An Analysis of Potential Carcinogenic Risk From Formaldehyde

8/13/2019 An Analysis of Potential Carcinogenic Risk From Formaldehyde

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REGULATORY TOXICOLCSY AND PHARMACOLOGY 4, 107-129 (1984)

An Analysis of Potential Carcinogenic Risk from FormaldehydeROBERT A. SQUIRE AN D LORRAINE L. CAMERON

Division of Comparative Medicine, Johns Hopkins University School of Medicine, and Departmentof Environmental Health Sciences, Division of Occupational Medicine, Johns HopkinsUniversity School of Hygiene and Public Health, Baltimore, Maryland 21205

Received December 22, 1983

Formaldehyde was recently shown to be carcinogenic in the nasal cavit ies of rats and micefollowing chronic inhalation at vapor concentrations which were cytotoxic. The epidemiological,physiological, and toxicological data on formaldehyde are evaluated as they pertain to the analysiiof carcinogenic risk. I t is concluded that humans are likely to be less susceptible than test rodentsto potential carcinogenic effects and that the risk at low-level exposure would not be linearlyrelated to that observed at the higher levels which were found to be carcinogenic in animals.Risk assessmentprocedures and risk management decisions should incorporate all of the relevantbiological information, such as that discussed, rather than rely solely on a mathematical approachwhich is likely to yield inaccurate and misleading conclusions.

1. INTRODUCTIONIn the absence of adequate human data, chemical carcinogen policyin the United

States has been based upon the principle that a positive and valid animal bioassayprovides presumptive evidence for human carcinogenic risk. This evidence is regardedas largely qualitative, although it has further been presumed that no-effect, or threshold,exposure levels for populations cannot be established. The evidence for these pre-sumptions is indirect and/or based upon hypothetical assumptions. Thus, when achemical as important as formaldehyde is found to induce cancer in test animals,particularly since there is widespread exogenous and endogenous exposure, it isnecessary to reexamine these presumptions.The recent demonstration in rats and, to a lesser extent, in mice that chronicinhalation of formaldehyde at toxic levels induced squamous cell carcinomas of thenasal cavities has prompted extensive interest and discussion on possible carcinogenichazards for man. Although formaldehyde was first discovered in 1859 and has beencommercially manufactured since the early 19OOs, there has been no prior concernfor carcinogenic risk based upon evidence in either man or animals. The acute toxicityand irritability of formaldehyde are well known, but evidence for progressive or

This paper was supported in part by USPHS Grant RR00 130.107

0273-2300184 $3.00Copvisbt 6 1984 by Acadanii Press, Inc.All rights of reproduction in any form resewed


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108 SQUIRE AND CAMERONirreversible toxicity has not been available. The fact that formaldehyde has also beendemonstrated to be genotoxic in certain tests has heightened the concern for potentialcarcinogenicity.It is the objective of this review to bring together and assess he available scientificevidence that is relevant to carcinogenesis risk assessment of formaldehyde. Thefindings of carcinogenic effects in rats and mice have prompted several new researchprojects aimed at elucidating possible mechanisms of formaldehyde carcinogenicityand comparing the relative risks among man and test animals. The early results fromthese experiments as well as the considerable accumulated information on the me-tabolism and toxicity of formaldehyde, if viewed in the total perspective, allow foran objective and rational appraisal of potential carcinogenic risk to humans. Thisrisk analysis is based upon a review of sources and levels of human exposure; humaneffects which have been confirmed; chronic and subchronic animal bioassays usingthe inhalation route; animal studies which may elucidate possible carcinogenic orprotective mechanisms; comparative anatomical and physiological data; and short-term in vivo and in vitro studies. Finally, discussions of mathematical and biologicalconsiderations in human risk assessment based upon the relevant toxicological dataare presented.

2. NATURE OF THE CHEMICALA. Chemistry

Formaldehyde (CAS No. 50-00-00) is the simplest of the aldehydes, with themolecular formula HCHO, and molecular weight of 30.3. It is a colorless, pungentgas at ordinary temperatures and is highly reactive. Aqueous formaldehyde, calledFormalin, is a solution of 37% (by weight) formaldehyde gas in water, usually withlo- 15% methanol added to prevent polymerization (Merck Index, 1976). Formal-dehyde is also commercially available as polymers, such as the solid pamformaldehyde(HCHO),, and the stable cyclic polymer trioxane or trioxymethylene (HCHO),(Meyer, 1979).

B. Sources And UsesThere are two major categories of sources of formaldehyde: direct commercialproduction and indirect production. Formaldehyde is produced by 15 companies at52 plants, located in the eastern United States, along the Gulf Coast, and in thePacific Northwest (SRI 1983). Almost all (99+%) of the 2710 million kg of formal-dehyde directly produced in the United States in 1979 was consumed domestically(IARC, 1982a). indirect production of formaldehyde may occur through the pho-tochemical oxidation of airborne hydrocarbons from vehicle exhausts, the incompletecombustion of hydrocarbons in fuels, and other sources. In 1978, an estimated 107

million kg of formaldehyde was released into the air from stationary sources such asoil refineries, power plants, incinerators, homes, and businesses, and approximately223 million kg was released from mobile sources, primarily buses, trucks, and jetengines (Kitchens et al., 1976); these releases occur primarily in urban and industrialareas. Emissions of unburned hydrocarbons, such as those from auto and diesel


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FORMALDEHYDE CARCINOGENIC RISK 109exhausts, are a major source of formaldehyde in the atmosphere (NBC, 1976); theEPA estimates formaldehyde production from this source at 180 million kg (EPA,1980). Other sources of formaldehyde in the atmosphere include cigarette smoking(Weber et al. 1976) and anaerobic decomposition of methane by microbes (Sawyerand McCarty, 1978).

3. COMPARATIVE ANATOMY, PHYSIOLOGY AND METABOLISMA. Comparative Anatomy and Physiology

As described in a recent report on safety assessment (Food Safety Council, 1980),an important procedure in risk assessment is an evaluation of the comparative anatomyand physiology of the test species and man. Particularly relevant is pharmacokineticssince determination of potential carcinogenic risk at any tissue site requires consid-eration of the actual target dose. The precise cellular or subcellular targets forcarcinogenic transformation by formaldehyde in rodents are not known, although itis postulated that DNA is the ultimate target for most, if not all, chemical carcinogens.In any event, the determination of the dose of a chemical delivered to the targettissue is an initial step in estimating actual exposure levels. This is generally verydifficult to measure or estimate following systemic exposure because of the uncertaintiesand complexities involved in absorption, tissue distribution, metabolism, and excretion.In the case of formaldehyde-induced cancer in rodents, however, the effect was alocal one, comparable to the induction of skin cancer in skin painting experiments.Exposure at the target site may, therefore, be determined by such measurements asairflow to surface relationships, mucociliary activity, vapor absorption, and particledeposition in the nasal cavities.It is apparent that there are major species differences with respect to nasal anatomyand physiology, and these have recently been reviewed in a comprehensive chapterby Proctor and Chang (1983). The nasal cavities in most animals except man andother primates are adapted to their primary function of olfaction. Thus, the rat andmouse are obligatory nose breathers due to the close apposition of the epiglottis andsoft palate. However, in man the anatomy of the nasal and oral cavities is arrangedin such a manner that breathing can readily occur both nasally and orally. At theoutset, then, one may conclude that the rat and mouse have more in common witheach other than with man. They have proportionally greater nasal exposure to materialin inspired air.There are other significant differences between man and animals in the functionalanatomy of the nasal passages which can influence doses of chemical vapors orparticulates deposited on nasal surfaces. For example, the distance from the nostrilsto the nasopharynx is usually proportional to the head and snout length which varieswidely. Total surface area varies with nasal complexity and shape, and total bodysize, and there are differences in amounts of respiratory versus olfactory epitheliumwhich determine air filtering capacity per unit volume in the nasal cavity. The structuraldifferences that exist between man and animals influence the course of air currentswhich, in turn, affect deposition on epithelial surfaces. For example, mouse and rathave atrioturbinates in the nasal vestibule that act as ballles which deflect large volumesof air. Man lacks these structures.


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110 SQUIRE AND CAMERONAll of these differences influence the airflow to surface relationships that are basicto estimating possible adverse health effects of inhaled materials (Proctor and Chang,1983). Comparisons between the B6C3Fl mouse, the F344 rat, and man, based on

normal minute ventilation and the surface area of the nasal epithelium, indicate thatboth rodents have approximately twice the relative surface area than man for filteringinspired air. This difference may be interpreted to indicate that man would receivea smaller target dose than rodents if both were exposed to similar concentrations. Itdoes demonstrate that, in all probability, direct interspecies extrapolation is notappropriate in the case of inhalation exposures. Furthermore, it suggests that rat andmouse are more susceptible than man to the local nasal effects of formaldehyde orother inhaled materials at any given concentration.Because of the partial mouth breathing in humans, one may assume that relativelymore formaldehyde may reach the trachea and bronchi. This is probably the case,although levels sufficient to cause irritation in the lower respiratory tract are high,i.e., 5-30 ppm (NAS, 1981), and even higher levels would probably be required toproduce cytotoxicity. Furthermore, it has been shown that sulfur dioxide, anotherhighly water-soluble gas, is virtually entirely removed by the nose in human volunteersat concentrations of up to 25 ppm (Anderson et al., 1974).

B. MetabolismWith regard to formaldehyde metabolism studies in general, it should be recognized

that measurements are of the radiolabel and not the intact molecule, which is veryrapidly broken down. Formaldehyde can enter the body through inhalation, ingestion,or dermal absorption. Absorption through the respiratory route in dogs has beenestimated to exceed 95% (Egle, 1972). Absorption through ingestion produces com-parable blood levels, but dermal absorption is relatively small. Inhalation studies inrats at levels of 15 ppm also demonstrated absorption to be primarily in the upperrespiratory tract, which would be expected due to high aqueous solubility of form-aldehyde (Heck et al., ,1983). Absorption was directly proportional to the airborneconcentration and was not influenced by prior exposures.Species differences in the absorption of formaldehyde in the nasal cavities areapparently related to minute volumes of air inspired, at least in the case of mice andrats. Because of greater sensitivity to the irritant effects of formaldehyde, mice decreasetheir respiratory rates and, thus, the effective exposures to about one-half that of rats(Jaeger and Gearhart 1982; Chang et al., 1983). This correlates well with the observedcarcinogenic responses which were considerably less in mice.Formaldehyde is a normal metabolite and necessary component in the synthesisof certain essential biochemical substances in man and other animals and, thus, isnot considered to be toxic at low levels of exposure (NAS, 198 1). Following systemicexposure, it is rapidly metabolized to formic acid, largely in the liver, but also inerythrocytes, brain, kidney, and muscle. Formic acid is subsequently either oxidizedto carbon dioxide and water, eliminated in urine as a sodium salt, or enters the single-carbon metabolic pool. The single-carbon pool is a biosynthetic pathway leading toformation of amino acids such as serine, choline, and glycine. The conversion offormaldehyde to formic acid is very rapid, the half-life being estimated at 1.5 min.The half-life of formate is approximately 80-90 min (McMartin et al., 1979).


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FORMALDEHYDE CARCINOGENIC RISK 111Following inhalation in rat, metabolic profiles as determined by radioactivity inplasma and tissues are similar to those following other systemic exposure routes (Heck

et al., 198 3). Tissue distributions were also determined following inhalation exposure,and radioactivity was much higher in nasal mucosa than in any other tissue examined,with levels in the trachea not differing widely from those in plasma. There are speciesdifferences in metabolism but these are largely quantitative. For example, formaldehydeoxidation is greater in human than in rat liver (NAS, 198 l), whereas the rat convertsformate to carbon dioxide at more than twice the rate of man or monkey and, thus,has lower blood formate levels (McMartin et al., 1977).There are several endogenous, as well as exogenous metabolic sources of formal-dehyde. These include degradation of certain amino acids such as hi&dine, tryptophan,serine, and glycine. Formaldehyde or formic acid can also result from the metabolismof certain drugs or chemicals, e.g., aminopyrine and dihalomethanes (Palese andTephly, 1975). A recent report describes the formation by nasal microsomes in ratof formaldehyde as the result of nasal exposure to several substances including nasaldecongestants, cocaine, nicotine, essences, and solvents (Dahl and Hadley, 1983).Formaldehyde is a highly reactive compound and, in addition to its oxidation toformic acid, may react with amines through methyl01 and methylene bridges to formadducts with proteins, histones, and nucleic acids (Williams, 1959). Formaldehydereacts with proteins and RNA more readily than with DNA because of the stabilityof the DNA double helix. In fact, formaldehyde does not react with double-strandedDNA and it is likely that unwinding of the double helix, as during cell division, isnecessary for formaldehyde to form DNA adducts (Singer and Kusmierik, 1982).This may be particularly relevant to considerations of no-effect or threshold levelsin carcinogenesis risk assessment.A recent study by Casanova-Schmitz et al. (1984) examined covalent binding offormaldehyde to DNA in rat nasal mucosa following exposure to vapor concentrationsof 0.3,2,6, 10 or 15 ppm. The results indicate covalent binding to respiratory mucosalDNA at concentrations of 2 ppm and above. The extent of formaldehyde binding at6 ppm was 10.5 fold higher than at 2 ppm, indicating significant non-linearity withrespeti to vapor concentrations. This may be an important consideration in quantitativerisk assessment.

4. EFFECTS IN HUMANSA. Exposure Levels

Formaldehyde is ubiquitous in the human environment and there is widespreadexposure. A large percentage of the formaldehyde released from mans activities andfrom natural sources enters the outdoor or indoor air. Although it is continually beingformed as an intermediate in the oxidation of methane in the atmosphere as well,formaldehyde does not persist, for it is rapidly photolyzed into hydrogen and carbonmonoxide, or photoxidized to formyl radicals and water. The half-life of formaldehydein the sunlight-irradiated lower troposphere is estimated at 75 min; therefore noaccumulation occurs in the outdoor atmosphere (Calvert et al., 1972). Formaldehydeis also a natural metabolite and is generated and degraded by living organisms in theenvironment (NRC, 1976). In water, formaldehyde is rapidly hydrated and convertedinto glycols, which are biodegraded (Walker, 1975).


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112 SQUIRE AND CAMERONIn reviewing the above information, the U. S. Environmental Protection Agencyconcluded that formaldehyde released outdoors will not build up in concentration,as about 95% of a point source emission would be degraded within 5 hr of emission.Therefore outdoor concentrations of formaldehyde will be dependent upon continualemission of point sources, such as auto and diesel exhaust in urban areas. However,in the indoor atmosphere photodegradation would not occur.Based on the above information on exposure and environmental fate, it appearsthat the predominant exposure route to formaldehyde in humans is through inhalation(EPA, 1980). In its review of the available monitoring data, the EPA concluded thatthe highest potential exposures to formaldehyde for humans are the result of itsproduction and use, or the production and use of its products; and certain workplacelevels are typically one to two orders of magnitude above outdoor ambient levels.As a consequence, major concern and interest have been focused on the workplace

environment. Based on information obtained by NIOSH in a series of walk-throughsurveys of the workplaces utilizing formaldehyde or its products, the EPA has estimatedtypical atmospheric concentrations of formaldehyde by industry (Table 1). In addition,it has estimated the number of workers in these industries most likely to be exposed,utilizing data from the Bureau of the Census on numbers of establishments in anindustry, and number of workers employed in these establishments. These estimateshave been modified incorporating information from industrial hygiene and engineering.Although the figures are considered by many to be controversial, they are cited inthis report to provide some perspective of occupational exposures. The total numberof U. S. workers occupationally exposed to formaldehyde, including industries thatuse formaldehyde or its derivatives, ranged from 1.4 to 1.75 million in one recentestimate (Booz, Allen and Hamilton, Inc., 1979). Consumers in the general populationmay also be exposed to many of the same sources of formaldehyde.Formaldehyde may occur in indoor air as an emission from urea-formaldehydefoam insulation or from particle board containing adhesive bond or urea-formaldehyderesins. The EPA, in their integrated exposure analysis, attempted to estimate airborne

TABLE 1ESTIMATED TYPICAL WORKPLACE FORMALDEHYDE LEVELSAND NUMBERSOF WORKERS POTENTUALLY EXPOSED

Industry Mean cone Estimated no.hm-n) exooseda. Production of formaldehydeb. Production of formaldehyde resinsc. Production of plywood and particle boardd. Production, handling, and installation ofurea-formaldehyde foam insulatione. Cotton textile manufacture and storagef. Paper products manufactureg. Embalmers and pathologistsh. Biological and health sciences

1.12-1.60.11-1.71up to 5.50.19-1.5(production only)0.31-0.850.05-0.590.52-4.88.3

i. Rubber and pk+stic.,productsj. Leather productsk. Metal productsAbstracted from Tables 4.and 8 (EPA, 1981).

Not availableNot availableNot available

4162,050-6,15020,768-29,7782,032-15,0801,6877,15082,600

35,000 (instructors)1,487,500 (students)6,128-27,5843,003800-3,075


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FORMALDEHYDE CARCINOGENIC RISK 113exposure levels in several populations. They concluded in their analysis of the availabledata that there were no data from which to get a realistic estimate of the averagetypical exposures in this category [residential exposures] (EPA, 198 1). Thus, althoughit appears that urea-formaldehyde foam insulation does contribute some to indoorformaldehyde air concentrations, the magnitude of its contribution is difficult toassess. For additional information on this matter, see U. S. Court of Appeals FifthCircuit (1983).Other sources of airborne formaldehyde in the home, besides urea-formaldehydefoam insulation and particle board, include consumer products containing formal-dehyde and combustion products from heating fuels and cooking (NAS, 198 1). Gasstoves can generate extremely high formaldehyde levels. A gas stove operated withoutvent or hood for 1 hr at 350F emitted 233 ppm, with hood alone, 217 ppm, andwith both hood and fan, 29 ppm (Hollowell et al., 1979).

Consumers are exposed to formaldehyde through many of the products they use,such as textiles, paper, pharmaceuticals, wood products, etc. Smoking can be asignificant source of formaldehyde exposure. The side stream smoke of cigarettes canalso contribute to indoor air pollution; levels over 0.2 ppm have been observed (Weberet al., 1976).Exposures can also occur through food (as both a natural constituent or contaminantor food additive). These exposures of course would be through ingestion, not airborne.B. Epidemiologic Studies of Carcinogenicity

Epidemiology is the study of the distribution of human disease and of the factorswhich influence its distribution (Lilienfeld, 1976). There are two principal methodsin epidemiology for exploring associations between an exposure and a disease. Onemethod, the cohort study, is appropriate when the exposure is rare but the disease isnot. The cuse-control study is better suited for studying an uncommon disease anda common exposure. (Clinical observations or case reports will sometimes suggest arelationship between an exposure and a human disease. However, this type of anecdotalinformation is of itself insufficient to demonstrate an association; epidemiologic studiesare necessary for this.)The carcinogenicity of formaldehyde in humans has been studied using both meth-ods. Because there is approximately 80% correlation between chemically inducedcarcinogenic sites in man and test animals to date (Tomatis et al., 1978) and theprimary exposure sites for formaldehyde are similar, one would look for increasedincidences of tumors of the nasal or nasopharyngeal epithelium if formaldehyde werecarcinogenic in humans. The primary route of exposure in humans is through in-halation, and since formaldehyde is so reactive, one would expect almost all absorptionto take place in the upper respiratory tract, primarily the anterior nose. This has, infact, been demonstrated to be the case in rats (Heck et al., 1983). Since humans arealso mouth breathers, other cancers of the respiratory system may also be considered.It is unlikely, however, that formaldehyde exposure will induce cancer at more distantsites, because of its high solubility and reactivity at the site of exposure.

Cancers of the nose and paranasal sinuses are rare in the United States with about1300 cases occurring per year (Redmond et al., 1982). Risk increases with age andis greater in males than females at all ages over 45 years. Data from the United Statesand Europe indicate that the incidence has remained stable or decreased slightly sincethe 1950s. Increased risk has been associated with low social class and with exposureto nickel, chrome pigments, mustard gas, wood, and other organic dusts.


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114 SQUIRE AND CAMERONNasopharyngeal cancer is also an uncommon disease in the Western world. Itsincidence is highest in Asians, especially those who are of southern Chinese descent(Hirayama, 1978). Genetic factors and viral agents, especially Epstein-Barr virus,appear to be important global determinants of this type of cancer (Ablashi et al.,1983). The age-adjusted incidence of nasopharyngeal cancer for U. S. males from1973 to 1977 was 0.4 per 100,000, a rate similar to that of male breast cancer; fornasal cancer (nose, nasal cavities, middle ear, and accessory sinuses), the rate was0.8 per 100,000 (NCI, 1981).Numerous epidemiologic studies have been and are being conducted on formal-dehyde-exposed populations. Several case-control studies of nasal cancer have beendone in Europe and the United States which examined environmental and occupationalexposures as risk factors (Bross et al., 1978; Decoufle, 1979; Moss and Lee, 1974;Ulitsky et al., 1981; Acheson et al., 1981; Roush et al., 1980; Tola et al., 1980;Hemberg et al., 1983).Cohort studies of workers in jobs with high potential formaldehyde exposure havealso been carried out (Harrington and Shannon, 1975; Doll and Peto, 1977; Jenson,1980; Anderson et al., 1982; Jenson and Anderson, 1982; Kreiger, 1983; Goldmannet al., 1982; Marsh, 1982; Walrath and Fraumeni, 1983; Wang, 1983; Bierre et al.,1981; Fayerweather et al., 1982, 1983; Matanowski, 1980).In reviewing the epidemiologic evidence on formaldehyde carcinogenicity, theFederal Panel on Formaldehyde (1982) concluded that the results suggest the pos-sibility of formaldehyde being carcinogenic in humans; but the lack of informationon exposure, coupled with confounding due to multiple exposures, hampered inter-

pretation of the data. The Second IARC Working Group on Formaldehyde, however,reached a different conclusion. It reviewed all relevant epidemiologic data in 198 1,including the (then) unpublished studies by Marsh, Wong, and Walrath and Fraumeni(IARC, 1982a). They noted that none of the studies reported measurements of form-aldehyde exposure and that all three of the cohort studies had short durations ofpossible exposure. They calculated the power to detect a doubling in lung cancermortality for these studies to be relatively good (71 to 99%); however, none of thestudies had sufficient power to detect a trebling of nasal cancer mortality (7 to 12%).(Nasal cancer is so rare that it would be difficult to detect an increase in risk or oddsusing a cohort design.) The conclusion of the IARC Working Group was that therewas sufficient evidence that formaldehyde gas is carcinogenic to rats, but inadequateevidence to evaluate its carcinogenicity to humans.C. Other Toxic Effects in Humans

Because formaldehyde has been known and used for many years, much is knownof its acute toxicity in humans. The reader is referred to two review articles (NAS,198 1; NIOSH 1976). Acute effects of exposure to formaldehyde gas relate primarilyto its irritative effect. Although the severity of symptoms appears related to dose,there is wide variability among individual responses at any given dose level. Symptomsof eye irritation have been reported at concentrations as low as 0.05 ppm and of noseand throat irritation as low as 0.1 ppm. These reports are controversial and difficultto confirm; there is more firm evidence for symptoms at levels of l-l 1 ppm (NAS,198 1). In addition, some persons develop tolerance to the irritative effects on the eye,nasal, or upper respiratory tract (NAS, 198 1).


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FORMALDEHYDE CARCINOGENIC RISK 1155. EFFECTS IN ANIMALS

The present interest in the carcinogenic potential of formaldehyde was stimulatedlargely on the basis of chronic inhalation assays in rodents. The initial study showingthe induction of nasal tumors in rats and mice was conducted for the ChemicalIndustry Institute of Toxicology (CIIT). No other compound-related tumors werereported. The results were subsequently reproduced in another study in rats. Therewas initially great controversy surrounding the validity of these positive studies andquestions about the accuracy of tumor diagnoses. This controversy has subsided andinterest has settled upon possible mechanisms and the relevance of the findings tohuman risk.This section briefly reviews the pertinent animal studies, plus short-term studieswhich contribute to an understanding of possible carcinogenic mechanisms.

A. Chronic Animal BioassaysSeveral chronic inhalation bioassays of formaldehyde have been conducted inlaboratory animals. In an early study by Horton et al. (1963), C3H mice were exposedto 0,40.4, 80.8, or 161.7 ppm 1 hr per day for 35 weeks. Mice exposed to the lowestconcentration were subsequently exposed to 12 1 ppm for 29 weeks. Animals exposedto the higher concentration showed severe toxicity and treatment was discontinuedafter 11 days. Remaining animals were killed and examined after 35 or 70 weeks.

Nasal cavities were not examined; however, tracheas and bronchi showed hyperplasiaand metaplasia in treated animals. No lung tumors were induced.A recent study in rodents, conducted for the CIIT, first demonstrated a carcinogenicpotential for formaldehyde and is the basis for the current interest (Swenberg et al.,1980; Kerns et al., 1983). Fischer 344 rats and B6C3Fl mice [120 per species persex] were exposed to formaldehyde by inhalation for 6 hr per day, 5 days per weekfor 24 months. Doses administered were 0,2,6, or 15 ppm (actual mean concentrationsand standard deviations were 0,2.0 + 0.6,5.6 -+ 1.2, 14.3 f 2.8, respectively). Selectedanimals were observed for extended periods following the 24-month exposure period,i.e., female mice were terminated at 27 months and male and female rats at 27 and30 months, respectively.Male and female rat survival was adversely affected only at the 15 ppm level, andmouse survival was apparently unaffected at any exposure level. This may be relatedto the reduced minute volume of air inspired by mice exposed to formaldehyde, asdescribed in Section 3, which reduces the effective exposures actually received. Theonly clinical abnormality noted was dyspnea in rats of both sexes at the 15ppm level.The pathological findings of interest were squamous cell carcinomas in the nasalcavities. These occurred in 2 male mice in the 15 ppm group, 2 rats [ 1 maIe and1 female] in the 6 ppm groups, and 103 rats [5 1 males and 52 females] in the 15ppm groups. Two nasal carcinomas, one carcinosarcoma, one undifferentiated car-cinoma, and one undifferentiated sarcoma were also found in rats in the 15 ppmgroups. There was also a formaldehyde-related increase in polypoid adenomas inmale rats at all dose levels, although there was no indication of progression to car-cinomas in these benign lesions. In addition, epithelial hyperplasia, dysplasia, and


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116 SQUIRE AND CAMERONmetaplasia were noted in some animals at all exposure levels in rats, and at 6 and15 ppm in mice. The 2 ppm level was apparently a no-effect level for mice. All ofthese observations reflect very steep dose-response curves for carcinogenic effects inboth species. An important finding recently reported was regression of the rhinitis,dysplasia, and metaplasia at all exposure levels in both species at the 27-month (3-month postexposure) sacrifice period (Kerns et al., 1983).At the high exposure level in rats (14.3 ppm), epithelial hyperplasia, dysplasia, andmetaplasia were also seen in the proximal trachea. These were all reversible after the24-month exposure, and no lesions were observed at lower exposures.In another study, rats were exposed by inhalation to mixtures of formaldehydeand hydrochloric acid (HCl) or to either chemical alone (Albert et al., 1982). Exposurelevels of formaldehyde were approximately 14.0 ppm, which was similar to the highdose employed in the CIIT study. Both formaldehyde alone and in combination withHCl produced squamous cell carcinomas in the nasal cavities, but exposure to HClalone at 10 ppm was not carcinogenic. The authors indicate that these results suggestthat irritation alone may not be responsible for the carcinogenic effects of formaldehyde,since HCl did not enhance the effect nor was it carcinogenic alone. However, nocomparison of the irritant levels induced by the two chemicals was reported.Formaldehyde was also tested by chronic inhalation in male Syrian golden hamsters(Dalbey, 1982). Animals were exposed to 10 ppm five times per week for life (lengthof exposure periods was not given), or to 30 ppm 1 day per week for 5 hr for life.Minimal hyperplastic and metaplastic changes in the nasal cavity were noted, butno tumors were observed. In the same experiment, some animals received injectionsof diethylmtrosamine following the 30 ppm formaldehyde exposures. It is stated thatthese animals had more tracheal tumors than did animals receiving diethylmtrosaminealone, indicating an apparent cocarcinogenic effect of the formaldehyde on the trachea.

B. Other Animal StudiesA 26-week inhalation study with formaldehyde in monkeys, rats, and hamstersprovides some useful information on dose response in different species (Rusch et al.,1983). Six male cynomolgus monkeys, 29 male and 20 female Fischer 344 rats, and

10 male and 10 female Syrian golden hamsters were exposed to formaldehyde vapor22 hr per day, 7 days per week, for 26 weeks. Cumulative mean exposure groupswere 0,O. 19,0.98, and 2.95 ppm. In monkeys, hoarseness, congestion, and squamouscell metaplasia and epithelial hyperplasia in the nasal turbinates were present in the2.95 ppm group, with no clinical or pathological abnormalities at the lower levels.Similar results were noted in rats. Hamsters showed no evidence of toxicity at anylevel. When these results are compared to the 6-month findings in the CIIT study,it appears that formaldehyde concentration is more critical than cumulative dose.Exposure time in the 26-week study was approximately 5 times as long as in theCIIT study; thus, the total dose at 1.0 ppm was 2.5 times higher than the 2.0 ppmlevel in the CIIT study. Yet, squamous metaplasia was present at 2.0 ppm in theCIIT study, but not at 1.0 ppm in the 26-week study. It is important to note herethat specific signs of irritation occur in humans at levels as low as 1.2 ppm (Weber-Tschopp et al., 1977), or even lower (NAS, 1981), levels which induced no cellular


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FORMALDEHYDE CARCINOGENIC RISK 117alterations in monkeys, rats, or hamsters, as detected by either light or electronmicroscopic examination. Apparently sensory irritation has a lower threshold thancellular alteration which would lead to avoidance of cytotoxic exposures.In another study, rats were exposed to continuous formaldehyde vapor for 45-90days at levels to 8.0 ppm (Dubreuil et al., 1976), but histopathological examinationof the nasal cavities was not reported. Coon et al. (1970) exposed rats, guinea pigs,rabbits, dogs, and monkeys continuously to 3.8 ppm of formaldehyde for 90 days.Interstitial inflammation was reported in the lungs in all species, but nasal cavitieswere apparently not examined.Swenberg et al. (1983) investigated possible mechanisms of formaldehyde toxicityin rats and mice subsequent to the findings of nasal cavity carcinogenesis. Using14C-labeled formaldehyde, it was shown that the main deposition was in the anteriornasal cavity of rats and mice where the lesions were also most severe, except for theventral cavity where deposition was noted with minimal lesions. This suggests thenormal squamous epithelium in this area is protective. Morphometric studies of ratand mouse nasal cavity surfaces and measurements of minute volumes of inspiredair showed that, at a level of 15 ppm, the nasal mucosa in mice is exposed to ap-proximately one-half the amount of formaldehyde as rats, which correlates with theobserved tumor response data. Dose-response relationships with formaldehyde withrespect to nasal toxicity are, therefore, dependent upon nasal anatomic and physi-ological factors, as well as ambient air levels. Based upon known species differences,as discussed in Section 3, this is not unexpected.The toxicological responses in nasal cavities of rats exposed for 1 to 9 days to15 ppm formaldehyde were cellular degeneration, necrosis and inflammation. Squa-mous metaplasia also occurred with as little as 5 days exposure. Responses in micewere similar, but less severe. The authors report that, based upon their work and thatof Rusch et al. (1983), adaptive changes apparently occur and the extent and severityof the toxicity diminish with time. Other studies have shown inhibition of mucociharyaction and mucous flow at toxic levels of exposure, i.e., 20-100 ppm (Dalhamn andRosengren, 197 1). Recently, mucociliary clearance in rats has been studied moreextensively (Morgan et al., 1983). Ciliastasis occurred in several areas of the nasalcavity at concentrations of 15 ppm. At 2 and 6 ppm, the effect was more focal andthere was no impaired mucociliary function at 0.5 ppm.Extensive evidence derived from experimental carcinogenesis studies and humanobservations indicate that cellular proliferation is an essential step in the pathogenesisof neoplasms (Farber, 1982). The effects of formaldehyde on cellular proliferation inthe nasal cavity may, therefore, be helpful in assessing potential carcinogenic risk.Swenherg et al. (1983) demonstrated that 5 days exposure to formaldehyde at15 ppm resulted in a 7 l-fold increase over control levels in [3H]thymidine labelingin the nasal epithelium. A IO- to 20-fold increase in cell replication occurred whenrats were exposed to 6 or 15 ppm or when mice were exposed to 15 ppm for only 3days. However, at lower rates, i.e., 0.5 or 2.0 ppm in rats and 0.5, 2.0, or 6.0 ppmin mice, there was no increase in cell proliferation. As stated by Swenberg, The factthat only exposure concentrations associated with squamous cell carcinoma in ratsand mice resulted in increased cell proliferation lends strong support to the hypothesisthat increased cell proliferation is a critical event in formaldehyde carcinogene&It is,also stated in the International Agency for Research on Cancer Monograph,


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118 SQUIRE AND CAMERONLevels of formaldehyde that cause nasal tumors also cause acute degeneration, ne-crosis, inflammation and increased cell replication in the nasal mucosa of rats andmice following inhalation exposure (IARC, 1982a). Such observations may provideuseful markers for apparent no-effect levels which may impact on carcinogenesis riskassessment.Two recent initiation-promotion studies in mice, using traditional two-stage skinpainting techniques, have been reported. In one study (Krivanek et al., 1983), form-aldehyde lacked either initiator or promoter activity after 180 days of observation.In the second study, Spangler and Ward (1983) reported that through 48 weeks ofobservation, formaldehyde showed no activity as an initiator or as a completecarcinogen, but may have had weak promoting activity. In both studies, acetone wasused as the vehicle and the formaldehyde was applied at levels which produced skinirritation.

6. SHORT-TERM IN VITRO AND IN VZVO TESTSA review of the genotoxicity of formaldehyde was presented by Auerbach et al.( 1977), and the International Agency for Research on Cancer more recently reviewedthe results of short-term tests with formaldehyde ( 1982). Mutations have been reportedin several bacteria, including Escherichiu cob psuedomonas, and staphylococcus;however, both positive and negative results have been noted with salmonella. Mutationshave also been reported in several species of yeast.Several studies have been conducted in mammalian cells n vitro using formaldehyde

solutions. Mutagenic effects were not induced in Chinese hamster ovary (CHO) cells;however, sister chromatid exchanges were induced in CHO cells and were also reportedin human lymphocytes in culture. Unscheduled DNA synthesis was induced in HeLacells, and DNA-protein crosslinks were produced in Ll2 10 and Chinese hamsterV79 cells. These crosslinks were repaired, however, in both cell lines within 24 hrafter removal of the formaldehyde. Recently, Grafstrom et al. (1983) reported thatformaldehyde inhibited methylguanine excision repair in human bronchial cells inculture, and Goldmacher and Thilley (1983) demonstrated forward mutations in ahuman lymphoblastoid cell line.Formaldehyde has caused x-chromosome breakages in grasshopper spermatocytes,but did not cause mutations in silkworm. In Drosophila melanogaster exposure toformaldehyde in food but not aerosol induced dominant lethal mutations and chro-mosomal aberrations. In Swiss mice, intraperitoneal injections of formaldehyde failedto induce dominant lethal effects (IARC, 1982a,b). In another mouse, strain (Q strain),formaldehyde solution injected intraperitoneally gave an increased frequency ofdominant lethal effects, although analysis of spermatocytes failed to reveal any lesions(Fontingine-Housbrechts, 198 1).In vitro cell transformation studies using formaldehyde solutions have providedsupportive evidence for formaldehyde carcinogenicity in animals. In experimentsusing C3H/lOT1/2 cells formaldehyde alone did not induce cellular transformation;however, enhanced transformation did occur when formaldehyde exposure wasfollowed by continuous incubation with 12-0-tetradecanoylphorbol 13-acetate (TPA)(Ragan and Boreiko, 1981). Formaldehyde also had weak promoting activity in thesame cells following initiation with N-methyl-N-nitro-N-nitrosoguanidine (Frazelle et


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FORMALDEHYDE CARCINOGENIC RISK 119al., 1983). Sivak reported dose-dependent transformation of mouse Balb/c3T3 cellsby exposure to formaldehyde alone at levels of 2-20 clg/ml (IARC, 1982a,b).Brusick recently reported results of a series of short-term tests of formaldehyde(1983). His findings were interpreted as follows: The Ames test was negative atconcentrations up to 1000 &plate, both with and without activation. The mouselymphoma forward mutation assay produced activity at 7.5 &ml without activationand at 1.9 pdml with activation. The sister chromatid exchange assay (SCE) producednon-dose-related effects starting at 1.0 &ml without activation and at 0.5 &mlwith activation. No chromosome aberrations were observed in Chinese hamster ovarycells with or without activation. Cell transformation using Balb/c3T3 cells was reportedas positive over a range of 0.5-2.5 Clg/ml.It appears that only two species have been tested with formaldehyde vapor. InDrosophilia, the results were negative for dominant lethal mutations and chromosomalaberrations (IARC, 1982a,b), and Brusick (1983) conducted an in vivo assay forgenotoxicity in mice exposed to formaldehyde vapor. He reported that SCE wasnegative at levels up to 25 ppm. Higher, toxic levels produced elevated SCE overnegative controls. Chromosome aberration and somatic mutation assays (mouse spottest) were negative at all levels.In summary, although there are conflicting results, formaldehyde solutions areapparently capable of inducing in vitro DNA damage, chromosome aberrations,mutations, and cell transformation in some mammalian and nonmammalian systems.Whether or not such effects occur at noncytotoxic levels is not clear. Furthermore,neither mutagenic effects nor chromosomal aberrations have been demonstrated inan intact mammalian system utilizing the inhalation route.

7. RISK ASSESSMENTA. Introduction

Evidence for carcinogenicity in humans derived from analytical epidemiologicalstudies, which is the most direct and persuasive, is lacking in the case of formaldehyde.In fact, relatively high exposures in several occupational settings over many yearshave provided no evidence of human carcinogenic potential and nasal cancer is raredespite the ubiquitous presence of formaldehyde in the environment (see Table 1).At present, analysis of potential human carcinogenic risk from formaldehyde mustrely upon analysis of the experimental animal data, which is a very inexact exercise.All such risk assessments are based upon assumptions concerning interspeciesextrapolation (Food Safety Council, 1980). Initially, the relevance of the animal studymust be determined. In this case, because of the qualitative similarities of exposure,metabolism, and tissue response between man and the test species, the animal studiesmay be considered to be relevant. The question to be addressed in risk assessmentis, thus, mainly a quantitative one related to interspecies di&rences and dose-responserelationships.For noncarcinogenic risks, safety factors are traditionally applied which take somefraction of the highest no-effect level in animals, e.g., l/100, and consider this to bean adequate margin of safety for an acceptable human daily intake (ADI). Since


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120 SQUIRE AND CAMERONpassage of the Delaney Clause to the Food, Drug, and Cosmetic Act in 1958, regulatorypolicy has tended to assume no threshold or no-effect levels for the human populationfor substances which are carcinogenic in animals. However, in the two and one-halfdecades since the enactment of the Delaney Clause, many more substances have beenshown to be animal carcinogens than anticipated, including materials which occurnaturally in our food supply and environment or are essential to society as presentlystructured. These substances have varied widely in their chemical and biologicalproperties and their carcinogenic potencies and effects. The strength of evidenceincriminating different chemicals as carcinogens, therefore, indicates that they do notpose equal hazards to man, and a uniform approach to carcinogen regulation isdifficult to support (Squire, 198 1). Furthermore, analytical techniques have advancedto the point of detecting very minute amounts (e.g., parts per trillion) of chemicalswhere previously their presence would not be suspected.

All of this has prompted the development of alternatives to the Delaney approachwhich attempt to estimate carcinogenic risks at actual exposure levels by extrapolationfrom effects observed in animals receiving high test doses. It is important to recognizethat this process of risk assessment should involve both mathematical and biologicalconsiderations, taking into account all available information on biochemical reactivity,pharmacokinetics, and toxicity and repair mechanisms as they apply to man and thetest species. Recent attempts to apply one of several mathematical models to animaltumor incidences without considering all of the available biological data constitutean oversimplification which cannot help but yield inaccurate and misleading results.B. Mathematical Considerations

Risk assessment has been defined by the Commission on Life Sciences, NationalAcademy of Sciences, as the quantitative or qualitative characterization of the adversehealth effects of human exposure to an agent (Committee on the Institutional Meansfor Assessment of Risks to Public Health, 1983). Quantitative risk assessment attemptsto calculate the risk of disease or death in exposed populations, based upon assumeddose-response relationships. However, the necessary principles or techniques forquantitative cancer risk assessment are not yet well developed (IARC, 1982). Often,critical information is not available. Therefore, there are many points in the riskassessment process where the analyst must choose among alternatives, relying onlyupon his subjective judgment. These choices are often arbitrary and are based uponhypothetical assumptions. Yet they can radically influence the final risk estimate andthe conclusions drawn therefrom (see Table 2). In the case of carcinogenic riskassessment performed for regulatory purposes, there has been a policy that, wheneveruncertainty exists at any point in a risk assessment, the decision or assumption ismade that will most likely avoid underestimating the risk. The effect of these policieshas been to produce carcinogenic risk assessments that consistently overstate the truerisk, sometimes substantially (Rodricks and Taylor, 1983). Many mathematical modelshave been developed for low-dose extrapolation. These include:(a) models based on the frequency distribution of responses in the test population,such as the log normal or probit model, or the log logistic or logit model;(b) models derived from assumptions of the mechanisms of cancer induction and


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FORMALDEHYDE CARCINOGENIC RISK 121include the linear or single-hit model, the multihit model, the multistage model, andthe Weibull or multicell model (Crump et al. 1976);(c) the newest models based upon theories of nonlinear pharmacokinetics in themetabolism of carcinogens (Hoe1 et al. 1983);(d) selection of a mathematical model which will provide an upper confidencelimit to the true response curve (Mantel and Bryan, 196 1; Hoe1 et al. 1975), theseupper confidence limits being approximately linear if one assumes an additive effectof a direct-acting carcinogen (Guess et al. 1977).

Although all models can give an equally good fit to data in the observed range,the estimates of risk at low dose can vary widely. Particularly, the linear model givesa very extreme measure of risk as illustrated in Table 2. A fact often overlooked inthe use of mathematical models for quantitative risk estimation is that the resultsapply to the test animals, not to humans. Models predict low-dose risks in the testedspecies; they do not consider interspecies differences in biological responses, which,in the case of formaldehyde, are significant. Models are most useful to indicate relativepotency of a chemical in a defined species as compared to other chemicals testedunder equal conditions. There is little biological basis to assume they can predict theactual levels of risk in a human population.In addition to the biological uncertainties in interspecies comparisons, there arealso several uncertainties in mathematical extrapolation from high- to low-dose risksin the test species themselves. With respect to carcinogenesis, there are several dose-dependent differences which current mathematical models do not take into consid-eration. They include:(a) dose-dependent changes in metabolic handling of chemicals;(b) dose-dependent differences in efficiency of DNA or of other repair systems;(c) contributions to carcinogenesis of cell division induced by overt toxic doses ofchemicals;

(d) number of sequential mutations or other events within a cell population requiredto produce carcinogenic transformation.All of the above variables, which have been demonstrated to exist in biological systems,are overlooked, particularly in assumptions of low-dose, linear responses.

TABLE 2DOSEPOFFORMALDEHYDE INCURRINGARISKOF 1 PERMILLIONFORNASAL

CARCINOMAINRATSUSING SEV ERAL MODELSModel Ihe (mm)

Probit 2.14Multihit 1.52Logit 0.89Weibull 0.76Multistage 0.65Linear 0.00059

Adapted from Gibson ( 1983, Table 4).a Inhalation 6 hr/day, 5 days/week for 24 months.


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122 SQUIRE AND CAMERONC. Biological Considerations

Quantitative risk assessment generally assumes that humans will respond to chem-icals similarly to the test animals, both qualitatively and quantitatively. From thepoint of view of protecting the public health, this assumption may be justified wherethere are no available data indicating otherwise. Under such circumstances, it maybe a reasonable and prudent regulatory position. However, the availability of specificcomparative data on a chemical with which to predict interspecies differences inpotential toxicity can permit a more accurate estimation of actual risk and shouldbe applied. In the case of formaldehyde, there are considerable data relating to mech-anism of action and interspecies differences in respiratory anatomy and physiologywhich are discussed in previous sections, and a simple mathematical approach whichignores these data is not appropriate.Formaldehyde presents a difficult challenge in risk assessment. It appears to begenotoxic in certain in vitro systems, and therefore may be considered to have thecapacity to damage DNA. According to present operational definitions, formaldehydewould, therefore, be a potential initiator. Because of its ability to cause cellulartoxicity and regenerative proliferation, it could also be a promoter, and as describedearlier, formaldehyde solution acts both as a weak initiator and promoter in in vitrocell transformation. However, as indicated in Section 5, in vivo initiation-promotionstudies using mouse skin have demonstrated only possible weak promoter activity,and no evidence of initiation.Present theories on carcinogenic mechanisms allow that nongenotoxic compounds,i.e., promoters or modifiers, are likely to have exposure levels which would notincrease cancer risks, so-called threshold levels (Weisburger and Williams, 198 1).They are presumed to increase cancer risks only secondary to some prerequisite effecton cells which includes stimulation of cellular proliferation. It should be recognized,however, that certain so-called initiators may also have threshold levels of exposureif it can be demonstrated that, below certain target exposure levels, DNA damageeither does not occur or is repaired prior to cell division. Swenberg et al. ( 1983) pointout that, in V79 cells, DNA-protein crosslinks, which can be rapidly repaired beforecell division, appear to be the adduct formed with formaldehyde. Even followingactual mutagenic effects induced by low doses of a potent material, repair may alsooccur (Russell et al., 1982). In this study, specific-locus mutations in mouse sper-matogonia induced by ethylnitrosourea were shown to be repaired at exposures below100 mg/kg.As discussed in Section 3, it is apparent that formaldehyde-DNA adduct formationmay require single-stranded DNA, as would be present during cell proliferation.Studies in several species of experimental animals, including monkey, have shownthat increased celiular proliferation in the nasal cavity occurs only if critical levelsof toxicity occur, and there are apparent thresholds for such cytotoxicity. At levelsof 6 ppm or below in mice, and 2 ppm or below in rats, no increased cellularproliferation occurs and these are also noncarcinogenic doses. Absolutely no cellularalterations as determined by light or electron microscopic examination were observedin monkey, rat, or hamster at 1.0 ppm.Evidence of no-effect levels for genotoxic chemicals may also be derived fromindirect observations of several substances. Formaldehyde is a normal metabolite inmammalian tissues. Recently studies have shown that acetaldehyde, a chemical with


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FORMALDEHYDE CARCINOGENIC RISK 123wide exposure and a significant intermediary metabolite in the catabolism of aminoacids and of alcohol, is also carcinogenic in the nasal cavities of hamsters and ratsfollowing chronic inhalation exposure at high, toxic levels (Feron et al., 1983). In anin vitro system, acetaldehyde, metabolically derived from ethanol, has recently beenshown to form adducts with proteins in rat liver homogenates at levels in the rangeof reported hepatic ethanol oxidation in vivo (Donohue et al., 1983).Major essential metabolic constituents have also recently been shown to be mu-tagenic under certain experimental conditions. Both glutathione and cysteine werereported to be positive mutagens in the Ames assay, even at concentrations foundin mammalian tissues (Glatt et al., 1983). In light of such observations, it seems tobe an inescapable conclusion that threshold levels for genotoxic and carcinogeniceffects in animal tissues must exist for certain chemicals.The counterargument is often presented that, although this may be true for mostindividuals, no threshhold levels can be established for an entire population, includingparticularly susceptible individuals. If one concedes this point for carcinogenic effects,it must also be conceded for other forms of toxicity. No AD1 can be set for the entirepopulation for any toxic effect if zero-risk levels are required. It must also be stressedthat the nonthreshhold assumptions for carcinogenicity are theoretical and basedupon a presumption of single-hit, irreversible, and cumulative events in the geneticmaterial of cells. The existence of such cellular events as a result of exposure tochemicals has not been directly demonstrated, and based upon our knowledge ofdose-dependent repair systems and the multistage progression and reversibility of theearly stages of neoplasia, there is sufficient basis to question whether such phenomenaindeed occur. In fact, there is no more direct evidence for absence of threshholds forcarcinogenic effects than for any other toxic effect.The distinction between risks posed by genotoxic and nongenotoxic chemicals isfurther obscured by the evidence that promoters or modifiers may indirectly damageDNA, e.g., through the generation of free oxygen radicals, which is an ubiquitousprocess associated with inflammation and cytotoxicity (Freeman and Crapo, 1982;Birnboim, 1982). Evidence linking chromosomal defects and the activation or expres-sion of oncogenes, already present in human and animal tissues, with the carcinogenicprocess also raises questions about the relevance of a chemicals genotoxicity (Yunis,1983). Nongenotoxic chemicals, i.e., promoters, as well as genotoxins are capable ofinducing chromosome damage which may permit oncogene expression (Rigby, 198 1).One or more of these mechanisms may be the basis for the induction of relativelyrare forms of cancer in animals by nongenotoxic chemicals, such as saccharin andbladder cancer, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and tongue cancer, andbutylated hydroxyanisole (BHA) and stomach cancer. The often cited notion thatpromoters only cause an increase in background tumors ignores these and otherexamples of promoters apparently acting as complete carcinogens. The genotoxicityof a chemical or its metabolites as demonstrated in short-term tests may, therefore,have less relevance for carcinogenic risk than a determination of the levels of cyto-toxicity in vivo which cause DNA or chromosomal damage.

The biological evidence relating to the potential carcinogenic effects of formaldehydedoes not support assumptions of low-dose linearity in risk assessment. In fact, a recentstudy by Casanova-Schmitz (1984) demonstrates that levels of covalent binding toDNA in rat nasal mucosa are not linear with respect to formaldehyde vapor con-centrations. Formaldehyde gas does not reach the lungs to any degree, and the rare


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124 SQUIRE AND CAMERONoccurrence of upper respiratory cancer in humans does not support assumptions ofbackground additivity. These observations, plus the steep dose-response curves inchronic animal studies, and the evident requirements for critical levels of cytotoxicityto induce neoplastic transformation, indicate that carcinogenic threshholds or, atleast, nonlinear, low-dose responses prevail.If mathematical models are to be used to estimate human risk, they should takeinto consideration all of the available biological data, not only dose-response rela-tionships in test animals. With formaldehyde, models that do not a priori assumelow-dose linearity as the prevailing phenomenon would appear to be most appropriate.

8. SUMMARY AND CONCLUSIONEvidence for potential carcinogenic risk from environmental chemicals derivesfrom three sources: epidemiological studies in humans, animal experiments, andshort-term assays for genotoxicity or cell transformation. Although there are limitationsassociated with the available studies in humans, mainly relating to lack of quantitativeexposure information, several well-defined human populations have been exposed tounusually high concentrations of formaldehyde for many years. Among certain oc-cupational groups, particularly in fields of biology, medicine, mortuary science, andsome manufacturing processes, exposures have been among the highest that can betolerated without severe irritation. Yet, there is no adequate evidence of increasedcancer risks at any tissue site, including the upper and lower respiratory tracts. Thesite of greatest exposure is the nasal cavity, where tumors are normally rare in humans,and sensory irritation generally occurs at concentrations below those that cause cy-totoxicity in the nasal cavity, which would provide a protective mechanism. Becauseof mouth breathing in man, one may suspect that the lungs may also be at increasedrisk. However, it has been demonstrated that, because of the high solubility andreactivity of formaldehyde, virtually none reaches the lungs except at very high exposurelevels and such levels also induce severe irritation to the eyes and upper respiratorypassages.Animal studies have demonstrated that formaldehyde is carcinogenic in the nasalcavities of rodents when chronically administered at levels which are cytotoxic andresult in increased cellular proliferation. At lower levels, carcinogenicity has not beendemonstrated. Because of similarities of metabolism and routes of exposure betweentest animals and humans, the results of these studies must be considered relevant tohuman risk. The issues to be addressed in a proper risk assessment concern interspeciesdifferences in respiratory anatomy and physiology as well as differences in toxicresponses at various exposure levels.An important question in the risk assessment of formaldehyde is the possibility ofa carcinogenic threshhold, or no-effect level, which is suggested by both the humanand animal studies. The terms initiator and promoter are operational definitions

which may or may not reflect actual mechanisms of neopiastic transformation; yet,threshhold assumptions are more readily accepted for promoters (or modifiers) thanfor initiators. As discussed in Section 7, however, such distinctions are becoming lessapparent and arguments for or against threshholds for either type of carcinogen canbe presented. The fact is that there is no direct evidence to rule out either possibility.


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FORMALDEHYDE CARCINOGENIC RISK 125Formaldehyde exhibits properties of both an initiator and a promoter. It is positivein several short-term assays for genotoxicity although it has not been shown to be

positive in a mammalian in vivo system by inhalation. It is also a strong irritantwhich stimulates cellular proliferation at certain exposure levels-a characteristic ofpromoters. In two-stage initiation-promotion studies on mouse skin, there was evidenceof weak promotion but no initiator activity was seen. DNA adducts can be formedwith formaldehyde, but they appear to be limited to single-stranded DNA whichwould be available during cell replication. The extent of DNA covalent binding inrat nasal mucosa increases with exposure levels above 2 ppm, but in less than linearfashion. Thus, even if one assumes that DNA damage is the mechanism of neoplastictransformation, the effect is apparently limited to cytotoxic concentrations whichresult in enhanced cell proliferation. Concentrations which were carcinogenic in testanimals were also levels which induced cell proliferation, i.e., greater than 2 ppm inrats and greater than 6 ppm in mice. No pathological alterations at all were inducedat 1 ppm in either rats, hamsters, or monkeys. Since humans generally exhibit nasalor eye irritation at 1 ppm or even less, chronic exposures to cytotoxic levels areunlikely.There is additional circumstantial evidence for threshholds for carcinogenic effectsby formaldehyde and a related compound. Specifically, formaldehyde and acetal-dehyde, both normal and ubiquitous metabolites in mammalian systems, are car-cinogenic in animals at the site of chronic exposure when administered at cytotoxiclevels. It is difficult to reconcile assumptions of low-dose linearity with materialswhich are normally present and functional in mammalian tissues.Comparative anatomical and physiological studies have shown that tissue effectsfrom formaldehyde are related to target dose, which depends upon airflow to surfacerelationships, rather than simply vapor concentrations of the chemical. There aremajor species differences in responses which influence target dose, as indicated bythe difference in responses between rats and mice exposed to similar concentrations.Based upon actual comparisons of normal minute ventilation and surface areas, itis estimated that humans have approximately one-half the nasal capacity to filterinspired air than either mice or rats.In conclusion, evidence presently available on formaldehyde carcinogenic risk gen-erally supports a threshhold. At the least, an assumption of nonlinearity at low exposurelevels is warranted. Also, based upon comparative studies, humans are likely to beless rather than more susceptible than rodents to the potential carcinogenic effects.The use of any risk assessment procedures which fail to incorporate such evidenceshould explicitly describe the basis for the assessment and the likely overestimatesof risk.REFERENCES

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126 SQUIRE AND CAMERONANDERSEN, S. K., JENSON,0. M., AND OLIVA, D. (1982). [Exposure to formaldehyde and cancer of thelung in Danish physicians.] Ugeskr. L&g. 144, 1571-1573. [In Danish, English Abstmct]ANDERSON, I., LUNDQUIST, G. R., JENSON, P. L., AND PROCTOR, D. F. (1974). Human response to

controlled levels of sulfur dioxide. Arch. Environ. Health 28, 3 l-39.AUERBACH, C., MOUTSCHEN-DAHMEN, M., AND MOUTXHEN, J. (1977). Genetic and cytogenet& ef fectsof formaldehyde and related compounds. Mutut.Res. 39, 3 17-62; 1977.BIERRE, T. H., TUNNICLIFF, M. J., AND DARBY, F. W. (1981). A Review of the Occupational HealthProblems Associated with Formaldehyde Exposure, unpublished report. Department of Health, SouthernRegional Occupational Health Unit, New Zealand.BIRNBOIM, H. C. (1982). DNA strand breakage in human leucocytes exposed to a tumor promoter, phorbolmyristate acetate. Science 215, 1247-1249.Booz, Allen and Hamilton, Inc. (1979). Preliminary Study of the Costs of Increased Regulation of Form-aldehyde Exposure in the V. S. Workplace. Prepared for the Formaldehyde Task Force, Synthetic OrganicChemical Manufacturers Association, Florham Park, N. J.BROSS, I. D., VIADANA, E., AND HOUTEN, L. (1978). Occupational cancer in men exposed to dust andother environmental hazards. Arch. Environ. Health 33, 300-307.BRUSICK, D. J. (1983). Genetic and transforming activity of formaldehyde. In Formaldehyde Toxicity(J. E. Gibson, ed.). Hemisphere, Washington, D. C.CALVERT, J. G., KERR, J. A., DEMERJIAN, K. L., AND MCQUIGG, R. D. (1972). Photolysis of formaldehydeas a hydrogen atom source in the lower atmosphere. ScienCe 175, 75 l-752.CASANOVA-SCHMITZ, M., STARR, T., AND HECK, H. Differentiat ion Between Metabolic Incorporation andCovalent Binding in the Labeling of Macromolecules in the Rat Nasal Mucosa and Bone Marrow ByInhaled [I%]- And [HI Formaldehyde, Toxicol. Appl. Pharmacol. In press.CHANG, J. C. F., GROIN, E. A., SWENBERG,J. A., AND BARROW, C. S. (1983). Nasal cav ity deposition,histopathology, and cell proliferation after single or repeated formaldehyde exposures in B6C3Fl miceand F-344 rats. Toxicol. Appl. Pharmacol. 68, 161-116.CIIT (Chemical Industry Institute of Toxicology) (1980). Progress Report on CIIT Formaldehyde Studies,Docket No. 112D0, Dec. 12.Committee on the Institutional Means fo r Assessment of Risks to Public Health ( 1983). Risk Assessmentin the Federal Government: Managing the Process. Nat. Acad. Sci., Washington, D. C.COON, R. A., JONES, R. A., JENKINS, L. J., JR., AND SIEGEL, J. (1970). Animal inhalation studies onammonia, ethylene glycol, formaldehyde, dimethylamine, and ethanol. Toxicol. Appl. Pharmacol. 16,646-655.CRUMP, K. S., HOEL, D. G., LANGLEY, C. H., AND PETO, R. (1976). Fundamental carcinogenic processesand their implications for low-dose risk assessment. Cancer Res. 36, 973-979.DAHL, A., AND HADLEY, W. (1983). Formaldehyde production promoted by rat nasal cytochrome P-450-dependent monooxygenascs with nasal decongestants, essences, solvents, air pollutants, nicotine, andcocaine as substrates. Toxicol. Appl. Pharmacol. 67,2CQ-205.DALBEY, W. E. (1982). Formaldehyde and tumors in hamster respiratory tract. Toxicology 24,9-14.

DALHAMN, T., AND ROSENGREN,A. (1971). Effect of different aldehydes on tracheal mucosa. Arch. Oto-laryngol. 93, 496-500.DECOUFLE,P. (1979). Cancer risks associated with employment in the leather and leather products industry.Arch. Environ. Heafth 34, 33-37.DOLL, R., AND PETO, R. (1977). Mortality among doctors in difR.rent occupations. Brit. Med. J. 1, 1433-1436.DONOHUE, T. M., JR., TUMA, D. J., AND SORRELL, M. F. (1983). Binding of metabolically derived ac-etaldehyde to hepatic proteins in vi tro. Lnb. Invest. 49, 226-229.DUBREUIL, A., I~XJLEY, G., GODIN, J., BOUDENE, C. (1976). Inhalation en continu, de faibles doses deformaldehyde: Etude experimentale chez le rat. J. Eur. Toxicol. 9, 245-250.F .GLE, J. L. (1972). Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the dog. Arch.Environ. Health 25, 119- 124.EPA (U. S. Environmental Protection Agency) (1980). Carcinogen assessment group. Fed. Regist. 45(231),

79,350-79,355.EPA (1981). Technical Document: Formaldehyde, Nov . 16. Office of Toxic Substances, Washington,D. C.FARBER, E. (1982). Chemical carcinogenesia: A biologic perspective. Amer. J. Pathol. 106, 272-296.FAYERWEATHER, W. E., PELL, S., AND BENDER, J. R. (1982). Case-Control Study of Cancer Deaths inDuPont Workers with Potential Exposure to Formaldehyde, unpublished report.


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An Analysis of Potential Carcinogenic Risk From Formaldehyde

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