canadian environmental protection act, 1999...environment from natural sources (including forest...

Environment EnvironnementCanada Canada

Health SantéCanada Canada

PRIORITY SUBSTANCES LIST ASSESSMENT REPORT

Canadian EnvironmentalProtection Act, 1999

Formaldehyde

© Minister of Public Works and Government Services Canada 2001

Canadian Cataloguing in Publication Data

Formaldehyde

(Priority substances list assessment report)Issued also in French under title: Formaldéhyde.At head of title: Canadian Environmental Protection Act, 1999.Co-published by Health Canada.Includes bibliographical references.Issued also on the Internet.ISBN 0-662-29447-5Cat. no. En40-215/61E

1. Formaldehyde – Toxicology – Canada.2. Formaldehyde – Environmental aspects – Canada.3. Environmental monitoring – Canada.I. Canada. Environment Canada.II. Canada. Health Canada.III. Series.

TD196.F65F65 2000 363.738'4 C00-980493-5

Additional information can be obtained at Environment Canada’s Web site atwww.ec.gc.ca or at the Inquiry Centre at 1-800-668-6767.

Canadian Environmental Protection Act, 1999

PRIORITY SUBSTANCES LIST ASSESSMENT REPORT

Formaldehyde

Environment CanadaHealth Canada

February 2001

TABLE OF CONTENTS

SYNOPSIS ..................................................................................................................1

1.0 INTRODUCTION ..............................................................................................3

2.0 SUMMARY OF INFORMATION CRITICAL TO ASSESSMENT OF “TOXIC” UNDER CEPA 1999 ......................................................................................7

2.1 Identity and physical/chemical properties............................................7

2.2 Entry characterization ..........................................................................72.2.1 Production, importation, exportation and use....................................72.2.2 Sources and releases ..........................................................................9

2.2.2.1 Natural sources ................................................................92.2.2.2 Anthropogenic sources ....................................................92.2.2.3 Secondary formation......................................................11

2.3 Exposure characterization ..................................................................112.3.1 Environmental fate ............................................................................11

2.3.1.1 Air ..................................................................................112.3.1.2 Water..............................................................................122.3.1.3 Sediment ........................................................................132.3.1.4 Soil ................................................................................132.3.1.5 Biota ..............................................................................132.3.1.6 Environmental distribution............................................13

2.3.2 Environmental concentrations ..........................................................132.3.2.1 Air..................................................................................13

2.3.2.1.1 Ambient air ..................................................132.3.2.1.2 Indoor air ....................................................14

2.3.2.2 Water..............................................................................152.3.2.2.1 Drinking water ............................................152.3.2.2.2 Surface water ..............................................152.3.2.2.3 Effluent ........................................................162.3.2.2.4 Groundwater ................................................162.3.2.2.5 Atmospheric water ......................................16

2.3.2.3 Sediment ........................................................................172.3.2.4 Soil ................................................................................172.3.2.5 Biota ..............................................................................172.3.2.6 Food ..............................................................................172.3.2.7 Consumer products........................................................182.3.2.8 Clothing and fabrics ......................................................192.3.2.9 Building materials ........................................................20

PSL ASSESSMENT REPORT — FORMALDEHYDE iii

2.4 Effects characterization ......................................................................212.4.1 Ecotoxicology....................................................................................21

2.4.1.1 Terrestrial organisms ....................................................212.4.1.2 Aquatic organisms ........................................................22

2.4.2 Abiotic atmospheric effects ..............................................................232.4.3 Experimental animals and in vitro ..................................................24

2.4.3.1 Acute toxicity ................................................................242.4.3.2 Short-term and subchronic toxicity ..............................29

2.4.3.2.1 Inhalation ....................................................292.4.3.2.2 Oral exposure ..............................................29

2.4.3.3 Chronic toxicity and carcinogenicity ............................292.4.3.3.1 Chronic toxicity............................................292.4.3.3.2 Carcinogenicity ............................................29

2.4.3.4 Genotoxicity and related endpoints ..............................322.4.3.5 Reproductive and developmental toxicity ....................352.4.3.6 Immunological and neurological effects ......................352.4.3.7 Toxicokinetics/metabolism and mode of

carcinogenesis................................................................352.4.4 Humans ............................................................................................37

2.4.4.1 Case reports and clinical studies ..................................372.4.4.2 Epidemiological studies ................................................37

2.4.4.2.1 Cancer..........................................................372.4.4.2.2 Genotoxicity ................................................452.4.4.2.3 Respiratory irritancy and function ..............452.4.4.2.4 Immunological effects ..................................472.4.4.2.5 Other effects ................................................48

3.0 ASSESSMENT OF “TOXIC” UNDER CEPA 1999 ..........................................49

3.1 CEPA 1999 64(a): Environment ..........................................................493.1.1 Assessment endpoints ........................................................................49

3.1.1.1 Terrestrial ......................................................................493.1.1.2 Aquatic ..........................................................................50

3.1.2 Environmental risk characterization ................................................503.1.2.1 Terrestrial organisms ....................................................50

3.1.2.1.1 Hyperconservative analysis ........................503.1.2.1.2 Conservative analysis ..................................51

3.1.2.2 Aquatic organisms ........................................................543.1.2.2.1 Hyperconservative analysis ........................543.1.2.2.2 Conservative analysis ..................................55

3.1.2.3 Discussion of uncertainty ..............................................56

3.2 CEPA 1999 64(b): Environment upon which life depends ..............57

PSL ASSESSMENT REPORT — FORMALDEHYDEiv

3.3 CEPA 1999 64(c): Human health ......................................................................573.3.1 Estimated population exposure ........................................................573.3.2 Hazard characterization ..................................................................60

3.3.2.1 Genotoxicity and carcinogenicity..................................613.3.2.1.1 Genotoxicity ................................................613.3.2.1.2 Carcinogenicity ............................................61

3.3.2.2 Non-neoplastic effects ..................................................633.3.3 Exposure–response analysis..............................................................64

3.3.3.1 Inhalation ......................................................................653.3.3.1.1 Carcinogenicity ............................................653.3.3.1.2 Non-neoplastic effects ..................................69

3.3.3.2 Oral exposure ................................................................703.3.4 Human health risk characterization ................................................703.3.5 Uncertainties and degree of confidence in

human health risk characterization ..................................................71

3.4 Conclusions ............................................................................................73

3.5 Considerations for follow-up (further action)....................................74

4.0 REFERENCES ................................................................................................75

APPENDIX A SEARCH STRATEGIES EMPLOYED FOR IDENTIFICATION OF

RELEVANT DATA..............................................................................101

PSL ASSESSMENT REPORT — FORMALDEHYDE v

vi

LIST OF TABLES

TABLE 1 Physical and chemical properties of formaldehyde reported in literature.................8

TABLE 2 Summary of non-neoplastic effect levels (inhalation) for formaldehyde................25

TABLE 3 Summary of non-neoplastic effect levels (oral exposure) for formaldehyde..........28

TABLE 4 Comparative effects of formaldehyde exposure upon cell proliferation, DNA–protein crosslinking and tumour incidence ...................................................34

TABLE 5 Summary of risk measures from case–control studies ............................................38

TABLE 6 Summary of risk measures from cohort studies ......................................................40

TABLE 7 Summary of the environmental risk analysis for terrestrial organisms...................53

TABLE 8 Summary of the environmental risk analysis for aquatic organisms.......................56

TABLE 9 Concentrations of formaldehyde in outdoor air and residential indoor air in Canada .................................................................................................................58

TABLE 10 Probabilistic estimates of 24-hour time-weighted average concentrations of formaldehyde in air ..................................................................................................60

LIST OF FIGURES

FIGURE 1 Formaldehyde carcinogenicity.................................................................................30

FIGURE 2 Two-stage clonal growth model...............................................................................66

FIGURE 3 Roadmap for the rat clonal growth model ...............................................................67

FIGURE 4 Roadmap for the human clonal growth model ........................................................68

PSL ASSESSMENT REPORT — FORMALDEHYDE

LIST OF ACRONYMS AND ABBREVIATIONS

CAS Chemical Abstracts ServiceCEPA Canadian Environmental Protection ActCEPA 1999 Canadian Environmental Protection Act, 1999CFD computational fluid dynamicsCI confidence intervalCIIT Chemical Industry Institute of ToxicologyCTV Critical Toxicity ValueDPX DNA–protein crosslinkingEEV Estimated Exposure ValueENEV Estimated No-Effects ValueEPA Environmental Protection AgencyETS environmental tobacco smokeGWP Global Warming Potentialkg-bw kilogram body weightKaw air/water partition coefficientKoc organic carbon/water partition coefficientKow octanol/water partition coefficientLCL lower confidence limitLOEC Lowest-Observed-Effect ConcentrationMDF medium-density fibreboardMIR maximum incremental reactivityMS mainstreamNAPS National Air Pollution SurveillanceNOEC No-Observed-Effect ConcentrationNOEL No-Observed-Effect LevelNOX nitrogen oxidesNPRI National Pollutant Release InventoryODP Ozone Depletion PotentialOR odds ratioPEFR peak expiratory flow ratePMR proportionate mortality ratioPOCP Photochemical Ozone Creation PotentialPSL Priority Substances ListRR relative riskSIR standardized incidence ratioSMR standardized mortality ratioSPIR standardized proportionate incidence ratio SS sidestream

PSL ASSESSMENT REPORT — FORMALDEHYDE vii

TC Tolerable ConcentrationTC05 tumorigenic concentration associated with a 5% increase in tumour

incidence over backgroundUF urea-formaldehydeUFFI urea-formaldehyde foam insulationVOC volatile organic compound

PSL ASSESSMENT REPORT — FORMALDEHYDEviii

In Canada, formaldehyde is used primarily inthe production of resins and fertilizers and for avariety of minor uses. The Canadian domesticdemand for formaldehyde was 191 000 tonnesin 1996.

Formaldehyde enters the Canadianenvironment from natural sources (includingforest fires) and from direct human sources, suchas automotive and other fuel combustion andindustrial on-site uses. Secondary formationalso occurs, by the oxidation of natural andanthropogenic organic compounds present inair. Although there are no quantitative estimates,releases from natural and secondary sourcesin Canada are likely greater than direct humanreleases. However, the highest concentrationsmeasured in the environment occur nearanthropogenic sources; these are of prime concernfor the exposure of humans and other biota.Motor vehicles, the largest direct human sourceof formaldehyde in the Canadian environment,released an estimated 11 284 tonnes into the airin 1997. The amount of formaldehyde releasedinto the Canadian environment from industrialprocesses was 1424 tonnes in 1997.

When formaldehyde is released to orformed in air, most of it will undergo variousdegradation processes in air, and a very smallamount will move into water. When formaldehydeis released into water, it does not move intoother media but is broken down in the water.Formaldehyde does not persist in the environment,but its continuous release and formation canresult in chronic exposure of biota near sourcesof release and formation.

Extensive recent data are available forconcentrations of formaldehyde in air at industrial,urban, suburban, rural and remote locations inCanada. Data for concentrations in water arelimited to surface water from four rivers, effluentsfrom industrial plants and groundwater from three

industrial sites and six cemeteries. Environmentaltoxicity data are available for a wide range ofterrestrial and aquatic organisms.

Based on the maximum concentrationsmeasured in air, surface water, effluents andgroundwater in Canada, and on the Estimated No-Effects Values derived from experimental data forterrestrial and aquatic biota, formaldehyde is notlikely to cause adverse effects on terrestrial oraquatic organisms.

Formaldehyde is not involved in thedepletion of stratospheric ozone or in climatechange. Because of its photoreactivity and itsrelatively high concentrations in Canadian cities,formaldehyde plays a role in the photochemicalformation of ground-level ozone.

Critical health effects in mammalsassociated with exposure to formaldehyde occurprimarily at the site of first contact (i.e., therespiratory tract following inhalation and thegastrointestinal tract following ingestion) and arerelated to concentration in the relevant medium,rather than to total intake. The focus of the humanhealth assessment is airborne exposure, dueprimarily to the lack of representative data onconcentrations in media other than air and limiteddata on effects following ingestion.

Sensory irritation of the eyes andrespiratory tract by formaldehyde has beenobserved consistently in clinical studies andepidemiological surveys in occupational andresidential environments. At concentrations higherthan those generally associated with sensoryirritation, formaldehyde may also contribute tothe induction of generally small, reversible effectson lung function.

Following inhalation in laboratoryanimals, formaldehyde causes degenerative non-neoplastic effects and nasal tumours in rats.

PSL ASSESSMENT REPORT — FORMALDEHYDE 1

SYNOPSIS

PSL ASSESSMENT REPORT — FORMALDEHYDE2

Both sustained cellular proliferation andinteraction with genetic material likely contributeto induction of these tumours, and, under similarconditions, formaldehyde is considered to presenta carcinogenic hazard to humans.

The majority of the population is exposedto airborne concentrations of formaldehyde lessthan those associated with sensory irritation.However, in some indoor locations, concentrationsmay approach those associated with eye andrespiratory tract sensory irritation in humans.Based on comparison of risks of cancer estimatedon the basis of a biologically motivated case-specific model with calculated exposure in air ofthe general population in Canada, priority forinvestigation of options to reduce exposure on thebasis of carcinogenicity is considered to be low.

Based on the information available,it is concluded that formaldehyde is not enteringthe Canadian environment in a quantity orconcentration or under conditions that have ormay have an immediate or long-term harmfuleffect on the environment or its biologicaldiversity. Formaldehyde is entering theCanadian environment in a quantity orconcentration or under conditions that constituteor may constitute a danger to the environmenton which life depends and a danger in Canadato human life or health. Therefore, formaldehydeis considered “toxic” as defined in Section 64 ofthe Canadian Environmental Protection Act, 1999(CEPA 1999).

Formaldehyde contributes to thephotochemical formation of ground-level ozone. Itis recommended that key sources of formaldehydebe addressed, therefore, as part of managementplans for volatile organic chemicals that contributeto the formation of ground-level ozone. Whileindications are that concentrations currently in airand water are not causing environmental harm tobiota, continued and improved monitoring at siteslikely to release formaldehyde is desirable, notablywith regards to industrial uses for resins and forfertilizers as well as releases from pulp and papermills.

It is also recommended that continuedinvestigation of options to reduce exposure toformaldehyde in indoor air be considered underthe authority of acts other than CEPA 1999 aspart of an overall program to reduce exposure toother aldehydes (e.g., acrolein, acetaldehyde) inindoor air deemed to be “toxic” under Paragraph64(c) of CEPA 1999.

The Canadian Environmental Protection Act, 1999(CEPA 1999) requires the federal Ministers of theEnvironment and of Health to prepare and publisha Priority Substances List (PSL) that identifiessubstances, including chemicals, groups ofchemicals, effluents and wastes, that may beharmful to the environment or constitute a dangerto human health. The Act also requires bothMinisters to assess these substances and determinewhether they are “toxic” or capable of becoming“toxic” as defined in Section 64 of the Act, whichstates:

... a substance is toxic if it is entering or may enterthe environment in a quantity or concentrationor under conditions that

(a) have or may have an immediate or long-termharmful effect on the environment or itsbiological diversity;

(b) constitute or may constitute a danger tothe environment on which life depends; or

(c) constitute or may constitute a danger inCanada to human life or health.

Substances that are assessed as “toxic” asdefined in Section 64 may be placed on ScheduleI of the Act and considered for possible riskmanagement measures, such as regulations,guidelines, pollution prevention plans or codes ofpractice to control any aspect of their life cycle,from the research and development stage throughmanufacture, use, storage, transport and ultimatedisposal.

Based on an initial screening of readilyaccessible information, the rationale for assessingformaldehyde provided by the Ministers’ ExpertAdvisory Panel on the Second Priority SubstancesList (Ministers’ Expert Advisory Panel, 1995) wasas follows:

Canadians are exposed to formaldehyde through itsproduction; its use in the production of resins; inautomobile exhaust and cigarette smoke; andthrough the “off-gassing” of building materials andconsumer products including cosmetics andhousehold cleaning agents. Toxicological effects in

animals and humans have been observed at levelssimilar to the concentrations to which the generalpopulation may be exposed. Formaldehyde isgenotoxic and carcinogenic in rodents and may becarcinogenic in humans. An assessment is neededto determine the potential risk to human health.

Descriptions of the approaches toassessment of the effects of Priority Substanceson the environment and human health areavailable in published companion documents.The document entitled “EnvironmentalAssessments of Priority Substances underthe Canadian Environmental Protection Act.Guidance Manual Version 1.0 — March 1997”(Environment Canada, 1997a) provides guidancefor conducting environmental assessments ofPriority Substances in Canada. This documentmay be purchased from:

Environmental Protection Publications Environmental Technology Advancement

Directorate Environment Canada Ottawa, Ontario K1A 0H3

It is also available on the Commercial ChemicalsEvaluation Branch web site at www.ec.gc.ca/cceb1/ese/eng/esehome.htm under the heading“Guidance Manual.” It should be noted thatthe approach outlined therein has evolved toincorporate recent developments in risk assessmentmethodology that will be addressed in futurereleases of the guidance manual for environmentalassessments of Priority Substances.

The approach to assessment of effectson human health is outlined in the followingpublication of the Environmental HealthDirectorate of Health Canada: “CanadianEnvironmental Protection Act — Human HealthRisk Assessment for Priority Substances” (HealthCanada, 1994), copies of which are availablefrom:


1.0 INTRODUCTION

Environmental Health CentreRoom 104Health CanadaTunney’s PastureOttawa, Ontario K1A 0L2

or on the Environmental Health Directoratepublications web site (www.hc-sc.gc.ca/ehp/ehd/catalogue/bch.htm). The approach is alsodescribed in an article published in the Journal of Environmental Science and Health —Environmental Carcinogenesis & EcotoxicologyReviews (Meek et al., 1994). It should be notedthat the approach outlined therein has evolved to incorporate recent developments in riskassessment methodology, which are described onthe Environmental Substances Division web site(www.hc-sc.gc.ca/ehp/ehd/bch/env_contaminants/psap/psap.htm) and which will be addressed infuture releases of the approach paper for theassessment of effects on human health.

The search strategies employed in theidentification of data relevant to assessment ofpotential effects on the environment (prior toDecember 1999) and human health (prior toJanuary 1999) are presented in Appendix A.Available Canadian data on sources, use patternsand fate of formaldehyde in the environment havebeen emphasized. In supporting documentationfor this assessment, a report on the health effectsof formaldehyde prepared previously by theBureau of Chemical Hazards, Health Canada(BCH, 1988), was updated. This was based, inpart, on a background report compiled by BIBRAToxicology International (BIBRA, 1994). Reviewarticles were consulted where appropriate.However, all original studies that form the basisfor determining whether formaldehyde is “toxic”under CEPA 1999 have been critically evaluatedby staff of Environment Canada (entry andenvironmental exposure and effects) and HealthCanada (human exposure and effects on humanhealth).

An Environmental Resource Group wasestablished by Environment Canada to assist inthe preparation of the environmental assessment.Members participated in the preparation andreview of the environmental sections of theAssessment Report and the environmentalsupporting document (Environment Canada,1999a). Members included:

G. Bird, Natural Resources CanadaB. Brownlee, Environment CanadaN. Bunce, University of GuelphR. Chénier, Environment CanadaT. Currah, OxyChem DurezT. Dann, Environment CanadaE. Dowdall, Environment CanadaF. Edgecomb, Canadian Plastics Industry

AssociationM. Eggleton, Environment CanadaG. Granville, Shell Canada LimitedL. Kamboj, MonsantoR. Keefe, Imperial Oil LimitedG. Rideout, Environment CanadaA. Stelzig, Environment CanadaM. Tushingham, Environment CanadaJ. Wittwer, Environment Canada

The environmental assessment was led byR. Chénier and coordinated by A. Bobra(AMBEC Environmental Consultants) onbehalf of Environment Canada.

The sections of the Assessment Reportrelevant to the environmental assessment and theenvironmental supporting document werereviewed by members of the EnvironmentalResource Group, as well as by A. Day (CelaneseCanada Inc.), D. Mackay (University of Toronto)and P. Makar (Environment Canada).

The content of the health-related sectionsof this Assessment Report and the supportingdocumentation (Health Canada, 1999, 2000) wasprepared by the following staff of Health Canada:

R. BeauchampR.G. Liteplo M.E. Meek


M. Walker and J. Zielenski, Divisionof Biostatistics and Research Coordination,Health Canada, and D. Blakey and G. Douglas,Environmental and Occupational ToxicologyDivision, Health Canada, contributed to thepreparation of sections on dose–response analysesfor cancer and genotoxicity, respectively.

In the first stage of external review,background sections of the supportingdocumentation pertaining to human health werereviewed primarily to address adequacy ofcoverage. Written comments were provided byJ. Acquavella (Monsanto Company), S. Felter(Toxicology Excellence for Risk Assessment),O. Hernandez (U.S. Environmental ProtectionAgency [EPA]), R. Keefe (Imperial Oil Limited),N. Krivanek (Dupont Haskell Laboratory),J. Martin (consultant) and F. Miller (ChemicalIndustry Institute of Toxicology [CIIT])(June 1997).

In 1996, a government–private SteeringCommittee was formed in the United States todevelop a model for dose–response analyses forformaldehyde that takes into account as muchof the biological database on formaldehyde aspossible. This partnership involved primarily theCIIT and the U.S. EPA. Toxicology Excellencefor Risk Assessment, commissioned by theFormaldehyde Epidemiology, Toxicology, andEnvironmental Group, Inc., also participated,preparing sections of draft documentation relatedto hazard assessment. Health Canada joined thispartnership later, contributing by organizing,in collaboration with the U.S. EPA, an externalpeer review workshop and revising somesections of the draft documentation related tohazard assessment (in particular, those addressingepidemiological data).

The product of this joint effort was adraft document entitled “Formaldehyde: HazardCharacterization and Dose–Response Assessmentfor Carcinogenicity by the Route of Inhalation”(CIIT, 1999). This report, which was developedprimarily by CIIT (with input from J. Overton,U.S. EPA), was reviewed at an external peer

review workshop of the following invitees,convened by Health Canada and the U.S. EPA onMarch 18–20, 1998, in Ottawa, Ontario (HealthCanada, 1998):

B. Allen, RAS AssociatesM. Andersen, ICF Kaiser Engineering

(Chair)D. Blakey, Health CanadaA. Dahl, Lovelace Respiratory Research

InstituteD. Gaylor, U.S. Food and Drug

AdministrationJ. Harkema, Michigan State UniversityD. Jacobson-Kram, MA BioServicesD. Krewski, Health CanadaR. Maronpot, National Institute of

Environmental Health SciencesG. Marsh, University of PittsburghJ. Siemiatycki, Institut Armand-FrappierJ. Ultman, Pennsylvania State University

Written comments were also provided byS. Moolgavkar (Fred Hutchinson Cancer ResearchCenter).

Following the workshop, the reportwas revised to reflect comments of the externalreviewers and recirculated; written commentson the subsequently revised draft were submittedby all members of the external review panel(November 1998). The final draft (datedSeptember 28, 1999) (CIIT, 1999) was reviewedby the Chair of the workshop (M. Andersen)to ensure that comments had been adequatelyaddressed (Andersen, 1999).

In this assessment, the outcome of thiscollaborative exercise and additional data on non-cancer effects and routes of exposure otherthan ingestion have been considered in the contextof the approach to assessment of “toxic” underParagraph 64(c) of CEPA 1999.

R. Vincent, Environmental ToxicologyDivision, Health Canada, provided comments onthe Assessment Report. Accuracy of reporting,adequacy of coverage and defensibility of



conclusions with respect to hazardcharacterization and dose–response analyseswere considered in written review byM. Andersen (Colorado State University),V. Feron, (TNO-Nutrition and Food ResearchInstitute) and J. Swenberg (University ofNorth Carolina).

The health-related sections of theAssessment Report were reviewed and approvedby the Healthy Environments and ConsumerSafety Branch Risk Management meeting ofHealth Canada.

The entire Assessment Report wasreviewed and approved by the EnvironmentCanada/Health Canada CEPA ManagementCommittee.

A draft of the Assessment Report wasmade available for a 60-day public commentperiod (July 22 to September 20, 2000)(Environment Canada and Health Canada, 2000).Following consideration of comments received,the Assessment Report was revised as appropriate.A summary of the comments and responses isavailable on the Internet at:

www.ec.gc.ca/cceb1/eng/final/index_e.html

The text of the Assessment Report hasbeen structured to address environmental effectsinitially (relevant to determination of “toxic”under Paragraphs 64(a) and (b)), followed byeffects on human health (relevant to determinationof “toxic” under Paragraph 64(c)).

Copies of this Assessment Report areavailable upon request from:

Inquiry CentreEnvironment CanadaMain Floor, Place Vincent Massey351 St. Joseph Blvd.Hull, QuebecK1A 0H3

or on the Internet at:www.ec.gc.ca/cceb1/eng/final/index_e.html

Unpublished supporting documentationon the environmental assessment (EnvironmentCanada, 1999a) or health assessment (BCH, 1988;Health Canada, 1998, 1999, 2000; Andersen,1999; CIIT, 1999), which presents additionalinformation, is available upon request from:

Commercial Chemicals EvaluationBranch

Environment Canada14th Floor, Place Vincent Massey351 St. Joseph Blvd.Hull, QuebecK1A 0H3

or

Environmental Health CentreRoom 104Health CanadaTunney’s PastureOttawa, OntarioK1A 0L2

2.1 Identity and physical/chemicalproperties

Pure formaldehyde is also known as methanal,methylene oxide, oxymethylene, methylaldehyde,oxomethane, formic aldehyde and methyleneglycol. Its Chemical Abstracts Service (CAS)number is 50-00-0. The molecular formula isCH2O.

At room temperature, formaldehyde isa colourless gas with a pungent, irritating odour.It is highly reactive, readily undergoespolymerization, is highly flammable and canform explosive mixtures in air. It decomposesat temperatures above 150°C. Formaldehyde isreadily soluble in water, alcohols and other polarsolvents. In aqueous solutions, formaldehydehydrates and polymerizes and can exist asmethylene glycol, polyoxymethylene andhemiformals. Solutions with high concentrations(>30%) of formaldehyde become turbid as thepolymer precipitates (WHO, 1989). As a reactivealdehyde, formaldehyde can undergo a numberof self-association reactions, and it can associatewith water to form a variety of chemical specieswith properties different from those of the puremonomolecular substance. These associationstend to be most prevalent at high concentrationsof formaldehyde, when molecules have anincreased opportunity to associate with otherlike species. Partition coefficients of mostpure organic substances such as benzene orhexane reflect the properties of the individualmonomolecular species at all concentrations —namely, they do not self-associate. This is notthe case for formaldehyde, and it is thereforenot advisable to use property data at highconcentrations to estimate properties under diluteconditions. For example, the common practiceof calculating the air/water partition coefficient(Kaw) from solubility and vapour pressure can be

invalid for substances such as formaldehyde.The most environmentally relevant andmeaningful properties, such as the octanol/waterpartition coefficient (Kow), Kaw, the organiccarbon/water partition coefficient (Koc), etc.,should be measured at low concentrations.Extrapolation from concentrations exceedingpercent levels should be avoided, and thus anyuse of structure–property relationships and inter-property correlations (such as Kow and solubility)should be examined critically for validity (Bobraand Mackay, 1999).

Values reported for the physical andchemical properties of formaldehyde are given inTable 1.

Pure formaldehyde is not availablecommercially but is sold as 30–50% (by weight)aqueous solutions. Formalin (37% CH2O) isthe most common solution. Methanol or othersubstances are usually added to the solution asstabilizers to reduce the intrinsic polymerizationof formaldehyde (WHO, 1989; EnvironmentCanada, 1995). In solid form, formaldehydeis marketed as trioxane, (CH2O)3 , and itspolymer paraformaldehyde, with 8–100 unitsof formaldehyde (WHO, 1989).

2.2 Entry characterization

2.2.1 Production, importation, exportationand use

Formaldehyde is produced commercially by thecatalytic air oxidation of methanol (EnvironmentCanada, 1985; Kroschwitz, 1991). In Canada,about 222 000 tonnes of formaldehydewere produced in 1996. In the same year,approximately 7600 tonnes of formaldehydewere imported, and more than 30 000 tonnes of


2.0 SUMMARY OF INFORMATION CRITICAL TO

ASSESSMENT OF “TOXIC” UNDER CEPA 1999

formaldehyde were exported (EnvironmentCanada, 1997c).

Total Canadian domestic consumptionof formaldehyde was reported at about 191 000tonnes for 1996 (Environment Canada, 1997c).Formaldehyde is used predominantly in thesynthesis of resins, with urea-formaldehyde(UF) resins, phenolic-formaldehyde resins,pentaerythritol and other resins accounting forabout 92% of Canadian consumption. About 6%of uses were related to fertilizer production, while2% was used for various other purposes, such aspreservatives and disinfectants (EnvironmentCanada, 1997c). Formaldehyde can be used ina variety of industries, including the medical,detergent, cosmetic, food, rubber, fertilizer,metal, wood, leather, petroleum and agriculturalindustries (WHO, 1989), and as a hydrogensulfide scavenger in oil operations (Tiemstra,1989).

In Canada, formaldehyde is acceptablefor use in non-aerosol cosmetics provided theconcentration does not exceed 0.2% (BND, 1994).Formaldehyde is included in the Cosmetic

Notification Hot List maintained by HealthCanada’s Product Safety Bureau with therecommendation to limit its concentration incosmetics to less than 0.3%, except for fingernailhardeners, for which a maximum concentrationof 5% applies (Richardson, 1999).

Approximately 80% of the slow-releasefertilizer market is based on UF-containingproducts (ATSDR, 1999; HSDB, 1999).

In the agriculture industry, formaldehydehas been used as a fumigant, as a preventative formildew and spelt in wheat and for rot in oats. Ithas also been used as a germicide and fungicidefor plants and vegetables and as an insecticide fordestroying flies and other insects. In Canada,there are currently 59 pest control productscontaining formaldehyde registered under the PestControl Products Act. Formaldehyde is present asa formulant in 56 of these products, atconcentrations ranging from 0.002% to 1% byweight. Formaldehyde is an active ingredientin the remaining three products, at concentrationsranging from 2.3% to 37% in the commerciallyavailable products (Moore, 2000). Pesticidal uses


TABLE 1 Physical and chemical properties of formaldehyde reported in literature 1

Property Range of reported values 2

Molecular weight (g/mol) 30.03Melting point (°C) –118 to –92Boiling point (°C, 101.3 kPa) –21 to –19 Vapour pressure (calculated) (Pa, at 25°C) 516 000Water solubility (mg/L, at 25°C) 3 400 000 to 550 000 Henry’s law constant (Pa·m3/mol, 25°C) 2.2 × 10–2 to 3.4 × 10–2

Log octanol/water partition coefficient (log Kow) –0.75 to 0.35Log organic carbon/water partition coefficient (log Koc) 0.70 to 1.57

1 Because of polymerization and other reactions, care should be taken in interpreting or using reported values. See also text. 2 Includes experimental and calculated values from Hansch and Leo (1979, 1981); Karickhoff et al. (1979); Kenaga and Goring

(1980); Weast (1982–1983); Verschueren (1983); Perry and Green (1984); Dean (1985); U.S. EPA (1985); Betterton andHoffmann (1988); Deneer et al. (1988); Howard (1989); Sangster (1989); Zhou and Mopper (1990); Mackay et al. (1995);Staudinger and Roberts (1996).

3 Water solubility of a chemical is defined as the maximum amount of the chemical that will dissolve in water at a specifiedtemperature, pressure and pH. Results such as 1 220 000 mg/L (Dean, 1985) and 1.0 × 108 mg/L (DMER and AEL, 1996)have been quoted. These values are pseudo-solubilities, since solutions become turbid as the polymer precipitates atconcentrations of approximately 55% and greater.

are not considered in this assessment becausethey are regulated by the Pest Control ProductsAct.

Section 15 of Health Canada’s Foodand Drugs Act allows up to 2 ppm (i.e., 2 mg/kg)formaldehyde in maple syrup resulting fromthe use of paraformaldehyde to deter bacterialgrowth in the tap holes of maple trees (Feeley,1996). However, such use has not been registeredin Canada since 1990 (Smith, 2000).

2.2.2 Sources and releases

Formaldehyde is formed primarily by thecombustion of organic materials and by avariety of natural and anthropogenic activities.Secondary formation of formaldehyde occurs inthe atmosphere through the oxidation of naturaland anthropogenic volatile organic compounds(VOCs) in the air. While there are no reliableestimates for releases from natural sources andfor secondary formation, these may be expectedto be much larger than direct emissions fromanthropogenic activities. However, highestconcentrations have been measured near keyanthropogenic sources, such as automotiveand industrial emissions (see below).

2.2.2.1 Natural sources

Formaldehyde occurs naturally in theenvironment and is the product of many naturalprocesses. It is released during biomasscombustion, such as forest and brush fires(Howard, 1989; Reinhardt, 1991). In water, it isalso formed by the irradiation of humicsubstances by sunlight (Kieber et al., 1990).

As a metabolic intermediate,formaldehyde is present at low levels in mostliving organisms (WHO, 1989; IARC, 1995).Studies have found it to be emitted by bacteria,algae, plankton and vegetation (Hellebust, 1974;Zimmermann et al., 1978; Eberhardt andSieburth, 1985; Yamada and Matsui, 1992;Nuccio et al., 1995).

2.2.2.2 Anthropogenic sources

Anthropogenic sources of formaldehydeinclude direct sources such as fuel combustion,industrial on-site uses and off-gassing frombuilding materials and consumer products.

Although formaldehyde is not presentin gasoline, it is a product of incompletecombustion. All internal combustion engines havethe potential to produce it. The amount generateddepends primarily on the composition of the fuel,the type of engine, the emission control applied,the operating temperature and the age and state ofrepair of the vehicle. Therefore, emission rates arevariable (Environment Canada, 1999a).

Based on data for 1997 reported to theNational Pollutant Release Inventory (NPRI), on-road motor vehicles are the largest direct sourceof formaldehyde released into the Canadianenvironment. The amount estimated by modellingto have been released in 1997 from on-road motorvehicles was 11 284 tonnes (Environment Canada,1999b). While Environment Canada (1999b) didnot distinguish between gasoline-powered anddiesel-powered vehicles, it has been estimated,based on emission data from these vehicles, thatthey account for about 40% and 60% of on-roadautomotive releases, respectively. Aircraft emittedan estimated 1730 tonnes, and the marine sectorreleased about 1175 tonnes (Environment Canada,1999b). Data on releases from on-road vehicleswere estimated by modelling (Mobile 5C model),using assumptions outlined in EnvironmentCanada (1996). It can be expected that the rates ofreleases of formaldehyde from automotivesources have changed and will continue tochange; many current and planned modificationsto automotive emission control technology andgasoline quality would lead to decreases in thereleases of formaldehyde and other VOCs(Environment Canada, 1999b).

Other anthropogenic combustionsources (covering a range of fuels from wood toplastics) include wood-burning stoves, fireplaces,



furnaces, power plants, agricultural burns, wasteincinerators, cigarette smoking and the cooking offood (Jermini et al., 1976; Kitchens et al., 1976;Klus and Kuhn, 1982; Ramdahl et al., 1982;Schriever et al., 1983; Lipari et al., 1984; WHO,1989; Walker and Cooper, 1992; Baker, 1994;Guski and Raczynski, 1994). Cigarette smokingin Canada is estimated to produce less than 84tonnes per year, based on estimated emissionrates (WHO, 1989) and a consumption rate ofapproximately 50 billion cigarettes per year(Health Canada, 1997). Canadian coal-basedelectricity generating plants are estimated to emit0.7–23 tonnes per year, based on U.S. emissionfactors (Lipari et al., 1984; Sverdrup et al., 1994),the high heating value of fuel and Canadiancoal consumption in 1995 (Rose, 1998). Agross estimate of formaldehyde emissions frommunicipal, hazardous and biomedical wastein Canada is 10.6 tonnes per year, based onmeasured emission rates from one municipalincinerator in Ontario (Novamann International,1997; Environment Canada, 1999a).

Industrial releases of formaldehydecan occur at any stage during the production,use, storage, transport or disposal of productswith residual formaldehyde. Formaldehydehas been detected in emissions from chemicalmanufacturing plants (Environment Canada,1997c,d, 1999a), pulp and paper mills, forestryproduct plants (U.S. EPA, 1990; Fisher et al.,1991; Environment Canada, 1997c, 1999a;O’Connor and Voss, 1997), tire and rubberplants (Environment Canada, 1997b), petroleumrefining and coal processing plants (IARC, 1981;U.S. EPA, 1993), textile mills, automotivemanufacturing plants and the metal productsindustry (Environment Canada, 1999a).

NPRI data for 1997 indicated totalenvironmental releases from 101 facilities of1423.9 tonnes, with reported releases to differentmedia as follows: 1339.3 tonnes to air, 60.5tonnes to deep-well injection, 19.4 tonnes tosurface water and 0 tonnes to soil. Largestemissions to air were reported from WeyerhaeuserCanada Ltd. in Edson, Alberta (121.5 tonnes), andDrayton Valley, Alberta (111.7 tonnes). Only four

plants reported releases of formaldehyde tosurface water, in quantities of 13.3 tonnes(Abitibi-Consolidated, La Baie, Quebec), 4.1tonnes (Abitibi Consolidated, Grand-Mère,Quebec), 1.6 tonnes (Tembec Inc., Témiscaming,Quebec) and 0.4 tonnes (Grant Forest ProductsCorp., Englehart, Ontario). Formaldehydedisposed of through deep-well injection is notconsidered to interact with biologically activesoil strata. From 1979 to 1989, about 76.9 tonnesof formaldehyde were spilled or released to theenvironment as a result of 35 reported incidents(NATES, 1996).

Releases of formaldehyde to groundwaterfrom embalming fluids in bodies buried incemeteries are expected to be very small based ongroundwater samples and the estimated loadingrates of six cemeteries in Ontario (Chan et al.,1992).

Formaldehyde has been detected in theoff-gassing of formaldehyde products such aswood panels, latex paints, new carpets, textileproducts and resins. While emission rates havebeen estimated for some of these sources, thereare insufficient data for estimating total releases(Little et al., 1994; NCASI, 1994; EnvironmentCanada, 1995).

Regulatory and voluntary initiatives havebeen directed at the control of emissions frombuilding materials and furnishings, since theseare recognized as the major sources of elevatedconcentrations of formaldehyde in indoor air.Urea-formaldehyde foam insulation (UFFI) wasbanned from use in Canada in 1980. Voluntarystandards have been established to limit theemission of formaldehyde from particleboard(ANSI A208.1-1993) and medium-densityfibreboard (MDF) (ANSI A208.2-1994).According to information provided by theComposite Panel Association (formerly theNational Particleboard Association and theCanadian Particleboard Association), a dramaticreduction in the emission rates of formaldehydefrom composite wood products has been achievedthrough the use of low-emitting resins, chemicalscavengers and improved manufacturing control

(Tardif, 1998). The Canadian Carpet Institute hasestablished a voluntary carpet emission guidelineof 0.05 mg/m2 per hour (Piersol, 1995).

2.2.2.3 Secondary formation

Formaldehyde is formed in the troposphere bythe photochemical oxidation of many types oforganic compounds, including naturally occurringcompounds, such as methane (WHO, 1989; U.S.EPA, 1993) and isoprene (Tanner et al., 1994),and pollutants from mobile and stationarysources, such as alkanes, alkenes (e.g., ethene,propene), aldehydes (e.g., acetaldehyde, acrolein)and alcohols (e.g., allyl alcohol, methanol,ethanol) (U.S. EPA, 1985; Atkinson et al., 1989,1993; Grosjean, 1990a,b, 1991a,b,c; Skov et al.,1992; Grosjean et al., 1993a,b, 1996a,b; Bierbachet al., 1994; Kao, 1994).

Given the diversity and abundance offormaldehyde precursors in urban air, secondaryatmospheric formation frequently exceeds directemissions from combustion sources, especiallyduring photochemical air pollution episodes, andit may contribute up to 70–90% of the totalatmospheric formaldehyde (Grosjean, 1982;Grosjean et al., 1983; Lowe and Schmidt, 1983).In California, Harley and Cass (1994) estimatedthat photochemical formation was more importantthan direct emissions in Los Angeles during thesummertime days studied; in winter or at nightand early morning, direct emissions can be moreimportant. This was also observed in Japan, wherethe concentrations of formaldehyde in the centralmountainous region were not associated directlywith motor exhaust but rather with thephotochemical oxidation of anthropogenicpollutants occurring there through long-rangetransport (Satsumabayashi et al., 1995).

2.3 Exposure characterization

2.3.1 Environmental fate

The sections below summarize the availableinformation on the distribution and fate of

formaldehyde released into the environment.More detailed fate information is provided inEnvironment Canada (1999a).

2.3.1.1 Air

Formaldehyde emitted to air primarily reactswith photochemically generated hydroxyl (OH)radicals in the troposphere or undergoes directphotolysis (Howard et al., 1991; U.S. EPA, 1993).Minor fate processes include reactions withnitrate (NO3) radicals, hydroperoxyl (HO2)radicals, hydrogen peroxide (H2O2), ozone (O3)and chlorine (Cl2) (U.S. EPA, 1993). Smallamounts of formaldehyde may also transfer intorain, fog and clouds or be removed by drydeposition (Warneck et al., 1978; Zafiriou et al.,1980; Howard, 1989; Atkinson et al., 1990; U.S.EPA, 1993).

Reaction with the hydroxyl radicalis considered to be the most importantphotooxidation process, based on the rateconstants and the concentrations of thereactants (Howard et al., 1991; U.S. EPA, 1993).Factors influencing the atmospheric lifetimeof formaldehyde, such as time of day, intensityof sunlight, temperature, etc., are mainly thoseaffecting the availability of hydroxyl and nitrateradicals (U.S. EPA, 1993). The atmospheric half-life of formaldehyde, based on hydroxyl radicalreaction rate constants, is calculated to bebetween 7.1 and 71.3 hours (Atkinson, 1985;Atkinson et al., 1990). Products that can beformed from hydroxyl radical reactioninclude water (H2O), formic acid (HCOOH),carbon monoxide (CO) and the hydroperoxyl/formaldehyde adduct (HCO3) (Atkinson et al.,1990).

Photolysis can take two pathways.The dominant pathway produces stable molecularhydrogen and carbon monoxide. The otherpathway produces the formyl (HCO) radical anda hydrogen atom (Lowe et al., 1980), which reactquickly with oxygen to form the hydroperoxylradical and carbon monoxide. Under manyconditions, the radicals from formaldehydephotolysis are the most important net source


of smog generation (U.S. EPA, 1993). When therates of these reactions are combined withestimates of actinic radiance, the estimated half-life of formaldehyde due to photolysis is 1.6hours in the lower troposphere at a solar zenithangle of 40° (Calvert et al., 1972). A half-lifeof 6 hours was measured based on simulatedsunlight (Lowe et al., 1980).

The nighttime destruction offormaldehyde is expected to occur by the gas-phase reaction with nitrate radicals (NRC, 1981);this tends to be more significant in urban areas,where the concentration of the nitrate radical ishigher than in rural areas (Altshuller and Cohen,1964; Gay and Bufalini, 1971). A half-life of 160days was calculated using an average atmosphericnitrate radical concentration typical of a mildlypolluted urban centre (Atkinson et al., 1990),while a half-life of 77 days was estimated basedon measured rate constants (Atkinson et al.,1993). Nitric acid (HNO3) and formyl radical havebeen identified as products of this reaction. Theyreact rapidly with atmospheric oxygen to producecarbon monoxide and hydroperoxyl radicals,which can react with formaldehyde to formformic acid. However, because of this rapid back-reaction, the reaction of nitrate radicals withformaldehyde is not expected to be a major lossprocess under tropospheric conditions.

Overall half-lives for formaldehyde in aircan vary considerably under different conditions.Estimations for atmospheric residence time inseveral U.S. cities ranged from 0.3 hours underconditions typical of a rainy winter night to 250hours under conditions typical of a clear summernight (assuming no reaction with hydroperoxylradicals) (U.S. EPA, 1993). During the daytime,under clear-sky conditions, the residence timeis determined primarily by its reaction with thehydroxyl radical. Photolysis accounted for only2–5% of the removal.

Given the generally short daytimeresidence times for formaldehyde, there islimited potential for long-range transport ofthis compound. However, in cases whereorganic precursors are transported long distances,

secondary formation of formaldehyde may occurfar from the actual anthropogenic sources of theprecursors (Tanner et al., 1994).

Because of its high solubility in water,formaldehyde will transfer into clouds andprecipitation. A washout ratio (concentration inrain/concentration in air) of 73 000 at 25°C isestimated by Atkinson (1990). Gas-phase organiccompounds that have a washout ratio of greaterthan 105 are generally estimated to be efficientlyrained out (ARB, 1993). The washout ratiosuggests that the wet deposition (removal of gasesand particles by precipitation) of formaldehydecould be significant as a tropospheric loss process(Atkinson, 1989). However, Zafiriou et al. (1980)estimated that rainout was responsible forremoving only 1% of formaldehyde producedin the atmosphere by the oxidation of methane.Warneck et al. (1978) showed that washout isimportant only in polluted regions. Nevertheless,it is expected that wet deposition can lead toa somewhat shorter tropospheric lifetime offormaldehyde than that calculated from gas-phaseprocesses alone.

2.3.1.2 Water

In water, formaldehyde is rapidly hydrated toform a glycol (CH2(OH)2). Equilibrium almosttotally favours the glycol (Dong and Dasgupta,1986); less than 0.04% by weight of unhydratedformaldehyde is found in highly concentratedsolutions (Kroschwitz, 1991). In surface wateror groundwater, formaldehyde can undergobiodegradation (U.S. EPA, 1985; Howard, 1989).Incorporated into atmospheric water,formaldehyde or its hydrate can undergooxidation.

Formaldehyde is degraded by variousmixed microbial cultures obtained from sludgesand sewage (Kitchens et al., 1976; Verschueren,1983; U.S. EPA, 1985). Formaldehyde in lakewater decomposed in approximately 30 hoursunder aerobic conditions at 20°C and inapproximately 48 hours under anaerobicconditions (Kamata, 1966). Howard et al. (1991)estimated half-lives of 24–168 hours in surface


water and 48–336 hours in groundwater based onscientific judgment and estimated aqueous aerobicbiodegradation half-lives.

When incorporated from air into cloudwater, fog water or rain, formaldehyde can reactwith aqueous hydroxyl radicals in the presenceof oxygen to produce formic acid, water andhydroperoxide (aqueous). The formaldehydeglycol can also react with ozone (Atkinson et al.,1990).

2.3.1.3 Sediment

Due to its low Koc and high water solubility,formaldehyde is not expected to significantly sorbto suspended solids and sediments from water.Biotic and abiotic degradation are expected tobe the significant environmental fate processesin sediment (U.S. EPA, 1985; Howard, 1989).

2.3.1.4 Soil

Formaldehyde is not expected to adsorb tosoil particles to a great degree and would beconsidered mobile in the soil, based on itsestimated Koc. According to Kenaga (1980),compounds with a Koc of <100 are consideredto be moderately mobile. Formaldehyde can betransported to surface water through runoff andto groundwater as a result of leaching.Parameters other than Koc affecting its leachingto groundwater include the soil type, the amountand frequency of rainfall, the depth of thegroundwater and the extent of degradation offormaldehyde. Formaldehyde is susceptible todegradation by various soil microorganisms (U.S.EPA, 1985). Howard et al. (1991) estimated a soilhalf-life of 24–168 hours, based on estimatedaqueous aerobic biodegradation half-lives.

2.3.1.5 Biota

In view of the very low bioconcentration factorof 0.19, based on a log Kow of 0.65 (Veith et al.,1980; Hansch and Leo, 1981), formaldehydeis not expected to bioaccumulate. Nobioconcentration was observed in fish or shrimp(Stills and Allen, 1979; Hose and Lightner, 1980).

No significant aquatic magnification in the foodchain is predicted from the model calculations andempirical observations of Thomann (1989).

2.3.1.6 Environmental distribution

Fugacity modelling was carried out to provide anoverview of key reaction, intercompartment andadvection (movement out of a system) pathwaysfor formaldehyde and its overall distribution inthe environment. A steady-state, non-equilibriummodel (Level III fugacity model) was run usingthe methods developed by Mackay (1991) andMackay and Paterson (1991). Assumptions, inputparameters and results are presented in Mackayet al. (1995) and Environment Canada (1999a).

Based on its physical-chemical properties,Level III fugacity modelling indicates that whenformaldehyde is continuously discharged into onemedium, most of it can be expected to be foundin that medium (Mackay et al., 1995; DMERand AEL, 1996). However, given the uncertaintiesrelating to use of pseudo-solubility, hydrationin water, and the complex atmospheric formationand degradation processes for formaldehyde,quantitative estimates of mass distribution arenot considered reliable for formaldehyde.

2.3.2 Environmental concentrations

2.3.2.1 Air

2.3.2.1.1 Ambient air

Available sampling and analytical methodologiesare sufficiently sensitive to detect formaldehyde inmost samples of ambient (outdoor) air in Canada.Formaldehyde was detected (detection limit0.05 µg/m3) in 3810 of 3842 24-hour samplesfrom rural, suburban and urban areas, collected at16 sites in six provinces surveyed from August1989 to August 1998 (Environment Canada,1999a). Concentrations ranged from below thedetection limit (0.05 µg/m3) to a maximum of27.5 µg/m3 for eight urban sites (Montréal,Quebec [two sites]; Ottawa, Ontario; Windsor,Ontario [two sites]; Toronto, Ontario; Winnipeg,Manitoba; Vancouver, B.C.), to a maximum of



12.03 µg/m3 for two suburban sites (Saint John,New Brunswick; Montréal, Quebec), to amaximum of 9.11 µg/m3 for two rural sitesconsidered to be affected by urban and/orindustrial influences (L’Assomption, Quebec;Simcoe, Ontario) and to a maximum of9.88 µg/m3 for four rural sites considered tobe regionally representative (Kejimkujik Park,Nova Scotia; Mount Sutton, Quebec; St. Anicet,Quebec; Egbert, Ontario). Long-term (1 monthto 1 year) mean concentrations for these sitesranged from 0.78 to 8.76 µg/m3. The singlehighest 24-hour concentration measured was27.5 µg/m3, obtained for an urban samplecollected from Toronto, Ontario, on August 8,1995. The mean concentration for six 24-hourmeasurements made at this site during the 30-day period from July 14 to August 12 was22.15 µg/m3. Pooled monthly mean concentrationsof formaldehyde determined from data inCanada’s National Air Pollution Surveillance(NAPS) program for suburban and urban sitesin Canada between 1990 and 1998 are highestbetween June and August (Health Canada, 2000).

Concentrations of formaldehyde weremeasured in 96 air samples (12- to 25-hour)collected from the roofs of buildings at foursites in urban, residential and industrial areasof Prince Rupert, B.C., during 1994 and 1995.Concentrations ranged from 0.08 to 14.7 µg/m3

(detection limit 0.03 µg/m3). Reported averagesranged from 0.73 to 3.94 µg/m3 (SEAM Database,1996).

Quarterly mean concentrations offormaldehyde in outdoor air during the periodfrom 1990 to 1998 were calculated for twosuburban (i.e., in Montréal and Vancouver) andtwo urban (i.e., in Ottawa and Toronto) NAPSsites and examined for temporal trends. There isno evidence that concentrations of formaldehydewere systematically increasing or decreasing atthese sites over this 9-year period (Health Canada,2000).

Formaldehyde was also measured in108 6-hour samples collected 4 times daily from

August 1 to 28, 1993, at Chebogue Point, NovaScotia. Concentrations ranged from less than0.6 µg/m3 to approximately 4.2 µg/m3 (detectionlimit not specified) (Tanner et al., 1994). Thisarea was assumed to be affected not only bylocal sources but also by air masses transportingprecursors from the northeastern United States.

Atmospheric measurements made in 1992during the dark winter and sunlit spring of anextremely remote site at Alert, Nunavut, rangedfrom 0.04 to 0.84 µg/m3 on a 5-minute basis(detection limit 0.04 µg/m3), with a mean of0.48 µg/m3 (De Serves, 1994).

Concentrations of formaldehyde weredetermined in air near a forest product plant.The maximum 24-hour average concentrationsfor March–June 1995, July–September 1995and October 1995 – March 1996 were 3.01, 1.71and 4.40 µg/m3, respectively (detection limit notspecified) (Environment Canada, 1997c).

2.3.2.1.2 Indoor air

Few recent data were identified concerningconcentrations of formaldehyde in residentialindoor air in Canada. In contrast, large numbersof measurements of formaldehyde in the indoorair of Canadian homes were made during the1970s and 1980s (Government of Canada, 1982)in response to concerns about emissions offormaldehyde from UFFI. These older data,reflecting higher concentrations of formaldehydein the residential indoor air of “complaint” homes,were not considered to be representative of theconcentrations in indoor air to which the generalpopulation is currently exposed.

Data concerning concentrations offormaldehyde in residential indoor air fromseven studies conducted in Canada between 1989and 1995 were examined (Health Canada, 2000).Despite differences in sampling mode andduration (i.e., active sampling for 24 hours orpassive sampling for 7 days), the distributions ofconcentrations were similar in five of the studies.The median, arithmetic mean, 95th percentile and

99th percentile concentrations of the pooled data(n = 151 samples) from these five studies were30, 36, 85 and 116 µg/m3, respectively (HealthCanada, 2000). Similar concentrations have beenmeasured in non-workplace indoor air in othercountries.

Concurrent 24-hour measurements inoutdoor air and indoor air of Canadian residenceswere available from some of these studies.Average concentrations of formaldehyde werean order of magnitude higher in indoor air thanin outdoor air, indicating the presence of indoorsources of formaldehyde and confirming similarfindings in other countries (WHO, 1989; ATSDR,1999). Information concerning the presence ofenvironmental tobacco smoke (ETS) in the homessampled was available from some of thesestudies; however, there was no clear indicationthat concentrations of formaldehyde were greaterin homes where ETS was present. Acetaldehyde,rather than formaldehyde, is the most abundantcarbonyl compound in mainstream (MS) andsidestream (SS) cigarette smoke. Based on datafrom the United States and elsewhere, ETS doesnot increase concentrations of formaldehyde inindoor air, except in areas with high rates ofsmoking and minimal rates of ventilation (Godish,1989; Guerin et al., 1992).

The available Canadian data wereinadequate to permit the assessment of the extentof contributions from other combustion sources(e.g., woodstoves, vehicles in attached garages,etc.) or other potential sources (e.g., furniture,building materials) to the measuredconcentrations of formaldehyde in indoor air.

2.3.2.2 Water

2.3.2.2.1 Drinking water

Representative data concerning concentrationsin drinking water in Canada were not available.The concentration of formaldehyde in drinkingwater is likely dependent upon the quality of theraw source water and purification steps utilized(Krasner et al., 1989). Ozonation may slightly

increase the levels of formaldehyde in drinkingwater, but subsequent purification steps mayattenuate these elevated concentrations (Hucket al., 1990). Elevated concentrations have beenmeasured in U.S. houses equipped with polyacetalplumbing elbows and tees. Normally, an interiorprotective coating prevents water from contactingthe polyacetal resin (Owen et al., 1990).However, if routine stress on the supply linesresults in a break or fracture of the coating, watermay contact the resin directly. The resultantconcentrations of formaldehyde in the water arelargely determined by the residence time of thewater in the pipes. Owen et al. (1990) estimatedthat at normal water usage rates in occupieddwellings, the resulting concentration offormaldehyde in water would be about 20 µg/L.In general, concentrations of formaldehyde indrinking water are expected to be less than100 µg/L (WHO, 1989; IARC, 1995).

2.3.2.2.2 Surface water

Concentrations of formaldehyde in raw waterfrom the North Saskatchewan River weremeasured at the Rossdale drinking watertreatment plant in Edmonton, Alberta.Concentrations between March 1989 and January1990 averaged 1.2 µg/L, with a peak value of9.0 µg/L. These concentrations were influencedby climatological events such as spring runoff,major rainfall events and the onset of winter, asevidenced by concentration increases duringspring runoff and major rainfall and concentrationdecreases (<0.2 µg/L) following river freeze-up(Huck et al., 1990).

Anderson et al. (1995) measuredformaldehyde concentrations in the raw waterof three drinking water treatment pilot plantsin Ontario. The study included three distincttypes of surface waters, covering a range ofcharacteristics and regional influences: amoderately hard waterway with agriculturalimpacts (Grand River at Brantford), a soft,coloured river (Ottawa River at Ottawa) and ariver with moderate values for most parameters,typical of the Great Lakes waterways (Detroit


River at Windsor). Concentrations were less thanthe detection limit (1.0 µg/L) and 8.4 µg/L in rawwater samples collected on December 2, 1993,and February 15, 1994, respectively, from theDetroit River. In the Ottawa River, concentrationswere below the detection limit (1.0 µg/L) in threeprofiles taken between April 12 and June 7, 1994.In the Grand River, a mean concentration of1.1 µg/L was obtained for seven sampling datesbetween May 11 and June 21, 1994.

2.3.2.2.3 Effluent

Formaldehyde is not routinely measured aspart of most industrial permitting or monitoringof effluent releases. Recent follow-up withindividual plants reporting releases indicatedthat plants that had previously released effluentsto surface waters now release to municipalwastewater systems or divert their effluents toactivated sludge treatment prior to release intothe environment, thereby reducing or eliminatingreleases of formaldehyde. The highest reportedconcentration from one of the four plantsreporting releases for 1997 (Environment Canada,1999b) was a 1-day mean of 325 µg/L, with a 4-day mean of 240 µg/L (Environment Canada,1999a).

2.3.2.2.4 Groundwater

Extensive monitoring of groundwater from a siteof production and use of formaldehyde included10 samples in which formaldehyde concentrationswere below the detection limit (50 µg/L) and43 samples with concentrations ranging from65 to 690 000 µg/L (mean of two duplicates) fromNovember 1991 to February 1992 (EnvironmentCanada, 1997c). Data had been collected as partof a monitoring program to delineate theboundaries of groundwater contamination at thefacility and were used to design a groundwatercontainment and recovery system. Formaldehydewas not detected in samples taken from outsidethe contaminated zone. Waste ponds associatedwith the formaldehyde releases are no longer inservice and have been capped, and the wastewateris now treated in an effluent treatment unit(Environment Canada, 1999a).

Quarterly analyses of five monitoringwells on the property of a plant that producesUF resins were carried out during 1996–1997.Concentrations ranged from below the detectionlimit (50 µg/L) to 8200 µg/L, with an overallmedian of 100 µg/L. Concentrations for differentwells indicated little dispersion from wells closeto the source of contamination (EnvironmentCanada, 1997c).

Samples from eight monitoring wellsat a fibreglass insulation plant were reportedto have concentrations ranging from belowdetection (5 µg/L) to 190 µg/L on March 24,1997. Groundwater data from 1996 indicateconcentrations from below the detection limit(0.5–5.4 µg/L) up to 120 µg/L. However, reviewof the analytical methods used indicates that theseresults may be unreliable (Environment Canada,1997c).

Groundwater samples were collected fromwells downstream from six cemeteries in Ontario.They contained formaldehyde concentrations of1–30 µg/L (detection limit not specified). Thesevalues could be overestimates, as a blank samplewas found to contain 7.3 µg/L (Chan et al., 1992).

2.3.2.2.5 Atmospheric water

While no data are available in Canada,concentrations of formaldehyde in rain, snow,fog and cloud water have been measured inother countries. Rain concentrations rangedfrom 0.44 µg/L (near Mexico City) to 3003 µg/L(during the burning season in Venezuela). Meanconcentrations ranged from 77 µg/L (in Germany)to 321 µg/L (during the non-burning season inVenezuela). In snow, formaldehyde concentrationsranged from 18 to 901 µg/L in California. A meansnow concentration of 4.9 µg/L is reported forGermany. In fog water, concentrations of480–17 027 µg/L have been measured in thePo valley, Italy, with a mean of 3904 µg/L (seeEnvironment Canada, 1999a).


2.3.2.3 Sediment

No data were identified on concentrations offormaldehyde in sediments in Canada.

2.3.2.4 Soil

Concentrations in soil were measuredat manufacturing plants that use phenol/formaldehyde resins. At a plywood plant,six soil samples collected in 1991 containedformaldehyde concentrations of 73–80 mg/kg,with a mean of 76 mg/kg (detection limit notspecified) (Alberta Environmental Protection,1996). At a fibreglass insulation plant,formaldehyde was not detected (detection limit0.1 mg/kg) in soil samples collected in 1996from six depths at four industrial areas on-site.Formaldehyde was also not detected in samplestaken from a non-industrial site 120 km awayfrom the plant.

2.3.2.5 Biota

No data were identified on concentrations offormaldehyde in Canadian biota.

2.3.2.6 Food

There have been no systematic investigationsof levels of formaldehyde in a range of foodstuffsas a basis for estimation of population exposure(Health Canada, 2000). Although formaldehydeis a natural component of a variety of foodstuffs(WHO, 1989; IARC, 1995), monitoring hasgenerally been sporadic and source-directed.Available data suggest that the highestconcentrations of formaldehyde naturallyoccurring in foods (i.e., up to 60 mg/kg) are insome fruits (Möhler and Denbsky, 1970; Tsuchiyaet al., 1975) and marine fish (Rehbein, 1986;Tsuda et al., 1988).

Formaldehyde develops post-mortemin marine fish and crustaceans, from theenzymatic reduction of trimethylamine oxide toformaldehyde and dimethylamine (Sotelo et al.,1995). While formaldehyde may be formed duringthe ageing and deterioration of fish flesh, high

levels do not accumulate in the fish tissues, dueto subsequent conversion of the formaldehydeformed to other chemical compounds (Tsudaet al., 1988). However, formaldehyde accumulatesduring the frozen storage of some fish species,including cod, pollack and haddock (Sotelo et al.,1995). Formaldehyde formed in fish reacts withprotein and subsequently causes muscle toughness(Yasuhara and Shibamoto, 1995), which suggeststhat fish containing the highest levels offormaldehyde (e.g., 10–20 mg/kg) may not beconsidered palatable as a human food source.No data regarding the formaldehyde content offreshwater fish, marine fish or shellfish in Canadawere identified.

Higher concentrations of formaldehyde(i.e., up to 800 mg/kg) have been reported in fruitand vegetable juices in Bulgaria (Tashkov, 1996);however, it is not clear if these elevated levelsarise during processing. Formaldehyde is usedin the sugar industry to inhibit bacterial growthduring juice production (ATSDR, 1999). In astudy conducted by Agriculture Canada,concentrations of formaldehyde were higher insap from maple trees that had been implantedwith paraformaldehyde to deter bacterial growthin tap holes (Baraniak et al., 1988). The resultingmaple syrup contained concentrations up to14 mg/kg, compared with less than 1 mg/kg insyrup from untreated trees.

In other processed foods, the highestconcentrations have been reported in the outerlayer of smoked ham (Brunn and Klostermeyer,1984) and in some varieties of Italian cheese,where formaldehyde is permitted for use underregulation as a bacteriostatic agent (Restani et al.,1992). Hexamethylenetetramine, a complex offormaldehyde and ammonia that decomposesslowly to its constituents under acid conditions,has been used as a food additive in fish productssuch as herring and caviar in the Scandinaviancountries (Scheuplein, 1985).

Concentrations of formaldehyde in avariety of alcoholic beverages ranged from 0.04to 1.7 mg/L in Japan (Tsuchiya et al., 1994) andfrom 0.02 to 3.8 mg/L in Brazil (de Andrade


et al., 1996). In earlier work conducted in Canada,Lawrence and Iyengar (1983) compared levelsof formaldehyde in bottled and canned cola softdrinks (7.4–8.7 mg/kg) and beer (0.1–1.5 mg/kg)and concluded that there was no significantincrease in the formaldehyde content of cannedbeverages due to the plastic inner coating ofthe metal containers. Concentrations of 3.4and 4.5 mg/kg in brewed coffee and 10 and16 mg/kg in instant coffee were reported inthe United States (Hayashi et al., 1986). Theseconcentrations reflect the levels in the beveragesas consumed.

Data from several studies indicate thatlow concentrations of formaldehyde may bepresent in various prepared foods and that variouscooking activities may contribute to the elevatedlevels of formaldehyde sometimes present inindoor air (Health Canada, 2000). In recentwork from the United States, the emission rateof formaldehyde from meat charbroiling over anatural gas-fired grill in a commercial facilitywas higher (i.e., 1.38 g/kg of meat cooked) thanemission rates of all other VOCs measured exceptfor ethylene (Schauer et al., 1999).

Formaldehyde is used in the animalfeed industry, where it is added to ruminantfeeds to improve handling characteristics. Thefood mixture contains less than 1% formaldehyde,and animals may ingest as much as 0.25%formaldehyde in their diet (Scheuplein, 1985).Formalin has been added as a preservative to skimmilk fed to pigs in the United Kingdom (Florenceand Milner, 1981) and to liquid whey (from themanufacture of cheddar and cottage cheeses)fed to calves and cows in Canada. Maximumconcentrations in the milk of cows fed wheywith the maximum level of formalin tested(i.e., 0.15%) were up to 10-fold greater (i.e.,0.22 mg/kg) than levels in milk from control cowsfed whey without added formalin (Buckley et al.,1986, 1988). In a more recent study, theconcentrations of formaldehyde in commercial2% milk and in fresh milk from cows fed on atypical North American dairy total mixed dietwere determined. Concentrations in the freshmilk (i.e., from Holstein cows, morning milking)

ranged from 0.013 to 0.057 mg/kg, with a meanconcentration (n = 18) of 0.027 mg/kg, whileconcentrations in processed milk (i.e., 2% milkfat, partly skimmed, pasteurized) ranged from0.075 to 0.255 mg/kg, with a mean concentration(n = 12) of 0.164 mg/kg. The somewhat higherconcentrations in the commercial 2% milk wereattributed to processing technique, packagingand storage, but these factors were not assessedfurther (Kaminski et al., 1993).

The degree to which formaldehyde invarious foods is bioavailable following ingestionis not known.

2.3.2.7 Consumer products

Formaldehyde and formaldehyde derivatives arepresent in a wide variety of consumer products(Preuss et al., 1985) to protect the productsfrom spoilage by microbial contamination.Formaldehyde is used as a preservative inhousehold cleaning agents, dishwashing liquids,fabric softeners, shoe-care agents, car shampoosand waxes, carpet cleaning agents, etc. (WHO,1989). Levels of formaldehyde in handdishwashing liquids and liquid personal cleansingproducts available in Canada are less than 0.1%(w/w) (McDonald, 1996).

Formaldehyde has been used in thecosmetics industry in three principal areas:preservation of cosmetic products and rawmaterials against microbial contamination,certain cosmetic treatments such as hardening offingernails, and plant and equipment sanitation(Jass, 1985). Formaldehyde is also used as anantimicrobial agent in hair preparations, lotions(e.g., suntan lotion and dry skin lotion), makeupand mouthwashes and is also present in handcream, bath products, mascara and eye makeup,cuticle softeners, nail creams, vaginal deodorantsand shaving cream (WHO, 1989; ATSDR, 1999).

Some preservatives are formaldehydereleasers. The release of formaldehyde upontheir decomposition is dependent mainly ontemperature and pH. Information on productcategories and typical concentrations for chemical


products containing formaldehyde andformaldehyde releasers was obtained from theDanish Product Register Data Base (PROBAS)by Flyvholm and Andersen (1993). Industrialand household cleaning agents, soaps, shampoos,paints/lacquers and cutting fluids comprisedthe most frequent product categories forformaldehyde releasers. The three most frequentlyregistered formaldehyde releasers werebromonitropropanediol, bromonitrodioxane andchloroallylhexaminium chloride (Flyvholm andAndersen, 1993).

Formaldehyde is present in the smokeresulting from the combustion of tobaccoproducts. Estimates of emission factors forformaldehyde (e.g., µg/cigarette) from MS andSS smoke and from ETS have been determinedby a number of different protocols for cigarettesin several countries, including Canada.

A range of MS smoke emission factorsfrom 73.8 to 283.8 µg/cigarette was reportedfor 26 U.S. brands, which included non-filter,filter and menthol cigarettes of various lengths(Miyake and Shibamoto, 1995). Differences inconcentrations reflect differences in tobacco typeand brand. More recent information is availablefrom the British Columbia Ministry of Healthfrom tests conducted on 11 brands of Canadiancigarettes. MS smoke emission factors rangedfrom 8 to 50 µg/cigarette when tested understandard conditions (British Columbia Ministryof Health, 1998).

Levels of formaldehyde are higher in SSsmoke than in MS smoke. Guerin et al. (1992)reported that popular commercial U.S. cigarettesdeliver approximately 1000–2000 µgformaldehyde per cigarette in their SS smoke.Schlitt and Knöppel (1989) reported a mean(n = 5) formaldehyde content of 2360 µg/cigarettein the SS smoke from a single brand in Italy.Information from the British Columbia Ministryof Health from tests conducted on 11 brandsof Canadian cigarettes indicates that emissionfactors from SS smoke ranged from 368 to448 µg/cigarette (British Columbia Ministryof Health, 1998).

Emission factors for toxic chemicals fromETS, rather than from MS or SS smoke, have alsobeen determined. This is in part due to concernsthat emission factors for SS smoke may be toolow for reactive chemicals such as formaldehyde,due to losses in the various apparati used todetermine SS smoke emission factors. Daiseyet al. (1994) indicated that ETS emission factorsfor formaldehyde from six U.S. commercialcigarettes ranged from 958 to 1880 µg/cigarette,with a mean of 1310 ± 349 µg/cigarette. Dataconcerning emission factors for formaldehydefrom ETS produced by Canadian cigarettes werenot identified.

2.3.2.8 Clothing and fabrics

Formaldehyde-releasing agents provide creaseresistance, dimensional stability and flameretardance for textiles and serve as binders intextile printing (Priha, 1995). Durable-pressresins or permanent-press resins containingformaldehyde have been used on cotton andcotton/polyester blend fabrics since the mid-1920sto impart wrinkle resistance during wear andlaundering. Hatch and Maibach (1995)identified nine major resins used. These differin formaldehyde-releasing potential during wearand use.

Priha (1995) indicated that formaldehyde-based resins, such as UF resin, were once morecommonly used for crease resistance treatment;more recently, however, better finishing agentswith lower formaldehyde release have beendeveloped. Totally formaldehyde-free crosslinkingagents are now available, and some countries havelegally limited the formaldehyde content of textileproducts. In 1990, the percentage of durable-pressfabric manufactured in the United States finishedwith resins rated as having high formaldehyderelease was 27%, about one-half the percentagein 1980, according to Hatch and Maibach (1995).It has been reported that the average levelcontained by textiles made in the United States isapproximately 100–200 ppm free formaldehyde(Scheman et al., 1998).


Piletta-Zanin et al. (1996) studied thepresence of formaldehyde in moist baby toilettissues and tested 10 of the most frequently soldproducts in Switzerland. One product containedmore than 100 ppm (i.e., µg/g), five productscontained between 30 and 100 ppm, and theremaining four products contained less than30 ppm formaldehyde.

2.3.2.9 Building materials

The emission of formaldehyde from buildingmaterials has long been recognized as asignificant source of the elevated concentrationsof formaldehyde frequently measured in indoorair. Historically, the most important indoor sourceamong the many materials used in building andconstruction has been UFFI, which is producedby the aeration of a mixture of UF resin and anaqueous surfactant solution containing a curingcatalyst (Meek et al., 1985). UFFI was bannedfrom use in Canada in 1980 and in the UnitedStates in 1982, although the U.S. ban wassubsequently overturned.

Pressed wood products (i.e.,particleboard, MDF and hardwood plywood) arenow considered the major sources of residentialformaldehyde contamination (Godish, 1988;Etkin, 1996). Pressed wood products are bondedwith UF resin; it is this adhesive portion that isresponsible for the emission of formaldehyde intoindoor air. The emission rate of formaldehyde isstrongly influenced by the nature of the material.Generally, release of formaldehyde is highestfrom newly made wood products. Emissionsthen decrease over time, to very low rates, aftera period of years (Godish, 1988).

Concentrations of formaldehyde in indoorair are primarily determined by source factorsthat include source strength, loading factors andthe presence of source combinations (Godish,1988). The best currently available approach toevaluating the source strength of indoor materialsand products is to test their emission rates(Tucker, 1990). Emission rates of formaldehyde

from pressed wood products determined byemission chamber testing in Canada (Figleyand Makohon, 1993; Piersol, 1995), the UnitedKingdom (Crump et al., 1996) and the UnitedStates (Kelly et al., 1999) are now typically lessthan 0.3 mg/m2 per hour (Health Canada, 2000).

Formaldehyde release from pressedwood materials is greater in mobile homes thanin conventional housing, since mobile homestypically have higher loading ratios (e.g.,exceeding 1 m2/m3) of these materials. In addition,mobile homes can have minimal ventilation, areminimally insulated and are often situated inexposed sites subject to temperature extremes(Meyer and Hermanns, 1985).

The use of scavengers (e.g., urea) tochemically remove unreacted formaldehydewhile the curing process is taking place hasbeen investigated as a control measure. Otherreactants could be used to chemically modify theformaldehyde to a non-toxic derivative or convertit to a non-volatile reaction product. Work hasalso been done on resin sealants to effectively sealthe resin and prevent the residual formaldehydefrom escaping (Tabor, 1988). Surface coatingsand treatments (e.g., paper and vinyl decorativelaminates) can significantly affect an originalmaterial’s off-gassing characteristics and insome cases can result in an order of magnitudereduction in the emission rates of formaldehydefrom pressed wood products (Figley andMakohon, 1993; Kelly et al., 1999). On the otherhand, high emissions of formaldehyde during thecuring of some commercially availableconversion varnishes (also known as acid-catalystvarnishes) have been reported. An initialformaldehyde emission rate of 29 mg/m2 per hourwas determined for one product (McCrillis et al.,1999).

Emission rates of formaldehyde fromcarpets and carpet backings, vinyl flooringsand wall coverings are now generally less than0.1 mg/m2 per hour (Health Canada, 2000).


2.4 Effects characterization

2.4.1 Ecotoxicology

Below, a brief summary is presented of the mostsensitive organisms for the terrestrial and aquaticendpoints. More extensive description of availabledata on environmental effects is provided inseveral reviews (NRC, 1982; WHO, 1989; RIVM,1992) and in the databases given in Appendix A.

2.4.1.1 Terrestrial organisms

The most sensitive effect for terrestrial organismsresulting from exposure to formaldehyde in airwas an increase in the growth of shoots, but notof roots, of the common bean (Phaseolusvulgaris) after exposure to average measuredconcentrations of 78, 128, 239 and 438 µg/m3 inair (day: 25°C, 40% humidity; night: 14°C, 60%humidity) for 7 hours per day, 3 days per week,for 4 weeks, beginning at the appearance of thefirst macroscopic floral bud, 20 days afteremergence (Mutters et al., 1993). Although theauthors concluded that there were no short-termharmful effects, it has been suggested that animbalance between shoot and root growth mayincrease a plant’s vulnerability to environmentalstresses such as drought, because the root systemmay not be large enough to provide water andnutrients for healthy plant growth (Barker andShimabuku, 1992). Other sensitive effects onterrestrial vegetation include a significantreduction of the pollen tube length of lily (Liliumlongiflorum) following a 5-hour exposure to440 µg/m3 in air; total inhibition of pollen tubeelongation occurred at 1680 µg/m3 (Masaru et al.,1976). A 5-hour exposure to 840 µg/m3 causedmild atypical signs of injury in alfalfa (Medicosativa), but no injury to spinach (Spinaciaoleracea), beets (Beta vulgaris) or oats (Avenasativa) (Haagen-Smit et al., 1952).

Effects on plants were also studiedfollowing exposure to formaldehyde in fog water.Seedlings of winter wheat (Triticum aestivum),aspen (Populus tremuloides), rapeseed (Brassicarapa) and slash pine (Pinus elliotti) were exposed

to formaldehyde concentrations of 0, 9000 or27 000 µg/L in fog for 4.5 hours per night, 3nights per week, for 40 days. Based on anunspecified Henry’s law constant, calculatedcorresponding atmospheric gas-phaseformaldehyde concentrations were 0, 18 and54 µg/m3, respectively. In rapeseed grown in theformaldehyde fog, significant (p ≤ 0.1) reductionsin leaf area, leaf dry weight, stem dry weight,flower number and number of mature siliques(seed pods that produce seed) were observedcompared with control plants. The slash pineshowed a significant increase in needle andstem growth. No effects were observed in thewheat or aspen at test concentrations (Barker andShimabuku, 1992).

Formaldehyde is known to be an effectivedisinfectant that kills microorganisms such asbacteria, viruses, fungi and parasites at relativelyhigh concentrations (WHO, 1989). Exposure to2 ppm (2400 µg/m3) gaseous formaldehyde for24 hours killed 100% of spores from cultures ofvarious species of Aspergillus, Scopulariopsis andPenicillium crustosum (Dennis and Gaunt, 1974).In a fumigation study, the death rate of spores ofBacillus globigii increased from low to high withformaldehyde concentrations ranging from 50 000to 400 000 µg/m3, respectively. Humidity (>50%)appeared to shorten the delay before death (Crossand Lach, 1990).

For terrestrial invertebrates, nematodesin peat were killed by fumigation applicationsof 370 g/L formaldehyde solutions at a rate of179 mL/m3 (66 g/m3) (Lockhart, 1972). Solutionsof 1% and 5% formalin (37% formaldehyde)destroyed the eggs and affected larvae,respectively, of the cattle parasites Ostertagiaostertagi and Cooperia oncophora in liquid cowmanure (Persson, 1973).

No acute or chronic toxicity data wereidentified for wild mammals, birds, reptiles orterrestrial invertebrates. Effects on laboratorymammals are presented in Section 2.4.3.


2.4.1.2 Aquatic organisms

Data on the aquatic toxicity of formaldehydeare numerous. The most sensitive aquatic effectsidentified were observed for marine algae.Formaldehyde concentrations of 0.1 and 1 mg/Lin water caused 40–50% mortality after 96 hoursin day-old zygotes of Phyllospora comosa, abrown marine macroalga endemic to southeasternAustralia. Total (100%) mortality resulted fromexposures to 100 mg/L for 24 hours and 10 mg/Lfor 96 hours. The 96-hour No-Observed-EffectConcentration (NOEC) and Lowest-Observed-Effect Concentration (LOEC) (percent mortalitynot specified) of 7-day-old embryos of thesame species were reported as 1 and 10 mg/L,respectively, indicating that older organismsare more tolerant (Burridge et al., 1995a).Concentrations of 0.1, 1 and 10 mg/L alsoreduced germination and growth rates of thezygotes and embryos (Burridge et al., 1995b).

Freshwater algae may be slightlymore tolerant of formaldehyde, based on a cellmultiplication inhibition test (Bringmann andKühn, 1980a). The premise of this test is thatthe number of cells in a test culture free fromdissolved toxic substances will exceed that of acontaminated culture after a certain period withotherwise identical conditions and nutrientsupplies. The number of cells in suspension canbe measured turbidimetrically and is expressedas the extinction of primary light at 578 nm for a 10-mm layer of cells. A mean extinction of ≥3%lower than that of controls is described as thetoxicity threshold. In this study, the green alga,Scenedesmus quadricauda, was exposed tovarious dilutions of formalin (35% CH2O w/w)for 7 days (shaken once a day). The toxicitythreshold was 0.9 mg formaldehyde/L (2.5 mgformalin/L) (Bringmann and Kühn, 1980a).

Other freshwater microorganisms weresimilarly sensitive in analogous cell multiplicationstudies. A 48-hour toxicity threshold (5%below average cell counts of controls) of 1.6 mgformaldehyde/L (4.5 mg formalin/L, 35%CH2O w/w) was determined for the saprozoicflagellate protozoan, Chilomona paramaecium

(Bringmann et al., 1980), and a 72-hour toxicitythreshold (≥3% inhibition of cell multiplication,25°C) of 7.7 mg/L (22 mg formalin/L, 35%CH2O w/w) was reported for the protozoan,Entosiphon sulcatum (Bringmann and Kühn,1980b). For bacteria, the 16-hour toxicitythreshold (≥3% inhibition of cell multiplication)was 4.9 mg formaldehyde/L (14 mg formalin/L,35% CH2O w/w) for Pseudomonas putida(Bringmann and Kühn, 1980a), and a 25-minuteEC50 (light emission inhibition) of 2.5 mgformaldehyde/L (242 µM formalin, 37%CH2O w/w) was observed in the Photobacteriumphosphoreum Microtox test (Chou and Que Hee,1992).

The sensitivity of freshwater invertebratesto formaldehyde varies widely. The seed shrimp,Cypridopsis sp., appears to be the most sensitive,with a 96-hour EC50 (immobility) of 0.36 mgformaldehyde/L (1.05 µL formalin/L, 37%CH2O w/w). The snail, Helisoma sp., bivalve,Corbicula sp., freshwater prawn, Palaemoneteshadiakensis, and backswimmer, Notonecta sp.,have 96-hour EC50 values (immobility, delayedresponse to tactile stimuli) of 32, 43, 160 and287 µg/L (93, 126, 465 and 835 µL formalin/L,37% CH2O w/w), respectively, assuming 1 µLformalin/L = 0.34 mg formaldehyde/L (Billset al., 1977). Reported 24-hour LC50 values forDaphnia magna range from 2 to 1000 mg/L(WHO, 1989).

Formaldehyde toxicity is variable forfish as well. The most sensitive freshwater fishwere fingerlings of striped bass (Roccus saxatilis).Reardon and Harrell (1990) found 96-hour LC50

values of 1.8, 5.0, 5.7 and 4.0 mg/L (4.96, 13.52,15.48 and 10.84 mg formalin/L, 37% CH2O w/w)in water with 0, 5, 10 and 15‰ salinity,respectively. These values were calculated fromnominal test concentrations using probit analyses.Salinity may have an effect on the tolerance ofstriped bass to formaldehyde. Although the fishhad been acclimated to water with a salinity of10–30‰ prior to testing, they were most tolerantof formaldehyde in isosmotic medium (9–10‰).Since controls were not affected by the changes in


salinity, there may be a compounded effect ofchemical and environmental (e.g., salinity)interaction on fish survival. Wellborn (1969)reported a 96-hour LC50 of 6.7 mg/L for stripedbass under static conditions. Other short-term (3- to 96-hour) LC50s of between 10 and10 000 mg/L were reported for 19 species andthree life stages of freshwater fish (U.S. EPA,1985; WHO, 1989). In some studies,formaldehyde caused disruption of normal gillfunction (Reardon and Harrell, 1990).

The only data identified for marinefish were for the juvenile marine pompano(Trachinotus carolinus), with 24-, 48- and 72-hour LC50 values of 28.8, 27.3 and 25.6 mgformaldehyde/L (78.0, 73.7 and 69.1 mgformalin/L, assumed to contain 37% CH2O),respectively, in 30‰ salinity. Salinity (10, 20,30‰) did not significantly affect the tolerance offish to formaldehyde (Birdsong and Avault, 1971).

The sensitivity of amphibians toformaldehyde is similar to that of fish. The lowest24-, 48- and 72-hour LC50 values were 8.4, 8.0and 8.0 mg/L, respectively, for larvae of theleopard frog (Rana pipiens). Tadpoles of bullfrogsappear more tolerant, with 24-, 48- and 72-hourLC50 values of 20.1, 17.9 and 17.9 mg/L,respectively. Larvae of the toad, Bufo sp., had 72-hour LC50 and LC100 values of 17.1 and19.0 mg/L, respectively (Helms, 1964). Mortality(13–100%) in tadpoles of the Rio Grande leopardfrog (Rana berlandieri) was observed after24 hours in formaldehyde (9.2–30.5 mg/L)(Carmichael, 1983). A NOEC (mortality) of6.0 mg/L was reported.

2.4.2 Abiotic atmospheric effects

The potential for formaldehyde to contribute tothe depletion of stratospheric ozone, to climatechange or to formation of ground-level ozone wasexamined.

Since formaldehyde is not a halogenatedcompound, its Ozone Depletion Potential (ODP)

is 0, and it will therefore not contribute to thedepletion of stratospheric ozone (Bunce, 1996).

Gases involved in climate change stronglyabsorb infrared radiation of wavelengths between7 and 13 µm, enabling them to trap and re-radiatethe Earth’s thermal radiation (Wang et al., 1976;Ramanathan et al., 1985). Worst-case calculationswere made to determine if formaldehyde has thepotential to contribute to climate change (Bunce,1996), assuming it has the same infraredabsorption strength as the reference compound,CFC-11. The Global Warming Potential (GWP)was calculated to be 3.2 × 10–4 (relative to thereference compound CFC-11, which has a GWPof 1), based on the following formula:

GWP = (tformaldehyde /tCFC-11) × (MCFC-11 /Mformaldehyde) ×(Sformaldehyde /SCFC-11)

where:• tformaldehyde is the lifetime of formaldehyde

(4.1 × 10–3 years), • tCFC-11 is the lifetime of CFC-11 (60 years),• MCFC-11 is the molecular weight of CFC-11

(137.5 g/mol),• Mformaldehyde is the molecular weight of

formaldehyde (30 g/mol),• Sformaldehyde is the infrared absorption strength

of formaldehyde (2389/cm2 per atmosphere,default), and

• SCFC-11 is the infrared absorption strength ofCFC-11 (2389/cm2 per atmosphere).

Since this estimate for the GWP is much lessthan 1% of that of the reference compound,it is unlikely that formaldehyde could contributesignificantly to climate change (Bunce, 1996).

The contribution of VOCs to theformation of ground-level ozone, and the resultingcontribution to smog formation, is a complexprocess and has been studied extensively. Theterms reactivity, incremental reactivity andphotochemical ozone formation potentialdenote the ability of an organic compound in theatmosphere to influence the formation of ozone



(Paraskevopoulos et al., 1995). Estimates ofreactivity of a substance depend on the definitionand method of calculation of the reactivity, theVOC/NOX ratio, the age of the air mass, thechemical mechanisms in the model, the chemicalcomposition of the hydrocarbon mixture intowhich the VOC is emitted, the geographicaland meteorological conditions of the airshedof interest (including temperature and intensityand quality of light) and the extent of dilution(Paraskevopoulos et al., 1995).

The Photochemical Ozone CreationPotential (POCP) is one of the simpler indices ofthe potential contribution of an organic compoundto the formation of ground-level ozone, based onthe rate of reaction of the substance with thehydroxyl radical relative to ethene (CEU, 1995).Ethene, a chemical that is considered to beimportant in ozone formation, has an assignedPOCP value of 100. The POCP for formaldehydewas estimated to be 105 relative to ethene, usingthe following formula (Bunce, 1996):

POCP = (kformaldehyde /kethene) × (Methene /Mformaldehyde) ×100

where:• kformaldehyde is the rate constant for the reaction

of formaldehyde with OH radicals(9.6 × 10–12 cm3/mol per second),

• kethene is the rate constant for the reaction ofethene with OH radicals (8.5 × 10–12 cm3/molper second),

• Methene is the molecular weight of ethene(28.1 g/mol), and

• Mformaldehyde is the molecular weight offormaldehyde (30 g/mol).

Various published reactivity valuesfor formaldehyde and other selected VOCs arepresented by Paraskevopoulos et al. (1995). Theuse of a maximum incremental reactivity (MIR)scale has been recommended by Carter (1994)as optimal when applied to the wide variety ofconditions where ozone is sensitive to VOCs,being fairly robust to the choices of scenariosused to derive it. Experimental data indicate thatfor formaldehyde, direct radical formation from

its photolysis is the key factor leading to netcontribution to ozone formation under conditionsof low reactive organic gas to NOX ratios (Carteret al., 1995).

Recently, formaldehyde was one of theVOCs identified in the Canadian 1996 NOX/VOCScience Assessment as part of the Multi-Stakeholder NOX /VOC Science Program (Dannand Summers, 1997). Based on air measurementstaken at nine urban and suburban sites in Canadafrom June to August from 1989 to 1993,formaldehyde was ranked 16th of the mostabundant non-methane hydrocarbon and carbonylspecies. Based on these measurements and onan MIR value of 4.39 mol ozone/mol carbon,formaldehyde represented approximately 7.8%of the total volatile organic carbon reactivity andwas ranked 4th when sorted by the total volatileorganic carbon reactivities. Total volatile organiccarbon reactivity denotes the ability of organiccompounds to contribute to the formation ofozone.

Therefore, based on its reactivity andthe concentrations encountered in Canada,formaldehyde is likely to play a role in thephotochemical formation of ground-level ozonein urban areas in Canada.

2.4.3 Experimental animals and in vitro

Information on non-neoplastic effects associatedwith the repeated inhalation or oral exposure oflaboratory animals to formaldehyde issummarized in Tables 2 and 3, respectively.

2.4.3.1 Acute toxicity

Reported LC50s in rodents for the inhalationof formaldehyde range from 493 to 984 mg/m3

(WHO, 1989). For rats and guinea pigs, oralLD50s of 800 and 260 mg/kg-bw have beenreported (WHO, 1989). Acute exposure ofanimals to elevated concentrations offormaldehyde (e.g., >120 mg/m3) producesdyspnea, vomiting, hypersalivation, musclespasms and death (WHO, 1989). Alterations in

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re to

0.6

mg/

m3

(and

to a

less

er e

xten

t to

2.4

mg/

m3 ) a

fter

1da

y of

exp

osur

e on

ly. [

num

ber

and

sex

of a

nim

als

not s

peci

fied]

His

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

. Inh

ibiti

on o

f muc

ocili

ary

clea

ranc

e.

His

topa

thol

ogic

al e

ffec

ts a

nd in

crea

sed

cell

prol

ifera

tion

in n

asal

cavi

ty. I

n an

imal

s w

ith th

e sa

me

daily

cum

ulat

ive

expo

sure

tofo

rmal

dehy

de, t

he e

ffec

ts w

ere

grea

ter i

n an

imal

s ex

pose

din

term

itten

tly to

the

high

er c

once

ntra

tion.

His

topa

thol

ogic

al e

ffec

ts a

nd in

crea

sed

cell

prol

ifera

tion

inna

salc

avity

and

upp

er p

ortio

ns o

f res

pira

tory

trac

t. [e

xpos

ure

tofo

rmal

dehy

de h

ad n

o hi

stop

atho

logi

cal e

ffect

on

the

lung

s or

othe

r in

tern

al o

rgan

s]

His

topa

thol

ogic

al e

ffec

ts a

nd in

crea

sed

cell

prol

ifera

tion

in n

asal

cavi

ty.

His

topa

thol

ogic

al e

ffec

ts a

nd in

crea

sed

cell

prol

ifera

tion

in n

asal

cavi

ty. [

expo

sure

to fo

rmal

dehy

de h

ad n

o hi

stop

atho

logi

cal e

ffect

on th

e lu

ngs,

trac

hea

or c

arin

a]

His

topa

thol

ogic

al e

ffec

ts a

nd in

crea

sed

cell

prol

ifera

tion

in n

asal

cavi

ty.

His

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

. [ex

posu

re o

f mal

esto

23.8

mg/

m3pr

oduc

ed n

on-s

igni

fican

t inc

reas

e in

inci

denc

e of

hist

opat

holo

gica

l effe

cts

in th

e la

rynx

. The

aut

hors

not

ed m

inim

alfo

cal s

quam

ous

met

apla

sia

with

in th

e re

spir

ator

y ep

ithel

ium

in a

smal

l num

ber

(2/1

0 m

ales

, 1/1

0 fe

mal

es) o

f ani

mal

s ex

pose

d to

1.2

mg/

m3 ]

Swen

berg

et

al.,

1983

, 198

6

Mor

gan

et a

l., 1

986b

Wilm

er

et a

l., 1

987

Mon

ticel

lo

et a

l., 1

989

Reu

zel

et a

l., 1

990

Mon

ticel

lo

et a

l., 1

991

Cas

see

et a

l., 1

996

Wou

ters

en

et a

l., 1

987

2.4

mg/

m3

(rat

s)7.

2 m

g/m

3(m

ice)

2.4

mg/

m3

1.3

mg/

m3

2.4

mg/

m3

1.2

mg/

m3

1.2

mg/

m3

7.2

mg/

m3

(rat

s)18

mg/

m3

(mic

e)

7.1

mg/

m3

6 m

g/m

3

7.2

mg/

m3

3.7

mg/

m3

7.4

mg/

m3

3.8

mg/

m3

11.6

mg/

m3


TA

BL

E2

(con

tinue

d)

Pro

toco

lR

esul

tsC

riti

cal e

ffec

tR

efer

ence

[com

men

ts]

NO

(A)E

LL

O(A

)EL

Gro

ups

of 1

0 m

ale

Wis

tar

rats

exp

osed

to 0

, 0.1

, 1.0

or 9

.4 p

pm (

0, 0

.12,

1.2

or

11.3

mg/

m3 )

for

mal

dehy

defo

r 6

hour

s/da

y, 5

day

s/w

eek,

for

13

wee

ks.

Gro

ups

of 5

0 m

ale

and

fem

ale

Wis

tar

rats

exp

osed

to0,

0.3

, 1 o

r 3

ppm

(0,

0.4

, 1.2

or

3.6

mg/

m3 )

form

alde

hyde

for

6 h

ours

/day

, 5 d

ays/

wee

k, f

or13

wee

ks.

Gro

ups

of 2

5 m

ale

Wis

tar

rats

exp

osed

to 0

, 1 o

r2

ppm

(0,

1.2

or

2.4

mg/

m3 )

for

mal

dehy

de f

or 8

hour

s/da

y (c

ontin

uous

exp

osur

e) o

r to

2 o

r 4

ppm

(2.4

or 4

.8 m

g/m

3 ) f

orm

alde

hyde

in e

ight

30-

min

ute

expo

sure

per

iods

sep

arat

ed b

y 30

-min

ute

inte

rval

s(i

nter

mitt

ent e

xpos

ure)

, 5 d

ays/

wee

k fo

r 13

wee

ks.

Gro

ups

of 1

0 m

ale

F344

rat

s ex

pose

d to

0, 0

.7, 2

.0,

5.9,

10.

5 or

14.

5 pp

m (

0, 0

.8, 2

.4, 7

.1, 1

2.6

or17

.4m

g/m

3 ) f

orm

alde

hyde

for

6 h

ours

/day

, 5da

ys/w

eek,

for

11

wee

ks a

nd 4

day

s.

Chr

onic

tox

icit

yG

roup

s of

cyn

omol

gus

mon

keys

(6

mal

e), r

ats

(20

mal

e an

d fe

mal

e) a

nd h

amst

ers

(10

mal

e an

d fe

mal

e)ex

pose

d to

0, 0

.2, 1

or

3 pp

m (

0, 0

.24,

1.2

or

3.6

mg/

m3 )

for

mal

dehy

de f

or 2

2 ho

urs/

day,

7da

ys/w

eek,

for

26

wee

ks.

Gro

ups

of a

ppro

xim

atel

y 12

0 m

ale

and

fem

ale

F344

rats

and

B6C

3F1

mic

e ex

pose

d to

0, 2

.0, 5

.6 o

r14

.3pp

m (

0, 2

.4, 6

.7 o

r 17

.2 m

g/m

3 ) f

orm

alde

hyde

for

6 ho

urs/

day,

5 d

ays/

wee

k, f

or u

p to

24

mon

ths,

follo

wed

by

an o

bser

vatio

n pe

riod

of

6 m

onth

s.

Gro

ups

of 1

0 m

ale

Wis

tar

rats

exp

osed

to 0

, 0.1

, 1.0

or 9

.4pp

m (

0, 0

.12,

1.2

or

11.3

mg/

m3 )

for

mal

dehy

defo

r 6

hour

s/da

y, 5

day

s/w

eek,

for

52

wee

ks.

His

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

. [ex

posu

re to

form

alde

hyde

had

no

effe

ct u

pon

hepa

tic p

rote

in o

rgl

utat

hion

e le

vels

]

His

topa

thol

ogic

al e

ffec

ts a

nd in

crea

sed

cell

prol

ifera

tion

inna

sal c

avity

. [m

ostly

qua

litat

ive

desc

ript

ion

ofhi

stop

atho

logi

cal c

hang

es in

the

nasa

l cav

ity. E

vide

nce

pres

ente

d of

som

e tr

ansi

ently

incr

ease

d ce

ll pr

olife

ratio

n at

low

er c

once

ntra

tions

]

His

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

. In

anim

als

with

the

sam

e cu

mul

ativ

e ex

posu

re to

form

alde

hyde

(i.e

.,19

.2m

g/m

3 -hou

rs p

er d

ay),

the

inci

denc

e of

sub

stan

ce-r

elat

edhi

stop

atho

logi

cal c

hang

es in

the

resp

irato

ry e

pith

eliu

m w

asin

crea

sed

in a

nim

als

expo

sed

inte

rmitt

ently

to th

e hi

gher

conc

entra

tion.

[the

se c

once

ntra

tions

of f

orm

alde

hyde

had

no

sign

ifica

nt e

ffect

upo

n ce

ll pr

olife

ratio

n in

the

nasa

l cav

ity]

His

topa

thol

ogic

al e

ffec

ts a

nd in

crea

sed

cell

prol

ifera

tion

inna

sal c

avity

.

Mon

keys

and

rats

(his

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

).C

ompa

rabl

e ef

fect

s ob

serv

ed in

bot

h sp

ecie

s.

Rat

s an

d m

ice

(his

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

).

His

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

.

App

elm

an

et a

l., 1

988

Zw

art e

t al

., 19

88

Wilm

er e

t al

., 19

89

Cas

anov

a et

al.,

199

4

Rus

ch e

t al

., 19

83

Swen

berg

et

al.,

198

0; K

erns

et

al.,

198

3

App

elm

an

et a

l., 1

988

1.2

mg/

m3

1.2

mg/

m3

2.4

mg/

m3

2.4

mg/

m3

1.2

mg/

m3

2.4

mg/

m3

(mic

e)

1.2

mg/

m3

11.3

mg/

m

3.6

mg/

m3

4.8

mg/

m3

7.1

mg/

m3

3.6

mg/

m3

2.4

mg/

m3

(rat

s)

11.3

mg/

m3


TA

BL

E2

(con

tinue

d)

Pro

toco

lR

esul

tsC

riti

cal e

ffec

tR

efer

ence

[com

men

ts]

NO

(A)E

LL

O(A

)EL

Chr

onic

tox

icit

yG

roup

s of

30

mal

e W

ista

r ra

ts e

xpos

ed to

0, 0

.1, 1

or

9.8

ppm

(0,

0.1

2, 1

.2 o

r 11

.8m

g/m

3 ) f

orm

alde

hyde

for

6 ho

urs/

day,

5 d

ays/

wee

k, f

or 2

8 m

onth

s.

Gro

ups

of 3

0 W

ista

r ra

ts e

xpos

ed to

0, 0

.1, 1

or

9.2

ppm

(0,

0.1

2, 1

.2 o

r 11

mg/

m3 )

for

mal

dehy

defo

r6

hour

s/da

y, 5

day

s/w

eek,

for

3 m

onth

s an

d th

enob

serv

ed f

or a

fur

ther

25-

mon

th p

erio

d.

Gro

ups

of a

ppro

xim

atel

y 90

–150

mal

e F3

44 r

ats

expo

sed

to 0

, 0.7

, 2, 6

, 10

or 1

5 pp

m (

0, 0

.8, 2

.4, 7

.2,

12 o

r 18

mg/

m3 )

for

mal

dehy

de f

or 6

hou

rs/d

ay,

5da

ys/w

eek,

for

up

to 2

4 m

onth

s.

Gro

ups

of 3

2 m

ale

F344

rat

s ex

pose

d to

0, 0

.3, 2

.17

or 1

4.85

ppm

(0,

0.4

, 2.6

or

17.8

mg/

m3 )

form

alde

hyde

for

6 h

ours

/day

, 5 d

ays/

wee

k, f

or u

pto

28 m

onth

s.

1.2

mg/

m3

1.2

mg/

m3

2.4

mg/

m3

0.4

mg/

m3

11.8

mg/

m3

11 m

g/m

3

7.2

mg/

m3

2.6

mg/

m3

Wou

ters

en

et a

l., 1

989

Wou

ters

en

et a

l., 1

989

Mon

ticel

lo

et a

l., 1

996

Kam

ata

et a

l., 1

997

His

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

.

His

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

. [re

lativ

ely

shor

tpe

riod

of e

xpos

ure

to fo

rmal

dehy

de]

His

topa

thol

ogic

al e

ffec

ts a

nd in

crea

sed

cell

prol

ifera

tion

inna

sal c

avity

.

His

topa

thol

ogic

al e

ffec

ts in

nas

al c

avity

. [in

cide

nce

sum

med

for

all a

nim

als

exam

ined

dur

ing

inte

rim

and

term

inal

sacr

ifice

s]


TA

BL

E3

Sum

mar

y of

non

-neo

plas

tic e

ffec

t lev

els

(ora

l exp

osur

e) f

or f

orm

alde

hyde

Pro

toco

lR

esul

tsC

riti

cal e

ffec

tR

efer

ence

[com

men

ts]

NO

EL

LO

(A)E

LSh

ort-

term

tox

icit

yG

roup

s of

10

mal

e an

d fe

mal

e W

ista

r ra

ts a

dmin

iste

red

drin

king

wat

er c

onta

inin

g am

ount

s of

for

mal

dehy

dees

timat

ed s

uffi

cien

t to

prov

ide

targ

et in

take

s of

0, 5

,25

or 1

25 m

g/kg

-bw

per

day

for

4 w

eeks

.

Subc

hron

ic t

oxic

ity

Gro

ups

of 1

5 m

ale

and

fem

ale

Spra

gue-

Daw

ley

rats

adm

inis

tere

d dr

inki

ng w

ater

con

tain

ing

amou

nts

offo

rmal

dehy

de e

stim

ated

suf

fici

ent t

o ac

hiev

e ta

rget

dose

s of

0, 5

0, 1

00 o

r 15

0 m

g/kg

-bw

per

day

for

13w

eeks

.

Gro

ups

of f

our

mal

e an

d fe

mal

e be

agle

dog

sad

min

iste

red

diet

s co

ntai

ning

sol

utio

ns o

ffo

rmal

dehy

de in

am

ount

s es

timat

ed s

uffi

cien

t to

achi

eve

targ

et d

oses

of

0, 5

0, 7

5 or

100

mg/

kg-b

wpe

rda

y fo

r 90

day

s.

Chr

onic

tox

icit

yG

roup

s of

70

mal

e an

d fe

mal

e W

ista

r ra

ts a

dmin

iste

red

drin

king

wat

er c

onta

inin

g fo

rmal

dehy

de a

djus

ted

toac

hiev

e ta

rget

inta

kes

rang

ing

from

0 to

125

mg/

kg-b

wpe

r da

y fo

r up

to 2

yea

rs. [

The

ave

rage

con

cent

ratio

nof

form

alde

hyde

in th

e dr

inki

ng w

ater

was

0, 2

0, 2

60or

1900

mg/

Lin

the

cont

rol,

low

-, m

id-

and

high

-dos

egr

oups

, res

pect

ivel

y.]

Gro

ups

of 2

0 m

ale

and

fem

ale

Wis

tar

rats

adm

inis

tere

ddr

inki

ng w

ater

con

tain

ing

0, 0

.02%

, 0.1

% o

r 0.

5%(0

,200

, 100

0 or

500

0 m

g/L

) fo

rmal

dehy

de f

or 2

4m

onth

s (f

or a

ppro

xim

ate

inta

kes

of 0

, 10,

50

and

300

mg/

kg-b

w p

er d

ay, r

espe

ctiv

ely)

.

25 m

g/kg

-bw

per

day

50 m

g/kg

-bw

per

day

75 m

g/kg

-bw

per

day

15 m

g/kg

-bw

per

day

10 m

g/kg

-bw

per

day

125

mg/

kg-b

wpe

rda

y

100

mg/

kg-b

wpe

rda

y

100

mg/

kg-b

wpe

rda

y

82 m

g/kg

-bw

per

day

300

mg/

kg-b

wpe

rda

y

His

topa

thol

ogic

al e

ffec

ts in

the

fore

stom

ach

and

incr

ease

in r

elat

ive

kidn

ey w

eigh

t. [e

xpos

ure

to fo

rmal

dehy

de h

adno

effe

ct u

pon

the

mor

phol

ogy

of th

e liv

er o

r ki

dney

s]

Red

uctio

n in

wei

ght g

ain.

[ex

posu

re to

form

alde

hyde

had

no e

ffect

on

the

bloo

d or

uri

ne a

nd p

rodu

ced

nohi

stop

atho

logi

cal c

hang

es in

inte

rnal

org

ans

(inc

ludi

ngth

e ga

stro

inte

stin

al m

ucos

a);

limite

d nu

mbe

r of

endp

oint

s ex

amin

ed;

targ

et in

take

s m

ay n

ot h

ave

been

achi

eved

]

Red

uctio

n in

wei

ght g

ain.

[ex

posu

re to

form

alde

hyde

had

no e

ffect

upo

n he

mat

olog

ical

or

clin

ical

par

amet

ers

or o

rgan

his

topa

thol

ogy

(inc

ludi

ng th

e ga

stro

inte

stin

alm

ucos

a);

limite

d nu

mbe

r of

end

poin

ts e

xam

ined

; ta

rget

inta

kes

may

not

hav

e be

en a

chie

ved]

His

topa

thol

ogic

al e

ffec

ts in

the

fore

stom

ach

and

glan

dula

r st

omac

h. R

educ

ed w

eigh

t gai

n. [

expo

sure

tofo

rmal

dehy

de h

ad n

o ef

fect

upo

n he

mat

olog

ical

para

met

ers]

Red

uced

wei

ght g

ain,

alte

red

clin

ical

che

mis

trie

san

dhi

stop

atho

logi

cal e

ffec

ts in

the

fore

stom

ach

and

glan

dula

rst

omac

h. [

smal

l gro

up s

izes

]

Til

et a

l., 1

988

Joha

nnse

n et

al.,

1986

Joha

nnse

n et

al.,

1986

Til

et a

l., 1

989

Tobe

et

al.,

1989

mucociliary clearance and histopathologicalchanges within the nasal cavity have beenobserved in rats exposed acutely to formaldehydeat concentrations of ≥2.6 mg/m3 (Monteiro-Riviere and Popp, 1986; Morgan et al., 1986a;Bhalla et al., 1991).

2.4.3.2 Short-term and subchronic toxicity

2.4.3.2.1 Inhalation

Histopathological effects and an increase in cellproliferation have been observed in the nasal andrespiratory tracts of laboratory animals repeatedlyexposed by inhalation to formaldehyde for upto 13 weeks. Most short-term and subchronicinhalation toxicity studies have been conductedin rats, with histopathological effects (e.g.,hyperplasia, squamous metaplasia, inflammation,erosion, ulceration, disarrangements) andsustained proliferative response in the nasal cavityat concentrations of 3.7 mg/m3 and above. Effectswere generally not observed at 1.2 or 2.4 mg/m3,although there have been occasional reportsof small, transient increases in epithelial cellproliferation at lower concentrations (Swenberget al., 1983; Zwart et al., 1988). Owing tothe reactivity of this substance as well as todifferences in breathing patterns between rodentsand primates, adverse effects following short-terminhalation exposure of formaldehyde in rodentsare generally restricted to the nasal cavity,while in primates effects may be observed deeperwithin the respiratory tract. The developmentof histopathological changes and/or increases inepithelial cell proliferation within the nasal cavityof rats appears to be more closely related to theconcentration of formaldehyde to which theanimals are exposed than to the total dose(i.e., cumulative exposure) (Swenberg et al.,1983, 1986; Wilmer et al., 1987, 1989).

2.4.3.2.2 Oral exposure

Data on toxicological effects arising from theshort-term oral exposure of laboratory animals toformaldehyde are limited to one study in whichhistopathological effects in the forestomach werenot observed in Wistar rats receiving 25 mg/kg-bw

per day in drinking water over a period of 4 weeks(Til et al., 1988). Information on toxicologicaleffects of the subchronic oral exposure oflaboratory animals to formaldehyde is limited tosingle studies in rats and dogs, in which the targetintakes may not have been achieved (Johannsenet al., 1986). Reduction of weight gain in bothspecies was observed at 100 mg/kg-bw per day;No-Observed-Effect Levels (NOELs) were 50 and75 mg/kg-bw per day, respectively.

2.4.3.3 Chronic toxicity and carcinogenicity

2.4.3.3.1 Chronic toxicity

The principal non-neoplastic effects in animalsexposed to formaldehyde by inhalation arehistopathological changes (e.g., squamousmetaplasia, basal hyperplasia, rhinitis) within thenasal cavity and respiratory tract. Most chronicinhalation toxicity studies have been conductedin rats, with the development of histopathologicaleffects in the nasal cavity being observed atformaldehyde concentrations of 2.4 mg/m3 andhigher (Swenberg et al., 1980; Kerns et al., 1983;Rusch et al., 1983; Appelman et al., 1988;Woutersen et al., 1989; Monticello et al., 1996).The principal non-neoplastic effect inanimals exposed orally to formaldehyde is thedevelopment of histopathological changes withinthe forestomach and glandular stomach, witheffects in rats at 82 mg/kg-bw per day and above(Til et al., 1989; Tobe et al., 1989).

2.4.3.3.2 Carcinogenicity

An increased incidence of tumours in the nasalcavity was observed in five investigations inwhich rats were exposed via inhalation toconcentrations of formaldehyde greater than7.2 mg/m3. Currently, there is no definitiveevidence indicating that formaldehyde iscarcinogenic when administered orally tolaboratory animals. Limited chronic dermaltoxicity studies (Krivanek et al., 1983; Iversen,1988) and older investigations in which animalswere injected with formaldehyde (WHO, 1989)add little additional weight to the evidence forthe carcinogenicity of formaldehyde in animals.


FIGURE 1 Formaldehyde carcinogenicity

Inhalation

The results of carcinogenesis bioassays bythe inhalation route in rats in which therewere increases in nasal tumour incidence arepresented in Figure 1. Exposure–response in theseinvestigations was similar and highly non-linear,with sharp increases in tumour incidence in thenasal cavity occurring only at concentrationsgreater than 6 ppm (7.2 mg/m3) formaldehyde.The most extensive bioassay conducted to datein which proliferative responses in the epitheliumof various regions of the nasal cavity wereinvestigated is that by Monticello et al. (1996).

In a study in which groups of maleand female F344 rats were exposed to 0, 2.0,5.6 or 14.3 ppm (0, 2.4, 6.7 or 17.2 mg/m3)formaldehyde for 6 hours per day, 5 days perweek, for up to 24 months, followed by anobservation period of 6 months, the incidence ofsquamous cell carcinoma in the nasal cavity wasmarkedly increased only in the high-concentrationgroups compared with the unexposed controls.

The incidence of this tumour was 0/118, 0/118,1/119 (1%) and 51/117 (44%) in males and 0/118,0/118, 1/116 (1%) and 52/119 (44%) in females inthe control, low-, mid- and high-concentrationgroups, respectively (Kerns et al., 1983). Precisehistopathological analysis revealed that inanimals exposed to the highest concentrationof formaldehyde, more than half of the nasalsquamous tumours were located on the lateral sideof the nasal turbinate and adjacent lateral wall atthe front of the nose (Morgan et al., 1986c). Twonasal carcinomas (in male and female rats) andtwo undifferentiated carcinomas or sarcomas (inmale rats) were also observed in animals from thehigh-concentration groups.

In a follow-up study, Monticello et al.(1996) exposed male F344 rats to 0, 0.7, 2, 6,10 or 15 ppm (0, 0.8, 2.4, 7.2, 12 or 18 mg/m3)formaldehyde for 6 hours per day, 5 days perweek, for up to 24 months and assessed tumourincidence within the nasal cavity. Epithelial cellproliferation at seven sites within the nasal cavity(e.g., anterior lateral meatus, posterior lateral


[Formaldehyde] (mg/m3)

meatus, anterior mid-septum, posterior mid-septum, anterior dorsal septum, medialmaxilloturbinate and maxillary sinus) wasalso determined after 3, 6, 12 and 18 monthsof exposure. The overall incidence of nasalsquamous cell carcinoma in animals exposed to0, 0.8, 2.4, 7.2, 12 or 18 mg/m3 formaldehydewas 0/90, 0/90, 0/90, 1/90 (1%), 20/90 (22%)and 69/147 (47%), respectively. Tumours werelocated primarily in the anterior lateral meatus,the posterior lateral meatus as well as the mid-septum.

In a more limited study in whichdose–response was not examined, Sellakumaret al. (1985) exposed male Sprague-Dawley ratsto 0 or 14.8 ppm (0 or 17.8 mg/m3) formaldehydefor 6 hours per day, 5 days per week, forapproximately 2 years. These authors reporteda marked increase in the incidence of nasalsquamous cell carcinoma — 0/99 and 38/100 inthe control and formaldehyde-exposed animals,respectively. These tumours were considered tohave arisen primarily from the naso-maxillaryturbinates and nasal septum. An increase in theincidence of nasal squamous cell carcinoma wasalso reported in a study by Tobe et al. (1985), inwhich groups of male F344 rats were exposed toformaldehyde at 0, 0.36, 2.4 or 17 mg/m3 for 6hours per day, 5 days per week, for 28 months.Fourteen of 32 animals in the high-concentrationgroup (i.e., 44%) developed nasal squamous cellcarcinoma, compared with none in the unexposed(control), low- or mid-concentration groups.In another study in which male F344 rats wereexposed to 0, 0.3, 2.17 or 14.85 ppm (0, 0.36, 2.6or 17.8 mg/m3) formaldehyde for 6 hours per day,5 days per week, for up to 28 months, anincreased incidence of nasal squamous cellcarcinoma was observed in the high-concentrationgroup (Kamata et al., 1997); the overall incidenceof nasal tumours among these formaldehyde-exposed animals, dead or sacrificed after 12,18, 24 and 28 months on study, was 13/32 (41%),compared with 0/32 and 0/32 in two groups ofunexposed controls.

Compared with unexposed controls, theincidence of nasal squamous cell carcinoma was

not significantly increased in male Wistar ratsexposed to formaldehyde at concentrations of0.12, 1.2 or 11.8 mg/m3 for 6 hours per day,5 days per week, for 28 months (i.e., 0%and 4% of the controls and animals exposedto 11.8 mg/m3, respectively, had nasal cellcarcinomas) (Woutersen et al., 1989).However, when animals with noses damaged byelectrocoagulation were similarly exposed, theincidence of this tumour type was markedlyincreased in the high-concentration group(i.e., 1/54, 1/58, 0/56 and 15/58 in animalsexposed to 0, 0.12, 1.2 or 11.8 mg/m3,respectively) (Woutersen et al., 1989).

In other studies in rats, a small but notstatistically significant increase in the incidenceof tumours of the nasal cavity was observed inanimals exposed daily to 20 ppm (24 mg/m3)formaldehyde for 13 weeks and then observeduntil 130 weeks (Feron et al., 1988), but notin animals exposed to 9.4 ppm (11.3 mg/m3)formaldehyde for 52 weeks (Appelman et al.,1988) or to 12.4 ppm (14.9 mg/m3) formaldehydefor 104 weeks (in either the presence or absenceof wood dust at a concentration of 25 mg/m3)(Holmström et al., 1989a). The lack of observedstatistically significant increases in tumourincidence in these investigations may be afunction of small group sizes and/or shortperiods of exposure.

In a study in which groups of male andfemale B6C3F1 mice were exposed to 0, 2.0,5.6 or 14.3 ppm (0, 2.4, 6.7 or 17.2 mg/m3)formaldehyde for 6 hours per day, 5 days perweek, for up to 24 months, followed by anobservation period of 6 months, there wereno statistically significant increases in theincidence of nasal cavity tumours, compared withunexposed controls (Kerns et al., 1983). After24 months’ exposure to formaldehyde, two malemice in the high-concentration group developedsquamous cell carcinoma in the nasal cavity. Theabsence of a significant increase in the incidenceof nasal tumours in mice has been attributed, atleast in part, to the greater reduction in minutevolume in mice than in rats exposed toformaldehyde (Chang et al., 1981; Barrow et al.,



1983). The incidence of lung tumours was notincreased in an early study in which groups of42–60 C3H mice (sex not specified) were exposedto formaldehyde at concentrations of 0, 50, 100or 200 mg/m3 for three 1-hour periods per weekfor 35 weeks, although, due to high mortality,treatment in the high-dose group wasdiscontinued in the 4th week, and there was noevaluation of the nasal tissues (Horton et al.,1963). Compared with 132 unexposed controls,there was no increase in the incidence ofrespiratory tract tumours in 88 male Syrianhamsters exposed to 12 mg formaldehyde/m3 fortheir entire lives (Dalbey, 1982).

Oral exposure

In the most comprehensive study identifiedin male and female Wistar rats administereddrinking water containing formaldehyde inamounts estimated to achieve target intakesranging up to 125 mg/kg-bw per day for up to2 years, there was no significant increase intumour incidence compared with unexposedcontrols (Til et al., 1989). Tobe et al. (1989) alsoreported, although data were not presented, that,compared with unexposed controls, tumourincidence was not increased in small groups ofmale and female Wistar rats administereddrinking water containing up to 5000 mgformaldehyde/L (i.e., providing intakes up to 300mg/kg-bw per day).

In contrast, increases in tumours of thehematopoietic system were reported by Soffrittiet al. (1989), based upon the results of a studyin which Sprague-Dawley rats were administereddrinking water containing formaldehyde atconcentrations ranging from 0 to 1500 mg/Lfor 104 weeks and the animals observed untildeath (estimated intakes up to approximately200 mg/kg-bw per day). The proportion ofmales and females with leukemias (all“hemolymphoreticular neoplasias,” e.g.,lymphoblastic leukemias and lymphosarcomas,immunoblastic lymphosarcomas and “other”leukemias) increased from 4% and 3%,respectively, in the controls to 22% and 14%,respectively, in the animals receiving drinking

water containing 1500 mg formaldehyde/L.Compared with unexposed controls, there was nodose-related increase in the incidence of stomachtumours in animals receiving formaldehyde.Limitations of this study include the “pooling” oftumour types, the lack of statistical analysis andlimited examination of non-neoplastic endpoints.Parenthetically, it should be noted that theincidence of hematopoietic tumours (e.g., myeloidleukemia, generalized histiocytic sarcoma) wasnot increased in Wistar rats receiving up to 109 mg formaldehyde/kg-bw per day in drinkingwater for up to 2 years (Til et al., 1989).

Using a rodent model for gastriccarcinogenesis in which Wistar rats were“initiated” with N-methyl-N'-nitro-N-nitrosoguanidine, Takahashi et al. (1986) providedlimited evidence for the tumour-promotingactivity of formaldehyde following oral exposure.

2.4.3.4 Genotoxicity and related endpoints

A wide variety of endpoints have been assessedin in vitro assays of the genotoxicity offormaldehyde (see IARC, 1995, for a review).Generally, the results of these studies haveindicated that formaldehyde is genotoxic athigh concentrations (i.e., weakly genotoxic)in both bacterial and mammalian cells in vitro(inducing both point and large-scale mutations).Formaldehyde induces mutations in Salmonellatyphimurium and in Escherichia coli, with positiveresults obtained in the presence or absence ofmetabolic activation systems. Formaldehydeincreases the frequency of chromatid/chromosomeaberrations, sister chromatid exchange, as well asgene mutations in a variety of rodent and humancell types. Exposure to formaldehyde increasedDNA damage (strand breaks) in human fibroblastsand rat tracheal epithelial cells and increasedunscheduled DNA synthesis in rat nasoturbinateand maxilloturbinate cells.

Exposure of male Sprague-Dawleyrats to 0.5, 3 or 15 ppm (0.6, 3.6 or 18 mg/m3)formaldehyde for 6 hours per day, 5 days perweek, for 1 or 8 weeks had no effect upon theproportion of bone marrow cells with cytogenetic


anomalies (e.g., chromatid or chromosomebreaks, centric fusions) compared with unexposedcontrols, although animals in the group exposedto the highest concentration had a modest (1.7-to 1.8-fold), statistically significant (i.e., p < 0.05)increase in the proportion of pulmonarymacrophage with chromosomal aberrationscompared with controls (approximately 7% and4%, respectively) (Dallas et al., 1992). However,Kitaeva et al. (1990) observed a statisticallysignificant increase in the proportion of bonemarrow cells with chromosomal aberrations(chromatid or chromosome breaks) from femaleWistar rats exposed to low concentrations offormaldehyde for 4 hours per day for 4 months —approximately 0.7%, 2.4% and 4% in animalsexposed to 0, 0.5 or 1.5 mg/m3, respectively. Inolder studies, exposure of male and female F344rats to approximately 0.5, 5.9 or 14.8 ppm (0.6,7.1 or 17.8 mg/m3) formaldehyde for 6 hoursper day for 5 consecutive days had no effect uponthe frequency of sister chromatid exchange orchromosomal aberrations and mitotic index inblood lymphocytes (Kligerman et al., 1984).Statistically significant (p < 0.05) increases inthe proportion of cells with micronuclei andnuclear anomalies (e.g., karyorrhexis, pyknosis,vacuolated bodies) were observed in the stomach,duodenum, ileum and colon within 30 hoursof administration (by gavage) of 200 mgformaldehyde/kg-bw to male Sprague-Dawleyrats (Migliore et al., 1989). No significantevidence of genotoxicity (e.g., micronuclei,chromosomal aberrations) in bone marrow cells,splenic cells or spermatocytes was reported inearlier studies in which various strains of micewere injected intraperitoneally with formaldehyde(Fontignie-Houbrechts, 1981; Gocke et al., 1981;Natarajan et al., 1983).

The mutational profile for formaldehydevaries among cell types and concentration offormaldehyde to which the cells were exposedand includes both point and large-scale changes.In human lymphoblasts, about half of the mutantsat the X-linked hprt locus had deletions of someor all of the hprt gene bands; the other half wereassumed to have point mutations (Crosby et al.,1988). In a subsequent study, six of seven

formaldehyde-induced mutants with normalrestriction fragment patterns had point mutationsat AT sites, with four of these six occurring atone specific site (Liber et al., 1989). Crosby et al.(1988) also examined the mutational spectrainduced by formaldehyde at the gpt gene inE. coli (Crosby et al., 1988). A 1-hour exposure to4 mmol formaldehyde/L induced a spectrum ofmutants that included large insertions (41%), largedeletions (18%) and point mutations (41%), themajority of which were transversions occurring atGC base pairs. Increasing the concentration offormaldehyde to 40 mmol/L resulted in a muchmore homogeneous spectrum, with 92% of themutants being produced by a point mutation, 62%of which were transitions at a single AT base pair.In contrast to these findings, when naked plasmidDNA containing the gpt gene was treated withformaldehyde and shuttled through E. coli, mostof the mutations were found to be frameshifts.

It is the interaction with the genome atthe site of first contact, however, that is of greatestinterest with respect to the carcinogenicity offormaldehyde (i.e., in the induction of nasal tumoursin rats). Formaldehyde-induced DNA–proteincrosslinking (DPX) has been observed in the nasalepithelium of rats (Casanova and Heck, 1987; Heckand Casanova, 1987; Casanova et al., 1989, 1994),as well as in epithelia lining the respiratory tractof monkeys (Casanova et al., 1991) exposed viainhalation. DNA–protein crosslinks are considereda marker of mutagenic potential, since theymay initiate DNA replication errors, resulting inmutation. The exposure–response relationship ishighly non-linear, with a sharp increase in DPXat concentrations above 4 ppm (4.8 mg/m3)formaldehyde (see also Table 4) withoutaccumulation on repeated exposure (Casanova et al.,1994). Formaldehyde has also induced the formationof DNA–protein crosslinks in a variety of humanand rat cell types (Saladino et al., 1985; Bermudezand Delehanty, 1986; Snyder and van Houten, 1986;Craft et al., 1987; Heck and Casanova, 1987; Cosmaet al., 1988; Olin et al., 1996). In 5 of 11 squamouscell carcinomas from rats exposed to 15 ppm(18 mg/m3) for up to 2 years, there were pointmutations at the GC base pairs in the p53 cDNAsequence (Recio et al., 1992).


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2.4.3.5 Reproductive and developmentaltoxicity

Other than a significant (p < 0.01) weight lossin the dams and a 21% reduction in the meanweight of the fetuses from dams in the highestconcentration group, the exposure of pregnantSprague-Dawley rats to 0, 5.2, 9.9, 20 or 39 ppm(0, 6.2, 11.9, 24 or 46.8 mg/m3) formaldehydefor 6 hours per day from days 6 though 20 ofgestation had no effect upon the mean number oflive fetuses, resorptions and implantation sites, orfetal losses per litter; although the occurrence ofmissing sternebra and delayed ossification of thethoracic vertebra was increased in fetuses fromthe highest exposure group, the increases wereneither statistically significant (i.e., p > 0.05) norconcentration-dependent (Saillenfait et al., 1989).

Similarly, although weight gain wassignificantly (p < 0.05) reduced in dams exposedto the highest concentration, exposure of pregnantSprague-Dawley rats to approximately 2, 5 or10 ppm (2.4, 6 or 12 mg/m3) formaldehyde for6 hours per day on days 6 through 15 of gestationhad no substance-related effect upon the numberof fetuses with major malformations or skeletalanomalies; reduced ossification of the pubic andischial bones in fetuses from dams exposed to thetwo highest concentrations of formaldehyde wasattributed to larger litter sizes and small fetalweights. Indices of embryotoxicity (e.g., numberof corpora lutea, implantation sites, live fetuses,resorptions, etc.) were not affected by exposure toformaldehyde (Martin, 1990).

2.4.3.6 Immunological and neurological effects

Other than a significant (p < 0.05) 9% increasein bacterial pulmonary survival in one study ofmice exposed to 15 ppm (18 mg/m3) (Jakab,1992), as well as a statistically significant(p < 0.05 or 0.01) reduction in serum IgM titres inanimals administered 40 or 80 mg/kg-bw per dayorally, 5 days per week, for 4 weeks (Vargováet al., 1993), adverse effects on either cell- orhumoral-mediated immune responses havegenerally not been observed in rats or miceexposed to formaldehyde (Dean et al., 1984;

Adams et al., 1987; Holmstrom et al., 1989b).Endpoints examined in these studies (Dean et al.,1984; Adams et al., 1987; Holmstrom et al.,1989b) included splenic or thymic weights, bonemarrow cellularity, the proportion of splenic B-and T-cells, NK-cell activity, lymphocyteproliferation, the number, function or maturationof peritoneal macrophages, host resistance tobacterial or tumour challenge, and B-cell functionthrough induction of (IgG and IgM) antibodies,with exposures ranging from 1 to 15 ppm (1.2 to18 mg/m3) formaldehyde.

Results of studies in laboratory animalshave indicated that formaldehyde may enhancetheir sensitization to inhaled allergens. In femaleBalb/c mice sensitized to ovalbumin, the serumtitre of IgE anti-ovalbumin antibodies wasincreased approximately 3-fold in animals pre-exposed to 2.0 mg formaldehyde/m3 for 6 hoursper day on 10 consecutive days (Tarkowski andGorski, 1995). Similarly, exposure of femaleDunkin-Hartley guinea pigs, sensitized to airborneovalbumin, to 0.3 mg formaldehyde/m3 produceda significant (p < 0.01) 3-fold increase inbronchial sensitization, as well as a significant(p < 0.05) 1.3-fold increase in serum anti-ovalbumin antibodies (Riedel et al., 1996).

2.4.3.7 Toxicokinetics/metabolism and modeof carcinogenesis

Formaldehyde is formed endogenously duringthe metabolism of amino acids and xenobiotics.In vivo, most formaldehyde is probably bound(reversibly) to macromolecules.

Owing to its reactivity with biologicalmacromolecules, most of the formaldehyde thatis inhaled is deposited and absorbed in regionsof the upper respiratory tract with which thesubstance comes into first contact (Heck et al.,1983; Swenberg et al., 1983; Patterson et al.,1986). In rodents, which are obligate nosebreathers, deposition and absorption occurprimarily in the nasal passages, while in oronasalbreathers (such as monkeys and humans), theylikely occur primarily in the nasal passages andoral cavity but also in the trachea and bronchus.


Species-specific differences in the actual sitesof uptake of formaldehyde and associated lesionsof the upper respiratory tract are determinedby complex interactions among nasal anatomy,ventilation and breathing patterns (e.g., nasalversus oronasal) (Monticello et al., 1991).

Formaldehyde produces intra- andintermolecular crosslinks within proteins andnucleic acids upon absorption at the site ofcontact (Swenberg et al., 1983). It is also rapidlymetabolized to formate by a number of widelydistributed cellular enzymes, the most importantof which is NAD+-dependent formaldehydedehydrogenase. Metabolism by formaldehydedehydrogenase occurs subsequent to formationof a formaldehyde–glutathione conjugate.Formaldehyde dehydrogenase has been detectedin human liver and red blood cells and in anumber of tissues (e.g., respiratory and olfactoryepithelium, kidney, brain) in the rat.

Due to its deposition principallywithin the respiratory tract and rapid metabolism,exposure to high atmospheric concentrations offormaldehyde does not result in an increase inblood concentrations in humans (Heck et al.,1985).

In animal species, the half-life offormaldehyde in the circulation ranges fromapproximately 1 to 1.5 minutes (Rietbrock, 1969;McMartin et al., 1979). Formaldehyde andformate are incorporated into the one-carbonpathways involved with the biosynthesis ofproteins and nucleic acids. Owing to the rapidmetabolism of formaldehyde, much of thismaterial is eliminated in the expired air (ascarbon dioxide) shortly after exposure. Excretionof formate in the urine is the other major routeof elimination of formaldehyde (Johansson andTjälve, 1978; Heck et al., 1983; Billings et al.,1984; Keefer et al., 1987; Upreti et al., 1987;Bhatt et al., 1988).

The mechanisms by which formaldehydeinduces tumours in the respiratory tract of ratsare not fully understood. Inhibition of mucociliary

clearance is observed in rats exposed acutely toconcentrations of formaldehyde greater than2.4 mg/m3 (Morgan et al., 1986a). There is alsoevidence that glutathione-mediated detoxificationof formaldehyde within nasal tissues becomessaturated in rats at inhalation exposures above4 ppm (4.8 mg/m3) (Casanova and Heck, 1987).This correlates with the non-linear increase inDNA–protein crosslink formation at exposuresabove this level.

A sustained increase in nasalepithelial cell regenerative proliferation resultingfrom cytotoxicity and mutation, for whichDNA–protein crosslinks serve as markers ofpotential, have been identified as likely, althoughnot sufficient, factors contributing to the inductionof nasal tumours in rats induced by formaldehyde.This hypothesis is based primarily on observationof consistent, non-linear dose–responserelationships for all three endpoints (DPX,sustained increases in proliferation and tumours)and concordance of incidence of these effectsacross regions of the nasal passages (see Table 4).

Increased cellular proliferation as aconsequence of epithelial cell toxicity is the mostsignificant determinant of neoplastic progression.The effect of formaldehyde exposure on cellproliferation within the respiratory epithelium ofrats has been examined in a number of short-term,subchronic and chronic studies (Swenberg et al.,1983; Wilmer et al., 1987, 1989; Zwart et al.,1988; Reuzel et al., 1990; Monticello et al., 1991,1996; Casanova et al., 1994). A sustained increasein proliferation of nasal epithelial cells has notbeen observed following the exposure of rats toconcentrations of formaldehyde of ≤2.4 mg/m3

(2 ppm) irrespective of the exposure period.In rats exposed to formaldehyde, increasedrespiratory epithelial cell proliferation in thenasal cavity was more closely related to theconcentration to which the animals were exposedthan to the total cumulative dose (Swenberg et al.,1983). The relative magnitude of increase inproliferative response is dependent upon thespecific site within the nasal cavity and notalways directly related to the length of exposure


(Swenberg et al., 1986; Monticello et al., 1991,1996; Monticello and Morgan, 1994). The extentof the carcinogenic response following exposureto formaldehyde is also dependent upon thesize of the target cell population within specificregions of the nasal cavity (Monticello et al.,1996).

Although direct evidence in humans islacking, increased epithelial cell proliferation(respiratory and olfactory epithelia) andDNA–protein crosslink formation (middleturbinates, lateral wall and septum andnasopharynx) within the upper respiratory tracthave been observed in monkeys exposed toformaldehyde by inhalation (Monticello et al.,1989; Casanova et al., 1991). At similar levelsof exposure, concentrations of DNA–proteincrosslinks were approximately an order ofmagnitude less in monkeys than in rats. In rats,the cumulative yield of DNA–protein crosslinkswas similar after acute and subchronic exposure,suggesting rapid repair (Casanova et al., 1994).Using a model system in which rat tracheapopulated with human tracheobronchial epithelialcells were xenotransplanted into athymic mice,Ura et al. (1989) reported increased humanepithelial cell proliferation following in situexposure to formaldehyde.

2.4.4 Humans

2.4.4.1 Case reports and clinical studies

Reports of death following acute inhalationexposure to formaldehyde were not identified.Ulceration and damage along the gastrointestinaltract have been observed in cases whereformaldehyde had been ingested (Kochhar et al.,1986; Nishi et al., 1988; WHO, 1989). Thereare frequent reports on cases of systemic (e.g.,anaphylaxis) or more often localized (e.g., contactdermatitis) allergic reactions attributed to theformaldehyde (or formaldehyde-containing resins)present in household and personal care (anddental) products, clothing and textiles, bank notepaper, and medical treatments and devices(Maurice et al., 1986; Feinman, 1988; Ebner and

Kraft, 1991; Norton, 1991; Flyvholm and Menné,1992; Fowler et al., 1992; Ross et al., 1992;Vincenzi et al., 1992; Bracamonte et al., 1995; ElSayed et al., 1995; Wantke et al., 1995).

In a number of clinical studies, eye,nose and throat irritation were experienced byvolunteers exposed for short periods to levelsof formaldehyde ranging from 0.3 to 3.6 mg/m3

(Andersen and Mølhave, 1983; Sauder et al.,1986, 1987; Schachter et al., 1986; Green et al.,1987, 1989; Witek et al., 1987; Kulle, 1993;Pazdrak et al., 1993). Mucociliary clearancein the anterior portion of the nasal cavity wasreduced following exposure of volunteers to0.3 mg formaldehyde/m3 (Andersen and Mølhave,1983). Based upon the results of experimentalstudies, it appears that in healthy individuals aswell as those with asthma, brief exposure (upto 3 hours) to concentrations of formaldehydeup to 3.6 mg/m3 had no significant clinicallydetrimental effect upon lung function (Day et al.,1984; Sauder et al., 1986, 1987; Schachter et al.,1986, 1987; Green et al., 1987; Witek et al.,1987; Harving et al., 1990).

2.4.4.2 Epidemiological studies

2.4.4.2.1 Cancer

Possible associations between formaldehyde andcancers of various organs have been examinedextensively in epidemiological studies inoccupationally exposed populations. Indeed, therehave been over 30 cohort and case–control studiesof professionals, including pathologists andembalmers, and industrial workers. In addition,several authors have conducted meta-analyses ofthe available data.

Relevant risk measures from recentcase–control and cohort studies are presented inTables 5 and 6, respectively.

In most epidemiological studies, thepotential association between exposure toformaldehyde and cancer of the respiratorytract has been examined. However, in some


TA

BL

E5

Sum

mar

y of

ris

k m

easu

res

from

cas

e–co

ntro

l stu

dies

Can

cer

1F

orm

alde

hyde

exp

osur

eR

isk

mea

sure

(95

% C

I)R

efer

ence

(co

mm

ents

)


Oro

phar

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or h

ypop

hary

nxSE

ER

pop

ulat

ion

base

d –

Was

hing

ton

Stat

e

Nas

opha

rynx

SEE

R p

opul

atio

n ba

sed–

Was

hing

ton

Stat

e

Nas

opha

rynx

SEE

R p

opul

atio

n ba

sed

– W

ashi

ngto

nSt

ate

Nas

al s

quam

ous

cell

carc

inom

aH

ospi

tal b

ased

– N

ethe

rlan

ds

Squa

mou

s ce

ll ca

rcin

oma

of n

asal

cavi

ty/p

aran

asal

sin

usD

anis

h C

ance

r R

egis

try

Nas

opha

rynx

Con

nect

icut

Tum

our

Reg

istr

y

Ora

l/oro

phar

ynx

Popu

latio

n ba

sed

– T

urin

, Ita

ly

Lar

ynx

SEE

R p

opul

atio

n ba

sed

– W

ashi

ngto

nSt

ate

Nas

al c

avity

/par

anas

al s

inus

(a

deno

carc

inom

a)

Popu

latio

n ba

sed

– Fr

ance

≥10

year

s oc

cupa

tiona

l exp

osur

e oc

cupa

tiona

lexp

osur

e sc

ore

of ≥

20

expo

sure

sco

re o

f ≥2

0

resi

dent

ial e

xpos

ure

of ≥

10 y

ears

resi

dent

ial e

xpos

ure

of <

10 y

ears

occu

patio

nal e

xpos

ure

asse

ssm

ent A

occu

patio

nal e

xpos

ure

asse

ssm

ent B

occu

patio

nal e

xpos

ure

with

out e

xpos

ure

tow

ood

dust

high

est p

oten

tial e

xpos

ure

cate

gory

high

est p

oten

tial e

xpos

ure

cate

gory

an

d dy

ing

at 6

8+ y

ears

of

age

“any

” oc

cupa

tiona

l exp

osur

e“p

roba

ble

or d

efin

ite”

occu

patio

nal e

xpos

ure

“hig

h” o

ccup

atio

nal e

xpos

ure

occu

patio

nal e

xpos

ure

of ≥

10 y

ears

occu

patio

nal e

xpos

ure

scor

e of

≥20

“any

” ex

posu

re w

ithou

t exp

osur

e to

woo

d du

st“a

ny”

expo

sure

with

med

ium

to h

igh

expo

sure

to w

ood

dust

“n

o” e

xpos

ure

but m

ediu

m to

hig

h ex

posu

re to

woo

d du

st

OR

= 1

.3 (

0.7–

2.5)

OR

= 1

.5 (

0.7–

3.0)

OR

= 2

.1 (

0.6–

7.8)

OR

= 5

.5 (

1.6–

19.4

)O

R =

2.1

(0.

7–6.

6)

OR

= 3

.0 (

1.3–

6.4)

2

OR

= 1

.9 (

1.0–

3.6)

2

OR

= 2

.0 (

0.7–

5.9)

OR

= 2

.3 (

0.9–

6.0)

OR

= 4

.0 (

1.3–

12)

OR

= 1

.6 (

0.9–

2.8)

OR

= 1

.8 (

0.6–

5.5)

OR

= 2

.0 (

0.2–

19.5

)O

R =

1.3

(0.

6–3.

1)O

R =

1.3

(0.

5–3.

3)

OR

= 8

.1 (

0.9–

72.9

)O

R =

692

(91

.9–5

210)

OR

= 1

30 (

14.1

–119

1)

Vau

ghan

et a

l., 1

986a

(IA

RC

Wor

king

Gro

up n

oted

that

diff

eren

t pro

porti

ons

ofin

terv

iew

s co

nduc

ted

with

nex

t-of-

kin

case

s an

d co

ntro

lsm

ay h

ave

affe

cted

odd

s ra

tios)

Vau

ghan

et a

l., 1

986a

(IA

RC

Wor

king

Gro

up n

oted

that

diff

eren

t pro

porti

ons

ofin

terv

iew

s co

nduc

ted

with

nex

t-of-

kin

case

s an

d co

ntro

lsm

ay h

ave

affe

cted

odd

s ra

tios)

Vau

ghan

et a

l., 1

986b

( IA

RC

Wor

king

Gro

up c

onsi

dere

d liv

ing

in a

mob

ileho

me

a po

or p

roxy

for e

xpos

ure

Hay

es e

t al.,

198

6

(IA

RC

Wor

king

Gro

up n

oted

that

a g

reat

er p

ropo

rtio

nof

cas

es th

an c

ontr

ols

wer

e de

ad a

nd v

aria

ble

num

bers

of n

ext-

of-k

in w

ere

inte

rvie

wed

, 10%

of

cont

rols

but

none

of

case

s, b

y te

leph

one.

Not

ed a

lso

that

, alth

ough

diff

eren

t, re

sults

for

ass

essm

ents

A&

B w

ere

both

posi

tive)

Ols

en a

nd A

snae

s, 1

986

(IA

RC

Wor

king

Gro

up n

oted

pos

sibl

y in

com

plet

ead

just

men

t for

con

foun

ding

for

woo

d du

st f

orad

enoc

arci

nom

a; f

elt t

hat s

quam

ous

cell

carc

inom

ale

ss li

kely

to b

e af

fect

ed, s

ince

no

clea

r as

soci

atio

nw

ith w

ood

dust

) (S

mal

l num

ber

of c

ases

)

Rou

sh e

t al.,

198

7

Mer

letti

et a

l., 1

991

(Sm

all n

umbe

r of

cas

es w

ith “

defi

nite

” ex

posu

re to

form

alde

hyde

)

Wor

tley

et a

l., 1

992

Luc

e et

al.,

199

3

(IA

RC

Wor

king

Gro

up n

oted

pos

sibl

e re

sidu

alco

nfou

ndin

g by

exp

osur

e to

woo

d du

st)


TA

BL

E5

(con

tinue

d)

Can

cer

1F

orm

alde

hyde

exp

osur

eR

isk

mea

sure

(95

% C

I)R

efer

ence

(co

mm

ents

)N

asop

hary

nxH

ospi

tal b

ased

– P

hilip

pine

s

Lun

g N

este

d –

coho

rt o

f ch

emic

al w

orke

rs –

Texa

s

Lun

g

Lun

g (a

deno

carc

inom

a)Po

pula

tion

base

d –

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tréa

l, Q

uebe

c

Res

pira

tory

can

cer

Nes

ted

– co

hort

of

Finn

ish

woo

dwor

kers

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pula

tion

base

d –

Mis

sour

i

Lun

gN

este

d –

coho

rt o

f U

.S. a

utom

otiv

efo

undr

y w

orke

rs

Mul

tiple

mye

lom

aIn

cide

nt c

ases

in f

ollo

w-u

p of

can

cer

prev

entio

n st

udy

in U

nite

d St

ates

Mul

tiple

mye

lom

aD

anis

h C

ance

r R

egis

try

Non

-Hod

gkin

’s ly

mph

oma

Iow

a St

ate

Hea

lth R

egis

try

Ocu

lar

mel

anom

aC

ases

dia

gnos

ed o

r tr

eate

d at

UC

SFO

cula

r O

ncol

ogy

Uni

t

<15

year

s of

exp

osur

e >2

5 ye

ars

sinc

e fi

rst e

xpos

ure

<25

year

s of

age

at f

irst

exp

osur

e

likel

y oc

cupa

tiona

l exp

osur

e

“lon

g–hi

gh”

occu

patio

nal e

xpos

ure/

(c

ance

r co

ntro

ls/p

opul

atio

n co

ntro

ls)

“lon

g–hi

gh”

occu

patio

nal e

xpos

ure/

(can

cer

cont

rols

/pop

ulat

ion

cont

rols

)

cum

ulat

ive

expo

sure

of

≥3.6

mg/

m3 -

mon

ths,

with

out m

inim

um 1

0-ye

ar in

duct

ion

peri

odcu

mul

ativ

e ex

posu

re o

f ≥3

.6 m

g/m

3 -m

onth

s,

with

min

imum

10-

year

indu

ctio

n pe

riod

expo

sure

to f

orm

alde

hyde

in w

ood

dust

pote

ntia

lly e

xpos

ed n

on-s

mok

ers

occu

patio

nal e

xpos

ure

with

late

ncy

peri

od o

f:0

year

s10

yea

rs15

yea

rs20

yea

rs

prob

ably

exp

osed

mal

es w

ith p

roba

ble

occu

patio

nal e

xpos

ure

fem

ales

with

pro

babl

e oc

cupa

tiona

l exp

osur

e

pote

ntia

l “lo

wer

inte

nsity

” of

exp

osur

epo

tent

ial “

high

er in

tens

ity”

of e

xpos

ure

“eve

r” e

xpos

ed to

for

mal

dehy

de

OR

= 2

.7 (

1.1–

6.6)

OR

= 2

.9 (

1.1–

7.6)

OR

= 2

.7 (

1.1–

6.6)

OR

= 0

.62

(0.2

9–1.

36)

OR

= 1

.5 (

0.8–

2.8)

/O

R =

1.0

(0.

4–2.

4)

OR

= 2

.3 (

0.9–

6.0)

/O

R =

2.2

(0.

7–7.

6)

OR

= 0

.69

(0.2

1–2.

24)2

OR

= 0

.89

(0.2

6–3.

0)2

OR

= 1

.19

(0.3

1–4.

56)2

OR

= 0

.9 (

0.2–

3.3)

OR

= 1

.31

(0.9

3–1.

85)

OR

= 1

.04

(0.7

1–1.

52)

OR

= 0

.98

(0.6

5–1.

47)

OR

= 0

.99

(0.6

0–1.

62)

OR

= 1

.8 (

0.6–

5.7)

OR

= 1

.1 (

0.7–

1.6)

OR

= 1

.6 (

0.4–

5.3)

OR

= 1

.2 (

0.9–

1.7)

OR

= 1

.3 (

0.5–

3.8)

OR

= 2

.9 (

1.2–

7.0)

Wes

t et a

l., 1

993

(IA

RC

Wor

king

Gro

up n

oted

no

cont

rol f

or th

e pr

esen

ceof

Eps

tein

-Bar

r vi

ral a

ntib

odie

s, f

or w

hich

pre

viou

s st

rong

asso

ciat

ion

with

nas

opha

ryng

eal c

ance

r w

as o

bser

ved)

Bon

d et

al.,

198

6

Gér

in e

t al.,

198

9

Part

anen

et a

l., 1

990

(IA

RC

Wor

king

Gro

up n

oted

that

ther

e w

ere

too

few

canc

ers

at s

ites

othe

r th

an th

e lu

ng f

or m

eani

ngfu

lan

alys

is)

Bro

wns

on e

t al.,

199

3

And

jelk

ovic

h et

al.,

199

4

Bof

fetta

et a

l., 1

989

Hei

nem

an e

t al.,

199

2Po

ttern

et a

l., 1

992

Bla

ir e

t al.,

199

3

Hol

ly e

t al.,

199

6

1SE

ER

= S

urve

illan

ce, E

pide

mio

logy

and

End

Res

ults

pro

gram

of

the

Nat

iona

l Can

cer

Inst

itute

; UC

SF =

Uni

vers

ity o

f C

alif

orni

a at

San

Fra

ncis

co.

2D

ata

in p

aren

thes

es r

epre

sent

90%

con

fide

nce

inte

rval

.

TA

BL

E6

Sum

mar

y of

ris

k m

easu

res

from

coh

ort s

tudi

es

Can

cer

Coh

ort

expo

sed

Ris

k m

easu

re1

Ref

eren

ce (

com

men

ts)


Bra

inL

euke

mia

“O

ther

lym

phat

ic ti

ssue

s”N

asal

cav

ity a

nd s

inus

Lar

ynx

Lun

g

Mul

tiple

mye

lom

aLy

mph

oma

Panc

reas

Lun

g

Buc

cal c

avity

Con

nect

ive

tissu

eT

rach

ea, b

ronc

hus

and

lung

Ph

aryn

x

Alim

enta

ry tr

act

Stom

ach

Liv

erL

ung

Buc

cal c

avity

and

pha

rynx

Res

pira

tory

sys

tem

Hyp

opha

rynx

Panc

reas

Leu

kem

ia

Buc

cal c

avity

and

pha

rynx

Nas

opha

rynx

Lym

phat

ic a

nd h

emat

opoi

etic

Col

onT

rach

ea, b

ronc

hus

and

lung

Lun

gB

ucca

l cav

ityPh

aryn

x

Lun

g

Nas

al c

avity

N

asop

hary

nx

Lun

gL

aryn

xO

ral c

avity

and

pha

rynx

mal

e an

atom

ists

mal

e ab

rasi

ves

prod

uctio

n w

orke

rs

garm

ent m

anuf

actu

ring

wor

kers

resi

n m

anuf

actu

ring

wor

kers

mal

e pa

thol

ogis

ts

mal

e m

ortu

ary

wor

kers

mal

e ch

emic

al w

orke

rs e

mpl

oyed

bef

ore

1965

wor

kers

exp

osed

to >

2.4

mg

form

alde

hyde

/m3

at o

ne s

peci

fic

plan

t

mal

e in

dust

rial

wor

kers

SMR

= 2

.7 (

1.3–

5.0)

: 10

SMR

= 1

.5 (

0.7–

2.7)

: 10

SMR

= 2

.0 (

0.7–

4.4)

: 6SM

R =

0 (

0.7–

7.2)

: 0SM

R =

0.3

(0–

2): 1

SMR

= 0

.3 (

0.1–

0.5)

: 12

SIR

= 4

(0.

5–14

): 2

SIR

= 2

(0.

2–7.

2): 2

SIR

= 1

.8 (

0.2–

6.6)

: 2SI

R =

0.5

7 (0

.1–2

.1):

2

SMR

= 3

43 (

118–

786)

2 : 4SM

R =

364

(12

3–82

5)2 : 4

SMR

= 1

14 (

86–1

49)2 : 3

9SM

R =

111

(20

–359

)2 : 2

SMR

= 1

34 (

p >

0.05

): 1

1SM

R =

164

(p

> 0.

05):

5SM

R =

244

(p

> 0.

05):

2SM

R =

69:

6

SMR

= 0

.52

(0.2

8–0.

89):

13

SMR

= 0

.56

(0.4

4–0.

77):

77

SMR

= 4

.7 (

0.97

–13.

4): 3

SMR

= 1

.4 (

1.04

–1.8

8): 4

7SM

R =

1.6

8 (1

.14–

2.38

): 3

1

PMR

= 1

20 (

81–1

71):

30

PMR

= 2

16 (

59–5

54):

4PM

R =

139

(11

5–16

7): 1

15PM

R =

127

(10

4–15

3): 1

11PM

R =

94.

9: 3

08

SMR

= 1

23 (

110–

136)

: 348

SMR

= 1

37 (

28–1

41):

3SM

R =

147

(59

–303

): 7

SMR

= 1

26 (

107–

147)

: 165

SPIR

= 2

.3 (

1.3–

4.0)

: 13

SPIR

= 1

.3 (

0.3–

3.2)

: 4SP

IR =

1.0

(0.

9–1.

1): 4

10SP

IR =

0.9

(0.

6–1.

2): 3

2SP

IR =

1.1

(0.

7–1.

7): 2

3

Stro

up e

t al.,

198

6(L

ikel

y ex

posu

re to

oth

er s

ubst

ance

s; n

oqu

antit

ativ

e da

ta o

n ex

posu

re)

Edl

ing

et a

l., 1

987

(Inc

reas

es b

ased

on

only

two

case

s ea

ch)

Stay

ner

et a

l., 1

988

Ber

tazz

i et a

l., 1

989

(Sm

all c

ohor

t exp

osed

pri

mar

ily to

low

con

cen-

trat

ions

; few

dea

ths

duri

ng o

bser

vatio

n pe

riod

)

Mat

anos

ki, 1

989

Hay

es e

t al.,

199

0

Gar

dner

et a

l., 1

993

(35%

of

coho

rt e

xpos

ed to

>2

ppm

[2.

4m

g/m

3 ])

Han

sen

and

Ols

en, 1

995


TA

BL

E6

(con

tinue

d)

Can

cer

Coh

ort

expo

sed

Ris

k m

easu

re1

Ref

eren

ce (

com

men

ts)

Nas

al c

avity

Buc

cal c

avity

and

pha

rynx

Tra

chea

, bro

nchu

s an

d lu

ng

Nas

opha

rynx

Nas

opha

rynx

Nas

opha

rynx

Nas

opha

rynx

Nas

opha

rynx

Lun

g

mal

e in

dust

rial

wor

kers

exp

osed

abo

veba

selin

e le

vels

mal

e au

tom

otiv

e fo

undr

y w

orke

rs

whi

te m

ale

indu

stri

al w

orke

rs e

xpos

ed to

≥0.1

ppm

for

mal

dehy

de

whi

te m

ale

indu

stri

al w

orke

rs w

ithcu

mul

ativ

e ex

posu

res

of:

0 pp

m-y

ears

≤0.5

ppm

-yea

rs

0.51

–5.5

ppm

-yea

rs≥5

.5 p

pm-y

ears

whi

te m

ale

indu

stri

al w

orke

rs c

o-ex

pose

d to

part

icul

ates

with

cum

ulat

ive

form

alde

hyde

expo

sure

s of

:0

ppm

-yea

rs

<0.5

ppm

-yea

rs

0.5–

<5.5

ppm

-yea

rs

≥5.5

ppm

-yea

rs

whi

te m

ale

indu

stri

al w

orke

rs:

expo

sed

for

<1 y

ear

expo

sed

for

≥1 y

ear

expo

sed

at o

ne p

lant

with

par

ticul

ates

whi

te m

ale

wor

kers

, hir

ed b

etw

een

1947

and

1956

, em

ploy

ed a

t one

spe

cifi

c pl

ant

for:

<1 y

ear

≥1 y

ear

whi

te m

ale

indu

stri

al w

orke

rs e

xpos

ed to

≥0.1

ppm

for

mal

dehy

de

whi

te m

ale

indu

stri

al w

orke

rs w

ith

≥20

year

s si

nce

firs

t exp

osur

e

SPIR

= 3

.0 (

1.4–

5.7)

: 9

SMR

= 1

31 (

48–2

66):

6SM

R =

120

(89

–158

): 5

1

SMR

= 2

.7 (

p <

0.05

): 6

SMR

= 5

30: 1

SMR

= 2

71 (

p >

0.05

): 2

SMR

= 2

56 (

p >

0.05

): 2

SMR

= 4

33 (

p >

0.05

): 2

SMR

= 0

: 0SM

R =

192

: 1SM

R =

403

: 2SM

R =

746

: 2

SMR

= 5

17 (

p ≤

0.05

): 3

SMR

= 2

18 (

p >

0.05

): 3

SMR

= 1

031

(p ≤

0.01

): 4

SMR

= 7

68 (

p >

0.05

): 2

SMR

= 1

049

(p <

0.0

5): 2

SMR

= 1

11 (

96–1

27):

210

SMR

= 1

32 (

p ≤

0.05

): 1

51

And

jelk

ovic

h et

al.,

199

5

(25%

of

coho

rt e

xpos

ed to

>1.

5 pp

m[1

.8m

g/m

3 ])

Bla

ir e

t al.,

198

6

(4%

of

coho

rt e

xpos

ed to

≥2

ppm

[2.

4 m

g/m

3 ])

Bla

ir e

t al.,

198

6

(4%

of

coho

rt e

xpos

ed to

≥2 p

pm [

2.4

mg/

m3 ])

Bla

ir e

t al.,

198

7

Col

lins

et a

l., 1

988

Mar

sh e

t al.,

199

6

Bla

ir e

t al.,

198

6

(4%

of

coho

rt e

xpos

ed to

≥2

ppm

[2.

4 m

g/m

3 ])


TA

BL

E6

(con

tinue

d)

Can

cer

Coh

ort

expo

sed

Ris

k m

easu

re1

Ref

eren

ce (

com

men

ts)

Lun

g

Lun

g

Lun

g

Lun

g

Lun

g

SMR

= 6

8 (3

7–11

3): 1

4SM

R =

122

(98

–150

): 8

8SM

R =

100

(80

–124

): 8

6SM

R =

111

(85

–143

): 6

2

SMR

= 1

.4 (

p ≤

0.05

): 1

24

SMR

= 1

.0 (

p >

0.05

): 8

8

RR

= 1

.0R

R =

1.4

7 (1

.03–

2.12

) 2

RR

= 1

.08

(0.6

7–1.

70)

2

RR

= 1

.83

(1.0

9–3.

08)

2

RR

= 1

.0R

R =

1.5

0 (1

.03–

2.19

) 2

RR

= 1

.18

(0.7

3–1.

90)

2

RR

= 1

.94

(1.1

3–3.

34)

2

(no

obse

rved

dea

ths)

SMR

= 1

.1 (

p >

0.05

): 9

SMR

= 2

.8 (

p <

0.05

): 1

7SM

R =

1.0

(p

> 0.

05):

10

SMR

= 1

34 (

p <

0.05

): 6

3SM

R =

119

(p

> 0.

05):

50

RR

= 1

.00

RR

= 1

.46

(0.8

1–2.

61)

RR

= 1

.27

(0.7

2–2.

26)

RR

= 1

.38

(0.7

7–2.

48)

Bla

ir e

t al.,

199

0a

Ster

ling

and

Wei

nkam

, 199

4

Bla

ir a

nd S

tew

art,

1994

Mar

sh e

t al.,

199

6

(25%

exp

osed

to >

0.7

ppm

[0.

9 m

g/m

3 ])

Cal

las

et a

l., 1

996

whi

te m

ale

indu

stri

al w

orke

rs w

ithcu

mul

ativ

e ex

posu

res

of:

0 pp

m-y

ears

≤0.5

ppm

-yea

rs

0.51

–5.5

ppm

-yea

rs>5

.5 p

pm-y

ears

wag

e-ea

rnin

g w

hite

mal

es in

indu

stri

alco

hort

exp

osed

to f

orm

alde

hyde

and

oth

ersu

bsta

nces

wag

e-ea

rnin

g w

hite

mal

es in

indu

stri

alco

hort

exp

osed

to f

orm

alde

hyde

subj

ects

in in

dust

rial

coh

ort l

ess

than

65

year

s of

age

with

cum

ulat

ive

expo

sure

s of

:<0

.1 p

pm-y

ears

0.1–

0.5

ppm

-yea

rs0.

5–2.

0 pp

m-y

ears

>2.0

ppm

-yea

rs

mal

es in

indu

stri

al c

ohor

t les

s th

an 6

5 ye

ars

of a

ge w

ith c

umul

ativ

e ex

posu

res

of:

<0.1

ppm

-yea

rs0.

1–0.

5 pp

m-y

ears

0.5–

2.0

ppm

-yea

rs>2

.0 p

pm-y

ears

whi

te w

age-

earn

ing

mal

es in

indu

stri

alco

hort

with

>2

ppm

-yea

rs o

f cu

mul

ativ

eex

posu

re a

nd e

xpos

ure

dura

tions

of:

<1 y

ear

1–<5

yea

rs5–

<10

year

s>1

0 ye

ars

whi

te m

ale

wor

kers

em

ploy

ed a

t one

spec

ific

pla

nt f

or:

<1 y

ear

≥1 y

ear

whi

te m

ales

in in

dust

rial

coh

ort w

ithcu

mul

ativ

e ex

posu

res

of:

0 pp

m-y

ears

0.05

–0.5

ppm

-yea

rs0.

51–5

.5 p

pm-y

ears

>5.5

ppm

-yea

rs

1U

nles

s ot

herw

ise

note

d, v

alue

s in

par

enth

eses

are

95%

con

fide

nce

inte

rval

or

leve

l of

stat

istic

al s

igni

fica

nce.

Ris

k m

easu

res

are

pres

ente

d he

re in

the

form

at r

epor

ted

in th

e re

fere

nces

cite

d. V

alue

s in

ital

ics

are

the

num

ber

of o

bser

ved

deat

hs o

r ca

ses,

whe

n sp

ecif

ied

in th

e re

fere

nce

cite

d. A

bbre

viat

ions

are

as

follo

ws:

SM

R =

sta

ndar

dize

d m

orta

lity

ratio

; SIR

=st

anda

rdiz

ed in

cide

nce

ratio

; PM

R =

pro

port

iona

te m

orta

lity

ratio

; SPI

R =

sta

ndar

dize

d pr

opor

tiona

te in

cide

nce

ratio

; RR

= r

elat

ive

risk

.2

Val

ues

in p

aren

thes

es r

epre

sent

90%

con

fide

nce

inte

rval

.


case–control and cohort studies, increasedrisks of various non-respiratory tract cancers(e.g., multiple myeloma, non-Hodgkin’slymphoma, ocular melanoma, brain, connectivetissue, pancreatic, leukemic, lymphoid andhematopoietic, colon) have occasionally beenobserved. However, such increases have beenreported only sporadically, with little consistentpattern. Moreover, results of toxicokinetic andmetabolic studies in laboratory animals andhumans indicate that most inhaled formaldehydeis deposited within the upper respiratory tract.Available evidence for these tumours at sites otherthan the respiratory tract does not, therefore, fulfiltraditional criteria of causality (e.g., consistency,biological plausibility) for associations observedin epidemiological studies, and the remainder ofthis section addresses the tumours for which theweight of evidence is greatest — initially nasaland, subsequently, lung.

In case–control studies (Table 5), whilesometimes no increase was observed overall(Vaughan et al., 1986a), significantly increasedrisks of nasopharyngeal cancer (up to 5.5-fold)were observed among workers with 10–25 yearsof exposure or in the highest exposure categoryin three out of four investigations (Vaughan et al.,1986a; Roush et al., 1987; West et al., 1993),although there were limitations associated withmost of these studies, as noted in Table 5. Therewas no increase in an additional investigationthat is also considered to be limited (Olsen andAsnaes, 1986). In three studies in which theassociation between formaldehyde and nasalsquamous cell carcinomas was examined, therewere non-significant increases in two (Olsen andAsnaes, 1986; Hayes et al., 1990) and no increasein another (Luce et al., 1993), although therewere limitations (as noted in Table 5) associatedwith all of these investigations. In the onlyinvestigation in which the association betweenexposure to formaldehyde and adenocarcinomaof the nasal cavity was examined, there was anon-significant increase that was exacerbated inthe presence of wood dust (Luce et al., 1993),although possible residual confounding by wooddust exposure could not be excluded (Table 5).

There is little convincing evidence ofincreased risks of nasopharyngeal cancer incohort studies of populations of professionalsor industrial workers occupationally exposed toformaldehyde, although it should be noted thatthe total number of cases of this rare cancer inall of the studies was small (approximately 15cases in all studies in Table 6, with some overlap).Risks were not increased in smaller studies ofanatomists or mortuary workers (Hayes et al.,1990) or in an investigation of proportionateincidence in industrial workers (Hansen andOlsen, 1995); in the latter study, however, thestandardized proportionate incidence ratio (SPIR)for cancers of the “nasal cavity” was significantlyincreased (3-fold) in more exposed workers. In acohort of 11 000 garment workers, the numberof deaths due to cancer of the nasal cavity wasconsidered too small to evaluate (Stayner et al.,1988). In a cohort of 14 000 workers employedin six chemical and plastic factories in theUnited Kingdom for which 35% of the cohort wasexposed to >2 ppm (2.4 mg/m3), only one nasalcancer was observed versus 1.7 expected(Gardner et al., 1993). The results of the largestindustrial cohort mortality study of 26 561workers first employed before 1966 at 10 plantsin the United States (4% of cohort exposed to≥2 ppm [2.4 mg/m3]) indicated an approximately3-fold excess of deaths due to nasopharyngealcancer associated with occupational exposure toformaldehyde (Blair et al., 1986). However,subsequent analyses revealed that five of theseven observed deaths were among individualswho had also been exposed to particulates; fourof the seven observed deaths occurred at onespecific industrial plant (Blair et al., 1987; Collinset al., 1988; Marsh et al., 1996). Three of theseven observed deaths due to nasopharyngealcancer occurred in individuals with less than 1 year of employment (Collins et al., 1988), andthe four deaths at one specific plant occurredequally in both short-term and long-term workers(Marsh et al., 1996).

In most case–control studies, there havebeen no increases in lung cancer (Bond et al.,1986; Gérin et al., 1989; Brownson et al., 1993;Andjelkovich et al., 1994). In the single study


where exposure–response was examined, therewas no significant increase in adenocarcinomaof the lung for those with “long–high”occupational exposure; although the odds ratio(OR) was greater than for “lung cancer,” thenumber of cases on which this observation wasbased was small (Gerin et al., 1989). There wasno association of relative risks (RR) with latencyperiod (Andjelkovich et al., 1994). In the mostextensive investigation of exposure–response,there were no increases in lung cancer in workerssubdivided by latency period, although there wasa non-significant increase for those co-exposed towood dust. There was no statistically significantincreased risk for “all respiratory cancer” bylevel, duration, cumulative exposure, durationof repeated exposures to peak levels or durationof exposure to dust-borne formaldehyde, exceptin one category (Partanen et al., 1990).

In smaller cohort studies of professionaland industrial workers (Table 6), there havebeen no significant excesses of cancers of thetrachea, bronchus or lung (Hayes et al., 1990;Andjelkovich et al., 1995), the buccal cavity orpharynx (Matanoski, 1989; Hayes et al., 1990;Andjelkovich et al., 1995), the lung (Stroup et al.,1986; Bertazzi et al., 1989; Hansen and Olsen,1995) or the respiratory system (Matanoski,1989). In a cohort of 11 000 garment workers,there was no increase in cancers of the trachea,bronchus or lung, buccal cavity or pharynx(Stayner et al., 1988). In a cohort of 14 000workers employed in six chemical and plasticfactories in the United Kingdom for which 35%of the cohort was exposed to >2 ppm (2.4 mg/m3),there was a non-significant excess (comparisonwith local rates) of lung cancers in workers firstemployed prior to 1965. Among groups employedat individual plants, the standardized mortalityratio (SMR) for lung cancer was significantlyincreased only in the “highly exposed” subgroupat one plant. However, there was no significantrelationship with years of employment orcumulative exposure (Gardner et al., 1993).There was no excess of cancers of the buccalcavity or pharynx in this cohort.

In the largest industrial cohort mortalitystudy of 26 561 workers first employed before1966 at 10 plants in the United States (4% ofcohort exposed to ≥2 ppm [2.4 mg/m3]), Blairet al. (1986) observed a slight but significant (1.3-fold) excess of deaths due to lung canceramong the sub-cohort of white male industrialworkers with ≥20 years since first exposure.However, results of a number of follow-up studieswithin this industrial group have provided littleadditional evidence of exposure–response (i.e.,cumulative, average, peak, duration, intensity)except in the presence of other substances (Blairet al., 1986, 1990a; Marsh et al., 1992, 1996;Blair and Stewart, 1994; Callas et al., 1996).

Meta-analyses of data fromepidemiological studies published between 1975and 1991 were conducted by Blair et al. (1990b)and Partanen (1993). These analyses revealed noincreased risk of cancer of the oral cavityassociated with exposure to formaldehyde (Blairet al., 1990b; Partanen, 1993). Blair et al. (1990b)indicated that the cumulative relative risk of nasalcancer was not significantly increased amongthose with lower (RR = 0.8) or higher (RR = 1.1)exposure to formaldehyde, while Partanen (1993)reported that the cumulative relative risk ofsinonasal cancer among those with substantialexposure to formaldehyde was significantlyelevated (i.e., RR = 1.75). In both meta-analyses,there was a significantly increased cumulativerelative risk (ranging from 2.1 to 2.74) ofnasopharyngeal cancer among those in the highestcategory of exposure to formaldehyde; in thelower or low-medium exposure categories, thecumulative relative risks for nasopharyngealcancer ranged from 1.10 to 1.59 (Blair et al.,1990b; Partanen, 1993). The analysis ofexposure–response in Blair et al. (1990b) andPartanen (1993) was based on three and fivestudies, respectively, in which increased risksof nasopharyngeal cancer had been observed.

Both meta-analyses revealed no increasedrisk of lung cancer among professionals havingexposure to formaldehyde; however, amongindustrial workers, the cumulative relative risk

for lung cancer was marginally (but significantly)increased for those with lower and low-medium(both RR = 1.2) exposure to formaldehyde,compared with those with higher (RR = 1.0)or substantial (RR = 1.1) exposure (Blair et al.,1990b; Partanen, 1993).

More recently, Collins et al. (1997)determined the cumulative relative risks ofdeath due to nasal, nasopharyngeal and lungcancer associated with potential exposure toformaldehyde, based upon a meta-analysis ofdata from case–control and cohort investigationspublished between 1975 and 1995. For nasalcancer, cumulative relative risks (designated asmeta RR) were 0.3 (95% confidence interval [CI] = 0.1–0.9) and 1.8 (95% CI = 1.4–2.3), onthe basis of the cohort and case–control studies,respectively. In contrast to the findings of Blairet al. (1990b) and Partanen (1993), Collins et al.(1997) concluded that there was no evidenceof increased risk of nasopharyngeal cancerassociated with exposure to formaldehyde; thediffering results were attributed to inclusion ofadditional more recent studies for which resultswere negative (particularly Gardner et al., 1993)and correction for under-reporting of expectednumbers. The authors also considered that theprevious analyses of exposure–response werequestionable, focusing on only one cohort studyand combining the unquantified medium/high-level exposure groups from the case–controlstudies with the quantified highest exposure groupin the one positive cohort study. Although ananalysis of exposure–response was not conductedby Collins et al. (1997), the authors felt that thecase–control data should have been combinedwith the low-exposure cohort data. Based uponthe results of the cohort investigations ofindustrial workers, pathologists and embalmers,the relative risks for lung cancer were 1.1 (95%CI = 1.0–1.2), 0.5 (95% CI = 0.4–0.6) and 1.0(95% CI = 0.9–1.1), respectively; the relativerisk for lung cancer derived from the case–controlstudies was 0.8 (95% CI = 0.7–0.9).

2.4.4.2.2 Genotoxicity

An increased incidence of micronucleated buccalor nasal mucosal cells has been reported in somesurveys of individuals occupationally exposedto formaldehyde (Ballarin et al., 1992; Surudaet al., 1993; Kitaeva et al., 1996; Titenko-Hollandet al., 1996). Evidence of genetic effects(i.e., chromosomal aberrations, sister chromatidexchanges) in peripheral lymphocytes fromindividuals exposed to formaldehyde vapour hasalso been reported in some studies (Suskov andSazonova, 1982; Bauchinger and Schmid, 1985;Yager et al., 1986; Dobiás et al., 1988, 1989;Kitaeva et al., 1996), but not others (Fleig et al.,1982; Thomson et al., 1984; Vasudeva and Anand,1996; Zhitkovich et al., 1996). Available dataare consistent with a pattern of weak positiveresponses, with good evidence of effects at thesite of first contact and equivocal evidence ofsystemic effects, although the contribution of co-exposures cannot be precluded.

2.4.4.2.3 Respiratory irritancy and function

Symptoms of respiratory irritancy and effectson pulmonary function have been examined instudies of populations exposed to formaldehyde(and other compounds) in both the occupationaland general environments.

In a number of studies of relatively smallnumbers of workers (38–84) in which exposurewas monitored for individuals, there was a higherprevalence of symptoms primarily of irritationof the eye and respiratory tract in workersexposed to formaldehyde in the production ofresin-embedded fibreglass (Kilburn et al., 1985a),chemicals, and furniture and wood products(Alexandersson and Hedenstierna, 1988, 1989;Holmström and Wilhelmsson, 1988; Malaka andKodama, 1990) or through employment in thefuneral services industry (Holness and Nethercott,1989), compared with various unexposed controlgroups. Due to the small numbers of exposedworkers, however, it was not possible tomeaningfully examine exposure–response inmost of these investigations. In the one survey



in which it was considered (Horvath et al., 1988),formaldehyde was a statistically significantpredictor of symptoms of eye, nose and throatirritation, phlegm, cough and chest complaints.Workers in these studies were exposed to meanformaldehyde concentrations of 0.17 ppm(0.2 mg/m3) and greater.

Results of investigations of effects onpulmonary function in occupationally exposedpopulations are somewhat conflicting. Pre-shiftreductions (considered indicative of chronicoccupational exposure) of up to 12% inparameters of lung function (e.g., forced vitalcapacity, forced expiratory volume, forcedexpiratory flow rate) were reported in a numberof smaller studies of chemical, furnitureand plywood workers (Alexandersson andHedenstierna, 1988, 1989; Holmström andWilhelmsson, 1988; Malaka and Kodama, 1990;Herbert et al., 1994). In general, these effects onlung function were small and transient over aworkshift, with a cumulative effect over severalyears that was reversible after relatively shortperiods without exposure (e.g., 4 weeks); effectswere more obvious in non-smokers than insmokers (Alexandersson and Hedenstierna, 1989).In the subset of these investigations in whichexposure was monitored for individuals (i.e.,excluding only that of Malaka and Kodama,1990), workers were exposed to meanconcentrations of formaldehyde of 0.4 mg/m3

(0.3 ppm) and greater. In the only study in whichit was examined, there was a dose–responserelationship between exposure to formaldehydeand decrease in lung function (Alexanderssonand Hedenstierna, 1989). However, evidenceof diminished lung function was not observedin other studies of larger numbers of workers(84–254) exposed to formaldehyde throughemployment in wood product (cross-shiftdecreases that correlated with exposure toformaldehyde but not pre-shift) (Horvath et al.,1988) or resin (Nunn et al., 1990) manufacturingor in the funeral services industry (Holness andNethercott, 1989). These groups of workers wereexposed to mean concentrations of formaldehydeof up to >2 ppm (2.4 mg/m3).

In a survey of residences in Minnesota,prevalences of nose and throat irritationamong residents were low for exposures toconcentrations of formaldehyde less than0.12 mg/m3 (0.1 ppm) but considerable at levelsgreater than 0.4 mg/m3 (0.3 ppm) (Ritchie andLehnen, 1987). This study involved analysisof the relation between measured levels offormaldehyde and reported symptoms fornearly 2000 residents in 397 mobile and 494conventional homes. Analyses for formaldehydein samples collected in two rooms on oneoccasion were conducted and classified as“low” (<0.1 ppm [0.12 mg/m3]), “medium”(0.1–0.3 ppm [0.12–0.4 mg/m3]) and “high”(>0.3 ppm [0.4 mg/m3]), based on the averagevalue for the two samples. Each of therespondents (who were not aware of the resultsof the monitoring) was classified by fourdependent variables for health effects (yes/nofor eye irritation, nose/throat irritation, headachesand skin rash) and four potentially explanatoryvariables — age, sex, smoking status and low,medium or high exposure to formaldehyde.In all cases, the effects of formaldehyde weresubstantially greater at concentrations above0.3 ppm (0.4 mg/m3) than for levels below0.3 ppm (0.4 mg/m3). Reports of eye irritationwere most frequent, followed by nose and throatirritation, headaches and skin rash. Whileproportions of the population reporting eye,nose and throat irritation or headaches at above0.3 ppm (0.4 mg/m3) were high (71–99%), thosereporting effects at below 0.1 ppm (0.12 mg/m3)were small (1–2% for eye irritation, 0–11%for nose or throat irritation and 2–10% forheadaches). The prevalence of skin rash wasbetween 5% and 44% for >0.3 ppm (0.4 mg/m3)and between 0% and 3% for <0.1 ppm(0.12 mg/m3).

There has been preliminary indicationof effects on pulmonary function in children in theresidential environment associated with relativelylow concentrations of formaldehyde, of whichfurther study seems warranted. Although there wasno increase in symptoms (chronic cough andphlegm, wheeze, attacks of breathlessness)indicated in self-administered questionnaires, the

prevalence of physician-reported chronic bronchitisor asthma in 298 children aged 6–15 years exposedto concentrations between 60 and 140 ppb (72and 168 µg/m3) in their homes was increased,especially among those also exposed to ETS(Krzyzanowski et al., 1990). There was anassociation between exposure and responsebased on subdivision of the population into groupsfor which indoor concentrations were ≤40 ppb(48 µg/m3), 41–60 ppb (48–72 µg/m3) and >60 ppb(72 µg/m3), although the proportions of thepopulation in the mid- and highest exposure groupwere small (<10 and <4%, respectively). Exposureto formaldehyde was characterized based onmonitoring in the kitchen, the main living area andeach subject’s bedroom for two 1-week periods.There was no indication of whether respondentswere blinded to the results of the monitoring whenresponding to the questionnaires. Levels of peakexpiratory flow rates (PEFR) also decreasedlinearly with exposure, with the decrease at 60 ppb(72 µg/m3) equivalent to 22% of the level of PEFRin non-exposed children; this value was 10% atlevels as low as 30 ppb (36 µg/m3). Effects in alarger sample of 613 adults were less evident, withno increase in symptoms or respiratory disease andsmall transient decrements in PEFR only in themorning and mainly in smokers, the significance ofwhich is unclear. Results of exposure–responseanalyses in adults were not presented.

In a survey of 1726 occupants of homescontaining UFFI and 720 residents of controlhomes, health questionnaires were administered anda series of objective tests of pulmonary function,nasal airway resistance, sense of smell and nasalsurface cytology conducted (Broder et al., 1988).The distributions of the age groups in thispopulation were 80%, 10% and 10% for 16 andover, <10 and 10–15, respectively; only thequestionnaire was completed for children under theage of 10. Monitoring for formaldehyde wasconducted in homes of these residents during 2successive days, one of which included the dayon which the occupants were examined, in a centrallocation, in all bedrooms and in the yard. Uponanalysis, there were increases in prevalences ofsymptoms primarily at values greater than

0.12 ppm (0.14 mg/m3) formaldehyde, althoughthere was evidence of interaction between UFFIand formaldehyde associated with these effects.There were no effects on other parametersinvestigated, with the exception of a small increasein nasal epithelial squamous metaplasia in UFFIsubjects intending to have their UFFI removed. Themedian concentration of formaldehyde in the UFFIhomes was 0.038 ppm (0.046 mg/m3) (maximum,0.227 ppm [0.272 mg/m3]); in the control homes,the comparable value was 0.031 ppm(0.037 mg/m3) (maximum, 0.112 ppm[0.134 mg/m3]). Notably, health complaintsof residents in UFFI homes were significantlydecreased after remediation, although the levelsof formaldehyde were unchanged.

2.4.4.2.4 Immunological effects

Epidemiological studies on the effects ofexposure to formaldehyde on the immune systemhave focused primarily upon allergic reactions(reviewed in Feinman, 1988; Bardana andMontanaro, 1991; Stenton and Hendrick, 1994).Case reports of systemic or localized allergicreactions have been attributed to theformaldehyde present in a wide variety ofproducts. Formaldehyde is an irritant to therespiratory tract, and some reports havesuggested that the development of bronchialasthma following inhalation of formaldehydemay be due to immunological mechanisms.The specific conditions of exposure as well asidiosyncratic characteristics among individualsare likely important factors in determiningwhether inhalation exposure to formaldehyde canresult in adverse effects on pulmonary functionmediated through immunological means. Immuneeffects (e.g., contact dermatitis) resulting fromdermal exposure to formaldehyde have been moreclearly defined. The concentration offormaldehyde likely to elicit contact dermatitisreactions in hypersensitive individuals may be aslow as 30 ppm. Based on the results of surveysconducted in North America, less than 10% ofpatients presenting with contact dermatitis may beimmunologically hypersensitive to formaldehyde.


2.4.4.2.5 Other effects

Histopathological changes within the nasalepithelium have been examined in surveys ofworkers occupationally exposed to formaldehydevapour (Berke, 1987; Edling et al., 1988;Holmström et al., 1989c; Boysen et al., 1990;Ballarin et al., 1992).

In all but one of the most limited of theseinvestigations (Berke, 1987), the prevalence ofmetaplasia of the nasal epithelium was increasedin populations exposed occupationally principallyto formaldehyde compared with age-matchedcontrol populations; occasionally, also, dysplasticchanges were reported in those exposed toformaldehyde. In the most extensive of theseinvestigations and the only one in which therewere individual estimates of exposure based onpersonal and area sampling (Holmström et al.,1989c), mean histological scores were increasedin 70 workers principally exposed toformaldehyde (mean 0.3 mg/m3, standarddeviation 0.16 mg/m3) compared with 36unexposed controls. Where confounders wereexamined, they have not explained the effects.For example, in the most extensive study byHolmström et al. (1989c), changes were notsignificant in a population exposed to wooddust–formaldehyde that was also examined.Edling et al. (1988) observed no variation inmean histological score in workers exposed toboth formaldehyde and wood dust compared withthose exposed only to formaldehyde. In caseswhere it was examined, there was no relationshipof histological scores with duration of exposure,although this may be attributable to the smallnumbers in the subgroups (Edling et al., 1988).

The available data are consistent,therefore, with the hypothesis that formaldehydeis primarily responsible for induction of thesehistopathological lesions in the nose. The weightof evidence of causality is weak, however, dueprimarily to the limited number of investigationsof relatively small populations of workers that donot permit adequate investigation of, for example,exposure–response.

Based upon recent epidemiological studies,there is no clear evidence to indicate that maternal(Hemminki et al., 1985; John et al., 1994; Taskinenet al., 1994) or paternal (Lindbohm et al., 1991)exposure to formaldehyde is associated with anincreased risk of spontaneous abortion.

There is little convincing evidence thatformaldehyde is neurotoxic in occupationallyexposed populations, although it has beenimplicated as the responsible agent in thedevelopment of neurobehavioural disorders suchas insomnia, lack of concentration, memory loss,and mood and balance alterations, as well as lossof appetite in case reports and a series of cross-sectional surveys by the same investigators(Kilburn et al., 1985a,b, 1987, 1989; Kilburnand Warshaw, 1992; Kilburn, 1994). However,the reported effects, which included increases inself-reported symptoms (for which frequenciesof behavioural, neurological and dermatologicalsymptoms were sometimes combined foranalyses), or impacts on more objective measuresof neurobehavioural function were confinedprimarily to histology workers. Attribution ofthe effects to formaldehyde in this group iscomplicated by co-exposures; indeed, samplingand analyses in a small number of histologylaboratories confirmed the widely rangingconcentrations of formaldehyde, xylene,chloroform and toluene to which such workerswere likely exposed. Further, there was noverification of the crude measures by whichexposure to formaldehyde was distinguished fromthat to solvents, which was based on worker recallof time spent conducting various tasks.


3.1 CEPA 1999 64(a): Environment

The environmental risk assessment of a PSLsubstance is based on the procedures outlinedin Environment Canada (1997a). Analysis ofexposure pathways and subsequent identificationof sensitive receptors are used to selectenvironmental assessment endpoints (e.g., adversereproductive effects on sensitive fish species ina community). For each endpoint, a conservativeEstimated Exposure Value (EEV) is selectedand an Estimated No-Effects Value (ENEV) isdetermined by dividing a Critical Toxicity Value(CTV) by an application factor. A conservative(or hyperconservative) quotient (EEV/ENEV) iscalculated for each of the assessment endpointsin order to determine whether there is potentialecological risk in Canada. If these quotientsare less than one, it can be concluded thatthe substance poses no significant risk tothe environment, and the risk assessment iscompleted. If, however, the quotient is greaterthan one for a particular assessment endpoint,then the risk assessment for that endpointproceeds to an analysis where more realisticassumptions are used and the probability andmagnitude of effects are considered. This latterapproach involves a more thorough considerationof sources of variability and uncertainty in therisk analysis.

3.1.1 Assessment endpoints

Formaldehyde enters the Canadian environmentmainly from natural and anthropogeniccombustion sources, from industrial on-sitereleases, from off-gassing of formaldehydeproducts, and through secondary formation as aresult of oxidation of anthropogenic and naturalorganic compounds in air. Almost all releases andformation in the ambient environment are in air,with small amounts released to water.

Given its physical-chemical properties,formaldehyde is degraded by various processesin air, with very small amounts transferringinto water. When released to water or soil,formaldehyde is expected to remain primarilyin the original compartment of release, whereit undergoes various biological and physicaldegradation processes. Formaldehyde is notbioaccumulative or persistent in any compartmentof the environment.

Based on the sources and fate offormaldehyde in the ambient environment, biotaare expected to be exposed to formaldehydeprimarily in air and, to a lesser extent, in water.Little exposure of soil or benthic organisms isexpected. While formaldehyde occurs naturally inplants and animals, it is readily metabolized anddoes not bioaccumulate in organisms. Therefore,the focus of the environmental risk characterizationwill be on terrestrial and aquatic organismsexposed directly to ambient formaldehyde inair and water.

3.1.1.1 Terrestrial

Data on terrestrial toxicity are available fora variety of microorganisms, plants andinvertebrates (Section 2.4.1.1), as well as frommammalian toxicology studies (Section 2.4.3).The most sensitive identified endpoints includeprimarily effects on the growth and developmentof plants (Haagen-Smit et al., 1952; Barker andShimabuku, 1992; Mutters et al., 1993).

Bacteria and fungi are ubiquitous interrestrial ecosystems and, as saprophytes, areessential for nutrient cycling. Terrestrial plantsare primary producers, provide food and coverfor animals, and provide soil cover to reduceerosion and moisture loss. Invertebrates are animportant component of the terrestrial ecosystem,consuming both plant and animal matter while


3.0 ASSESSMENT OF “TOXIC” UNDER CEPA 1999


serving as forage for other animals. Vertebratewildlife are key consumers in most terrestrialecosystems.

Therefore, although limited, the availabletoxicity studies cover an array of organisms fromdifferent taxa and ecological niches and areconsidered adequate for an assessment of risksto terrestrial biota. The single most sensitiveresponse for all of these endpoints will be used asthe CTV for the risk characterization forterrestrial effects.

3.1.1.2 Aquatic

Aquatic toxicity data are available for a varietyof algae, microorganisms, invertebrates, fish andamphibians (Section 2.4.1.2). Identified sensitiveendpoints include effects on the developmentand survival of algae and invertebrates (Billset al., 1977; Bringmann and Kühn, 1980a;Burridge et al., 1995a,b), inhibition of cellmultiplication in protozoa (Bringmann and Kühn,1980a), immobilization of crustaceans (Billset al., 1977) and mortality in fish (Reardon andHarrell, 1990).

Algae are primary producers in aquaticsystems, forming the base of the aquatic foodchain, while zooplankton, including protozoansand crustaceans, are consumed by many speciesof invertebrates and vertebrates. Fish areconsumers in aquatic communities andthemselves feed piscivorous fish, birds andmammals.

Therefore, although limited, the availablestudies cover an array of organisms from differenttaxa and ecological niches and are consideredadequate for an assessment of risks to aquaticbiota. The response for all of these endpoints thatoccurs at lowest concentration is the CTV for therisk characterization for aquatic effects.

3.1.2 Environmental risk characterization

3.1.2.1 Terrestrial organisms

Environmental exposure to formaldehyde in air isexpected to be greatest near sites of continuousrelease or formation of formaldehyde, namelyin urban centres and near industrial facilitiesreleasing formaldehyde. Extensive recent data forconcentrations in air are available for 27 sites,covering a range of industrial, urban, suburban,rural and remote locations in Canada.

3.1.2.1.1 Hyperconservative analysis

The highest reported concentration offormaldehyde in ambient air in Canada is27.5 µg/m3. This value was obtained for a 24-hoururban sample collected in Toronto, Ontario, onAugust 8, 1995. The mean concentration for sixmeasurements made at this site during a 30-dayperiod encompassing this date (July 14 toAugust 12, 1995) is 22.15 µg/m3. This meanconcentration will be used as the EEV in thehyperconservative analysis of the chronicexposure scenario for terrestrial organisms. A1-month mean is selected for the EEV because itcorresponds to a longer exposure period relativeto the life span of test organisms for which dataare available.

For the exposure of terrestrial organismsto formaldehyde in air, the CTV is 18 µg/m3,based on the corresponding amount in fog(9000 µg/L) that affects the growth andreproduction potential of rapeseed (Brassicarapa) exposed 4.5 hours per night, 3 nights perweek, for 40 days (Barker and Shimabuku, 1992).This value is the lowest from a moderate data setcomposed of acute and chronic toxicity studiesconducted on at least 18 species of terrestrialplants, microorganisms, invertebrates andmammals exposed to air and/or fog water.

The 40-day intermittent exposure ofBrassica rapa can be considered as chronicexposure (covering a significant portion of a life

stage of the organism). For the hyperconservativeanalysis, the ENEV for terrestrial organisms isderived by dividing the CTV by a factor of 10.This factor accounts for the uncertaintysurrounding the conversion of the effectconcentration to a no-effect value, theextrapolation from laboratory to field conditions,and interspecies and intraspecies variations insensitivity. As a result, the ENEV is 1.8 µg/m3.

The hyperconservative quotient iscalculated by dividing the EEV by the ENEV asfollows:

Quotient = EEVENEV

= 22.15 µg/m3

1.8 µg/m3

= 12.3

Since the hyperconservative quotient is morethan 1, there is a need to proceed to a morerealistic analysis of whether formaldehydeemissions cause adverse effects on terrestrialorganisms in Canada.

3.1.2.1.2 Conservative analysis

For a conservative analysis, a more realisticestimate of long-term terrestrial exposurewould be the highest of 90th percentile valuescalculated for each monitored site. A highest 90thpercentile value is still representative of high-endconcentrations at the site of greatest concern, yet italso excludes unusually high measurements, someof which may have been caused by rare ambientconditions or undetected analytical error. Analysisof the abundant data available shows that onlyonce in the last 10 years were such high airconcentrations measured in Canada for as longa period (1 month) as that from which the meanwas selected for the hyperconservative EEV. Basedon these data, the highest 90th percentile value is7.48 µg/m3, calculated from 354 measurementsmade in Toronto, Ontario, between December 6,

1989 and December 18, 1997. This value will beused as the EEV for the conservative analysis ofthe exposure scenario for terrestrial organisms. Forcomparison, the 90th percentile value calculated forall 3842 NAPS measurements available between1997 and 1998 is 5.50 µg/m3. The overall mean andmedian are 2.95 and 2.45 µg/m3, respectively.

For a conservative analysis, a morerealistic ENEV could be calculated by dividingthe hyperconservative CTV of 18 µg/m3

(rapeseed) by a more refined application factor.According to Fletcher et al. (1990), there isremarkable agreement between field andlaboratory EC50 values for plant species. In astudy of sensitivity to pesticides in a wide rangeof plants, only 3 of 20 field EC50 values were 2-fold higher than laboratory EC50 values, and only3 of 20 laboratory EC50 values were 2-fold higherthan field EC50 values. Therefore, no applicationfactor may be necessary for laboratory to fieldextrapolations for plant effects. Furthermore, dataindicated that extrapolations among plant specieswithin a genus can be confidently made withoutuncertainty factors. When extrapolating from onegenus to another within a family, an uncertaintyfactor of 2 captured 80% of the potentialvariability. Extrapolations across families withinan order or across orders within a class should bediscouraged, but, if necessary, factors of 15 and300 should be used for intraorder and intraclassextrapolations, respectively, to capture 80% of thevariability (Chapman et al., 1998). In the case ofthe Barker and Shimabuku (1992) study fromwhich the CTV was selected, the four test speciesconsisted of a deciduous tree (aspen), a coniferoustree (slash pine), a grain crop (wheat) and a seedcrop (rapeseed), representing diverse growthforms and morphology from four orders andtwo classes (monocots and dicots). In two ofthese, there were no adverse effects at testconcentrations, while in a third species (slashpine), there was an arguably adverse increasein top growth at the lowest concentration.Other studies indicate that other acute andchronic effects begin to occur only at airborneconcentrations clearly higher than for the rapeseed


in fog, even in developmental stages (e.g., lilypollen LOEC of 440 µg/m3). The rapeseedseedling therefore appears to be by far the mostsensitive of a variety of species tested. Giventhe diversity of the data set, only a minimalapplication factor may be required for interspeciesextrapolation. Regarding the extrapolation fromeffect concentration to no-effect concentration,it should be noted that Barker and Shimabuku(1992) used a relatively low threshold ofstatistical significance (α = 0.1), and effects onthe rapeseed did not include any of the visualsymptoms such as necrosis observed in otherliquid- and gas-phase formaldehyde studies.This may therefore allow for a smaller applicationfactor to be used on the CTV for rapeseed.Therefore, keeping a CTV of 18 µg/m3, theapplication factor of 10 used in thehyperconservative scenario can be reduced to2 for the conservative assessment. As a result,the ENEV for the conservative analysis of theexposure scenario for terrestrial organisms willbe 9 µg/m3.

The conservative quotient is calculated bydividing the EEV by the ENEV as follows:

Quotient = EEVENEV

= 7.48 µg/m3

9 µg/m3

= 0.83

Alternatively, for a conservative analysis,it may also be more realistic to use a CTVfrom a toxicity study involving exposure toformaldehyde in gas phase in air rather than back-calculating from exposure in fog. Reasons to dothis include the exploratory nature of the fogstudy (Barker and Shimabuku, 1992) from whichthe hyperconservative CTV was selected. Theconversion of fog water concentrations toexpected air concentrations in the study could notbe verified because variables (temperature, vapourpressure, water solubility, Henry’s law constant)required for the conversion were not specified in

the study. Reported exposure concentrationsrepresented an estimated average based on theobserved rate of degradation in the experimentalsystem. Since formaldehyde in the fog waterreadily undergoes hydration and degradation, itis not certain how its properties may changeits toxicity. Analysis of the terrestrial data setavailable indicates no other reports of studieson effects of fog or effects as sensitive as thosein Barker and Shimabuku (1992). In addition,no data were found on concentrations offormaldehyde in fog in Canada or frequency offog incidence in urban areas to be able to supportan assumption that Canadian biota are beingexposed to formaldehyde under such conditionsas those used in the experiment. Also, the studydid not seem to take into consideration potentialexposure to gas-phase formaldehyde in betweenexposures to formaldehyde in fog. A study ofchronic exposure to formaldehyde in gas phasein air may be more realistic.

For the conservative analysis of theexposure of terrestrial organisms to formaldehydein air, the CTV is 78 µg/m3, based on the lowestaverage concentration in air that caused a slightimbalance in the growth of shoots and roots in thecommon bean (Phaseolus vulgaris) exposed for 7 hours per day, 3 days per week, for 4 weeks inair (day: 25°C, 40% humidity; night: 14°C, 60%humidity) (Mutters et al., 1993). This value wasselected as the most sensitive endpoint from amoderate data set composed of acute and chronictoxicity studies conducted on at least 18 speciesof terrestrial plants, microorganisms, invertebratesand mammals exposed to air and/or fog water.

The 28-day intermittent exposure of thebean plant can be considered as chronic exposure(covering a significant portion of a life stage ofthe organism). Dividing the CTV by a factor of10 to account for the uncertainty surrounding theconversion of the effect concentration to a no-effect value, the extrapolation from laboratory tofield conditions, and interspecies and intraspeciesvariations in sensitivity, the resulting ENEV is7.8 µg/m3. This yields the following conservativequotient:


Quotient = EEVENEV

= 7.48 µg/m3

7.8 µg/m3

= 0.96

This quotient is very close to one.

Given the arguments for reducing theapplication factor of the hyperconservativerapeseed CTV and the even milder effectsobserved for the common bean plant (Mutterset al. [1993] themselves did not conclude any illeffects from formaldehyde), the application factorcan be reduced from 10 to 2 for a more realisticENEV of 39 µg/m3. This results in a lowerconservative quotient:

Quotient = EEVENEV

= 7.48 µg/m3

39 µg/m3

= 0.19

Since all three conservative quotients are less than1, it is unlikely that formaldehyde in air causesadverse effects on terrestrial organisms in Canada.

In considering a weight-of-evidenceapproach, other data similarly do not indicatethe likelihood of high risks associated withatmospheric exposure. It is uncertain what thepotential ecological impacts could be for sensitiveeffects such as imbalance in growth of roots andshoots. Based on the toxicity data set available, itappears that plants are most sensitive during theirearly life stages. In Canada, sensitive early lifestages of plants usually occur in the spring.Highest air concentrations of formaldehyde havegenerally been measured in late summer (August)(Environment Canada, 1999a), when atmosphericformaldehyde formation and photochemical smogformation are greatest. It would therefore appearthat only the more tolerant adult plants would beexposed to the highest concentrations. Inaddition, in studies other than those used in thehyperconservative and conservative scenariosabove, there has been considerably more toleranceto exposure to formaldehyde (e.g., no injury atconcentrations below 840 µg/m3 for alfalfa;Haagen-Smit et al., 1952), with no effects onplants at concentrations of 44 mg/m3 (Wolvertonet al., 1984).

A summary of the values used in theenvironmental risk analysis of formaldehyde inthe terrestrial environment is presented in Table 7.


TABLE 7 Summary of the environmental risk analysis for terrestrial organisms

Terrestrial EEV CTV Application ENEV Quotientorganisms (µg/m3) (µg/m3) factor (µg/m3)Tier 1: HyperconservativeHighest urban mean, 22.15 18 10 1.8 12.3

rapeseed in fogTier 2: ConservativeHighest 90th percentile, 7.48 18 2 9 0.83

rapeseed in fogHighest 90th percentile, 7.48 78 10 7.8 0.96

bean plant in airHighest 90th percentile, 7.48 78 2 39 0.19

bean plant in air

3.1.2.2 Aquatic organisms

Environmental exposure to formaldehyde inwater is expected to be greatest near areas ofhigh atmospheric concentrations (where someformaldehyde can partition from air into water)and near spills or effluent outfalls. Measuredconcentrations are available in Canada for surfacewaters, effluents and groundwater. For surfacewater, data are available on limited sampling atfour drinking water treatment plants in urbanareas of Ontario and Alberta. Measuredconcentrations in effluent are available for oneof the four industrial plants reporting releasesof formaldehyde to water. Groundwater data areavailable for three industrial sites associated withspills or chronic contamination and six cemeteriesin Ontario.

3.1.2.2.1 Hyperconservative analysis

A hyperconservative analysis has been conductedfor aquatic organisms exposed to concentrationsmeasured in surface water, effluents andgroundwater.

The highest concentration offormaldehyde reported in surface water is9.0 µg/L, obtained for a sample collected fromthe North Saskatchewan River near a treatmentplant in Edmonton, Alberta (Huck et al., 1990).The highest 1-day concentration identified in anindustrial effluent was 325 µg/L (EnvironmentCanada, 1999a). In various groundwater samples,the highest concentration of formaldehyde was690 000 µg/L at an industrial site (EnvironmentCanada, 1997c). These values will be used asthe EEVs in the hyperconservative analysis ofaquatic organisms in surface water, effluentand groundwater, respectively. The effluentEEV is based on the conservative assumptionthat organisms could be living at the point ofdischarge. The groundwater EEV is based on theconservative assumption that the groundwatercould recharge directly to surface water at its fullconcentration.

For exposure of aquatic animals toformaldehyde in water, the CTV is 100 µg/L,based on the concentration that causes 40–50%mortality after 96 hours in day-old zygotes ofthe marine alga, Phyllospora comosa (Burridgeet al., 1995a). This value was selected as the mostsensitive endpoint from a large data set composedof toxicity studies conducted on at least 36species of freshwater and marine aquatic algae,microorganisms, invertebrates, fish andamphibians.

The 96-hour exposure for Phyllosporacomosa zygotes can be considered as chronicexposure (covering a significant portion of thelifetime of the organism). For a hyperconservativeanalysis, the ENEV is derived by dividing theCTV by a factor of 10. This factor accountsfor the uncertainty in the extrapolation from achronic EC50 to a chronic no-effects value, theextrapolation from laboratory to field conditions,and interspecies and intraspecies variations insensitivity. The resulting ENEV is 10 µg/L.

The hyperconservative quotients arecalculated by dividing the EEV by the ENEV asfollows:

Surface water analysis

Quotient = EEVENEV

= 9.0 µg/L10 µg/L

= 0.9

Since the hyperconservative quotient is less than1, it is unlikely that formaldehyde causes adverseeffects on aquatic organisms in ambient surfacewater in Canada, and more realistic exposurescenarios need not be considered.


Effluent analysis

Quotient = EEVENEV

= 325 µg/L10 µg/L

= 32.5

Since the hyperconservative quotient is greaterthan 1, it is necessary to consider further thelikelihood of biota being exposed to suchconcentrations in surface water near point sourcesin Canada.

Groundwater analysis

Quotient = EEVENEV

= 690 000 µg/L10 µg/L

= 69 000

Since the hyperconservative quotient is greaterthan 1, it is necessary to consider further thelikelihood of biota being exposed to suchconcentrations in Canada.

3.1.2.2.2 Conservative analysis

For a conservative analysis, more realisticestimates of aquatic exposure must be used. Inthe case of effluent, dilution can be considered.For a conservative analysis, the hyperconservativeEEV of 325 µg/L can be divided by a genericand conservative dilution factor of 10 derivedfor all types of water bodies to estimate ambientconcentrations of formaldehyde near outfalls.This results in a conservative effluent EEV of32.5 µg/L.

In the case of groundwater, the very highconcentrations at one contaminated site wererelated to a recognized historical contamination

that has since been contained and remediated(Environment Canada, 1999a). The next highestconcentration reported for groundwater was foran industrial site in New Brunswick (maximumof 8200 µg/L). It is highly unlikely that thegroundwater at a single sampling station wouldrecharge directly to surface water. A more realisticrepresentation of groundwater quality at the sitecould be achieved using the median concentrationin groundwater at all sampling stations. Themedian was 100 µg/L for measurements takenat five wells at the contaminated site during1996–1997. Assuming some degree of dilutionsimilar to that of effluent in receiving waterbodies, the median value can also be divided bythe generic and conservative dilution factor of 10to obtain a conservative estimate of possibleconcentrations in the event of surface recharge.As a result, the conservative EEV for groundwateris 10 µg/L.

For a conservative analysis, an endpointshould be selected that is more appropriate thanthat for the CTV used in the hyperconservativeanalysis, which was based on toxicity to a marinealga endemic to Australia. A more meaningfulvalue can be derived by considering toxicity tothe seed shrimp, Cypridopsis sp., a commonfreshwater ostracod, yielding a CTV of 360 µg/L,based on the 96-hour EC50 (immobility) for thisorganism (Bills et al., 1977). This value wasselected as the most sensitive endpoint from alarge data set composed of toxicity studiesconducted on at least 34 freshwater species ofaquatic algae, microorganisms, invertebrates, fishand amphibians.

For the conservative analysis, the ENEVis derived by dividing the CTV by a factor of 10.This factor accounts for the uncertaintysurrounding the extrapolation from the EC50 to achronic no-effects value, the extrapolation fromlaboratory to field conditions, and interspeciesand intraspecies variations in sensitivity. Theresulting ENEV is 36 µg/L.


The conservative quotients are calculatedby dividing the EEV by the ENEV as follows:

Effluent analysis

Quotient = EEVENEV

= 32.5 µg/L36 µg/L

= 0.9

Since the conservative quotient is less than 1,it is unlikely that exposure to concentrationsin water resulting from effluent discharge arecausing adverse effects on populations of aquaticorganisms in Canada.

Groundwater analysis

Quotient = EEVENEV

= 10 µg/L36 µg/L

= 0.28

Since the conservative quotient is less than 1, itis unlikely that concentrations of formaldehydein groundwater are causing adverse effects onpopulations of aquatic organisms in Canada.

A summary of the values used in theenvironmental risk analysis of formaldehyde inthe aquatic environment is presented in Table 8.

3.1.2.3 Discussion of uncertainty

There are a number of potential sources ofuncertainty in this environmental risk assessment.Regarding effects of formaldehyde on terrestrialand aquatic organisms, uncertainty surrounds theextrapolation from available toxicity data topotential ecosystem effects. While the toxicitydata set included studies on organisms from avariety of ecological niches and taxa, there arerelatively few good chronic studies available. Toaccount for these uncertainties, application factorswere used in the environmental risk analysis toderive ENEVs.

Regarding environmental exposure,there could be concentrations of formaldehyde inCanada that are higher than those identified andused in this assessment.


TABLE 8 Summary of the environmental risk analysis for aquatic organisms

Aquatic EEV CTV Application ENEV Quotientorganisms (µg/L) (µg/L) factor (µg/L)Tier 1: HyperconservativeSurface water – 9.0 100 10 10 0.9

marine algaeEffluent – marine algae 325 100 10 10 32.5Groundwater – 690 000 100 10 10 69 000

marine algaeTier 2: ConservativeEffluent – seed shrimp 32.5 360 10 36 0.9Groundwater – 10 360 10 36 0.28

seed shrimp

For exposure in air, the measurementsused in this assessment are considered acceptablebecause they were selected from an extensive setof recent air monitoring data of urban and othersites, including from sites at or near industrialfacilities that use and release formaldehyde inCanada. These sites can also be associated withhigh concentrations of VOCs associated withsecondary formation of formaldehyde. Thus,available data on atmospheric concentrationsare considered representative of the highestconcentrations likely to be encountered in airin Canada.

Only limited data are available for water,although concentrations of formaldehyde areexpected to be low because of the limited releasesto these media that have been identified and thelimited partitioning of formaldehyde to thesecompartments from air. The available data onconcentrations in groundwater include data fromindustrial sites of the users of formaldehyde.Since data are not available regarding surfacerecharge of the contaminated groundwater, theassessment very conservatively assumed thatrecharge occurred at concentrations equivalent tothose measured in the groundwater with minimaldilution.

Despite some data gaps regardingthe environmental effects and exposure offormaldehyde, the data available at this time areconsidered adequate for making a conclusion onthe environmental risk of formaldehyde in Canada.

3.2 CEPA 1999 64(b): Environmentupon which life depends

Formaldehyde does not deplete stratosphericozone, and its potential for climate change isnegligible. The photolysis of formaldehyde leadsto the direct formation of radicals that are activein the formation of ground-level ozone (Carteret al., 1995). In addition, formaldehyde is morereactive with hydroxyl radicals (POCP of 105)than compounds such as ethene that arerecognized as important in the formation of

ground-level ozone (Bunce, 1996). Given itsreactivity and concentrations measured in air inCanada, formaldehyde represented approximately7.8% of the total volatile organic carbonreactivity, ranking it 4th among non-methanehydrocarbons and carbonyl compoundscontributing to the formation of ground-levelozone (Dann and Summers, 1997). Formaldehydeis therefore important in the photochemicalformation of ground-level ozone.

3.3 CEPA 1999 64(c): Human health

3.3.1 Estimated population exposure

Estimates of the total daily intake offormaldehyde by six age groups of the generalpopulation of Canada were developed primarilyto determine the relative contributions fromvarious media. These estimates indicate that thedaily intake of formaldehyde via inhalation isconsistently less than that estimated for theingestion of foodstuffs. However, it should benoted that critical effects associated with exposureto formaldehyde occur primarily at the site offirst contact (i.e., the respiratory tract followinginhalation and the gastrointestinal tract followingingestion) and are related to the concentration offormaldehyde in media to which humans areexposed, rather than the total intake of thissubstance. For this reason, effects of exposure byinhalation and ingestion are addressed separately.

Due primarily to limitations of availabledata as a basis for characterization of exposure viaingestion, the principal focus of the assessmentis airborne exposure. The less representativeassessment for ingestion involves comparison ofthe concentration of formaldehyde in a limitednumber of food products with a TolerableConcentration (ingestion).

The general population in Canada isexposed to low concentrations of formaldehyde inoutdoor air and to generally higher concentrationsin indoor air. A subset of data from the NAPSprogram was selected to represent the range and


distribution of concentrations to which the generalpopulation of Canada is currently assumed to beexposed via inhalation of outdoor air. Theselected data are from sites classified as suburban(n = 4) or urban (n = 4) and include all 24-hourconcentrations of formaldehyde (n = 2818)measured at these sites between January 1990and December 1998 (Health Canada, 2000).The distribution of concentrations is positivelyskewed, with median, arithmetic mean and upper-percentile concentrations as summarized in Table9. The distribution of concentrations at one of thefour urban sites (i.e., in Toronto) was selectedas a reasonable worst case. The distribution ofconcentrations of formaldehyde at this site is alsopositively skewed, and statistical parameters ofthis distribution are summarized in Table 9.

Pooled data (n = 151) from five studiesin which concentrations of formaldehyde weremeasured in the indoor air of residences inCanada between 1989 and 1995 were the basisfor the range and distribution of concentrations

to which the general population of Canada iscurrently assumed to be exposed via inhalationof residential indoor air (Health Canada, 2000).Sampling duration was 24 hours in two of thestudies selected (n = 47 samples). These sampleswere collected and analyzed by the samemethodologies and by the same laboratory asfor the NAPS data referred to above. Passivesampling for 7-day periods and differentanalytical methodology were employed inthe remaining three studies (n = 104). Thedistributions of concentrations of formaldehydefrom the 24-hour active and the 7-day passivesamples were compared. These distributions werejudged to be sufficiently similar to justify poolingthe data from the five studies. Median, arithmeticmean and upper-percentile concentrations of thedistribution of pooled concentrations aresummarized in Table 9.

The distribution of pooled concentrationsis positively skewed. When plotted in 10 µg/m3

bins, there is a good fit to a lognormal distribution


TABLE 9 Concentrations of formaldehyde in outdoor air and residential indoor air in Canada

Medium of exposure Number Mid-points of Upper percentiles of distributionsof samples distributions (µg/m3) of concentrations (µg/m3)

Median Mean 5 75th 90th 95th 97.5thOutdoor air – NAPS data 1 2818 2.8 3.3 4.1 6.0 7.3 9.1Outdoor air – reasonable 371 2.9 4.0 4.8 7.3 10.4 17.3

worst-case site 2

Indoor air – five studies 3 151 29.8 35.9 46.2 64.8 84.6 104.8Indoor air – lognormal – 28.7 – 46.1 70.7 91.2 113.8

distribution 4

1 Data are for selected suburban (n = 4) and urban (n = 4) sites of the NAPS Program (Dann, 1997, 1999) for the period1990–1998. Concentrations are slightly lower for the subset of suburban sites and slightly higher for the subset of urban sites.Distributions are positively skewed.

2 One of the four urban sites (i.e., NAPS site 060418 in Toronto) was selected for the reasonable worst-case purpose.3 Data were pooled from five studies of concentrations of formaldehyde in residential indoor air. These studies were conducted

at various locations in Canada between 1989 and 1995.4 The geometric mean and standard deviation of the pooled data (n = 151) from the five Canadian studies were calculated. A

lognormal distribution with the same geometric mean and standard deviation was generated and the upper percentiles of thisdistribution were estimated.

5 These are the arithmetic mean concentrations. Since formaldehyde was detected in more than 99% of the samples, censoringof the data for limit of detection was not required.

characterized by the same geometric mean (i.e.,28.7 µg/m3) and standard deviation (2.92). Upperpercentiles of this lognormal distribution werecalculated and are shown for comparison inTable 9. The values of these percentiles are higherfor the lognormal distribution than for the morelimited data set. This is to be expected, since thelognormal distribution approaches the x-axisasymptotically.

These data are used to estimate thedistribution of time-weighted 24-hourconcentrations of formaldehyde to which thegeneral population is exposed (Health Canada,2000). This requires consideration of theproportion of the 24-hour day that is spentindoors versus the time spent outdoors. Recentdeterministic (i.e., point) estimates (EHD, 1998)indicate that, in general, all age groups spend adaily average of 21 hours in indoor environmentsand 3 hours outdoors in Canada. Probabilisticestimates of the proportion of time spent indoorsversus outdoors are more desirable, as thesewould provide an indication of the distributionsof these average estimates, but these estimateswere not available. Instead, a mean time spentoutdoors of 3 hours is assumed based on the pointestimates of time spent indoors and outdoors(EHD, 1998). The distribution of the time spentoutdoors is arbitrarily assumed to be normal inshape with an arithmetic standard deviation of2 hours. In the probabilistic simulation, thisdistribution is truncated at 0 hours and 9 hours.The time spent indoors is calculated as 24 hoursminus the time spent outdoors.

Estimates of the distribution of time-weighted 24-hour concentrations of formaldehydeto which the general population is exposed weredeveloped using simple random sampling withCrystal Ball™ Version 4.0 (Decisioneering, Inc.,1996) and simulations of 10 000 trials. Each trialinvolves random sampling of the distribution ofconcentrations in outdoor air and multiplying thisby a random sample of the time spent outdoors.This results in an estimate of the concentration-time product for formaldehyde (CO, in µg-hour/m3) resulting from exposure to outdoor air.The “time spent indoors” is then calculated as 24

hours minus “time spent outdoors.” This “timespent indoors” is then multiplied by a randomsample from the distribution of concentrationsin indoor air and results in an estimate of theconcentration-time product for formaldehyde(C1, in µg-hour/m3) resulting from exposure toindoor air. The average 24-hour time-weightedconcentration of formaldehyde for each trialis then calculated as (1/24) × (CO + CI ) forexposure to outdoor and indoor air.

Two simulations were run. In bothsimulations, the distribution of concentrations offormaldehyde in outdoor air is represented by afrequency histogram of the data from the eightselected NAPS sites (n = 2818 samples). In thefirst simulation, the distribution of concentrationsof formaldehyde in residential indoor air isrepresented by a frequency histogram of thepooled data from the five selected studies(n = 151 samples). In the second simulation, thedistribution of concentrations of formaldehydein residential indoor air is represented by anassumed lognormal distribution with the samegeometric mean (28.7 µg/m3) and standarddeviation (2.92) as for the pooled data. Thisassumed lognormal distribution is truncated at150 µg/m3, the highest concentration measuredamong the five studies. It is assumed that thegeneral population is exposed to similardistributions of concentrations in the indoor airof public places. Exposure to formaldehyde inthe indoor air of workplaces is not addressedspecifically; therefore, the general population isassumed to be exposed to similar concentrationsof formaldehyde in the indoor air of allworkplaces. Estimates of the median, arithmeticmean and upper percentiles of the distributions of24-hour time-weighted average concentrations offormaldehyde determined from these probabilisticsimulations are summarized in Table 10. The twosimulations were each run five times. The relativestandard deviations of the upper-percentileestimates of time-weighted average concentrationswere calculated to determine the stability of theseupper-percentile estimates. These relative standarddeviations are also summarized in Table 10.Examples of the shapes of the distributionsresulting from the two simulations are available in


Health Canada (2000). Based on the assumptionsunderlying these probabilistic simulations, theestimates summarized in Table 10 indicate thatone of every two persons would be exposed to 24-hour average concentrations of formaldehydein air of 24–29 µg/m3 or greater (i.e., medianconcentrations). Similarly, 1 in 20 persons (i.e.,95th percentile) would be exposed to 24-houraverage concentrations of formaldehyde in air of80–94 µg/m3 or greater.

Based on limited data from the UnitedStates, concentrations in drinking water mayrange up to approximately 10 µg/L, in the absenceof specific contributions from the formation offormaldehyde by ozonation during watertreatment or from leaching of formaldehydefrom polyacetal plumbing fixtures. One-half thisconcentration (i.e., 5 µg/L) was judged to be areasonable estimate of the average concentrationof formaldehyde in Canadian drinking water,in the absence of other data. Concentrationsapproaching 100 µg/L were observed in a U.S.study assessing the leaching of formaldehydefrom domestic polyacetal plumbing fixtures, andthis concentration is assumed to be representativeof a reasonable worst case.

Similarly, very few data are availablewith which to estimate the range and distributionof concentrations of formaldehyde in foods

to which the general population in Canada isexposed. According to the limited available data,concentrations of formaldehyde in food are highlyvariable. In the few studies of the formaldehydecontent of foods in Canada, the concentrationsof formaldehyde were within the range from lessthan 0.03 to 14 mg/kg (Health Canada, 2000).However, the proportion of formaldehyde in foodsthat is bioavailable is unknown.

3.3.2 Hazard characterization

Inhalation, the likely principal route of exposureof the general population to formaldehyde, hasbeen the focus of most studies on the effects ofthis substance in humans and laboratory animals.Available data on effects following ingestion ordermal exposure to formaldehyde are limited.Since formaldehyde is water soluble, highlyreactive with biological macromolecules andrapidly metabolized, adverse effects resultingfrom exposure are observed primarily in thosetissues or organs with which formaldehyde firstcomes into contact (i.e., the respiratory andgastrointestinal tracts following inhalation andingestion, respectively).

Effects following inhalation that occurprimarily at the site of contact are, therefore, theprincipal focus of this section.


TABLE 10 Probabilistic estimates of 24-hour time-weighted average concentrations of formaldehydein air

Mid-points of Upper percentiles of distributions of concentrations distributions (µg/m3) (µg/m3) and relative standard deviations (%)Median Mean 3 75th 90th 95th 97.5th

Simulation 1 1 29 36 46 (± 0.5%) 62 (± 1.3%) 80 (± 1.9%) 97 (± 0.7%)Simulation 2 2 24 33 45 (± 1.2%) 75 (± 1.2%) 94 (± 1.6%) 109 (± 1.3%)

1 In simulation 1, the distribution of concentrations of formaldehyde is represented by a frequency histogram of the pooled datafrom the five selected studies (n = 151 samples).

2 For simulation 2, a lognormal distribution of concentrations, truncated at 150 µg/m3, is assumed. This lognormal distributionhas the same geometric mean (28.7 µg/m3) and standard deviation (2.92) as the distribution of concentrations for the pooleddata from the five selected studies.

3 This is the arithmetic mean concentration.

3.3.2.1 Genotoxicity and carcinogenicity

3.3.2.1.1 Genotoxicity

Results of epidemiological studies in occupationallyexposed populations are consistent with a pattern ofweak positive responses for genotoxicity, with goodevidence of an effect at site of contact (e.g.,micronucleated buccal or nasal mucosal cells).Evidence for distal (i.e., systemic) effects isequivocal (chromosomal aberrations and sisterchromatid exchanges in peripheral lymphocytes).The contribution of co-exposures to observed effectscannot be precluded.

The results of a large number of in vitroassays of a variety of endpoints indicate thatformaldehyde is weakly genotoxic in both bacterialand mammalian cells. The spectrum of mutationinduced by formaldehyde in vitro varies among celltypes and concentrations to which cells wereexposed but includes both point and large-scalechanges. The results of in vivo studies in animals aresimilar to those in humans, with effects at site ofcontact being observed (e.g., modest increase in theproportion of pulmonary macrophages withchromosomal aberrations in rats followinginhalation and cytogenetic alterations in thegastrointestinal epithelium of rats following oralexposure). Evidence of distal (systemic) effects isless convincing. Indeed, in the majority of studies ofrats exposed to formaldehyde via inhalation, geneticeffects within peripheral lymphocytes or bonemarrow cells have not been observed.

Formaldehyde also induces the formation ofDNA–protein crosslinks in a variety of human andrat cell types in vitro and in the epithelium of thenasal cavity of rats and respiratory tract of monkeysfollowing inhalation, which may contribute to thecarcinogenicity of the compound in the nasal cavityof rats through replication errors, resulting inmutation.

Overall, formaldehyde is weakly genotoxic,with effects most likely to be observed in vivo incells from tissues or organs with which the aldehydecomes into first contact.


Inhalation

In epidemiological studies of occupationallyexposed populations, there has been little evidenceof a causal association between exposure toformaldehyde and lung cancer. Indeed, results ofstudies in a rather extensive database of cohort andcase–control studies do not fulfil traditional criteriaof causality in this regard, such as consistency,strength and exposure–response. Increases inmortality or incidence have not been observedconsistently, and, where examined, there hasconsistently been no evidence of exposure–response.The data for nasal and nasopharyngeal cancer areless clear. In case–control studies, there have beenincreases in cancers of the nasal or nasopharyngealcavities that fulfil, at least in part, traditional criteriaof causality, with tumours having been observedin workers with highest levels or duration ofexposure. It should be noted, though, that measuresof exposure in these population-based investigationsare rather less reliable than those in the larger, mostextensive cohort studies of occupationally exposedpopulations; moreover, methodological limitationscomplicate interpretation of several of thecase–control studies. Excesses of cancers of thenasal or nasopharyngeal cavities have not beenobserved consistently in cohort studies. Where therehave been excesses, there has been little evidence ofexposure–response, although the total numberof observed tumours was small.

Five carcinogenicity bioassays haveprovided consistent evidence that formaldehydeis carcinogenic in rats exposed via inhalation (Kernset al., 1983; Sellakumar et al., 1985; Tobe et al.,1985; Monticello et al., 1996; Kamata et al., 1997).The incidence of nasal tumours was not significantlyincreased in mice exposed to formaldehyde byinhalation (Kerns et al., 1983). This has beenattributed, at least in part, to the greater reduction inminute volume in mice than in rats exposed toformaldehyde (Chang et al., 1981; Barrow et al.,1983), resulting in lower exposures in mice than inrats (Barrow et al., 1983).


Observation of tumours at the siteof contact is consistent with toxicokineticconsiderations. Formaldehyde is a highly water-soluble, highly reactive gas that is absorbedquickly at the site of contact. It is also rapidlymetabolized, such that exposure to even highconcentrations of atmospheric formaldehyde doesnot result in an increase in blood concentrations.

As described in Section 2.4.3.7, themechanisms by which formaldehyde inducesnasal tumours in rats are not fully understood.However, it has been hypothesized that asustained increase in epithelial cell regenerativeproliferation resulting from cytotoxicity is arequisite precursor in the mode of inductionof tumours. Mutation, for which the formationof DNA–protein crosslinks serves as a markerof potential, may also contribute to thecarcinogenicity of the compound in the nasalcavity of rats. Studies relevant to assessment ofthe mode of action include a cancer bioassay(Monticello et al., 1996) in which intermediateendpoints (proliferative response in variousregions of the nasal epithelium) have beeninvestigated. The relevant database also includesnumerous shorter-term studies in whichproliferative response and the formation ofDNA–protein crosslinks in the nasal epitheliumof rats and other species have been examinedfollowing exposure via regimens often similar tothose in the cancer bioassays (Swenberg et al.,1983; Casanova and Heck, 1987; Heck andCasanova, 1987; Casanova et al., 1989, 1991,1994; Monticello et al., 1989, 1991). It should benoted, though, that due to the limited data onintermediate endpoints in most of the cancerbioassays, information available as a basis fordirect comparison of the incidence of intermediatelesions (i.e., proliferative response as a measureof cytotoxicity and DPX) and tumours is limitedto that presented in Table 4.

In all cases where examined, withoutexception, sustained cytotoxicity and cellularproliferation were observed in the nasal cavitiesof the same strain of rats exposed in a similarmanner in short-term studies to concentrations or

doses that induced nasal tumours in the cancerbioassays (Monticello et al., 1991, 1996).However, the converse is not always true.Similarly, tumours have been observed only atconcentrations at which increases in DNA–proteincrosslinks have been observed in shorter-termstudies in the same strain (Casanova and Heck,1987; Heck and Casanova, 1987; Casanova et al.,1989, 1994).

In addition, where proliferative response(Monticello et al., 1991, 1996) and DPX(Casanova et al., 1994) have been examined invarious regions of the nasal passages, sites atwhich there are increases are similar to thosewhere tumours have been observed. Theconcentration–response relationships for DPX,cytotoxicity, proliferative response and tumoursare highly non-linear, with significant increases inall endpoints being observed at concentrations of4 ppm (4.8 mg/m3) and above (Table 4). Thiscorrelates well with the concentration at whichmucociliary clearance is inhibited andglutathione-mediated metabolism saturated(i.e., 4 ppm [4.8 mg/m3]). Histological changes,increased epithelial cell proliferation and DPXare all more closely related to the exposureconcentration than to the total cumulative intakeor dose of formaldehyde (Swenberg et al., 1983;Casanova et al., 1994).

While the respective roles of DPX,mutation and cellular proliferation in theinduction of tumours in the rat nose are notfully delineated, the hypothesized mode ofcarcinogenesis is in keeping with the growingbody of evidence supporting the biologicalplausibility that prolonged regenerative cellproliferation can be a causal mechanism inchemical carcinogenesis. Regenerative cellproliferation following formaldehyde-inducedcytotoxicity increases the number of DNAreplications and thus increases the probabilityof a DNA–protein crosslink initiating a DNAreplication error, resulting in a mutation. Thisproposed mode of action is consistent with theobserved inhibition of DNA replication in therat nose at elevated concentrations (Heck and


Casanova, 1994) and point mutations in the p53tumour suppressor gene in tumours from thenoses of rats exposed to formaldehyde (Recioet al., 1992).

The hypothesized mode of inductionof formaldehyde-induced tumours that satisfiesseveral criteria for weight of evidence, includingconsistency, concordance of exposure–responserelationships across intermediate endpoints andbiological plausibility and coherence of thedatabase, is likely relevant to humans, at leastqualitatively. Increased cell proliferation(Monticello et al., 1989) and DNA–proteincrosslink formation (Casanova et al. 1991)within epithelia of the upper respiratory tracthave been observed in monkeys exposed toformaldehyde vapour. Although not sufficient initself as a basis for inferring causality, directevidence on histopathological lesions in the noseof humans exposed primarily to formaldehydein the occupational environment is consistentwith a qualitatively similar response of the upperrespiratory tract in humans and experimentalanimals to formaldehyde. Increased humanepithelial cell proliferation following in situexposure to formaldehyde has also been observedin a model system in which rat trachea populatedwith human tracheobronchial epithelial cellswere xenotransplanted into athymic mice (Uraet al., 1989).

Because formaldehyde is highly reactiveat the site of contact, dosimetry is of criticalimportance when extrapolating across species thathave significantly different anatomical features ofthe nasal and respiratory passages and patterns offlow of inhaled air. Since humans as well as otherprimates are oronasal breathers, compared withrats, which are obligate nose breathers, effectsassociated with the inhalation of formaldehydeare likely to be observed in a wider area deeperwithin the respiratory tract. Indeed, in ratsexposed to moderate levels of formaldehyde,histopathological changes, increased epithelialcell proliferation as well as DNA–proteincrosslink formation are restricted to the nasalcavity; in formaldehyde-exposed monkeys(as surrogates for humans), on the other hand,

these effects have been observed further alongwithin the upper respiratory tract. While theepidemiological studies taken as a whole do notprovide strong evidence for a causal associationbetween formaldehyde exposure and humancancer, the possibility of increased risk ofrespiratory cancers, particularly those of the upperrespiratory tract, cannot be excluded on the basisof available data.

Based primarily upon data derivedfrom laboratory studies, therefore, the inhalationof formaldehyde under conditions that inducecytotoxicity and sustained regenerativeproliferation is considered to present acarcinogenic hazard to humans.

Oral exposure

Epidemiological studies of potential carcinogenichazards associated with the ingestion offormaldehyde were not identified. Currently,there is no definitive evidence to indicate thatformaldehyde is carcinogenic when administeredorally to laboratory animals. However, consistentwith the known reactivity of this substance withbiological macromolecules in the tissue or organof first contact, histopathological and cytogeneticchanges within the gastrointestinal tract havebeen observed in rats administered formaldehydeorally. These observations and additionalconsideration of the mode of induction of tumoursby formaldehyde lead to the conclusion thatunder certain conditions of exposure, potentialcarcinogenic hazard associated with the ingestionof formaldehyde cannot be eliminated.

3.3.2.2 Non-neoplastic effects

Sensory irritation of the eyes and respiratory tractby formaldehyde has been observed consistentlyin clinical studies and epidemiological (primarilycross-sectional) surveys in occupational andresidential environments. The pattern of effectsis consistent with increases in symptoms beingreported at lowest concentrations, with the eyegenerally being most sensitive.


At concentrations higher than thosegenerally associated with sensory irritation,generally small, reversible effects on lungfunction have been noted, although evidence ofcumulative decrement in pulmonary function islimited.

Results are consistent with the increasedprevalence of histological changes in the nasalepithelium in cross-sectional studies of workersbeing attributable to formaldehyde (Edling et al.,1988; Holmström et al., 1989c; Boysen et al.,1990; Ballarin et al., 1992). The criterion ofbiological plausibility for weight of evidenceof causality is also satisfied by the convincingevidence in monkeys (Rusch et al., 1983)and rodents of histopathological alterations(degenerative changes consistent withcytotoxicity) within the upper respiratory tract.Other than damage to the gastric epitheliumobserved following the acute ingestion of largeamounts of formaldehyde (Kochhar et al., 1986;Nishi et al., 1988; WHO, 1989), studies onpotential changes within the gastrointestinal tractin humans following the long-term ingestion ofthis substance were not identified. However,histological changes within the surface epitheliumof the gastrointestinal tract of rats (e.g., erosionsand/or ulcers, hyperkeratosis, hyperplasia,gastritis) have been observed following chronicoral exposure to formaldehyde administered indrinking water, at high concentrations (Til et al.,1989; Tobe et al., 1989).

Formaldehyde is not likely to affectreproduction or development at levels of exposurelower than those associated with adverse healtheffects at the site of contact. Based upon recentepidemiological studies of occupationally exposedindividuals, there is no clear evidence indicatingthat either maternal or paternal inhalationexposure to formaldehyde is associated withan increased risk of spontaneous abortion(Hemminki et al., 1985; Lindbohm et al., 1991;John et al., 1994; Taskinen et al., 1994). Instudies of laboratory animals exposed viainhalation (Saillenfait et al., 1989; Martin, 1990)or oral administration (Seidenberg and Becker,1987; Wickramaratne, 1987), formaldehyde had

no effect on reproduction or fetal development, atlevels of exposure less than those causing notableadverse health effects at the site of contact.

Based upon the available although limiteddata, exposure to formaldehyde is unlikely tobe associated with suppression of the immuneresponse. Indeed, the dermal hypersensitivity ofsome individuals to formaldehyde as well as theresults of studies in animals indicate heightenedimmune responses linked to formaldehydeexposure. Information from epidemiologicalstudies on suppression of the immune responseassociated with exposure to formaldehyde wasnot identified. Adverse effects on either cell- orhumoral-mediated immune responses have notbeen consistently observed in studies conductedin laboratory animals (Dean et al., 1984; Adamset al., 1987; Holmström et al., 1989b; Jakab,1992; Vargová et al., 1993). Although suggestedin case reports for some individuals, no clearevidence that formaldehyde-induced asthma wasattributable to immunological mechanisms hasbeen identified. However, studies with laboratoryanimals have revealed that formaldehyde mayenhance their sensitization to inhaled allergens(Tarkowski and Gorski, 1995; Riedel et al., 1996).

For the general population, dermalexposure to concentrations of formaldehyde in thevicinity of 1–2% (10 000–20 000 ppm) is likelyto cause skin irritation; however, in hypersensitiveindividuals, contact dermatitis can occurfollowing exposure to formaldehyde atconcentrations as low as 0.003% (30 ppm).In North America, less than 10% of patientspresenting with contact dermatitis may beimmunologically hypersensitive to formaldehyde.

3.3.3 Exposure–response analysis

Cancer and non-neoplastic effects are addressedseparately here. However, the weight of evidenceindicates that formaldehyde is carcinogeniconly at concentrations that induce the obligatoryprecursor lesion of proliferative regenerativeresponse associated with cytotoxicity, althoughinteraction with DNA must also be taken intoaccount. For consistency with other assessments


and for ease of presentation, cancer and non-cancer effects are considered separately here,although, based on consideration of mode ofaction, they are inextricably linked.

Emphasis in the dose–response analysesfor cancer presented below is on a biologicallymotivated case-specific model that incorporatesa two-stage clonal growth model. This modelis supported by dosimetry calculations fromcomputational fluid dynamics (CFD) modelling offormaldehyde flux in various regions of the noseand a single-path model for the lower respiratorytract. While this model entails simplification ofcancer biology, which requires selection of anumber of parameters and use of simplifyingassumptions, it is considered to offerimprovement over default methodology dueto incorporation of as many biological data aspossible.

There has been no sensitivity analysisconducted to determine which of the modelparameters has greatest impact on risk estimatesor to identify which parameters are known withthe highest degree of certainty. However, outputof the model is considered adequate as a basis toensure that measures taken to prevent sensoryirritation 1 in human populations are sufficientlyprotective with respect to carcinogenic potential.

3.3.3.1 Inhalation


There is indisputable evidence that formaldehydeis carcinogenic in rats following inhalation, withthe carcinogenic response being limited to the siteof contact (e.g., the nasal passages of rodents).While the mechanism of action is not wellunderstood, based primarily upon data derivedfrom laboratory studies, regenerative proliferationassociated with cytotoxicity appears to be anobligatory intermediate step in the induction ofcancer by formaldehyde. Interaction with geneticmaterial, the potential for which is indicated by

DPX, likely also contributes, although theprobability of mutation resulting from DPX isunknown.

Available data are also consistentwith the hypothesis that humans would respondqualitatively similarly to experimental animalsin this regard. However, since formaldehyde ishighly reactive at the site of contact, dosimetry isof critical importance in predicting interspeciesvariations in response, as a function of flux tothe tissue and regional tissue susceptibility, dueto the significantly different anatomical featuresof the nasal and respiratory passages betweenexperimental animals and humans.

The approach to dose–responsemodelling emphasized here, therefore, isbiologically based, reflecting the non-linearityin concentration–response relationships forformaldehyde-induced nasal cancer andassociated intermediate endpoints andincorporating, to the extent possible, mechanisticdata and state-of-the-art analyses for species-specific dosimetry. It incorporates regenerativecell proliferation as a required step in theinduction of tumours by formaldehyde and acontribution from mutagenicity (not definedspecifically by DPX) that has greatest impact atlow exposures through modelling of complexfunctional relationships for cancer due to actionsof formaldehyde on mutation, cell replication andexponential clonal expansion. Species variationsin dosimetry are taken into account by CFDmodelling of formaldehyde flux in variousregions of the nose and a single-path model forthe lower respiratory tract of humans.

The outcome is compared with thatderived based on empirical default methodologyfor estimation of tumorigenic concentrations inthe experimental range for Priority Substances(Health Canada, 1994). However, it is thebiologically motivated case-specific model thatis considered to provide the most defensibleestimates of cancer risk, on the basis that it


1 Occurs at lower concentrations than effects on mucociliary clearance or histopathological damage to the nose of humans.

encompasses more of the available biologicaldata, thereby offering considerable improvementover default (Health Canada, 1998). Moreover,in view of the clear emphasis herein andpreference for the biologically motivated case-specific model, there has been no attempt toincorporate more of the biological data in thecalculation of tumorigenic concentrations bydefault methodology (e.g., dose and timedependence to derive an empirical dose metricfor rats).

Biologically motivated case-specific model

Derivation of the dose–response model andselection of various parameters are presentedin greater detail in CIIT (1999); only a briefsummary is provided here. The biologicallybased, two-stage clonal growth model developed(Figure 2) is identical in biological structure toother such models (also known as MVK models),incorporating information on normal growth, cellcycle time and cells at risk (in various regions ofthe respiratory tract).

Formaldehyde is assumed to act asa direct mutagen, with the effect consideredproportional to the estimated tissue concentrationof DNA–protein crosslinks. The dose–responsecurve for DNA–protein crosslink formation

is linear at low exposure concentrations andincreases in a greater than linear manner at highconcentrations, similar to those administeredin the rodent carcinogenicity bioassays. Thesecond mode of carcinogenic action considerscytotoxicity and the subsequent regenerativecellular proliferation associated with exposureto formaldehyde, incorporating a “hockey stick”dose–response curve (i.e., dose threshold curve)within the model. Values for parameters relatedto the effects of formaldehyde exposure uponthe mutagenic (i.e., DNA–protein crosslinkformation) and proliferative response(i.e., regenerative cell proliferation resulting fromformaldehyde-induced cytotoxicity) were derivedfrom a two-stage clonal growth model developedfor rats (Figure 3), which describes the formationof nasal tumours in animals exposed toformaldehyde.

Species-specific dosimetry within variousregions of the respiratory tract in laboratoryanimals and humans was also incorporated.Regional dose is a function of the amount offormaldehyde delivered by inhaled air and theabsorption characteristics of the lining withinvarious regions of the respiratory tract. The amount of formaldehyde delivered by inhaled airdepends upon major airflow patterns, air-phasediffusion and absorption at the air–lining interface.


FIGURE 2 Two-stage clonal growth model (reproduced from CIIT, 1999)

The “dose” (flux) of formaldehyde to cells dependsupon the amount absorbed at the air–lininginterface, mucus/tissue-phase diffusion, chemicalinteractions such as reactions and solubility, andclearance rates. Species differences in these factorsinfluence the site-specific distribution of lesions.

The F344 rat and rhesus monkey nasalsurface for one side of the nose and the nasalsurface for both sides of the human nose weremapped at high resolution to develop three-dimensional, anatomically accurate CFD models ofrat, primate and human nasal airflow and inhaledgas uptake (Kimbell et al., 1997; Kepler et al.,1998; Subramaniam et al., 1998). The approximatelocations of squamous epithelium and the portionof squamous epithelium coated with mucus weremapped onto the reconstructed nasal geometry ofthe CFD models. These CFD models provide ameans for estimating the amount of inhaled gasreaching any site along the nasal passage wallsand allow the direct extrapolation of exposuresassociated with tissue damage from animals tohumans via regional nasal uptake. Although

development of the biologically based, two-stageclonal growth model for rats required analysis ofonly the nasal cavity, for humans, carcinogenicrisks were based on estimates of formaldehydedose to regions (i.e., regional flux) along the entirerespiratory tract.

The exposure–response model developedfor humans (see Figure 4) predicts the additionalrisk of formaldehyde-induced cancer within therespiratory tract under various exposure scenarios.

Two of the parameters in the humanclonal growth model — the probability ofmutation per cell division and the growthadvantage for preneoplastic cells, both inthe absence of formaldehyde exposure, wereestimated statistically by fitting the model tohuman 5-year age group lung cancer incidencedata for non-smokers. 2 The parameterrepresenting the time for a malignant cell toexpand clonally into a clinically detectabletumour was set at 3.5 years.


FIGURE 3 Roadmap for the rat clonal growth model. SCC = squamous cell carcinoma (reproducedfrom CIIT, 1999)

(Reproduced from CIIT, 1999)

2 Data on predicted risks of upper respiratory tract cancers for smokers are also presented in CIIT (1999).

In addition to the human nasal CFD model,a typical-path, one-dimensional model offormaldehyde uptake was developed for the lowerrespiratory tract. The latter model consisted of thetracheobronchial and pulmonary regions in whichuptake was simulated for four ventilatory states,based on an ICRP (1994) activity pattern for aheavy-working adult male. Nasal uptake in thelower respiratory model was calibrated to matchoverall nasal uptake predicted by the human CFDmodel. While rodents are obligate nasal breathers,humans switch to oronasal breathing when the levelof activity requires a minute ventilation of about 35L/minute. Thus, two anatomical models for theupper respiratory tract encompassing oral and nasalbreathing were developed, each of which consistedbasically of a tubular geometry. For the mouthcavity, the choice of tubular geometry wasconsistent with Fredberg et al. (1980). The rationalefor using the simple tubular geometry for the nasalairway was based primarily upon the need toremove formaldehyde from the inhaled air at thesame rate as in a corresponding three-dimensionalCFD simulation. However, in calculations ofcarcinogenic risk, the nasal airway fluxes predictedby the CFD simulations, and not those predicted bythe single-path model, were used to determine upperrespiratory tract fluxes.

To account for oronasal breathing, therewere two simulations. In one simulation, the nasalairway model represented the proximal upperrespiratory tract, while for the other simulation, themouth cavity model was used for this region. Inboth simulations, the fractional airflow rate in themouth cavity or in the nasal airway was taken intoaccount. For each segment distal to the proximalupper respiratory tract, the doses (fluxes) offormaldehyde from both simulations were added toobtain the estimated dose for oronasal breathing.The site-specific deposition of formaldehyde alongthe human respiratory tract coupled with data oneffects upon regional DPX and cell proliferation(derived from studies in animals) (Casanova et al.,1994; Monticello et al., 1996) were reflected incalculations of carcinogenic risks associated withthe inhalation of formaldehyde in humans.

Estimates of carcinogenic risks usingthe human two-stage clonal growth model weredeveloped for typical environmental exposures(i.e., continuous exposure throughout an 80-yearlifetime to concentrations of formaldehyderanging from 0.001 to 0.1 ppm [0.0012 to0.12 mg/m3]). The human clonal growth modelpredicted non-zero additional risks throughout theexposure ranges examined. The two-stage model


FIGURE 4 Roadmap for the human clonal growth model (reproduced from CIIT, 1999)

describes a low-dose, linear carcinogenic responsefor humans exposed to levels of formaldehyde of≤0.1 ppm (0.12 mg/m3), where cytotoxicity andsustained cellular regenerative proliferation do notappear to play a role in tumour induction. Indeed,the effect of formaldehyde upon regenerativecellular proliferation did not have a significantimpact upon the predicted carcinogenic risks atexposures between 0.001 and 0.1 ppm (0.0012and 0.12 mg/m3). Based upon the two-stage clonalgrowth model, the predicted additional risks ofupper respiratory tract cancer for non-smokers,associated with an 80-year continuous exposureto levels of formaldehyde between 0.001 and0.1 ppm (1.2 and 120 µg/m3), range from2.3 × 10–10 to 2.7 × 10–8, respectively (CIIT, 1999).

No excess risk was predicted by the humanclonal growth model in a cohort exposed toformaldehyde at a specific plant examined in twoepidemiological studies (Blair et al., 1986; Marsh etal., 1996). This was consistent with the observednumber of cases of respiratory tract cancer (113observed deaths; 120 expected) in the cohort. Thus,the outcome of the model was consistent with theresults of the epidemiological studies.

Default modelling

For comparison, based upon the approach typicallyemployed in the assessment of Priority Substances,a Tumorigenic Concentration05 (TC05) (i.e., theconcentration associated with a 5% increase intumour incidence over background) of 7.9 ppm(9.5 mg/m3) (95% lower confidence limit [LCL] =6.6 ppm [7.9 mg/m3]) formaldehyde was derivedfrom data on the incidence of nasal squamoustumours in rats exposed to this substance in thesingle study (i.e., Monticello et al., 1996) in whichexposure–response was best characterized. 3 TheTC05 is calculated by first fitting a multistage modelto the exposure–response data. The multistagemodel is given by

where d is dose, k is the number of dose groups inthe study minus one, P(d) is the probability of theanimal developing a tumour at dose d and qi > 0, i = 1, ..., k are parameters to be estimated.

The model was fit using GLOBAL82(Howe and Crump, 1982), and the TC05 wascalculated as the concentration C that satisfies

P(C) – P(0) = 0.051 – P(0)

A chi-square lack of fit test wasperformed for each of the three model fits. Thedegrees of freedom for this test are equal to kminus the number of qi’s whose estimates arenon-zero. A p-value less than 0.05 indicatesa significant lack of fit. In this case, chi-square = 3.7, df = 4 and p = 0.45.

3.3.3.1.2 Non-neoplastic effects

There are considered to be sufficient datafrom clinical studies and cross-sectional surveysof human populations, as well as supportingobservations from experimental studies conductedwith laboratory animals, to indicate that theirritant effects of formaldehyde on the eyes,nose and throat occur at lowest concentration.Although individual sensitivity and exposureconditions such as temperature, humidity, durationand co-exposure to other irritants are likely toinfluence response levels, in well-conductedstudies, only a very small proportion of thepopulation experiences symptoms of irritationfollowing exposure to ≤0.1 ppm (0.12 mg/m3)formaldehyde. This is less than the levels thatreduce mucociliary clearance in the anterior portionof the nasal cavity in available clinical studies inhuman volunteers (0.3 mg/m3) and induce histopathological effects in the nasal epithelium in


3Based upon the incidence of nasal tumours in rats exposed to formaldehyde, combined from the studies conducted byKerns et al. (1983) and Monticello et al. (1996), the concentration of formaldehyde associated with a 5% increase in tumourincidence (maximum likelihood estimate) was approximately 6.1 ppm (7.3 mg/m3) (CIIT, 1999).

cross-sectional studies of formaldehyde-exposedworkers (0.3 mg/m3). Additional investigation ofpreliminary indication of effects on pulmonaryfunction in children in the residential environmentassociated with lower concentrations offormaldehyde (40–60 ppb [48–72 µg/m3])(Krzyzanowski et al., 1990) is warranted.

3.3.3.2 Oral exposure

Lack of evidence for the potential carcinogenicity ofingested formaldehyde precludes an analysis ofexposure–response for this effect.

Data on non-neoplastic effects associatedwith the ingestion of formaldehyde are much morelimited than for inhalation. Owing to its highreactivity, non-neoplastic effects in the tissue of firstcontact following ingestion (i.e., the gastrointestinaltract) are more likely related to the concentration ofthe formaldehyde consumed, rather than to itscumulative (total) intake. Information from studieson humans is inadequate to identify putativeexposure–response relationships with respect totoxicological effects associated with the long-termingestion of formaldehyde. However, a TolerableConcentration (TC) for formaldehyde in ingestedproducts may be derived on the basis of the NOELfor the development of histological changes in thegastrointestinal tract of rats as follows:

TC = 260 mg/L100

= 2.6 mg/L

where:• 260 mg/L is the NOEL for effects

(i.e., histopathological changes) in thegastrointestinal tract of rats administeredformaldehyde in drinking water for 2 yearsin the most comprehensive study conducted(Til et al., 1989), and

• 100 is the uncertainty factor (×10 forinterspecies variation, ×10 for intraspeciesvariation).

3.3.4 Human health risk characterization

Characterization of human health risks associatedwith exposure to formaldehyde is based uponanalysis of the concentrations of this substance in airand some food products, rather than estimates oftotal daily intake per se, since effects are observedprimarily in the tissue of first contact and are relatedto the level of exposure rather than to total systemicintake.

Emphasis for the characterization of healthrisks associated with the inhalation of formaldehydein the environment in Canada is on non-neoplasticeffects that occur at lowest concentrations (i.e.,sensory irritation). The adequacy of this approach toprotect for potential carcinogenicity is considered inthe context of the biologically motivated case-specific model described above.

In humans (as well as laboratory animals),signs of ocular and upper respiratory tract sensoryirritation have been observed at exposures typicallygreater than 0.1 ppm [120 µg/m3]). The estimatedmedian and mean 24-hour time-weighted averageexposures to formaldehyde in air in Canada are, atmost, one-third of this value. This value is alsogreater than the estimated time-weighted averageexposure to which 95% of the population isexposed. In some indoor locations, however,concentrations may approach the level associatedwith signs of eye and respiratory tract sensoryirritation in humans.

The risks of upper respiratory tractcancer predicted by the biologically motivated case-specific model to be associated with exposure to themedian, mean and 95th percentile concentrations offormaldehyde in air in Canada are also exceedinglylow (i.e., <2.7 × 10–8). Based on this estimate of risk,priority for investigation of options to reduceexposure in relation to the carcinogenicity offormaldehyde is low.


Available information is consideredinsufficient to fully characterize the exposureof individuals in Canada to formaldehyde infoodstuffs. However, based upon limitedinformation, the levels of formaldehyde indrinking water appear to be more than 2 orders ofmagnitude less than the Tolerable Concentration(2.6 mg/L). Although the concentration offormaldehyde in some food products wouldappear to exceed the Tolerable Concentration, theextent of its bioavailability therein is unknown.

3.3.5 Uncertainties and degree ofconfidence in human health riskcharacterization

There is a moderate degree of confidence inthe characterization of the principal sourceof exposure of the general population (i.e.,residential indoor air). In the two studies wherethere was active sampling for a 24-hour duration,the analytical and sampling methodologies wereoptimum, all of the samples were analyzed by asingle specialized laboratory, and the effects ofdiurnal variation were minimized by the 24-hoursampling duration. The data are also reasonablycurrent (i.e., 1991–1993) and the measured valuesconsistent with those determined in surveys inother countries. While some uncertainty isintroduced by pooling of these data with thosefrom the remaining three studies, which involvedpassive sampling, the ranges and distributionsof concentrations in these subsets of data weresimilar. Some uncertainty is introduced by thelimited size and representation of the data set(n = 151 homes in Windsor, Hamilton, Trois-Rivières, Québec, Saskatoon and variouslocations in the Northwest Territories), lack ofrandom sampling of the homes and involvementof volunteers.

Although it contributes less to totalexposure, there is a high degree of confidencein the characterization of the concentrations offormaldehyde in ambient air in Canada, due tothe magnitude and sensitivity of the relevantmonitoring data. Analytical and samplingmethodologies were optimum, all of the samples

were analyzed by a single specialized laboratory,and the effects of diurnal variation wereminimized by the 24-hour sampling duration.The data set is large (n = 2819) and reasonablycurrent (i.e., 1990–1998), and the concentrationsof formaldehyde are consistent with thosereported for outdoor air in other Canadian andinternational studies. However, the locations ofNAPS sites were not determined by a randomsampling scheme, and a subset of only eightNAPS sites was selected. The data may also notbe strictly representative of population exposure,since the air is sampled at elevations higher thanthe breathing zone at some sites and may beremote from populated areas. However, samplesfrom Canada’s three major urban centres (i.e.,Montréal with two sites, Toronto and Vancouver)account for 54% of the 2819 samples, andsamples from two sites in Windsor, Ontario,account for an additional 21% of the samplesin this data set.

Uncertainty concerning the timespent indoors by Canadians is judged to be low,since the estimate is based on the most currentCanadian data, the time–activity data wereobtained based on a random sampling scheme,and analysis of the data involved populationweighting. However, the same mean time spentoutdoors is assumed for Canadians of all agegroups and in all regions of the country, a normaldistribution is assumed for the hours per day spentoutdoors, and the variance of the assumed normaldistribution is also assumed (i.e., standarddeviation of 2).

The degree of uncertainty concerning theformaldehyde content of food currently consumedby Canadians is sufficiently high so as to precludemeaningful estimation of exposure from thissource, except as a basis for determining potentialrelative proportions of total intake from variousmedia. Identified data on concentrations in thismedium are restricted to a small number of foodsamples collected in other countries, sometimes inearly studies for which there is some suspicion ofproduction of formaldehyde due to the relativelyhigh temperatures and acidic reagents employed.


There are no indications that food items wereselected on a random basis and often noindication whether the reported concentrationsreflect formaldehyde content in the food asconsumed. Due to its high volatility, theformaldehyde content would be expected tobe reduced during processing and cooking.Formaldehyde is not expected to partition into thefatty compartments of foods, and direct contactof formaldehyde in food applications is verylimited. Also, while there is some suggestion thatformaldehyde is present in food in bound(unavailable) form, data to substantiate thiscontention were not identified.

There is a moderate degree of certaintythat consumption of drinking water does notcontribute significantly to the daily intake offormaldehyde by Canadians, since formaldehydeis relatively unstable in water. However, nodata concerning the range and distribution ofconcentrations of formaldehyde in Canadiandrinking water were identified.

With respect to toxicity, the degreeof confidence that critical effects are wellcharacterized is high. A relatively extensivedatabase in both humans and animals indicatesthat critical effects occur at the initial site ofexposure to this substance. The database inhumans is also sufficiently robust to serve as abasis for confident conclusion concerning theconsistently lowest levels at which effects (i.e.,sensory irritation) occur, although additionalinvestigation of an unconfirmed report of effectson respiratory function in children exposed tolower levels of formaldehyde is desirable.

The degree of confidence in the databasethat supports an obligatory role of regenerativeproliferation in the induction of nasal tumours inrats is moderate to high, although the mechanismof carcinogenicity of formaldehyde is unclear.Although the biologically motivated case-specificmodel for estimation of cancer risks is clearlypreferred due to incorporation of as manybiological data as possible, there are a number ofuncertainties described in more detail in CIIT(1999) and summarized briefly here, although

sensitivity analyses were not conducted. Fordosimetry, sources of uncertainty for whichsensitivity analyses would have been appropriateinclude the use of individual rat, primate andhuman nasal anatomies as representative of thegeneral population, the use of a typical-pathhuman lung structure to represent people withcompromised lungs, the sizes of specific airways,the use of a symmetric Weibel model for the lung, the estimation of the location and extentof squamous and olfactory epithelium and ofmucus- and non-mucus-coated nasal regions inthe human, and the values of mass transfer anddispersion coefficients. The lack of human data onformaldehyde-related changes in the values of keyparameters of the clonal growth model accountsfor much of its uncertainty.

In order to better define the mode ofaction of induction of tumours, elaboration ofthe quantitative relationship between DPXand mutation and the time course of loss ofDNA–protein crosslinks is desirable. Additionalcharacterization of the shape of theconcentration–response relationship forregenerative proliferative response would alsobe informative.

For Priority Substances where theinduction of cancer through direct interaction withgenetic material cannot be ruled out and availabledata are inadequate as a basis for developmentof biologically motivated case-specific models,cancer potency is estimated based on empiricalmodelling of experimental data within or closeto the experimental range, as described above(Section 3.3.3). Estimates of exposure are thencompared with these quantitative estimates ofcarcinogenic potency (Exposure Potency Index)to characterize risk and provide guidance inestablishing priorities for further action (i.e.,analysis of options to reduce exposure)(Health Canada, 1994) under CEPA 1999. Whilethe biologically motivated case-specific model isclearly preferred as a basis for characterizationof exposure–response for cancer for formaldehydedue to its incorporation of as many of thebiological data as possible, the priority forinvestigation of options to reduce exposure


based on default methodology is presentedhere for comparison.

Utilization of this default approach inthe case of formaldehyde would indicate thatprobabilistic estimates of the 24-hour median,mean and 97.5th percentile concentrations offormaldehyde in air in Canada (generally and fora worst-case site) would be approximately 327-,263- and 98-fold lower, respectively, than themaximum likelihood estimate of the carcinogenicpotency (i.e., TC05 = 9.5 mg/m3)4 derived from acarcinogenesis bioassay in rats (Monticello et al.,1996). Overall, based upon these ExposurePotency Indices (ranging from 3 × 10–3 to1.0 × 10–2), the priority for the investigation ofoptions to reduce exposure to formaldehyde inair would have been considered to be high.

3.4 Conclusions

CEPA 1999 64(a): Based on analyses of worst-case situations that are likelyto be encountered in Canada,risk quotients for water andair are less than 1. Theenvironmental risks associatedwith concentrations offormaldehyde likely to befound in Canada thereforeappear to be low. Therefore,available data indicate that itis unlikely that formaldehydeis entering or may enter theenvironment in a quantityor concentration or underconditions that have or mayhave an immediate or long-term harmful effect on theenvironment or its biologicaldiversity, and it is notconsidered to be “toxic”as defined in CEPA 1999Paragraph 64(a).

CEPA 1999 64(b): Formaldehyde is not involvedin depletion of stratosphericozone and likely does notcontribute significantly toclimate change. Because of itsreactivity and abundance inair, formaldehyde contributes,along with other reactivevolatile organic chemicals, tothe formation of troposphericozone. Therefore, based onavailable data, formaldehydeis entering the environmentin a quantity or concentrationor under conditions thatconstitute or may constitutea danger to the environmenton which life depends, andit is considered to be “toxic”as defined in CEPA 1999Paragraph 64(b).

CEPA 1999 64(c): Although other factors(such as sustained cellularproliferation) play animportant role, there islikely a genetic component(i.e., mutation, for whichDNA–protein crosslinks serveas a marker for potential)in the induction of tumoursfollowing the inhalation offormaldehyde. Therefore,formaldehyde is consideredto be “toxic” as defined inParagraph 64(c) of CEPA1999. For compounds wherethe induction of cancerthrough direct interaction withgenetic material cannot beruled out, this approach isconsistent with the objectivethat exposure be reducedwherever possible andobviates the need to establishan arbitrary “de minimis”


4 Concentration of formaldehyde causing a 5% increase in tumour incidence over background.

level of risk for thedetermination of “toxic” underCEPA 1999. However, basedon comparison of risks ofcancer estimated on the basisof a biologically motivatedcase-specific model withcalculated exposure in airof the general populationin Canada, the priority forinvestigation of options toreduce exposure on thebasis of carcinogenicity isconsidered to be low. Whilethe majority of the populationis exposed to concentrationsof formaldehyde less thanthose associated withsensory irritation, continuedinvestigation of optionsto reduce exposure toformaldehyde in indoor air isrecommended as part of anoverall program to reduceexposure to other aldehydesconsidered to be “toxic”under Paragraph 64(c) ofCEPA 1999.

Overall conclusion: Based on critical assessment

of relevant information,formaldehyde is consideredto be “toxic” as defined inSection 64 of CEPA 1999.

3.5 Considerations for follow-up(further action)

Formaldehyde contributes to the photochemicalformation of ground-level ozone. It isrecommended that key sources of formaldehyde

be addressed, therefore, as part of management plans for volatile organic chemicals thatcontribute to the formation of ground-levelozone. While indications are that concentrationscurrently in air and water are not causingenvironmental harm to biota, continued andimproved monitoring at sites likely to releaseformaldehyde are desirable, notably with regardsto industrial uses for resins and for fertilizers aswell as releases from pulp and paper mills.

Although the priority for investigationof options to reduce exposure in the generalenvironment is generally considered to be low, inrelation to carcinogenic potential, in some indoorlocations, concentrations are only slightly lowerthan, and may even approach, the level associatedwith signs of eye and respiratory tract sensoryirritation in humans. Therefore, it is recommendedthat continued investigation of options to reduceexposure to formaldehyde in indoor air beconsidered under the authority of acts other thanCEPA 1999 as part of an overall program toreduce exposure to other aldehydes (e.g., acrolein,acetaldehyde) in indoor air deemed to be “toxic”under Paragraph 64(c) of CEPA 1999. Where thecontrol of any identified sources falls within theauthority of an Act other than CEPA 1999, theresults of these investigations should be forwardedto the appropriate authority for furtherconsideration.


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Environmental assessment

Data relevant to the assessment of whetherformaldehyde is “toxic” to the environment underCEPA 1999 were identified from original literature,existing review documents, published referencetexts and on-line searches conducted betweenJanuary and May 1996 of the followingcommercial and government databases: Aqualine(1990–1996), ASFA (Aquatic Sciences andFisheries Abstracts, Cambridge ScientificAbstracts; 1996), BIOSIS (Biosciences InformationServices; 1990–1996), CAB (CommonwealthAgriculture Bureaux; 1990–1996), CESARS(Chemical Evaluation Search and Retrieval System,Ontario Ministry of the Environment and MichiganDepartment of Natural Resources; 1996), ChemicalAbstracts (Chemical Abstracts Service, Columbus,Ohio; 1990–1996), CHRIS (Chemical HazardRelease Information System; 1964–1985), CurrentContents (Institute for Scientific Information;1990–1992, 1996), ELIAS (Environmental LibraryIntegrated Automated System, EnvironmentCanada library; January 1996), Enviroline(R.R. Bowker Publishing Co.; November 1995 –June 1996), Environmental Abstracts (1975 –February 1996), Environmental Bibliography(Environmental Studies Institute, InternationalAcademy at Santa Barbara; 1990–1996), GEOREF(Geo Reference Information System, AmericanGeological Institute; 1990–1996), HSDB(Hazardous Substances Data Bank, U.S. NationalLibrary of Medicine; 1990–1996), Life Sciences(Cambridge Scientific Abstracts; 1990–1996),NTIS (National Technical Information Service,U.S. Department of Commerce; 1990–1996),Pollution Abstracts (Cambridge ScientificAbstracts, U.S. National Library of Medicine;1990–1996), POLTOX (Cambridge ScientificAbstracts, U.S. National Library of Medicine;1990–1995), RTECS (Registry of Toxic Effects of

Chemical Substances, U.S. National Institute forOccupational Safety and Health; 1996), Toxline(U.S. National Library of Medicine; 1990–1996),TRI93 (Toxic Chemical Release Inventory, U.S.Environmental Protection Agency, Office ofToxic Substances; 1993), USEPA-ASTER(Assessment Tools for the Evaluation of Risk, U.S.Environmental Protection Agency; up to December21, 1994), WASTEINFO (Waste ManagementInformation Bureau of the American EnergyAgency; 1973 – September 1995) and WaterResources Abstracts (U.S. Geological Survey,U.S. Department of the Interior; 1990–1996).A survey of Canadian industry was carriedout under authority of Section 16 of theCanadian Environmental Protection Act (CEPA)(Environment Canada, 1997b,c). Targetedcompanies with commercial activities involvingmore than 1000 kg of formaldehyde wererequired to provide information on uses, releases,environmental concentrations, effects or other datathat were available to them for formaldehyde.Canadian monitoring data, unpublished reportsfrom Canadian producers and users, and personalcommunications from experts in the fieldcompleted the information consulted in preparingthis report. Reveal Alert was used to maintain anongoing record of the current scientific literaturepertaining to the potential environmental effectsof formaldehyde. Data obtained after December1999 were not considered in this assessmentunless they were critical data received during the60-day public review of the report (July 22 toSeptember 20, 2000).

Health assessment

Data relevant to the assessment of the potentialrisks of formaldehyde to human health wereidentified through evaluation of existing review


APPENDIX A SEARCH STRATEGIES EMPLOYED FOR

IDENTIFICATION OF RELEVANT DATA

documents of the Department of National Healthand Welfare (BCH, 1988), the Agency for ToxicSubstances and Disease Registry (ATSDR, 1997),the World Health Organization (WHO, 1989),the International Agency for Research on Cancer(IARC, 1995), as well as a review prepared undercontract by BIBRA Toxicology International(BIBRA, 1994). To identify additional relevanttoxicological data, literature searches onformaldehyde were conducted using the strategyof searching by its name or CAS registry numberin the following databases: CCRIS (ChemicalCarcinogenesis Research Information System,U.S. National Cancer Institute), DART(Developmental and Reproductive Toxicology,U.S. National Library of Medicine), EMIC(Environmental Mutagen Information Centerdatabase, Oak Ridge National Laboratory) andEMICBACK (backfile of EMIC), ETICBACK(backfile of Environmental TeratologyInformation Center database, U.S. EnvironmentalProtection Agency and U.S. National Institute ofEnvironmental Health Sciences), GENE-TOX

(Genetic Toxicology, U.S. EnvironmentalProtection Agency), HSDB, IRIS (IntegratedRisk Information System, U.S. EnvironmentalProtection Agency) and RTECS. Its name, registrynumber and major synonyms were searched in theToxlinePlus (1985–1999) and Toxline (before1985) databases. The CAS registry number wassearched in the Toxlit (1981–1999) database. TheEMBASE (on-line version of Excerpta Medica)database, for 1981–1999, was searched using thename, registry number and major synonyms,combined with a link to toxicological information.In addition to the above sources of information,numerous provincial and federal governmentofficials and representatives of various industrialsectors were contacted between February andAugust of 1996 for data relevant to exposureand/or effects.


canadian environmental protection act, 1999...environment from natural sources (including forest...

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