B4 Formaldehyde

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/m3

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.



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants B4 Formaldehyde 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/m3 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.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants There is insufficient information to estimate the potential exposure level of formaldehyde. However, Soviet cosmonauts gained sensitivity to formaldehyde 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 Delrin (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.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Acute Toxicity Most human studies have been done in the workplace so that the reported 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 exposed to formaldehyde at an average peak level of 0.6 ppm (Alexandersson and Hedenstierna, 1988). Another group of investigators reported that workers complained of mucosal 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 (FEV1) 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 experimental 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 formaldehyde'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 predicted 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

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Spacecraft Maximum Allowable Concentrations 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 FEV1 and FVC in humans (Green et al., 1987; Sauder et al., 1986). However, at 1 or 2 ppm, formaldehyde 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

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 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 mucosal 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 hyperplasia of the nasal mucosal 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 impairment 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 repetitive 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), resuited 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

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Spacecraft Maximum Allowable Concentrations 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. Generally, a 13-w formaldehyde exposure at 6 h/d, 5 d/w produces no histopathology, 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 discontinuous 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 concentration is sufficiently high, the rat does not recover from the morphological injuries of formaldehyde. Feron'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 × T) (Wilmer et al., 1989). Feron's group demonstrated that a 13-w formaldehyde 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 discontinuous exposures. There has been only one report on formaldehyde's toxicity after a subchronic near-continuous exposure. A 26-w formaldehyde exposure, 22 h/d, 7 d/w at 0.2 ppm resulted in increased nasal discharge, 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

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants also produced squamous cell carcinoma in B6C3F1 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 87 of 160 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 formaldehyde's respiratory-depression effect than the mouse, the rat also tends to recover from the respiratory-depression effect during a 10-min formaldehyde 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 concentrations at 0.1 to greater than 2 ppm), there was a significant increase in

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Spacecraft Maximum Allowable Concentrations 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 × T. The excesses of cancers in the other sites were not statistically correlated with either C or C × 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 formaldehyde 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 formaldehyde 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 lymphopoietic 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 lymphopoietic neoplasms 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).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 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 carcinogenicity in humans limited and sufficient for carcinogenicity in animals (IARC, 1987). Formaldehyde has been classified by the American Conference of Governmental Industrial Hygienists as a suspected human carcinogen (TLV Committee, 1989). Genetic Toxicity Formaldehyde causes forward mutation in Salmonella typhimurium, strain TM677, and it also initiates cell transformation of C3H/10T1/2 cells, a cell line of mouse embryo fibroblasts (Boreiko et al., 1982). Data from in vitro genotoxicity assays performed with formaldehyde should be interpreted 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).

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Spacecraft Maximum Allowable Concentrations 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 function 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).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 4-1 Toxicity Summarya Concentration Exposure Duration Species Effects Reference 0.04 to 0.4 ppm (mean 0.2 ppm) ca. 10.4 y Human (workers) Nasal and eye discomfort, nasal mucosal swelling, deeper airway discomfort, headache, reduced sense of smell, impaired nasal mucociliary clearance and reduced FVC. Holmstrom and Wilhelmsson, 1988 0.04 to 1.3 ppm (mean 0.4 ppm N.S.b Human (workers) Eye and throat irritation, chest oppression. Reduction in FEV1 and maximum mid-expiratory flow. Increase in closing volume. Alexandersson et al., 1982 0.04 to 1.3 ppm (mean 0.4 ppm >5 y Human (workers) A slow progressive impairment in FEV.75-25 that returned to normal in a 4-w vacation among nonsmokers. Alexandersson, 1988 0.05 to 0.4 ppm N.S. Human (workers) Increased % of workers complained of throat irritation, but not statistically significant. Horvath et al., 1988 0.08 to 0.9 ppm ca. 10.5 y Human (workers) Running nose, running eyes, squamous metaplasia, dysplasia, goblet cell hyperplasia, and loss of cilia. Histological changes not correlated with exposure duration. Edling et al., 1988 <0.1 ppm N.S. Human (residents of mobile homes) 1-2% complained of eye irritation. Ritchie and Lehnen, 1987 0.1 ppm 90 min Human (asthmatics) No difference in symptom ratings compared with the 0.007 ppm group. No changes in FEV1, airway resistance, flow-volume curves, and bronchial reactivity. Harving et al., 1990

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Spacecraft Maximum Allowable Concentrations 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 mucosal 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).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 4-4 Molecular Dosimetry Tumor Incidence In Rats Airborne Formaldehyde Conc. (ppm) DNA Binding in Rats in 6 h (pmol/mg DNA) DNA Binding in Monkeys in 6 h (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 — a Obtained 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 quantitative risk assessment using the airborne formaldehyde concentrations would probably overestimate the tumor risk at low exposure concentrations. 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 h is 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 1-ppm formaldehyde at 6 h/d, 5 d/w would yield the same tumor risk. Assuming that the

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Spacecraft Maximum Allowable Concentrations 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 1 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 = (140/106) × (24 h/d × 7 d/w)/(6 h/d × 5 d/w) = 784/106 = 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 formaldehyde 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,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants and s1 = 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 × 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 × 3728 = 23 ppm. 30-d exposure level that would yield an excess tumor risk of 10−4 = 0.0063 ppm × 871 = 6 ppm. 180-d exposure level that would yield an excess tumor risk of 10−4 = 0.0063 ppm × 146.7 = 0.9 ppm. Establishment of SMACs After the ACs for mucosal 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 corresponding ACs based on mucosal 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 carcinogenicity of formaldehyde, the SMACs are not adjusted for any microgravity-induced physiological effects.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 4-5 Acceptable Concentrations   Acceptable Concentrations, ppm   Toxic End Points 1 h 24 h 7 d 30 d 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 formaldehyde 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. Bernstein. 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.F. Fraumeni, Jr., J. Walrath, M. O'Berg, and W. Gaffey. 1987. Cancers of the naso/pharynx and

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