# 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

CH 2 

# O 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 039-104.qxp 13/12/2006 11:27 Page 39

# ( 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/m 3 

# = 1.23 × ppm 1



# 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 ((CH 2 

# O) 3 

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

1995; Reuss et al ., 2003). IARC MONOGRAPHS VOLUME 88 40

1 

# Calculated from: mg/m 3 

# = (relative molecular mass/24.45) × ppm, assuming normal temperature (25 °C) and pressure (103.5 kPa) 039-104.qxp 13/12/2006 11:13 Page 40

# 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/m 3 

# 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 μ g/m 3 

# 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/m 3 

# [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 μ g/m 3 

# [1–110 ppb] are often used to monitor workplace atmospheres. Based on these methods, several standards have been established to determine levels offormaldehyde 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 usesadsorption to 2,4-dinitrophenylhydrazine-coated sorbents followed by HPLC with ultraviolet (UV)/diode array detection. The detection limit decreased from approximately

15 μ g/m 3 

# for the original method to 0.07 μ g/m 3 

# 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 41 039-104.qxp 13/12/2006 11:13 Page 41

# IARC MONOGRAPHS VOLUME 88 42



# 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 μ g/m 3 

# 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 μ g/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 μ g/sample

2 μ g/sample

20 μ g/m 3 

# NIOSH (1994b) [Method 2541] NIOSH (1994c) [Method 2539] Occupational Safety and Health

Administration (1990a) [Method 52]

Draw air through impingercontaining hydrochloric acid/2,4-dinitrophenylhydrazine reagent andisooctane; extract with hexane/dichloromethane HPLC/UV 2 μ g/m 3 

# Environmental Protection Agency (1988) [Method TO5]

Draw air through a glassfibre filterimpregnated with 2,4-dinitrophenylhydrazine; extract with acetonitrile HPLC/UV 15 μ g/m 3 

# DeutscheForschungsgemeinschaft (1993) [Method 1]

Draw air through silica gel coatedwith acidified 2,4-dinitrophenylhydrazine reagent HPLC/UV 2 μ g/m 3



# (0.6–123

μ g/m 3 

# ) 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 μ g/m 3 

# Sandner et al . (2001)

Draw air through a cartridge containing silica gel coated with 2,4-dinitrophenylhydrazine; extract

with acetonitrile HPLC/UV 0.07 μ g/ sample NIOSH (2003a) [Method 2016] 039-104.qxp 13/12/2006 11:13 Page 42

# 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 μ g/m 3 

# Occupational Safety and Health

Administration (1990b) [Method ID-205]

Collect gases with portable directreading instrument; compare spectra

with references FTIRS 0.49 μ g/m 3 

# 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 μ g/ 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; addbromine hydrate solution; purplishpink colour indicates presence of formaldehyde HehnerFulton test NR AOAC (2003) [Method 931.08]

FTIRS, Fourier transform infrared spectrometry; GC/F ID, gas chromatography/flame ionization detection; GC/MS, gas chromatography/mass spectrometry; GC/N SD, gas chromatography/nitrogen selective detection; HPLC/UV, high-performance liquid chromatography/ultraviolet detection; NR, not reported; PTFE, polytetrafluoroethylene; PVC, polyvinyl chloride 039-104.qxp 13/12/2006 11:13 Page 43

# 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–(CH 2 

# O)

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 cyclictrimer 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 selectedcountries is shown in Table 2. Worldwide capacity, production and consumption of formaldehyde in 2000 are shown in Table 3. IARC MONOGRAPHS VOLUME 88 44 039-104.qxp 13/12/2006 11:13 Page 44

# 1.2.2 Use

Worldwide patterns of use for formaldehyde in 2000 are shown in Table 4. The mostextensive 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-linkingagent 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

2520 a 

# 288

106

2663 288

118

3402 521

139

3946 675

136

4650 Western Europe b 

# 3757 3991 4899 5596 6846 c



# 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 039-104.qxp 13/12/2006 11:13 Page 45

# 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, IARC MONOGRAPHS VOLUME 88 46



# 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 America a 

# 638 636 Western Europe b 

# 7 100 7 054 Eastern Europe c 

# 1 582 1 577

Middle East d 

# 454 438 Japan 1 396 1 395

Africa e 

# 102 102

Asia

China 1 750 1 752

Indonesia 891 892 Malaysia 350 350 Republic of Korea 580 580

Other f 

# 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, Switzer

land and the United Kingdom

c 

# Includes Bulgaria, the Czech Re public, 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 Phi lippines, Singapore, Sri Lanka, Thailand and Viet Nam 039-104.qxp 13/12/2006 11:13 Page 46

# FORMALDEHYDE 47Table 4. Worldwide use patterns (%) of formaldehyde in 2000Region or countryUse(milliontonnes)UFRPFRPARMFRBDOMDIPEHMTATMPOtheraUSA4.524.216.612.73.111.26.85.02.617.8bCanada0.6251.332.33.212.9Mexico0.1470.811.75.111.70.7South and CentralAmericac0.6455.818.97.91.610.85.0Western Europed7.144.48.67.17.56.75.45.42.02.110.9Eastern Europee1.671.55.13.24.48.86.9Africaf0.1070.614.77.86.9Middle Eastg0.4375.14.614.85.5Japan1.412.37.732.94.82.18.46.72.22.220.7hAsiai4.454.29.88.48.75.82.910.2Oceaniaj0.3067.412.220.4From Bizzari (2000)UFR, urea–formaldehyde resins; PFR, phenol–formaldehyde resins; PAR, polyacetal resins; MFR, melamine–formaldehyde resins; BDO, 1,4-butanediol; MDI, 4,4′-diphenylmethane diisocyanate; PE, pentaerythritol; HMTA, hexamethylenetetramine; TMP, trimethylolpropaneaNot definedbIncluding chelating agents, trimethylolpropane, trimethylolethane, paraformaldehyde, herbicides, neopentyl glycol, pyridine chemicals, nitroparaffinderivatives, textile treating and controlled-release fertilizercIncludes Argentina, Brazil, Chile, Colombia, Ecuador, Peru, Uruguay and VenezueladIncludes Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Norway, Portugal, Spain, Sweden,Switzerland and the United KingdomeIncludes Bulgaria, the Czech Republic, Hungary, Lithuania, Poland, Romania, Russia, Slovakia, Slovenia, the Ukraine and YugoslaviafIncludes Algeria, Nigeria, South Africa and TunisiagIncludes Iran, Israel, Saudi Arabia and TurkeyhIncluding 6.4% for paraformaldehydeiIncludes Bangladesh, Cambodia, China, China (Province of Taiwan), Democratic People’s Republic of Korea, India, Indonesia, Laos, Malaysia,Myanmar, Pakistan, the Philippines, Republic of Korea, Singapore, Sri Lanka, Thailand and Viet NamjIncludes Australia and New Zealand 

# 039-104.qxp 13/12/2006 11:13 Page 47

# 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 itis 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). IARC MONOGRAPHS VOLUME 88 48 039-104.qxp 13/12/2006 11:13 Page 48

# 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 wereexposed 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/m 3 

# ] are presented by major industry sectorin 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/m 3 

# ]. 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/m 3 

# ]. 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). Someprocesses require the addition of ammonia, and alcohols are used as solvents in the production of liquid resins (Stewart et al ., 1987). FORMALDEHYDE 49 039-104.qxp 13/12/2006 11:13 Page 49

# IARC MONOGRAPHS VOLUME 88 50



# 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) 039-104.qxp 13/12/2006 11:13 Page 50

# FORMALDEHYDE 51Table 6. Concentrations of formaldehyde in the workroom air in formaldehyde and resin manufacturing plantsIndustry and operationNo. ofmeasurementsMeana(ppm [mg/m3])Range(ppm [mg/m3])YearReferenceSpecial chemical manufacturing plant (USA)8NR< 0.03–1.6 [0.04–2.0]NRBlade (1983)Production of formaldehyde (Sweden)90.3 [0.3]NR1980sRosénet al.(1984)Resin manufacture (Sweden)220.5 [0.6]NR1980sRosénet al.(1984)Formaldehyde manufacture (USA)1983Stewartet al.(1987)Plant no. 2, summer150.6b[0.7]0.03–1.9 [0.04–2.3]Plant no. 10, summer90.7b[0.9]0.6–0.8 [0.7–1.0]Resin manufacture (USA)1983–84Stewartet al.(1987)Plant no. 1, summer243.4b[4.2]0.2–13.2 [0.3–16.2]Plant no. 6, summerc60.2b[0.3]0.1–0.2 [0.1–0.3]Plant no. 7, summer90.2b[0.3]0.1–0.3 [0.1–0.4]Plant no. 7, winter90.6b[0.7]0.4–0.9 [0.5–1.1]Plant no. 8, summerc,d130.4b[0.7]0.2–0.8 [0.3–1.0]Plant no. 8, winterc,d90.1b[0.1]0.1–0.2 [0.1–0.3]Plant no. 9, summerc,d814.2b[17.5]4.1–30.5 [5.0–37.5]Plant no. 9, winter91.7b[2.1]1.1–2.5 [1.4–3.1]Plant no. 10, summerd230.7b[0.9]0.3–1.2 [0.4–1.5]Chemical factory producing formaldehydeand formaldehyde resins (Sweden)620.2 [0.3]0.04–0.4 [0.05–0.5]1979–85Holmströmet al. (1989a)Resin plant (Finland)Heikkiläet al.(1991)Furan resin production32.3 [2.9]1.0–3.4 [1.3–4.2]1982Maintenance42.9 [3.6]1.4–5.5 [1.8–6.9]1981Urea–formaldehyde resinproduction70.7 [0.9]0.6–0.8 [0.7–1.1]1981NR, not reportedaArithmetic mean unless otherwise specifiedbMean and range of geometric meansSome of the results were affected by the simultaneous occurrence in the samples (Stewartet al., 1987) of:cphenol (leading to low values)dparticulates that contained nascent formaldehyde (leading to high values). 

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# 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/m 3 

# ]. 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 areasamplers 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/m 3 

# (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/m 3 

# ), which included laboratory assistants and technicians, and those who had high exposure (mean, 2.8 mg/m 3 

# ), 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/m 3 

# and personal measurements of 3.4–3.8 mg/m 3 

# 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/m 3 

# ]. 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/m 3 

# ] 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/m 3 

# formaldehyde were found in 44% of the breathing zone samples and IARC MONOGRAPHS VOLUME 88 52 039-104.qxp 13/12/2006 11:13 Page 52

# FORMALDEHYDE 53Table 7. Concentrations of formaldehyde in the workroom air of mortuaries, hospitals and laboratoriesIndustry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceHistopathology laboratoriesPathology laboratory (Sweden)130.5 [0.7]NR1980sRosénet al.(1984)Histology laboratory, tissue specimenpreparation and sampling (USA)NRNR0.2–1.9 [0.25–2.3]NRKilburnet al. (1985)Pathology laboratories (Germany)210.5b[0.6]< 0.01–1.2 [< 0.01–1.6]1980–88Triebiget al.(1989)Hospital laboratories (Finland)800.5 [0.6]0.01–7.3 [0.01–9.1]1981–86Heikkiläet al.(1991)Histology laboratory (Israel)Area samplesPersonal samplesNRNRNRNR1.4–1.6 [1.7–2.0]2.8–3.1 [3.4–3.8]NRShahamet al.(1996a,b)Teaching laboratory (USA)160.3 [0.4]NRTanet al. (1999)Pathology laboratories (Turkey)10NRmax., < 2 [< 2.5]NRBurgazet al. (2001)Histology laboratory (Israel)Laboratory assistants/technicians (15 min)Physicians and orderlies (15 min)NR0.4 [0.5]2.2 [2.8]0.04–0.7 [0.05–0.9]0.7–5.6 [0.9–7.0]NRShahamet al. (2002)Disinfection in hospitalsCleaning hospital floors with detergentcontaining formaldehyde (Italy)Personal samples (38–74 min)40.18 [0.22]0.15–0.21 [0.18–0.26]NRBernardiniet al.(1983)Disinfection of dialysis clinic (USA)Personal samples (37–63 min)70.6 [0.8]0.09–1.8 [0.12–2.2]1983Salisbury (1983)Disinfecting operating theatres (Germany)430.4c[0.5]0.04–1.4 [0.05–1.7]NRElias (1987)Bedrooms in hospital (Germany)140.05 [0.06]< 0.01–0.7 [< 0.01–0.9]1980–88Triebiget al.(1989)Disinfecting operating theatres (Germany)d3% cleaning solution430.8 [1.1]0.01–5.1 [0.01–6.3]NRBinding & Witting (1990)0.5 % cleaning solution260.2 [0.2]0.01–0.4 [0.01–0.5]Disinfection in hospitals (Finland)180.1 [0.1]0.03–0.2 [0.04–0.3]1981–86Heikkiläet al.(1991) 

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# IARC MONOGRAPHS VOLUME 88 54Table 7 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceEmbalmingEmbalming, six funeral homes (USA)NR0.7 [0.9]0.09–5.3 [0.1–6.5]NRKerfoot & Mooney (1975)Autopsy service (USA)dPersonal samples271.3c[1.7]0.4–3.3 [0.5–4.0]NRColdironet al.(1983)Area samples234.2 [5]0.1–13.6 [0.1–16.7]Museum, taxidermy (Sweden)80.2 [0.3]NR1980sRosénet al. (1984)Embalming, seven funeral homesIntact bodies (personal samples)Autopsied bodies (personal samples)8150.3 [0.4]0.9 [1.1]0.18–0.3 [0.2–0.4]0–2.1 [0–2.6]1980Williamset al.(1984)Embalming, 23 mortuaries (USA)8-h TWANR1.1 [1.4]0.2 [0.2]0.03–3.2 [0.04–3.9]0.01–0.5 [0.01–0.6]NRLamont Moore &Ogrodnik (1986)Autopsy (Finland)50.7 [0.8]< 0.1–1.4 [< 0.1–1.7]1981–86Heikkiläet al.(1991)Embalming (USA)Personal samplesArea 1Area 22525252.6 [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]NRStewartet al.(1992)Embalming (Canada)Intact bodies (personal samples)Autopsied bodies (personal samples)Area samples2424720.6 [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]NRKorczynski (1994)Funeral home, embalming (USA)Area samplesPersonal samples44NR0.16 [0.19]< 0.1–0.15 [< 0.1–0.19]NRNRKorczynski (1996)Anatomy laboratoriesAnatomy laboratory, dissecting (USA)Personal samples54NR0.3–2.6 [0.4–3.2]NRSkisak (1983) 

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# FORMALDEHYDE 55Table 7 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceAnatomy laboratory, dissecting (USA)LaboratoryStock roomPublic hallwayNRNRNRNRNRNR7–16.5 [8.6–20.3]2.0–2.6 [2.4–3.2]max., < 1 [< 1.2]1982–83Korky (1987)Anatomical theatre (Germany)291.1b[1.4]0.7–1.7 [0.9–2.2]1980–88Triebiget al.(1989)Anatomy laboratory, dissecting (USA)Personal samples (1.2–3.1 h)Personal samples (TWA)Area samples (2.5 min)Area samples (TWA)32NR1321.2 [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]NRAkbar-Khanzadehet al.(1994)Anatomy laboratory, dissecting (USA)Personal samplesArea samples44761.9 [2.3]1.0 [1.2]0.3–4.5 [0.4–5.5]0.6–1.7 [0.7–2.1]NRAkbar-Kahnzadeh &Mlynek (1997)Anatomy laboratory, dissecting (China)250.4 [0.5]0.06–1.04 [0.07–1.28]NRYinget al. (1997, 1999)Anatomy laboratory, dissecting (China)NR2.4 [2.9]NRNRHeet al. (1998)Anatomy/histology laboratory, dissecting483.0 [3.7]0.2–9.1 [0.2–11.2]NRKimet al.(1999)Anatomy laboratory, dissecting (Austria)Two locations in a room over 4 weeksNRNR0.22 [0.27]0.12 [0.15]0.11–0.33 [0.13–0.41]0.06–0.22 [0.07–0.27]NRNRWantkeet al. (2000)Wantkeet al. (1996b)Anatomy laboratory, dissecting (Turkey)NRNRmax., < 4 [< 5]NRBurgazet al. (2001)Anatomy laboratory, dissecting (USA)150.9 [1.1]0.3–2.6 [0.3–3.1]NRKeilet al. (2001)Biology laboratory, dissecting (Canada)Laboratory 1Laboratory 218180.20 [0.25]0.51 [0.63]0.08–0.62 [0.11–0.76]0.3–1.2 [0.3–1.5]NRDufresneet al. (2002)Anatomy laboratory, dissecting (Japan)NRNR0.11–0.62 [0.14–0.76]NRTanakaet al. (2003)NR, not reported; TWA, time-weighted averageaArithmetic means unless otherwise specifiedbMediancMean of arithmetic meansd8-h TWA 

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# 11 ambient air samples; the levels in breathing zone samples were in the range of 0.4–3.2 mg/m 3 

# , and 50% of the samples contained 0.7–1.2 mg/m 3



# . 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/m 3 

# ] in the laboratory, 1.97–2.62 ppm [2.4–3.2 mg/m 3 

# ] in the stockroom and < 1 ppm [< 1.2 mg/m 3 

# ] 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/m 3 

# [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/m 3 

# with a mean of 3.74 mg/m 3 

# (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/m 3 

# (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/m 3 

# formaldehyde (Wantke et al ., 2000). Levels of formaldehyde measured in anatomy laboratories in China for a cytogenetic study averaged 0.51 mg/m 3 

# 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/m 3 

# (He et al ., 1998). In a study of respiratory function, 34 personal samples and short-term area samples werecollected in a gross anatomy laboratory in the USA. The mean concentration of formaldehyde in the room was 1.53 mg/m 3 

# during the 1.2–3.1-h dissecting period. The direct-reading short-term area samples (2.5-min) averaged 1.68 mg/m 3 

# . Eight-hour time-weighted average (TWA) personal exposures ranged from 0.11 to 1.17 mg/m 3 

# , with a mean of 0.52 mg/m 3 

# (96% of subjects were exposed to levels of formaldehyde above the 0.38 mg/m 3 

# ceiling, and the 8-h TWA exposure of 3% of them was above 0.94 mg/m 3 

# ) (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/m 3 

# (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/m 3 

# (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. IARC MONOGRAPHS VOLUME 88 56 039-104.qxp 13/12/2006 11:13 Page 56

# The concentration of formaldehyde in the air in pathology and anatomy laboratories in Turkey did not exceed 2 and 4 mg/m 3 

# , 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/m 3 

# and 0.63 mg/m 3 

# 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/m 3 

# after 10 min of class; 30 min later, the formaldehyde concentration had decreased to 0.14 mg/m 3 

# (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). Forexample, 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 andgaseous formaldehyde. Levels of formaldehyde gas behind the inhalable dust sampler averaged [132 μ g/m 3 

# (standard deviation [SD], 14 μ g/m 3 

# ; four samples)] and those of bound formaldehyde from inhalable dust averaged [11 μ g/m 3 

# (SD, 4 μ g/m 3 

# ; 12 samples)]. Respective measurements for the closed cassettes averaged [147 μ g/m 3 

# (SD, 9 μ g/m 3 

# ; four samples)] and [8 μ g/m 3 

# (SD, 2 μ g/m 3 

# ; 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 57 039-104.qxp 13/12/2006 11:13 Page 57

# IARC MONOGRAPHS VOLUME 88 58Table 8. Concentrations of formaldehyde in the workroom air of plywood mills, particle-board mills,furniture factories, other wood product plants, paper mills and the construction industryIndustry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferencePlywood millsPlywood production (Sweden)470.3 [0.4]NR1980sRosénet al.(1984)Plywood mills (Finland)Glue preparation, short-term152.2 [2.7]0.6–5.0 [0.7–6.2]1965–74Kauppinen (1986)Glue preparation, short-term190.7 [0.9]0.1–2.3 [0.1–2.8]1975–84Assembling321.5 [1.9]< 0.1–4.4 [< 0.1–5.4]1965–74Assembling550.6 [0.7]0.02–6.8 [0.03–8.3]1975–84Hot pressing412.0 [2.5]< 0.1–7.7 [< 0.1–9.5]1965–74Hot pressing430.5 [0.6]0.06–2.1 [0.07–2.6]1975–84Sawing of plywood50.5 [0.6]0.3–0.8 [0.4–1.0]1965–74Sawing of plywood120.1 [0.1]0.02–0.2 [0.03–0.3]1975–84Coating of plywood71.0 [1.2]0.5–1.8 [0.6–2.2]1965–74Coating of plywood280.3 [0.4]0.02–0.6 [0.03–0.7]1975–84Plywood panelling manufacture (USA)Plant no. 3, winterPlant no. 3, summer27260.2b[0.3]0.1b[0.1]0.08–0.4 [1.0–0.5]0.01–0.5 [0.01–0.6]1983–84Stewartet al.(1987)Plywood mill (Indonesia)400.6 [0.8]0.2–2.3 [0.3–2.8]NRMalaka & Kodama (1990)Plywood factory (Italy)Warehouse30.3 [0.4]0.1–0.5 [0.2–0.6]NRBallarinet al. (1992)Shearing press80.08 [0.1]0.06–0.11 [0.08–0.14]Plywood mill (Finland)Personal samples1996–97Mäkinenet al.(1999)Patching60.06 [0.07]0.02–0.08 [0.03–0.10]Feeding of drying machine60.05 [0.06]0.01–0.12 [0.01–0.15]Forklift driving60.06 [0.07]0.02–0.16 [0.02–0.20]Scaring60.11 [0.14]0.06–0.20 [0.07–0.24]Assembly (machine I)40.24 [0.30]0.08–0.66 [0.10–0.81]Assembly (machine II)60.12 [0.15]0.08–0.22 [0.10–0.27]Hot pressing (machine I)50.11 [0.13]0.07–0.19 [0.08–0.23] 

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# FORMALDEHYDE 59Table 8 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceGlue preparation20.12 [0.15]0.06–0.19 [0.07–0.23]Finishing (puttying)40.07 [0.09]0.06–0.11 [0.07–0.14]Carrying plywood piles20.05 [0.06]0.04–0.06 [0.05–0.07]Finishing (sanding)20.04 [0.05]0.01–0.06 [0.01–0.07]Plywood mill (New Zealand)[2000]Fransmanet al.(2003)Dryers140.06b[0.07]GSD, [3.2]Composers20.02b[0.03]GSD, [1.0]Pressing50.13b[0.16]GSD, [2.7]Finishing end10.03b[0.04]NAParticle-and other board millsParticle-board production (Sweden)210.3 [0.4]NR1980sRosénet al.(1984)Medium-density fibre board (Sweden)190.2 [0.3]NR1980sRosénet al.(1984)Particle-board mills (Finland)Glue preparation102.2 [2.7]0.3–4.9 [0.4–6.0]1975–84Kauppinen & Niemelä(1985)Blending101.0 [1.2]0.1–2.0 [0.1–2.5]1965–74Blending80.7 [0.9]< 0.1–1.4 [< 0.1–1.7]1975–84Forming261.7 [2.1]< 0.5–4.6 [< 0.6–5.7]1965–74Forming321.4 [1.7]0.1–4.8 [0.1–5.9]1975–84Hot pressing353.4 [4.2]1.1–9.5 [1.4–11.7]1965–74Hot pressing611.7 [2.1]0.2–4.6 [0.25–5.7]1975–84Sawing174.8 [5.9]0.7–9.2[0.9–11.3]1965–74Sawing361.0 [1.2]< 0.1–3.3 [< 0.1–4.1]1975–84Coating71.0 [1.2]0.5–1.8 [0.6–2.2]1965–74Coating120.4 [0.5]0.1–1.2 [0.1–1.5]1975–84Chip-board production (Germany)241.5 [1.9]< 0.01–8.4 [< 0.01–10]1980–88Triebiget al.(1989)Particle-board mill (Indonesia)92.4 [3.0]1.2–3.5 [1.5–4.3]NRMalaka & Kodama (1990)Block-board mill (Indonesia)60.5 [0.6]0.4–0.6 [0.5–0.7]NRMalaka & Kodama (1990) 

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# IARC MONOGRAPHS VOLUME 88 60Table 8 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceOriented strand board plant (Canada)1990sHerbertet al.(1995)Debarking5≤0.05 [0.06]NRPre-heat conveyor5≤0.05 [0.06]NRPost-heat press conveyor5≤0.05 [0.06]NRPackaging/storage5≤0.05 [0.06]NRFibreboard, sawing and sanding (UnitedKingdom)1990sChunget al.(2000)Standard MDF (Caberwood)Gaseous formExtracted from dust560.06 [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 formExtracted from dust560.05 [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 formExtracted from dust660.04 [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 formExtracted from dust660.03 [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 varnishes320.7 [0.9]NR1980sRosénet al.(1984)Furniture factories (Finland)Feeding painting machine141.1 [1.4]0.3–2.7 [0.4–3.3]1975–84Prihaet al.(1986)Spray painting601.0 [1.2]0.2–4.0 [0.3–5.0]Spray painting assistance101.0 [1.2]0.2–1.6 [0.3–2.0]Curtain painting181.1 [1.4]0.2–6.1 [0.3–7.5]Before drying of varnished furniture341.5 [1.8]0.1–4.2 [0.1–5.2]After drying of varnished furniture141.4 [1.7]0.2–5.4 [0.3–6.6] 

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# FORMALDEHYDE 61Table 8 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceCabinet-making (Canada)48NRmax., < 0.1 [< 0.1]NRSass-Kortsaket al.(1986)Furniture factories, surfacefinishing withacid curing paints (Sweden)NRAlexandersson &Hedenstierna (1988)Paint mixer/supervisor60.2 [0.3]0.1–0.4 [0.2–0.5]Mixed duties on the line50.4 [0.5]0.3–0.5 [0.3–0.6]Assistant painters30.5 [0.6]0.2–0.7 [0.2–0.9]Spray painters100.4 [0.5]0.1–1.1 [0.2–1.3]Feeder/receiver130.2 [0.3]0.1–0.8 [0.1–0.9]Furniture factories (Finland)Glueing730.3 [0.4]0.07–1.0 [0.09–1.2]1981–86Heikkiläet al.(1991)Machining in finishing department90.3 [0.4]0.1–0.9 [0.1–1.1]Varnishing1501.1 [1.4]0.1–6.3 [0.1–7.9]Manufacture of furniture (Denmark)Painting430.16 [0.20]bGSD, [2.25]NRVinzents & Laursen(1993)Glueing680.12 [0.15]bGSD, [2.87]Wood-working shops (Egypt)1990sVentilated workshop140.42 [0.52]0.28–0.54 [0.34–0.66]Abdel Hameedet al.(2000)Unventilated workshop140.64 [0.79]0.48–0.84 [0.59–1.03]Other wood product plantsGlueing in wood industry (Sweden)650.2 [0.3]NR1980sRosénet al.(1984)Parquet plant (Finland)Machining30.3 [0.4]0.16–0.5 [0.2–0.6]1981Heikkiläet al.(1991)Varnishing50.8 [1.0]0.2–1.4 [0.3–1.7]Production of wooden structures (Finland)1981–86Heikkiläet al.(1991)Glueing360.7 [0.8]0.07–1.8 [0.1–2.2]Machining190.4 [0.4]0.1–0.8 [0.1–0.9]Manufacture of wooden bars (Finland)1983Heikkiläet al.(1991)Glueing330.6 [0.7]0.2–1.9 [0.2–2.4]Machining71.2 [1.5]0.2–2.2 [0.3–2.7] 

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# IARC MONOGRAPHS VOLUME 88 62Table 8 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceMatch mill, impregnation of matchbox parts(Finland)Short-term22.0 [2.5]1.9–2.1 [2.3–2.6]1963FinnishInstitute ofOccupational Health(1994)Wooden container mill, glueing and sawing(Finland)60.3 [0.4]0.2–0.4 [0.3–0.5]1961Finnish Institute ofOccupational Health(1994)Paper millsLaminated paper production (Sweden)230.3 [0.4]NR1980sRosénet al.(1984)Manufacture of offset paper (Sweden)80.2 [0.2]NR1980sRosénet al.(1984)Lamination and impregnation of paper withmelamine and phenol resins (USA)Plant no. 6, summerc,d530.7b[0.9]< 0.01–7.4 [< 0.01–9.1]1983Stewartet al.(1987)Plant no. 6, winterd390.3b[0.4]0.05–0.7 [0.06–0.9]Paper mill (Finland)Coating of paper300.7 [0.9]0.4–31 [0.5–39]1975–84Heikkiläet al.(1991)Gum paper production40.4 [0.5]0.3–0.6 [0.3–0.8]Impregnation of paper with amino resin63.1 [3.9]0.5–13 [0.6–16]Impregnation of paper with phenol resin200.1 [0.1]0.05–0.3 [0.06–0.4]Paper mill (Finland)Glueing, hardening, lamination androlling of special paper120.9 [1.1]0.3–2.5 [0.4–3.1]1971–73Finnish Institute ofOccupational Health(1994)Impregnation of paper with phenol resin,partly short-term387.4 [9.1]< 1.0–33.0 [< 1.1–40.6]1968–69Paper storage, diesel truck traffic50.3 [0.4]0.2–0.4 [0.25–0.5]1969Pulp and paper industries (12 countries)1950–94Korhonenet al.(2004)Pulping, refining of stock (8 mills)250.5 [0.6]0–3.1 [0–3.8]Newsprint and uncoated paper machine(2 mills)70.15 [0.18]0.04–0.46 [0.05–0.57]Fine and coated paper machine (6 mills)511.1 [1.4]0.01–9.9 [0.01–12.2] 

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# FORMALDEHYDE 63Table 8 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferencePaperboard machine (1 mill)80.5 [0.6]0.2–2.2 [0.2–2.7]Paper/paperboard machine from morethan oneof above categories (24 mills)2280.4 [0.5]0–6.6 [0–8.1]Calendering or on-machine coating(10 mills)1664.2 [5.2]0–50 [0–61.5]Winding, cutting and grading (17 mills)1110.2 [0.3]0–1.1 [0–1.4]Recycled paper industry (12 countries)Re-pulping of waste paper (2 mills)80.2 [0.3]0.05–0.4 [0.06–0.5]Construction industryInsulating buildings with urea–formaldehydefoam (Sweden)60.1 [0.2]NR1980sRosénet al. (1984)Insulating buildings with urea–formaldehydefoam (USA)661.3e[1.6]0.3–3.1 [0.4–3.8]NRWHO (1989)Varnishing parquet with urea–formaldehydevarnish (Finland)102.9 [3.6]0.3–6.6 [0.4–8.1]1976Heikkiläet al. (1991)Varnishing parquet with urea–formaldehydevarnish (Finland)64.3 [5.3]2.6–6.1 [3.2–7.5]1987Riala & Riihimäki (1991)Sawing particle-board at construction site(Finland)5< 0.5 [< 0.6]NR1967Finnish Institute ofOccupational Health(1994)GSD, geometric standard deviation; NA, not applicable; NR, not reportedaArithmetic mean unless otherwise specifiedbGeometric meanSome of the results in the Stewartet al. (1987) study were affected by the simultaneous occurrence in the samples of:cphenol (leading to low values)dparticulates that contained nascent formaldehyde (leading to high values).eMean of arithmetic means 

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# 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/m 3 

# . In contrast, mean levels of 2 ppm [2.5 mg/m 3 

# ] 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 aredestined for applications that require durability under adverse conditions, while ureabased resins are used for less demanding, interior applications. Melamine–formaldehyderesins 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/m 3 

# 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/m 3 

# ] 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/m 3 

# ] 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/m 3 

# ] 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/m 3 

# ]. One coat of varnish IARC MONOGRAPHS VOLUME 88 64 039-104.qxp 13/12/2006 11:13 Page 64

# 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). Thecutting 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 intextile 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/m 3 

# ]. 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/m 3 

# ] in a post-cure garment manufacturing plant and 0.3–2.7 ppm [0.4–3.3 mg/m 3 

# ] 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/m 3 

# ] in 1968 to less than 2 ppm [2.4 mg/m 3 

# ] 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/m 3 

# ] 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/m 3 

# ]. 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 65 039-104.qxp 13/12/2006 11:13 Page 65

# IARC MONOGRAPHS VOLUME 88 66Table 9. Concentrations of formaldehyde in the workroom air of textile mills and garment factoriesIndustry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range or SD in ppm[mg/m3]YearReferenceTextile millsTextile plants (Finland)Finishing department, mixing80.8 [1.1]< 0.2–>5 [< 0.2–> 6]1975–78Nousiainen &Lindqvist (1979)Crease-resistant treatment520.4 [0.5]< 0.2–>3 [< 0.2–> 4]Finishing department (excluding creaseresistant and flame-retardant treatment)170.3 [0.4]max., 1.3 [1.5]Flame-retardant treatment671.9 [2.5]< 0.2–>10 [< 0.2–> 11]Fabric store60.8 [1.1]0.1–1.3 [0.1–1.6]Textile mills (Sweden)Crease-resistant treatment290.2 [0.2]NR1980sRosénet al.(1984)Flame-retardant treatment21.2 [1.5]NRGarment factoriesManufacture from crease-resistant cloth (USA)181NR< 0.1–0.9 [< 0.1–1.1]NRBlade (1983)Manufacture of shirts from fabric treated withformaldehyde-based resins (USA)326~0.2 [~0.25]< 0.1–0.4 [< 0.1–0.5]1980sElliottet al.(1987)Garment industry (Finland)Handling of leather30.1 [0.1]0.02–0.1 [0.03–0.1]1981–86Heikkiläet al.(1991)Pressing320.2 [0.3]0.02–0.7 [0.03–0.9]Sewing150.1 [0.1]0.02–0.3 [0.03–0.3]Sewing plant (USA)Processing of 0.04% formaldehyde fabricProcessing of 0.015% formaldehyde fabric991.0 [1.2]0.1 [0.1]0.5–1.1 [0.6–1.4]< 0.1–0.2 [< 0.1–0.3]NRLuker & Van Houten(1990)Garment manufacturing (USA)Sewers, cutters and bundlersPersonal samples8-h TWAArea samples8-h TWA88880.21 [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]NREcht& Burr (1997) 

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# FORMALDEHYDE 67Table 9 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range or SD in ppm[mg/m3]YearReferenceCut and spreadFormaldehyde gas (inhalable dust)60.03SD, 0.01NRKennedyet al. (1992)Boundformaldehyde (inhalable dust)6< 0.01SD, < 0.01Formaldehyde gas (total dust)60.04SD, 0.01Bound formaldehyde (total dust)6< 0.01bSD, < 0.01Turn and ticketFormaldehyde gas (inhalable dust)6< 0.01SD, < 0.01Bound formaldehyde (inhalable dust)6< 0.01SD, < 0.01Formaldehyde gas (total dust)60.03SD, 0.01Bound formaldehyde (total dust)6< 0.01SD, < 0.01Retail dress shops (USA)NRNR0.1–0.5 [0.1–0.6]1959Elliottet al.(1987)Fabric shops (Finland)30.17 [0.21]0.12–0.24 [0.15–0.30]1985–87Prihaet al.(1988)Fabric stores (USA)24-h area samplesIndependent storesChain stores7733440.14 [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]NRMcGuireet al. (1992)NR, not reported; SD, standard deviationaArithmetic meanbFive samples with non-detectable levels 

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# the USA. Levels of exposure to formaldehyde for sewers, cutters and bundlers ranged from 0.22 to 0.28 mg/m 3 

# (8-h TWA, 0.17–0.21 mg/m 3 

# ). Area measurements of formaldehyde at cutting, sewing, pressing, spreading and receiving (storage) locations ranged from 0.21 to 0.37 mg/m 3 

# (8-h TWA; 0.20–0.31 mg/m 3 

# ). Full-shift (for 5.8–6.4 h; eight samples) personal measurements of formaldehyde in inhalable dust showed levels of up to 29 μ g/mg dust; settled dust samples showed concentrations of 0.7 and 0.8 μ g/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 μ g/m 3 

# and 0.2–0.7 μ g/m 3 

# , 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/m 3 

# ] (Elliott et al. , 1987). The air in three Finnish fabric shops in the 1980s contained 0.15–0.3 mg/m 3 

# 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/m 3 

# (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/m 3 

# ]; however, measurements made before 1975 suggest that past exposures may have been considerably higher (Heikkilä et al ., 1991). Many other chemicalsoccur 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/m 3 

# ] formaldehyde. Very high levels were measured IARC MONOGRAPHS VOLUME 88 68 039-104.qxp 13/12/2006 11:13 Page 68

# FORMALDEHYDE 69Table 10. Concentrations of formaldehyde in the workroom air of foundries and during the manufacture ofsynthetic vitreous fibres and plasticsIndustry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceFoundriesFoundry (Sweden)Hot-box method51.5 [1.9]NR1980sRosénet al.(1984)Moulding170.1 [0.1]NRFoundries (Sweden)Moulders and core-maker handling furanresin sand8-h TWA360.1 [0.1]0.02–0.22 [0.02–0.27]NRÅhmanet al.(1991)Foundries (Finland)Core-making432.8 [3.4]< 0.1–> 10 [< 0.1–> 11]Before 1975Heikkiläet al.(1991)Core-making170.3 [0.4]0.02–1.4 [0.03–1.8]1981–86Casting100.2 [0.2]0.02–0.2 [0.03–0.8]1981–86Moulding250.3 [0.4]0.04–2.0 [0.05–2.5]1981–86Synthetic vitreous fibre plants(Sweden)Production160.15 [0.19]NR1980sRosénet al.(1984)Form pressing40.16 [0.20]NR(Finland)ProductionForm pressing36240.20 [0.25]0.09 [0.11]0.02–1.5 [0.03–1.7]0.01–0.3 [0.01–0.4]1981–86Heikkiläet al.(1991)Fibrous glass manufacturing plant (USA)NRFixed location workers (n= 17)970.07; 0.05bGSD, 4.0Miltonet al.(1996)Forming attendant (n= 2)110.07; 0.03bGSD, 8.2Forming attendant leader (n= 3)180.09; 0.07bGSD, 1.9Binder water leader (n= 1)40.05; 0.01bGSD, 10.9Binder water operator (n= 1)60.06; 0.05bGSD, 2.1Pipefitter (n= 1)50.05; 0.05bGSD, 1.4Forehearth operator (n= 6)350.07; 0.05bGSD, 4.4Curing oven machine operator (n= 3)180.08; 0.07bGSD, 1.7 

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# IARC MONOGRAPHS VOLUME 88 70Table 10 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceMobile workers (n= 20)< 1000.03; 0.02bGSD, 3.1Crew (packaging) (n= 2)120.02; 0.01bGSD, 4.1Washwater tender (n= 1)30.04; 0.04bGSD, 1.5Mechanical repair (n= 7)350.02; 0.01bGSD, 3.4Electrician (n= 5)250.03; 0.02bGSD, 3.1Sheet metal worker (n= 2)100.03; 0.02bGSD, 2.7Welder (n= 2)100.04; 0.03bGSD, 2.6Pipefitter (n= 1)50.03; 0.02bGSD, 1.9Plastics productionProduction of moulded plastic products (USA)Plant no. 8, phenol resin, summerPlant no. 9, melamine resin, summer10130.5b[0.6]9.2b[11.3]0.1–0.9 [0.1–1.1]< 0.01–26.5 [< 0.01–32.6]1983–84Stewartet al.(1987)Moulding compound manufacture (USA)Plant no. 9, winter92.8b[3.4]0.04–6.7 [0.05–8.2]Plant no. 9, summerc1838.2b[47.0]9.5–60.8 [11.7–74.8]Plant no. 1, winter121.5b[1.8]0.9–2.0 [1.1–2.1]Plant no. 1, summer249.7b[11.9]3.8–14.4 [4.7–17.7]Plant no. 8, winter130.3b[0.4]0.07–0.7 [0.09–0.9]Plant no. 7, summer430.3b[0.4]0.05–0.6 [0.06–0.8]Plant no. 2, summer156.5b[8.0]0.3–20.6 [0.4–25.3]Plastics production (Finland)Casting of polyacetal resin100.3 [0.4]0.06–0.7 [0.08–0.8]1981–86Heikkiläet al.(1991)Casting of urea–formaldehyde resin40.4 [0.5]0.2–0.5 [0.3–0.6]Casting of other plastics29< 0.1 [< 0.1]< 0.1–0.2 [< 0.1–0.3]Plastics manufacturing (Canada)Polyethylene extrusion9NRmax., [< 0.12]NRTikuisiset al.(1995)GSD, geometric standard deviation; NR, not reported; TWA, time-weighted averageaArithmetic mean unless otherwise specifiedbGeometric meancSome of the results were affected by the simultaneous occurrence in the samples of particulates that contained formaldehyde (leading to highvalues). 

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# 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/m 3 

# . 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/m 3 

# . 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/m 3 

# ], 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/m 3 

# (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/m 3 

# ], with a second highest concentration of 3.3 ppm [4.1 mg/m 3 

# ] (BrandtRauf et al ., 1988). In another study in the USA, levels of formaldehyde ranged from the limit of detection (0.13 mg/m 3 

# ) to 9.8 mg/m 3 

# 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/m 3 

# , 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/m 3 

# . Two of the measurements during knockdown exceeded the 15-min short-term exposure limit (STEL) of 2.5 mg/m 3



# . FORMALDEHYDE 71 039-104.qxp 13/12/2006 11:13 Page 71

# IARC MONOGRAPHS VOLUME 88 72Table 11. Concentrations of formaldehyde duringfirefighting and exposure to engine exhaustsIndustry and operation (location)Type of sampleNo. ofmeasurementsMeana(ppm [mg/m3])Range (ppm [mg/m3])YearReferenceFirefightingCity fire (USA)240.55 [0.68]b0.1–8.3 [0.1–10.2]b1986Brandt-Raufet al. (1988)City fire (USA)22 firesNRJankovicet al. (1991)KnockdowncNRND–8 [ND–9.8]OverhaulcNRND–0.4 [ND–0.5]Inside maskNRND–0.3 [ND–0.4]Wildland fire (USA)50.05 [0.06]0.02–0.07 [0.02–0.09]1990Rehet al.(1994)Wildland fire (USA)300.13 [0.16]0.04–0.3 [0.05–0.4]1989Maternaet al. (1992)City fire (USA)960.25 [0.31]0.02–1.2 [0.02–1.5]1998Bolstad-Johnsonet al. (2000)Engine exhaustChain-sawing(Sweden)NR0.05 [0.06]0.02–0.11 [0.03–0.13]NRHagberget al. (1985)Chain-sawing (Finland)8-h TWANR< 0.1 [< 0.1]< 0.1–0.5 [< 0.1–0.6]NRHeikkiläet al. (1991)Automobile garagePersonal samples530.03 [0.04]NRNRZhanget al.(2003)ND, not detected; NR, not reported; TWA, time-weighted averageaArithmetic meanbExcluding 18 values noted as 0cSee text for definitions 

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# A comprehensive study that monitored air was conducted to characterize exposures of firefighters during 25 structure fires. Exposures of firefighters during overhaul, whenthey 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/m 3 

# ]) 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/m 3 

# ; the mean was 0.16 mg/m 3 

# (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/m 3 

# ] and the mean was 0.05 ppm [0.06 mg/m 3 

# ] (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 μ g/m 3 

# in the summer and 21 μ g/m 3 

# in the winter. Zhang et al . (2003) examined whether work in an automobile garage and tobaccosmoke can significantly affect personal exposure to a number of important carbonyl compounds, including formaldehyde. The study was carried out on 22 garage workers (ninesmokers 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 μ g/m 3 

# for smoking garage workers, 41.1 μ g/m 3 

# for nonsmoking garage workers, 34.6 μ g/m 3 

# for smoking nongarage workers and 30.2 μ g/m 3 

# for nonsmoking non-garage workers (total range,

14.1–80.1 μ g/m 3 

# ).

( 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/m 3 

# in conventional offices and 1.4 mg/m 3 

# 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 73 039-104.qxp 13/12/2006 11:13 Page 73

# IARC MONOGRAPHS VOLUME 88 74Table 12. Concentrations of formaldehyde in offices and miscellaneous other workplacesIndustry and operation (location)Type of sampleNo. ofmeasurementsMean(ppm [mg/m3])aRange(ppm [mg/m3])aYearReferenceOfficesOffices (USA)2580.0bμg/m3NR1981–84Shah & Singh (1988)Non-industrial office workplaces and restaurants(Brazil)1220.4μg/m34.7–60.7μg/m31993Miguelet al. (1995)Four offices on several floors of an officebuilding (Brazil)1140μg/m312.2–99.7μg/m31995Brickuset al. (1998)Offices (Sweden)Recently painted with low-emitting paintThree months laterControl (at the time and 3 months later)NRNRNR18μg/m38μg/m38μg/m316–20μg/m37–10μg/m38–9μg/m31995–96Wieslanderet al.(1999a)Offices (Australia)Conventional offices (18 sites)Portable office buildings (20 sites)NR4027μg/m31400μg/m312–96μg/m3516–2595μg/m3NRDingleet al. (2000)Six office buildings (USA)[72]1.7–13.3μg/m3cNR1996–97Reynoldset al. (2001)Five office buildings (Taiwan, China)8-h average during working time frommeasurements conducted continuously≥24h54140–1190μg/m3dNRNRWuet al. (2003)MiscellaneousCoal coking plant (former Czechoslovakia)NR0.05e[0.06]< 0.01–0.25 [< 0.01–0.3]NRMašek (1972)Pitch coking plant (former Czechoslovakia)NR0.4e[0.5]0.05–1.6 [0.07–2.0]NRMašek (1972)Electrical machinery manufacture (Finland)Soldering47< 0.1 [< 0.1]NR1977–79Niemelä & Vainio(1981)Lacquering and treatment of melamine plastics80.35 [0.4]NRRubber processing (USA)NRNR0.4–0.8 [0.5–0.98]1975IARC (1982)Painting with bake-drying paints (Sweden)13< 0.1 [< 0.1]NR1980sRosénet al.(1984)Abrasive production (Sweden)200.2 [0.3]NR1980sRosénet al.(1984) 

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# FORMALDEHYDE 75Table 12 (contd)Industry and operation (location)Type of sampleNo. ofmeasurementsMean(ppm [mg/m3])aRange(ppm [mg/m3])aYearReferenceSugar mill (Sweden)Preservation of sugar beets260.4 [0.5]NR1980sRosénet al.(1984)Fur processing8-h TWA16NR0.8–1.6 [1.0–2.0]1980sRosénet al.(1984)Photographic film manufacture (USA)Plants no. 4 and 5, summer490.1e[0.1]< 0.01–0.4 [< 0.01–0.5]1983–84Stewartet al.(1987)Plants no. 4 and 5, winter290.3e[0.4]0.02–0.9 [0.03–1.1]Agriculture (Finland)Handling of fodderNRNR0.02–0.4 [0.03–0.5]1982Heikkiläet al.(1991)Disinfection of eggs112.6 [3.2]0.2–7.8 [0.3–9.6]1981–86Metalware plant, bake painting (Finland)180.3 [0.4]0.03–0.7 [0.04–0.9]1981–86Heikkiläet al.(1991)Print (Finland)Development of photographs110.04 [0.05]0.02–0.1 [0.03–0.13]1981–86Heikkiläet al.(1991)Malt barley production (Finland)Preservation of malt barley60.7 [0.9]0.4–1.5 [0.5–1.8]1981Heikkiläet al.(1991)Photographic laboratories (Finland)100.07 [0.09]0.02–0.3 [0.03–0.40]1981–86Heikkiläet al.(1991)Fish hatchery (USA)Treating fish eggs (6 sites)8-h TWA60.02 [0.02]0.006–0.038 [0.007–0.05]NRLee & Radtke (1998)NR, not reported;TWA, time-weighted averageaArithmetic mean unless otherwise specified; values in ppm [mg/m3], unless stated otherwisebMediancRange of geometric meansdRange of arithmetic meanseMean of arithmetic means 

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# 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 μ g/m 3 

# (range, 16–

20 μ g/m 3 

# ); those taken 3 months later averaged 8 μ g/m 3 

# (range, 7–10 μ g/m 3 

# ) (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 μ g/m 3 

# ). 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 μ g/m 3



# , 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 μ g/m 3 

# (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 timesper 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/m 3 

# ], 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/m 3 

# ], 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/m 3 

# . Area measurements during treatment were < 0.062–0.84 mg/m 3 

# , and 8-h TWAs were reported to be < 0.01– 0.05 mg/m 3 

# (mean, 0.02 mg/m 3 

# ) (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/m 3 

# ] 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/m 3 

# ] (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/m 3 

# ] IARC MONOGRAPHS VOLUME 88 76 039-104.qxp 13/12/2006 11:13 Page 76

# (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/m 3 

# . 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 μ g/m 3 

# in remote areas. For example, in the unpopulated Eniwetok Atoll in the Pacific Ocean, a mean of 0.5 μ g/m 3 

# and a maximum of 1.0 μ g/m 3 

# 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 μ g/m 3 

# (Preuss et al

., 1985; IARC, 1995; Jurvelin, 2001). Urban air concentrations in heavy traffic or during severe inversions can range up to 100 μ g/m 3 

# (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 fromautomobile 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 77 039-104.qxp 13/12/2006 11:13 Page 77

# IARC MONOGRAPHS VOLUME 88 78Table 13. Occurrence of formaldehyde in outdoor(ambient) airCountryLocation/regionSettingsSamplingperiodNo. ofsamplesMean concen-tration or range ofmeans (μg/m3)aRange(μg/m3)aCommentsReferenceAlgeriaAlgiersOuarglaAlgiersUrbanUrbanSuburban2000–011041412.74.011.95.2–27.12.6–5.26.0–21.2Cecinatoet al.(2002)AustriaExelbergRaasdorfSchoenebenSemi-ruralSemi-ruralRural1986–872118206.4–13.4 ppb6.6–11.1 ppb4.0–8.9 ppbNRNRNRMeasured in July and AugustMeasured in July and AugustMeasured in SeptemberPuxbaumet al.(1988)BrazilSão Paulo andRio de JaneiroUrban19931210.74.0–27.7Measured outside non-industrial office workplacesand restaurantsMiguelet al. (1995)Salvador, BahiaUrbanNR682.9–80 ppb1.3–88 ppbCollected at six sites around thecityde Andradeet al.(1998)Rio de JaneiroRuralUrban199537111.2–1.5 ppb14.5 ppb0.2–4.6 ppb7.1–21.0 ppbCollected at two sites in ruralareaMeasured outside of an officebuildingBrickuset al. (1998)São PauloUrban19993716.4–18.0 ppb10.7–13.1 ppb9.8–10.7 ppb1.1–46.3 ppb1.2–28.3 ppb2.7–38.1 ppbCollected in winter at two sites:MorningMiddayEveningMonteroet al.(2001)São PauloUrban1997115.0 ppb1.4–9.7 ppbMeasured in February duringuse of alcohol fuelNguyenet al. (2001)TheobromaRural19951512.8 ppbdaytime, 16.5 ppbnighttime, 8.6 ppb5–25 ppbMeasured during 1 week of anopen agricultural and silvicultural biomass burning periodReinhardtet al.(2001)Rio de JaneiroUrban20001310.8NRCollected from May toNovember during morningcommuteGrosjeanet al.(2002)Rio de JaneiroUrban1998–20012813.7 ppb1.5–54.3 ppbMeasured on a high trafficstreet in the downtown areaCorrêaet al.(2003) 

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# FORMALDEHYDE 79Table 13 (contd)CountryLocation/regionSettingsSamplingperiodNo. ofsamplesMean concentration or range ofmeans (μg/m3)aRange(μg/m3)aCommentsReferenceCanadaOntarioRural198849471.6 ppb1.8 ppb0.6–4.4 ppb0.7–4.2 ppbDorset siteEgbert siteShepsonet al.(1991)Alert, NunavutRemote1992NR0.48NR0.04–0.740.12–0.86Polar nightSunlit periodDe Serves (1994)Nova ScotiaRemote1993108NR< 0.6–4.2Summer measurementsTanneret al. (1994),cited in EnvironmentCanada/HealthCanada (2001)Six provincesVarious1989–98NRNRNRNRNRNRND–27.5ND–12.0ND–9.9Measured at eight urban sitesMeasured at two suburban sitesMeasured at six rural sitesEnvironment Canada(1999), cited inEnvironmentCanada/HealthCanada (2001)Rural1995–96SpringSummerWinterNRNRmax., 3.0max., 1.7max., 4.4Near a forest product plantEnvironment Canada(1997), cited inEnvironmentCanada/HealthCanada (2001)Prince Rupert,BCUrban,residential,andindustrialareas1994–95960.7–3.90.08–14.7Collected from the roofs at foursitesEnvironmentCanada/HealthCanada (2001)VariousUrban andsuburban1990–9828193.3 (2.8)bFour urban and four suburbansites from the National AirPollution Survey programmeLiteplo & Meek(2003) 

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# IARC MONOGRAPHS VOLUME 88 80Table 13 (contd)CountryLocation/regionSettingsSamplingperiodNo. ofsamplesMean concen-tration or range ofmeans (μg/m3)aRange(μg/m3)aCommentsReferenceChinaHong KongUrban1997–20001823.6–4.24.8–5.10.6–101.9–11Residential and commercialResidential, commercial andlight industrialSinet al. (2001)Hong KongUrban1999–2000414.15.92.61.0–11.3NRNROverall average (12 months)Summer average (May–August)Winter average (November–February)Hoet al. (2002)GuangzhouUrban20022512.46.4–29.0Measured outside a hotel in theevening on 7 consecutive daysFenget al.(2004)DenmarkCopenhagenUrban1994372.6 ppb0.2–6.4 ppbWinter measurements(February)Granbyet al. (1997)Lille ValbySemi-rural18280.9 ppb0.8 ppb0.1–2.8 ppb0.3–1.8 ppbWinter measurements(February)Spring measurements (April)Lille ValbySemi-rural19952441.2 ppb0.1–4.7 ppbMeasured in May–JulyChristensenet al.(2000)EgyptCairoUrban199998494933 ppb29 ppb37 ppbSD, 8.6SD, 7.1SD, 9.5Residential areaSpringSummerKhoderet al.(2000)FranceGrenobleUrban1995NRNR2–18 ppbMeasured during 1 week inMayFerrariet al. (1998)ParisUrban andsemi-urban1985NR2–32 ppbNRMeasured at one urban site andthree rural sites with someurban influenceKalabokaset al.(1988) 

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# FORMALDEHYDE 81Table 13 (contd)CountryLocation/regionSettingsSamplingperiodNo. ofsamplesMean concentration or range ofmeans (μg/m3)aRange(μg/m3)aCommentsReferenceGermanyMainz-FinthenSemi-rural1979141.9 ppb0.7–5.1 ppbMeasured during July–OctoberNeitzert & Seiler(1981)DeuselbachRural141.7 ppb0.4–3.8 ppbMeasured during NovemberThe AlpsRural1991NR1.3 ppb0.4–3.3 ppbMeasurement at summit ofWank mountain in OctoberSlemr & Junkermann(1992)SchauinslandRural1992221.0 ppb0.4–2.3 ppbMeasured continuously over11 daysSlemret al. (1996)HungaryBudapestUrban1987–8918514.9 ppb34.6 ppbND–58 ppb7–176 ppbMeasured at downtown siteMeasured at the border ofdowntown with a possible localemission sourceHaszpraet al. (1991)ItalyRomeUrban1994–95565717.0 ppb11.2 ppb8.8–27.7 ppb8.2–17.0 ppbMeasured in summer 1994Measured in winter 1995Possanziniet al.(1996)MilanUrban1998–99NRNR5.98.0–15.74.1–53.4NRNRWinter measurements (six sites)Rural-industrial (one site)Urban (five sites)Andreiniet al.(2000)JapanTakasakiUrban198438NR2.5–11.4 ppbMeasured during July andAugustSatsumabayashiet al. (1995)OsakaUrban1997NR1.9 ppb0.1–4.3 ppbMeasured in October–DecemberNguyenet al. (2001)NagoyaNR1998375.8cGSD, 1.5Measured in FebruarySakaiet al. (2004)LithuaniaKaunasNR1998NR3.11.4–5.3Measured at 12 municipalmonitoring sitesMaroziene &Grazuleviciene(2002)MexicoMexico CityUrban19934835.5 ppb5.9–110 ppbMeasured at the University ofMexico campusBáezet al. (1995)Mexico City andXalapaUrban1996–98145d4–322–63Measured outside two houses,three museums and two officesBáezet al. (2003) 

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# IARC MONOGRAPHS VOLUME 88 82Table 13 (contd)CountryLocation/regionSettingsSamplingperiodNo. ofsamplesMean concen-tration or range ofmeans (μg/m3)aRange(μg/m3)aCommentsReferenceNorwayDrammenUrban1994–971998–20009749738.92.9NRNRReduction of mean levelsattributed to increase invehicles with catalystsHagenet al.(2000);Oftedalet al. (2003)SouthAfricaCape PointSemi-rural197950.5 ppb0.2–1.0 ppbMeasured during DecemberNeitzert & Seiler(1981)SpainMadridUrban1996NR9.04.7–20Air sampling in September–October from 8 h to 16 hGarcía-Alonso &Pérez-Pastor (1998)SwedenUppsalaUrban1998271.3cGSD, 1.8Measured in February–Maynear 22 houses and fiveapartmentsSakaiet al. (2004)Taiwan,ChinaTaipeiUrban1999NR7.2–9.8 ppbrange ofmax., 20.6–34.8 ppbMeasured from February–Juneat five locationsMathewet al. (2001)UnitedKingdomLondonUrban1991–929719.2 ppb7.4 ppbND–98 ppb0.8–13.5 ppbWest London, residential areaNorth London, residential areaWilliamset al.(1996)USACountry-wideVarious1975–856298.3 ppb (4.1 ppb)bNRAll sites combinedeUrban3326.5 ppbbNRShah & Singh(1988)fSuburban2812.7 ppbbNRRural122.7 ppbvbNRAtlanta, GAUrban19922172.7–3.0 ppbmax., 8.3 ppbMeasured at four locationsduring July and AugustGrosjeanet al.(1993)Albany, NYSemi-urban1991NRNR0.6–3.7 ppbMeasured during OctoberKhwaja (1995)Boston, MAResidential19938183.1 ppb2.6 ppb0–3.1 ppb1.2–5.9 ppbWinter measurements, outsidefour residencesSummer measurements, outsidenine residencesReisset al. (1995) 

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# FORMALDEHYDE 83Table 13 (contd)CountryLocation/regionSettingsSamplingperiodNo. ofsamplesMean concentration or range ofmeans (μg/m3)aRange(μg/m3)aCommentsReferenceUSA(contd)Denver, COUrban1987–91NR3.9 ppb2.3 ppb2.7 ppbNRNRNRMeasured in winterMeasured in springMeasured in summerAndersonet al.(1996)Los Angeles,CAUrbanRural1993325.3 ppb0.8 ppb1.4–10.6 ppb0.7–1.0 ppbMeasured during the smogseason (September)Background locationGrosjeanet al.(1996)Eniwetok AtollRemote198070.4 ppbmax., 0.8 ppbSouth PacificPreusset al.(1985)MinnesotaMixed1991–9924941.7 (1.37)b< 0.05–21Collected at 25 sites throughoutthe state for varying periods oftimePrattet al. (2000)New York City,NYUrban199936362.15.3Winter measurementsSummer measurementsKinneyet al. (2002)Los AngelesCounty, CASemi-urban1999–2000697.2 ppb4.3–14.0 ppbDelfinoet al. (2003)CaliforniaUrban1990–2002NR2.0–4.3NRRange of annual averagesCalifornia AirResources Board(2004)GSD, geometric standard deviation; NR, not reported; SD, standard deviationaUnless otherwise specifiedbMediancGeometric meandNumber of indoor and outdoor measurements combined(see Table 14)eIncludes urban, suburban, rural, remote and source-dominated sources.fData collected from literature searches, direct contacts with individuals and organisations, reports, computer tapes and direct electronic transfers 

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# 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 μ g/m 3 

# (Spitzer, 1997). Local air concentrations as high as 35.4, 41.8 and 44.2 μ g/m 3 

# have been reported inside vehicles, in parking garages and at service stations, respectively (Spitzer, 1997). Formaldehyde was detected (detection limit, 0.05 μ g/m 3 

# ) 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 μ g/m 3 

# for eight urban sites, a maximum of

12.03 μ g/m 3 

# for two suburban sites and a maximum of 9.88 μ g/m 3 

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

8.76 μ g/m 3 

# . 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 isalso 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 IARC MONOGRAPHS VOLUME 88 84 039-104.qxp 13/12/2006 11:13 Page 84

# FORMALDEHYDE 85Table 14. Occurrence of formaldehyde in indoor air in residentialand public settingsCountryLocation/regionSamplingperiodNo. ofsamplesMean concentration or range ofmeans (μg/m3)aRange(μg/m3)aCommentsReferenceResidentialAustraliaVictoria1994–95NR12.6 ppbb13.8 ppbb11.3 ppbb11.4 ppbb< 0.3–105< 0.3–108< 0.3–108Eighty householdsBedroomLiving-roomKitchenGarrettet al.(1997, 1999)AustriaBurgenland,Carinthia andStyria1988–89234apartments< 30–100 ppb100–500ppb> 500 ppbMeasured in 33% of the apartmentsMeasured in 48% of the apartmentsMeasured in 19% of the apartmentsKoecket al. (1997)CanadaQuebec City,QCNR2833467.39.28.29.9max., 20.2max., 19.7max., 23.4max., 19.5Basement, with combustion applianceBasement, without combustion applianceGround floor, with combustion applianceGround floor, without combustion applianceLévesqueet al.(2001)Various1989–9515135.9 (29.8b)NRPooled data from five studies at variouslocationsLiteplo & Meek(2003)EgyptCairo199929414714789 ppb100 ppb100 ppb87.6 ppb105.6 ppb35–192 ppb30–213 ppb28–225 ppbNRNRSeven apartmentsKitchenBedroomLiving roomMeasured in springMeasured in summerKhoderet al.(2000)FranceParis200161616121.7c24.2c24.5cNRNRNRSixty-one dwellings in Paris and suburbsKitchenLiving roomBedroomClarisseet al.(2003)Hungary199812317.50.6–56.7Homes in six medium-sized citiesErdeiet al. (2003) 

# 039-104.qxp 13/12/2006 11:13 Page 85

# IARC MONOGRAPHS VOLUME 88 86Table 14 (contd)CountryLocation/regionSamplingperiodNo. ofsamplesMean concen-tration or range ofmeans (μg/m3)aRange(μg/m3)aCommentsReferenceJapanCountry-wide1998–20011642120(95.7b)max., 979From 1422 homes distributed throughout thecountryPark & Ikeda(2003)NR2000171110 ppb120 ppb20–872 ppb11–840 ppbRooms from 81 housesActive DNPH methodDetector tube methodAzumaet al.(2003)NiigataPrefecture1999104NR0–740Data from figure; 29% greater than100μg/m3Sakaguchi &Akabayashi (2003)Nagoya19983717.6cmax., 73Dwelling factors and airborne concentrationswere also comparedSakaiet al. (2004)MexicoMexico Cityand Xalapa1996–9850d37–4712–81Measured in two housesBáezet al. (2003)SwedenUppsala1998278.3cmax., 19Dwelling factors and airborne concentrationswere also comparedSakaiet al. (2004)UnitedKingdomLondon1991–92174015.0 ppb3.4 ppbND–93.1 ppbND–10.3 ppbWest London, residential areaNorth London, residential areaWilliamset al.(1996)USASanFranciscoBay Area,CA1984484541 ppb36 ppbNRNRKitchenMain bedroomSextonet al.(1986)Various1981–8427344.0bNRMixed locationsShah & Singh(1988)eColorado1992–93926d49d8–6633–81Prior to occupancyAfter 5 months of occupancyLindstromet al.(1995)Boston, MA1993142611.1 ppb16.1 ppb6.0–16.1 ppb5.9–53.8 ppbWinter measurements, four residencesSummer measurements, nine residencesReisset al. (1995)LouisianaNR419460ND–6600Measured in 53 houses (75% urban,25%rural); also measured seasonal differencesLemuset al.(1998) 

# 039-104.qxp 13/12/2006 11:13 Page 86

# FORMALDEHYDE 87Table 14 (contd)CountryLocation/regionSamplingperiodNo. ofsamplesMean concentration or range ofmeans (μg/m3)aRange(μg/m3)aCommentsReferenceUSA(contd)East andSouth-East1997–984734 ppbd36 ppbd21–47 ppb14–58 ppbManufactured housesSite–built housesHodgsonet al.(2000)Florida2000NR94.9NRNew manufactured houseHodgsonet al.(2002)New YorkCity, NY1999384112.120.9NRNRWinter measurementsSummer measurementsKinneyet al.(2002)Public settingsChinaHotelballroom20022829.726.3–63.0Measured in four hotel ballrooms in theevening on 7 consecutive daysFenget al. (2004)ItalyLibrary1995–961632.71.7–67.8Sixteen libraries at the University of Modena;10 samples with detectablelevelsFantuzziet al.(1996)MexicoMuseum1996–9860d11–344–59Three museumsBáezet al.(2003)SwedenHospital1997452–7Geriatric hospitals built in 1925, 1985, 1993and 1994Wieslanderet al.(1999b)Primaryschool1993, 1995489.53–16Twelve randomly selected primary schoolsNorbäcket al.(2000)ND, not detected; NR, not reportedaUnless stated otherwisebMediancGeometric meandNumber of indoor and outdoor measurements combined (see Table 13)eData collected from literaturesearches, direct contacts with individuals and organisations, reports, computer tapes and direct electronic transfers 

# 039-104.qxp 13/12/2006 11:13 Page 87

# (Hodgson et al ., 1993). The emission rates in single samples were 57.2 and 18.2 μ g/m 2 

# /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 μ g/m 3 

# and

16 μ g/m 3 

# 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/m 3 

# ] formaldehyde would inhale about 1 mg/h formaldehyde vapour when breathing normally (15 L/min). In the presence of 1 mg/m 3 

# 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 μ g/m 3 

# , 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 μ g/m 3 

# ]; the mean indoor residential concentration was 33.3 ppb [41.0 μ g/m 3 

# ]; the mean outdoor residential concentration was 2.6 ppb [3.2 μ g/m 3 

# ]; and the mean workplace concentration was 12.0 ppb [14.8 μ g/m 3 

# ] (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 μ g/m 3 

# . 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 IARC MONOGRAPHS VOLUME 88 88 039-104.qxp 13/12/2006 11:13 Page 88

# the early 1980s, mean concentrations of 0.4 ppm [0.5 mg/m 3 

# ] and individual values as high as several parts per million were measured in new mobile homes. As a result of newstandards 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/m 3 

# ] 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 ( μ g/m 2 

# 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 μ g/m 2 

# per day for some panelling. Other release rates were 15–550 μ g/m 2 

# per day for articles of new clothing that had not previously been washed, 52–620 μ g/m 2 

# per day for insulation products,

75–1000 μ g/m 2 

# per day for paper plates and cups, from below the limit of detection to

350 μ g/m 2 

# per day for fabrics and from below the limit of detection to 65 μ g/m 2 

# 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 μ g/m 2 

# /h for a variety of bare urea–formaldehyde wood products, from 1 to 461 μ g/m 2 

# /h for coated

urea

− formaldehyde wood products, from 42 to 214 μ g/m 2 

# /h for permanent press fabrics,

from 4 to 50 μ g/m 2 

# /h for decorative laminates, from 16 to 32 μ g/m 2 

# /h for fibreglass products and from 4 to 9 μ g/m 2 

# /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 μ g/m 2 

# /h, respectively. For wet products, the emission rates were: latex paint, 326–854 μ g/m 2 

# /h; fingernail hardener, 178 000–354 000 μ g/m 2 

# /h; nail polish, 20 700 μ g/m 2 

# /h; and commercially applied urea–formaldehyde floor finish, 1 050 000 and 421 000 μ g/m 2 

# /h for base and topcoats, respectively (Kelly et al ., 1999). FORMALDEHYDE 89 039-104.qxp 13/12/2006 11:13 Page 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 μ g 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 careproducts 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 resultof 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 μ g/g for mackerel to 5.31 μ g/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/m 3 

# ]; the high levels were attributed to the processes used tofreeze 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 μ g/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 IARC MONOGRAPHS VOLUME 88 90 039-104.qxp 13/12/2006 11:13 Page 90

# 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/m 3 

# ] (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 dialysiscentres 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 μ g/mL. However, the dialysers still contained up to 13 mgformaldehyde 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 formaldehydeand 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 useas 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 91 039-104.qxp 13/12/2006 11:13 Page 91

# IARC MONOGRAPHS VOLUME 88 92



# Table 15. Occupational exposure standards and guidelines for formaldehyde

Country or region Concentration (mg/m 3 

# ) [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 A2 a



# 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 A2 b



# 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 A2 b



# Netherlands 1.2 [1] 2.5 [2] TWA

STEL

New Zealand 1.2 [1] Ceiling A2 b



# Norway 0.6 [0.5] 1.2 [1] TWA Ceiling Ca c 

# ; 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 Ca d 

# ; Sen

Switzerland 0.37 [0.3] 0.74 [0.6] TWA

STEL Sen

United Kingdom (MEL) 2.5 [2] 2.5 [2] TWA

STEL 039-104.qxp 13/12/2006 11:13 Page 92

# 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/m 3 

# ], with a preference for 0.1 ppm [0.12 mg/m 3 

# ] (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/m 3 

# , 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, asexpressed as air concentrations using standard conditions: plywood materials and particleboard flooring products (including urea–formaldehyde-bonded particle-board), 0.25 mg/m 3 

# ; particle-board materials and medium-density fibre-board, 0.37 mg/m 3 

# (Composite Panel Association, 1999, 2002; Department of Housing and Urban Development, 2003). FORMALDEHYDE 93



# Table 15 (contd)

Country or region Concentration (mg/m 3 

# ) [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 A2 b 

# ; Sen

Ca d



# Ca d



# 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. 039-104.qxp 13/12/2006 11:13 Page 93

# 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, thenature 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 includingcancers 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 IARC MONOGRAPHS VOLUME 88 94 039-104.qxp 13/12/2006 11:13 Page 94

# FORMALDEHYDE 95Table 16. Cohort studies of industrial workers exposed to formaldehydeReference,location,years of studyCohort descriptionType of analysis(cohort size)ExposureassessmentOrgan site (ICD code)aNo. of cases/deathsSMR (95% CI)CommentsAll cancers1511 deaths1.10 (1.04–1.16)Nasopharynx1 deathNR2.0 expectedNose and nasal sinuses2 deaths0.87 (0.11–3.14)Two additional cases identified fromregistry that could not be used intheanalysisLymphohaematopoieticLeukaemiaNR31 deathsNR0.91 (0.47–1.59)Chemical factories that used orproduced formaldehydeStandardized mortality(14014 men)Mouth (ICD-9, 143–145)6 deaths1.28 (0.47–2.78)Level ofexposure(background,low, moderate,high); amonghighly exposed,time period andduration ofexposureLung594 deaths1.22 (1.12–1.32)Increased risk among highly exposed(1.58; 95% CI, 1.40–1.78); inverse trendwith duration of exposureCoggonet al.(2003), UnitedKingdom,1941–2000(update ofAchesonet al.,1984a; Gardneret al., 1993)Brain and centralnervous system30 deaths0.85 (0.57–1.21)All cancers1723 deaths0.90 (0.86–0.95)15-year lag forsolid cancers; 2-year lagfor lymphohaematopoietic cancersNasopharynx8 deaths2.10 (1.05–4.21)The authors noted that the exact CI is0.91–4.14; statistically significant trendwith highest peak exposure; weaker trendsobserved with duration of, cumulative andaverage exposuresHauptmannetal. (2003,2004), USA,1966–94(update of Blairetal., 1986,1987)Duration;quantitativeestimates ofcumulative,average andhighest peakexposureNose and nasal sinuses3 deaths1.19(0.38–3.68)Manufacturer of formaldehyde,formaldehyde resins, mouldingcompounds, moulded plasticproducts, photographic filmsand plywoodStandardized mortality(25 619 workers; 22 493 men,3126 women)Lymphohaematopoietic161 deaths0.80 (0.69–0.94)Leukaemia65 deaths0.85 (0.67–1.09)Statistically significant trend with peakexposure, particularly for myeloidleukaemia; weaker trend with averageexposure; no trend with duration of orcumulative exposureBuccal cavity49 deaths1.01 (0.77–1.34)LungBrain and centralnervous system641 deaths43 deaths0.97 (0.90–1.05)0.92 (0.68–1.23) 

# 039-104.qxp 13/12/2006 11:13 Page 95

# IARC MONOGRAPHS VOLUME 88 96Table 16 (contd)Reference,location,years of studyCohort descriptionType of analysis(cohort size)ExposureassessmentOrgan site (ICD code)aNo. of cases/deathsSMR (95% CI)CommentsBertazziet al.(1986, 1989),Italy, 1959–86Formaldehyde resin makersStandardized mortality(1332 men)All cancers62 deaths1.23 [0.94–1.58]bMortality was close to expected whenlocal rates were used as the referent (1.00[95% CI, 0.64–1.49])NasopharynxNRNRNasal cavity0 deathsNALymphohaematopoietic7 deaths1.77 [0.71–3.65]bSMR with local rates as the referent, 1.43[95% CI, 0.57–2.95]LeukaemiaNRNRDuration ofexposure,latency, age atemployment,year ofemployment,time sincebeginning ofemploymentBuccal cavity/pharynxNRNRLung24 deaths1.56 [1.00–2.32]BrainNRNRNone (areameasurements)All cancers24 inc. cases0.84 [0.54–1.25]cAll cancer mortality SMR, 0.93 [95% CI,0.54–1.49]Edlinget al.(1987a),Sweden,1955–83Abrasives industryStandardized mortality,standardized incidence(521 male blue-collar workers)NasopharynxNasal cavityLymphohaematopoieticLeukaemiaBuccal cavityLungBrain and central nervoussystem1 inc. case0 inc. cases4 inc. cases0 inc. cases0 inc. cases2 inc. cases1 inc. caseNRNANRNANA0.57 [0.07–2.06]NRAll cancers608 deaths0.89 (0.82–0.97)NasopharynxNasal cavity0 deaths0 deathsNANA0.96 expected0.16expectedGarment industryStandardized mortality(11 039 workers; 2015 men,9024 women)Duration, timesince firstexposure, yearof firstexposureLymphohaematopoieticLeukaemia59 deaths24 deaths0.97 (0.74–1.26)1.09 (0.70–1.62)Pinkertonet al.(2004), USA,1955–98(update ofStayneret al.,1988)Myeloid leukaemia15 deaths1.44 (0.80–2.37)Statistically significant excess amongworkers with both≥10 years of exposureand≥20 years since first exposure (SMR,2.43; 95% CI, 0.98–5.01)Buccal cavity/pharynx4 deaths1.33 (0.36–3.41)LungBrain and central nervoussystem147 deaths19 deaths0.98 (0.82–1.15)1.09 (0.66–1.71) 

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# FORMALDEHYDE 97Table 16 (contd)Reference,location,years of studyCohort descriptionType of analysis(cohort size)ExposureassessmentOrgan site (ICD code)aNo. of cases/deathsSMR (95% CI)CommentsAll cancers127 deaths0.99 (0.82–1.17)Nasopharynx0 deathsNANasal cavity0 deathsNAAndjelkovichet al. (1995),USA, 1960–89Foundry workersStandardized mortality(3929 men with potentialexposure)Lymphohaematopoietic7 deaths0.59 (0.23–1.21)Exposed/unexposed;none, low,medium andhigh exposureLeukaemia2 deaths0.43 (0.05–1.57)Buccal cavity/pharynx6 deaths1.31 (0.48–2.86)1.16 (0.20–6.51)dLung51 deaths1.20 (0.89–1.58)0.59 (0.28–1.20)dBrain and central nervoussystem2 deaths0.62 (0.07–2.23)ICD-7NasopharynxMen4 cases1.3 (0.3–3.2)Low (whitecollar) andabove baseline(blue-collar)Nasal cavity13 cases2.3 (1.3–4.0)Risk increased among more highlyexposed workers with (SPIR, 5.0; 95% CI,0.5–13.4) or without (SPIR, 3.0; 95% CI,1.4–5.7) exposure to wood dustLymphohaematopoieticNRNRLeukaemia (204)39 cases0.8 (0.6–1.6)Risk not increased among more highlyexposedBuccal cavity/pharynx23 cases1.1 (0.7–1.7)Hansen &Olsen (1995,1996),DenmarkWorkers from companies witha history of use or manufactureof formaldehydeStandardized proportionateincidence (eligible cancercases: 2041 men, 1263 womendiagnosed in 1970–84)LungBrain and nervous system(193)410 cases54 cases1.0 (0.9–1.1)1.1 (0.9–1.5)Risk not increased among more highlyexposedRisk not increased among more highlyexposedNasal cavityLymphohaematopoieticLeukaemiaLungBrain and nervous system(193)Women4 casesNR21 cases108 cases39 cases2.4 (0.6–6.0)NR1.2 (0.7–1.8)1.2 (0.96–1.4)1.2 (0.8–1.6) 

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# IARC MONOGRAPHS VOLUME 88 98Table 16 (contd)Reference,location,years of studyCohort descriptionType of analysis(cohort size)ExposureassessmentOrgan site (ICD code)aNo. of cases/deathsSMR (95% CI)CommentsAll cancers96 deaths0.94 (0.77–1.15)bAnalysis restricted to 2933 white menNasopharynxNRNRCumulativeexposureNasal cavityNRNRChiazzeet al.(1997), USA,1951–91Fibreglass manufacturing plantworkersStandardized mortality andnested case–control(4631 men and women)LymphohaematopoieticLeukaemia5 deaths1 death0.46 (0.15–1.08)0.24 (0.006–1.36)Buccal cavity/pharynx2 deaths0.70 (0.08–2.52)Lung47 deaths1.26 (0.93–1.68)Excess risk for lung cancer reduced whenlocal rates were used (SMR, 1.17; 95% CI,0.86–1.55); positive trend in case–controlstudy with cumulative exposure toformaldehyde among smokersBrain and nervoussystem6 deaths1.48 (0.54–3.23)All cancersFormaldehyde aloneFormaldehyde + wood367 deaths14 deaths0.98 (0.86–1.12)1.61 (0.95–2.72)Stellmanet al.(1998), USA,1982–88NasopharynxNasal cavityNRNRNRNRLymphohaematopoieticFormaldehyde aloneFormaldehyde + wood28 deaths3 deaths1.22 (0.84–1.77)3.44 (1.11–10.68)Dichotomous(yes/no) withand withoutemployment ina woodoccupationLeukaemiaFormaldehyde aloneFormaldehyde + wood12 deaths2 deaths0.96 (0.54–1.71)5.79 (1.44–23.25)Workers in the AmericanCancer Society CPS-II studyemployed in wood-relatedoccupations or who reportedexposure to wood dustRetrospective cohort mortality(45 399 men, of whom 387reported exposure toformaldehyde)Buccal cavity/pharynxNRNRLungFormaldehyde aloneFormaldehyde + wood104 deaths7 deaths0.93 (0.73–1.18)2.63 (1.25–5.51)Brain (ICD-9, 191)NRNR 

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# FORMALDEHYDE 99Table 16 (contd)Reference,location,years of studyCohort descriptionType of analysis(cohort size)ExposureassessmentOrgan site (ICD code)aNo. of cases/deathsSMR (95% CI)CommentsAll cancers2243 deaths0.98 (0.94–1.02)bNasopharynxNasal cavityNRNRNRNRMarshet al.(2001); Youket al. (2001),USA, 1945–92Fibreglass workersStandardized mortality andnested case–control (32 000men and women, 22% ofperson–years exposed toformaldehyde)Duration of,cumulative andaverageexposureLymphohaematopoieticLeukaemia199 deathsNR0.92 (0.80–1.06)NRBuccal cavity/pharynx63 deaths1.07 (0.82–1.37)Lung838 deaths1.17 (1.09–1.25)SMR was reduced and no longersignificant when local rates were used(SMR, 1.06; 95% CI, 1.00–1.14); astatistically significant excess amongformaldehyde-exposed workers observedin the case–control study (smokingadjusted odds ratio, 1.61; 95% CI, 1.02–2.56); no significant trend with duration ofor cumulative exposure; some evidence fora trend with average exposureBrain and central nervoussystem50 deaths0.78 (0.58–1.03)Nested case–control studiesReference,location,years of studyCharacteristics of cases andcontrolsExposureassessmentOrgan site/exposure categoryNo. of cases(exposed)Odds ratio(95% CI)CommentsBondet al.(1986), USA,1944–80308 male incident cases of lungcancer from a cohort of 19 608employees at a chemicalcompany; two controls percase matched on race, year ofbirth (5 years) and year of firstemploymentExposureprofiledevelopedbased on workhistory at thecompanyLungNo lag periodLag period≥15 years(9)(4)0.62 (0.29–1.34)0.31 (0.11–0.86)Formaldehyde was not assessed in greatdetail. 

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# IARC MONOGRAPHS VOLUME 88 100Table 16 (contd)Reference,location,years of studyCharacteristics of cases andcontrolsExposureassessmentOrgan site/exposure categoryNo. of cases(exposed)Odds ratio(95% CI)CommentsOttet al.(1989), USA,1940–78Deaths identified within acohort of 29 139 male workersat two chemical manufacturingfacilities and a research anddevelopment centre; fivecontrols per case selected fromcohort and frequency-matchedby decade of first employmentUse offormaldehydein departmentwhere subjectsworkedEver exposedNon-Hodgkin lymphomaMultiple myelomaNon-lymphocytic leukaemiaLymphocytic leukaemia52 (2)20 (1)39 (2)18 (1)2.01.02.62.6Number of controls overall by exposurestatus and confidence intervals not given;adjustment for age was evaluated butdropped due to substantial change in riskestimates.Partanenet al.(1990),Finland,1957–80(updated fromPartanenet al.,1985)136 male incident cases* froma cohort of 7307 workers in 35particle-board, plywood andformaldehyde glue factoriesand sawmills who entered thefactories in 1944–66; threecontrols per case selectedrandomly among the samecohort, matched by year ofbirth, alive at the time ofdiagnosis of the correspondingcasePlant- andtime-specificjob–exposurematrices; workhistory basedon factoryregisters,interviews offactorypersonnel andquestionnairesto studysubjects orrelativesAll cancers combined*Ever exposedPeak exposureDustborne formaldehydeLungEver exposedPeak exposureDustborne formaldehyde136(20)(7)(14)118(18)(7)(12)1.40 (0.72–2.74)e0.95 (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)eAdjusted for vital status; adjustment forcigarette smoking did not affect theresults.*Tongue, mouth, pharynx, nose and nasalsinuses, larynx and lung/trachea (ICD-7141, 143–8, 160–1, 162,0–1)CI, confidence interval; ICD, international classification of diseases; inc., incident; NA, not applicable; NR, not reported; SMR, standardized mortality ratio; SPIR, standardized proportionateincidence ratioaThe ICD code is only mentioned when the organ site studied is different from that in the other studies.bThe authors presented results using either the national population or the local population as the referent. The results presented here are based on the national population.cData on cancer incidence and mortality were presented. The results in this column are for cancer incidence.dRelative risk of medium- plus high-exposed groups versus unexposed, adjusted for race, smoking and exposure to silicae90% confidence interval 

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# 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 101 039-104.qxp 13/12/2006 11:13 Page 101

# A statistically significant exposure–response relationship was observed between peak exposure to formaldehyde and all lymphatic and haematopoietic neoplasms ( p trend 

# = 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 ( p trend 

# = 0.004) and, to a lesser extent, for Hodgkin disease ( p trend 

# = 0.04). The relationship was stronger for myeloid leukaemia ( p trend 

# = 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 ( p trend 

# = 0.24) and myeloid leukaemia ( p trend 

# = 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 wasobserved among formaldehyde-exposed workers in comparison with the national population (SMR, 2.10; 95% CI, 1.05–4.21). A highly statistically significant ( p trend 

# < 0.001) exposure–response relationship was observed between peak exposure to formaldehyde and risk 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 analysisexcluded 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 ( p trend 

# = 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 exposurewere elevated (relative risks, 1.89, 1.83 and 1.74, respectively), but trends were not significant or only of borderline significance ( p trend 

# = 0.50, 0.07 and 0.37, respectively). Noconsistent 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; p trend 

# = 0.12 among the IARC MONOGRAPHS VOLUME 88 102 039-104.qxp 13/12/2006 11:13 Page 102

# exposed only) and with peak exposure, but not with cumulative exposure or duration ofexposure. 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 ( p trend 

# = 0.03) and with cumulative exposure ( p trend 

# = 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 103 039-104.qxp 13/12/2006 11:13 Page 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 IARC MONOGRAPHS VOLUME 88 104 039-104.qxp 13/12/2006 11:13 Page 104

# 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 tobe 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 105 105-172.qxp 13/12/2006 11:39 Page 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 localgeographical 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 highlyexposed 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 ( p trend 

# = 0.13) and showed no trend with time since first employment in a job that entailed high exposure ( p trend 

# = 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 amonghighly 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 excessmortality, 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, IARC MONOGRAPHS VOLUME 88 106 105-172.qxp 13/12/2006 11:39 Page 106

# 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’semployment 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 associationwas 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;

SMR US 

# , 0.98; 95% CI, 0.94–1.02) and local rates (SMR local 

# , 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; SMR US 

# , 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 (SMR local 

# , 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;

SMR US 

# , 1.17; 95% CI, 1.09–1.25; SMR local 

# , 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 107 105-172.qxp 13/12/2006 11:39 Page 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. Ofthe 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 ofexposure 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 interviewson 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 analysiswere 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. IARC MONOGRAPHS VOLUME 88 108 105-172.qxp 13/12/2006 11:39 Page 108

# ( 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 andwere 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/m 3 

# ) 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 cumulativeexposure, 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 wereprovided 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/m 3 

# ] 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/m 3 

# ], 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 109 105-172.qxp 13/12/2006 11:39 Page 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 ageand 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 IARC MONOGRAPHS VOLUME 88 110 105-172.qxp 13/12/2006 11:39 Page 110

# 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 ratiofor 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 2032cohort 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 bythe 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 deathrates, 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 111 105-172.qxp 13/12/2006 11:39 Page 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/m 3 

# [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 and1978 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 fromthe 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 workarea 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 monthsbetween 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 IARC MONOGRAPHS VOLUME 88 112 105-172.qxp 13/12/2006 11:39 Page 112

# 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/m 3 

# . 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 DanishCancer 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, whomet 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 exposureand 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 113 105-172.qxp 13/12/2006 11:39 Page 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. Theexcess 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 bestrong 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 notpresented 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 IARC MONOGRAPHS VOLUME 88 114 105-172.qxp 13/12/2006 11:39 Page 114

# 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 andwomen 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 115 105-172.qxp 13/12/2006 11:39 Page 115

# IARC MONOGRAPHS VOLUME 88 116Table 17. Cohort and proportionatemortality studies of cancer in professionals exposed to formaldehydeReference, country,years of studyStudy population,design (study size)ExposureassessmentOrgan siteNo. ofcases/deathsSMRa(95% CI)CommentsBritish pathologists and medical techniciansHallet al. (1991),United Kingdom,1974–87(update ofHarrington &Oakes, 1984, plusnew members since1973)Pathologists,SMR(4512 men andwomen)[sex distributionnot reported]NoneAll cancersNasopharynxNasal cavityLymphohaematopoieticLeukaemiaLungBrain and central nervoussystem53 deathsNRNR10 deaths4 deaths9 deaths6 deaths0.45 (0.34–0.59)NRNR1.44 (0.69–2.65)1.52 (0.41–3.89)0.19 (0.09–0.36)2.18 (0.80–4.75)Data presented for men andwomen from England andWales (n= 3872)Anatomists and pathologists in the USAStroupet al.(1986), USA,1925–79Anatomists,SMR(2239 men)DurationAll cancersNasopharynxNasal cavityLymphohaematopoieticLymphomaLeukaemiaChronic myeloidleukaemiaOther lymphatic tissueBuccal cavity/pharynxLungBrain and central nervoussystem118 deathsNR0 deaths18 deaths2 deaths10 deaths3 deaths6 deaths1 death12 deaths10 deaths0.64 (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)0.5 expectedAnalysis limited to 1969–79No trend with durationTrend with durationLogueet al. (1986),USA, 1962–77Pathologists,SMR(5585 men)NoneNasopharynxNasal cavityLymphohaematopoieticLeukaemiaBuccal cavity/pharynxRespiratory systemNRNRNRNRNRNRNRNR0.48 (NR)1.06 (NR)0.71 (NR)0.24 (p< 0.01)Rate of buccal cavity/pharyngeal cancer was twice as highamong pathologists than amongradiologists. 

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# FORMALDEHYDE 117Table 17 (contd)Reference, country,years of studyStudy population,design (study size)ExposureassessmentOrgan siteNo. ofcases/deathsSMRa(95% CI)CommentsEmbalmers and funeral directorsWalrath &Fraumeni (1983),New York, USA,1925–80Embalmers andembalmers/funeraldirectors,PMR/PCMR(1132 white men)Time sincefirst licence,age at firstlicenceAll cancersNasopharynxNasal cavityLymphohaematopoieticLympho- andreticulosarcomaOther lymphatic cancersLeukaemiaMyeloid leukaemiaBuccal cavity/pharynxLungBrain and central nervoussystem243 deathsNR0 deaths25 deaths5 deaths6 deaths12 deaths6 deaths8 deaths7 deaths1 death70 deaths9 deaths6 deaths3 deaths1.00NRNA1.210.821.231.19[1.5]1.032.010.281.111.382.340.93PCMR0.5 expectedPMRPCMRPMRPCMRPMRPCMR; 0 deaths fromnasopharyngeal cancerPMR, embalmers onlyPMR, funeral directorsPCMR (+ two deaths frompleural cancer)PCMRPMR, embalmers only,p< 0.05PMR, funeral directorsWalrath &Fraumeni (1984),California, USA,1925–80Embalmers,PMR/PCMR(1007 white men)DurationAll cancersNasopharynxNasal cavityLymphohaematopoieticLympho- andreticulosarcomaLeukaemiaMyeloid leukaemiaBuccal cavity/pharynxLungBrain205 deathsNR0 deaths19 deaths3 deaths12 deaths6 deaths8 deaths41 deaths9 deaths1.00NRNA1.22[1.0]1.40[1.50]0.990.871.68PCMR;p< 0.05 for PMR0.6 expectedPMRPMRPCMR;p< 0.05 for PMR;trend with durationPMRPCMR, inverse trend withduration;0 deaths from nasopharyngealcancerPCMR, no trend with durationPCMR;p< 0.05 for PMR; notrend with duration 

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# IARC MONOGRAPHS VOLUME 88 118Table 17 (contd)Reference, country,years of studyStudy population,design (study size)ExposureassessmentOrgan siteNo. ofcases/deathsSMRa(95% CI)CommentsLevineet al.(1984), Canada,1950–77Embalmers,SMR(1413 men)NoneAll cancersNasopharynxNasal cavityLymphohaematopoieticLeukaemiaBuccal cavity/pharynxLungBrain and central nervoussystem58 deathsNR0 deaths8 deaths4 deaths1 death19 deaths3 deaths0.87 [0.66–1.12]NRNA1.23 [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]0.2 expectedHistological type not mentionedHayeset al. (1990),USA, 1975–85NoneAll cancers900 deaths102 deaths1.07 (1.01–1.15)1.08 (0.87–1.31)WhiteNon-whiteNasopharynx3 deaths1 death1.89 (0.39–5.48)4.00 (0.10–22.3)WhiteNon-whiteEmbalmers/funeraldirectors,PMR(3649 white men,397 non-whitemen)Nasal cavity0 deathsNAWhite and non-white,1.7 expectedLymphohaematopoieticLympho- andreticulosarcomaLymphatic leukaemiaMyeloid leukaemiaOther and unspecifiedleukaemia100 deaths15 deaths11 deaths1 death5 deaths2 deaths23 deaths1 death17 deaths3 deaths1.31 (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)WhiteNon-whiteWhiteNon-whiteWhiteNon-whiteWhiteNon-whiteWhiteNon-whiteBuccal cavity/pharynx26 deaths4 deaths1.19 (0.78–1.74)1.25 (0.34–3.20)WhiteNon-whiteLungBrain and central nervoussystem285 deaths23 deaths24 deaths0 deaths0.97 (0.86–1.09)0.75 (0.47–1.13)1.23 (0.80–1.84)NAWhiteNon-white menWhiteNon-white, 0.8 expectedCI, confidence interval; NA, not applicable; NR, not reported; PCMR, proportionate cancer mortality ratio; PMR, proportionate mortality ratio; SMR, standardizedmortality ratioaUnless otherwise stated 

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# 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. Theexpected 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 ofAmerican 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 119 105-172.qxp 13/12/2006 11:39 Page 119

# age and calendar time for large categories of death (e.g. all cancers). Indirect comparisonsthat 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 observedamong 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 IARC MONOGRAPHS VOLUME 88 120 105-172.qxp 13/12/2006 11:39 Page 120

# 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-whitemen, 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-specificproportions 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 timewere 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 121 105-172.qxp 13/12/2006 11:39 Page 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 casesand 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 IARC MONOGRAPHS VOLUME 88 122 105-172.qxp 13/12/2006 11:39 Page 122

# 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 thegeneral 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 controlshad 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 123 105-172.qxp 13/12/2006 11:39 Page 123

# IARC MONOGRAPHS VOLUME 88 124Table 18. Case–control studies of cancers of the nasal cavity, paranasal sinuses, nasopharynx and hypopharynxReference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustmentfor potentialconfoundersCommentsHernberget al.(1983a),Denmark,Finland,Sweden,1977–80Nasal cavityand parasinuses(160.0–160.9;ICD revisionnot given)167 patients [sexdistribution notreported] with primarymalignant tumours167 patients with cancerof the colon and rectum,matched by country, sexand ageEmployment inparticle-board orplywood industryPainting, lacqueringand glazingYes/noYes/no0 cases, 0 controls18 cases, 6 controlsConcomitant exposureof 15 cases to wooddustBrintonet al.(1984), USA,1970–80Nasal cavityand parasinuses(ICD-8 160.0,160.2–160.5,160.8–160.9)160 (93 men, 67women), including 86squamous-cell carci-nomas and 24 adeno-carcinomas or adenoidcystic carcinomas; 61 innasal cavity, 71 inmaxillary sinus and28 other sinus oroverlapping sites290 (178 hospitalcontrols, 112 deathcertificate controls);hospital controls wererequired to be alive forliving cases; deathcertificate controls wereidentified for deceasedcases; matched on age,sex, race and county ofresidenceTelephoneinterviews withsubjects or next ofkin included achecklist ofindustries and self-reported exposuresincludingformaldehyde.Men and women combinedUnexposedExposed1.00.35 (0.1–1.8)Adjusted forsex; controlfor tobaccouse did notchangeresults.Formaldehyde exposureassessment was self-reported; only 33% ofcases and 39% ofcontrols were inter-viewed directly; for theremainder, exposuresrelied on recall of nextof kin.Olsenet al.(1984),Denmark,1970–82Nasal cavity,nasal sinuses(160.0, 160.2,160.9) andnasopharynx(146) (ICDrevision notgiven)754 incident patients[sex distribution notreported] selected fromthe Danish CancerRegistry including 488carcinomas of the nasalcavity and sinuses and266 carcinomas of thenasopharynx2465 patients withcancers of the colon,rectum, prostate andbreast; frequencymatched by sex, age(±5 years) and year ofdiagnosis (±5 years);4.2% of men and 0.1% ofwomen exposed toformaldehydeIndustries and occupationswith certain exposure toformaldehydeEver exposedUnexposed to wood dustExposed to wood dustExposure for > 10 yearsbefore diagnosisUnexposed to wood dustExposed to wood dustAdjusted for wood dustSinonasal2.8 (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)UnadjustedData for sinonasalcancer reported for menonlyRecord linkage withpension fund withcompulsorymembership; jobtitle from CentralPension Registry;exposure assessedblindly as certain,probable, unlikely,unknownIndustries and occupationswith certain or possibleexposureMenWomenNasopharynx0.7 (0.3–1.7)2.6 (0.3–21.9)Unadjusted 

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# FORMALDEHYDE 125Table 18 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustmentfor potentialconfoundersCommentsAny exposure toformaldehydeAssessment AAssessment B2.5 (1.5–4.3)a1.9 (1.2–3.0)aHayeset al.(1986a),Netherlands,1978–81Nasal cavityand accessorysinuses (ICD-9160.0, 160.2–160.5)91 male patients histologically confirmed,alive or deceased195 age-stratified randomsample of living menresident in theNetherlands in 1982 ordeceased in theNetherlands in 1980No or little exposure towood dustAssessment AAssessment BModerate to high exposureto wood dustAssessment AAssessment B2.5 [1.0–5.9]1.6 [0.8–3.1]1.9 [0.6–6.5]NRStandardizedfor age in 10-year groups;control forusual numberof cigarettessmoked didnot modifythe results.Taking into accountjob history, timeperiod and potentialfrequency ofexposure, exposurewas classified into10 groupsindependently bytwo occupationalhygienists(assessment A andB)Squamous-cell carcinomaonlyAssessment AAssessment B3.0 [1.2–7.8]1.9 [0.9–4.1]No or littleexposure towood dustRelative risk for adenocarcinoma for thoseever employed in thewood and paperindustry, 11.3 (90% CI,4.0–35.1); moderateincrease associated withincrease in level ofexposure toformaldehyde with noconcomitant exposureto wood dustOlsen &Asnaes (1986),Denmark,1970–82Nasal cavity,paranasalsinuses (160.0,160.2–160.9)and nasopharynx (146)(ICD revisionnot given)759 (509 men, 250women) histologicallyconfirmed cancers of thenasal cavity and paranasal sinuses (466 cases;310 men, 156 women)and nasopharynx(293 cases; 199 men,94 women)2465 patients withcancers of the colon,rectum, prostate andbreast frequency-matchedby sex, age (±5 years)and year of diagnosis(±5 years); 4.2% of menand 0.1% of womenexposed to formaldehydeRecord linkage withpension fund withcompulsorymembership; jobtitle from CentralPension Registry;exposure assessedblindly as certain,probable, unlikely,unknownLikely or possible exposureto formaldehyde 

# ≥10 yearsbefore diagnosisSquamous-cell carcinoma(215)Adenocarcinoma (39)2.4 (0.8–7.4)1.8 (0.5–6.0)Adjusted forexposure towood dustData presented for menfor cancer of the nasalcavity and paranasalsinuses; no associationobserved with nasopharyngeal cancer 

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# IARC MONOGRAPHS VOLUME 88 126Table 18 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustmentfor potentialconfoundersCommentsVaughanet al.(1986a), USA,1979–83552 identified byrandom-digit diallingLow exposureMedium or high exposureHighest exposure scoreSinonasal0.8 (0.4–1.7)0.3 (0.0–1.3)0.3 (0.0–2.3)Nasal cavity(160) andpharynx (146–149) (ICDrevision notgiven)Job–exposurelinkage system,resulting in fourcategories: high,medium, low andbackgroundLow exposureMedium or high exposureHighest exposure scoreNasopharynx1.2 (0.5–3.3)1.4 (0.4–4.7)2.1 (0.6–7.8)Age, sex,cigarettesmoking andalcohol con-sumption285 incident cases[sex distribution notreported] identified bythe local CancerSurveillance System,aged 20–74 years,including oro- andhypopharynx (205),nasopharynx (27) andsinuses (53)Low exposureMedium exposureHigh exposureHighest exposure scoreOro-/hypopharynx0.8 (0.5–1.4)0.8 (0.4–1.7)0.6 (0.1–2.7)1.5 (0.7–3.0)552 identified byrandom-digit diallingResidentialexposure:residential historysince 1950Mobile homeParticle-board at home1–9 years≥10 yearsSinonasal0.6 (0.2–1.7)1.8 (0.9–3.8)1.5 (0.7–3.2)Sex, age,cigarettesmoking andalcohol con-sumptionVaughanet al.(1986b), USA,1979–83Nasal cavity(160) andpharynx, (146–149) (ICDrevision notgiven)285 incident cases [sexdistribution notreported] identified bythe local CancerSurveillance System,aged 20–74 years,including oro- andhypopharynx (205),nasopharynx (27) andsinuses (53)Mobile home1–9 years≥10 yearsParticle-board at home1–9 years≥10 yearsNasopharynx2.1 (0.7–6.6)5.5 (1.6–19.4)1.4 (0.5–3.4)0.6 (0.2–2.3)Cigarettesmoking andraceMobile home1–9 years≥10 yearsParticle-board at home1–9 years≥10 yearsOro-/hypopharynx0.9 (0.5–1.8)0.8 (0.2–2.7)1.1 (0.7–1.9)0.8 (0.5–1.4)Sex, age,cigarettesmoking andalcohol consumption 

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# FORMALDEHYDE 127Table 18 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustmentfor potentialconfoundersCommentsRouschet al.(1987), USA,1935–75Nasal cavityand sinuses,and nasopharynx (ICDcode not given)198 men with sinonasalcancer and 173 withnasopharyngeal cancerregistered at theConnecticut TumorRegistry605 men who died duringthe same period, selectedby random samplingwithout matching orstratificationJob title, industry,specificemployment, yearof employment,obtained from deathcertificates and citydirectoriesProbably exposed for mostof working lifePlus exposure≥20 yearsbefore deathPlus exposure to highlevel for some yearsPlus exposure to highlevel≥20 years beforedeathSinonasal0.8 (0.5–1.3)1.0 (0.5–1.8)1.0 (0.5–2.2)1.5 (0.6–3.9)Age andcalendarperiodProbably exposed for mostof working lifePlus exposure≥20 yearsbefore deathPlus exposure to highlevel for some yearsPlus exposure to highlevel≥20 years beforedeathNasopharynx1.0 (0.6–1.7)1.3 (0.7–2.4)1.4 (0.6–3.1)2.3 (0.9–6.0) 

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# IARC MONOGRAPHS VOLUME 88 128Table 18 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustmentfor potentialconfoundersCommentsLuceet al.(1993),France,1986–88Nasal cavityand parasinuses(ICD-9 160.0,160.2–160.9)207 cases (167 men,40 women): 59 menand 18 women withsquamous-cell carci-nomas, 82 men and fivewomen with adeno-carcinomas and 25 menand 17 women withother histology409 from two sources:323 hospital cancercontrols (15 sites)frequency-matched byage and sex; 86 proposedby cases, matched by age(±10 years), sex andresidenceSquamous-cell carcinomaPossibly exposedProbably or definitelyAverage level≤2Average level > 2Duration≤20 yearsDuration > 20 yearsCumulative level≤30> 30Men0.96 (0.38–2.42)0.70 (0.28–1.73)1.32 (0.54–3.24)1.09 (0.48–2.50)0.76 (0.29–2.01)1.26 (0.54–2.94)0.68 (0.27–1.75)Adjusted forage, exposureto wood dustand exposureto glues andadhesivesAdjustment for usualcigarette use or forsmoking history did notchange results.Industrial hygienistreview of structuredjob interview,classifying expo-sure by frequency,concentration andduration; compu-tation of cumulativeexposure level andlifetime averagelevelAdenocarcinomaPossibly exposedProbably or definitelyAverage level≤2Average level > 2Duration≤20 yearsDuration > 20 yearsCumulative level≤3030–60> 601.28 (0.16–10.42)4.15 (0.96–17.84)5.33 (1.28–22.20)1.03 (0.18–5.77)6.86 (1.69–27.80)1.13 (0.19–6.90)2.66 (0.38–18.70)6.91 (1.69–28.23)Other histologyPossibly exposedProbably or definitelyAverage level≤2Average level > 2Duration≤20 yearsDuration > 20 yearsCumulative level≤30> 300.81 (0.15–4.36)1.67 (0.51–5.42)3.04 (0.95–9.70)2.82 (0.94–8.43)1.62 (0.48–5.51)2.18 (0.65–7.31)2.21 (0.73–6.73)Most cases of adenocarcinomas exposed toboth formaldehydewood dust; very largeodds ratio (288) forwood dust; therefore,there is concern aboutthe possibility ofincomplete adjustmentfor wood dust in theseresults. 

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# FORMALDEHYDE 129Table 18 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustmentfor potentialconfoundersCommentsWestet al.(1993),Philippines[study yearsnot reported]Nasopharynx(ICD code notgiven)104 incident cases (76men, 28 women) histologically confirmed104 hospital controlsmatched for sex, age andhospital ward type;101 community controlsmatched for sex, age andneighbourhoodOccupationclassified as likelyor unlikely toinvolve exposure toformaldehyde;duration of exposure; 10-year lagperiod; years sincefirst exposure; ageat start of exposure< 15 years≥15 years< 15 years (10-year lag)≥15 years (10-year lag)Age≥25 years at firstexposureAge < 25 years at firstexposureFirst exposure < 25 yearsbefore diagnosisFirst exposure≥25 yearsbefore diagnosis2.7 (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)Years sincefirst exposureto dust and/orexhaust fumesGustavssonet al.(1998),Sweden,1988–91Oro- andhypopharynx(ICD-9 146,148)545 incident male casesamong residents of tworegions, aged 40–79years [including at least124 cases of pharyngealcancer]641 selected by stratifiedrandom sampling;frequency-matched tocases by age (10–15-yeargroups) and regionWork historyreviewed by occupational hygienist;occupations codedby intensity andprobability ofexposureEver exposed1.01 (0.49–2.07)Age, region,alcohol, consumption andsmokinghabitsArmstronget al. (2000),Malaysia,(Selagor andFederalTerritory),1987–92Nasopharyngealsquamous-cellcarcinoma(ICD code notgiven)282 Chinese men andwomen from fourcentres (prevalent andincident cases) [no information on age distribution]One Chinese controlselected by multistagearea sampling per case;matched by age and sexStructured in-homeinterviews; occupational exposuresassessed by a job–exposure matrixAny (unadjusted)Any (adjusted)1.24 (0.67–2.32)0.71 (0.34–1.41)Diet andtobacco useMixture of prevalent(42%) and incident(58%) cases 

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# IARC MONOGRAPHS VOLUME 88 130Table 18 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustmentfor potentialconfoundersCommentsLaforestet al.(2000),France,1989–91Hypopharynx(squamous-cell) (ICD codenot given)201 men withconfirmed histologyfrom 15 hospitals [noinformation on age]296 male patients withother (selected) primarytumours from the same ornearby hospitals;recruited 1987–91;matched by ageStructured in-person interviews;occupationalexposures assessedwith a job–exposurematrix earlierdevelopedEver exposedProbability of exposure (%)< 1010–50> 50Duration (years)< 77–20> 20Cumulative levelLowMediumHighExclusion of subjects withexposure probability< 10%Ever exposedDuration (years)< 77–20> 20Cumulative levelLowMediumHigh1.35 (0.86–2.14)1.08 (0.62–1.88)1.01 (0.44–2.31)3.78 (1.50–9.49)1.09 (0.50–2.38)1.39 (0.74–2.62)1.51 (0.78–2.92)1.03 (0.51–2.07)1.57 (0.81–3.06)1.51 (0.74–3.10)1.74 (0.91–3.34)0.74 (0.20–2.68)1.65 (0.67–4.08)2.70 (1.08–6.73)0.78 (0.11–5.45)1.77 (0.65–4.78)1.92 (0.86–4.32)Age, tobaccosmoking,alcohol consumption,coal dust andasbestos 

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# FORMALDEHYDE 131Table 18 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustmentfor potentialconfoundersCommentsVaughanet al.(2000), USA(Connecticut,metropolitanDetroit, Iowa,Utah,Washington),1987–93196 men and women[sex distribution notreported] from fivecancer registries, aged18–74 years244 population-basedselected by random digitdialling; frequencymatched by sex, cancerregistry and age (5-yeargroups)Structuredtelephoneinterviews;occupationalexposures assessedby a job–exposurematrixEver exposedMax. exposure (ppm)< 0.10.1–0.5> 0.5pfor trendDuration (years)1–56–17≥18pfor trendDifferentiated squamouscell and epithelial NOSonlyEver exposed1.3 (0.8–2.1)1.4 (0.8–2.4)0.9 (0.4–2.3)1.6 (0.3–7.1)0.570.8 (0.4–1.6)1.6 (0.7–3.4)2.1 (1.0–4.5)0.0701.6 (1.0–2.8)Age, sex,race, centre,cigarette use,proxy statusand educationData presented for anypotential exposure(possible, probable ordefinite); not influencedby a 10-year lag periodor adding wood dustexposure to modelsEpithelialnasopharyngealcarcinoma: epithelial NOS(801x–804x),undifferentiated or nonkeratinizing(8020–1, 8072–3, 8082) andsquamous-cell(805x–808x,except 8072–3)Duration (years)1–56–17≥18pfor trendCumulative exposure(ppm–years)0.05–0.4> 0.4–1.10> 1.10pfor trend0.9 (0.4–2.1)1.9 (0.9–4.4)2.7 (1.2–6.0)0.0140.9 (0.4–2.0)1.8 (0.8–4.1)3.0 (1.3–6.6)0.033 

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# IARC MONOGRAPHS VOLUME 88 132Table 18 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustmentfor potentialconfoundersCommentsHildesheimet al. (2001)Taiwan,China,1991–94Nasopharynx;> 90% non-keratinizing andundifferentiatedand remaindersquamous-cellcarcinomas(ICD code notgiven)375 histologicallyconfirmed hospitalcases (31% women),aged < 75 years325 community controls,individually matched onsex, age (5 years) anddistrict of residenceStructured in-person interviews;occupationalexposures assessedby an industrialhygienist; bloodspecimen wastested for anti-EBVantibodies.Ever exposedDuration1–10 years>10 yearspfor trendCumulative exposure< 25≥25pfor trend1.4 (0.93–2.2)1.3 (0.69–2.3)1.6 (0.91–2.9)0.081.3 (0.70–2.4)1.5 (0.88–2.7)0.10Age, sex,education andethnicityObservations were notinfluenced by addingwood dust exposure tomodels; in a sub-analysis restricted to360 cases and 94controls seropositive forat least one type ofantibody against EBV,the association betweenexposure to formalde-hyde and nasopharyn-geal cancer appearedsomewhat stronger.Berrinoet al.(2003),France, Italy,Spain,Switzerland,1979–82Hypopharynxand epilarynx(ICD code notgiven)100 men, incident caseshistologically con-firmed from six centres,aged≤55 years819 men from the generallocal population of eachcentre; age- and sex-stratifiedStructured in-person interviews;occupationalexposures assessedby an expert panelusing a previouslyestablished job–exposure matrixProbability of exposurePossibleProbable and certain1.3 (0.6–2.6)0.5 (0.1–1.8)Age, centre,tobacco use,alcohol con-sumption,diet, socio-economicstatus,asbestos,PAHs,chromium,arsenic, wooddust, solvents,other dustsand gases[The credibility of thenegative finding islimited because formaldehyde was the agentfor which the validity ofthe job–exposure matrixwas lowest.]CI, confidence interval; EBV, Epstein-Barr virus; ICD, international code of diseases; NOS, not otherwise specified; PAHs, polycyclic aromatic hydrocarbonsa90% confidence interval 

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# 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 thestudy 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 thebuccal 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), toyield 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 entailedexposure 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 133 105-172.qxp 13/12/2006 11:39 Page 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 withsquamous-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 forsquamous-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 exposureto 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 IARC MONOGRAPHS VOLUME 88 134 105-172.qxp 13/12/2006 11:39 Page 134

# 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 betweenthe 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 wasalso 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 135 105-172.qxp 13/12/2006 11:39 Page 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 exposurescore. [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 IARC MONOGRAPHS VOLUME 88 136 105-172.qxp 13/12/2006 11:39 Page 136

# 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 anumber 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 137 105-172.qxp 13/12/2006 11:39 Page 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 yearsor 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 IARC MONOGRAPHS VOLUME 88 138 105-172.qxp 13/12/2006 11:39 Page 138

# 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 andthose 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 139 105-172.qxp 13/12/2006 11:39 Page 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 andmatched 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 perweek) 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 ofnasopharyngeal 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 IARC MONOGRAPHS VOLUME 88 140 105-172.qxp 13/12/2006 11:39 Page 140

# each of the five cancer registries conducted structured telephone interviews with the studysubjects, 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 whichemployment 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 andeducation 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 patternof 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 ( p trend 

# = 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 p trend 

# value for a dose–response relationship was 0.014. A similar dose–response pattern within this group was seen for estimated cumulative exposure ( p trend 

# = 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 exposureto 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 141 105-172.qxp 13/12/2006 11:39 Page 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 toage (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 wasassigned 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 IARC MONOGRAPHS VOLUME 88 142 105-172.qxp 13/12/2006 11:39 Page 142

# 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 wasblind 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 classedas 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 143 105-172.qxp 13/12/2006 11:39 Page 143

# occupational history. Each job was coded with respect to occupation and industry, and occupational exposures, including formaldehyde, were assessed using a previously developedjob–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 ( p trend 

# < 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 ( p trend 

# < 0.04) and with cumulative level of exposure ( p trend 

# < 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 betweenalcohol 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.] IARC MONOGRAPHS VOLUME 88 144 105-172.qxp 13/12/2006 11:39 Page 144

# 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 fromamong 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 canceramong 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 hadbeen 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–exposurematrix 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 andyear 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 allowedfor, 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 145 105-172.qxp 13/12/2006 11:39 Page 145

# IARC MONOGRAPHS VOLUME 88 146Table 19. Case–control studies of cancers of the lung and larynxReference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustment forpotentialconfoundersCommentsAndersenet al.(1982),Denmark,1943–77Lung84 doctors (79 men,five women) registeredin Denmark who diedof lung cancer252 randomly selectedfrom official list ofDanish doctors, matchedon sex and ageInformation onpostgraduatespecialization andprofessional careeremploymentEver employed inpathology, forensicmedicine or anatomy1.0 (0.4–2.4)Both cases andcontrols weremedical doctors.Fayerweatheret al.(1983),USA, 1957–79Lung andlarynxActive or pensionedemployees (all men)who died of cancer(181 lung, eightlarynx)189 employees matchedon sex, age, pay classand date at firstemployment, selectedfrom annual payrollroster among employeesactive during the case’slast year of employmentJob–exposurematrix to classifyexposure accor-ding to frequencyand intensity(continuous/direct, inter-mittent, back-ground) based onpersonnel andmedical recordsand interviewswith colleaguesLung< 5 years≥5 years1.20 [0.6–2.8]0.79 [0.4–1.6]TobaccosmokingAnalysis included alatency period of20 years betweenexposure anddisease.Coggonet al.(1984), UnitedKingdom,1975–79Lung(bronchialcarcinoma)598 men≤40 years oldwho died of bronchialcarcinoma in Englandand Wales1180 men who had diedfrom any other cause,matched by year ofdeath, district of residence and date of birth(±2 years)Job–exposurematrix based onclassificationcoding in threecategories (none,low, high) ofexposureAll exposed occupationsOccupations with highexposure1.5 (1.2–1.8)0.9 (0.6–1.4)p< 0.001 

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# FORMALDEHYDE 147Table 19 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustment forpotentialconfoundersCommentsGérinet al.(1989), Canada,1979–85Lung (oatcell carcinoma;squamouscell carcinoma;adenocarcinoma;othersincludingunspecified)857 men aged 35–70years resident in thearea of Montréal1523 men with cancer atother sites (cancercontrols) and 533 menselected from electorallist (populationcontrols), stratified byageSemi-structuredquestionnaire onlifetime workhistory; exposureprofile developedbased on probability, frequency,concentration andduration of exposure and period offirst exposureCancer controlsEverShortLong-lowLong-mediumLong-highPopulation controlsEverShortLong-lowLong-mediumLong-high0.8 (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)Age, ethnicgroup, socioeconomic status,cigarettesmoking,dirtiness of joband various otherpotentialconfoundersIncreased relativerisk for adenocarcinoma of thelung with longexposure to highconcentrationWortleyet al.(1992), UnitedKingdom,1983–87Larynx(ICD-0161.0–161.9)235 [sex distributionnot given] identifiedthrough local cancersurveillance system547 identified byrandom-digit diallingselected to be similar inage and same sexIn-personinterview; job–exposure matrixbased on bothlikelihood anddegree of exposurePeakLowMediumHighDuration< 1 year1–9 years≥10 yearsExposure scores< 55–19≥201.0 (0.6–1.7)1.0 (0.4–2.1)2.0 (0.2–19.5)1.00.8 (0.4–1.3)1.3 (0.6–3.1)1.01.0 (0.5–2.0)1.3 (0.5–3.3)Age, tobaccosmoking, alcoholdrinking andeducationBrownsonet al.(1993), USA,1986–91Lung429 white women aged30–84 years, former ornever smokers1021 women selectedfrom state driver’slicence files (< 65 yearsold) or health careroaster (≥65 years old),group- matched for ageTelephone and inperson interviewEver exposed0.9 (0.2–3.3)Age and historyof previous lungdiseaseAll exposed casesand controls werelifelong nonsmokers. 

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# IARC MONOGRAPHS VOLUME 88 148Table 19 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustment forpotentialconfoundersCommentsGustavssonet al.(1998),Sweden,1988–91Larynx(ICD-9 161)157 male incidentcases aged 40–79 years641 selected bystratified randomsampling; frequency-matched to cases by age(10–15-year groups) andregionWork historyreviewed byoccupationalhygienist; occu-pations coded byintensity andprobability ofexposureEver exposed1.45 (0.83–2.51)Region ofincidence, age,alcohol intakeand tobaccosmoking statusLaforestet al.(2000), France,1989–91Larynx(ICD codenot given)296 men withconfirmed histology ofcancer of the epi-larynx, glottis, supra-glottis, subglottis andlarynx unspecified296 men with other(selected) primarytumours selected fromthe same or nearbyhospitals, recruited in1987–91, matched byageStructured in-person interviews;occupationalexposures wereassessed with ajob–exposurematrix developedearlierEver exposedExposure probability< 10%10–50%> 50%Excluding subjects withexposure probability< 10%Ever exposedDuration of exposure< 7 years7–20 years> 20 yearsCumulative exposureLowMediumHigh1.14 (0.76–1.70)1.16 (0.73–1.86)1.12 (0.55–2.30)1.04 (0.44–2.47)1.17 (0.63–2.17)1.68 (0.60–4.72)0.86 (0.33–2.24)1.14 (0.47–2.74)0.68 (0.12–3.90)1.86 (0.76–4.55)0.91 (0.42–1.99)Age, tobaccosmoking, alcoholdrinking andexposure to coaldust 

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# FORMALDEHYDE 149Table 19 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics of casesCharacteristics ofcontrolsExposureassessmentExposure categoriesRelative risk(95% CI)Adjustment forpotentialconfoundersCommentsBerrinoet al.(2003), France,Italy, Spain,Switzerland,1979–82Larynx(glottis,supraglottis)213 male incidentcases aged≤55 years819 men from generallocal population of eachcentre, stratified by ageStructured inperson interviews;occupational exposures assessed byan expert panelusing a previouslyestablished job–exposure matrixProbability of exposurePossibleProbable or definite1.4 (0.8–2.7)1.0 (0.4–2.3)Age, centre,tobacco use,alcohol drinking,diet, socioeconomic status,asbestos, PAHs,chromium,arsenic, wooddust, solvents,other dusts andgases[The credibility ofthe negative findingis limited becauseformaldehyde wasthe agent for whichthe validity of thejob–exposure matrixwas lowest.]Elciet al.(2003), Turkey,1979–84Larynx(ICD-0161.0–2, –9)940 male incidentcases at OncologyTreatment Center1519 male patients withmalignant or benignpathologyStandardizedquestionnaireadministered athospital on occupational history;job–exposurematrixEver exposedIntensityLowMediumHighProbabilityLowMediumHigh1.0 (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)Age, tobacco useand alcoholdrinkingAnalysis by subtypeof cancer (glottis,supraglottis, other)did not show anyelevation of risk. Notrend with intensityor probability ofexposureCI, confidence interval; ICD, international code of diseases; PAHs, polycyclic aromatic hydrocarbons 

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# 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. Thegroup 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 menwho were selected from electoral lists of the Montréal area. Interviews or completed questionnaires that yielded lifelong job history and information on potential non-occupationalconfounders 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/m 3 

# ] 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/m 3 

# ], 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/m 3 

# ] and 1.5 (95% CI, 0.8–2.8) for ≥ 10 years of presumedexposure 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 IARC MONOGRAPHS VOLUME 88 150 105-172.qxp 13/12/2006 11:39 Page 150

# 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 forat 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 regionof 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 was1.45 (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 151 105-172.qxp 13/12/2006 11:39 Page 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 cancerwho 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 with1308 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 ofrisk 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, IARC MONOGRAPHS VOLUME 88 152 105-172.qxp 13/12/2006 11:39 Page 152

# FORMALDEHYDE 153Table 20.Case–control studies of lymphohaematopoietic malignanciesReference,study location,years of studyOrgan site(ICD code)Characteristics ofcasesCharacteristics ofcontrolsExposure assessmentExposure categoriesRelative risk(95% CI)Adjustment forpotential confoundersCommentsGérinet al.(1989),Canada,1979–85HodgkinlymphomaNon-Hodgkinlymphoma53 male incidentcases206 male incidentcases533 populationbasedLifetime job historiesobtained by interview and translatedinto level of exposure to formaldehydeEver< 10 years duration≥10 years durationLowaMediumaHigha0.5 (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)Age, ethnic group,self-reported income,tobacco smoking,dirtiness of jobs heldand potentiallyconfoundingoccupational and nonoccupational factorsSimilar results wereobtained when 2599cases of other cancerswere used as controlgroup.Linoset al.(1990), USA(years of studynot given)LeukaemiaNon-Hodgkinlymphoma578 male incidentcases622 male incidentcases1245 populationbasedLifetime occupa-tional historyobtainedEver employed infuneral home orcrematorium2.1 [0.4–10.0]based on fourexposed cases3.2 [0.8–13.4]based on sixexposed casesAdjusted for age andstate of residenceSignificantly elevatedrelative risks of 6.7and 6.7 for acutemyeloid leukaemiaand follicular nonHodgkin lymphoma,but based on smallnumbersPartanenet al.(1993),Finland,1957–1982LeukaemiaHodgkindiseaseNon-Hodgkinlymphoma12 male casesdiagnosed among acohort of 7307production workersin wood industryFour male casesEight male cases79 randomlyselected from cohortand matched byyear of birth andvital status in 19832152Work history fromcompany recordscomplemented forcases only byinterviews with plantpersonnel and questionnaires completedby subjects or next ofkin; plant- andperiod-specific job–exposure matrix< 3 ppm–months≥3 ppm–months< 3 ppm–months≥3 ppm–months< 3 ppm–months≥3 ppm–months1.001.40 (0.25–7.91)(two exposedcases)1.00NA(one exposedcase)1.004.24 (0.68–26.6)(four exposedcases)Matching factorsaccounted for byconditional logisticregressionData collection wasmore exhaustive forcases than for controls,which could have ledto bias. Relative riskfor all three outcomescombined did notsubstantially changewhen adjusted forwood dust or forsolvents. 

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# IARC MONOGRAPHS VOLUME 88 154Table 20 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics ofcasesCharacteristics ofcontrolsExposure assessmentExposure categoriesRelative risk(95% CI)Adjustment forpotential confoundersCommentsWestet al.(1995), UnitedKingdom(years of studynot given)Myelo-dysplasticsyndrome400 (216 men,184 women) newlydiagnosed, residentin study area andaged > 15 years400 cancer-freepatients from out-patient clinics andinpatient wards;matched 1:1 by age(±3 years), sex,area of residenceand hospital andyear of diagnosis(±2 years)Personal interviewon work history andfor duration andintensity of exposureto formaldehyde; allquestionnairesreviewed by team ofexperts> 10 h lifetimeexposure of anyintensity> 50 h lifetimeexposure of mediumor high intensity> 2500 h lifetimeexposure of mediumor high intensity1.17 [0.51–2.68]2.33 [0.55–11.35]2.00 [0.32–15.67]No adjustment forsmoking or otherfactorsTathamet al.(1997), USA,1984–88Non-Hodgkinlymphomaand sub-groups1048 men (185small-cell diffuselymphoma, 268follicular lym-phoma and 526large-cell diffuselymphoma) frompopulation-basedcancer registries,born 1929–531659 selected byrandom-digitdialling, matched byarea of registry and5-year categories ofdate of birthTelephone interviewincluding questionson specific materialswhich participantsmay have workedwithEver exposedAll combinedSmall-cell diffuseFollicularLarge-cell diffuse1.20 (0.86–1.50)1.40 (0.87–2.40)0.71 (0.41–1.20)1.10 (0.79–1.70)Matching factors, ageat diagnosis, yearentered the study,ethnicity, education,Jewish religion, neverhaving married, AIDSrisk behaviours, useof seizure medication,service in or off thecoast of Viet Namand cigarette smoking 

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# FORMALDEHYDE 155Table 20 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics ofcasesCharacteristics ofcontrolsExposure assessmentExposure categoriesRelative risk(95% CI)Adjustment forpotential confoundersCommentsBlairet al.(2001), USA,1980–83Leukaemiaand myelodysplasia513 white men, 30years or older,identified from theCancer Registry ofIowa and among allmen from asurveillancenetwork ofhospitals inMinnesota; 214chronic lymphoid,132 acute myeloid,46 chronic myeloid,13 acute lymphoid,58 myelodysplasiaand 50 others1087 selected byrandom-digitdialling from HealthCare FinancingAdministration listsand from state deathcertificate files,frequency-matchedby 5-year agegroup, vital status attime of interviewand state ofresidencePersonal interviewsincluding lifetimeoccupational history;formaldehydeassessed in a blindedfashion in terms ofprobability andintensity, each on a4-point scale basedon job title andindustryAcute myeloidLow-mediumHighChronic myeloidLow-mediumHighChronic lymphoidLow-mediumHighMyelodysplasiaLow-mediumHighAll combinedLow-mediumHigh0.9 (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)Matching factors,post-secondaryeducation, hair dyeuse, tobacco smoking,first degree relativewith hematolymphopoietic tumour andagricultural use ofpesticidesNone of the acutelymphocyticlymphoma cases wasexposed.AIDS, acquired immunodeficiency syndrome; CI, confidence interval; ICD, international code of diseases; NA, not applicableaAverage exposure index 

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# 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), Fritschiand 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 2357patients 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 ajob–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 IARC MONOGRAPHS VOLUME 88 156 105-172.qxp 13/12/2006 11:39 Page 156

# 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 fromoutpatient 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, includingformaldehyde. 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 eligiblecases 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 157 105-172.qxp 13/12/2006 11:39 Page 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-yearage 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 afirst-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/ IARC MONOGRAPHS VOLUME 88 158 105-172.qxp 13/12/2006 11:39 Page 158

# 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 (northernFrance) 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 cancersat 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 weremade 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 159 105-172.qxp 13/12/2006 11:39 Page 159

# IARC MONOGRAPHS VOLUME 88 160Table 21. Case–control studies of cancers at other sitesReference,study location,years of studyOrgan site(ICD code)Characteristics ofcasesCharacteristics ofcontrolsExposureassessmentExposurecategoriesOdds ratio(95% CI)Adjustment forpotential confoundersCommentsGérinet al.(1989),Canada,1979–85OesophagusStomachColorectumLiverPancreasProstateBladderKidneySkin melanomaMen aged 35–70years resident inMontréal10725078750117452486181121Pool of populationselected fromelectoral list, andcancer controls;depending of thecancer site understudy, the numberof controls variedfrom 1733 to 2741.Semi-structuralprobing interview,assessment ofexposures bychemists andindustrialhygienistsShortLong-lowLong-mediumLong-highNo associationfor any of thesesites (most oddsratios very closeto 1.0)Selection of data-based confounders(variables accordingto each specificcancer), plus age,ethnic group, socio-economic status,cigarette smoking anddirtiness of jobShort and long refer tothe duration, and low,medium and high tothe intensity ofexposure.Merlettiet al.(1991), Italy,1982–84Oral cavity ororopharynx86 male incidentcasesRandom sample of385 men, stratifiedby age, from thefiles of residentsFull occupationalhistory linked to ajob–exposurematrixAny exposureProbable ordefinite1.6 (0.9–2.8)1.8 (0.6–5.5)Age, education, areaof birth, tobaccosmoking and alcoholdrinkingOnly six exposedcases in the probableor definite exposuregroupGoldoftet al.(1993), USA,1979–89Melanoma ofthe nasal cavityor nasopharynxNine cases [sexdistribution notreported]Random-digit dial-ling, frequency-matched on sexand age at dia-gnosis (controlsfrom Vaughanet al., 1986a,b)InterviewLiving in aresidence withfoam insulationOccupationalexposureEmployed inindustries withpotentialexposurea3.57 (0.09–19.8)Obs./exp. 0/0.27Obs./exp. 0/0.8Siemiatyckiet al.(1994),Canada,1979–86Bladder484 men aged35–70 yearsresident inMontréal533 population and1879 cancercontrolsSee Gérinet al.(1989)Non-substantialSubstantial1.2 (0.9–1.6)0.9 (0.5–1.7)Age, ethnicity,socioeconomic status,tobacco smoking,coffee consumption,status of respondentand other occupational exposuresResults based onpooled controls 

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# FORMALDEHYDE 161Table 21 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics ofcasesCharacteristics ofcontrolsExposureassessmentExposurecategoriesOdds ratio(95% CI)Adjustment forpotential confoundersCommentsCantoret al.(1995), USA,1984–89Breast (female)33 509 womenwith breast canceras the cause ofdeath117 794 womenwho died fromnon-cancer causes;frequency-matchedfor age and raceUsual occupationon death certificatelinked to a job–exposure matrix,with levels of probability and ofintensity ofexposureExposure levelsLowMediumHighLowMediumHighBlacks1.14p< 0.050.931.20p< 0.05Whites1.38p< 0.051.30p< 0.051.36p< 0.05Age at death,socioeconomic statusand excluding womenwith lowest probability of exposureNo trend wasobserved.Hollyet al.(1996), USA,1978–87Uvealmelanoma221 white menaged 20–74 years447 white menselected byrandom-digitdialling; matchedfor area and ageRecall throughtelephoneinterviewsEver2.9 (1.2–7.0)Age, number ofnaevis, eye colour andskin response toexposure to middaysummer sunGustavssonet al.(1998),Sweden,1988–91Oral cavity andoesophagus(ICD-9 141,143-5, 150)250 incident casesamong men aged40–79 yearsresident in tworegions (oralcavity, 128;oesophagus, 122)641 men selectedby stratifiedrandom sampling;frequency-matchedto cases by age(10–15-yeargroups) and regionWork historyreviewed byoccupationalhygienist; occupations coded byintensity andprobability ofexposureEverOral cavityOesophagus1.28 (0.64–2.54)1.90 (0.99–3.63)Region, age, alcoholconsumption andtobacco smokinghabitsKernanet al.(1999), USA,1984–93Pancreas63 097 personswith pancreaticcancer as the causeof death [sex andrace distributionnot reported]252 386 personswho died fromnon-cancer causes;frequency-matchedby state, sex, raceand age (5-yeargroups)Usual occupationon death certificatelinked to a job–exposure matrix,with levels ofprobability and ofintensity ofexposureExposure levelLowMediumHighExposure probabilityLowMediumHigh1.2 (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)Age, marital status,residential status, sexand raceNo trend wasobserved; analysis byrace and sex alsoprovided 

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# IARC MONOGRAPHS VOLUME 88 162Table 21 (contd)Reference,study location,years of studyOrgan site(ICD code)Characteristics ofcasesCharacteristics ofcontrolsExposureassessmentExposurecategoriesOdds ratio(95% CI)Adjustment forpotential confoundersCommentsDumaset al.(2000),Canada,1979–85Rectum257 men aged35–70 yearsresident inMontréal533 population and1295 cancercontrolsSee Gérinet al.(1989)AnySubstantial1.2 (0.8–1.9)2.4 (1.2–4.7)Age, education,cigarette smoking,beer drinking, bodymass index andrespondent statusResults based oncancer controls andnot in accordance withthose of Gérinet al.(1989)Wilsonet al.(2004), USA,1984–89Salivary gland(ICD-9, 142.0–1, –9)[2405] personswith cancer of thesalivary gland asthe cause of death(whites: 1347men, 890 women;African–Ameri-cans: 93 men,75 women)[9420] personswho died fromnon-cancer causes,excluding infec-tious diseases;frequency-matchedfor age, race, sexand regionUsual occupationon death certificatelinked to a job–exposure matrix,with levels ofprobability and ofintensity ofexposureMid–highprobability andintensityWhite men andwomen1.6 (1.3–2.0)Black women1.9 (0.8–5.1)Age, marital statusand socioeconomicstatusHigh level of dia-gnosis misclassifi-cation suspectedCI, confidence interval; ICD, international code of diseasesaWood-work, furniture manufacture, pulp and paper mill, textile, foundry and smelter 

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# 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 oddsratios 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 socioeconomicstatus 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 163 105-172.qxp 13/12/2006 11:39 Page 163

# for age, marital status and socioeconomic status, of 1.6 (95% CI, 1.3–2.0) was observedwith ‘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 cancerwas 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 bypotential 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 weregrouped into three categories of presumed frequency and intensity of exposure to formaldehyde (no, any, probable or definite exposure), with the ‘no exposure’ group (exposure nothigher 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 withexposure 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 beexcluded from the interpretation of the observed association between exposure to formaldehyde and oral cancer.] IARC MONOGRAPHS VOLUME 88 164 105-172.qxp 13/12/2006 11:39 Page 164

# 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. Twohundred 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 fromthe 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, anelevated 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 thepharynx 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 165 105-172.qxp 13/12/2006 11:39 Page 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 exposureto 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 andleather 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 IARC MONOGRAPHS VOLUME 88 166 105-172.qxp 13/12/2006 11:39 Page 166

# 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 forthose 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 maybe 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 risksfor 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 167 105-172.qxp 13/12/2006 11:39 Page 167

# IARC MONOGRAPHS VOLUME 88 168Table 22. Summary of results from three meta-analyses on respiratory cancers and exposure to formaldehydeSiteLungNose and nasal sinusesNasopharynxOther respiratoryLevel or duration ofexposure toformaldehydeO/EmRR(95% CI)O/EmRR(95% CI)O/EmRR(95% CI)O/EmRR(95% CI)AnyBlairet 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)]NRNRPartanen (1993)b,c833/7521.11 (1.03–1.19)93/781.11 (0.81–1.53)36/212.00 (1.36–2.90)69/571.18 (0.87–1.59)Collinset al.(1997)d2080/25061.0 (0.9–1.0)936/8081.0 (1.0–1.1)455/4121.3 (1.2–1.5)NRNRLow/mediumBlairet al.(1990b)a514/4221.2 [1.1–1.3]38/460.8 [0.6–1.1]30/271.1 [0.7–1.6]NRNRPartanen (1993)b,c518/4251.2(1.1–1.3)33/301.10 (0.67–1.79)23/161.59 (0.95–2.65)52/481.05 (0.74–1.51)SubstantialBlairet al.(1990b)a250/2401.0 [0.9–1.2]30/281.1 [0.7–1.5]13/62.1 [1.1–3.5]NRNRPartanen (1993)b,c233/2161.1 (0.95–1.2)36/211.68 (1.00–2.82)11/42.74 (1.36–5.55)23/201.15 (0.64–2.09)CI, confidence interval; mRR, meta-relative risk; NR, not reported; O/E, observed/expectedaBlairetal.(1990b) included the following studies in their analysis: Harrington & Shannon (1975), Petersen & Milham (1980), Jensen & Andersen (1982),Fayerweatheret al. (1983), Friedman & Ury (1983), Marsh (1983), Milham (1983), Walrath & Fraumeni (1983), Wong (1983), Achesonetal.(1984a,b), Coggonetal. (1984), Harrington & Oakes (1984), Levineet al. (1984), Lieblinget al. (1984), Malker & Weiner (1984), Olsenet al. (1984), Walrath & Fraumeni (1984),Partanenet al. (1985), Stayneretal. (1985), Walrathet al. (1985), Bertazziet al. (1986), Blairet al. (1986), Bondet al. (1986), Gallagheret al. (1986), Hayeset al.(1986a,b), Logueet al. (1986), Stroupet al. (1986), Vaughanet al. (1986a,b), Blairet al. (1987), Roushet al. (1987), Stayneret al. (1988), Bertazziet al. (1989),Gérinet al. (1989), Blairet al. (1990a) and Hayeset al.(1990).bThe analysis for lung cancer was performed for industrial workers only, as at least some of the data for professionals were confoundedby social class.cPartanen (1993) included in his analysis the above studies and: Brintonet al.(1984), Merlettiet al. (1991); in addition, Partanenet al.(1985) was updated withPartanenet al.(1990), and Gallagheret al.(1986) was updated with Gallagheret al.(1989).dCollinset al.(1997) included in their analysis the above studies (except for Petersen & Milham (1980), Friedman & Ury (1983), Marsh (1983), Milham (1983),Wong (1983), Achesonet al. (1984a,b), Harrington & Oakes (1984), Lieblinget al. (1984), Malker & Weiner (1984), Stayneret al. (1985), Walrathet al.(1985),Gallagheretal. (1986), Logueet al. (1986), Blairet al. (1987, 1990a) and Merlettiet al. (1991)) and added the following studies: Hernberget al.(1983a,b), Olsen &Asnaes (1986),Hallet al. (1991), Matanoski (1991),Chiazzeet al.(1993), Gardneret al. (1993), Luceet al.(1993),Westet al. (1993), Marshet al. (1994) andAndjelkovichetal. (1995). 

# 105-172.qxp 13/12/2006 11:39 Page 168

# 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) wascalculated 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 studiesthat 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 169 105-172.qxp 13/12/2006 11:39 Page 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 IARC MONOGRAPHS VOLUME 88 170



# 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/pro

portionate incidence ratio; SMR/SIR, standardized mortality ratio/standardized incidence ratio

a 

# Ojajärvi et al. (2000) studied occupational exposures and pancreatic can cer 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). 105-172.qxp 13/12/2006 11:39 Page 170

# 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 observedin 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 comparisonsfrom 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/m 3 

# formaldehyde (US Pharmacopeia grade) vapour for 1 h perday, 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/m 3 

# for 35 weeks were subsequently exposed to 150 mg/m 3 

# 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 B6C3F 1 

# 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/m 3 

# ] 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 171 105-172.qxp 13/12/2006 11:39 Page 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/m 3 

# ] 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 allmajor 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 nasalcavity 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 IARC MONOGRAPHS VOLUME 88 172 105-172.qxp 13/12/2006 11:39 Page 172

# 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 ininhalation 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/m 3 

# ] formaldehyde [purity unspecified] vapour and 10.6 ppm [15.8 mg/m 3 

# ] 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 μ g/m 3 

# ]. 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 examinedmicroscopically. 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 51 a 

# 52 a



# Nasal carcinoma 0 0 0 0 0 0 1 b 

# 1

Undifferentiated carcinoma

or sarcoma 0 0 0 0 0 0 2 b 

# 0

Carcinosarcoma 0 0 0 0 0 0 1 0

Osteochondroma 1 0 0 0 0 0 0 0 Polypoid adenoma 1 0 { 4 4 c 

# 6 d 

# 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] pp173-186.qxd 13/12/2006 11:43 Page 173

# 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/m 3 

# ] formaldehyde [purity unspecified] and 10 ppm [14.9 mg/m 3 

# ] hydrogen chloride gas mixed before dilution in the exposure chamber to maximize formation of bis(chloromethyl)ether; (2) 14.1 ppm [17.3 mg/m 3 

# ] formaldehyde and 9.5 ppm [14.2 mg/m 3 

# ] hydrogen chloride gas not mixed before introduction into the exposure chamber; (3) 14.2 ppm [17.5 mg/m 3 

# ] formaldehyde vapour alone; (4) 10.2 ppm [15.2 mg/m 3 

# ] hydrogen chloride gas alone; or (5) air (sham-exposed controls). A control group of 99 rats was also available. The findingsin 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/m 3 

# ] 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 survivorswere 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 IARC MONOGRAPHS VOLUME 88 174

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 r espiratory tract 22 12 10 19 25 24

From Sellakumar et al. (1985) pp173-186.qxd 13/12/2006 11:43 Page 174

# 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/m 2 

# ]) Exposure time;

no. of rats Tumour

0 10 [12.3] 20 [25]

4 weeks

No. of rats 44 44 45 Polypoid adenoma 0 0 1 a 

# Squamous-cell carcinoma 0 0 1

8 weeks

No. of rats 45 44 43 Polypoid adenoma 0 0 1 a 

# Squamous-cell carcinoma 2 1 1

13 weeks

No. of rats 45 44 44 Squamous-cell carcinoma 0 1 3 a 

# Cystic squamous-cell carcinoma 0 0 1

Carcinoma in situ 0 0 1 a



# Ameloblastoma 0 0 1

From Feron et al . (1988)

a 

# Considered by the authors to be related to exposure to formaldehyde pp173-186.qxd 13/12/2006 11:43 Page 175

# 180 rats were exposed to 0, 0.1, 1.0 or 10 ppm [0, 0.123, 1.23 or 12.3 mg/m 3 

# ] 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/m 3 

# ]. 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 IARC MONOGRAPHS VOLUME 88 176

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/m 3 

# ])

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 pp173-186.qxd 13/12/2006 11:43 Page 176

# 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 offormaldehyde-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/m 3 

# ] 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 pergroup 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 twolowest 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, hyperplasiaand 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/m 3 

# ] 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 pp173-186.qxd 13/12/2006 11:43 Page 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 extremisalso 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, nasaltumours 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/m 3 

# ] 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/m 3 

# ] formaldehyde [purity unspecified] for 5 h once a week for life. A group of 50 untreated hamster served as controls. When the animals died, IARC MONOGRAPHS VOLUME 88 178 pp173-186.qxd 13/12/2006 11:43 Page 178

# 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, stomachand 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 pp173-186.qxd 13/12/2006 11:43 Page 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,

χ 2 

# 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 asstabilizer; 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 adenomasin 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 adose–response relationship [no statistics given] for the increased incidences of haemolymphoreticular tumours. Gastrointestinal leiomyomas and leiomyosarcomas, which arevery 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 groupand 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) IARC MONOGRAPHS VOLUME 88 180 pp173-186.qxd 13/12/2006 11:43 Page 180

# FORMALDEHYDE 181Table 28. Incidences (%) of leukaemia and tumours (benign and malignant) of the gastrointestinal tract after administration offormaldehydein the drinking-water to Sprague-Dawley breeder rats and their offspringLeukaemiasStomachIntestineTreatmentNo. ofratsLymphoblasticleukaemias andlymphosarcomasImmunoblasticlymphosarcomasOthersTotalPapilloma/acanthoma/adenomaAdenocarcinoma/squamous-cellcarcinomaLeiomyosarcomaAdenomaAdeno-carcinomaLeiomyo-sarcomaBreeders (25 weeks old)0 ppmMaleFemaleMale + female2500 ppmMaleFemaleMale + female202040181836–5.02.5–5.62.8–––5.65.65.6–––5.6–2.8–5.02.511.111.111.1––––5.62.8–––5.6–2.8––––––––––––––––––––––––Offspring0 ppmMaleFemaleMale + female2500 ppmMaleFemaleMale + female5949108363773–––2.8–1.43.44.13.78.2–4.11.72.01.8–––5.16.15.511.1–5.5–––2.8–1.4–––2.82.72.8–––2.82.72.7–––2.8–1.4–––2.82.72.7––––13.5a6.8aFrom Soffrittiet al.(1989)a[p≤0.01;χ2test, calculated by the Working Group] 

# pp173-186.qxd 13/12/2006 11:43 Page 181

# IARC MONOGRAPHS VOLUME 88 182Table 29. Percentage of animals that had malignant tumours and incidence of selected types of tumour in a number of organs ofSprague-Dawley rats after administration of formaldehyde in the drinking-water for up to 24 monthsFormaldehyde dose (mg/L)MalesFemalesSite and type of tumour00a10501005001000150000a105010050010001500No. of animals1005050505050505010050505050505050Animals bearing malignant tumours (%)3842282444484672b,c4346404050385854Mammary glandAdenocarcinoma100000021114481661822Fibrosarcoma0200000000204220Liposarcoma0000200002020402Angiosarcoma0000020000000000Total12002202111661020122024dForestomachLeiomyosarcoma0020000000000000Glandular stomachLeiomyosarcoma0000002000000000IntestineLeiomyoma0000000000220006Leiomyosarcoma0000000400020000TestesInterstitial-cell adenoma106612122024d,e18Haemolymphoreticular tissuesfLymphomas and leukaemias82082026b24d22d46b,c,g7101014161422d20dFrom Soffrittiet al. (2002)a15 mg/L methanolbp< 0.01,χ2test, versus untreated controlsc[p< 0.01,χ2test, versus methanol group; calculated by the Working Group]dp< 0.05,χ2test, versus untreated controls [the Working Group noted that this category is an aggregate of tumours of differentcellular origin]e[p< 0.01, 2-tail Fisher exact test, versus methanol group; calculated by the Working Group]fIncluding thymus, spleen and subcutaneous, mesenteric and pancreatic lymph nodesg[p< 0.01 for trend, Cochran Armitage; calculated by theWorking Group] 

# pp173-186.qxd 13/12/2006 11:43 Page 182

# 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. TheWorking 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 μ L 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 changeswere 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 μ g DMBA in 100 μ L 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 μ L 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 pp173-186.qxd 13/12/2006 11:43 Page 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/m 3 

# 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/m 3 

# , respectively). In addition, IARC MONOGRAPHS VOLUME 88 184 pp173-186.qxd 13/12/2006 11:43 Page 184

# 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/m 3 

# ] 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 thenreceived 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 wereexamined 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 pp173-186.qxd 13/12/2006 11:43 Page 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 μ g/g blood (mean ± standard error [SE]; range, 2.05–3.09 μ g/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/cm 3 

# (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/m 3 

# ] for 40 min was

2.77 ± 0.28 μ g/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 IARC MONOGRAPHS VOLUME 88 186 pp173-186.qxd 13/12/2006 11:43 Page 186

# 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/m 3 

# ]. 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 μ g/g of blood (mean ± SE)) (Heck et al. , 1985) and three rhesus monkeys (2.04 ± 0.40 μ g/g of blood; range, 1.24–2.45 μ g/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/m 3 

# ] (for 2 h) or subacute exposure of monkeys to 6 ppm [7.3 mg/m 3 

# ] (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 andcarbon 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 [ 14 

# C]formaldehyde (at 0.63 or 13.1 ppm [0.8 or 16.0 mg/m 3 

# ]) for 6 h. About 40% of the inhaled 14 

# C was eliminated as FORMALDEHYDE 187 187-272.qxp 13/12/2006 11:53 Page 187

# expired [ 14 

# C]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 [ 14 

# C]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 courseof residual radioactivity in plasma and erythrocytes after inhalation or intravenous injection of [ 14 

# C]formaldehyde or intravenous injection of [ 14 

# C]formate showed that the radioactivity is due to incorporation of 14 

# C (as [ 14 

# C]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). IARC MONOGRAPHS VOLUME 88 188



# 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 CH 2 

# OH

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 CH 2 

# OH

protein NH CH 2 

# NH DNA protein NH CH 2 

# NH protein OC(NH 2 

# ) 2 

# +

CO 2 

# + H 2 

# O one carbon pool HOCH 2 

# NH C NH

O CH 2 

# OH HOCH 2 

# NH C NH 2 

# O S

N

H COOH 

# 187-272.qxp 13/12/2006 11:53 Page 188

# The fate of [ 14 

# C]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 [ 14 

# C]formaldehyde evaporated from the skin. Monkeys were seated in a restraining chair and were fitted with a plexiglass helmet for collection of exhaled [ 14 

# C]carbon dioxide. The concentrations of 14 

# C 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 over72 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 14 

# C) was due to [ 14 

# C]carbon dioxide.

Rodent carcass contained 22–28% of the 14 

# C and total blood about 0.1%; a substantial

fraction of 14 

# C (3.6–16%) remained in the skin at the site of application. In monkeys, only 0.24% of the dermally applied [ 14 

# C]formaldehyde was excreted in the urine, and 0.37% was accounted for as [ 14 

# C]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 14 

# C 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 [ 14 

# C]formaldehyde (7 mg/kg) was eliminated as [ 14 

# C]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 thecarcass as products of metabolic incorporation. In another study in which SpragueDawley rats were injected intraperitoneally with 4 or 40 mg/kg bw [ 14 

# C]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 [ 14 

# C]formaldehyde (defined as the uptake of 14 

# C into phosphate-buffered saline, pH 7.4, that flowed unidirectionally beneath the sample) was

16.7 μ g/cm 2 

# /h when a 3.7% solution of formaldehyde was used, and increased to

319 μ g/cm 2 

# /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 14 

# C was due only to formaldehyde. Skin retention of formaldehyde-derived radioactivity represented a significant fraction of the total amount of formaldehyde absorbed. FORMALDEHYDE 189 187-272.qxp 13/12/2006 11:53 Page 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 (seeFig. 1) by refining earlier models of formaldehyde deposition and DNA–protein crosslinks in nasal mucosa. Anatomically accurate CFD models of nasal airways of Fischer 344rats, 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–proteincross-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/(mm 2 

# 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/(mm 2 

# 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 IARC MONOGRAPHS VOLUME 88 190 187-272.qxp 13/12/2006 11:53 Page 190

# carbon black particles showed that only 2 ppb [0.0025 mg/m 3 

# ] of an airborne formaldehyde concentration of 6 ppm [7.4 mg/m 3 

# ] 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-% 13 

# C and 98 atom-% deuterium ( 2 

# H) 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 insamples of venous blood that were collected before and after exposure of six human volunteers to 1.9 ppm [2.3 mg/m 3 

# ] formaldehyde by inhalation for 40 min. Average concentrations of formaldehyde were 2.61 ± 0.14 μ g/g blood before and 2.77 ± 0.28 μ g/g blood after exposure. These values were not significantly different. However, the subjects exhibitedsignificant 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 191 187-272.qxp 13/12/2006 11:53 Page 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, wherethey 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/m 3 

# ]. 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 areattributed 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 offormation 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 muchlower 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 IARC MONOGRAPHS VOLUME 88 192 187-272.qxp 13/12/2006 11:53 Page 192

# nasal respiration (Ballenger, 1984). In recent years, the metabolic capacities of nasal cavitytissues 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, formaldehydedehydrogenase (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 + 

# H 2 

# O 2



# H 2 

# O 

# methanol

one

carbon

pool NAD +



# NADH +H +



# CO 2 

# + H 2 

# O ADH3 ALDH1A1

ALDH2 catalase endogenous

sources exogenous

sources 

# Figure 2. Fate and metabolism of formaldehyde

Adapted from Hedberg et al . (2002) 187-272.qxp 13/12/2006 11:53 Page 193

# 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 isoften present in millimolar concentration levels (Meister & Anderson, 1983). The equilibrium constant (K eq 

# ) 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 (K

m 

# ) is less than micromolar for aldehyde substrates, they are called low-K

m 

# ALDHs (Petersen & Lindahl, 1997), except for free formaldehyde for which the K

m 

# values are high (in the range of 0.6 mM; Mukerjee & Pietruszko, 1992). This value is about 100-fold higher than the K

m 

# displayed by ADH3 for

S

-hydroxymethylglutathione (4 μ M) (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-K

m 

# 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 forsynthesis 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, N 5 

# -hydroxymethyl-, N 5



# , N 10 

# -methylene, and N 5 

# - and N 10 

# -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 IARC MONOGRAPHS VOLUME 88 194 187-272.qxp 13/12/2006 11:53 Page 194

# 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 B 4 

# 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 195 187-272.qxp 13/12/2006 11:53 Page 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 wereremoved 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 andthe 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 IARC MONOGRAPHS VOLUME 88 196 187-272.qxp 13/12/2006 11:53 Page 196

# 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/m 3 

# ] 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% with2 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/m 3 

# formaldehyde (range, 0.2–0.7 mg/m 3 

# ) 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 197 187-272.qxp 13/12/2006 11:53 Page 197

# IARC MONOGRAPHS VOLUME 88 198



# 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/m 3 

# ] 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/m 3 

# 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/m 3



# [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/m 3 

# ] 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 187-272.qxp 13/12/2006 11:53 Page 198

# 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 innasal 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/m 3 

# ). An in-vitro study of human nasal ciliated epithelial cells showed reduced frequency of ciliary beat after exposure to 5000 μ g/m 3 

# formaldehyde for 2 h, but no effect after exposure to 5000 μ g/m 3 

# for 1 h or 500 μ g/m 3 

# 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) 187-272.qxp 13/12/2006 11:53 Page 199

# not control for confounding factors, particularly lack of ventilation and other allergens. Itis 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 tendedto 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 ofexposure (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/m 3 

# ] 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 (FEV 1 

# ), +1.2%; control, +2.1% at 1 h; exposed FEV 1 

# , + 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/m 3 

# (mean, 1.22 mg/m 3 

# )] IARC MONOGRAPHS VOLUME 88 200 187-272.qxp 13/12/2006 11:53 Page 200

# 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

FEV 1 

# 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 inthe 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/m 3 

# ], with occasional peaks as high as 9 ppm [11.0 mg/m 3 

# ], 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/m 3



# , with peak concentrations of up to 5 mg/m 3 

# . 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/m 3 

# , with frequent peaks of over 1 mg/m 3 

# , and those in the furniture factories were 0.2–0.3 mg/m 3 

# , with rare peaks up to to 0.5 mg/m 3 

# ; the latter workers were also exposed to wood dust (1–2 mg/m 3 

# ). The control group was exposed to concentrations of 0.09–0.17 mg/m 3 

# 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 201 187-272.qxp 13/12/2006 11:53 Page 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 wereproduced and 37 age-matched controls. The concentrations of formaldehyde in the company ranged from 0.5 to > 2 ppm [0.6–> 2.4 mg/m 3 

# ], and the average length of employment was 20 years. Hyperplasia and squamous metaplasia were more common among theexposed 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/m 3 

# in the sawmill and shearingpress department and 0.39 mg/m 3 

# in the warehouse area. Peak exposure levels were not given. Concurrent exposure to low levels of wood dust (respirable mass, 0.23 mg/m 3 

# in the warehouse, 0.73 mg/m 3 

# during sawing and 0.41 mg/m 3 

# 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 toformaldehyde in a nurse who had no reaction after a control exposure. An asthmatic pathoIARC MONOGRAPHS VOLUME 88 202 187-272.qxp 13/12/2006 11:53 Page 202

# FORMALDEHYDE 203Table 31. Findings in the nasal mucosa of peoplewho had occupational exposure to formaldehydeIndustryConcentration offormaldehyde(mg/m3)No. ofexposedNo. ofcontrolsMethodFindingsReferenceFormaldehyde(laminate plant)0.5–1.13825Nasal biopsyHistological score: exposed, 2.8; controls,1.8 (p< 0.05). Four exposed men had milddysplasia.Edlinget al.(1987b)FormaldehydeWood dust (laminatedparticle-board)0.1–1.1(peaks to 5)0.6–1.17525Nasal biopsyHistological score: exposed, 2.9; controls,1.8 (p< 0.05). Six men had mild dysplasia.Edlinget al.(1988)Formaldehyde(phenol?) (laminate)0.02–2.4(peaks to 11–18.5)4238Swab smearsNo positive correlation between exposureto formaldehyde and abnormal cytologyBerke (1987)ClinicalexaminationMore mucosal abnormalities in nonsmoking exposed workers (p= 0.04)Formaldehyde(production offormaldehyde andformaldehyde resins)0.6–> 2.43737Nasal biopsyHistological score: exposed, 1.9; controls,1.4 (p> 0.05). Three exposed and nocontrols had dysplasia.Boysenet al.(1990)Formaldehyde (resinsfor laminateproduction)0.05–0.5(peaks to > 1)6232Nasal biopsyHistological score: exposed, 2.16; controls,1.56 (p< 0.05). No case of dysplasiaHolmströmet al. (1989a)FormaldehydeWood dust (plywoodfactory)0.1–0.390.23–0.731515Nasal scrapesMicronuclei in nasal mucosal cells:exposed, 0.90; controls, 0.25 (p< 0.010).Cytological score: exposed, 2.3; controls,1.6 (p< 0.01). One exposed had milddysplasia.Ballarinet al.(1992) 

# 187-272.qxp 13/12/2006 11:53 Page 203

# IARC MONOGRAPHS VOLUME 88 204

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 crossreaction with glutaraldehyde (12.4%) and glyoxal (1.9%) Kiec-Swierczynska

et al . (1998)

Men and

women Inhalation 2.3 mg/m 3



# 4.8 mg/m 3



# 31 mg/m 3



# 4.8 mg/m 3 

# 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/m 3



# 2.5 mg/m 3 

# 30 min

30 min 1 worker, early response 11 workers, 6 late

response12/230 exposed symptomatic workers + specificchallenge 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 187-272.qxp 13/12/2006 11:53 Page 204

# logist had no reaction following a similar 60-min exposure to 5 ppm [6 mg/m 3 

# ] 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/m 3 

# ] 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/m 3 

# and two after exposure to 4.8 mg/m 3 

# . Control asthmatics had no asthma attack provoked by exposures to 4.8 mg/m 3 

# ; one asthmatic exposed to a sheep dip that contained formaldehyde had an irritant reaction following a 7-min exposure to 31 mg/m 3



# . 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/m 3 

# formaldehyde and 11 reacted to 2.5 mg/m 3 

# formaldehyde. No reaction was

observed at 2.5 μ g/m 3 

# 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/m 3 

# ], but not to 0.01 ppm [0.01 mg/m 3 

# ] 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 μ g/mL residual formaldehyde. She hadpreviously 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 μ g/dL formaldehyde, 44 mg/dL formate and 42 mg/dL methanol. She died after 28 h (Eells et al. , 1981). FORMALDEHYDE 205 187-272.qxp 13/12/2006 11:53 Page 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, wasdecreased 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 Ca 2+ 

# 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 Ca 2+ 

# , 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 oxygenspecies. 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 IARC MONOGRAPHS VOLUME 88 206 187-272.qxp 13/12/2006 11:53 Page 206

# protected against toxicity. Prevention of toxicity by cyclosporine or carnitine, agents thatprevent 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) wereassociated 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 μ g/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 frogrespiratory 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 ameasure 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 207 187-272.qxp 13/12/2006 11:53 Page 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 respective0-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 B6C3F 1 

# mice at 4.9 ppm [6.0 mg/m 3 

# ] and in Fischer 344 rats at 31.7 ppm [38.7 mg/m 3 

# ] (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/m 3 

# ]) 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/m 3 

# ] 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/F 1 

# mice and CD rats (Jaeger & Gearhart, 1982). Rats exposed to 28 ppm [34.2 mg/m 3 

# ] formaldehyde for 4 days developed tolerance to its sensory irritancy, but those exposed to 15 ppm [18.3 mg/m 3 

# ] 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 decreasedrespiratory frequency by 50%. Formaldehyde vapours were produced by thermal depolymerization of paraformaldehyde in water and evaporation into the in-flow airstream. Themaximal decrease in breathing frequency was observed within 3 min of exposure; desensitization occurred within a few minutes after maximal decrease in breathing frequencyand 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 IARC MONOGRAPHS VOLUME 88 208 187-272.qxp 13/12/2006 11:53 Page 208

# FORMALDEHYDE 209Adapted from Changet al.(1983)Data shown arex 

# −±SE for each time point;n= 6 for each groupFigure 4. Time−response curves for respiratory rate, tidal and minute volume from naive andformaldehyde-pretreated mice and rats (6 ppm, 6 h/day, 4 days) during a 6-h exposure to 6 ppmformaldehyde 

# 187-272.qxp 13/12/2006 11:53 Page 209

# [12.3 mg/m 3 

# ]. 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 μ L of a buffered (pH 7.4) phosphate-saline solution that contained1% methanol, 0.1% or 1.0% formaldehyde or 1% formate. The final vitreous concentrations were 700 μ g/mL methanol, 70 μ g/mL formaldehyde, 700 μ g/mL formaldehyde and

700 μ g/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 andjuxtapapillary 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/m 3 

# ] for 8 h caused transient bronchoconstriction and hyper-reactivity to infused acetylcholine; exposure to higher concentrations (> 9 ppm [> 11 mg/m 3 

# ]) for 2 h induced bronchoconstriction. No evidence of tracheal epithelial damage was observed after exposure to 3.4 ppm [4.2 mg/m 3 

# ] 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/m 3 

# ] 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/m 3 

# ]), ozone (0.6 ppm [1 mg/m 3 

# ]) (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, whichraised 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 IARC MONOGRAPHS VOLUME 88 210 187-272.qxp 13/12/2006 11:53 Page 210

# 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 tothe 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, undilutedformalin 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 μ L 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 wereinjected 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 μ L 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 μ L 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 211 187-272.qxp 13/12/2006 11:53 Page 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 anaerosol 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 mRNAlevels. 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/m 3 

# ];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/m 3 

# ] (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/m 3 

# ] (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 IARC MONOGRAPHS VOLUME 88 212 187-272.qxp 13/12/2006 11:53 Page 212

# FORMALDEHYDE 213Table 33. Cytotoxicity and cell proliferation induced by acute and subacute exposure to formaldehydeStrain, species, sexExposureEffectsReferenceFischer 344 rat,male; B6C3F1mouse, male0, 0.6, 2.4, 7.4, 18.5 mg/m3, 6 h/day, 3days0.6, 2.4: no increase in cell replication rate in nasalmucosa; 7.4: increased cell turnover (rats only);18.5: cell proliferation (rats and mice)Swenbergetal. (1983)Fischer 334 rat,male; B6C3F1mouse, male0, 18.5 mg/m3, 6 h/day, 1 or 5 days18.5: cell proliferation induced in nasal mucosa ofboth species; rat responses exceeded those of mice.Changet al.(1983)Fischer 344 rat,male3.7 mg/m3×12 h/day, 7.4 mg/m3×6h/day,14.8 mg/m3×3 h/day (C×t= 44mg/m3–h/day), 3 or 10 daysCell proliferation relatedmore closely to concentration than to time; less proliferation after 10 thanafter 3 days of exposure, indicating adaptationSwenbergetal. (1983)Fischer 344 rat,male0, 0.6, 2.4, 7.4, 18.5 mg/m3, 6 h/day, 1, 2, 4, 9or 14 days0.6: no effects on mucociliary function; 2.4: minimal effects; 7.4: moderate inhibition; 18.5: markedinhibitionMorganet al.(1986b)Fischer 344 rat,male0, 2.4, 18.5 mg/m3, 10, 20, 45 or 90 min or 6 h2.4: no effect on mucociliary function; 18.5: inhibition of mucociliary function, marked recovery1h after exposureMorganet al.(1986c)Fischer 344 rat,male0, 0.6, 2.4 mg/m3, 6 h/day, 1 or 4 days;7.4mg/m3, 6 h/day, 1, 2 or 4 days;18.5mg/m3, 6 h/day, 1 or 2 days0.6, 2.4: no lesions; 7.4, 18.5: non-cell-specific,dose-related injury, including hypertrophy, nonkeratinized squamous cells, nucleolar segregationMonteiroRiviere &Popp (1986)Wistar rat, male0, 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 weeksLabelling index increased at all concentrations;cell proliferation more closely related to concentration than to total doseWilmeret al.(1987)Wistar rat, maleand female0, 0.37, 1.2, 3.7 mg/m3, 6 h/day, 3 daysSignificant, transient increase in cell turnover at1.2 and 3.7 mg/m3but not confirmed in laterstudies at concentration of 1.2 ppm (Reuzelet al.,1990)Zwartet al.(1988) 

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# IARC MONOGRAPHS VOLUME 88 214Table 33 (contd)Strain, species, sexExposureEffectsReferenceRhesus monkey,male0, 7.4 mg/m3, 6 h/day, 5 days/week, 1 or6weeksLesions similar to those in rats (Monticelloet al.,1991) but more widespread, extending to tracheaand major bronchi; increased cell replication innasal passages, trachea and carina; percentage ofnasal surface area affected increased between 1and 6 weeks.Monticelloetal. (1989)Wistar rat, male0, 0.37, 1.2, 3.7 mg/m3, 22 h/day, 3 daysAlso investigated effect ofsimultaneousexposure to 0.4, 0.8 or 1.6 mg/m3ozone0.37, 1.2: either no increase in or inhibition of cellproliferation; 3.7: increased cell replication;0.8mg/m3ozone + 1.2 or 3.7 mg/m3formal-dehyde: synergistic increase in cell turnover;1.6mg/m3ozone + 1.2 mg/m3formaldehyde: inhi-bition of cell turnoverReuzelet al.(1990)Fischer 344 rat,male0, 0.86, 2.4, 7.4, 12.3, 18.5 mg/m3, 6h/day,5days/week, 1, 4, or 9 days or 6weeks0.86, 2.4: no effect on cell turnover; 7.4, 12.3,18.5: concentration-and site-dependent cell proli-feration induced at all exposure timesMonticelloetal. (1991)Wistar rat, male0, 4.43 mg/m3; 8 h followed by 4 h noexposure for 6 consecutive 12-h cyclesAlso investigated effect of simultaneousexposure to 0.4 ppmozone.4.43 mg/m3resulted in increased GSH peroxidasein nasal respiratory tissue and increased PCNAexpression by immunohistochemistry.Cassee &Feron (1994)Wistar rat, male0, 1.23, 3.94, 7.87 mg/m3, 6 h/day, 1 or 3daysAlso investigated effect ofsimultaneousexposure to acetaldehyde (750, 1500 ppm) andacrolein (0.25, 0.67 ppm).The mixture resulted in more extensive and severehistopathology of the nose than the individualexposure.Casseeet al.(1996b)BN/Crj rat, male;Fischer 344/DuCrjrat,male0 or 18.45–24.6 mg/m3(estimate), 3 h/day,5daysNasal respiratory degeneration and necrosis moresevere in Fischer 344 ratsOhtsukaet al.(1997)C, concentration;t, time; PCNA, proliferating cell nuclear antigen 

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# 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/m 3 

# ] (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/m 3 

# ]) 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/m 3 

# ] (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 andscanning 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 severelyaffected. 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 215 187-272.qxp 13/12/2006 11:53 Page 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/m 3 

# ] formaldehyde, 0.2, 0.4 or 0.8 ppm [0.4, 0.8 or 1.6 mg/m 3 

# ] 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 irritatingconcentrations. 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/m 3 

# ] in the individual or ozone mixture exposure groups, respectively (concentration of ozone, 0.4 ppm [0.8 mg/m 3 

# ]). 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 epithelialsamples 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 indegenerative 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 IARC MONOGRAPHS VOLUME 88 216 187-272.qxp 13/12/2006 11:53 Page 216

# 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/m 3 

# ] 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 forhistology (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 groupsof 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 comparableconcentrations 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 217 187-272.qxp 13/12/2006 11:53 Page 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/m 3 

# ] 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/m 3 

# ] (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/m 3 

# ] 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 LD 50 

# 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 LD 50 

# 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 μ M 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 afterthe 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 IARC MONOGRAPHS VOLUME 88 218 187-272.qxp 13/12/2006 11:53 Page 218

# 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/m 3 

# ; 2.6 ppm) or 0.7% (equivalent to 5.55 ± 1.27 mg/m 3 

# ; 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/m 3 

# , 0.62 mg/m 3 

# or 6.64 mg/m 3 

# ] 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 wereexamined microscopically. All rats exposed to formaldehyde made more errors in completing the maze, but no difference was observed between exposure groups or sexes. After10 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 wasnot 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/m 3 

# or 12.2 mg/m 3 

# 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 219 187-272.qxp 13/12/2006 11:53 Page 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 significantlydecreased 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, triiodothyroninewas 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/m 3 

# ] 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 DNAsynthesis was found in the nasal mucosa after subchronic or chronic exposure to concentrations of ≤ 2 ppm [ ≤ 2.4 mg/m 3 

# ] 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/m 3 

# ] (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/m 3 

# ] (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/m 3 

# ] 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/m 3 

# ] (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. IARC MONOGRAPHS VOLUME 88 220 187-272.qxp 13/12/2006 11:53 Page 220

# FORMALDEHYDE 221Table 34. Cytotoxicity and cell proliferation induced by subchronic and chronic exposures to formaldehydeStrain, species, sexExposureEffectsReferenceFischer 344 rat,Syrian hamster,male and female;cynomolgusmonkey, male0, 0.25, 1.2, 3.7 mg/m3, 22 h/day,7 days/week, 26 weeksRat: squamous metaplasia in nasal turbinates at 3.7 mg/m3only;hamster: no significant toxic response; monkey: squamousmetaplasia in nasal turbinates at 3.7 mg/m3onlyRuschet al.(1983)B6C3F1 mouse,male0, 2.5, 4.9, 12.3, 24.6, 49.2 mg/m3,6 h/day, 5 days/week, 13 weeks2.5, 4.9: no lesion induced; 12.3, 24.7, 49.2: squamous metaplasia, inflammation of nasal passages, trachea and larynx; 80%mortality at 49.2 mg/m3Maronpotet al. (1986)Wistar rat, maleand female0, 0.37, 1.2, 3.7 mg/m3, 6 h/day,5 days/week, 13 weeks0.37, 1.2: no increase in cell replication; 3.7: increased cell turnover in nasal epithelium but cell proliferation lower than after3 days of exposureZwartet al.(1988)Wistar rat, maleand female0, 1.2, 12.3, 24.7 mg/m3, 6 h/day,5 days/week, 13 weeks1.2: results inconclusive; 12.3, 24.7: squamous metaplasia, epithelial erosion, cell proliferation in nasal passages and larynx; nohepatotoxicityWoutersenet al. (1987)Wistar rat, male0, 0.12, 1.2, 12.3 mg/m3, 6 h/day,5 days/week, 13 or 52 weeksNasal mucosa of some rats injured bybilateral intranasal electrocoagulation toinduce cell proliferation0: electrocoagulation induced hyperplasia and squamous metaplasia, still visible after 13 weeks but slight after 52 weeks; 0.12,1.2: focal squamous metaplasia after 13 or 52 weeks; no adverseeffects in animals with undamaged nasal mucosa; 12.3: squamous metaplasia in respiratory epithelium (both intact anddamaged nose); degeneration with or without hyperplasia ofolfactory epithelium (damaged nose only)Appelmanet al. (1988) 

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# IARC MONOGRAPHS VOLUME 88 222Table 34 (contd)Strain, species, sexExposureEffectsReferenceWistar rat, male0, 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 or19.7 mg/m3–h/day), 5 days/week,13 weeks1.2, 2.5: no observed toxic effect; 4.9: epithelial damage,squamous metaplasia, occasional keratinization; concentration,not total dose, determined severity of toxic effectWilmeret al.(1989)Fischer 344 rat,male0, 0.86, 2.5, 7.4, 12.3, 18.5 mg/m3,6 h/day, 5 days/week, 6 weeks0.86, 2.5: no increase in cell replication detected; 7.4: increase incell proliferation; 12.3, 18.5: sustained cell proliferationMonticelloet al.(1991)Fischer 334 rat,male0, 0.86, 2.5, 7.4, 18.5 ppm, 6 h/day,5 days/week, 12 weeks0.86, 2.5: DNA synthesis rates in nasal mucosa similar in naive(previously unexposed) and subchronically exposed rats; 7.4,18.5: DNA synthesis rates higher in subchronically exposed thanin naive rats, especially at 18.5 mg/m3Casanovaet al.(1994)Fischer 344 rat,male0, 0.86, 2.5, 7.4, 12.3, 18.5 mg/m3,6 h/day, 5 days/week, 3 months0.86, 2.5, 7.4: no increase in cell replication detected; 12.3, 18.5:sustained cell proliferation. Site-specific increase in cellreplication corresponded to location of squamous-cellcarcinomas.Monticelloet al.(1996)C, concentration;t, time 

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# 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/m 3 

# ] (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 at0.1 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 14 

# C derived from inhaled [ 14 

# C]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/m 3 

# ] 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 [ 14 

# C]formaldehyde occurred on the 5th day of the 12th week. The asterisk denotes a significant difference between pre-exposed and naive rats. 187-272.qxp 13/12/2006 11:53 Page 223

# 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/m 3 

# , 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- 3 

# H]thymidine for incorporation ofthe 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 orless. 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. Theseverity 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 IARC MONOGRAPHS VOLUME 88 224 187-272.qxp 13/12/2006 11:53 Page 224

# FORMALDEHYDE 225Table 35. Incidences of nasal squamous-cell carcinomas in male Fischer 344 rats exposed by inhalation toformaldehydeNasal locationConcentrationof formaldehyde (ppm)No. ofnasalcavitiesexaminedAnteriorlateralmeatusPosteriorlateralmeatusAnteriormidseptumPosteriormidseptumAnteriordorsalseptumAnteriormedialmaxilloturbinateMaxillarysinusNo. of animalswith squamouscell carcinomaa090000000000.79000000000296000000006901000000110901220000020151471798134069From Monticelloet al. (1996)aTotal number of animals with squamous-cell carcinoma, including those too large to allocate and those located in a site not listed in thistable 

# 187-272.qxp 13/12/2006 11:53 Page 225

# 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-inducedsquamous 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/m 3 

# ] 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 formaldehydeuptake 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/m 3 

# ] 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/m 3 

# ] (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/m 3 

# ] (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 usingairflow parameters of 0.63–3.8 L/min. The nasal cavity of rhesus monkeys has two airIARC MONOGRAPHS VOLUME 88 226 187-272.qxp 13/12/2006 11:53 Page 226

# FORMALDEHYDE 227Figure 6. Calculated total proliferative population in areas of the nose of rats after exposure to formaldehyde for3 months and T-site where tumours developedAdapted from Monticelloet al.(1996)010203040506070809000.7261015

Population-weighted unit l ength labelling index ( × 10 6 )Formaldehyde concentration (ppm)TTTTTTTTTAnterior lateral meatusPosterior lateral meatusAnterior mid-spetumPosterior mid-septumAnterior dorsal septumAnterior medial maxilloturbinateMaxillary sinus 

# 187-272.qxp 13/12/2006 11:53 Page 227

# IARC MONOGRAPHS VOLUME 88 228Figure 7. Sum of calculated total proliferative population in areas of the nose of rats after exposure to formaldehyde overtime and T-site where tumours developedAdapted from Monticelloet al.(1996)025507510012515017520022525027500.7261015Formaldehyde concentration (ppm)

Population-weighted unit l ength labelling index ( × 10 6 )TTTTTTTTTAnterior lateral meatusPosterior lateral meatusAnterior mid-spetumPosterior mid-septumAnterior dorsal septumAnterior medial maxilloturbinateMaxillary sinus 

# 187-272.qxp 13/12/2006 11:53 Page 228

# 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 or150 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 229 187-272.qxp 13/12/2006 11:53 Page 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 B6C3F 1 

# mice exposed to 15 ppm [18.3 mg/m 3 

# ] 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/m 3 

# 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/m 3 

# ] formaldehyde (6 h perday 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. Theoutcomes 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 sterilizeinstruments. 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 IARC MONOGRAPHS VOLUME 88 230 187-272.qxp 13/12/2006 11:53 Page 230

# 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 obtainedfrom 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 forage, 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 pregnantbetween 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 laboratoriesin 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 231 187-272.qxp 13/12/2006 11:53 Page 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 IARC MONOGRAPHS VOLUME 88 232 187-272.qxp 13/12/2006 11:53 Page 232

# 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 weighedless 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/m 3 

# ] (weekly exposure, 3–40 ppm·h [3.7–48.8 mg/m 3 

# ·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 233 187-272.qxp 13/12/2006 11:53 Page 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 [ 14 

# C]-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 [C 14 

# ]- labelling would be consistent with the entry of the [ 14 

# C]-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/m 3 

# ]) for 6 h per day on days 6–20 of gestation. On day 21, the rats were killed and maternal and fetal parameters wereevaluated. 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/m 3 

# ]) 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, theanimals were anaesthetized with nembutal (13 mg intraperitoneally) during the 2-h treatIARC MONOGRAPHS VOLUME 88 234 187-272.qxp 13/12/2006 11:53 Page 234

# 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 onfetal 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/m 3 

# or 1.5 mg/m 3 

# 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/m 3 

# . 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 LD 50 

# 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 235 187-272.qxp 13/12/2006 11:53 Page 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 399workers 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) fromthe 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/m 3 

# ]; range, 0.04–0.7 ppm [0.5– 0.62 mg/m 3 

# ]); and (2) high-level exposure (mean, 2.24 ppm [2.75 mg/m 3 

# ]; range, 0.72– 5.6 ppm [0.88–6.9 mg/m 3 

# ). 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 amongexposed 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.] IARC MONOGRAPHS VOLUME 88 236 187-272.qxp 13/12/2006 11:53 Page 236

# FORMALDEHYDE 237Table 36. Genetic effects of formaldehyde in humansTarget tissueEnd-pointResponseCommentsReferencePeripheral blood lymphocytesChromosomal aberrationsMicronucleiSister chromatid exchange+ (p< 0.01)+ (p< 0.01)+ (p< 0.05)Exposed, 13; unexposed, 10; chromosomalaberrations included breaks and gaps, whichrenders interpretation difficult.Heet al. (1988)Nasal mucosaMicronuclei+ (p< 0.01)Exposed, 15; unexposed (control), 15;concurrent exposure to wood dust; no dose–responseBallarinet al.(1992)Peripheral blood lymphocytesChromosomal aberrations–Exposed,20; unexposed (control), 19; highfrequency in controlsVargovaet al.(1992)Peripheral blood lymphocytesDNA–protein cross-links+ (p= 0.03)Exposed, 12; unexposed, 8; pilot studyShahamet al.(1996a)Oral mucosaNasal mucosaMicronuclei+ (p= 0.007)+ (NS)Exposed, 28; pre-versus post-exposure; nodetails on tobacco smoking habitsTitenko-Hollandetal. (1996)Peripheral blood lymphocytesSister chromatid exchange+ (p= 0.05)Exposed, 13; unexposed, 20; linear relationship between years of exposure and meannumber of sister chromatid exchangesShahamet al.(1997)Nasal mucosaOral mucosaPeripheral blood lymphocytesMicronuclei+ (p< 0.001)+ (p< 0.01)+ (NS)Exposed, 25; pre-versus post-exposure;control for age, sex and tobacco smokinghabits questionableYinget al.(1997)Peripheral blood lymphocytesSister chromatid exchange–Exposed, 23; pre-versus post-exposureYinget al.(1999)Nasal mucosaMicronuclei+ (p< 0.01)Exposed, 23; unexposed, 25; no dose–responseBurgazet al.(2001) 

# 187-272.qxp 13/12/2006 11:53 Page 237

# IARC MONOGRAPHS VOLUME 88 238Table 36 (contd)Target tissueEnd-pointResponseCommentsReferenceOral mucosaMicronuclei+ (p< 0.05)Exposed: 22 variable exposures, 28exposedto formaldehyde; unexposed, 28; unexposed(control), 18; correlation with duration ofexposure only ingroup with variable expo-sures (not exposed to formaldehyde)Burgazet al.(2002)Peripheral blood lymphocytesSister chromatid exchange+ (p< 0.01)Exposed, 90; unexposed, 52; no dose–response relationshipShahamet al.(2002)Peripheral blood lymphocytesSerumDNA–protein cross-linksp53 protein+ (p< 0.01)+ (p< 0.01)Exposed, 186; unexposed, 213; high levelsof p53 proteinShahamet al.(2003)NS, not significant 

# 187-272.qxp 13/12/2006 11:53 Page 238

# ( 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/m 3 

# 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/m 3 

# , 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). Nodose–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 mucosaof 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 239 187-272.qxp 13/12/2006 11:53 Page 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/m 3 

# ] in the breathing zone of the pathology laboratory workers and 4 ppm [4.9 mg/m 3 

# ] 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 groupsincluded 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/m 3 

# ]. 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 wassampled 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/m 3 

# –h] for the entire 90-day period and 1.2 ± 2.1 ppm–h [1.5 ± 2.6 mg/m 3 

# –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/m 3 

# –h] for the entire 90-day period and 1.9 ± 2.5 ppm–h [2.3 ± 3 mg/m 3 

# –h] during the 7–10 days before the postexposure sampling. Air samples of glutaraldehyde, phenol, methanol and isopropanol IARC MONOGRAPHS VOLUME 88 240 187-272.qxp 13/12/2006 11:53 Page 240

# 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 cellsamples, 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/m 3 

# (range, 0.071–1.284 mg/m 3 

# ) and 0.012 ± 0.0025 mg/m 3 

# (range, 0.011–0.016 mg/m 3 

# ), 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, chromosomalaberrations 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/m 3 

# ]. 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 241 187-272.qxp 13/12/2006 11:53 Page 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/m 3 

# (range, 0.071–1.284 mg/m 3 

# ) in the laboratory rooms compared with 0.012 ± 0.0025 mg/m 3 

# (range, 0.011–0.016 mg/m 3 

# ) in the dormitories. Blood samples were taken at the beginning of the anatomy classes and againafter 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 chromatidexchange 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/m 3 

# ] in the rooms and 6.9 ppm [8.5 mg/m 3 

# ] in the laminar flow. Personal samples showed a range of 2.8–3.1 ppm [3.5–3.7 mg/m 3 

# ] formaldehyde at the period when most of the work was in progress and 1.46 ppm [1.8 mg/m 3 

# ] 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 tothe 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 threeexposed 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 IARC MONOGRAPHS VOLUME 88 242 187-272.qxp 13/12/2006 11:53 Page 242

# formaldehyde (low-level exposure: mean, 0.4 ppm [0.5 mg/m 3 

# ]; range, 0.04–0.7 ppm [0.05–0.86 mg/m 3 

# ]; high-level exposure: mean, 2.24 ppm [2.8 mg/m 3 

# ]; range, 0.72– 5.6 ppm [0.9–6.9 mg/m 3 

# ]). 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 tolevels 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 O 6 

# -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 about1.5 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/m 3 

# –h] (mean ± SD,

18.4 ± 15.6 ppm [22.5 ± 19.2 mg/m 3 

# ]). 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 243 187-272.qxp 13/12/2006 11:53 Page 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, O 6 

# -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/m 3 

# and 0.3 mg/m 3 

# (mean ± SD, 0.2 ± 0.05 mg/m 3 

# ). The mean MGMT activity ( ± 95% CI) was 133.2 ± 14.9 fmol MGMT/10 6 

# cells. No significant difference wasobserved 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/m 3 

# . No significant difference in MGMT activity was observed between this exposed group and the controls (146.9 ± 22.3 fmol MGMT/10 6 

# cells

and 138.9 ± 22.1 fmol MGMT/10 6 

# 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/m 3 

# ]. Urine (150–200 mL from each subject) was treated with β -glucuronidase and IARC MONOGRAPHS VOLUME 88 244 187-272.qxp 13/12/2006 11:53 Page 244

# 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/m 3 

# ] [ 14 

# C]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 [ 14 

# C]formaldehyde in a head-only inhalation chamber. DNA–protein cross-links induced by exposure to formaldehyde were measured in the nasal mucosa of severalregions 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 notdetected 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/m 3 

# ] 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 [ 14 

# C]-labelled formaldehyde at the same concentrations as those used for pre-exposure to quantitate the acute yield of DNA–protein cross-links andto 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 245 187-272.qxp 13/12/2006 11:53 Page 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 [ 14 

# C] 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 and2 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 [ 14 

# C] 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 naiverats. 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 medialand 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-linksin the medial and posterior meatus at any concentration of formaldehyde. Since measurement of the percentage of interfacial DNA does not require the use of [ 14 

# C]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, thepercentage 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.] IARC MONOGRAPHS VOLUME 88 246 187-272.qxp 13/12/2006 11:53 Page 246

# FORMALDEHYDE 247Table 37. Genetic and related effects of formaldehyde in experimental systems and animalsResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceMisincorporation of DNA bases into synthetic polynucleotidesinvitro+NT30Snyder & Van Houten(1986)pUC13 plasmid DNA bound to calf-thymus histones, DNA–proteincross-links+NT0.0075Kuykendall & Bogdanffy(1992)Escherichia coliPQ37, SOS repair test, DNA strand breaks,cross-links or related damage+NT20Le Curieuxet al.(1993)Escherichia coliK12 (orE. coliDNA), DNA strand breaks,cross-links or related damage; DNA repair+NT60Poverennyet al.(1975)Escherichia coliK12, DNA strand breaks, cross-links or relateddamage; DNA repair+NT600Wilkins & MacLeod(1976)Escherichia coliK12 KS160-KS66polAI, differential toxicity+NT60Poverennyet al.(1975)Escherichia coli polA+/W3110 andpolA–p3478, differentialtoxicity (spot test)+NT10μL of puresubstanceLeiferet al.(1981)Salmonella typhimuriumTA100,TA1535, TA1537, TA1538,TA98, reverse mutation––60μg/plateGockeet al.(1981)Salmonella typhimuriumTA100,reverse mutation–+10μg/plateHaworthet al.(1983)Salmonella typhimuriumTA100,reverse mutation(+)+30μg/plate (toxicabove 125μg/plate)cConnoret al.(1983)Salmonella typhimuriumTA100,reverse mutation++d9μg/platePoolet al.(1984)Salmonella typhimuriumTA100,reverse mutation(+)NT51μg/platecMarnettet al.(1985)Salmonella typhimuriumTA100,reverse mutation+NT6μg/plateTakahashiet al.(1985)Salmonella typhimuriumTA100,reverse mutation(+)+3Schmidet al.(1986)Salmonella typhimuriumTA100,reverse mutation+NT9.3O’Donovan & Mee(1993)Salmonella typhimuriumTA100,TA104, reverse mutation++6.25–50μg/plateDillonet al. (1998)Salmonella typhimuriumTA102,TA104, reverse mutation+NT21μg/platecMarnettet al.(1985) 

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# IARC MONOGRAPHS VOLUME 88 248Table 37 (contd)ResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceSalmonella typhimuriumTA102,reverse mutation+NT10Le Curieuxet al.(1993)Salmonella typhimuriumTA102,reverse mutation+NT25μg/plateO’Donovan & Mee(1993)Salmonella typhimuriumTA102,reverse mutation+NT0.1–0.25μg/plateChanget al. (1997)Salmonella typhimuriumTA102,reverse mutation+?6.25–50μg/plateDillonet al. (1998)Salmonella typhimuriumTA1535,TA1537, reverse mutation––100–200μg/plateHaworthet al.(1983)Salmonella typhimuriumTA1535,reverse mutationNT–d18μg/platePoolet al.(1984)Salmonella typhimuriumTA1535,TA1537, TA1538, reversemutation–NT100μg/plateO’Donovan & Mee(1993)Salmonella typhimuriumTA98,reverse mutation+NT12μg/plateMarnettet al.(1985)Salmonella typhimuriumTA98,reverse mutation–(+)10μg/plateHaworthet al.(1983)Salmonella typhimuriumTA98,reverse mutation(+)(+)30μg/plate (toxicabove 100μg/plate)Connoret al.(1983)Salmonella typhimuriumTA98,reverse mutationNT(+)d9μg/platePoolet al.(1984)Salmonella typhimuriumTA98,reverse mutation+NT12.5μg/plateO’Donovan & Mee(1993)Salmonella typhimurium(othermiscellaneous strains), reversemutation––100μg/plate (toxic at250μg/plate)Connoret al.(1983)Salmonella typhimuriumTM677,forward mutation to 8-azaguanine++5; 10eTemcharoen & Thilly(1983)Salmonella typhimuriumTA97, reverse mutation+NT12μg/platecMarnettet al.(1985)Salmonella typhimuriumTA7005 (his+), reverse mutation+NT1.5μg/plateOhtaet al. (2000)Escherichia coliK12, forward or reverse mutation (gptlocus)+NT120Crosbyet al.(1988)Escherichia coliK12, forward orreverse mutation+NT60Zijlstra (1989)Escherichia coliK12, forward or reverse mutation+NT18.8Graveset al.(1994) 

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# FORMALDEHYDE 249Table 37 (contd)ResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceEscherichia coliWP2uvrA, reverse mutation+NT15Takahashiet al.(1985)Escherichia coliWP2uvrA (pKM101), reverse mutation+NT12.5μg/plateO’Donovan & Mee(1993)Escherichia coliWP2, reverse mutation+NT1200Nishioka (1973)Escherichia coliWP2, reverse mutation+NT60Takahashiet al.(1985)Escherichia coliWP2 (pKM101), reverse mutation+NT25μg/plateO’Donovan & Mee(1993)Escherichia coli(other miscellaneous strains), reverse mutation+NT100Demerecet al.(1951)Escherichia coli(other miscellaneous strains), reverse mutation+NT900Panfilovaet al.(1966)Escherichia coli(other miscellaneous strains), reverse mutation+NT30Takahashiet al.(1985)Escherichia coliWP3104P, reverse mutation(+)NT5μg/plateOhtaet al. (1999)Escherichia coliWP3104P, reverse mutation+NT~2μg/plateOhtaet al. (2000)Saccharomycesspecies, DNA strand breaks and DNA repair+NT990Magaña-Schwenckeet al.(1978)Saccharomycesspecies, DNA strand breaks, DNA–protein crosslinks or related damage+NT500Magaña-Schwencke &Ekert (1978); MagañaSchwencke & Moustacchi(1980)Saccharomyces cerevisiae,gene conversion+NT540Chanetet al.(1975)Saccharomyces cerevisiae,homozygosis by mitotic recombinationor gene conversion+NT18.5Zimmermann & Mohr(1992)Neurospora crassaheterokaryons H-12 strain, forward mutation(+)NT250de Serreset al.(1988);deSerres & Brockman(1999) 

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# IARC MONOGRAPHS VOLUME 88 250Table 37 (contd)ResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceNeurospora crassaheterokaryons H-59 strain, forward mutation+NT100de Serreset al.(1988);deSerres & Brockman(1999)Neurospora crassa, reverse mutation–NT732Dickeyet al.(1949)Neurospora crassa, reverse mutation+NT300Jensenet al.(1951)Neurospora crassa, reverse mutation–NT300Kölmark & Westergaard(1953)Agaricus bisporus, Glycine max, Lycopersicon esculentum,P.americana, Pinus resinosa, Pisum sativum, Populus 

# ×eur-americana, Vicia faba, Zea mays, DNA damage+NT3.7% solution, pH 3and 7, 37 000μg/mLDouglas & Rogers (1998)Plants (other), mutation+NTNGAuerbachet al.(1977)Tradescantia pallida, micronucleus formation+NT250 ppm [250μg/mL], 6 hBatalhaet al. (1999)Drosophila melanogaster, genetic crossing over or recombination+1260Sobels & van Steenis(1957)Drosophila melanogaster, genetic crossing over or recombination+420Alderson (1967)Drosophila melanogaster, genetic crossing over or recombination+2500Ratnayake (1970)Drosophila melanogaster, sex-linked recessive lethal mutations+1000Kaplan (1948)Drosophila melanogaster, sex-linked recessive lethalmutations+1800Auerbach & Moser(1953)Drosophila melanogaster, sex-linked recessive lethal mutations+1260Sobels & van Steenis(1957)Drosophila melanogaster, sex-linked recessive lethal mutations+420Alderson (1967)Drosophila melanogaster, sex-linked recessive lethal mutations+420Khan (1967)Drosophila melanogaster, sex-linked recessive lethal mutations(+)2000Ratnayake (1968)Drosophila melanogaster, sex-linked recessive lethal mutations+250Stumm-Tegethoff (1969) 

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# FORMALDEHYDE 251Table 37 (contd)ResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceDrosophila melanogaster, sex-linked recessive lethal mutations+2200Ratnayake (1970)Drosophila melanogaster, heritable translocation+420Khan (1967)Drosophila melanogaster, heritable translocation+2500Ratnayake (1970)Drosophila melanogaster, dominant lethal mutation+1800Auerbach & Moser(1953)Drosophila melanogaster, dominant lethal mutation+1300Šrám (1970)Caenorhabditis elegans,recessive lethal mutations+700Johnsen & Baillie (1988)DNA strand breaks, DNA–protein cross-links or related damage,mouse leukaemia L1210 cellsin vitro+NT6Ross & Shipley (1980)DNA–protein cross-links, mouse leukaemia L1210 cellsin vitro+NT3.75Rosset al.(1981)DNA single strand breaks, DNA–protein cross-links or relateddamage, sarcoma rat cell linein vitro+NT7.5O’Connor & Fox (1987)DNA single strand breaks or related damage, rat hepatocytesinvitro+NT22.5Demkowicz-Dobrzanski& Castonguay (1992)DNA–protein cross-links, Chinese hamster ovary cellsin vitro+NT7.5Olinet al. (1996)DNA–protein cross-links, male B6C3F1mouse hepatocytesinvitro+NT15Casanovaet al. (1997)DNA–protein cross-links, Chinese hamster V79 lung fibroblastcellsinvitro+NT4Merk & Speit (1998,1999)Unscheduled DNA synthesis, Syrian hamster embryo cellsin vitro+NT3Hamaguchiet al. (2000)Gene mutation, Chinese hamster V79 cells,Hprtlocus+NT9Grafströmet al.(1993)Gene mutation, Chinese hamster V79 cells,Hprtlocus–NT15Merk & Speit (1998,1999)Gene mutation, mouse lymphoma L5178Y cells,Tk+/–locusinvitroNT+24Mackereret al. (1996)Gene mutation, mouse lymphoma L5178Y cellsin vitro+NT> 2Speit & Merk (2002)Sister chromatid exchange, Chinese hamster cellsin vitro+NT1Obe & Beek (1979)Sister chromatid exchange, Chinese hamster cellsin vitro++3.2Natarajanet al.(1983) 

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# IARC MONOGRAPHS VOLUME 88 252Table 37 (contd)ResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceSister chromatid exchange, Chinese hamster cellsin vitro+–2Basleret al.(1985)Sister chromatid exchange, Chinese hamster V79 cellsin vitro+NT4Merk & Speit (1998,1999)Micronucleus formation, Chinese hamster V79 cellsin vitro+NT4Merk & Speit (1998,1999)Chromosomal aberrations, Chinese hamster cellsin vitro+NT18Ishidateet al.(1981)Chromosomal aberrations, Chinese hamster cellsin vitro++6.3Natarajanet al.(1983)Cell transformation, C3H10T1/2 mouse cells+fNT0.5Ragan & Boreiko (1981)DNA single strand breaks, DNA–protein cross-links, humanbronchial cellsin vitro+NT24Fornaceet al.(1982)DNA single strand breaks, DNA–protein cross-links or relateddamage, human bronchial and skin cellsin vitro+NT3Grafströmet al.(1984)DNA single strand breaks, DNA–protein cross-links or relateddamage, human bronchial cellsinvitro+NT3Saladinoet al.(1985)DNA single strand breaks, DNA–protein cross-links or relateddamage, human bronchial cellsin vitro+NT3Grafströmet al.(1986)DNA strand breaks, cross-links or related damage, humanfibroblast cellsin vitro+NT3Snyder & Van Houten(1986)DNA strand breaks, DNA–protein cross-links or related damage,human lymphoblast cellsin vitro+NT1.5Craftet al.(1987)DNA strand breaks, DNA–protein cross-links or related damage,human bronchial cellsin vitro+NT12Grafström (1990)DNA–protein cross-links, human fibroblastsin vitro+NT7.5Olinet al. (1996)DNA–protein cross-links, human white blood cellsin vitro+NT3Shahamet al. (1996)DNA–protein cross-links, EBV-BL human lymphoma cellsin vitro+NT37×18 hCostaet al. (1997) 

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# FORMALDEHYDE 253Table 37 (contd)ResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceDNA double-strand breaks, human lung epithelial (A549) cellsinvitro+NT30 (8, 24, 72 h)Vocket al. (1999)DNA–protein cross-links, Comet assay, human gastric mucosacellsinvitro+NT30Blasiaket al. (2000)DNA–protein cross-links, human lymphocytesin vitro+–3Anderssonet al. (2003)DNA repair exclusive of unscheduled DNA synthesis, humanbronchial and skin cellsinvitro+NT6Grafströmet al.(1984)DNA repair, human MRC5CV1 normal cell line, XP12 ROSVcell line, GMO6914 FA cell line,in vitro+NT3.75Speitet al. (2000)Unscheduled DNA synthesis, human bronchial epithelial cellsinvitro-NT3 (>3 was lethal)Doolittleet al.(1985)Gene mutation, human lymphoblasts TK6 line (TKlocus)in vitro+NT3.9Goldmacher & Thilly(1983)Gene mutation, human fibroblastsin vitro+NT3Grafströmet al.(1985)Gene mutation, human lymphoblastsTK6 line (TKlocus)in vitro+NT0.9Craftet al.(1987)Gene mutation, human lymphoblasts TK6 line (HPRTlocus)invitro+NT4.5, 2 h,×8 timesCrosbyet al.(1988)Gene mutation, human lymphoblasts TK6 line (HPRTlocus)invitro+NT4.5, 2 h,×8 timesLiberet al.(1989)Gene mutation, human bronchial fibroblasts (HPRTlocus)in vitro+NT3Grafström (1990)Sister chromatid exchange, human lymphocytesin vitro+NT5Obe & Beek (1979)Sister chromatid exchange, human lymphocytesin vitro+NT5Kreiger & Garry (1983)Sister chromatid exchange, human lymphocytesin vitro++3.75Schmidet al.(1986)Micronucleus formation, human MRC5CV1 normal cell line,XP12 ROSV cell line, GMO6914 FA cell line,in vitro+NT3.75Speitet al. (2000)Chromosomal aberrations, human fibroblastsin vitro+NT60Levyet al.(1983) 

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# IARC MONOGRAPHS VOLUME 88 254Table 37 (contd)ResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceChromosomal aberrations, human lymphocytesin vitro+NT10Miretskaya & Shvartsman(1982)Chromosomal aberrations,human lymphocytesin vitro++7.5Schmidet al.(1986)Chromosomal aberrations, premature chromosome condensationtechnique, human lymphocytesin vitro+NT3.75Dresp & Bauchinger(1988)DNA–protein cross-links, rat respiratory and olfactory mucosaand bone marrowin vivo+2 ppm [2.5 mg/m3],6hCasanova-Schmitzet al.(1984b)DNA–protein cross-links, rat nasalmucosain vivo+6 ppm [7.4 mg/m3],6hLamet al.(1985)DNA–protein cross-links, rat respiratory mucosain vivo+2 ppm [2.5 mg/m3],3hHecket al.(1986)DNA–protein cross-links, rat respiratory and olfactory mucosaand bone marrowin vivo+2 ppm [2.5 mg/m3],3hCasanova & Heck (1987)DNA–protein cross-links, rat tracheal implant cellsin vivo+50 ppm [50μg/mL],instil.Cosmaet al.(1988)DNA–protein cross-links, rat nasal respiratory mucosain vivo+0.3 ppm [0.4 mg/m3],inhal. 6 hCasanovaet al.(1989)DNA–protein cross-links, rhesus monkey nasal turbinate cellsinvivo+0.7 ppm [0.9 mg/m3],inhal. 6 hHecket al.(1989)DNA–protein cross-links, rhesus monkey nasal turbinate cellsinvivo+0.7 ppm [0.9 mg/m3],inhal. 6 hCasanovaet al.(1991)Gene mutation, rat cellsin vivo(p53point mutations in nasalsquamous-cell carcinomas)+15 ppm [18.45mg/m3], inhal. 6 h/d,5d/wk, 2 yRecioet al.(1992)Mouse spot test–15 ppm [18 mg/m3],inhal. 6 h/d×3Jensen & Cohr (1983)[Abstract] 

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# FORMALDEHYDE 255Table 37 (contd)ResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceSister chromatid exchange, rat cellsin vivo–15 ppm [18.45mg/m3],inhal. 6 h/d×5Kligermanet al.(1984)Micronucleus formation, mouse bone-marrow cellsin vivo–30 ip×1Gockeet al.(1981)Micronucleus formation, mouse bone-marrow cellsin vivo–25 ip×1Natarajanet al.(1983)Micronucleus formation, rat gastrointestinal tractin vivo+200 po×1Miglioreet al.(1989)Micronucleus formation, newt (Pleurodeles waltl)in vivo–5μg/mL, 8 dSibouletet al.(1984)Chromosomal aberrations, mouse bone-marrow cellsin vivo–25 ip×1Natarajanet al.(1983)Chromosomal aberrations, rat bone-marrow cellsin vivo+0.4 ppm [0.5 mg/m3]inhal. 4 h/d, 4 moKitaevaet al.(1990)Chromosomal aberrations, rat bone-marrow cellsin vivo–15 ppm [18.45mg/m3],inhal. 6 h/d×5, 8wkDallaset al.(1992)Chromosomal aberrations, rat leukocytesin vivo–15ppm [18.45 mg/m3],inhal. 6 h/d×5Kligermanet al.(1984)Chromosomal aberrations, mouse spermatocytes treatedin vivo,spermatocytes observed–50 ip×1Fontignie-Houbrechts(1981)Chromosomal aberrations, mouse spleen cellsin vivo–25ip×1Natarajanet al.(1983)Chromosomal aberrations, rat pulmonary lavage cellsin vivo+15 ppm [18.45 mg/m3]inhal. 6 h/d×5Dallaset al.(1992) 

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# IARC MONOGRAPHS VOLUME 88 256Table 37 (contd)ResultaTest systemWithoutexogenousmetabolicsystemWithexogenousmetabolicsystemDoseb(LED/HID)ReferenceDominant lethal mutation, mouse–20 ip×1Epstein & Shafner (1968)Dominant lethal mutation, mouse–20 ip×1Epsteinet al.(1972)Dominant lethal mutation, mouse(+)50 ip×1Fontignie-Houbrechts(1981)Dominant lethal mutation, rat(+)1.2 ppm [1.5 mg/m3]inhal. 4 h/d, 4 moKitaevaet al.(1990)EBV, Epstein–Barr virus; BL, Burkitt lymphoma; XP, xeroderma pigmentosum; FA, Fanconi anaemiaa+, positive; (+) weak positive;–, negative; NT, not tested; ?, inconclusive (variable response in several experiments within an adequate study)bIn-vitro tests,μg/mL; in-vivo tests, mg/kg bw; d, day; inhal., inhalation; instil., instillation; ip, intraperitoneal; mo, month; NG, not given; po, oral;wk, weeks; y,yearcEstimated from the graph in the paperdTested with exogenous metabolic system without co-factorseLED with exogenous metabolic system is 0.33 mM[10μg/mL].fPositiveonly in presence of 12-O-tetradecanoylphorbol 13-acetate 

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# ( 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 wereexamined 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/m 3 

# ] 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 chromosomalaberrations 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 cellsfrom 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/m 3 

# ) every day for 4 h (except for non-working days) for 4 months (Kitaeva et al., 1990). The concentration of 1.5 mg/m 3 

# 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 257 187-272.qxp 13/12/2006 11:53 Page 257

# concentrations (0.5 and 1.5 mg/m 3 

# ) caused a significantly increased number of chromosomal aberrations in the bone marrow that were of the chromatid (at 0.5 mg/m 3 

# ) and chromosomal (at 1.5 mg/m 3 

# ) type. The number of hypoploidal and hyperploidal cells wasincreased. The increase in aneuploidy was due only to chromosomal loss, not to chromosomal gain. At the higher exposure, chromosomal type aberrations were observed. [TheWorking 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/m 3 

# formaldehyde caused a decrease in the mitotic index in bone-marrow cells while, at 1.5 mg/m 3 

# , 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 pSV2 gpt plasmid DNA (Crosby et al.

, 1988). Thirty mutant TK6 X-linked HPRT

– 

# human lymphoblast colonies induced by eight repetitive treatments with 150 μ mol/L [4.5 μ g/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 ofDNA 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 μ g/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 IARC MONOGRAPHS VOLUME 88 258 187-272.qxp 13/12/2006 11:53 Page 258

# 40 mmol/L formaldehyde for 1 h produced 92% point mutations, 62% of which weretransitions at a single AT base-pair in the gene. Therefore, formaldehyde produced different genetic alterations in E. coli at different concentrations. When naked pSV2 gpt plasmid DNA was exposed to 3.3 or 10 mmol/L [99 or 300 μ g/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 μ M [1.9–

15 μ g/mL]). The mouse lymphoma assay detects gross alterations as large deletions andrearrangements. 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 themutagenesis 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-3B R 

# / ad-3A R 

# 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/m 3 

# ] 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 259 187-272.qxp 13/12/2006 11:53 Page 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- αin 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 thatthese 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 formalIARC MONOGRAPHS VOLUME 88 260



# Table 38. DNA sequence analysis of p53 cDNA (PCR fragment D) from squamous-cell carcinomas of nasal passages induced in rats by formaldehyde

DNA

sequence a 

# Mutation (codon) b 

# Equivalent

human p53

codon no. Location in

conserved region

396 

# C → A TTC → TTA (132) phe → leu 134 II

398 

# G → T TG C → TT C (133) cys → phe 135 II

638 

# G → T AG C → AT C (213) ser → ile 215

812 

# G → A CG T → CA T (271) arg → his 273 V

842 

# G → C CG G → CC G (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. 187-272.qxp 13/12/2006 11:53 Page 260

# 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-inducedsquamous-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 μ L 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 samplesfrom four controls and three formaldehyde-treated rats. Significance analysis of microarray hybridization data using Clontech TM 

# 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 andinterruption 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 valueswere 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 oflower levels of expression of nine apoptic genes that represent three of the major apoptosis regulation pathways, including receptor-mediated, caspase and the mitochondrialFORMALDEHYDE 261 187-272.qxp 13/12/2006 11:53 Page 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 areinvolved 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 ofDNA–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 IARC MONOGRAPHS VOLUME 88 262 187-272.qxp 13/12/2006 11:53 Page 262

# 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 uptakein 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 K

m 

# for the initial binding of hydroxymethylglutathione with ADH3 is in the

order of 4 μ M 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–proteincross-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 263 187-272.qxp 13/12/2006 11:53 Page 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 significantlyslower 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 peripherallymphocytes 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 observedin 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/m 3 

# ] 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 [ 3 

# H]- and [ 14 

# C]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 [ 14 

# C]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 [ 14 

# C]formaldehyde (0.7, 2 or 6 ppm [0.9, 2.4 or 7.4 mg/m 3 

# ]) (Casanova et al. , 1991). The concentrations of cross-linked formaldehyde in the nose of monkeys decreased in the order: middle IARC MONOGRAPHS VOLUME 88 264 187-272.qxp 13/12/2006 11:53 Page 264

# 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/m 3 

# ]) 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 (CH 2 

# O)

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. 187-272.qxp 13/12/2006 11:53 Page 265

# 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/m 3 

# ], necrosis and sloughing of respiratory epithelium was evident immediately after a single6-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/m 3 

# ] 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). IARC MONOGRAPHS VOLUME 88 266 187-272.qxp 13/12/2006 11:53 Page 266

# 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 informationon 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, althoughthere 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 followingexposure 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 267 187-272.qxp 13/12/2006 11:53 Page 267

# 4.5.6 Computational dose–response modelling

A theoretical model for DNA replication in the presence of DNA cross-links wasdeveloped 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/m 3 

# ] formaldehyde. A biologically based model of carcinogenesis of formaldehyde was described byConolly (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 thethreshold 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 uncertaintyremains 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. IARC MONOGRAPHS VOLUME 88 268 187-272.qxp 13/12/2006 11:53 Page 268

# 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 μ g/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 μ g/mL], although it does not appear to be associated with oxidative stress. Formaldehyde inhibits cell growth at 0.2 mM [6 μ g/mL] and 0.6 mM FORMALDEHYDE 269 187-272.qxp 13/12/2006 11:53 Page 269

# [18 μ g/mL], as expressed by loss of clonal growth rate and colony-forming efficiency, respectively. It alters membrane integrity, which leads to increases in cellular Ca 2+ 

# 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 byHPLC. 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 thecarcinogenesis of formaldehyde in nasal tissues. DNA–protein cross-links provide a potentially useful marker of genotoxicity. The concentration–response curve for the formation ofDNA–protein cross-links is bi-phasic, and the slope increases at concentrations of formaldehyde of about 2–3 ppm [2.5–3.7 mg/m 3 

# ] in Fischer 344 rats. Similar results have been IARC MONOGRAPHS VOLUME 88 270 187-272.qxp 13/12/2006 11:53 Page 270

# 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/m 3 

# ], 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 maydemonstrate 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/m 3 

# ] (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 possibilitythat 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 187-272.qxp 13/12/2006 11:53 Page 271

# 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/m 3 

# ] 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/m 3 

# ] (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/m 3 

# ], respectively (Casanova-Schmitz et al. , 1984b; Heck et al. , 1989). Known human myeloid leukaemogens include ionizing radiation, benzene andchemotherapeutic 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. IARC MONOGRAPHS VOLUME 88 272 187-272.qxp 13/12/2006 11:53 Page 272

# [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/m 3 

# ] 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/m 3 

# 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, paintsand 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/m 3 

# in remote areas and below 0.02 mg/m 3 

# in urban settings. The levels of formaldehyde in the indoor air of houses are typically 0.02–0.06 mg/m 3 

# . Average levels of 0.5 mg/m 3 

# or more have been measured in ‘mobile homes’, but these have declined since the late 1980s as a result of standards that require that building materials emit lower concentrations of formaldehyde. FORMALDEHYDE 273 273-328.qxp 13/12/2006 12:02 Page 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 particularlyfrom 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 ofseven studies of professional workers (i.e. embalmers, funeral parlour workers, pathologists and anatomists). A recently published meta-analysis of exposure to formaldehydeamong 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 IARC MONOGRAPHS VOLUME 88 274 273-328.qxp 13/12/2006 12:02 Page 274

# 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 formaldehydeand 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 thechoice 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 mortalityamong 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 275 273-328.qxp 13/12/2006 12:02 Page 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 datafrom 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 ofcumulative 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 wasfound 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 effecton 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 studiesmight 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 IARC MONOGRAPHS VOLUME 88 276 273-328.qxp 13/12/2006 12:02 Page 276

# 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 ofhaemolymphoreticular 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 byinhalation 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 betweenindividuals. No significant changes in urinary formate were detected in humans after exposure to 0.5 ppm [0.6 mg/m 3 

# ] formaldehyde for up to 3 weeks. More than 90% of inhaled FORMALDEHYDE 277 273-328.qxp 13/12/2006 12:02 Page 277

# formaldehyde is absorbed in the upper respiratory tract. In rats, it is absorbed almost entirelyin 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 andcarbon 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 [ 14 

# C]formaldehyde eliminated about 40% of the 14 

# C 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 [ 14 

# C]formaldehyde, approximately7% of the dose was excreted in the urine by rodents and 0.2% by monkeys. After oral administration, about 40% of [ 14 

# C]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 becomeincreasingly prevalent in studies in exposure chambers as concentrations increase. Exposures to up to 3 ppm [3.7 mg/m 3 

# ] 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/m 3 

# 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 thereactions 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 reactionsby 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, asmeasured 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. IARC MONOGRAPHS VOLUME 88 278 273-328.qxp 13/12/2006 12:02 Page 278

# 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 Ca 2+ 

# -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 thesestudies included spontaneous abortions, congenital malformations, birth weights, infertility and endometriosis. Inconsistent reports of higher rates of spontaneous abortion andlowered 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 theformation 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/m 3 

# ] 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/m 3 

# ], and results in a marked increase in the occurrence of malignant lesions in the nasal passages of rats at concentrations above this level. FORMALDEHYDE 279 273-328.qxp 13/12/2006 12:02 Page 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

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Impeded lung function in moulders and coremakers handling furan resin sand. Int. Arch. occup. environ. Health

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