Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 2 (1996)

King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

Houston, Texas

Acrolein is a colorless or yellowish, volatile, flammable liquid with an extremely sharp, irritating odor (Sax, 1984).

Acrolein is not used in the spacecraft, but acrolein is a potential atmospheric contaminant in spacecraft because it was found to be off-gassed from the hardware of two Spacelab missions at a rate of 0.007 mg/d (Geiger, 1984).

In dogs, inhaled acrolein is primarily retained by the upper respiratory tract (Bowes and Cater, 1968). In the rat, the evidence suggests that acrolein is oxidized by two pathways. The liver and lung microsomes oxidize acrolein in vitro to its epoxide metabolite, glycidaldehyde (Patel et al., 1980), which is converted to glyceraldehyde by epoxide hydrase (Hayakawa et al., 1975). Acrolein is also oxidized to acrylic acid probably involving aldehyde dehydrogenase (Patel et al., 1980). In rats given acrolein orally, S-carboxyethylmercapturic acid is the metabolite found in urine (Draminski et al., 1983).

The major toxicity of acrolein is mucosal irritation.

The NRC's Committee on Toxicology cited a report by the Shell Chemical Corporation that acrolein produced moderate mucosal irritation at a concentration as low as 0.25 ppm in humans, but no information on the exposure duration was given (Shell Chemical Corp., 1958). In comparison, Weber-Tschopp et al. (1977) reported that an exposure to acrolein at 0.3 ppm resulted in only a little eye discomfort in 1.5 min and moderate eye irritation in 1 h. Darley et al. (1960) demonstrated that a 5-min exposure to acrolein at 1.3-1.6 ppm was found to produce only moderate eye irritation in college students. In contrast, Sim and Pattle (1957) found that 1.2 ppm was extremely irritating to the mucosal surfaces in 5 min. Because of these variations in human test results, comparisons of the qualitative descriptions of acrolein's irritancy in different studies should be made with care.

Some studies show that acrolein's eye irritancy tends to increase progressively within the first 40 min of the exposure. Stephens et al.

(1961) showed that an exposure to acrolein at 0.5 ppm resulted in eye irritation in 10-35 % of subjects within 5 min and in 91% within 12 min (Stephens et al., 1961). Exposure to acrolein at 0.3 ppm produced mild eye irritation in human subjects in 10 min, mild-to-moderate eye irritation in 20 min, and moderate eye irritation in 40 min (Weber-Tschopp et al., 1977). From 40 to 60 min, the degree of eye, nose, and throat irritation stayed constant (Weber-Tschopp et al., 1977).

The relative sensitivity of human eyes and nose toward acrolein's irritation depends on the exposure concentration and duration. For exposures lasting about an hour, acrolein is more irritating to the eyes than the nose; the reverse is true for short exposures at below 0.3 ppm (Weber-Tschopp et al., 1977). A 40-60 min exposure to acrolein at 0.3 ppm caused moderate eye irritation and slight nose irritation (Weber-Tschopp et al., 1977). In a 1.5-min exposure of human volunteers to acrolein, 0.6 ppm produced the same degree of irritation in the eyes and the nose (somewhat slight irritation) (Weber-Tschopp et al., 1977). However, in a similar exposure, 0.15 ppm caused a little bit of nose discomfort, although it was not irritating to the eyes (Weber-Tschopp et al., 1977).

There are some data on acrolein's dose-response relationship in the literature. Darley et al. (1960) showed that in a 5-min exposure of humans to acrolein, the eye irritation was moderate at a concentration of 1.3-1.6 ppm and moderate-to-severe at 2.0-2.3 ppm. Weber-Tschopp et al. (1977) reported that in human volunteers exposed to acrolein for 1.5 min, mild irritation to the eyes and nose was detected at 0.60 ppm, a little bit of discomfort to the eyes and nose was detected at 0.30 ppm, and a little bit of discomfort to the nose and no effect on the eye was detected at 0.15 ppm (Weber-Tschopp et al., 1977). Probably because of the little bit of discomfort to the nose, some of the test subjects expressed a desire to leave the room when questioned in a survey, and they characterized the air quality as acceptable, versus good by the control group (Weber-Tschopp et al., 1977).

The exposure concentration seems to be more important than the exposure duration in causing acute irritating effects in humans. Sim and Pattle (1957) found that an exposure to acrolein at 0.8 ppm produced lacrimation in humans in 20 s. However, at a slightly higher concentration of 1.2 ppm, acrolein produced lacrimation in only 5 s. Had ac-

rolein's mucosal irritancy followed Haber's rule, 1.2 ppm would not be expected to produce lacrimation until 13 s into an exposure. That means C x T was not constant in that study.

Like most sensory irritants, acrolein also affects respiration. In about half of the human volunteers exposed to acrolein at 0.3 ppm, respiratory rates were decreased by 10% after 10 min of exposure (Weber-Tschopp et al., 1977). A 10-min exposure of Swiss-Webster mice to acrolein at 0.22 ppm also resulted in a decrease of approximately 25% in the respiratory rate (Steinhagen and Barrow, 1984). Even an exposure as low as 0.04 ppm resulted in a decrease of about 10% in the respiratory rate in the mouse (Steinhagen and Barrow, 1984). In guinea pigs exposed to acrolein at 0.4-1.0 ppm for 2 h, there were decreases in the respiratory rate and increases in the total pulmonary resistance (Murphy et al., 1963). The respiratory effects of acrolein in both the mouse and guinea pig are readily reversible when the exposure ends (Steinhagen and Barrow, 1984; Murphy et al., 1963). In a recent study, a 2-h exposure of guinea pigs to acrolein at 0.3 ppm increased the pulmonary resistance and bronchial responsiveness (Leikauf et al., 1989). In the lung lavage fluid, the exposure also increased the amount of thromboxane B₂ and prostaglandin F₂ immediately after exposure and the number of neutrophils 24 h after exposure (Leikauf et al., 1989).

Acrolein readily reacts with sulfhydryl groups. As a result, a 3-h inhalation exposure of rats to acrolein at 2.5 ppm decreased mucosal glutathione in the respiratory region of the nose (Lam et al., 1985). A 6-h exposure of rats to acrolein at 2 ppm did not cause DNA-protein cross-links in the respiratory mucosa of the nose (Lam et al., 1985).

Finally, acrolein exposures at a sufficiently high concentration could be lethal. The 6-h LC₅₀ of acrolein in mice was 66 ppm (Philippin et al., 1970) and one man died 10 min after exposure at 150 ppm (Prentiss, 1937).

Subchronic exposures to acrolein generally produced signs of mucosal irritation and pathology of the respiratory system. An exposure of mice to acrolein at 6 ppm for 2 w, 6 h/d, 5 d/w caused atelectasis, inflammation, and edema in the lung and body-weight reduction (Philippin et al., 1970). When the acrolein exposure was extended to 6 w, 8 h/d, 5 d/w, Lyon et al. (1970) found that 3.7 ppm produced eye irritation, squamous metaplasia, and basal-cell hyperplasia in the trachea of monkeys. Dogs, rats, and guinea pigs were similarly exposed in the same study, but the rats and guinea pigs appeared to be less susceptible to acrolein than the monkeys; the rats and guinea pigs did not show any gross sign of irritation, tracheal metaplasia, or tracheal hyperplasia (Lyon et al., 1970). Only two dogs were used in each exposure group, and in general the clinical signs of eye and nose irritation as well as lung injury in the dogs were similar to those in the monkeys. An exposure of acrolein at 0.7 ppm for 6 w, 8 h/d, 5 d/w caused chronic peribronchial inflammation in all exposed animals, indicating chronic bronchial irritation (Lyon et al., 1970).

Unfortunately, the nose was not examined microscopically in any of the experimental animals in either of the subchronic studies reviewed above. Feron et al. (1978) were the first to look for any nasal histopathology produced by acrolein. In an exposure of hamsters, rats, and rabbits to acrolein for 13 w, 6 h/d, 5 d/w, Feron et al. found that the rat was the most susceptible species, and the rabbit appeared to be the least susceptible. The 13-w exposure at 1.4 ppm resulted in metaplasia and inflammation of the nasal mucosa in the rats, only minimal nasal inflammation in the hamsters, and no adverse effects in the rabbits (Feron et al., 1978). The no-observed-adverse-effect level (NOAEL) was 0.4 ppm for this exposure of hamsters and rats to acrolein for 13 w, 6 h/d, 5 d/w (Feron et al., 1978).

In a 6-w exposure of mice, acrolein at 2 ppm for 6 h/d had no effect on the body-weight gain and the wet-to-dry lung-weight ratio in the mice (Northrop, 1985). However, it is of interest that a 6-w exposure of mice to acrolein at 4 ppm for 3 h/d or at 8 ppm for 1.5 h/d also did

not affect the wet-to-dry lung-weight ratio, but it did reduce the body-weight gain (Northrop, 1985). These results show that, in subchronic exposures to acrolein, the exposure concentrations seem to be more important than the exposure times. As discussed above, a similar conclusion was drawn for the acute mucosal irritancy of acrolein in humans.

Lyon et al. (1970) exposed monkeys, dogs, rats, and guinea pigs to acrolein continuously for 90 d, but no nasal microscopic examinations were conducted. Lyon et al. did observe that exposure to acrolein at 1.0 ppm produced ocular and nasal discharge, squamous metaplasia, and basal-cell hyperplasia in the tracheas of the monkeys. The effects from the exposure on the internal organs of the monkeys might not be reliable, because parasitic infestation was found in the lungs, livers, hearts, and brains of these monkeys (Lyon et al., 1970). The 1.0-ppm exposure did not cause any exposure-related histopathological changes in the tracheas or lungs of the guinea pigs and rats (Lyon et al., 1970). Lyon et al. used only two dogs in the 1.0-ppm exposure group, and the dogs reacted to acrolein exposure similarly to the monkeys. A 90-d continuous exposure of four dogs to acrolein at 0.22 ppm led to emphysema and lung congestion in two dogs.

In the 90-d continuous exposure of four dogs to acrolein conducted by Lyon et al. (1970), an exposure at 0.22 ppm resulted in splenic hemorrhage in two dogs and thyroid hyperplasia in the other two dogs. However, no exposure-related histopathological changes were detected in the internal organs of the monkeys, guinea pigs, and rats. (Lyon et al. did not examine the trachea in the 0.22-ppm exposure groups.) A similar exposure at 1.0 ppm was found to cause focal liver necrosis in guinea pigs and rats. The meaning of the finding of liver necrosis is uncertain, because a 90-d continuous exposure at a higher concentration of 1.8 ppm failed to induce liver necrosis in the guinea pigs and rats (Lyon et al., 1970).

In addition to the Lyon et al. investigation, Sinkuvene (1970) investigated the toxic effects of a continuous subchronic exposure to acrolein. The latter study showed that a 16-d continuous exposure of rats to acrolein at 0.056 ppm produced some changes, but they were not specified

(Sinkuvene, 1970). A similar exposure at 0.011 ppm failed to change the blood cholinesterase activity, the "chronaxy" of antagonistic muscles, and body-weight gain (Sinkuvene, 1970).

The U.S. Environmental Protection Agency (EPA) classified acrolein as a possible human carcinogen on the basis of limited animal carcinogenicity data, mutagenicity in bacteria, and structural similarity with two probable human carcinogens, formaldehyde and acetaldehyde (EPA, 1990). A 1-y exposure of hamsters to acrolein at 4 ppm failed to cause any increase in tumor incidence (Feron and Kruysse, 1977). However, the hamster study did not prove that acrolein is noncarcinogenic in laboratory animals for two reasons. First, it is likely that 1 y is not of sufficient duration for exposure. Second, the hamster has not been shown to be the most sensitive test species, at least on the basis of noncarcinogenic end points, to the toxicity of acrolein in subchronic exposures (Feron et al., 1978). Lijinski and Reuber (1987) found an increased incidence of adrenal cortical adenomas in female rats given acrolein at a concentration of 625 ppm in drinking water for 5 d/w for 100 w, but the increase was not statistically significant. (Evidence of the carcinogenicity of acrolein in this study is inconclusive, however, because of the p difference and the small number of rats, 20 in each group used.) It should be noted that there is no evidence of the carcinogenicity of acrolein in humans (EPA, 1990). The International Agency for Research on Cancer (IARC) characterized acrolein as a compound with inadequate evidence of carcinogenicity in both humans and animals (IARC, 1987).

There are some indications that acrolein might be genotoxic. It induced mutations in Salmonella typhimurium strain TA104 but not in strains TA98, TA1535, TA1537, and TA1538 (Lutz et al., 1982; Hales, 1982; Marnett et al., 1985). Acrolein induced recessive lethal mutations in Drosophila melanogaster (Zimmering et al., 1985) and

sister chromatid exchange in Chinese hamster ovary cells (Au et al., 1980). However, acrolein failed to affect the dominant lethal assay in mice after an intraperitoneal injection (Epstein et al., 1972).

Mucosal irritation is the most important toxic end point to be used in setting SMACs for acrolein because mucosal irritation was detected in humans and mice after exposure to concentrations lower than those that produced histopathological changes in the respiratory systems of various laboratory animal species (Weber-Tschopp et al., 1977; Steinhagen and Barrow, 1984; Lyon et al., 1970; Feron et al., 1978). The eyes and nose differ in their sensitivities to acrolein's irritation. Weber-Tschopp et al. found that a 1-h exposure of human volunteers to acrolein at 0.3 ppm caused moderate eye irritation and only slight nose irritation

(Weber-Tschopp et al., 1977). Because the eye appears to be more sensitive than the nose, SMACs for acrolein are set on the basis of eye irritation.

The 1-h and 24-h SMACs are designed for contingency scenarios, so they are aimed at preventing irreversible injuries and significant performance decrements. It is acceptable that these short-term SMACs might not protect against slight mucosal irritation.

The goal is to find an exposure concentration that would produce only slight eye irritation in 1 h. A 1-h exposure to acrolein at 0.3 ppm produced, on the average, moderate eye irritation in humans (Weber-Tschopp et al., 1977). Darley et al. (1960) showed that, after a 5-min exposure to acrolein, eye irritancy in humans decreased by half a grade, from moderate-to-severe to moderate, when the concentration was reduced 35-40% (from 2.0-2.3 ppm to 1.3-1.6 ppm). According to Figure 4 in the report of Weber-Tschopp et al. (1977), as the concentration of acrolein was reduced from 0.6 ppm to 0.3 ppm in a 1.5-min exposure of human volunteers to acrolein, the effect on the eye was reduced from being mild irritation to a little bit of discomfort. There was no effect on the eye when the concentration was further reduced to 0.15 ppm. From the data of Darley et al. and Weber-Tschopp et al., lowering the 1-h exposure concentration of 0.3 ppm, which was moderately irritating to the eye, fourfold should result in a concentration that is only mildly irritating to the eye.

Because Weber-Tschopp et al. (1977) showed that the mucosal irritancy caused by exposure to acrolein at 0.3 ppm stayed constant from

40 min to 60 min, the irritancy concentration should remain unchanged when extending the exposure from 1 h to 24 h. Therefore, theoretically, the 24-h SMAC could be set equal to the 1-h SMAC. However, to reduce the degree of mucosal irritation that the astronauts have to endure in a 24-h emergency, the 24-h SMAC is derived by dividing the 1-h SMAC by two. The factor of two is selected because Weber-Tschopp et al. (1977) demonstrated that, when the concentration of acrolein in a 1.5-min exposure was lowered twofold (from 0.6 ppm to 0.3 ppm), the severity of the eye irritation was reduced from slight irritation to only a little bit of discomfort. As a result, dividing the mildly irritating 1-h SMAC by two should yield a concentration that will cause only a little eye discomfort.

24-h SMAC based on eye irritation

= 1-h slightly irritating concentration x 1/extrapolation factor

= 75 ppb x 1/2

= 35 ppb.

If the irritancy of acrolein at 24 h is likely to be the same as that at 1 h, it stands to reason that the irritancy would not worsen when exposure is extended to 180 d. That is because mucosal irritation is a surface phenomenon and is generally not considered to be exposure-duration-dependent after the initial exposure period. Acute eye-irritation effects of exposure to acrolein in humans (Sim and Pattle, 1957) and subchronic depressive effects on body-weight gain in mice (Northrop, 1985) are more dependent on the exposure concentration than on the exposure duration (Northrop, 1985). Moreover, in dogs exposed repetitively or continuously to acrolein, the signs of mucosal irritation were found to diminish after the first week, indicating the development of reduced susceptibility as acrolein exposure is lengthened (Lyon et al., 1970). Therefore, long-term SMACs could be established by basing an estimate for a nonirritating concentration of acrolein on data of 1-h exposures.

As discussed above, a 1-h exposure at 75 ppb is expected to be only slightly irritating to the eye. To estimate a 1-h exposure concentration

that is nonirritating to the eye, an extrapolation factor of 4 is applied on 75 ppb. This factor of 4 was derived from the data of Weber-Tschopp et al. (1977), who showed that, in a 1.5-min exposure of human subjects to acrolein, 0.60 ppm produced a slight eye irritation, 0.30 ppm caused a little eye discomfort, and 0.15 ppm resulted in no adverse effects on the eye (going from 0.60 ppm to 0.15 ppm is a factor of 2 x 2, or 4). With a lack of data, the concentration-response relationship of acrolein exposure and mucosal irritation in a 1-h exposure is assumed to be the same as that in a 1.5-min exposure. An additional safety factor of 10/(square root of n) is applied for the potential differences among individuals in a human population.

7-d, 30-d, and 180-d SMACs based on eye irritation

= 1-h slightly irritating concentration x 1/extrapolation factor x 1/small n factor

= 75 ppb x 1/4 x (square root of n)/10

= 75 ppb x 1/4 x (square root of 53)/10

= 15 ppb.

Consequently, the 1-h, 24-h, 7-d, 30-d, and 180-d SMACs are set at 75, 35, 15, 15, and 15 ppb, respectively, to prevent mucosal irritation. Because mucosal irritation is not expected to be significantly influenced by physiological changes caused by microgravity, the SMAC values are not adjusted for any microgravity-induced physiological changes.

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