote 1980 7 0.4 ppb max., 0.8 ppb South Pacific Minnesota Mixed 1991–99 2494 1.7 (1.37)b < 0.05–21 Collected at 25 s

the state for varytime 

New York City, NY 

Urban 1999 36 

 36 

2.1 5.3 

Winter measuremSummer measur

Los Angeles County, CA 

Semi-urban 1999–2000 69 7.2 ppb 4.3–14.0 ppb 

California Urban 1990–2002 NR 2.0–4.3 NR Range of annual 

GSD, geometric standard deviation; NR, not reported; SD, standard deviation a Unless otherwise specified b Median c Geometric mean d Number of indoor and outdoor measurements combined (see Table 14) e Includes urban, suburban, rural, remote and source-dominated sources. f Data collected from literature searches, direct contacts with individuals and organisations, reports, computer tapes and direct electron
formaldehyde in vehicle emissions in 1994 were found to increase by 13% within 2 months

after the average oxygen content of fuels sold in the San Francisco Bay (CA, USA) area

increased from 0.3 to 2.0% by weight (Kirchstetter et al., 1996). In the Denver (CO, USA)

area, use of oxygenated fuels was associated with a 20–75% increase in ambient air levels

of formaldehyde, although nearly all ambient air measurements remained below 6 μg/m3

(Spitzer, 1997). Local air concentrations as high as 35.4, 41.8 and 44.2 μg/m3 have been

reported inside vehicles, in parking garages and at service stations, respectively (Spitzer,

1997).

Formaldehyde was detected (detection limit, 0.05 μg/m3) in 3810 of 3842 24-h

samples from rural, suburban and urban areas in Canada that were collected at 16 sites in

six provinces surveyed from August 1989 to August 1998 (Environment Canada, 1999,

cited in Environment Canada/Health Canada, 2001). Concentrations ranged from below

the detection limit to a maximum of 27.5 μg/m3 for eight urban sites, a maximum of

12.03 μg/m3 for two suburban sites and a maximum of 9.88 μg/m3 for six rural sites.

Long-term (1 month–1 year) mean concentrations for the rural sites ranged from 0.78 to

8.76 μg/m3. Monthly mean concentrations were highest during the summer, but there was

no apparent long-term trend in concentrations of formaldehyde at these sites over this 9-

year period (Environment Canada/Health Canada, 2001).

In addition to primary emissions of formaldehyde in vehicle exhaust, secondary

formation of formaldehyde by oxidation of alkenes in the atmosphere is also an important

source (Altshuller, 1993; Seila et al., 2001). Patterns of diurnal and seasonal variation in

levels of formaldehyde and formaldehyde:acetaldehyde ratios have led to the suggestion

that natural sources of alkenes add significantly to anthropogenic emissions, particularly

during the summer months (Gaffney et al., 1997; Viskari et al., 2000). Photo-oxidation is

also a primary degradation pathway for formaldehyde in the atmosphere, with an estimated half-life in the range of a few hours (ATSDR, 1999).

1.3.4 Residential indoor air

The occurrence of formaldehyde in indoor air in private housing and public settings

is summarized in Table 14.

Levels of formaldehyde in indoor air are often higher by one order of magnitude or

more than those outdoors. The concentrations in dwellings depend on the sources of

formaldehyde that are present, the age of the source materials, ventilation, temperature and

humidity. Indoor sources include pressed wood products (e.g. plywood, particle-board),

some insulation materials, carpets, paints and varnishes, clothing and fabrics, cooking,

tobacco smoke and the use of formaldehyde as a disinfectant (Gammage & Gupta, 1984;

IARC, 1995; Dingle et al., 2000; Hodgson et al., 2000, 2002; Jurvelin, 2003). Off-gassing

of urea–formaldehyde foam insulation and particle-board has been reported historically to

be a major source of formaldehyde in some dwellings.

In a study on indoor emissions of formaldehyde, quasi steady-state emission rates of

formaldehyde from new carpets were measured in a large-scale environmental chamber

84 IARC MONOGRAPHS VOLUME 88
Table 14. Occurrence of formaldehyde in indoor air in residential and public settingsCountry Location/

region

Sampling period

No. of samples

Mean concentration or range of means (μg/m3)a

Range(μg/m3)a

Comments 

ResidentialAustralia Victoria 1994–95 NR 12.6 ppbb

13.8 ppbb11.3 ppbb11.4 ppbb

< 0.3–105< 0.3–108< 0.3–108

Eighty householdsBedroomLiving-roomKitchen

Austria Burgenland, 

Carinthia and Styria

1988–89 234

apartments

< 30–100 ppb100–500 ppb> 500 ppb

Measured in 33% of the apartmMeasured in 48% of the apartmMeasured in 19% of the apartm

Canada Quebec City, 

QC

NR 28

3

34

6

7.39.28.29.9

max., 20.2max., 19.7max., 23.4max., 19.5

Basement, with combustion apBasement, without combustion Ground floor, with combustion Ground floor, without combust

Various 1989–95 151 35.9 (29.8b) NR Pooled data from five studies a

locations

Egypt Cairo 1999 294

147147

89 ppb100 ppb100 ppb87.6 ppb105.6 ppb

35–192 ppb30–213 ppb28–225 ppbNRNR

Seven apartmentsKitchenBedroomLiving roomMeasured in springMeasured in summer

France Paris 2001

616161

21.7c24.2c24.5c

NRNRNR

Sixty-one dwellings in Paris anKitchenLiving roomBedroom

Hungary 1998 123 17.5 0.6–56.7 Homes in six medium-sized cit
Table 14 (contd) Country Location/ region Sampling period No. of samples Mean concen- tration or range of means (μg/m3)a Range (μg/m3)a Comments Japan Country-wide 1998–2001 1642 120 (95.7b) max., 979 From 1422 homes distributed t

country 

NR 2000 171 110 ppb 120 ppb 20–872 ppb 11–840 ppb Rooms from 81 houses Active DNPH method Detector tube method Niigata Prefecture 1999 104 NR 0–740 Data from figure; 29% greater 

100 μg/m3 

Nagoya 1998 37 17.6c max., 73 Dwelling factors and airborne 

were also compared 

Mexico Mexico City and Xalapa 1996–98 50d 37–47 12–81 Measured in two houses Sweden Uppsala 1998 27 8.3c max., 19 Dwelling factors and airborne 

were also compared 

United Kingdom London 1991–92 1740 15.0 ppb 3.4 ppb ND–93.1 ppb ND–10.3 ppb West London, residential area North London, residential area USA San Francisco Bay Area, 

CA

1984 48

45

41 ppb36 ppb

NRNR

KitchenMain bedroom

Various 1981–84 273 44.0b NR Mixed locations Colorado 1992–93 9 26d

49d

8–6633–81

Prior to occupancyAfter 5 months of occupancy

Boston, MA 1993 14

26

11.1 ppb 16.1 ppb 

6.0–16.1 ppb5.9–53.8 ppb

Winter measurements, four resSummer measurements, nine r

Louisiana NR 419 460 ND–6600 Measured in 53 houses (75% u

rural); also measured seasonal 
Table 14 (contd)Country Location/

region

Sampling period

No. of samples

Mean concentration or range of means (μg/m3)a

Range(μg/m3)a

Comments 

USA (contd)

East and South-East

1997–98 4

7

34 ppbd36 ppbd

21–47 ppb14–58 ppb

Manufactured housesSite–built houses

Florida 2000 NR 94.9 NR New manufactured house New York City, NY

1999 38

41

12.120.9

NRNR

Winter measurementsSummer measurements

Public settingsChina Hotel 

ballroom

2002 28 29.7 26.3–63.0 Measured in four hotel ballroom

evening on 7 consecutive days

Italy Library 1995–96 16 32.7 1.7–67.8 Sixteen libraries at the Univers

10 samples with detectable leve

Mexico Museum 1996–98 60d 11–34 4–59 Three museums Sweden Hospital 1997 4 5 2–7 Geriatric hospitals built in 1925

and 1994

Primary school

1993, 1995 48 9.5 3–16 Twelve randomly selected prim

ND, not detected; NR, not reporteda Unless stated otherwiseb Medianc Geometric meand Number of indoor and outdoor measurements combined (see Table 13)e Data collected from literature searches, direct contacts with individuals and organisations, reports, computer tapes and direct ele
(Hodgson et al., 1993). The emission rates in single samples were 57.2 and 18.2 μg/m2/h

at 24 and 168 h, respectively, after the start of each experiment. Similar results were

observed in a Swedish study in which indoor levels of formaldehyde were found to be

higher in homes that had wall-to-wall carpeting (Norbäck et al., 1995).

The release of formaldehyde and volatile organic compounds from newly painted

indoor surfaces was investigated in a sample of 62 dwellings in Uppsala, Sweden, in

1991–92. Concentrations of formaldehyde were significantly increased in dwellings where

wood paint had been used, but were not related to other types of painting. Wall-to-wall

carpeting and wood painting made approximately equal contributions of 13 μg/m3 and

16 μg/m3 formaldehyde, respectively (Wieslander et al., 1997). The adsorption of formaldehyde to dust particles on wipe samples from homes and offices was investigated to

evaluate the extent to which such particles could act as carriers for volatile pollutants and

contribute to exposure to formaldehyde. A person exposed to an ambient concentration of

1 ppm [1.2 mg/m3] formaldehyde would inhale about 1 mg/h formaldehyde vapour when

breathing normally (15 L/min). In the presence of 1 mg/m3 dust (that contains 10 ng/mg

formaldehyde based on analysis of the dust samples), the amount of particle-associated

formaldehyde inhaled would be approximately 10 ng/h, i.e. five orders of magnitude lower

(Rothenberg et al., 1989). The dose of particle-associated formaldehyde to the lower respiratory tract is predicted to be at least four orders of magnitude smaller than the vapourphase dose to the upper respiratory tract. [The Working Group noted that the conditions of

this investigation are also relevant to industrial environments.]

Data on concentrations of formaldehyde in residential indoor air from five studies

conducted in Canada between 1989 and 1995 were examined (Health Canada, 2000).

Despite differences in sampling mode and duration (i.e. active sampling for 24 h or

passive sampling for 7 days), the distribution of concentrations was similar in the five

studies. The median, arithmetic mean, 95th percentile and 99th percentile concentrations

of the pooled data (151 samples) were 29.8, 35.9, 84.6 and 116 μg/m3, respectively

(Health Canada, 2000). Similar concentrations have been measured in non-workplace

indoor air in other countries.

Personal 48-h exposures of 15 randomly selected participants as well as microenvironment concentrations in each participant’s residence and workplace were measured for

16 carbonyl compounds, including formaldehyde, during the summer and autumn of 1997

as part of the Air Pollution Exposure of Adult Urban Populations in Europe (EXPOLIS)

study in Helsinki, Finland. The mean personal exposure concentration of formaldehyde

was 21.4 ppb [26.3 μg/m3]; the mean indoor residential concentration was 33.3 ppb

[41.0 μg/m3]; the mean outdoor residential concentration was 2.6 ppb [3.2 μg/m3]; and the

mean workplace concentration was 12.0 ppb [14.8 μg/m3] (Jurvelin et al., 2003).

In earlier studies summarized by Preuss et al. (1985), the mean concentrations in conventional homes with no urea–formaldehyde foam insulation were 25–60 μg/m3. Since

the late 1970s, many studies have reported formaldehyde levels in ‘mobile homes’

(caravans) (see, for example, the review of Gammage & Travis, 1989). The levels appear

to decrease as the mobile home ages, with a half-life of 4–5 years (Preuss et al., 1985). In

88 IARC MONOGRAPHS VOLUME 88
the early 1980s, mean concentrations of 0.4 ppm [0.5 mg/m3] and individual values as

high as several parts per million were measured in new mobile homes. As a result of new

standards and regulations established in the mid-1980s for building materials and voluntary reductions by the manufacturers, concentrations of formaldehyde in mobile homes

have decreased to approximately 0.1 ppm [0.12 mg/m3] or less (Gammage & Travis,

1989; Sexton et al., 1989; Gylseth & Digernes, 1992; Lehmann & Roffael, 1992). 

Formaldehyde may also occur in indoor air through the degradation of other organic

compounds. Naturally occurring unsaturated hydrocarbons, such as limonene and pinene

(which may also be released from consumer products), anthropogenic compounds, such

as 4-vinylcyclohexene (an emission from carpet padding), and other alkenes that are

commonly found in indoor air have been found to produce formaldehyde via their initial

reaction with ozone (Zhang et al., 1994; Weschler & Shields, 1996). Reiss et al. (1995)

estimated that the effective average rate of emissions of formaldehyde from this process

in four residences in Boston (MA, USA) was about three times higher in the summer than

in the winter.

In a study conducted at the Inhalation Toxicology Research Institute, release rates of

formaldehyde were measured for six types of consumer product (Pickrell et al., 1983,

1984). Release rates calculated per unit surface area (μg/m2 per day) were used to rank the

products in the following order: pressed wood products >> clothes ∼ insulation products

∼ paper products > fabric > carpet. Release rates from pressed wood products ranged from

below the limit of detection for an exterior plywood to 36 000 μg/m2 per day for some

panelling. Other release rates were 15–550 μg/m2 per day for articles of new clothing that

had not previously been washed, 52–620 μg/m2 per day for insulation products,

75–1000 μg/m2 per day for paper plates and cups, from below the limit of detection to

350 μg/m2 per day for fabrics and from below the limit of detection to 65 μg/m2 per day

for carpets.

In a follow-up study that was performed as a result of changes in product manufacturing processes, many of these release rates were re-investigated (Kelly et al., 1999).

Release rates of formaldehyde were reported to range typically from 9 to 1578 μg/m2/h

for a variety of bare urea–formaldehyde wood products, from 1 to 461 μg/m2/h for coated

urea−formaldehyde wood products, from 42 to 214 μg/m2/h for permanent press fabrics,

from 4 to 50 μg/m2/h for decorative laminates, from 16 to 32 μg/m2/h for fibreglass products and from 4 to 9 μg/m2/h for bare phenol–formaldehyde wood products (Kelly et al.,

1999). Paper grocery bags and towels had emission rates of < 0.5 and < 0.6 μg/m2/h,

respectively. For wet products, the emission rates were: latex paint, 326–854 μg/m2/h;

fingernail hardener, 178 000–354 000 μg/m2/h; nail polish, 20 700 μg/m2/h; and commercially applied urea–formaldehyde floor finish, 1 050 000 and 421 000 μg/m2/h for base

and topcoats, respectively (Kelly et al., 1999). 

FORMALDEHYDE 89
1.3.5 Other exposures

According to the Environmental Protection Agency Toxics Release Inventory (TRI), in

2001, approximately 9500 tonnes of formaldehyde were released into the environment

from 800 domestic manufacturing and processing facilities in the USA. This number

represents the sum of all releases of formaldehyde to air (4800 tonnes), water (160 tonnes),

soil (70 tonnes) and underground injection wells (4500 tonnes). The TRI data should be

used with caution because not all facilities are required to report releases of formaldehyde

into the environment (National Library of Medicine, 2004).

Cigarette smoke has been reported to contain levels of a few to over 100 μg formaldehyde per cigarette (IARC, 2004). A ‘pack-a-day’ smoker may inhale as much as 0.4–

2.0 mg formaldehyde (IARC, 1995; ACGIH® Worldwide, 2003).

Cosmetic products that contain formaldehyde, formalin and/or paraformaldehyde may

come into contact with hair (e.g. shampoos and hair preparations), skin (deodorants, bath

products, skin preparations and lotions), eyes (mascara and eye make-up), oral mucosa

(mouthwashes and breath fresheners), vaginal mucosa (vaginal deodorants) and nails

(cuticle softeners, nail creams and lotions). Use of aerosol products (e.g. shaving creams)

may result in potential inhalation of formaldehyde (Cosmetic Ingredient Review Expert

Panel, 1984). A Swedish study on indoor emissions reported that oil-based skin care

products that are known to contain formaldehyde precursors (donors) still release formaldehyde into the air after storage for 1 year (Karlberg et al., 1998). 

Formaldehyde occurs naturally in foods, and foods may be contaminated as a result

of fumigation (e.g. grain), cooking (as a combustion product) and release from formaldehyde resin-based tableware (WHO, 1989). It has been used as a bacteriostatic agent in

some foods, such as cheese (Restani et al., 1992). Fruit and vegetables typically contain

3–60 mg/kg, milk and milk products contain about 1 mg/kg, meat and fish contain

6–20 mg/kg and shellfish contain 1–100 mg/kg. Drinking-water generally contains

< 0.1 mg/L (WHO, 1989).

Formaldehyde can also be emitted into indoor air during the cooking of fish. Amounts

of formaldehyde that formed in a headspace when various kinds of fish flesh were heated

to 200 °C ranged from 0.48 μg/g for mackerel to 5.31 μg/g for sardine (Yasuhara &

Shibamoto, 1995). Free formaldehyde was found in fish at levels ranging from 1.4 to

40.3 ppm [1.7 to 49.6 mg/m3]; the high levels were attributed to the processes used to

freeze the fish products (Nielsen, 2002). When cooking oils are heated to high temperatures (240–280 °C) that are typical of Chinese wok cooking, several volatile mutagenic

organic compounds are released, including formaldehyde. Emissions of formaldehyde

from several cooking oils (rapeseed, canola, soya bean, peanut) ranged from 23 to 71 μg/L

(Shields et al., 1995).

Composting of household waste was also found to generate formaldehyde (Eitzer

et al., 1997). [Composting may also be of concern for occupational exposures.]

In some regions, mosquito coils are burned in residences for mosquito control. In a

study of the combustion products from two common brands of mosquito coil, formaldehyde

90 IARC MONOGRAPHS VOLUME 88
was generated at a level of approximately 2–4 mg/g of mosquito coil, which would result in

air concentrations in the range of 0.16–0.40 ppm [0.19–0.49 mg/m3] (Chang & Lin, 1998).

Formaldehyde has been used as a chemical germicide to control bacterial contamination in water distribution systems and in the dialysis fluid pathways of artificial kidney

machines. In addition, formaldehyde has been used to disinfect hollow fibre dialysers

(artificial kidneys) that are reprocessed and re-used only by the same patient (Centers for

Disease Control, 1986).

When formalin-sterilized dialysers were rinsed by the technique used in many dialysis

centres in the 1970s, undesirable concentrations of formaldehyde were found in the apparatuses at the start of dialysis. When the technique was modified by passing part of the saline

through the blood compartment immediately before connection and discarding the saline

left in the dialyser at the time of connection, the concentration of formaldehyde infused

into the patient fell to below 2 μg/mL. However, the dialysers still contained up to 13 mg

formaldehyde which leached slowly during simulated dialysis. Some residual formaldehyde was found in several components of the dialyser, but the majority was contained in

the cellulose membrane (Lewis et al., 1981).

Stragier et al. (1995) studied the influence of the type of disinfecting agent used on the

necessary rinsing time and rebound release after rinsing re-used dialysers. The rinsing time

required to reach undetectable levels of disinfecting agent was longest for formaldehyde and

the rebound release 30 min after completion of rinsing was the highest for formaldehyde.

In the USA, the proportion of dialysis centres that use formaldehyde to reprocess

dialysers decreased from 94 to 31% during 1983–2000 (Tokars et al., 2000).

1.4 Regulations and guidelines

Occupational exposure limits and guidelines for formaldehyde are presented in

Table 15. International regulations and guidelines related to emissions of and exposures

to formaldehyde in occupational settings, indoor air and building materials have been

reviewed (IARC, 1995; Paustenbach et al., 1997; ATSDR, 1999).

The European Union has adopted a Directive that imposes concentration limits for formaldehyde and paraformaldehyde in cosmetics. These substances are permitted at a maximal concentration of 0.2% by weight or volume (expressed as free formaldehyde) in all cosmetic formulations except nail hardeners, oral hygiene products and aerosol dispensers. Nail

hardeners and oral hygiene products may contain maximal concentrations of 5 and 0.1%,

respectively, whereas formaldehyde and paraformaldehyde are prohibited for use in aerosol

dispensers (except for foams). Labels of cosmetic products are required to list formaldehyde

and paraformaldehyde as ingredients when the concentration of either exceeds 0.05% (Cosmetic Ingredient Review Expert Panel, 1984; European Commission, 1990).

The Food and Drug Administration (2003) in the USA identifies formaldehyde: as a

secondary direct food additive that is permitted in food for human consumption; for use

as a preservative in defoaming agents; as an indirect food additive for use only as a component of adhesives; as an indirect food additive for use only as paper and paperboard

FORMALDEHYDE 91
92 IARC MONOGRAPHS VOLUME 88

Table 15. Occupational exposure standards and guidelines 

for formaldehyde 

Country or region Concentration 

(mg/m3

) [ppm] 

Interpretation Carcinogen 

classification

Australia 1.2 [1] 

2.5 [2] 

TWA 

STEL 

2; Sen 

Belgium 0.37 [0.3] Ceiling 

Brazil 2 [1.6] Ceiling 

China 0.5 Ceiling 

Canada 

 Alberta 

 Ontario 

 Quebec 

2.5 [2] 

0.37 [0.3] 

2.5 [2] 

Ceiling 

Ceiling 

Ceiling A2a

Denmark 0.4 [0.3] STEL L, K 

Finland 0.37 [0.3] 

1.2 [1] 

TWA 

Ceiling 

 

France 0.6 [0.5] 

1.2 [1] 

TWA 

STEL 

Germany 0.37 [0.3] 

0.7 [0.6] 

1.2 [1] 

TWA (MAK) 

STEL 

Ceiling 

4; Sh; I 

Hong Kong 0.37 [0.3] Ceiling A2b

Ireland 2.5 [2] 

2.5 [2] 

TWA 

STEL 

Japan 0.6 [0.5] TWA 2A 

Malaysia 0.37 [0.3] Ceiling 

Mexico 2.5 [2] Ceiling A2b

Netherlands 1.2 [1] 

2.5 [2] 

TWA 

STEL 

New Zealand 1.2 [1] Ceiling A2b

Norway 0.6 [0.5] 

1.2 [1] 

TWA 

Ceiling 

Cac; Sen 

Poland 0.5 

1 

TWA 

STEL 

South Africa 2.5 [2] 

2.5 [2] 

TWA 

STEL 

Spain 0.37 [0.3] STEL 

Sweden 0.6 [0.5] 

1.2 [1] 

TWA 

Ceiling 

Cad; Sen 

Switzerland 0.37 [0.3] 

0.74 [0.6] 

TWA 

STEL 

Sen 

United Kingdom (MEL) 2.5 [2] 

2.5 [2] 

TWA 

STEL 
components; as an indirect food additive for use as a preservative in textile and textile

fibre polymers; as an indirect food additive for use as an adjuvant in animal glue; and,

under specified conditions, as an animal drug and in the manufacture of animal feeds.

Guidelines for levels of formaldehyde in ambient air in living spaces have been set in

several countries and range from 0.05 to 0.4 ppm [0.06–0.5 mg/m3], with a preference for

0.1 ppm [0.12 mg/m3] (Lehmann & Roffael, 1992).

Some European countries have established maximum limits for emissions of formaldehyde from particle-boards, other wood products, furniture and insulation foam: for instance,

Denmark, Finland and Sweden have set a maximum of 0.15 mg/m3, measured in a test room

of 225 L under standard conditions; in France, the content of formaldehyde that arises from

walls insulated with urea–formaldehyde foam should not exceed 0.2 ppm (European Union,

1989).

In the USA, all plywood and particle-board materials that are bonded with a resin

system or coated with a surface finish that contains formaldehyde cannot exceed the

following formaldehyde emission levels when installed in manufactured homes, as

expressed as air concentrations using standard conditions: plywood materials and particleboard flooring products (including urea–formaldehyde-bonded particle-board), 0.25 mg/m3;

particle-board materials and medium-density fibre-board, 0.37 mg/m3 (Composite Panel

Association, 1999, 2002; Department of Housing and Urban Development, 2003).

FORMALDEHYDE 93

Table 15 (contd) 

Country or region Concentration 

(mg/m3

) [ppm] 

Interpretation Carcinogen 

classification

USA 

 ACGIH (TLV) 

 NIOSH (REL) 

 OSHA (PEL) 

0.37 [0.3] 

0.02 [0.016] 

0.12 [0.1] 

0.9 [0.75] 

2.5 [2] 

Ceiling 

TWA 

Ceiling 

TWA 

STEL 

A2b; Sen 

Cad

Cad

From Arbejdstilsynet (2002); Health & Safety Executive (2002); Työsuojelusäädöksiä (2002); ACGIH® Worldwide (2003); Deutsche Forschungsgemeinschaft (2003); Suva (2003); INRS (2005) 

I, local irritant; K, carcinogenic; L, substance with ceiling value; MEL, 

maximum exposure limit; PEL, permissible exposure limit; REL, recommended 

exposure limit; Sen, sensitizer; Sh, skin sensitizer; STEL, short-term exposure 

limit; TLV, threshold limit value; TWA, time-weighted average; 2, probable 

human carcinogen; 2A, probably carcinogenic to humans (IARC classification); 

4, carcinogenic potential with no or little genotoxicity 

a

 A2: carcinogenic effects suspected in humans

b

 A2: suspected human carcinogen 

c

 Ca: potential cancer-causing agent 

d

 Ca: Substance is carcinogenic. 
2. Studies of Cancer in Humans

2.1 Cohort studies

More than 25 cohort studies have examined the association between formaldehyde

and cancer. Since the previous IARC monograph in 1994 (IARC, 1995), three of these

have been updated, and six new studies have been published. The following review

divides the studies into those that concern professionals (e.g. pathologists, anatomists and

embalmers) and those that concern industrial workers (e.g. formaldehyde producers,

formaldehyde resin makers, plywood and particle-board manufacturers, garment workers

and workers in the abrasives industry). This division was also made in the previous IARC

monograph because of differences between these studies with regard to their findings, the

nature of the exposure to formaldehyde and the potential for exposures to other carcinogens or other factors that might confound the findings. 

The following discussion is focused largely on the results for sites that may come into

direct contact with airborne formaldehyde (cancers of the respiratory tract including

cancers of the trachea, bronchus and lung, laryngeal cancer, sinonasal cancer, nasopharyngeal cancer, oral cancer and other pharyngeal cancers) and on leukaemia and brain cancer,

for which excess mortality has been reported in several studies. 

2.1.1 Cohorts of industrial workers

Key study features and findings from the cohort and nested case–control studies of

industrial workers are summarized chronologically in Table 16, based on the year of

publication of the first report of the cohort. Studies have been conducted on workers who

were exposed to formaldehyde in the chemical, garment, fibreglass, iron, wood-working,

plastics and paper, pulp and plywood industries. Several of these cohort studies have

recently been updated, and the results presented below are largely limited to the updated

data, grouped by industry.

(a) The National Cancer Institute (NCI) Cohort

Blair et al. (1986, 1990a) at the NCI, USA, conducted the largest of the cohort studies,

which included over 25 000 workers (88% men) who had first been employed before 1966

in one of 10 industrial facilities in the USA. These facilities manufactured formaldehyde

(three plants), formaldehyde resins (six plants), moulding compounds (six plants), moulded

plastic products (two plants), photographic films (two plants) and plywood (one plant).

Among all of the workers, 11% were considered to be unexposed.

This study included workers from facilities that were also included in studies by Marsh

(1982), Wong (1983) and Liebling et al. (1984) and in a case–control study by Fayerweather

94 IARC MONOGRAPHS VOLUME 88
Table 16. Cohort studies of industrial workers exposed to formaldehydeReference,location,years of study

Cohort descriptionType of analysis(cohort size)

Exposure assessment

Organ site (ICD code)a No. of cases/

deaths

SMR (95% CI) 

All cancers 1511 deaths 1.10 (1.04–1.16)Nasopharynx 1 death NR Nose and nasal sinuses 2 deaths 0.87 (0.11–3.14) Lymphohaematopoietic

Leukaemia

NR31 deaths

NR0.91 (0.47–1.59)

Chemical factories that used or produced formaldehydeStandardized mortality (14 014 men)

Mouth (ICD-9, 143–145) 6 deaths 1.28 (0.47–2.78)

Level of exposure (background, low, moderate, high); among highly exposed, time period and duration of exposure Lung 594 deaths 1.22 (1.12–1.32) 

Coggon et al. (2003), United Kingdom,1941–2000(update of Acheson et al., 1984a; Gardner et al., 1993)

Brain and central 

nervous system

30 deaths 0.85 (0.57–1.21)

All cancers 1723 deaths 0.90 (0.86–0.95) Nasopharynx 8 deaths 2.10 (1.05–4.21) 

Hauptmann et al. (2003, 2004), USA, 1966–94 (update of Blair et al., 1986, 1987)

Duration; quantitative estimates of cumulative, average and highest peak exposure

Nose and nasal sinuses 3 deaths 1.19 (0.38–3.68)

Manufacturer of formaldehyde, formaldehyde resins, moulding compounds, moulded plastic products, photographic films and plywoodStandardized mortality (25 619 workers; 22 493 men, 3126 women)

Lymphohaematopoietic 161 deaths 0.80 (0.69–0.94)

Leukaemia 65 deaths 0.85 (0.67–1.09) 

Buccal cavity 49 deaths 1.01 (0.77–1.34)LungBrain and central

nervous system

641 deaths

43 deaths

0.97 (0.90–1.05)0.92 (0.68–1.23)
Table 16 (contd) Reference, location, years of study Cohort description Type of analysis (cohort size) Exposure assessment Organ site (ICD code)a No. of cases/ deaths SMR (95% CI) Bertazzi et al. (1986, 1989), Italy, 1959–86 Formaldehyde resin makers Standardized mortality (1332 men) All cancers 62 deaths 1.23 [0.94–1.58]b 

Nasopharynx NR NR Nasal cavity 0 deaths NA Lymphohaematopoietic 7 deaths 1.77 [0.71–3.65]b 

Leukaemia NR NR Duration of exposure, latency, age at employment, year of employment, time since beginning of employment Buccal cavity/pharynx NR NR Lung 24 deaths 1.56 [1.00–2.32] Brain NR NR None (area measurements) All cancers 24 inc. cases 0.84 [0.54–1.25]c 

Edling et al. (1987a), Sweden, 1955–83 Abrasives industry Standardized mortality, standardized incidence (521 male blue-collar workers) Nasopharynx Nasal cavity Lymphohaematopoietic Leukaemia Buccal cavity Lung Brain and central nervous system 1 inc. case 0 inc. cases 4 inc. cases 0 inc. cases 0 inc. cases 2 inc. cases 1 inc. case NRNANRNANA0.57 [0.07–2.06] NR All cancers 608 deaths 0.89 (0.82–0.97)

NasopharynxNasal cavity

0 deaths0 deaths

NANA

Garment industryStandardized mortality (11 039 workers; 2015 men, 9024 women)

Duration, time since first exposure, year of first exposure

Lymphohaematopoietic

Leukaemia

59 deaths24 deaths

0.97 (0.74–1.26)1.09 (0.70–1.62)

Pinkerton et al. (2004), USA, 1955–98 (update of Stayner et al., 1988) Myeloid leukaemia 15 deaths 1.44 (0.80–2.37) 

Buccal cavity/pharynx 4 deaths 1.33 (0.36–3.41)LungBrain and central nervous

system

147 deaths

19 deaths

0.98 (0.82–1.15)1.09 (0.66–1.71)
Table 16 (contd)Reference,location,years of study

Cohort descriptionType of analysis(cohort size)

Exposure assessment

Organ site (ICD code)a No. of cases/

deaths

SMR (95% CI) 

All cancers 127 deaths 0.99 (0.82–1.17)Nasopharynx 0 deaths NANasal cavity 0 deaths NA

Andjelkovich et al. (1995), USA, 1960–89

Foundry workersStandardized mortality (3929 men with potential exposure) Lymphohaematopoietic 7 deaths 0.59 (0.23–1.21)

Exposed/ unexposed; none, low, medium and high exposure Leukaemia 2 deaths 0.43 (0.05–1.57)

Buccal cavity/pharynx 6 deaths 1.31 (0.48–2.86)

1.16 (0.20–6.51)d

Lung 51 deaths 1.20 (0.89–1.58)

0.59 (0.28–1.20)d

Brain and central nervous

system

2 deaths 0.62 (0.07–2.23)

ICD-7Nasopharynx

Men

4 cases 1.3 (0.3–3.2)

Low (whitecollar) and above baseline (blue-collar)

Nasal cavity 13 cases 2.3 (1.3–4.0) Lymphohaematopoietic NR NR

Leukaemia (204) 39 cases 0.8 (0.6–1.6) 

Buccal cavity/pharynx 23 cases 1.1 (0.7–1.7)

Hansen & Olsen (1995, 1996), Denmark

Workers from companies with a history of use or manufacture of formaldehydeStandardized proportionate incidence (eligible cancer cases: 2041 men, 1263 women diagnosed in 1970–84)

LungBrain and nervous system (193)

410 cases

54 cases

1.0 (0.9–1.1)1.1 (0.9–1.5)

Nasal cavity Lymphohaematopoietic

Leukaemia

LungBrain and nervous system (193)

Women

4 cases

NR21 cases

108 cases

39 cases

2.4 (0.6–6.0)NR1.2 (0.7–1.8)1.2 (0.96–1.4)1.2 (0.8–1.6)
Table 16 (contd) Reference, location, years of study Cohort description Type of analysis (cohort size) Exposure assessment Organ site (ICD code)a No. of cases/ deaths SMR (95% CI) 

All cancers 96 deaths 0.94 (0.77–1.15)b Nasopharynx NR NR Cumulative exposure Nasal cavity NR NR Chiazze et al. (1997), USA, 1951–91 Fibreglass manufacturing plant workers Standardized mortality and nested case–control (4631 men and women) Lymphohaematopoietic Leukaemia 5 deaths 1 death 0.46 (0.15–1.08) 0.24 (0.006–1.36) Buccal cavity/pharynx 2 deaths 0.70 (0.08–2.52) Lung 47 deaths 1.26 (0.93–1.68) Brain and nervous system 6 deaths 1.48 (0.54–3.23) All cancers Formaldehyde alone Formaldehyde + wood 367 deaths 14 deaths 0.98 (0.86–1.12) 1.61 (0.95–2.72) Stellman et al. (1998), USA, 1982–88 Nasopharynx Nasal cavity NR NR NR NR Lymphohaematopoietic Formaldehyde alone  Formaldehyde + wood 

 28 deaths  3 deaths 

1.22 (0.84–1.77) 3.44 (1.11–10.68) 

Dichotomous (yes/no) with and without employment in a wood occupation 

 Leukaemia  Formaldehyde alone  Formaldehyde + wood 

 12 deaths  2 deaths 

0.96 (0.54–1.71) 5.79 (1.44–23.25) 

Workers in the American Cancer Society CPS-II study employed in wood-related occupations or who reported exposure to wood dust Retrospective cohort mortality (45 399 men, of whom 387 reported exposure to formaldehyde) 

Buccal cavity/pharynx NR NR Lung  Formaldehyde alone  Formaldehyde + wood

 104 deaths  7 deaths 

0.93 (0.73–1.18) 2.63 (1.25–5.51) 

Brain (ICD-9, 191) NR NR 
Table 16 (contd)Reference,location,years of study

Cohort descriptionType of analysis(cohort size)

Exposure assessment

Organ site (ICD code)a No. of cases/

deaths

SMR (95% CI) 

All cancers 2243 deaths 0.98 (0.94–1.02)bNasopharynx Nasal cavity 

 NR  NR 

NR NR 

Marsh et al. 

(2001); Youk et al. (2001), USA, 1945–92 

Fibreglass workers Standardized mortality and nested case–control (32 000 men and women, 22% of person–years exposed to formaldehyde) 

Duration of, cumulative and average exposure Lymphohaematopoietic 

 Leukaemia 

 199 deaths  NR 

0.92 (0.80–1.06) NR 

Buccal cavity/pharynx 63 deaths 1.07 (0.82–1.37) Lung 838 deaths 1.17 (1.09–1.25) Brain and central nervous  system 

 50 deaths 0.78 (0.58–1.03) 

Nested case–control studies Reference, location, years of study 

Characteristics of cases and controls 

Exposure assessment 

Organ site/exposure category No. of cases 

(exposed) 

Odds ratio (95% CI) 

Bond et al. (1986), USA, 1944–80 

308 male incident cases of lung cancer from a cohort of 19 608 employees at a chemical company; two controls per case matched on race, year of birth (5 years) and year of first employment 

Exposure profile developed based on work history at the company 

Lung  No lag period  Lag period ≥ 15 years 

 (9)  (4) 

0.62 (0.29–1.34) 0.31 (0.11–0.86) 
Table 16 (contd) Reference, location, years of study Characteristics of cases and controls Exposure assessment Organ site/exposure category No. of cases (exposed) Odds ratio (95% CI) Ott et al. (1989), USA, 1940–78 Deaths identified within a cohort of 29 139 male workers at two chemical manufacturing facilities and a research and development centre; five controls per case selected from cohort and frequency-matched by decade of first employment Use of formaldehyde in department where subjects worked Ever exposed Non-Hodgkin lymphoma Multiple myeloma Non-lymphocytic leukaemia Lymphocytic leukaemia 52 (2) 20 (1) 39 (2) 18 (1) 2.0 1.0 2.6 2.6 Partanen et al. (1990), Finland, 1957–80 (updated from Partanen et al., 1985) 136 male incident cases* from a cohort of 7307 workers in 35 particle-board, plywood and formaldehyde glue factories and sawmills who entered the factories in 1944–66; three controls per case selected randomly among the same cohort, matched by year of birth, alive at the time of diagnosis of the corresponding case Plant- and time-specific job–exposure matrices; work history based on factory registers, interviews of factory personnel and questionnaires to study subjects or 

relatives 

All cancers combined*  Ever exposed  Peak exposure  Dustborne formaldehyde Lung  Ever exposed  Peak exposure  Dustborne formaldehyde 

136 (20)  (7) (14) 118 (18)  (7) (12) 

1.40 (0.72–2.74)e

0.95 (0.30–3.05)e1.37 (0.66–2.82)e1.25 (0.60–2.60)e1.10 (0.31–3.85)e1.13 (0.51–2.52)e

CI, confidence interval; ICD, international classification of diseases; inc., incident; NA, not applicable; NR, not reported; SMR, standardized mort

incidence ratio 

a The ICD code is only mentioned when the organ site studied is different from that in the other studies. b The authors presented results using either the national population or the local population as the referent. The results presented here are based on the nc Data on cancer incidence and mortality were presented. The results in this column are for cancer incidence.d Relative risk of medium- plus high-exposed groups versus unexposed, adjusted for race, smoking and exposure to silicae 90% confidence interval 
et al. (1983). For the purposes of this review, the results from these earlier studies were

considered to be subsumed by the NCI study. In the earlier follow-up (Blair et al., 1986),

the NCI study had found an excess of lung cancer in white men in comparison with the

national population of the USA, but the excess did not appear to increase with increasing

cumulative exposure to formaldehyde. Several investigators performed re-analyses of the

results on lung cancer (Robins et al., 1988; Sterling & Weinkam, 1988, 1989a,b; Marsh

et al., 1992a,b, 1994; Sterling & Weinkam 1994, 1995; Callas et al., 1996). The re-analyses

by Sterling and Weinkam (1988, 1989a,b, 1994, 1995) did suggest a relationship between

cumulative exposure and mortality from lung cancer, although their first two reports were

found to have errors (Blair & Stewart, 1989; Sterling & Weinkam, 1989b). A positive

exposure–response relationship between cumulative exposure to formaldehyde and lung

cancer was not suggested in the re-analyses by Robins et al. (1988), Marsh et al. (1992a,b,

1994) or Callas et al. (1996). The results from these re-analyses are superseded by the most

recent findings in the NCI cohort, which are described below.

The cohort that was originally followed for vital status through to 1980 was recently

updated by Hauptmann et al. (2003, 2004) through to 1994. This study included a comprehensive evaluation of historical levels of exposure to formaldehyde and of other potentially

confounding exposures (Stewart et al., 1986; Blair & Stewart, 1990). Time-dependent

estimates were developed for duration of exposure (years), average exposure (parts per

million [ppm]), cumulative exposure (ppm–years) and highest peak exposure (ppm) to

formaldehyde. Concomitant exposure to particulates that contained formaldehyde was also

assessed. Expected numbers of deaths were estimated using the person–years method and

age-, race- and sex-specific rates for the general population in the USA; log-linear Poisson

regression models were used to analyse the relationship between the various measures of

exposure to formaldehyde and cancer mortality. In the analyses, exposures to formaldehyde

were lagged by 2 years for lymphatic and haematopoetic neoplasms and by 15 years for

solid cancers. Potential confounding by age, calendar time, sex, race and pay category

(Poisson regression only) was controlled for in the analyses. In addition, potential confounding was evaluated for duration of exposure to each of 11 other substances (i.e. antioxidants,

asbestos, carbon black, dyes and pigments, hexamethylenetetramine, melamine, phenol,

plasticizers, urea, wood dust and benzene) and for duration of work as a chemist or laboratory technician.

Based on comparisons with the national population, mortality from all cancers was

lower than expected in the unexposed (376 deaths; standardized mortality ratio [SMR],

0.76; 95% confidence interval [CI], 0.69–0.84) and, but to a lesser extent, in the population

exposed to formaldehyde (1723 deaths; SMR, 0.90; 95% CI, 0.86–0.95) (Hauptmann

et al., 2004). Decreased mortality was observed in both groups for lymphohaematopoietic

neoplasms (exposed: 161 deaths; SMR, 0.80; 95% CI, 0.69–0.94; unexposed: 17 deaths;

SMR, 0.62; 95% CI, 0.39–1.00) (Hauptmann et al., 2003) and solid tumours (exposed:

1580 deaths; SMR, 0.91; 95% CI, 0.87–0.96; unexposed: 341 deaths; SMR, 0.78; 95% CI,

0.70–0.86) (Hauptmann et al., 2004). 

FORMALDEHYDE 101
A statistically significant exposure–response relationship was observed between peak

exposure to formaldehyde and all lymphatic and haematopoietic neoplasms (ptrend = 0.002)

in the Poisson regression analysis. (The trend tests presented here and subsequently were

based on analyses that were restricted to the exposed workers.) This relationship was largely

due to a strong exposure–response relationship for leukaemia (ptrend = 0.004) and, to a lesser

extent, for Hodgkin disease (ptrend = 0.04). The relationship was stronger for myeloid

leukaemia (ptrend = 0.009) than for the other histological subtypes of leukaemia. The relative

risk for the highest category of peak exposure (≥ 4.0 ppm) was 2.46 (29 deaths; 95% CI,

1.31–4.62) for all leukaemia and 3.46 (14 deaths; 95% CI, 1.27–9.43) for myeloid

leukaemia. Weaker and statistically non-significant exposure–response relationships were

observed with average intensity of exposure for leukaemia (ptrend = 0.24) and myeloid

leukaemia (ptrend = 0.09). There was little evidence for a relationship between cumulative

exposure or duration of exposure and risk for either leukaemia or myeloid leukaemia

(Hauptmann et al., 2003). [The Working Group noted the contrast between the findings from

the person–years analysis, which did not reveal an excess of leukaemia, and the Poisson

regression analysis which demonstrated a significant exposure–response relationship

between peak exposure and leukaemia. The Working Group also noted that Poisson

regression, which uses internal analysis, is less prone to confounding by socioeconomic

status and other factors.]

Based on eight cases, a significant excess mortality from nasopharyngeal cancer was

observed among formaldehyde-exposed workers in comparison with the national population (SMR, 2.10; 95% CI, 1.05–4.21). A highly statistically significant (ptrend < 0.001)

exposure–response relationship was observed between peak exposure to formaldehyde and

risk for nasopharyngeal cancer in the Poisson regression analysis. 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, cumulative and duration of exposure (ptrend = 0.07, 0.03 and

0.15, respectively).

Three cases of cancer of the nose and nasal cavity were observed in the exposed group,

which were slightly in excess of the expected (SMR, 1.19; 95% CI, 0.38–3.68). A total of

49 deaths from cancer of the buccal cavity occurred among exposed subjects, which was

as expected with respect to mortality in the national population in the USA. Relative risks

for the highest exposure categories of average intensity, peak and cumulative exposure

were elevated (relative risks, 1.89, 1.83 and 1.74, respectively), but trends were not significant or only of borderline significance (ptrend = 0.50, 0.07 and 0.37, respectively). No

consistent positive association was observed for cancer of the larynx for any of the exposure metrics and the number of deaths (23) was as expected with respect to mortality in the

national population. Combination of cancers of the nasopharynx, mouth, salivary gland,

nasal cavity and larynx (upper respiratory tract) resulted in increasing relative risks with

increasing average intensity (a twofold significantly elevated relative risk in the highest

exposure category compared with the low exposure category; ptrend = 0.12 among the

102 IARC MONOGRAPHS VOLUME 88
exposed only) and with peak exposure, but not with cumulative exposure or duration of

exposure. Mortality from lung cancer was slightly lower than expected among the formaldehyde-exposed group (641 deaths; SMR, 0.97; 95% CI, 0.90–1.05). No evidence of a

positive relationship between mortality from lung cancer and any of the exposure measures

was observed. In fact, mortality from lung cancer appeared to decrease with duration of

exposure (ptrend = 0.03) and with cumulative exposure (ptrend = 0.14) to formaldehyde

(Hauptmann et al., 2004). [The Working Group noted that the strengths of this study

included its relatively large number of workers, long period of follow-up and the high

quality of the exposure assessment.]

Marsh and Youk (2004) re-analysed the updated data from the NCI cohort (Hauptmann

et al., 2003). In addition to reproducing the results presented by Hauptmann et al. (2003),

three further analyses were performed in relation to risk for mortality from leukaemia.

Using the cut-off points for exposure categories defined in Hauptmann et al. (2003), exposure category-specific SMRs, based on mortality rates for the national population, increased

with increasing peak and average intensity of exposure for all leukaemias combined and for

myeloid leukaemia; the SMRs for myeloid leukaemia ranged from 0.43 and 0.71 in the

lowest exposed category of peak and average intensity, respectively, to 1.42 and 1.45 in the

highest category of these metrics. Findings were similar when regional mortality rates were

used. The use of alternative cut-off points for average intensity of exposure, in order to

achieve similar numbers of deaths from all leukaemias combined in each exposed category,

resulted in relative risk estimates similar to those observed by Hauptmann et al. (2003).

Analyses of duration of time worked in the highest peak category did not generally indicate

higher risks among those who had experienced high peaks for a longer time.

Marsh et al. (1996) studied one plant (in Wallingford, CT) that was also included in

the NCI cohort study (Hauptmann et al., 2003). They enumerated the cohort independently

and conducted their own exposure assessment, but their general approach was similar.

More recently, Marsh et al. (2002) analysed mortality through to 1998 and exposure

through to 1995 for the 7328 workers (82% white men) who were employed during

1941–84. Overall, vital status was determined for 98% of the cohort and cause of death for

95% of 2872 deaths. The majority of subjects (54%) had worked for less than 1 year at the

plant. More than 1300 workers (18%) had been employed for more than 10 years. The

updated exposure assessment used the same methods as the earlier study (Marsh et al.,

1996), and included an examination of data on sporadic measurements from the period

1965–87 and the use of protective equipment. The analysis evaluated malignancies of the

upper and lower respiratory tract. Compared with local county mortality rates, SMRs were

elevated for cancers of the nasopharynx (seven deaths; SMR, 5.00; 95% CI, 2.01–10.30),

all pharynx (22 deaths; SMR, 2.23; 95% CI, 1.40–3.38), all buccal cavity and pharynx (31

deaths; SMR, 1.52; 95% CI, 1.03–2.15), nasal sinus (three deaths; SMR, 3.06; 95% CI,

0.63–8.93), larynx (13 deaths; SMR, 1.59; 95% CI, 0.84–2.71) and lung (262 deaths;

SMR, 1.21; 95% CI, 1.06–1.36). SMRs for nasopharyngeal cancer based on local county

rates increased monotonically with cumulative exposure to formaldehyde (no death; SMR,

0; 95% CI, 0–15.41 for unexposed; one death; SMR, 3.97; 95% CI, 0.10–22.10 for

FORMALDEHYDE 103
> 0–< 0.004 ppm–years; three deaths; SMR, 5.89; 95% CI, 1.22–17.22 for 0.004–0.219

ppm–years; and three deaths; SMR, 7.51; 95% CI, 1.55–21.93 for ≥ 0.22 ppm–years). In a

case–control study of pharyngeal cancer nested in the cohort, deaths from cancer of the

oropharynx (five), nasopharynx (seven), hypopharynx (three) and unspecified pharynx

(seven) were compared with 67 controls matched on race, sex, age and year of birth (within

2 years) with respect to occupational exposure to formaldehyde, and additional information

on occupational and non-occupational exposures was obtained by telephone interviews,

partly with next of kin [proportion of next-of-kin interviews not reported]. Based on exact

conditional logistic regression, relative risks for the combined group of pharyngeal cancers,

adjusted for tobacco smoking and years of employment in the factory, increased with

increasing duration of exposure to formaldehyde and particularly with increasing duration

of exposure to levels of formaldehyde > 0.2 ppm, but not with average intensity of

exposure or cumulative exposure. Separate analyses for nasopharyngeal cancer were not

presented due to small numbers.

[The earliest year of entry into this cohort was earlier than that in the NCI cohort, the

cohort was enumerated independently from the NCI cohort and exposures were assessed

separately using measurements and other information provided by the company but not

those made by an industrial hygienist for the NCI study. The exposure estimates were

generally about 10 times lower than those reported in Hauptmann et al. (2003, 2004).

Marsh et al. (2002) suggested that this difference was because Hauptmann et al. (2003,

2004) used data from several plants to estimate exposure in each plant, whereas Marsh

et al. (2002) based the assessment only on the plant under study. However, this suggestion

is incorrect (Blair & Stewart, 1990). All data considered in the exposure estimates in a

given plant in the Hauptmann et al. (2003, 2004) study were only from that plant.]

(b) Garment workers: The National Institute for Occupational Safety and

Health (NIOSH) Cohort

Stayner et al. (1985, 1988) at NIOSH, USA, conducted a proportionate mortality study

and a retrospective cohort study of mortality of garment workers exposed to formaldehyde.

The cohort study included approximately 11 000 predominantly female (82%) workers

from three facilities that manufactured shirts from fabrics that were treated with formaldehyde resins to impart permanent press characteristics. Workers who were included in the

cohort study had worked for at least 3 months after the time that formaldehyde-treated

fabrics were introduced into the process, which was 1959 in two of the facilities and 1955

in the third. Time-weighted 8-h geometric mean exposure levels in different departments

in the three plants were found to range from 0.09 to 0.20 ppm at the time the study was

initiated. Continuous air monitoring suggested no substantial peaks. Historical exposure

levels were not available; however, exposure levels are believed to have been substantially

higher in the earlier years of the study because the methods of treatment with formaldehyde

resin have been steadily improved over time to reduce the amount of free formaldehyde in

the fabrics. Exposure measurements reported at other facilities before 1970 ranged from

0.3 to 10 ppm (Stayner et al., 1988) (see Section 1.3.2(f)). The investigators reported

104 IARC MONOGRAPHS VOLUME 88
finding no evidence that other potentially carcinogenic exposures were present at the study

facilities. Follow-up of the cohort for vital status, which was originally through to 1982,

was recently extended to 1998 (Pinkerton et al., 2004). Life-table methods that applied

national and state rates were used. The results from analyses were similar for the cancer

sites of a-priori interest when both national and state rates were used. Life-table analyses

that used a multiple cause-of-death approach (Steenland et al., 1992) were also conducted.

Poisson regression models were used to analyse the relationship between duration of exposure and risk for cancer.

Mortality from all cancers (608 deaths; SMR, 0.89; 95% CI, 0.82–0.97) was shown to

be significantly lower than that expected based upon comparisons with the national population. The observed numbers of cases of respiratory cancer (152 deaths; SMR, 0.98; 95%

CI, 0.83–1.14) and of cancer of the brain and central nervous system (19 deaths; SMR,

1.09; 95% CI, 0.66–1.71) were found to be close to expectation. Mortality from buccal

cancer, which was found to be elevated (four deaths; SMR, 3.53; 95% CI, 0.96–9.02) in

the original study (Stayner et al., 1988), was only slightly elevated (four deaths; SMR,

1.33; 95% CI, 0.36–3.41) in the updated study (Pinkerton et al., 2004). No cases of nasopharyngeal (0.96 expected) or nasal (0.16 expected) cancer were observed. A slight excess

of mortality from leukaemia (24 deaths; SMR, 1.09; 95% CI, 0.70–1.62) was observed,

which was a certain degree higher for myeloid leukaemia (15 deaths; SMR, 1.44; 95% CI,

0.80–2.37). The excess mortality from myeloid leukaemia was greatest among workers

who were first exposed during the earliest years of the study (before 1963) when exposures

to formaldehyde were presumably higher (11 deaths; SMR, 1.61 [95% CI, 0.80–2.88]),

among workers with 10 or more years of exposure (eight deaths; SMR, 2.19 [95% CI,

0.95–4.32]) and among workers with 20 or more years since first exposure (13 deaths;

SMR, 1.91 [95% CI, 1.02–3.27]). A greater than twofold excess in mortality from myeloid

leukaemia was observed among workers with both more than 10 years of exposure and 20

or more years since first exposure to formaldehyde (seven deaths; SMR, 2.43; 95% CI,

0.98–5.01). In contrast to leukaemia, the risk for respiratory cancer decreased with

duration of employment and time since first exposure. [The Working Group noted that

strengths of this study were the apparent absence of other potentially confounding

carcinogenic exposures in the workplace and the long follow-up.]

(c) Chemical industry workers 

Acheson et al. (1984a) assembled a large cohort of workers from six chemical facilities

in the United Kingdom, and Coggon et al. (2003) reported the findings from an update of

the vital status of the cohort to 2000. The cohort included approximately 14 000 workers

who had been employed after 1937 and before 1965, at a time when formaldehyde was

used or produced, and personnel records at the plants were believed to be complete. Jobs

were classified into one of five categories of exposure to formaldehyde, i.e. background,

low, moderate, high or unknown. No exposure measurements were available before 1970.

Based on the later measurements and workers’ recall of irritant symptoms, it was estimated

that the TWA exposure concentrations corresponded to: background, < 0.1 ppm; low

FORMALDEHYDE 105
exposure, 0.1–0.5 ppm; moderate exposure, 0.6–2.0 ppm; and high exposure, > 2.0 ppm.

Person–years and Poisson regression analyses were conducted. An adjustment for local

geographical variations in mortality was made in some analyses, which entailed multiplying the expected deaths by SMRs for the area in which the plant was located. 

Mortality was elevated to some extent for all cancers (1511 deaths; SMR, 1.10;

95% CI, 1.04–1.16), and this was more pronounced among workers who had ever worked

in a job that was classified as entailing high exposure to formaldehyde (621 deaths; SMR,

1.31; 95% CI, 1.21–1.42). This excess mortality was largely attributable to a statistically

significant excess of mortality from cancers of the stomach (150 deaths; SMR, 1.31;

95% CI, 1.11–1.54) and lung (594 deaths; SMR, 1.22; 95% CI, 1.12–1.32). The excess of

mortality from lung cancer was greatest among men who had high exposure (272 deaths;

SMR, 1.58; 95% CI, 1.40–1.78). The excess incidence of lung cancer among the highly

exposed decreased with adjustment for local rates, although it remained statistically significant (SMR, 1.28; 95% CI, 1.13–1.44). Mortality from lung cancer was higher among

workers who were highly exposed before 1965 when levels of exposure to formaldehyde

would be expected to be higher (243 deaths; SMR, 1.61; 95% CI, 1.41–1.82). Mortality

from lung cancer demonstrated a non-significant inverse relationship with the number of

years worked in high-exposure jobs (ptrend = 0.13) and showed no trend with time since first

employment in a job that entailed high exposure (ptrend = 0.93).

A statistically non-significant excess mortality from pharyngeal cancer was observed

(15 deaths; SMR, 1.55; 95% CI, 0.87–2.56), which was to some degree greater among

highly exposed workers (six deaths; SMR, 1.91; 95% CI, 0.70–4.17). One death from nasopharyngeal cancer was observed where 2.0 were expected; two cases of sinonasal cancer

were observed where 2.3 were expected, but neither individual was highly exposed.

A review of tumour registry data identified two additional cases of sinonasal cancer, both

in individuals who were highly exposed, but it was not possible to determine the expected

number of incident cases because of limitations in the tumour registry system. Slight excess

mortality, based on a small number of cases, was observed in men who had had high exposure for cancers of the tongue (three deaths; SMR, 1.91; 95% CI, 0.39–5.58) and mouth

(two deaths; SMR, 1.32; 95% CI, 0.16–4.75). Mortality from cancer of the brain and

central nervous system and from leukaemia was lower than expected among the entire

cohort (SMRs, 0.85 and 0.91, respectively) and among the high-exposure group (SMRs,

0.63 and 0.71, respectively). [The Working Group noted that this study probably included

a substantial number of workers who had relatively high exposures: 4000 workers had ever

worked in jobs that were classified as entailing exposures greater than 2 ppm. The Working

Group also noted the long follow-up. However, there was a lack of exposure measurements

before 1970, and this may have led to some misclassification of exposures.]

Bond et al. (1986) conducted a case–control study in a cohort of 19 608 men who had

been employed for 1 year or longer at a large chemical production facility in Texas, USA,

between 1940 and 1980, which included all 308 workers who had died from lung cancer and

588 controls chosen at random from among men in the same cohort. Two series of controls,

individually matched to cases on race, year of birth (± 5 years) and year of first employment,

106 IARC MONOGRAPHS VOLUME 88
were selected: one among men who were still alive when the matched subjects died of lung

cancer, and one among men who had died ≤ 5 years after the matched subjects. Exposures

(ever or never) to 171 chemical and physical agents, including formaldehyde, were assessed

by an industrial hygienist on the basis of a review of documentation on the subject’s

employment history at the facility and industrial hygiene records; six exposures, not including formaldehyde, were assessed in greater detail. Only nine men who had lung cancer

(3%) were judged ever to have been exposed to formaldehyde, and a negative association

was seen between this exposure and mortality from lung cancer (not adjusted for other exposure variables), with an odds ratio of 0.62 (95% CI, 0.29–1.34); incorporation into the analysis of a 15-year minimal latency gave an odds ratio of 0.31 (95% CI, 0.11–0.86).

(d ) Fibreglass workers

Marsh et al. (2001) updated and expanded an earlier cohort study of mortality of

workers who had been employed at any of 10 fibreglass manufacturing plants in the USA

that had been previously studied by Enterline et al. (1987). The study included over 32 000

workers who had been employed for at least 1 year between 1945 and 1978 in one of the

10 study facilities. The cohort was expanded to include women, workers who had been

employed after the original 1963 end date and workers from additional worksites; the vital

status of the cohort was established until the end of 1992. In addition to expanding and

updating the cohort, the study introduced new information on potential exposures to

several known and potential carcinogens other than fibreglass (asbestos, arsenic, asphalt,

epoxy, polycyclic aromatic hydrocarbons, phenolics, silica, styrene and urea), including

formaldehyde. Exposure to formaldehyde was the most common exposure [22% of the

person–years] after respirable fibres [28% of the person–years] in the study. The median

exposure to formaldehyde for the cohort was 0.066 ppm and ranged from 0.03 to 0.13 ppm

in the different plants. Person–years methods were used to analyse the mortality of the

cohort in comparison with both national population and local death rates. Overall cancer

mortality was slightly lower than expected in comparison with both national (2243 deaths;

SMRUS, 0.98; 95% CI, 0.94–1.02) and local rates (SMRlocal, 0.94; 95% CI, 0.90–0.98). A

statistically significant excess of mortality from respiratory cancer was observed for the

whole cohort when national rates were used (874 deaths; SMRUS, 1.16; 95% CI,

1.08–1.24), which was weaker and of borderline significance (p = 0.05) when local rates

were used as a referent (SMRlocal, 1.06; 95% CI, 1.00–1.14). This excess was largely attributable to an excess mortality from cancers of the trachea, bronchus and lung (838 deaths;

SMRUS, 1.17; 95% CI, 1.09–1.25; SMRlocal, 1.07; 95% CI, 1.00–1.14).

The association of respiratory cancer with specific exposures was examined in a nested

case–control study in which the cases were male members of the cohort who had died from

respiratory tumours during 1970–92 (Marsh et al., 2001; Stone et al., 2001; Youk et al.,

2001). Each case was randomly matched with a control who had the same date of birth to

within 1 year, who was at risk during 1970–92 and who was alive and at risk at the age when

the case died. Smoking histories were ascertained through telephone interviews with the

subjects themselves or a proxy. Complete data were available for 502 of 713 matched pairs,

FORMALDEHYDE 107
and unmatched cases and controls were combined with the matched set nearest in age (at the

time of death of the case). Thus, the analysis was based on 631 cases and 570 controls. Of

the cases, 96% had been diagnosed with carcinoma of the trachea, bronchus or lung. Individual exposures in the matched set to formaldehyde, respirable fibres and silica before the

age at which the case died were estimated from industrial hygiene data using a job–exposure

matrix that took into account time period, plant and department. Analysis was performed

using conditional logistic regression with adjustment for smoking. In a first analysis (Youk

et al., 2001), nine different configurations of time lag and window of exposure were examined for average intensity of exposure and cumulative exposure. When exposure was not

weighted in relation to the time of case death, the odds ratio for ever exposure to

formaldehyde was 1.61 (95% CI, 1.02–2.56) and a similar risk estimate was obtained when

a 5-year lag was applied (odds ratio, 1.62; 95% CI, 1.04–2.54). Otherwise, however, the risk

estimates for ever exposure were lower, and there were no clear trends with cumulative or

average intensity of exposure (which for most subjects were < 2 ppm–years and < 0.14 ppm,

respectively).

This analysis was then extended by application of a conditional logistic regression

model that adjusted for exposure to respirable fibres as well as tobacco smoking, and used

piecewise linear functions (linear splines) with knots at the deciles of the distributions of

exposure in the cases. Cumulative exposure to formaldehyde was not significantly associated with increased risk in any of the models examined, but there was a suggestion of

increased risk (of borderline statistical significance) with average intensity of exposure at

the upper end of the range (Stone et al., 2001). [The Working Group noted that exposures

to formaldehyde in this cohort of fibreglass workers appeared to be lower than those in

the studies of industrial and textile workers reviewed earlier in this section.] 

Chiazze et al. (1997) conducted a retrospective cohort study of mortality of 4631

workers at a fibreglass manufacturing plant in Anderson, SC, USA. This included a nested

case–control study for lung cancer (47 cases) which collected information from interviews

on tobacco smoking, socioeconomic factors and a historical reconstruction of several exposures at the plant, including formaldehyde. Controls for this analysis were individuals in

the cohort who had not died from lung cancer, or from suicide or homicide (for ethical

reasons). The controls were matched to the cases based on year of birth (± 2 years) and

survival to the end of follow-up or death (± 2 years). Person–years methods of analysis

were used to analyse the cohort study, and conditional logistic regression was used to analyse the case–control study. Cumulative exposure to formaldehyde was the only exposure

in the case–control analysis to exhibit a positive relationship with risk for lung cancer.

Among smokers only, lung cancer was elevated in the highest (> 1000 ppm–days; odds

ratio, 2.07; 95% CI, 0.17–25.5) and next to highest (100–999 ppm–days; odds ratio, 1.72;

95% CI, 0.57–5.23) cumulative exposure groups, but these excesses were based on a small

number of cases and were statistically non-significant. 

108 IARC MONOGRAPHS VOLUME 88
(e) Woodworkers

Partanen et al. (1985) conducted a case–control study in a cohort of 3805 male production workers who had been employed for at least 1 year in one of three particle-board

factories, seven plywood factories, eight sawmills and one formaldehyde glue factory

between 1944 and 1966. Of these, 57 men were declared to the Finnish Cancer Registry as

having cancer of the respiratory tract (including at least 51 cases of lung cancer), oral cavity

or pharynx in 1957–80. Three controls were selected at random from the same cohort and

were individually matched to the case by year of birth. Plant- and time-specific job–exposure matrices were constructed for 12 chemicals, including formaldehyde (Kauppinen &

Partanen, 1988), and were combined with the work histories of the subjects to yield several

indicators of exposure; supplementary information on tobacco smoking was collected for

68% of cases and 76% of controls, by means of a postal questionnaire, from study subjects

or their relatives. A slight, non-significant increase in risk for all cancers combined was seen

among workers who had had any exposure to at least 0.1 ppm (0.12 mg/m3) formaldehyde

in contrast to workers who had had no exposure to formaldehyde, which yielded an odds

ratio of 1.44 [95% CI, 0.6–3.5]; an odds ratio of 1.27 [95% CI, 0.5–3.5] was obtained when

a minimal latency of 10 years before diagnosis was assumed. No significant association was

found with other indicators of exposure to formaldehyde (mean level of and cumulative

exposure, repeated peak exposures and ‘formaldehyde in wood dust’). Adjustment for cigarette smoking did not change the overall results. 

In an expansion of the study to include a total of 35 Finnish factories and 7307 woodworkers who had been employed during 1944–65, Partanen et al. (1990) identified 136

newly diagnosed cases of cancer of the respiratory tract (118 lung cancers, 12 laryngeal

cancers and one sinonasal cancer), oral cavity (four cases) and pharynx (one case) from the

files of the Finnish Cancer Registry for 1957–82. The additional factories were mainly

involved in construction carpentry and furniture manufacture. Three controls were

provided for each new cancer case, and exposure to formaldehyde and 11 other occupational agents was assessed by the same methods as those described in the initial study

(Partanen et al., 1985; Kauppinen & Partanen, 1988). Of 20 cases who had had any exposure to formaldehyde (odds ratio, 1.4 [95% CI, 0.6–3.1]), 18 were cancers of the lung (odds

ratio, 1.3 [95% CI, 0.5–3.0]) and two were cancers at other sites (odds ratio, 2.4 [95% CI,

0.3–18]). Adjustment for tobacco smoking reduced the odds ratios to 1.1 for all cancers

combined and to 0.7 for lung cancer separately and rendered the odds ratio for cancers at

other sites unassessable. The unadjusted odds ratios for all cancer cases were 1.5 [95% CI,

0.7–3.6] for an estimated mean level of formaldehyde of 0.1–1 ppm [0.12–1.23 mg/m3]

and 1.0 [95% CI, 0.1–8.2] for > 1 ppm, in comparison with no exposure. Other indicators

of exposure to formaldehyde, which included an estimate of cumulative exposure and

duration of exposure to peak levels > 2 ppm [2.46 mg/m3], showed similarly inconsistent

dose–response relationships, i.e. the lowest risks in the highest exposure categories.

Allowance for a minimal latency of 10 years further reduced the risk estimates for the

subgroups who had had the presumed highest exposures to odds ratios generally below 1.0.

FORMALDEHYDE 109
[The Working Group noted that there were too few cancers at sites other than the lung to

allow a meaningful analysis; consequently, this was essentially a study of lung cancer.]

Stellman et al. (1998) studied mortality among workers exposed to wood dust in the

American Cancer Society’s Cancer Prevention Study. From the original cohort of over half

a million men, sufficient data were available for 362 823 who were included in the study.

Of these, 45 399 reported either employment in a wood-related occupation or exposure to

wood dust. As part of the investigation, data were also collected on self-reported exposure

to formaldehyde, and incidence density ratios according to exposure were derived for death

from each of several cancers during 6 years of follow-up. This analysis adjusted for age

and for smoking habits. In comparison with men who had never been employed in a woodworking occupation and who did not report regular exposure to wood dust, those who had

been wood-workers and who reported exposure to formaldehyde had elevated mortality

from lung cancer (seven deaths; relative risk, 2.63; 95% CI, 1.25–5.51) and leukaemia (two

deaths; relative risk, 5.79; 95% CI, 1.44–23.25). In men exposed to formaldehyde who had

not worked in wood-related occupations, the corresponding risk estimates for lung cancer

and leukaemia were 0.93 (95% CI, 0.73–1.18) based on 104 deaths and 0.96 (95% CI,

0.54–1.71) based on 12 deaths, respectively. Results for sinonasal and nasopharyngeal

cancers were not reported. [The Working Group noted that this study should be given little

weight in the evaluation because of the small number of formaldehyde-exposed workers

and the limitations in the subjective exposure assessment for formaldehyde.]

(f) Iron foundry workers

Andjelkovich et al. (1990) studied a cohort of 8147 men who had been employed for

6 months or longer at an iron foundry in the USA. In a nested case–control study

(Andjelkovich et al., 1994), the case group comprised all members of the cohort who died

from primary lung cancer during 1950–89 and were ascertained from various sources.

They included 200 men in whom lung cancer was certified as the underlying cause of

death, 13 in whom it was a contributory cause and seven who died from carcinomatosis

with a primary lung tumour that was confirmed from hospital records or through the local

cancer registry. Ten controls were selected for each case by incidence density sampling;

they were of the same race and had attained at least the same age as their matched case.

Just over half of the controls (52.2%) were still alive at the end of the follow-up period. In

total, 50.9% of cases and controls were white. Exposure to silica (high, medium or low)

and formaldehyde (high, medium, low or none) was classified by means of a job–exposure

matrix based on industrial hygiene data, walk-through surveys, job description, knowledge

of the tasks performed in a job and reports in the scientific literature. [In the analysis

reported, exposure to formaldehyde was dichotomized as some versus none; no data were

provided on the probable levels of airborne concentrations.] Data on tobacco smoking (yes

or no) were available for 75.5% of cases and 68.6% of a random subset of two controls per

case and were obtained from various sources including the subject himself, his next of kin,

plant medical records, hospital medical records and death certificates. Analysis was

performed using conditional logistic regression with and without the inclusion of lag

110 IARC MONOGRAPHS VOLUME 88
periods. Overall, 25% each of cases and controls were classed as having been exposed to

formaldehyde. After adjustment for tobacco smoking, birth cohort (< 1915 versus ≥ 1915)

and cumulative exposure to silica (partitioned to four levels at the quartiles), the odds ratio

for unlagged exposure to formaldehyde was 1.31 (95% CI, 0.83–2.07); with the incorporation of increasing lag periods, this risk estimate decreased progressively to 0.84 (95% CI,

0.44–1.60) for a 20-year lag. Risk estimates were little affected by the inclusion of tobacco

smoking in the regression models, and there was no evidence of an interaction between

formaldehyde and smoking. [The Working Group noted that data to support this statement

were not shown.]

The relation of formaldehyde to risk for cancer was examined further in a subset of

3929 men from the full cohort who had worked in jobs that entailed potential exposure to

formaldehyde for at least 6 months between January 1960 and May 1987 (Andjelkovich

et al., 1995). The mortality of this group was compared with that of the national population (by the person–years method), with that of an internal reference population of 2032

cohort members who had worked during the same period in jobs that did not entail exposure to formaldehyde and with that of an occupational referent population assembled by

the NCI and NIOSH, using Poisson regression analysis. Cumulative exposure to formaldehyde and silica was estimated for each worker based on detailed occupational histories

and evaluation of job-specific exposure levels by an occupational hygienist. Smoking

status was ascertained for 65.4% of the exposed subcohort and 55.1% of the unexposed

control subcohort. In the follow-up through to 1989 and in comparison with national death

rates, mortality from all cancers was close to that expected in both the formaldehydeexposed (127 deaths; SMR, 0.99; 95% CI, 0.82–1.17) and unexposed (95 deaths; SMR,

0.97; 95% CI, 0.79–1.19) populations. In both the exposed and unexposed subcohorts, a

statistically non-significant excess of mortality from cancers of the buccal cavity and

pharynx (exposed: six deaths; SMR, 1.31; 95% CI, 0.48–2.86; unexposed: five deaths;

SMR, 1.69; 95% CI, 0.54–3.95) and lung cancer (exposed: 51 deaths; SMR, 1.20; 95% CI,

0.89–1.58; unexposed: 38 deaths; SMR, 1.19; 95% CI, 0.84–1.63) was observed. Mortality from cancers of the lung, buccal cavity and pharynx was not found to increase with

cumulative exposure in the Poisson regression analysis. Mortality from laryngeal cancer

(two deaths; SMR, 0.98; 95% CI, 0.11–3.53), cancer of the brain and central nervous

system (two deaths; SMR, 0.62; 95% CI, 0.07–2.23) and leukaemia (two deaths; SMR,

0.43; 95% CI, 0.05–1.57) was lower than expected among the exposed. 

(g) Other chemical workers and plastics manufacturers

A study of mortality among workers at a formaldehyde resin plant in Italy (Bertazzi

et al., 1986) included 1332 male workers who had ever been employed for at least 30 days

between the launch of the plant in 1959 and 1980. Follow-up for vital status was extended

from 1980 to 1986 in a second study (Bertazzi et al., 1989). Work histories of past

employees were reconstructed from interviews with retired workers, current workers and

foremen. Actual or reconstructed work histories were available for all but 16.5% of the

cohort. Job mobility was low, and 79% of the workers had held a single job throughout their

FORMALDEHYDE 111
career. On the basis of their work histories, workers were placed into one of three categories:

exposed to formaldehyde, exposed to compounds other than formaldehyde and exposure

unknown. Individual exposures could not be estimated, but the mean concentrations in fixed

area samples that were taken between 1974 and 1979 were 0.2–3.8 mg/m3 [0.2–3.1 ppm].

SMRs were calculated using the person–years methods to estimate expected numbers based

on national and local mortality rates, and were adjusted for age and calendar time. A deficit

of lung cancer was observed among workers who had been exposed to formaldehyde; six

cases of lung cancer were observed and 8.7 were expected. Excess mortality from lymphatic

and haematopoietic neoplasms was observed among formaldehyde-exposed workers based

on only three deaths (SMR, 1.73 [95% CI, 0.36–5.06]). During the first follow-up (Bertazzi

et al., 1986), no nasal cancer was recorded (0.03 expected).

Ott et al. (1989) evaluated data from a nested case–control study within a cohort of

29 139 men who had been employed in two chemical manufacturing facilities and a

research and development centre. Cases were subjects who had died between 1940 and

1978 from non-Hodgkin lymphoma (52 cases), multiple myeloma (20 cases), non-lymphocytic leukaemia (39 cases) and lymphocytic leukaemia (18 cases); information on death

certificates was used to determine cause of death. Five controls per case were selected from

the total employee cohort and were frequency-matched to cases by decade of first employment and duration of survival after first employment. Potential exposure to several

chemicals, including formaldehyde, was assessed based on use of the chemical in the work

area or in an activity in which the subject was involved at a specific time. Because adjustment for age did not substantially change the risk estimates, crude odds ratios were

presented. Odds ratios for ever versus never exposed to formaldehyde for non-Hodgkin

lymphoma (two exposed cases), multiple myeloma (one exposed case), non-lymphocytic

(two exposed cases) and lymphocytic (one exposed case) leukaemia were 2.0, 1.0, 2.6 and

2.6, respectively. [The Working Group noted that confidence intervals were not provided

and could not be calculated because the number of exposed controls was not given.]

Dell and Teta (1995) conducted a retrospective cohort study of mortality of 5932 male

employees at a plastics manufacturing and research and development facility in Bound

Brook, NJ, USA. Workers who were included in the cohort had worked for at least 7 months

between 1946 and 1967 at the facility where they had been exposed to a number of chemicals, including asbestos, polyvinyl chloride and formaldehyde. The cohort was followed for

vital status through to 1988. Only 111 of the cohort members had held jobs that involved

potential exposure to formaldehyde. Person–years methods were applied in which national

and state mortality rates were used as the referent. The analysis was stratified by whether

workers were paid hourly or were salaried, by duration of employment with lag intervals of

0, 10 and 15 years and by time since first employment. Mortality for all cancers was close

to expected (using national rates) among hourly workers (334 deaths; SMR, 1.02; 95% CI,

0.92–1.14). Excess mortality was observed among hourly workers for cancers of the

pancreas (25 deaths; SMR, 1.46; 95% CI, 0.95–2.16), lung (124 deaths; SMR, 1.10; 95% CI,

0.92–1.31) and other parts of the respiratory system (five deaths; SMR, 3.73; 95% CI,

1.21–8.70). The excess mortality from cancers of other parts of the respiratory system was

112 IARC MONOGRAPHS VOLUME 88
entirely due to an excess mortality from pleural mesothelioma, which was most probably

attributable to exposure to asbestos. An excess of mortality from lung cancer (4 observed,

1.1 expected) was noted among 57 workers who had been exposed to formaldehyde in the

hexamethylenetetramine process. No cases of nasal or nasopharyngeal cancer were

observed. [The Working Group and the authors noted that, because of its small size, this

study was relatively uninformative with regard to formaldehyde.]

(h) Abrasives industry 

Cancer mortality and incidence among workers in the abrasives industry in Sweden

was evaluated by Edling et al. (1987a) in plants that manufactured grinding wheels and

employed abrasives bound with formaldehyde resins. The levels of formaldehyde were

reported to be 0.1–1.0 mg/m3. A cohort of 911 workers (211 women in administration and

production and 700 men, of whom 521 were blue-collar workers) who had been employed

for at least 5 years between 1955 and 1983 was followed for mortality through to 1983 and

for cancer incidence through to 1981, yielding 79 deaths and 24 incident cancers. Deaths

and morbidity that occurred at the age of 75 years or older were excluded because of

concerns about diagnostic validity. Person–years methods were used to generate expected

numbers based on rates for the general population, stratified for age, calendar year and sex.

No significant excesses of mortality or morbidity were seen among male blue-collar

workers, administrative personnel or among women. All cancer mortality (17 deaths;

SMR, 0.93 [95% CI, 0.54–1.49]) and incidence (24 cases; standardized incidence ratio

(SIR), 0.84 [95% CI, 0.54–1.25]) were slightly lower than expected. Lung cancer incidence was lower than expected (two cases; SIR, 0.57 [95% CI, 0.07–2.06]). No cases of

leukaemia, or nasal or buccal cancer were observed. One case of nasopharyngeal cancer

and one of cancer of the nervous system were reported.

(i) Mixed industrial exposures

Hansen and Olsen (1995) conducted a standardized proportionate cancer incidence

study of workers in Denmark. Individuals who were born between 1897 and 1964 and had

been diagnosed with cancer between 1970 and 1984 were identified from the Danish

Cancer Registry. Employment histories were established through linkage to the Supplementary Pension Fund, which began in 1964. A total of 91 182 men who had cancer, who

met the study criteria and who had records in the Supplementary Pension Fund were identified. The companies in which individuals worked were identified by the Fund and the use

of formaldehyde by these companies was retrieved from the Danish Product Register.

Cancer patients whose longest work experience after 1964 was at one of the companies

that used formaldehyde and was at least 10 years before the date of diagnosis were

regarded as being potentially exposed to formaldehyde. White-collar workers were

assumed to have low exposure, blue-collar workers were assumed to have high exposure

and workers with a missing job title were assumed to have unknown exposure to formaldehyde. [The Working Group noted that this may not be a very reliable means of classifying workers with regard to exposure.] Blue-collar cases who had worked in wood and

FORMALDEHYDE 113
furniture companies and carpentry enterprises or had worked as a cabinet maker, joiner or

carpenter were classified as having potential exposure to wood dust. A parallel study

included 73 423 women with incident cancer and records of the Supplementary Pension

Fund (Hansen & Olsen, 1996). Standardized proportionate incidence of cancer ratios

(SPICR) were estimated using age-, sex- and calender period-specific proportions among

all employees in Denmark as the reference. A statistically significant excess of mortality

from cancer of the nasal cavity and paranasal sinuses (SPICR, 2.3; 95% CI, 1.3–4.0) was

observed among male workers who were potentially exposed to formaldehyde, based on

13 cases. Among women, the SPICR was 2.4 (95% CI, 0.6–6.0), based on four cases. The

excess mortality from nasal cancer observed in men was more pronounced among bluecollar workers who were exposed to formaldehyde only (nine cases; SPICR, 3.0; 95% CI,

1.4–5.7) or who had co-exposure to formaldehyde and wood dust (two cases; SPICR, 5.0;

95% CI, 0.5–13.4). The observed number of cases was close to expected for cancers of the

buccal cavity and pharynx (23 cases; SPICR, 1.1; 95% CI, 0.7–1.7), nasopharynx (four

cases; SPICR, 1.3; 95% CI, 0.3–3.2), brain and nervous system (54 cases; SPICR, 1.1; 95%

CI, 0.9–1.5), larynx (32 cases; SPICR, 0.9; 95% CI, 0.6–1.2) and lung (410 cases; SPICR,

1.0; 95% CI, 0.9–1.1) and for leukaemia (39 cases; SPICR, 0.8; 95% CI, 0.6–1.6). No

cancer site showed risk estimates that were significantly different from unity among

women.

2.1.2 Cohort and proportionate mortality studies of professional groups

Pathologists, anatomists, embalmers and funeral directors have been studied because

they use formaldehyde as a tissue preservative. Investigations of these occupations have

several methodological problems. The use of national statistics to generate expected

numbers may bias estimates of relative risks downwards for some cancers and upwards

for others because some of these groups have a higher socioeconomic level than the

general population; only a few investigations included a special referent population that

was designed to diminish potential socioeconomic confounding. None of these studies

presented the data necessary to adjust for tobacco use. Since anatomists and pathologists

in the USA generally smoke less than the general population (Sterling & Weinkam, 1976),

estimates of relative risks for smoking-related cancers will be artificially low. Without

adjustments, the biases introduced by socioeconomic factors and tobacco smoking may be

strong enough to preclude any possibility of detecting an excess occurrence of tobaccorelated cancers. This may be less of a problem for embalmers, however, because their

smoking habits may not differ from those of the general population (Sterling & Weinkam,

1976). In no study were risk estimates developed by level of exposure, and in only a few

studies were risks evaluated by duration of exposure. When exposure estimates are not

presented in the following text, they were not provided in the original study. Non-differential error in exposure assessment, which occurs when the measures of exposure are

about equally inaccurate for study subjects who do and do not have the cancer of interest,

diminishes the chances of uncovering an underlying association, as it biases estimates of

114 IARC MONOGRAPHS VOLUME 88
the relative risk towards the null. Key study features and findings from the cohort and proportionate mortality studies of professional groups are summarized in Table 17 by subgroups of profession. 

(a) Cohort of British pathologists and medical technicians

Harrington and Shannon (1975) evaluated the mortality of pathologists and medical

laboratory technicians in Great Britain in 1975. A total of 2079 members of the Royal

College of Pathologists and the Pathological Society who were alive in 1955 were enrolled

and followed for vital status through to 1973. The Council for Professions Supplementary

to Medicine enabled the identification of 12 944 technicians. Ten of the pathologists who

died and 20 of the medical technicians who died were women, but the number of women

included in the cohort was not provided. Expected numbers of deaths were calculated from

sex-, 5-year calendar period- and 5-year age group-specific rates for England and Wales or

Scotland. A deficit in mortality from cancer was observed in both pathologists (40

observed, 66.9 expected) and medical technicians (37 observed, 59.8 expected). The SMR

for lymphatic and haematopoietic cancer was significantly elevated among pathologists

(eight deaths [SMR, 2.00; 95% CI, 0.86–3.94]), but not among technicians (three deaths

[SMR, 0.55; 95% CI, 0.11–1.59]). No excess incidence of leukaemia was observed in

either group. The SMRs for cancers at other sites were all below 1.0.

The study of British pathologists was extended and expanded by Harrington and Oakes

(1984), who added new entrants and traced new and previously studied subjects from 1974

through to 1980. The population now included 2307 men and 413 women. SMRs were

calculated using expected rates based on age-, sex- and calendar time-specific data from

England and Wales. The SMR for all cancers among men was 0.61 (32 deaths [95% CI,

0.42–0.86] and that among women was 1.41 (seven deaths [95% CI, 0.57–2.90]). Mortality

from brain cancer was significantly elevated among men (four deaths; SMR, 3.33 [95% CI,

0.91–8.53] p < 0.05), but not among women. No cases of nasal or nasal sinus cancer were

observed, but the expected number was small (0.12). Mortality from lung cancer among

men was significantly lower than expected (nine deaths; SMR, 0.41 [95% CI, 0.19–0.78]).

Mortality from leukaemia and other lymphatic and hematopoetic neoplasms was close to

that expected [men and women combined: three deaths; SMR, 0.92; 95% CI, 0.18–2.68].

This cohort was further evaluated by Hall et al. (1991), who extended follow-up of

mortality from 1980 through to 1986 and added new members of the Pathological Society,

which resulted in 4512 individuals available for study (3069 men and 803 women in

England and Wales; 409 men in Scotland; and 231 members from Northern Ireland and

women from Scotland for whom corresponding reference rates were not available). Sexspecific SMRs were based on expected rates for England and Wales or Scotland (for men

only), as appropriate, and were adjusted for age (5-year groups) and calendar time. The

SMRs for all causes of death were all considerably below 1.0: men from England and

Wales, 0.43 (176 deaths; 95% CI, 0.37–0.50); women from England and Wales, 0.65 (18

deaths; 95% CI, 0.38–1.03); and men from Scotland, 0.50 (29 deaths; 95% CI, 0.34–0.72).

The SMRs for cancers at all sites were 0.40 (44 deaths; 95% CI, 0.29–0.54) and 0.59 (nine

FORMALDEHYDE 115
Table 17. Cohort and proportionate mortality studies of cancer in professionals exposed to formaldReference, country, years of study Study population, design (study size) Exposure assessment Organ site No. of cases/ deaths SMRa (95% CI) British pathologists and medical technicians Hall et al. (1991), United Kingdom, 1974–87 (update of Harrington & Oakes, 1984, plus new members since 1973) Pathologists, SMR (4512 men and women) [sex distribution not reported] None All cancers Nasopharynx Nasal cavity Lymphohaematopoietic Leukaemia Lung Brain and central nervous system 53 deaths NR NR 10 deaths 4 deaths 9 deaths 6 deaths 0.45 (0.34–0.59) NR NR 1.44 (0.69–2.65) 1.52 (0.41–3.89) 0.19 (0.09–0.36) 2.18 (0.80–4.75) Anatomists and pathologists in the USA Stroup et al. (1986), USA, 1925–79 Anatomists, SMR (2239 men) Duration All cancers Nasopharynx Nasal cavity Lymphohaematopoietic Lymphoma Leukaemia Chronic myeloid leukaemia Other lymphatic tissue Buccal cavity/pharynx 

Lung Brain and central nervous  system 

118 deaths NR  0 deaths  18 deaths  2 deaths  10 deaths  3 deaths  6 deaths  1 death  12 deaths  10 deaths 

0.64 (0.53–0.76) NR (0.0–7.2) 1.2 (0.7–2.0) 0.7 (0.1–2.5) 1.5 (0.7–2.7) 8.8 (1.8–25.5) 2.0 (0.7–4.4) 0.2 (0.0–0.8) 0.3 (0.1–0.5) 2.7 (1.3–5.0) 

Logue et al. (1986), USA, 1962–77 

Pathologists, SMR (5585 men) 

None Nasopharynx 

Nasal cavity Lymphohaematopoietic  Leukaemia Buccal cavity/pharynx Respiratory system 

NR NR NR NR NR NR 

NR NR 0.48 (NR) 1.06 (NR) 0.71 (NR) 0.24 (p < 0.01) 
Table 17 (contd) Reference, country, years of study 

Study population, design (study size) 

Exposure assessment 

Organ site No. of 

cases/ deaths 

SMRa (95% CI) 

Embalmers and funeral directors Walrath & Fraumeni (1983), New York, USA, 1925–80 

Embalmers and embalmers/funeral directors, PMR/PCMR (1132 white men) 

Time since first licence, age at first licence 

All cancers Nasopharynx Nasal cavity Lymphohaematopoietic  Lympho- and  reticulosarcoma  Other lymphatic cancers  Leukaemia  Myeloid leukaemia Buccal cavity/pharynx Lung Brain and central nervous  system 

243 deaths NR  0 deaths  25 deaths  5 deaths  6 deaths  12 deaths  6 deaths  8 deaths  7 deaths  1 death  70 deaths  9 deaths  6 deaths  3 deaths 

1.00 NR NA 1.21 0.82 1.23 1.19 [1.5] 1.03 2.01 0.28 1.11 1.38 2.34 0.93 

Walrath & Fraumeni (1984), California, USA, 1925–80 

Embalmers, PMR/PCMR (1007 white men) 

Duration All cancers 

Nasopharynx Nasal cavity Lymphohaematopoietic  Lympho- and  reticulosarcoma  Leukaemia  Myeloid leukaemia Buccal cavity/pharynx Lung Brain 

205 deaths NR  0 deaths  19 deaths  3 deaths  12 deaths  6 deaths  8 deaths  41 deaths  9 deaths 

1.00 NR NA 1.22 [1.0] 1.40 [1.50] 0.99 0.87 1.68 
Table 17 (contd) Reference, country, years of study Study population, design (study size) Exposure assessment Organ site No. of cases/ deaths SMRa (95% CI) Levine et al. (1984), Canada, 1950–77 Embalmers, SMR (1413 men) None All cancers Nasopharynx Nasal cavity Lymphohaematopoietic Leukaemia Buccal cavity/pharynx Lung Brain and central nervous system 58 deaths NR 0 deaths 8 deaths 4 deaths 1 death 19 deaths 3 deaths 0.87 [0.66–1.12] NR NA 1.23 [0.53–2.43] [1.60] [0.44–4.10] [0.48] [0.01–2.65] 0.94 [0.57–1.47] [1.15] [0.24–3.37] Hayes et al. (1990), USA, 1975–85 None All cancers 900 deaths 102 deaths 1.07 (1.01–1.15) 1.08 (0.87–1.31) 

Nasopharynx 3 deaths 1 death 1.89 (0.39–5.48) 4.00 (0.10–22.3) 

Embalmers/funeral directors, PMR (3649 white men, 397 non-white men) Nasal cavity 0 deaths NA 

Lymphohaematopoietic Lympho- and reticulosarcoma Lymphatic leukaemia Myeloid leukaemia  Other and unspecified  leukaemia 

100 deaths  15 deaths  11 deaths  1 death  5 deaths  2 deaths  23 deaths  1 death  17 deaths  3 deaths 

1.31 (1.06–1.59) 2.41 (1.35–3.97) 1.08 (0.54–1.93) 1.89 (0.05–10.5) 0.57 (0.19–1.33) 2.99 (0.36–10.7) 1.61 (1.02–2.41) 1.06 (0.02–5.93) 2.08 (1.21–3.34) 4.92 (1.01–14.36) 

Buccal cavity/pharynx 26 deaths 

 4 deaths 

1.19 (0.78–1.74) 1.25 (0.34–3.20) 

Lung Brain and central nervous  system 

285 deaths  23 deaths  24 deaths  0 deaths 

0.97 (0.86–1.09) 0.75 (0.47–1.13) 1.23 (0.80–1.84) NA 

CI, confidence interval; NA, not applicable; NR, not reported; PCMR, proportionate cancer mortality ratio; PMR, proportionate mortality ratio a Unless otherwise stated 
deaths; 95% CI, 0.27–1.12) among men from England and Wales and Scotland, respectively, and 0.95 (nine deaths; 95% CI, 0.43–1.80) among women from England and Wales.

No significant excess was seen for cancer at any site. Non-significant excess mortality

occurred for brain cancer (six deaths; SMR, 2.40; 95% CI, 0.88–5.22) and lymphatic and

haematopoietic cancer (nine deaths; SMR, 1.42; 95% CI, 0.65–2.69) among men from

England and Wales, breast cancer (four deaths; SMR, 1.61; 95% CI, 0.44–4.11) among

women from England and Wales and prostatic cancer (two deaths; SMR, 3.30; 95% CI,

0.39–11.8) among men from Scotland. 

(b) Anatomists and pathologists in the USA

Stroup et al. (1986) evaluated mortality among members of the American Association

of Anatomists. A total of 2317 men had joined the Association between 1888 and 1969;

because only 299 women had joined during this period, they were not included. Ninetyeight of the men were excluded because they had died, moved or were lost to follow-up

before 1925, which resulted in a final study size of 2239. Follow-up of the cohort for vital

status was accomplished from the date the person joined the association until 1979. The

expected numbers of deaths were calculated from age-, race-, sex- and calendar timespecific rates for the general population of the USA for the period 1925–79 or for male

members of the American Psychiatric Association, a population that should be similar to

anatomists with regard to socioeconomic status, in 1900–69. In comparison with the general

population, the cohort showed a very large ‘healthy worker effect’, with SMRs of 0.65 for

all causes (738 deaths) and 0.64 (118 deaths; 95% CI, 0.53–0.76) for cancer at all sites.

Excess mortality was observed for cancers of the brain and central nervous system

(10 deaths; SMR, 2.7; 95% CI, 1.3–5.0), leukaemia (10 deaths; SMR, 1.5; 95% CI, 0.7–2.7)

and lymphatic tissues other than lymphosarcoma, reticulosarcoma, Hodgkin disease and

leukaemia (six deaths; SMR, 2.0; 95% CI, 0.7–4.4). The risk for brain cancer increased with

duration of membership, from 2.0 for < 20 years to 2.8 for 20–39 years and to 7.0 for

≥ 40 years; no such pattern was seen for lung cancer or leukaemia. Of the 10 deaths from

leukaemia, five were myeloid and the SMR for chronic myeloid leukaemia was statistically

significantly elevated (three deaths; SMR, 8.8; 95% CI, 1.8–25.5) in the period 1969–79 for

which cell type-specific mortality rates were available. The SMRs were below 1.0 for lung

cancer (12 deaths; SMR, 0.3; 95% CI, 0.1–0.5) and oral and pharyngeal cancer (one death;

SMR, 0.2; 95% CI, 0.0–0.8). No death from nasal cancer occurred (0.5 expected). When

compared with members of the American Psychiatric Association, anatomists had deficits

in mortality from lung cancer (seven deaths; SMR, 0.5; 95% CI, 0.2–1.1) and leukaemia

(three deaths; SMR, 0.8; 95% CI, 0.2–2.9), but they still had an excess mortality from brain

cancer (nine deaths; SMR, 6.0; 95% CI, 2.3–15.6).

Logue et al. (1986) evaluated mortality among 5585 members of the College of

American Pathologists listed in the Radiation Registry of Physicians. The cohort was established by enrolling members between 1962 and 1972 and following them up through to

1977. Direct comparisons were made between the mortality rates of pathologists and a

cohort of 4418 radiologists and used the Mantel-Haenszel procedure with adjustment for

FORMALDEHYDE 119
age and calendar time for large categories of death (e.g. all cancers). Indirect comparisons

that used mortality rates for white men in the USA in 1970 as the referent were also performed to compute SMRs. The age-adjusted mortality rate for all cancers was found to be

slightly lower in pathologists than in radiologists (1.37 versus 1.51 per 1000 person–years).

Based on comparisons with the national population, a deficit in mortality was observed

among pathologists for cancers of the buccal cavity and pharnyx (SMR, 0.71) and respiratory system (SMR, 0.24) and for lymphatic and haematopoietic neoplasms other than

leukaemia (SMR, 0.48). Mortality from leukaemia was slightly elevated (SMR, 1.06)

among pathologists. [The number of deaths for each cancer site was not reported.]

However, the age-adjusted mortality rate for leukaemia was higher among radiologists than

among pathologists (0.15 versus 0.10 per 1000 person–years). [Confidence intervals were

not reported and could not be estimated since observed and expected numbers of deaths

were not reported.]

(c) Embalmers and funeral directors

Walrath and Fraumeni (1983) used licensing records from the New York State (USA)

Department of Health, Bureau of Funeral Directing and Embalming to identify 1678

embalmers who had been licensed between 1902 and 1980 and who had died between 1925

and 1980. Death certificates were obtained for 1263 (75%) decedents (1132 white men,

79 non-white men, 42 men of unknown race and 10 women); proportionate mortality ratios

(PMRs) and proportionate cancer mortality ratios (PCMRs) were calculated for white men

and non-white men on the basis of age-, race-, sex- and calendar time-specific proportions

in the general population. Observed and expected numbers were generally not provided for

non-white men, but it was indicated that there was a significant excess mortality from

cancers of the larynx (two deaths) and lymphatic and haematopoietic system (three deaths)

in this group. Among white men, the PCMR was 1.00 (243 deaths) for all cancers combined. PCMRs for specific cancers were 1.03 (eight deaths) for buccal cavity and pharynx,

1.11 (70 deaths) for lung, 1.38 (nine deaths) for brain, 1.21 (PMR; 25 deaths) for lymphatic

and haematopoietic system, 0.82 (five deaths) for lymphosarcoma and reticulosarcoma

(ICD-8 200) and 1.19 (12 deaths) for leukaemia. Six of the leukaemia deaths (4.1 expected)

were from myeloid leukaemia [PMR, 1.5]. No deaths occurred from cancer of the nasal

sinuses or nasopharynx. There was little difference in PMRs by time since first licence. The

subjects who were recruited had been licensed as either embalmers or as both embalmers

and funeral directors. Mortality patterns were analysed separately for the two groups

because the authors assumed that persons who were licensed only as embalmers would

have had more exposure to formaldehyde than embalmers who were also funeral directors.

The PMR for cancer of the brain and central nervous system was significantly increased

among people who were licensed only as embalmers (six deaths; PMR, 2.34; p < 0.05) but

not among those who also were licensed as a funeral director (three deaths; PMR, 0.93).

A difference was also observed for mortality from cancer of the buccal cavity and pharynx:

the PMR for embalmers was 2.01 (seven deaths) and that for embalmers/funeral directors

was 0.28 (one death). Neoplasms of the lymphatic and haematopoietic system were only

120 IARC MONOGRAPHS VOLUME 88
elevated among individuals who were licensed as both an embalmer and funeral director

(16 deaths; PMR, 1.39).

Walrath and Fraumeni (1984) used the records of the California (USA) Bureau of

Funeral Directing and Embalming to examine proportionate mortality among embalmers

who had first been licensed in California between 1916 and 1978. They identified 1109

embalmers who died between 1925 and 1980, comprised of 1007 white men, 39 non-white

men, 58 white women and five non-white women. Only mortality of white men was analysed. PMRs and PCMRs were calculated using age-, race-, sex- and calendar year-specific

proportions from the general population of the USA. Total cancer mortality was significantly greater than that expected (205 deaths; PMR, 1.21 for all cancers combined). Also,

a statistically significant excess of proportionate mortality was observed for cancers of the

colon (30 deaths; PMR, 1.87), prostate (23 deaths; PMR, 1.75), brain and central nervous

system (nine deaths; PMR, 1.94) and leukaemia (12 deaths; PMR, 1.75). The magnitude

of these excesses was reduced and no longer statistically significant in the PCMR analyses

(Table 17). Mortality from cancers of the buccal cavity and pharynx was slightly elevated

in the PMR analysis (eight deaths; PMR, 1.31) but not in the PCMR analysis (PCMR,

0.99). Mortality from lung and pleural cancers was close to expected in both the PMR (41

observed, 42.9 expected; PMR, 0.96) and PCMR (0.87) analyses. There was no death from

cancer of the nasal passages (0.6 expected). Mortality from leukaemia was found to be

increased predominantly among embalmers who had had a licence for 20 or more years

(eight deaths; PMR, 2.21). Six of the 12 cases of leukaemia were of the myeloid type

[PMR, 1.5]. 

Mortality among 1477 male embalmers who had been licensed by the Ontario

(Canada) Board of Funeral Services between 1928 and 1957 was evaluated by Levine et al.

(1984). The cohort was followed for mortality from the date of first licence through to

1977. Expected numbers of deaths were derived from the mortality rates for men in

Ontario in 1950–77, adjusted for age and calendar year. Since mortality rates for Ontario

were not available before 1950, person–years and deaths in the cohort before that time

were excluded from the analysis, which left 1413 men known to be alive in 1950. Mortality from all cancers was observed to be slightly lower than expected (58 deaths; SMR,

0.87 [95% CI, 0.66–1.12]). A small and statistically non-significant excess in mortality was

observed for cancers of the lymphatic and haematopoietic system (eight deaths; SMR, 1.23

[95% CI, 0.53–2.43]) and leukaemia (four deaths [SMR, 1.60; 95% CI, 0.44–4.10]).

Mortality from cancers of the buccal cavity and pharynx (one death [SMR, 0.48; 95% CI,

0.01–2.65]), lung (19 deaths; SMR, 0.94 [95% CI, 0.57–1.47]) and brain (three deaths

[SMR, 1.15; 95% CI, 0.24–3.37]) was close to or lower than expected. No death from

cancer of the nose, middle ear or sinuses was observed (0.2 expected). 

Hayes et al. (1990) identified 6651 deceased embalmers/funeral directors from the

records of licensing boards and state funeral directors’ associations in 32 states and the

District of Columbia and from the vital statistics offices of nine states and New York City

in the USA between 1975 and 1985. Death certificates were received for 5265. Exclusion

of 449 decedents included in previous studies of embalmers in New York (Walrath &

FORMALDEHYDE 121
Fraumeni, 1983) and California (Walrath & Fraumeni, 1984), 376 subjects who probably

did not work in the funeral industry, eight subjects of unknown race or age at death and 386

women left 4046 male decedents available for analysis (3649 whites and 397 non-whites).

PMRs and PCMRs were calculated on the basis of expected numbers from race- and sexspecific groups of the general population, adjusted for 5-year age and calendar-time categories. The PMR for all cancers was 1.07 (900 deaths; 95% CI, 1.01–1.15) for whites and

1.08 (102 deaths; 95% CI, 0.87–1.31) for non-whites. The PMRs for specific cancers were:

buccal cavity and pharynx (whites: 26 deaths; PMR, 1.19; 95% CI, 0.78–1.74; non-whites:

four deaths; PMR, 1.25; 95% CI, 0.34–3.20), nasopharynx (whites: three deaths; PMR, 1.89;

95% CI, 0.39–5.48; non-whites: one death; PMR, 4.00; 95% CI, 0.10–22.3), nasal sinuses

(whites and non-whites: 0 observed, 1.7 expected), lung (whites: 285 deaths; PMR, 0.97;

95% CI, 0.86–1.09; non-whites: 23 deaths; PMR, 0.75; 95% CI, 0.47–1.13), brain and

central nervous system (whites: 24 deaths; PMR, 1.23; 95% CI, 0.80–1.84; non-whites: 0

observed, 0.8 expected) and lymphatic and haematopoietic system (whites: 100 deaths;

PMR, 1.31; 95% CI, 1.06–1.59; non-whites: 15 deaths; PMR, 2.41; 95% CI, 1.35–3.97).

The risks for cancers of the lymphatic and haematopoietic system and brain and central

nervous system did not vary substantially by licensing category (embalmer versus funeral

director), by geographical region, by age at death or by source of data on mortality. Among

the lymphatic and haematopoietic cancers, the PMRs were significantly elevated for

myeloid leukaemia (both groups combined: 24 deaths; PMR, 1.57; 95% CI, 1.01–2.34) and

other and unspecified leukaemia (both groups combined: 20 deaths; PMR, 2.28; 95% CI,

1.39–3.52); non-significant excesses of mortality were observed for several other histological types.

2.1.3 Other cohort studies

In a study of users of various medicinal drugs based on computer-stored hospitalization

records of the outpatient pharmacy at the Kaiser–Permanente Medical Center in San

Francisco (CA, USA), Friedman and Ury (1983) evaluated cancer incidence in a cohort of

143 574 pharmacy users from July 1969 through August 1973 and followed them up to the

end of 1978. The number of cases among users of specific drugs was compared with the

number expected on the basis of rates for all pharmacy users, adjusted for age and sex.

Since many analyses were performed (56 cancers and 120 drugs, for 6720 combinations),

chance findings would be expected. Five cancers were associated with use of formaldehyde

solution (topically for warts) (morbidity ratio, 0.8 [95% CI, 0.3–2.0]). The morbidity ratio

for lung cancer was significantly elevated (four cases; morbidity ratio, 5.7 [95% CI,

1.6–15]) for people who used formaldehyde. Information on tobacco smoking was not provided. [The Working Group noted the short period of follow-up, the small number of cases

and the lack of detailed information on exposure that made this study largely uninformative.] 

Several studies have evaluated risk for cancer in haemodialysis patients who may

have been potentially exposed to formaldehyde (see Section 1.3.2). [The Working Group

122 IARC MONOGRAPHS VOLUME 88
considered these studies to be largely uninformative since some patients with chronic

renal failure receive immunosuppressive drugs, which are known to increase their risk for

cancer, and because these studies are generally small, have short follow-up and provide

limited or no information on exposures to formaldehyde.]

2.2 Case–control studies

Case–control studies have been used to examine the association between exposure to

formaldehyde and various cancers. For rare tumours such as sinonasal and nasopharyngeal

cancer, they have the potential to provide greater statistical power than can normally be

achieved in cohort studies. Against this advantage, however, must be set the difficulties in

assessing exposure to formaldehyde retrospectively in community-based studies. This

requirement is usually addressed through expert evaluation of job histories by an

occupational hygienist, or through the use of a job–exposure matrix. For a chemical such

as formaldehyde, however, these methods tend to lack specificity when applied to the

general population. Thus, the subjects who are classed as having been exposed to formaldehyde in community-based case–control studies usually have lower exposures on average

than those in occupational cohorts that are specially selected for investigation because they

are known to experience high exposures. Exposures to formaldehyde were assessed in

some studies by asking study subjects whether they had been exposed to formaldehyde.

This use of self-reported exposures is of questionable validity and in particular may lead

to recall bias. 

2.2.1 Cancers of the nasal cavity and paranasal sinuses 

The study design of and results from case–control studies on cancers of the nasal

cavity, paranasal sinuses, nasopharynx and hypopharynx associated with exposure to

formaldehyde are summarized in Table 18.

With the purpose of investigating the carcinogenic effects of exposure to wood dust,

Hernberg et al. (1983a) conducted a joint Nordic case–control study of 167 patients in

Finland, Sweden and most of Denmark in whom primary malignant tumours of the nasal

cavity and paranasal sinuses had been diagnosed between July 1977 and December 1980

and 167 country-, age- and sex-matched controls who had been diagnosed with cancers

of the colon and rectum. The study subjects represented 58% of all cancers identified at

these anatomical sites; the exclusions were due to early deaths or to non-responding or

missing controls. Information on the occupations and tobacco smoking habits of the study

subjects was obtained by standardized telephone interview. None of the cases or controls

had worked in the particle-board or plywood industry or in the production of formaldehyde or formaldehyde-based glues. No association was found between sinonasal cancer

and other occupations in which exposure to formaldehyde was considered to be most

probable. A total of 18 cases and six controls had worked in ‘painting, lacquering and

glueing’, a category that the authors considered may have entailed minimal exposure to

FORMALDEHYDE 123
Table 18. Case–control studies of cancers of the nasal cavity, paranasal sinuses, nasopharynx and hypopharynx Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Relative risk (95% CI) Hernberg et al. (1983a), Denmark, Finland, Sweden, 1977–80 Nasal cavity and parasinuses (160.0–160.9; ICD revision not given) 167 patients [sex distribution not reported] with primary malignant tumours 167 patients with cancer of the colon and rectum, matched by country, sex and age Employment in particle-board or plywood industry Painting, lacquering and glazing Yes/no Yes/no 0 cases, 0 contr

18 cases, 6 cont

Brinton et al. (1984), USA, 1970–80 Nasal cavity and parasinuses (ICD-8 160.0, 160.2–160.5, 160.8–160.9) 160 (93 men, 67 women), including 86 squamous-cell carci- nomas and 24 adeno- carcinomas or adenoid cystic carcinomas; 61 in nasal cavity, 71 in maxillary sinus and 28 other sinus or overlapping sites 290 (178 hospital controls, 112 death certificate controls); hospital controls were required to be alive for living cases; death certificate controls were identified for deceased cases; matched on age, sex, race and county of residence Telephone interviews with subjects or next of kin included a checklist of industries and self- reported exposures including formaldehyde. Men and women combined Unexposed Exposed 1.0 0.35 (0.1–1.8) Olsen et al. (1984), Denmark, 1970–82 Nasal cavity, nasal sinuses (160.0, 160.2, 160.9) and nasopharynx (146) (ICD 

revision not given) 

754 incident patients [sex distribution not reported] selected from the Danish Cancer Registry including 488 carcinomas of the nasal cavity and sinuses and 266 carcinomas of the nasopharynx 

2465 patients with cancers of the colon, rectum, prostate and breast; frequencymatched by sex, age (± 5 years) and year of diagnosis (± 5 years); 4.2% of men and 0.1% of women exposed to formaldehyde 

Industries and occupations with certain exposure to formaldehydeEver exposed  Unexposed to wood dust  Exposed to wood dust Exposure for > 10 years before diagnosis  Unexposed to wood dust  Exposed to wood dust  Adjusted for wood dust 

Sinonasal2.8 (1.8–4.3) 1.8 (0.7–4.9) 3.5 (2.2–5.6) 3.1 (1.8–5.4) 1.5 (0.4–5.3) 4.1 (2.3–7.3) 1.6 (0.7–3.6) 

Record linkage with pension fund with compulsory membership; job title from Central Pension Registry; exposure assessed blindly as certain, probable, unlikely, unknown 

Industries and occupations with certain or possible exposure Men Women 

Nasopharynx0.7 (0.3–1.7) 2.6 (0.3–21.9) 
Table 18 (contd) Reference, study location, years of study 

Organ site (ICD code) 

Characteristics of cases Characteristics of 

controls 

Exposure assessment 

Exposure categories Relative risk 

(95% CI) 

Any exposure to formaldehydeAssessment A Assessment B 

2.5 (1.5–4.3)a 1.9 (1.2–3.0)a

Hayes et al. (1986a), Netherlands, 1978–81 

Nasal cavity and accessory sinuses (ICD-9 160.0, 160.2–160.5) 

91 male patients histologically confirmed, alive or deceased 

195 age-stratified random sample of living men resident in the Netherlands in 1982 or deceased in the Netherlands in 1980 

No or little exposure to wood dust Assessment A Assessment B Moderate to high exposure to wood dustAssessment A Assessment B 

2.5 [1.0–5.9] 1.6 [0.8–3.1] 1.9 [0.6–6.5] NR 

Taking into account job history, time period and potential frequency of exposure, exposure was classified into 10 groups independently by two occupational hygienists (assessment A and B) 

Squamous-cell carcinoma onlyAssessment A Assessment B 

3.0 [1.2–7.8] 1.9 [0.9–4.1] 

Olsen & Asnaes (1986), Denmark, 1970–82 

Nasal cavity, paranasal sinuses (160.0, 160.2–160.9) and nasopharynx (146) (ICD revision not given) 

759 (509 men, 250 women) histologically confirmed cancers of the nasal cavity and paranasal sinuses (466 cases; 310 men, 156 women) and nasopharynx (293 cases; 199 men, 94 women) 

2465 patients with cancers of the colon, rectum, prostate and breast frequency-matched by sex, age (± 5 years) and year of diagnosis (± 5 years); 4.2% of men and 0.1% of women exposed to formaldehyde 

Record linkage with pension fund with compulsory membership; job title from Central Pension Registry; exposure assessed blindly as certain, probable, unlikely, unknown 

Likely or possible exposure to formaldehyde ≥ 10 years 

before diagnosisSquamous-cell carcinoma (215) Adenocarcinoma (39) 

2.4 (0.8–7.4) 1.8 (0.5–6.0) 
Table 18 (contd) Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Relative risk (95% CI) Vaughan et al. (1986a), USA, 1979–83 552 identified by random-digit dialling Low exposure Medium or high exposure Highest exposure score Sinonasal 0.8 (0.4–1.7) 0.3 (0.0–1.3) 0.3 (0.0–2.3) Nasal cavity (160) and pharynx (146– 149) (ICD revision not given) Job–exposure linkage system, resulting in four categories: high, medium, low and background Low exposure Medium or high exposure Highest exposure score Nasopharynx 1.2 (0.5–3.3) 1.4 (0.4–4.7) 2.1 (0.6–7.8) 

285 incident cases [sex distribution not reported] identified by the local Cancer Surveillance System, aged 20–74 years, including oro- and hypopharynx (205), nasopharynx (27) and sinuses (53) Low exposure Medium exposure High exposure Highest exposure score Oro-/hypophary

0.8 (0.5–1.4) 0.8 (0.4–1.7) 0.6 (0.1–2.7) 1.5 (0.7–3.0) 552 identified by random-digit dialling Residential exposure: residential history since 1950 Mobile home Particle-board at home 1–9 years ≥ 10 years Sinonasal 0.6 (0.2–1.7) 1.8 (0.9–3.8) 1.5 (0.7–3.2) 

Vaughan et al. (1986b), USA, 1979–83 Nasal cavity (160) and pharynx, (146– 149) (ICD revision not given) 285 incident cases [sex distribution not reported] identified by the local Cancer Surveillance System, aged 20–74 years, including oro- and hypopharynx (205), nasopharynx (27) and sinuses (53) Mobile home 1–9 years ≥ 10 years Particle-board at home 

 1–9 years 

≥ 10 years

Nasopharynx2.1 (0.7–6.6) 5.5 (1.6–19.4) 1.4 (0.5–3.4) 0.6 (0.2–2.3) 

Mobile home  1–9 years 

≥ 10 years 

Particle-board at home  1–9 years 

≥ 10 years

Oro-/hypophary0.9 (0.5–1.8) 0.8 (0.2–2.7) 1.1 (0.7–1.9) 0.8 (0.5–1.4) 
Table 18 (contd) Reference, study location, years of study 

Organ site (ICD code) 

Characteristics of cases Characteristics of 

controls 

Exposure assessment 

Exposure categories Relative risk 

(95% CI) 

Rousch et al. (1987), USA, 1935–75 

Nasal cavity and sinuses, and nasopharynx (ICD code not given) 

198 men with sinonasal cancer and 173 with nasopharyngeal cancer registered at the Connecticut Tumor Registry 

605 men who died during the same period, selected by random sampling without matching or stratification 

Job title, industry, specific employment, year of employment, obtained from death certificates and city directories 

Probably exposed for most of working life  Plus exposure ≥ 20 years  before death  Plus exposure to high  level for some years  Plus exposure to high  level ≥ 20 years before  death 

Sinonasal0.8 (0.5–1.3) 1.0 (0.5–1.8) 1.0 (0.5–2.2) 1.5 (0.6–3.9) 

Probably exposed for most of working life  Plus exposure ≥ 20 years  before death  Plus exposure to high  level for some years  Plus exposure to high  level ≥ 20 years before  death

Nasopharynx1.0 (0.6–1.7) 1.3 (0.7–2.4) 1.4 (0.6–3.1) 2.3 (0.9–6.0) 
Table 18 (contd) Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Relative risk (95% CI) Luce et al. (1993), France, 1986–88 Nasal cavity and parasinuses (ICD-9 160.0, 160.2–160.9) 207 cases (167 men, 40 women): 59 men and 18 women with squamous-cell carci- nomas, 82 men and five women with adeno- carcinomas and 25 men and 17 women with other histology 409 from two sources: 323 hospital cancer controls (15 sites) frequency-matched by age and sex; 86 proposed by cases, matched by age (± 10 years), sex and residence Squamous-cell carcinoma Possibly exposed Probably or definitely Average level ≤ 2 Average level > 2 Duration ≤ 20 years Duration > 20 years Cumulative level ≤ 30 > 30 Men 0.96 (0.38–2.42

0.70 (0.28–1.731.32 (0.54–3.241.09 (0.48–2.500.76 (0.29–2.01.26 (0.54–2.940.68 (0.27–1.75

Industrial hygienist review of structured job interview, classifying expo- sure by frequency, concentration and duration; compu- tation of cumulative exposure level and lifetime average level Adenocarcinoma Possibly exposed Probably or definitely Average level ≤ 2 Average level > 2 Duration ≤ 20 years Duration > 20 years Cumulative level ≤ 30 30–60 > 60 1.28 (0.16–10.4

4.15 (0.96–17.85.33 (1.28–22.21.03 (0.18–5.776.86 (1.69–27.81.13 (0.19–6.902.66 (0.38–18.76.91 (1.69–28.2

Other histology Possibly exposed Probably or definitely  Average level ≤ 2  Average level > 2  Duration ≤ 20 years  Duration > 20 years  Cumulative level 

≤ 30 

 > 30 

0.81 (0.15–4.361.67 (0.51–5.423.04 (0.95–9.702.82 (0.94–8.431.62 (0.48–5.52.18 (0.65–7.32.21 (0.73–6.73
Table 18 (contd) Reference, study location, years of study 

Organ site (ICD code) 

Characteristics of cases Characteristics of 

controls 

Exposure assessment 

Exposure categories Relative risk 

(95% CI) 

West et al. (1993), Philippines [study years not reported] 

Nasopharynx (ICD code not given) 

104 incident cases (76 men, 28 women) histologically confirmed 

104 hospital controls matched for sex, age and hospital ward type; 101 community controls matched for sex, age and neighbourhood 

Occupation classified as likely or unlikely to involve exposure to formaldehyde; duration of exposure; 10-year lag period; years since first exposure; age at start of exposure 

< 15 years ≥ 15 years < 15 years (10-year lag) ≥ 15 years (10-year lag) Age ≥ 25 years at first exposure Age < 25 years at first exposure First exposure < 25 years before diagnosis First exposure ≥ 25 years 

before diagnosis 

2.7 (1.1–6.6) 1.2 (0.5–3.2) 1.6 (0.6–3.8) 2.1 (0.7–6.2) 1.2 (0.5–3.3) 2.7 (1.1–6.6) 1.3 (0.6–3.2) 2.9 (1.1–7.6) 

Gustavsson et al. (1998), Sweden, 1988–91 

Oro- and hypopharynx (ICD-9 146, 148) 

545 incident male cases among residents of two regions, aged 40–79 years [including at least 124 cases of pharyngeal cancer] 

641 selected by stratified random sampling; frequency-matched to cases by age (10–15-year groups) and region 

Work history reviewed by occupational hygienist; occupations coded by intensity and probability of exposure 

Ever exposed 1.01 (0.49–2.07

Armstrong et al. (2000), Malaysia, (Selagor and Federal Territory), 1987–92 

Nasopharyngeal squamous-cell carcinoma (ICD code not given) 

282 Chinese men and women from four centres (prevalent and incident cases) [no information on age distribution] 

One Chinese control selected by multistage area sampling per case; matched by age and sex 

Structured in-home interviews; occupational exposures assessed by a job–exposure matrix 

Any (unadjusted) Any (adjusted) 

1.24 (0.67–2.320.71 (0.34–1.41
Table 18 (contd) Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Relative risk (95% CI) Laforest et al. (2000), France, 1989–91 Hypopharynx (squamous- cell) (ICD code not given) 201 men with confirmed histology from 15 hospitals [no information on age] 296 male patients with other (selected) primary tumours from the same or nearby hospitals; recruited 1987–91; matched by age Structured in- person interviews; occupational exposures assessed with a job–exposure matrix earlier developed Ever exposed Probability of exposure (%) < 10 10–50 > 50 Duration (years) < 7 7–20 > 20 Cumulative level Low Medium High Exclusion of subjects with exposure probability < 10% Ever exposed Duration (years) < 7 7–20 

 > 20 Cumulative level Low  Medium  High 

1.35 (0.86–2.141.08 (0.62–1.881.01 (0.44–2.313.78 (1.50–9.491.09 (0.50–2.381.39 (0.74–2.621.51 (0.78–2.921.03 (0.51–2.071.57 (0.81–3.061.51 (0.74–3.101.74 (0.91–3.340.74 (0.20–2.681.65 (0.67–4.082.70 (1.08–6.730.78 (0.11–5.451.77 (0.65–4.781.92 (0.86–4.32
Table 18 (contd) Reference, study location, years of study 

Organ site (ICD code) 

Characteristics of cases Characteristics of 

controls 

Exposure assessment 

Exposure categories Relative risk 

(95% CI) 

Vaughan et al. (2000), USA (Connecticut, metropolitan Detroit, Iowa, Utah, Washington), 1987–93 

196 men and women [sex distribution not reported] from five cancer registries, aged 18–74 years 

244 population-based selected by random digit dialling; frequencymatched by sex, cancer registry and age (5-year groups) 

Structured telephone interviews; occupational exposures assessed by a job–exposure matrix 

Ever exposed Max. exposure (ppm) < 0.1  0.1–0.5  > 0.5 

p for trend 

Duration (years) 1–5  6–17 

≥ 18 p for trend 

Differentiated squamouscell and epithelial NOS onlyEver exposed 

1.3 (0.8–2.1) 1.4 (0.8–2.4) 0.9 (0.4–2.3) 1.6 (0.3–7.1) 0.57 0.8 (0.4–1.6) 1.6 (0.7–3.4) 2.1 (1.0–4.5) 0.070 1.6 (1.0–2.8) 

Epithelial nasopharyngeal carcinoma: epithelial NOS (801x–804x), undifferentiated or nonkeratinizing (8020–1, 8072–3, 8082) and squamous-cell (805x–808x, except 8072–3) 

Duration (years)  1–5  6–17 

≥ 18 p for trend 

Cumulative exposure (ppm–years)  0.05–0.4  > 0.4–1.10  > 1.10 

p for trend 

0.9 (0.4–2.1) 1.9 (0.9–4.4) 2.7 (1.2–6.0) 0.014 0.9 (0.4–2.0) 1.8 (0.8–4.1) 3.0 (1.3–6.6) 0.033 
Table 18 (contd) Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Relative risk (95% CI) Hildesheim et al. (2001) Taiwan, China, 1991–94 Nasopharynx; > 90% non- keratinizing and undifferentiated and remainder squamous-cell carcinomas (ICD code not given) 375 histologically confirmed hospital cases (31% women), aged < 75 years 325 community controls, individually matched on sex, age (5 years) and district of residence Structured in- person interviews; occupational exposures assessed by an industrial hygienist; blood specimen was tested for anti-EBV antibodies. Ever exposed Duration 1–10 years >10 years p for trend Cumulative exposure < 25 ≥ 25 p for trend 1.4 (0.93–2.2) 1.3 (0.69–2.3) 1.6 (0.91–2.9) 0.08 1.3 (0.70–2.4) 1.5 (0.88–2.7) 0.10 Berrino et al. (2003), France, Italy, Spain, Switzerland, 1979–82 Hypopharynx and epilarynx (ICD code not given) 100 men, incident cases histologically con- firmed from six centres, aged ≤ 55 years 819 men from the general local population of each centre; age- and sex- stratified Structured in- person interviews; occupational exposures assessed by an expert panel using a previously established job– exposure matrix Probability of exposure Possible Probable and certain 1.3 (0.6–2.6) 0.5 (0.1–1.8) CI, confidence interval; EBV, Epstein-Barr virus; ICD, international code of diseases; NOS, not otherwise specified; PAHs, polycyclic aromatic hydrocarbons a 90% confidence interval 
formaldehyde; when workers exposed to wood dust were excluded, more controls than

cases had been exposed (three cases, six controls). [The Working Group noted that the

study was not designed to address exposure to formaldehyde and that all the cases in Denmark were also included in the study of Olsen et al. (1984).]

In a case–control study conducted in four hospitals in North Carolina and Virginia,

USA, in 1970–80, 193 men and women who had primary malignancies of the nasal cavity

and sinuses were identified (Brinton et al., 1984). Two hospital controls who were alive at

the date of the interview were selected for each living patient and matched on hospital, year

of admission, age, sex, race and administrative area; for deceased patients, two similarly

matched controls were chosen: one patient who had attended the same hospital but who

was not necessarily alive at the date of the interview, and one deceased person who was

identified from records of the state vital statistics offices. Patients who had cancer of the

buccal cavity and pharynx, nasal cavity, middle ear and accessory sinuses, larynx and oesophagus and patients who had various nasal disorders were excluded from the control group.

Telephone interviews were completed for 160 of the nasal cancer patients (83%) and 290

of the controls (78%), either directly with the patients themselves (33% of cases and 39%

of controls) or with their next of kin. Occupational exposures were assessed by the interviewee’s recall in response to a checklist of exposures, including formaldehyde. Exposure

to formaldehyde was reported for two nasal cancer patients (one man and one woman), to

yield an odds ratio of 0.35 (95% CI, 0.1–1.8). [The Working Group noted that the exposure assessment was limited as it relied on self-reports and, furthermore, that a high proportion of interviews were with next of kin. The informativeness of the study was further

limited by the small number of exposed subjects.]

In a population-based study in Denmark (Olsen et al., 1984), 488 men and women in

whom cancer of the sinonasal cavities had been diagnosed during the period 1970–82 and

reported to the national cancer registry were matched to 2465 controls for sex, age and

year of diagnosis, who were selected from all patients in whom cancer of the colon,

rectum, prostate or breast had been diagnosed during the same period. Histories of exposure to formaldehyde, wood dust and 10 other specified compounds or industrial procedures were assessed by industrial hygienists who were unaware of the case or control

status of the study subjects, on the basis of individual employment histories obtained from

a national pension scheme in operation since 1964. The industrial hygienists classified

subjects according to whether they had definitely or probably been exposed, had not been

exposed or had undetermined exposure to individual compounds during 1964–82. Of the

controls, 4.2% of men and 0.1% of women had held occupations that presumably entailed

exposure to formaldehyde. The odds ratios for definite exposures to formaldehyde (unadjusted for any other occupational exposure and using the no exposure category as the

reference level) were 2.8 (95% CI, 1.8–4.3) for men and 2.8 (95% CI, 0.5–14) for women.

Further results were not presented for women. Adjustment for exposure to wood dust

reduced the risk estimate for men to 1.6, which was no longer significant. Only five men

in the group of 33 workers with definite exposure to formaldehyde had not been exposed

to wood dust. Probable exposure to formaldehyde was associated with a slightly increased

FORMALDEHYDE 133
risk for sinonasal cancer in men (odds ratio, 1.2; 95% CI, 0.8–1.7). [The Working Group

noted that the employment histories of study subjects were restricted to 1964 or later and

that the study was limited by the fact that the industries that used formaldehyde in

Denmark in this study seemed to be dominated by exposure to wood dust, which makes

assessment of the separate effect of exposure to formaldehyde on the risk for sinonasal

cancer difficult.]

A re-analysis was performed (Olsen & Asnaes, 1986) in which data on 215 men with

squamous-cell carcinoma and 39 with adenocarcinoma of the sinonasal cavities were examined separately. An odds ratio (adjusted for exposure to wood dust) of 2.3 (95% CI,

0.9–5.8) for squamous-cell carcinoma was found for 13 cases who had ever been exposed

to formaldehyde; of these, four had not been exposed to wood dust, which gave an odds

ratio of 2.0 (95% CI, 0.7–5.9). Introduction of a 10-year lag period into the analysis yielded

odds ratios of 2.4 (95% CI, 0.8–7.4) and 1.4 (95% CI, 0.3–6.4), respectively. The analysis

revealed an association between exposure to wood dust and adenocarcinoma (odds ratios

for any exposure, 16.3; 95% CI, 5.2–50.9) but only a weak association with squamous-cell

carcinoma (odds ratio, 1.3; 95% CI, 0.5–3.6). For the 17 cases of adenocarcinoma in men

who had ever been exposed to formaldehyde, the odds ratio, after adjustment for exposure

to wood dust, was 2.2 (95% CI, 0.7–7.2), and that among men who had been exposed 10

or more years before diagnosis was 1.8 (95% CI, 0.5–6.0); however, only one man who had

an adenocarcinoma had been exposed to formaldehyde alone. [The Working Group noted

a concern that possibly incomplete adjustment for confounding from exposure to wood

dust in the assessment of the risk for adenocarcinoma could explain the weak association

observed with exposure to formaldehyde, but also noted that the assessment of risk for

squamous-cell carcinoma was unlikely to have been affected because squamous-cell carcinoma was not clearly associated with exposure to wood dust.]

From an examination of medical records in the six major institutions in the Netherlands

for surgical and radiographic treatment of tumours of the head and neck, Hayes et al.

(1986a) identified 116 men, aged 35–79 years, in whom a histologically confirmed epithelial

cancer of the nasal cavity or paranasal sinuses had been diagnosed during 1978–81. The

cases were frequency-matched on age with 259 population controls who were chosen

randomly from among living male residents of the Netherlands in 1982 (in a ratio of 2:1 for

all patients) and from among deceased men in 1980 (in an approximate ratio of 1:1 for dead

cases). Detailed histories, including information on exposure to a selected list of substances

in the workplace and subjects’ tobacco smoking habits, were obtained by personal interview

of study subjects or their next of kin, with a participation of 78% for 91 case patients and

75% for 195 controls. Independently of one another, two industrial hygienists (A and B)

reviewed job histories and graded possible exposure to formaldehyde. Exposure to wood

dust was assessed similarly by one hygienist. At least some potential occupational exposure

to formaldehyde was considered to have occurred for 23% of all study subjects by assessment A and for 44% by assessment B; among 224 subjects with little or no exposure to wood

dust, exposure to formaldehyde was considered by assessments A and B to have occurred in

15 and 30%, respectively. For 62 subjects who were classed as having moderate or high

134 IARC MONOGRAPHS VOLUME 88
exposure to wood dust, there was a weak association with exposure to formaldehyde as

assessed by hygienist A (odds ratio, 1.9 [95% CI, 0.6–6.5]), but no odds ratio could be

derived for exposure as assessed by hygienist B. For the 224 subjects who had little or no

exposure to wood dust, the odds ratios for exposure to formaldehyde were 2.5 [95% CI,

1.0–5.9] (hygienist A) and 1.6 [95% CI, 0.8–3.1] (hygienist B). When the analysis was

restricted to 45 cases of squamous-cell carcinoma of the paranasal sinuses who had little or

no exposure to wood dust, the odds ratios for high exposure to formaldehyde were 3.1

[95% CI, 0.7–13.5] (hygienist A) and 2.4 [95% CI, 0.9–6.1] (hygienist B). [The Working

Group noted that a greater proportion of case patients than controls were deceased (36%

versus 14%) and variable numbers of next of kin were interviewed; furthermore, 10% of

controls but none of the case patients were interviewed by telephone. The Group noted,

however, that, although assessments A and B differed, both gave positive results.]

Vaughan et al. (1986a) conducted a population-based case–control study in a 13-

county area in western Washington State, USA. The study included incident cases of sinonasal and pharyngeal cancer that were identified from a cancer registry that was reported

to identify 98–99% of the cancers in the study area. Cases eligible for study were between

the ages of 20 and 74 years and had a date of diagnosis between 1979 and 1983 for sinonasal cancer, and from 1980 to 1983 for pharyngeal cancer. Control subjects were identified by random-digit dialling and were frequency-matched to be similar in age and sex as

the cases. Medical, tobacco smoking, alcohol use, residential and occupational histories

were collected in a telephone interview with study subjects or their next of kin. Of the 415

cases eligible for study, 59 could not be located or were deceased with no known next of

kin and 61 were not interviewed due to physician or subject refusal. Of the 295 cases who

were successfully interviewed, 10 did not meet the eligibility requirements of the study,

resulting in 285 cases being included in the analysis (53 sinonasal, 27 nasopharyngeal and

205 oro- or hypopharyngeal cancers). Approximately half of the case interviews were with

their next of kin. Of a total of 690 persons eligible as controls, 573 were interviewed; 21 of

these were excluded because they did not meet the eligibility requirements of the study,

which resulted in 552 controls being available for analysis. [Although not explicitly stated,

it appears that none of the interviews of the controls were by proxy.] Occupational exposure to formaldehyde was assessed by means of a job–exposure linkage system in which

each job within each industry was classified according to the likelihood of exposure

(unlikely, possible or probable). Those jobs that were defined as probably exposed were

further classified into high or low exposure intensity. These two measures of exposure

were then combined into a summary variable that resulted in the following four levels:

(1) high (probable exposure to high levels), (2) medium (probable exposure to low levels),

(3) low (possible exposure at any level) and (4) background. For the analysis, an estimate

of the duration of exposure and the maximum exposure level (low, medium or high)

reached in any job was developed for each individual. A cumulative exposure score was

also developed by combining the information on duration and level of exposure. Unconditional logistic regression was used for the analysis in which age, sex and other potential

confounders were controlled for when necessary. The odds ratios for sinonasal cancer,

FORMALDEHYDE 135
adjusted for sex, age, cigarette smoking and alcohol consumption, decreased with increasing exposure by all of the measures. The odds ratios observed were: 0.8 (95% CI, 0.4–1.7)

for low and 0.3 (95% CI, 0.0–1.3) for medium or high maximum exposure level attained;

0.7 (95% CI, 0.3–1.4) for 1–9 years and 0.4 (95% CI, 0.1–1.9) for ≥ 10 years of exposure;

and 0.5 (95% CI, 0.1–1.6) for 5–19 and 0.3 (95% CI, 0.0–2.3) for ≥ 20 units of the exposure

score. [The number of exposed cases could not be determined for these analyses.] An analysis was also performed in which the exposure score was estimated at 16 years before the

date of diagnosis for the case and 16 years before the date of interview for the controls (i.e.

lagged by 16 years). Lagging the exposures in this way resulted in no cases in the high

exposure group, and did not produce interpretable findings. [The Working Group noted that

the different proportions of interviews conducted with next of kin of cases and controls

may have affected the odds ratios.]

Vaughan et al. (1986b) also explored the relationships between these types of tumour

and residential exposure to formaldehyde. Living in a mobile home and the presence of

urea–formaldehyde foam insulation, particle-board or plywood in residences were taken as

indirect measures of residential exposure. Five of the patients with sinonasal cancer had

lived in a mobile home (odds ratio, 0.6; 95% CI, 0.2–1.7), all for fewer than 10 years; 25

had lived in residences constructed with particle-board or plywood, which yielded odds

ratios of 1.8 (95% CI, 0.9–3.8) for periods of < 10 years and 1.5 (95% CI, 0.7–3.2) for

≥ 10 years. The risks associated with exposure to formaldehyde foam insulation could not

be estimated, because of low exposure frequencies. 

Roush et al. (1987) reported on a population-based case–control study of 371 men registered at the Connecticut (USA) Tumor Registry with a diagnosis of sinonasal cancer (198

cases) or nasopharyngeal cancer (173 cases), who had died of any cause in Connecticut in

1935–75, and 605 male controls who had died during the same period and were selected

randomly from the files of Connecticut death certificates, without stratification or matching.

Information on the occupations of the study subjects was derived from death certificates and

from annual city directories; the latter were consulted 1, 10, 20, 25, 30, 40 and 50 years

before death, when available. Odds ratios for occupation–cancer relationships based on

occupational information obtained from death certificates were similar to the corresponding

odds ratios based on city directory information in two previous studies. Each occupation

held by case patients and controls was assessed by an industrial hygienist (blinded to

case–control status) with regard to the likelihood (none, possibly, probably, definitely) and

level (0, < 1 ppm, ≥ 1 ppm) of workplace exposure to formaldehyde, and study subjects were

subsequently categorized into one unexposed and four exposed groups according to degrees

of probable exposure to formaldehyde. For sinonasal cancer, the odds ratio, adjusted for age

at death, year of death and number of jobs reported, was 0.8 (95% CI, 0.5–1.3) for those who

had probably been exposed to some level of formaldehyde for most of their working life

compared with all others. In order to evaluate high short-term exposures, the odds ratio for

those who fulfilled the more restricted exposure criteria of being probably exposed to some

level for most of their working life and probably exposed to high levels for some years was

1.0 (95% CI, 0.5–2.2) and, for those who had probably been exposed to some level for most

136 IARC MONOGRAPHS VOLUME 88
of their working life and probably exposed to high levels at some point 20 or more years

before death, the odds ratio was 1.5 (95% CI, 0.6–3.9). 

Luce et al. (1993) conducted a case–control study of men and women who had primary

malignancies of the nasal cavities and paranasal sinuses and were diagnosed in one of

27 hospitals in France between January 1986 and February 1988. Three hundred and three

cases were identified; 57 had died and, of the remaining 246 cases, 32 could not be located

or were too ill and seven refused to participate. Histological confirmation was available in

the medical records of all but one of the remaining 207 case patients. Four hundred and

forty-three control subjects were selected by frequency matching for age and sex among

patients in whom another cancer had been diagnosed during the same period at the same

or a nearby hospital (340 subjects) or from a list of names of healthy individuals provided

by the cases (103 subjects). Sixteen could not be located or were too ill and 18 declined to

participate, which left 409 controls for analysis. Occupational exposures to formaldehyde

and 14 other substances or groups of substances were assessed by an industrial hygienist

on the basis of information that was obtained during a personal interview at the hospital

(for the cancer patients) or at home (for the healthy controls) on job histories, a number of

pre-defined occupational exposures, socioeconomic variables and tobacco smoking habits.

Study subjects were classified according to the likelihood of exposure to each of the

suspected determinants of sinonasal cancer and were grouped into one of four categories:

none, possible, probable or definite exposure; the latter two were further split into a

number of subgroups according to three levels and calendar periods of exposure and combinations thereof. For formaldehyde, a cumulative index was calculated from the levels

and duration of exposure, as well as lifetime occupational exposure. Among men, 36% of

the controls and 55% of the cases were classified as potentially exposed to formaldehyde.

The risks associated with exposure to formaldehyde were reported for men only. For the

59 cases who had squamous-cell carcinoma, odds ratios (adjusted for age and exposure to

wood and glue) were 1.26 (95% CI, 0.54–2.94) and 0.68 (95% CI, 0.27–1.75) for the index

categories of lower and higher cumulative exposure among the probable/definite exposure

group. Similar patterns were evident by lifetime average level and duration of exposure.

Among the 82 cases of adenocarcinoma, 67 were in the probable/definite exposure group.

Odds ratios (adjusted for age and exposure to wood and glue) categorized into three levels

of the cumulative exposure index were 1.13 (95% CI, 0.19–6.90), 2.66 (95% CI, 0.38–

18.70) and 6.91 (95% CI, 1.69–28.23), respectively. However, most (71/82) of the formaldehyde-exposed cases of adenocarcinoma had also been exposed to wood dust, and the

odds ratio for being exposed to wood dust and formaldehyde versus neither was very large

(odds ratio, 692; 95% CI, 91.9–5210). Only four cases of adenocarcinoma were classified

as exposed to formaldehyde but not wood dust (odds ratio, 8.1; 95% CI, 0.9–72.9). [The

Working Group noted that residual confounding by exposure to wood dust may have

occurred.] 

FORMALDEHYDE 137
2.2.2 Nasopharyngeal carcinoma

The study design of and results from case–control studies of the association of exposure to formaldehyde with cancer of the nasopharynx are summarized in Table 18.

The study by Olsen et al. (1984) (described in detail in Section 2.2.1) also evaluated the

risk of exposure to formaldehyde among 266 men and women who had been diagnosed with

nasopharyngeal cancer. The odds ratio, unadjusted for other occupational exposures, for

exposure to formaldehyde was 0.7 (95% CI, 0.3–1.7) for men and 2.6 (95% CI, 0.3–21.9)

for women. 

The association between nasopharyngeal carcinoma and exposure to formaldehyde was

also examined in the population-based case–control study in 13 counties of Washington

State conducted by Vaughan et al. (1986a,b) (described in Section 2.2.1). The odds ratios

increased slightly with all of the measures of occupational exposure examined in this study.

The observed odds ratios in the analysis of the maximum exposure level achieved were: 1.2

(seven exposed cases; 95% CI, 0.5–3.3) for low exposure and 1.4 (four exposed cases;

95% CI, 0.4–4.7) for medium or high exposures; 1.2 (eight exposed cases; 95% CI, 0.5–3.1)

for 1–9 years and 1.6 (three exposed cases; 95% CI, 0.4–5.8) for ≥ 10 years of exposure; and

0.9 (three exposed cases; 95% CI, 0.2–3.2) for 5–19 units and 2.1 (three exposed cases; 95%

CI, 0.6–7.8) for ≥ 20 units of the cumulative exposure score. When a lag period of 15 years

or more was introduced into the analysis, the odds ratio associated with the highest cumulative exposure score to formaldehyde was unchanged (two exposed cases; odds ratio, 2.1;

95% CI, 0.4–10). An association was found between living in a mobile home and risk for

nasopharyngeal cancer, with odds ratios of 2.1 (four exposed cases; 95% CI, 0.7–6.6) for

< 10 years and 5.5 (four exposed cases; 95% CI, 1.6–19.4) for ≥ 10 years of residence. An

analysis was performed that considered the joint effect of occupational exposure and

residence in a mobile home. Subjects were considered to be occupationally exposed in this

analysis if they had a cumulative exposure score of 5 or more. A relatively strong association

was observed among individuals who were exposed occupationally and had ever lived in a

mobile home compared with those who had neither exposure (odds ratio, 6.7; 95% CI,

1.2–38.9), although this finding was based on only two cases and seven controls with joint

exposure. 

In the study by Roush et al. (1987) (described in Section 2.2.1), the odds ratios for

men with nasopharyngeal cancer were presented in the following categories: those who

had probably been exposed to some level for most of their working life; those who had

probably been exposed to some level for most of their working life and probably been

exposed to high levels for some years; and those who had probably been exposed to some

level for most of their working life and probably been exposed to high levels at some point

20 or more years before death. The odds ratios were, respectively, 1.0 (95% CI, 0.6–1.7),

1.4 (95% CI, 0.6–3.1) and 2.3 (95% CI, 0.9–6.0).

The etiology of nasopharyngeal carcinoma was studied in the Philippines; both viral

(Hildesheim et al., 1992) and non-viral (West et al., 1993) risk factors were addressed.

West et al. (1993) conducted a case–control study of 104 histologically confirmed cases of

138 IARC MONOGRAPHS VOLUME 88
nasopharyngeal carcinoma in Rizal Province, where the incidence rates of this tumour

(4.7/100 000 men and 2.6/100 000 women) were intermediate between those in China and

those in western countries. The cases (100% response rate) were identified at the Philippines General Hospital, as were 104 hospital controls (100% response rate), who were

matched to cases on sex, age and type of hospital ward; 101 community controls (77%

response rate), who were matched on sex, age and neighbourhood, were also available.

Hospital controls were selected from the rosters of patients who were present on the same

day that a suspected case was confirmed by biopsy; patients who had disorders that were

possibly linked to dietary patterns were excluded (gastrointestinal cancer, peptic ulcer,

chronic cirrhosis, gallbladder disease). Community controls were asked to participate on

the basis of their living in a house close to that of their matched case. A personal interview

included questions on tobacco smoking and areca nut habits, diet, sociodemographic

variables and occupational history. An industrial hygienist classified each job held by the

study subjects as likely or unlikely to involve exposure to formaldehyde, solvents, exhaust

fumes, wood dust, dust in general and pesticides, and combined the classification with

information on period and duration of employment in such occupations. Since the findings

on occupational exposures did not differ when hospital and community controls were

considered separately, only results from the comparison of cases versus all controls are

shown. Four exposure indices were established for each subject: total duration, duration

lagged by 10 years, number of years since first exposure and age at first exposure. The risk

for nasopharyngeal carcinoma was associated with exposure to formaldehyde; the odds

ratios, adjusted for the effects of dusts and exhaust fumes and other suspected risk factors,

were 1.2 (12 exposed cases; 95% CI, 0.41–3.6) for subjects who were first exposed

< 25 years before diagnosis and 4.0 (14 exposed cases; 95% CI, 1.3–12.3) for those who

were first exposed ≥ 25 years before diagnosis. In the subgroup of subjects who were first

exposed to formaldehyde ≥ 25 years before diagnosis and first exposed to dust and/or

exhaust fumes ≥ 35 years before diagnosis, an odds ratio of 15.7 (95% CI, 2.7–91.2) was

found relative to people who were not exposed to either factor [numbers exposed not

given]. The odds ratio for an overall exposure of ≥ 15 years (eight exposed cases; odds

ratio, 1.2; 95% CI, 0.48–3.2) was lower than that for a duration of < 15 years (19 exposed

cases; odds ratio, 2.7; 95% CI, 1.1–6.6). However, when exposure was lagged by 10 years,

those exposed for ≥ 15 years showed an odds ratio of 2.1 (eight exposed cases; 95% CI,

0.70–6.2). Subjects who were first exposed before the age of 25 years had an odds ratio of

2.7 (16 exposed cases; 95% CI, 1.1–6.6), while the odds ratio for those who were first

exposed at age 25 or more years was 1.2 (11 exposed cases; 95% CI, 0.47–3.3). Subjects

who reported daily use of anti-mosquito coils had a 5.9-fold (95% CI, 1.7–20.1) increase

in risk compared with those who reported never using coils in a model that adjusted for

potential confounders (West et al., 1993). [The Working Group noted that formaldehyde

has been reported to occur in the smoke released from anti-mosquito coils (see Section 1),

and that the authors did not control for the presence of Epstein-Barr viral (EBV) antibodies, which showed a strong association with nasopharyngeal cancer (odds ratio, 21) in

the study of Hildesheim et al. (1992).]

FORMALDEHYDE 139
A study from Malaysia investigated nasopharyngeal cancer based on cases that were

ascertained through records of histologically confirmed diagnoses at four centres that had

a radiotherapy unit (Armstrong et al., 2000). In total, 530 Chinese cases of squamous-cell

carcinomas of the nasopharynx who had resided in the study area for at least 5 years were

diagnosed between 1 January 1987 and 30 June 1992. Among these, only 282 (53%) were

included in the study (69% men), since 121 (23%) had died, 63 (12%) could not be

located, four (1%) were too ill to participate and 60 (11%) refused to participate. One

control with no history of cancer of the head, neck or the respiratory system was selected

from the Chinese population who had resided for at least 5 years in the study area and

matched to each case by sex and age (within 3 years). Information on exposures (complete residential and occupational history, alcohol and tobacco use and consumption of

55 food items at age 10 and 5 years before diagnosis) of cases and controls was obtained

by structured in-home interviews by trained interviewers. Occupational history included

job description, work performed, calendar time, machines, tools and substances used, size

and type of workplace, and exposure to dusts, smoke, gases and chemicals. [It appears that

additional questionnaires that collected more detailed information on some jobs were also

used.] Exposure to 22 agents, which were selected for their ability to deposit on or be

absorbed into the nasopharynx, was identified by job, calendar years, frequency (days per

week) and duration (hours per day). Jobs were coded using the official Malaysian classification scheme. Four levels of exposure (none, low, medium and high) were established.

[It was not clear whether the exposure assessment was made using a job–exposure matrix

approach or on an individual level, because both approaches are referenced.] Dermal

exposure was considered. The proportion of study participants with exposure to

formaldehyde was 9.9% of cases and 8.2% of controls. For any versus no occupational

exposure to formaldehyde, the odds ratio for both sexes combined was 1.24 (95% CI,

0.67–2.32) and 0.71 (95% CI, 0.34–1.43) after adjustment for diet and tobacco use. No

dose–response relationship appeared with increasing duration of formaldehyde exposure. 

In a multicentred, population-based case–control study from five cancer registries in the

USA, associations between occupational exposure to formaldehyde and wood dust and

nasopharyngeal cancer were investigated (Vaughan et al., 2000). At four of the five

registries, the investigators identified cases diagnosed between 1 April 1987 and 30 June

1991, while case ascertainment at the fifth registry was extended for an additional 2 years.

Eligible cases were men and women aged 18–74 years who had any histological type of

nasopharyngeal cancer. Interviews were completed for 231 of the 294 eligible cases identified, and included 44 (19%) that were conducted with the next of kin (usually the spouse).

The 196 cases who had epithelial cancers were further classified into three histological

subgroups: differentiated squamous-cell (118 cases), undifferentiated or non-keratinizing

(54 cases) or epithelial not otherwise specified (24 cases). Controls were identified by

random-digit dialling and were frequency-matched by age (5-year age groups), sex and

cancer registry. Among 324 eligible controls, 246 were interviewed (76%), two of whom

were excluded because they had no telephone, which left 244 controls for analysis; for three

controls, the interview was conducted with the next of kin. Experienced interviewers from

140 IARC MONOGRAPHS VOLUME 88
each of the five cancer registries conducted structured telephone interviews with the study

subjects, which included questions on demographic background, previous medical conditions and use of medication, family history of cancer, use of alcohol and tobacco, and a lifetime history of occupational and chemical exposures, including those to formaldehyde and

wood dust. For each job that had been held for at least 6 months, information was collected

on job title, typical activities within the job, the type of industry and the dates at which

employment began and ended. Industrial hygienists blindly assessed exposure to formaldehyde and wood dust on a job-by-job basis for each subject, based on all the available

information. For each job held, both the probability (none or unlikely, possible, probable,

definite) of exposure to formaldehyde and a related estimated concentration of exposure to

formaldehyde (low, moderate, high) which represented an 8-h TWA were assigned. Cut-off

points for analyses by duration and cumulative exposure were based on the 50th and 75th

percentiles among exposed controls. The proportion of subjects who were potentially

exposed to formaldehyde was 40.3% of cases compared with 32.4% of controls. For persons

who were ever exposed occupationally to formaldehyde versus those who were unexposed,

the odds ratio adjusted for age, sex, race, cancer registry, cigarette use, next-of-kin status and

education for all epithelial nasopharyngeal cancer was 1.3 (95% CI, 0.8–2.1); for the histological subcategories of undifferentiated and non-keratinizing, differentiated squamous-cell

and epithelial not otherwise specified, the odds ratios were 0.9 (95% CI, 0.4–2.0), 1.5

(95% CI, 0.8–2.7) and 3.1 (95% CI, 1.0–9.6), respectively. There was no consistent pattern

of association or trend in risk with estimated maximum exposure concentration for all histological types combined. A trend of increasing risk was seen with increasing duration of

exposure (ptrend = 0.07). The odds ratio for persons who had worked at least 18 years in jobs

with potential exposure was 2.1 (95% CI, 1.0–4.5). Further analyses were conducted that

excluded cancers of undifferentiated and non-keratinizing histology. The adjusted odds ratio

by estimated probability of exposure to formaldehyde was 1.6 (95% CI, 1.0–2.8) for ever

having held a job classified as ‘possible, probable or definite’, 2.1 (95% CI, 1.1–4.2) for

‘probable or definite’ and 13.3 (95% CI, 2.5–70) for ‘definite’. Within the group classified

with ‘possible, probable or definite’ exposure to formaldehyde, the subgroups with duration

of exposure of 1–5 years, 6–17 years and over 18 years had odds ratios of 0.9 (95% CI,

0.4–2.1), 1.9 (95% CI, 0.9–4.4) and 2.7 (95% CI, 1.2–6.0), respectively, and the ptrend value

for a dose–response relationship was 0.014. A similar dose–response pattern within this

group was seen for estimated cumulative exposure (ptrend = 0.033). When the group was

restricted to subjects with probable or definite exposure, the significance of trends lessened

with respect to duration of exposure (p = 0.069) and cumulative exposure (p = 0.13). When

a 10-year lag period was included, the overall findings remained similar. Moreover, the odds

ratios for exposure to formaldehyde were essentially unaffected by adding exposure to

wood dust to the models. 

Hildesheim et al. (2001) investigated the associations between occupational exposure

to formaldehyde, wood dust and organic solvents and risk for nasopharyngeal cancer. Incident cases (< 75 years) with histologically confirmed diagnoses were identified from two

hospitals in Taipei, China (Province of Taiwan). Of 378 eligible cases that were identified,

FORMALDEHYDE 141
375 agreed to participate in the study. About one third (31%) of the cases were women. One

control with no history of nasopharyngeal cancer was matched to each case with respect to

age (5 years), sex and district of residence. In total, 87% of eligible controls agreed to participate, which left 325 controls for the analysis. All study participants were interviewed by

trained interviewers (nurses). Cases were interviewed at the time of biopsy and before

treatment. The interviews obtained information on sociodemographic characteristics, diet,

cigarette smoking and betel-quid chewing, residential and medical history and a complete

occupational history for all jobs that had been held for at least 1 year since the age of 16

years. Living mothers were interviewed about the childhood diet of study participants. Data

on occupational history were reviewed blindly by an industrial hygienist. Standard

industrial and occupational classification codes were assigned to each job. Each code was

assigned a classification (10 levels) for probability and intensity of exposure to formaldehyde, wood dust and organic solvents. In total, 156 of 2034 jobs (7.7%) were classified

as entailing exposure to formaldehyde. Blood specimens were collected from 369 cases

and 320 controls, and serum was tested for various antibodies against EBV, which is known

to be associated with nasopharyngeal cancer. After adjustment for age, sex, education and

ethnicity, the odds ratio (both sexes combined) for ever exposure to formaldehyde was 1.4

(95% CI, 0.93–2.2). The odds ratios for ≤ 10 years and > 10 years of exposure to formaldehyde were 1.3 (95% CI, 0.69–2.3) and 1.6 (95% CI, 0.91–2.9), respectively. Those

exposed for > 20 years had an odds ratio of 1.7 (95% CI, 0.77–3.5), but the trend for ≤ 10,

10–20, and > 20 years of exposure did not reach statistical significance. The odds ratios by

estimated cumulative exposure (intensity × duration) gave a similar pattern. The observed

associations were not substantially affected by additional adjustment for exposure to wood

dust or organic solvent. In the sub-analyses that were restricted to 360 cases and 94 controls

who were seropositive for at least one of five antibodies against EBV, the association

between exposure to formaldehyde and nasopharyngeal cancer appeared to be stronger to

some extent. Thus, the odds ratio of ever versus never having been exposed was 2.7

(95% CI, 1.2–6.2). However, no clear dose–response pattern was observed with increasing

duration of exposure or estimated cumulative exposure. 

2.2.3 Cancers of the oro- and hypopharynx

The study design of and results from case–control studies of the association of exposure to formaldehyde with cancer of the oro- and hypopharynx are summarized in

Table 18.

The association between oro- and hypopharyngeal cancer and exposure to formaldehyde was examined in the population-based case–control study by Vaughan et al.

(1986a,b) (described in detail in Section 2.2.1). Evidence for a weak trend in the odds

ratios was observed with the number of years of occupational exposure to formaldehyde

(odds ratio, 0.6; 95% CI, 0.3–1.0 for 1–9 years; odds ratio, 1.3; 95% CI, 0.7–2.5 for

≥ 10 years) and the exposure score (odds ratio, 0.6; 95% CI, 0.3–1.2 for 5–19 units; odds

ratio, 1.5; 95% CI, 0.7–3.0 for ≥ 20 units), but not with the maximum exposure level

142 IARC MONOGRAPHS VOLUME 88
attained (odds ratio, 0.8; 95% CI, 0.5–1.4 for low; odds ratio, 0.8; 95% CI, 0.4–1.7 for

medium; odds ratio, 0.6; 95% CI, 0.1–2.7 for high). No association was observed between

risk for oro- and hypopharyngeal cancer and living in a mobile home (odds ratio, 0.9;

95% CI, 0.5–1.8 for 1–9 years; odds ratio, 0.8; 95% CI, 0.2–2.7 for ≥ 10 years), or duration of living in residences with internal construction or renovation using particle-board

or plywood (odds ratio, 1.1; 95% CI, 0.7–1.9 for 1–9 years; odds ratio, 0.8; 95% CI,

0.5–1.4 for ≥ 10 years). 

Gustavsson et al. (1998) carried out a case–control study of histologically verified

squamous-cell carcinoma of the oral cavity, pharynx, larynx and oesophagus among men

aged 40–79 years who were born in Sweden and were resident in two regions of the

country. Between 1 January 1988 and 31 January 1991, the investigators sought to identify

all incident cases of these tumours in the study population through weekly reports from

departments of otorhinolaryngology, oncology and surgery, supplemented by information

from regional cancer registries. Cases identified incidentally at autopsy were excluded. The

referents were selected by stratified random sampling from population registers, and were

frequency-matched to the cases for region and age in 10- or 15-year age groups. All

subjects were interviewed by one of two nurses (the cases were mostly interviewed in

hospital and the referents mainly at home), who used a structured questionnaire to obtain

information on smoking, oral snuff use, alcohol consumption and lifetime history of jobs

held for > 1 year. The work histories were reviewed by an occupational hygienist who was

blind to the case or referent status of the subject, and were coded for intensity and probability of exposure to 17 agents, including formaldehyde; 9.4% of the referents were classed

as exposed. An index of cumulative exposure was derived from the product of the probability, intensity and duration of exposure across the entire work history. Exposure histories

were available for 90% of the 605 cases identified (including 138 who had pharyngeal

cancer) and for 85% of the 756 referents. [The exact number of cases of pharyngeal cancer

included in study was not reported.] Unconditional logistic regression was used to estimate

incidence rate ratios adjusted for region, age (in 10- or 15-year bands), average alcohol

intake over the past 5 years (four levels) and smoking status (current, former or never). The

incidence rate ratio for pharyngeal cancer and formaldehyde was 1.01 (95% CI, 0.49–2.07)

based on 13 exposed cases. 

A case–control study of incident male cases of hypopharyngeal and laryngeal

squamous-cell cancers was conducted at 15 hospitals in France between 1 January 1989 and

30 April 1991 (Laforest et al., 2000). Initially, 664 such patients were identified, but 21%

of cases from the combined group were excluded due to health problems, death before interview, refusal, being non-alcohol drinkers or because they could not be contacted, which left

201 cases of hypopharyngeal cancer for analysis. Potential controls were male patients with

primary cancers at other sites who were selected from the same or nearby hospitals as the

cases, were recruited between 1987 and 1991 and were frequency-matched to the cases by

age. Of the 355 controls who were initially identified, 59 [17%] were excluded for similar

reasons as the cases. Specially trained occupational physicians interviewed the study

subjects on demographic characteristics, alcohol consumption, use of tobacco and lifetime

FORMALDEHYDE 143
occupational history. Each job was coded with respect to occupation and industry, and occupational exposures, including formaldehyde, were assessed using a previously developed

job–exposure matrix to estimate the probability and level of exposure. An index of cumulative exposure was derived for each subject based on the product of probability, level and

duration of exposure in each job. Altogether, [29%] of controls and [41%] of the cases of

hypopharyngeal cancer were classified as ever having been exposed to formaldehyde. The

age-, asbestos-, coal dust-, alcohol- and smoking-adjusted odds ratio for ever versus never

exposure to formaldehyde was 1.35 (95% CI, 0.86–2.14). There was a trend of increasing

odds ratios with increasing probability of exposure to formaldehyde (ptrend < 0.005); a probability of exposure of over 50% showed an odds ratio of 3.78 (95% CI, 1.50–9.49). No significant trends were noted by duration of exposure or estimated cumulative exposure. After

exclusion of study subjects who had a probability of exposure to formaldehyde of less than

10%, the odds ratio increased with duration of exposure (ptrend< 0.04) and with cumulative

level of exposure (ptrend < 0.14). [The Working Group noted that the controls were interviewed at a later date than cases and did not necessarily come from the same hospital, and

that interviewers were not blind to the case–control status, although they were not aware of

the study hypotheses.]

A case–control study of incident laryngeal and hypopharyngeal cancer was conducted

during 1979–82 in six centres in four European countries (Berrino et al., 2003). An attempt

was made to include all incident cases from the centres, and 304 cases of hypopharyngeal

cancer (including the epilarynx) were included. The participation rate varied by centre from

70 to 92%. Initially, the purpose of the study was to investigate the association between

alcohol consumption, use of tobacco and diet and cancer at the two sites. An age- and sexstratified random sample of controls was selected from the general population from each

centre with an average participation rate of 74%. Information on alcohol consumption,

tobacco smoking, diet and all jobs held for at least 1 year after 1944 was obtained by inperson interviews at the hospital before the treatment of cases; controls were interviewed

at home. A panel of occupational physicians, industrial hygienists and chemical engineers

assessed blindly the probability of exposure to 16 industrial chemicals, including

formaldehyde. Among persons younger than 55 years [for whom a lifelong complete job

history was available], the odds ratio for hypopharyngeal cancer (100 cases) adjusted for

age, centre, tobacco use, alcohol consumption, socioeconomic status, diet and exposure to

potential chemical confounders was 1.3 (95% CI, 0.6–2.6) in the group that was possibly

exposed versus those who were never exposed and 0.5 (95% CI, 0.1–1.8) in the group that

was probably and certainly exposed versus those who were never exposed to

formaldehyde. [It is unclear whether controls were all from the catchment populations of

the hospitals at which the cases were diagnosed. In research outside this study to evaluate

the job–exposure matrix used, it was found that its performance for formaldehyde was

poor. Any resultant misclassification of exposures would be expected to bias risk estimates

towards unity.]

144 IARC MONOGRAPHS VOLUME 88
2.2.4 Cancers of the lung and larynx

The study design of and results from case–control studies of the association of cancers

of the lung and larynx with exposure to formaldehyde are summarized in Table 19.

Andersen et al. (1982) conducted a case–control study in Denmark of doctors

(79 men and five women) for whom a notification of lung cancer had been made in the

files of the nationwide Danish Cancer Registry during the period 1943–77. Three control

subjects per case, matched individually on sex and age, were selected at random from

among individuals on official lists of Danish doctors. Information on postgraduate specialization and places of work during the professional career of cases and controls was

obtained from medical directories and supplementary files at the Danish Medical Society.

Potential exposure to formaldehyde was assumed to be associated with working in pathology, forensic medicine and anatomy. None of the doctors who had lung cancer had

specialized in any of these fields, but one control doctor was a pathologist. Eight male

case patients and 23 controls had been employed at some time in pathology, forensic

medicine or anatomy, to give an odds ratio of 1.0 (95% CI, 0.4–2.4).

Fayerweather et al. (1983) reported on a case–control study of mortality from cancer

among chemical workers in eight plants in the USA where formaldehyde was manufactured or used. A total of 493 active or pensioned men were known to have died from

cancer during 1957–79, but 12 were excluded from the study because their work histories

were unavailable. The remaining 481 men were individually matched on age, pay class,

sex and date of first employment to 481 controls selected from among employees who had

been on the company’s active pay rolls during the last year of employment of the corresponding case. The cases included 181 lung cancers and eight laryngeal cancers. The work

histories of both case and control subjects were ascertained principally from personnel

records, but also from medical records and interviews with colleagues; a job–exposure

matrix was used to classify jobs according to the nature and level of exposure to formaldehyde that they entailed into three categories: ‘continuous-direct’, ‘intermittent’or ‘background’. Smoking histories were obtained for about 90% of subjects, primarily by interviewing living co-workers. Of the 481 cases, 142 (30%) had had potential exposure to

formaldehyde. The data were analysed by latency period, duration of exposure, exposure

level and frequency, cumulative exposure index, age at and year of death and age at and

year of first exposure. In none of the analyses was the relative risk for lung cancer significantly greater than 1.0 (p > 0.05). When a cancer induction period of 20 years was allowed

for, 39 subjects with lung cancer and 39 controls had potentially been exposed to formaldehyde; the odds ratios were 1.20 [95% CI, 0.6–2.8] and 0.79 [95% CI, 0.4–1.6] for subgroups with < 5 years and ≥ 5 years of exposure, respectively. 

In a population-based case–control study, Coggon et al. (1984) used death certificates

to obtain information on the occupations of all men under the age of 40 years in England

and Wales who had died from bronchial carcinoma during 1975–79. These were compared

with controls who had died from any other cause, and who were matched for sex, year of

death, local authority district of residence and date of birth (within 2 years). Of 598 cases

FORMALDEHYDE 145
Table 19. Case–control studies of cancers of the lung and larynx Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Relative risk (95% CI) Andersen et al. (1982), Denmark, 1943–77 Lung 84 doctors (79 men, five women) registered in Denmark who died of lung cancer 252 randomly selected from official list of Danish doctors, matched on sex and age Information on postgraduate specialization and professional career employment Ever employed in pathology, forensic medicine or anatomy 1.0 (0.4–2.4) Fayerweather et al. (1983), USA, 1957–79 Lung and larynx Active or pensioned employees (all men) who died of cancer (181 lung, eight larynx) 189 employees matched on sex, age, pay class and date at first employment, selected from annual payroll roster among employees active during the case’s last year of employment Job–exposure matrix to classify exposure accor- ding to frequency and intensity (continuous/ direct, inter- mittent, back- ground) based on personnel and medical records and interviews with colleagues Lung < 5 years 

≥ 5 years 

1.20 [0.6–2.8] 0.79 [0.4–1.6] 

Coggon et al.

(1984), United Kingdom, 1975–79 

Lung (bronchial carcinoma) 

598 men ≤ 40 years old 

who died of bronchial carcinoma in England and Wales 

1180 men who had died from any other cause, matched by year of death, district of residence and date of birth (± 2 years) 

Job–exposure matrix based on classification coding in three categories (none, low, high) of exposure 

All exposed occupations Occupations with high exposure 

1.5 (1.2–1.8) 0.9 (0.6–1.4) 
Table 19 (contd) Reference, study location, years of study 

Organ site (ICD code) 

Characteristics of cases Characteristics of 

controls 

Exposure assessment 

Exposure categories Relative risk 

(95% CI) 

Gérin et al.(1989), Canada, 1979–85 

Lung (oatcell carcinoma; squamouscell carcinoma; adenocarcinoma; others including unspecified) 

857 men aged 35–70 years resident in the area of Montréal 

1523 men with cancer at other sites (cancer controls) and 533 men selected from electoral list (population controls), stratified by age 

Semi-structured questionnaire on lifetime work history; exposure profile developed based on probability, frequency, concentration and duration of exposure and period of first exposure 

Cancer controls  Ever  Short  Long-low  Long-medium  Long-high Population controls  Ever  Short  Long-low  Long-medium  Long-high 

0.8 (0.6–1.0) 0.8 (0.6–1.2) 0.5 (0.3–0.8) 1.0 (0.7–1.4) 1.5 (0.8–2.8) 0.8 (0.6–1.1) 1.0 (0.6–1.8) 0.5 (0.3–0.8) 0.9 (0.5–1.6) 1.0 (0.4–2.4) 

Wortley et al.(1992), United Kingdom, 1983–87 

Larynx (ICD-0 161.0–161.9) 

235 [sex distribution not given] identified through local cancer surveillance system 

547 identified by random-digit dialling selected to be similar in age and same sex 

In-person interview; job–exposure matrix based on both likelihood and degree of exposure 

Peak  Low  Medium  High Duration  < 1 year  1–9 years 

≥ 10 years 

Exposure scores  < 5  5–19 

≥ 20 

1.0 (0.6–1.7) 1.0 (0.4–2.1) 2.0 (0.2–19.5) 1.0 0.8 (0.4–1.3) 1.3 (0.6–3.1) 1.0 1.0 (0.5–2.0) 1.3 (0.5–3.3) 

Brownson et al.

(1993), USA, 1986–91 

Lung 429 white women aged 

30–84 years, former or never smokers 

1021 women selected from state driver’s licence files (< 65 years old) or health care roaster (≥ 65 years old), 

group- matched for age 

Telephone and inperson interview Ever exposed 0.9 (0.2–3.3) 
Table 19 (contd) Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Relative risk (95% CI) Gustavsson et al. (1998), Sweden, 1988–91 Larynx (ICD-9 161) 157 male incident cases aged 40–79 years 641 selected by stratified random sampling; frequency- matched to cases by age (10–15-year groups) and region Work history reviewed by occupational hygienist; occu- pations coded by intensity and probability of exposure Ever exposed 1.45 (0.83–2.5Laforest et al. (2000), France, 1989–91 Larynx (ICD code not given) 296 men with confirmed histology of cancer of the epi- larynx, glottis, supra- glottis, subglottis and larynx unspecified 296 men with other (selected) primary tumours selected from the same or nearby hospitals, recruited in 1987–91, matched by age Structured in- person interviews; occupational exposures were assessed with a job–exposure matrix developed earlier Ever exposed Exposure probability < 10% 10–50% > 50% Excluding subjects with exposure probability < 10% Ever exposed Duration of exposure < 7 years 

 7–20 years  > 20 years  Cumulative exposure  Low  Medium  High 

1.14 (0.76–1.71.16 (0.73–1.81.12 (0.55–2.31.04 (0.44–2.41.17 (0.63–2.11.68 (0.60–4.70.86 (0.33–2.21.14 (0.47–2.70.68 (0.12–3.91.86 (0.76–4.50.91 (0.42–1.9
Table 19 (contd) Reference, study location, years of study 

Organ site (ICD code) 

Characteristics of cases Characteristics of 

controls 

Exposure assessment 

Exposure categories Relative risk 

(95% CI) 

Berrino et al.

(2003), France, Italy, Spain, Switzerland, 1979–82 

Larynx (glottis, supraglottis) 

213 male incident cases aged ≤ 55 years 

819 men from general local population of each centre, stratified by age 

Structured inperson interviews; occupational exposures assessed by an expert panel using a previously established job–exposure matrix 

Probability of exposure  Possible  Probable or definite 

1.4 (0.8–2.7) 1.0 (0.4–2.3) 

Elci et al.(2003), Turkey, 1979–84 

Larynx (ICD-0 161.0–2, –9) 

940 male incident cases at Oncology Treatment Center 

1519 male patients with malignant or benign pathology 

Standardized questionnaire administered at hospital on occupational history; job–exposure matrix 

Ever exposed Intensity  Low  Medium  High Probability  Low  Medium  High 

1.0 (0.8–1.3) 1.1 (0.8–1.5) 0.5 (0.2–1.3) 0.7 (0.1–7.1) 1.0 (0.7–1.4) 1.1 (0.6–2.2) 1.0 (0.1–11.2) 

CI, confidence interval; ICD, international code of diseases; PAHs, polycyclic aromatic hydrocarbons 
who were identified, 582 were matched with two controls and the remainder with one

control. Occupations were coded according to the Office of Population Census and Surveys

1970 classification, and a job–exposure matrix was constructed by an occupational

hygienist, in which the occupations were grouped according to three levels (high, low and

none) of exposure to nine known or putative carcinogens, including formaldehyde. The

group of occupations that were classed as entailing exposure to formaldehyde was associated with an elevated odds ratio for bronchial carcinoma of 1.5 (95% CI, 1.2–1.8); for

those occupations in which exposure was presumed to be high, the odds ratio was 0.9

(95% CI, 0.6–1.4). [The Working Group noted that information on occupation from death

certificates is limited; they also noted the young age of the subjects and the consequent short

exposure and latency.]

In a population-based case–control study in the area of Montréal, Canada, 857 men

who were diagnosed with histologically confirmed primary lung cancer during 1979–85

were identified (Gérin et al., 1989). Two groups of control subjects were established: one

was composed of 1523 men who were diagnosed during the same years as cases with

cancers of other organs (oesophagus, stomach, colorectum, liver, pancreas, prostate,

bladder, kidney, melanoma and lymphoid tissue) and the other was composed of 533 men

who were selected from electoral lists of the Montréal area. Interviews or completed questionnaires that yielded lifelong job history and information on potential non-occupational

confounders were obtained from the cancer patients or their next of kin and from the population controls, with response rates of 82% and 72%, respectively. Each job was classified

by a group of chemists and hygienists according to the probability, intensity and frequency

of exposure to some 300 agents, including formaldehyde. Nearly one-quarter of all men

had potentially been exposed to formaldehyde in at least one of the jobs they had held

during their working life; however, only 3.7% were considered to be definitely exposed and

only 0.2% were considered to have had high exposure, defined as more than 1.0 ppm [1.23

mg/m3] formaldehyde in the ambient air. Odds ratios, adjusted for age, ethnic group, socioeconomic status, cigarette smoking, the ‘dirtiness’ of the jobs held and various other potentially confounding workplace exposures, were 0.8 (95% CI, 0.6–1.2) for < 10 years of

exposure to formaldehyde, 0.5 (95% CI, 0.3–0.8) for ≥ 10 years of presumed exposure to

< 0.1 ppm [0.12 mg/m3], 1.0 (95% CI, 0.7–1.4) for ≥ 10 years of presumed exposure to

0.1–1.0 ppm [0.12–1.23 mg/m3] and 1.5 (95% CI, 0.8–2.8) for ≥ 10 years of presumed

exposure to > 1.0 ppm formaldehyde compared with controls with other cancers. In comparison with the population controls, the equivalent odds ratios were 1.0 (95% CI, 0.6–1.8),

0.5 (95% CI, 0.3–0.8), 0.9 (95% CI, 0.5–1.6) and 1.0 (95% CI, 0.4–2.4), respectively.

Marginally increased risks were seen for subjects with the adenocarcinoma subtype of lung

cancer who had had long exposure to a high concentration of formaldehyde, with odds

ratios of 2.3 (95% CI, 0.9–6.0) and 2.2 (95% CI, 0.7–7.6) in comparison with the cancer

and population control groups, respectively; however, the estimates were based on only

seven exposed cases. 

Wortley et al. (1992) studied 291 male and female residents aged 20–74 years of a 13-

county area of western Washington, USA, in whom laryngeal cancer was diagnosed in

150 IARC MONOGRAPHS VOLUME 88
1983–87 and notified to a population-based cancer registry in the area; 81% were successfully interviewed. Control subjects were identified by random-digit dialling and were

selected when similar in age and of the same sex as cases; 80% of eligible subjects were

interviewed, which left 547 for analysis. Lifetime histories of occupational, tobacco

smoking and alcohol drinking were obtained by personal interview, and each job held for

at least 6 months was coded according to the US census codes for industries and occupations. A job–exposure matrix was used to classify each job according to the probability

and degree of exposure to formaldehyde and five other agents. Summary measures were

derived for each subject’s lifetime peak exposure, duration of exposure and a score based

on both duration and level of exposure. The risk for laryngeal cancer, adjusted for age,

smoking and drinking habits and length of education, was not associated with exposure to

formaldehyde to a significant degree. The odds ratios were 1.0 (95% CI, 0.6–1.7) for

patients with any ‘low’ exposure, 1.0 (95% CI, 0.4–2.1) for any ‘medium’ exposure and

2.0 (two exposed cases; 95% CI, 0.2–20) for any ‘high’ exposure. Odds ratios of 0.8

(95% CI, 0.4–1.3) and 1.3 (95% CI, 0.6–3.1) were seen for exposure for < 10 years and

≥ 10 years and of 1.0 (95% CI, 0.5–2.0) and 1.3 (95% CI, 0.5–3.3) for medium and high

formaldehyde score, respectively. [The report suggests that the cases in fact came from

only three of the 13 counties, whereas the controls came from the larger area. If this is the

case, there may have been important potential for bias.]

A case–control study in Missouri, USA, focused on white women aged 30–84 years,

who were lifelong nonsmokers or who had stopped smoking for at least 15 years

(Brownson et al., 1993). Incident cases of lung cancer during 1986 to mid-1991 were

identified through the local cancer registry; information for inclusion in the study was

successfully obtained for 429 (69%) of the 650 eligible subjects. This was achieved

through two series of interviews completed either by the subject (42%) or her next of kin,

during which questions were asked on demographic characteristics, non-occupational risk

factors and 28 occupational risk factors, including formaldehyde. For cases under the age

of 65 years, controls were obtained from state drivers’ licence files, while controls for

older cases were selected from Medicare files, group-matched to the cases for age, with a

ratio of approximately 2.2:1. Of 1527 potentially eligible controls, 1021 (73%) completed

two interviews similar to those for the cases. Analysis was performed using multiple

logistic regression. Three cases and 10 controls, all of whom were lifelong nonsmokers,

reported occupational exposure to formaldehyde which, with adjustment for age and

history of previous lung disease, gave an odds ratio of 0.9 (95% CI, 0.2–3.3).

A case–control study in Sweden of squamous-cell carcinoma of the upper airways and

upper digestive tract (Gustavsson et al., 1998) (described in detail in Section 2.2.3) compared 157 men who had laryngeal cancer with 641 referents. After adjustment for region

of incidence, age, average alcohol intake over the past 5 years and smoking status, the estimated incidence rate ratio for cancer of the larynx in men exposed to formaldehyde was

1.45 (95% CI, 0.83–2.51) based on 23 exposed cases. No dose–response trend was apparent for either cumulative exposure or duration of exposure.

FORMALDEHYDE 151
A case–control study at 15 hospitals in France (Laforest et al., 2000) (described in detail

in Section 2.2.3) included 296 patients with laryngeal cancer. For this disease, comparison

with the 296 controls gave an odds ratio (adjusted for age, alcohol consumption, smoking

and exposure to coal dust) of 1.14 (95% CI, 0.76–1.70) for exposure to formaldehyde

overall. No clear pattern of risk estimates was observed in relation to probability, duration

or cumulative levels of exposure.

A case–control study by Berrino et al. (2003) at six centres in France, Italy, Spain and

Switzerland (described in detail in Section 2.2.3) included 213 cases of laryngeal cancer

who were under 55 years of age. No association was found with probable or definite exposure to formaldehyde at levels above the background for the general population (odds ratio,

1.0; 95% CI, 0.4–2.3).

A case–control study of laryngeal cancer in Turkey (Elci et al., 2003) focused on

patients who were admitted to the oncology centre of a hospital in Istanbul during 1979–84.

Information on occupational history and consumption of alcohol and tobacco was elicited at

the time of admission by a trained interviewer using a standardized questionnaire, and a

job–exposure matrix was applied to the occupational history to assign probability and

intensity of exposure to each of five substances including formaldehyde. After exclusion of

women and patients with incomplete information on risk factors or tumour site, 940 of 958

cases were available for analysis (mean age, 52.9 years). These men were compared with

1308 controls who had various cancers that are not thought to have the same causes as carcinoma of the larynx and 211 who had benign pathologies. Analysis was performed using

unconditional logistic regression with adjustment for age, use of tobacco (ever versus never)

and consumption of alcohol (ever versus never). The odds ratio for any exposure to formaldehyde was 1.0 (95% CI, 0.8–1.3) based on 89 exposed cases. No significant elevation of

risk was found for subsets of cases classified by anatomical location of the tumour (supraglottis, glottis, others), and there were no significant trends in risk by intensity or probability

of exposure. [It is unclear how completely the occupational information in this study

reflected lifetime histories of work.]

2.2.5 Lymphohaematopoietic malignancies

The study design of and results from the case–control studies of the association of

lymphohaematopoietic malignancies and exposure to formaldehyde are summarized in

Table 20.

In the study of Gérin et al. (1989) (described in detail in Section 2.2.4) in Montréal,

Canada, levels of occupational exposure to formaldehyde of 53 cases of Hodgkin lymphoma and 206 cases of non-Hodgkin lymphoma were compared with those of 2599 cases

of other cancers and 533 population controls. Using population controls and adjusting for

age, ethnic group, self-reported income, tobacco smoking and dirtiness of jobs held, plus

occupational and non-occupational factors that were identified as potential confounders,

odds ratios for non-Hodgkin lymphoma were 0.7 (13 exposed cases; 95% CI, 0.3–1.6) for

< 10 years of exposure compared with non-exposed and 1.1 (15 exposed cases; 95% CI,

152 IARC MONOGRAPHS VOLUME 88
Table 20. Case–control studies of lymphohaematopoietic malignancies Reference, study location, years of study 

Organ site (ICD code) 

Characteristics of cases 

Characteristics of controls 

Exposure assessment Exposure categories Relative risk 

(95% CI) 

Ap

Gérin et al.(1989), Canada, 1979–85 

Hodgkin lymphoma Non-Hodgkin lymphoma 

53 male incident cases 206 male incident cases 

533 populationbased Lifetime job histories obtained by interview and translated 

into level of exposure to formaldehyde 

Ever < 10 years duration ≥ 10 years duration  Lowa

 Mediuma

 Higha

0.5 (0.2–1.4) 0.7 (0.3–1.6) 1.1 (0.5–2.2) 1.0 (0.5–2.1) 0.5 (0.1–1.7) 

Astodacoo

Linos et al. (1990), USA (years of study not given) 

Leukaemia Non-Hodgkin lymphoma 

578 male incident cases 622 male incident cases 

1245 populationbased Lifetime occupa- tional history 

obtained 

Ever employed in funeral home or crematorium 

2.1 [0.4–10.0] based on four exposed cases 3.2 [0.8–13.4] based on six exposed cases 

As

Partanen et al.

(1993), Finland, 1957–1982 

Leukaemia Hodgkin disease Non-Hodgkin lymphoma 

12 male cases diagnosed among a cohort of 7307 production workers in wood industry Four male cases Eight male cases 

79 randomly selected from cohort and matched by year of birth and vital status in 1983 21 52 

Work history from company records complemented for cases only by interviews with plant personnel and questionnaires completed by subjects or next of kin; plant- and period-specific job–exposure matrix 

< 3 ppm–months ≥ 3 ppm–months < 3 ppm–months ≥ 3 ppm–months < 3 ppm–months ≥ 3 ppm–months 

1.00 1.40 (0.25–7.91) (two exposed cases) 1.00 NA (one exposed case) 1.00 4.24 (0.68–26.6) (four exposed cases) 

Macre
Table 20 (contd) Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Relative risk (95% CI) A

p

West et al. (1995), United Kingdom (years of study not given) Myelo- dysplastic syndrome 400 (216 men, 184 women) newly diagnosed, resident in study area and aged > 15 years 400 cancer-free patients from out- patient clinics and inpatient wards; matched 1:1 by age (± 3 years), sex, area of residence and hospital and year of diagnosis (± 2 years) Personal interview on work history and for duration and intensity of exposure to formaldehyde; all questionnaires reviewed by team of experts > 10 h lifetime exposure of any intensity > 50 h lifetime exposure of medium or high intensity > 2500 h lifetime exposure of medium or high intensity 1.17 [0.51–2.68] 2.33 [0.55–11.35] 2.00 [0.32–15.67] N

sf

Tatham et al. (1997), USA, 1984–88 Non-Hodgkin lymphoma and sub- groups 1048 men (185 small-cell diffuse lymphoma, 268 follicular lym- phoma and 526 large-cell diffuse lymphoma) from 

population-based cancer registries, born 1929–53 

1659 selected by random-digit dialling, matched by area of registry and 5-year categories of date of birth 

Telephone interview including questions on specific materials which participants may have worked with 

Ever exposed  All combined  Small-cell diffuse  Follicular  Large-cell diffuse 

1.20 (0.86–1.50) 1.40 (0.87–2.40) 0.71 (0.41–1.20) 1.10 (0.79–1.70) 

MaeeJhrosca
Table 20 (contd) Reference, study location, years of study 

Organ site (ICD code) 

Characteristics of cases 

Characteristics of controls 

Exposure assessment Exposure categories Relative risk 

(95% CI) 

Ap

Blair et al. (2001), USA, 1980–83 

Leukaemia and myelodysplasia 

513 white men, 30 years or older, identified from the Cancer Registry of Iowa and among all men from a surveillance network of hospitals in Minnesota; 214 chronic lymphoid, 132 acute myeloid, 46 chronic myeloid, 13 acute lymphoid, 58 myelodysplasia and 50 others 

1087 selected by random-digit dialling from Health Care Financing Administration lists and from state death certificate files, frequency-matched by 5-year age group, vital status at time of interview and state of residence 

Personal interviews including lifetime occupational history; formaldehyde assessed in a blinded fashion in terms of probability and intensity, each on a 4-point scale based on job title and industry 

Acute myeloid Low-medium High Chronic myeloid Low-medium High Chronic lymphoid Low-medium High Myelodysplasia Low-medium High All combined Low-medium High 

0.9 (0.5–1.6) – (no case) 1.3 (0.6–3.1) 2.9 (0.3–24.5) 1.2 (0.7–1.8) 0.6 (0.1–5.3) 0.8 (0.3–1.9) – (no cases) 1.0 (0.7–1.4) 0.7 (0.2–2.6) 

Mpeufwpap

AIDS, acquired immunodeficiency syndrome; CI, confidence interval; ICD, international code of diseases; NA, not applicable a Average exposure index 
0.5–2.2), 1.0 (14 exposed cases; 95% CI, 0.5–2.1) and 0.5 (five exposed cases; 95% CI,

0.1–1.7) for > 10 years of exposure to low, medium and high cumulative levels, respectively. Because there were only eight exposed cases of Hodgkin lymphoma, the odds ratio

for ever versus never exposed was calculated to be 0.5 (95% CI, 0.2–1.4). Odds ratios did

not differ substantially when cases of other cancers were used as the control group.

In an analysis of the same multi-site case–control study of Gérin et al. (1989), Fritschi

and Siemiatycki (1996) evaluated risk from occupational exposure to 294 substances, including formaldehyde, with slightly different numbers of cases of Hodgkin lymphoma (54) and

non-Hodgkin lymphoma (215) and 23 cases of myeloma. Cases were compared with a pool

of 1066 controls that comprised 533 population controls who were selected from electoral

lists of the Montréal area and by random-digit dialling and a random sample of 533 of 2357

patients who had other cancers (excluding lung cancer). Results for exposure to formaldehyde were not presented for Hodgkin or non-Hodgkin lymphoma due to a lack of previous

evidence of an association, or for myeloma due to the same lack of previous evidence and

because fewer than four cases had been exposed.

In a study of 578 male cases of leukaemia, 622 male cases of non-Hodgkin lymphoma

and 1245 population-based controls in Iowa and Minnesota (USA), Linos et al. (1990)

observed elevated risks for both leukaemia (four exposed cases; odds ratio, 2.1 [95% CI,

0.4–10]) and non-Hodgkin lymphoma (six exposed cases; odds ratio, 3.2 [95% CI,

0.8–13.4]) among men who had been employed in funeral homes and crematoria, which

indicated some degree of occupational exposure to formaldehyde and other compounds. The

risks were particularly high for the acute myeloid subtype of leukaemia (odds ratio, 6.7

[95% CI, 1.2–36]) and the follicular subtype of non-Hodgkin lymphoma (odds ratio, 6.7

[95% CI, 1.2–37]). However, each of these estimates was based on only three exposed cases.

In Finland, Partanen et al. (1993) identified eight cases of non-Hodgkin lymphoma, four

cases of Hodgkin disease and 12 cases of leukaemia that were diagnosed between 1957 and

1982 and reported to the Finnish Cancer Registry among a cohort of 7307 production

workers who were first employed in the wood industry between 1945 and 1963. One to eight

referents were matched to each case by year of birth and vital status in 1983 from among

cancer-free cohort members, which resulted in a total of 152 referents. Exposure to a number

of substances, including formaldehyde, was estimated based on company records and a

job–exposure matrix. For cases, but not for controls, job histories were completed by interviews of selected persons at the plants and by questionnaires sent to the cases or their next

of kin in 1982–83. Using a 10-year lag interval, subjects were classified as exposed to

formaldehyde when their estimated cumulative exposure reached 3 ppm–months. For

leukaemia and lymphomas combined, exposure to formaldehyde was associated with an

odds ratio of 2.49 (seven exposed cases; 95% CI, 0.81–7.59) based on conditional logistic

regression. Adjustment of the analysis for exposure to solvents or for wood dust or exclusion

of subjects who were exposed to solvents did not substantially alter the result. Odds ratios

for specific cancers were 4.24 (four exposed cases; 95% CI, 0.68–26.6) for non-Hodgkin

lymphoma and 1.40 (two exposed cases; 95% CI, 0.25–7.91) for leukaemia. Only one case

of Hodgkin disease was exposed and the odds ratio was not calculated. [The Working Group

156 IARC MONOGRAPHS VOLUME 88
as well as the authors noted the small number of cases and the possibility of bias due to the

higher accuracy and completeness in the collection of exposure data for cases compared

with controls that most probably resulted in an upward bias of odds ratios for all exposures

evaluated. However, the odds ratio for all cancers combined was not elevated for wood dust,

terpenes, chlorophenols or engine exhaust.]

West et al. (1995) evaluated lifetime exposures through occupation, environment and

hobby among 400 patients over 15 years of age who had been newly diagnosed with

myelodysplastic syndrome in South Wales, Wessex and West Yorkshire, United Kingdom.

Of 635 eligible cases, 28% died before the interview, 3% were too ill, 2% had moved out

of the study area and 5% refused to participate. Cancer-free controls were selected from

outpatient clinics and inpatient wards of medicine, ear, nose and throat surgery, orthopaedics and geriatrics and were individually matched to cases by age (± 3 years), sex, area

of residence and hospital, and year of diagnosis (± 2 years). The personal interviews

collected, among other information, data on work history and probed study subjects for

duration and intensity (low, medium, high) of exposure to more than 70 hazards, including

formaldehyde. Lifetime duration of exposure was estimated after consultation with industrial chemists and occupational hygienists. A minimal practical background level of exposure was set at 10 h in a lifetime, under which people were considered to be unexposed.

Odds ratios were calculated as the ratio of discordant pairs and were 1.17 (15 exposed

cases [95% CI, 0.51–2.68]) for ≥ 10 h lifetime exposure of any intensity versus no exposure, 2.33 ([95% CI, 0.55–11.35]) for > 50 h lifetime exposure of medium or high intensity versus no exposure and 2.00 ([95% CI, 0.32–15.67]) for > 2500 h lifetime exposure of

medium or high intensity versus no exposure.

In a population-based case–control study, Tatham et al. (1997) evaluated the risks for

subtypes of non-Hodgkin lymphoma with respect to exposure to formaldehyde among 1048

male cases that included 185 cases of small-cell diffuse lymphoma, 268 cases of follicular

lymphoma and 526 cases of large-cell diffuse lymphoma who were born between 1929 and

1953, diagnosed between 1984 and 1988 and listed in the population-based cancer registries

of the states or cities of Connecticut, Iowa, Kansas, Atlanta, Miami, San Francisco, Detroit

or Seattle, USA. Diagnosis was confirmed by a panel of three pathologists. A total of 1659

controls were selected by random-digit dialling and were frequency-matched to cases on

area of the registry and 5-year categories of date of birth. Of the 2354 and 2299 eligible

cases and controls, respectively, 2073 [88%] and 1910 [83%] were alive and could be interviewed, while a further 1025 cases and 251 controls were excluded for various reasons, that

included non-confirmation of diagnosis [562 cases], not being a resident in the USA before

1969, a history of acquired immunodeficiency syndrome (AIDS) or related illness, systemic

lupus erythematosus, non-AIDS-related immunodeficiency, rheumatoid arthritis or a history

of treatment with immunosuppressive drugs, chemotherapy or radiation. Cases and controls

were interviewed by telephone on their background characteristics, lifestyle and medical,

military and work history. The job history included questions on specific materials with or

around which participants may have worked, including formaldehyde. Relative risks were

based on conditional logistic regression, stratified for the matching factors (area of registry

FORMALDEHYDE 157
and date of birth) and adjusted for age at diagnosis, year of entry into the study, ethnicity,

education, Jewish religion, never having married, AIDS risk behaviours, use of seizure

medication, service in or off the coast of Viet Nam and cigarette smoking. For ever versus

never having been exposed to formaldehyde, relative risks were 1.40 (21 exposed cases;

95% CI, 0.87–2.40) for small-cell diffuse lymphoma, 0.71 (17 exposed cases; 95% CI,

0.41–1.20) for follicular lymphoma, 1.10 (46 exposed cases; 95% CI, 0.79–1.70) for largecell diffuse lymphoma and 1.20 (93 exposed cases; 95% CI, 0.86–1.50) for all cases of nonHodgkin lymphoma combined. Of all the controls, 130 (7.8%) reported having been

exposed to formaldehyde.

Blair et al. (2000) evaluated occupational exposure to formaldehyde in a populationbased case–control study of leukaemia and myelodysplasia. Cases were identified among

white men who were 30 years or older from the Cancer Registry of Iowa (1981–83) and

among all men from a surveillance network of hospitals in Minnesota which covered 97%

of hospital beds in this area (1980–82). Controls were identified by random-digit dialling,

from Health Care Financing Administration lists or from state death certificate files,

depending on their age and vital status, and were frequency-matched to cases by 5-year

age group, vital status at the time of interview and state of residence. A total of 669 eligible cases was identified, and interviews were conducted with 340 cases of leukaemia and

238 surrogates for deceased subjects and those who were too ill to interview. Cases and

controls who lived in four large cities were excluded because the main purpose of the

study was to evaluate agricultural risks; furthermore, subjects who had farming as their

sole occupation were excluded from this analysis because the incidence of leukaemia has

been shown to be elevated among farmers. This left 214 cases of chronic lymphocytic

leukaemia, 132 of acute myeloid leukaemia, 46 of chronic myeloid leukaemia, 13 of acute

lymphocytic leukaemia, 58 of myelodysplasia and 50 others and 1087 controls. Interviews

were conducted in 1981–84 and included a lifetime occupational history with job titles

and industries. Exposure to selected substances, including formaldehyde, was assigned by

an industrial hygienist in terms of probability and intensity in a blinded fashion, each on

a four-point scale (non-exposed, low, medium and high intensity). Odds ratios were based

on unconditional logistic regression adjusted for the matching factors and agricultural use

of pesticides, post-secondary education, use of hair dyes, tobacco smoking and having a

first-degree relative who had a haematolymphopoietic tumour. Compared with no exposure to formaldehyde, odds ratios were 0.9 (14 exposed cases; 95% CI, 0.5–1.6) for low/

medium intensity of exposure for acute myeloid leukaemia (no cases with high exposure);

1.3 (seven exposed cases; 95% CI, 0.6–3.1) for low/medium exposure and 2.9 (one

exposed case; 95% CI, 0.3–24.5) for high exposure for chronic myeloid leukaemia; 1.2

(29 exposed cases; 95% CI, 0.7–1.8) for low/medium exposure and 0.6 (one exposed case;

95% CI, 0.1–5.3) for high exposure for chronic lymphocytic leukaemia; 0.8 (six exposed

cases; 95% CI, 0.3–1.9) for low/medium exposure for myelodysplasia (no cases with high

exposure); and 1.0 (61 exposed cases; 95% CI, 0.7–1.4) for low/medium exposure and 0.7

(three exposed cases; 95% CI, 0.2–2.6) for high exposure for all leukaemias and myelodysplasia combined. Of the 1087 controls, 128 [11.8%] were estimated to have low/

158 IARC MONOGRAPHS VOLUME 88
medium and nine [0.8%] to have high exposure to formaldehyde. None of the cases of

acute lymphocytic leukaemia was exposed. 

Nisse et al. (2001) evaluated the risk for myelodysplastic syndrome among 204 incident

cases who were diagnosed during 1991–96 at the University Hospital of Lille (northern

France) and 204 controls who were randomly selected from the electoral register and individually matched to cases by size of town of residence, sex and age (± 3 years). Cases who

had secondary myelodysplastic syndrome after treatment for cancer and those who were

unable to answer the questionnaire were excluded. The questionnaire was the same as that

used in the study by West et al. (1995) and exposure evaluation was based on the method

of Siemiatycki et al. (1981). Odds ratios for exposure to formaldehyde were not reported

because the 95% CI for the univariate odds ratio for ever versus never having been exposed

included 1, or because there were fewer than four exposed subjects.

2.2.6 Cancers at other sites

The study design of and results from the case–control studies of exposure to formaldehyde and cancer at sites other than those presented in the above sections are summarized in Table 21, in chronological order. The description of the studies below, in contrast,

groups the reports by study population.

Within the Montréal multisite cancer study, the database that was analysed for lung

cancer (see Section 2.2.4), Hodgkin disease, non-Hodgkin lymphoma and myeloma (see

Section 2.2.5) was also used to study various other cancer sites in relation to exposure to

formaldehyde. The results were published in separate reports and are presented below.

In addition to the sites cited above, Gérin et al. (1989) (see Section 2.2.4) analysed

data for cancer of the oesophagus, stomach, colorectum, liver, pancreas, prostate, urinary

bladder and kidney and for melanoma of the skin. Odds ratios were not elevated for any

of these cancers. 

Siemiatycki et al. (1994) conducted an analysis of urinary bladder cancer using a set

of 484 pathologically confirmed cases of bladder cancer, 1879 controls who had cancers

at other sites, excluding lung and kidney cancers, and 533 population controls. No evidence of an association was found between exposure to formaldehyde and the risk for

bladder cancer: odds ratios, adjusted for non-occupational and occupational confounders,

were 1.2 (67 exposed cases; 95% CI, 0.9–1.6) for non-substantial exposure and 0.9 (17

exposed cases; 95% CI, 0.5–1.7) for substantial exposure.

Dumas et al. (2000) analysed the association between occupational exposure to a

large number of substances, occupations and industries and rectal cancer. A total of 257

men, who were aged 35–70 years and diagnosed with a rectal cancer between 1979 and

1985, were compared with 1295 controls who had cancers at sites other than the rectum,

lung, colon, rectosigmoid junction, small intestine and peritoneum; adjustments were

made for potential non-occupational (age, education, cigarette smoking, beer consumption, body mass index and respondent status) but not for occupational variables. Exposure

to formaldehyde was associated with rectal cancer: the odds ratios were 1.2 (36 exposed

FORMALDEHYDE 159
Table 21. Case–control studies of cancers at other sites Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Odds ratio (95% CI) Ad

po

Gérin et al. (1989), Canada, 1979–85 Oesophagus Stomach Colorectum Liver Pancreas Prostate Bladder Kidney Skin melanoma Men aged 35–70 years resident in Montréal 107 250 787 50 117 452 486 181 121 Pool of population selected from electoral list, and cancer controls; depending of the cancer site under study, the number of controls varied from 1733 to 2741. Semi-structural probing interview, assessment of exposures by chemists and industrial hygienists Short Long-low Long-medium Long-high No association for any of these sites (most odds ratios very close to 1.0) Se

ba(vato caetheccigdir

Merletti et al. (1991), Italy, 1982–84 Oral cavity or oropharynx 86 male incident cases Random sample of 385 men, stratified by age, from the files of residents Full occupational history linked to a job–exposure matrix Any exposure Probable or definite 1.6 (0.9–2.8) 1.8 (0.6–5.5) Ag

of smdr

Goldoft et al. (1993), USA, 1979–89 Melanoma of the nasal cavity or nasopharynx Nine cases [sex distribution not reported] Random-digit dial- ling, frequency- matched on sex and age at dia- gnosis (controls from Vaughan 

et al., 1986a,b) 

Interview Living in a 

residence with foam insulation Occupational exposure Employed in industries with potential exposurea

3.57 (0.09–19.8) Obs./exp. 0/0.27 Obs./exp. 0/0.8 

Siemiatycki et al. (1994), Canada, 1979–86 

Bladder 484 men aged 

35–70 years resident in Montréal 

533 population and 1879 cancer controls 

See Gérin et al.

(1989) 

Non-substantial Substantial 

1.2 (0.9–1.6) 0.9 (0.5–1.7) 

Agsotobcostaantio
Table 21 (contd) Reference, study location, years of study 

Organ site (ICD code) 

Characteristics of cases 

Characteristics of controls 

Exposure assessment 

Exposure categories 

Odds ratio (95% CI) 

Apo

Cantor et al.(1995), USA, 1984–89 

Breast (female) 33 509 women 

with breast cancer as the cause of death 

117 794 women who died from non-cancer causes; frequency-matched for age and race 

Usual occupation on death certificate linked to a job–exposure matrix, with levels of probability and of intensity of exposure 

Exposure levels  Low  Medium  High  Low  Medium  High 

Blacks1.14 p < 0.05 0.93 1.20 p < 0.05 Whites1.38 p < 0.05 1.30 p < 0.05 1.36 p < 0.05 

Asoanwbi

Holly et al.(1996), USA, 1978–87 

Uveal melanoma 

221 white men aged 20–74 years 

447 white men selected by random-digit dialling; matched for area and age 

Recall through telephone interviews 

Ever 2.9 (1.2–7.0) A

naskexsu

Gustavsson et al. (1998), Sweden, 1988–91 

Oral cavity and oesophagus (ICD-9 141, 143-5, 150) 

250 incident cases among men aged 40–79 years resident in two regions (oral cavity, 128; oesophagus, 122) 

641 men selected by stratified random sampling; frequency-matched to cases by age (10–15-year groups) and region 

Work history reviewed by occupational hygienist; occupations coded by intensity and probability of exposure 

Ever  Oral cavity  Oesophagus 

1.28 (0.64–2.54) 1.90 (0.99–3.63) 

Recotoha

Kernan et al.(1999), USA, 1984–93 

Pancreas 63 097 persons 

with pancreatic cancer as the cause of death [sex and race distribution not reported] 

252 386 persons who died from non-cancer causes; frequency-matched by state, sex, race and age (5-year groups) 

Usual occupation on death certificate linked to a job–exposure matrix, with levels of probability and of intensity of exposure 

Exposure level  Low  Medium  High Exposure probability  Low  Medium  High 

1.2 (1.1–1.3) 1.2 (1.1–1.3) 1.1 (1.0–1.3) 1.2 (1.1–1.3) 1.2 (1.1–1.3) 1.4 (1.2–1.6) 

Arean
Table 21 (contd) Reference, study location, years of study Organ site (ICD code) Characteristics of cases Characteristics of controls Exposure assessment Exposure categories Odds ratio (95% CI) Ad

po

Dumas et al. (2000), Canada, 1979–85 Rectum 257 men aged 35–70 years resident in Montréal 533 population and 1295 cancer controls See Gérin et al. (1989) Any Substantial 1.2 (0.8–1.9) 2.4 (1.2–4.7) Ag

cigbemares

Wilson et al. (2004), USA, 1984–89 Salivary gland (ICD-9, 142.0– 1, –9) [2405] persons with cancer of the salivary gland as the cause of death (whites: 1347 men, 890 women; African–Ameri- cans: 93 men, 75 women) [9420] persons who died from non-cancer causes, excluding infec- tious diseases; frequency-matched for age, race, sex and region Usual occupation on death certificate linked to a job– exposure matrix, with levels of probability and of intensity of exposure Mid–high probability and intensity White men and women 1.6 (1.3–2.0) Black women 1.9 (0.8–5.1) Ag

ansta

CI, confidence interval; ICD, international code of diseases a Wood-work, furniture manufacture, pulp and paper mill, textile, foundry and smelter 
cases; 95% CI, 0.8–1.9) for any exposure and 2.4 (13 exposed cases; 95% CI, 1.2–4.7) for

substantial exposure, with an increase in risk by concentration and duration of exposure.

[This result contrasts with the findings of Gérin et al. (1989), in which none of the odds

ratios for colorectal cancer was greater than 1.0 in any of the exposure subgroups, including the highest. These odds ratios were for all colorectal cancers, but the authors stated

that “the results for subsites of the colorectum — colon, rectosigmoid and rectum — were

essentially similar to those of the entire category”.]

A series of systematic case–control analyses of various cancers in relation to exposure

to different occupational agents, including formaldehyde, were conducted using death

certificates collected from 1984 to 1989 in 24 states of the USA (Cantor et al., 1995;

Kernan et al., 1999; Wilson et al., 2004). Death certificates were coded for usual occupation and industry according to the classification designed for the 1980 US census. Individual exposures were derived by linking the occupation–industry codes with a job–exposure

matrix that assessed the probability and level of exposure to 31 occupational agents.

Cantor et al. (1995) conducted a case–control study of occupational exposure and

female breast cancer mortality in the USA. After excluding homemakers, 33 509 cases and

117 794 controls remained. Estimates were adjusted for age at death and socioeconomic

status and excluded women who had a low probability of exposure. Exposure to formaldehyde was associated with the risk for breast cancer among white and black women: for

whites, odds ratios were 1.14 (p < 0.05), 0.93 and 1.2 (p < 0.05) for women who had low,

medium and high intensity of exposure, respectively; among black women, significantly

elevated (p < 0.05) odds ratios of 1.38, 1.30 and 1.36 were found for those who had low,

medium and high intensity of exposure, respectively [confidence intervals not shown].

Kernan et al. (1999) conducted a case–control study of pancreatic cancer. Cases were

63 097 persons who had died from pancreatic cancer in 1984–93. Controls were 252 386

persons who had died from causes other than cancer during the same period. Occupational

exposure to formaldehyde was associated with a moderately increased risk for pancreatic

cancer for both men and women and for both racial groups (blacks and whites), with odds

ratios of 1.2 (95% CI, 1.1–1.3), 1.2 (95% CI, 1.1–1.3), 1.1 (95% CI, 1.0–1.3) for subjects

with low, medium and high intensity of exposure, respectively, and 1.2 (95% CI, 1.1–1.3),

1.2 (95% CI, 1.1–1.3) and 1.4 (95% CI, 1.2–1.6) for subjects with low, medium and high

probabilities of exposure, respectively. There was no apparent exposure–response pattern

with intensity, but the exposure–response relationships by probability of exposure were

consistent across each level of exposure intensity.

Using the same database as Cantor et al. (1995), Wilson et al. (2004) conducted a study

of salivary gland cancer. The cases were [2405] persons who had died from salivary gland

cancer between 1984 and 1989. Four controls per case, frequency-matched for sex, age,

race and region, were selected from among persons who had died during the same period

from other causes, excluding infectious diseases (because of a suspected viral etiology of

salivary gland cancer); a total of 9420 controls were included. Occupation as coded on the

death certificate was available for 95.3% of white and 87.3% of black men and for 45% of

white and 30.9% of black women. Among white men and women, an odds ratio, adjusted

FORMALDEHYDE 163
for age, marital status and socioeconomic status, of 1.6 (95% CI, 1.3–2.0) was observed

with ‘mid–high’ probability and ‘mid–high’ intensity of exposure to formaldehyde [categories not further defined]. The trend was significant (p < 0.001), but there was no dose–

response pattern of monotonically increasing risk with increasing intensity and probability

of exposure. No association between exposure to formaldehyde and salivary gland cancer

was observed among African-American men and women combined. Among AfricanAmerican women, the adjusted odds ratio for ‘mid–high’ intensity of exposure was 1.9

(95% CI, 0.8–5.1). No results were given separately for African-American men.

[The Working Group considered that this series of systematic analyses was limited by

potential misclassification of some specific cancers when ascertained through death certificates, and by the use of occupation codes from death certificates to assess lifelong occupational exposure to formaldehyde.]

Merletti et al. (1991) reported a case–control study of 86 male residents of Turin, Italy,

who had a diagnosis of cancer of the oral cavity or oropharynx that was notified to the

population-based cancer registry of the city between 1 July 1982 and 31 December 1984,

and a random sample of 385 men, stratified by age, who were chosen from files of residents of Turin. The cancers among the cases were: oropharynx (12), tongue (15), floor of

the mouth (24), soft palate complex (14), other sites (11) and unspecified sites of the oral

cavity (10). Detailed occupational history since 1945 and lifelong histories of tobacco

smoking and alcohol drinking were obtained by personal interview. Each job that had been

held for at least 6 months was coded according to the International Standard Classification

of Occupations and the International Standard Industrial Classification, and a job–exposure

matrix for 13 agents (including formaldehyde) which are known or suspected carcinogens

of the respiratory tract and three non-specific exposures (dust, gas and solvents) was

applied to the occupation–industry code combination of study subjects; the matrix was

developed at the IARC for use in a similar study of laryngeal cancer. Study subjects were

grouped into three categories of presumed frequency and intensity of exposure to formaldehyde (no, any, probable or definite exposure), with the ‘no exposure’ group (exposure not

higher than that of the general population) as the reference level. Odds ratios were calculated using unconditional logistic regression adjusting for age, tobacco smoking, alcohol

drinking, education and place of birth. An association was suggested between cancer of the

oral cavity or oropharynx and exposure to formaldehyde, with odds ratios of 1.6 (95% CI,

0.9–2.8) for ‘any exposure’ and 1.8 (95% CI, 0.6–5.5) for ‘probable or definite’ exposure;

however, only 25 and six cases were exposed, respectively. No relationship was seen with

duration of exposure to formaldehyde, with odds ratios of 1.7 for 1–15 years of exposure

and 1.5 for ≥ 16 years within the ‘any exposure’ category, and of 2.1 and 1.4, respectively,

within the ‘probable or definite’ exposure category. Separate results for an association with

exposure to formaldehyde were not reported for the 12 men who had oropharyngeal cancer. [The Working Group noted that confounding by tobacco and alcohol could not be

excluded from the interpretation of the observed association between exposure to formaldehyde and oral cancer.]

164 IARC MONOGRAPHS VOLUME 88
As part of the population-based case–control study of sinonasal cancer by Vaughan

et al. (1986a,b) (see Section 2.2.1), Goldoft et al. (1993) interviewed nine of 14 patients

who had been diagnosed with melanoma of the nose or nasopharynx between 1979 and

1989. The frequency of their exposure to formaldehyde was compared with that of the

control subjects included in the study of Vaughan et al. (1986a,b). One subject had lived

in a residence that was insulated with formaldehyde-based foam [0.3 expected]. None of

the melanoma patients reported specific occupational exposure to formaldehyde (0.3

expected), and none reported having been employed in industries that would probably

entail exposure to formaldehyde (0.8 expected). [The Working Group noted that it was

unclear how the expected numbers were calculated.]

Holly et al. (1996) conducted a case–control study in the western USA to determine the

relation of occupations and chemical exposures to the risk for uveal melanoma. Two

hundred and twenty-one white men, aged 20–74 years and referred for treatment to a specialized unit in San Francisco between 1978 and 1987, were included and successfully interviewed. A group of 447 controls were selected by random-digit dialling (white men from

the same geographical area and within the same 5-year age group), and 77% were successfully interviewed by telephone. Exposure to chemicals, including formaldehyde, was

determined by asking the subjects whether they thought they were ever regularly exposed

(at least 3 h per week for at least 6 months) in their jobs, hobbies, leisure or home maintenance. When ever to never having been exposed to formaldehyde was compared, an

elevated odds ratio of 2.9 (13 exposed cases; 95% CI, 1.2–7.0), adjusted for potential nonoccupational confounders, was found. [The Working Group and the authors noted the

potential for recall bias when chemical exposures are ascertained from the subject’s

memory.]

A case–control study by Gustavsson et al. (1998) (see Section 2.2.3) included 128

cases of oral cancer and 122 cases of oesophageal cancer (in addition to cancers of the

pharynx and larynx). There was no significant association between exposure to formaldehyde and the risk for oral cancer (14 exposed cases; odds ratio, 1.28; 95% CI,

0.64–2.54), but the risk for cancer of the oesophagus was elevated and bordered on statistical significance (19 exposed cases; odds ratio, 1.90; 95% CI, 0.99–3.63).

2.3 Pooled analysis and meta-analyses

2.3.1 Pooled analysis

Luce et al. (2002) performed a pooled analysis of data from 12 case–control studies on

sinonasal cancer [cancer of the nasal cavity and paranasal sinuses, ICD-9 code 160] that

were conducted in China (Zheng et al., 1992), France (Luce et al., 1992, 1993; Leclerc

et al., 1994), Germany (Bolm-Audorff et al., 1990), Italy (Merler et al., 1986; Comba et al.,

1992a,b; Magnani et al., 1993), the Netherlands (Hayes et al., 1986a,b), Sweden (Hardell

et al., 1982) and the USA (Brinton et al., 1984, 1985; Vaughan et al., 1986a; Vaughan, 1989;

Vaughan & Davis, 1991). An earlier pooled analysis (’t Mannetje et al., 1999) used data

FORMALDEHYDE 165
from eight of these 12 studies. As the earlier study is subsumed by the more extensive analysis of Luce et al. (2002), results from ’t Mannetje et al. (1999) are not presented.

The analysis by Luce et al. (2002) included data from four (Brinton et al., 1984;

Vaughan et al., 1986a; Hayes et al., 1986a; Luce et al., 1993) of the six case–control studies

that primarily focused on exposure to formaldehyde that are described in Section 2.2.1, but

not those by Olsen et al. (1989) or Roush et al. (1987). In addition, data were obtained from

a further seven studies that were originally designed to address exposures to substances

other than formaldehyde (particularly wood dust) and one unpublished study. A total of 195

cases of adenocarcinoma (169 men, 26 women) and 432 cases of squamous-cell carcinoma

(330 men, 102 women) were compared with 3136 controls (2349 men, 787 women). The

study by Luce et al. (1993) in France contributed approximately half of the cases of adenocarcinoma. Cases were diagnosed between 1968 and 1990 and were ascertained from

different sources; study subjects were interviewed between 1979 and 1990 using different

methods. Studies also varied with respect to the mode of selection of controls and the vital

status of subjects at recruitment. Lifetime occupational histories collected in the individual

studies were recoded with the occupation and industry codes from International Standard

Classifications. These codes and industrial hygiene data were the basis for the development

of a job–exposure matrix that provided estimates of the probability (unexposed, 1–10%,

10–50%, 50–90%, > 90%) and intensity (< 0.25 ppm, 0.25–1 ppm, > 1 ppm) of exposure

to formaldehyde. Numerical values were assigned to each exposure category, and the jobspecific products of the assigned value and duration of employment were summed over

each individual’s total work history (using 0-, 10- and 20-year lag intervals) to estimate

cumulative exposure. For the analysis, the cumulative exposure index was categorized into

one of four classes (unexposed and tertiles among controls) that were denoted as no, low,

medium and high exposure. Odds ratios were derived by unconditional logistic regression

and were stratified by sex and histology with adjustment for age (three categories) and

study. In analyses of adenocarcinoma in men, adjustment was also made for wood and

leather dust. Tobacco smoking was evaluated as a potential confounder, but was not included in the final models because effect estimates did not change substantially after adjustment. Among subjects exposed to low, medium or high levels of formaldehyde compared

with unexposed subjects, estimated odds ratios were 1.2 (43 exposed cases; 95% CI,

0.8–1.8), 1.1 (40 exposed cases; 95% CI, 0.8–1.6) and 1.2 (30 exposed cases; 95% CI,

0.8–1.8) for squamous-cell carcinoma among men; 0.7 (six exposed cases; 95% CI,

0.3–1.9), 2.4 (31 exposed cases; 95% CI, 1.3–4.5) and 3.0 (91 exposed cases; 95% CI,

1.5–5.7) for adenocarcinoma among men; 0.6 (six exposed cases; 95% CI, 0.2–1.4), 1.3

(seven exposed cases; 95% CI, 0.6–3.2) and 1.5 (six exposed cases; 95% CI, 0.6–3.8) for

squamous-cell carcinoma among women; and 0.9 (two exposed cases; 95% CI, 0.2–4.1),

0.0 (no cases) and 6.2 (five exposed cases; 95% CI, 2.0–19.7) for adenocarcinoma among

women, respectively. Slight increases in these odds ratios were observed with 10- and 20-

year lag intervals. Among men, studies were heterogeneous with respect to the effects of

exposure to formaldehyde on adenocarcinoma, with a significantly better fit of a model that

included interaction terms between exposure effects and study compared with a model with

166 IARC MONOGRAPHS VOLUME 88
no such interaction terms (p < 0.01). [The Working Group noted that this heterogeneity

may have led to inappropriately narrow confidence intervals since the analytical model did

not account for random effects.] Among men with little or no exposure to wood dust, the

odds ratios for adenocarcinoma with high level exposure to formaldehyde was 2.2

(95% CI, 0.8–6.3). [The Working Group considered that, for adenocarcinoma, residual

confounding by exposure to wood dust was possible despite the attempts to control for it.

This is because of the high degree of correlation between exposure to wood dust and exposure to formaldehyde, and the very strong association between adenocarcinoma and exposure to wood dust. Only 11 male cases of adenocarcinoma who had low, medium or high

exposure to formaldehyde were categorized as never having been exposed to wood dust.] 

2.3.2 Meta-analyses

(a) Respiratory cancers (Table 22)

In a meta-analysis on the relationship between exposure to formaldehyde and cancer,

Blair et al. (1990b) added up the observed and expected numbers of various cancers across

32 cohort and case–control studies. They found no substantially elevated mortality from

cancer of the lung or of the nasal nasal cavity for persons who were ever exposed or for

those who had a higher level or duration of exposure. For cancer of the nasopharynx, mortality in persons who had a higher level or duration of exposure was elevated 2.1-fold [95%

CI, 1.1–3.5] with 13 observed deaths. Among professionals, mortality from leukaemia

(SMR, 1.6 [95% CI, 1.3–1.9]) and that from brain cancer (SMR, 1.5 [95% CI, 1.1–1.9])

were elevated. No significant associations were observed for other cancers.

In addition to the studies evaluated by Blair et al. (1990b), a meta-analysis of respiratory cancers by Partanen (1993) included two additional studies (Brinton et al., 1984;

Merletti et al., 1991) and two updates (Gallagher et al., 1989; Partanen et al., 1990). The

analysis used lagged and confounder-adjusted inputs, whenever available, and derived

summary relative risks using a log-Gaussian, fixed effects model. For nasopharyngeal

cancer, risk ratios were 1.59 (23 deaths; 95% CI, 0.95–2.65) and 2.74 (11 deaths; 95% CI,

1.36–5.55) for low/medium and substantial level or duration of exposure, respectively.

Partanen (1993) found a relative risk for cancer of the nasal cavities and paranasal sinuses

of 1.68 (95% CI, 1.00–2.82) for the highest category of exposure, while the corresponding

risk calculated by Blair et al. (1990b) was 1.1 [95% CI, 0.7–1.5]. [This discrepancy may

be explained by differences in the selection of studies for inclusion in the two metaanalyses or by differences in the way in which exposure categories were defined]. For the

combined category of cancers of the oropharynx, lip, tongue, salivary glands and mouth,

the aggregated data did not suggest associations with exposure to formaldehyde. Overall,

Blair et al. (1990b) and Partanen (1993) were in good agreement with regard to the risks

for lung cancer, nasopharyngeal carcinoma and miscellaneous cancers of the upper respiratory tract. 

Collins et al. (1997) calculated meta-relative risks for cancers of the lung, nose or

nasopharynx based on results from 11 cohort studies, three proportionate mortality studies

FORMALDEHYDE 167
Table 22. Summary of results from three meta-analyses on respiratory cancers and exposure to fo

Site Lung Nose and nasal sinuses Nasopharynx 

Level or duration of exposure to formaldehyde O/E mRR (95% CI) O/E mRR (95% CI) O/E mRR (95% CI) Any Blair et al. (1990b)a [1692/1681] [1.0 (0.95–1.06)] [61/58] [1.0 (0.8–1.3)] [35/27] [1.3 (0.9–1.8)] Partanen (1993)b,c 833/752 1.11 (1.03–1.19) 93/78 1.11 (0.81–1.53) 36/21 2.00 (1.36–2.9Collins et al. (1997)d 2080/2506 1.0 (0.9–1.0) 936/808 1.0 (1.0–1.1) 455/412 1.3 (1.2–1.5) Low/medium Blair et al. (1990b)a 514/422 1.2 [1.1–1.3] 38/46 0.8 [0.6–1.1] 30/27 1.1 [0.7–1.6] Partanen (1993)b,c 518/425 1.2 (1.1–1.3) 33/30 1.10 (0.67–1.79) 23/16 1.59 (0.95–2.6Substantial Blair et al. (1990b)a 250/240 1.0 [0.9–1.2] 30/28 1.1 [0.7–1.5] 13/6 2.1 [1.1–3.5] Partanen (1993)b,c 233/216 1.1 (0.95–1.2) 36/21 1.68 (1.00–2.82) 11/4 2.74 (1.36–5.5CI, confidence interval; mRR, meta-relative risk; NR, not reported; O/E, observed/expected aBlair et al. (1990b) included the following studies in their analysis: Harrington & Shannon (1975), Petersen & Milham Fayerweather et al. (1983), Friedman & Ury (1983), Marsh (1983), Milham (1983), Walrath & Fraumeni (1983), Wong (198et al. (1984), Harrington & Oakes (1984), Levine et al. (1984), Liebling et al. (1984), Malker & Weiner (1984), Olsen et al. Partanen et al. (1985), Stayner et al. (1985), Walrath et al. (1985), Bertazzi et al. (1986), Blair et al. (1986), Bond et al. (1986(1986a,b), Logue et al. (1986), Stroup et al. (1986), Vaughan et al. (1986a,b), Blair et al. (1987), Roush et al. (1987), StayneGérin et al. (1989), Blair et al. (1990a) and Hayes et al. (1990).b The analysis for lung cancer was performed for industrial workers only, as at least some of the data for professionals were confoc Partanen (1993) included in his analysis the above studies and: Brinton et al. (1984), Merletti et al. (1991); in addition, ParPartanen et al. (1990), and Gallagher et al. (1986) was updated with Gallagher et al. (1989).dCollins et al. (1997) included in their analysis the above studies (except for Petersen & Milham (1980), Friedman & Ury (Wong (1983), Acheson et al. (1984a,b), Harrington & Oakes (1984), Liebling et al. (1984), Malker & Weiner (1984), StayneGallagher et al. (1986), Logue et al. (1986), Blair et al. (1987, 1990a) and Merletti et al. (1991)) and added the following studieAsnaes (1986), Hall et al. (1991), Matanoski (1991), Chiazze et al. (1993), Gardner et al. (1993), Luce et al. (1993), West eAndjelkovich et al. (1995).
and 15 case–control studies that were published between 1975 and 1995. The analysis did

not include all of the studies from the meta-analyses by Blair et al. (1990b) and Partanen

(1993), but added several studies, most of which were published after 1992. Using a fixed

effects model, an overall meta-relative risk for lung cancer of 1.0 (95% CI, 0.9–1.0) was

calculated based on 24 studies with 2080 observed cases, but there was substantial heterogeneity across studies (p < 0.00001) which was mainly due to the difference between

industrial cohort studies (meta-relative risk, 1.1; 95% CI, 1.0–1.2) and case–control studies

(meta-relative risk, 0.8; 95% CI, 0.7–0.9). For nasal cancer, the overall meta-relative risk

was 1.0 (95% CI, 1.0–1.1) based on 20 studies with 936 observed cases. Separate analyses

by study type gave a meta-relative risk of 0.3 (95% CI, 0.1–0.9) for cohort studies and 1.8

(95% CI, 1.4–2.3) for case–control studies. Meta-relative risks for nasopharyngeal cancer

were 1.3 (95% CI, 1.2–1.5) overall based on 12 studies with 455 cases, and 1.6 (95% CI,

0.8–3.0) for cohort studies with reported expected deaths. To address a potential publication bias, all cohort studies were combined and missing expected numbers were estimated

based on an approximation of the ratio of deaths from nasopharyngeal and lung cancer

from the corresponding ratio observed in another study; this gave a meta-relative risk of

1.0 (95% CI, 0.5–1.8).

(b) Pancreatic cancer (Table 23)

Ojajärvi et al. (2000) evaluated occupational exposures in relation to pancreatic cancer

in a meta-analysis based on 92 studies that represented 161 different exposed populations.

Eligible studies had to fulfil certain criteria and had to be agent-specific with direct risk

estimates for one or several of 23 agents or for job titles with verified exposures to the

agents. Proportionate mortality and incidence studies were excluded. For exposure to

formaldehyde, five eligible populations were identified with a meta-relative risk of 0.8

(95% CI, 0.5–1.0), and point estimates of the meta-relative risks for different subsets of the

meta-analysis by gender, type of diagnosis and study design ranged from 0.5 to 1.0. There

was no evidence of heterogeneity of point estimates between populations. [The studies or

populations included in the evaluation of formaldehyde were not clearly identified. The

NCI cohort study by Blair et al. (1986) (see Section 2.1.1(a)) was apparently not included.]

Collins et al. (2001a) calculated a meta-relative risk for pancreatic cancer based on

results from 14 studies, including eight cohort studies, four proportionate cancer mortality

or incidence studies and two case–control studies that were published between 1983 and

1999. Based on a fixed effects model, an overall meta-relative risk of 1.1 (95% CI,

1.0–1.2) was calculated with no substantial heterogeneity across studies (p = 0.12). Metarelative risks by type of job were 0.9 (95% CI, 0.8–1.1) for industrial workers (five studies

that included 137 pancreatic cancers), 1.3 (95% CI, 1.0–1.6) for embalmers (four studies

that included 88 pancreatic cancers) and 1.3 (95% CI, 1.0–1.7) for pathologists and anatomists (three studies that included 60 pancreatic cancers). There was no indication of

publication bias. It was mentioned that the two studies that evaluated risk for pancreatic

cancer at various exposure levels (Blair et al., 1986; Kernan et al., 1999) did not find

monotonically increasing risks with increasing exposure levels. [Four (three cohort

FORMALDEHYDE 169
studies and one proportionate incidence study) of the 14 studies included were also referenced in the meta-analysis by Ojajärvi et al. (2000).]

(c) Leukaemia

Collins and Lineker (2004) calculated meta-relative risks for leukaemia based on the

results from 12 cohort studies, four proportionate mortality or incidence studies and two

case–control studies that were published between 1975 and 2004. Using a fixed effects

model, an overall meta-relative risk for leukaemia of 1.1 (95% CI, 1.0–1.2) was calculated

170 IARC MONOGRAPHS VOLUME 88

Table 23. Summary of results from meta-analyses of pancreatic cancer 

and exposure to formaldehyde 

Ojajärvi et al. (2000)a Collins et al. (2001a)b

Populations mRR 

(95% CI) 

Studies No. of 

cases 

mRR 

(95% CI) 

All studies 5 0.8 (0.5–1.0) 14 364 1.1 (1.0–1.2) 

Sex 

 Men 3 0.8 (0.5–1.3) 

 Unspecified or both 2 0.6 (0.3–1.1) 

Histological diagnosis 

 Yes 2 0.5 (0.3–0.9) 

 No 3 0.9 (0.7–1.3) 

Study type 

 Case–control and cohort 

 with internal reference 

2 0.5 (0.3–1.6) 

 SMR/SIR 3 0.9 (0.7–1.3) 

 Cohort 8 132 1.0 (0.8–1.2) 

 Case–control 2 79 1.0 (0.5–2.0) 

 PMR/PIR 4 153 1.2 (1.0–1.4) 

Type of job 

 Industrial 5 137 0.9 (0.8–1.1) 

 Embalmer 4 88 1.3 (1.0–1.6) 

 Pathologist and anatomist 3 60 1.3 (1.0–1.7) 

CI, confidence interval; mRR, meta-relative risk; PMR/PIR, proportionate mortality ratio/proportionate incidence ratio; SMR/SIR, standardized mortality ratio/standardized incidence ratio

a

 Ojajärvi et al. (2000) studied occupational exposures and pancreatic cancer in 92 studies and 

161 different exposed populations. The studies used for their evaluation of formaldehyde are not 

listed specifically. However, the study by Blair et al. (1986) was apparently not included. b

 Collins et al. (2001a) included the following studies in their analyses: Walrath & Fraumeni 

(1983), Levine et al. (1984), Walrath & Fraumeni (1984), Blair et al. (1986), Stroup et al.

(1986), Stayner et al. (1988), Gérin et al. (1989), Hayes et al. (1990), Matanoski (1991), Hall 

et al. (1991), Gardner et al. (1993), Andjelkovich et al. (1995), Hansen & Olsen (1995) and 

Kernan et al. (1999). 
based on 287 observed cases with borderline heterogeneity across studies (p = 0.07). Separate analyses by study type showed heterogeneity among proportionate mortality or incidence studies (meta-relative risk, 1.2; 95% CI, 1.0–1.5; p-heterogeneity = 0.02), but not

among cohort studies (meta-relative risk, 1.0; 95% CI, 0.9–1.2) or among the two

case–control studies (meta-relative risk, 2.4; 95% CI, 0.9–6.5). Increased risk was observed

in studies of embalmers (meta-relative risk, 1.6; 95% CI, 1.2–2.0) and pathologists and anatomists (meta-relative risk, 1.4; 95% CI, 1.0–1.9), but not among industrial workers (metarelative risk, 0.9; 95% CI, 0.8–1.0). There was no indication of substantial publication bias.

[This meta-analysis did not include the studies by Logue et al. (1986), Partanen et al.

(1993), Stellman et al. (1998) or Blair et al. (2001). Results from Harrington and Shannon

(1975) and Harrington and Oakes (1984) were both included despite overlapping study

populations. The Working Group noted that the findings of the meta-analysis would be

sensitive to the choice of effect measures based on external rather than internal comparisons

from some studies. Also, the analysis did not take into account risk estimates for higherexposure subgroups or information on exposure–response relationships in the industrial

cohort studies.]

3. Studies of Cancer in Experimental Animals

3.1 Inhalation

3.1.1 Mouse

Groups of 42–60 C3H mice [sex and age unspecified] were exposed to concentrations

of 0, 50, 100 or 200 mg/m3 formaldehyde (US Pharmacopeia grade) vapour for 1 h per

day, three times a week, ostensibly for 35 weeks. Treatment of mice with the highest concentration was discontinued after the 11th exposure because of severe toxicity, and 36 of

the mice exposed to 50 mg/m3 for 35 weeks were subsequently exposed to 150 mg/m3 for

a further 29 weeks. Surviving animals in the initial groups were killed at 35 weeks and

those on extended treatment at 68 weeks. The nasal epithelium was not examined, either

grossly or microscopically. There was no evidence of induction of pulmonary tumours at

any dose. Basal-cell hyperplasia, squamous-cell metaplasia and atypical metaplasia were

seen in the trachea and bronchi of most of the exposed mice but not in untreated controls

(Horton et al., 1963). [The Working Group noted the high doses used, the short intervals

of exposure, the short duration of the experiment and the lack of pathological examination

of the nose.]

Groups of 119–120 male and 120–121 female B6C3F1 mice, 6 weeks of age, were

exposed to 0, 2.0, 5.6 or 14.3 ppm [0, 2.5, 6.9 or 17.6 mg/m3] formaldehyde (> 97.5% pure)

vapour by whole-body exposure for 6 h per day on 5 days per week for up to 24 months,

followed by a 6-month observation period with no further exposure. Ten males and

10 females from each group were killed at 6 and 12 months, no or one male and 19–20

FORMALDEHYDE 171
females at 18 months, 17–41 of each sex at 24 months and 9–16 females at 27 months.

Between 0 and 24 months, 78 male and 30 female controls, 77 males and 34 females

exposed to 2 ppm formaldehyde vapour, 81 males and 19 females exposed to 5.6 ppm and

82 males and 34 females exposed to 14.3 ppm died; all animals that died or were killed

were examined grossly. Thorough histopathological examinations were performed on

control and high-dose mice, on multiple sections of the nasal cavity and on all lesions that

were identified grossly in the other two groups. Squamous-cell carcinomas occurred in the

nasal cavities of 2/17 male mice in the high-dose group that were killed at 24 months. No

nasal cavity tumours developed in male mice treated with lower doses of formaldehyde, in

females at any dose or among 21 male or 31 female control mice killed at 24 months

(p > 0.05). A variety of non-neoplastic lesions (such as squamous-cell hyperplasia,

squamous-cell metaplasia and dysplasia) were commonly found in the nasal cavities of

mice exposed to formaldehyde, particularly at 14.3 ppm (Kerns et al., 1983a,b; Gibson,

1984).

3.1.2 Rat

Groups of 119–120 male and 120 female Fischer 344 rats, 7 weeks of age, were exposed

to 0, 2.0, 5.6 or 14.3 ppm [0, 2.5, 6.9 or 17.6 mg/m3] formaldehyde (> 97.5% pure) vapour

by whole-body exposure for 6 h per day on 5 days per week for up to 24 months and were

then observed for 6 months with no further exposure. Ten males and 10 females from each

group were killed at 6 and 12 months, 19–20 of each sex at 18 months, 13–54 at 24 months,

0–10 at 27 months and 0–6 at 30 months. Between 0 and 24 months, six males and

13 females in the control group, 10 males and 16 females exposed to 2 ppm, 19 of each sex

exposed to 5.6 ppm and 57 males and 67 females exposed to 14.3 ppm died; all animals that

died or were killed were examined grossly. Histopathological examinations were performed

on multiple sections of the nasal cavity, on all lesions that were identified grossly and on all

major tissues of each organ system (approximately 40 per animal) from control and highdose rats. The findings for the nasal cavity are summarized in Table 24. While no nasal

cavity malignancies were found in rats exposed to 0 or 2.0 ppm formaldehyde, two squamous-cell carcinomas (1/119 males and 1/116 females examined) occurred in the group

exposed to 5.6 ppm and 107 (51/117 males and 52/115 females examined) in those exposed

to 14.3 ppm (p < 0.001). Five additional nasal cavity tumours (classified as carcinoma,

undifferentiated carcinoma/sarcoma and carcinosarcoma) were identified in rats exposed to

14.3 ppm; two of these tumours were found in rats that also had squamous-cell carcinomas

of the nasal cavity. There was a significant overall increase in the incidence of polypoid

adenomas in treated animals (males and females combined) when compared with controls

(p = 0.02, Fisher’s exact test). The incidences of polypoid adenomas were marginally

significantly elevated in females at the low dose (p = 0.07, Fisher’s exact test) and in males

at the middle dose (p = 0.06, Fisher’s exact test) (see also Table 24). A variety of non-neoplastic lesions were commonly found in the nasal cavities of rats exposed to formaldehyde,

particularly at 14.3 ppm (Swenberg et al., 1980; Kerns et al., 1983a,b; Gibson, 1984). More

172 IARC MONOGRAPHS VOLUME 88
than half (57%) of the squamous-cell carcinomas in rats exposed to 14.3 ppm formaldehyde

were observed on the anterior portion of the lateral side of the nasoturbinate and the adjacent

lateral wall, 25% were located on the midventral nasal septum, 10% on the dorsal septum

and roof of the dorsal meatus and a small number (3%) on the maxilloturbinate (Morgan

et al., 1986a).

In a study to investigate the carcinogenicity of bis(chloromethyl)ether formed in situ in

inhalation chambers by mixing formaldehyde and hydrogen chloride gas at high concentrations before introduction into the chamber in order to maximize its formation, 99 male

Sprague–Dawley rats, 8 weeks of age, were exposed to a mixture of 14.7 ppm [18.1 mg/m3]

formaldehyde [purity unspecified] vapour and 10.6 ppm [15.8 mg/m3] hydrogen chloride

gas for 6 h per day on 5 days per week for life. The average level of bis(chloromethyl)ether

was 1 ppb [4.7 μg/m3]. Groups of 50 rats were sham-exposed to air or were untreated. The

animals were allowed to die naturally and were then necropsied. Histological sections of

nasal cavities, respiratory tract, major organs and gross lesions were prepared and examined

microscopically. No nasal cancers were found in the controls, but 28 of the treated rats developed tumours of the nasal cavity, 25 of which were squamous-cell carcinomas [p < 0.001,

Fisher’s exact test] and three of which were papillomas. Mortality was greater in the treated

group than in controls throughout the experiment; about 50% of the exposed rats were still

alive at 223 days, when the first nasal carcinoma was observed. About two-thirds of the

exposed rats showed squamous-cell metaplasia of the nasal mucosa; these lesions were not

seen in controls (Albert et al., 1982).

FORMALDEHYDE 173

Table 24. Neoplastic lesions in the nasal cavities of Fischer 344 rats exposed to 

formaldehyde vapour 

Exposure (ppm) 

0 2.0 5.6 14.3 

Lesion 

M F M F M F M F 

No. of nasal cavities examined 118 114 118 118 119 116 117 115 

Squamous-cell carcinoma 0 0 0 0 1 1 51a 52a

Nasal carcinoma 0 0 0 0 0 0 1b 1 

Undifferentiated carcinoma 

 or sarcoma 

 0 0 0 0 0 0 2b 0 

Carcinosarcoma 0 0 0 0 0 0 1 0 

Osteochondroma 1 0 0 0 0 0 0 0 

Polypoid adenoma 1 0 { 4 4c 6d 0 4 1 }e

From Kerns et al. (1983a) a p < 0.001, pair-wise comparisons b One animal in this group also had a squamous-cell carcinoma. 

c

 [p = 0.07, Fisher’s exact test in comparison with female controls] d

 [p = 0.06, Fisher’s exact test in comparison with male controls] e [p = 0.02, Fisher’s exact test in comparison of all treated rats with controls]
In a follow-up study, groups of 99–100 male Sprague-Dawley rats, 9 weeks of age,

were exposed for 6 h per day on 5 days per week for life to: (1) 14.3 ppm [17.6 mg/m3]

formaldehyde [purity unspecified] and 10 ppm [14.9 mg/m3] hydrogen chloride gas mixed

before dilution in the exposure chamber to maximize formation of bis(chloromethyl)ether;

(2) 14.1 ppm [17.3 mg/m3] formaldehyde and 9.5 ppm [14.2 mg/m3] hydrogen chloride gas

not mixed before introduction into the exposure chamber; (3) 14.2 ppm [17.5 mg/m3]

formaldehyde vapour alone; (4) 10.2 ppm [15.2 mg/m3] hydrogen chloride gas alone; or

(5) air (sham-exposed controls). A control group of 99 rats was also available. The findings

in the nasal cavity are summarized in Table 25. At the end of the experiment, 38 squamouscell carcinomas of the nasal cavities and 10 papillomas or polyps were observed in rats

exposed to formaldehyde alone; none were seen in the controls (p ≤ 0.001, Fisher’s exact

test). No differences were reported between groups in the incidences of tumours outside the

nasal cavity (Albert et al., 1982; Sellakumar et al., 1985).

Nine groups of 45 male Wistar rats [age unspecified], initially weighing 80 g, were

exposed to 0, 10 or 20 ppm [0, 12.3 or 25 mg/m3] formaldehyde [purity unspecified]

vapour beginning 1 week after acclimatization. Whole-body exposures for 6 h per day on

5 days per week were continued for 4, 8 or 13 weeks; thereafter, the rats were observed

during recovery periods of 126, 122 or 117 weeks, respectively, after which all survivors

were killed. All rats were autopsied and examined by gross pathology; histological examination was limited to six cross-sections of the nose of each rat. Hyperplasia and metaplasia of the nasal epithelium were found to persist in rats exposed to formaldehyde.

Significant tumour incidences are presented in Table 26. In control rats, the only nasal

tumours reported were two squamous-cell carcinomas among 45 rats that were exposed

to air for 8 weeks: one was a small tumour found at 130 weeks which appeared to involve

a nasolachrymal duct; the second was a large squamous-cell carcinoma in a rat killed at

174 IARC MONOGRAPHS VOLUME 88

Table 25. Neoplastic lesions in the nasal cavities of male Sprague-Dawley rats exposed 

to formaldehyde (HCHO) and/or hydrogen chloride (HCl) vapour

Lesion Group 1:

Premixed

HCl (10 ppm)

and HCHO

(14.3 ppm)

Group 2:

Non-premixed

HCl (9.5 ppm)

and HCHO

(14.1 ppm)

Group 3:

HCHO

(14.2 

ppm)

Group 4:

HCl

(10.2 

ppm) 

Group 5:

Air 

controls

Colony

controls

No. of rats examined 100 100 100 99 99 99

Squamous-cell carcinoma 45 27 38 0 0 0

Adenocarcinoma 1 2 0 0 0 0

Mixed carcinoma 0 0 1 0 0 0

Fibrosarcoma 1 0 1 0 0 0

Aesthesioneuroepithelioma 1 0 0 0 0 0

Papillomas or polyps 13 11 10 0 0 0

Tumours in organs outside

the respiratory tract

22 12 10 19 25 24

From Sellakumar et al. (1985)
week 94, which formed a large mass outside the nasal cavity and was thought to have

arisen in a nasolachrymal duct or maxillary sinus. The tumours were considered by the

authors not to resemble those observed in the rats exposed to formaldehyde. Rats exposed

to 10 ppm formaldehyde also had two squamous-cell carcinomas: one was reported to be

a small nasolachrymal-duct tumour in a survivor at 130 weeks, and the second occurred

largely outside the nasal cavity in association with an abnormal incisor tooth in a rat killed

at week 82. Rats exposed to 20 ppm formaldehyde had 10 tumours: polypoid adenomas

of the nasal cavity were found in one rat exposed for 4 weeks and killed at 100 weeks and

in another rat exposed for 8 weeks and killed at 110 weeks; six were squamous-cell

carcinomas, two of which were thought to originate in the nasolachrymal ducts, one of

which appeared to be derived from the palate and the three others, all in the group

exposed for 13 weeks, appeared to arise from the naso- or maxillo-turbinates and formed

large tumours that invaded the bone and subcutaneous tissues. The other two neoplasms

observed in treated animals were an ameloblastoma found at week 73 and an exophytic

tumour of the nasal septum of doubtful malignancy, which was designated a carcinoma

in situ, in a rat that died at 81 weeks. The authors concluded that the nasal tumours were

induced by formaldehyde only at 20 ppm and at an incidence of 4.5% (six tumours/132

rats) [p = 0.01, Fisher’s exact test] (Feron et al., 1988). [The Working Group noted that

positive findings were made in spite of the short duration of exposure.] 

A total of 720 male specific pathogen-free Wistar rats [age unspecified], initially

weighing 30–50 g, were acclimatized for 1 week, and then the nasal mucosa of 480 of the

rats was severely injured bilaterally by electrocoagulation. One week later, groups of

FORMALDEHYDE 175

Table 26. Nasal tumours in male Wistar rats exposed to formaldehyde 

for 4, 8 or 13 weeks followed by observation up to 126 weeks 

Dose (ppm [mg/m2 Exposure time; ]) 

no. of rats 

Tumour 

 0 10 [12.3] 20 [25] 

4 weeks 

No. of rats 44 44 45 

Polypoid adenoma 0 0 1a

Squamous-cell carcinoma 0 0 1 

8 weeks 

No. of rats 45 44 43 

Polypoid adenoma 0 0 1a

Squamous-cell carcinoma 2 1 1 

13 weeks 

No. of rats 45 44 44 

Squamous-cell carcinoma 0 1 3a

Cystic squamous-cell carcinoma 0 0 1 

Carcinoma in situ 0 0 1a

Ameloblastoma 0 0 1 

From Feron et al. (1988) a

 Considered by the authors to be related to exposure to formaldehyde
180 rats were exposed to 0, 0.1, 1.0 or 10 ppm [0, 0.123, 1.23 or 12.3 mg/m3] formaldehyde

[purity unspecified] vapour by whole-body exposure for 6 h per day on 5 days per week.

Half of the animals (30 undamaged and 60 damaged rats) were exposed for 28 months, and

the other half (30 undamaged and 60 damaged rats) were exposed for only 3 months and

then allowed to recover for 25 months with no further treatment. All surviving rats were

killed at 29 months, autopsied and examined grossly; histological examination was

restricted to six cross-sections of the nose of each rat. The neoplastic lesions found in the

nasal cavity are summarized in Table 27. A high incidence of nasal tumours (17/58) was

found in rats that had damaged noses and were exposed to 10 ppm formaldehyde for

28 months; only one was found in 54 controls [p < 0.001; Fisher’s exact test]; and only one

of the 26 rats that had undamaged noses and were exposed to 10 ppm formaldehyde for

28 months developed a nasal tumour. The tumour incidences in the other groups were low

(0–4%). Eight additional squamous-cell carcinomas found in this study that appeared to be

derived from the nasolachrymal ducts were excluded from the analysis (Woutersen et al.,

1989).

In a study to explore the interaction between formaldehyde and wood dust, two groups

of 16 female Sprague-Dawley rats, 11 weeks of age, were exposed either to air or to

formaldehyde [purity unspecified] at an average concentration of 12.4 ppm [15.3 mg/m3].

Exposures were for 6 h per day for 5 days a week for a total of 104 weeks. At the end of

the experiment, surviving animals were killed, and histological sections were prepared

from five cross-sections of the nose of each rat. Pronounced squamous-cell metaplasia or

metaplasia with dysplasia was observed in 10/16 rats exposed to formaldehyde and in

176 IARC MONOGRAPHS VOLUME 88

Table 27. Nasal tumours in male Wistar rats that had damaged or undamaged 

noses and were exposed to formaldehyde vapour for 28 months or 3 months 

followed by a 25-month recovery period

Exposure (ppm [mg/m3])

0 0.1 [0.123] 1.0 [1.23] 10.0 [12.3]

Exposure time;

no. of rats

Tumour

U D U D U D U D

28 months

Effective number 26 54 26 58 28 56 26 58

Squamous-cell carcinoma 0 1 1 1 1 0 1 15

Adenosquamous carcinoma 0 0 0 0 0 0 0 1

Adenocarcinoma 0 0 0 0 0 0 0 1

3 months

Effective number 26 57 30 57 29 53 26 54

Squamous-cell carcinoma 0 0 0 2 0 2 1 1

Carcinoma in situ 0 0 0 0 0 0 0 1

Polypoid adenoma 0 0 0 0 0 0 1 0

From Woutersen et al. (1989)

U, undamaged nose; D, damaged nose
0/15 controls. One exposed rat developed a squamous-cell carcinoma. Neither the frequency nor the latent periods of induction of tumours outside the nasal cavity differed

from those in controls (Holmström et al., 1989b). [The Working Group noted the small

numbers of animals used in the study.]

To study the correlation of indices of regional cell proliferation with the sites of

formaldehyde-induced nasal squamous-cell carcinomas, five groups of 90 and one (highdose) group of 147 male Fischer 344 (CDF(F344)CrlBr) rats, 8–9 weeks of age, were

exposed to 0, 0.69, 2.05, 6.01, 9.93 or 14.96 ppm [0, 0.84, 2.4, 7.2, 12 or 18 mg/m3]

formaldehyde vapour (produced by thermal depolymerization of paraformaldehyde) by

whole-body exposure for 6 h per day on 5 days per week for up to 24 months; six rats per

group were killed at 3, 6, 12 and 18 months for interim observation. Histopathological examination of the nasal cavities was performed on all rats. The distribution of the nasal

tumours was recorded on diagrams of the nasal passages at 30 selected levels that were

designed to permit accurate localization of nasal lesions. In the high-dose group, survival

was significantly decreased relative to that in the control group (18.8% versus 35.7%;

p < 0.001, life-table analysis using the product-limit procedure of Kaplan and Meier; Cox’s

method for pairwise comparisons). Survival in the other exposure groups was similar to

that in controls. According to the authors, formaldehyde induced nasal squamous-cell

carcinomas in a highly non-linear fashion: no such tumours were observed after exposure

to 2 ppm or lower or in controls; the incidences in the groups exposed to 6.01, 9.93 and

14.96 ppm were 1/90 [1%], 20/90 (22%) and 69/147 (45%) [47% according to the Working

Group], respectively. The single nasal tumour found in the 6.01-ppm group was located in

the anterior lateral meatus, a region that was predicted to receive a relatively high dose of

formaldehyde. The time-to-tumour appearance of nasal squamous-cell carcinomas was

622, 555 and 350 days in the 6.01-, 9.93- and 14.96-ppm groups, respectively. No other

type of nasal tumour was found among controls or among animals exposed to the two

lowest concentrations. Polypoid adenomas (5/90 (5.6%) and 14/147 (9.5%)), rhabdomyosarcomas (1/90 [1%] and 1/47 [1%]) and adenocarcinomas (1/90 [1%] and 1/147 [1%])

were observed in the nasal cavities of rats exposed to 9.93 and 14.96 ppm, respectively.

Formaldehyde-induced non-neoplastic nasal lesions were primarily confined to the transitional and respiratory epithelium of the anterior passages, were only found in the groups

exposed to the three highest concentrations and were most severe in the groups exposed to

9.93 and 14.96 ppm. These lesions mainly comprised epithelial hypertrophy, hyperplasia

and metaplasia, mixed inflammatory cell infiltrates, turbinate adhesions and, in many highdose animals, significant distortion and destruction of the nasoturbinate architecture. In

rats exposed to 6.01 ppm, non-neoplastic lesions were minimal or absent, and were limited

to focal squamous metaplasia in the anterior regions (Monticello et al., 1996).

Four groups of 32 male Fisher 344 rats (F-344/DuCrj), 5 weeks of age, were exposed

to 0, 0.3, 2.17 and 14.85 ppm [0, 0.36, 2.6 and 17.8 mg/m3] formaldehyde [purity unspecified] vapour by whole-body exposure for 6 h per day on 5 days per week for up to

28 months. A group of 32 rats served as unexposed room controls. The formaldehyde

vapour was produced from a 37% aqueous formaldehyde solution containing 10%

FORMALDEHYDE 177
methanol as an anti-polymerization agent. Rats in the 0-ppm control group were exposed

to the same concentration of methanol (4.2 ppm) as those of the high-dose group. At 12, 18

and 24 months, five (randomly selected) animals per group (in the high-dose group, only

two animals were alive at 24 months) were killed and examined grossly. At 28 months, all

survivors were killed and necropsied. Animals that were found dead or killed in extremis

also underwent necropsy. Histopathological examinations were performed on five anatomically specified cross-sections of the nose from all animals, on all lesions identified

grossly and on other major organs (approximately 23 per animal) [probably all control and

all exposed animals, although this was not mentioned specifically]. The total number of

animals that died or were killed in moribund condition were 11 room controls and eight,

six, 10 and 20 0-ppm control, low-, mid- and high-dose rats, respectively. Mortality rates

(calculated by the life-table technique) at 28 months were 59.6% of room controls, 45.5%

of 0-ppm controls, 31.8% of the 0.3-ppm group, 55.9% of the 2.17-ppm group and 88.3%

of the 14.85-ppm group (p ≤ 0.01 compared with the 0-ppm group; Fisher’s exact test).

Gross and microscopic pathological changes attributable to exposure to formaldehyde were

found only in the nose. Except for an unclassified sarcoma found in one room control, nasal

tumours were seen only in the high-dose group, and included three squamous-cell papillomas, 13 squamous-cell carcinomas (p ≤ 0.01; Fisher’s exact test) and one sarcoma. Grossly,

the first nasal tumour was observed in the high-dose group after 13 weeks of exposure.

Most of the nasal tumours were located in the incisor teeth and maxillary turbinate regions.

Large tumours invaded the subcutis through the nasal bones. Hyperplasia with squamouscell metaplasia of the nasal epithelium [not further specified] was found only in rats

exposed to formaldehyde, the incidences (combined for all animals examined at interim

and terminal sacrifices and found dead or killed in extremis) of which were 0/32, 0/32,

4/32, 7/32 (p ≤ 0.01; Fisher’s exact test) and 29/32 (p ≤ 0.01; Fisher’s exact test) for the

room-control, 0-, 0.3-, 2.17- and 14.96-ppm groups, respectively. Hyperkeratosis of the

nasal epithelium was found in 1/32 rats exposed to 2.17 ppm and in 26/32 rats exposed to

14.96 ppm (p ≤ 0.01; Fisher’s exact test); papillary hyperplasia of the nasal epithelium was

seen in 2/32 rats in the high-dose group (Kamata et al., 1997).

3.1.3 Hamster

A group of 88 male Syrian golden hamsters [age unspecified] was exposed to 10 ppm

[12.3 mg/m3] formaldehyde [purity unspecified] for 5 h a day on 5 days a week for life;

132 untreated controls were available. At necropsy, all major tissues were preserved, and

histological sections were prepared from two transverse sections of the nasal turbinates of

each animal; longitudinal sections were taken of the larynx and trachea, and all lung lobes

were cut through the major bronchus. No tumours of the nasal cavities or respiratory tract

were found in either controls or animals exposed to formaldehyde.

In a second study in the same report, 50 male Syrian golden hamsters [age unspecified]

were exposed to 30 ppm [36.9 mg/m3] formaldehyde [purity unspecified] for 5 h once a

week for life. A group of 50 untreated hamster served as controls. When the animals died,

178 IARC MONOGRAPHS VOLUME 88
their respiratory tract tissues were preserved, stained with Wright’s stain, rendered

semitransparent and evaluated for ‘subgross’ evidence of tumours. Areas of dense staining

of 1 mm or more were scored as tumours. Multiple transverse sections of the nasal

turbinates were evaluated similarly. No nasal tumours were observed in control or treated

hamsters (Dalbey, 1982).

3.2 Oral administration 

Rat

In a study to evaluate the effects of formaldehyde on gastric carcinogenesis induced by

oral administration of N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) (see Section 3.4.2),

two groups of 10 male Wistar rats, 7 weeks of age, received tap-water for the first 8 weeks

of the study. During weeks 8–40, one group was continued on tap-water and the other group

received 0.5% formaldehyde [purity unspecified] in the drinking-water. Animals that were

still alive at 40 weeks were killed; rats that survived beyond 30 weeks were considered as

effective animals for the study. Necropsy was performed on most animals that died and all

animals that were killed, and the stomach and other abdominal organs were examined

grossly and histologically. Eight of 10 animals that had received formaldehyde in the

drinking-water and none of the controls developed forestomach papillomas (p < 0.01,

Fisher’s exact test) (Takahashi et al., 1986).

Wistar rats, obtained at 5 weeks of age and acclimatized for 9 days, were divided into

four groups of 70 males and 70 females and were treated for up to 24 months with

drinking-water that contained formaldehyde generated from 95% pure paraformaldehyde

and 5% water. The mean doses of formaldehyde were 0, 1.2, 15 or 82 mg/kg bw per day

for males and 0, 1.8, 21 or 109 mg/kg bw per day for females. Selected animals were killed

at 53 and 79 weeks, and all surviving animals were killed at 105 weeks. Thorough

necropsies were performed on all animals. Extensive histological examinations were made

of animals in the control and high-dose groups; somewhat less extensive examinations

were made of animals that received the low and middle doses, but the liver, lung, stomach

and nose were examined in each case. Treatment-related atrophy, ulceration and hyperplastic lesions were found in the forestomachs and glandular stomachs, but the incidence

of tumours did not vary notably between groups. Two benign gastric papillomas were

observed (one in a male at the low dose and the other in a female control). The authors

noted that the other tumours observed were common in this strain of rat and that there was

no indication of a treatment-related tumour response (Til et al., 1989).

Two groups of male and female Sprague-Dawley breeder rats, 25 weeks of age, were

given 0 (20 males and 20 females) or 2500 (18 males and 18 females) ppm formaldehyde

[purity unspecified] in the drinking-water for life. The offspring of these breeders were initially exposed transplacentally to 0 (59 males and 49 females) or 2500 ppm (36 males and

37 females) formaldehyde via their mothers beginning on day 13 of gestation and then

received the same levels in the drinking-water for life. [The Working Group noted the lack

FORMALDEHYDE 179
of information on selection of the offspring.] All animals were necropsied and subjected to

histopathological examination. The survival rates in the treated groups were similar to

those of controls. According to the authors, the preliminary results of this study showed a

slight, statistically non-significant increase in the incidence of leukaemias (including

haemolymphoreticular lymphomas) in male and female breeders exposed to formaldehyde.

A statistically non-significant increase in the incidence of leukaemias was also reported in

the exposed male, but not in the exposed female, offspring (see Table 28). The authors also

reported a variety of malignant and benign tumours of the stomach and intestines in the

treated animals (see Table 28). Leiomyosarcoma was the most frequent malignant tumour.

[The incidence of leiomysarcomas in the intestines was statistically significantly increased

in the exposed offspring, both in females and in males and females combined; p ≤ 0.01,

χ2 test.] This gastrointestinal tumour was exceptionally rare in the historical controls of this

laboratory (Soffritti et al., 1989). Concerns about the results by Soffritti et al. (1989) and

their interpretation were published by Feron et al. (1990). One concern was that incidences

of leukaemia in untreated Sprague-Dawley rats vary widely and that incidences similar to

those seen in the group that received formaldehyde have been reported previously among

controls in the same laboratory and in others.

Seven groups of 50 male and 50 female Sprague-Dawley rats, 7 weeks of age, received

10, 50, 100, 500, 1000 or 1500 mg/L formaldehyde (purity > 99.0%; 0.3% methanol as

stabilizer; impurities: 0.6 mg/L iron, 0.1 mg/L lead, < 5.0 mg/L sulfur and < 5.0 mg/L chlorine) or 15 mg/L methanol in the drinking-water for 104 weeks. A control group of

100 males and 100 females received tap-water alone. By week 163, all animals had died.

The consumption of treated drinking-water decreased in males of the high-dose group and

in females of the three highest-dose groups (approximately 30% according to Soffritti

et al., 1989). No differences between treated and control animals were observed in food

consumption, body weight or survival. Moreover, no treatment-related non-neoplastic

changes were detected by gross or histopathological examination. Percentages of animals

that had malignant tumours and incidences of major tumours are presented in Table 29.

Tumour incidences in the treated groups were compared with those in the untreated control

group and statistically significantly increases were found in the number of males that had

malignant tumours in the high-dose group, and in the incidences of malignant mammary

gland tumours in females in the 1500-mg/L group, of testicular interstitial-cell adenomas

in the 1000-mg/L group and of haemolymphoreticular tumours in males in the four highestand in females in the two highest-dose groups. According to the authors, there was a

dose–response relationship [no statistics given] for the increased incidences of haemolymphoreticular tumours. Gastrointestinal leiomyomas and leiomyosarcomas, which are

very rare tumours in the strain of rats used, occurred sporadically in some formaldehydetreated animals but not in controls (Soffritti et al., 2002). [The Working Group performed

statistical analyses for trend and incidence in comparison with the methanol-treated group

and found that the only statistically significant increases were in the total number of animals that had malignant tumours (p < 0.01) and in the incidences of haemolymphoreticular

tumours (p < 0.01) in high-dose males and of testicular interstitial-cell adenomas (p < 0.01)

180 IARC MONOGRAPHS VOLUME 88
Table 28. Incidences (%) of leukaemia and tumours (benign and malignant) of the gastrointestinal tract after in the drinking-water to Sprague-Dawley breeder rats and their offspring Treatment No. of Leukaemias Stomach 

rats 

Lymphoblastic leukaemias and lymphosarcomas 

Immunoblastic lymphosarcomas 

Others Total Papilloma/ 

acanthoma/ adenoma 

Adenocarcinoma/ squamous-cell carcinoma 

Leiomyosarcoma 

Breeders (25 weeks old)  0 ppm  Male  Female  Male + female  2500 ppm  Male  Female  Male + female 

 20  20  40  18  18  36 

– 5.0 2.5 – 5.6 2.8 

– – – 5.6 5.6 5.6 

– – – 5.6 – 2.8 

–  5.0  2.5 11.1 11.1 11.1 

– – – – 5.6 2.8 

– – – 5.6 – 2.8 

– – – – – – 

Offspring  0 ppm  Male  Female  Male + female  2500 ppm  Male  Female  Male + female 

 59  49 108  36  37  73 

– – – 2.8 – 1.4 

3.4 4.1 3.7 8.2 – 4.1 

1.7 2.0 1.8 – – – 

 5.1  6.1  5.5 11.1 –  5.5 

– – – 2.8 – 1.4 

– – – 2.8 2.7 2.8 

– – – 2.8 2.7 2.7 

From Soffritti et al. (1989) a [p ≤ 0.01; χ2 test, calculated by the Working Group] 
Table 29. Percentage of animals that had malignant tumours and incidence of selected types of tumoSprague-Dawley rats after administration of formaldehyde in the drinking-water for up to 24 months Formaldehyde dose (mg/L) Males Females Site and type of tumour

0 0a 10 50 100 500 1000 1500 0 0a 10 

No. of animals 100 50 50 50 50 50 50 50 100 50 50 Animals bearing malignant tumours (%) 38 42 28 24 44 48 46 72b,c 43 46 40 Mammary gland

Adenocarcinoma 1 0 0 0 0 0 0 2 11 14 4 

Fibrosarcoma 0 2 0 0 0 0 0 0 0 0 2 Liposarcoma 0 0 0 0 2 0 0 0 0 2 0 

Angiosarcoma 0 0 0 0 0 2 0 0 0 0 0 Total 1 2 0 0 2 2 0 2 11 16 6 

Forestomach

Leiomyosarcoma 0 0 2 0 0 0 0 0 0 0 0 

Glandular stomach

Leiomyosarcoma 0 0 0 0 0 0 2 0 0 0 0 

Intestine

Leiomyoma 0 0 0 0 0 0 0 0 0 0 2 Leiomyosarcoma 0 0 0 0 0 0 0 4 0 0 0 

Testes

Interstitial-cell adenoma 10 6 6 12 12 20 24d,e 18

Haemolymphoreticular tissuesf

Lymphomas and leukaemias 8 20 8 20 26b 24d 22d 46b,c,g 7 10 10 

From Soffritti et al. (2002) a 15 mg/L methanolb p < 0.01, χ2 test, versus untreated controls c [p < 0.01, χ2 test, versus methanol group; calculated by the Working Group] d p < 0.05, χ2 test, versus untreated controls [the Working Group noted that this category is an aggregate of tumours of different cellular origin] e [p < 0.01, 2-tail Fisher exact test, versus methanol group; calculated by the Working Group] f Including thymus, spleen and subcutaneous, mesenteric and pancreatic lymph nodesg [p < 0.01 for trend, Cochran Armitage; calculated by the Working Group]
in the 1000-mg/L group. There was a statistically significant dose–response relationship

for the increased incidences of haemolymphoreticular tumours (p < 0.01) in males. The

Working Group noted the ‘pooling’ of lymphomas and leukaemias (designated as haemolymphoreticular neoplasias), the lack of reporting of non-neoplastic lesions and the

absence of information on incidences of haemolymphoreticular tumours in historical

controls.] Preliminary results of this study were published by Soffritti et al. (1989). [The

Working Group noted that, in spite of the extensive histopathological examinations on

which the preliminary data on tumours presented by Soffritti et al. (1989) were stated to

be based, the reported total number of animals that had haemolymphoreticular neoplasias

increased from 79 (Soffritti et al., 1989) to 150 (Soffritti et al., 2002).]

3.3 Dermal application

Mouse

In a study to evaluate the effects of formaldehyde on skin carcinogenesis induced by

7,12-dimethylbenz[a]anthracene (DMBA) (see Section 3.4.1), two groups of 16 male and

16 female Oslo hairless mice [age unspecified] received topical applications of 200 μL

aqueous solution of 1 or 10% formaldehyde on the skin of the back twice a week for

60 weeks. Animals were observed weekly for skin tumours. All of the animals treated

with 10% formaldehyde were necropsied and the brain, lungs, nasal cavities and all

tumours of the skin and other organs were examined histologically. Virtually no changes

were found in the mice treated with 1% formaldehyde. The 10% dose induced slight epidermal hyperplasia and a few skin ulcers. No benign or malignant skin tumours or

tumours in other organs were observed in either group (Iversen, 1986). [The Working

Group noted that no group treated with water only was included.]

3.4 Administration with known carcinogens and other modifying factors

3.4.1 Mouse

Oslo hairless mice [initial number and age unspecified] received a single topical

application of 51.2 μg DMBA in 100 μL reagent-grade acetone on the skin of the back.

Nine days later, a group of 16 male and 16 female mice received twice-weekly

applications of 200 μL 10% formaldehyde in water (technical-grade formalin) on the skin

of the back. Another group of 176 mice [sex unspecified] was given no further treatment.

Animals were observed weekly for skin tumours for 60 weeks (first group) or 80 weeks

(second group). All of the animals treated with 10% formaldehyde were necropsied, and

the brain, lungs, nasal cavities and all tumours of the skin and other organs were examined

histologically. In the first group, 3/32 mice had lung adenomas and 11/32 (34%) had

25 skin tumours, including three squamous-cell carcinomas and 22 papillomas. In mice

that received DMBA alone, 225 skin tumours (including six squamous-cell carcinomas)

occurred in 85/176 (48%) animals. Statistical analysis of the results for these two groups

FORMALDEHYDE 183
showed that formaldehyde significantly enhanced the rate of skin tumour induction

(p = 0.01, Peto’s test), and reduced the latency period for the tumours (Iversen, 1986).

[The Working Group noted the incomplete reporting of the tumours in the group of rats

treated with DMBA alone.]

3.4.2 Rat

Two groups of 30 and 21 male Wistar rats, 7 weeks of age, received 100 mg/L MNNG

in the drinking-water and a standard diet that contained 10% sodium chloride for 8 weeks.

Thereafter, the rats received the standard diet and 0 or 0.5% formaldehyde in the drinkingwater for a further 32 weeks. Animals still alive at 40 weeks were killed, and rats that

survived 30 weeks or more were considered as effective animals for the study. Necropsies

were performed on most animals that died and on all animals that were killed at week 40.

Malignant tumours of the stomach and duodenum were found in 4/30 (13%) rats that

received MNNG and in 5/17 (29%) rats that received both MNNG and formaldehyde [not

significant]. Adenocarcinomas of the glandular stomach were found in 4/17 (23.5%) rats

that received the combined treatment and in 1/30 rats that received MNNG alone

(p < 0.05, Fisher’s exact test). Papillomas of the forestomach were found in 15/17 rats that

received the combined treatment and in 0/30 that received MNNG alone (p < 0.01,

Fisher’s exact test). The incidence of adenomatous hyperplasia of the fundus of the

glandular stomach was significantly greater in the group that received the combined

treatment (15/17) than in those that received MNNG alone (0/30) (p < 0.01, Fisher’s exact

test) (Takahashi et al., 1986).

Groups of 50 female white non-inbred rats [strain and age not specified] received intratracheal injections of one of three doses of benzo[a]pyrene as a suspension in 5% albumin

in saline once every 2 weeks for 20 weeks (total doses, 0, 0.02, 0.1 or 5.0 mg/animal). One

group of 50 female rats served as an untreated control. All benzo[a]pyrene-treated groups

were then exposed by inhalation to 0, 0.003, 0.03 or 0.3 mg/m3 formaldehyde for 7 h per

day on 5 days per week for 12 months. All animals were maintained until natural death,

and organs and tissues that were suspected to have developed a tumour were subjected to

histological examination. Tumours developed in rats of all 16 groups. Two of 39 effective

(survived to the time of the first tumour development) rats in the control group developed

reticulosarcomas of the lung and two developed fibroadenomas of the mammary gland.

Similar tumours were observed at almost the same incidence in rats exposed to the three

doses of formaldehyde alone. The incidence of total tumours in benzo[a]pyrene-treated rats

was dose-dependent and varied from 13 to 28%. The incidence of lung tumours varied

from 9 to 19%. In the mid- and high-dose groups, squamous-cell cysts and carcinomas of

the lung were observed as well as lymphatic leukaemia. The tumour response to the

combined treatment with benzo[a]pyrene and formaldehyde was also dose-dependent. The

most prominent and statistically significant increase in the incidence of lung tumours

(43%) and all tumours (69%) occurred in rats that were treated with the highest doses of

benzo[a]pyrene and formaldehyde (5.0 mg and 0.3 mg/m3, respectively). In addition,

184 IARC MONOGRAPHS VOLUME 88
tumours developed earlier in this group and had greater multiplicity than those in animals

that were exposed to benzo[a]pyrene or formaldehyde alone. The authors concluded that

the combined treatment of rats with benzo[a]pyrene and formaldehyde leads to an increase

in tumour response which is manifested as an increased incidence of tumours, a reduction

in the latency period of tumour development and a broader spectrum of tumours

(Yanysheva et al., 1998). [The Working Group noted the very low level of exposure to

formaldehyde compared with levels used in other experiments in rats.]

3.4.3 Hamster

Groups of male Syrian golden hamsters [age unspecified] were treated in various

ways: 50 were exposed by inhalation to 30 ppm [36.9 mg/m3] formaldehyde [purity unspecified] for 5 h per day once a week for life; 100 hamsters were injected subcutaneously

with 0.5 mg N-nitrosodiethylamine (NDEA) once a week for 10 weeks and then given no

further treatment; 50 hamsters were injected with NDEA once a week for 10 weeks,

exposed to 30 ppm formaldehyde for 5 h, 48 h before each injection of NDEA, and then

received weekly exposure to 30 ppm formaldehyde for life; and the fifth group of [presumably] 50 hamsters was injected with NDEA once a week for 10 weeks and then exposed

to 30 ppm formaldehyde for 5 h per day once a week for life, beginning 2 weeks after the

last injection of NDEA. A group of 50 animals served as untreated controls. After the

animals had died, the respiratory tract tissues were removed, stained with Wright’s stain,

rendered semitransparent and evaluated for ‘subgross’ evidence of tumours. Areas of dense

staining greater than 1 mm in 2–3-mm transverse-step sections of nasal turbinates were

scored as tumours. No tumours were observed in untreated hamsters or those exposed only

to formaldehyde, but 77% of hamsters treated with NDEA alone had tumours at one or

more sites in the respiratory tract. Ten or more such lesions from each tissue were

examined histologically, and all were found to be adenomas. Lifetime exposure of NDEAtreated hamsters to formaldehyde did not increase the number of tumour-bearing animals.

The incidences of nasal tumours in NDEA-treated groups were low (0–2%). The only

significant increase was in the multiplicity of tracheal tumours in the group that received

formaldehyde concurrently with and subsequent to injections of NDEA compared with that

in animals that received NDEA alone (p < 0.05, Kolmogorov–Smirnoff test) (Dalbey,

1982).

FORMALDEHYDE 185
4. Other Data Relevant to an Evaluation of Carcinogenicity

and its Mechanisms

4.1 Absorption, distribution, metabolism and excretion

4.1.1 Toxicokinetics

(a) Humans

In humans, as in other animals, formaldehyde is an essential metabolic intermediate in

all cells. It is produced endogenously from serine, glycine, methionine and choline, and it

is generated in the demethylation of N-, O- and S-methyl compounds. It is an essential

intermediate in the biosynthesis of purines, thymidine and certain amino acids (Neuberger,

1981).

The endogenous concentration of formaldehyde, determined by GC–MS (Heck et al.,

1982), in the blood of human subjects not exposed to formaldehyde was 2.61 ± 0.14 μg/g

blood (mean ± standard error [SE]; range, 2.05–3.09 μg/g) (Heck et al., 1985), i.e. about

0.1 mmol/L (assuming that 90% of the blood volume is water and the density of human

blood is 1.06 g/cm3 (Smith et al., 1983)). This concentration represents the total concentration of both free and reversibly bound endogenous formaldehyde in the blood.

The concentration of formaldehyde measured in the blood of six human volunteers

immediately after exposure by inhalation to 1.9 ppm [2.3 mg/m3] for 40 min was

2.77 ± 0.28 μg/g, which did not differ from the pre-exposure concentration due to metabolically formed formaldehyde (see above). The absence of an increase is explained by

the fact that formaldehyde reacts rapidly at the site of contact and is swiftly metabolized

by human erythrocytes (Malorny et al., 1965), which contain formaldehyde dehydrogenase (FDH) (Uotila & Koivusalo, 1987) and aldehyde dehydrogenase (ALDH) (Inoue

et al., 1979).

Overton et al. (2001) developed a mathematical model to predict interactions of formaldehyde in the respiratory tract, based on a one-dimensional equation of mass transport to

each generation of an adult human, symmetric, bifurcating Weibel-type respiratory tract

anatomical model, augmented by an upper respiratory tract. This predicted that over 95%

of inhaled formaldehyde would be retained by the respiratory tract and that the flux is over

1000 times higher in the first tracheobronchial region compared with the first pulmonary

region with no flux in the alveolar sacs.

A GC method was used to examine the urinary excretion of formate by veterinary

medical students who were exposed to low concentrations of formaldehyde, in order to

determine whether monitoring of formate is a useful biomarker for human exposure to

formaldehyde (Gottschling et al., 1984). The average baseline level of formate in the urine

of 35 unexposed subjects was 12.5 mg/L, but this varied considerably both within and

186 IARC MONOGRAPHS VOLUME 88
among subjects (range, 2.4–28.4 mg/L). No significant changes in concentration were

detected over a 3-week period of exposure to formaldehyde at a concentration in air of less

than 0.5 ppm [0.61 mg/m3]. The authors concluded that biological monitoring of formic

acid in the urine to determine exposure to formaldehyde is not a feasible technique at this

concentration.

(b) Experimental systems

(i) In vivo

The steady-state concentrations of endogenous formaldehyde have been determined

by GC–MS (Heck et al., 1982) in the blood of Fischer 344 rats (2.24 ± 0.07 μg/g of blood

(mean ± SE)) (Heck et al., 1985) and three rhesus monkeys (2.04 ± 0.40 μg/g of blood;

range, 1.24–2.45 μg/g) (Casanova et al., 1988). These concentrations are similar to those

measured in humans by the same method (see Section 4.1.1(a)). The blood concentrations

of formaldehyde immediately after a single exposure of rats to 14.4 ppm [17.6 mg/m3]

(for 2 h) or subacute exposure of monkeys to 6 ppm [7.3 mg/m3] (for 6 h per day on

5 days per week for 4 weeks) were indistinguishable from those before exposure.

More than 93% of a dose of inhaled formaldehyde was absorbed readily by the tissues

of the respiratory tract (Kimbell et al., 2001a). In rats, formaldehyde is absorbed almost

entirely in the nasal passages (Chang et al., 1983; Heck et al., 1983). In rhesus monkeys,

absorption occurs primarily in the nasal passages but also in the trachea and proximal

regions of the major bronchi (Monticello et al., 1989; Casanova et al., 1991). The efficiency and sites of formaldehyde uptake are determined by nasal anatomy, which differs

greatly among species (Schreider, 1986). The structure of the nose gives rise to complex

airflow patterns, which have been correlated with the location of formaldehyde-induced

nasal lesions in both rats and monkeys (Morgan et al., 1991).

The mucocilliary apparatus is an important defence system in the respiratory tract and

may provide protection of the underlying epithelium from gases and vapours. Schlosser

(1999) performed limiting-case calculations to determine the significance of convective

mucus transport and chemical reaction to formaldehyde in rat nasal epithelial mucus. Less

than 4.6% of absorbed formaldehyde can be bound to amino groups (serum albumin) after

20 min of exposure; therefore, at the slowest mucus flow rates measured in rats

(~1 mm/min), a fluid element of mucus could travel more than 2 cm before binding 5% of

the absorbed formaldehyde by which time the element would probably have left the nose

(site of toxic response). Given the solubility of formaldehyde in mucus (water) and estimates of total mucus flow, as much as 22–42% of inhaled formaldehyde may be removed

by mucus flow.

After exposure by inhalation, absorbed formaldehyde can be oxidized to formate and

carbon dioxide or can be incorporated into biological macromolecules via tetrahydrofolate-dependent one-carbon biosynthetic pathways (see Fig. 1). The fate of inhaled

formaldehyde was studied in Fischer 344 rats exposed to [14C]formaldehyde (at 0.63 or

13.1 ppm [0.8 or 16.0 mg/m3]) for 6 h. About 40% of the inhaled 14C was eliminated as

FORMALDEHYDE 187
expired [14C]carbon dioxide over a 70-h period; 17% was excreted in the urine, 5% was

eliminated in the faeces and 35–39% remained in the tissues and carcass. Elimination of

radioactivity from the blood of rats after exposure by inhalation to 0.63 ppm or 13.1 ppm

[14C]formaldehyde is multiphasic. After inhalation, the terminal half-time of the radioactivity in the plasma was approximately 55 h (Heck et al., 1983). Analysis of the time course

of residual radioactivity in plasma and erythrocytes after inhalation or intravenous injection of [14C]formaldehyde or intravenous injection of [14C]formate showed that the radioactivity is due to incorporation of 14C (as [14C]formate) into serum proteins and

erythrocytes and subsequent release of labelled proteins and cells into the circulation (Heck

et al., 1983). The half-time of formaldehyde in rat plasma after intravenous administration

is reported to be approximately 1 min (Rietbrock, 1965).

188 IARC MONOGRAPHS VOLUME 88

Figure 1. Biological reactions and metabolism of formaldehyde

Adapted from Bolt (1987)

+ cys

-cross-linksbinding to

tetrahydrofolic acid

''metabolic incorporation''

into macromolecules

+ GSH

(γ-glu-cys-gly)

γ-glu-cys-gly

S CH2OH

FDH

+ NAD+

γ-glu-cys-gly

S

C

O H

γ-glu-cys-gly

SH

+ HCOOH

thiazolidine-4-carboxylate

-cross-linksFORMALDEHYDE

C O

H

H

protein NH CH2OH

protein NH CH2 NH DNA

protein NH CH2 NH protein

OC(NH2) + 2

CO2 + H2O

one carbon pool

HOCH2 NH C NH

O

CH2OH

HOCH2 NH C NH2

O

S

N

H COOH
The fate of [14C]formaldehyde after dermal application to Fischer 344 rats, Dunkin–

Hartley guinea-pigs and cynomolgus monkeys was described by Jeffcoat et al. (1983).

Aqueous formaldehyde was applied to a shaven area of the lower back, and the rodents

were placed in metabolism cages for collection of urine, faeces, expired air and [14C]formaldehyde evaporated from the skin. Monkeys were seated in a restraining chair and were

fitted with a plexiglass helmet for collection of exhaled [14C]carbon dioxide. The concentrations of 14C in the tissues, blood and carcass of rodents were determined at the end of

the experiment. Rodents excreted about 6.6% of the dermally applied dose in the urine over

72 h, while 21–28% was collected in the air traps. It was deduced that almost all of the airtrapped radioactivity was due to evaporation of formaldehyde from the skin, since less than

3% of the radioactivity (i.e. 0.6–0.8% of the applied 14C) was due to [14C]carbon dioxide.

Rodent carcass contained 22–28% of the 14C and total blood about 0.1%; a substantial

fraction of 14C (3.6–16%) remained in the skin at the site of application. In monkeys, only

0.24% of the dermally applied [14C]formaldehyde was excreted in the urine, and 0.37%

was accounted for as [14C]carbon dioxide in the air traps; about 0.015% of the radioactivity

was found in total blood and 9.5% in the skin at the site of application. Less than 1% of

the applied dose was excreted or exhaled, in contrast to rodents in which nearly 10% was

eliminated by these routes. Coupled with the observation of lower blood levels of 14C in

monkeys than in rodents, the results suggest that the skin of monkeys may be less

permeable to aqueous formaldehyde than that of rodents.

Formaldehyde is absorbed rapidly and almost completely from the rodent intestinal

tract (Buss et al., 1964). In rats, about 40% of an oral dose of [14C]formaldehyde

(7 mg/kg) was eliminated as [14C]carbon dioxide within 12 h, while 10% was excreted in

the urine and 1% in the faeces. A substantial portion of the radioactivity remained in the

carcass as products of metabolic incorporation. In another study in which SpragueDawley rats were injected intraperitoneally with 4 or 40 mg/kg bw [14C]formaldehyde, a

portion of the injected material (about 3–5% of a dose of 40 mg/kg bw) was excreted

unchanged in the urine within 12 h (Mashford & Jones, 1982).

(ii) In vitro

Since formaldehyde can induce allergic contact dermatitis in humans (see

Section 4.2.1), it can be concluded that formaldehyde or its metabolites penetrate human

skin (Maibach, 1983). The kinetics of this penetration was determined in vitro using an

excised full-thickness human skin sample mounted in a diffusion cell at 30 °C (Lodén,

1986). The rate of ‘resorption’ of [14C]formaldehyde (defined as the uptake of 14C into

phosphate-buffered saline, pH 7.4, that flowed unidirectionally beneath the sample) was

16.7 μg/cm2/h when a 3.7% solution of formaldehyde was used, and increased to

319 μg/cm2/h when a 37% solution was used. The presence of methanol in both of these

solutions (at 1–1.5% and 10–15%, respectively) may have affected the rate of uptake, and

it is unclear whether the resorbed 14C was due only to formaldehyde. Skin retention of

formaldehyde-derived radioactivity represented a significant fraction of the total amount

of formaldehyde absorbed.

FORMALDEHYDE 189
(iii) Predictive models to analyse the effects of formaldehyde

in the respiratory tract

Computational fluid dynamic models

Anatomically accurate, three-dimensional computational fluid dynamics (CFD)

models of formaldehyde in the nasal passages of rat, monkeys and humans have been developed to aid the understanding of absorption and mechanisms of action and risk assessment

(Conolly et al., 2000; Kimbell et al., 2001a,b; Georgieva et al., 2003). Conolly et al. (2000)

sought to increase confidence in predictions of human DNA–protein cross-links (see

Fig. 1) by refining earlier models of formaldehyde deposition and DNA–protein crosslinks in nasal mucosa. Anatomically accurate CFD models of nasal airways of Fischer 344

rats, rhesus monkeys and humans that were designed to predict the regional flux of formaldehyde were linked to a model of tissue disposition of formaldehyde and kinetics of

DNA–protein cross-links. Statistical optimization was used to identify parametric values,

and good simulations were obtained. The parametric values obtained for rats and monkeys

were used to extrapolate mathematically to the human situation. The results showed that

the levels of nasal mucosal DNA–protein cross-links in rats, rhesus monkeys and humans

varied with the concentration of formaldehyde inhaled and the predicted DNA–protein

cross-link dose–response curves for the three species were similar, in spite of the significant interspecies differences in nasal anatomy and breathing rates. 

Kimbell et al. (2001a) used anatomically accurate three-dimensional CFD models of

nasal air flow and transport of formaldehyde gas in Fischer 344 rats, rhesus monkeys and

humans to predict local patterns of wall mass flux (pmol/(mm2 h–ppm)). The nasal surface

of each species was partitioned by flux into smaller regions (flux bins), each of which was

characterized by surface area and an average flux value. Flux values higher than half the

maximum flux value were predicted for nearly 20% of human, 5% of rat and less than 1%

of monkey nasal surfaces at resting inspiratory flow rates. Human nasal flux patterns

shifted distally and the percentage of uptake decreased as inspiratory flow rate increased. 

Kimbell et al. (2001b) used anatomically accurate three-dimensional CFD models of

nasal passages in Fischer 344 rats, rhesus monkeys and humans to estimate and compare

the regional patterns of uptake of inhaled formaldehyde that were predicted among these

species. Maximum flux values, averaged over one breath, in non-squamous epithelium

were estimated to be 2620, 4492 and 2082 pmol/(mm2 h–ppm) in rats, monkeys and

humans, respectively. At sites where cell proliferation rates had been measured and found

to be similar in rats and monkeys, predicted flux values were also similar, as were

predicted fluxes in a region of high tumour incidence in the rat nose and anterior portion

of the human nose.

Thermodynamic model: exposure to particle-adsorbed formaldehyde

The possibility that gaseous formaldehyde may be adsorbed to respirable particles,

inhaled and subsequently released into the lung has been examined in a thermodynamic

model based on measurable physicochemical properties of particles and volatile pollutants.

In this model, analysis of the adsorption of formaldehyde to and its release from respirable

190 IARC MONOGRAPHS VOLUME 88
carbon black particles showed that only 2 ppb [0.0025 mg/m3] of an airborne formaldehyde

concentration of 6 ppm [7.4 mg/m3] would be adsorbed to carbon black (Risby et al.,

1990).

4.1.2 Biomonitoring and metabolism of formaldehyde 

(a) Humans

(i) Biological monitoring

A quantitative method that was developed for the determination of formaldehyde in

biological tissues used stable-isotope dilution combined with GC−MS. Multilabelled formaldehyde that contained 90 atom-% 13C and 98 atom-% deuterium (2H) was used as the isotopic diluent, which was added to homogenized tissue. Derivatization was conducted

in situ with pentafluorophenylhydrazine, followed by extraction and analysis of the pentafluorophenylhydrazone by selected ion monitoring. With this method, endogenous formaldehyde could be analysed quantitatively in tissue samples as small as 20 mg wet wt (Heck

et al., 1982).

Blood

Concentrations of formaldehyde were determined by the method described above in

samples of venous blood that were collected before and after exposure of six human volunteers to 1.9 ppm [2.3 mg/m3] formaldehyde by inhalation for 40 min. Average concentrations of formaldehyde were 2.61 ± 0.14 μg/g blood before and 2.77 ± 0.28 μg/g blood after

exposure. These values were not significantly different. However, the subjects exhibited

significant inter-individual variation with respect to their blood concentrations of formaldehyde, and some showed significant differences — either an increase or a decrease —

before and after exposure, which suggests that individual blood concentrations of formaldehyde vary with time. The results are consistent with the assumption that toxicity due to

exposure to formaldehyde is unlikely to occur at sites that are distant from the portal of entry

(Heck et al., 1985). The absence of an exposure-related increase in blood concentration of

formaldehyde in this study can be explained by the fact this chemical is rapidly metabolized

by human erythrocytes (Malorny et al., 1965), which contain FDH (Uotila & Koivusalo,

1987) and ALDH (Inoue et al., 1979) (see also Section 4.1.1(a)).

DNA–protein cross-links in blood leukocytes were used as a marker for exposure to

formaldehyde in a study that involved 12 workers (Anatomy Department and Pathology

Institute; duration of exposure, 2–31 years) and eight controls. Protein-bound DNA was

separated from protein-free DNA by precipitation with sodium dodecylsulfate

(Zhitkovich & Costa, 1992). A significantly higher (p = 0.03) level of cross-links was

measured among exposed workers (mean ± SD, 28 ± 5%; min., 21%; max., 38%) than

among the unexposed controls (mean ± SD, 22 ± 6%; min., 16%; max., 32%). Of the 12

exposed workers, four (33%) showed cross-link values above the upper range of the

controls. The level of cross-links was generally higher in workers exposed for longer

periods, and was reported not to be influenced by tobacco smoking. The data suggest that

FORMALDEHYDE 191
DNA–protein cross-links can be used as a method for the biological monitoring of exposure to formaldehyde (Shaham et al., 1996a).

Urine

Exposure to formaldehyde was monitored in a group of 35 students of veterinary

medicine who were enrolled for 3 consecutive weeks in a functional anatomy class, where

they worked extensively with animal tissue preserved in formalin. The biological monitoring was based on the known metabolism of formaldehyde to formic acid, which may

then be excreted in the urine. Urinary formic acid was converted to methyl formate and

measured by GC. The average concentration of formate in the urine of the subjects before

the class was 12.5 mg/L, and considerable variation was observed both within and among

subjects (range, 2.4–28.4 mg/L). No significant changes in concentration were detected

over the 3-week period of exposure to formaldehyde at a concentration in air of < 0.4 ppm

[0.5 mg/m3]. Biological monitoring of exposure to formaldehyde by measurement of

urinary formic acid does not appear to be a suitable method at these levels of exposure

(Gottschling et al., 1984) (see also Section 4.1.1(a)).

Respiratory tract: animal models and extrapolation to humans

The pharmacokinetics of formaldehyde-induced formation of DNA–protein crosslinks in the nose was investigated by use of a model in which the rate of formation is proportional to the tissue concentration of this chemical. The model includes both saturable

and non-saturable elimination pathways and regional differences in DNA binding are

attributed to anatomical rather than biochemical factors. Using this model, the concentration of DNA–protein cross-links formed in corresponding tissues of different species

can be predicted by scaling the pharmacokinetic parameter that depends on minute

volume and quantity of nasal mucosal DNA. The concentration–response curve for the

average rate of formation of cross-links in the turbinates, lateral wall and septum of rhesus

monkeys was predicted from that of Fischer 344 rats that were exposed under similar

conditions. A significant overlap was observed between predicted and fitted curves, which

implies that minute volume and nasal mucosal DNA are major determinants of the rate of

formation of DNA–protein cross-links in the nasal mucosa of different species. Concentrations of DNA–protein cross-links that may be produced in the nasal mucosa of adult

humans were predicted on the basis of experimental data in rats and monkeys. The authors

suggested from their results that formaldehyde would generate lower concentrations of

DNA–protein cross-links in the nasal mucosa of humans than that of monkeys, and much

lower concentrations in humans than in rats. The rate of formation of DNA–protein crosslinks can be regarded as a surrogate for the delivered concentration of formaldehyde

(Casanova et al., 1991).

(ii) Metabolism of formaldehyde

Formaldehyde is an endogenous metabolic product of N-, O- and S-demethylation

reactions in the cell (Neuberger, 1981). During exogenous exposure, gaseous formaldehyde

— which is highly soluble in water — is virtually completely removed by the nose during

192 IARC MONOGRAPHS VOLUME 88
nasal respiration (Ballenger, 1984). In recent years, the metabolic capacities of nasal cavity

tissues have been investigated extensively in mammals, including humans. ALDHs, cytochrome P450 (CYP)-dependent monooxygenases, glutathione (GSH) transferases (GSTs),

epoxide hydrolases, flavin-containing monooxygenases and carboxyl esterases have all

been reported to occur in substantial quantities in the nasal cavity. The contributions of some

of these enzyme activities to the induction of toxic effects from volatile chemicals have been

the subject of numerous studies (see reviews by Dahl & Hadley, 1991; Thornton-Manning

& Dahl, 1997). The two main enzymes involved in the metabolism of formaldehyde in

humans — a dehydrogenase and a hydrolase — are discussed in detail below.

Formaldehyde is detoxified by oxidation to formate by different enzyme systems

(Fig. 2; from Hedberg et al., 2002). The primary and generally most important system initially involves GSH-dependent FDH (Uotila & Koivusalo, 1974), which is identical to

alcohol dehydrogenase 3 (ADH3; Koivusalo et al., 1989), that oxidizes S-hydroxymethylglutathione (the thiohemiacetal that is formed spontaneously from formaldehyde and GSH)

to S-formylglutathione. The systematic name for the enzyme is formaldehyde:NAD+

oxidoreductase (glutathione-formylating) (CAS Registry No. 9028-84-6, IUBMB code

EC1.2.1.1). (Other names for this enzyme are formaldehyde dehydrogenase, formaldehyde

dehydrogenase (glutathione), NAD-linked formaldehyde dehydrogenase and formic dehydrogenase.) This intermediate is then further metabolized by S-formylglutathione

FORMALDEHYDE 193

formaldehyde

S-hydroxymethylglutathione

S-formylglutathione

formate

glutathione

glutathione

S-formylglutathione

hydrolase

adduct formation

NAD+

NADH +H +

H2O2

H2O

methanol

one

carbon

pool

NAD+

NADH +H +

CO2 + H2O

ADH3

ALDH1A1

ALDH2

catalase

endogenous

sources exogenous

sources

Figure 2. Fate and metabolism of formaldehyde

Adapted from Hedberg et al. (2002)
hydrolase to yield formate and reduced GSH (Uotila & Koivusalo, 1997). Analyses across

species and among various mammalian tissues and cell types imply that ADH3 represents

a ubiquitous enzyme, and that it is the ancestral form of ADH from which other types of

vertebrate ADH have evolved (Estonius et al., 1996; Hedberg et al., 2000; Jörnvall et al.,

2000; Hedberg et al., 2001; Höög et al., 2001, 2003). The activities of ADH3 are two to

three orders of magnitude lower than those of S-formylglutathione hydrolase and thus the

ADH3-catalysed step is rate-limiting (Uotila & Koivusalo, 1997). Formation of

S-hydroxymethylglutathione efficiently counteracts the existence of free formaldehyde, a

reaction that is determined by the fact that cellular GSH is an abundant molecule and is

often present in millimolar concentration levels (Meister & Anderson, 1983). The equilibrium constant (Keq) for the formation of this adduct — under conditions of excess GSH

— was determined to be 1.77 ± 0.13 mM (Naylor et al., 1988; Sanghani et al., 2000).

Furthermore, when formaldehyde is reacted with the thiols, cysteine and cysteinylglycine,

it can function as an alternative substrate to S-hydroxymethylglutathione for ADH3, but at

a far lower turnover (Holmquist & Vallee, 1991). The mechanism for the ADH3-dependent

step is identical to any alcohol oxidation by ADH enzymes; it requires catalysis by zinc and

uses NAD+/NADH as the electron acceptor and donor, respectively (Höög et al., 2001).

The second enzyme system is the ALDHs — class 1 (cytosolic ALDH; ALDH1A1) and

class 2 (mitochondrial ALDH; ALDH2) — which have an affinity for free formaldehyde.

Because the Michaelis-Menten constant (Km) is less than micromolar for aldehyde substrates, they are called low-Km ALDHs (Petersen & Lindahl, 1997), except for free

formaldehyde for which the Km values are high (in the range of 0.6 mM; Mukerjee &

Pietruszko, 1992). This value is about 100-fold higher than the Km displayed by ADH3 for

S-hydroxymethylglutathione (4 μM) (Holmquist & Vallee, 1991; Uotila & Koivusalo,

1997; Hedberg et al., 1998). Therefore, ADH3 is probably the predominant enzyme responsible for the oxidation of formaldehyde at physiologically relevant concentrations,

while low-Km ALDHs contribute increasingly when the concentrations of formaldehyde

increase (Dicker & Cederbaum, 1986). Catalase may also contribute to the oxidation of

formaldehyde to formate, but only under circumstances in which hydrogen peroxide is

formed (Jones et al., 1978; Uotila & Koivusalo, 1989). Formaldehyde may also be

reduced to methanol and then be re-converted to formaldehyde, when ADH1 is involved

(Pocker & Li, 1991). Many endogenous and exogenous factors can contribute to the generation of formaldehyde in cells (Grafström, 1990). Both formaldehyde and formate contribute to the ‘one-carbon pool’, which involves the folic acid metabolic pathway for

synthesis of certain nucleic acids and amino acids, and, eventually, cellular macromolecules (Neuberger, 1981). S-Hydroxymethylglutathione and S-formylglutathione are

among the most notable components of this pool, which also includes the tetrahydrofolate

adducts, N5-hydroxymethyl-, N5,N10-methylene, and N5- and N10-formyl-tetrahydrofolate,

serine, methionine, histamine and methylamine, other reversible amine adducts and

hydrated formaldehyde. 

ADH3 is the only ADH that can participate in the cellular detoxification of formaldehyde. The nomenclature recommended by Duester et al. (1999) defines the protein as

194 IARC MONOGRAPHS VOLUME 88
ADH3 and the gene as ADH3, whereas previous nomenclature used χ (chi) for the protein

and ADH5 for the gene (Jörnvall & Höög, 1995). The older nomenclature used ADH3 to

define the gene that codes for ADH1C, which is important for the oxidation of ethanol,

and studies of the latter protein, including the role of polymorphisms in the causation of

cancer (Schwartz et al., 2001; Yokoyama et al., 2002), should not be confused with the

enzyme that is involved in the oxidation of formaldehyde. S-Nitrosoglutathione constitutes an excellent substrate for reductive cleavage by ADH3, and, accordingly, ADH3 is

also termed S-nitrosoglutathione reductase (Jensen et al., 1998; Liu et al., 2001). Comparative analysis indicates that ADH3 oxidizes GSH-conjugated formaldehyde (i.e.

S-hydroxymethylglutathione) and reduces S-nitrosoglutathione with catalytic efficiencies

of 58 000 min–1•mM–1 and 90 000 min–1•mM–1, respectively (Hedberg et al., 2003). Considering both reactions, exposure to formaldehyde would naturally favour the oxidant

activity of ADH3, whereas nitrosative stress leading to the formation of S-nitrosoglutathione would favour reductive activity (Liu et al., 2001; Hedberg et al., 2003). The

cellular levels of NAD+ are normally two orders of magnitude higher than those of NADH

and thus, under physiological conditions, the oxidation of S-hydroxymethylglutathione

would be favoured rather than the reduction of S-nitrosoglutathione (Svensson et al.,

1999; Molotkov et al., 2002; Höög et al., 2003). Although it has a lower efficiency than

other ADH enzymes, ADH3 also mediates oxidation of all-trans-retinol to retinal, and

may also oxidize ethanol to acetaldehyde at levels of exposure that are reached during

alcohol intoxication (Svensson et al., 1999; Molotkov et al., 2003). ADH3 also shows

oxidizing activity towards longer-chain primary alcohols, methylglyoxal, ketoxal,

hydroxypyruvaldehyde, 20-hydroxy-leukotriene B4 and ω-hydroxy fatty acids, e.g. 12-

hydroxydodecanoic acid (Wagner et al., 1984; Gotoh et al., 1990; Jörnvall et al., 2000).

The physiological relevance of these activities remains unclear, since the catalytic efficiencies for these substrates are considerably lower than those of S-hydroxymethylglutathione and S-nitrosoglutathione. However, all of these substrates compete with S-hydroxymethylglutathione and S-nitrosoglutathione for the active site of ADH3, and thereby

influence the catalytic activity for formaldehyde scavenging. The ADH3 gene promoter

sequence shows several polymorphisms that might influence ADH3 transcription, but such

polymorphisms were not observed in exons that code for the ADH3 gene (Hedberg et al.,

2001). In contrast, polymorphisms in ALDH, including ALDH2, may reduce the capacity

for the oxidation of formaldehyde to less than half of that of the wild-type activity (Wang

et al., 2002). Transcription of ADH3 is coupled to proliferative states in human oral keratinocytes where ADH3 mRNA exhibits a short half-life (7 h); when the protein is formed,

it remains highly stable and metabolically active during cellular life expectancy (Hedberg

et al., 2000; Nilsson et al., 2004). Formaldehyde and S-hydroxymethylglutathione regulate

ADH3 transcription in the bacterium Rhodobacter sphaeriodes, and wounding and growth

hormones regulate ADH3 in the plant Arabidopsis, which provides examples of ADH3

regulation through feed-back control and from both external and internal signals (Barber

& Donohue, 1998; Diaz et al., 2003). [The Working Group did not find evidence of such

regulation in humans.] The biochemistry that underlies the metabolism of formaldehyde

FORMALDEHYDE 195
indicates that changes in glutathione levels, NAD+:NADH ratios, other redox changes and

oxidant stress in general, including from nitric oxide and S-nitrosoglutathione, protein

S-nitrosothiols and intermediates of the folic acid metabolic pathway should be considered

in the assessment of the consequences of exposure to formaldehyde.

(b) Experimental systems

The distribution of selected metabolizing enzymes in the respiratory tract was compared with that in the liver of beagle dogs. Four beagle dogs (two males, two females;

13–18 kg, 13–130 months of age) were euthanized, the liver and respiratory tract were

removed and tissues were prepared for isolation of metabolizing enzymes, including infusion of cold agarose into a lung lobe. The respiratory tract was separated into respiratory

nasal epithelium, olfactory nasal epithelium, tracheal epithelium, epithelium from proximal

middle and distal bronchus and lung parenchyma. The cytosolic fraction was isolated and

the activity of sulfite oxidase, ADH, ALDH, FDH, GST and protein contents were quantified. Sulfite oxidase with sulfite as the substrate had greatest activity in the liver

(9.95 nkat/mg protein); in the respiratory tract, the greatest activity was in the lung parenchyma (4.62 nkat/mg protein) and activity in the rest of the respiratory tract was below

4 nkat/mg protein. FDH with formaldehyde as the substrate had greatest activity in the nose

(10.5 nkat/mg protein) while the liver (2.28 nkat/mg protein) had less activity than any site

in the respiratory tract. ALDH with formaldehyde as the substrate had greatest activity in

the trachea (1.28 nkat/mg protein), and the rest of the respiratory tract and liver had levels

of activity below 1 nkat/mg protein. ADH with ethanol as the substrate had greatest activity

in the liver (4.40 nkat/mg protein), and the respiratory tract had levels below 1 nkat/mg

protein. All but one of the 1-chloro-2,4-dinitrobenzene-related GSTs had greatest activity

in the liver parenchyma, which ranged from 50 to 300% greater than that in the respiratory

tract. The cytosolic fraction of the epoxy-3-(para-nitrophenoxy)-propane-related GST had

greatest activity in the trachea (3.94 nkat/mg protein); activity in the liver (0.24 nkat/mg

protein) was less than 20% of that in any part of the respiratory tract on average. In general,

metabolizing enzymes are spread throughout the respiratory tract and can have a metabolic

capacity the same as or greater than the liver (Maier et al., 1999).

4.2 Toxic effects

4.2.1 Humans

(a) Irritation

There is extensive literature on domestic exposures to products that contain formaldehyde, such as plywood, and to urea–formaldehyde foam (see Section 1). Irritative effects

have consistently been reported after exposure to formaldehyde; these have also been

observed in children and a wide variation in susceptibility has been reported. Because these

domestic exposures also involve exposure to other agents, this literature is not reviewed in

196 IARC MONOGRAPHS VOLUME 88
detail here because the findings do not generally add any information on the specific mode

of action of formaldehyde as a potential carcinogen.

(i) Experimental studies of acute effects

Airborne formaldehyde irritates the eyes, nose and throat in healthy humans who had

clinical disease. Chamber studies and the symptoms reported therein are summarized in

Table 30.

Dose–response irritative effects were investigated (Kulle et al., 1987; Kulle, 1993) in

nonsmokers who received 3-h exposures to 0, 0.5, 1, 2 and 3 ppm [0, 0.61, 1.22, 2.44 and

3.66 mg/m3] formaldehyde. The results are shown in Figure 3. Eye irritation increased

linearly at doses of 0.5–3 ppm and was the dominant symptom; no effect was observed

with 0.5 ppm; 21% of the volunteers had mild eye irritation with 1 ppm and 35% with

2 ppm. Of the volunteers, 40% could smell formaldehyde at 0.5 ppm (5% when no formaldehyde was present). Nose and/or throat irritation was the least sensitive response with an

estimated threshold of 1 ppm.

Adult asthmatics

Green et al. (1987) exposed 22 healthy subjects and 16 asthmatics to 3 ppm formaldehyde for 1 h during exercise. In the healthy group, 32% of the subjects reported moderate-to-severe nose and throat irritation and 27% moderate-to-severe eye irritation. In the

asthmatics, these percentages were 31% and 19%, respectively.

Unsensitized adult asthmatics

The effects of inhaled formaldehyde on the airways of healthy people and unsensitized

asthmatics have been reviewed (Smedley, 1996; Krieger et al., 1998; Suh et al., 2000;

Bender, 2002; Liteplo & Meek, 2003).

Bender (2002) reviewed nine controlled chamber studies of exposure to formaldehyde

of asthmatic subjects (Reed & Frigas 1984; Sauder et al., 1986; Green et al., 1987; Kulle

et al., 1987; Schachter et al., 1987; Witek et al., 1987; Harving et al., 1990; Pazdrak et al.,

1993; Krakowiak et al., 1998). Exposure to 2–3 ppm formaldehyde for up to 3 h did not

provoke asthma in unsensitized asthmatics. There was no asthmatic response to 0.1–3 ppm

formaldehyde in 11 women and two men who reported chest tightness, cough and wheeze

attributed to exposure to formaldehyde at home or at work (Reed & Frigas, 1984). Similar

conclusions were reached in the review of Liteplo and Meek (2003) who included three

further studies (Day et al., 1984; Schachter et al., 1986; Sauder et al., 1987).

Studies on nasal lavage

Two studies have investigated the effect of exposure to formaldehyde on nasal lavage.

Krakowiak et al. (1998) reported on 10 healthy subjects and 10 asthmatics who reported

nasal or respiratory symptoms from formaldehyde at work (nurses, textile and shoe

workers), who received a single, blind exposure to clean air or 0.5 mg/m3 formaldehyde

(range, 0.2–0.7 mg/m3) for 2 h. Nasal washings were performed before and 0, 0.5, 4 and

24 h after exposure. During exposure to formaldehyde, all subjects developed sneezing,

FORMALDEHYDE 197
198 IARC MONOGRAPHS VOLUME 88

Table 30. Studies of acute exposure to formaldehyde that reported irritanttype symptoms 

Subjects (no.) Exposure to 

formaldehyde 

Effect Reference 

Normal (22) 

Asthmatics (16) 

3 ppm 

[3.7 mg/m3] for 

60 min 

Moderate/severe symptoms 

Eye, 27%; nose/throat, 32% 

Eye, 19%; nose/throat, 31% 

Green et al.

(1987) 

Normal with no 

exposure (10) 

Asthmatics with 

allergic symptoms 

due to exposure to 

formaldehyde (10) 

0.5 mg/m3 for 

2 h 

Scored on 0–7 point scale 

Nasal itching and congestion in 

all 

Score 4.3/7 in normal subjects 

Score 4.6/7 in asthmatics 

Krakowiak et al. 

(1998) 

Healthy nonsmokers 

(19) 

3 ppm for 3 h See Figure 3 Kulle et al.

(1987); Kulle 

(1993) 

Healthy (11) 

Formaldehyde contact dermatitis (9) 

0.5 mg/m3

[0.41 ppm] 

for 2 h 

Scored on 0–7 point scale 

(sneezes, nasal itching and 

congestion) 

Mean nasal score 4/7 at 10 min 

for allergic and healthy subjects

Pazdrak et al. 

(1993) 

Healthy nonsmokers 

(9)

3 ppm for 3 h Mean symptom scores 

(air/formaldehyde) 

Throat/nose, 0.22/1.33 

Eye irritation, 0/0.78 

Sauder et al.

(1986) 

Asthmatic nonsmokers (9) 3 ppm for 3 h Eye and nose irritation started 

after 2 min 

Sauder et al.

(1987) 

Normal formaldehyde-exposed (15) 2 ppm 

[2.5 mg/m3] for 

40 min 

Odour, 12/15 (80%) 

Sore throat, 0/15 (0%) 

Nasal irritation, 0/15 (0%) 

Eye irritation, 7/15 (47%) 

Schachter et al.

(1987) 

Asthmatics (15) 2 ppm for 

40 min 

Odour, 15/15 (100%) 

Sore throat, 5/15 (33%) 

Nasal irritation, 7/15 (47%) 

Eye irritation, 11/15 (73%) 

Witek et al.

(1987) 

Normal (9), 

asthmatics with 

UFFI symptoms (9) 

3 ppm for 2 h 

(1 ppm for 

90 min and 

2 ppm UFFI for 

30 min) 

Eye irritation, 15/18 

Nasal congestion, 7/18 

Throat irritation, 5/18 

Same in UFFI symptomatic and 

normal groups 

Day et al. (1984) 

UFFI, urea–formaldehyde foam insulation
itching and congestion, with substantial resolution by 4 h. An increase in total leukocytes

and eosinophils was observed immediately after exposure to formaldehyde that was similar

in both groups of subjects, with resolution after 4 h. An increase was also observed in the

albumin:total protein ratio with a similar time course that was interpreted as an increase in

nasal mucosal permeability. No significant increases in tryptase or eosinophil cationic protein were found in either group. An earlier study by the same group (Pazdrak et al., 1993)

that used a similar methodology investigated nine workers who had skin hypersensitivity

(positive patch test) to formaldehyde and 11 healthy men who had negative formaldehyde

patch tests. Nasal lavage was performed at 0, 10 min, 3 (or 4) and 18 h after exposure.

Eosinophils increased in the nasal lavage and were maximal immediately after exposure,

but were still increased at 4 and 18 h; the percentage of epithelial cells was reduced. Albumin levels were increased in the lavage and albumin:total protein ratios were increased

only immediately after exposure. The group that had dermatitis and the normal group had

similar responses. The authors concluded that the irritative effects of formaldehyde were

confirmed, and also suggested a non-specific, non-allergic pro-inflammatory effect when

formaldehyde was inhaled at a low dose (0.5 mg/m3).

An in-vitro study of human nasal ciliated epithelial cells showed reduced frequency

of ciliary beat after exposure to 5000 μg/m3 formaldehyde for 2 h, but no effect after

exposure to 5000 μg/m3 for 1 h or 500 μg/m3 for 2 h (Schäfer et al., 1999). 

(ii) Residential exposure

Studies have been conducted among residents who were exposed to formaldehyde in

the home and school children who were exposed to formaldehyde in classrooms (Broder

et al., 1991; Wantke et al., 1996a). These studies are difficult to interpret because they did

FORMALDEHYDE 199

Figure 3. Symptoms reported by 19 nonsmoking healthy adults exposed to formaldehyde for 3 h

0

10

20

30

40

50

60

70

80

0 0.51 1.01 2 3.02

Formaldehyde (ppm)

% of subjects reporting symptom

Odour >=mild

Odour >=moderate

Eye irritation >=mild

Eye irritation >=moderate

Nose/throat irritation mild

Adapted from Kulle (1993)
not control for confounding factors, particularly lack of ventilation and other allergens. It

is possible that co-exposures to irritants and allergens increases the risk for allergen sensitization, but this has not been shown reliably for exposures to formaldehyde. Some studies

looked for IgG and/or IgE antibodies to formaldehyde/human serum albumin conjugates,

but the results were inconsistent (Patterson et al., 1989; Wantke et al., 1996a; Kim et al.,

2001; Doi et al., 2003).

(b) Pulmonary function: effect of chronic occupational exposure

Kriebel et al. (1993) noted that epidemiological studies of irritants are difficult to

perform using standard epidemiological methods because of the reversible nature of the

health outcomes, the selection of sensitive individuals from the study population and the

wide heterogeneity of normal responses to irritants. Twenty-four physical therapy students,

who were exposed to formaldehyde during dissection for 3 h per week over 10 weeks with

breathing zone exposures to formaldehyde of 0.49–0.93 ppm, were included in the study.

Peak expiratory flow and a symptom questionnaire were completed before and after each

exposure, and again before and after 3-h laboratory sessions after several months with no

exposure to formaldehyde. Symptoms increased following exposure (eyes, +43%; nose,

+21%; throat, +15%; breathing, +20%; and cough, +5%). The intensity of symptoms tended

to decrease over time [this might be due to a repeated questionnaire effect with weekly questionnaires]. The peak expiratory flow declined by an average of 4.8 L/min during the

morning (pre-dissection to midday) and by 10 L/min before exposure over the 10 weeks of

exposure (2% of baseline) with recovery after 12 weeks with no exposure (daily measurements before exposure). The study group included five asthmatics whose peak expiratory

flow after exposure fell by 37 L/min (non-asthmatics, 3.9 L/min). [The Working Group

noted the lack of controls in this study, to adjust for any seasonal effects over time. The

Working Group also noted that this is a difficult study to interpret. The time of day of the

dissection sessions is not given, and the peak expiratory flow would be expected to increase

for the first 4–10 h after waking, so that the time of day may have affected the outcome of

the measurements.]

Akbar-Khanzadeh and Mlynek (1997) compared 50 nonsmoking first-year medical

students exposed to breathing zone levels of 1.36–2.58 ppm [1.66–3.2 mg/m3] formaldehyde with 36 second-year physiotherapy students who had no exposure to formaldehyde.

Lung function was measured before exposure, 1 h after exposure and at midday. An

increase in lung function was observed in both exposed and unexposed groups during the

morning (exposed forced expiry volume in 1 sec (FEV1), +1.2%; control, +2.1% at 1 h;

exposed FEV1, + 2.4%; control, +6.2% at 3 h). In the exposed group, 82% reported nose

irritation, 76% reported eye irritation (18% wore goggles), 36% reported throat irritation

and 14% reported airway irritation. The authors concluded that the reduced increase in lung

function during the morning in the exposed group was probably due to the exposure to

formaldehyde.

The same group reported a similar study of 34 medical students and instructors who

were exposed to 0.07–2.94 ppm (mean, 1.24 ppm) [0.08–3.6 mg/m3 (mean, 1.22 mg/m3)]

200 IARC MONOGRAPHS VOLUME 88
formaldehyde and 12 control students and instructors who had no exposure to formaldehyde

(Akbar-Khanzadeh et al., 1994). Pre- and post-morning sessions showed a 0.03% fall in

FEV1 in the formaldehyde-exposed group compared with a 1% increase in the controls.

(c) Effect of chronic exposure on nasal mucosa

(i) Occupational exposure

The possibility that formaldehyde may induce pathological or cytogenetic changes in

the nasal mucosa has been examined in subjects exposed either in residential environments or in occupational settings. 

Cell smears were collected by a swab that was inserted 6–8 cm into the nose of

42 workers who were employed in two phenol–formaldehyde plants and 38 controls who

had no known exposure to formaldehyde. The concentrations of formaldehyde in the

plants were 0.02–2.0 ppm [0.02–2.4 mg/m3], with occasional peaks as high as 9 ppm

[11.0 mg/m3], and the average length of employment in the plants was about 17 years.

Atypical squamous metaplasia was detected as a function of age > 50 years, but no association was found with exposure to formaldehyde (Berke, 1987).

Biopsy samples were taken from the anterior edge of the inferior turbinate of the nose

of 37 workers in two particle-board plants, 38 workers in a laminate plant and 25 controls

of similar age. The concentrations of formaldehyde in the three plants were 0.1–1.1 mg/m3,

with peak concentrations of up to 5 mg/m3. Simultaneous exposure to wood dust occurred

in the particle-board plants but not in the laminate plant. The average length of

employment was 10.5 years. Exposure to formaldehyde appeared to be associated with

squamous metaplasia and mild dysplasia, but no concentration–response relationship was

observed, and the histological score was not related to number of years of employment. No

difference was detected in the nasal histology of workers exposed to formaldehyde alone

or to formaldehyde and wood dust (Edling et al., 1987b, 1988).

Biopsy samples were collected from the medial or inferior aspect of the middle turbinate, 1 cm behind the anterior border, from 62 workers who were engaged in the manufacture of resins for laminate production, 89 workers who were employed in furniture

factories and who were exposed to particle-board and glue and 32 controls who were

mainly clerks in a local government office. The concentrations of formaldehyde in the resin

manufacturing plant were 0.05–0.5 mg/m3, with frequent peaks of over 1 mg/m3, and those

in the furniture factories were 0.2–0.3 mg/m3, with rare peaks up to to 0.5 mg/m3; the latter

workers were also exposed to wood dust (1–2 mg/m3). The control group was exposed to

concentrations of 0.09–0.17 mg/m3 formaldehyde. The average length of employment was

about 10 years. The histological scores of workers who were exposed to formaldehyde

alone were slightly but significantly higher than those of controls, but the histological

scores of workers who were exposed to formaldehyde and wood dust together did not

differ from those of controls. No correlation was found between histological score and

either duration or concentration of exposure (Holmström et al. (1989a). [The possible

effect of age on nasal cytology, as noted by Berke (1987), was not determined.]

FORMALDEHYDE 201
A nasal biopsy sample was taken from the anterior curvature of the middle turbinate of

37 workers who were exposed at a chemical company where formaldehyde resins were

produced and 37 age-matched controls. The concentrations of formaldehyde in the company ranged from 0.5 to > 2 ppm [0.6–> 2.4 mg/m3], and the average length of employment

was 20 years. Hyperplasia and squamous metaplasia were more common among the

exposed workers than among the controls, but the difference was not significant. The histological scores increased with age and with concentration and duration of exposure, but the

changes were not significant (Boysen et al., 1990).

Histopathological abnormalities of respiratory nasal mucosa cells were determined in

15 nonsmokers (seven women, eight men) who were exposed to formaldehyde that was

released from a urea–formaldehyde glue in a plywood factory. Each subject was paired

with a control who was matched for age and sex. The mean age of the controls was

30.6 ± 8.7 years and that of exposed workers was 31.0 ± 8.0 years. The mean levels of

exposure to formaldehyde (8-h TWA) were about 0.1 mg/m3 in the sawmill and shearingpress department and 0.39 mg/m3 in the warehouse area. Peak exposure levels were not

given. Concurrent exposure to low levels of wood dust (respirable mass, 0.23 mg/m3 in the

warehouse, 0.73 mg/m3 during sawing and 0.41 mg/m3 in shearing-press) occurred. Nasal

respiratory cell samples were collected from near the inner turbinate with an endocervical

cytology brush. The exposed group had chronic inflammation of the nasal respiratory

mucosa and a higher frequency of squamous metaplasia than the controls (mean scores,

2.3 ± 0.5 in the exposed group; 1.6 ± 0.5 in the control group; p < 0.01, Mann–Whitney U

test) (Ballarin et al., 1992).

(ii) Residential exposure 

Samples of cells were collected by a swab that was inserted 2–3 cm into the nostrils

of subjects who lived in urea–formaldehyde foam-insulated homes and of subjects who

lived in homes without this type of insulation and were examined cytologically. Small but

significant increases were observed in the prevalence of squamous metaplastic cells in the

samples from the occupants of urea–formaldehyde foam-insulated homes (Broder et al.,

1988a,b,c). A follow-up study 1 year later (Broder et al., 1991) showed a decrease in nasal

symptoms that was unrelated to any decrease in levels of formaldehyde.

The effects of formaldehyde, other than cancer, on the nasal mucosa are summarized

in Table 31.

(d ) Sensitization to formaldehyde

Formaldehyde is a well recognized cause of allergic contact dermatitis and an occasional cause of occupational asthma. Provided that suitable control exposures for the

affected patient are performed and that similar exposures of unsensitized asthmatics do not

provoke asthma, cause and effect can reasonably be implied. The studies on asthma are

summarized in Table 32.

Hendrick and Lane (1975) found a late asthmatic reaction following exposure to

formaldehyde in a nurse who had no reaction after a control exposure. An asthmatic patho202 IARC MONOGRAPHS VOLUME 88
Table 31. Findings in the nasal mucosa of people who had occupational exposure to formaIndustry Concentration of 

formaldehyde (mg/m3) 

No. of exposed 

No. of controls 

Method Findings 

Formaldehyde (laminate plant) 

0.5–1.1 38 25 Nasal biopsy Histological score: expos

1.8 (p < 0.05). Four expodysplasia. 

Formaldehyde Wood dust (laminated particle-board) 

0.1–1.1 (peaks to 5) 0.6–1.1 

75 25 Nasal biopsy Histological score: expos

1.8 (p < 0.05). Six men h

Formaldehyde (phenol?) (laminate) 

0.02–2.4 (peaks to 11–18.5) 

42 38 Swab smears No positive correlation be

to formaldehyde and abno

Clinical examination 

More mucosal abnormalitsmoking exposed worker

Formaldehyde (production of formaldehyde and formaldehyde resins) 

0.6–> 2.4 37 37 Nasal biopsy Histological score: expos

1.4 (p > 0.05). Three expocontrols had dysplasia. 

Formaldehyde (resins for laminate production) 

0.05–0.5 (peaks to > 1) 

62 32 Nasal biopsy Histological score: expos

1.56 (p < 0.05). No case o

Formaldehyde Wood dust (plywood factory) 

0.1–0.39 0.23–0.73 

15 15 Nasal scrapes Micronuclei in nasal muc

exposed, 0.90; controls, 0Cytological score: expose1.6 (p < 0.01). One exposdysplasia. 
204 IARC MONOGRAPHS VOLUME 88

Table 32. Studies of occupational asthma/dermatitis 

Sex Route Concentration of 

formaldehyde 

Duration Effects Reference 

Men (aged 

39 years) 

Inhalation 0.06 ppm, max. 

0.13 ppm 

0.01 ppm 

0.5 ppm 

6 months 

20 min 

20 min 

Asthma 

None 

Late asthmatic reaction, 

IgE negative 

Kim et al. (2001) 

Men and 

women 

Skin (patch 

test) 

1% in water Unspecified Case series of 280 health 

care workers; 13.9% 

positive patch test to 

formaldehyde, little cross 

reaction with glutaraldehyde (12.4%) and 

glyoxal (1.9%) 

Kiec-Swierczynska 

et al. (1998) 

Men and 

women 

Inhalation 2.3 mg/m3 

4.8 mg/m3 

31 mg/m3 

4.8 mg/m3

30 min 

30 min 

7 min 

30 min 

Late asthmatic reaction 

Dual immediate and late 

asthmatic reaction 

Irritant asthmatic reaction 

No reaction in unsensitized asthmatics 

Burge et al. (1985) 

Women Inhalation 5 ppm 

3 ppm 

15 min 

5 min 

Late asthmatic reaction 

Late asthmatic reaction 

No reaction in controls 

Hendrick & Lane 

(1975, 1977); 

Hendrick et al. 

(1982) 

Unspecified Inhalation Immediate and late 

reactions in 2 workers 

Popa et al. (1969) 

[few details] 

Men and 

women 

Inhalation 1.2 mg/m3 

2.5 mg/m3

30 min 

30 min 

1 worker, early response 

11 workers, 6 late 

response 

12/230 exposed symptomatic workers + specific 

challenge to formaldehyde negative in 218, 

71 with NSBR 

Nordman et al. 

(1985) 

Men Inhalation 

(cutting and 

preparing 

brain 

specimens) 

2 h Acute pneumonitis; 

breath smelled of 

formaldehyde; resolved 

Porter (1975) 

NSBR, non-specific bronchial hyper-reactivity 
logist had no reaction following a similar 60-min exposure to 5 ppm [6 mg/m3] formaldehyde. A later study (Hendrick et al., 1982) repeated the original exposures, which were

reported to be 5 ppm. A second report (Hendrick & Lane, 1977) mentioned a second case

who reacted to exposure to 3 ppm [3.6 mg/m3] formaldehyde for 5 min.

Burge et al. (1985) reported the results of challenge tests in 15 workers who were

exposed to formaldehyde. Three had late asthmatic reactions that suggested sensitization;

one reacted following exposure to 2.3 mg/m3 and two after exposure to 4.8 mg/m3. Control

asthmatics had no asthma attack provoked by exposures to 4.8 mg/m3; one asthmatic

exposed to a sheep dip that contained formaldehyde had an irritant reaction following a

7-min exposure to 31 mg/m3.

Nordman et al. (1985) reported the results of inhalation challenges in 230 workers who

were investigated at the Finnish Institute of Occupational Medicine. One worker reacted to

1.2 mg/m3 formaldehyde and 11 reacted to 2.5 mg/m3 formaldehyde. No reaction was

observed at 2.5 μg/m3 among the remaining 218 workers, 71 of whom had non-specific

hyper-responsiveness.

Kim et al. (2001) reported on a worker who made crease-resistant trousers and who

had a late asthmatic reaction 5 h after exposure to 0.5 ppm [0.6 mg/m3], but not to

0.01 ppm [0.01 mg/m3] formaldehyde (20-min exposures). His IgE to formaldehyde conjugates was negative.

One patient developed anaphylaxis during dialysis with a dialyser that had been sterilized with formaldehyde and contained 5–10 μg/mL residual formaldehyde. She had

previously been sensitized to formaldehyde on the skin through contact dermatitis. IgE antibodies to formaldehyde/human serum albumin were strongly positive (Maurice et al.

(1986).

One case of toxic pneumonitis following a 2-h exposure to a concentration of formaldehyde that was sufficient to be smelled on the breath has been reported (Porter, 1975).

(e) Oral poisoning

Two reports have been made of three patients who were poisoned following ingestion

of formaldehyde solution. All three patients died (Eells et al., 1981; Köppel et al., 1990).

Two patients had ingested unknown amounts of formalin that had not been contaminated

with methanol. Both developed acidosis with raised plasma formic acid levels (6.09 and

4.57 mmol/L) and additional lactic acidosis. Both survived the initial necrosis of the gut

mucosa and renal failure, but died from late acute respiratory distress syndrome and

cardiac failure at 3 weeks and 8 weeks after ingestion, respectively (Köppel et al., 1990).

The third patient had ingested 120 mL (37% w/v) formaldehyde that contained 12.5% v/v

methanol. Initial blood levels 30 min after ingestion were 0.48 μg/dL formaldehyde,

44 mg/dL formate and 42 mg/dL methanol. She died after 28 h (Eells et al., 1981).

FORMALDEHYDE 205
4.2.2 Experimental systems

(a) In-vitro studies

(i) Cytotoxicity

The toxicity of formaldehyde was assessed in cultured human bronchial epithelial cells

under defined serum- and thiol-free exposure conditions (Grafström et al., 1996). Results

obtained from studies of 1-h exposures showed that 0.2 mM and 0.6 mM formaldehyde

inhibited cell growth by 50% as measured by loss of clonal growth rate and colony-forming

efficiency, respectively. Membrane integrity, i.e. exclusion of trypan blue and cellular

uptake of neutral red, an energy-dependent lysosomal accumulation of the dye, was

decreased by 50% at concentrations of 2 mM and 6 mM formaldehyde, respectively. Inhibition of growth was also associated with significant decreases in GSH, which occurred

without concomitant formation of oxidized GSH and with no alteration of the levels of

protein thiols. This result indicated that exposure to formaldehyde was associated with the

expected formation of thiohemiacetal, but not with overt oxidative stress as assessed by

thiol status, in bronchial cells. Extensive loss of intracellular GSH coincided with loss of

membrane integrity, which implies that plasma membrane leakage may have contributed

to the effect. Moreover, active re-reduction of oxidized GSH to GSH by GSH reductase

could potentially have masked an oxidant effect. Formaldehyde-dependent decreases in

thiols provide a mechanism for formaldehyde-induced inhibition of growth, since minor

decreases in GSH levels are known to inhibit cell growth efficiently (Atzori et al., 1989,

1994). The steady-state concentration of intracellular Ca2+ was increased by 50% within a

few minutes after treatment with 0.5 mM formaldehyde, and transient increases were

recorded at lower concentrations (Grafström et al., 1996). The toxicity of formaldehyde to

keratinocytes is manifested as aberrant induction of terminal differentiation, i.e. increases

in involucrin expression and formation of cross-linked envelopes. This cellular response is

probably linked to the noted increases in cellular Ca2+, which activates transglutaminasedependent cross-linking of various proteins, including involucrin, into the cross-linked

envelope (Rice & Green, 1979). Various types of genetic damage and mutation are caused

by formaldehyde at levels as low as 0.1 mM (see Section 4.4), and may also underlie some

of the cytotoxic actions of formaldehyde. Inhibition of DNA repair was shown in bronchial

cells following treatment with 0.1–0.3 mM formaldehyde, which implies that inhibition of

enzyme function might be an essential aspect of the toxicity of formaldehyde. In this

respect, enzymes that carry a thiol moiety in their active site may be particularly sensitive

(Grafström et al., 1996).

The toxicity of formaldehyde was evaluated in isolated rat hepatocytes (Teng et al.,

2001); exposure to 4 mM for 2 h caused 50% cell lysis. Toxicity was associated with a dosedependent loss of GSH and mitochondrial membrane potential and, moreover, was associated with inhibition of mitochondrial respiration and the formation of reactive oxygen

species. Higher doses were associated with lipid peroxidation. Depletion of GSH and inhibition of ADH and ALDH activities increased the toxicity of formaldehyde, whereas antioxidants such as butylated hydroxytoluene and iron chelators such as desferoxamine

206 IARC MONOGRAPHS VOLUME 88
protected against toxicity. Prevention of toxicity by cyclosporine or carnitine, agents that

prevent the opening of the mitochondrial transition pore, provided evidence that formaldehyde targets mitochondria.

(ii) Proliferation and apoptosis

The toxicity of formaldehyde and the influences of exogenous and endogenous thiols

were studied in cultured human oral fibroblasts and epithelial cells (Nilsson et al., 1998).

The presence of serum and cysteine counteracted the toxicity of formaldehyde, and lower

levels of intracellular thiols, including GSH, in fibroblasts (relative to epithelial cells) were

associated with greater toxicity. The results emphasize the high thiol-reactivity of formaldehyde and the central role of cellular thiols in the scavenging of formaldehyde. The toxicity of formaldehyde was compared in human dental pulp fibroblasts, buccal epithelial

cells and HeLa cervical carcinoma cells (Lovschall et al., 2002). In assessments of proliferation (bromodeoxyuridine incorporation), methylthiazole tetrazolium conversion and

neutral red uptake, both of the normal cell types were shown to be more sensitive than the

carcinoma cells to the toxicity of formaldehyde. Formaldehyde, applied at concentrations

of 0.1–10 mM to HT-29 colon carcinoma and normal endothelial cell cultures, stimulated

proliferation at 0.1 mM, inhibited proliferation and induced apoptosis at 1 mM and induced

cell lysis at 10 mM (Tyihák et al., 2001). The authors concluded that formaldehyde may

either stimulate or inhibit proliferation or induce overt toxicity, depending on the dose.

Apoptosis was also induced in rat thymocytes by concentrations of 0.1 mM formaldehyde

or more after a 24-h exposure (Nakao et al., 2003). The proliferation-enhancing effects of

formaldehyde are supported by studies of gene expression in mouse fibroblast C3H/10T1/2

cells (Parfett, 2003). Formaldehyde at 0.05–0.1 mM, concentrations that are known to

induce cell transformation in this system, increased the transcription of proliferin, a

response that is also shared by other transformation-promoting agents.

Formaldehyde at doses of 1 ng/mL to 1 μg/mL induced expression of intercellular

adhesion molecule-1 and vascular cell adhesion molecule-1 in human microvascular

endothelial cells of the nasal mucosa (Kim et al., 2002). Exposures to formaldehyde were

also associated with increased adhesiveness of the endothelial cells to eosinophils. The

authors concluded that the noted effects and changes in gene expression of intercellular

and vascular cell adhesion molecules might underlie the irritant effects of formaldehyde

in the nasal mucosa.

(iii) Effect on the mucociliary apparatus of the respiratory mucosa 

In an ex-vivo study, dose-dependent changes in the mucociliary apparatus of frog

respiratory mucosa during exposure to formaldehyde in aqueous solutions were examined. Frog palates (10 per group) were removed and were refridgerated for 2 days to

allow the mucous to clear. The palates were then immersed in Ringer solution alone or

with 1.25, 2.5 or 5.0 ppm formaldehyde solution. The frequency of ciliary beat, as a

measure of the fluctuation of light patterns during the ciliary wave over time, and mucociliary clearance, as a function of the time it took a mucous plug to travel 6 mm of palate,

FORMALDEHYDE 207
were quantitated. Measurements were taken at time 0, before immersion in formaldehyde

solution, and then every 15 min for a total of four measurements over 60 min of exposure

at 20 °C and 100% humidity. The later time-points were all compared with their respective

0-time measurement to give a percentage of the baseline measurement. A dose- and timedependent decrease was observed in both mucociliary clearance and frequency of ciliary

beat (Flo-Neyret et al., 2001).

(b) In-vivo studies

(i) Acute effects

Irritation 

A quantitative measure of sensory irritation in rodents is provided by the reflex

decrease in respiratory rate of mice or rats that is caused by stimulation of trigeminal nerve

receptors in the nasal passages. In comparison with other aldehydes (Steinhagen & Barrow,

1984), formaldehyde is a potent respiratory tract irritant, and elicits a 50% decrease in

respiratory frequency in B6C3F1 mice at 4.9 ppm [6.0 mg/m3] and in Fischer 344 rats at

31.7 ppm [38.7 mg/m3] (Chang et al., 1981). Swiss-Webster mice exposed for 5 days (6 h

per day) to formaldehyde at a concentration that elicits a 50% decrease in respiratory

frequency (3.1 ppm [3.8 mg/m3]) developed mild histopathological lesions in the anterior

nasal cavity, but no lesions were found in the posterior nasal cavity or in the lung (Buckley

et al., 1984).

In addition to decreasing the respiratory rate, formaldehyde may also alter the tidal

volume, which results in a decrease in minute ventilation. Exposure to formaldehyde over

a 10-min test period induced prompt reductions in both respiratory rates and minute

volumes in mice and rats, whether or not they were exposed before testing to 6 ppm

[7.4 mg/m3] formaldehyde for 6 h per day for 4 days (Fig. 4). These effects were observed

at lower concentrations of formaldehyde in mice than in rats (Chang et al., 1983). A similar

effect has been demonstrated in C57Bl6/F1 mice and CD rats (Jaeger & Gearhart, 1982).

Rats exposed to 28 ppm [34.2 mg/m3] formaldehyde for 4 days developed tolerance to

its sensory irritancy, but those exposed to 15 ppm [18.3 mg/m3] for 1, 4 or 10 days did not

(Chang & Barrow, 1984).

Sensory irritation to formaldehyde, acrolein and acetaldehyde vapours and their

mixture was studied in groups of male Wistar rats weighing 240–300 g (four per group)

that were exposed to concentrations of the aldehyde vapours up to a level that decreased

respiratory frequency by 50%. Formaldehyde vapours were produced by thermal depolymerization of paraformaldehyde in water and evaporation into the in-flow airstream. The

maximal decrease in breathing frequency was observed within 3 min of exposure; desensitization occurred within a few minutes after maximal decrease in breathing frequency

and only partial recovery was achieved within 10 min after exposure. The authors proposed that the decreased breathing frequency within the first few minutes of exposure is

due to trigeminal nerve stimulation from the irritant effect of formaldehyde. The level of

exposure to formaldehyde that resulted in a 50% respiratory depression was 10 ppm

208 IARC MONOGRAPHS VOLUME 88
Adapted from Chang et al. (1983) Data shown are x− ± SE for each time point; n = 6 for each group

Figure 4. Time−response curves for respiratory rate, tidal and minute volume formaldehyde-pretreated mice and rats (6 ppm, 6 h/day, 4 days) during a 6-h exformaldehyde
[12.3 mg/m3]. Since this was a study of the mixture, the authors also found that the reduction in breathing frequency after exposure to the mixture was always greater than after

exposure to the same concentration of any of the components alone (Cassee et al., 1996a).

The retinal toxicity of a single dose of formaldehyde, methanol and formate was investigated in male albino rabbits weighing 2.1–2.3 kg (four per group) by injection into the

vitreous cavity of 100 μL of a buffered (pH 7.4) phosphate-saline solution that contained

1% methanol, 0.1% or 1.0% formaldehyde or 1% formate. The final vitreous concentrations were 700 μg/mL methanol, 70 μg/mL formaldehyde, 700 μg/mL formaldehyde and

700 μg/mL formate. The eyeballs were examined with a biomicroscope and ophthalmoscope before treatment and 1, 2, 7, 14 and 30 days after treatment. After 30 days, the rabbits

were euthanized and the eyeballs were fixed in formalin for microscopic examination of

the retina, choroid, sclera, optic disc and optic nerve. No lesions were observed in the

methanol- or formate-treated eyes at any time-point. The eyes treated with formaldehyde

had ophthalmoscopic alterations at all time-points and at both doses; the higher dose

induced more severe alterations including subcapsular cataract, retinal vessel dilatation and

juxtapapillary retinal haemorrhages. Histologically, the eyes treated with 0.1% formaldehyde had disorganization of the ganglion cell and outer nuclear layers of the retina; these

symptoms were more severe in eyes treated with 1.0% formaldehyde. The optic nerves had

vacuolization after treatment with either dose of formaldehyde (Hayasaka et al., 2001). 

Pulmonary hyper-reactivity

Formaldehyde induced pulmonary hyper-reactivity in guinea-pigs: exposure to 0.3 ppm

[0.37 mg/m3] for 8 h caused transient bronchoconstriction and hyper-reactivity to infused

acetylcholine; exposure to higher concentrations (> 9 ppm [> 11 mg/m3]) for 2 h induced

bronchoconstriction. No evidence of tracheal epithelial damage was observed after exposure

to 3.4 ppm [4.2 mg/m3] for 8 h. However, the mechanism by which these effects occur is

unknown (Swiecichowski et al., 1993).

The effects of formaldehyde (vaporized formalin) on pulmonary flow were determined in cynomolgus monkeys that were tranquilized before exposure and received an

endotracheal tube transorally. Pulmonary flow resistance was increased after exposure to

formaldehyde at a concentration of 2.5 ppm [3.0 mg/m3] for 2, 5 and 10 min. Narrowing

of the airways by formaldehyde was not correlated with methacholine reactivity (Biagini

et al., 1989). [The Working Group questioned the relevance of these findings, in view of

the method of administration.]

Male Sprague-Dawley rats, 6 weeks of age, were exposed to formaldehyde (10 ppm

[12.2 mg/m3]), ozone (0.6 ppm [1 mg/m3]) (with coefficients of variation of less than 12%

and 5%, respectively) or a combination of the two during exercise on a treadmill that was

modified to deliver a stream of control air or air that contained formaldehyde. The rats were

exercised at a moderately fast-walking gait of 15 m/min on a 20% gradient for 3 h, which

raised metabolic gas exchange over the resting rate by a factor of at least two. Resting exposure was conducted in a nose-only inhalation tube. Histology, including labelling indices,

was examined quantitatively for the nose and lung. Formaldehyde increased labelling in the

210 IARC MONOGRAPHS VOLUME 88
transitional epithelium in the nose after individual or mixed exposure at rest or after exercise

but ozone alone did not. Formaldehyde and ozone after exercice either individually or as a

mixture produced injury in the trachea; the mixture caused greater (approximately additive)

injury than either of the chemicals alone. The pulmonary parenchyma was unaffected by

exposure to formaldehyde. Functional changes included decreased breathing frequency

during exposure to formaldehyde; the response to the mixture was lower. Tidal volume

decreased after treatment with ozone or formaldehyde but was increased after exposure to

the mixture. Formaldehyde produced slow and shallow breathing which resulted in depressed minute ventilation (Mautz, 2003).

Sensitizing effect and inflammatory response

In order to investigate the induction of sensitization to formaldehyde, undiluted

formalin was painted on shaven and epilated dorsal sites of guinea-pigs; a second application was administered 2 days later at naive sites, to give a total dose of 74 mg/animal.

Other animals received diluted formalin at doses of 0.012–9.3 mg/animal. All animals that

received 74 mg formalin developed skin sensitivity when tested 7 days after exposure.

A significant dose–response relationship was observed for the degree of sensitization and

for the percentage of animals that were sensitized; however, pulmonary sensitization was

not induced when formaldehyde was administered dermally, by injection or by inhalation,

and no cytophilic antibodies were detected in the blood (Lee et al., 1984).

In the guinea-pig maximization test, 10 guinea-pigs (five per exposure group)

received six intradermal injections of saline or 0.25% [2.5 mg/mL] formaldehyde solution

followed 6–8 days later by an occlusive dressing of a patch soaked in 10% [100 mg/mL]

formaldehyde for 48 h. After an additional 12–14 days, another occlusive dressing was

applied for 24 h; 24 h after removal, the size of the area of the erythema was measured.

A similar study was conducted in guinea-pigs but only occlusive dressings were used.

Both studies resulted in a positive response (Hilton et al., 1996).

The local lymph node assay was conducted in BALB/c mice that received daily applications of 25 μL of 10%, 25% or 50% w/v solutions of formaldehyde on the pinna of both

ears for 3 consecutive days. Five days after the initiation of exposure, all mice were

injected with tritiated methyl thymidine and were killed 5 h later. The lymph nodes adjacent to the ear were removed and labelled cells were counted to measure the rate of cell

proliferation. Formalin induced a strong proliferative response that was considered to be

positive for a contact allergen (Hilton et al., 1996).

The mouse IgE test is thought to identify allergens that have the potential to cause sensitivity in the respiratory tract by stimulating a significant increase in serum IgE concentration. This test was conducted in groups of six BALB/c mice that received 50 μL of a 10%,

25% or 50% formalin solution (37% formaldehyde dissolved in dimethylformamide) on an

occlusive dressing applied to the shaved flank. Seven days later, 25 μL of the solution of

formaldehyde at half the concentration used previously was applied to the dorsum of both

ears. Fourteen days after the initial exposure, the mice were exsanguinated and blood was

FORMALDEHYDE 211
collected for analysis of IgE. There was no significant change in levels of circulating IgE

after treatment with formaldehyde (Hilton et al., 1996).

Production of the cytokines interferon-γ (IFN-γ) and interleukin (IL)-10 was measured

in draining lymph nodes of the skin of the flanks and the ears of 10 BALB/c mice that had

received skin applications of 10%, 25% or 50% formalin solutions (37% formaldehyde in

dimethylformamide) on the shaved flank twice a day for 5 days followed by 3 days on the

dorsum of the ears. Thirteen days after the initiation of exposure, draining auricular lymph

nodes were removed. Lymphocytes were isolated and cultured for up to 120 h, and the

supernatant was collected and analysed for IFN-γ and IL-10. The levels of IFN-γ were

significantly increased after all concentrations of formaldehyde but not those of IL-10. The

authors suggested that formaldehyde causes a contact sensitization reaction in the skin

(mediated by Th1-type lymphocytes that secrete IFN-γ) but not sensitization of the respiratory tract (Hilton et al., 1996).

Eighteen 8-week-old male BN/Crj and Fischer 344/DuCrj rats were exposed to an

aerosol of 1% formaldehyde solution (equivalent to 15–20 ppm) for 3 h per day for 5 days

in a whole-body inhalation exposure system; another nine animals were exposed to an

aerosol of ion-exchanged water only. After death by exsanguination, the nose was examined histologically or the nasal epithelium was removed by scraping and used to isolate

RNA. Measurements of cDNA were made by reverse-transcriptase polymerase chain

reaction (RT-PCR) for quantitative real-time analysis of IFN-γ, IL-2, IL-4 and IL-5 mRNA

levels. All samples were examined for levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA and quantities of gene were presented as the ratio to GAPDH.

The histological lesions were consistent with those reported previously and were of

greater severity in Fischer 344 than in BN rats (Ohtsuka et al., 1997). Compared with

GAPDH, IFN-γ and IL-2 (Th1-related cytokines involved in non-allergic inflammation)

were expressed at significantly lower levels in BN rats treated with formaldehyde. None

of the other mRNA levels were statistically significant, although the expression of IL-4

and IL-5 (Th2-related cytokines) in BN rats and that of IL-2 and IL-5 in Fischer 344 rats

were lower than the levels observed in controls (Ohtsuka et al., 2003). 

Cytotoxicity and cell proliferation in the respiratory tract

The acute and subacute effects of formaldehyde in experimental animals are summarized in Table 33. A critical issue for the mechanism of carcinogenesis is whether low

concentrations of formaldehyde increase or decrease the rate of cell turnover in the nasal

epithelium. Subacute exposure to a low concentration of formaldehyde (1 ppm [1.2 mg/m3];

6 h per day for 3 days) has been reported to induce a small, transient increase in nasal epithelial cell turnover in Wistar rats (Zwart et al., 1988), but this statistically significant

increase was not confirmed in later studies (Reuzel et al., 1990). Other investigators did not

detect an increase in cell turnover in the nasal epithelium of Fischer 344 rats exposed to 0.7

or 2 ppm [0.9 or 2.4 mg/m3] (6 h per day for 1, 4 or 9 days) (Monticello et al., 1991) or to

0.5 or 2 ppm [0.6 or 2.4 mg/m3] (6 h per day for 3 days) (Swenberg et al., 1983). Low concentrations of formaldehyde (0.5 or 2 ppm; 6 h per day for 1, 2, 4, 9 or 14 days) also did not

212 IARC MONOGRAPHS VOLUME 88
Table 33. Cytotoxicity and cell proliferation induced by acute and subacute exposure tStrain, species, sex Exposure Effects Fischer 344 rat, male; B6C3F1mouse, male

0, 0.6, 2.4, 7.4, 18.5 mg/m3, 6 h/day, 3 days 0.6, 2.4: no increase in cell replication 

mucosa; 7.4: increased cell turnover (ra18.5: cell proliferation (rats and mice)

Fischer 334 rat, male; B6C3F1mouse, male

0, 18.5 mg/m3, 6 h/day, 1 or 5 days 18.5: cell proliferation induced in nasal 

both species; rat responses exceeded th

Fischer 344 rat, male

3.7 mg/m3 × 12 h/day, 7.4 mg/m3 × 6 h/day, 14.8 mg/m3 × 3 h/day (

C × t = 44 mg/m3

–h/

day), 3 or 10 days

Cell proliferation related more closely tration than to time; less proliferation aafter 3 days of exposure, indicating ada

Fischer 344 rat, male

0, 0.6, 2.4, 7.4, 18.5 mg/m3, 6 h/day, 1, 2, 4, 9 or 14 days

0.6: no effects on mucociliary functionmal effects; 7.4: moderate inhibition; 1inhibition

Fischer 344 rat, male

0, 2.4, 18.5 mg/m3, 10, 20, 45 or 90 min or 6 h 2.4: no effect on mucociliary function; 

bition of mucociliary function, marked 1 h after exposure

Fischer 344 rat, male

0, 0.6, 2.4 mg/m3, 6 h/day, 1 or 4 days; 7.4 mg/m3, 6 h/day, 1, 2 or 4 days; 18.5 mg/m3, 6 h/day, 1 or 2 days

0.6, 2.4: no lesions; 7.4, 18.5: non-cell-dose-related injury, including hypertropkeratinized squamous cells, nucleolar s

Wistar rat, male 0, 6.2 mg/m3 × 8 h/day, 12.3 mg/m3 × 8 h/day 

(C × t = 49 or 98 mg/m3

–h/day); 12.3 mg/m3

× 8 × 0.5 h/day, 25 mg/m3 × 8 × 0.5 h/day (C × t = 49 or 98 mg/m3

–h/day), 5 days/week, 

4 weeks

Labelling index increased at all concencell proliferation more closely related ttration than to total dose

Wistar rat, male and female

0, 0.37, 1.2, 3.7 mg/m3, 6 h/day, 3 days Significant, transient increase in cell tu

1.2 and 3.7 mg/m3 but not confirmed in studies at concentration of 1.2 ppm (Re1990)
Table 33 (contd) Strain, species, sex Exposure Effects Rhesus monkey, male 0, 7.4 mg/m3, 6 h/day, 5 days/week, 1 or 6 weeks Lesions similar to those in rats (Montic

1991) but more widespread, extending and major bronchi; increased cell replicnasal passages, trachea and carina; percnasal surface area affected increased beand 6 weeks. 

Wistar rat, male 0, 0.37, 1.2, 3.7 mg/m3, 22 h/day, 3 days Also investigated effect of simultaneous exposure to 0.4, 0.8 or 1.6 mg/m3 ozone 0.37, 1.2: either no increase in or inhib

proliferation; 3.7: increased cell replica0.8 mg/m3 ozone + 1.2 or 3.7 mg/m3 fodehyde: synergistic increase in cell turn1.6 mg/m3 ozone + 1.2 mg/m3 formaldebition of cell turnover 

Fischer 344 rat, male 0, 0.86, 2.4, 7.4, 12.3, 18.5 mg/m3, 6 h/day, 5 days/week, 1, 4, or 9 days or 6 weeks 0.86, 2.4: no effect on cell turnover; 7.4

18.5: concentration- and site-dependenferation induced at all exposure times 

Wistar rat, male 0, 4.43 mg/m3; 8 h followed by 4 h no exposure for 6 consecutive 12-h cycles Also investigated effect of simultaneous exposure to 0.4 ppm ozone. 4.43 mg/m3 resulted in increased GSH 

in nasal respiratory tissue and increased expression by immunohistochemistry. 

Wistar rat, male 0, 1.23, 3.94, 7.87 mg/m3, 6 h/day, 1 or 3 days

Also investigated effect of simultaneous exposure to acetaldehyde (750, 1500 ppm) and acrolein (0.25, 0.67 ppm).

The mixture resulted in more extensive histopathology of the nose than the indexposure.

BN/Crj rat, male;Fischer 344/DuCrj rat, male

0 or 18.45–24.6 mg/m3 (estimate), 3 h/day, 5 days

Nasal respiratory degeneration and necsevere in Fischer 344 rats

C, concentration; t, time; PCNA, proliferating cell nuclear antigen
inhibit mucociliary function in the nasal passages of Fischer 344 rats (Morgan et al.,

1986b,c), and no injury to the nasal epithelium of rats of this strain was detected ultrastructurally after exposure to 0.5 or 2 ppm (6 h per day for 1 or 4 days) (Monteiro-Riviere &

Popp, 1986).

Wistar rats exposed to 3 ppm [3.7 mg/m3] (6 h per day for 3 days (Zwart et al., 1988)

or 22 h per day for 3 days (Reuzel et al., 1990)) had a transient increase in cell replication.

Higher concentrations of formaldehyde (≥ 6 ppm [7.3 mg/m3]) induced erosion, epithelial

hyperplasia, squamous metaplasia and inflammation in a site-specific manner in the nasal

mucosa of Wistar rats (Monticello et al., 1991). Mice are less responsive than rats,

probably because they are better able than rats to reduce their minute ventilation when

exposed to high concentrations of formaldehyde (Chang et al., 1983; Swenberg et al.,

1983). Fischer 344 rats exposed to 6, 10 or 15 ppm [7.3, 12.2 or 18.3 mg/m3] (6 h per day

for 1, 4 or 9 days, or 6 h per day on 5 days per week for 6 weeks) had an enhanced rate

of cell turnover (Monticello et al., 1991). The severity of nasal epithelial responses at

15 ppm was much greater than that at 6 ppm (Monteiro-Riviere & Popp, 1986). Rhesus

monkeys exposed to 6 ppm (6 h per day for 5 days) developed similar nasal lesions to rats.

Mild lesions, characterized as multifocal loss of cilia, were also detected in the larynx,

trachea and carina (Monticello et al., 1989).

The relative importance of concentration and total dose on cell proliferation was examined in Fischer 344 and Wistar rats exposed to a range of concentrations for various

lengths of time, such that the total inhaled dose was constant. Exposures were for 3 or 10

days (Swenberg et al., 1983) or 4 weeks (Wilmer et al., 1987). All of the investigators

concluded that concentration, not total dose, is the primary determinant of the cytotoxicity

of formaldehyde. A similar conclusion was reached when rats were exposed for 13 weeks

(Wilmer et al., 1989).

Ten 8-week-old male BN/Crj or Fischer 344/DuCrj rats were exposed to 100 L/min

(2 mg 1% formaldehyde solution/L air, equivalent to 15–20 ppm) aerosol or water for 3 h

per day on 5 days per week for 2 weeks. Clinical signs were monitored and light and

scanning electron microscopy were performed. Both strains of rat had abnormal respiration, nasal discharge and sneezing following treatment with formaldehyde; the Fischer

344 rats had a more severe response. Lesions were present only in the nose and trachea

from Fischer 344 rats and nose from BN rats; again, Fischer 344 rats were more severely

affected. The typical lesions of squamous metaplasia, respiratory hyperplasia and degeneration and necrosis in the nose that were described with Fischer 344 rats affected all

sections of the nose examined, whereas BN rats only had squamous metaplasia in the

ventral portion of level II. Epithelial hyperplasia was present in the trachea of Fischer 344

rats. By scanning electron microscopy, squamous epithelial-like changes were seen in the

anterior nose after treatment with formaldehyde in both rat strains. BN rats were less

sensitive to exposure to formaldehyde than Fischer 344 rats (Ohtsuka et al., 1997).

FORMALDEHYDE 215
Co-exposure with other agents

Ozone

The effects of simultaneous exposure to formaldehyde and ozone were investigated in

Wistar rats exposed to 0.3, 1 or 3 ppm [0.37, 1.2 and 3.7 mg/m3] formaldehyde, 0.2, 0.4 or

0.8 ppm [0.4, 0.8 or 1.6 mg/m3] ozone or mixtures of 0.4 ppm ozone with 0.3, 1 or 3 ppm

formaldehyde or 1 ppm formaldehyde with 0.2, 0.4 or 0.8 ppm ozone (22 h per day for

3 days). Both formaldehyde (3 ppm) and ozone (0.4 or 0.8 ppm) induced cell proliferation

in the most anterior region of the respiratory epithelium. In a slightly more posterior region,

ozone had no effect on cell replication, but formaldehyde either enhanced cell proliferation

(3 ppm) or appeared to inhibit it slightly (0.3 or 1 ppm). Combined exposures to low

concentrations (0.4 ppm ozone and 0.3 ppm formaldehyde, 0.4 or 0.8 ppm ozone and 1

ppm formaldehyde) induced less cell proliferation than ozone alone; however, more than

additive increases in cell proliferation were detected in the anterior nose after exposure to

0.4 ppm ozone in combination with 3 ppm formaldehyde, and in a slightly more posterior

region after exposure to 0.4 ppm ozone with 1 or 3 ppm formaldehyde. The results

suggested to the authors a complex response of the nasal epithelium to low (non-irritating)

concentrations of these irritants but a synergistic increase in cell proliferation at irritating

concentrations. To induce a synergistic effect on cell proliferation, at least one of the compounds must be present at a cytotoxic concentration (Reuzel et al., 1990).

The pathophysiology of nasal alterations was investigated in 80 8-week-old male Wistar

rats (20 per group) after nose-only exposure to formaldehyde or ozone, or their mixture for

8 h followed by 4 h of no exposure for six consecutive 12-h cycles. The formaldehyde was

generated from paraformaldehyde by thermal depolymerization in water and evaporation

into the air stream at a concentration of 3.6 ± 0.1 ppm or 3.5 ± 0.1 ppm [4.3 mg/m3] in the

individual or ozone mixture exposure groups, respectively (concentration of ozone, 0.4 ppm

[0.8 mg/m3]). After euthanasia, the respiratory portion of the nasal epithelium was collected

on ice from a subset of the rats and another subset [numbers not specified] was used for

microscopic examination of the nose with haematoxylin and eosin, periodic acid Schiff and

proliferating cell nuclear antigen immunohistochemistry. The nasal respiratory epithelial

samples were pooled (six rats), homogenized and centrifuged for extraction of the supernatant. The enzyme activities of GST, GSH peroxidase, glucose-6-phosphate dehydrogenase, GSH reductase, ADH and FDH were measured. In addition, GSH and protein levels

were quantified. All animals lost weight during the exposure period and weight loss was

significantly greater in the treated animals compared with controls. Ozone alone resulted in

degenerative changes in the respiratory epithelium but formaldehyde alone or in combination with ozone induced necrosis in the respiratory epithelium. Rhinitis was induced by all

three treatments but was more severe in rats treated with formaldehyde than in those treated

with ozone and was most severe after exposure to the mixture. Cell proliferation was

increased after all treatments compared with controls and a uniformly greater increase was

observed in rats exposed to formaldehyde combined with ozone compared with those

exposed to ozone alone. Rats treated with formaldehyde alone had proliferative rates in most

216 IARC MONOGRAPHS VOLUME 88
of the measured areas equivalent to those of the ozone–formaldehyde-exposed rats.

However, rats that received formaldehyde only had greater proliferation indices in the

septum and lateral wall of the posterior section than rats exposed to the mixture. Only GSH

peroxidase activity was increased after exposure to formaldehyde and only GST activity

was decreased after exposure to the mixture. Ozone alone did not alter any enzyme activities

significantly. The authors suggested that there appeared to be no major role for GSH or

GSH-dependent enzymes in the pathogenesis of toxicity induced by formaldehyde and/or

ozone (Cassee & Feron, 1994).

Other aldehydes 

The histological and biochemical effects of exposure to formaldehyde, acetaldehyde

and acrolein individually or as mixtures were examined in rats. Groups of male Wistar rats,

8 weeks of age, were exposed to formaldehyde at 0, 1.0, 3.2 or 6.4 ppm [0, 1.23, 3.94 or

7.87 mg/m3] for 6 h per day for 1 or 3 days in nose-only inhalation chambers. Additional

rats were exposed to mixtures of 1.0 ppm formaldehyde and 0.25 ppm acrolein, 1.0 ppm

formaldehyde, 0.25 ppm acrolein and 750 ppm acetaldehyde, or 3.2 ppm formaldehyde,

0.67 ppm acrolein and 1500 ppm acetaldehyde. After euthanasia, five or six treated animals

per exposure group and a total of 19 control animals from all substudies were used for

histology (haematoxylin and eosin and proliferating cell nuclear antigen immunohistochemistry) and nine animals from each exposure group were used for biochemical studies.

Respiratory and olfactory epithelium were removed separately and homogenized on ice for

extraction of the cytosolic fraction and analysis of GSH peroxidase, GST, GSH reductase,

ADH, FDH and total amount of protein and non-protein sulfhydryl groups. No histological

or biochemical alterations were observed after 1 day of exposure to formaldehyde at any

concentration. Only acrolein or the high-dose mixture of all three chemicals induced a

biochemical change after 1 day (a decrease in GSH reductase activity). Acetaldyde induced

a dose-dependent increase in non-protein sulfhydryls. After 3 days of exposure to 1.0 ppm

formaldehyde, no histological alterations were present. Only the group exposed to 3.2 ppm

formaldehyde had histopathology that was characterized by degeneration and necrosis of

the respiratory epithelium with basal-cell hyperplasia. The lesions were most pronounced

along the lateral walls of the naso- and maxilloturbinates. An associated significant

increase in cell proliferation was also observed after exposure to 3.2 ppm formaldehyde for

3 days. After 3 days of exposure to 3.2 or 6.4 ppm formaldehyde, only GSH peroxidase

activity had increased statistically significantly. Three days of exposure to 1.4 ppm acrolein

resulted in a decrease in GST and ADH and an increase in FDH activities while the groups

of rats exposed to the mixtures of all three compounds had increased GST and GSH peroxidase activities. Histological alterations of the nasal epithelium were more severe after

exposure to the mixture than after exposure to any of the components alone at comparable

concentrations and duration of exposure. The distribution of the lesions induced by formaldehyde was different from that produced by acetaldehyde or acrolein, in that lesions produced by formaldehyde were concentrated in the respiratory epithelium (Cassee et al.,

1996b).

FORMALDEHYDE 217
Enzyme induction

No increase in the activities of FDH or ALDH was seen in the nasal mucosa of Fischer

344 rats exposed to 15 ppm [18.3 mg/m3] formaldehyde (6 h per day on 5 days per week

for 2 weeks) (Casanova-Schmitz et al., 1984a). A large increase in the concentration of rat

pulmonary CYP was seen, however, after exposure to 0.5, 3 or 15 ppm formaldehyde [0.6,

3.7 or 18.3 mg/m3] (6 h per day for 4 days) (Dallas et al., 1989), although Dinsdale et al.

(1993) could not confirm these results in the same strain of rat and found no increase in

pulmonary concentration of CYP after exposure to 10 ppm [12.3 mg/m3] formaldehyde

(6 h per day for 4 days).

The relative contribution of three isoforms of ADH to ethanol, formaldehyde and

retinoic acid acute toxicity was examined in knockout mice that had induced deletions of

Adh1, Adh3 or Adh4 genes, which make the enzymes non-functional. The comparison

with formaldehyde was based on the LD50 after intraperitoneal injection of a 10% formalin solution that resulted in a dose range of 0.09–0.22 g/kg bw formaldehyde. A lethal dose

to wild-type mice resulted in death within 90 min. It was assumed in the interpretation of

these studies that formaldehyde and not a metabolite was the ultimate toxicant. Mice that

had Adh3 knocked out required significantly lower levels of formaldehyde (0.135 g/kg)

than the wild-type control (0.2 g/kg) to achieve an LD50 whereas there was no difference

between wild-type and mice that had Adh1 and Adh4 knocked out. These studies showed

that Adh3 is responsible for the clearance of formaldehyde but does not play a role in the

clearance of ethanol or retinoic acid. Adh1 and Adh4 demonstrate overlapping functions

in the metabolism of ethanol and retinol in vivo. Adh3 is conserved across most levels of

biological organization including all mammalian species, invertebrates and plants

(Deltour et al., 1999). 

Other effects

The nephrotoxicity of formaldehyde after intravascular injection was studied in male

Sprague-Dawley rats (eight animals per group) that weighed 200 g. The rats were injected

through the tail vein with 7.6 or 38 μM of a saline solution of formaldehyde or normal

saline. Blood samples were taken for determination of blood urea and creatinine levels 24

and 48 h after injection of the test solution. Urine was also collected 24 h after injection

and analysed for lactate dehydrogenase (LDH) and protein. All rats were killed 48 h after

the single injection and the kidneys were removed for histological examination. No histological alterations were present in the kidney. No statistical change in urinary protein or

LDH levels nor in blood creatinine was observed. A small but statistically significant

increase in blood urea was reported at 24 h (5.23 ± 0.3 versus 4.13 ± 0.5 for control [units

not reported]) after treatment which returned to normal levels at 48 h. These data suggested

that renal toxicity does not occur after acute intravascular exposure to formaldehyde (Boj

et al., 2003). 

Twenty-one male (weighing 250–280 g) and 19 female (weighing 180–200 g) 16-weekold Wistar rats were trained over 14 days to find food in a maze and were then tested in the

maze after exposure to formaldehyde. The number of mistakes and the length of time to find

218 IARC MONOGRAPHS VOLUME 88
the food were counted daily for 11 days as a baseline. The animals were exposed to aqueous

formaldehyde solutions of either 0.25% (equivalent to 3.06 ± 0.77 mg/m3; 2.6 ppm) or 0.7%

(equivalent to 5.55 ± 1.27 mg/m3; 4.6 ppm) for 10 min per day on 7 days per week for

90 days. Every 7th day, the animals were tested in the maze prior to exposure. After 90 days

of exposure, the animals were then allowed a 30-day recovery and were tested in the maze

every 10th day. At the end of the study, the animals were killed and the liver, trachea, lungs,

kidneys, heart, spleen, pancreas, testicles, brain and spinal cord were collected and fixed in

formalin. Both formaldehyde-exposed groups made more mistakes and took longer to

complete the maze than the controls but no difference was observed between the exposed

groups. None of the groups differed from one another after the recovery period. There were

no treatment-related histological lesions (Pitten et al., 2000). [There is no evidence that the

changes seen in this study are due to formaldehyde-induced neurotoxicity, and could have

just as easily have been from loss of olfactory capacity and visual difficulties from irritant

effects to the cornea which would have improved after the treatment was stopped.]

Lewis rats were exposed to formaldehyde vapours and placed in a water maze to test

the effect of formaldehyde on learning. A total of 120 male and female LEW.1K rats,

110–130 days of age, were separated into four groups and exposed to distilled water or

0.1 ± 0.02, 0.5 ± 0.1, or 5.4 ± 0.65 ppm [0.12 mg/m3, 0.62 mg/m3 or 6.64 mg/m3] volatilized

formaldehyde for 2 h per day for 10 days. Two hours after exposure, the rats were subjected

to the water maze test. The length of time taken to complete the maze and the number of

errors while attempting this were measured. At the conclusion of the study, the animals were

killed and the lungs, heart, thymus, kidneys, liver, pancreas, skeletal muscle and spleen were

examined microscopically. All rats exposed to formaldehyde made more errors in completing the maze, but no difference was observed between exposure groups or sexes. After

10 days, only the 0.5- and 5.4-ppm groups took longer to complete the water maze; no difference was observed between sexes. No histological lesions were found in the tissues examined. The authors suggested that formaldehyde vapours had a central effect on learning

and memory. However, none of the tissues sampled were target organs for formaldehyde

toxicity in the rat except at very high and prolonged exposure concentrations. [The nose was

not examined in this study. Formaldehyde is a surface irritant which would cause degeneration and necrosis of the olfactory epithelium as well as the surface epithelium lining the

cornea. The complications of blurry vision and loss of olfactory cues was not controlled for

in this study, which suggests that an effect on the central nervous system may not have

resulted in the treatment-related response] (Malek et al., 2003). 

Forty-two male Wistar rats (weighing approximately 250 g) were divided into six

groups (seven rats per group) and exposed by inhalation to 0, 6.1 mg/m3 or 12.2 mg/m3

formaldehyde for 8 h per day on 5 days per week for subacute (4 weeks) or subchronic

(13 weeks) periods. At the end of the exposure period, the animals were killed and the

brains were removed for analysis of zinc, copper and iron levels (mg metal/kg parietal

cortex). Both zinc and copper increased in concentration with increasing dose whereas

iron decreased in concentration. The increase in copper concentration and decrease in iron

concentration were both time-dependent. Exposure to formaldehyde altered the trace

FORMALDEHYDE 219
element level of copper, zinc and iron in the brain. The greatest change was a 54%

increase in levels of zinc after 4 weeks of exposure to the high dose which fell to a 33%

increase over controls after 13 weeks (Özen et al., 2003). 

Forty male albino Charles Foster rats, weighing 147–171 g, were given daily intraperitoneal injections of 0, 5, 10 or 15 mg/kg bw formaldehyde in saline for 30 days. On day

31, the animals were anaesthetized for blood collection then killed and the thyroid glands

were collected, weighed and processed for histology. Thyroid weights were significantly

decreased after treatment with 10 and 15 mg/kg per day and histological changes of follicular degeneration, atrophy and epithelial size were observed. Triiodothyronine and thyroxine were significantly decreased and thyroid-stimulating hormone was increased after

doses of 10 and 15 mg/kg per day. After treatment with 5 mg/kg per day, triiodothyronine

was decreased and thyroid-stimulating hormone was increased but thyroxine was unchanged and the thyroid glands did not differ histologically from those of controls (Patel

et al., 2003).

Levels of serum corticosterone were examined in Sprague-Dawley rats (weighing

260–280 g) exposed by inhalation to 0.7 or 2.4 ppm [0.86 or 2.95 mg/m3] formaldehyde

for 20 or 60 min per day on 5 days per week for 2 or 4 weeks. Treatment had no effect after

short-term exposure; however, rats exposed to 0.7 ppm for 4 weeks had increased baseline

serum corticosterone. Rats treated with 2.4 ppm formaldehyde for 2 or 4 weeks had

increased levels of serum corticosterone after a formaldehyde challenge (Sorg et al., 2001).

(ii) Chronic effects

Cytotoxicity and cell proliferation in the respiratory tract

The subchronic and chronic effects of formaldehyde in different animal species

exposed by inhalation are summarized in Table 34. No increase in cell turnover or DNA

synthesis was found in the nasal mucosa after subchronic or chronic exposure to concentrations of ≤ 2 ppm [≤ 2.4 mg/m3] formaldehyde (Rusch et al., 1983; Maronpot et al., 1986;

Zwart et al., 1988; Monticello et al., 1993; Casanova et al., 1994). Small, site-specific

increases in the rate of cell turnover were noted at 3 ppm [3.7 mg/m3] (6 h per day on

5 days per week for 13 weeks) in Wistar rats (Zwart et al., 1988) and in the rate of DNA

synthesis at 6 ppm [7.3 mg/m3] (6 h per day on 5 days per week for 12 weeks) in Fischer

344 rats (Casanova et al., 1994). At these concentrations, however, an adaptive response

occurred in rat nasal epithelium, as cell turnover rates after 6 weeks (Monticello et al.,

1991) or 13 weeks (Zwart et al., 1988) were lower than those after 1–3 or 4 days of exposure. Monticello et al. (1996) detected no increase in cell turnover in the nasal passages of

Fischer 344 rats exposed to 6 ppm [7.3 mg/m3] formaldehyde for 3 months (6 h per day on

5 days per week). However, as already noted, Casanova et al. (1994) detected a small

increase in DNA synthesis under these conditions, but after 12 weeks of treatment. Large,

sustained increases in cell turnover were observed at 10 and 15 ppm [12.2 and 18.3 mg/m3]

(6 h per day on 5 days per week for 3, 6, 12 or 18 months) (Monticello & Morgan, 1994;

Monticello et al., 1996). The effects of subchronic exposure to various concentrations of

formaldehyde on DNA synthesis in the rat nose are illustrated in Figure 5.

220 IARC MONOGRAPHS VOLUME 88
Table 34. Cytotoxicity and cell proliferation induced by subchronic and chronic exposureStrain, species, sex Exposure Effects Fischer 344 rat, Syrian hamster, male and female; cynomolgus monkey, male 

0, 0.25, 1.2, 3.7 mg/m3, 22 h/day, 7 days/week, 26 weeks 

Rat: squamous metaplasia in nasal turbinates at 3

hamster: no significant toxic response; monkey: smetaplasia in nasal turbinates at 3.7 mg/m3 only 

B6C3F1 mouse, male 

0, 2.5, 4.9, 12.3, 24.6, 49.2 mg/m3, 

6 h/day, 5 days/week, 13 weeks 

2.5, 4.9: no lesion induced; 12.3, 24.7, 49.2: squaplasia, inflammation of nasal passages, trachea anmortality at 49.2 mg/m3

Wistar rat, male and female 

0, 0.37, 1.2, 3.7 mg/m3, 6 h/day, 5 days/week, 13 weeks 

0.37, 1.2: no increase in cell replication; 3.7: incrover in nasal epithelium but cell proliferation low3 days of exposure 

Wistar rat, male and female 

0, 1.2, 12.3, 24.7 mg/m3, 6 h/day, 

5 days/week, 13 weeks 

1.2: results inconclusive; 12.3, 24.7: squamous mthelial erosion, cell proliferation in nasal passagehepatotoxicity 

Wistar rat, male 0, 0.12, 1.2, 12.3 mg/m3, 6 h/day, 

5 days/week, 13 or 52 weeks Nasal mucosa of some rats injured by bilateral intranasal electrocoagulation to induce cell proliferation 

0: electrocoagulation induced hyperplasia and squplasia, still visible after 13 weeks but slight after 1.2: focal squamous metaplasia after 13 or 52 weeffects in animals with undamaged nasal mucosamous metaplasia in respiratory epithelium (both idamaged nose); degeneration with or without hypolfactory epithelium (damaged nose only) 
Table 34 (contd) Strain, species, sex Exposure Effects Wistar rat, male 0, 1.2 mg/m3 × 8 h/day, 2.4 mg/m3 × 8 h/day (C × t = 9.8 or 19.7 mg/m3– h/day), 5 days/week, 13 weeks; 2.4 mg/m3 × 8 × 0.5 h/day, 4.9 mg/m3 × 8 × 0.5 h/day (C × t = 9.8 or 19.7 mg/m3–h/day), 5 days/week, 13 weeks 1.2, 2.5: no observed toxic effect; 4.9: epithelial d

squamous metaplasia, occasional keratinization; cnot total dose, determined severity of toxic effect 

Fischer 344 rat, male 0, 0.86, 2.5, 7.4, 12.3, 18.5 mg/m3, 6 h/day, 5 days/week, 6 weeks 0.86, 2.5: no increase in cell replication detected; 

cell proliferation; 12.3, 18.5: sustained cell prolif

Fischer 334 rat, male 0, 0.86, 2.5, 7.4, 18.5 ppm, 6 h/day, 5 days/week, 12 weeks 0.86, 2.5: DNA synthesis rates in nasal mucosa si

(previously unexposed) and subchronically expos18.5: DNA synthesis rates higher in subchronicalin naive rats, especially at 18.5 mg/m3 

Fischer 344 rat, male 

0, 0.86, 2.5, 7.4, 12.3, 18.5 mg/m3, 

6 h/day, 5 days/week, 3 months 

0.86, 2.5, 7.4: no increase in cell replication detecsustained cell proliferation. Site-specific increase replication corresponded to location of squamouscarcinomas. 

C, concentration; t, time 
Additional studies have shown the importance of increased cell turnover in the induction of rat nasal tumours (Appelman et al., 1988; Woutersen et al., 1989). The nasal mucosa

of Wistar rats was damaged by bilateral intranasal electrocoagulation and the susceptibility

of the rats to inhalation of formaldehyde at concentrations of 0.1, 1 or 10 ppm [0.1, 1.2 or

12.2 mg/m3] (for 6 h per day on 5 days per week for 13 or 52 weeks (Appelman et al., 1988),

28 months or 3 months followed by a 25-month observation period (Woutersen et al., 1989))

was evaluated. In rats with undamaged mucosa, the effects of exposure were seen only at

10 ppm; these effects were limited to degenerative, inflammatory and hyperplastic changes,

and were increased by electrocoagulation. In the group exposed to 10 ppm for 28 months,

nasal tumours were induced in 17/58 rats. No compound-related tumours were induced at

0.1 or 1 ppm. It was concluded that the damaged mucosa was more susceptible to the cytotoxic effects of formaldehyde and that severe damage contributes to the induction of nasal

tumours.

FORMALDEHYDE 223

Figure 5. Cell turnover in the lateral meatus (LM) and medial and posterior

meatuses (M:PM) of pre-exposed and naive (previously unexposed) Fischer 344 rats,

as measured by incorporation of 14C derived from inhaled [14C]formaldehyde

(HCHO) into nucleic acid bases (deoxyadenosine, deoxyguanosine and thymidine)

and thence into DNA, during a single 3-h exposure to 0.7, 2, 6 or 15 ppm [0.86, 2.5,

7.4 or 18.5 mg/m3] formaldehyde

Reproduced, with permission, from Casanova et al. (1994)

Pre-exposed rats were exposed subchronically to the same concentrations of unlabelled formaldehyde (6 h per

day on 5 days per week for 11 weeks and 4 days), while naive rats were exposed to room air. The exposure

to [14C]formaldehyde occurred on the 5th day of the 12th week. The asterisk denotes a significant difference

between pre-exposed and naive rats.
The time-dependent development of formaldehyde-induced lesions was examined in

180 male Fischer 344 rats (six per exposure group), 8–9 weeks of age, that were exposed

by inhalation to nominal concentrations of 0, 0.7, 2, 6, 10 or 15 ppm [0, 0.86, 2.46, 7.38,

12.3 or 18.45 mg/m3, respectively] formaldehyde [thermal depolymerization of paraformaldehyde, purity unspecified] for 6 h per day on 5 days per week for 3, 6, 12, 18 or

24 months. Five days before necropsy, the rats were anaesthetized and received an implant

of an osmotic minipump that contained 2mCi [methyl-3H]thymidine for incorporation of

the thymidine into DNA during S-phase to allow subsequent quantitation of cell proliferation. A detailed morphological analysis of the nasal cavity of each rat was made in order to

collect information on the development and distribution of lesions in seven separate

regions of the nose (anterior lateral meatus, posterior lateral meatus, anterior mid-septum,

posterior mid-septum, anterior dorsal septum, anterior medial maxilloturbinate and maxillary sinus). The unit length labelling index method was used to establish the proliferation

index in each area of the nose. The number of cells in each of the designated areas was also

determined through a combination of actual cell counts and estimates of numbers using

surface area measurements and a CFD model of the rat nose. A population-weighted unit

length labelling index was calculated for direct comparison across time and dose. Survival

was not different or greater in controls than in rats treated with 10 ppm formaldehyde or

less. Survival was decreased in rats treated with 15 ppm formaldehyde. Formaldehydeinduced lesions were primarily confined to areas lined by respiratory and transitional epithelium and were more prevalent and severe in the anterior portion of the nose. The

severity of the lesions was dose-dependent, with only minimal lesions present after exposure to 6 ppm and none after exposure to 2 ppm or 0.7 ppm. The predominant nonneoplastic formaldehyde-induced lesions were epithelial hypertrophy and hyperplasia,

squamous metaplasia and inflammatory cell infiltration. The majority of formaldehydeinduced neoplasms were squamous-cell carcinomas with much lower incidences of polypoid adenomas, adenocarcinomas and rhabdomyosarcomas. The 10- and 15-ppm groups

had parallel cumulative incidence curves, although the 10-ppm group had a later time to

onset of tumours. The squamous-cell carcinomas appeared to arise from regions lined by

transitional and respiratory epithelium and were most common in the lateral meatus and

mid-septum, the incidence was higher in the more anterior portions (Table 35). Significant

increases in the unit length labelling index were only observed in the 10- and 15-ppm

groups with the greatest increase in the more anterior portion of the nose where the tumour

response was greatest. An elevated unit length labelling index developed in the anterior

dorsal septum later in the course of the exposure. This belated elevation in the more

posterior nose of animals exposed to the high dose may have been secondary to changes in

airflow patterns and resultant local formaldehyde concentations associated with growth of

lesions and distortion of the airspace in the nose. The mapping of cell numbers per area

showed significant differences in the total populations of nasal epithelium at risk in the

different areas counted for this study. An additional method of examining the association

between cells at risk and the labelling index used in this study was the population-weighted

unit length labelling index which is the product of the total numbers of cells in the specified

224 IARC MONOGRAPHS VOLUME 88
Table 35. Incidences of nasal squamous-cell carcinomas in male Fischer 344 rats exformaldehydeConcentration Nasal locationof formaldehyde (ppm)

No. ofnasalcavities examined

Anterior lateral meatus

Posterior lateral meatus

Anterior midseptum

Posterior midseptum

Anterior dorsal septum

Anterior medial maxilloturbinate

Ms

 0 90 0 0 0 0 0 0 0  0.7 90 0 0 0 0 0 0 0  2 96 0 0 0 0 0 0 0  6 90 1 0 0 0 0 0 0 10 90 12 2 0 0 0 0 0 15 147 17 9 8 1 3 4 0 From Monticello et al. (1996)a Total number of animals with squamous-cell carcinoma, including those too large to allocate and those loctable
area and the unit length labelling index. This product corresponded very closely with

tumour development at all sites in the nose (Figs 6 and 7) (Monticello et al., 1996).

A rat CFD model was used to test whether the distribution of formaldehyde-induced

squamous metaplasia was related to the location of high-flux regions posterior to the squamous epithelium. Histological sections of nose corresponding to level 6 (Mery et al., 1994)

from male Fischer 344 rats exposed by whole-body inhalation to nominal concentrations

of 0, 0.7, 2, 6, 10 and 15 ppm [0, 0.86, 2.46, 7.38, 12.3 and 18.45 mg/m3] formaldehyde

were examined. Distribution of squamous epithelium within 20 subset areas within the

section was mapped. Squamous metaplasia was considered to be present when ≥ 50% of

the epithelium within a subsection was of the squamous type. The regions were then ranked

by presence of squamous metaplasia by dose group. Inspiratory airflow and formaldehyde

uptake were simulated based on a minute volume of 288 mL/min for a 315-g rat. Steadystate simulations were performed using air concentrations of 6, 10 or 15 ppm formaldehyde. Only these three concentrations were used because no squamous metaplasia was

present in sections of nose from rats exposed to 2 ppm or less. Squamous metaplasia was

present on the lateral and medial walls of the airway after exposure to 10 or 15 ppm; the

highest incidence was on wells of the lateral meatus in all three groups (6, 10 and 15 ppm).

The distribution of formaldehyde-induced squamous metaplasia was consistent with the

location of high formaldehyde flux in rat noses after exposure to 10 or 15 ppm for

6 months. The data were inconclusive for the 6-ppm group, probably due to the insufficient

number of rats examined (Kimbell et al., 1997). 

A larger percentage of the nasal mucosal surface area of rhesus monkeys exposed to

6 ppm [7.3 mg/m3] formaldehyde (6 h per day on 5 days per week) was affected after

6 weeks of exposure than after 5 days. Cell proliferation was detected in the nasal passages,

larynx, trachea and carina, but the effects in the lower airways were minimal in comparison with the effects in the nasal passages (Monticello et al., 1989). Other studies showed

that Fischer 344 rats exposed to 1 ppm [1.2 mg/m3] (22 h per day on 7 days per week for

26 weeks) formaldehyde did not develop detectable nasal lesions (Rusch et al., 1983), but

that rats exposed to 2 ppm [2.4 mg/m3] (6 h per day on 5 days per week for 24 months)

developed mild squamous metaplasia in the nasal turbinates (Kerns et al., 1983b).

Although the total dose received by the former group was 1.5 times higher than that

received by the latter group, the incidence and severity of lesions was smaller, which

demonstrates the greater importance of concentration than total dose (Rusch et al., 1983).

A computer simulation of the relationship between airflow and the development of

formaldehyde-induced lesions was developed for rhesus monkeys. A three-dimensional

computer model was developed using video image analysis of serial coronal sections from

an 11.9-kg, 7-year-old male rhesus monkey. Coordinates were taken for every 0.1 mm

over the 83 mm long nasal passage. Eighty cross sections were used for the final model

and spanned 75 mm of airway. Values for airflow simulation were estimated by allometric

scaling, using body weight and a calculated minute volume of 2.4 L/min and half

maximum nasal airflow calculated to be 3.8 L/min. Simulations were performed using

airflow parameters of 0.63–3.8 L/min. The nasal cavity of rhesus monkeys has two air226 IARC MONOGRAPHS VOLUME 88
Figure 6. Calculated total proliferative population in areas of the nose of rats after expo3 months and T-site where tumours developedAdapted from Monticello et al. (1996)

0

102030405060708090

0 0.7 2 6 10 15

Population-weighted unit length labelling index (×106) 

Formaldehyde concentration (ppm)

T 

T 

T 

T 

T 

T T 

T 

T 
Figure 7. Sum of calculated total proliferative population in areas of the nose of rats after exptime and T-site where tumours developed

Adapted from Monticello et al. (1996)

0

255075

100125150175200225250275

0 0.7 2 6 10 15

Formaldehyde concentration (ppm)

Population-weighted unit length labelling index (×106) 

T 

T 

T 

T 

T 

T 

T 

T T 
ways that are separated by a septum that extends approximately 71.5 mm from the

anterior tip of the nares to the nasopharynx. The nose has three distinct regions: the nasal

vestibule, the central nasal passage and the nasopharynx. The nasal vestibule extends

from the tip of the nostrils to the anterior margin of the middle turbinate. Airflow enters

the nasal vestibule in an undeviated pattern and flows along the septal wall to the ventral

medial, middle medial and dorsal airways in the central nasal passage. The central nasal

passage begins at the anterior margin of the middle turbinate, extends to the middle and

ventral turbinates and has a streamlined airflow in the middle portion of the nose which

is slower than that of the nasal vestibule. The nasopharynx extends from the posterior

nasal passage at the point where the middle turbinate attaches to the nasal wall dorsally

to the soft palate and has streamlined airflow in the anterior portion which increases in

velocity toward the posterior after the end of the dorsal meatus. The model predicted that

90% of gas uptake would be from the nostrils to the end of the septal wall. In general, the

regions where mass flux was predicted to be high (nasal vestibule, mid-septum, floor of

the anterior meatus, medial inferior turbinate and the middle turbinate) are also areas

where formaldehyde-induced lesions occurred (Monticello et al., 1989). Areas with low

mass flux (dorsal meatus and the wall of the ventral lateral meatus) did not develop

formaldehyde-induced lesions. An exception was the lateral wall where lesions occurred

but mass flux was predicted to be low (Kepler et al., 1998).

Toxicity in the gastrointestinal tract after oral administration

The toxic effects of formaldehyde administered orally have been reviewed (Restani

& Galli, 1991).

Formaldehyde was administered orally to rats and dogs at daily doses of 50, 100 or

150 mg/kg bw (rats) or 50, 75 or 100 mg/kg bw (dogs) for 90 consecutive days. Significant changes in body weight were observed at the higher doses, but clinical and pathological studies revealed no specific treatment-related effects on the kidney, liver or lung,

which were considered to be possible target organs, or on the gastrointestinal mucosa

(Johannsen et al., 1986).

Formaldehyde was administered in the drinking-water to male and female Wistar rats

for up to 2 years. In the chronic portion of the study, the mean daily doses of formaldehyde

were 1.2, 15 or 82 mg/kg bw (males) and 1.8, 21 or 109 mg/kg bw (females). Controls

received drinking-water either ad libitum or in an amount equal to that consumed by the

highest-dose group, which had a marked decrease in water consumption. Pathological

changes after 2 years were essentially restricted to the highest-dose group and consisted of

a thickened and raised limiting ridge of the forestomach and gastritis and hyperplasia of the

glandular stomach. The no-adverse-effect level was estimated to be 15 mg/kg bw per day

(males) or 21 mg/kg bw per day (females) (Til et al., 1989). In a 4-week study, the effects

of formaldehyde that were also observed only in the highest-dose group (125 mg/kg bw)

were thickening of the limiting ridge and hyperkeratosis in the forestomach and focal

gastritis in the glandular stomach (Til et al., 1988).

FORMALDEHYDE 229
In another experiment in which formaldehyde was administered in the drinking-water

to male and female Wistar rats, fixed concentrations (0, 0.02, 0.1 and 0.5%) were given

for up to 2 years. Estimated from the water intake and body weight, these concentrations

corresponded, on average, to 0, 10, 50 and 300 mg/kg bw per day. All rats that received

the highest dose died during the study. The lesions induced in the stomach were similar to

those reported by Til et al. (1988, 1989). No treatment-related tumour was found. The noeffect level was estimated to be 0.02% (10 mg/kg bw per day), as forestomach hyperkeratosis was observed in a small number of rats (2/14) that received 0.1% formaldehyde

(50 mg/kg bw per day) (Tobe et al., 1989).

(iii) Immunotoxicity

The possibility that formaldehyde may induce changes in the immune response was examined in B6C3F1 mice exposed to 15 ppm [18.3 mg/m3] formaldehyde (6 h per day on

5 days per week for 3 weeks). A variety of tests of immune function revealed no significant

changes, except for an increase in host resistance to challenge with the bacterium, Listeria

monocytogenes, which implied an increased resistance to infection. Exposure did not alter

the number or impair the function of resident peritoneal macrophages, but increased their

competence for release of hydrogen peroxide (Dean et al., 1984; Adams et al., 1987).

Formaldehyde enhanced the anti-ovalbumin IgE titre after pre-exposure of BALB/c mice to

2 mg/m3 formaldehyde for 6 h per day for 10 days (Tarkowski & Gorski, 1995) but did not

enhance the IgG1 response of ICR mice to a mite allergen in the respiratory tract after

exposure to an aerosol of 0.5% formaldehyde saline solution (Sadakane et al., 2002).

Sprague-Dawley rats were exposed to 12.6 ppm [15.5 mg/m3] formaldehyde (6 h per

day on 5 days per week for 22 months), then vaccinated with pneumococcal polysaccharide antigens and tetanus toxoid and were tested 3–4 weeks later for the development of

antibodies. An IgG response to pneumococcal polysaccharides and to tetanus toxoid and

an IgM response to tetanus toxoid were found in both exposed and control groups. No

evidence was obtained that long-term exposure to a high concentration of formaldehyde

impairs B-cell function, as measured by antibody production (Holmström et al., 1989c).

4.3 Reproductive and developmental effects

4.3.1 Humans

A variety of epidemiological studies are available that have evaluated the reproductive

effects of occupational exposures to formaldehyde both directly and indirectly. The

outcomes examined in these studies include spontaneous abortions, congenital malformations, birth weight and infertility.

The incidence of spontaneous abortion was studied among hospital staff in Finland

who used ethylene oxide (see IARC, 1994b), glutaraldehyde and formaldehyde to sterilize

instruments. Potentially exposed women were identified in 1980 with the help of supervising nurses at all of the approximately 80 general hospitals of the country. An equal

number of control women were selected by the supervising nurse from among nursing

230 IARC MONOGRAPHS VOLUME 88
auxiliaries in the same hospitals who had no exposure to sterilizing agents, anaesthetic

gases or X-rays. Study subjects were administered a postal questionnaire which requested

personal data and information on tobacco smoking habits, intake of alcohol, reproductive

history, including the number of pregnancies and their outcome, and occupation at the time

of each pregnancy. Information on exposure to chemical sterilizing agents was obtained

from the supervising nurses. The crude rates of spontaneous abortion were 16.7% for sterilizing staff who were considered to have been exposed during the first trimester of

pregnancy, 6.0% for sterilizing staff who left employment when they learned that they

were pregnant (the difference being significant) and 10.6% for controls. When adjusted for

age, parity, decade of pregnancy, tobacco smoking habits and alcohol and coffee consumption, the rate associated with exposure to ethylene oxide, with or without other agents, was

12.7%, which was significantly increased (p < 0.05), whereas that associated with formaldehyde, with or without other agents, was 8.4%, which was comparable with the reference

level of 10.5% and was thus not significantly correlated with spontaneous abortions

(Hemminki et al., 1982).

In a nationwide record linkage study in Finland, all nurses who had been pregnant

between 1973 and 1979 and who had worked in anaesthesia, surgery, intensive care, operating rooms or internal departments of a general hospital (and in paediatric, gynaecological, cancer and lung departments for the part of the study that was concerned with malformations) were identified. Each of the 217 women treated for spontaneous abortion

according to the files of the Finnish hospital discharge register and the 46 women notified

to the Register of Congenital Malformations was individually matched on age and hospital

with three control women, who were selected at random from the same population of

nurses and matched for age and hospital where they were employed. Information was

obtained from supervising nurses by postal questionnaires on the exposure of cases and

controls to sterilizing agents (ethylene oxide, glutaraldehyde and formaldehyde),

anaesthetic gases, disinfectant soaps, cytostatic drugs and X-radiation. Exposure to formaldehyde during pregnancy was reported for 3.7% of the nurses who were later treated for

spontaneous abortion and for 5.2% of their controls, yielding a crude odds ratio of 0.7

[95% CI, 0.28–1.7]. Exposure to formaldehyde was also reported for 8.8% of nurses who

gave birth to a malformed child and 5.3% of matched controls, to give an odds ratio of 1.74

[95% CI, 0.39–7.7]; the latter analysis was based on eight exposed subjects (Hemminki

et al., 1985). [The Working Group noted that these numbers appear to be recalculated from

published reports.]

The occurrence of spontaneous abortions among women who worked in laboratories

in Finland, and congenital malformations and birth weights of the children were investigated in a matched retrospective case–control study using a case–referent design. The

final population in the study of spontaneous abortion was 206 cases and 329 controls; that

in the study of congenital malformations was 36 cases and 105 controls. Information on

occupational exposure, health status, medication, contraception, tobacco smoking and

alcohol consumption during the first trimester of the pregnancy was collected by postal

questionnaire. The exposure to individual chemicals was estimated on the basis of a

FORMALDEHYDE 231
reported frequency of chemical use. An occupational hygienic assessment was conducted

and an exposure index was calculated. The odds ratio for spontaneous abortion was

increased among women who had been exposed to formalin for at least 3 days per week

(odds ratio, 3.5; 95% CI, 1.1–11.2). A greater proportion of the cases (8/10) than the

controls (4/7) who had been exposed to formalin had been employed in pathology and

histology laboratories. Most of the cases (8/10) and controls (5/7) who were exposed to

formalin were also exposed to xylene (see IARC, 1989). The authors stated that the results

for individual chemicals should be interpreted with caution because laboratory personnel

are often exposed to several solvents and other chemicals simultaneously. No association

was observed between exposure to formalin and congenital malformations [data not

shown] (Taskinen et al., 1994).

Reduced fertility was investigated in a retrospective study of time to pregnancy that

was conducted among female wood workers who were exposed to formaldehyde and who

had given birth between 1985 and 1995 (Taskinen et al., 1999). Time to pregnancy was

analysed using a discrete proportional hazards regression approach. Study criteria included

women who had worked in the wood-processing industry for at least 1 month and for

whom employment in wood-related work had started at least 6 months before pregnancy.

Exposure assessment was based on responses from a detailed questionnaire that asked

women to describe their occupational title and their work tasks. Women estimated the

number of hours they spent in various types of factories/enterprises in the industry and the

number of hours they were exposed to various chemicals including formaldehyde, organic

solvents, wood preservatives, glues or wood-protecting chemicals. The questionnaire also

collected information on the use of personal protective equipment, and exposure to welding

fumes, exhaust gases, pesticides and tobacco smoke. An occupational hygienist assessed

the exposures and calculated a daily exposure index. The authors used workplace exposure

measurements to support these exposure estimates. Among the 699 female wood workers,

exposure to formaldehyde was significantly associated with delayed conception density, as

assessed by an adjusted fecundability density ratio, which was 0.64 (95% CI, 0.43–0.92).

When no gloves were used during high levels of exposure, the fecundability density ratio

was 0.51 (95% CI, 0.28–0.92). Exposure to phenols, dusts, wood dusts or organic solvents

was not related to the time to pregnancy. All women exposed to phenols were also exposed

to formaldehyde but the opposite was not true.

Although the study focus was time to pregnancy, other analyses of these workers

showed an increased odds ratio for spontaneous abortion (52 pregnancies) of 3.2 (95% CI,

1.2–8.3) in the high-exposure and 2.4 (95% CI, 1.2–4.8) in the low-exposure categories.

Exposure to formaldehyde at high levels was also associated with an increased risk (odds

ratio, 4.5; 95% CI, 1.0–20.0) for endometriosis (Taskinen et al., 1999).

A meta-risk analysis conducted by Collins et al. (2001b) noted that, of the 11 epidemiological studies that they reviewed for their evaluation of reproductive effects among workers

exposed to formaldehyde, nine evaluated spontaneous abortions. Four of these studies

reported significantly higher rates of spontaneous abortion among women who were

occupationally exposed to formaldehyde (Axelsson et al., 1984; John et al., 1994; Taskinen

232 IARC MONOGRAPHS VOLUME 88
et al., 1994, 1999). Four other studies did not find an increased association (Hemminki

et al., 1982, 1985; Stücker et al., 1990; Lindbohm et al., 1991). One study did not report

relative risks but showed no increased risk for spontaneous abortion (Shumilina, 1975).

Collins et al. (2001b) suggested that there is a reporting bias against negative studies and

described some of the difficulties in conducting studies of spontaneous abortions. 

Collins et al. (2001b) discussed the four epidemiological studies that used a case–

control design to evaluate congenital defects among children of women exposed to formaldehyde (Axelsson et al., 1984; Ericson et al., 1984; Hemminki et al., 1985; Taskinen

et al., 1994).

Three epidemiological studies evaluated birth weights. Neither Taskinen et al. (1994)

nor Axelsson et al. (1984) reported associations between exposure to formaldehyde and

decreased birth weight among the 500 and 968 births examined, respectively. A study in

Russia by Shumilina (1975) reported an elevated number of births of babies that weighed

less than 3000 g among 81 newborns of women who were potentially exposed to formaldehyde; however, if the cut-point of below 2500 g is used (more traditional definition of

low birth weight), then these increases disappear.

It is important to note that most of the epidemiological studies reported in this section

were not designed to evaluate exposures to formaldehyde specifically. For example, the

studies by Taskinen et al. (1994), Hemminki et al. (1982, 1985), Ericson et al. (1984) and

Axelsson et al. (1984) were designed to investigate pregnancy outcomes in laboratory

workers and that of John et al. (1994) to investigate pregnancy outcomes in cosmetologists. All of these studies are confounded by significant co-exposures and, in general,

have directed research to examine specific exposures in follow-up studies. 

Other studies of reproductive effects in humans have investigated sperm abnormality.

Eleven hospital autopsy service workers and 11 matched controls were evaluated for sperm

count, abnormal sperm morphology and the frequency of one or two fluorescent F-bodies.

Subjects were matched for age and use of alcohol, tobacco and marijuana; additional

information was collected on health, medications and other exposure to toxins. Exposed

and control subjects were sampled three times at 2–3-month intervals. Ten exposed

subjects had been employed for 4.3 months (range, 1–11 months) before the first sample

was taken, and one had been employed for several years. Exposure to formaldehyde was

intermittent, with a time-weighted average of 0.61–1.32 ppm [0.75–1.6 mg/m3] (weekly

exposure, 3–40 ppm·h [3.7–48.8 mg/m3·h]). No significant difference was observed

between the exposed and control groups with regard to sperm parameters (Ward et al.,

1984).

4.3.2 Experimental systems

The reproductive and developmental toxicity of formaldehyde has been reviewed

(Feinman, 1988; WHO, 1989; Collins et al., 2001b). 

Numerous studies have been performed to examine the potential effects of formaldehyde on pregnancy and fetal development in rats, mice, hamsters, rabbits and dogs.

FORMALDEHYDE 233
Routes of exposure have included inhalation, oral gavage, administration in the drinkingwater and dermal application. The inhalation studies (Gofmekler, 1968; Gofmekler et al.,

1968; Pushkina et al., 1968; Gofmekler & Bonashevskaya, 1969; Shevelera, 1971;

Kilburn & Moro, 1985; Saillenfait et al., 1989; Martin, 1990) and studies of dermal exposure (Overman, 1985) use relevant routes of exposure for evaluation. Studies conducted

before 1970 (Gofmekler, 1968; Gofmekler et al., 1968; Pushkina et al., 1968; Gofmekler

& Bonashevskaya, 1969) reported a prolongation of pregnancy, changes in fetal organ

weight and a variety of clinical and biochemical changes in the spleen, liver, kidney,

thymus and lymphocytes in rats (Thrasher & Kilburn, 2001; Collins et al., 2001b).

Thrasher and Kilburn (2001) reviewed studies of embryotoxicity and teratogenicity

(Katakura et al., 1990, 1991, 1993) and reported that [14C]-labelled formaldehyde crossed

the placenta and entered fetal tissues at levels greater than those in the dam. Embryotoxic

and teratogenic outcomes were a function of the exposure regimen. Rats exposed before

mating had increased embryo mortality and those exposed during mating had increased

fetal anomalies. [The Working Group agreed with the authors’ suggestion that this [C14]-

labelling would be consistent with the entry of the [14C]-label from formaldehyde into the

one-carbon pool.]

Groups of 25 pregnant Sprague–Dawley rats were exposed by inhalation to formaldehyde (0, 5, 10, 20 or 40 ppm [0, 6.2, 12.3, 24.6 or 49.2 mg/m3]) for 6 h per day on days

6–20 of gestation. On day 21, the rats were killed and maternal and fetal parameters were

evaluated. The authors concluded that formaldehyde was neither embryolethal nor teratogenic when administered under these conditions. The mean fetal body weight at 20 ppm

was 5% less than that of controls (p < 0.05) in males but was not reduced in females; at

40 ppm, mean fetal body weight was about 20% less than that in controls (p < 0.01) in

both males and females. The decrease in fetal weight in the group given the high dose was

attributed to maternal toxicity. However, the authors stated that the significant reductions

in fetal body weight observed at 20 ppm did not cause overt signs of maternal toxicity

(Saillenfait et al., 1989). [The Working Group noted that 20-ppm exposures in other

studies would be considered to be ‘toxic’ doses.] 

Groups of 25 mated female Sprague–Dawley rats were exposed by inhalation to formaldehyde (0, 2, 5 or 10 ppm [2.5, 6.2 or 12.3 mg/m3]) for 6 h per day on days 6–15 of

gestation. At 10 ppm, there was a significant decrease in maternal food consumption and

weight gain. None of the parameters of pregnancy, including numbers of corpora lutea,

implantation sites, live fetuses, dead fetuses and resorptions or fetal weights, were

affected by treatment. An increased incidence of reduced ossification was observed at 5

and 10 ppm in the absence of maternal toxicity (10 ppm) (Martin, 1990). The author of

this study noted that the effects at both 5 and 10 ppm were attributed to larger litter sizes

which could have reduced fetal body weights (Martin, 1990).

Formaldehyde was applied topically to pregnant Syrian hamsters on day 8, 9, 10 or 11

of gestation by clipping the hair on the dorsal body and applying 0.5 mL formalin (37%

formaldehyde) with a syringe directly onto the skin. In order to prevent grooming, the

animals were anaesthetized with nembutal (13 mg intraperitoneally) during the 2-h treat234 IARC MONOGRAPHS VOLUME 88
ment. On day 15, fetuses were removed from four to six hamsters per group and examined. The number of resorptions was increased, but no teratogenic effects or effects on

fetal weight or length were detected. The authors suggested that the increase in resorptions may have been caused by stress, as females were anaesthetized during formaldehyde

exposures. No effect on maternal weight gain was observed (Overman, 1985).

In a study of post-implantation effects, 27 mature female Wistar rats were exposed by

inhalation to 0.5 mg/m3 or 1.5 mg/m3 formaldehyde every day for 4 h for up to 4 months.

On day 120, treated females were mated with untreated males. The effect of formaldehyde

was evaluated in developing embryos at the 2nd and 3rd day after mating. The authors

reported a significant increase in the number of degenerating embryos only from pregnant

females who had been exposed to 1.5 mg/m3. The impaired embryonic morphology was

reported as structural impairment in blastomers. In a cytogenetic analysis, no increase was

found in the number of embryos with chromosomal aberrations in comparison with the

controls (Kitaeva et al., 1990). 

Reproductive effects were observed in a study of sperm head abnormalities and dominant lethal mutations. Male albino rats (six per group) received five daily intraperitoneal

injections of 37% formaldehyde solution to provide 0.125, 0.25 or 0.5 mg/kg bw based on

the LD50 and a lethal dose of 2 mg/kg bw to examine sperm head abnormalities 3 weeks

after the last injection. A separate group of 12 male albino rats was injected intraperitoneally

with the same doses, then housed with two untreated virgin female rats that were replaced

weekly for 3 weeks to provide 24 females for each treatment group. Mating was detected

by the presence of vaginal plugs. All females were killed and necropsied 13 days after the

midweek of housing with the males. Total implant scores per female were collected and a

dominant lethal mutation index was calculated based on the formula [1–(live implants

treated/live implants control)] × 100. Formaldehyde induced sperm head abnormalities at all

doses tested, which included pinhead, short hook, long hook, hook at wrong angle, unusual

head and wide acrosome; short and long hook were the most common. Only total numbers

of abnormalities were compared statistically, and only the incidence of wide acrosome was

much greater than that in controls at the lowest dose tested (46 versus 0). In general, there

was a decrease in sperm count with increasing dose of formaldehyde. A lower frequency of

fertile matings was observed in females within the first 2 weeks after treatment, and the

severity of effect was greater when mating took place earlier after treatment. The highest

dose with the shortest time between final treatment and mating had the most severe effect

and showed a dose- and time-dependent response. By 3 weeks after the last treatment, there

was no longer a difference from controls (Odeigah, 1997). Morphological changes in sperm

from mice were also identified after five daily intraperitoneal injections of 4, 10 or 30 mg/kg

bw formaldehyde. Sperm counts were decreased after 10 and 30 mg/kg bw and deformed

sperm were present after all doses (Yi et al., 2000). [The Working Group noted that, because

of the reactivity of formaldehyde, the positive results seen after intraperitoneal injection are

of questionable biological significance.]

FORMALDEHYDE 235
4.4 Genetic and related effects

The genotoxicity of formaldehyde has been reviewed extensively (IARC, 1982,

1987a; Ma & Haris, 1988; WHO, 1989; Feron et al., 1991; Monticello & Morgan, 1994;

IARC, 1995; Conaway et al., 1996; Mathison et al., 1997; Monticello & Morgan, 1997;

Bolt, 2003; Liteplo & Meek, 2003).

4.4.1 Humans 

(a) DNA–protein cross-links 

The induction of DNA–protein cross-links due to exposure to formaldehyde was

studied in humans (Shaham et al., 1996a,b, 2003) (see Table 36). The number of DNA–

protein cross-links and the amount of p53 protein, both pantropic (wild-type + mutant) and

mutant, were measured in peripheral blood lymphocytes and serum, respectively, of 399

workers from 14 hospital pathology departments, 186 of whom were exposed to formaldehyde (59 men and 127 women), and 213 control workers (127 men and 86 women) from

the administrative section of the same hospitals. The mean period of exposure to formaldehyde was 15.9 years (range, 1–51 years). The exposed group was divided into two subgroups: (1) low-level exposure (mean, 0.4 ppm [0.5 mg/m3]; range, 0.04–0.7 ppm [0.5–

0.62 mg/m3]); and (2) high-level exposure (mean, 2.24 ppm [2.75 mg/m3]; range, 0.72–

5.6 ppm [0.88–6.9 mg/m3). Before comparing the results obtained in the exposed and the

unexposed group, adjustment was made for age, sex, origin and education. The amount of

DNA–protein cross-links was expressed as a ratio to total DNA. The adjusted mean

number of DNA–protein cross-links was significantly higher (p < 0.01) in all exposed

subjects (adjusted mean, 0.21; SE, 0.006) compared with that in all unexposed subjects

(adjusted mean, 0.14; SE, 0.006). It was also significantly higher (p < 0.01) in the subgroups of exposed men (adjusted mean, 0.21; SE, 0.011) and women (adjusted mean, 0.20;

SE, 0.008) compared with that of unexposed men and women (adjusted mean, 0.15 and

0.12; SE, 0.008 and 0.008, respectively). Age, tobacco smoking habits, years of education

and origin were not significant confounders. The study population was divided into those

who had levels of pantropic p53 protein above or below 150 pg/mL. High levels of p53

(> 150 pg/mL) were more prevalent in the exposed group than in the unexposed (44.1%

and 36.3%, respectively). The difference between high and low p53 was significant among

exposed men, and exposure to formaldehyde was associated with a higher level of pantropic p53 (> 150 pg/mL). In the exposed group, a significantly (p < 0.05) higher proportion of p53 > 150 pg/mL was found among workers with DNA–protein cross-links above

the median (0.19). Studies have shown elevated serum levels of p53 protein years before

the diagnosis of malignant tumours such as lung cancer (Luo et al., 1994; Hemminki et al.,

1996). [The Working Group noted that the reported increases in p53 occurred in the serum

and its relationship to the toxicity of formaldehyde is not known.]

236 IARC MONOGRAPHS VOLUME 88
Table 36. Genetic effects of formaldehyde in humansTarget tissue End-point Response Comments Peripheral blood lymphocytes Chromosomal aberrations

MicronucleiSister chromatid exchange

+ (p < 0.01)+ (p < 0.01)+ (p < 0.05)

Exposed, 13; unexposed, 10; chaberrations included breaks and renders interpretation difficult. 

Nasal mucosa Micronuclei + (p < 0.01) Exposed, 15; unexposed (contro

concurrent exposure to wood duresponse

Peripheral blood lymphocytes Chromosomal aberrations

– Exposed, 20; unexposed (contro

frequency in controls

Peripheral blood lymphocytes DNA–protein cross-links + (p = 0.03) Exposed, 12; unexposed, 8; piloOral mucosaNasal mucosa

Micronuclei + (p = 0.007)

+ (NS)

Exposed, 28; pre- versus post-edetails on tobacco smoking hab

Peripheral blood lymphocytes Sister chromatid exchange + (p = 0.05) Exposed, 13; unexposed, 20; lin

ship between years of exposure number of sister chromatid exch

Nasal mucosaOral mucosaPeripheral blood lymphocytes

Micronuclei + (p < 0.001)

+ (p < 0.01)+ (NS)

Exposed, 25; pre- versus post-econtrol for age, sex and tobacco habits questionable

Peripheral blood lymphocytes Sister chromatid exchange

– Exposed, 23; pre- versus post-e

Nasal mucosa Micronuclei + (p < 0.01) Exposed, 23; unexposed, 25; no 

response
Table 36 (contd) Target tissue End-point Response Comments Oral mucosa Micronuclei + (p < 0.05) Exposed: 22 variable exposure

to formaldehyde; unexposed, 2(control), 18; correlation with dexposure only in group with vasures (not exposed to formaldeh

Peripheral blood lymphocytes Sister chromatid exchange + (p < 0.01) Exposed, 90; unexposed, 52; no 

response relationship 

Peripheral blood lymphocytes Serum DNA–protein cross-links p53 protein + (p < 0.01) + (p < 0.01) Exposed, 186; unexposed, 213; 

of p53 protein 

NS, not significant
(b) Chromosomal effects

The effects of formaldehyde on the frequencies of chromosomal aberrations and sister

chromatid exchange in peripheral blood lymphocytes and micronuclei in nasal mucosa

cells from workers exposed to formaldehyde have been reviewed previously (IARC,

1987a, 1995). Since that time, several further studies have assessed the induction of

micronuclei, chromosomal aberrations and sister chromatid exchange in workers exposed

to formaldehyde (see Table 36).

In a study of exposure to formaldehyde in a factory that manufactured wood-splinter

materials, short-term cultures of peripheral lymphocytes were examined from a group of

20 workers (10 men and 10 women) aged 27–57 years (mean, 42.3 years) who were

exposed to 8-h TWA concentrations of 0.55–10.36 mg/m3 formaldehyde for periods of

5–≥ 16 years. The unexposed group consisted of 19 people [sex and age unspecified] who

were employed in the same plant and whose habits and social status were similar to those

of the exposed group. No significant difference was observed between control and exposed

groups with respect to any chromosomal anomaly (including chromatid and chromosome

gaps, breaks, exchanges, breaks per cell, percentage of cells with aberrations) scored in the

study (controls: 3.6% aberrant cells, 0.03 breaks per cell; exposed: 3.08% aberrant cells,

0.045 breaks per cell). The authors noted that the frequency of aberrations in the control

group was higher than that seen in the general population (1.2–2% aberrant cells) (Vargová

et al., 1992). [The Working Group noted that, although the text states that there were 20

people in the exposed group, Table II of the paper gives a figure of 25. The Group also

noted the lack of detail on tobacco smoking habits of the subjects.]

In the study of Ballarin et al. (1992), the frequency of micronuclei in respiratory nasal

mucosa cells was investigated in 15 nonsmokers who were exposed to formaldehyde in a

plywood factory. Mean exposure levels were 0.1–0.39 mg/m3, with simultaneous exposure

to wood dust at a very low level (about one tenth below the threshold limit value). At least

6000 cells from the nasal turbinate area from each individual were scored for micronuclei.

A significant increase in the incidence of micronucleated cells was seen in the exposed

group (mean percentage of micronucleated cells in the exposed group, 0.90 ± 0.47; range,

0.17–1.83; in controls, 0.25 ± 0.22; range, 0.0–0.66; Mann–Whitney U test, p < 0.01). No

dose–response relationship between exposure to formaldehyde and the frequency of micronuclei was found. Concurrent exposure to wood dust could have contributed to the

increased incidence of micronucleated cells seen in the exposed group.

Burgaz et al. (2001) studied the frequency of micronuclei in cells of the nasal mucosa

of 23 individuals (11 women and 12 men) who were exposed to formaldehyde in pathology and anatomy laboratories and 25 healthy men who were not exposed to formaldehyde.

The mean age of the exposed group was lower than that of the controls (mean ± SD,

30.56 ± 5.52 and 35.42 ± 9.63 years, respectively). More smokers were included in the

control group (n = 19) than in the exposed group (n = 9). Mean duration of exposure to

formaldehyde was 5.06 years (range, 1–13 years). From each individual, 3000 cells were

scored for micronuclei. The mean frequency of micronuclei was significantly higher

FORMALDEHYDE 239
(p < 0.01) in the exposed group than in the control group (mean ± SD, 1.01 ± 0.62‰ and

0.61 ± 0.27‰, respectively). No significant difference in the mean frequency of micronuclei was observed between smokers and nonsmokers in the controls or in the exposed

group (p > 0.05), but significantly higher (p < 0.01) mean frequencies of micronuclei were

found in unexposed than in exposed smokers (1.18 ± 0.47‰ and 0.63 ± 0.29‰, respectively). No significant difference in the mean frequency of micronuclei was observed

between men and women in the exposed group. The air concentration of formaldehyde was

2 ppm [2.4 mg/m3] in the breathing zone of the pathology laboratory workers and 4 ppm

[4.9 mg/m3] in that of the anatomy laboratory workers. No dose–response was found

between years of exposure and the frequency of micronuclei. 

In another study, Burgaz et al. (2002) compared the frequency of micronuclei in buccal

cells in three groups: group I, 22 workers (all men) from a shoe factory who were exposed

to n-hexane, toluene and methyl ethyl ketone; group II, 28 workers (15 men and 13 women)

who were pathologists or staff in pathology or anatomy laboratories and were exposed to

formaldehyde; and group III, 18 unexposed workers (controls), none of whom had been

occupationally exposed to potential genotoxic chemicals. The mean duration of exposure to

formaldehyde was 4.7 ± 3.33 years (range, 1–13 years). Both exposed and control groups

included smokers, most of whom were moderate smokers. There were no significant differences in mean age and smoking habits between the controls and the exposed groups. From

each individual, 3000 cells were scored for micronuclei. The concentration of formaldehyde

in the breathing zone of the laboratory workers was 2–4 ppm [2.4–4.9 mg/m3]. A significant

increase in the frequency of micronucleated cells (p < 0.05) was seen in the exposed groups

(mean ± SD for workers in group I, group II and controls, 0.62 ± 0.45%, 0.71 ± 0.56% and

0.33 ± 0.30%, respectively). Analysis of variance indicated that only occupational exposure,

but not smoking habits or sex, was associated with an increased frequency of micronuclei in

groups I and II (p < 0.05). Duration of exposure was significantly associated with the frequency of micronuclei only in group I who were not exposed to formaldehyde (p < 0.05). 

Titenko-Holland et al. (1996) assessed the induction of micronuclei in exfoliated buccal

and nasal cells from 28 mortality science students who were exposed to embalming fluid

that contained formaldehyde. The original study population included 35 students (seven

women and 24 men [specifications of the additional four subjects not given]). Seven were

excluded. The students were mainly nonsmokers. Previously unstained and unanalysed

slides from the participants in a study by Suruda et al. (1993) were used. Each student was

sampled before and after the 90-day embalming class. Exposure to formaldehyde was estimated for the 7–10 days before the post-exposure sample in order to correct for the possibility of exposure misclassification. The mean exposure to formaldehyde for the 19 subjects

who had data on buccal cell micronuclei was 14.8 ± 7.2 ppm–h [18.2 ± 8.8 mg/m3–h] for

the entire 90-day period and 1.2 ± 2.1 ppm–h [1.5 ± 2.6 mg/m3–h] for the 7–10 days before

the post-exposure sample. For the 13 subjects who had data on nasal cell micronuclei, the

mean exposure to formaldehyde was 16.5 ± 5.8 ppm–h [20.3 ± 7.1 mg/m3–h] for the entire

90-day period and 1.9 ± 2.5 ppm–h [2.3 ± 3 mg/m3–h] during the 7–10 days before the postexposure sampling. Air samples of glutaraldehyde, phenol, methanol and isopropanol

240 IARC MONOGRAPHS VOLUME 88
revealed undetectable or very low exposure below the Occupational Safety and Health

Administration permissible exposure limits. Quantification of micronuclei was performed

by fluorescent in-situ hybridization with a centromeric probe. The mean total frequency of

micronuclei was significantly increased in the buccal mucosa (mean ± SD per 1000 epithelial cells, 0.6 ± 0.5 pre-exposure, 2.0 ± 2.0 post-exposure; Wilcoxon rank sum test twotailed p = 0.007), whereas in nasal cells, it was almost the same (2.0 ± 1.3 and 2.5 ± 1.3, respectively; Wilcoxon rank sum test two-tailed p = 0.2). Cells with multiple micronuclei were

present only in buccal cell samples after exposure to embalming fluid, while in the nasal cell

samples, nearly all cells with micronuclei had only one micronucleus per cell in both preand post-exposure samples. A weak statistical association (assessed by a Spearman rank

order correlation) between cumulative exposure to embalming fluid (90 days) and the

change in total micronucleus frequency was observed only in buccal cells (r = 0.44;

p = 0.06). The authors suggested that the main mechanism of micronucleus induction by

formaldehyde is due to chromosome breaks.

The frequency of micronuclei in cells of the nasal mucosa, oral mucosa and lymphocytes was evaluated for 25 students (13 men and 12 women; average age, 18.8 ± 1.0 years;

all nonsmokers) from anatomy classes. The duration of the anatomy classes was 3 h, three

times a week for a period of 8 weeks. The TWA concentrations (mean ± SD) of exposure

during the anatomy classes and in the dormitories were 0.508 ± 0.299 mg/m3 (range,

0.071–1.284 mg/m3) and 0.012 ± 0.0025 mg/m3 (range, 0.011–0.016 mg/m3), respectively.

Samples of nasal and oral mucosa cells and venous blood were taken before the beginning

of the first class and after the end of the last class, so that every student served as his/her

own control. A significant difference (paired t-test p < 0.001) was found in the mean frequency of micronuclei in the nasal and oral mucosa (mean ± SD per 1000 cells): 1.2 ± 0.67

versus 3.84 ± 1.48 (paired t-test, p < 0.001) and 0.568 ± 0.317 versus 0.857 ± 0.558 (paired

t-test p < 0.01), respectively. The mean frequency of micronuclei in lymphocytes was higher

after exposure (1.11 ± 0.543) than before exposure (0.913 ± 0.389), but this difference was

not significant (Ying et al., 1997). [The Working Group noted that there were no data related

to the possible influence of factors such as age, sex and smoking on the results.]

He et al. (1998) studied the frequency of sister chromatid exchange, chromosomal

aberrations and micronuclei in peripheral blood lymphocytes of 13 students from an anatomy class. The duration of the anatomy classes was 10 h per week for 12 weeks. Average

exposure to formaldehyde (from breathing-zone air samples) during dissection

procedures was 2.37 ppm [3.17 mg/m3]. The unexposed group included 10 students. The

sex and age of the two groups were similar and all were nonsmokers. The mean frequency

of micronuclei and chromosomal aberrations in the exposed group was significantly

higher (p < 0.01) than that in the control group (6.38 ± 2.50‰ versus 3.15 ± 1.46‰ and

5.92 ± 2.40% versus 3.40 ± 1.57%, respectively). The main types of chromosomal aberration in the exposed group were chromatid breakages and gaps. A significantly higher

(p < 0.05) frequency of sister chromatid exchange was observed in the exposed students

(5.91 ± 0.71/cell) than in the controls (5.26 ± 0.51/cell). A correlation between micronuclei and chromosomal aberrations was observed. [The Working Group noted that the

FORMALDEHYDE 241
evaluation of chromosomal aberrations included chromosomal breaks and gaps together,

which makes the results difficult to interpret. In addition, the baseline frequencies of sister

chromatid exchange and micronuclei in the controls were unusually low.] 

Ying et al. (1999) studied the frequency of sister chromatid exchange in peripheral

blood lymphocytes of 23 students from an anatomy class (11 men and 12 women), all of

whom were nonsmokers. The duration of the anatomy classes was 3 h, three times a week

for 8 weeks. Peak exposure was during cadaver dissection. TWA (mean ± SD) concentrations of formaldehyde were 0.508 ± 0.299 mg/m3 (range, 0.071–1.284 mg/m3) in the

laboratory rooms compared with 0.012 ± 0.0025 mg/m3 (range, 0.011–0.016 mg/m3) in the

dormitories. Blood samples were taken at the beginning of the anatomy classes and again

after 8 weeks. No significant difference was found in the mean frequency of sister chromatid exchange before and after exposure, either in the total population (6.383 ± 0.405 versus

6.613 ± 0.786, respectively) or in the subgroups of men and women.

In a pilot study, Shaham et al. (1997) studied the frequency of sister chromatid

exchange in the peripheral blood lymphocytes of 33 workers, including 13 from a pathology institute who were exposed to formaldehyde and 20 unexposed controls. The mean

age of the exposed workers was 42 ± 10 years and that of the control group was 39 ± 14

years. The range of concentrations of formaldehyde was 1.38–1.6 ppm [1.7–2 mg/m3] in

the rooms and 6.9 ppm [8.5 mg/m3] in the laminar flow. Personal samples showed a range

of 2.8–3.1 ppm [3.5–3.7 mg/m3] formaldehyde at the period when most of the work was in

progress and 1.46 ppm [1.8 mg/m3] at midday, when most of the work had already been

carried out. In order to score sister chromatid exchange, cells that had 44–48 clearly visible

chromosomes were examined and the sister chromatid exchange count was normalized to

the frequency expected for 46 chromosomes. The mean numbers of cells scored per individual were 28 for the exposed group (range, 25–32; SD, 2.36) and 32 for the controls

(range, 25–34; SD, 2.0). A significant difference (p = 0.05) was found between the mean

number of sister chromatid exchanges per chromosome in the exposed workers

(mean ± SD, 0.212 ± 0.039) and the controls (mean ± SD, 0.186 ± 0.035). A significant

difference (p < 0.05) was found between the mean number of sister chromatid exchanges

per chromosome of nine exposed and six unexposed nonsmokers and those of three

exposed and two unexposed smokers. The group of smokers who were exposed to formaldehyde had the highest mean number of sister chromatid exchanges per chromosome, and

a linear relationship was reported between years of exposure and the mean number of sister

chromatid exchanges per chromosome. 

In a second study, Shaham et al. (2002) evaluated the frequency of sister chromatid

exchange in peripheral blood lymphocytes of pathology staff exposed to formaldehyde

compared with that in unexposed workers. The study population included 90 workers

(25 men and 65 women) from 14 hospital pathology departments who were exposed to

formaldehyde (mean age, 44.2 ± 8.5 years) and 52 unexposed workers (44 men and

eight women) from the administrative section of the same hospitals (mean age, 41.7 ± 11.4

years). Tobacco smoking habits did not differ significantly between the study groups.

The exposed group was divided into two subgroups according to levels of exposure to

242 IARC MONOGRAPHS VOLUME 88
formaldehyde (low-level exposure: mean, 0.4 ppm [0.5 mg/m3]; range, 0.04–0.7 ppm

[0.05–0.86 mg/m3]; high-level exposure: mean, 2.24 ppm [2.8 mg/m3]; range, 0.72–

5.6 ppm [0.9–6.9 mg/m3]). The mean duration of exposure to formaldehyde was 15.4 years

(range, 1–39 years). The results on the frequency of sister chromatid exchange were

expressed in two variables: (a) mean number of sister chromatid exchanges per chromosome; and (b) proportion of high-frequency cells (namely, the proportion of cells with

more than eight sister chromatid exchanges). A high correlation between these two

variables (rs = 0.94; p < 0.01) was found in the study population and in each of the two

subgroups (exposed rs = 0.79; p < 0.01; unexposed rs = 0.92; p < 0.01). Before the results

obtained from the exposed and the unexposed groups were compared, adjustment was

made for age, sex, origin, education and tobacco smoking. The adjusted mean number of

sister chromatid exchanges per chromosome was significantly higher (p < 0.01) among the

exposed group (0.27; SE, 0.003) than the unexposed group (0.19; SE, 0.004). The adjusted

mean of the proportion of high-frequency cells was also significantly higher (p < 0.01)

among the exposed group (0.88; SE, 0.01) than the controls (0.44; SE, 0.02). After adjustment for potential confounders, the adjusted mean of the two variables of sister chromatid

exchange were similar for the two periods of exposure (up to 15 years and more than

15 years). Tobacco smoking was found to be a significant confounder. With regard to

levels of exposure, both variables of sister chromatid exchange were similar in the lowand high-level exposure subgroups. However, among smokers, both variables of sister

chromatid exchange were higher in the high-exposure subgroup than in the low-exposure

subgroup. 

(c) DNA repair 

Hayes et al. (1997) studied the effect of formaldehyde on DNA repair capacity by

assessing the activity of O6-alkylguanine–DNA alkyltransferase (AGT), which was found

to be involved in the repair of DNA damage due to exposure to formaldehyde in vitro. AGT

activity was measured in peripheral blood lymphocytes of 23 mortuary science students

(seven women and 16 men), of whom 17 were nonsmokers and six were smokers. Blood

samples were taken before the beginning of the course and after 9 weeks of practice. The

number of embalmings that the students experienced varied, both before and during the

course. The average air concentration of formaldehyde during embalming was about

1.5 ppm and, during some peak exposures, was three to nine times that of the corresponding TWA. Measurements of glutaraldehyde and phenol were below the limit of detection.

Total exposure to formaldehyde during the study period, including embalming carried out

outside the school, was within the range of 5.7–82.0 ppm–h [7–100 mg/m3–h] (mean ± SD,

18.4 ± 15.6 ppm [22.5 ± 19.2 mg/m3]). The total number of embalmings was correlated

with the estimated total exposure to formaldehyde (r = 0.59; p < 0.01). Students who had

had previous experience of embalming had greater estimated exposure to formaldehyde

during the study period (p < 0.05), and their DNA repair capacity at baseline was reduced

(p = 0.08). No exposure–response relationship was found between the number of embalmings during the 90 days before the course and the AGT activity (r = –0.29; p = 0.19). Sex,

FORMALDEHYDE 243
age and tobacco smoking were not clearly related to pre-exposure DNA repair activity.

Post-exposure and pre-exposure AGT activity were correlated (r = 0.42; p < 0.05). At the

end of the course, a reduction in DNA repair capacity was found in 17 students and an

increase in DNA repair capacity in six (p < 0.05). These findings were confirmed after analysis of variance, including adjustment for age, sex and tobacco smoking status. Among the

eight students who had no embalming experience during the 90 days before the study,

seven (88%) had decreased and only one had increased AGT activity during the study

period (p < 0.05). Of the 15 students who had had previous embalming experience, 10

(67%) had decreased and five (33%) had increased AGT activity (p > 0.05). No relation

was found between the extent of the decrease in AGT activity and the levels of exposure to

formaldehyde throughout the 9-week study period or during the last 28 days. As was also

noted by the authors, the limitation of the study was the small study population and the fact

that many of the students had previous embalming experience. 

Schlink et al. (1999) studied the activitity of the DNA repair enzyme, O6-methylguanine−DNA methyltransferase (MGMT). The study population included 57 medical

students from two universities who were exposed to formaldehyde during anatomy

courses. Blood samples of 41 students from the first university were collected before

(day 0, control group No. 1), during (day 50) and after (day 111) the course, which lasted

111 days; two 3-h courses were held per week. Additional blood samples from 16 students

from the second university were taken at the end of their course, namely 98 days after the

start, and an additional 10 blood samples were taken from unexposed students (control

group No. 2). The first group of 41 students was exposed to levels of formaldehyde

between 0.14 mg/m3 and 0.3 mg/m3 (mean ± SD, 0.2 ± 0.05 mg/m3). The mean MGMT

activity (± 95% CI) was 133.2 ± 14.9 fmol MGMT/106 cells. No significant difference was

observed before and after 50 days of exposure or after 111 days of exposure. Age, sex, cigarette smoking, alcohol consumption and allergic disease had no influence on MGMT activities in either the exposed group or the controls. The exposure level of the second group

of 16 students was 0.8 ± 0.6 mg/m3. No significant difference in MGMT activity was

observed between this exposed group and the controls (146.9 ± 22.3 fmol MGMT/106 cells

and 138.9 ± 22.1 fmol MGMT/106 cells, respectively). In addition, the activity of MGMT

of students at the second university who were exposed to a higher level of formaldehyde

than those at the first university was not statistically significant from that of control group

No. 1, and very similar results were obtained in both control groups. 

(d) Urinary mutagenicity

Hospital autopsy service workers in Galveston, TX (USA) (15 men and four women),

aged < 30–> 50 years, and a control group from the local medical school (15 men and five

women), who were in the same age range and were matched for consumption of tobacco,

marijuana, alcohol and coffee, were studied for urinary mutagenicity (Connor et al., 1985).

Individuals were sampled three times at approximately 2-month intervals. The TWA exposures to formaldehyde in the work areas were estimated to be 0.61–1.32 ppm [0.73–

1.58 mg/m3]. Urine (150–200 mL from each subject) was treated with β-glucuronidase and

244 IARC MONOGRAPHS VOLUME 88
passed through an XAD-2 column, which was then washed with water. The fraction that

eluted with acetone was assayed for mutagenicity in Salmonella typhimurium TA98 and

TA100 in the presence and absence of an exogenous metabolic activation system from the

livers of Aroclor-1254-induced rats. No increase in mutagenicity was seen in the autopsy

workers compared with the control group.

4.4.2 Experimental systems

(a) DNA–protein cross-links

(i) In-vitro studies

Formaldehyde induces DNA–protein cross-links in animal and human cells in vitro

(see Table 37). The precise nature of these cross-links is unknown. 

(ii) In-vivo studies in animals

Groups of four male Fischer 344 rats were exposed for 6 h to 0.3, 0.7, 2, 6 or 10 ppm

[0.37, 0.9, 2.4, 7.4 or 12.3 mg/m3] [14C]formaldehyde in a nose-only inhalation chamber.

Individual male rhesus monkeys (Macaca mulatta) were exposed for 6 h to 0.7, 2 or

6 ppm [14C]formaldehyde in a head-only inhalation chamber. DNA–protein cross-links

induced by exposure to formaldehyde were measured in the nasal mucosa of several

regions of the upper respiratory tract of exposed animals. The concentrations of crosslinks increased non-linearly with the airborne concentration in both species, but those in

the turbinates and anterior nasal mucosa were significantly lower in monkeys than in rats.

Cross-links were also formed in the nasopharynx and trachea of monkeys, but were not

detected in the sinus, proximal lung or bone marrow. The authors suggested that the differences between the species with respect to DNA–protein cross-link formation may be due

to differences in nasal cavity deposition and in the elimination of absorbed formaldehyde

(Heck et al., 1989; Casanova et al., 1991).

In order to determine whether the yields of DNA–protein cross-links after chronic and

acute exposures are equivalent and to locate the site of DNA–protein cross-links and of

DNA replication in the rat nasal respiratory mucosa in relation to tumour incidence,

groups of rats were exposed (whole body) to concentrations of 0.7, 2, 6 or 15 ppm [0.8,

2.4, 7.4 or 18.5 mg/m3] unlabelled formaldehyde for 6 h per day on 5 days per week for

11 weeks and 4 days (pre-exposed rats) while other groups were exposed to room air

(naive rats). On day 5 of week 12, the pre-exposed and naive rats were simultaneously

exposed (nose only) for 3 h to [14C]-labelled formaldehyde at the same concentrations as

those used for pre-exposure to quantitate the acute yield of DNA–protein cross-links and

to measure cell proliferation in specific sites of the nose. Alternatively, in order to determine the cumulative yield of DNA–protein cross-links in comparison with unexposed

rats, rats that were pre-exposed to 6 or 10 ppm formaldehyde and naive rats that were

exposed to room air were simultaneously exposed for 3 h to the same concentration of

unlabelled formaldehyde on day 5 or at week 12. The cumulative yield of DNA–protein

cross-links was measured immediately after exposure. Nasal mucosal DNA was extracted

FORMALDEHYDE 245
from proteins, and the percentage of interfacial DNA (an indicator for the concentration

of DNA–protein cross-links) was determined. The percentage of interfacial DNA was also

determined in a group of unexposed rats. Increases in the percentage of interfacial DNA,

namely, decreases in the extractability of DNA from proteins in the exposed rats, was

found by the authors to correlate highly with the yield of DNA–protein cross-links

(Casanova-Schmitz et al., 1984b). The amount of [14C] incorporation into DNA was an

indicator of cell replication. Comparison of cell replication rates in the lateral meatus with

those in the medial and posterior meatus showed no significant difference at 0.7 and

2 ppm formaldehyde, but this difference became significant at 6 and 15 ppm formaldehyde in pre-exposed rats (p ≤ 0.02, Scheffé’s test). At 6 and 15 ppm formaldehyde, a

significantly (p ≤ 0.01, Scheffé’s test) greater amount of [14C] was incorporated into the

DNA in the lateral meatus of pre-exposed rats compared with naive rats and, at 15 ppm,

into the DNA in the medial and posterior meatus of pre-exposed rats compared with naive

rats. The acute yield of DNA–protein cross-links increased non-linearly with concentrations and, in naive rats, was approximately sixfold greater in the lateral than in the medial

and posterior meatus at all concentrations. At 0.7 and 2 ppm, the acute yield was not significantly different between naive and pre-exposed rats. However, at both 6 and 15 ppm

formaldehyde, a greater acute yield of DNA–protein cross-links was found in the lateral

meatus of naive rats than in that of pre-exposed rats, a difference that was significant at

15 ppm formaldehyde (p = 0.028, paired t test). Based on histopathological evidence, this

difference can be attributed to an increase in the quantity of DNA due to an increase in the

number of cells in the nasal mucosa of the lateral meatus at high concentrations, which

results in a dilution of the DNA–protein cross-links. No significant difference was found

between naive and pre-exposed rats in relation to acute yield of DNA–protein cross-links

in the medial and posterior meatus at any concentration of formaldehyde. Since measurement of the percentage of interfacial DNA does not require the use of [14C]formaldehyde,

this parameter was used to investigate whether DNA–protein cross-links accumulated

during subchronic, whole-body exposure to formaldehyde. The percentage of interfacial

DNA following acute exposure (3-h nose-only exposure) to formaldehyde increased

significantly (p < 0.02, Scheffé’s test) at 6 and 10 ppm. However, at these levels, the

percentage of interfacial DNA was lower in pre-exposed rats than in naive rats, a difference that was significant at 10 ppm formaldehyde (p = 0.01, Scheffé’s test). The authors

suggested that the cumulative and acute yields of DNA–protein cross-links in rats exposed

to formaldehyde are essentially identical (Casanova et al., 1994). [The Working Group

noted that there is doubt about the adequacy of the methods that use interfacial DNA to

detect DNA–protein cross-links; the connection between DNA yield needs to be

clarified.] 

246 IARC MONOGRAPHS VOLUME 88
Table 37. Genetic and related effects of formaldehyde in experimental systems and anim

Resulta Test systemWithoutexogenous metabolicsystem

Withexogenousmetabolicsystem

Doseb (LED/HI

Misincorporation of DNA bases into synthetic polynucleotides

in vitro

+ NT 30 

pUC13 plasmid DNA bound to calf-thymus histones, DNA–protein

cross-links

+ NT 0.0075 

Escherichia coli PQ37, SOS repair test, DNA strand breaks,

cross-links or related damage

+ NT 20 

Escherichia coli K12 (or E. coli DNA), DNA strand breaks,

cross-links or related damage; DNA repair

+ NT 60 

Escherichia coli K12, DNA strand breaks, cross-links or related

damage; DNA repair

+ NT 600 

Escherichia coli K12 KS160-KS66 polAI, differential toxicity

+ NT 60 

Escherichia coli polA+/W3110 and polA– p3478, differential

toxicity (spot test)

+ NT 10 μL of pure 

substance

Salmonella typhimurium TA100, TA1535, TA1537, TA1538,

TA98, reverse mutation

–

– 60 μg/plate 

Salmonella typhimurium TA100, reverse mutation

–

+ 10 μg/plate 

Salmonella typhimurium TA100, reverse mutation (+)

+ 30 μg/plate (tox

above 125 μg/p

Salmonella typhimurium TA100, reverse mutation

+

+d 9 μg/plate 

Salmonella typhimurium TA100, reverse mutation (+) NT 51 μg/platec Salmonella typhimurium TA100, reverse mutation

+ NT 6 μg/plate 

Salmonella typhimurium TA100, reverse mutation (+)

+ 3 

Salmonella typhimurium TA100, reverse mutation

+ NT 9.3 

Salmonella typhimurium TA100, TA104, reverse mutation

+

+ 6.25

–50 μg/plat

Salmonella typhimurium TA102, TA104, reverse mutation

+ NT 21 μg/platec 
Table 37 (contd) Resulta Test system Without exogenous metabolic system With exogenous metabolic system Doseb (LED/HIDSalmonella typhimurium TA102, reverse mutation + NT 10 Salmonella typhimurium TA102, reverse mutation + NT 25 μg/plate Salmonella typhimurium TA102, reverse mutation + NT 0.1–0.25 μg/platSalmonella typhimurium TA102, reverse mutation + ? 6.25–50 μg/plate Salmonella typhimurium TA1535, TA1537, reverse mutation – – 100–200 μg/platSalmonella typhimurium TA1535, reverse mutation NT –d 18 μg/plate Salmonella typhimurium TA1535, TA1537, TA1538, reverse mutation – NT 100 μg/plate Salmonella typhimurium TA98, reverse mutation + NT 12 μg/plate Salmonella typhimurium TA98, reverse mutation – (+) 10 μg/plate Salmonella typhimurium TA98, reverse mutation (+) (+) 30 μg/plate (toxi

above 100 μg/pl

Salmonella typhimurium TA98, reverse mutation NT (+)d 9 μg/plate Salmonella typhimurium TA98, reverse mutation + NT 12.5 μg/plate Salmonella typhimurium (other miscellaneous strains), reverse

mutation

– – 100 μg/plate (tox

250 μg/plate)

Salmonella typhimurium TM677, forward mutation to 8-azaguanine + + 5; 10e Salmonella typhimurium TA97, reverse mutation + NT 12 μg/platec Salmonella typhimurium TA7005 (his+), reverse mutation + NT 1.5 μg/plate Escherichia coli K12, forward or reverse mutation (gpt locus) + NT 120 Escherichia coli K12, forward or reverse mutation + NT 60 Escherichia coli K12, forward or reverse mutation + NT 18.8 
Table 37 (contd)

Resulta Test systemWithoutexogenous metabolicsystem

Withexogenousmetabolicsystem

Doseb (LED/HID

Escherichia coli WP2 uvrA, reverse mutation + NT 15 Escherichia coli WP2 uvrA (pKM101), reverse mutation + NT 12.5 μg/plate Escherichia coli WP2, reverse mutation + NT 1200 Escherichia coli WP2, reverse mutation + NT 60 Escherichia coli WP2 (pKM101), reverse mutation + NT 25 μg/plate Escherichia coli (other miscellaneous strains), reverse mutation + NT 100 Escherichia coli (other miscellaneous strains), reverse mutation + NT 900 Escherichia coli (other miscellaneous strains), reverse mutation + NT 30 Escherichia coli WP3104P, reverse mutation (+) NT 5 μg/plate Escherichia coli WP3104P, reverse mutation + NT ~2 μg/plate Saccharomyces species, DNA strand breaks and DNA repair + NT 990 Saccharomyces species, DNA strand breaks, DNA–protein cross

links or related damage 

+ NT 500 

Saccharomyces cerevisiae, gene conversion + NT 540 Saccharomyces cerevisiae, homozygosis by mitotic recombination

or gene conversion

+ NT 18.5 

Neurospora crassa heterokaryons H-12 strain, forward mutation (+) NT 250 
Table 37 (contd) Resulta Test system Without exogenous metabolic system With exogenous metabolic system Doseb (LED/HIDNeurospora crassa heterokaryons H-59 strain, forward mutation + NT 100 Neurospora crassa, reverse mutation – NT 732 Neurospora crassa, reverse mutation + NT 300 Neurospora crassa, reverse mutation – NT 300 Agaricus bisporus, Glycine max, Lycopersicon esculentum, P. americana, Pinus resinosa, Pisum sativum, Populus × eur- americana, Vicia faba, Zea mays, DNA damage + NT 3.7% solution, pH 

and 7, 37 000 μg

Plants (other), mutation + NT NG Tradescantia pallida, micronucleus formation + NT 250 ppm [250 μg/mL], 6 h Drosophila melanogaster, genetic crossing over or recombination + 1260 Drosophila melanogaster, genetic crossing over or recombination + 420 Drosophila melanogaster, genetic crossing over or recombination + 2500 Drosophila melanogaster, sex-linked recessive lethal mutations + 1000 Drosophila melanogaster, sex-linked recessive lethal mutations + 1800 Drosophila melanogaster, sex-linked recessive lethal mutations + 1260 Drosophila melanogaster, sex-linked recessive lethal mutations + 420 Drosophila melanogaster, sex-linked recessive lethal mutations + 420 Drosophila melanogaster, sex-linked recessive lethal mutations (+) 2000 Drosophila melanogaster, sex-linked recessive lethal mutations + 250 
Table 37 (contd)

Resulta Test systemWithoutexogenous metabolicsystem

Withexogenousmetabolicsystem

Doseb (LED/HI

Drosophila melanogaster, sex-linked recessive lethal mutations + 2200 Drosophila melanogaster, heritable translocation + 420 Drosophila melanogaster, heritable translocation + 2500 Drosophila melanogaster, dominant lethal mutation + 1800 Drosophila melanogaster, dominant lethal mutation + 1300 Caenorhabditis elegans, recessive lethal mutations + 700 DNA strand breaks, DNA–protein cross-links or related damage,

mouse leukaemia L1210 cells in vitro

+ NT 6 

DNA–protein cross-links, mouse leukaemia L1210 cells in vitro + NT 3.75 DNA single strand breaks, DNA–protein cross-links or related

damage, sarcoma rat cell line in vitro

+ NT 7.5 

DNA single strand breaks or related damage, rat hepatocytes

in vitro

+ NT 22.5 

DNA–protein cross-links, Chinese hamster ovary cells in vitro + NT 7.5 DNA–protein cross-links, male B6C3F1 mouse hepatocytes in vitro + NT 15 DNA–protein cross-links, Chinese hamster V79 lung fibroblast

cells in vitro

+ NT 4 

Unscheduled DNA synthesis, Syrian hamster embryo cells in vitro + NT 3 Gene mutation, Chinese hamster V79 cells, Hprt locus + NT 9 Gene mutation, Chinese hamster V79 cells, Hprt locus – NT 15 Gene mutation, mouse lymphoma L5178Y cells, Tk+/– locus in vitro NT + 24 Gene mutation, mouse lymphoma L5178Y cells in vitro + NT > 2 Sister chromatid exchange, Chinese hamster cells in vitro + NT 1 Sister chromatid exchange, Chinese hamster cells in vitro + + 3.2 
Table 37 (contd) Resulta Test system Without exogenous metabolic system With exogenous metabolic system Doseb (LED/HISister chromatid exchange, Chinese hamster cells in vitro + – 2 Sister chromatid exchange, Chinese hamster V79 cells in vitro + NT 4 Micronucleus formation, Chinese hamster V79 cells in vitro + NT 4 Chromosomal aberrations, Chinese hamster cells in vitro + NT 18 Chromosomal aberrations, Chinese hamster cells in vitro + + 6.3 Cell transformation, C3H10T1/2 mouse cells +f NT 0.5 DNA single strand breaks, DNA–protein cross-links, human bronchial cells in vitro + NT 24 DNA single strand breaks, DNA–protein cross-links or related damage, human bronchial and skin cells in vitro + NT 3 DNA single strand breaks, DNA–protein cross-links or related damage, human bronchial cells in vitro + NT 3 DNA single strand breaks, DNA–protein cross-links or related

damage, human bronchial cells in vitro

+ NT 3 

DNA strand breaks, cross-links or related damage, human

fibroblast cells in vitro

+ NT 3 

DNA strand breaks, DNA–protein cross-links or related damage,

human lymphoblast cells in vitro

+ NT 1.5 

DNA strand breaks, DNA–protein cross-links or related damage,

human bronchial cells in vitro

+ NT 12 

DNA–protein cross-links, human fibroblasts in vitro + NT 7.5 DNA–protein cross-links, human white blood cells in vitro + NT 3 DNA–protein cross-links, EBV-BL human lymphoma cells in vitro + NT 37 × 18 h 
Table 37 (contd)

Resulta Test systemWithoutexogenous metabolicsystem

Withexogenousmetabolicsystem

Doseb (LED/HI

DNA double-strand breaks, human lung epithelial (A549) cells

in vitro

+ NT 30 (8, 24, 72 h) 

DNA–protein cross-links, Comet assay, human gastric mucosa

cells in vitro

+ NT 30 

DNA–protein cross-links, human lymphocytes in vitro + – 3 DNA repair exclusive of unscheduled DNA synthesis, human

bronchial and skin cells in vitro

+ NT 6 

DNA repair, human MRC5CV1 normal cell line, XP12 ROSV

cell line, GMO6914 FA cell line, in vitro

+ NT 3.75 

Unscheduled DNA synthesis, human bronchial epithelial cells

in vitro

- NT 3 (> 3 was letha

Gene mutation, human lymphoblasts TK6 line (TK locus) in vitro + NT 3.9 Gene mutation, human fibroblasts in vitro + NT 3 Gene mutation, human lymphoblasts TK6 line (TK locus) in vitro + NT 0.9 Gene mutation, human lymphoblasts TK6 line (HPRT locus)

in vitro

+ NT 4.5, 2 h, × 8 tim

Gene mutation, human lymphoblasts TK6 line (HPRT locus)

in vitro

+ NT 4.5, 2 h, × 8 tim

Gene mutation, human bronchial fibroblasts (HPRT locus) in vitro + NT 3 Sister chromatid exchange, human lymphocytes in vitro + NT 5 Sister chromatid exchange, human lymphocytes in vitro + NT 5 Sister chromatid exchange, human lymphocytes in vitro + + 3.75 Micronucleus formation, human MRC5CV1 normal cell line,

XP12 ROSV cell line, GMO6914 FA cell line, in vitro

+ NT 3.75 

Chromosomal aberrations, human fibroblasts in vitro + NT 60 
Table 37 (contd) Resulta Test system Without exogenous metabolic system With exogenous metabolic system Doseb (LED/HIDChromosomal aberrations, human lymphocytes in vitro + NT 10 Chromosomal aberrations, human lymphocytes in vitro + + 7.5 Chromosomal aberrations, premature chromosome condensation technique, human lymphocytes in vitro + NT 3.75 DNA–protein cross-links, rat respiratory and olfactory mucosa and bone marrow in vivo + 2 ppm [2.5 mg/m

6 h 

DNA–protein cross-links, rat nasal mucosa in vivo + 6 ppm [7.4 mg/m

6 h 

DNA–protein cross-links, rat respiratory mucosa in vivo + 2 ppm [2.5 mg/m

3 h 

DNA–protein cross-links, rat respiratory and olfactory mucosa and bone marrow in vivo + 2 ppm [2.5 mg/m

3 h 

DNA–protein cross-links, rat tracheal implant cells in vivo + 50 ppm [50 μg/m

instil. 

DNA–protein cross-links, rat nasal respiratory mucosa in vivo + 0.3 ppm [0.4 mg/

inhal. 6 h

DNA–protein cross-links, rhesus monkey nasal turbinate cells

in vivo

+ 0.7 ppm [0.9 mg/

inhal. 6 h

DNA–protein cross-links, rhesus monkey nasal turbinate cells

in vivo

+ 0.7 ppm [0.9 mg/

inhal. 6 h

Gene mutation, rat cells in vivo (p53 point mutations in nasal

squamous-cell carcinomas)

+ 15 ppm [18.45 

mg/m3], inhal. 6 h5 d/wk, 2 y

Mouse spot test – 15 ppm [18 mg/m

inhal. 6 h/d × 3 
Table 37 (contd)

Resulta Test systemWithoutexogenous metabolicsystem

Withexogenousmetabolicsystem

Doseb (LED/HID

Sister chromatid exchange, rat cells in vivo – 15 ppm [18.45 m

inhal. 6 h/d × 5 

Micronucleus formation, mouse bone-marrow cells in vivo – 30 ip × 1 Micronucleus formation, mouse bone-marrow cells in vivo – 25 ip × 1 Micronucleus formation, rat gastrointestinal tract in vivo + 200 po × 1 Micronucleus formation, newt (Pleurodeles waltl) in vivo – 5 μg/mL, 8 d Chromosomal aberrations, mouse bone-marrow cells in vivo – 25 ip × 1 Chromosomal aberrations, rat bone-marrow cells in vivo + 0.4 ppm [0.5 mg/

inhal. 4 h/d, 4 mo

Chromosomal aberrations, rat bone-marrow cells in vivo – 15 ppm [18.45 m

inhal. 6 h/d × 5, 8 

Chromosomal aberrations, rat leukocytes in vivo – 15 ppm [18.45 m

inhal. 6 h/d × 5

Chromosomal aberrations, mouse spermatocytes treated in vivo,

spermatocytes observed

– 50 ip × 1 

Chromosomal aberrations, mouse spleen cells in vivo – 25 ip × 1 Chromosomal aberrations, rat pulmonary lavage cells in vivo + 15 ppm [18.45 m

inhal. 6 h/d × 5
Table 37 (contd) Resulta Test system Without exogenous metabolic system With exogenous metabolic system Doseb (LED/HIDDominant lethal mutation, mouse – 20 ip × 1 Dominant lethal mutation, mouse – 20 ip × 1 Dominant lethal mutation, mouse (+) 50 ip × 1 Dominant lethal mutation, rat (+) 1.2 ppm [1.5 mg/

inhal. 4 h/d, 4 mo 

EBV, Epstein–Barr virus; BL, Burkitt lymphoma; XP, xeroderma pigmentosum; FA, Fanconi anaemia a +, positive; (+) weak positive; –, negative; NT, not tested; ?, inconclusive (variable response in several experimentb In-vitro tests, μg/mL; in-vivo tests, mg/kg bw; d, day; inhal., inhalation; instil., instillation; ip, intraperitoneal; mowk, weeks; y, yearc Estimated from the graph in the paperd Tested with exogenous metabolic system without co-factorse LED with exogenous metabolic system is 0.33 mM [10 μg/mL].f Positive only in presence of 12-O-tetradecanoylphorbol 13-acetate 
(b) Mutation and allied effects (see also Table 37)

(i) In-vitro studies

Formaldehyde induced mutation and DNA damage in bacteria, mutation, gene conversion, DNA strand breaks and DNA–protein cross-links in fungi and DNA damage in

plants. In Drosophila melanogaster, administration of formaldehyde in the diet induced

sex-linked recessive lethal mutations, dominant lethal effects, heritable translocations and

crossing-over in spermatogonia. In a single study, it induced recessive lethal mutations in

a nematode. It induced chromosomal aberrations, sister chromatid exchange, DNA strand

breaks and DNA–protein cross-links in animal cells and, in single studies, gene mutation,

sister chromatid exchange and micronuclei in Chinese hamster V79 cells and transformation of mouse C3H10T1/2 cells in vitro. Formaldehyde induced DNA–protein cross-links,

chromosomal aberrations, sister chromatid exchange and gene mutation in human cells

in vitro. Experiments in human and Chinese hamster lung cells indicate that formaldehyde

can inhibit repair of DNA lesions caused by the agent itself or by other mutagens, such as

N-nitroso-N-methylurea or ionizing radiation (Grafström, 1990; Grafström et al., 1993).

(ii) In-vivo studies in animals

Formaldehyde induces cytogenetic damage in the cells of tissues of animals exposed

either by gavage or by inhalation. Groups of five male Sprague–Dawley rats were given

200 mg/kg bw formaldehyde orally, were killed 16, 24 or 30 h after treatment and were

examined for the induction of micronuclei and nuclear anomalies in cells of the gastrointestinal epithelium. The frequency of mitotic figures was used as an index of cell proliferation. Treated rats had significant (greater than fivefold) increases in the frequency of

micronucleated cells in the stomach, duodenum, ileum and colon; the stomach was the

most sensitive, with a 20-fold increase in the frequency of micronucleated cells 30 h after

treatment, and the colon was the least sensitive. The frequency of nuclear anomalies was

also significantly increased at these sites. These effects were observed in conjunction with

signs of severe local irritation (Migliore et al., 1989).

Male Sprague–Dawley rats were exposed by inhalation to 0, 0.5, 3 or 15 ppm [0, 0.62,

3.7 or 18.5 mg/m3] formaldehyde for 6 h per day on 5 days per week for 1 and 8 weeks.

No significant increase in chromosomal abnormalities in the bone-marrow cells of formaldehyde-exposed rats was observed relative to controls, but the frequency of chromosomal

aberrations was significantly increased in pulmonary lavage cells (lung alveolar macrophages) from rats that inhaled 15 ppm formaldehyde. Aberrations, which were predominantly chromatid breaks, were seen in 8.0 and 9.2% of the scored pulmonary lavage cells

from treated animals and in 3.5 and 4.4% of cells from controls after 1 and 8 weeks, respectively (Dallas et al., 1992).

In a second in-vivo study on bone-marrow cytogenetics, Wistar rats were exposed by

inhalation to formaldehyde (0.5 or 1.5 mg/m3) every day for 4 h (except for non-working

days) for 4 months (Kitaeva et al., 1990). The concentration of 1.5 mg/m3 formaldehyde

caused diverse effects on germ cells that the authors correlated with their subsequent

studies that showed impairment of early embryonic development (see Section 4.3.2). Both

FORMALDEHYDE 257
concentrations (0.5 and 1.5 mg/m3) caused a significantly increased number of chromosomal aberrations in the bone marrow that were of the chromatid (at 0.5 mg/m3) and chromosomal (at 1.5 mg/m3) type. The number of hypoploidal and hyperploidal cells was

increased. The increase in aneuploidy was due only to chromosomal loss, not to chromosomal gain. At the higher exposure, chromosomal type aberrations were observed. [The

Working Group noted that this was the only study that evaluated bone-marrow cytogenetics. Since chromosomal loss can frequently occur as an artefact of sample preparation, these studies should be repeated.] The study showed that exposure to formaldehyde

at the lower dose was cytotoxic and mutagenic to bone-marrow cells. In an in-vitro part of

this study, exposure to 0.5 mg/m3 formaldehyde caused a decrease in the mitotic index in

bone-marrow cells while, at 1.5 mg/m3, the mitotic index was increased (Kitaeva et al.,

1990). [The Working Group noted that this is the only in-vivo study that showed positive

cytogenetic effects of formaldehyde in the bone marrow.]

(c) Mutational spectra

(i) In-vitro studies (see also Table 37 and references therein)

The spectrum of mutations induced by formaldehyde was studied in human lymphoblasts in vitro, in Escherichia coli and in naked pSV2gpt plasmid DNA (Crosby et al.,

1988). Thirty mutant TK6 X-linked HPRT– human lymphoblast colonies induced by eight

repetitive treatments with 150 μmol/L [4.5 μg/mL] formaldehyde were characterized by

southern blot analysis. Fourteen (47%) of these mutants had visible deletions of some or

all of the X-linked HPRT bands, indicating that formaldehyde can induce large losses of

DNA in human TK6 lymphoblasts. The remainder of the mutants showed normal restriction patterns, which, according to the authors, probably consisted of point mutations or

smaller insertions or deletions that were too small to detect by southern blot analysis.

Sixteen of the 30 formaldehyde-induced human lymphoblast TK6 X-linked HPRT

mutants referred to above that were not attributable to deletion were examined by southern

blot, northern blot and DNA sequence analysis (Liber et al., 1989). Of these, nine produced

mRNA of normal size and amount, three produced mRNA of normal size but in reduced

amounts, one had a smaller size of mRNA and three produced no detectable mRNA.

Sequence analyses of cDNA prepared from HPRT mRNA were performed on one spontaneous and seven formaldehyde-induced mutants indicated by normal northern blotting. The

spontaneous mutant was caused by an AT→GC transition. Six of the formaldehyde-induced

mutants were base substitutions, all of which occurred at AT base-pairs. There was an

apparent hot spot, in that four of six independent mutants were AT→CG transversions at a

specific site. The remaining mutant had lost exon 8.

In E. coli, the mutations induced by formaldehyde were characterized with the use of

the xanthine guanine phosphoribosyl transferase gene as the target gene. Exposure of

E. coli to 4 mmol/L [120 μg/mL] formaldehyde for 1 h induced large insertions (41%),

large deletions (18%) and point mutations (41%). DNA sequencing revealed that most of

the point mutations were transversions at GC base-pairs. In contrast, exposure of E. coli to

258 IARC MONOGRAPHS VOLUME 88
40 mmol/L formaldehyde for 1 h produced 92% point mutations, 62% of which were

transitions at a single AT base-pair in the gene. Therefore, formaldehyde produced different genetic alterations in E. coli at different concentrations. When naked pSV2gpt plasmid

DNA was exposed to 3.3 or 10 mmol/L [99 or 300 μg/mL] formaldehyde and used to transform E. coli, most of the resulting mutations were frameshifts that resulted from the addition or deletion of one base, which again suggests a different mechanism of mutation. 

The potential of formaldehyde to induce mutation was determined in mouse lymphoma L5178Y cells treated for 2 h with different concentrations (62.5–500 μM [1.9–

15 μg/mL]). The mouse lymphoma assay detects gross alterations as large deletions and

rearrangements. Treated cells showed a concentration-related increase in mutation frequency. While the frequency of small colonies was increased, only a marginal increase

was observed in the frequency of large colonies. The extent of loss of heterozygosity was

studied at five polymorphic markers — D11Agll, D11Mit67, D11Mit29, D11Mit21 and

D11Mit63 — all of which are equally distributed along chromosome 11. The analysis

showed increased loss of heterozygosity at the marker D11Agll, which is located in the

tirosine kinase gene. The authors suggested that the main mechanism involved in the

mutagenesis of formaldehyde in the mouse lymphoma assay is the production of smallscale chromosomal deletion or recombination (Speit & Merk, 2002).

Exposure of Chinese hamster V79 cells to formaldehyde did not induce gene mutation

at the Hprt locus, while DNA–protein cross-links, sister chromatid exchange and micronuclei were induced (Merk & Speit, 1998). Formaldehyde induced G:C→T:A transversion

in E. coli Lac+ WP3104P and in S. typhimurium His+ TA7005 (Ohta et al., 1999, 2000).

Specific locus mutations at two closely linked loci in the adenine-3 (ad-3) region were

compared in two strains of Neurospora crassa (H-12, a DNA repair-proficient heterokaryon; and H-59, a DNA repair-deficient heterokaryon) exposed to formaldehyde. The

majority (93.2%) of formaldehyde-induced ad-3 mutations in H-12 resulted from gene/

point mutations and only 6.8% resulted from multilocus deletion mutations. In contrast, a

greater percentage of formaldehyde-induced ad-3 mutations (62.8%) observed in H-59

resulted from multilocus deletion mutations. The distribution of ad-3 mutation in this mutational spectra is highly significantly different (p << 0.001). While formaldehyde induced

only a 12.8-fold increase in the frequency of ad-3 mutations over that which occurs spontaneously in H-12, it induced a 412-fold increase in H-59. Formaldehyde induced a 3.4-fold

higher (p << 0.001) ad-3BR/ad-3AR ratio in H-12 than in H-59. According to the authors,

these results indicated that there was a quantitative and qualitative strain difference in

formaldehyde-induced mutagenesis (de Serres et al., 1988; de Serres & Brockman, 1999).

(ii) In-vivo studies in animals

DNA sequence analysis of PCR-amplified cDNA fragments that contain the evolutionarily conserved regions II–V of the rat p53 gene was used to examine p53 mutations

in 11 primary nasal squamous-cell carcinomas induced in rats that had been exposed by

inhalation to 15 ppm [18.5 mg/m3] formaldehyde for up to 2 years. Point mutations at GC

base-pairs in the p53 complementary DNA sequence were found in five of the tumours

FORMALDEHYDE 259
(Table 38). The authors pointed out that all five human counterparts of the mutated p53

codons listed in Table 38 have been identified as mutants in a variety of human cancers;

the CpG dinucleotide at codon 273 (codon 271 in the rat) is a mutational hot spot that

occurs in many human cancers (Recio et al., 1992).

An immunohistochemical technique was used to assess the presence of p53 protein, a

marker of cell proliferation (proliferating cell nuclear antigen) and tumour growth factor-α

in the histopathological sections of the above tumours. In addition to the positive p53 immunostaining in squamous-cell carcinomas, especially in cells with keratization, p53-positive

immunostaining was also observed in preneoplastic hyperkeratotic plaques while normal

nasal mucosa immunostained negatively. A correlation was found between both the pattern

and the distribution of immunostaining of proliferating cell nuclear antigen and p53 (Wolf

et al., 1995).

Cell lines were established from the above set of squamous-cell carcinomas and, when

injected into nude mice, two of them that contained the p53 mutation were tumorigenic

while the two cell lines that contained wild-type p53 were not. The author suggested that

these findings indicate that p53 mutation occurs in the development of certain rodent nasal

squamous-cell carcinomas and that it is associated with tumorigenicity (Recio, 1997). All

the mutated p53 codons that were identified in formaldehyde-induced rat squamous-cell

carcinomas have also been found to be mutated in a variety of human cancers (for example,

rat codon 271, human codon 273). P53 is mutated in various human squamous-cell carcinomas including those of the respiratory tract, skin and oesophagus. It was suggested that

these data indicate that the development of certain human and rat squamous-cell carcinomas share a molecular change. The author proposed a possible mechanistic explanation,

which is based on the fact that the induction of nasal squamous-cell carcinomas by formal260 IARC MONOGRAPHS VOLUME 88

Table 38. DNA sequence analysis of p53 cDNA (PCR 

fragment D) from squamous-cell carcinomas of nasal 

passages induced in rats by formaldehyde 

DNA 

sequencea

Mutation (codon)b Equivalent 

human p53

codon no. 

Location in 

conserved 

region 

396C→A TTC→TTA (132) phe→leu 134 II 

398G→T TGC→TTC (133) cys→phe 135 II 

638G→T AGC→ATC (213) ser→ile 215 

812G→A CGT→CAT (271) arg→his 273 V 

842G→C CGG→CCG (281) arg→pro 283 V 

From Recio et al. (1992) a The A in the start codon is designated as base position 1. 

b The start codon ATG is designated as codon 1. 
dehyde is accompanied by cytotoxicity and inflammation followed by cell proliferation

that may induce genetic alterations.

Formaldehyde is also known to be genotoxic; a number of lesions have been proposed

to explain this genotoxic effect, including DNA–protein cross-links (reviewed in IARC,

1995). Studies on the HPRT mutation spectrum in formaldehyde-exposed human cells

revealed that 50% of the mutations are deletions, while 50% are due to point mutation at

the A:T base-pair (Liber et al., 1989). The finding of deletions as part of the formaldehyde

mutation spectrum may explain the homozygous nature of pair mutations observed in p53

in formaldehyde-induced squamous-cell carcinomas. However, there is an inconsistency

with regard to the base-pair that is found to be A:T in HPRT in human (Liber et al., 1989)

and mammalian cell lines (Graves et al., 1996) and G:C in p53 in formaldehyde-induced

squamous-cell carcinomas. The author suggested that an indirect mechanism of genotoxicity and not a direct effect of formaldehyde on the genome is involved in the carcinogenic

process of formaldehyde (Recio, 1997).

In order to evaluate transcriptional changes involved with acute exposure to formaldehyde, two groups of male Fischer 344 rats received either 40 μL distilled water or

formaldehyde (400 mM [12 mg/mL]) instilled into each nostril. Twenty-four hours after

this treatment, total RNA was extracted from the nasal epithelium to generate cDNA.

Adjusted signal intensity was obtained from image analysis of 1185 genes from samples

from four controls and three formaldehyde-treated rats. Significance analysis of microarray hybridization data using ClontechTM Rat Atlas 1.2 arrays revealed that 24/1185 genes

studied were significantly up-regulated and 22 genes were significantly down-regulated.

Ten of the most highly expressed genes for formaldehyde-treated animals included the

N-methyl-D-aspartate receptor, inducible nitric oxide synthase, macrophage inflammatory

protein 1 α and macrophage inflammatory protein 2, Wilms tumour protein homologue 1,

tumour necrosis factor ligand, methyl-CpG-binding protein 2, GABA receptor, Fos-responsive gene 1 and presomatotrophin. Of the 24 significantly up-regulated genes, six were

receptors, six were involved in extracellular cell signalling and four were oncogene/

tumour-suppressor genes, all of which are pathways that could be affected by treatment

with formaldehyde. Of the 22 significantly down-regulated genes, five were involved in

ion channel regulation and four were involved in protein turnover which suggests that an

early response to treatment with formaldehyde may be impaired ion channel function and

interruption of protein processing. Many phase I and phase II genes that regulate xenobiotic metabolism and oxidative stress — the CYP and glutathione family, respectively —

were altered in treated but not in controls rats. In order to validate the direction of gene

expression observed on the microarray, results for 10 of the differentially expressed genes

were confirmed by quantitative real-time PCR. Eight of the 10 gene expression values

were in positive agreement. No significant difference was found between formaldehydetreated and control groups in relation to the expression of apoptosis genes. However, in

comparison with the control group, the formaldehyde-treated group had a general trend of

lower levels of expression of nine apoptic genes that represent three of the major apoptosis regulation pathways, including receptor-mediated, caspase and the mitochondrialFORMALDEHYDE 261
associated bcl2 family of genes. The authors suggested that their results indicated that

exposure to formaldehyde can cause alteration in the levels of expression of genes that are

involved in several functional categories including xenobiotic metabolism, cell cycle regulation, DNA synthesis and repair, oncogenes and apoptosis (Hester et al., 2003).

4.5 Mechanistic considerations 

4.5.1 Deposition (airway deposition models)

Anatomically accurate CFD models have been applied to study the role of nasal airflow and formaldehyde flux in rats, monkeys and humans in order to achieve more accurate risk assessments (Kimbell & Subramaniam, 2001; Kimbell et al., 2002). The use of

DNA–protein cross-links as a measure of internal dose, as opposed to the use of air concentration, coupled with the use of monkey-based as opposed to rat-based predictions,

resulted in a 50-fold reduction in risk for humans (McClellan, 1995).

Using the Fischer 344 rat CFD model, a sharp anterior to posterior gradient of formaldehyde deposition in the rat nose is predicted, which agrees with observed patterns of formation of DNA–protein cross-links and effects on cell replication (Monticello et al., 1996;

Cohen Hubal et al., 1997). In another study, predictions of formaldehyde dosimetry in the

non-squamous epithelium in the rat CFD model were used to analyse the role of local flux

on the distribution of squamous metaplasia induced by 10 ppm and 15 ppm formaldehyde

(Kimbell et al., 1997). Squamous metaplasia is a useful indicator for formaldehydeinduced squamous-cell carcinoma in rodents due to its temporal relevance and consistency

(McMillan et al., 1994). Predictions obtained with the model illustrate how, as squamous

metaplasia develops, the sites of maximum absorption of formaldehyde move further back

in the nose. 

In the rhesus monkey, a CFD model of the nasal passages was used to facilitate speciesto-species extrapolation of data on the toxicity of formaldehyde (Kepler et al., 1998). As

with rats, an anterior to posterior gradient in formaldehyde deposition was predicted and a

strong correlation was observed between patterns of airflow and the occurrence of nasal

lesions.

In a comparison of Fischer 344 rats, rhesus monkeys and humans, the role of mucousand non-mucous-coated tissue on formaldehyde uptake was analysed (Kimbell et al.,

2001b). Flux values for rats and monkeys were found to be very similar at sites where the

effects of formaldehyde on cell proliferation had previously been observed. Similar flux

values were predicted in a region of the nasal passage where a high incidence of tumours

had been observed in rats and in an anterior region of the human nasal passage. It was

suggested that a similar formaldehyde-induced response in rats might be expected in

humans when regional fluxes are similar. 

CFD models of Fischer 344 rat, rhesus monkey and human nasal passages were also

used to predict patterns of wall mass flux in order to reduce the uncertainty in interspecies

extrapolation of dose within the nasal passages (Kimbell et al., 2001a). In all cases, steep

262 IARC MONOGRAPHS VOLUME 88
anterior-to-posterior gradients of formaldehyde deposition were predicted. The surface

area and average flux were estimated for the flux bins at different airflow rates. At a minute

volume of 15 L/min, approximately 20% of the surface area of the human nasal passages

had a predicted flux value greater than the median flux value. Increasing airflow in humans

was also associated with a distal shift in flux patterns and a reduced percentage of uptake

in the nasal passages. Differences across species in nasal anatomy and associated differences in flux were also suggested to play a potentially large role in the occurrence of local

adverse effects due to the non-linear relationships of flux with DNA–protein cross-links

and with cell proliferation. The adsorption of formaldehyde on inhaled particles does not

appreciably alter the patterns of formaldehyde deposition associated with the inhalation of

formaldehyde vapour (Rothenberg et al., 1989; Risby et al., 1990).

4.5.2 Metabolism

Formaldehyde is an endogenous metabolite that is formed by demethylation reactions

and used in the biosynthesis of macromolecules. Average concentrations, including bound

and free forms, in cells and biological fluids are reported to be about 0.1 mM (Heck et al.,

1985). Formaldehyde readily combines with GSH to form hydroxymethylglutathione,

which is converted to formate in a two-step enzymatic reaction that initially involves

ADH3. The Km for the initial binding of hydroxymethylglutathione with ADH3 is in the

order of 4 μM and the level of free formaldehyde is probably even lower (Holmquist &

Vallee, 1991; Uotila & Koivusalo, 1997; Hedberg et al., 1998). The half-life of formaldehyde in plasma is very short, and is approximately 1 min in rats exposed intravenously

(Rietbrock, 1965). 

4.5.3 Genotoxicity

Formaldehyde induced DNA–protein cross-links in vitro in human bronchial epithelial

cells, fibroblasts and lymphocytes, in Chinese hamster ovary cells and in non-transformed

human fibroblasts (Grafström et al., 1984; Olin et al., 1996; Shaham et al., 1996a,b). The

formation of DNA–protein cross-links showed a consistent dose–effect relationship and

was induced at concentrations of formaldehyde that allowed survival of up to 75% of the

cells (Merk & Speit, 1998, 1999). A range of half-lives for the removal of DNA–protein

cross-links from the cells has been reported (3–66 h), but most of the values are in the vicinity of 24 h (Gräfstrom et al., 1984; Merk & Speit, 1998, 1999; Quievryn & Zhitkovich,

2000). 

Several studies that compared the kinetics of the formation and removal of DNA–

protein cross-links in a variety of cell types reported no differences among normal and DNA

repair-deficient cell types (Grafström et al., 1984; Speit et al., 2000). DNA single-strand

breaks and/or alkali-labile sites are generated from the repair of formaldehyde damage in

normal cells (Grafström et al., 1984). Formaldehyde is more toxic to Xeroderma Pigmentosum cells, which also show a higher percentage of micronuclei than normal cells. The data

FORMALDEHYDE 263
suggested that neither defective nucleotide excision repair (Xeroderma Pigmentosum cells)

nor defective cross-link repair (Fanconi anaemia cells) seem to delay the removal of formaldehyde-induced DNA–protein cross-links significantly and that more than one repair pathway may be involved in the removal of cross-links (Grafström et al., 1984; Speit et al.,

2000). Human peripheral blood lymphocytes lost DNA–protein cross-links at a significantly

slower rate than established cell lines (Quievryn & Zhitkovich, 2000). Repair of formaldehyde-induced DNA–protein cross-links was not changed significantly due to loss of GSH.

Additional studies have indicated that the active removal of DNA–protein cross-links from

cells may involve proteolytic degradation of cross-link proteins (Quievryn & Zhitkovich,

2000). Several studies indicate that formaldehyde may also interfere with the processes of

repair of DNA by (a) inhibiting DNA repair enzymes, (b) inhibiting the removal of DNA

lesions and (c) altering gene expression (Grafström et al., 1996).

Assessment of DNA–protein cross-links and sister chromatid exchange in peripheral

lymphocytes from formaldehyde-exposed workers demonstrated an association with overall exposure (Shaham et al., 1996a,b, 2003). It remains unclear to what extent these endpoints contribute to the mutagenesis and carcinogenicity of formaldehyde (Recio et al.,

1992; Merk & Speit, 1998; Speit et al., 2000; Liteplo & Meek, 2003). 

Studies in humans have reported both positive and negative results for the incidence of

micronuclei in nasal and buccal mucosa in workers exposed to formaldehyde (see

Table 36). In one study of both buccal and nasal mucosa, a greater increase was observed

in centromere-negative micronuclei than centromere-positive micronuclei, which implicates chromosome breakage as the major mechanism responsible for these effects (TitenkoHolland et al., 1996). Although micronuclei are correlated with risk for cancer in animals,

the association between micronuclei and cancer in humans requires clarification because of

the high degree of inter-individual variability within the human population (Fenech et al.,

1999).

The formation of DNA–protein cross-links in the nasal respiratory mucosa of rats after

inhalation exposure to 6 ppm [7.4 mg/m3] formaldehyde and higher has been demonstrated

by a variety of techniques, including decreased extractability of DNA from proteins

(Casanova-Schmitz & Heck, 1983), double-labelling studies with [3H]- and [14C]formaldehyde (Casanova-Schmitz et al., 1984b; Casanova & Heck, 1987; Heck & Casanova, 1987)

and isolation of DNA from respiratory mucosal tissue and quantification by HPLC of formaldehyde released from cross-links after exposure to [14C]formaldehyde (Casanova et al.,

1989, 1994). The formation of DNA–protein cross-links is a non-linear function of concentration (Casanova & Heck, 1987; Casanova et al., 1989, 1994; Heck & Casanova, 1995; see

Fig. 8) and correlates with the site-specificity of tumours (Casanova et al., 1994). Crosslinks were not detected in the olfactory mucosa or in the bone marrow of rats (CasanovaSchmitz et al., 1984b; Casanova & Heck, 1987).

DNA–protein cross-links were also measured in the respiratory tract of groups of

three rhesus monkeys immediately after single 6-h exposures to airborne [14C]formaldehyde (0.7, 2 or 6 ppm [0.9, 2.4 or 7.4 mg/m3]) (Casanova et al., 1991). The concentrations of cross-linked formaldehyde in the nose of monkeys decreased in the order: middle

264 IARC MONOGRAPHS VOLUME 88
turbinates > lateral wall–septum > nasopharynx, which is consistent with the location and

severity of lesions in monkeys exposed to 6 ppm (Monticello et al., 1989). Very low

levels of cross-links were also found in the trachea and carina of some monkeys. The yield

of cross-links in the nose of monkeys was an order of magnitude lower than that in the

nose of rats, due largely to species differences in minute volume and quantity of exposed

tissue (Casanova et al., 1991; Fig. 8). A pharmacokinetic model based on these results

indicated that the concentrations of DNA–protein cross-links in the human nose would be

lower than those in the noses of monkeys and rats (Casanova et al., 1991).

In order to determine whether DNA–protein cross-links accumulate with repeated

exposure, the yield of formaldehyde from cross-links was investigated in rats that were

exposed either once or subchronically to unlabelled formaldehyde (6 or 10 ppm [7.4 or

12.3 mg/m3]) for 6 h per day on 5 days per week for 11 weeks and 4 days (Casanova et al.,

1994). The yield was not higher in pre-exposed than in naive rats, which suggests that no

accumulation had occurred in the former. The results also suggest that DNA–protein

cross-links in the rat nasal mucosa are removed rapidly.

FORMALDEHYDE 265

Figure 8. Average concentration of DNA–protein cross-links formed per unit time in

the turbinates and lateral wall/septum of Fischer 344 rats and rhesus monkeys

versus the airborne concentration of formaldehyde (CH2O) 

Adapted from Casanova et al. (1991)

All animals were exposed to formaldehyde for 6 h. Data in rats are taken from Casanova et al. (1989). (Results

obtained in rats at 10 ppm are omitted for clarity.) Dashed lines are the 95% confidence limits about the mean

for each species.
Conolly et al. (2000) described a model of tissue disposition of formaldehyde, which

included CFD and measurements of mucosal epithelial thickness in order to refine previous

predictions of the occurrence of DNA–protein cross-links in rats, monkeys and humans.

The thickness of the epithelial tissue is approximately 4.5 times greater in humans than in

rats, which results in a lesser net dose of formaldehyde in humans at concentrations that

saturate the metabolic capacity of rats (Schlosser et al., 2003). Good correlations of model

predictions and data of cross-links were obtained in association with the regions of high

and low tumour response in the rat nose (Conolly et al., 2000).

Merk and Speit (1998) evaluated the significance of DNA–protein cross-links for

mutagenesis in V79 Chinese hamster cells. Formaldehyde was seen to induce DNA–

protein cross-links, sister chromatid exchange and micronuclei in conjunction with a

reduction in relative cloning efficiency. However, no gene mutations were observed in the

Hprt test. It was concluded that DNA–protein cross-links were related to chromosomal

effects, but not directly to gene mutations.

Shaham et al. (2003) reported that the formation of DNA–protein cross-links in peripheral lymphocytes in exposed workers was associated with increased serum p53 protein,

including wild-type and mutant forms. Recio et al. (1992) found p53 point mutations in

5/11 squamous-cell carcinomas in formaldehdye-exposed rats. Studies have shown (Luo

et al., 1994; Hemminki et al., 1996) that higher levels of p53 protein are found in serum

years before the diagnosis of malignant tumours such as lung cancer. [The Working Group

felt that there may be an association, although further studies are needed to clarify the

association between DNA–protein cross-links and effects on the state of p53.]

4.5.4 Cytotoxicity and cell proliferation

Formaldehyde is well established as a toxicant at the site of contact. Following inhalation exposure, cytotoxicity was evident in the nasal passages of rats and mice (Chang

et al., 1983). Toxicity was greatest in the respiratory epithelium of rats, and the median

septum and nasoturbinates were the sites most affected. At 15 ppm [18.45 mg/m3],

necrosis and sloughing of respiratory epithelium was evident immediately after a single

6-h exposure and early hyperplasia was present 18 h after a single exposure. Mice exhibited lower toxicity in the nasal epithelium associated with reduced exposure due to

reduced minute volume. Severe ulcerative rhinitis, inflammation, epithelial hyperplasia

and increased cell proliferation were observed in rats exposed to 15 ppm formaldehyde

for 5 days (6 h per day). A second study examined cell proliferation and histopathology in

rats exposed to 0, 0.7, 2, 6, 10 or 15 ppm [0, 0.86, 2.46, 7.38, 12.3, 18.45 mg/m3] formaldehyde. Increased cell proliferation was evident at 6 and 15 ppm, but not at 2 ppm or

lower following 9 days or 6 weeks of exposure (Monticello et al., 1991).

In a mechanistic 24-month carcinogenesis bioassay with interim sacrifices at 1, 4 and

9 days, 6 weeks, and 3, 6, 12 and 18 months, increased cell proliferation was demonstrated

at all time-points in rats exposed to 6, 10 and 15 ppm (Monticello et al., 1991, 1996).

266 IARC MONOGRAPHS VOLUME 88
Monticello et al. (1996) evaluated the relationship of regional increases in nasal epithelial cell proliferation with nasal cancer in rats. Sublinear increases in both cell proliferation and squamous-cell carcinoma were observed with increasing concentration of

formaldehyde. A good correlation was observed between site-specific tumour occurrence

and the population-weighted unit length labelling index, which incorporates information

on both the rate of cell replication and the numbers of cells at specific sites. It was therefore suggested that not only the rate at which cells divided but also the size of the target

cell population that underwent DNA replication were crucial factors in the development

of formaldehyde-induced nasal squamous-cell carcinoma. Both the rate of cell division

and the number of cells in the proliferative pool are thought to increase the chance for

mutation at a given dose of formaldehyde. Monticello et al. (1996) stated that, although

there is evidence to suggest that concentration is more important than duration of exposure in determining the extent of formaldehyde-induced nasal epithelial damage, the

development of formaldehyde-induced nasal squamous-cell carcinoma probably requires

repeated and prolonged damage to the nasal epithelium. Sustained cellular proliferation,

which was seen at 6, 10 and 15 ppm, is thought to play a crucial role in carcinogenesis

through the transformation of cells with damaged DNA to mutated cells and the clonal

expansion of the mutated cell population (McClellan, 1995).

Studies of cell cultures provide some support that proliferation is stimulated after

exposure to formaldehyde (Tyihák et al., 2001). Transcription of ADH3 was associated

with proliferative states (Nilsson et al., 2004), formaldehyde and formate were shown to

serve as donors to the one-carbon pool synthesis of macromolecules and, in one study,

exposure to formaldehyde was shown to increase cell proliferation (Tyihák et al., 2001).

4.5.5 Cancer

Nasal squamous-cell carcinomas have been observed in toxicological studies of rats

exposed to concentrations of at least 6 ppm formaldehyde (Swenberg et al., 1980; Kerns

et al., 1983a,b). Epidemiological studies have also suggested increases in risk for sinonasal carcinomas and particularly for nasopharyngeal carcinoma in humans following

exposure to formaldehyde. The exact biological mechanism by which exposure to formaldehyde may cause cancer is currently unknown (Conolly, 2002; Liteplo & Meek, 2003);

however, formaldehyde causes formation of DNA–protein cross-links and increases

cellular proliferation in the upper respiratory tracts of rats and monkeys.

However, most epidemiological studies of sinonasal cancer have not distinguished

tumours that arise in the nose from 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 easily be undetectable

through the lack of statistical power.

FORMALDEHYDE 267
4.5.6 Computational dose–response modelling

A theoretical model for DNA replication in the presence of DNA cross-links was

developed by Heck and Casanova (1999). This model assumes that DNA–protein crosslinks are formed randomly in the DNA and that replication can advance up to but not past

a DNA–protein cross-link. This analysis is consistent with the experimental observation

of decreased cell proliferation in the nasal epithelium of rats exposed to concentrations of

0.7 and 2.0 ppm [0.86 and 2.46 mg/m3] formaldehyde.

A biologically based model of carcinogenesis of formaldehyde was described by

Conolly (2002), which included a two-stage clonal growth model and used the incorporation of both DNA–protein cross-links and cell proliferation, together with linked regional

dosimetry predictions, into the model to predict tumour incidence. Through inclusion of

this information, the author suggested that a smaller degree of uncertainty was associated

with the model.

Since both squamous-cell carcinoma and preneoplastic lesions develop in a characteristic site-specific pattern, Conolly et al. (2003) used anatomically accurate three-dimensional CFD models to predict the site-specific flux of formaldehyde from inhaled air into

the tissues in rats. Flux into tissues was used as a dose metric for two modes of action:

direct mutagenicity and cytolethality–regenerative cellular proliferation (CRCP). The two

modes were linked to key parameters of a two-stage model of clonal growth. The direct

mutagenic mode of action was represented by a low linear dose–response model of DNA–

protein cross-link formation. An empirical J-shaped dose–response model and a threshold

model fit to experimental data were used to describe CRCP. The J-shaped dose–response

for CRCP provided a better description of the data on squamous-cell carcinoma than the

threshold model. Sensitivity analysis indicated that the rodent tumour response is primarily due to the CRCP mode of action and the direct mutagenic pathway has little or no

influence. The study suggests a J-shaped dose–response for formaldehyde-mediated nasal

squamous-cell carcinoma in Fischer 344 rats. [The Working Group felt that uncertainty

remains on some components and parameters of this model, which can affect both predictions of risk and qualitative aspects of model behaviour, and warrants further developmental work.]

Gaylor et al. (2004) conducted an analysis of the concentration–response relationship

for formaldehyde-induced cell proliferation in rats using statistical methods designed to

identify J-shaped concentration–response curves. Such J-shaped curves demonstrate an

initial decline in response, followed by a return to background response rates at the zero

equivalent dose and then an increase above background response at concentrations above

the zero equivalent dose. This analysis demonstrated a statistically significant reduction

in cytotoxicity at concentrations below the zero equivalent dose. The authors suggested

that, at low doses, the increased risk for nasal cancer due to DNA damage may be offset

by a reduction in cell proliferation, a postulate that is consistent with the threshold-like

behaviour of the concentration–response curve observed for nasal cancer in rats. 

268 IARC MONOGRAPHS VOLUME 88
Schlosser et al. (2003) described a dose–response assessment of formaldehyde that

used a combination of benchmark dose and pharmacokinetic methods. Following the

identification of points of departure for both tumours and cell proliferation in rats by

analysis of the benchmark dose, extrapolation to humans was performed using either a

CFD model alone to predict formaldehyde flux or a CFD model in combination with a

pharmacokinetic model to predict the tissue dose and the formaldehyde-induced DNA–

protein cross-links as a dose metric. Risk predictions obtained with the benchmark dose

model are similar to earlier risk predictions obtained with previous benchmark dose

models. The benchmark dose risk predictions are substantially higher than those obtained

from the clonal growth time-to-tumour model (Liteplo & Meek, 2003). 

4.5.7 Summary of experimental data

Formaldehyde is an essential metabolic intermediate in all cells, and average concentrations in the blood of unexposed subjects has been reported to be about 0.1 mmol/L. It is

a potent nasal irritant, is cytotoxic at high doses and induces nasal cancer in rats exposed

to high airborne concentrations. Nasal squamous-cell carcinomas have been observed in

toxicological studies of rats exposed to concentrations of at least 6 ppm; the incidence of

these tumours increases sharply with further increases in concentration (Monticello et al.,

1996). In addition, at concentrations of 2 ppm or less, no histological changes have been

observed in rodents, although changes at these concentrations have been seen in humans

(IARC, 1995; Liteplo & Meek, 2003).

Early assessments estimated the risk for cancer from exposure to low concentrations

of formaldehyde using linear extrapolations from data on high concentrations in animals.

However, linear low-dose extrapolation does not account for the sublinearities in the

observed concentration–response relationship (Casanova et al., 1994; Monticello et al.,

1996; Bolt, 2003). It was suggested that the risk for cancer in humans was probably overestimated by linear low-dose extrapolation from rats at concentrations that do not increase

cell proliferation or the size of the cell population at risk (Monticello et al., 1996). Bolt

(2003) recommended that predictions of risk at low (≤ 2 ppm) versus high (≥ 6 ppm) concentrations be made separately.

Formaldehyde demonstrates positive effects in a large number of in-vitro tests for

genotoxicity, including bacterial mutation, DNA strand breaks, chromosomal aberrations

and sister chromatid exchange. Studies in humans showed inconsistent results with regard

to cytogenetic changes (micronuclei, chromosomal aberrations and sister chromatid

exchange). The frequency of DNA–protein cross-links was found to be significantly higher

in peripheral lymphocytes from exposed workers (Shaham et al., 1996, 2003).

In-vitro studies have shown that 0.1 mM [3 μg/mL] formaldehyde increases cell

proliferation without detectable cytotoxicity (Tyihák et al., 2001). Formaldehyde also

induces genetic damage at concentrations as low as 0.1 mM and inhibits DNA repair in

bronchial cells at 0.1–0.3 mM [3–9 μg/mL], although it does not appear to be associated

with oxidative stress. Formaldehyde inhibits cell growth at 0.2 mM [6 μg/mL] and 0.6 mM

FORMALDEHYDE 269
[18 μg/mL], as expressed by loss of clonal growth rate and colony-forming efficiency, respectively. It alters membrane integrity, which leads to increases in cellular Ca2+ and could

affect cell death rates by accelerating terminal differentiation (Grafström et al., 1996).

Apoptosis has been demonstrated in rat thymocytes at concentrations at or above 0.1 mM

(Nakao et al., 2003). HeLa cervical carcinoma cells have been shown to be fairly resistant

to the toxic effects of formaldehyde in comparison with untransformed human dental pulp

fibroblasts and buccal epithelial cells (Lovschall et al., 2002). In contrast, formaldehyde is

only weakly genotoxic in in-vivo tests.

Using a variety of techniques, inhalation of formaldehyde has been shown to induce

the formation of DNA–protein cross-links in nasal tissue from rats and monkeys, including

decreased extractability of DNA from proteins, labelling studies and isolation of DNA by

HPLC. The formation of DNA–protein cross-links is a non-linear function of formaldehyde concentration, described by an initial linear component with a shallow slope and a

second linear component with a steeper slope that follows a significant decrease in survival

of the cells and depletion of GSH at about 0.1 mM (Merk & Speit, 1998).

Species-specific differences in the rate of formation of DNA–protein cross-links, in the

prevalence of squamous metaplasia (McMillan et al., 1994) and in the occurrence of nasal

cancer have also been observed at given concentrations of formaldehyde in rats, mice and

monkeys (McMillan et al., 1994; McClellan, 1995). Differences in nasal anatomy and

regional airflow as well as differences in the absorptive properties of the nasal lining

between species have been suggested to influence greatly the dose of formaldehyde that

reaches different anatomical regions and subsequent formaldehyde-induced lesions at a

given exposure concentration (Kimbell et al., 1997; Kepler et al., 1998; Zito, 1999; Kimbell

et al,. 2001b; Conolly, 2002). 

Anatomically accurate CFD models have been developed to describe the nasal uptake

of formaldehyde in rats, monkeys and humans (Conolly, 2000). Interspecies differences in

formaldehyde-induced DNA–protein cross-links and nasal lesions appear to be related to

species-specific patterns in formaldehyde flux in different regions within the nasal

passages (see Fig. 9; Kimbell et al., 2001a). CFD modelling predicts anterior-to-posterior

gradients of formaldehyde deposition in the noses of rats, rhesus monkeys and humans

(Kimbell et al., 2001a). This might suggest that formaldehyde is more likely to cause

cancer of the nose than of the nasopharynx in humans.

Although formaldehyde is mainly deposited in the upper respiratory tract, the distribution of the deposition is expected to vary by species (Conaway et al., 1996; Liteplo &

Meek, 2003). The lack of parallel data on the formation of nasal mucosal DNA–protein

cross-links and on cell proliferation in humans complicates the extrapolation of the animal

data, in particular rodent data, to humans (Conolly et al., 2000; Liteplo & Meek, 2003).

The current data indicate that both genotoxicty and cytoxicity play important roles in the

carcinogenesis of formaldehyde in nasal tissues. DNA–protein cross-links provide a potentially useful marker of genotoxicity. The concentration–response curve for the formation of

DNA–protein cross-links is bi-phasic, and the slope increases at concentrations of formaldehyde of about 2–3 ppm [2.5–3.7 mg/m3] in Fischer 344 rats. Similar results have been

270 IARC MONOGRAPHS VOLUME 88
observed in rhesus monkeys, although the dose–response curve for DNA–protein crosslinks is less well defined in this species. Cellular proliferation, which appears to amplify the

genotoxic effects of formaldehyde greatly, increases considerably at concentrations of

formaldehyde of about 6 ppm [7.4 mg/m3], and results in a marked increase in the occurrence of malignant lesions in the nasal passages of rats at concentrations of formaldehyde

above this level (Monticello et al., 1996). Recent evidence suggests that cytotoxicity may

demonstrate a J-shaped concentration–response curve, with a significant reduction in cellular proliferation rates at concentrations of 0.7–2 ppm [0.86–2.5 mg/m3] (Conolly & Lutz,

2004; Gaylor et al., 2004). 

4.5.8 Leukaemia

The epidemiological evidence that formaldehyde may cause acute myelogenous leukaemia raises a number of mechanistic questions, including the processes by which inhaled

formaldehyde may reach a myeloid progenitor (Heck & Casanova, 2004). The possibility

that formaldehyde causes leukaemia is supported by the detection of cytogenetic abnormalities and an increase in the fraction of DNA–protein cross-links in circulating lymphocytes

following occupational exposure to formaldehyde, as well as chromosomal aberrations in

FORMALDEHYDE 271

Adapted from Kimbell et al. (2001a)

Low bin numbers are associated with low flux values. Inspiratory airflow rates were 0.576 L/min in rats,

4.8 L/min in monkeys and 15 L/min in humans. 

Figure 9. Allocation of nasal surface area to flux bins in rats, monkeys and humans
bone marrow in a single inhalation study in rats (Kitaeva et al., 1990, 1996; Shaham et al.,

1996a,b, 1997, 2003).

It is possible that formaldehyde itself can reach the bone marrow following inhalation,

although the evidence is inconsistent (Kitaeva et al., 1990; Dallas et al., 1992; Heck &

Casanova, 2004). The relatively rapid rate of metabolism of formaldehyde by circulating

red blood cells suggests that little if any inhaled formaldehyde could reach any tissue

beyond the respiratory tract. [The Working Group noted that a clastogenic product of

formaldehyde could conceivably be formed in the blood and circulate to the bone marrow,

although this has not been suggested in the literature. Alternatively, it is possible that circulating myeloid progenitor stem cells could be the source of leukaemia. Such stem cells are

known to be present in the blood and plausibly could be exposed to formaldehyde in the

respiratory tract vasculature; however, there is currently no known prototype for such a

mechanism of leukaemogenesis.]

Another mechanistic issue is the relation of cellular background levels of formaldehyde, as part of the one-carbon pool, to any risk from exogenous formaldehyde. Cellular

background concentrations of formaldehyde are about 0.1 mM. In one study in humans,

inhalation of 1.9 ppm [2.3 mg/m3] formaldehyde for 40 min did not alter blood concentrations (Heck et al., 1985). Elevated concentrations of formaldehyde were not observed in

the blood of rats and rhesus monkeys exposed to formaldehyde at concentrations of up to

14.4 ppm [17.7 mg/m3] (Heck et al., 1985; Casanova et al., 1988); nor were protein adducts

or DNA–protein cross-links observed in the bone marrow of rats or rhesus monkeys

exposed to formaldehyde at concentrations of up to 15 or 6 ppm [18.4 or 7.4 mg/m3], respectively (Casanova-Schmitz et al., 1984b; Heck et al., 1989). 

Known human myeloid leukaemogens include ionizing radiation, benzene and

chemotherapeutic agents such as alkylators, DNA topoisomerase inhibitors and DNAcomplexing agents. All of these agents produce overt bone marrow toxicity, including

pancytopenia and aplastic anaemia in both laboratory animals and humans. Agents known

to cause leukaemia in humans and animals are also known to induce chromosomal aberrations in peripheral lymphocytes. The absence of clear evidence of bone-marrow toxicity,

even at high doses, indicates that, if formaldehyde is a human myeloid leukaemogen, its

mechanism of action differs from those by which the known myeloid leukaemogens noted

above operate. This is not inconceivable, because there is epidemiological evidence that

butadiene and ethylene oxide are probably human leukaemogens, although neither is a

classic bone-marrow toxicant.

Studies of workers exposed to benzene and of individuals who received cancer

chemotherapy suggest that the induction period for acute myeloid leukaemia is less than

20 years, and is usually in the range of 2–15 years (Goldstein, 1990). This relatively short

lag time for carcinogenesis reflects the intrinsic biology of the myeloid progenitor cell,

irrespective of the mechanism that caused the initial cancer mutation. The epidemiological

reports that suggest an association of formaldehyde with myeloid leukaemia have not

clearly defined an induction period for the effect. 

272 IARC MONOGRAPHS VOLUME 88
[The Working Group could not identify any rodent model for acute myeloid leukaemia.

The lack of evidence of increased risk for leukaemia in long-term studies of formaldehyde

in rodents is not informative with respect to myeloid leukaemogenesis in humans. The

Working Group felt that, based on the data available at this time, it was not possible to

identify a mechanism for the induction of myeloid leukaemia in humans by formaldehyde.]

5. Summary of Data Reported and Evaluation

5.1 Exposure data

Formaldehyde is produced worldwide on a large scale by catalytic, vapour-phase oxidation of methanol. Annual world production is about 21 million tonnes. Formaldehyde is

used mainly in the production of phenolic, urea, melamine and polyacetal resins. Phenolic,

urea and melamine resins have wide uses as adhesives and binders in wood product, pulp

and paper, and synthetic vitreous fibre industries, in the production of plastics and coatings

and in textile finishing. Polyacetal resins are widely used in the production of plastics.

Formaldehyde is also used extensively as an intermediate in the manufacture of industrial

chemicals, such as 1,4-butanediol, 4,4′-methylenediphenyl diisocyanate, pentaerythritol and

hexamethylenetetramine. Formaldehyde is used directly in aqueous solution (formalin) as a

disinfectant and preservative in many applications.

Occupational exposure to formaldehyde occurs in a wide variety of occupations and

industries. The highest continuous exposures (2–5 ppm) [2.5–6.1 mg/m3] were measured in

the past during the varnishing of furniture and wooden floors, in the finishing of textiles, in

the garment industry, in the treatment of fur and in certain jobs within manufactured board

mills and foundries. Shorter-term exposures to high levels (3 ppm and higher) [3.7 mg/m3

and higher] have been reported for embalmers, pathologists and paper workers. Lower

levels have usually been encountered during the manufacture of man-made vitreous fibres,

abrasives and rubber, and in formaldehyde production industries. 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 ventilation have

resulted in decreased levels of exposure in many industrial settings in recent decades.

Formaldehyde occurs as a natural product in most living systems and in the environment. In addition to these natural sources, common non-occupational sources of exposure

include vehicle emissions, particle boards and similar building materials, carpets, paints

and varnishes, food and cooking, tobacco smoke and the use of formaldehyde as a disinfectant. Levels of formaldehyde in outdoor air are generally below 0.001 mg/m3 in remote

areas and below 0.02 mg/m3 in urban settings. The levels of formaldehyde in the indoor air

of houses are typically 0.02–0.06 mg/m3. Average levels of 0.5 mg/m3 or more have been

measured in ‘mobile homes’, but these have declined since the late 1980s as a result of

standards that require that building materials emit lower concentrations of formaldehyde.

FORMALDEHYDE 273
5.2 Human data

Nasopharyngeal cancer

Since the last monograph on formaldehyde (in 1995), the follow-up of three major

cohort studies has been extended and three new case–control studies have been published.

In the largest and most informative cohort study of industrial workers exposed to

formaldehyde, a statistically significant excess of deaths from nasopharyngeal cancer was

observed in comparison with the US national population, with statistically significant

exposure–response relationships for peak and cumulative exposure. An excess of deaths

from nasopharyngeal cancer was also observed in a proportionate mortality analysis of the

largest US cohort of embalmers and in a Danish study of proportionate cancer incidence

among workers at companies that used or manufactured formaldehyde. In three other

cohort studies of US garment manufacturers, British chemical workers and US embalmers,

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.

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 exposure categories, including one in

which the increase in risk was statistically significant; three studies (two of which have

been published since the last monograph) found higher risks among subjects who had the

highest probability, level or duration of exposure.

The most recent meta-analysis, which was published in 1997, included some but not all

of the above studies and found an increased overall meta-relative risk for nasopharyngeal

cancer.

The Working Group considered it improbable that all of the positive findings for nasopharyngeal cancer that were reported from the epidemiological studies, and particularly

from the large study of industrial workers in the USA, could be explained by bias or unrecognized confounding effects.

Overall, the Working Group concluded that the results of the study of industrial

workers in the USA, supported by the largely positive findings from other studies,

provided sufficient epidemiological evidence that formaldehyde causes nasopharyngeal

cancer in humans.

Leukaemia

Excess mortality from leukaemia has been observed relatively consistently in six of

seven studies of professional workers (i.e. embalmers, funeral parlour workers, pathologists and anatomists). A recently published meta-analysis of exposure to formaldehyde

among professionals and the risk for leukaemia reported increased overall summary relative risk estimates for embalmers, and for pathologists and anatomists, which did not vary

significantly between studies (i.e. the results were found to be homogeneous). The excess

incidence of leukaemia seen in several studies appeared to be predominantly of a myeloid

274 IARC MONOGRAPHS VOLUME 88
type. There has been speculation in the past that these findings might be explained by exposures to viruses that are experienced by anatomists, pathologists and perhaps funeral

workers. However, there is currently little direct evidence that these occupations have a

higher incidence of viral infections than that of the general population or that viruses play

a causal role in myeloid leukaemia. Professionals may also be exposed to other chemicals,

but they have no material exposure to known leukaemogens. Furthermore, the exposure to

other chemicals would differ between anatomists, pathologists and funeral workers, which

reduces the likelihood that such exposures could explain the observed increases in risk. 

Until recently, the findings for leukaemia in studies of professional 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. A statistically significant

exposure–response relationship was observed between peak exposures to formaldehyde

and mortality from leukaemia in the study of industrial workers in the USA. This relationship was found to be particularly strong for myeloid leukaemia, a finding that was also

observed in the study of anatomists and in several of the studies of embalmers. However,

in the study of industrial workers in the USA, mortality from leukaemia was lower than

expected when comparisons were made using the general population as the referent

group. This raises concerns about whether these findings are robust with respect to the

choice of a comparison group. Leukaemia has been found to be associated with socioeconomic status, and that of industrial workers tends to be low. Thus, the lack of an overall

finding of an excess of deaths from leukaemia in the cohort of industrial workers in the

USA might be explained by biases in the comparison between the study and referent

populations. The study also failed to demonstrate an exposure–response relationship with

cumulative exposure, although other metrics may sometimes be more relevant. 

Mortality from leukaemia was also found to be in excess in the recent update of the

study of garment workers exposed to formaldehyde in the USA. A small and statistically

non-significant excess was observed for the entire cohort in comparison with rates among

the general population. This excess was somewhat stronger for myeloid leukaemia, 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 who had a long duration of exposure and long follow-up, and who had

been employed early in the study period when exposures to formaldehyde were believed

to be highest. This pattern of findings is generally consistent with what might be expected

if, in fact, exposure to formaldehyde were causally associated with a risk for leukaemia.

The positive associations observed in many of the subgroup analyses presented in the study

of garment workers in the USA were based on a relatively small number of deaths, and

were thus not statistically stable.

The updated study of British industrial workers failed to demonstrate excess mortality

among workers exposed to formaldehyde. The lack of positive findings in this study is difficult to reconcile with the findings from the studies of garment workers and industrial

workers in the USA and studies of professionals. This was a high-quality study of adequate

FORMALDEHYDE 275
size and with sufficiently long follow-up to have had a reasonable chance to detect an excess

of deaths from leukaemia. The British study did not include an evaluation of peak exposures,

but neither did the study of garments workers in the USA nor the studies of professionals.

Also, the British study did not examine specifically the risk for myeloid leukaemia, which

represented the strongest findings in the studies of garment workers and industrial workers

in the USA and in several of the studies of medical professionals and funeral workers.

In summary, there is strong but not sufficient evidence for a causal association between

leukaemia and occupational exposure to formaldehyde. Increased risk for leukaemia has

consistently been observed in studies of professional workers and in two of three of the

most relevant studies of industrial workers. These findings fall slightly short of being fully

persuasive because of some limitations in the findings from the cohorts of industrial and

garment workers in the USA and because they conflict with the non-positive findings from

the British cohort of industrial workers.

Sinonasal cancer

The association between exposure to formaldehyde and the risk for sinonasal cancer

has been evaluated in six case–control studies that primarily focused on formaldehyde.

Four of these studies also contributed to a pooled analysis that collated occupational data

from 12 case–control investigations. After adjustment for known occupational confounders, this analysis showed an increased risk for adenocarcinoma in both men and

women and also (although on the basis of only a small number of exposed cases) in the

subset of subjects who were thought never to have been occupationally exposed to wood

or leather dust. Moreover, a dose–response trend was observed in relation to an index of

cumulative exposure. There was little evidence of an association with squamous-cell carcinoma, although in one of the two other case–control studies, a positive association was

found particularly for squamous-cell carcinomas. An analysis of proportionate cancer incidence among industrial workers in Denmark also showed an increased risk for squamouscell carcinomas.

Against these largely positive findings, no excess of mortality from sinonasal cancer

was observed in other cohort studies of formaldehyde-exposed workers, including the three

recently updated studies of industrial and garment workers in the USA and of chemical

workers in the United Kingdom.

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 would thus mask its detection, particularly in cohort studies that 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

276 IARC MONOGRAPHS VOLUME 88
resulted in a high relative risk, particularly for adenocarcinomas. Thus, there is only limited

epidemiological evidence that formaldehyde causes sinonasal cancer in humans.

Cancer at other sites

A number of studies have found associations between exposure to formaldehyde and

cancer at other sites, including the oral cavity, oro- and hypopharynx, pancreas, larynx,

lung and brain. However, the Working Group considered that the overall balance of epidemiological evidence did not support a causal role for formaldehyde in relation to these

other cancers.

5.3 Animal carcinogenicity data 

Several studies in which formaldehyde was administered to rats by inhalation showed

evidence of carcinogenicity, particularly the induction of squamous-cell carcinomas of the

nasal cavities. A similar study in hamsters showed no evidence of carcinogenicity, and

one study in mice showed no effect.

In four studies, formaldehyde was administered in the drinking-water to rats. One

study in male rats showed an increased incidence of forestomach papillomas. In a second

study in male and female rats, the incidence of gastrointestinal leiomyosarcomas was

increased in females and in males and females combined. In a third study in male and

female rats, the number of males that developed malignant tumours and the incidences of

haemolymphoreticular tumours (lymphomas and leukaemias) and testicular interstitialcell adenomas in males were increased. A fourth study gave negative results.

Skin application of formaldehyde concomitantly with 7,12-dimethylbenz[a]anthracene reduced the latency of skin tumours in mice. In rats, concomitant administration of

formaldehyde and N-methyl-N′-nitro-N-nitrosoguanidine in the drinking-water increased

the incidence of adenocarcinomas of the glandular stomach. Exposure of hamsters by

inhalation to formaldehyde increased the multiplicity of tracheal tumours induced by subcutaneous injections of N-nitrosodiethylamine. 

5.4 Other relevant data

Toxicokinetics and metabolism

The concentration of endogenous formaldehyde in human blood is about 2–3 mg/L;

similar concentrations are found in the blood of monkeys and rats. Exposure of humans,

monkeys or rats to formaldehyde by inhalation has not been found to alter these concentrations. The average level of formate in the urine of people who are not occupationally

exposed to formaldehyde is 12.5 mg/L and varies considerably both within and between

individuals. No significant changes in urinary formate were detected in humans after exposure to 0.5 ppm [0.6 mg/m3] formaldehyde for up to 3 weeks. More than 90% of inhaled

FORMALDEHYDE 277
formaldehyde is absorbed in the upper respiratory tract. In rats, it is absorbed almost entirely

in the nasal passages; in monkeys, it is also absorbed in the nasopharynx, trachea and proximal regions of the major bronchi. Absorbed formaldehyde can be oxidized to formate and

carbon dioxide or may be incorporated into biological macromolecules via tetrahydrofolatedependent one-carbon biosynthetic pathways. Formaldehyde has a half-life of about 1 min

in rat plasma. Rats exposed to [14C]formaldehyde eliminated about 40% of the 14C as

exhaled carbon dioxide, 17% in the urine and 5% in the faeces; 35–39% remained in the

tissues and carcass. After dermal application of aqueous [14C]formaldehyde, approximately

7% of the dose was excreted in the urine by rodents and 0.2% by monkeys. After oral administration, about 40% of [14C]formaldehyde was excreted as exhaled carbon dioxide, 10%

in the urine and 1% in the faeces within 12 h.

Toxic effects in humans 

Many studies have evaluated the health effects of inhalation of formaldehyde in

humans. Most were carried out in unsensitized subjects and revealed consistent evidence

of irritation of the eyes, nose and throat. Symptoms are rare below 0.5 ppm, and become

increasingly prevalent in studies in exposure chambers as concentrations increase. Exposures to up to 3 ppm [3.7 mg/m3] formaldehyde are unlikely to provoke asthma in an unsensitized individual. 

Nasal lavage studies show increased numbers of eosinophils and protein exudation

following exposures to 0.5 mg/m3 formaldehyde. Bronchial provocation tests have confirmed the occurrence of occupational asthma due to formaldehyde in small numbers of

workers from several centres. The mechanism is probably hypersensitivity, because the

reactions are often delayed, there is a latent period of symptomless exposure and unexposed asthmatics do not react to the same concentrations. One case of pneumonitis was

reported in a worker who was exposed for 2 h to a level that was sufficient for his breath

to smell of formaldehyde. High levels of formaldehyde probably cause asthmatic reactions

by an irritant mechanism. Formaldehyde is one of the commoner causes of contact dermatitis and is thought to act as a sensitizer on the skin.

Toxic effects in animals

Formaldehyde is a well documented irritant that causes mild inflammation to severe

ulceration. It caused direct toxicity in the upper respiratory system in a concentration- and

location-specific manner. There is evidence that formaldehyde can induce irritation to the

forestomach after high-dose oral exposure. Formaldehyde is also a sensory irritant that

induces a decrease in respiratory rate in rodents; mice are more sensitive than rats, as

measured by respiratory depression. This respiratory depression is thought to be secondary to stimulation of the trigeminal nerve by the irritant effect of formaldehyde. Formaldehyde can also result in pulmonary hyperactivity through transient bronchoconstriction.

278 IARC MONOGRAPHS VOLUME 88
It can also act as a skin contact sensitizer via a type IV T-cell mediated hypersensitivity

reaction. Formaldehyde does not induce haematological effects.

In-vitro toxicity

Formaldehyde exerts dose-dependent toxicity in cell cultures. Cytotoxicity involves

loss of glutathione, altered Ca2+-homeostatis and impairment of mitochondrial function.

Thiols, including glutathione, and metabolism through alcohol dehydrogenase 3, act in a

protective manner.

Reproductive and developmental effects

Eleven epidemiological studies have evaluated directly or indirectly the reproductive

effects of occupational exposures to formaldehyde. The outcomes examined in these

studies included spontaneous abortions, congenital malformations, birth weights, infertility and endometriosis. Inconsistent reports of higher rates of spontaneous abortion and

lowered birth weights were reported among women occupationally exposed to formaldehyde. Studies of inhalation exposure to formaldehyde in animal models have evaluated

the effects of formaldehyde on pregnancy and fetal development, which have not been

clearly shown to occur at exposures below maternally toxic doses.

Genetic and related effects

There is evidence that formaldehyde is genotoxic in multiple in-vitro models and in

exposed humans and laboratory animals. Studies in humans revealed increased DNA–

protein cross-links in workers exposed to formaldehyde. This is consistent with laboratory

studies, in which inhaled formaldehyde reproducibly caused DNA–protein cross-links in rat

and monkey nasal mucosa. A single study reported cytogenetic abnormalities in the bone

marrow of rats that inhaled formaldehyde, while other studies did not report effects in bone

marrow.

Mechanistic considerations

The current data indicate that both genotoxicty and cytoxicity play important roles in

the carcinogenesis of formaldehyde in nasal tissues. DNA–protein cross-links provide a

potentially useful marker of genotoxicity. The concentration–response curve for the

formation of DNA–protein cross-links is bi-phasic, and the slope increases at formaldehyde concentrations of about 2–3 ppm [2.4–3.7 mg/m3] in Fischer 344 rats. Similar

results are found in rhesus monkeys, although the dose–response curve is less well

defined in this species. Cell proliferation, which appears to amplify greatly the genotoxic

effects of formaldehyde, is increased considerably at concentrations of formaldehyde of

about 6 ppm [7.4 mg/m3], and results in a marked increase in the occurrence of malignant

lesions in the nasal passages of rats at concentrations above this level. 

FORMALDEHYDE 279
Several possible mechanisms were considered for the induction of human leukaemia,

such as clastogenic damage to circulatory stem cells. The Working Group was not aware

of any good rodent models that simulate the occurrence of acute myeloid leukaemia in

humans. Therefore, on the basis of the data available at this time, it was not possible to

identify a mechanism for the induction of myeloid leukaemia in humans.

5.5 Evaluation

There is sufficient evidence in humans for the carcinogenicity of formaldehyde.

There is sufficient evidence in experimental animals for the carcinogenicity of

formaldehyde.

Overall evaluation

Formaldehyde is carcinogenic to humans (Group 1). 

6. References

Abdel Hameed, A.A., Khoder, M.I. & Farag, S.A. (2000) Organic dust and gaseous contaminants

at wood working shops. J. environ. Monit., 2, 73–76

ACGIH® Worldwide (2003) Documentation of the TLVs® and BEIs® with Other Worldwide Occupational Exposure Values — 2003 CD-ROM, Cincinnati, OH, American Conference of Government Industrial Hygienists

Acheson, E.D., Barnes, H.R., Gardner, M.J., Osmond, C., Pannett, B. & Taylor, C.P. (1984a) Formaldehyde in the British chemical industry: An occupational cohort study. Lancet, i, 611–616

Acheson, E.D., Barnes, H.R., Gardner, M.J., Osmond, C., Pannett, B. & Taylor, C.P. (1984b) Formaldehyde process workers and lung cancer. Lancet, i, 1066–1067

Adams, D.O., Hamilton, T.A., Lauer, L.D. & Dean, J.H. (1987) The effect of formaldehyde exposure upon the mononuclear phagocyte system of mice. Toxicol. appl. Pharmacol., 88, 165–174

Åhman, M., Alexandersson, R., Ekholm, U., Bergström, B., Dahlqvist, M. & Ulfvarsson, U. (1991)

Impeded lung function in moulders and coremakers handling furan resin sand. Int. Arch.

occup. environ. Health, 63, 175–180

Akbar-Khanzadeh, F. & Mlynek, J.S. (1997) Changes in respiratory function after one and three hours

of exposure to formaldehyde in non-smoking subjects. Occup. environ. Med., 54, 296–300

Akbar-Khanzadeh, F., Vaquerano, M.U., Akbar-Khanzadeh, M. & Bisesi, M.S. (1994) Formaldehyde exposure, acute pulmonary response, and exposure control options in a gross anatomy

laboratory. Am. J. ind. Med., 26, 61–75

Albert, R.E., Sellakumar, A.R., Laskin, S., Kuschner, M., Nelson, N. & Snyder, C.A. (1982) Gaseous

formaldehyde and hydrogen chloride induction of nasal cancer in the rat. J. natl Cancer Inst., 68,

597–603

Alderson, T. (1967) Induction of genetically recombinant chromosomes in the absence of induced

mutation. Nature, 215, 1281–1283

280 IARC MONOGRAPHS VOLUME 88
Alexandersson, R. & Hedenstierna, G. (1988) Respiratory hazards associated with exposure to

formaldehyde and solvents in acid-curing paints. Arch. environ. Health, 43, 222–227

Altshuller, A.P. (1993) Production of aldehydes as primary emissions and from secondary atmospheric reactions of alkenes and alkanes during the night and early morning hours. Atmos.

Environ., 27, 21–32

Alves Pereira, E., Carrilho, E. & Tavares, M.F.M. (2002) Laser-induced fluorescence and UV detection of derivatized aldehydes in air samples using capillary electrophoresis. J. Chromatogr.,

A979, 409–416

Andersen, S.K., Jensen, O.M. & Oliva, D. (1982) [Exposure to formaldehyde and lung cancer in

Danish physicians.] Ugeskr. Laeg., 144, 1571–1573 (in Danish)

Anderson, L.G., Lanning, J.A., Barrell, R., Miyagishima, J., Jones, R.H. & Wolfe, P. (1996) Sources

and sinks of formaldehyde and acetaldehyde: An analysis of Denver’s ambient concentration

data. Atmos. Environ., 30, 2113–2123

Andersson, M., Agurell, E., Vaghef, H., Bolcsfoldi, G. & Hellman, B. (2003) Extended-term cultures

of human T-lymphocytes and the comet assay: A useful combination when testing for genotoxicity in vitro? Mutat. Res., 540, 43–55

Andjelkovich, D.A., Mathew, R.M., Richardson, R.B. & Levine, R.J. (1990) Mortality of iron

foundry workers. I. Overall findings. J. occup. Med., 32, 529–540

Andjelkovich, D.A., Shy, C.M., Brown, M.H., Janszen, D.B., Levine, R.J. & Richardson, R.B.

(1994) Mortality of iron foundry workers. III. Lung cancer case–control study. J. occup. Med.,

36, 1301–1309

Andjelkovich, D.A., Janszen, D.B., Brown, M.H., Richardson, R.B. & Miller, F.J. (1995) Mortality

of iron foundry workers: IV. Analysis of a subcohort exposed to formaldehyde. J. occup.

environ. Med., 37, 826–837

de Andrade, J.B., Andrade, M.V. & Pinheiro, H.L.C. (1998) Atmospheric levels of formaldehyde

and acetaldehyde and their relationship with the vehicular fleet composition in Salvador, Bahia,

Brazil. J. Braz. chem. Soc., 9, 219–223

Andreini, B.P., Baroni, R., Galimberti, E. & Sesana, G. (2000) Aldehydes in the atmospheric environment: Evaluation of human exposure in the north-west area of Milan. Microchem. J., 67,

11–19

AOAC (Association of Official Analytical Chemists) (2003) Official Methods of Analysis of AOAC

International, 17th Ed., Rev. 2, Gaithersburg, MD [CD-ROM]

Appelman, L.M., Woutersen, R.A., Zwart, A., Falke, H.E. & Feron, V.J. (1988) One-year inhalation toxicity study of formaldehyde in male rats with a damaged or undamaged nasal mucosa.

J. appl. Toxicol., 8, 85–90

Arbejdstilsynet [Danish Working Environment Authority] (2002) Limit Values for Substances and

Material, Copenhagen, WEA-Guide

Armstrong, R.W., Imrey, P.B., Lye, M.S., Armstrong, M.J., Yu, M.C. & Sani, S. (2000) Nasopharyngeal carcinoma in Malaysian Chinese: Occupational exposures to particles, formaldehyde and

heat. Int. J. Epidemiol., 29, 991–998

ASTM International (1990) Standard Test Method for Determining Formaldehyde Levels from

Wood Products Under Defined Test Conditions Using a Large Chamber (Method E1333-90),

Philadelphia, American Society for Testing and Materials 

FORMALDEHYDE 281
ASTM International (2000) Standard Test Method for Determining Formaldehyde Levels from

Wood Products using a Desiccator (ASTM D5582-00), Philadelphia, American Society for

Testing and Materials

ASTM International (2002a) Standard Test Method for Determining Formaldehyde Concentration

in Air from Wood Products Using a Small Scale Chamber (ASTM D6007-02), Philadelphia,

American Society for Testing and Materials

ASTM International (2002b) Standard Test Method for Determining Formaldehyde Concentrations in Air and Emission Rates from Wood Products Using a Large Chamber (ASTM

E1333-96, Reapproved 2002), Philadelphia, American Society for Testing and Materials

ATSDR (Agency for Toxic Substances and Disease Registry) (1999) Toxicological Profile for Formaldehyde, Atlanta, GA, US Department of Health and Human Services, Public Health Service

[http://atsdr.cdc.gov/toxprofiles/tp111.html]

Atzori, L., Dore, M. & Congiu, L. (1989) Aspects of allyl alcohol toxicity. Drug Metabol. Drug.

Interactions, 7, 295–319

Atzori, L., Dypbukt, J.M., Hybbinette, S.S., Moldéus, P. & Grafström, R.C. (1994) Modifications

of cellular thiols during growth and squamous differentiation of cultured human bronchial epithelial cells. Exp. Cell Res., 211, 115–120

Auerbach, C. & Moser, H. (1953) Analysis of the mutagenic action of formaldehyde on food. II. The

mutagenic potentialities of the treatment. Zeitschr. indukt. Abstamm. Verebungs., 85, 547–563

Auerbach, C., Moutschen-Dahmen, M. & Moutschen, J. (1977) Genetic and cytogenetical effects

of formaldehyde and related compounds. Mutat. Res., 39, 317–361

Axelsson, G., Lütz, C. & Rylander, R. (1984) Exposure to solvents and outcome of pregnancy in

university laboratory employees. Br. J. ind. Med., 41, 305–312

Azuma, M., Endo, Y., Miyazaki, T., Hikita, Y., Ikeda, H., Moriya, Y., Hara, I. & Araki, S. (2003)

Efficacy of a detector tube method in formaldehyde measurement. Ind. Health, 41, 306-312

Baez, A.P., Belmont, R. & Padilla, H. (1995) Measurements of formaldehyde and acetaldehyde in

the atmosphere of Mexico City. Environ. Pollut., 89, 163–167

Báez, A., Padilla, H., García, R., Torres, M.C., Rosas, I. & Belmont, R. (2003) Carbonyl levels in

indoor and outdoor air in Mexico City and Xalapa, Mexico. Sci. total Environ., 302, 211–226

Ballarin, C., Sarto, F., Giacomelli, L., Bartolucci, G.B. & Clonfero, E. (1992) Micronucleated cells

in nasal mucosa of formaldehyde-exposed workers. Mutat. Res., 280, 1–7

Ballenger, J.J. (1984) Some effects of formaldehyde on the upper respiratory tract. Laryngoscope,

94, 1411–1413

Barber, R.D. & Donohue, T.J. (1998) Pathways for transcriptional activation of a glutathionedependent formaldehyde dehydrogenase gene. J. mol. Biol., 280, 775–784

Basler, A., van der Hude, W. & Scheutwinkel-Reich, M. (1985) Formaldehyde-induced sister chromatid exchanges in vitro and the influence of the exogenous metabolizing systems S9 mix and

primary hepatocytes. Arch. Toxicol., 58, 10–13

Batalha, J.R.F., Guimarães, E.T., Lobo, D.J.A., Lichtenfels, A.J.F.C, Deur, T., Carvalho, H.A.,

Alves, E.S., Domingos, M., Rodrigues, G.S. & Saldiva, P.H.N. (1999) Exploring the clastogenic effects of air pollutants in São Paulo (Brazil) using the Tradescantia micronuclei assay.

Mutat. Res., 426, 229–232

Baumann, K. & Angerer, J. (1979) Occupational chronic exposure to organic solvents. VI. Formic

acid concentration in blood and urine as an indicator of methanol exposure. Int. Arch. occup.

environ. Health, 42, 241–249

282 IARC MONOGRAPHS VOLUME 88
Belanger, P.L. & Kilburn, K.H. (1981) California Society for Histotechnology, Los Angeles, CA,

Health Hazard Evaluation Report (NIOSH Report No. HETA 81-422-1387), Cincinnati, OH,

US Department of Health and Human Services, Public Health Service, Centers for Disease

Control, National Institute for Occupational Safety and Health

Bender, J. (2002) The use of noncancer endpoints as a basis for establishing a reference concentration for formaldehyde. Regul. Toxicol. Pharmacol., 35, 23–31

Berke, J.H. (1987) Cytologic examination of the nasal mucosa in formaldehyde-exposed workers.

J. occup. Med., 29, 681–684

Bernardini, P., Carelli, G., Rimatori, V. & Contegiacomo, P. (1983) Health hazard for hospital

workers from exposure to formaldehyde. Med. Lav., 74, 106–110

Berrino, F., Richiardi, L., Boffetta, P., Estève, J., Belletti, I., Raymond, L., Troschel, L., Pisani, P.,

Zubiri, L., Ascunce, N., Gubéran, E., Tuyns, A., Terracini, B., Merletti, F. & the Milan JEM

Working Group (2003) Occupation and larynx and hypopharynx cancer: A job–exposure matrix

approach in an international case–control study in France, Italy, Spain and Switzerland. Cancer

Causes Control, 14, 213–223

Bertazzi, P.A., Pesatori, A.C., Radice, L., Zocchetti, C. & Vai, T. (1986) Exposure to formaldehyde

and cancer mortality in a cohort of workers producing resins. Scand. J. Work Environ. Health,

12, 461–468

Bertazzi, P.A., Pesatori, A.C., Guercilena, S., Consonni, D. & Zocchetti, C. (1989) [Cancer risk

among workers producing formaldehyde-based resins: Extension of follow-up.] Med. Lav., 80,

111–122 (in Italian)

Biagini, R.E., Moorman, W.J., Knecht, E.A., Clark, J.C. & Bernstein, I.L. (1989) Acute airway

narrowing in monkeys from challenge with 2.5 ppm formaldehyde generated from formalin.

Arch. environ. Health, 44, 12–17 

Binding, N. & Witting, U. (1990) Exposure to formaldehyde and glutardialdehyde in operating

theatres. Int. Arch. occup. environ. Health, 62, 233–238

Bizzari, S.N. (2000) CEH Marketing Research Report: Formaldehyde, Palo Alto, CA, SRI International

Blade, L.M. (1983) Occupational exposure to formaldehyde — Recent NIOSH involvement. In:

Clary, J.J., Gibson, J.E. & Waritz, R.S., eds, Formaldehyde — Toxicology, Epidemiology, Mechanisms, New York, Marcel Dekker, pp. 1–23

Blair, A. & Stewart, P.A. (1989) Comments on the reanalysis of the National Cancer Institute study

of workers exposed to formaldehyde. J. occup. Med., 31, 881

Blair, A. & Stewart, P.A. (1990) Correlation between different measures of occupational exposure

to formaldehyde. Am. J. Epidemiol., 131, 510–516

Blair, A., Stewart, P.A., O’Berg, M., Gaffey, W., Walrath, J., Ward, J., Bales, R., Kaplan, S. & Cubit,

D. (1986) Mortality among industrial workers exposed to formaldehyde. J. natl Cancer Inst.,

76, 1071–1084

Blair, A., Stewart, P.A., Hoover, R.N., Fraumeni, J.F., Jr, Walrath, J., O’Berg, M. & Gaffey, W.

(1987) Cancers of the nasopharynx and oropharynx and formaldehyde exposure (Letter to the

Editor). J. natl Cancer Inst., 78, 191–193

Blair, A., Stewart, P.A. & Hoover, R.N. (1990a) Mortality from lung cancer among workers

employed in formaldehyde industries. Am. J. ind. Med., 17, 683–699

FORMALDEHYDE 283
Blair, A., Saracci, R., Stewart, P.A., Hayes, R.B. & Shy, C. (1990b) Epidemiologic evidence on the

relationship between formaldehyde exposure and cancer. Scand. J. Work Environ. Health, 16,

381–393

Blair, A., Zheng, T., Linos, A., Stewart, P.A., Zhang, Y.W. & Cantor, K.P. (2000) Occupation and

leukemia: A population-based case–control study in Iowa and Minnesota. Am. J. ind. Med., 40,

3–14

Blasiak, J., Trzeciak, A., Malecka-Panas, E., Drzewoski, J. & Wojewódzka, M. (2000) In vitro genotoxicity of ethanol and acetaldehyde in human lymphocytes and the gastrointestinal tract

mucosa cells. Toxicol. in Vitro, 14, 287–295

Boj, J.R., Marco, I., Cortès, O. & Canalda, C. (2003) The acute nephrotoxicity of systemically

administered formaldehyde in rats. Eur. J. paediat. Dent., 4, 16–20

Bolm-Audorff, U., Vogel, C. & Woitowitz, H. (1990) Occupation and smoking as risk factors of

nasal and nasopharyngeal cancer. In: Sakurai, H., ed., Occupational Epidemiology, New York,

Elsevier Science, pp. 71–74

Bolstad-Johnson, D.M., Burgess, J.L., Crutchfield, C.D., Storment, S., Gerkin, R. & Wilson, J.R.

(2000) Characterization of firefighter exposures during fire overhaul. Am. ind. Hyg. Assoc. J.,

61, 636–641

Bolt, H.M. (1987) Experimental toxicology of formaldehyde. Cancer Res. clin. Oncol., 113, 305–309 

Bolt, H.M. (2003) Genotoxicity — Threshold or not? Introduction of cases of industrial chemicals.

Toxicol. Lett., 140–141, 43–51

Bond, G.G., Flores, G.H., Shellenberger, R.J., Cartmill, J.B., Fishbeck, W.A. & Cook, R.R. (1986)

Nested case–control study of lung cancer among chemical workers. Am. J. Epidemiol., 124,

53–66

Boysen, M., Zadig, E., Digernes, V., Abeler, V. & Reith, A. (1990) Nasal mucosa in workers

exposed to formaldehyde: A pilot study. Br. J. ind. Med., 47, 116–121

Brandt-Rauf, P.W., Fallon, L.F., Jr, Tarantini, T., Idema, C. & Andrews, L. (1988) Health hazards

of fire fighters: Exposure assessment. Br. J. ind. Med., 45, 606–612 

Brickus, L.S.R., Cardoso, J.N. & Aquino Neto, F.R. (1998) Distributions of indoor and outdoor air

pollutants in Rio de Janeiro, Brazil: Implications to indoor air quality in bayside offices.

Environ. Sci. Technol., 32, 3485–3490

Brinton, L.A., Blot, W.J., Becker, J.A., Winn, D.M., Browder, J.P., Farmer, J.C., Jr & Fraumeni,

J.F., Jr (1984) A case–control study of cancers of the nasal cavity and paranasal sinuses. Am.

J. Epidemiol., 119, 896–906

Brinton, L.A., Blot, W.J. & Fraumeni, J.F., Jr (1985) Nasal cancer in the textile and clothing

industries. Br. J. ind. Med., 42, 469–474

Broder, I., Corey, P., Cole, P., Lipa, M., Mintz, S. & Nethercott, J.R. (1988a) Comparison of health

of occupants and characteristics of houses among control homes and homes insulated with

urea formaldehyde foam. I. Methodology. Environ. Res., 45, 141–155

Broder, I., Corey, P., Cole, P., Lipa, M., Mintz, S. & Nethercott, J.R. (1988b) Comparison of health

of occupants and characteristics of houses among control homes and homes insulated with urea

formaldehyde foam. II. Initial health and house variables and exposure–response relationships.

Environ. Res., 45, 156–178

Broder, I., Corey, P., Brasher, P., Lipa, M. & Cole, P. (1988c) Comparison of health of occupants and

characteristics of houses among control homes and homes insulated with urea formaldehyde

foam. III. Health and house variables following remedial work. Environ. Res., 45, 179–203

284 IARC MONOGRAPHS VOLUME 88
Broder, I., Corey, P., Brasher, P., Lipa, M. & Cole, P. (1991) Formaldehyde exposure and health

status in households. Environ. Health Perspect., 95, 101–104

Brownson, R.C., Alavanja, M.C.R. & Chang, J.C. (1993) Occupational risk factors for lung cancer

among nonsmoking women: A case–control study in Missouri (United States). Cancer Causes

Control, 4, 449–454

Buckley, L.A., Jiang, X.Z., James, R.A., Morgan, K.T. & Barrow, C.S. (1984) Respiratory tract

lesions induced by sensory irritants at the RD50 concentration. Toxicol. appl. Pharmacol., 74,

417–429 

Burgaz, S., Cakmak, G., Erdem, O., Yilmaz, M. & Karakaya, A.E. (2001) Micronuclei frequencies

in exfoliated nasal mucosa cells from pathology and anatomy laboratory workers exposed to

formaldehyde. Neoplasma, 48, 144–147 

Burgaz, S., Erdem, O., Çakmak, G., Erdem, N., Karakaya, A. & Karakaya, A.E. (2002) Cytogenetic

analysis of buccal cells from shoe-workers and pathology and anatomy laboratory workers

exposed to n-hexane, toluene, methyl ethyl ketone and formaldehyde. Biomarkers, 7, 151–161

Burge, P.S., Harries, M.G., Lam, W.K., O’Brien, I.M. & Patchett, P. (1985) Occupational asthma

due to formaldehyde. Thorax, 40, 255–260

Buss, J., Kuschinsky, K., Kewitz, H. & Koransky, W. (1964) [Enteric resorption of formaldehyde.]

Naunyn-Schmiedeberg’s Arch. exp. Pathol. Pharmakol., 247, 380–381 (in German)

California Air Resources Board (2004) California Ambient Air Quality Data 1990–2002,

Los Angeles, CA, Planning & Technical Support Division

Callas, P.W., Pastides, H. & Hosmer, D.W., Jr (1996) Lung cancer mortality among workers in

formaldehyde industries. J. occup. environ. Med., 38, 747–748

Cantor, K.P., Stewart, P.A., Brinton, L.A. & Dosemeci, M. (1995) Occupational exposures and

female breast cancer mortality in the United States. J. occup. environ. Med., 37, 336–348

CAREX (2003) Available at http://www.ttl.fi/NR/rdonlyres/407B368B-26EF-475D-8F2BDA0024B853E0/0/5_exposures_by_agent_and_industry.pdf

Carraro, E., Gasparini, S. & Gilli, G. (1999) Identification of a chemical marker of environmental

exposure to formaldehyde. Environ. Res., A80, 132–137 

Casanova, M. & Heck, H.d’A. (1987) Further studies of the metabolic incorporation and covalent

binding of inhaled [3H]- and [14C]formaldehyde in Fischer-344 rats: Effects of glutathione

depletion. Toxicol. appl. Pharmacol., 89, 105–121

Casanova, M., Heck, H.d’A., Everitt, J.I., Harrington, W.W., Jr & Popp, J.A. (1988) Formaldehyde

concentrations in the blood of rhesus monkeys after inhalation exposure. Food chem. Toxicol.,

26, 715–716

Casanova, M., Deyo, D.F. & Heck, H.d’A. (1989) Covalent binding of inhaled formaldehyde to

DNA in the nasal mucosa of Fischer 344 rats: Analysis of formaldehyde and DNA by highperformance liquid chromatography and provisional pharmacokinetic interpretation. Fundam.

appl. Toxicol., 12, 397–417

Casanova, M., Morgan, K.T., Steinhagen, W.H., Everitt, J.I., Popp, J.A. & Heck, H.d’A. (1991)

Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkeys:

Pharmacokinetics, rat-to-monkey interspecies scaling, and extrapolation to man. Fundam.

appl. Toxicol., 17, 409–428

Casanova, M., Morgan, K.T., Gross, E.A., Moss, O.R. & Heck, H.d’A. (1994) DNA–protein crosslinks and cell replication at specific sites in the nose of F344 rats exposed subchronically to

formaldehyde. Fundam. appl. Toxicol., 23, 525–536

FORMALDEHYDE 285
Casanova, M., Bell, D.A. & Heck, H.d’A. (1997) Dichloromethane metabolism to formaldehyde

and reaction of formaldehyde with nucleic acids in hepatocytes of rodents and humans with

and without glutathione S-transferase T1 and M1 genes. Fundam. appl. Toxicol., 37, 168–180

Casanova-Schmitz, M. & Heck, H.d’A. (1983) Effects of formaldehyde exposure on the extractability of DNA from proteins in the rat nasal mucosa. Toxicol. appl. Pharmacol., 70, 121–132

Casanova-Schmitz, M., David, R.M. & Heck, H.d’A. (1984a) Oxidation of formaldehyde and

acetaldehyde by NAD+-dependent dehydrogenases in rat nasal mucosal homogenates. Biochem. Pharmacol., 33, 1137–1142

Casanova-Schmitz, M., Starr, T.B. & Heck, H.d’A. (1984b) Differentiation between metabolic incorporation and covalent binding in the labeling of macromolecules in the rat nasal mucosa and

bone marrow by inhaled [14C]- and [3H]formaldehyde. Toxicol. appl. Pharmacol., 76, 26–44

Cassee, F.R. & Feron, V.J. (1994) Biochemical and histopathological changes in nasal epithelium

of rats after 3-day intermittent exposure to formaldehyde and ozone alone or in combination.

Toxicol. Lett., 72, 257–268

Cassee, F.R., Arts, J.H.E., Groten, J.P. & Feron, V.J. (1996a) Sensory irritation to mixtures of

formaldehyde, acrolein and acetaldehyde in rats. Arch. Toxicol., 70, 329–337

Cassee, F.R., Groten, J.P. & Feron, V.J. (1996b) Changes in the nasal epithelium of rats exposed by

inhalation to mixtures of formaldehyde, acetaldehyde, and acrolein. Fundam. appl. Toxicol.,

29, 208–218

Cecinato, A., Yassaa, N., Di Palo, V. & Possanzini, M. (2002) Observation of volatile and semivolatile carbonyls in an Algerian urban environment using dinitrophenylhydrazine/silicaHPLC and pentafluorophenylhydrazine/silica-GC-MS. J. environ. Monit., 4, 223–228 

Centers for Disease Control (1986) Occupational exposure to formaldehyde in dialysis units. J. Am.

med. Assoc., 256, 698–703

Chan, W.H., Shuang, S. & Choi, M.M.F. (2001) Determination of airborne formaldehyde by active

sampling on 3-methyl-2-benzothiazolinone hydrazone hydrochloride-coated glass fibre filters.

Analyst, 126, 720–723 

Chanet, R., Izard, C. & Moustacchi, E. (1975) Genetic effects of formaldehyde in yeast. I. Influence

of the growth stages on killing and recombination. Mutat. Res., 33, 179–186

Chang, J.C.F. & Barrow, C.S. (1984) Sensory irritation tolerance and cross-tolerance in F-344 rats

exposed to chlorine or formaldehyde gas. Toxicol. appl. Pharmacol., 76, 319–327

Chang, J.-Y. & Lin, J.-M. (1998) Aliphatic aldehydes and allethrin in mosquito-coil smoke.

Chemosphere, 36, 617–624 

Chang, J.C.F., Steinhagen, W.H. & Barrow, C.S. (1981) Effect of single or repeated formaldehyde

exposure on minute volume of B6C3F1 mice and F-344 rats. Toxicol. appl. Pharmacol., 61,

451–459 

Chang, J.C.F., Gross, E.A., Swenberg, J.A. & Barrow, C.S. (1983) Nasal cavity deposition, histopathology and cell proliferation after single or repeated formaldehyde exposures in B6C3F1

mice and F-344 rats. Toxicol. appl. Pharmacol., 68, 161–176

Chang, H.L., Kuo, M.L. & Lin J.M. (1997) Mutagenic activity of incense smoke in comparison to

formaldehyde and acetaldehyde in Salmonella typhimurium TA102. Bull. environ. Contam.

Toxicol., 58, 394–401

Chemical Information Services (2004) Directory of World Chemical Producers, Dallas, TX

[www.chemicalinfo.com]

286 IARC MONOGRAPHS VOLUME 88
Chiazze, L., Jr, Watkins, D.K., Fryar, C. & Kozono, J. (1993) A case–control study of malignant

and non-malignant respiratory disease among employees of a fiberglass manufacturing facility. II. Exposure assessment. Br. J. ind. Med., 50, 717–725

Chiazze, L., Watkins, D.K. & Fryar, C. (1997) Historical cohort mortality study of a continuous

filament fiberglass manufacturing plant. I. White men. J. occup. environ. Med., 39, 432–441

Christensen, C.S., Skov, H., Nielsen, T. & Lohse, C. (2000) Temporal variation of carbonyl compound concentrations at a semi-rural site in Denmark. Atmos. Environ., 34, 287–296

Chung, K.Y.K., Cuthbert, R.J., Revell, G.S., Wassel, S.G. & Summers, N. (2000) A study on dust

emission, particle size distribution and formaldehyde concentration during machining of

medium density fibreboard. Ann. occup. Hyg., 44, 455–466

Clarisse, B., Laurent, A.M., Seta, N., Le Moullec, Y., El Hasnaoui, A. & Momas, I. (2003) Indoor

aldehydes: Measurement of contamination levels and identification of their determinants in

Paris dwellings. Environ. Res., 92, 245–253

Coggon, D., Pannett, B. & Acheson, E.D. (1984) Use of job–exposure matrix in an occupational

analysis of lung and bladder cancers on the basis of death certificates. J. natl Cancer Inst., 72,

61–65

Coggon, D., Harris, E.C., Poole, J. & Palmer, K.T. (2003) Extended follow-up of a cohort of

British chemical workers exposed to formaldehyde. J. natl Cancer Inst., 95, 1608–1615

Cohen Hubal, E.A., Schlosser, P.M., Conolly, R.B. & Kimbell, J.S. (1997) Comparison of inhaled

formaldehyde dosimetry predictions with DNA–protein cross-link measurements in the rat

nasal passages. Toxicol. appl. Pharmacol., 143, 47–55

Coldiron, V.R., Ward, J.B., Jr, Trieff, N.M., Janssen, E., Jr & Smith, J.H. (1983) Occupational

exposure to formaldehyde in a medical center autopsy service. J. occup. Med., 25, 544–548

Collins, J.J. & Lineker, G.A. (2004) A review and meta-analysis of formaldehyde exposure and

leukemia. Regul. Toxicol. Pharmacol., 40, 81–91

Collins, J.J., Acquavella, J.F. & Esmen, N.A. (1997) An updated meta-analysis of formaldehyde

exposure and upper respiratory tract cancers. J. occup. environ. Med., 39, 639–651

Collins, J.J., Esmen, N.A. & Hall, T.A. (2001a) A review and meta-analysis of formaldehyde exposure and pancreatic cancer. Am. J. ind. Med., 39, 336–345

Collins, J.J., Ness, R., Tyl, R.W., Krivanek, N., Esmen, N.A. & Hall, T.A. (2001b) A review of

adverse pregnancy outcomes and formaldehyde exposure in human and animal studies. Regul.

Toxicol. Pharmacol., 34, 17–34

Comba, P., Barbieri, P.G., Battista, G., Belli, S., Ponterio, F., Zanetti, D. & Axelson, O. (1992a)

Cancer of the nose and paranasal sinuses in the metal industry: A case–control study. Br. J. ind.

Med., 49, 193–196

Comba, P., Battista, G., Belli, S., de Capua, B., Merler, E., Orsi, D., Rodella, S., Vindigni, C. &

Axelson, O. (1992b) A case–control study of cancer of the nose and paranasal sinuses and

occupational exposures. Am. J. ind. Med., 22, 511–520

Composite Panel Association (1999) American National Standard — Particleboard (ANSI

A208.1-1999), Gaithersburg, MD

Composite Panel Association (2002) American National Standard — Medium Density Fiberboard

(MDF) for Interior Applications (ANSI A208.2-2002), Gaithersburg, MD

Conaway, C.C., Whysner, J., Verna, L.K. & Williams, G.M. (1996) Formaldehyde mechanistic data

and risk assessment: Endogenous protection from DNA adduct formation. Pharmacol. Ther.,

71, 29–55

FORMALDEHYDE 287
Connor, T.H., Barrie, M.D., Theiss, J.C., Matney, T.S. & Ward, J.B., Jr (1983) Mutagenicity of

formalin in the Ames assay. Mutat. Res., 119, 145–149

Connor, T.H., Ward, J.B., Jr & Legator, M.S. (1985) Absence of mutagenicity in the urine of autopsy

service workers exposed to formaldehyde: Factors influencing mutagenicity testing of urine.

Arch. occup. environ. Health, 56, 225–237 

Conolly, R.B. (2002) The use of biologically based modeling in risk assessment. Toxicology,

181–182, 275–279

Conolly, R.B. & Lutz, W.K. (2004) Nonmonotonic dose–response relationships: Mechanistic basis,

kinetic modeling, and implications for risk assessment. Toxicol. Sci., 77, 151–157

Conolly, R.B., Lilly, P.D. & Kimbell, J.S. (2000) Simulation modeling of the tissue disposition of

formaldehyde to predict nasal DNA–protein cross-links in Fischer 344 rats, rhesus monkeys

and humans. Environ. Health Perspect., 108 (Suppl. 5), 919–924

Conolly, R.B., Kimbell, J.S., Janszen, D., Schlosser, P.M., Kalisak, D., Preston, J. & Miller, F.J.

(2003) Biologically motivated computational modeling of formaldehyde carcinogenicity in the

F344 rat. Toxicol. Sci., 75, 432–447

Corrêa, S.M., Martins, E.M. & Arbilla, G. (2003) Formaldehyde and acetaldehyde in a high traffic

street of Rio de Janeiro, Brazil. Atmos. Environ., 37, 23–29

Cosma, G.N., Wilhite, A.S. & Marchok, A.C. (1988) The detection of DNA–protein cross-links in

rat tracheal implants exposed in vivo to benzo[a]pyrene and formaldehyde. Cancer Lett., 42,

13–21

Cosmetic Ingredient Review Expert Panel (1984) Final report on the safety assessment of formaldehyde. J. Am. Coll. Toxicol., 3, 157–184

Costa, M., Zhitkovich, A., Harris, M., Paustenbach, D. & Gargas, M. (1997) DNA–protein crosslinks produced by various chemicals in cultured human lymphoma cells. J. Toxicol. environ.

Health, 50, 433–449 

Craft, T.R., Bermudez, E. & Skopek, T.R. (1987) Formaldehyde mutagenesis and formation of

DNA–protein crosslinks in human lymphoblasts in vitro. Mutat. Res., 176, 147–155

Crosby, R.M., Richardson, K.K., Craft, T.R., Benforado, K.B., Liber, H.L. & Skopek, T.R. (1988)

Molecular analysis of formaldehyde-induced mutations in human lymphoblasts and E. coli.

Environ. mol. Mutag., 12, 155–166

Dahl, A.R. & Hadley, W.M. (1991) Nasal cavity enzymes involved in xenobiotic metabolism:

Effects on the toxicity of inhalants. Crit. Rev. Toxicol., 21, 345–372

Dalbey, W.E. (1982) Formaldehyde and tumors in hamster respiratory tract. Toxicology, 24, 9–14

Dallas, C.E., Badeaux, P., Theiss, J.C. & Fairchild, E.J. (1989) The influence of inhaled

formaldehyde on rat lung cytochrome P450. Environ. Res., 49, 50–59

Dallas, C.E., Scott, M.J., Ward, J.B., Jr & Theiss, J.C. (1992) Cytogenetic analysis of pulmonary

lavage and bone marrow cells of rats after repeated formaldehyde inhalation. J. appl. Toxicol.,

12, 199–203

Day, J.H., Lees, R.E.M., Clark, R.H. & Pattee, P.L. (1984) Respiratory response to formaldehyde

and off-gas of urea formaldehyde foam insulation. Can. med. Assoc. J., 131, 1061–1065

Dean, J.H., Lauer, L.D., House, R.V., Murray, M.J., Stillman, W.S., Irons, R.D., Steinhagen, W.H.,

Phelps, M.C. & Adams, D.O. (1984) Studies of immune function and host resistance in

B6C3F1 mice exposed to formaldehyde. Toxicol. appl. Pharmacol., 72, 519–529 

288 IARC MONOGRAPHS VOLUME 88
Delfino, R.J., Gong, H., Jr, Linn, W.S., Pellizzari, E.D. & Hu, Y. (2003) Asthma symptoms in

Hispanic children and daily ambient exposures to toxic and criteria air pollutants. Environ.

Health Perspect., 111, 647–656

Dell, L. & Teta, M.J. (1995) Mortality among workers at a plastics manufacturing and research and

development facility: 1946–1988. Am. J. ind. Med., 28, 373–384

Deltour, L., Foglio, M.H. & Duester, G. (1999) Metabolic deficiencies in alcohol dehydrogenase

Adh1, Adh3, and Adh4 null mutant mice. Overlapping roles of Adh1 and Adh4 in ethanol

clearance and metabolism of retinol to retinoic acid. J. biol. Chem., 274, 16796–16801

Demerec, M., Bertani, G. & Flint, J. (1951) A survey of chemicals for mutagenic action on E. coli.

Am. Naturalist, 85, 119–136

Demkowicz-Dobrzanski, K. & Castonguay, A. (1992) Modulation by glutathione of DNA strand

breaks induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and its aldehyde metabolites in rat hepatocytes. Carcinogenesis, 13, 1447–1454

Department of Housing and Urban Development (2003) Manufactured home construction and

safety standards. US Code fed. Regul., Title 24, Part 3280.308, pp. 133–134

Deutsche Forschungsgemeinschaft (1993) Aldehydes (formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, glutaraldehyde). In: Henschler, D. & Kettrup, A., eds, Analyses of

Hazardous Substances in Air, Vol. 2, Weinheim, VCH, Commission for the Investigation of

Health Hazards of Chemical Compounds in the Work Area, pp. 15–28

Deutsche Forschungsgemeinschaft (2003) List of MAK and BAT Values 2003 — Commission for

the Investigation of Health Hazards of Chemical Compounds in the Work Area (Report

No. 39), Weinheim, Wiley-VCH Verlag GmbH, pp. 64, 132, 157–169

Deutsche Norm (1992) Wood-based Panels Products. Determination of Formaldehyde Content.

Extraction Method (Known as Perforator Method) (DIN EN 120:1992), Berlin, German Norm

Institute

Deutsche Norm (1994) Wood-based Panel Products. Determination of Formaldehyde Release by

the Gas Analysis Method (DIN EN 717-2:1994), Berlin, German Norm Institute 

Deutsche Norm (1996) Wood-based Panel Products. Determination of Formaldehyde Release by

the Flask Method (DIN EN 717-3:1996), Berlin, German Norm Institute 

Diaz, M., Achkor, H., Titarenko, E. & Martinez, M.C. (2003) The gene encoding glutathione-dependent formaldehyde dehydrogenase/GSNO reductase is responsive to wounding, jasmonic acid

and salicylic acid. FEBS Lett., 543, 136–139

Dicker, E. & Cederbaum, A.I. (1986) Inhibition of the low-Km mitochondrial aldehyde dehydrogenase by diethyl maleate and phorone in vivo and in vitro. Implications for formaldehyde

metabolism. Biochem. J., 240, 821–827

Dickey, F.H., Cleland, G.H. & Lotz, C. (1949) The role of organic peroxides in the induction of

mutations. Proc. natl Acad. Sci. USA, 35, 581–586

Dillon, D., Combes, R. & Zeiger, E. (1998) The effectiveness of Salmonella strains TA100, TA102

and TA104 for detecting mutagenicity of some aldehydes and peroxides. Mutagenesis, 13,

19–26

Dingle P., Tapsell, P. & Hu, S. (2000) Reducing formaldehyde exposure in office environments

using plants. Bull. environ. Contam. Toxicol., 64, 302–308

Dinsdale, D., Riley, R.A. & Verschoyle, R.D. (1993) Pulmonary cytochrome P450 in rats exposed

to formaldehyde vapor. Environ. Res., 62, 19–27

FORMALDEHYDE 289
Doi, S., Suzuki, S., Morishita, M., Yamada, M., Kanda, Y., Torii, S. & Sakamoto, T. (2003) The

prevalence of IgE sensitization in asthmatic children. Allergy, 58, 668–671

Doolittle, D.J., Furlong, J.W. & Butterworth, B.E. (1985) Assessment of chemically induced DNA

repair in primary cultures of human bronchial epithelial cells. Toxicol. appl. Pharmacol., 79,

28–38

Douglas, M.P. & Rogers, S.O. (1998) DNA damage caused by common cytological fixatives. Mutat.

Res., 401, 77–88

Draeger Safety (undated) Draeger-Tubes® and Accuro® Pump, Pittsburgh, PA

Dresp, J. & Bauchinger, M. (1988) Direct analysis of the clastogenic effect of formaldehyde in unstimulated human lymphocytes by means of the premature chromosome condensation technique.

Mutat. Res., 204, 349–352

Duester, G., Farrés, J., Felder, M.R., Holmes, R.S., Höög, J.-O., Parés, X., Plapp, B.V., Yin, S.-J.

& Jörnvall, H. (1999) Recommended nomenclature for the vertebrate alcohol dehydrogenase

gene family. Biochem. Pharmacol., 58, 389–395

Dufresne, A., Infante-Rivard, C., Malo, J.L. & Gautrin, D. (2002) Exposure to formaldehyde among

animal health students. Am. ind. Hyg. Assoc. J., 63, 647–650 

Dumas, S., Parent, M.-E., Siemiatycki, J. & Brisson, J. (2000) Rectal cancer and occupational risk

factors: A hypothesis-generating, exposure-based case–control study. Int. J. Cancer, 87, 874–879

Echt, A. & Burr, G.A. (1997) Exposure to formaldehyde during garment manufacturing. Appl.

occup. environ. Hyg., 12, 451–455 

Edling, C., Järvholm, B., Andersson, L. & Axelson, O. (1987a) Mortality and cancer incidence

among workers in an abrasive manufacturing industry. Br. J. ind. Med., 44, 57–59

Edling, C., Hellquist, H. & Ödkvist, L. (1987b) Occupational formaldehyde exposure and the nasal

mucosa. Rhinology, 25, 181–187

Edling, C., Hellquist, H. & Ödkvist, L. (1988) Occupational exposure to formaldehyde and histopathological changes in the nasal mucosa. Br. J. ind. Med., 45, 761–765

Eells, J.T., McMartin, K.E., Black, K., Virayotha, V., Tisdell, R.H. & Tephly, T.R. (1981) Formaldehyde poisoning. Rapid metabolism to formic acid. J. am. Med. Assoc., 246, 1237–1238

Eitzer, B.D., Iannucci-Berger, W.A., Mark, G. & Zito, C. (1997) Fate of toxic compounds during

composting. Bull. environ. Contam. Toxicol., 58, 953–960

Elci, O.C., Akpinar-Elci, M., Blair, A. & Dosemeci, M. (2003) Risk of laryngeal cancer by occupational chemical exposure in Turkey. J. occup. environ. Med., 45, 1100–1106

Elias, I. (1987) [Evaluation of methods for disinfection of operating theatres in hospitals according

to the concentration of formaldehyde in the air.] Zbl. Arbeitsmed., 37, 389–397 (in German)

Elliott, L.J., Stayner, L.T., Blade, L.M., Halperin, W. & Keenlyside, R. (1987) Formaldehyde

Exposure Characterization in Garment Manufacturing Plants: A Composite Summary of

Three In-depth Industrial Hygiene Surveys, Cincinnati, OH, US Department of Health and

Human Services, Public Health Service, Centers for Disease Control, National Institute for

Occupational Safety and Health

Enterline, P.E., Marsh, G.M., Henderson, V. & Callahan, C. (1987) Mortality update of a cohort of

US man-made mineral fibre workers. Ann. occup. Hyg., 31, 625–656

Environment Canada (1997) Results of the CEPA Section 16 Notice to Industry Respecting the

Second Priority Substances List and Di(2-ethylhexyl) Phthalate, Hull, Quebec, Use Patterns

Section, Commercial Chemicals Evaluation Branch

290 IARC MONOGRAPHS VOLUME 88
Environment Canada (1999) Canadian Environmental Protection Act — Priority Substances List

— Supporting Document for the Environmental Assessment of Formaldehyde, Hull, Quebec,

Commercial Chemicals Evaluation Branch

Environment Canada/Health Canada (2001) Canadian Environmental Protection Act, 1999.

Priority Substances List Assessment Report: Formaldehyde, Ottawa, Ontario 

Environmental Protection Agency (1976) Investigation of Selected Potential Environmental

Contaminants: Formaldehyde (Report No. EPA-560/2-76-009; PB 256 839), Washington DC,

Office of Toxic Substances 

Environmental Protection Agency (1988) Compendium of Methods for the Determination of Toxic

Organic Compounds in Ambient Air (Report No. EPA-600/4-89-017; US NTIS PB90-116989),

Research Triangle Park, NC, Office of Research and Development, pp. TO5-1–TO5-22

Environmental Protection Agency (1999a) Method 318 — Extractive FTIR method for the Measurement of Emissions from the Mineral Wool and Wool Fiberglass Industries, Washington DC

Environmental Protection Agency (1999b) Test Method 320 — Measurement of Vapor Phase Organic

and Inorganic Emissions by Extractive Fourier Transform Infrared (FTIR) Spectroscopy,

Washington DC

Environmental Protection Agency (1999c) Compendium of Methods for the Determination of Toxic

Organic Compounds in Ambient Air (Report No. EPA-625/R-96-010b), 2nd Ed., Cincinnati,

OH, Office of Research and Development, pp. TO11A-1–TO11A-56

Epstein, S.S. & Shafner, H. (1968) Chemical mutagens in the human environment. Nature, 219,

385–387

Epstein, S.S., Arnold, E., Andrea, J., Bass, W. & Bishop, Y. (1972) Detection of chemical mutagens

by the dominant lethal assay in the mouse. Toxicol. appl. Pharmacol., 23, 288–325

Erdei, E., Bobvos, J., Brózik, M., Páldy, A., Farkas, I., Vaskövi, E. & Rudnai, P. (2003) Indoor air

pollutants and immune biomarkers among Hungarian asthmatic children. Arch. environ.

Health, 58, 337–347 

Ericson, A., Källén, B., Zetterström, R., Eriksson, M. & Westerholm, P. (1984) Delivery outcome

of women working in laboratories during pregnancy. Arch. environ. Health, 39, 5–10

Estonius, M., Svensson, S. & Höög, J.-O. (1996) Alcohol dehydrogenase in human tissues: localisation of transcripts coding for five classes of the enzyme. FEBS Lett., 397, 338–342

European Commission (1989) Formaldehyde Emission from Wood Based Materials: Guideline for

the Determination of Steady State Concentrations in Test Chambers (EUR 12196 EN; Report

No. 2), Luxembourg, European Concerted Action: Indoor Air Quality and Its Impact on Man

(COST Project 613)

European Commission (1990) Proposal for a Council Directive on the approximation of the laws

of the Member States relating to cosmetic products (90/C322/06). Off. J. Eur. Commun.,

C322, 29–77

European Union (1989) Council Directive 89/106/EEC of 21 December 1988 on the Approximation

of the Laws, Regulations and Administrative Provisions of the Member States Relating to Construction Products, Annex on Legislation on the Release of Dangerous Substances (89/106/EEC)

[Available at: http://europa.eu.int/comm/enterprise/construction/internal/dangsub/dangcount.

htm; accessed 01/03/2004]

Fantuzzi, G., Aggazzotti, G., Righi, E., Cavazzuti, L., Predieri, G. & Franceschelli, A. (1996)

Indoor air quality in the university libraries of Modena (Italy). Sci. total Environ., 193, 49–56

FORMALDEHYDE 291
Fayerweather, W.E., Pell, S. & Bender, J.R. (1983) Case–control study of cancer deaths in DuPont

workers with potential exposure to formaldehyde. In: Clary, J.C., Gibson, J.E. & Waritz, R.S.,

eds, Formaldehyde. Toxicology, Epidemiology, and Mechanisms, New York, Marcel Dekker,

pp. 47–121

Feinman, S.E. (1988) Formaldehyde genotoxicity and teratogenicity. In: Feinman, S.E., ed.,

Formaldehyde. Sensitivity and Toxicity, Boca Raton, FL, CRC Press, pp. 167–178

Fenech, M., Holland, N., Chang, W.P., Zeiger, E. & Bonassi, S. (1999) The Human Micronucleus

Project — An international collaborative study on the use of the micronucleus technique for

measuring DNA damage in humans. Mutat. Res., 428, 271–283

Feng, Y., Wen, S., Wang, X., Sheng, G., He, Q., Tang, J. & Fu, J. (2004) Indoor and outdoor carbonyl

compounds in the hotel ballrooms in Guangzhou, China. Atmos. Environ., 38, 103–112

Feron, V.J., Bruyntjes, J.P., Woutersen, R.A., Immel, H.R. & Appelman, L.M. (1988) Nasal tumours

in rats after short-term exposure to a cytotoxic concentration of formaldehyde. Cancer Lett., 39,

101–111

Feron, V.J., Til, H.P. & Woutersen, R.A. (1990) Letter to the Editor. Toxicol. ind. Health, 6, 637–639

Feron, V.J., Til, H.P., de Vrijer, F., Woutersen, R.A., Cassee, F.R. & van Bladeren, P.J. (1991)

Aldehydes: Occurrence, carcinogenic potential, mechanism of action and risk assessment. Mutat.

Res., 259, 363–385

Ferrari, C.P., Kaluzny, P., Roche, A., Jacob, V. & Foster, P. (1998) Aromatic hydrocarbons and

aldehydes in the atmosphere of Grenoble, France. Chemosphere, 37, 1587–1601

Finnish Institute of Occupational Health (1994) Measurements of Formaldehyde, Industrial

Hygiene Data Base, Helsinki

Fló-Neyret, C., Lorenzi-Filho, G., Macchione, M., Garcia, M.L.B. & Saldiva, P.H.N. (2001) Effects

of formaldehyde on the frog’s mucociliary epithelium as a surrogate to evaluate air pollution

effects on the respiratory epithelium. Braz. J. med. biol. Res., 34, 639–643

Fontignie-Houbrechts, N. (1981) Genetic effects of formaldehyde in the mouse. Mutat. Res., 88,

109–114

Food & Drug Administration (2003) Food and drugs. US Code fed. Regul., Title 21, Parts 173.340,

175.105, 176.170, 176.180, 176.200, 176.210, 177.2800, 178.3120, 529.1030, 573.460

[www.fda.gov]

Fornace, A.J., Jr, Lechner, J.F., Grafström, R.C. & Harris, C.C. (1982) DNA repair in human

bronchial epithelial cells. Carcinogenesis, 3, 1373–1377

Fransman, W., McLean, D., Douwes, J., Demers, P.A., Leung, V. & Pearce, N. (2003) Respiratory

symptoms and occupational exposures in New Zealand plywood mill workers. Ann. occup.

Hyg., 47, 287–295

Friedfeld, S., Fraser, M., Lancaster, D., Leleux, D., Rehle, D. & Tittel, F. (2000) Field intercomparison of a novel optical sensor for formaldehyde quantification. Geophys. Res. Lett., 27,

2093–2096

Friedman, G.D. & Ury, H.K. (1983) Screening for possible drug carcinogenicity: Second report of

findings. J. natl Cancer Inst., 71, 1165–1175

Fritschi, L. & Siemiatycki, J. (1996) Lymphoma, myeloma and occupation: Results of a case–

control study. Int. J. Cancer, 67, 498–503

Gaffney, J.S., Marley, N.A., Martin, R.S., Dixon, R.W., Reyes, L.G. & Popp, C.J. (1997) Potential

air quality effects of using ethanol–gasoline fuel blends: A field study in Albuquerque, New

Mexico. Environ. Sci. Technol., 31, 3053–3061 

292 IARC MONOGRAPHS VOLUME 88
Gallagher, R.P., Threlfall, W.J., Band, P.R., Spinelli, J.J. & Coldman, A.J. (1986) Occupational

Mortality in British Columbia 1950–1978, Ottawa, Statistics Canada, Health and Welfare

Canada

Gallagher, R.P., Threlfall, W.J., Band, P.R. & Spinelli, J.J. (1989) Occupational Mortality in

British Columbia 1950–1984, Vancouver, Canadian Cancer Association of British Columbia

Gammage, R.B. & Gupta, K.C. (1984) Formaldehyde. In: Walsh, P.J., Dudney, C.S. & Copenhaver,

E.D., eds, Indoor Air Quality, Boca Raton, FL, CRC Press, pp. 109–142

Gammage, R.G. & Travis, C.C. (1989) Formaldehyde exposure and risk in mobile homes. In:

Paustenbach, D.J., ed., The Risk Assessment of Environmental and Human Health Hazards:

A Textbook of Case Studies, New York, John Wiley & Sons, pp. 601–611

García-Alonso, S. & Pérez-Pastor, R.M. (1998) Use of C18 and silica-gel coated Sep-Pak cartridges

for the determination of carbonyls in air by liquid chromatography. Anal. chim. Acta, 367,

93–99

Gardner, M.J., Pannett, B., Winter, P.D. & Cruddas, A.M. (1993) A cohort study of workers exposed

to formaldehyde in the British chemical industry: An update. Br. J. ind. Med., 50, 827–834

Garrett, M.H., Hooper, M.A. & Hooper, B.M. (1997) Formaldehyde in Australian homes; levels

and sources. Clean Air, 31, 28–32

Garrett, M.H., Hooper, M.A., Hooper, B.M., Rayment, P.R. & Abramson, M.J. (1999) Increased

risk of allergy in children due to formaldehyde exposure in homes. Allergy, 54, 330–337

Gaylor, D.W., Lutz, W.K. & Conolly, R.B. (2004) Statistical analysis of nonmonotonic dose–

response relationships: Research design and analysis of nasal cell proliferation in rats exposed

to formaldehyde. Toxicol. Sci., 77, 158–164

Georghiou, P.E., Winsor, L., Sliwinski, J.F. & Shirtliffe, C.J. (1993) Method 11. Determination of

formaldehyde in indoor air by a liquid sorbent technique. In: Seifert, B., van de Wiel, H.,

Dodet, B. & O’Neill, I.K., eds, Environmental Carcinogens: Methods of Analysis and Exposure Measurement. Vol. 12: Indoor Air Contaminants (IARC Scientific Publications No. 109),

Lyon, IARC, pp. 245–249

Georgieva, A.V., Kimbell, J.S. & Schlosser, P.M. (2003) A distributed-parameter model for formaldehyde uptake and disposition in the rat nasal lining. Inhal. Toxicol., 15, 1435–1463

Gerberich, H.R. & Seaman, G.C. (2004) Formaldehyde. In: Kroschwitz, J.I. & Howe-Grant, M.,

eds, Kirk–Othmer Encyclopedia of Chemical Technology, 5th Ed., Vol. 11, New York, John

Wiley & Sons, pp. 929–951

Gérin, M., Siemiatycki, J., Nadon, L., Dewar, R. & Krewski, D. (1989) Cancer risks due to occupational exposure to formaldehyde: Results of a multi-site case–control study in Montreal. Int.

J. Cancer, 44, 53–58

Gibson, J.E. (1984) Coordinated toxicology: An example study with formaldehyde. Concepts

Toxicol., 1, 276–282

Gocke, E., King, M.-T., Eckhardt, K. & Wild, D. (1981) Mutagenicity of cosmetics ingredients

licensed by the European Communities. Mutat. Res., 90, 91–109

Gofmekler, V.A. (1968) [Embryotropic action of benzol and formaldehyde on experimental introduction by the respiratory route.] Gig. Sanit., 33, 327–332 (in Russian)

Gofmekler, V.A. & Bonashevskaya, T.I. (1969) [Experimental studies of teratogenic properties of

formaldehyde, based on pathological investigations.] Hyg. Sanit., 34, 266–268 (in Russian)

Gofmekler, V.A., Pushkina, N.N. & Klevtsova. G.N. (1968) [Some biochemical aspects of the

embryotropic effect of benzene and formaldehyde.] Hyg. Sanit., 33, 112–116 (in Russian)

FORMALDEHYDE 293
Goldmacher, V.S. & Thilly, W.G. (1983) Formaldehyde is mutagenic for cultured human cells.

Mutat. Res., 116, 417–422

Goldoft, M., Weiss, N., Vaughan, T. & Lee, J. (1993) Nasal melanoma. Br. J. ind. Med., 50,

767–768

Goldstein, H.B. (1973) Textiles and the chemical industry: A marriage. J. am. Assoc. Text. Chem.

Color., 5, 209–214 

Goldstein, B.D. (1990) Is exposure to benzene a cause of human multiple myeloma? Ann. N.Y.

Acad. Sci., 609, 225–234

Gosselin, N.H., Brunet, R.C. & Carrier, G. (2003) Comparative occupational exposures to formaldehyde released from inhaled wood product dusts versus that in vapor form. Appl. occup.

environ. Hyg., 18, 384–393

Gotoh, Y., Sumimoto, H. & Minakami, S. (1990) Formation of 20-oxoleukotriene B4 by an alcohol

dehydrogenase isolated from human neutrophils. Biochim. biophys. Acta, 1043, 52–56

Gottschling, L.M., Beaulieu, H.J. & Melvin, W.W. (1984) Monitoring of formic acid in urine of

humans exposed to low levels of formaldehyde. Am. ind. Hyg. Assoc. J., 45, 19–23

Grafström, R.C (1990) In vitro studies of aldehyde effects related to human respiratory carcinogenesis. Mutat. Res., 238, 175–184

Grafström, R.C., Fornace, A., Jr & Harris, C.C. (1984) Repair of DNA damage caused by formaldehyde in human cells. Cancer Res., 44, 4323–4327

Grafström, R.C., Curren, R.D., Yang, L.L. & Harris, C.C. (1985) Genotoxicity of formaldehyde in

cultured human bronchial fibroblasts. Science, 228, 89–91

Grafström, R.C., Willey, J.C., Sundqvist, K. & Harris, C.C. (1986) Pathobiological effects of

tobacco smoke-related aldehydes in cultured human bronchial epithelial cells. In: Hoffmann, D.

& Harris, C.C., eds, Mechanisms in Tobacco Carcinogenesis (Banbury Report 23), Cold Spring

Harbor, NY, CSH Press, pp. 273–285

Grafström, R.C., Hsu, I.-C. & Harris, C.C. (1993) Mutagenicity of formaldehyde in Chinese

hamster lung fibroblasts: Synergy with ionizing radiation and N-nitroso-N-methylurea. Chem.-

biol. Interactions, 86, 41–49

Grafström, R.C., Jernelöv, M.I., Dypbukt, J.M., Sundqvist, K., Atzori, L. & Zheng, X. (1996) Aldehyde toxicity and thiol redox state in cell cultures from human aerodigestive tract. In: Mohr, U.,

Adler, K.B., Dungworth, D.I., Harris, C.C., Plopper, C.G. & Saracci, R., eds, Correlations

Between In Vitro and In Vivo Investigations in Inhalation Toxicology, Washington DC, ILSI

Press, pp. 319–336

Granby, K., Christensen, C.S. & Lohse, C. (1997) Urban and semi-rural observations of carboxylic

acids and carbonyls. Atmos. Environ., 31, 1403–1415

Graves, R.J., Callander, R.D. & Green, T. (1994) The role of formaldehyde and S-chloromethylglutathione in the bacterial mutagenicity of methylene chloride. Mutat. Res., 320, 235–243

Graves, R.J., Trueman, P., Jones, S. & Green, T. (1996) DNA sequence analysis of methylene

chloride-induced HPRT mutations in Chinese hamster ovary cells: Comparison with the mutation spectrum obtained for 1,2-dibromoethane and formaldehyde. Mutagenesis, 11, 229–233

Green, D.J., Sauder, L.R., Kulle, T.J. & Bascom, R. (1987) Acute response to 3.0 ppm formaldehyde

in exercising healthy nonsmokers and asthmatics. Am. Rev. respir. Dis., 135, 1261–1266

Groah, W.J., Bradfield, J., Gramp, G., Rudzinski, R. & Heroux, G. (1991) Comparative response of

reconstituted wood products to European and North American test methods for determining

formaldehyde emissions. Environ. Sci. Technol., 25, 117–122

294 IARC MONOGRAPHS VOLUME 88
Grosjean, E., Williams, E.L., II & Grosjean, D. (1993) Ambient levels of formaldehyde and

acetaldehyde in Atlanta, Georgia. J. Air Waste Manage. Assoc., 43, 469–474

Grosjean, E., Grosjean, D., Fraser, M.P. & Cass, G.R. (1996) Air quality model evaluation data for

organics. 2. C1-C14 carbonyls in Los Angeles air. Environ. Sci. Technol., 30, 2687–2703

Grosjean, D., Grosjean, E. & Moreira, L.F.R. (2002) Speciated ambient carbonyls in Rio de

Janeiro, Brazil. Environ. Sci. Technol., 36, 1389–1395

Gustavsson, P., Jakobsson, R., Johansson, H., Lewin, F., Norell, S. & Rutkvist, L.-E. (1998) Occupational exposures and squamous cell carcinoma of the oral cavity, pharynx, larynx, and oesophagus: A case–control study in Sweden. Occup. environ. Med., 55, 393–400

Gylseth, B. & Digernes, V. (1992) The European development of regulations and standards for

formaldehyde in air and in wood composite boards. In: Proceedings of the Pacific Rim Biobased Composites Symposium, 9–13 November 1992, Rotorua, New Zealand, Rotorua, Forest

Products Research Institute, pp. 199–206

Hagberg, M., Kolmodin-Hedman, B., Lindahl, R., Nilsson, C.-A. & Nordström, Å. (1985) Irritative complaints, carboxyhemoglobin increase and minor ventilatory function changes due to

exposure to chain-saw exhaust. Eur. J. respir. Dis., 66, 240–247

Hagen, J.A., Nafstad, P., Skrondal, A., Bjørkly, S. & Magnus, P. (2000) Associations between outdoor air pollutants and hospitalization for respiratory diseases. Epidemiology, 11, 136–140 

Hall, A., Harrington, J.M. & Aw, T.-C. (1991) Mortality study of British pathologists. Am. J. ind.

Med., 20, 83–89

Hamaguchi, F. & Tsutsui, T. (2000) Assessment of genotoxicity of dental antiseptics: Ability of

phenol, guaiacol, p-phenolsulfonic acid, sodium hypochlorite, p-chlorophenol, m-cresol or

formaldehyde to induce unscheduled DNA synthesis in cultured Syrian hamster embryo cells.

Jpn J. Pharmacol., 83, 273–276

Hansch, C., Leo, A. & Hoekman (1995) Exploring QSAR — Hydrophobic, Electronic, and Steric

Constants, Washington DC, American Chemical Society

Hansen, J. & Olsen, J.H. (1995) Formaldehyde and cancer morbidity among male employees in

Denmark. Cancer Causes Control, 6, 354–360

Hansen, J. & Olsen, J.H. (1996) [Occupational exposure to formaldehyde and risk for cancer.]

Ugeskr. Laeger., 158, 4191–4194 (in Danish)

Hardell, L., Johansson, B. & Axelson, O. (1982) Epidemiological study of nasal and nasopharyngeal cancer and their relation to phenoxy acid or chlorophenol exposure. Am. J. ind. Med., 3,

247–257

Harrington, J.M. & Oakes, D. (1984) Mortality study of British pathologists 1974–80. Br. J. ind.

Med., 41, 188–191

Harrington, J.M. & Shannon, H.S. (1975) Mortality study of pathologists and medical laboratory

technicians. Br. med. J., i, 329–332

Harving, H., Korsgaard, J., Pedersen, O.F., Mølhave, L. & Dahl, R. (1990) Pulmonary function and

bronchial reactivity in asthmatics during low-level formaldehyde exposure. Lung, 168, 15–21 

Haszpra, L. Szilágyi, I., Demeter, A., Turányi, T. & Bérces, T. (1991) Non-methane hydrocarbon

and aldehyde measurements in Budapest, Hungary. Atmos. Environ., 25, 2103–2110

Hauptmann, M., Lubin, J.H., Stewart, P.A., Hayes, R.B. & Blair, A. (2003) Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries. J. natl Cancer Inst.,

95, 1615–1623

FORMALDEHYDE 295
Hauptmann, M., Lubin, J.H., Stewart, P.A., Hayes, R.B. & Blair, A. (2004) Mortality from solid

cancers among workers in formaldehyde industries. Am. J. Epidemiol., 159, 1117–1130

Haworth, S., Lawlor, T., Mortelmans, K., Speck, W. & Zeiger, E. (1983) Salmonella mutagenicity

test results for 250 chemicals. Environ. Mutag., Suppl. 1, 3–142

Hayasaka, Y., Yayasaka, S. & Nagaki, Y. (2001) Ocular changes after intravitreal injection of

methanol, formaldehyde, or formate in rabbits. Pharmacol. Toxicol., 89, 74–78

Hayes, R.B., Raatgever, J.W., de Bruyn, A. & Gerin, M. (1986a) Cancer of the nasal cavity and

paranasal sinuses, and formaldehyde exposure. Int. J. Cancer, 37, 487–492

Hayes, R.B., Gérin, M., Raatgever, J.W. & de Bruyn, A. (1986b) Wood-related occupations, wood

dust exposure, and sinonasal cancer. Am. J. Epidemiol., 124, 569–577

Hayes, R.B., Blair, A., Stewart, P.A., Herrick, R.F. & Mahar, H. (1990) Mortality of US embalmers

and funeral directors. Am. J. ind. Med., 18, 641–652

Hayes, R.B., Klein, S., Suruda, A., Schulte, P., Boeniger, M., Stewart, P., Livingston, G.K. &

Oesch, F. (1997) O6-Alkylguanine DNA alkyltansferase activity in student embalmers. Am. J.

ind. Med., 31, 361–365 

He, J.-L., Jin, L.-F. & Jin, H.-Y. (1998) Detection of cytogenetic effects in peripheral lymphocytes

of students exposed to formaldehyde with cytokinesis-blocked micronucleus assay. Biomed.

environ. Sci., 11, 87–92

Health & Safety Executive (2002) Occupational Exposure Limits 2002 (EH40/2002), Norwich,

Her Majesty’ Stationery Office 

Health Canada (2000) Draft Supporting Documentation for PSL2 Assessments. Human Exposure

Assessment for Formaldehyde, Ottawa, Ontario, Priority Substances Section, Health Protection

Branch

Heck, H.d’A. & Casanova, M. (1987) Isotope effects and their implications for the covalent

binding of inhaled [3H]- and [14C]formaldehyde in the rat nasal mucosa. Toxicol. appl. Pharmacol., 89, 122–134

Heck, H.d’A. & Casanova, M. (1995) Nasal dosimetry of formaldehyde: Modelling site specificity

and the effects of pre-exposure. In: Miller, F.J., ed., Nasal Toxicity and Dosimetry of Inhaled

Xenobiotics: Implications for Human Health, Washington DC, Taylor Francis, pp. 159–175 

Heck, H.d’A. & Casanova, M. (1999) Pharmacodynamics of formaldehyde: Applications of a

model for the arrest of DNA replication by DNA–protein cross-links. Toxicol. appl. Pharmacol., 160, 86–100

Heck, H.d’A. & Casanova, M. (2004) The implausibility of leukemia induction by formaldehyde:

A critical review of the biological evidence on distant-site toxicity. Regul. Toxicol. Pharmacol., 40, 92–106

Heck, H.d’A., White, E.L. & Casanova-Schmitz, M. (1982) Determination of formaldehyde in biological tissues by gas chromatography/mass spectrometry. Biomed. mass Spectrom., 9, 347–353

Heck, H.d’A., Chin, T.Y. & Schmitz, M.C. (1983) Distribution of [14C]formaldehyde in rats after

inhalation exposure. In: Gibson, J.E., ed., Formaldehyde Toxicity, Washington DC, Hemisphere, pp. 26–37

Heck, H.d’A., Casanova-Schmitz, M., Dodd, P.B., Schachter, E.N., Witek, T.J. & Tosun, T. (1985)

Formaldehyde (CH2O) concentrations in the blood of humans and Fischer-344 rats exposed to

CH2O under controlled conditions. Am. ind. Hyg. Assoc. J., 46, 1–3

Heck, H.d’A., Casanova, M., Lam, C.-W. & Swenberg, J.A. (1986) The formation of DNA–protein

cross-links by aldehydes present in tobacco smoke. In: Hoffmann, D. & Harris, C.C., eds,

296 IARC MONOGRAPHS VOLUME 88
Mechanisms in Tobacco Carcinogenesis (Banbury Report 23), Cold Spring Harbor, NY, CSH

Press, pp. 215–230

Heck, H.d’A., Casanova, M., Steinhagen, W.H., Everitt, J.I., Morgan, K.T. & Popp, J.A. (1989)

Formaldehyde toxicity: DNA–protein cross-linking studies in rats and nonhuman primates. In:

Feron, V.J. & Bosland, M.C., eds, Nasal Carcinogenesis in Rodents: Relevance to Human

Risk, Wageningen, Pudoc, pp. 159–164

Hedberg, J.J., Strömberg, P. & Höög, J.-O. (1998) An attempt to transform class characteristics

within the alcohol dehydrogenase family. FEBS Lett., 436, 67–70

Hedberg, J.J., Höög, J.-O., Nilsson, J.A., Zheng, X., Elfwing, A. & Grafström, R.C. (2000) Expression of alcohol dehydrogenase 3 in tissue and cultured cells from human oral mucosa. Am. J.

Pathol., 157, 1745–1755

Hedberg, J.J., Backlund, M., Strömberg, P., Lönn, S., Dahl, M.-L., Ingelman-Sundberg, M. & Höög,

J.-O. (2001) Functional polymorphism in the alcohol dehydrogenase 3 (ADH3) promoter.

Pharmacogenetics, 11, 815–824

Hedberg, J.J., Höög, J.-O. & Grafström R.C. (2002) Assessment of formaldehyde metabolizing

enzymes in human oral mucosa and cultured oral keratinocytes indicate high capacity for detoxification of formaldehyde. In: Heinrich, U. & Mohr, U., eds, Crucial Issues in Inhalation

Research — Mechanistic, Clinical and Epidemiologic (INIS Monographs), Stuttgart, Fraunhofer

IRB Verlag, pp. 103–115 

Hedberg, J.J., Griffiths, W.J., Nilsson, S.J.F. & Höög, J.-O. (2003) Reduction of S-nitrosoglutathione by human alcohol dehydrogenase 3 is an irreversible reaction as analysed by electrospray mass spectrometry. Eur. J. Biochem., 270, 1249–1256

Heikkilä, P., Priha, E. & Savela, A. (1991) [Formaldehyde (Exposures at Work No. 14)], Helsinki,

Finnish Institute of Occupational Health and Finnish Work Environment Fund (in Finnish)

Hemminki, K., Mutanen, P., Saloniemi, I., Niemi, M.-L. & Vainio, H. (1982) Spontaneous abortions in hospital staff engaged in sterilising instruments with chemical agents. Br. med. J., 285,

1461–1463

Hemminki, K., Kyyrönen, P. & Lindbohm, M.-L. (1985) Spontaneous abortions and malformations

in the offspring of nurses exposed to anaesthetic gases, cytostatic drugs, and other potential

hazards in hospitals, based on registered information of outcome. J. Epidemiol. Community

Health, 39, 141–147

Hemminki, K., Partanen, R., Koskinen, H., Smith, S., Carney, W. & Brandt-Rauf, P.W. (1996) The

molecular epidemiology of oncogens. Serum p53 protein in patients with asbestosis. Chest,

109, 22S–26S

Hendrick, D.J. & Lane, D.J. (1975) Formalin asthma in hospital staff. Br. med. J., i, 607–608

Hendrick, D.J. & Lane, D.J. (1977) Occupational formalin asthma. Br. J. ind. Med., 34, 11–18

Hendrick, D.J., Rando, R.J., Lane, D.J. & Morris, M.J. (1982) Formaldehyde asthma: Challenge

exposure levels and fate after five years. J. occup. Med., 24, 893–897

Herbert, F.A., Hessel, P.A., Melenka, L.S., Yoshida, K. & Nakaza, M. (1995) Pulmonary effects of

simultaneous exposures to MDI formaldehyde and wood dust on workers in an oriented strand

board plant. J. occup. environ. Med., 37, 461–465

Hernberg, S., Westerholm, P., Schultz-Larsen, K., Degerth, R., Kuosma, E., Englund, A., Engzell,

U., Sand Hansen, H. & Mutanen, P. (1983a) Nasal and sinonasal cancer. Connection with

occupational exposures in Denmark, Finland and Sweden. Scand. J. Work Environ. Health, 9,

315–326

FORMALDEHYDE 297
Hernberg, S., Collan, Y., Degerth, R., Englund, A., Engzell, U., Kuosma, E., Mutanen, P.,

Nordlinder, H., Sand Hansen, H., Schultz-Larsen, K., Søgaard, H. & Westerholm, P. (1983b)

Nasal cancer and occupational exposures. Preliminary report of a joint Nordic case–referent

study. Scand. J. Work Environ. Health, 9, 208–213

Hester, S.D., Benavides, G.B., Yoon, L., Morgan, K.T., Zou, F., Barry, W. & Wolf, D.C. (2003)

Formaldehyde-induced gene expression in F344 rat nasal respiratory epithelium. Toxicology,

187, 13–24

Hildesheim, A., West, S., DeVeyra, E., De Guzman, M.F., Jurado, A., Jones, C., Imai, J. & Hinuma,

Y. (1992) Herbal medicine use, Epstein–Barr virus, and risk of nasopharyngeal carcinoma.

Cancer Res., 52, 3048–3051

Hildesheim, A., Dosemeci, M., Chan, C.-C., Chen, C.-J., Cheng, Y.-J., Hsu, M.-M., Chen, I.-H.,

Mittl, B.F., Sun, B., Levine, P.H., Chen, J.-Y., Brinton, L.A. & Yang, C.-S. (2001) Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma.

Cancer Epidemiol. Biomarkers Prev., 10, 1145–1153

Hilton, J., Dearman, R.J., Basketter, D.A., Scholes, E.W. & Kimber, I. (1996) Experimental assessment of the sensitizing properties of formaldehyde. Food chem. Toxicol., 34, 571–578

Ho, K.F., Lee, S.C., Louie, P.K.K. & Zou, S.C. (2002) Seasonal variation of carbonyl compound

concentrations in urban area of Hong Kong. Atmos. Environ., 36, 1259–1265

Hodgson, A.T., Wooley, J.D. & Daisey, J.M. (1993) Emissions of volatile organic compounds from

new carpets measured in a large-scale environmental chamber. J. Air Waste Manage. Assoc.,

43, 316–324

Hodgson, A.T., Rudd, A.F., Beal, D. & Chandra, S. (2000) Volatile organic compound concentrations and emission rates in new manufactured and site-built houses. Indoor Air, 10, 178–192

Hodgson, A.T., Beal, D. & McIlvane, J.E.R. (2002) Sources of formaldehyde, other aldehydes and

terpenes in a new manufactured house. Indoor Air, 12, 235–242

Holly, E.A., Aston, D.A., Ahn, D.K. & Smith, A.H. (1996) Intraocular melanoma linked to occupations and chemical exposures. Epidemiology, 7, 55–61

Holmquist, B. & Vallee, B.L. (1991) Human liver class III alcohol and glutathione dependent

formaldehyde dehydrogenase are the same enzyme. Biochem. biophys. Res. Commun., 178,

1371–1377

Holmström, M., Wilhelmsson, B., Hellquist, H. & Rosén, G. (1989a) Histological changes in the

nasal mucosa in persons occupationally exposed to formaldehyde alone and in combination

with wood dust. Acta otolaryngol., 107, 120–129

Holmström, M., Wilhelmsson, B. & Hellquist, H. (1989b) Histological changes in the nasal mucosa

in rats after long-term exposure to formaldehyde and wood dust. Acta otolaryngol., 108,

274–283

Holmström, M., Rynnel-Dagöö, B. & Wilhelmsson, B. (1989c) Antibody production in rats after

long-term exposure to formaldehyde. Toxicol. appl. Pharmacol., 100, 328–333 

Höög, J.-O., Hedberg, J.J., Strömberg, P. & Svensson, S. (2001) Mammalian alcohol dehydrogenase — Functional and structural implications. J. biomed. Sci., 8, 71–76

Höög, J.-O., Strömberg, P., Hedberg, J.J. & Griffiths, W.J. (2003) The mammalian alcohol dehydrogenases interact in several metabolic pathways. Chem.-biol. Interactions, 143–144, 175–181

Horton, A.W., Tye, R. & Stemmer, K.L. (1963) Experimental carcinogenesis of the lung. Inhalation

of gaseous formaldehyde or an aerosol of coal tar by C3H mice. J. natl Cancer Inst., 30, 31–43

298 IARC MONOGRAPHS VOLUME 88
IARC (1979) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to

Humans, Vol. 19, Some Monomers, Plastics and Synthetic Elastomers, and Acrolein, Lyon,

pp. 314–340

IARC (1982) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to

Humans, Vol. 29, Some Industrial Chemicals and Dyestuffs, Lyon, pp. 345–389

IARC (1983) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to

Humans, Vol. 32, Polynuclear Aromatic Compounds, Part 1, Chemical, Environmental and

Experimental Data, Lyon

IARC (1984) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to

Humans, Vol. 34, Polynuclear Aromatic Compounds, Part 3, Industrial Exposures in Aluminium Production, Coal Gasification, Coke Production, and Iron and Steel Founding, Lyon

IARC (1986) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to

Humans, Vol. 39, Some Chemicals Used in Plastics and Elastomers, Lyon, pp. 287–323

IARC (1987a) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Suppl. 7,

Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1–42,

Lyon, pp. 211–216

IARC (1987b) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Suppl. 7,

Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1–42,

Lyon, pp. 131–134

IARC (1987c) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Suppl. 7,

Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1–42,

Lyon, pp. 152–154

IARC (1987d) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to

Humans, Vol. 42, Silica and Some Silicates, Lyon, pp. 39–143

IARC (1987e) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Suppl. 7,

Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1–42,

Lyon, pp. 106–116

IARC (1989a) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 47,

Some Organic Solvents, Resin Monomers and Related Compounds, Pigments and Occupational Exposures in Paint Manufacture and Painting, Lyon, pp. 125–156

IARC (1989b) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 47,

Some Organic Solvents, Resin Monomers and Related Compounds, Pigments and Occupational Exposures in Paint Manufacture and Painting, Lyon, pp. 79–123

IARC (1989c) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 47,

Some Organic Solvents, Resin Monomers and Related Compounds, Pigments and

Occupational Exposures in Paint Manufacture and Painting, Lyon, pp. 263–287

IARC (1990a) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 48,

Some Flame Retardants and Textile Chemicals, and Exposures in the Textile Manufacturing

Industry, Lyon, pp. 181–212

IARC (1990b) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 48,

Some Flame Retardants and Textile Chemicals, and Exposures in the Textile Manufacturing

Industry, Lyon, pp. 215–280

IARC (1994a) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 60,

Some Industrial Chemicals, pp. 445–474

FORMALDEHYDE 299
IARC (1994b) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 60,

Some Industrial Chemicals, pp. 73–159

IARC (1995) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 62,

Wood Dust and Formaldehyde, Lyon, pp. 217–362 

IARC (1999) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 71, Reevaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide, Lyon

IARC (2002) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 81,

Man-made Vitreous Fibres, Lyon

IARC (2004) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 83,

Tobacco Smoke and Involuntary Smoking, Lyon

Inoue, K., Nishimukai, H. & Yamasawa, K. (1979) Purification and partial characterization of

aldehyde dehydrogenase from human erythrocytes. Biochim. biophys. Acta, 569, 117–123

INRS (Institut national de Recherche et de Sécurité) (2005) [Threshold Limit Values for Occupational Exposure to Chemicals in France] (Notes documentaires 2098), Paris, Hygiène et Sécurité du Travail (in French)

International Labour Office (2001) Safety in the Use of Synthetic Vitreous Fibre Insulation Wool

(Glass Wool, Rockwool, Slag Wool), Geneva, International Labour Organization, p. 20

Interscan Corporation (undated) Portable Analyzer (4000 Series) with Digital Display — Formaldehyde, Chatsworth, CA

Ishidate, M., Jr, Sofuni, T. & Yoshikawa, K. (1981) Chromosomal aberration tests in vitro as a

primary screening tool for environmental mutagens and/or carcinogens. Gann Monogr. Cancer

Res., 27, 95–108

Iversen, O.H. (1986) Formaldehyde and skin carcinogenesis. Environ. int., 12, 541–544

Jaeger, R.J. & Gearhart, J.M. (1982) Respiratory and metabolic response of rats and mice to

formalin vapor. Toxicology, 25, 299–309

James, J.T. (1997) Carcinogens in spacecraft air. Radiat. Res., 148, S11–S16

Jankovic, J., Jones, W., Burkhart, J. & Noonan, G. (1991) Environmental study of firefighters. Ann.

occup. Hyg., 35, 581–602 

Jann, O. (1991) Present state and developments in formaldehyde regulations and testing methods in

Germany. In: Proceedings of the 25th International Particleboard/Composite Materials Symposium, Pullman, WA, Washington State University

Japanese Standards Association (2001) Japanese Industrial Standard: Building Boards. Determination of Formaldehdye Emission — Dessicator Method (JIS A-1460:2001), Tokyo 

Jeffcoat, A.R., Chasalow, F., Feldman, D.B. & Marr, H. (1983) Disposition of [14C]formaldehyde

after topical exposure to rats, guinea pigs, and monkeys. In: Gibson, J.E., ed., Formaldehyde

Toxicity, Washington DC, Hemisphere, pp. 38–50

Jensen, O.M. & Andersen, S.K. (1982) Lung cancer risk from formaldehyde. Lancet, i, 913

Jensen, N.J. & Cohr, K.-H. (1983) Testing of formaldehyde in the mammalian spot test by inhalation (Abstract No. 73). Mutat. Res., 113, 266

Jensen, K.A., Kirk, I., Kølmark, G. & Westergaard, M. (1951) Chemically induced mutations in

Neurospora. Cold Spring Harbor Symp. quant. Biol., 16, 245–261

Jensen, D.E., Belka, G.K. & Du Bois, G.C. (1998) S-Nitrosoglutathione is a substrate for rat alcohol

dehydrogenase class III isoenzyme. Biochem. J., 331, 659–668

Johannsen, F.R., Levinskas, G.J. & Tegeris, A.S. (1986) Effects of formaldehyde in the rat and dog

following oral exposure. Toxicol. Lett., 30, 1–6

300 IARC MONOGRAPHS VOLUME 88
John, E.M., Savitz, D.A. & Shy, C.M. (1994) Spontaneous abortions among cosmetologists. Epidemiology, 5, 147–155

Johnsen, R.C. & Baillie, D.L. (1988) Formaldehyde mutagenesis of the eT1 balanced region in

Caenorhabditis elegans: Dose–response curve and the analysis of mutation events. Mutat.

Res., 201, 137–147

Jones, D.P., Thor, H., Andersson, B. & Orrenius, S. (1978) Detoxification reactions in isolated

hepatocytes. Role of glutathione peroxidase, catalase, and formaldehyde dehydrogenase in

reactions relating to N-demethylation by the cytochrome P-450 system. J. biol. Chem., 253,

6031–6037

Jörnvall, H. & Höög, J.-O. (1995) Nomenclature of alcohol dehydrogenases. Alcohol Alcohol., 30,

153–161

Jörnvall, H., Höög, J.-O., Persson, B. & Parés, X. (2000) Pharmacogenetics of the alcohol

dehydrogenase system. Pharmacology, 61, 184–191

Jurvelin, J., Vartiainen, M., Jantunen, M. & Pasanen, P. (2001) Personal exposure levels and microenvironmental concentrations of formaldehyde and acetaldehyde in the Helsinki metropolitan

area, Finland. J. Air Waste Manage. Assoc., 51, 17–24

Jurvelin, J.A., Edwards, R.D., Vartiainen, M., Pasanen, P. & Jantunen, M.J. (2003) Residential

indoor, outdoor, and workplace concentrations of carbonyl compounds: Relationships with

personal exposure concentrations and correlation with sources. J. Air Waste Manage. Assoc.,

53, 560–573

Kalabokas, P., Carlier, P., Fresnet, P., Mouvier, G. & Toupance, G. (1988) Field studies of aldehyde

chemistry in the Paris area. Atmos. Environ., 22, 147–155

Kalász, H. (2003) Biological role of formaldehyde, and cycles related to methylation, demethylation,

and formaldehyde production. Mini Rev. med. Chem., 3, 175–192

Kamata, E., Nakadate, M., Uchida, O., Ogawa, Y., Suzuki, S., Kaneko, T., Saito, M. & Kurokawa,

Y. (1997) Results of a 28-month chronic inhalation toxicity study of formaldehyde in male

Fisher-344 rats. J. toxicol. Sci., 22, 239–254

Kaplan, W.D. (1948) Formaldehyde as a mutagen in Drosophila. Science, 108, 43

Karlberg, A.-T., Skare, L., Lindberg, I. & Nyhammar, E. (1998) A method for quantification of

formaldehyde in the presence of formaldehyde donors in skin-care products. Contact Derm.,

38, 20–28

Katakura, Y., Kishi, R., Ikeda, T. & Miyake, H. (1990) [Distributions of [14C]-formaldehyde and

their metabolites in pregnant mice.] Sangyo Igaku, 32, 42–43 (in Japanese)

Katakura, Y., Okui, T., Kishi, R., Ikeda, T. & Miyake, H. (1991) [Distribution of 14C-formaldehyde

in pregnant mice: A study by liquid scintillation counter and binding to DNA.] Sangyo Igaku,

33, 264–265 (in Japanese)

Katakura, Y., Kishi, R., Okui, T., Ikeda, T. & Miyake, H. (1993) Distribution of radioactivity from 14C-formaldehyde in pregnant mice and their fetuses. Br. J. ind. Med., 50, 176–182

Kato, S., Burke, P.J., Koch, T.H. & Bierbaum, V.M. (2001) Formaldehyde in human cancer cells:

Detection by preconcentration-chemical ionization mass spectrometry. Anal. Chem., 73,

2992–2997

Kauppinen, T. (1986) Occupational exposure to chemical agents in the plywood industry. Ann.

occup. Hyg., 30, 19–29

Kauppinen, T. & Niemelä, R. (1985) Occupational exposure to chemical agents in the

particleboard industry. Scand. J. Work Environ. Health, 11, 357–363

FORMALDEHYDE 301
Kauppinen, T. & Partanen, T. (1988) Use of plant- and period-specific job–exposure matrices in

studies on occupational cancer. Scand. J. Work Environ. Health, 14, 161–167

Kauppinen, T., Toikkanen, J., Pedersen, D., Young, R., Ahrens, W., Boffetta, P., Hansen, J.,

Kromhout, H., Maqueda Blasco J., Mirabelli, D., de la Orden-Rivera, V., Pannett, B., Plato,

N., Savela, A., Vincent, R. & Kogevinas, M. (2000) Occupational exposure to carcinogens in

the European Union. Occup. environ. Med., 57, 10–18

Keil, C.B., Akbar-Khanzadeh, F. & Konecny, K.A. (2001) Characterizing formaldehyde emission

rates in a gross anatomy laboratory. Appl. occup. environ. Hyg., 16, 967–972 

Kelly, T.J., Smith, D.L. & Satola, J. (1999) Emission rates of formaldehyde from materials and

consumer products found in California homes. Environ. Sci. Technol., 33, 81–88

Kennedy, E.R., Gagnon, Y.T., Teass, A.W. & Seitz, T. (1992) Development and evaluation of a

method to estimate potential formaldehyde dose from inhalable dust/fibers. Appl. occup.

environ. Hyg., 7, 231–240 

Kepler, G.M., Richardson, R.B., Morgan, K.T. & Kimbell, J.S. (1998) Computer simulation of inspiratory nasal airflow and inhaled gas uptake in a rhesus monkey. Toxicol. appl. Pharmacol., 150,

1–11

Kerfoot, E.J. & Mooney, T.F., Jr (1975) Formaldehyde and paraformaldehyde study in funeral

homes. Am. ind. Hyg. Assoc. J., 36, 533–537 

Kernan, G.J., Ji, B.-T., Dosemeci, M., Silverman, D.T., Balbus, J. & Zahm, S.H. (1999) Occupational risk factors for pancreatic cancer: A case–control study based on death certificates from

24 US states. Am. J. ind. Med., 36, 260–270

Kerns, W.D., Pavkov, K.L., Donofrio, D.J., Gralla, E.J. & Swenberg, J.A. (1983a) Carcinogenicity

of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res., 43,

4382–4392

Kerns, W.D., Donofrio, D.J. & Pavkov, K.L. (1983b) The chronic effects of formaldehyde inhalation

in rats and mice: A preliminary report. In: Gibson, J.E., ed., Formaldehyde Toxicity, Washington

DC, Hemisphere, pp. 111–131

Khan, A.H. (1967) The induction of crossing over in the absence of mutation. Sind Univ. Sci. Res.

J., 3, 103–106

Khoder, M.I., Shakour, A.A., Farag, S.A. & Abdel Hameed, A.A. (2000) Indoor and outdoor

formaldehyde concentrations in homes in residential areas in Greater Cairo. J. environ. Monit.,

2, 123–126

Khwaja, H.A. (1995) Atmospheric concentrations of carboxylic acids and related compounds at a

semiurban site. Atmos. Environ., 29, 127–139

Kiec-Swierczynska, M., Krecisz, B., Krysiak, B., Kuchowicz, E. & Rydzynski, K. (1998) Occupational allergy to aldehydes in health care workers. Clinical observations. Experiments. Int. J.

occup. Med. environ. Health, 11, 349–358

Kilburn, K.H. & Moro, A. (1985) Reproductive and maternal effects of formaldehyde (HCHO) in

rats (Abstract). Fed. Proc., 44, 535 

Kilburn, K.H., Seidman, B.C. & Warshaw, R. (1985) Neurobehavioral and respiratory symptoms

of formaldehyde and xylene exposure in histology technicians. Arch. environ Health, 40,

229–233 

Kim, H., Kim, Y.-D. & Cho, S.-H. (1999) Formaldehyde exposure levels and serum antibodies to

formaldehyde–human serum albumin of Korean medical students. Arch. environ. Health, 54,

115–118 

302 IARC MONOGRAPHS VOLUME 88
Kim, C.-W., Song, J.-S., Ahn, Y.-S., Park, S.-H., Park, J.-W., Noh, J.-H. & Hong, C.-S. (2001)

Occupational asthma due to formaldehyde. Yonsei med. J., 42, 440–445

Kim, W.J., Terada, N., Nomura, T., Takahashi, R., Lee, S.D., Park, J.H. & Konno, A. (2002) Effect

of formaldehyde on the expression of adhesion molecules in nasal microvascular endothelial

cells: The role of formaldehyde in the pathogenesis of sick building syndrome. Clin. exp. Allergy,

32, 287–295

Kimbell, J.S. & Subramaniam, R.P. (2001) Use of computational fluid dynamics models for dosimetry of inhaled gases in the nasal passages. Inhal. Toxicol., 13, 325–334

Kimbell, J.S., Gross, E.A., Richardson, R.B., Conolly, R.B. & Morgan, K.T. (1997) Correlation of

regional formaldehyde flux predictions with the distribution of formaldehyde-induced

squamous metaplasia in F344 rat nasal passages. Mutat. Res., 380, 143–154

Kimbell, J.S., Overton, J.H., Subramaniam, R.P., Schlosser, P.M., Morgan, K.T., Conolly, R.B. &

Miller, F.J. (2001a) Dosimetry modeling of inhaled formaldehyde: Binning nasal flux predictions for quantitative risk assessment. Toxicol. Sci., 64, 111–121

Kimbell, J.S., Subramaniam, R.P., Gross, E.A., Schlosser, P.M. & Morgan, K.T. (2001b) Dosimetry modeling of inhaled formaldehyde: Comparisons of local flux predictions in the rat,

monkey, and human nasal passages. Toxicol. Sci., 64, 100–110

Kimbell, J.S., Schlosser, P.M., Conolly, R.B. & Miller, F.J. (2002) Dosimetry modelling of inhaled

formaldehyde. CIIT Activities, 22, 1–8

Kinney, P.L., Chillrud, S.N., Ramstrom, S., Ross, J. & Spengler, J.D. (2002) Exposures to multiple

air toxics in New York City. Environ. Health Perspect., 110 (Suppl. 4), 539–546

Kirchstetter, T.W., Singer, B.C., Harley, R.A., Kendall, G.R. & Chan, W. (1996) Impact of oxygenated gasoline use on California light-duty vehicle emissions. Environ. Sci. Technol., 30,

661–670 

Kitaeva, L.V., Kitaev, E.M. & Pimenova, M.N. (1990) [The cytopathic and cytogenetic effects of

chronic inhalation of formaldehyde on germ and marrow cells of the female rat.] Tsitologiia,

32, 1212–1216 (in Russian)

Kitaeva, L.V., Mikheeva, E.A., Shelomova, L.F. & Shvartsman, P.Y. (1996) [Genotoxic effect of

formaldehyde in somatic human cells in vivo.] Genetika, 32, 1298–1290 (in Russian)

Kligerman, A.D., Phelps, M.C. & Erexson, G.L. (1984) Cytogenetic analysis of lymphocytes from

rats following formaldehyde inhalation. Toxicol. Lett., 21, 241–246

Koeck, M., Pichler-Semmelrock, F.P. & Schlacher, R. (1997) Formaldehyde — Study of indoor air

pollution in Austria. Centr. Eur. J. public Health, 5, 127–130

Koivusalo, M., Baumann, M. & Uotila, L. (1989) Evidence for the identity of glutathione-dependent

formaldehyde dehydrogenase and class III alcohol dehydrogenase. FEBS Lett., 257, 105–109 

Kölmark, G. & Westergaard, M. (1953) Further studies on chemically induced reversions at the

adenine locus of Neurospora. Hereditas, 39, 209–224

Köppel, C., Baudisch, H., Schneider, V. & Ibe, K. (1990) Suicidal ingestion of formalin with fatal

complications. Intensive Care Med., 16, 212–214

Korczynski, R.E. (1994) Formaldehyde exposure in the funeral industry. Appl. occup. environ.

Hyg., 9, 575–579

Korczynski, R.E. (1996) Effectiveness of downdraft ventilation in morgues. Appl. occup. environ.

Hyg., 11, 5–8 

Korhonen, K., Liukkonen,T., Ahrens, W., Astrakianakis, G., Boffetta, P., Burdorf, A., Heederik, D.,

Kauppinen, T., Kogevinas, M., Osvoll, P., Rix, B.A., Saalo, A., Sunyer, J., SzadkowskaFORMALDEHYDE 303
Stanczyk, I., Teschke, K., Westberg, H. & Widerkiewicz, K. (2004) Occupational exposure to

chemical agents in the paper industry. Int. Arch. occup. environ. Health, 77, 451–460

Korky, J.K., Schwarz, S.R. & Lustigman, B.K. (1987) Formaldehyde concentrations in biology

department teaching facilities. Bull. environ. Contam. Toxicol., 38, 907–910

Krakowiak, A., Górski, P., Pazdrak, K. & Ruta, U. (1998) Airway response to formaldehyde inhalation in asthmatic subjects with suspected respiratory formaldehyde sensitization. Am. J. ind.

Med., 33, 274–281

Kreiger, R.A. & Garry, V.F. (1983) Formaldehyde-induced cytotoxicity and sister-chromatid

exchanges in human lymphocyte cultures. Mutat. Res., 120, 51–55

Kriebel, D., Sama, S.R. & Cocanour, B. (1993) Reversible pulmonary responses to formaldehyde.

A study of clinical anatomy students. Am. Rev. respir. Dis., 148, 1509–1515

Krieger, P., De Blay, F., Pauli, G. & Kopferschmitt, M.-C. (1998) [Asthma and domestic chemical

pollutants (except for tobacco).] Rev. Mal. respir., 15, 11–24 (in French)

Kulle, T.J. (1993) Acute odor and irritation response in healthy nonsmokers with formaldehyde

exposure. Inhal. Toxicol., 5, 323–332 

Kulle, T.J., Sauder, L.R., Hebel, J.R., Green, D.J. & Chatham, M.D. (1987) Formaldehyde dose–

response in healthy nonsmokers. J. Air Pollut. Control Assoc., 37, 919–924 

Kuykendall, J.R. & Bogdanffy, M.S. (1992) Efficiency of DNA–histone crosslinking induced by

saturated and unsaturated aldehydes in vitro. Mutat. Res., 283, 131–136

Laforest, L., Luce, D., Goldberg, P., Bégin, D., Gérin, M., Demers, P.A., Brugère, J. & Leclerc, A.

(2000) Laryngeal and hypopharyngeal cancers and occupational exposure to formaldehyde

and various dusts: A case–control study in France. Occup. environ. Med., 57, 767–773

Lam, C.-W., Casanova, M. & Heck, H.d’A. (1985) Depletion of nasal mucosal glutathione by acrolein and enhancement of formaldehyde-induced DNA–protein cross-linking by simultaneous

exposure to acrolein. Arch. Toxicol., 58, 67–71

Lamont Moore, L. & Ogrodnik, E.C. (1986) Occupational exposure to formaldehyde in mortuaries.

J. environ. Health, 49, 32–35

Lancaster, D.G., Fried, A., Wert, B., Henry, B. & Tittel, F.K. (2000) Difference-frequency-based

tunable absorption spectrometer for detection of atmospheric formaldehyde. Appl. Optics, 39,

4436–4443

Leclerc, A., Martinez Cortes, M., Gérin, M., Luce, D. & Brugère, J. (1994) Sinonasal cancer and

wood dust exposure: Results from a case–control study. Am. J. Epidemiol., 140, 340–349

Le Curieux, F., Marzin, D. & Erb, F. (1993) Comparison of three short-term assays: Results on

seven chemicals. Potential contribution to the control of water genotoxicity. Mutat. Res., 319,

223–236

Lee, S. & Radtke, T. (1998) Exposure to formaldehyde among fish hatchery workers. Appl. occup.

environ. Hyg., 13, 3–6 

Lee, H.K., Alarie, Y. & Karol, M.H. (1984) Induction of formaldehyde sensitivity in guinea pigs.

Toxicol. appl. Pharmacol., 75, 147–155 

Lehmann, W.F. & Roffael, E. (1992) International guidelines and regulations for formaldehyde

emissions. In: Proceedings of the 26th Washington State University International Particleboard/Composite Materials Symposium, Pullman, WA, Washington State University,

pp. 124–150

304 IARC MONOGRAPHS VOLUME 88
Leifer, Z., Hyman, J. & Rosenkranz, H.S. (1981) Determination of genotoxic activity using DNA

polymerase-deficient and -proficient E. coli. In: Stich, H.F. & San, R.H.C., eds, Short-term

Tests for Chemical Carcinogenesis, New York, Springer, pp. 127–139

Lemus, R., Abdelghani, A.A., Akers, T.G. & Horner, W.E. (1998) Potential health risks from exposure to indoor formaldehyde. Rev. environ. Health, 13, 91–98

Lévesque, B., Allaire, S., Gauvin, D., Koutrakis, P., Gingras, S., Rhainds, M., Prud’Homme, H. &

Duchesne, J.-F. (2001) Wood-burning appliances and indoor air quality. Sci. total Environ.,

281, 47–62

Levine, R.J., Andjelkovich, D.A., & Shaw, L.K. (1984) The mortality of Ontario undertakers and

a review of formaldehyde-related mortality studies. J. occup. Med., 26, 740–746

Levy, S., Nocentini, S. & Billardon, C. (1983) Induction of cytogenetic effects in human fibroblast

cultures after exposure to formaldehyde or X-rays. Mutat. Res., 119, 309–317

Lewis, B. (1998) Formaldehyde in dentistry: A review for the millennium. J. clin. pediatr. Dent.,

22, 167–177 

Lewis, K.J., Ward, M.K. & Kerr, D.N.S. (1981) Residual formaldehyde in dialyzers: Quantity,

location, and the effect of different methods of rinsing. Artif. Organs, 5, 269–277

Liber, H.L., Benforado, K., Crosby, R.M., Simpson, D. & Skopek, T.R. (1989) Formaldehydeinduced and spontaneous alterations in human hprt DNA sequence and mRNA expression.

Mutat. Res., 226, 31–37

Lide, D.R., ed. (2003) CRC Handbook of Chemistry and Physics, 84th Ed., Boca Raton, FL, CRC

Press, p. 3-288

Liebling, T., Rosenman, K.D., Pastides, H., Griffith, R.G., & Lemeshow, S. (1984) Cancer mortality among workers exposed to formaldehyde. Am. J. ind. Med., 5, 423–428

Lindbohm, M.-L., Hemminki, K., Bonhomme, M.G., Anttila, A., Rantala, K., Heikkilä, P. &

Rosenberg, M.J. (1991) Effects of paternal occupational exposure on spontaneous abortions.

Am. J. public Health, 81, 1029–1033 

Lindstrom, A.B., Proffitt, D. & Fortune, C.R. (1995) Effects of modified residential construction

on indoor air quality. Indoor Air, 5, 258–269 

Linos, A., Blair, A., Cantor, K.P., Burmeister, L., VanLier, S., Gibson, R.W., Schuman, L. &

Everett, G. (1990) Leukemia and non-Hodgkin’s lymphoma among embalmers and funeral

directors (Letter to the Editor). J. natl Cancer Inst., 82, 66

Liteplo, R.G. & Meek, M.E. (2003) Inhaled formaldehyde: Exposure estimation, hazard characterization, and exposure–response analysis. J. Toxicol. environ. Health, B6, 85–114

Liu, L., Hausladen, A., Zeng, M., Que, L., Heitman, J. & Stamler, J.S. (2001) A metabolic enzyme

for S-nitrosothiol conserved from bacteria to humans. Nature, 410, 490–494 

Lodén, M. (1986) The in vitro permeability of human skin to benzene, ethylene glycol, formaldehyde, and n-hexane. Acta pharmacol. toxicol., 58, 382–389

Logue, J.N., Barrick, M.K. & Jessup, G.L., Jr (1986) Mortality of radiologists and pathologists in

the radiation registry of physicians. J. occup. Med., 28, 91–99

Lovschall, H., Eiskjaer, M. & Arenholt-Bindslev, D. (2002) Formaldehyde cytotoxicity in three

human cell types assessed in three different assays. Toxicol. in Vitro, 16, 63–69 

Luce, D., Leclerc, A., Morcet, J.F., Casal-Lareo, A., Gérin, M., Brugère, J., Haguenoer, J.M. &

Goldberg, M. (1992) Occupational risk factors for sinonasal cancer: A case–control study in

France. Am. J. ind. Med., 21, 163–175

FORMALDEHYDE 305
Luce, D., Gérin, M., Leclerc, A., Morcet, J.-F., Brugère, J. & Goldberg, M. (1993) Sinonasal cancer

and occupational exposure to formaldehyde and other substances. Int. J. Cancer, 53, 224–231

Luce, D., Leclerc, A., Bégin, D., Demers, P.A., Gérin, M., Orlowski, E., Kogevinas, M., Belli, S.,

Bugel, I., Bolm-Audorff, U., Brinton, L.A., Comba, P., Hardell, L., Hayes, R.B., Magnani, C.,

Merler, E., Preston-Martin, S., Vaughan, T.L., Zheng, W. & Boffetta, P. (2002) Sinonasal

cancer and occupational exposures: A pooled analysis of 12 case–control studies. Cancer

Causes Control, 13, 147–157

Luker, M.A. & Van Houten, R.W. (1990) Control of formaldehyde in a garment sewing plant. Am.

ind. Hyg. Assoc. J., 51, 541–544

Luo, J.-C., Zehab, R., Anttila, S., Ridanpaa, M., Husgafvel-Pursiainen, K., Vainio, H., Carney, W.,

DeVivo, I., Milling, C. & Brandt-Rauf, P.W. (1994) Detection of serum p53 protein in lung

cancer patients. J. occup. Med., 36, 155–160

Luo, W., Li, H., Zhang, Y. & Ang, C.Y.W. (2001) Determination of formaldehyde in blood plasma

by high-performance liquid chromatography with fluorescence detection. J. Chromatogr.,

B753, 253–257

Ma, T.-H. & Harris, M.M. (1988) Review of the genotoxicity of formaldehyde. Mutat. Res., 196,

37–59

Mackerer, C.R., Angelosanto, F.A., Blackburn, G.R. & Schreiner, C.A. (1996) Identification of

formaldehyde as the metabolite responsible for the mutagenicity of methyl tertiary-butyl ether

in the activiated mouse lymphoma assay. Proc. Soc. exp. Biol. Med., 212, 338–341

Magaña-Schwencke, N. & Ekert, B. (1978) Biochemical analysis of damage induced in yeast by

formaldehyde. II. Induction of cross-links between DNA and protein. Mutat. Res., 51, 11–19

Magaña-Schwencke, N. & Moustacchi, E. (1980) Biochemical analysis of damage induced in yeast

by formaldehyde. III. Repair of induced cross-links between DNA and proteins in the wildtype and in excision-deficient strains. Mutat. Res., 70, 29–35

Magaña-Schwencke, N., Ekert, B. & Moustacchi, E. (1978) Biochemical analysis of damage

induced in yeast by formaldehyde. I. Induction of single-strand breaks in DNA and their repair.

Mutat. Res., 50, 181–193

Magnani, C., Comba, P., Ferraris, F., Ivaldi, C., Meneghin, M. & Terracini, B. (1993) A case–control

study of carcinomas of the nose and paranasal sinuses in the woolen textile manufacturing

industry. Arch. environ. Health, 48, 94–97

Maibach, H. (1983) Formaldehyde: Effects on animal and human skin. In: Gibson, J.E., ed., Formaldehyde Toxicity, Washington DC, Hemisphere, pp. 166–174

Maier, K.L., Wippermann, U., Leuschel, L., Josten, M., Pflugmacher, S., Schröder, P., Sandermann,

H., Jr, Takenaka, S., Ziesenis, A. & Heyder, J. (1999) Xenobiotic-metabolizing enzymes in the

canine respiratory tract. Inhal. Toxicol., 11, 19–35

Maître, A., Soulat, J.-M., Masclet, P., Stoklov, M., Marquès, M. & de Gaudemaris, R. (2002) Exposure to carcinogenic air pollutants among policemen working close to traffic in an urban area.

Scand. J. Work Environ. Health, 28, 402–410

Mäkinen, M., Kalliokoski, P. & Kangas, J. (1999) Assessment of total exposure to phenol–formaldehyde resin glue in plywood manufacturing. Int. Arch. occup. environ. Health, 72, 309–314

Malaka, T. & Kodama, A.M. (1990) Respiratory health of plywood workers occupationally

exposed to formaldehyde. Arch. environ. Health, 45, 288–294

Malek, F.A., Möritz, K.-U. & Fanghänel, J. (2003) A study on the effect of inhalative formaldehyde

exposure on water labyrinth test performance in rats. Ann. Anat., 185, 277–285

306 IARC MONOGRAPHS VOLUME 88
Malker, H.R. & Weiner, J. (1984) [Cancer–Environment Registry: Examples of the Use of Register

Epidemiology in Studies of the Work Environment] (Arbete och Hälsa 1984;9), Stockholm,

Arbetarskyddsverket (in Swedish)

Malorny, G., Rietbrock, N. & Schneider, M. (1965) [Oxidation of formaldehyde to formic acid in

blood, a contribution to the metabolism of formaldehyde.] Naunyn–Schmiedeberg’s Arch. exp.

Pathol. Pharmakol., 250, 419–436 (in German)

’t Mannetje, A., Kogevinas, M., Luce, D., Demers, P.A., Bégin, D., Bolm-Audorff, U., Comba, P.,

Gérin, M., Hardell, L., Hayes, R.B., Leclerc, A., Magnani, C., Merler, E., Tobías, A. &

Boffetta, P. (1999) Sinonasal cancer, occupation, and tobacco smoking in European women

and men. Am. J. ind. Med., 36, 101–107

Marnett, L.J., Hurd, H.K., Hollstein, M.C., Levin, D.E., Esterbauer, H. & Ames, B.N. (1985) Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104. Mutat.

Res., 148, 25–34

Maronpot, R.A., Miller, R.A., Clarke, W.J., Westerberg, R.B., Decker, J.R. & Moss, O.R. (1986)

Toxicity of formaldehyde vapor in B6C3F1 mice exposed for 13 weeks. Toxicology, 41,

253–266 

Maroziene, L. & Grazuleviciene, R. (2002) Maternal exposure to low-level air pollution and

pregnancy outcomes: A population-based study. Environ. Health, 1, 6–12

Marsh, G.M. (1982) Proportional mortality patterns among chemical plant workers exposed to

formaldehyde. Br. J. ind. Med., 39, 313–322

Marsh, G.M. (1983) Proportional mortality among chemical workers exposed to formaldehyde. In:

Gibson, J.E., ed., Formaldehyde Toxicity, Washington DC, Hemisphere, pp. 237–255

Marsh, G.M. & Youk, A.O. (2004) Reevaluation of mortality risks from leukemia in the formaldehyde cohort study of the National Cancer Institute. Regul. Toxicol. Pharmacol., 40, 113–124

Marsh, G.M., Stone, R.A. & Henderson, V.L. (1992a) A reanalysis of the National Cancer Institute

study on lung cancer mortality among industrial workers exposed to formaldehyde. J. occup.

Med., 34, 42–44

Marsh, G.M., Stone, R.A. & Henderson, V.L. (1992b) Lung cancer mortality among industrial

workers exposed to formaldehyde: A Poisson regression analysis of the National Cancer Institute study. Am. ind. Hyg. Assoc. J., 53, 681–691

Marsh, G.M., Stone, R.A., Esmen, N.A. & Henderson, V.L. (1994) Mortality patterns among

chemical plant workers exposed to formaldehyde and other substances (Brief

communication). J. natl Cancer Inst., 86, 384–386

Marsh, G.M., Stone, R.A., Esmen, N.A., Henderson, V.L. & Lee, K.Y. (1996) Mortality among

chemical workers in a factory where formaldehyde was used. Occup. environ. Med., 53,

613–627

Marsh, G.M., Youk, A.O., Stone, R.A., Buchanich, J.M., Gula, M.J., Smith, T.J. & Quinn, M.M.

(2001) Historical cohort study of US man-made vitreous fiber production workers: I. 1992

fiberglass cohort follow-up: Initial findings. J. occup. environ. Med., 43, 741–756

Marsh, G.M., Youk, A.O., Buchanich, J.M., Cassidy, L.D., Lucas, L.J., Esmen, N.A. & Gathuru,

I.M. (2002) Pharyngeal cancer mortality among chemical plant workers exposed to formaldehyde. Toxicol. ind. Health, 18, 257–268

Martin, W.J. (1990) A teratology study of inhaled formaldehyde in rat. Reprod. Toxicol., 4,

237–239 

FORMALDEHYDE 307
Mašek, V. (1972) [Aldehydes in the air of workplaces in coal coking and pitch coking plants.]

Staub-Reinhalt Luft, 32, 335–336 (in German)

Mashford, P.M. & Jones, A.R. (1982) Formaldehyde metabolism by the rat: A re-appraisal. Xenobiotica, 12, 119–124

Matanoski, G.M. (1991) Risk of Pathologists Exposed to Formaldehyde (NTIS/PB91-173682),

Springfield, VA, National Technical Information Service

Materna, B.L., Jones, J.R., Sutton, P.M., Rothman, N. & Harrison, R.J. (1992) Occupational exposures in California wildland fire fighting. Am. ind. Hyg. Assoc. J., 53, 69–76 

Matheson Tri-Gas® (2004) Detector Tube Listing for Matheson-Kitagawa Toxic Gas Detector

System (Technical Bulletin 102-1, Issue 3), Irving, TX

Mathew, L., Tai, W.R. & Lo, J.-G. (2001) Measurements of sulfur dioxide and formaldehyde in

Taipei using a differential optical absorption spetrometer. J. Air Waste Manage. Assoc., 51,

94–101

Mathison, B.H., Harman, A.E. & Bogdanffy, M.S. (1997) DNA damage in the nasal passageway:

A literature review. Mutat. Res., 380, 77–96

Maurice, F., Rivory, J.-P., Larsson, P.H., Johansson, S.G.O. & Bousquet, J. (1986) Anaphylactic

shock caused by formaldehyde in a patient undergoing long-term hemodialysis. J. Allergy clin.

Immunol., 77, 594–597

Mautz, W.J. (2003) Exercising animal models in inhalation toxicology: Interactions with ozone and

formaldehyde. Environ. Res., 92, 14–26

McClellan, R.O. (1995) Risk assessment and biological mechanisms: Lessons learned, future

opportunities. Toxicology, 102, 239–258

McGuire, M.T., Casserly, D.M. & Greff, R.M. (1992) Formaldehyde concentrations in fabric

stores. Appl. occup. environ. Hyg., 7, 112–119 

McMillan, A., Whittemore, A.S., Silvers, A. & DiCiccio, Y. (1994) Use of biological markers in

risk assessment. Risk Anal., 14, 807–813

Meister, A. & Anderson, M.E. (1983) Glutathione. Annu. Rev. Biochem., 52, 711–760

Merk, O. & Speit, G. (1998) Significance of formaldehyde-induced DNA–protein crosslinks for

mutagenesis. Environ. mol. Mutag., 32, 260–268

Merk, O. & Speit, G. (1999) Detection of crosslinks with the comet assay in relationship to genotoxicity and cytotoxicity. Environ. mol. Mutag., 33, 167–172

Merler, E., Baldasseroni, A., Laria, R., Faravelli, P., Agostini, R., Pisa, R. & Berrino, F. (1986) On

the causal association between exposure to leather dust and nasal cancer: Further evidence

from a case–control study. Br. J. ind. Med., 43, 91–95

Merletti, F., Boffetta, P., Ferro, G., Pisani, P. & Terracini, B. (1991) Occupation and cancer of the

oral cavity or oropharynx in Turin, Italy. Scand. J. Work Environ. Health, 17, 248–254

Mery, S., Gross, E.A., Joyner, D.R., Godo, M. & Morgan, K.T. (1994) Nasal diagrams: A tool for

recording the distribution of nasal lesions in rats and mice. Toxicol. Pathol., 22, 353–372 

Migliore, L., Ventura, L., Barale, R., Loprieno, N., Castellino, S. & Pulci, R. (1989) Micronuclei

and nuclear anomalies induced in the gastro-intestinal epithelium of rats treated with formaldehyde. Mutagenesis, 4, 327–334

Miguel, A.H., De Aquino Neto, F.R., Cardoso, J.N., Vasconcellos, P.C., Pereira, A.S. & Marquez,

K.S.G. (1995) Characterization of indoor air quality in the cities of São Paulo and Rio de

Janeiro, Brazil. Environ. Sci. Technol., 29, 338–345

308 IARC MONOGRAPHS VOLUME 88
Milham, S. (1983) Occupational Mortality in Washington State 1950–1979 (DHHS (NIOSH) Publication No. 83-116), Cincinatti, OH, National Institute for Occupational Safety and Health

Milton, D.K., Walters, M.D., Hammond, K. & Evans, J.S. (1996) Worker exposure to endotoxin,

phenolic compounds, and formaldehyde in a fiberglass insulation manufacturing plant. Am.

ind. Hyg. Assoc. J., 57, 889–896 

Miretskaya, L.M. & Shvartsman, P.Y. (1982) [Studies of chromosome aberrations in human lymphocytes under the influence of formaldehyde. 1. Formaldehyde treatment of lymphocytes

in vitro.] Tsitologiia, 24, 1056–1060 (in Russian)

MKS Instruments (2004a) Application Note: Formaldehyde Emissions Monitoring with MultiGasTM 2030 (App. Note #06/03), Wilmington, MA

MKS Instruments (2004b) MultiGasTM 2030 On-line Gas Analysis, Wilmington, MA

Molotkov, A., Fan, X., Deltour, L., Foglio, M.H., Martras, S., Farrés, J., Parés, X. & Duester, G.

(2002) Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol

dehydrogenase Adh3. Proc. natl Acad. Sci. USA, 99, 5337–5342

Monteiro-Riviere, N.A. & Popp, J.A. (1986) Ultrastructural evaluation of acute nasal toxicity in the

rat respiratory epithelium in response to formaldehyde gas. Fundam. appl. Toxicol., 6, 251–262

Montero, L., Vasconcellos, P.C., Souza, S.R., Pires, M.A.F., Sanchez-Ccoyllo, O.R., Andrade, M.F.

& Carvalho, L.R.F. (2001) Measurements of atmospheric carboxylic acids and carbonyl compounds in São Paulo City, Brazil. Environ. Sci. Technol., 35, 3071–3081 

Monticello, T.M. & Morgan, K.T. (1994) Cell proliferation and formaldehyde-induced respiratory

carcinogenesis. Risk Anal., 14, 313–319

Monticello, T.M. & Morgan, K.T. (1997) Chemically-induced nasal carcinogenesis and epithelial

cell proliferation: A brief review. Mutat. Res., 380, 33–41

Monticello, T.M., Morgan, K.T., Everitt, J.I. & Popp, J.A. (1989) Effects of formaldehyde gas on

the respiratory tract of rhesus monkeys. Pathology and cell proliferation. Am. J. Pathol., 134,

515–527

Monticello, T.M., Miller, F.J. & Morgan, K.T. (1991) Regional increases in rat nasal epithelial cell

proliferation following acute and subchronic inhalation of formaldehyde. Toxicol. appl. Pharmacol., 111, 409–421

Monticello, T.M., Gross, E.A. & Morgan, K.T. (1993) Cell proliferation and nasal carcinogenesis.

Environ. Health Perspect., 101 (Suppl. 5), 121–124 

Monticello, T.M., Swenberg, J.A., Gross, E.A., Leininger, J.R., Kimbell, J.S., Seilkop, S., Starr,

T.B., Gibson, J.E. & Morgan, K.T. (1996) Correlation of regional and nonlinear

formaldehyde-induced nasal cancer with proliferating populations of cells. Cancer Res., 56,

1012–1022

Morgan, K.T., Jiang, X.-Z., Starr, T.B. & Kerns, W.D. (1986a) More precise localization of nasal

tumors associated with chronic exposure of F-344 rats to formaldehyde gas. Toxicol. appl.

Pharmacol., 82, 264–271

Morgan, K.T., Patterson, D.L. & Gross, E.A. (1986b) Responses of the nasal mucociliary

apparatus of F-344 rats to formaldehyde gas. Toxicol. appl. Pharmacol., 82, 1–13

Morgan, K.T., Gross, E.A. & Patterson, D.L. (1986c) Distribution, progression, and recovery of

acute formaldehyde-induced inhibition of nasal mucociliary function in F-344 rats. Toxicol.

appl. Pharmacol., 86, 448–456

FORMALDEHYDE 309
Morgan, K.T., Kimbell, J.S., Monticello, T.M., Patra, A.L. & Fleishman, A. (1991) Studies of inspiratory airflow patterns in the nasal passages of the F344 rat and rhesus monkey using nasal

molds: Relevance to formaldehyde toxicity. Toxicol. appl. Pharmacol., 110, 223–240

MSA (1998) Detector Tubes and Pumps (Bulletin 08-00-02-MC), Pittsburgh, PA

Mukerjee, N. & Pietruszko, R. (1992) Human mitochondrial aldehyde dehydrogenase substrate

specificity: Comparison of esterase with dehydrogenase reaction. Arch. Biochem. Biophys.,

299, 23–29

Nakao, H., Umebayashi, C., Nakata, M., Nishizaki, Y., Noda, K., Okano, Y. & Oyama, Y. (2003)

Formaldehyde-induced shrinkage of rat thymocytes. J. pharmacol. Sci., 91, 83–86

Natarajan, A.T., Darroudi, F., Bussman, C.J.M. & van Kesteren-van Leeuwen, A.C. (1983) Evaluation of the mutagenicity of formaldehyde in mammalian cytogenetic assays in vivo and

in vitro. Mutat. Res., 122, 355–360

National Library of Medicine (NLM) (2004) TRI2001 — Toxics Release Inventory, Bethesda, MD

Naylor, S., Mason, R.P., Sanders, J.K.M., Williams, D.H. & Moneti, G. (1988) Formaldehyde adducts

of glutathione. Structure elucidation by two-dimensional n.m.r. spectroscopy and fast-atom-bombardment tandem mass spectrometry. Biochem. J., 249, 573–579

Neitzert, V. & Seiler, W. (1981) Measurement of formaldehyde in clean air. Geophys. Res. Lett., 8,

79–82

Neuberger, A. (1981) The metabolism of glycine and serine. In: Neuberger, A. & van Deenen,

L.L.M., eds, Comprehensive Biochemistry, Vol. 19A, Amino Acid Metabolism and Sulphur

Metabolism, Amsterdam, Elsevier, pp. 257–303

Nguyen, H.T.-H., Takenaka, N., Bandow, H., Maeda, Y., de Oliva, S.T., Botelho, M.M. & Tavares,

T.M. (2001) Atmospheric alcohols and aldehydes concentrations measured in Osaka, Japan

and in Sao Paulo, Brazil. Atmos. Environ., 35, 3075–3083

Nielsen, J. (2002) [Introduction to research in frozen fish and fishing.] In: [Proceedings of a Workshop on ‘High Quality Frozen Fish’, March 7, 2002], Copenhagen (in Danish)

Niemelä, R. & Vainio, H. (1981) Formaldehyde exposure in work and the general environment.

Occurrence and possibilities for prevention. Scand. J. Work Environ. Health, 7, 95–100

Nilsson, J.A., Zheng, X., Sundqvist, K., Liu, Y., Atzori, L., Elfwing, Å., Arvidson, K. & Grafström,

R.C. (1998) Toxicity of formaldehyde to human oral fibroblasts and epithelial cells: Influences

of culture conditions and role of thiol status. J. dent. Res., 77, 1896–1903

Nilsson, J.A., Hedberg, J.J., Vondracek, M., Staab, C.A., Hansson, A., Höög, J.-O. & Grafström,

R.C. (2004) Alcohol dehydrogenase 3 transcription associates with proliferation of human oral

keratinocytes. Cell. mol. Life Sci., 61, 610–617

NIOSH (National Institute for Occupational Safety and Health) (1994a) NIOSH Manual of Analytical Methods (NMAM®) (DHHS (NIOSH) Publ. No. 94-113), 4th Ed., Cincinnati, OH,

pp. 3500-1–3500-5 [http://www.cdc.gov/niosh/nmam/]

NIOSH (National Institute for Occupational Safety and Health) (1994b) NIOSH Manual of Analytical Methods (NMAM®) (DHHS (NIOSH) Publ. No. 94-113), 4th Ed., Cincinnati, OH,

pp. 2539-1–2539-10 [http://www.cdc.gov/niosh/nmam/]

NIOSH (National Institute for Occupational Safety and Health) (1994c) NIOSH Manual of Analytical Methods (NMAM®) (DHHS (NIOSH) Publ. No. 94-113), 4th Ed., Cincinnati, OH,

pp. 2541-1–2541-5 [http://www.cdc.gov/niosh/nmam/]

310 IARC MONOGRAPHS VOLUME 88
NIOSH (National Institute for Occupational Safety and Health) (1994d) NIOSH Manual of Analytical Methods (NMAM®) (DHHS (NIOSH) Publ. No. 94-113), 4th Ed., Cincinnati, OH,

pp. 5700-1–5700-5 [http://www.cdc.gov/niosh/nmam/]

NIOSH (National Institute for Occupational Safety and Health) (2003a) NIOSH Manual of Analytical Methods (NMAM®) (DHHS (NIOSH) Publ. 2003-154), 4th Ed., Supplement 3,

Cincinnati, OH, pp. 2016-1–2016-7 [http://www.cdc.gov/niosh/nmam/]

NIOSH (National Institute for Occupational Safety and Health) (2003b) NIOSH Manual of Analytical Methods (NMAM®) (DHHS (NIOSH) Publ. 2003-154), 4th Ed., Supplement 3,

Cincinnati, OH, pp. 3800-1–3800-47 [http://www.cdc.gov/niosh/nmam/]

Nishioka, H. (1973) Lethal and mutagenic action of formaldehyde in Hcr+ and Hcr– strains of

Escherichia coli. Mutat. Res., 17, 261–265

Nisse, C., Haguenoer, J.M., Grandbastien, B., Preudhomme, C., Fontaine, B., Brillet, J.M.,

Lejeune, R. & Fenaux, P. (2001) Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France. Br. J. Haematol., 112, 927–935

Norbäck, D., Björnsson, E., Janson, C., Widström, J. & Boman, G. (1995) Asthmatic symptoms

and volatile organic compounds, formaldehyde, and carbon dioxide in dwellings. Occup. environ. Med., 52, 388–395

Norbäck, D., Wålinder, R., Wieslander, G., Smedje, G., Erwall, C. & Venge, P. (2000) Indoor air

pollutants in schools: Nasal patency and biomarkers in nasal lavage. Allergy, 55, 163–170

Nordman, H., Keskinen, H. & Tuppurainen, M. (1985) Formaldehyde asthma — Rare or overlooked. J. Allergy clin. Immunol., 75, 91–99

Nousiainen, P. & Lindqvist, J. (1979) [Chemical Hazards in the Textile Industry. Air Contaminants] (Tiedonanto 16), Tampere, Valtion teknillinen tutkimuskeskus (in Finnish)

Obe, G. & Beek, B. (1979) Mutagenic activity of aldehydes. Drug Alcohol Dependence, 4, 91–94

Occupational Safety & Health Administration (1990a) OSHA Analytical Methods Manual, 2nd Ed.,

Part 1, Vol. 2 (Methods 29–54), Salt Lake City, UT, Method 52 [www.osha.gov]

Occupational Safety & Health Administration (1990b) OSHA Analytical Methods Manual, 2nd Ed.,

Part 2, Vol. 2 (Methods ID-160 to ID-210), Salt Lake City, UT, Method ID-205 [www.osha.gov]

O’Connor, P.M. & Fox, B.W. (1987) Comparative studies of DNA cross-linking reactions

following methylene dimethanesulphonate and its hydrolytic product, formaldehyde. Cancer

Chemother. Pharmacol., 19, 11–15

Odeigah, P.G.C. (1997) Sperm head abnormalities and dominant lethal effects of formaldehyde in

albino rats. Mutat. Res., 389, 141–148

O’Donovan, M.R. & Mee, C.D. (1993) Formaldehyde is a bacterial mutagen in a range of Salmonella and Escherichia indicator strains. Mutagenesis, 8, 577–581

Oftedal, B., Nafstad, P., Magnus, P., Bjørkly, S. & Skrondal, A. (2003) Traffic related air pollution

and acute hospital admission for respiratory diseases in Drammen, Norway 1995–2000. Eur.

J. Epidemiol., 18, 671–675

Ohta, T., Watanabe-Akanuma, M., Tokishita, S.-I. & Yamagata, H. (1999) Mutation spectra of

chemical mutagens determined by Lac+ reversion assay with Escherichia coli WP3101P–

WP3106P tester strains. Mutat. Res., 440, 59–74

Ohta, T., Watanabe-Akanuma, M. & Yamagata, H. (2000) A comparison of mutation spectra

detected by the Escherichia coli Lac+ reversion assay and the Salmonella typhimurium His+

reversion assay. Mutagenesis, 15, 317–323

FORMALDEHYDE 311
Ohtsuka, R., Shuto, Y., Fujie, H., Takeda, M., Harada, T. & Itagaki, S.-J. (1997) Response of respiratory epithelium of BN and F344 rats to formaldehyde inhalation. Exp. Anim., 46, 279–286

Ohtsuka, R., Shutoh, Y., Fujie, H., Yamaguchi, S., Takeda, M., Harada, T. & Doi, K. (2003) Rat

strain difference in histology and expression of Th1- and Th2-related cytokines in nasal

mucosa after short-term formaldehyde inhalation. Exp. Toxicol. Pathol., 54, 287–291

Ojajärvi, I.A., Partanen, T.J., Ahlbom, A., Boffetta, P., Hakulinen, T., Jourenkova, N., Kauppinen,

T.P., Kogevinas, M., Porta, M., Vainio, H.U., Weiderpass, E. & Wesseling, C.H. (2000) Occupational exposures and pancreatic cancer: A meta-analysis. Occup. environ. Med., 57, 316–324

Olin, K.L., Cherr, G.N., Rifkin, E. & Keen, C.L. (1996) The effects of some redox-active metals

and reactive aldehydes on DNA–protein cross-links in vitro. Toxicology, 110, 1–8

Olsen, J.H. & Asnaes, S. (1986) Formaldehyde and the risk of squamous cell carcinoma of the

sinonasal cavities. Br. J. ind. Med., 43, 769–774

Olsen, J.H., Plough Jensen, S., Hink, M., Faurbo, K., Breum, N.O. & Møller Jensen, O. (1984)

Occupational formaldehyde exposure and increased nasal cancer risk in man. Int. J. Cancer,

34, 639–644

Ott, M.G., Teta, M.J. & Greenberg, H.L. (1989) Lymphatic and hematopoietic tissue cancer in a

chemical manufacturing environment. Am. J. ind. Med., 16, 631–643

Overman, D.O. (1985) Absence of embryotoxic effects of formaldehyde after percutaneous exposure in hamsters. Toxicol. Lett., 24, 107–110

Overton, J.H., Kimbell, J.S. & Miller, F.J. (2001) Dosimetry modeling of inhaled formaldehyde:

The human respiratory tract. Toxicol. Sci., 64, 122–134

Özen, O.A., Songur, A., Sarsilmaz, M., Yaman, M. & Kus, I. (2003) Zinc, copper and iron concentrations in cerebral cortex of male rats exposed to formaldehyde inhalation. J. trace Elem.

Med. Biol., 17, 207–209

Panfilova, Z.I., Voronina, E.N., Poslovina, A.S., Goryukhova, N.M. & Salganik, R.I. (1966) Study

of the joint action of chemical mutagens and ultra-violet rays upon the appearance of back

mutations in Escherichia coli. Sov. Genet., 2, 35–40

Parfett, C.L. (2003) Combined effects of tumor promoters and serum on proliferin mRNA induction: A biomarker sensitive to saccharin, 2,3,7,8-TCDD, and other compounds at minimal concentrations promoting C3H/10T1/2 cell transformation. J. Toxicol. environ. Health, A66,

1943–1966

Park, J.S. & Ikeda, K. (2003) Database system, AFoDAS/AVODAS, on indoor air organic compounds in Japan. Indoor Air, 13 (Suppl. 6), 35–41

Partanen, T. (1993) Formaldehyde exposure and respiratory cancer — A meta-analysis of the epidemiologic evidence. Scand. J. Work Environ. Health, 19, 8–15

Partanen, T., Kauppinen, T., Nurminen, M., Nickels, J., Hernberg, S., Hakulinen, T., Pukkala, E. &

Savonen, E. (1985) Formaldehyde exposure and respiratory and related cancers: A case–

referent study among Finnish woodworkers. Scand. J. Work Environ. Health, 11, 409–415

Partanen, T., Kauppinen, T., Hernberg, S., Nickels, J., Luukkonen, R., Hakulinen, T. & Pukkala, E.

(1990) Formaldehyde exposure and respiratory cancer among woodworkers — An update.

Scand. J. Work Environ. Health, 16, 394–400

Partanen, T., Kauppinen, T., Luukkonen, R., Hakulinen, T. & Pukkala, E. (1993) Malignant lymphomas and leukemias, and exposures in the wood industry: An industry-based case–referent

study. Int. Arch. occup. environ. Health, 64, 593–596

312 IARC MONOGRAPHS VOLUME 88
Patel, K.G., Bhatt, H.V. & Choudhury, A.R. (2003) Alteration in thyroid after formaldehyde

(HCHO) treatment in rats. Ind. Health, 41, 295–297

Patterson, R., Dykewicz, M.S., Evans, R.III, Grammer, L.C., Greenberger, P.A., Harris, K.E.,

Lawrence, I.D., Pruzansky, J.J., Roberts, M., Shaughnessy, M.A. & Zeiss, C.R. (1989) IgG

antibody against formaldehyde human serum proteins: A comparison with other IgG antibodies against inhalant proteins and reactive chemicals. J. Allergy clin. Immunol., 84, 359–366 

Paustenbach, D., Alarie, Y., Kulle, T., Schachter, N., Smith, R., Swenberg, J., Witschi, H. &

Horowitz, S.B. (1997) A recommended occupational exposure limit for formaldehyde based

on irritation. J. Toxicol. environ. Health, 50, 217–263

Pazdrak, K., Górski, P., Krakowiak, A. & Ruta, U. (1993) Changes in nasal lavage fluid due to

formaldehyde inhalation. Int. Arch. occup. environ. Health, 64, 515–519

Petersen, D. & Lindahl, R. (1997) Aldehyde dehydrogenases. In: Guengerich, F.P., ed., Comprehensive Toxicology, New York, Pergamon, pp. 97–118

Petersen, G.R. & Milham, S. (1980) Occupational Mortality in the State of California 1959–1961

(DHEW (NIOSH) Publication No. 80-104), Cincinatti, OH, National Institute for Occupational Safety and Health

Pickrell, J.A., Mokler, B.V., Griffis, L.C., Hobbs, C.H. & Bathija, A. (1983) Formaldehyde release

rate coefficients from selected consumer products. Environ. Sci. Technol., 17, 753–757

Pickrell, J.A., Griffis, L.C., Mokler, B.V., Kanapilly, G.M. & Hobbs, C.H. (1984) Formaldehyde

release from selected consumer products: Influence of chamber loading, multiple products,

relative humidity, and temperature. Environ. Sci. Technol., 18, 682–686

Pinkerton, L.E., Hein, M.J. & Stayner, L.T. (2004) Mortality among a cohort of garment workers

exposed to formaldehyde: An update. Occup. environ. Med., 61, 193–200

Pitten, F.-A., Kramer, A., Herrmann, K., Bremer, J. & Koch, S. (2000) Formaldehyde neurotoxicity

in animal experiments. Pathol. Res. Pract., 196, 193–198

Pocker, Y. & Li, H. (1991) Kinetics and mechanism of methanol and formaldehyde interconversion

and formaldehyde oxidation catalyzed by liver alcohol dehydrogenase. Adv. exp. Med. Biol.,

284, 315–325

Pohanish, R.P. (2002) Sittig’s Handbook of Toxic and Hazardous Chemicals and Carcinogens, 4th

Ed., Norwich, NY, Noyes Publications/William Andrew Publishing, pp. 1179–1182 

Pool, B.L., Frei, E., Plesch, W.J., Romruen, K. & Wiessler, M. (1984) Formaldehyde as a possible

mutagenic metabolite of N-nitrodimethylamine and of other agents which are suggested to

yield non-alkylating species in vitro. Carcinogenesis, 5, 809–814

Popa, V., Teculescu, D., Stanescu, D. & Gavrilescu, N. (1969) Bronchial asthma and asthmatic

bronchitis determined by simple chemicals. Dis. Chest, 56, 395–404

Porter, J.A.H. (1975) Acute respiratory disease following formalin inhalation. Lancet, ii, 603–604

Possanzini, M., Di Palo, V., Petricca, M., Fratarcangeli, R. & Brocco, D. (1996) Measurements of

lower carbonyls in Rome ambient air. Atmos. Environ., 30, 3757–3764

Poverenny, A.M., Siomin, Y.A., Saenko, A.S. & Sinzinis, B.I. (1975) Possible mechanisms of

lethal and mutagenic action of formaldehyde. Mutat. Res., 27, 123–126

Pratt, G.C., Palmer, K., Wu, C.Y., Oliaei, F., Hollerbach, C. & Fenske, M.J. (2000) An assessment

of air toxics in Minnesota. Environ. Health Perspect., 108, 815–825

Preuss, P.W., Dailey, R.L. & Lehman, E.S. (1985) Exposure to formaldehyde. In: Turoski, V., ed.,

Formaldehyde. Analytical Chemistry and Toxicology (Advances in Chemistry Series,

Vol. 210), Washington DC, American Chemical Society, pp. 247–259

FORMALDEHYDE 313
Priha, E., Riipinen, H. & Korhonen, K. (1986) Exposure to formaldehyde and solvents in Finnish

furniture factories in 1975–1984. Ann. occup. Hyg., 30, 289–294

Priha, E., Vuorinen, R. & Schimberg, R. (1988) [Textile Finishing Agents] (Työolot 65), Helsinki,

Finnish Institute of Occupational Health (in Finnish) 

Pushkina, N.N., Gofmekler, V.A. & Klevtsova, T.N. (1968) [Changes in the ascorbic acid titer and

in the nucleinic acids following action of benzol and formaldehyde.] Bjull. eksp. Biol. Med.,

66, 51–53 (in Russian)

Puxbaum, H., Rosenberg, C., Gregori, M., Lanzerstorfer, C., Ober, E. & Winiwarter, W. (1988)

Atmospheric concentrations of formic and acetic acid and related compounds in eastern and

northern Austria. Atmos. Environ., 22, 2841–2850

Quievryn, G. & Zhitkovich, A. (2000) Loss of DNA–protein crosslinks from formaldehydeexposed cells occurs through spontaneous hydrolysis and an active repair process linked to

proteosome function. Carcinogenesis, 21, 1573–1580

Ragan, D.L. & Boreiko, C.J. (1981) Initiation of C3H/10T1/2 cell transformation by formaldehyde.

Cancer Lett., 13, 325–331

Ratnayake, W.E. (1968) Tests for an effect of the Y-chromosome on the mutagenic action of

formaldehyde and X-rays in Drosophila melanogaster. Genet. Res. Camb., 12, 65–69

Ratnayake, W.E. (1970) Studies on the relationship between induced crossing-over and mutation

in Drosophila melanogaster. Mutat. Res., 9, 71–83

Recio, L. (1997) Oncogene and tumor suppressor gene alterations in nasal tumors. Mutat. Res., 380,

27–31

Recio, L., Sisk, S., Pluta, L., Bermudez, E., Gross, E.A., Chen, Z., Morgan, K. & Walker, C. (1992)

p53 Mutations in formaldehyde-induced nasal squamous cell carcinomas in rats. Cancer Res.,

52, 6113–6116

Reed, C.E. & Frigas, E. (1984) Does formaldehyde cause allergic respiratory disease? In:

Gammage, R.B. & Kay, S.V., eds, Indoor Air and Human Health, Boca Raton, FL, Lewis,

pp. 379–386

Reh, C.M., Letts, D. & Deitchman, S. (1994) National Park Service, Yosemite National Park, CA

(Health Hazard Evaluation Report, HETA 90-0365-2415), Cincinnati, OH, National Institute

of Occupational Safety and Health, Centers for Disease Control and Prevention

Reinhardt, T.E., Ottmar, R.D. & Castilla, C. (2001) Smoke impacts from agricultural burning in a

rural Brazilian town. J. Air Waste Manage. Assoc., 51, 443–450

Reiss, R., Ryan, P.B., Tibbetts, S.J. & Koutrakis, P. (1995) Measurement of organic acids, aldehydes, and ketones in residential environments and their relation to ozone. J. Air Waste

Manage. Assoc., 45, 811–822 

Restani, P. & Galli, C.L. (1991) Oral toxicity of formaldehyde and its derivatives. Crit. Rev. Toxicol., 21, 315–328

Restani, P., Restelli, A.R. & Galli, C.L. (1992) Formaldehyde and hexamethylenetetramine as food

additives: Chemical interactions and toxicology. Food Addit. Contam., 9, 597–605

Reuss, G., Disteldorf, W., Gamer, A.O. & Hilt, A. (2003) Formaldehyde. In: Ullmann’s Encyclopedia of Industrial Chemistry, 6th rev. Ed., Vol. 15, Weinheim, Wiley-VCH Verlag GmbH &

Co., pp. 1–34

Reuzel, P.G.J., Wilmer, J.W.G.M., Woutersen, R.A. & Zwart, A. (1990) Interactive effects of ozone

and formaldehyde on the nasal respiratory lining epithelium in rats. J. Toxicol. environ. Health,

29, 279–292

314 IARC MONOGRAPHS VOLUME 88
Reynolds, S.J., Black, D.W., Borin, S.S., Breuer, G., Burmeister, L.F., Fuortes, L.J., Smith, T.F.,

Stein, M.A., Subramanian, P., Thorne, P.S. & Whitten, P. (2001) Indoor environmental quality

in six commercial office buildings in the Midwest United States. Appl. occup. environ. Hyg.,

16, 1065–1077

Riala, R.E. & Riihimäki, H.A. (1991) Solvent and formaldehyde exposure in parquet and carpet

work. Appl. occup. environ. Hyg., 6, 301–308

Rice, R.H. & Green, H. (1979) Presence in human epidermal cells of a soluble protein precursor of

the cross-linked envelope: Activation of the cross-linking by calcium ions. Cell, 18, 681–694

Rietbrock, N. (1965) [Formaldehyde oxidation in the rat.] Naunyn-Schmiedeberg’s Arch. exp.

Pathol. Pharmakol., 251, 189–190 (in German)

Risby, T.H., Sehnert, S.S., Jakab, G.J. & Hemenway, D.R. (1990) Model to estimate effective doses

of adsorbed pollutants on respirable particles and their subsequent release into alveolar surfactant. I. Validation of the model for the adsorption and release of formaldehyde on a respirable

carbon black. Inhal. Toxicol., 2, 223–239

Robins, J.M., Pambrun, M., Chute, C. & Blevins, D. (1988) Estimating the effect of formaldehyde

exposure on lung cancer and non-malignant respiratory disease (NMRD) mortality using a

new method to control for the healthy worker survivor effect. In: Hogstedt, C. & Reuterwall,

C., eds, Progress in Occupational Epidemiology, Amsterdam, Elsevier Science, pp. 75–78

Rosén, G., Bergström, B. & Ekholm, U. (1984) [Occupational exposure to formaldehyde in

Sweden.] Arbete Hälsa, 50, 16–21 (in Swedish)

Ross, W.E. & Shipley, N. (1980) Relationship between DNA damage and survival in formaldehyde-treated mouse cells. Mutat. Res., 79, 277–283

Ross, W.E., McMillan, D.R. & Ross, C.F. (1981) Comparison of DNA damage by methylmelamines and formaldehyde. J. natl Cancer Inst., 67, 217–221

Rothenberg, S.J., Nagy, P.A., Pickrell, J.A. & Hobbs, C.H. (1989) Surface area, adsorption, and

desorption studies on indoor dust samples. Am. ind. hyg. Assoc. J., 50, 15–23 

Roush, G.C., Walrath, J., Stayner, L.T., Kaplan, S.A., Flannery, J.T. & Blair, A. (1987) Nasopharyngeal cancer, sinonasal cancer, and occupations related to formaldehyde: A case–control

study. J natl Cancer Inst., 79, 1221–1224

Rusch, G.M., Clary, J.J., Rinehart, W.E. & Bolte, H.F. (1983) A 26-week inhalation toxicity study

with formaldehyde in the monkey, rat, and hamster. Toxicol. appl. Pharmacol., 68, 329–343 

Sadakane, K., Takano, H., Ichinose, T., Yanagisawa, R. & Shibamoto, T. (2002) Formaldehyde

enhances mite allergen-induced eosinophilic inflammation in the murine airway. J. environ.

Pathol. Toxicol. Oncol., 21, 267–276

Sadtler Research Laboratories (1991) Sadtler Standard Spectra. 1981–1991 Supplementary Index,

Philadelphia, PA

Saillenfait, A.M., Bonnet, P. & de Ceaurriz, J. (1989) The effects of maternally inhaled formaldehyde on embryonal and foetal development in rats. Food chem. Toxicol., 27, 545–548 

Sakaguchi, J. & Akabayashi, S. (2003) Field survey of indoor air quality in detached houses in

Niigata Prefecture. Indoor Air, 13 (Suppl. 6), 42–49

Sakai, K., Norbäck, D., Mi, Y., Shibata, E., Kamijima, M., Yamada, T. & Takeuchi, Y. (2004) A

comparison of indoor air pollutants in Japan and Sweden: Formaldehyde, nitrogen dioxide,

and chlorinated volatile organic compounds. Environ. Res., 94, 75–85

FORMALDEHYDE 315
Saladino, A.J., Willey, J.C., Lechner, J.F., Grafström, R.C., LaVeck, M. & Harris, C.C. (1985)

Effects of formaldehyde, acetaldehyde, benzoyl peroxide, and hydrogen peroxide on cultured

normal human bronchial epithelial cells. Cancer Res., 45, 2522–2526

Salisbury, S. (1983) Dialysis Clinic Inc., Atlanta, GA, Health Hazard Evaluation Report (NIOSH

Report No. HETA 83-284-1536), Cincinnati, OH, US Department of Health and Human

Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health

Sandner, F., Dott, W. & Hollender, J. (2001) Sensitive indoor air monitoring of formaldehyde and

other carbonyl compounds using the 2,4-dinitrophenylhydrazine method. Int. J. Hyg. environ.

Health, 203, 275–279

Sanghani, P.C., Stone, C.L., Ray, B.D., Pindel, E.V., Hurley, T.D. & Bosron, W.F. (2000) Kinetic

mechanism of human glutathione-dependent formaldehyde dehydrogenase. Biochemistry, 39,

10720–10729

Sass-Kortsak, A.M., Holness, D.L., Pilger, C.W. & Nethercott, J.R. (1986) Wood dust and formaldehyde exposures in the cabinet-making industry. Am. ind. Hyg. Assoc. J., 47, 747–753

Satsumabayashi, H., Kurita, H., Chang, Y.-S., Carmichael, G.R. & Ueda, H. (1995) Photochemical

formations of lower aldehydes and lower fatty acids under long-range transport in central

Japan. Atmos. Environ., 29, 255–266

Sauder, L.R., Chatham, M.D., Green, D.J. & Kulle, T.J. (1986) Acute pulmonary response to

formaldehyde exposure in healthy nonsmokers. J. occup. Med., 28, 420–424

Sauder, L.R., Green, D.J., Chatham, M.D. & Kulle, T.J. (1987) Acute pulmonary response of asthmatics to 3.0 ppm formaldehyde. Toxicol. ind. Health, 3, 569–578

Schachter, E.N., Witek, T.J., Jr, Tosun, T. & Beck, G.J. (1986) A study of respiratory effects from

exposure to 2 ppm formaldehyde in healthy subjects. Arch. environ. Health, 41, 229–239

Schachter, E.N., Witek, T.J., Jr, Brody, D.J., Tosun, T., Beck, G.J. & Leaderer, B.P. (1987) A study

of respiratory effects from exposure to 2 ppm formaldehyde in occupationally exposed

workers. Environ. Res., 44, 188–205

Schäfer, D., Brommer, C., Riechelmann, H. & Mann, J.W. (1999) In vivo and in vitro effect of

ozone and formaldehyde on human mucociliary transport system. Rhinology, 37, 56–60

Schifter, I., Vera, M., Díaz, L., Guzmán, E., Ramos, F. & López-Salinas, E. (2001) Environmental

implications on the oxygenation of gasoline with ethanol in the metropolitan area of Mexico

City. Environ. Sci. Technol., 35, 1893–1901

Schlink, K., Janssen, K., Nitzsche, S., Gebhard, S., Hengstler, J.G., Klein, S. & Oesch, F. (1999)

Activity of O6-methylguanine DNA methyltransferase in mononuclear blood cells of formaldehyde-exposed medical students. Arch. Toxicol., 73, 15–21

Schlosser, P.M. (1999) Relative roles of convection and chemical reaction for the disposition of

formaldehyde and ozone in nasal mucus. Inhal. Toxicol., 11, 967–980

Schlosser, P.M., Lilly, P.D., Conolly, R.B., Janszen, D.B. & Kimbell, J.S. (2003) Benchmark dose risk

assessment for formaldehyde using airflow modeling and a single-compartment, DNA–protein

cross-link dosimetry model to estimate human equivalent doses. Risk Anal., 23, 473–487

Schmid, E., Göggelmann, W. & Bauchinger, M. (1986) Formaldehyde-induced cytotoxic, genotoxic and mutagenic response in human lymphocytes and Salmonella typhimurium. Mutagenesis, 1, 427–431

Schreider, J.P. (1986) Comparative anatomy and function of the nasal passages. In: Barrow, C.S.,

ed., Toxicology of the Nasal Passages, Washington DC, Hemisphere, pp. 1–25 

316 IARC MONOGRAPHS VOLUME 88
Schwartz, S.M., Doody, D.R., Fitzgibbons, E.D., Ricks, S., Porter, P.L. & Chen, C. (2001) Oral

squamous cell cancer risk in relation to alcohol consumption and alcohol dehydrogenase-3

genotypes. Cancer Epidemiol. Biomarkers Prev., 10, 1137–1144

Seila, R.L., Main, H.H., Arriaga, J.L., Martínez, G.V. & Ramadan, A.B. (2001) Atmospheric volatile organic compound measurements during the 1996 Paso del Norte Ozone Study. Sci. total

Environ., 276, 153–169

Sellakumar, A.R., Snyder, C.A., Solomon, J.J. & Albert, R.E. (1985) Carcinogenicity of formaldehyde and hydrogen chloride in rats. Toxicol. appl. Pharmacol., 81, 401–406

Sensidyne (2004) Sensidyne Detector Tube Selection Guide, Clearwater, FL

Sensidyne (undated) Sensidyne Gas Detector Tube Handbook, Clearwater, FL, pp. 129–131

de Serres, F.J. & Brockman, H.E. (1999) Comparison of the spectra of genetic damage in formaldehyde-induced ad-3 mutations between DNA repair-proficient and deficient heterokaryons

of neurospora crassa. Mutat. Res., 437, 151–163

de Serres, F.J., Brockman, H.E. & Hung, C.Y. (1988) Effect of the homokaryotic state of the uvs-2

allele in Neurospora crassa on formaldehyde-induced killing and ad-3 mutation. Mutat. Res.,

199, 235–242

de Serves, C. (1994) Gas phase formaldehyde and peroxide measurements in the Arctic atmosphere. J. geophys. Res., 99, 25391–25398

Sexton, K., Liu, K.-S. & Petreas, M.X. (1986) Formaldehyde concentrations inside private residences: A mail-out approach to indoor air monitoring. J. Air Pollut. Control Assoc., 36,

698–704 

Sexton, K., Petreas, M.X. & Liu, K.-S. (1989) Formaldehyde exposures inside mobile homes.

Environ. Sci. Technol., 23, 985–988

Shah, J.J. & Singh, H.B. (1988) Distribution of volatile organic chemicals in outdoor and indoor

air. A national VOCs data base. Environ. Sci. Technol., 22, 1381–1388

Shaham, J., Bomstein, Y., Meltzer, A., Kaufman, Z., Palma, E. & Ribak, J. (1996a) DNA–protein

crosslinks, a biomarker of exposure to formaldehyde — In vitro and in vivo studies. Carcinogenesis, 17, 121–125

Shaham, J., Bomstein, Y., Meltzer, A. & Ribak, J. (1996b) Response. Carcinogenesis, 17, 2098–2101

Shaham, J., Bomstein, Y., Melzer, A. & Ribak, J. (1997) DNA–protein crosslinks and sister chromatid exchanges as biomarkers of exposure to formaldehyde. Int. J. occup. environ. Health,

3, 95–104 

Shaham, J., Gurvich, R. & Kaufman, Z. (2002) Sister chromatid exchange in pathology staff occupationally exposed to formaldehyde. Mutat. Res., 514, 115–123 

Shaham, J., Bomstein, Y., Gurvich, R., Rashkovsky, M. & Kaufman, Z. (2003) DNA–protein

crosslinks and p53 protein expression in relation to occupational exposure to formaldehyde.

Occup. environ. Med., 60, 403–409 

Shepson, P.B., Hastie, D.R., Schiff, H.I., Polizzi, M., Bottenheim, J.W., Anlauf, K., Mackay, G.I. &

Karecki, D.R. (1991) Atmospheric concentrations and temporal variations of C1–C3 carbonyl

compounds at two rural sites in central Ontario. Atmos. Environ., 25A, 2001–2015

Shields, P.G., Xu, G.X., Blot, W.J., Fraumeni, J.F., Jr, Trivers, G.E., Pellizzari, E.D., Qu, Y.H., Gao,

Y.T. & Harris, C.C. (1995) Mutagens from heated Chinese and US cooking oils. J. natl Cancer

Inst., 87, 836–841

Shumilina, A.V. (1975) [Menstrual and child-bearing functions of female workers occupationally

exposed to the effects of formaldehyde.] Gig. Tr. prof. Zabol., 12, 18–21 (in Russian)

FORMALDEHYDE 317
Siboulet, R., Grinfeld, S., Deparis, P. & Jaylet, A. (1984) Micronuclei in red blood cells of the newt

Pleurodeles waltl Michah: Induction with X-rays and chemicals. Mutat. Res., 125, 275–281

Siemiatycki, J., Day, N.E., Fabry, J. & Cooper, J.A. (1981) Discovering carcinogens in the occupational environment: A novel epidemiological approach. J. natl Cancer Inst., 66, 217–225

Siemiatycki, J., Dewar, R., Nadon, L. & Gérin, M. (1994) Occupational risk factors for bladder

cancer: Results from a case–control study in Montreal, Quebec, Canada. Am. J. Epidemiol.,

140, 1061–1080

Sin, D.W.M., Wong, Y.-C. & Louie, P.K.K. (2001) Trends of ambient carbonyl compounds in the

urban environment of Hong Kong. Atmos. Environ., 35, 5961–5969

SKC® (2005) Gastec® Color Detector Tubes Price List, Eighty Four, PA

Skisak, C.M. (1983) Formaldehyde vapor exposures in anatomy laboratories. Am. ind. Hyg. Assoc.

J., 44, 948–950

Slemr, J. (1992) Development of techniques for the determination of major carbonyl compounds

in clean air. In: EUROTRAC Annual Report for 1991, Part 9, Mainz, Max Planck Institute for

Chemistry, pp. 110–113

Slemr, J., Junkermann, W. & Volz-Thomas, A. (1996) Temporal variations in formaldehyde, acetaldehyde and acetone and budget of formaldehyde at a rural site in southern Germany. Atmos.

Environ., 30, 3667–3676

Smedley, J. (1996) Is formaldehyde an important cause of allergic respiratory disease? Clin. exp.

Allergy, 26, 247–249

Smith, E.L., Hill, R.L., Lehman, I.R., Lefkowitz, R.J., Handler, P. & White, A. (1983) Principles

of Biochemistry: Mammalian Biochemistry, New York, McGraw-Hill, pp. 3–4, 142

Snyder, R.D. & Van Houten, B. (1986) Genotoxicity of formaldehyde and an evaluation of its

effects on the DNA repair process in human diploid fibroblasts. Mutat. Res., 165, 21–30

Sobels, F.H. & van Steenis, H. (1957) Chemical induction of crossing-over in Drosophila males.

Nature, 179, 29–31

Soffritti, M., Maltoni, C., Maffei, F. & Biagi, R. (1989) Formaldehyde: An experimental multipotential carcinogen. Toxicol. ind. Health, 5, 699–730

Soffritti, M., Belpoggi, F., Lambertini, L., Lauriola, M., Padovani, M. & Maltoni, C. (2002) Results

of long-term experimental studies on the carcinogenicity of formaldehyde and acetaldehyde in

rats. Ann. N.Y. Acad. Sci., 982, 87–105

Sorg, B.A., Bailie, T.M., Tschirgi, M.L., Li, N. & Wu, W.-R. (2001) Exposure to repeated low-level

formaldehyde in rats increases basal corticosterone levels and enhances the corticosterone

response to subsequent formaldehyde. Brain Res., 898, 314–320

Spanel, P., Smith, D., Holland, T.A., Al Singary, W. & Elder, J.B. (1999) Analysis of formaldehyde

in the headspace of urine from bladder and prostate cancer patients using selected ion flow

tube mass spectrometry. Rapid Commun. mass Spectrom., 13, 1354–1359 

Speit, G. & Merk, O. (2002) Evaluation of mutagenic effects of formaldehyde in vitro: Detection

of crosslinks and mutations in mouse lymphoma cells. Mutagenesis, 17, 183–187

Speit, G., Schütz, P. & Merk, O. (2000) Induction and repair of formaldehyde-induced DNA–

protein crosslinks in repair-deficient human cell lines. Mutagenesis, 15, 85–90

Spitzer, H.L. (1997) An analysis of the health benefits associated with the use of MTBE reformulated gasoline and oxygenated fuels in reducing atmospheric concentrations of selected volatile organic compounds. Risk Anal., 17, 683–691

318 IARC MONOGRAPHS VOLUME 88
Šrám, R.J. (1970) The effect of storage on the frequency of dominant lethals in Drosophila

melanogaster. Mol. gen. Genet., 106, 286–288

Standardiseringen i Sverige (1996) [Plywood — Formaldehyde Release Classes Determined by

the Gas Analysis Method] (SS EN 1084:1995), Stockholm, Swedish Standards Institute

(in Swedish)

Stayner, L., Smith, A.B., Reeve, G., Blade, L., Elliott, L., Keenlyside, R. & Halperin, W. (1985)

Proportionate mortality study of workers in the garment industry exposed to formaldehyde.

Am. J. ind. Med., 7, 229–240

Stayner, L.T., Elliott, L., Blade, L., Keenlyside, R. & Halperin, W. (1988) A retrospective cohort

mortality study of workers exposed to formaldehyde in the garment industry. Am. J. ind. Med.,

13, 667–681

Steenland, K., Nowlin, S., Ryan, B. & Adams, S. (1992) Use of multiple-cause mortality data in

epidemiologic analyses: US rate and proportion files developed by the National Institute for

Occupational Safety and Health and the National Cancer Institute. Am. J. Epidemiol., 136,

855–862

Steinhagen, W.H. & Barrow, C.S. (1984) Sensory irritation structure–activity study of inhaled

aldehydes in B6C3F1 and Swiss-Webster mice. Toxicol. appl. Pharmacol., 72, 495–503

Stellman, S.D., Demers, P.A., Colin, D. & Boffetta, P. (1998) Cancer mortality and wood dust

exposure among participants in the American Cancer Society Cancer Prevention Study-II

(CPS-II). Am. J. ind. Med., 34, 229–237

Sterling, T.D. & Weinkam, J.J. (1976) Smoking characteristics by type of employment. J. occup.

Med., 18, 743–754

Sterling, T.D. & Weinkam, J.J. (1988) Reanalysis of lung cancer mortality in a National Cancer

Institute study on mortality among industrial workers exposed to formaldehyde. J. occup.

Med., 30, 895–901

Sterling, T.D. & Weinkam, J.J. (1989a) Reanalysis of lung cancer mortality in a National Cancer

Institute study on ‘Mortality among industrial workers exposed to formaldehyde’. Exp. Pathol.,

37, 128–132

Sterling, T.D. & Weinkam, J.J. (1989b) Reanalysis of lung cancer mortality in a National Cancer

Institute study of ‘Mortality among industrial workers exposed to formaldehyde’: Additional

discussion. J. occup. Med., 31, 881–884

Sterling, T.D. & Weinkam, J.J. (1994) Mortality from respiratory cancers (including lung cancer)

among workers employed in formaldehyde industries. Am. J. ind. Med., 25, 593–602

Sterling, T.D. & Weinkam, J.J. (1995) Comments on the Blair and Stewart comments on the

Sterling and Weinkam analysis of data from the National Cancer Institute Formaldehyde

Study. Am. J. ind. Med., 27, 301–305

Stewart, P.A., Blair, A., Cubit, D.A., Bales, R.E., Kaplan, S.A., Ward, J., Gaffey, W., O’Berg, M.T.

& Walrath, J. (1986) Estimating historical exposures to formaldehyde in a retrospective mortality study. Appl. ind. Hyg., 1, 34–41

Stewart, P.A., Cubit, D.A. & Blair, A. (1987) Formaldehyde levels in seven industries. Appl. ind.

Hyg., 2, 231–236

Stewart, P.A., Herrick, R.F., Feigley, C.E., Utterback, D.F., Hornung, R., Mahar, H., Hayes, R.,

Douthit, D.E. & Blair, A. (1992) Study design for assessing exposures of embalmers for a

case–control study. Part I. Monitoring results. Appl. occup. environ. Hyg., 7, 532–540

FORMALDEHYDE 319
Stone, R.A., Youk, A.O., Marsh, G.M., Buchanich, J.M., McHenry, M.B. & Smith, T.J. (2001) Historical cohort study of US man-made vitreous fiber production workers: IV. Quantitative exposure–response analysis of the nested case–control study of respiratory system cancer. J. occup.

environ. Med., 43, 779–792

Stragier, A, Wenderickx, D. & Jadoul, M. (1995) Rinsing time and disinfectant release of reused

dialyzers: Comparison of formaldehyde, hypochlorite, Warexin, and Renalin. Am. J. Kidney

Dis., 26, 549–553

Stroup, N.E., Blair, A. & Erikson, G.E. (1986) Brain cancer and other causes of death in anatomists.

J. natl Cancer Inst., 77, 1217–1224

Stücker, I., Caillard, J.-F., Collin, R., Gout, M., Poyen, D. & Hémon, D. (1990) Risk of spontaneous abortion among nurses handling antineoplastic drugs. Scand. J. Work Environ. Health,

16, 102–107

Stumm-Tegethoff, B.F.A. (1969) Formaldehyde-induced mutations in Drosophila melanogaster in

dependence of the presence of acids. Theoret. appl. Genet., 39, 330–334

Suh, H.H., Bahadori,T., Vallarino, J. & Spengler, J.D. (2000) Criteria air pollutants and toxic air

pollutants. Environ. Health Perspect., 108 (Suppl. 4), 625–633

Suruda, A., Schulte, P., Boeniger, M., Hayes, R.B., Livingston, G.K., Steenland, K., Stewart, P.,

Herrick, R., Douthit, D. & Fingerhut, M.A. (1993) Cytogenetic effects of formaldehyde exposure in students of mortuary science. Cancer Epidemiol. Biomarkers Prev., 2, 453–460

Suva (2003) Grenzwerte am Arbeitsplatz 2003, Luzern, Swiss Accident Insurance [Swiss OELs]

Svensson, S., Some, M., Lundsjö, A., Helander, A., Cronholm, T. & Höög, J.-O. (1999) Activities

of human alcohol dehydrogenases in the metabolic pathways of ethanol and serotonin. Eur. J.

Biochem., 262, 324–329

Swenberg, J.A., Kerns, W.D., Mitchell, R.I., Gralla, E.J. & Pavkov, K.L. (1980) Induction of

squamous cell carcinomas of the rat nasal cavity by inhalation exposure to formaldehyde vapor.

Cancer Res., 40, 3398–3402

Swenberg, J.A., Gross, E.A., Randall, H.W. & Barrow, C.S. (1983) The effect of formaldehyde exposure on cytotoxicity and cell proliferation. In: Clary, J.J., Gibson, J.E. & Waritz, R.S., eds,

Formaldehyde: Toxicology, Epidemiology, Mechanisms, New York, Marcel Dekker, pp. 225–236

Swiecichowski, A.L., Long, K.J., Miller, M.L. & Leikauf, G.D. (1993) Formaldehyde-induced airway hyperreactivity in vivo and ex vivo in guinea pigs. Environ. Res., 61, 185–199

Takahashi, K., Morita, T. & Kawazoe, Y. (1985) Mutagenic characteristics of formaldehyde on

bacterial systems. Mutat. Res., 156, 153–161

Takahashi, M., Hasegawa, R., Furukawa, F., Toyoda, K., Sato, H. & Hayashi, Y. (1986) Effects of

ethanol, potassium metabisulfite, formaldehyde and hydrogen peroxide on gastric carcinogenesis in rats after initiation with N-methyl-N′-nitro-N-nitrosoguanidine. Jpn. J. Cancer Res.,

77, 118–124

Tan, Y.-M., DiBerardinis, L. & Smith, T. (1999) Exposure assessment of laboratory students. Appl.

occup. environ. Hyg., 14, 530–538 

Tanaka, K., Nishiyama, K., Yaginuma, H., Sasaki, A., Maeda, T., Kaneko, S.-y., Onami, T. &

Tanaka, M. (2003) [Formaldehyde exposure levels and exposure control measure during an

anatomy dissecting course.] Kaibogaku Zasshi, 78, 43–51 (in Japanese) 

Tanner, R.L., Zielinska, B., Uberna, E., Harshfield, G. & McNichol, A.P. (1996) Concentrations of

carbonyl compounds and the carbon isotopy of formaldehyde at a coastal site in Nova Scotia

during the NARE summer intensive. J. geophys. Res., 101, 28961–28970

320 IARC MONOGRAPHS VOLUME 88
Tarkowski, M. & Gorski, P. (1995) Increased IgE antiovalbumin level in mice exposed to formaldehyde. Int. Arch. Allergy Immunol., 106, 422–424

Taskinen, H., Kyyrönen, P., Hemminki, K., Hoikkala, M., Lajunen, K. & Lindbohm, M.-L. (1994)

Laboratory work and pregnancy outcome. J. occup. Med., 36, 311–319

Taskinen, H.K., Kyyrönen, P., Sallmén, M., Virtanen, S.V., Liukkonen, T.A., Huida, O., Lindbohm,

M.-L. & Anttila, A. (1999) Reduced fertility among female wood workers exposed to formaldehyde. Am. J. ind. Med., 36, 206–212

Tatham, L., Tolbert, P. & Kjeldsberg, C. (1997) Occupational risk factors for subgroups of nonHodgkin’s lymphoma. Epidemiology, 8, 551–558

Temcharoen, P. & Thilly, W.G. (1983) Toxic and mutagenic effects of formaldehyde in Salmonella

typhimurium. Mutat. Res., 119, 89–93

Teng, S., Beard, K., Pourahmad, J., Moridani, M., Easson, E., Poon, R. & O’Brien, P.J. (2001) The

formaldehyde metabolic detoxification enzyme systems and molecular cytotoxic mechanism

in isolated rat hepatocytes. Chem.-biol. Interactions, 130–132, 285–296

Thermo Electron Corporation (2005) Product Specifications: MIRAN SapphIRe ML Portable

Infrared Ambient Analyzer for the Medical Industry, Franklin, MA

Thornton-Manning, J.R. & Dahl, A.R. (1997) Metabolic capacity of nasal tissue interspecies comparisons of xenobiotic-metabolizing enzymes. Mutat. Res., 380, 43–59

Thrasher, J.D. & Kilburn, K.H. (2001) Embryo toxicity and teratogenicity of formaldehyde. Arch.

environ. Health, 56, 300–311

Tikuisis, T., Phibbs, M.R. & Sonnenberg, K.L. (1995) Quantitation of employee exposure to

emission products generated by commercial-scale processing of polyethylene. Am. ind. Hyg.

Assoc. J., 56, 809–814 

Til, H.P., Woutersen, R.A., Feron, V.J. & Clary, J.J. (1988) Evaluation of the oral toxicity of acetaldehyde and formaldehyde in a 4-week drinking-water study in rats. Food chem. Toxicol., 26,

447–452

Til, H.P., Woutersen, R.A., Feron, V.J., Hollanders, V.H.M. & Falke, H.E. (1989) Two-year

drinking-water study of formaldehyde in rats. Food. chem. Toxicol., 27, 77–87

Titenko-Holland, N., Levine, A.J. , Smith, M.T., Quintana, P.J.E., Boeniger, M., Hayes, R., Suruda,

A. & Schulte, P. (1996) Quantification of epithelial cell micronuclei by fluorescence in situ

hybridization (FISH) in mortuary science students exposed to formaldehyde. Mutat. Res., 371,

237–248

Tobe, M., Naito, K. & Kurokawa, Y. (1989) Chronic toxicity study on formaldehyde administered

orally to rats. Toxicology, 56, 79–86

Tokars, J.I., Miller, E.R., Alter, M.J. & Arduino, M.J. (2000) National Surveillance of Dialysisassociated Diseases in the United States, 1997, Atlanta, GA, National Center for Infectious

Diseases, Centers for Disease Control and Prevention

Triebig, G., Schaller, K.-H., Berger, B., Müller, J. & Valentin, H. (1989) Formaldehyde exposure

at various workplaces. Sci. total Environ., 79, 191–195

Tuomi, T., Engström, B., Niemelä, R., Svinhufvud, J. & Reijula, K. (2000) Emission of ozone and

organic volatiles from a selection of laser printers and photocopiers. Appl. occup. environ.

Hyg., 15, 629–634

Tyihák, E., Bocsi, J., Timár, F., Rácz, G. & Szende, B. (2001) Formaldehyde promotes and inhibits

proliferation of cultured tumour and endothelial cells. Cell Prolif., 34, 135–141

FORMALDEHYDE 321
Työsuojelusäädöksiä (2002) HTP arvot 2002, Helsinki, Sosiaali-ja terveysministeriön [Finnish

OELs]

Uotila, L. & Koivusalo, M. (1974) Formaldehyde dehydrogenase from human liver. Purification,

properties, and evidence for the formation of glutathione thiol esters by the enzyme. J. biol.

Chem., 249, 7653–7663

Uotila, L. & Koivusalo, M. (1987) Multiple forms of formaldehyde dehydrogenase from human

red blood cells. Hum. Hered., 37, 102–106

Uotila, L. & Koivusalo, M. (1989) Glutathione-dependent oxidoreductases: Formaldehyde

dehydrogenase. In: Dolphin, D., Poulson, R. & Avramovic, O., eds, Coenzymes and Cofactors,

Vol. III, Glutathione. Chemical, Biochemical and Medical Aspects, Part A, New York, John

Wiley & Sons, pp. 517–551

Uotila, L. & Koivusalo, M. (1997) Expression of formaldehyde dehydrogenase and S-formylglutathione hydrolase activities in different rat tissues. Adv. exp. Med. Biol., 414, 365–371

Vargová, M., Janota, S., Karelová, J., Barancokova, M. & Šulcová, M. (1992) Analysis of the

health risk of occupational exposure to formaldehyde using biological markers. Analysis, 20,

451–454

Vaughan, T.L. (1989) Occupation and squamous cell cancers of the pharynx and sinonasal cavity.

Am. J. ind. Med., 16, 493–510

Vaughan, T.L. & Davis, S. (1991) Wood dust exposure and squamous cell cancers of the upper

respiratory tract. Am. J. Epidemiol., 133, 560–564

Vaughan, T.L., Strader, C., Davis, S. & Daling, J.R. (1986a) Formaldehyde and cancers of the

pharynx, sinus and nasal cavity: I. Occupational exposures. Int. J. Cancer, 38, 677–683

Vaughan, T.L., Strader, C., Davis, S. & Daling, J.R. (1986b) Formaldehyde and cancers of the

pharynx, sinus and nasal cavity: II. Residential exposures. Int. J. Cancer, 38, 685–688

Vaughan, T.L., Stewart, P.A., Teschke, K., Lynch, C.F., Swanson, G.M., Lyon, J.L. & Berwick, M.

(2000) Occupational exposure to formaldehyde and wood dust and nasopharyngeal carcinoma.

Occup. environ. Med., 57, 376–384

Vaught, C. (1991) Locating and Estimating Air Emissions From Sources of Formaldehyde

(Revised) (Report No. EPA-450/4-91-012; US NTIS PB91-181842), Research Triangle Park,

NC, Environmental Protection Agency

Vinzents, P. & Laursen, B. (1993) A national cross-sectional study of the working environment in

the Danish wood and furniture industry — Air pollution and noise. Ann. occup. Hyg., 37, 25–34

Viskari, E.-L., Vartiainen, M. & Pasanen, P. (2000) Seasonal and diurnal variation in formaldehyde

and acetaldehyde concentrations along a highway in Eastern Finland. Atmos. Environ., 34,

917–923

Vock, E.H., Lutz, W. K., Ilinskaya, O. & Vamvakas, S. (1999) Discrimination between genotoxicity and cytotoxicity for the induction of DNA double-strand breaks in cells treated with aldehydes and diepoxides. Mutat. Res., 441, 85–93

Wagner, F.W., Parés, X., Holmquist, B. & Vallee, B.L. (1984) Physical and enzymatic properties

of a class III isozyme of human liver alcohol dehydrogenase: χ-ADH. Biochemistry, 23,

2193–2199

Walrath, J. & Fraumeni, J.F., Jr (1983) Mortality patterns among embalmers. Int. J. Cancer, 31,

407–411

Walrath, J. & Fraumeni, J.F., Jr (1984) Cancer and other causes of death among embalmers. Cancer

Res., 44, 4638–4641

322 IARC MONOGRAPHS VOLUME 88
Walrath, J., Rogot, E., Murray, J. & Blair, A. (1985) Mortality Patterns among US Veterans by

Occupation and Smoking Status (NIH Publ. No. 85-2756), Bethesda, MD, Department of

Health and Human Services

Wang, R.-S., Nakajima, T., Kawamoto, T. & Honma, T. (2002) Effects of aldehyde dehydrogenase2 genetic polymorphisms on metabolism of structurally different aldehydes in human liver.

Drug Metab. Dispos., 30, 69–73

Wantke, F., Demmer, C.M., Tappler, P., Götz, M. & Jarisch, R. (1996a) Exposure to gaseous

formaldehyde induces IgE-mediated sensitization to formaldehyde in school-children. Clin.

exp. Allergy, 26, 276–280

Wantke, F., Focke, M., Hemmer, W., Tschabitscher, M., Gann, M., Tappler, P., Götz, M. & Jarisch,

R. (1996b) Formaldehyde and phenol exposure during an anatomy dissection course: A possible

source of IgE-mediated sensitization? Allergy, 51, 837–841 

Wantke, F., Focke, M., Hemmer, W., Bracun, R., Wolf-Abdolvahab, S., Götz, M., Jarisch, R.,

Tschabitscher, M., Gann, M. & Tappler, P. (2000) Exposure to formaldehyde and phenol during

an anatomy dissecting course: Sensitizing potency of formaldehyde in medical students.

Allergy, 55, 84–87 

Ward, J.B., Jr, Hokanson, J.A., Smith, E.R., Chang, L.W., Pereira, M.A., Whorton, E.B., Jr &

Legator, M.S. (1984) Sperm count, morphology and fluorescent body frequency in autopsy

service workers exposed to formaldehyde. Mutat. Res., 130, 417–424

Weast, R.C. & Astle, M.J., eds (1985) CRC Handbook of Data on Organic Compounds, Vol. I,

Boca Raton, FL, CRC Press, p. 641

Werle, P., Maurer, K., Kormann, R., Mücke, R., D’Amato, F., Lancia, T. & Popov, A. (2002)

Spectroscopic gas analyzers based on indium-phosphide, antimonide and lead-salt diodelasers. Spectrochim. Acta, A58, 2361–2372

Weschler, C.J. & Shields, H.C. (1996) Production of the hydroxyl radical in indoor air. Environ.

Sci. Technol., 30, 3250–3258

West, S., Hildesheim, A. & Dosemeci, M. (1993) Non-viral risk factors for nasopharyngeal carcinoma in the Philippines: Results from a case–control study. Int. J. Cancer, 55, 722–727

West, R.R., Stafford, D.A., Farrow, A. & Jacobs, A. (1995) Occupational and environmental exposures and myelodysplasia: A case–control study. Leuk. Res., 19, 127–139

WHO (1989) Formaldehyde (Environmental Health Criteria 89), Geneva, International Programme on Chemical Safety

WHO (1991) Formaldehyde Health and Safety Guide (Health and Safety Guide No. 57), Geneva,

International Programme on Chemical Safety

Wieslander, G., Norbäck, D., Björnsson, E., Janson, C. & Boman, G. (1997) Asthma and the indoor

environment: The significance of emission of formaldehyde and volatile organic compounds

from newly painted indoor surfaces. Int. Arch. occup. environ. Health, 69, 115–124

Wieslander, G., Norbäck, D., Wålinder, R., Erwall, C. & Venge, P. (1999a) Inflammation markers

in nasal lavage, and nasal symptoms in relation to relocation to a newly painted building: A

longitudinal study. Int. Arch. occup. environ. Health, 72, 507–515 

Wieslander, G., Norbäck, D., Nordström, K., Wålinder, R. & Venge, P. (1999b) Nasal and ocular

symptoms, tear film stability and biomarkers in nasal lavage, in relation to building-dampness

and building design in hospitals. Int. Arch. occup. environ. Health, 72, 451–461 

Wilkins, R.J., & MacLeod, H.D. (1976) Formaldehyde induced DNA–protein crosslinks in

Escherichia coli. Mutat. Res., 36, 11–16

FORMALDEHYDE 323
Williams, T.M., Levine, R.J. & Blunden, P.B. (1984) Exposure of embalmers to formaldehyde and

other chemicals. Am. ind. Hyg. Assoc. J., 45, 172–176

Williams, I.D., Revitt, D.M. & Hamilton, R.S. (1996) A comparison of carbonyl compound concentrations at urban roadside and indoor sites. Sci. total Environ., 189/190, 475–483

Wilmer, J.W.G.M., Woutersen, R.A., Appelman, L.M., Leeman, W.R. & Feron, V.J. (1987) Subacute (4-week) inhalation toxicity study of formaldehyde in male rats: 8-hour intermittent

versus 8-hour continuous exposures. J. appl. Toxicol., 7, 15–16 

Wilmer, J.W.G.M., Woutersen, R.A., Appelman, L.M., Leeman, W.R. & Feron, V.J. (1989) Subchronic (13-week) inhalation toxicity study of formaldehyde in male rats: 8-hour intermittent

versus 8-hour continuous exposures. Toxicol. Lett., 47, 287–293

Wilson, R.T., Moore, L.E. & Dosemeci, M. (2004) Occupational exposures and salivary gland

cancer mortality among African American and white workers in the United States. J. occup.

environ. Med., 46, 287–297

Witek, T.J., Jr, Schachter, E.N., Tosun, T., Beck, G.J. & Leaderer, B.P. (1987) An evaluation of

respiratory effects following exposure to 2.0 ppm formaldehyde in asthmatics: Lung function,

symptoms, and airway reactivity. Arch. environ. Health, 42, 231–237

Wolf, D.C., Gross, E.A., Lyght O., Bermudez, E., Recio, L. & Morgan, K. T. (1995) Immunohistochemical localization of p53, PCNA, and TGF-α proteins in formaldehyde-induced rat nasal

squamous cell carcinomas. Toxicol. appl. Pharmacol., 132, 27–35

Wolkoff, P., Johnsen, C.R., Franck, C., Wilhardt, P. & Albrechtsen, O. (1992) A study of human

reactions to office machines in a climatic chamber. J. Expo. Anal. environ. Epidemiol., Suppl. 1,

71–96

Wong, O. (1983) An epidemiologic mortality study of a cohort of chemical workers potentially

exposed to formaldehyde, with a discussion on SMR and PMR. In: Gibson, J.E., ed., Formaldehyde Toxicity, Washington DC, Hemisphere, pp. 256–272

Wortley, P., Vaughan, T.L., Davis, S., Morgan, M.S. & Thomas, D.B. (1992) A case–control study

of occupational risk factors for laryngeal cancer. Br. J. ind. Med., 49, 837–844

Woutersen, R.A., Appelman, L.M., Wilmer, J.W.G.M., Falke, H.E. & Feron, V.J. (1987) Subchronic

(13-week) inhalation toxicity study of formaldehyde in rats. J. appl. Toxicol., 7, 43–49

Woutersen, R.A., van Garderen-Hoetmer, A., Bruijntjes, J.P., Zwart, A. & Feron, V.J. (1989) Nasal

tumours in rats after severe injury to the nasal mucosa and prolonged exposure to 10 ppm

formaldehyde. J. appl. Toxicol., 9, 39–46

Wu, P.-C., Li, Y.-Y., Lee, C.-C., Chiang, C.-M. & Su, H.-J.J. (2003) Risk assessment of formaldehyde in typical office buildings in Taiwan. Indoor Air, 13, 359–363

Yanysheva, N.A., Balenko, N.V., Chernichenko, I.A., Litvichenko, O.N., Sovertkova, L.S. &

Babij, V.F. (1998) [Characteristics of modifying effects of formaldehyde on carcinogenesis.]

Gig. Sanit., 8, 51–54 (in Russian)

Yasuhara, A. & Shibamoto, T. (1995) Quantitative analysis of volatile aldehydes formed from

various kinds of fish flesh during heat treatment. J. agric. Food Chem., 43, 94–97

Yi, J., Zhang, J. & Gao, Y. (2000) [Experiment on effect of formaldehyde on sperm toxicity of

mice] (Abstract). Gongye Weisheng Yu Zhiyebing, 26, 263–264 (in Chinese)

Ying, C.-J., Yan, W.-S., Zhao, M.-Y., Ye, X.-L., Xie, H., Yin, S.-Y. & Zhu, X.-S. (1997) Micronuclei in nasal mucosa, oral mucosa and lymphocytes in students exposed to formaldehyde

vapor in anatomy class. Biomed. environ. Sci., 10, 451–455 

324 IARC MONOGRAPHS VOLUME 88
Ying, C.-J., Ye, X.-L., Xie, H., Yan, W.-S., Zhao, M.-Y., Xia, T. & Yin, S.-Y. (1999) Lymphocyte

subsets and sister-chromatid exchanges in the students exposed to formaldehyde vapor. Biomed. environ. Sci., 12, 88–94 

Yokoyama, A., Kato, H., Yokoyama, T., Tsujinaka, T., Muto, M., Omori, T., Haneda, T., Kumagai,

Y., Igaki, H., Yokoyama, M., Watanabe, H., Fukuda, H. & Yoshimizu, H. (2002) Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and

drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma.

Carcinogenesis, 23, 1851–1859

Youk, A.O., Marsh, G.M., Stone, R.A., Buchanich, J.M. & Smith, T.J. (2001) Historical cohort

study of US man-made vitreous fiber production workers: III. Analysis of exposure-weighted

measures of respirable fibers and formaldehyde in the nested case–control study of respiratory

system cancer. J. occup. environ. Med., 43, 767–778

Zhang, J., Wilson, W.E. & Lloy, P.J. (1994) Indoor air chemistry: Formation of organic acids and

aldehydes. Environ. Sci. Technol., 28, 1975–1982

Zhang, L., Chung, F.-L., Boccia, L., Colosimo, S., Liu, W. & Zhang, J. (2003) Effects of garage

employment and tobacco smoking on breathing-zone concentrations of carbonyl compounds.

Am. ind. Hyg. Assoc. J., 64, 388–393

Zheng, W., Blot, W.J., Shu, X.O., Diamond, E.L., Gao, Y.T., Ji, B.T. & Fraumeni, J.F., Jr (1992) A

population-based case–control study of cancers of the nasal cavity and paranasal sinuses in

Shanghai. Int. J. Cancer, 52, 557–561

Zhitkovich, A. & Costa, M. (1992) A simple, sensitive assay to detect DNA–protein crosslinks in

intact cells and in vivo. Carcinogenesis, 13, 1485–1489

Zijlstra, J.A. (1989) Liquid holding increases mutation induction by formaldehyde and some other

cross-linking agents in Escherichia coli K12. Mutat. Res., 210, 255–261

Zimmermann, F.K. & Mohr, A. (1992) Formaldehyde, glyoxal, urethane, methyl carbamate, 2,3-

butanedione, 2,3-hexanedione, ethyl acrylate, dibromoacetonitrile and 2-hydroxypropionitrile

induce chromosome loss in Saccharomyces cerevisiae. Mutat. Res., 270, 151–166

Zito, R. (1999) Cancer risk assessment of direct acting carcinogens. J. exp. clin. Cancer Res., 18,

273–278

Zwart, A., Woutersen, R.A., Wilmer, J.W.G.M., Spit, B.J. & Feron, V.J. (1988) Cytotoxic and adaptive effects in rat nasal epithelium after 3-day and 13-week exposure to low concentrations of

formaldehyde vapour. Toxicology, 51, 87–99

Zweidinger, R.B., Sigsby, J.E., Jr, Tejada, S.B., Stump, F.D., Dropkin, D.L., Ray, W.D. & Duncan,

J.W. (1988) Detailed hydrocarbon and aldehyde mobile source emissions from roadway

studies. Environ. Sci. Technol., 22, 956–962 

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