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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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Suggested Citation:"B 4: Formaldehyde." National Research Council. 1994. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/9062.
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B4 Formaldehvde . King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Formaldehyde is a colorless gas with a strong, pungent odor (TLV Committee, 1989; Sax, 1984). Synonyms: Formic aldehyde; methyl aldehyde; methanal Formula: HCHO CAS number: 50-00-0 Molecular weight: 30.0 Boiling point: -19.5°C Melting point: -92°C Lower explosive limit: 7.0% Upper explosive limit: 73.0% Vapor pressure: 10 mm Hg at -88°C Vapor density: 1.08 (air's density = 1) Conversion factors at 25°C, 1 atm: 1 ppm = 1.23 mg/m 3 1 mg/m3 = 0.82 ppm OCCURRENCE AND USE Formaldehyde is not used in the operation of spacecraft, but it has occasionally been used as a fixative in biological payload experiments. 91

92 SMACS FOR SELECTED AIRBORNE CONTAMINANTS There is insufficient information to estimate the potential exposure level of formaldehyde. However, Soviet cosmonauts gained sensitivity to for- maldehyde during space missions (Peto, 1981). In addition, formaldehyde might be released into the space-shuttle cabin air as a result of thermodegradation of polymers, such as Delrio (James, 1991). PHARMACOKINETICS AND METABOLISM Inhaled formaldehyde does not appear to accumulate in blood. An inhalation exposure to 14.4 ppm for 2 h in rats or 1.9 ppm for 40 min in humans failed to increase the formaldehyde level in blood (Heck et al., 1985). Likewise, no significant increase in formaldehyde in blood was detected after a subchronic exposure (6 h/d, 5 d/w for 4 w) at 6 ppm in monkeys (Casanova et al., 1988). The blood data support the hypothesis that formaldehyde, being a highly water soluble compound, is retained primarily by the mucosa of the upper respiratory tract, so that very little enters the lung. After an intravenous injection in monkeys, formaldehyde is rapidly eliminated from the blood, with a half-life of about 1.5 min (McMartin et al., 1979). In mammals, formaldehyde is metabolized mainly via oxidation by formaldehyde dehydrogenase into formate and some formaldehyde is incorporated into biological macromolecules via tetrahydrofolate-dependent one-carbon biosynthetic pathways (Huennekens and Osborne, 1959; Koivusalo et al., 1982). Formaldehyde dehydrogenase has been found in many tissues, including the human liver (Uotila and Koivusalo, 1974) and the rat nasal mucosa (Casanova-Schmitz et al., 1984). TOXICITY SUMMARY Acute formaldehyde exposure produces mainly mucosal irritation of the eye and upper respiratory tract in humans, and a long-term exposure leads to the production of nasal tumors in rodents. Formaldehyde also causes pulmonary function impairment and asthmatic reactions in sensitized individuals.

FORMAWEHYDE 93 Acute Toxicity Most human studies have been done in the workplace so that the re- ported formaldehyde exposure concentrations typically spanned a wide range, making it difficult to determine the exact concentration-response relationship or the no-observed-adverse-effect level (NOAEL). One study showed that eye, nose, and throat irritation was detected in workers ex- posed to formaldehyde at an average peak level of 0.6 ppm (Alexandersson and Hedenstierna, 1988). Another group of investigators reported that workers complained of mucosa} discomfort at formaldehyde concentrations ranging from 0.04 to 0.4 ppm (Holmstrom and Wilhelmsson, 1988). These data do not reveal formaldehyde's nonirritating level. Exposure concentrations are better controlled in experimental studies. The few experimental human studies reported, unfortunately, used very high levels of formaldehyde. For instance, two studies presented evidence that formaldehyde exposure at 3 ppm, lasting more than an hour, caused mild to severe irritation of the eye and upper respiratory tract (Green et al., 1987; Sauder et al., 1986). Evidently, formaldehyde at 3 ppm was so high that sufficient formaldehyde got past the nose to affect the lung, reducing the forced expiratory volume in 1 s (FEY 1) or forced expiratory flow rate and forced vital capacity (FVC) in these test subjects. Another experimental study demonstrated that formaldehyde is irritating to the mucous membrane at 0.5, 1, or 2 ppm (Kulle et al., 1987). These experi- mental studies show that formaldehyde is irritating at as low as 0.5 ppm. Two studies of residents in mobile homes and a recent occupational study provide data on the concentration-response relationship of formal- dehyde's irritation effects. Formaldehyde has been shown to make 1-2% of 87 residents in the mobile homes in Minnesota complain of eye irritation at less than 0.1 ppm (Ritchie and Lehnen, 1987). At a formaldehyde concentration of 0.1-0.3 ppm, 22% of 181 residents complained of eye irritation and, when the concentration was above 0.3 ppm, about 90% of 336 residents complained of eye irritation. From the data gathered in a survey conducted with 61 mobile-home residents in Wisconsin, the pre- dicted percentages of residents with eye irritation at different formaldehyde concentrations were as follows (Hanrahan et al., 1984). Formaldehyde Concentration (ppm): 0.1 0.2 0.5 0.8 Mean Responding Rate(%): 4 18 65 82 95% Confidence Limits: 1, 18 8, 35 33, 86 44, 96

94 SMACS FOR SELECTED AIRBORNE CONTAMINANTS Similarly, the predicted percentages of formaldehyde-exposed workers afflicted with nose irritation obtained in a occupational study by Horvath et al. (1988) using 109 test subjects and 254 control subjects are shown below. Formaldehyde Concentration (ppm): 0.1 0.2 0.5 0.8 Mean Responding Rate(%): 2 4 21 32 95 % Confidence Limits: 1, 4 2, 8 16, 28 22, 44 Therefore, these studies suggest that the irritation threshold is below 0.1 ppm. In fact, the National Research Council concluded 10 years ago that formaldehyde causes irritation at as low as 0.1 ppm, and it is irritating in a higher fraction of people at 1.0 ppm (NRC, 1980). It is, however, difficult to accurately estimate the threshold concentration for formaldehyde's mucosal irritation effect. A few percentage of individuals respond to formaldehyde at as low as 0.1 ppm. From the concentration-response data, it appears that in a population there would always be a small group of individuals who are sensitive to formaldehyde's irritation. The Minnesota mobile-home study indicates that some individuals are more sensitive to formaldehyde than others (Ritchie and Lehnen, 1987), an observation also made by Horvath's group who detected wide individual variability in response to formaldehyde (Horvath et al., 1988). Similarly, Green et al. (1987) reported that, when 22 normal subjects were exposed to formaldehyde at 3 ppm for 1 h, some of the subjects rated the eye, nose, and throat irritation as nonexistent, and some rated them severe. Unlike the irritation sensation, there are no human data on the structural effect of formaldehyde on the mucosa at concentrations that are not too irritating. A 6-h exposure to formaldehyde at 0.5 or 2 ppm is known to lead to the development of abnormal cilia in the nose of rats (Monteiro- Riviere and Popp, 1986). However, a 6-h formaldehyde exposure at 2 ppm failed to affect the mucociliary function in the nose of rats (Morgan et al., 1986). It takes a 6-h exposure at 15 ppm to impair the mucociliary function (Morgan et al., 1986). As mentioned above, as the formaldehyde concentration gets sufficiently high, formaldehyde gas might reach the lung to affect lung function. Formaldehyde at 3 ppm is known to reduce the FEV 1 and PVC in humans (Green et al., 1987; Sauder et al., 1986). However, at 1or2 ppm, form- aldehyde has no effect on lung function in volunteers (Kulle et al., 1987; Schachter et al., 1987; Day et al., 1984). There are species differences in

FORMAI.DEHYDE 95 the pulmonary effects of formaldehyde because formaldehyde has been shown to increase pulmonary resistance and decrease lung compliance at as low as 0.3 ppm in guinea pigs (Alexandersson and Hedenstierna, 1988). Subchronic and Chronic Toxicity Subchronic Data In the workplace, repetitive formaldehyde exposures are known to produce mucosa! irritation and pulmonary function impairment similar to acute exposures. Nasal and eye discomfort, as well as chest discomfort, have been reported in individuals working for up to 10.4 y in facilities with the formaldehyde concentration ranging from 0.04 to 0.4 ppm (mean = 0.22 ppm) (Holmstrom and Wilhelmsson, 1988). In another report, runny nose, runny eyes, squamous metaplasia, dysplasia, and goblet-cell hyper- plasia of the nasal mucosa! have been found in workers exposed to 0.08-0.9 ppm of formaldehyde for about 10.5 y (Edling et al., 1988). A slow progressive impairment in FEV75 _25 was reported in workers exposed to 0.04-1.3 ppm (mean = 0.4 ppm) of formaldehyde for greater than 5 y (Alexandersson, 1988). It is of interest that the pulmonary function impair- ment went away during a 4-w vacation. Unlike occupational studies, very few reports on experimental studies of the subchronic effects of formaldehyde in humans can be found. A repeti- tive exposure of human subjects to formaldehyde at 2 ppm, 40 min/d for 4 d, produced an unusual odor and eye irritation, but no pulmonary function impairment (Schachter et al., 1987). A 7-mo exposure of medical students to formaldehyde at less than 1 ppm, time-weighted average (TWA), re- sulted in eye and upper respiratory irritation, but no bronchoconstriction, even in asthmatics (Uba et al., 1989). Asthmatic reactions to formaldehyde have been demonstrated. Five of 28 nurses in a renal dialysis unit, where formalin was used to sterilize the dialysis machines, developed hypersensitivity to formaldehyde (Hendrick and Lane, 1977). Inhalation provocation challenge of these sensitized individuals to unknown concentrations of formaldehyde produced wheezing attacks with productive cough and reduction in peak expiratory flow rates beginning 2-3 h after the challenge and the symptoms and signs lasted for hours. There is also epidemiological evidence linking formaldehyde with asthma. A telephone survey in Massachusetts showed that indoor

96 SMACS FOR SELECTED AIRBORNE CONTAMINANTS formaldehyde exposures, due to off-gassing from recently remodeled or constructed houses, newly upholstered furniture, foam insulation in walls, or mobile homes, were significantly associated with asthma, chronic bronchitis, or allergies in the youngest child in the household (Tuthill, 1984). There are many reports on the subchronic effects of formaldehyde on laboratory animals and only a few of them will be discussed here. Gen- erally, a 13-w formaldehyde exposure at 6 h/d, 5 d/w produces no his- topathology, at the light microscopic level, at 1 or 2 ppm in rats (Wilmer et al., 1989; Woutersen et al., 1987), but a similar exposure at 10 ppm causes squamous metaplasia of the nasal mucosa (Woutersen et al., 1987; Feron et al., 1988). However, 2 ppm is not the NOAEL in subchronic discontinu- ous exposures, because, based on electron microscopic examinations, a 4-d formaldehyde exposure at 6 h/d produced abnormal cilia at 0.5 ppm in rats (Monteiro-Riviere and Popp, 1986). If the formaldehyde exposure concen- tration is sufficiently high, the rat does not recover from the morphological injuries of formaldehyde. Peron's group has shown that the squamous metaplasia produced by a 4-, 8-, or 13-w formaldehyde exposure at 20 ppm still remained after a 126-w nonexposure period (Feron et al., 1988). In terms of histopathology in animals, the concentration of formaldehyde appears to be more important than the degree of cumulative exposure (C x T) (Wilmer et al., 1989). Peron's group demonstrated that a 13-w formal- dehyde exposure at 2 ppm for 8 h/d, 5 d/w produced no histopathology in rats, but an exposure at 4 ppm for 4 h/d, 5 d/w resulted in squamous metaplasia and basal cell hyperplasia of the nasal mucosa (Wilmer et al., 1989). Most of the subchronic data on formaldehyde were based on discon- tinuous exposures. There has been only one report on formaldehyde's toxicity after a subchronic near-continuous exposure. A 26-w formalde- hyde exposure, 22 hid, 7 d/w at 0.2 ppm resulted in increased nasal dis- charge, but no histopathology, in monkeys, rats, and hamsters (Rusch et al., 1983). Chronic Data Long-term formaldehyde exposures at 6 h/d, 5 d/w for 84 or 104 w led to nasal squamous cell carcinoma in Fischer F-344 rats at about 14 ppm (Albert et al., 1982; Kerns et al., 1983). A 104-w exposure at 14.3 ppm

FORMALDEHYDE 91 also produced squamous cell carcinoma in B6C3F 1 mice (Kerns et al., 1983). The study with the 104-w exposure showed that the rat was more sensitive than the mouse. The incidence in rats was 87of160 rats exposed versus 0 of 160 controls, and the incidence in mice was 2 of 88 exposed versus 0 of 89 controls (Kerns et al., 1983; EPA, 1990; Starr, 1990). Even a subchronic exposure to formaldehyde could be carcinogenic in rats if the exposure concentration is sufficiently high. As mentioned above, a 13-w formaldehyde exposure at 10 ppm produced non-neoplastic changes in the nasal mucosa of rats (Woutersen et al., 1987; Feron et al., 1988). However, a 13-w exposure at 20 ppm is known to cause squamous cell carcinoma, carcinoma in situ, and polyploid adenomas in rats (Feron et al., 1988). It appears that the subchronic exposure has to be also sufficiently long to result in carcinogenesis because a 4- or 8-w exposure at 20 ppm failed to produce nasal cancers in rats (Feron et al., 1988). The difference between rat and mouse sensitivity to formaldehyde's carcinogenic effect appears to be related to the different responses to formaldehyde's sensory irritation in the two species. Formaldehyde gas depresses the respiration of rats and mice within a minute or two (Chang et al., 1981). The mouse is more sensitive than the rat because it takes only 5 ppm to decrease the minute volume by 50% in the mouse, compared with 32 ppm in the rat. The minute volume reduction is due to a corresponding decrease in respiratory rate. Other than being less sensitive to formalde- hyde's respiratory-depression effect than the mouse, the rat also tends to recover from the respiratory-depression effect during a 10-min formalde- hyde exposure, and the respiration of the mouse remains depressed during the 10 min. The respiratory depression effect is the same in naive rats and mice or rats and mice pre-exposed to formaldehyde at 2-15 ppm for 6 h/d for 4 d. Epidemiological Data Quite a number of epidemiology studies have been performed with formaldehyde and only some of the more recent ones will be discussed here. In general, the results are inconclusive, but there are indications that certain tumors might be related to formaldehyde exposure in humans. In a retrospective cohort study, conducted by Blair et al. ( 1986), of workers employed in formaldehyde-using or -producing facilities (exposure concen- trations at 0.1 to greater than 2 ppm), there was a significant increase in

98 SMACS FOR SELECTED AIRBORNE CONTAMINANTS mortality from nasopharyngeal cancer (Blair et al., 1986). There were also slight, but statistically insignificant, excesses of Hodgkin's disease and cancers of the lung, prostate gland, and oropharynx (Blair et al., 1986). Among these excesses, Hodgkin's disease was statistically correlated with the concentration of exposure, but not with the degree of cumulative exposure, i.e., C x T. The excesses of cancers in the other sites were not statistically correlated with either C or C x T (Blair et al., 1986; Blair et al., 1987). However, a reanalysis of the data by two other investigators demonstrated a significantly higher risk for lung cancer, as well as for all cancers, in workers with higher levels of formaldehyde exposure than those with little or no exposure (Sterling and Weinkam, 1988). In a follow-up study, mortality from lung cancer actually exhibited a slightly negative correlation with formaldehyde exposure in workers exposed to formalde- hyde alone (Blair et al., 1990). The mortality from lung cancer, however, was associated with exposure to wood dust, urea, melamine, and phenol rather than with exposure to formaldehyde in workers co-exposed to these substances and formaldehyde, suggesting that exposure to these substances may play a more important role than formaldehyde in causing hung cancer mortality. In another retrospective cohort mortality study conducted by Stayner et al. (1988), where garment workers were potentially exposed to for- maldehyde at 0.15 ppm or higher, there were significant excesses in mortality from cancers of the connective tissue and buccal cavity. The excesses in mortality from leukemia and other lymphopoietic neoplasms were not statistically significant. However, the mortality from buccal cavity cancers, leukemia, and other Iymphopoietic neoplasms increased with duration of formaldehyde exposure or latency. The investigators' conclusion was that formaldehyde exposure was possibly related to the development of buccal cancers, leukemias, and other Iymphopoietic neo- plasms in humans. Unlike the study by Blair et al. (1987), the study by Stayner et al. (1988) did not show any excess in nasal cancer, probably due to the limited statistical power of the study. Another case-control study with 544 woodworkers exposed to formaldehyde also failed to show a significant increase in the odds ratio for cancer in the upper respiratory tract (Partanen et al., 1990). However, two case-control studies showed that employment in jobs with known formaldehyde exposures was associated with increased risks of nasal and sinus cancers (Hayes et al., 1986; Vaughn et al., 1986a,b).

FORMAWEHYDE 99 A similarity of the two epidemiology studies (Blair et al., 1986; Stayner et al., 1988) is that they both demonstrated a potential link of formaldehyde exposure and lymphopoietic neoplasms, which has also been shown in embalmers and pathologists (Levine et al., 1984; Harrington and Shannon, 1975). Interestingly, lymphopoietic neoplasms were not found in the animal bioassays (Albert et al., 1982; Kerns et al., 1983). The U.S. Environmental Protection Agency has classified formaldehyde as a probable human carcinogen on the basis of limited evidence in humans and sufficient evidence in animals (EPA, 1990). The International Agency for Research on Cancer considers the evidence for formaldehyde carcino- genicity in humans limited and sufficient for carcinogenicity in animals (IARC, 1987). Formaldehyde has been classified by the American Confer- ence of Governmental Industrial Hygienists as a suspected human carcino- gen (TLV Committee, 1989). Genetic Toxicity Formaldehyde causes forward mutation in Salmonella typhimurium, strain TM677, and it also initiates cell transformation of C3H/10Tl/2 cells, a cell line of mouse embryo fibroblasts (Boreiko et al., 1982). Data from in vitro genotoxicity assays performed with formaldehyde should be inter- preted with care for two reasons. First, formaldehyde's volatility is so great that 90% of the formaldehyde in a 250-ppm solution is lost to the head space in closed vials after incubation at room temperature for 1 h (Proctor et al., 1986). Second, formaldehyde is extremely reactive in culture medium with fetal calf serum, and many interaction products were formed in the medium after a 1-h incubation at 38°C (Proctor et al. , 1986). These data suggest that only a small portion of formaldehyde remains to act on the genome in in vitro assays. Nevertheless, formaldehyde has been demonstrated to react with the genome in vitro. Developmental Toxicity Formaldehyde is not teratogenic in the rat (Saillenfait, 1989). Inhalation exposure of pregnant rats, on days 6-20 of gestation, to 20- or 40-ppm formaldehyde reduced fetal body weight, but it caused no malformations (Saillenfait, 1989).

100 SMACS FOR SELECTED AIRBORNE CONTAMINANTS Synergistic Effects Some evidence indicate that formaldehyde might act synergistically with inert particles in causing certain, but not all, of its toxic end points. Due to the fact that carbon particles have been known to exacerbate the mucosal irritation of ammonia (Dalhamn and Reid, 1967), an irritant gas like formaldehyde, it is of interest to determine if inert particles will also potentiate formaldehyde's irritancy. In a Swedish study, in which the exposure levels were not measured, the respiratory symptoms and lung function in workers exposed to formaldehyde alone or formaldehyde with wood dust were compared (Holmstrom and Wilhelmsson, 1988). The formaldehyde-only group developed nasal and eye discomfort sooner than the formaldehyde-wood-dust group; these symptoms started 4.3 y after the start of employment in the formaldehyde-only group versus 9. 9 y in the other group. Both groups suffered significant reduction in olfactory func- tion and forced vital capacity, but no change in forced expiratory volume in 1 s as a fraction of the forced vital capacity (Holmstrom and Wilhelmsson, 1988). The amount of reduction in olfactory function and forced vital capacity were similar between the formaldehyde-only and formaldehyde- wood-dust groups (Holmstrom and Wilhelmsson, 1988). In contrast, there appears to be synergism between formaldehyde and wood dust in causing nasal cancers. In a Danish epidemiology study, a nonstatistically significant higher risk ratio of carcinomas of the nasal cavity and sinuses was found with occupational formaldehyde exposure, but the risk ratio became statistically significant if there had been exposure to both formaldehyde and wood dust (Olsen et al., 1984).

TABLE4-1 Toxicity Summary8 Exposure Concentration Duration Species Effects Reference 0.04 to 0.4 ppm ca. 10.4 y Human Nasal and eye discomfort, nasal mucosa) swelling, Holmstrom and (mean 0.2 ppm) (workers) deeper airway discomfort, headache, reduced sense Wilhelmsson, 1988 of smell, impaired nasal mucociliary clearance and reduced FVC. 0.04 to 1.3 ppm N.S.b Human Eye and throat irritation, chest oppression. Alexandersson et al., (mean 0.4 ppm (workers) Reduction in FEV 1 and maximum mid-expiratory 1982 flow. Increase in closing volume. 0.04 to 1.3 ppm >5 y Human A slow progressive impairment in FEV7s. 25 that Alexandersson, (mean 0.4 ppm (workers) returned to normal in a 4-w vacation among 1988 nonsmokers. 0.05 to 0.4 ppm N.S. Human Increased% of workers complained of throat Horvath et al., 1988 (workers) irritation, but not statistically significant. 0.08 to 0.9 ppm ca. 10.5 y Human Running nose, running eyes, squamous metaplasia, Edling et al., 1988 (workers) dysplasia, goblet cell hyperplasia, and loss of cilia. Histological changes not correlated with exposure duration. <0.1 ppm N.S. Human 1-2% complained of eye irritation. Ritchie and Lehnen, (residents of 1987 mobile homes) 0.1 ppm 90min Human No difference in symptom ratings compared with the Harving et al., 1990 (asthmatics) 0.007 ppm group. No changes in FEVI> airway resistance, flow-volume curves, and bronchial reactivity. ~ Q ~

..... TABLE4-1 (Continued) ~ Exposure Concentration Duration S~cies Effects Reference 0.1to0.3 ppm N.S. Human 22% complained of eye irritation. Ritchie and Lehnen, (residents of 1987 mobile homes) 0.1 to>2 ppm Up to about 40 y Human An increase of death due to nasopharyngeal cancer. Blair et al., 1986 (workers) 0.12 ppm 5.5 h Human No effects on short-term memory and the abilities to Bach et al., 1990 concentrate or add. 0.13 to 0.45 ppm N.S. Human Eye irritation. Bourne and (workers) Seferian, 1959 0.15 to ca. 10 ca. 3.2 y Human Mortality from buccal cancers, leukemias, and other Stayner et al., 1988 ppm (workers) lymphopoietic neoplasms increased with duration of exposure or latency. 0.3 ppm TWA, 8 h/d for weeks Human Eye, nose and throat irritation. No change in lung Alexandersson and 0.6 ppm mean (workers) functions during the 8-h shift, but FVC and FEV 1 Hedenstierna, 1988 peaks were reduced on return to work Monday a.m. 0.33 ppm 5.5 h Human Abilities to add and concentrate were affected. Bach et al., 1990 (workers) >0.3 ppm N.S. Human >90% complained of nose and throat irritation. Ritchie and Lehnen, (residents of 1987 mobile homes)

0.35 ppm N.S. Human Increased symptoms of mucosa! irritation, headache, Olsen and Dossing, (employees in a tiredness, and menstrual irregularities in workers in a 1982 building with building with particle boards (0.066 ppm) than in ureaNCHO controls. glued particle boards) 0.35 to l ppm 6min Human Slight eye irritation at 0.35 ppm. Eye irritation Bender et al., 1983 approached moderate at l ppm. 0.4 to l ppm N.S. Human 20% of the workers complained of throat irritation. Horvath et al., 1988 (workers) 0.5, 1, or 2 ppm N.S. Human Unusual odor and eye irritation. No changes in Kulle et al., 1987 pulmonary function. No increases in bronchial reactivity to methacholine. 0.7 ppm 90min Human No difference in symptom ratings than the 0.007 Harving et al., 1990 (asthmatics) ppm group. No changes in FEV1' airway resistance, flow-volume curves, and bronchial reactivity. 0.9 to 1.6 ppm N.S. Human Eye and throat irritation, unusual thirst, and disturbed Morrill, 1961 (workers) sleep. l ppm 5.5 h Human Ability to add was affected 10 min into the exposure. Bach et al., 1990 (workers) l or 1.2 ppm 90min Human No changes in forced vital capacity, FEV 1, or Day et al., 1984 maximal mid-expiratory flow rate. But 83%, 39%, and 28% of the subjects complained of eye, nose, and throat irritation, respectively. 1to3 ppm N.S. Human 32% of the workers complained of throat irritation. Horvath et al., 1988 (workers) ..... Q ~

.... TABLE4-l (Continued) = """ Exposure Concentration Duration S~cies Effects Reference 1or3 ppm via 10 min while Human No increase in specific airway resistance. Sheppard et al., mouth piece doing moderate (asthmatic 1984 exercise subjects) 1.2 ppm 1.5 min Human Very mild nose irritation. No eye or throat irritation. Weber-Tschopp et al., 1977 2ppm 40 min/d for 4 d Human Unusual odor and eye irritation. No change in forced Schachter et al., (routinely expiratory volume at 1 s and peak expiratory flow 1987 exposed to the rate during and after exposure. gas before) 2.1 ppm 1.5 min Human Mild nose irritation. Very mild eye and throat Weber-Tschopp et irritation. al., 1977 2.8 ppm 1.5 min Human Mild nose and eye irritation. Very mild throat Weber-Tschopp et irritation. al., 1977 3ppm 1h Human (a 15- Moderate or severe eye, nose, and throat irritation in Green et al., 1987 min exercise at one-third of the subjects (average score for all 15 and 45 min subjects was mild to moderate). About a 3% into exposure) reduction in forced expiratory volume in 1 s and forced vital capacity. 3 ppm 3 h (exercised Human Mild to moderate eye and upper respiratory tract Sauder et al., 1986 for 8 min every irritation. Small transient decreases in forced 0.5 h) expiratory volume in 1 s and forced mid-expiratory flow rate. <5 ppm peak (<l 7mo Human (medical Eye and upper respiratory irritation. No Uba et al., 1989 ppm TWA) students) brochoconstriction even in asthmatics.

0.2or1 ppm 22 hid, 7 d/w for Monkey, rat, Increased nasal discharge, but no histopathology in Rusch et al., 1983 26w hamster the respiratory tract and alveoli. 0.3 ppm 1h Guinea pig Increase in pulmonary resistance, decrease in lung Alexandersson and compliance. Hedenstierna, 1988 0.3, l,or3 ppm 6 hid, 5 d/w for Rat Increased cell turnover in nasal mucosa after 3 d, Zwart et al., 1988 3dor13w which recovered after 13 w of exposure 0.5 ppm 2min Rat Increased firing rate of the nasopalatine nerve. Kulle and Cooper, 1975 0.5, 1, or 2 ppm 1h Rat Decreased response of the nasopalatine nerve toward Kulle and Cooper, amyl alcohol. 1975 0.5 or2 ppm 6 h/d for 1 or4 d Rat Abnormal cilia in the nose. Monteiro-Riviere and Popp, 1986 0.5, 3, or I 5 ppm 6 h/d for4 d Rat Increases in lung P-450 levels. Dallas, 1989 0.5, 3, or I 5 ppm 6 hid, 5 d/w for Rat Reduction in minute volume, less at 16 w than 8 w. Dallas et al, 1985 8 or 16 w 1 ppm 6 h/d, 5 d/w for Rat Minimal focal epithelial hyperplasia and squamous Woutersen et al., 13w metaplasia in the nose. No increase in 3H-thymidine 1987 labeling index in the nasal mucosa. 2ppm 8 h/d, 5 d/w for Rat No histopathology in the nose. Wilmer et al., 1989 13 w 2ppm 6h Rat No effect on the mucociliary function. Morgan et al., 1986 2 or4 ppm 6 h/d, 5 d/w for Mouse No histopathology. Maronpot et al., 13 w 1986 2.55 ppm 2, 5, or 10 min Monkey Increase in pulmonary flow resistance. Biagini et al., 1989 ~ c:> !.It

TABLE4-1 (Continued) """" 0 C'\ Exposure Concentration Duration S~cies Effects Reference 3ppm 22 h/d, 7 d/w for Monkey, rat, Hoarseness and congestion in the monkey. Rusch et al., 1983 26w hamster Squamous metaplasia in the nose of the monkey and rat. No histopathology in hamster. Increased nasal discharge in all species. 3.8 ppm 24 h/d for 90 d Monkey, dog, Lung inflammation that the investigators were not Coon et al., 1970 rabbit, rat, certain whether it was caused by NCHO. guinea pig 4ppm 4 h/d (8 30-min Rat Squamous metaplasia, basal cell hyperplasia, and Wilmer et al., 1989 exposure periods occasional keratinization of the respiratory epithelium separated by 8 in the nose. 30-min nonexpo-sure periods a day), 5 d/w for 13 w 5.6 ppm 6 h/d, 5 d/w for Rat, mouse Nasal squamous carcinoma in rats (21153 versus Kerns et al., 1983 24 mo 0/156 in controls). 5.7 ppm 8 h/d, 5 d/w for Rat No changes in functional residual capacity, residual Saldiva et al., 1985 5w volume, total lung capacity, and respiratory rate. 6ppm 6 h/d for 1, 2, or Rat Hypertrophy of goblet and ciliated cells in the nose. Monteiro-Riviere 4d and Popp, 1986 10ppm 6 hid, 5 d/w for Rat Reduced growth (4-, 8-, or 13-w group). Slight Feron et al., 1988 4, 8or13 w squamous metaplasia (13-w group only). 10 ppm 6 h/d, 5 d/w for Rat Moderate squamous metaplasia of nasal respiratory Woutersen et al., 13w epithelium. 1987

10, 20, or40 ppm 6 hid, 5 d/w for Mouse Squamous metaplasia and inflammation of nasal Maronpot et al., 13w mucosa. Similar changes were found in the larynx 1986 and trachea at 20 and 40 ppm and down to the bronchi at 40 ppm. The 40-ppm group: hypoplasia of the uterus and ovaries. 14 ppm 6 hid, 5 d/w for Rat Nasal squamous carcinoma (l 0/62 vs 0/72 in Albert et al., 1982 84w controls). 14.3 ppm 6 hid, 5 d/w for Rat, mouse Nasal squamous carcinoma (rats: 94/140 vs 0/156 Kerns et al., 1983 24mo in controls; mice: 2/88 vs 0/89 in controls). 15 ppm 6h Rat Mucostasis and ciliostasis. Marked recovery Morgan et al., 1986 1 h after the end of the exposure. 20ppm 6 hid, 5 d/w for Rat Growth retardation, extensive stratified squamous Woutersen et al., 13w metaplasia of nasal respiratory epithelium. In males 1987 only: squamous metaplasia oflaryngeal epithelium, increased activities of plasma aspartate amino transferase, alanine amino transferase, and alkaline phosphatase. 20ppm 6 hid, 5 d/w for Rat Reduced growth, squamous metaplasia, rhinitis (4, 8, Feron et al., 1988 4, 8, or 13 w or 13-w groups). The non-neoplastic histopathology remained after a 126-w nonexposure period. Squamous cell carcinomas, carcinoma in situ, and polyploid adenomas were seen in 4/44 rats in the 13- w group versus 0/45 in the control. 20 or40 ppm 6 hid on days 6- Rat Reduced fetal body weight. No teratogenesis. Olsen et al., 1984 20 of gestation ~nly the results from inhalation studies were included . .S. = not specified. .... Q '-I

108 SMACS FOR SELECTED AIRBORNE CONTAMINANTS TABLE 4-2 Exposure Limits Set by Other Organizations Organization Concentration, ppm ACGIH's TLV 1 (0.3 proposed ceiling) OSHA's PEL 3 (TWA) 5 (ceiling) NIOSH's REL Limit exposure to the lowest feasible level NIOSH's IDLH 100 TLV = threshold limit value. PEL = pennissible exposure limit. REL = recommended exposure limit. IDLH = immediately dangerous to life and health. TABLE4-3 Spacecraft Maximum Allowable Concentrations Durationa ppm mg/m3 Target Toxicity lh 0.4 0.50 Mucosal irritation 24h 0.1 0.10 Mucosal irritation 7 db 0.04 0.05 Mucosal irritation 30d 0.04 0.05 Mucosal irritation 180 d 0.04 0.05 Mucosa! irritation 8ceiling limits. bFormer 7-d SMAC = 0.1 ppm RATIONALE In setting the SMACs for formaldehyde, we compared the acceptable concentration (AC) based on noncarcinogenic end points with that based on carcinogenesis for each exposure duration. Among the noncarcinogenic end points, mucosa! irritation appears to be the most important. This is because formaldehyde was irritating at as low as 0.1 ppm (Ritchie and Lehnen, 1987; Horvath et al., 1988), but it did not impair lung function until the level reached 3 ppm (Green et al., 1987; Sauder et al., 1986; Kulle et al., 1987; Schachter et al., 1987, Day et al., 1984). Therefore, a formaldehyde level low enough to prevent mucosa! irritation will also prevent lung function impairment. There are no data on the formaldehyde concentrations required to sensitize individuals. In the absence of data, a nonirritating formaldehyde

FORMAI.DEHYDE 109 level is assumed not to sensitize the astronauts. Therefore, the SMACs set to prevent mucosal irritation would probably also prevent the sensitization of individuals exposed to formaldehyde. It has been reported that formaldehyde-sensitized nurses developed asthmatic attacks upon re-exposures to formaldehyde (Hendrick and Lane, 1977). If there were astronauts sensitized by prior formaldehyde exposures not related to space flights, the SMACs ideally should be set at levels that would not trigger any reaction in these sensitized astronauts. Unfortunately, in the study with nurses, the formaldehyde concentration required to induce the asthmatic reaction was unknown (Hendrick and Lane, 1977). However, data from two studies have shown that even irritating levels, as high as 3 ppm, did not produce any asthmatic attack in asthmatic individuals (Uba et al., 1989; Sheppard et al., 1984). Even though individuals sensitized with formaldehyde cannot be equated with asthmatic individuals, due to the lack of better information, a nonirritating formaldehyde concentration is assumed not to trigger an asthmatic reaction in sensitized astronauts. Mucosal Irritation The short-term SMACs are designed for contingencies, so a minor degree of irritation is acceptable. Based on the Wisconsin mobile-home study, 0.4 ppm would cause eye irritation in about half of the individuals (or 75 % of the individuals based on the upper 95 % confidence limit) (Hanrahan et al., 1984), and based on a human study, 0.35 ppm would cause only slight eye irritation (Bender et al., 1983); therefore, based on mucosal irritation, the 1-h AC is set at 0.4 ppm. To reduce the probability of the crew having to endure mild eye irritation for 24 h, a lower 24-h AC is desirable. The 24-h AC is, therefore, set at 0.1 ppm, which could produce eye irritation in only 4 % of the subjects (or 18 % of the subjects based on the upper 95% confidence limit) (Hanrahan et al., 1984). Because a little mucosal irritation is acceptable in 1 h and 24 h, no adjustment is made for using data generated from a population of only 61 individuals. Ideally, the long-term SMACs should be set at nonirritating levels, but the threshold concentration for formaldehyde's irritation effect could not be accurately estimated. Lacking a better approach, the "normal" ambient

110 SMACS FOR SELECTED AIRBORNE CONTAMINANTS level of formaldehyde is taken to be the practical irritation threshold. In the Wisconsin mobile-home study, the outdoor formaldehyde level was 0.04 ± 0.03 ppm (mean ± S.D.) (Hanrahan et al., 1984). The indoor formaldehyde level in homes without urea formaldehyde construction materials was 0.03 ± 0.004 ppm (mean ± S.D.) (Gupta et al., 1982). From these measurements, the "normal" ambient level appears to be about 0.04 ppm. The 180-d, 30-d, and 7-d ACs for irritation are, therefore, set at 0.04 ppm. Based on an extrapolation of the concentration-response data of the Wisconsin mobile-home study (Hanraham et al., 1984), the long- term ACs of 0.4 ppm are expected to result in mucosa! irritation in less than 1% of the individuals (or less than 10% of the individuals based on the upper 95% confidence limit). Carcinogenesis Some genotoxic carcinogens are known to produce tumors even after a single exposure (Williams and Weisburger, 1985). Formaldehyde is genotoxic and, consequently, its carcinogenicity has to be considered in setting even the 24-h SMAC. Quantitative risk assessments of carcinogens have traditionally been done using the exposure concentration as a measurement of the extent of the carcinogen exposure. However, to quantify the tumor risk of a carcinogen, such as formaldehyde, which shows a tumor response nonlinearly proportional to the exposure concentration in a bioassay, the dose at the target site is preferred over the exposure concentration as a measurement of the extent of exposure (Hoel et al., 1983). The dose at the target site is also preferred if interspecies extrapolation will be done. This is because, for the same exposure concentration, the dose at the target site could differ between the test species and humans owing to species differences in anatomy and physiology. A group in the Chemical Industry Institute of Toxicology has measured the dose, represented by the amount of formaldehyde bound to DNA, as DNA-protein crosslinks, in the nasal mucosa of rats and monkeys (Starr, 1990; Heck et al., 1990). Their data are shown in the table below together with the tumor data from the 2-y bioassay (Kerns et al., 1983; Starr, 1990).

FORMAI.DEHYDE 111 TABLE 4-4 Molecular Dosimetry Tumor Airborne DNA Binding DNA Binding in Incidence Formaldehyde in Rats in 6 h Monkeys in 6 h In Rats Cone. (ppm) (pmol/mg DNA) (pmol/mg DNA) 0/160 0 0.3 1.4 0.7 3.9 0.36 0/160 2.0 20 2.5 2/160 5.6 98a 6.0 106 18.2 10.0 266 87/160 14.3 439a aObtained by interpolation or extrapolation from the data. They found that the target dose in the nasal mucosa was not linearly proportional to the airborne formaldehyde concentration, so that a linear extrapolation of the target doses at concentrations above 5.6 ppm would overestimate the target doses at low concentrations. That means a quan- titative risk assessment using the airborne formaldehyde concentrations would probably overestimate the tumor risk at low exposure concentra- tions. They also discovered that the doses in the monkey were about 5-10 times lower than that in the rat, indicating that the tumor risk for primates would also be overestimated if the quantitative risk assessment were done using the dosimetry data in the rat. Starr performed a quantitative risk assessment with the linearized multistage model using the target dose in the nasal mucosa in rats and the tumor incidence data from the bioassay (Starr, 1990). From the DNA binding-data in the monkey, he calculated that inhalation of formaldehyde at 1 ppm for 6 his equivalent to a dose of formaldehyde at 0.85 pmol/mg of DNA in the monkey. He then assumed that a given dose in the nasal mucosa has the same tumor-induction potency in the rat and the monkey (Starr, 1990). Because the quantitative risk assessment with the molecular dosimetry data from the rat shows that a dose of 0.85 pmol/mg of DNA in the bioassay would yield a tumor risk of 140 cases/106 (the upper 95% confidence limit), a lifetime exposure of monkeys to I-ppm formaldehyde at 6 h/d, 5 d/w would yield the same tumor risk. Assuming that the

112 SMACS FOR SELECTED AIRBORNE CONTAMINANTS molecular dosimetry of formaldehyde in humans and monkeys is the same, and assuming that the human is as sensitive as the rat toward formaldehyde's carcinogenicity, a formaldehyde exposure at l ppm, 6 h/d, 5 d/w for 70 y would yield 140 cases of tumors/ 106 exposed human beings (the upper 95 % confidence limit) (Starr, 1990). Assuming a linear dose response in the region of interest to us, a lifetime continuous exposure at 1 ppm would produce in astronauts, based on the molecular dosimetry approach, a lifetime tumor risk 6 = (140/10 ) x (24 h/d x 7 d/w)/(6 h/d x 5 d/w) 6 = 784/10 = 7.84/104 • To get a 10-4 lifetime tumor risk in astronauts, based on the molecular dosimetry approach, formaldehyde concentration = 1 ppm/7.84 = 0.13 ppm. Because NRC's Subcommittee on Guidelines for Developing SMACs felt that the molecular dosimetry approach had not been reviewed by the full Committee on Toxicology (COT) and that it might be more appropriate to express risk on the basis of picomole of formaldehyde bound per cell rather than on per milligram of DNA, the carcinogenic risk was also estimated by the traditional approach. Based on the EPA's quantitative risk assessment using airborne for- maldehyde concentrations as a measure of exposure (EPA, 1990), the lifetime exposure concentration that would yield an upper 95 % confidence limit tumor risk of 10-4 was calculated to be 0.0063 ppm. Therefore, the lifetime exposure concentration yielding a 10-4 tumor risk from the traditional approach is about 20 times lower than that estimated with the Chemical Industrial Institute of Toxicology's molecular dosimetry approach. According to the NRC subcommittee, the ACs, using carcinogenesis as the basis, are calculated below with the traditional approach. Based on that approach (NRC, 1990) and setting k = 3, t = 25,550 d,

FORMAI.DEHYDE 113 and s 1 = 10,950 d, the adjustment factor is calculated to be 26,082 for calculating a near-instantaneous exposure level that would yield the same excess tumor risk as a continuous lifetime exposure. 24-h exposure level that would yield an excess tumor risk of 10-4 = 0.0063 ppm x 26,082 = 164 ppm. For the 7-d, 30-d, and 180-d ACs, adjustment factors are calculated with the COT approach (NRC, 1990), setting k = 3, t = 25,550 d, and assuming that the earliest age of exposure is 30 y. The adjustment factors are 3728, 871, and 146.7 for a continuous 7-d, 30-d, and 180-d exposure, respectively, that would yield the same excess tumor risk as a continuous life-time exposure. 7-d exposure level that would yield an excess tumor risk of 10-4 = 0.0063 ppm x 3728 = 23 ppm. 30-d exposure level that would yield an excess tumor risk of 10-4 = 0.0063 ppm x 871 = 6 ppm. 180-d exposure level that would yield an excess tumor risk of 10-4 = 0.0063 ppm x 146.7 = 0.9 ppm. Establishment of SMACs After the ACs for mucosa! irritation and carcinogenesis are tabulated below, it is quite apparent that mucosal irritation is a more sensitive end point. The 1-h, 24-h, 7-d, 30-d, and 180-d SMACs are set at the cor- responding ACs based on mucosa! irritation and they are 0.4, 0.1, 0.04, 0.04, and 0.04 ppm, respectively. Finally, because it is not anticipated that microgravity effects on the body would affect the irritancy or car- cinogenicity of formaldehyde, the SMACs are not adjusted for any microgravity-induced physiological effects.

114 SMACS FOR SELECTED AIRBORNE CONTAMINANTS TABLE4-5 Acceptable Concentrations Acceptable Concentrations, ppm Toxic End Points lh 24 h 7d 30d 180 d Mucosal irritation 0.4 0.1 0.04 0.04 0.04 Carcinogenesis 3400 164 23 6 0.9 SMAC 0.4 0.1 0.04 0.04 0.04 REFERENCES Albert, R.E., A.R. Sellakumar, S. Laskin, M. Kruschner, and N. Nelson. 1982. Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat. J. Natl. Cancer Inst. 68:597-603. Alexandersson, R. 1988. Decreased lung function and exposure to form- aldehyde in the wood working industry. A five-year follow-up. Arh. Hig. Rada Toksikol./Arch. Ind. Hyg. Toxicol. 39:421-424. Alexandersson, R. and G. Hedenstierna. 1988. Respiratory hazards associated with exposure to formaldehyde and solvents in acid-curing paints. Arch. Environ. Health 43:222-227. Alexandersson, R., B. Kolmodin-Hedman, and G. Hedenstierna. 1982. Exposure to formaldehyde: Effects on pulmonary function. Arch. Environ. Health 37:279-284. Bach, B., O.F. Pedersen, and L. Molhave. 1990. Human performance during experimental formaldehyde exposure. Environ. Int. 16:105-113. Bender, J.R., L.S. Mullin, J. Graepel, and W.E. Wilson. 1983. Eye irritation response of humans to formaldehyde. Am. Ind. Hyg. Assoc. J. 44:463-465. Biagini, R.E., W.J. Moorman, E.A. Knecht, J.C. Clark, and I.L. Bern- stein. 1989. Acute airway narrowing in monkeys from challenge with 2.5 ppm formaldehyde generated from formalin. Arch. Environ. Health 44: 12-17. Blair, A., P. Stewart, M. O'Berg, W. Gaffey, J. Walrath, J. Ward, R. Bales, S. Kaplan, and D. Cubit. 1986. Mortality among industrial workers exposed to formaldehyde. J. Natl. Cancer Inst. 76: 1071-1084. Blair, A., P.A. Stewart, R.N. Hoover, J.P. Fraumeni, Jr., J. Walrath, M. O'Berg, and W. Gaffey. 1987. Cancers of the naso/pharynx and

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