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INTRODUCTION Over the last few years, the Consumer Product Safety Commission (CPSC) has received complaints from individuals who experienced a variety of adverse health effects reportedly associated with exposure to formaldehyde, including upper respiratory tract and eye irritation, headaches, nosebleeds, and gastrointestinal symptoms. As a result, the CPSC has asked the National Research Council's Committee on Toxicology to evaluate the pertinent literature on the toxicity of formaldehyde and to consider whether a tolerable concentration of airborne formaldehyde can be recommended f or Jong-term continuous exposure in the household environment. In its pure form, formaldehyde is a colorless gas wi th a pungent odor. An American Chemical Society monograph on formaldehyde includes a comprehensive discussion of its physical and chemical properties (Walker, 1964~. Formaldehyde has high chemical reactivity, good thermal stability, and readily polymerizes; all of these characteristics make it a useful material in the synthesis of a wide variety of products. Aqueous solutions are the most colon form of formaldehyde, although alcohol solutions are also available. Formalin is an aqueous solution with a formaldehyde content of 37-50Z, by weight. These solutions may contain stabilizers to inhibit polymer formation. Methanol is most of ten used for this purpose ~ at concentrations of 10-15% by weight. Paraformaldehyde, a solid polymer of formaldehyde, can be vaporized to its monomeric form, which makes it a useful material as a source of formaldehyde in laboratory experiments. Several billion pounds of formaldehyde are produced each year in the United States. Its reactions with amino acids, proteins, and nucleic acids are important in yielding protein denaturants for use in leather tanning, as preservatives, and in the preparation of vaccines. It is widely used in the manufacture of phenolic, urea, and melamine resins. These materials are used in bonding particle board, in laminating veneers and plywood ~ and as insulating ~ serials, dinnerware, protective coatings, and special treatments for textiles and paper products. Under certain coed, Lions, formaldehyde is released from resinous products by diffusion, decomposition, or environmental degradation. Products known to release formaldehyde over a prolonged period include urea-formaldehyde foam insulation, particle board, and plywood. The consumer may also encounter formaldehyde in pesticides, cosmetics, and pharmaceuticals. This report deals with the effects of formaldehyde on animals, humans, and in in vitro tests. The Committee conducted an extensive search of the literature on formaldehyde. From a review of several hundred references, it selected material pertinent to an assessment of the health risks associated with exposure to airborne formaldehyde. For more details and inclusive surveys of potential health ef feces, the reader is referred to several reviews on this sub ject ~ Battelle Columbus Laboratories, 19775; CIIT, 1979a;. Loomis, 1979; NRC, [19803; USI)HEW, 1976a). PUBL IC EXPOSURE Formaldehyde emiss ions from incus trial processes are generally conf ined to the immediate vicinity of the plant. Primary sources of potential public exposure include cigarette smoke, automotive exhaust, photochemical smog, in- cinerators, and degassing of urea-formaldehyte resinous produc ts. Formaidehyte in outdoor air can derive from a number of sources. Incomplete
combustion of hydrocarbons accounts for much of the formaldehyde present in the atmosphere. Automotive exhausts have been reported to contain formaldehyde at 29-43 ppm (Altshuller et al., 1961~. Approximately 6 pounds of formaldehyde is produced during combustion of 1,000 pounds of gasoline (Kitchens et al., 1976)e Mobile sources (automobiles, diesel engines, and aircraft engines) emit about 666 million pounds of formaldehyde annually. Local concentrations may vary with traffic patterns and vehicular density. Municipal incinerators em' t about 0. 6-0. 9 pounds of formaldehyde per ton of refuse, or 13.1 million pounds of formaldehyde annually (Kitchens et al., 1976~. Ground level air concentrations of 0.1 ppb beve been pro jeered from incinerator emissions (Battelle Columbus Laboratories, 19775~. Experimental incinerator exhaust contains formaldehyde at 0.1-1 ppm (Altshuller et al. 1961~. Stationary and mobile combustion sources emit about 840 mi llion pounds of formaldehyde a year (Kitchens et al., 1976 ~ . Photochemical smog can be an important source of formaldehyde. Stupfel (1976) reported that outdoor air in Los Angeles contained formaldehyde at 0. 05- 0.12 pp~m over the course of 26 days of measurements. Measurements taken during the fall of 1961 averaged 0.04 ppm, with an average tally maximum of 0.06 ppm (Altshuller and McPherson, 1963~. Approximately 13: of the daily maximums exceeded 0.1 ppm. The highest measured concentration Is 0.16 ppm. More recent measurements of outdoor air in Mission Vie~o, California indicated average concentra- tions of total aldehydes (as formaldehyde) of 0.014 ppm (Hollowell et al., 1979a). At a research facility in Ames, Iowa' outdoor formaldehyde concentrations were below 0. 005 ppm (Hollowell et al., 197 9a) . A heavy smoker can be exposes to a considerable amount of formaldehyde. Cigarette smoke contains as much as 40 ppm of formaldehyde by volume (Battelle Columbus Laboratories, 1977b; Kensler and Battista, 1963~. With 95: retention from 10 40~ml puffs on each of 20 cigarettes, a smoker court receive a total tally burden of 0.38 mg of fomaitehyde. It has also been reported that, when 5 cigarettes were smoked in a 30-m climatic chamber, the concentration of formal- dehyde reached 0.23 ppm; acrolein and carbon monoxide were present at 0.05 and 12 ppm, respectively (Weber-Tschopp et al., 1976~. Other potential sources of formaldehyde in the home include combustion in gas stoves and heaters and breakdown of cooking oils. Formaldehyde is emitted from urea-formaldehyte foam insulation. It is also released from particleboard and plywood in which urea-formaldehyde is used as a bonding agent. The rate of release varies with temperature, humidity, light exposure, quality and age of component s, f ormulation, and expertise of the installer (Hollowel1 et al., 1979a; Rumack, 1978~. A.ndersen et al. (1975) developed a mathematical model that reproduced the measurements of airborne formaldehyde in dwellings and in a climate chamber containing shipboard, with correlation coefficients of 0. BB ant 0. 94, respectively. There are no studies that document the contri- bution of per~anent-press fabrics . and other textiles to formaldehyde concentrations in domestic environments. Ilollawell et al. (1979a) measured total aliphatic aldehyte in indoor air. After human occupation of an experimental house, total altehydes increased threefold to 0.116 ppm. The ventilation rate was 0. 2 air exchanges each hour. A recent study of 15 occupied residential units revealed formaldehyde concen- trations of less than 0.12 ppm in 11 of the units (USCPSC, 1979~. Concentrations as high as 0.38 and 0.31 ppm were found in two of the units, which were mobile homes containing particleboard. 2
Formaldehyde concentrations of 0.03-2.5 ppm were measured in 74 mobile homes whose occupants complained of odor and irritation thought to be associated with the use of particle board (Breysse, 1977~. Approximately two-thirds of the measurements showed concentrations of less than 0.5 ppm and 90: below 1 ppm. Symptoms experienced by the occupants included drowsiness, nausea, headache, and irritation of eyes, nose, and respiratory tract. Repeat measurements on two homes indicated half-lives ~ time for concentrations to decrease by 50Z ~ of AS and 110 d. A Scandinavian study using f ield tests and mathemA tical models indicated a half-life of 2 yr (Hollowel1 et al., 1979~. The ventilation rate ms 0. 3 air charges each hour. She half-lives depend heavily on air temperature ~ ventilation rate, surface area of the various products , type of material, and volume of the res idence. The original Breysse ( 19t7 ) study was extended from 74 to 278 mobile homes and 325 person who experienced symptoms (Tabershaw et al., 197 9 ~ . Data on the airborne formaldehyde concentrations were not available. Approximately 30;` reported eye irritation, 33% irritation of the respiratory tract, and 2: nasal irritation. Headaches and drowsiness were present in 19: and 10Z, res pect imply. Since 1978, the U. S. Consumer Product Safety Commission ( 1978) has received more than 50~) complaints from consumers whose homes had urea-for~ldehyde foam insulation. In-depth investigations of only 100 cases have been completed. Tabulations of complaints indicated that most symptoms were associated with upper airway and eye irritation. Airborne formaldehyde concentrations ranged from 0.01 to 31.7 ppm. The Connecticut State Department of Health investigated 80 complaints from consumers who had installed urea-formaldehyde foam insulation in their homes ~ Sardinas _ al., 1979~. The insulation had been installed 3 wl`-1. 5 yr before the survey. With formaldehyde at 0. 5-10 ppm, 69Z of the occupants reported eye irritation, 51: upper respiratory tract complaints, 44Z gastrointestinal tract symptoms, 59Z headaches, and 40Z skin problems. In homes with formaldehyde at less than 0.5 ppm, 31;: complained of eye irritation, 49: upper respiratory symptoms, 41: headaches, and 60X skin problems. More than 50X of the individuals questioned reported symptoms when formaldehyde was not detectable using Drager Tubes (minimum detection limit, 0. 5 ppm) . The Wisconsin Division of Health (1978) investigated 47 camplaints involving BS consumers. Air sampling for formaldehyde in 20 homes, including 17 mobile homes, revealed a range of 0.02-4.15 ppm and a median of 0.51 ppm. A review of symptoms in 62 of the consumers indicated that 7 3X hat eye irritation, 53Z upper respiratory tract irritation, 24;` respiratory difficulty, 23Z headache and tired- ness, 13: nausea, and 14Z a history of allergies. Hospitalizations were reported for 2 adults, and for 6 infants wi th exposures at 0. 67-4.82 ppm. The study included 11 pregnant women. Low birth weight and apnea were reported in 3 infants delivered among this exposed group. Detailed investigations of the infants ant pregnant women were not available.
EFFECTS ON Anti LMALS SHORT-TER`I STUDIES Metabolism - Formaldehyde is a normal metabolite in mammalian systems and, in small quantities, is rapidly metabolized (Akabane, 1970~. The major route of biotransformation appears to be oxidation to formic acid followed by further oxidation to carbon dioxide and water ~ Buss et al., 1964 ; Williams , 1959) o Administration of radiolabeled formaldehyde to rats by the oral or intraperitoneal route resulted in 40~ and 82CX, respectively, of the label being found in respiratory carbon dioxide (Neely, 1964; Williams, 1959~. The rmaining iso Cope in the intraperitoneal study was in urine as methionine, serine, and an adduct formed from cisterns and formaldehyde (Neely, 1964~. Numerous enzymes capable of catalyzing the reaction of formaldehyde to formic acid have been identified in liver preparations and erythrocytes (Tephly_ al. 1974; Utolia and Koi`?usalo, 1974~. Williams (1959) characterized formaldehyde as a cc~pound that reacts rapidly wi th amino acids, histones, and proteins to form both reversible methylol adducts and stable methylene bridges. Mortality Reported LD:o values of formaldehyde for the rat after oral administration ranged from 550 to 800 mg/kg (Tsuchiya et al., 1975; Smyth et al., 19413. The I~C5 values for rats at 0. ~ and 4 h were 620 and 482 ppm, respectively (Skog, i950; Nagornyi en al., 1979). Pulmonary edema was the predominant pathologic change at these concentrations. Similar results were obtained in mice and cats (Nagornyi et ale' 1979; Iwanoff, 1911~. Effects on the Eve Formaldehyde is a severe eye irritant. Application of a drop of formalin to rabbit eyes caused edema of the cornea and conjunctive and incites, graded ~ on a scale of 1-10 ~ Carpenter and Smyth, 1946~. Exposure of rabbits and guinea pigs to airborne formaldehyde at 40-70 ppm for 10 d produced some lacrimation, but no c orneal injury (Grant, 1974 ~ . Potts et al. (1955) injected formaldehyde intravenously (0.9 g/kg) in monkeys over several hours and observed an immediate change in the electroretinogram, but no blir~dness. Ef f ects on the Skin Formaldehyde can cause skin irritation and is a pa tent allergen. Mild to moderate irritation developed when formaldehyde was applied to guinea pig skin in concentrations of 0.1-20: (Colburn, 1970~. Guinea pigs are readily sensitized with intrader~al injections (Draize method), topical occluded applications (Buehler method) and open epicutaneous tests (OET method) (Klecak, 1977; Magnusson and Kligman, 1977; Marsulli and Maibach, 1977~. With open applications, ~ 3Z solution of fo`=al- debyde sensitized guinea pigs, whereas a-1% solution did not (Haibach, 197 B). Pre- 4
existing sensitivity was elicited with concentrations down to 3Z by open challenge and 1Z or less by closed-patch challenge. In another study, nine guinea pigs were administered formaldehyde intradermally or topically at 0.1-1;` over a 2-wk period (Colburn, 1970) . Af ter a hawk rest period, the animals were challenged with forma. tehyde at 0. 01-5Y and ~ d later at 0. 02~; five became sensitized. I:ffects on the Respiratory Tract Formaldehyde is extremely soluble in mucous membranes of the respiratory tract. EgLe (1972) concluded that retention is nearly 100;` in dogs, regardless of ventilation rate, tidal volume, region of the respiratory tract exposed, or formaldehyde concentration. Exposure for 10 min to 3.1 ppm produc ed a 50;: decrease in respiratory rate (RD 0) of mice (Kane and Alarie, 1977~. Utilizing a tracheal cannula to deliver Formaldehyde, these authors showed that the upper respiratory tract was the site of reactions that provoked the decrease in respiratory rate. Repeated exposures at 1.0 and 3.1 ppm, 3 h/ d for 4 d revealed that the maximum percent decrease in respiratory rate was reached after about 4-8 min. and increased each day. After the plateau was reached, there was a reduction in the percentage decrease during the rest of the exposure. There was complete recovery between the daily exposures. Concentrations of formaldehyde at 0. 3-50 ppm signif Scantly increased airway resistance and decreased lung compliance in guinea pig s af ter 1 h of exposure (Amdur, 1960~. The magnitude of the effects were dose-dependent over the range of concentrations tested. These effects were reversible within 1 h after exposure at concentrations of 0. 3-11 ppm. No ef feet was observed in guinea pigs exposes at 0.05 ppm for 1 h. Tracheal cannulation resulted in a greater increase in airway resistance, and the combination of formaldehyde and submicron particle size sodium chloride aerosol at 3-30 mg/m increased resistance even further. Other research has shown formaldehyde to depress ciliary activity within 10 min when tracheal preparations were exposed at concentrations of 20-100 ppm (Cralley, 1942; Dalhamn and Rosengren, 1971~. Effects on the Nervous System . Kulle and Cooper ( 1975) reported that a 1 h exposure to formaldehyde at 0. 5-2. 5 ppm decreased rat nasopalatine nerve response to ~myl alcohol. A partial recovery of the neural response occurred when the nasal cavities were perfused with air for 1 h af ter the formaldehyde exposure. Bonashevskaya ~ 1973) exposed rats at 0.83 and 2.5 ppm for 3 mot Histologic and histochemical changes were observed in the neurons and dendrite receptor synaptic apparatus in the cerebral "ygdaloid complex. No histologic changes were observed in the central nervous system of monkeys injected with formaldehyde intravenously (0.9 g/icg) over several hours (Potts et al., 1955~. PROLONGED STUDIES A 90-d study was conducted with formaldehyde administered in the drinking water of rats on a weight/volume basis at 50, 100, and 150 mg/kg body weight/d (Monsanto, 1973a) or mixed in the diet so that dogs received 50, 75, and 100 mg/kg body weight/d (Monsanto, 1973b). There were no significant effects on he~tologic (hematocrit,
hemoglobin, and total and differential leukocyte counts) and biochemical ( blood sugar, blood urea nitrogen ~ alkaline phosphatase, and serum glutamic oxaloacetic trans- aminase ) parameters ~ or in several organs examined histologically. The highest dose administered to each species produced a decrease in weight gain. Groups of 25 male rats were continuously exposed to formaldehyde by inhalation at 1. 6, 4.6, or 8 ppm for up to 3 mo (Dubreuil et al., 1976~. The only effect observed at the low dose wa s a yellowing of fur . The intermediate-dose group also showed decreased body weight. The group exposed at ~ ppm for 60 t showed eye and upper respiratory irritation, decreased body weight gain, and decreased liver weight. In another inhalation study, rats, guinea pigs, rabbits, monkeys, and togs were exposed continuously at 3.8 ppm for- 90 d (Coon et al., 1970~. One of 15 exposed rats died, but no other signs of toxicity were observed. Various degrees of interstitial inflammation were seen in the lungs of all exposed animals. Focal chronic infl ammation was also observed in the hearts and kidneys of the rats and guinea pigs. The authors were uncertain whether these inflamma tory changes resulted from exposure to formaldehyde. Groups of 60 mice were exposed to airborne formaldehyde at 41.5, 83, or 166 ppm ~ in/d, three times a week for up to 35 wk (Horton et al., 1963~. Pathologic examination of the trachea epithelium revealed basal cell hyperplasia, squamous cell metaplasia, and atypical metaplasia. Metaplasia extended into the major bronchi in the 41. 5~ppm group after exposure at 125 ppm for an additional 29 wk. Exposure of mice at 166 ppm was terminated after 11 d, owing to intoxication and high death rate. In a noncontinuous inhalation study, mice and rats were exposed at 4, 12. 7, and 39 ppm, 6 in/d, 5 d/wlc ~ Battelle Columbus Laboratories, 1977a) . No adverse effects were observed in the 4 ppm group exposed for 13 weeks. At 12.7 ppm for 13 weeks, decrease in body weight was observed; 2 of the 20 exposed rats showed evidence of nasal erosion. The 39-ppm exposure was terminated after 2 wk because of severe changes in nasal mucosa, including ulceration and necrosis. In another study, 25 rats each were exposed continuously for 3 ma at 0. 009B, 0. 028, 0. 82, and 2.4 ppm (Pel'dman and Bonashevskaya, 1971~ . The authors reported that at 2.4 ppm therewas a significant decrease in cholinesterase activity, and at 0.82 and 2.4 ppm proliferation of lymphocytes and histiocytes in the lungs and some peribronchia1 and perivascular hyperemia. Exposure at the two lowest concentrations resulted in no significant findings. CARCINOGENIC POTENTIAL Mice exposed to formaldehyde at &3 ppm, for ~ h, 3 d/wk for 35 wk or at 41.5 ppm for 1 h, 3 d/wk for 35 wk and at 125 ppm for an additional 29 wk showed basal cell hyperplasia and squamous cell me taplasia in the tracheobronchial epithelium but no tumors (Horton et al., 1963~. Hamsters exposed at 10 ppm for 5 h, 5 d/wk for their lifetime (average, 18 mo) showed increased cell proliferation and hyperplasia in the lungs (Nettshelm ~ 1976) . This investigator also reported that weekly 5-h exposures at 50 ppm for lifetime ~ IS mo) produced squamous metaplasia, but no tumors. Fischer 344 rats and B6C3F1 mice ( 120/sex/concentration) are being exposes to formaldehyde at 0, 2, 6, and 15 ppm for 6 in/d, 5 d/wk in a Chemical Industry Institute of Toxicology (CIIT) sponsored study at Battelle Columbus Laboratories (CRT, 1979b). Preliminary results indicated 6
that 15 ppm caused multifocal squamous cell metaplasia of nasal epitheliums in 6 of 20 rats at both the 6- and the 12-mo sacrif ice. Histologic examinations of 3 addi tional rats wi th enlarged noses af ter 15, 15, and 16 mo of exposure demonstrated squamous cell carcinomas in the nasomaxillary epithellum. A single squamous cell carcinoma of the skin was seen after 10 ma in the group of rats exposed at 6 ppm; this tumor was not of the same type observed at 15 ppm and did not invade the nasal epithelium. Additional preliminary results have shown the presence of nasal carcinomas in ~ of 40 rats exposed at 15 ppm and sacrif iced at 18 ma and nasal carcinomas in 29 other rats exposed at 15 ppm that wed e moribund or died spontaneously between the sixteenth and eighteenth months (CIIT, 198~)~. Additional tumors have slot been found in the group exposed at 6 ppm. A small adenomatous polyp was f ound in one of 40 rats exposed at 2 ppm and sacrificed at 18 mot Epithelial dysplasia and squamous metaplasia of the turbinates were observed in rats in all three exposure groups, the magnitude of the effects being dose-related. No control rats or any mice have shown histopathologic changes or tumor development of the kinds found in exposed rats. This is the f irst study to implicate formaldehyde as a potential experimental carcinogen, but the significance of these preliminary f indings can be evaluated only after completion of the study and analysis of the pathologic f indings. Inject$on-site sarcomas developed in 2 of 10 rats given weekly injections of 0.4: aqueous formaldehyde for 15 ma (Watanabe et al., 1954~. Fibrosarcomas were observed in the 1lver and amentum in 2 other rats. These resets are not meaningful, because of lack of controls and inappropriateness of the route of administration. Rusch et al. (~19803) exposed rats to lIC1 at a mean concentration of 30.7 ppm and formaldehyde at 10.3 ppm for 6 hit, 5 d/wk for 410 exposures over 618 d. Before dilution to the stated concentrations in the exposure chamber, the initial reaction mixture had average HC1 and formaldehyde concentrations of 6,567 and 1,021 ppm, respectively; alkylating-agent activity of 1,813 ppb was also detected, possibly as a result of the interaction of EC1 and formaldehyde in the gas phase. Alkylating-agent activity in the animal exposure chamber, as measured by chromatography, was 28 ppb. Preliminary results of histologic examinations on 56 exposed animals indicated a 14;: inc idence of squamous c ell carcinoma of the nasal epi thelium af ter 589 a. Tumors of this kind were not observed in controls. One of the alkylating agents identify ed in the chamber was bis~chloromethyl) ether (BCME), at a concentration of approximately 0.1 ppb. BCME: is a potent carcinogen; esthesioneuroepitheliomas of the nose, squamous cell carcinomas of the lung ant nasal turbir~ates, and adenocarcinomas of the lung and nasal cavity were produced in rats after exposure to BCME: at 0.1 ppm 6 in/d, 5 d/wic for 10~100 exposures (Kuschner et al., 1975~. The carcinogenic potential of hexamethylenetetr~ine (alit), which can decompose in an acid media to release formaldehyde and ammonia, has been exams ned (Della Porta et al., 1968~. Mice and rats were given fresh solutions of IMT in drinking mter every 24 h at 0. 5-5% for 30-60 wk and at 1-5: for 2-104 wk. respectively. Mice were observed for up to 130 wk and rats for up to 3 ye. At 5% HMI, there was 50% mortality in the Talcs af ter 2 wk. No s ignif leant effects on growth or survival were observed in any of the other groups of rats or the mice. Histologic examination indicated that no ef f ects were attributable to HAT. No carcinogenic activity was observed. 7
MUTAGENIC POTENTIAL Numerous studies have been conduc ted to determine the mutagenicity of formaldehyde, and Auerbach et al. (1977) have reviewed the sub ject extensively. Fomaidehyde has exhibited mutagenic activity in a wide variety of organisms, but the mechanism of formaldehyde mutagenesis has not been resolved. Formaldehyde may cause mutations by reacting directly with DNA; by forming mutagenic products on reaction with amino groups on simple amines, amino acids, nucleic acids, or proteins; or by oxidizing to peroxides that can react directly with BNA or indirectly by fsee-ratical formation. }mutagenic activity has been reported in E. cold (Bilimoria, 1975) and Pseudomonas fluorescent (Englesberg, 1952), but not in the Ames strains of Salmonella typhimurium (Koops and Butterworth, 1976~. Weak mutagenic acti~ri was observed when the fungi Neurospora crassa ant Aspergillus nidulans were treated (Auerbach et al., 1977~. The increase in mutagenic activity observed in these s tidies at ter treatment in the presence of catalase inhibitors suggested fit peroxides Are involved in the induction of mutations. Formaldehyde induced ~ totic recombination in Saccharomyces cerevisiae (Chanet et al., 1975~. The studies concerning fowaldebyte mutagenesis in Drosophila have been reviewed by several authors (Auerbach et al. ~ 1977; Rapoport, 1948; Solyanik et al., 1972~. Mutations were induced in male larvae fed formaldehyde-containing food and in adults injected with aqueous solutions of formaldheyde. The exposure of adults or larvae to formaldehyde vapors has not produced mutations. In one of f ive species of grasshoppers, formaldehyde caused chromosomal damage (Manna and Parida, 1967 ). Germinating barley seeds soaked in formaldehyde solutions ted not give evidence of mutation on maturation (Ehrenberg et al., 1956~. ty The mutagenic potential of formaldehyde is mammalian systems has not been thoroughly studied. An increase in mutation frequency was observed when formaldehyde was tested in the L517BY mouse lymphoma assay (Gosser and Butterworth, 1977), according to the published procedure (Clive and Spector, 1975~. A clear dose-response relationship As evident in only one of four experiments. No mutagenic activity was observed when formaldehyde was tested in the Chinese hamster ovary cell/HGERT assay (Elsie et al., 1978~. Likewise, no effect was observed in dominant lethal studies conducted with Swiss mice (Epstein et al., 1972~. Although formaldehyde exhibits mutagenic activity in a var~e~cy of microorganisms and in some insects, more work is necessary to ascertain the potential of this compound to cause mutations in germinal or somatic mammalian cells. MBRYOTOXIC /TERATOGENI C POTENTIAL There were no adverse gonadotropin or reproductive effects in male rats administered formaldehyde at O.1 ppm in drinking water or 0.4 ppm in the air for 6 ma (Guseva,1972~. Pregnant dogs fed diets containing 125 or 375 ppm on days 4-56 of pregnancy showed no evidence of teratoger~esi s (Hurni and Ohder, 1973 ~ . There was no effect on the course of pregnancy and no m~Ifonnations in the of f spring when rats were exposed at 4 ppm, 4 hid during days I-19 of pregnancy ~ Sheveleva, 1971) . _ ~ _
Gof~ekler ( 196&) exposed female rats to airborne formaldehyde at 0.~ ant 0.01 ppm for 10-15 d before placing them with males. All animals were then exposed for 6-10 d at the same concentrations of formaldehyde. Day of mating was not re- corded and duration of gestational exposure was unknown. ho gross abnormalities were observed in the offspring, but there was a 14-15% increase in duration of pregnancy, compared with controls. Although the surviving of f spring of exposed mothers averaged slightly greater body weights than the offspring of controls, the lungs and livess of offspring of exposed mothers were smaller than those of controls. Histologically, the livers of the offspring of mothers exposed at 0.01 ppm were not different from those of controls. In the group from mothers exposed at 0.S ppm, the livers showed increased extramedullary henatopoietic centers and epithelial proliferation in the colon bile duct. Additional studies are needed before firm conclusions can be made about the teratogenic potential of airborne formaldehyde at low concentrations. Dogs fed }MT at 600 and 1, 250 ppm on days 4-56 of pregnancy did not show evidence of teratogenesis (Hurni asked Ohder, 1973~. Likewise, long-term feeding studies of rats given 0.16: HAT showed no effect on the reproductive capacity of rat s (Na tvig et al., 197 1) . EFFECTS ON H131='S CONTROlLED EXP7RI~:N'TS WITH AIRBORNE FORMALDEHYDE Several controlled-exposure studies have provided valuable dose-response data on the irritant effects of airborne formaldehyde. The information from these studies on the percentages of the exposed populations responding at various formaldehyde concentrations is summarized in Tables 4 and 5. Sixteen healthy young sub jects were exposes to formaldehyde at 0.25 O. 42, O. 33, or l. 6 ppm 5 hit for 4 d (Andersen, 197 9). Measures of physiologic parameters, sub jective discomfort, and mathematical performance were made in the control period and af ter 1-3 asked 3-5 h of exposure. No s ignif icant changes were observed in pulmonary function, nor was there any difference in performance of mathematical tests between the control period and exposure to formaldehyde. The nasal-mucus flow rate wa s decreased at all concentra- tions except 0.83 ppm; the effect ms observed only in the upper third of the nose. When asked about their subjective response to formaldehyde, subjects exposed at the four increasing formaldehyde concentrations reported " slight discomfort" averaging 9, 5, 11, ant IS, respectively, on a scale of zero to 100. Specifically, the sub jects complained of con junctival irritation and dryness of the nose ant throat. In a second study, 33 subj ects (24 men and 9 women) were exposed to formaldehyde at 0.03-3.2 ppm for a total of 35 min. and 48 others (35 men arid 13 women) were exposed at 0.03-4 ppm for 1.5 min (Weber-Ischopp et;al., 1977~. Several responses were measured, such as eye, nose, and throat irritation, odor, "desire to leave the room, " and eye-blinking rate. An approx~ tely linear relationship was found for the average responses over the range of concentrations. At 0.03 ppm, there was no difference in the average response between exposure to formaldehyde and control air. Signif leant changes began to appear at 1. 2 ppm. The thresholds _ 9 _
for the specific responses (shown in Table 5) ranged from 1.2 to 2.1 ppm. There was some suggestion of adaptation to the irritating effects of formaldehyde: at the same concentrations, responses to 1.5-= n exposures were generally greater than the responses during 35-~ n exposures. The eye-irritation response to exposures to formaldehyde for 5 min at O.Ol to l.O ppm was investigated in 12 subjects (Schtick et al., 1966~. Subjective eye irritation was scored on a scale of zero to 24. Between 0.3 and l. O ppm , there was a linear increase in the average reported eye- irritation response, ranging from light irritation (just noticeable) to severe irritation. At concentrations below 0.3 ppm, a linear relationship was not found. Subjects experienced similar light irritation and eve-bli~king rates at 0.05 ppm as they did at 0.5 ppm. She range of sensitivity to formaldehyde was evident by comparing the effects in two subjects. At O.8 ppm, one reported barely noticeable irritation, while a second had severe irritation, including laceration. A complicating factor in this study was that, because of the method for generating formaldehyde, peroxyacetyl nitrate, nitrogen dioxide, and ethylene were present in the chamber. PHYSIOLOGIC ENDPOINTS Acute ingestion of formalin by humans has resulted in loss of consciousness, vascular collapse, pneumonia, hemorrhagic nephritis, and abortion. Formaldehyde has occasionally injured the larnyx and trachea, but damage to the gastrointestinal tract occurred primarily in the stomach and lower es ophagus. Fatalities have resulted from ingestion of as little as 30 ml of formalin (Bohmer, 1934; Kline, 1925~. The use of formaldehyde to devitalize dental pulp has produced paresthesia, soft-tissue necrosis, and sequestration of bone (Grossman, 1978; Heling et al., 1977; Montgomery, 1976~. Filters impregnated with melamine-formaltehyte resin were associated with an outbreak of hemolytic anemia among hemodialysis patients (Orringer and Mattern, 1976) . Skin Contact of the skin with formaldehyde may cause primary irritation or allergic dermatitis (Glass, 1961; Pirila and Rilpio, 1949~. Rostenberg et al. (1952) reported eczematous sensitivity to formalin in nurses who handled thermometers that had been immersed in a 10;: solution of formaldehyde. A similar outbreak occurred in a hemodialysis unit where a 2X formalin solution was used to sterilize open tanks (Blejer and Miller, 1966~. Dermatitis has been reported after contact with nail-hardeners, textiles, resins, and gaseous formaldehyde (Engle ant Calnan, 1966; Fisher et al., 1962; Lazar, 1966; Logan and Perry, 1973; O' Quinn and Kennedy, 1965~. Allergy to formaldehyde resins may be the result of unreacted fo~aidehyde or formaldehyde arising from decomposition, other resin ingredients, or the resin itself (US0HEW, 1976a). The hen data must be divided between two eras: earlier studies when 5~¢ formaldehyde (in water) was the standard diagnostic concentration; and recent studies with 2: ~ in mter) (Epstein and Maibach, 1966) . The 5: formaldehyde concentration was unusually high for diagnostic purposes; even the 2;` concentration is near the generally-accepted irritancy threshold ~ so these results also provide a Sensitization rate much greater than would be expected for the general population. (North American Contact Dermatitis Group, 1973~. - 10
Formaldehyde has been shown to be a potent experimer~tal allergen in humans. Skin sensitization was produced in about 8% of male subjects given repeated occlusive applications of ~ or 10% aqueous formaldehyde for 3. 5 wk an d then challenged with a 1% application 2 wk later (Marzulli and Maibach, 1973~. Approximately 4% of 1,200 dermatology patients exhibited positive slain reactions when tested with 2% formalin (0.8% formaldehyde) under an occlusive patch (Rudner et al. ~ I973~. Experiments suggest that most sensitized subjects can tolerate exposure to aqueous formaldehyde at 30 ppm (0. 003%), applied deco the axilla (Jordan er al., 1 979 ; Maibach and Franz , [1980 ~ ~ . Sensitized subjects who tolerate fosmaidebyde~containing products may react deco occluded- patch tests at lower concentrations; Marz',1li and Bach (1973) reported that 1/5 sensitized subjects reacted at a challenge concentration as low as 0.01%. Although formaldehyde is a potent a~perdmental allergen in man and animals, many of the daily exposures to formaldehyde (in shampoos, clothing, etc.) may involve quantities below the threshold for sensitization induction and elicitation or contact times less than that required to produce a response (Marzulli and Maibach, 1977~. More complete quantitative induction ant elicitation studies combined with provocative use tests should allow more realistic risk assessments. Contact ~ticaria also occurs wi th formaldehyde (Odom and Haibach, 1917 ); however, epidemiologic data are not available, nor has the mechanism ~ type A, B or C) been identified. Eyes Formaldehyde acts as a mucous-membrane irritant to cause conjunctivitis and lacrima Lion. Eye irritation is a c ommon complaint and has been re ported at airborne concentrations of 0. 3-0. 9 ppm in industrial workers (Bourne and Seferian, 195 9; Morrill, 1961) . Severe eye irritation can develop in the range o f 4-20 ppm (Barnes ant Speicher, 1942; Walker, 1964~. Controlled human exposures indicated that the group threshold for eye irritation was I. 2 prom, and for eye-bli~cing rate was I.7 ppm (Weber~Tschopp et al., 1977 ). The eye blinking rate was doubled in 33% of the sub jeers exposed at 2.1 ppm and in 11;: of those exposed at 0.5 ppm. A linear relationship was found for eye irritation in exposed subjects, from a group response of no irritation at 0.03 ppm to some irritation at 3.2 ppm. Tolerance to eye irritation was reported after exposure at 13. ~ ppm for 10 min (Sin and Pat tie, 1957 ~ . A complete ~risual-test battery and ophthalmologic examination of workers exposes at I. 5 ppm revealed no effects of formaldehyde on the eyes (USDHEW, 1976b) . However, Schuck et al. (~966) found a linear relationship between eye irritation and formaldehyde concentration over a range of 0. 3-1 ppm; these res ponses ranged from light to severe irritation. The authors determined that formaldehyde ant peroxyacetyl nitrate accounted for 80;: and 20:, respectively, of the eye irritation associated wl th pho tochemical air pollution. Respiratory System Formaldehyde has been reported to cause irritation and dryness of the nose and throat and olfactory fatigue. Upper airway irritation attributed to formaldehyde at 1-11 ppm occurred in employees handling nylon fabric coated with urea-formaldehyde resin (Ettinger and Jeremias ~ 19553. Customers in _ I] _
dress shops have complained of burning and stinging of the eyes, headaches, and nose and throst irritation with formaldehyde at 0.13-0. 45 ppm ~ Bourne and Seferian, 1959~. Similar complaints, along with disturbed sleep and unusual thirst, were reported by workers at a paper~conditioning installation (.Morrill, 1961) . Airborne formaldehyde concentrations released from paper treated with urea-formaldebyde or melamine-formaldehyde resin were found to be 0. 9-1. 6 ppm. Annoying odor, constant prickling irritation of mucous membranes, wheezing, tearing, excessive thirst, and disturbed sleep were reported by employees in eight textile plants (Shipko,?itz, 1968~. The prevalence of respiratory illness and complaints was more than 15: in four plants and 5-1~: in the other four. Airborne formaldehyde was measured at 0-2.7 ppm, with an average of 0.68 ppm. Workers in a garment f actory were examined by the California Department of Public Health; airborne concentrations ranged from 0. 9-2. 7 ppm (Ble jer and Stiller, 1966~. Employees reported increased eye and upper respiratory tract irritation in areas where large quantities of partially completed permanent-press fabrics accumulated. Olfactory adaptation to the irritant effects of formaldehyde occurred within 30 win of exposure, but af ter a 1- to 2-h interruption of exposure irritation returned ~ Blejer ant Miller, 1966; Kerfoot and Mooney, 1975; Shipkovitz, 1968~. Kerfoot and Mooney (1975) surveyed six funeral homes that used formaldehyde and paraformaldehyde in the embalming process. The average airborne concentrations in the embalming rooms were 0. 25-1. 39 ppm. The in~restigatior~s noted eye and upper respiratory tract irritation in some employees. A cross-sectional study of rubber workers exposed to a hexamethylene- tetr;~mine-resorcinol resin revealed significant decreases in small airway function over the course of the workshift and an excess of symptoms such as chest tightness, eye and nose irritation, ant cough (Gamble et al., 1976~. No dif ference was found in baseline lung function tests between exposed and control groups. Chemical analysis of respirable particles Is not performed and no association was found between airborne levels of resorcinol, formaldehyde, hydrogen cyanide, or ammonia and changes in pulmonary function. A study of employees producing filters with phenol-formaldehyde impregnated f ibers indicated that pulmonary function ~ FEV1 o/FVC and ME;F50~/F7C) measured at the beginning of the Monday shift Is significantly lower in employees who had worked more than 5 ye compared to those never involved in produc Lion (Shoenberg and `Mitchell, 1975~. Chronic symptoms chronic cough and excess phlegm-were increased in the group currently involved in productions Acute symptoms included eye, nose, and throat irritation and cough; however, little change was observed in the employees' FVC, FE\11 0, and HEF50: during the course of a workweek or workday. Formaldehyde was not systematically measured, but two surreys reported concentrations of 0.4-0.8 ppm and 9.14 ppm. The latter was thought to be atypical of the usual exposure conditions in the plant. Other pulmonary irritants present in the work environment included phenol and acrylic-fiber breakdown products. Lower airway irritation may be evidenced by cough, chest tightness, and wheezing. One In developed dyspnea and asthma after acute inhalation of forma1in vapor (Zannini and Russo, 1957~. Clinical examination revealed pulmonary edema with a 40: decrease in vital capacity. A neurology resident developed actue respiratory distress after 15 h of exposure to formaldehyde (Porter, 1975~. Auscultation of the chest revealed diffuse rates ant occasional rhonchi. Chest x-ray revealed early pulmonary edema. The resident was known to have me riced atopy to a wide range of allergens. Pulmonary edema, pne''monitis, and death may occur after inhalation of formaldehyde at concentrations exceeding 50 ppm (Fassett, 1963~.
Nervous SYS tem Olfactory fatigue with increased olfactory thresholds to rosemary, thymol, camphor, and tar were observed among plywood and particleboard worker s ~ Weger, 1927; Yefremov, 1970~. Numerous nonspecific symptoms related to nervous system response have been mentioned. Formaldehyde from resins used in construction produced thirst, headaches, dizziness, apathy, and inability to concentrate (Helwig, 1977) . Workers exposed to phenol-formaldehyde resins complained of headaches, dizziness, disturbed sleep, weakness, and apathy (Weger, 1927~. Studies in the ?~7SSR showed no electroencephalographic (EEG ~ changes in f ive sub jects exposed to fomaidehyde at O. 03 ppm, but these sub jects did respond with EEG changes at O. 044 ppm (Fel'dman and Bonashevskaya, 1971~. SUMMARY OF ANIMAL ARID HUMAN EXPOSURE TO FORMALDEHYDE ANIMAL EXPOSURE Formaldehyde is irritating to the eyes and upper respiratory tract of lab- oratory animals. When given orally, it i s moderately toxic ant causes severe erosion of gastrointestinal tissue. It is a known skin irritant and, through repeated contact with dilute solutions, can produce allergic sensitization. Concentrations of 0. 3-50 ppm increased airway resistance and decreased lung compliance after 1 h of exposure. Exposure of mice at 1 and 3 ppm produced a decrease in respiratory rate. Interim reset ts of a chronic inhalation study have shown squamous cell carcinomas in the nasomaxillary epitheliums of rats exposed at 15 ppm, 6 in/d, 5 d/wk for 18 mot There is no published evidence that formaldehyde is carcinogenic in animals. Formaldehyde, either itself or as ~IT, does not appear to interfere with reproduction, nor is there evidence of malformations in offspring of exposed parents. It has been shown to be mutagenic In several no~ammalian systems, particularly microorganisms and insects, but standard screens, such as the Ames test and Chinesee hamster ovary cell/HGPET assay, have shown no evidence of mutagenicity. Results of animal studies are summarized in Tables 1 and 2. HUMAN EXPOSURES People may be exposes to formaldehyde in industry and in the outdoor~ambient and indoor~residential environments. Automotive exhaust, smog, cigarette smoke, incinerators, and decomposition of fo`=aldehyde-derived products are sources of indoor and outdoor exposure.- Numerous consumer complaints have been associated with urea- formaldehyde products in the domestic environment. Eye and upper respiratory tract irritation, headaches, and gastrointestinal problems are the predominant symptoms associated wi th exposure to formaldehyde. Skin irritation ant allergic dermatitis have also resulted from exposure, and experiments have shown that individuals can became sensitized. Results of human studies can be found in Tables 3, 4, and 5. 13
ANALYTICAL METHODS Knowledge of the sensitivity and accuracy of the analytical method used in measuring a pollutant concentration is important not only in determining whether a concentration can be measured for comparison with a recommended airborne exposure limit, but also in evaluating inhalation studies on a particular compound. Of ten, methods of analysis are not reported; this makes it difficult to judge whether reported airborne concentrations are accurate. The analytical methods for measuring airborne fons~aldehdye have been extensively revived (USDREW, 1976a; N~C,[19803 ~ and are briefly summarized here. Spectrophotometric methods are most commonly used for determining the formaldehyde concentrations in indoor environments; chromotropic acid (4,5- dihydroxy-2, 7-naphthalenedisulfonic acid) and pararosaniline are the most widely used reagents. The APHA Intersociety Committee ( 1972 ~ and the National Institute for Occupational Safety and Health (USDlIEW, 1976a) have recommended a modified chrmotrop~c acid method for estimation of formaldehyde in air. The sensitivi ty of this method is 0.1 ~g~ml of sample solution, or approximately 0.04 ppm in sampled air. There are some deficiencies with this method, such as interferences from other substances , e. g., nitrogen dioxide , acrolein , and phenol, which can be encountered in indoor air. The Lawrence Berkeley Laboratory has been devel aping a pararosaniline technique that does not appear to be sub ject to interferences (Miksch et al., [1980] ). The estimated minimal detection concentration is 0.06 ppm. Methods using other reagents are also available, but either they have not been adequately tested or they have major drawbacks, such as instability or interference from other chemicals. Table 6 summarizes the spectrophotometric methods for formaldehyde. Microwave, infrared, and laser fluorescence spectroscopy have been studied as alternatives to spectrophotometry (NRC, [1980] ). However, these require sophisticated maintenance and support facilities and are seldom portable. Chromatographic methods have not gained acceptance, because of problems with interference and lack of sensitivity. A method for detecting formaldehyde by measuring the chemiluminescence resulting from the alkaline peroxide oxidation of formaldehyde and garlic acid has been reported to detect concentrations as low as 3.0 ng/ml. One drawback of this method is that it is not specific f or f o rmaldehyde . I.~;ElALATION EXPO SURE LIMITS Recommended and promulgated formaldehyde exposure limits issues by various countries are listed in Table 7. The present Occupational Safety and Health Administration (OSHA, 197 9) f ederal workplace standard for formaldehyde is 3 ppm, as a time-weighted average concentration over an 8-h workshift. ~ The American Conference of Governmental Industrial Hygienists (ACGIH, 1974) recommends a threshold limit value-ceiling (TLV-C) for formaldebyte of 2 ppm, because of "generalized complaints of irritation from formaldehyde at levels well below 5 ppm." ACGIH originally recommended a TLV-G of 5 ppm, but reduced the concentration to 2 ppm in 1972 (ACGTH, 1972~. .A TLV of 5 ppm was believed "low enough to prevent respiratory injury ·.e but does not provide freedom from irritation of all exposed individuals" (ACGTH, 1974~. The National Institute for Occupational Safety ant Health (USDHEW 9 1976a) recommends a workplace ceiling limit for formaldehyde of ~ ppm, because of reports of irritation 9 ob jectionable odor, and disturbed sleep after exposure at 0. 3 ppm arid generalized complaints 14
at concentrations above 1 ppm. It also states that individuals sensitized to formaldehyde should not be further exposed. The Environmental Protection Agency has not promulgated an ambient-air quality standard for formaldehyde in the United States. Kane et al. (1979) have suggested that an animal model be used to establish concentration ranges for exposure standards. On the basis of the RD50 in mice of 3.1 ppm and using a factor of 10 to protect the entire population, these authors arrived at 0.003 ppm as a no-effect level appropriate for an air-quality standard. Experimental evidence and commonly available analytical techniques do not exist to support such a standard. The suggested concentration is below the limits of detectability for most analytical methods for formaldehyde and lower than background concentrations of formaldehyde. The American Industrial Hygiene Association (1968) recommended a community air-quality standard for formaldehyde of 0.1 ppm; a concentration they believed would prevent sensory irritation in an exposed population. The West Germans have promulgated an outdoor ambient-air standard for formaldehyde of 0.025 ppm (Andersen et al, 1975~. Several foreign countries currently are establishing indoor~air formaldehyde standards. In 1978, the Netherlands promulgated a standard of 0.1 ppm (Hollowell et 81, 1979b). Sweden, Denmark, and West Germany are considering similar concentrations as indoor standards (Hollowell et al, 1979b) . The Danish scientist (Andersen, 1979) who recommended an indoor~air standard stated that the "basis for the setting of any standard for continuous exposure should be that all but the sensitized sub jects are protected against adverse health effects. " Further, the ma jority of the sub jects should not experience di sc omfo rt or dec rease of perf o mane e. It should be noted that the preliminary results of an ongoing study (CIIT, 1979b), which is showing squamous cell carcinomas in the nasomaxillary epithelium of rats, were not available when the above-mentioned foreign standards were established; the impact of these new findings on recent recommendations in those countries is not known. COMMITTEE SWAY HE'D ~CO`~NDATIONS SUGARY The health effects associated with exposure to formaldehyde cover a wide range of signs and symptoms. Most are related to the irritating properties of formaldehyde involving the eyes, nose, and throat. The severity of response is related to exposure concentration and can vary from person to person. Responses may be categorized as follows: (~) those which produce discomfort (irritation); (2) those which result in more significant effects, such as increased airway resistance and severe tissue damage in the respiratory tract; and (3) those which result in sensitization. The degree of hypersensitivity to these responses in the population has not been defined. Two kinds of studies were available for evaluating the above-mentionet responses to formaldehyde: human--including controlled, epidemiologic, and complaint-related investigations--and animal. Epidemiologic studies in the - 15 ~
workplace generally were limited because they could not isolate effects produced by formaldehyde. Also, reports of indoor residential exposure have not allowed separation of symptoms where there have been a va riety of environmental conditions or diseases. Such reports have been based on consumer complaints and have lacked random sampling and appropriate controlse The prevalence of morbidity associated with exposure to formaldehyde in the residence cannot be determined with the existing data. lle~rertheless, complaints have been associated with the use of products containing formaldehyde in homes, wheze~measusments have indicated a wide range of concentrations from 0.01 to 31. ~ ppm. Animal studies were limited; they did not provide dose-response data on the irritating ef fects reported by humans at low airborne concentration. There are no published data to indicate Chat fo rmaldebyde is carcinogenic . . in hens or animals. However, an ongoing lifetime inhalation experiment with rats and mice is showing malignant nasal tumors in rats exposes at IS ppm and lose-related histologic changes in the noses of rats exposed at 2 and 6 ppm. None of these effects has been found in the mice. Although the preliminary data in rats are not yet amenable to inclusion in an analysis of human risk, the CPSC is urged to reanalyze the risk associated with formaldehyde exposure when all the date of the study in question are available for review. In the Committee's best judgment, the available controlled human studies are currently the most relevant for evaluation of the risks of formaldehyde in indoor air. These studies measured primary irsitancy in test populations and provided dose-response data at various airborne concentrations of formaldehyde. The data from these studies are summarized in Tables 4 and 5. Small numbers of young healthy adults were exposed to various concentrations of formaldehyde for short periods. Concentrations of 1.S-3.0 ppm produced in many test sub jects (33: in one study and 947` in another) a variety of effects, including moderate irritation of mucous membranes, increase in odor threshold, decrease in nasal-mucus flow, and doubling of the eye-blinking rate. Fewer sub jeers (10-20~) experienced strong to moderate irritation and a desire to leave the test atmosphere. No changes in airway resistance were observed. When these test sub jeers were exposed to fo rmaldehyde vapo rs at 0.5-1.5 ppm, the following responses were reported: decrease in nasal- mucus flow, irritation of nose and throat, dryness in nose and throat (94ZO of sub jects in one study), moderate eye irritation (27), doubling of the eye-blinking rate (ill), and desire to leave the test atmosphere (3~. Airway resistance was measured, and no changes were observed. Some of these sub jects were also exposed to formaldehyde at 0.25 ppm. Slight eye irritation and aryness of the nose and throat were experienced by l9Z of the subjects, and a decrease in nasal-mucus flow was experienced by a f ew. The responses desc ribed in the foregoing we re obtained from limited test populations. When suck data are applied to the general population, several fac tors may influence the extent of response, including variability of health status, genetic predisposition to the effects of irritants, and such physiologic characteristics as age, sex, and pregnancy. Any of these factors may 16
cause some individuals to react with greater frequency and severity to concentrations of formaldehyde that produce milder effects in less susceptible individuals. In addition, responses reported in controlled studies may occur at an in- creased rate in the general population, because of the interactions between for- maldehyde and other irritants in the environment. Irritant effects of formaldehyde in humans are accelerated by the presence of cigarette smoke. The likelihood of interactions with other irritants, such as ozone and oxides of nitrogen, should not be discounted, but quantitative estimation of this combined effect is not now possible. The foregoing factors should be given serious consideration by the CPSC in the selection of an Indoor exposure limit for formaldehyde. Some of the factors might decrease susceptibility; most may increase it. RECO!DE~ATIONS On the basis of consumer complaints and controlled human studies, irritation appears to be the most sensitive response to formaldehyde. The Committee~s best judgment as to a range of irritation responses associated with exposure to various concentrations of formaldehyde is summarized in Table 8. This tabulation was devel- oped from the limited number of controlled human studies, which provide the only dose-response data from human exposure to low airborne concentrations of for~al- dehyde. Although the extent of irritancy has not been investigated in controlled human studies at concentrations below 0.25 ppm, the Committee expects that less than 20% of an exposed Harmon population would react to such formaldehyde exposure with slight irritation of the eyes, nose, and throat and possibly a slight decrease in nasal-mucus flow. As yet there is no evidence of a population threshold for the irritant effects of formaldehyde in humans. Although the Committee recognizes that the general population may react with greater frequency and severity to similar concentrations of formaldehyde than the test populations, no realistic estimate of the magnitude of this effect is possible on the basis of the available tata. The studies of public exposure to formaldehyde in indoor air suggest a wide range of sensitivity, with effects reported at 0. 01-31. 7 ppm. However ~ these studies were limited in scope ~ in that the subjects selected were only those who had reported responses to formaldehyde. Data were not available on the proportion of the total exposed population that this group might represent. Although irritation appears to be the most sensitive response, identification of the toxicologic reaction of greatest concern must await the conclusion of ongoing and planned studies. The prelimit ry results of an ongoing carcinogenicity study in rodents, the uncertainty about the variability of responses to formaldehyde in normal populations and in hypersensitive groups, and the current inadequacy of data (which leave unresolved the no~obse~ed-effect dose in humans) all point to the advisability of maintaining formaldehyde at the lowest practical concentration to minimlse adverse effects on public health. The Committee recognizes that the selection of a lowest practical concentration by CPSC must include consideration of - 17 -
such factors as acceptable degrees of risk and response, economic impacts, sensitivity of analytical methods, and background outdoor-air concentrations. There is need for a research program to resolve certain questions of health effects from airborne formaldehyde at low concentrations. Such research as identified by the Committee includes: o the significance of hyperplasia and metaplasia from exposure to nasal irritants in relation to tar development. Me Commi tree suggests that the nasal epitheliums of persons Amos to ~ frequently exposed to formaldehyde be examined, to determine another such individuals have developed lesions similar to those observed in the upper respiratory tract and nasal passages of animals. O development of quantitative information on the extent of the population that has a marked sensitivity to formaldehyde and the extent of that sensitivity and investigations to ascertain why this group has an increased sensitivity. A double~blint study in persons exposed to formaldehyde for short periods is needed, to explore the range of sensitivity to the irritating effect of formaldehyde at several concentrations below 1 ppm. O further investigations on possibly susceptible members of the population, such as infants, the elderly, and those with respiratory diseases or other chronic illnesses, to ascertain whether they are indeed more susceptible. This information ~11 be extremely user ul in the development of a public indoor-air quality standard. A means for identifying those individuals who may be at higher risk is also needed. o acquisition of exposure data from extensive epidemiologic studies on select occupational and environmental cohorts, to identify the health effect associated with exposure and to assess the overall health risk associated with a given degree of formaldehyde exposure. O an evaluation of the human risks associated with decal exposure to formaldehyde . The steps of percutaneous penetration have not been identif led in animals or men. Epidemiologic studies are also not available. O studies on the ef fects of formaldehyde on the defense mechani ems ant physiology of the respiratory tract and the potential human-health implications of such effects. Disturbance of normal defense mechanisms might make individuals more susceptible to disease from air pollutants and other kinds of respiratory stress. O investigation of the mechanisms of action of formaldehyde, including its ability to produce sensitization of the airways or other tissues. O pharmacokinetic studies in animals and comparison with similar data in man, including a study of the movement of formaldehyde across membranes. These studies should also evaluate the importance of the metabolic products of formaldehyde with respect to its toxicity. o effects of prolonged continuous exposures of various animal species to airborne formaldehyde at low concentrations. The reproductive and teratogenic effects of formaldehyde also need further investigations. O the importance of possible interactions between formaldehyde and other air pollutants, with emphasis on the likelihood of such reactions at the pollutant _ Ia _
concentrations likely to occur in indoor, outdoor, and workplace air . o an analysis of the atmospheric fate of formaldehyde in indoor air, including decay rates and effects of such variables as temperature and humidity o an analysis of sources of formaldehyde other than urea-formaldehyde resins that contribute to the overall formaldehyde burden in indoor air. - - 19 - r e
