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Bl Acetaldehvde ... King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Acetaldehyde is a colorless liquid with a fruity, pungent odor (Sax, 1984). Synonyms: Ethanol, ethyl aldehyde, acetic aldehyde Formula: CH3 CHO CAS number: 75-07-0 Molecular weight: 44 Boiling point: 20.8Â°C Melting point: -123.5Â°C Vapor pressure: 740 mm Hg at 20Â°C Conversion factors at 25Â°C, 1 atm: 1 ppm = 1.80 mg/m 3 1 mg/m3 = 0.56 ppm OCCURRENCE AND USE Acetaldehyde is used as a solvent in the rubber, paper, and tanning in- dustries. We are not aware of any use of acetaldehyde in the spacecraft, but acetaldehyde has been found in the cabin atmosphere during several space-shuttle missions (NASA, 1988-90). The concentration detected usually ranged from 2 to 7 ppb. However, a sample in one space-shuttle mission was found to contain 140 ppb of acetaldehyde. 19
20 SMACS FOR SELECTED AIRBORNE CONTAMINANTS The human is a potential source of acetaldehyde in space shuttles. It has been estimated that acetaldehyde is produced at a rate of about 83 Âµg/d per human (Olcott, 1972). One production mechanism is the cleavage of L-threonine into glycine and acetaldehyde by threonine aldolase or serine hydroxy-methyltransferase (White et al., 1978; Diamondstone, 1982). It is also possible that acetaldehyde is absorbed during anaerobic metabolism of glucose by microorganisms in human intestines via decarboxylation of pyruvate by pyruvate decarboxylase (White et al., 1978; Harris, 1982). In human subjects fasted for 9 h previously, acetaldehyde was found in the expired air at an average rate of 17 Âµg/h (standard deviation = 25 Âµg/h), with the data corrected for compounds present in the bottled, zero-grade air they breathed (Conkle et al., 1975). PHARMA CO KINETICS AND METABOLISM When human volunteers inhaled acetaldehyde at 84-168 ppm for about 1 min, the respiratory tract retained 66-68 % of acetaldehyde at a respiratory rate of 10 bpm (Egle, 1970). The respiratory retention of acetaldehyde was somewhat concentration dependent because the retention dropped to 55 % when the acetaldehyde concentration was raised to 336 ppm (Egle, 1970). The respiratory rate also inversely affected acetaldehyde's respira- tory retention. At an exposure concentration ranging from 84 to 336 ppm, the percent retention of acetaldehyde linearly decreased by 25 as the respiratory rate was increased from 5 to 40 bpm (Egle, 1970). Unlike the respiratory rate, the tidal volume does not affect acetaldehyde's respiratory retention. Varying the tidal volume between 500 and 2000 mL did not change acetaldehyde's respiratory retention (Egle, 1970). Similar respira- tory retention results were obtained in dogs (Egle, 1972). Acetaldehyde is oxidized mainly in the liver to acetic acid by aldehyde dehydrogenase, aldehyde oxidase, and xanthine oxidase (White et al., 1978). In the liver, aldehyde dehydrogenase is found in the cytosol, mitochondria, and microsomes, but most of the hepatic aldehyde dehy- drogenase activity exists in the mitochondria (Sipes and Gandolfi, 1986). Aldehyde dehydrogenase is present in many mammalian tissues (Sipes and Gandolfi, 1986), which probably include nasal mucosa because nasal
ACETALDEHYDE 21 mucosal homogenates of rats could oxidize acetaldehyde (Casanova- Schmitz et al., 1984). After a 1-h inhalation exposure of rats to acetaldehyde at 24,500 to 491,000 ppm, acetaldehyde disappeared from blood monoexponentially with a half-life of 3.1 min (Hobara et al., 1985). During a 90-min, in vitro incubation of acetaldehyde with human blood, the acetaldehyde concentration showed an exponential biphasic decrease (Freundt, 1975). The half-lives of the first and second phases were 57 and 110 min, re- spectively (Freundt, 1975). TOXICITY SUMMARY Acute Toxicity Mucosal Irritation The eye is the most sensitive organ to acetaldehyde' s acute toxicity. In a study, 12 human subjects were exposed to acetaldehyde vapor for 15 min while being shown a movie "to divert their attention," most of the subjects developed eye irritation at 50 ppm, but it took more than 200 ppm to cause nose or throat irritation in the majority of the subjects (Silverman et al., 1946). Other than comparing the sensitivities of several organs to acetalde- hyde' s irritancy, the investigators in that study also obtained concentra- tion-response data on acetaldehyde's irritancy on the eyes: 50 ppm ir- ritated the eyes of most of the subjects, and several subjects strenuously objected to the vapor at as low as 25 ppm (Silverman et al., 1946). Even those who reported no eye irritation at 50 ppm showed erythematous eyelids and bloodshot eyes when exposed to 200 ppm of acetaldehyde (Silverman et al., 1946). Based on a mouse model, acetaldehyde vapor is not as strong a sensory irritant as acrolein or formaldehyde (Steinhagen and Barrow, 1984). In this mouse model, a chemical's sensory irritancy slows down the breathing via a trigeminal nerve reflex (Alarie, 1973). Acetaldehyde at 2845 ppm reduced the mouse's respiratory rate by 50% in 10 min, but it took only
22 SMACS FOR SELECTED AIRBORNE CONTAMINANTS 1.4 ppm of acrolein or 5 ppm of formaldehyde to slow the mouse breathing by 50% (Steinhagen and Barrow, 1984). Miscellaneous Mucosal Effects In addition to causing mucosal irritation, acetaldehyde vapor can pro- duce ciliostasis at 560 ppm within 30 min in rabbit tracheal explants (Dalhamn and Rosengren, 1971). Acetaldehyde apparently also caused DNA-protein crosslinks in rats' nasal mucosa (Lam et al., 1986). There was evidence that DNA-protein crosslinks could be formed in the nasal respiratory mucosa after a 6-h exposure and olfactory mucosa after five daily 6-h exposures of rats to acetaldehyde at 1000 ppm (Lam et al., 1986). Lethality Acetaldehyde is lethal at sufficiently high exposure levels. Its 4-h LC50 in rats is 13,300 ppm (Appelman et al., 1982). Exposure of mice to 5600 ppm for 2 h led to 40% mortality and elevated SGOT, SGPT, and serum g-glutamyltransferase activities in the survivors (Wakasugi and Yamada, 1988). There was, however, no evidence of acetaldehyde causing liver injury in other studies. Subchronic and Chronic Toxicity Nasal Toxicity Consistent with acetaldehyde' s acute tox1c1ty, acetaldehyde causes primarily nasal injuries in subchronic and chronic exposures. In rats, exposures to acetaldehyde at 500 ppm, 6 h/d, 5 d/w for 4 w resulted in growth retardation, the degeneration of nasal olfactory epithelium and reduced phagocytic ability of pulmonary macrophages (Appelman et al., 1986). The no-observed-adverse-effect level (NOAEL) in that study in rats was 150 ppm. It is of interest that the NOAEL was 390 ppm in hamsters in a 90-d study performed in the same laboratory with similar end points (Kruysse et al., 1975). It thus appears that the rat is more sensitive than
ACETAI.DEHYDE 23 the hamster to acetaldehyde's subchronic toxicity. As the duration of acetaldehyde's repetitive exposure was lengthened to 52 w, nasal injuries similar to that seen in the 4-w study were also observed (Woutersen and Feron, 1987). However, some of the rats that developed degeneration of the olfactory epithelium, after a 52-w, 6-h/d, 5-d/w exposure to acetaldehyde at 750 ppm, recovered from the nasal injury in 26 or 52 w after the end of the exposure (Woutersen and Feron, 1987). This indicates that the nasal mucosa may regenerate after acetaldehyde exposure in rats. Pulmonary and Renal Toxicity In addition to injuring the nose, subchronic acetaldehyde exposures have been shown to affect the lung and kidney. A 5-w exposure of rats to acetaldehyde at 243 ppm, 8 h/d, 5 d/w produced increases in functional residual capacity, residual volume, total lung capacity, and respiratory rate, but no change in forced expiratory mean flows (Saldiva et al., 1985). No changes in lung morphology, however, were detected in these rats (Saldiva et al., 1985) or in rats repetitively exposed to acetaldehyde at concentrations as high as 2200 ppm for 4 to 52 w (Appelman et al., 1982; Appelman et al., 1986; Woutersen and Feron, 1987). A 90-d exposure of hamsters to acetaldehyde at 1340 ppm, 6 hid, 5 d/w increased the kidney weight (Kruysse et al., 1975). A 4-w exposure of rats to acetaldehyde at 1000 ppm has been shown to increase the urine output (Appelman et al., 1982). It was not known whether the increase in urine output was due to acetaldehyde's effect on the kidney. Carcinogenicity There was only one epidemiology study with acetaldehyde. It showed that the incidence of total cancer in acetaldehyde production workers was higher than that in the general population (Bittersohl, 1974). Out of 220 workers studied, nine cases of cancers were found: five cases of squamous cell carcinomas in the bronchial tress, two cases of squamous cell carcin- omas in the mouth, one case of adenocarcinoma in the stomach, and one case of adenocarcinoma in the cecum. The rates of bronchial cancers and oral cancers were both higher than that in the whole German population.
24 SMACS FOR SELECTED AIRBORNE CONTAMINANTS All nine men with cancers were smokers. Unfortunately, the study had several deficiencies, including a small number of subjects and the fact that the workers were exposed to a mixture of butyraldehyde, acetaldehyde, crotonaldehyde, n-butanol, and ethylhexanol, with butyraldehyde as the compound with the highest concentration. The measured concentration of acetaldehyde (1 to 7 mg/m3) was much lower than that of butyraldehyde (5 to 70 mg/m3). As a result, acetaldehyde's carcinogenicity could not be evaluated in this study. A carcinogenicity bioassay was performed in rats by Woutersen et al. (1986). They exposed rats to acetaldehyde at 0, 750, 1500, or 3000-1000 ppm, 6 hid, 5 d/w for up to 28 mo. The 3000-1000-ppm group was actually exposed at 3000 ppm for 20 w, 2000 ppm for 14 w, 1500 ppm for 17 w, and 1000 ppm for 69 w. Other than degeneration, hyperplasia, and metaplasia of the nasal mucosa, they found adenocarcinomas of the nasal olfactory epithelium and squamous cell carcinomas of the nasal respiratory epithelium in both the male and female rats. The combined incidences of nasal adenocarcinomas and squamous cell carcinoma in the male rats were 1of49, 17 of 52, 41of53, and 36 of 49 in the 0-, 750-, 1500-, and 3000- 1000-ppm groups, respectively (Woutersen et al., 1986). The International Agency for Research on Cancer (IARC) concluded that there is insufficient evidence of acetaldehyde's carcinogenicity in hu- mans, but there is sufficient evidence that acetaldehyde is a carcinogen in animals (IARC, 1987). Based on the carcinogenic findings in the rat, the U.S. Environmental Protection Agency (EPA) classified acetaldehyde as a probable human carcinogen (EPA, 1990). Genotoxicity There are some indications that acetaldehyde might be genotoxic. As mentioned earlier, acetaldehyde exposure at 1000 ppm, 6 h/d for 5 d could produce DNA-protein crosslinks in the nasal mucosa in rats (Lam et al., 1986). The data on the reaction with DNA in nasal mucosa of rats supports the carcinogenicity findings in rats. Incubation of human leukocytes with 10-20 mM acetaldehyde for 4 h in vitro has been shown by Lambert et al. to produce DNA crosslinks, but not DNA strand breaks (Lambert et al., 1985). Although acetaldehyde was negative in the Ames test (Mortelmans et al. ,
ACETAI.DEHYDE 25 1986), it was found to induce sex-linked recessive lethal mutations in Drosophila melanogaster (Woodruff et al., 1985) and sister chromatid exchange in human lymphocytes in vitro (Obe et al., 1979). Acetaldehyde was found to induce sister chromatid exchange in vitro without the addition of S-9 fraction, suggesting that metabolic activation was not required. Acetaldehyde also is known to produce chromosomal aberrations in mammalian cell culture (Bird et al., 1981). However, acetaldehyde failed to produce chromosomal aberrations in Drosophila (Woodruff et al., 1985). Reproductive and Developmental Toxicity No data were found on acetaldehyde's reproductive toxicity. However, acetaldehyde might affect the fetus. Acetaldehyde administered in- traperitoneally at 50, 75, or 100 mg/kg to pregnant rats on days 10, 11, and 12 of gestation led to fetal resorptions and decreased ossification of sternebrae and vertebrae in all three dose groups on day 21 (Sreenathan and Padmanabhan, 1982). Fetal growth was also severely impaired because there were reductions in crown-rump length, tail length, body weight, and transumbilical distance at all doses. The investigators ob- served malformations, such as reduction in the number of sternebrae, but they did not report results of statistical analyses of those malformation data, making interpretation difficult. They also did not mention if any maternal toxicity was detected. No conclusive assessment of acetaldehyde's teratogenicity can be made. Synergistic Effects There is no evidence that inhaled acetaldehyde acts synergistically with other chemicals. Pretreatment of rats with inhaled formaldehyde is known to decrease the rat's sensitivity toward acetaldehyde's sensory irritation (Babiuk et al., 1985). Inhalation exposures of mice to acetaldehyde have been shown to cause a metabolic tolerance to ethanol (Latge et al. , 1987). These findings should be considered in assessing the health risk of exposures to a mixture of these compounds.
N Q\ TABLE 1-1 Toxicity Summarl Exposure Concentration Duration S~cies Effects Reference 25ppm 15 min Human Several subjects, out of 12, strenously objected to the vapor. Silverman et al., 1946 SO ppm 15 min Human Some degree of eye irritation in a majority of subjects. Silverman et al., 1946 200 ppm 15 min Human Even the subjects that did not react to 50 ppm showed bloodshot eyes Silverman et al., and reddened eyelids at 200 ppm. 1946 ISO ppm 6 hid, 5 d/w Rat No histopathology in the nose, larynx, trachea, and lung. No effect on Appelman et al., for4w the phagocytic index of macrophages in lung lavages. 1986 200 ppm 3 hid, 5 d Mouse Increased killing of inhaled bacteria after one 3-h exposure. Aranyi et al., 1986 Decreased killing of inhaled bacteria after five 3-h exposures. 243 ppm 8 hid, 5 d/w Rat Increases in functional residual capacity, residual volume, total lung Saldiva et al., 1985 for 5 w capacity, and respiratory rate. No changes in forced expiratory mean flow. Nasal inflammation, but no histopathology of the lower respiratory tract and pulmonary parenchyma. 390 ppm 6 hid, 5 d/w Hamster No histopathology and no effects on body or organ weights. Kruysse et al., 1975 for 90 d 400 ppm 6 hid, 5 d/w Rat Growth retardation. Appelman et al., for4 w 1982 500 ppm 6 hid, 5 d/w Rat Degeneration of nasal olfactory epithelium. Reduced phagocytic Appelman et al., for4 w index of macrophages in lung lavages. 1986 560 ppm 60min Rabbit Ciliostasis in tracheal explants at 30 min. Dalhamnand Rosengren, 1971
750 or 1500 ppm 6 hid, 5 d/w Rat Degeneration of the olfactory epithelium, which regenerated in a few Woutersen and for 52 w rats 26 or 52 w after the end of exposure. Feron, 1987 750 ppm 6 hid, 5 d/w Rat Increased mortality and growth retardation. Degeneration, Woutersen et al., for28 mo hyperplasia, metaplasia, and adenocarcinomas of nasal olfactory 1986 epithelium. 1000 or 3000 oh Rat DNA-protein crosslinks in nasal respiratory mucosa, but not in nasal Lam et al., 1986 ppm olfactory mucosa. 1000 ppm 6 hid for 5 d Rat DNA-protein crosslinks in nasal respiratory and olfactory mucosa. Lam et al., 1986 1000 or2200 6 hid, 5 d/w Rat Growth retardation, increased urine output, slight to moderate Appelman et al., ppm for4w degeneration of nasal epithelium. 1982 1340 ppm 6 hid, 5 d/w Hamster Slight hyperplasia and metaplasia of tracheal mucosa. Increased Kruysse et al., 197 5 for90 d kidney weight. 1500 ppm 6 hid, 5 d/w Rat Increased mortality and growth retardation. Degeneration, Woutersen et al., for 28 mo hyperplasia, metaplasia, and adenocarcinomas of nasal olfactory 1986 epithelium. Keratinized squamous metaplasia and squamous cell carcinomas of nasal respiratory epithelium. Hyperplasia and keratinized squamous metaplasia of vocal cord. 2845 ppm 10 min Mouse 50% reduction in respiratory rate. Steinhagen and Barrow, 1984 3000 and 1500 6 hid, 5 d/w Rat Degeneration of the olfactory epithelium, hyperplasia and metaplasia Woutersen and ppm for20 w at of respiratory epithelium, and slight to moderate rhinitis. No recovery Feron, 1987 3000 ppm in 52 w after the end of exposure. followed by 32 w at 1500 ppm ~
N QO TABLE 1-1 (Continued) Exposure Concentration Duration S~cies Effects Reference 3000,2000, 6 h/d, 5 d/w for Rat Increased mortality, growth retardation, rhinitis, and sinusitis. Woutersen et al., 1500, 1000 20 wat3000 Degeneration, hyperplasia, metaplasia and adenocarcinomas of the 1986 ppm ppm, 14 wat nasal olfactory epithelium. Metaplasia with severe keratinization and 2000 ppm, 17 squamous cell carcinomas of the nasal respiratory epithelium. w at 1500 ppm, Hyperplasia and keratinized squamous metaplasia of the vocal cord. 69wat 1000 ppm 4560 ppm 6 h/d, 5 d/w for Hamster Necrosis, severe inflammation, hyperplasia, and metaplasia of the Kruysseetal., 1975 90d epithelium along respiratory tract, ocular and nasal irritation, increased kidney and heart weights, and growth retardation. 5000 ppm 6 h/d, 5 d/w for Rat Hyperexcitability and dyspnea during exposure. Fur discoloration, Appelman et al., 4w severe growth retardation, decreased neutrophil and increased 1982 lymphocyte counts, reduced urine volume, increased lung weight, and severe degeneration, hyperplasia, and metaplasia of nasal, laryngeal, and tracheal mucosa. 5600 ppm 2h Mouse 23/59 mice died. All survived mice showed elevated SGOT, SGPT, Wakasugiand and serum gamma-glutamyltransferase. Yamada, 1988 7340 ppm 80 min/d, 6 d/w Rat Increased specific activity of (Na+/K+)-ATPase in brain synaptosomal Shiohara et al., 1985 for 21 w membranes and microsomal membranes, but no changes in Mg++_ ATPase starting at 4 w into the exposure. 13,300 ppm 4h Rat Halfofthe rats died. Appelman et al., 1982 aOnly the results from inhalation studies were included.
ACETAIDEHYDE 29 TABLE 1-2 Exposure Limits Set by Other Organizations Organization Concentration, ppm ACGIH's TLV 100 (TWA) ACGIH's STEL 150 OSHA's PEL 200 (TWA) NIOSH's IDLH 10,000 ACGIH = American Conference of Governmental Industrial Hygienists. OSHA = Occupational Safety and Health Administration. NIOSH = National Institute for Occupational Safety and Health. TLV = threshold limit value. TWA = time-weighted average. STEL = short-term exposure limit. PEL = permissi- ble exposure limit. IDLH = immediately dangerous to life and health. TABLE 1-3 Spacecraft Maximum Allowable Concentrations Durationa ppm mg/m3 Target Toxicity 1h 10 18 Mucosal irritation 24 h 6 11 Mucosa! irritation 7 db 2 4 Mucosal irritation 30d 2 4 Mucosa! irritation 180 d 2 4 Mucosa! irritation :niese SMACs are ceiling values. Former 7-d SMAC = 30 ppm. RATIONALE To set acetaldehyde's SMACs, the acceptable concentrations according to carcinogenesis, for the various exposure durations, are compared with the corresponding concentrations based on noncarcinogenic end points. The noncarcinogenic end points produced by acetaldehyde include irritation sensation of the eyes, noncarcinogenic structural changes of nasal mucosa, lung function changes, and increased kidney weight (Silverman et al., 1946; Appelman et al., 1986; Kruysse et al., 1975; Saldiva et al., 1985). Among these noncarcinogenic end points, sensory irritation of the eyes is the most important because sensory irritation was detected in humans at as low as 25 ppm (Silverman et al., 1946), but much higher exposure concen- trations were required for other end points. For instance, the NOAEL in a 4-w repetitive exposure of rats was 150 ppm based on nasal histopathology
30 SMACS FOR SELECTED AIRBORNE CONTAMINANTS (Appelman et al., 1986). The lowest-observed-effect level (LOEL) based on kidney weight changes was 1340 ppm in a 4-w repetitive exposure of hamsters (Kruysse et al., 1975). Therefore, an exposure level low enough to prevent eye irritation will also prevent nasal histopathology and kidney weight changes. It took 243 ppm of acetaldehyde to cause lung function changes in a 5-w repetitive exposure of rats (Saldiva et al., 1985). In that study, the investigators used only one acetaldehyde exposure concentration. Without any concentration response data on the lung function, it is difficult to predict whether acetaldehyde, at a practically nonirritating level of 25 ppm, would affect the lung function of humans in a repetitive exposure. The lung function data of these investigators (Saldiva et al., 1985) were not relied on in estimating the acceptable level based on noncarcinogenic end points. The reason is that a 5-w repetitive exposure of rats to acetaldehyde at 243 ppm increased the functional residual capacity, residual volume, and total lung capacity (Saldiva et al., 1985). This pattern of lung function changes is typical for pulmonary emphysema (McCarthy, 1981), but no emphysematous changes were detected in that study or in other subchronic studies of acetaldehyde (Appelman et al., 1982, 1986; Kruysse et al., 1975). Until these lung function effects of acetaldehyde are reproduced and more data on acetaldehyde's lung function effects are available, lung function changes will not be considered in estimating the acceptable acetal- dehyde's exposure level for noncarcinogenic end points. The process used to set SMACs involves individual consideration of significant toxic end points. For each toxic end point, an acceptable con- centration (AC) for the appropriate length of exposure is estimated. After ACs are estimated for all the toxic end points under consideration, the lowest AC for a given duration of exposure is then selected as the SMAC. Carcinogenicity According to EPA's estimates based on the linearized multistage model (EPA, 1990), a life-time, continuous exposure to acetaldehyde at 0.046 mg/m 3 or 0.025 ppm would lead to an excess tumor risk of 1 x 10-4 in humans. Using the approach of the NRC's Committee on Toxicology (NRC, 1990) and setting k = 3, t = 25,550 d or 70 y, and s1 = 10,950 d or 30 y, an adjustment factor of 26,082 is obtained to calculate a
ACETAIDEHYDE 31 near-instantaneous exposure level that would yield the same excess tumor risk as a continuous life-time exposure. 24-h exposure level that would yield an excess tumor risk of 10-4 = 0.025 ppm x 26,082 = 660ppm. For the 7-d, 30-d, and 180-d acceptable exposure levels based on car- cinogenesis, adjustment factors are calculated with the approach of the NRC's Committee on Toxicology (NRC, 1990), setting k = 3, t = 25,550 d, and s 1 = 10,950 d. 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 = 0.025 ppm x 3728 = 94 ppm. 30-d exposure level that would yield an excess tumor risk of 10-4 = 0.025 ppm x 871 = 22ppm. 180-d exposure level that would yield an excess tumor risk of 10-4 0.025 ppm x 146.7 = 4ppm. Mucosa! Irritation Silverman et al. (1946) conducted a study in which 12 human volunteers were exposed to various organic compounds, one at a time, including acetaldehyde, while the volunteers were shown motion pictures during the 11 11 exposure to divert their thoughts from the atmospheric contamination. A 15-min exposure to acetaldehyde at 50 ppm resulted in some degree of eye irritation in a majority of the volunteers. Even though most of the subjects said that they were willing to work an 8-h day at 200 ppm (Silverman et al., 1946), it does not mean that 200 ppm is an acceptable concentration because the study of Silverman et al. was done in the mid-1940's, when workers were probably more willing to endure undesirable work conditions
32 SMACS FOR SELECTED AIRBORNE CONTAMINANTS due to the economic hard times. The finding that a 15-min exposure at 200 ppm produced bloodshot eyes and reddened eyelids in those subjects who did not respond to 50 ppm (Silverman et al., 1946) also tends to support the conclusion that 200 ppm could be quite irritating. Several of the 12 volun- teers strenuously objected to even 25 ppm of acetaldehyde, a concentration not irritating to the majority of the test subjects (Silverman et al., 1946). These data were prudently interpreted to mean that a 15-min acetaldehyde exposure at 200 and 50 ppm would probably result in moderate and mild eye irritation, respectively; and some individuals, however, are more sensi- tive to acetaldehyde's sensory irritation than others, so that 25 ppm is nonirritating except to supersusceptible individuals. Since the 1-h SMAC is designed for contingencies, slight eye irritation is acceptable. Although a 15-min acetaldehyde exposure at 25 ppm is not irritating except to a minority of the individuals (Silverman et al., 1946), 25 ppm is not acceptable as the 1-h SMAC because the irritation response to 25 ppm could increase if the acetaldehyde exposure is extended to 1 h. There is no time-response data on acetaldehyde's irritancy, but in humans the eye irritancy of acrolein, another irritating aldehyde, at 0.3 ppm in- creased when the exposure was extended from 15 to 40 min and it stayed constant from 40 to 60 min (Webber-Tschopp et al., 1977). Therefore, the 15-min acetaldehyde exposure level of 25 ppm should be lowered in estimating a 60-min exposure level that would not be irritating except to a minority of individuals. How much it should be lowered is determined from the acetaldehyde and acrolein data. The degree of eye irritation during an acrolein exposure increased by one grade, from slight to moderate, when the exposure was extended from 15 to 60 min (Weber-Tschopp et al., 1977). So to estimate a 60-min exposure concentration of acetaldehyde that is as irritating as a 15-min exposure concentration of acetaldehyde, the 15-min exposure concentration should be decreased by an amount that would drop the irritancy by one grade and this lower concentration is made the 60-min exposure concentration. When the acetaldehyde concentration was reduced two-fold from 50 ppm to 25 ppm in a 15-min acetaldehyde exposure, the degree of eye irritation was found to decrease by one grade, from mildly irritating in most of the 12 subjects to nonirritating in the majority of the subjects (Silverman et al., 1946). Therefore, a 60-min exposure concen- tration of acetaldehyde that is one half the 15-min exposure concentration would probably be as irritating as the 15-min exposure concentration.
ACETAl.DEHYDE 33 1-h acceptable exposure level that would be nonirritating to most people 15-rnin nonirritating exposure level x l/time factor (TF) 25 ppm x 1/2 12.5 ppm. It should be noted that, even though the 1-h AC based on irritation is derived from data generated from only 12 human subjects by Silverman et al. (1946), no correction is made for the small number of subjects. This is because some degree of mucosa! irritation is acceptable for a 1-h contin- gency, so the 1-h AC for irritation need not be too conservative. By the same token, no correction is made for the small number of subjects in deriving the 24-h AC based on Silverman's data. In setting the 24-h AC, a 24-h exposure concentration of acetaldehyde that is one half the 15-min exposure concentration is assumed to be as irritating as the 15-min concentration. Although there is no direct evidence that the irritancy of acetaldehyde' s vapor at 24 h would be the same as that at 1 h, data on the irritancy of acrolein and ammonia indicate that the irritancy of most sensory irritants reaches a plateau near 1 h. The irritancy of 0.3-ppm acrolein in humans stayed constant from 40 to 60 min into an exposure (Weber-Tschopp et al., 1977). There were no significant dif- ferences in ammonia's irritancy at 50 ppm in volunteers exposed for 0.5, 1, or 2 h (Verberk, 1977). As a result, it is safe to assume that the irri- tancy of acetaldehyde would not increase from 1 h to 24 h. This assump- tion is consistent with the general belief that mucosa! irritation is a surface phenomenon, affected mainly by the exposure concentration, not the exposure duration. So by applying the time adjustment factor of 2 on the 15-min exposure concentration of 25 ppm, which was nonirritating to most of the subjects in 15 min (Silverman et al., 1946), the resulting concentra- tion of 12.5 ppm should also be nonirritating to most of the people in a 24-h exposure. But because a few of the 12 exposed subjects "strenuously objected" to a 15-min acetaldehyde exposure at 25 ppm (Silverman et al., 1946), a number of sensitive individuals might also strenuously object to a 60-rnin exposure at 12.5 ppm. For this reason, the acceptable 24-h expo- sure concentration based on eye irritation should be lower than 12.5 ppm. There is another reason why it should be lower. Even though some probability of eye irritation is acceptable during a 24-h exposure to an irritant at its 24-h SMAC because 24-h SMACs are designed for con- tingency scenarios, the 24-h AC of an irritant is usually set slightly lower
34 SMACS FOR SELECTED AIRBORNE CONTAMINANTS than its 1-h AC to reduce the degree of irritation that the astronauts have to endure in 24-h contingencies. So in setting the 24-h AC, an additional uncertainty factor (UF) is needed compared with the derivation of the 1-h AC. Because it is known that a reduction of the 15-min exposure level of acetaldehyde by 2, from 50 ppm to 25 ppm, reduced acetaldehyde's irri- tancy from being slightly irritating to nonirritating in most of the subjects (Silverman et al., 1946), 2 is selected to be that UF. 24-h acceptable exposure level based on eye irritation 15-min nonirritating level x 1/TF x 1/UF = 25 ppm x 1/2 x 1/2 6ppm. As discussed above, it is safe to assume that acetaldehyde's irritancy would not increase from 1 h to 24 h. Similarly, the irritancy would not be expected to increase as the acetaldehyde exposure is further lengthened to 7, 30, or 180 d. Consequently, the same acceptable exposure level based on eye irritation may be used for 7, 30, or 180 d. To prevent eye irritation in practically all astronauts in a 7-d, 30-d, or 180-d exposure, a correction factor of 10/(square root of n) is applied because there were only 12 human subjects in Silverman's data (Silverman et al., 1946). This correction factor for "small n" would provide an added margin of safety. 7-, 30-, or 180-d acceptable exposure level that would prevent eye irritation 15-min nonirritating level x 1/TF x 1/UF x 1/small n factor = 25 ppm x 1/2 x 1/2 x (square root of n)/10 = 25 ppm x 1/2 x 1/2 x (square root of 12)/10 2ppm. The Establishment of SMACs All the ACs derived for carcinogenesis are tabulated below. The ACs based on eye irritation are lower than that based on carcinogenesis, so the ACs of 10, 6, 2, 2, and 2 ppm for mucosal irritation are chosen to be the 1-h, 24-h, 7-d, 30-d, and 180-d SMACs, respectively.
ACETAWEHYDE 35 TABLE 1-4 AcceEtahle Concentrations Acceptable Concentration, ppm Toxic End Point lh 24 h 7d 30d 180 d Carcinogenesis 660 94 22 4 Mucosal Irritation 12.5 6 2 2 2 SMAC 10 6 2 2 2 REFERENCES Alarie, Y. 1973. Sensory irritation of the upper airways by airborne chemicals. Toxicol. Appl. Pharmacol. 24:279-297. Appelman, L.M., R.N. Hooftman, and W.R.F. Notten. 1986. Effect of variable versus fixed exposure levels on the toxicity of acetaldehyde in rats. J. Appl. Toxicol. 6:331-336. Appelman, L.M., R.A. Woutersen, and V.J. Feron. 1982. Inhalation toxicity of acetaldehyde in rats. I. Acute and subacute studies. Toxi- cology 23 :293-307. Aranyi, C, W.J. O'Shea, J.A. Graham, and F.J. Miller. 1986. The effects of inhalation of organic chemical air contaminants on murine lung host defenses. Fund. Appl. Toxicol. 6:713-720. Babiuk, C., W.H. Steinhagen, and C.S. Barrow. 1985. Sensory irritation response to inhaled aldehydes after formaldehyde pretreatment. Toxi- col. Appl. Pharma col. 79: 143-149. Bird, R.P., H.H. Draper, and P.K. Basur. 1981. Effect of malonalde- hyde and acetaldehyde on cultured mammalian cells: Production of micronuclei and chromosomal aberrations. Mutat. Res. 101:237-246. Bittersohl, G. 1974. Epidemiologic investigations on cancer incidence in workers contacted by acetaldol and other aliphatic aldehydes. Arch. Geschwulstforsch. 43: 172-176. Casanova-Schmitz, M., R.M. David, and H.D. Heck. 1984. Oxidation of formaldehyde and acetaldehyde by NAD+ -dependent dehydrogenases in rat nasal mucosal homogenates. Biochem. Pharmacol. 33: 1137-1142. Conkle, J.P., B.J. Camp, and B.E. Welch. 1975. Trace composition of
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