Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 (2000)

John T. James, Ph.D.

Johnson Space Center Toxicology Group

Medical Operations Branch

Houston, Texas

The chemical and physical properties for C3 to C8, straight-chain, aliphatic aldehydes are shown in Table 2-1. Formaldehyde and acetaldehyde have been previously reviewed, and spacecraft maximum allowable concentrations (SMACs) have been set for those compounds (Wong 1994a,b).

The major use of saturated aldehydes of higher molecular weight than acetaldehyde is in flavorings, perfumes, and essential oils (Brabec 1993). Many saturated aldehydes also occur naturally in foods. Propanal and butanal are industrially important intermediates with U.S. production of 280 and 3000 million pounds, respectively (Brabec 1993). These aldehydes can enter spacecraft air by incomplete oxidation of alcohols in the air revitalization system, by human metabolism, by materials off-gassing, and during food preparation. The higher-molecular-weight aldehydes have not been seen often on the shuttle; however, each aldehyde (C3-C8) was present in air samples from Mir 18 (March to June 1995) at concentrations typically near or below 0.1 mg/m³ (J.T. James, Johnson Space Center, Houston, Tex., unpublished data, 1995).

No specific data were found on the absorption of C3-C8 aldehyde vapors in the respiratory tract. Based on data from acetaldehyde exposures in humans, the aliphatic saturated aldehydes should be well adsorbed in the respiratory tract at concentrations of 100 ppm or less (Egle 1970).

No specific data were found on the distribution of C3-C8 aliphatic saturated aldehydes absorbed from the respiratory tract.

No specific data were found on the excretion of C3-C8 aliphatic saturated aldehydes from living systems.

There are limited specific data on the metabolism of aliphatic saturated aldehydes with three or more carbon atoms. In principle, these aldehydes can be oxidized to their respective acids by aldehyde dehydrogenase (ALDH), alde-

hyde oxidase, and xanthine oxidase, or they can be reduced to alcohols by aldehyde reductases (McMahon 1982; Brabec 1993). The major route of oxidation is via ALDH (E.C.1.2.1.3), which is a soluble NAD⁺-dependent enzyme found in liver and many other tissues. Purified human-liver ALDH has been shown to facilitate the oxidation of propanal, butanal, and pentanal at relative rates that range from 0.81 to 1.1 when tested at substrate concentrations ranging from 0.05 to 3.0 mM (Blair and Bodley 1969). The rates for these three aldehydes were indexed to a value of 1.0 for acetaldehyde at 3.0 mM; hence, the rate of oxidation of the larger aldehydes is comparable to acetaldehyde.

In addition to ALDH, certain other enzymes might play a role in aldehyde metabolism. Reduction of aldehydes by aldehyde reductases might be a minor pathway in vivo (McMahon 1982). Cytochrome P-450 might also play a minor role in oxidation of aldehydes to carboxylic acids (Parkinson 1996); however, for certain C₅ branched aldehydes, olefinic products and formic acid are produced in reactions catalyzed by any one of five isozymes of cytochrome P-450 from rabbit liver or nasal mucosa (Roberts et al. 1991). Acetaldehyde is a substrate for ethanol-inducible cytochrome P-450 (CYP2E1) (Terelius et al., 1991). In a series of papers, Watanabe et al. (1990, 1992, 1995) showed that microsomal aldehyde oxygenase (CYP2C29) catalyzes the oxidation of tolualdehydes, other substituted cyclic aldehydes, and alpha or beta unsaturated aldehydes. In the 1992 study, saturated aldehydes (C8 to C11) were not readily oxidized by this form of cytochrome P-450.

Hepatic enzymes associated with peroxisomes (catalase and carnitine acetyltransferase) and the number of peroxisomes were induced in F344 rats fed either 2-ethylhexyl aldehyde or hexanal as 2% of their diet for 3 w (Moody and Reddy 1978). The branched aldehyde was a more effective inducer than the straight-chain aldehyde.

The toxicity data base on aliphatic saturated aldehydes was extensive; however, there are important deficiencies, especially in terms of the effects of acute exposures on humans, the sublethal effects of short-term exposures on animals, and the effects of chronic exposure in animals and humans.

The inhalation toxicity data base consists mostly of acute and short-term exposures of animals to various aldehydes. The sensory irritation properties

have been studied in rodents for many of the aliphatic saturated aldehydes, as shown in Table 2-2 (Steinhagen and Barrow 1984; Babiuk et al. 1985).

The RD₅₀ data show that sensory irritation properties within this group of aldehydes are roughly comparable, but there is no clear trend of decreased irritancy with increasing molecular weight or chain branching. Human irritation studies have been reported for the first four aldehydes listed in Table 2-2. Acetaldehyde was slightly irritating at 134 ppm in 14 test subjects exposed for 30 min (Sim and Pattle 1957). Irritancy data on three additional aldehydes are given in Table 2-3; however, the original report gave a confusing result on propanal. In their table 2, this aldehyde was listed as tested for 30 min on four subjects and found to be a nonirritant; however, in the text of the original

report, propanal was described as tested for 30 min on 12 subjects and found to be ''mildly irritating to the mucosal surfaces" (Sim and Pattle 1957). In addition, there is confusion on the duration of exposures to butanal, because the table lists the exposure time as 10 min and the text gives the exposure as 30 min. We chose to use the data reported in the text of Sim and Pattle (1957) in Table 2-3. Data on other effects of aldehyde exposures are also given in the table.

There is limited evidence in animals that C3-C8 aldehydes might affect the liver. Liver-cell vacuolization was noted in rats exposed six times for 6 h to propanal at 1300 ppm; however, 12 exposures for 6 h to either butanal or isobutanal at 1000 ppm did not cause liver-cell vacuolization (Gage 1970). Hypolipidemia was induced in male F344 rats given 2-ethylhexyl aldehyde or hexanal as 2% of their diet for 3 w (Moody and Reddy 1982). Serum cholesterol decreased 20% and 10%, respectively after the two aldehydes were administered. Serum triglycerides decreased 60% after administration of either of the aldehydes. Because hepatic peroxisome proliferators (e.g., 2-ethyl hexyl aldehyde and hexanal) are often promoting agents and can induce hepatic neoplasms in rodents after long-term administration at high doses (Reddy and Lalwani 1983), there is some concern that aldehydes could pose a liver-cancer risk. Peroxisome proliferators have not been shown to cause cancer in humans.

There is one report of an accidental exposure of seven chemists to "2-methylbutanal" in a chemical laboratory (Wilkinson 1940). Based on structures given in the report, the compound involved in the exposures was actually 3-methylbutanal (isovaleraldehyde). The victims experienced tightness of the chest, cough, and marked weakness. Some reported dizziness, headaches, and nausea. All recovered within a few days without special treatment. The duration and concentration of the exposures were unknown.

Originally, the only study that could be placed in this category is that of Gage (1970) in which four male and four female rats were exposed 20 times to propanal at 90 ppm for 6 h. The experimental design called for observation of clinical signs, urine chemistry tests at the end of exposures, hematology, gross pathology, and histopathology of the lungs, liver, kidney, spleen, adrenals, and occasionally the heart, jejunum, ileum, and thymus. No toxic signs were detected, the organs examined at autopsy were normal, and presumably the remainder of the end points were negative. Brabec (1993) commented without citing specific references that "in general, the aldehydes are remarkably free of actions that lead to definite cumulative organ damage to tissues other than those that may be associated with primary irritation or sensitization. However, the

questions of mutagenicity, carcinogenicity, and teratology hang over . . . [the] aldehydes."

A recent 13-w study of the effects of isobutanal vapor inhaled by rodents has added significantly to the subchronic toxicity data base. In preparation for a 2-y study, groups of 10 male and female F344 rats and B6C3F₁ mice were exposed to isobutanal at 500, 1000, 2000, 4000, and 8000 ppm, 6 h/d, 5 d/w, for 13 w (Abdo et al. 1998). Depressed weight gains and death were observed at concentrations of 4000 and 8000 ppm. Chemically related lesions were confined to the upper respiratory system of the rodents and consisted of inflammation, olfactory epithelial degeneration, epithelial hyperplasia, squamous metaplasia, and osteodystrophy. Effects on the trachea and larynx were noted only in the highest-concentration group of rats. In general, mice seemed to be more susceptible than rats to the formation of nasal lesions.

Although formaldehyde and acetaldehyde have been found to be carcinogenic to the rodent nasal mucosa, the only substantive test for carcinogenic potential in a larger aldehyde (isobutanal) was negative (Abdo et al. 1998). One reason for doing the cancer bioassay was that some larger saturated aldehydes induce hepatic peroxisome proliferation and could present a cancer risk at high doses administered for prolonged periods. A 2-y bioassay of isobutanal in rats and mice exposed at 500, 1000, and 2000 ppm for 6 h/d, 5 d/w showed only non-neoplastic lesions in the nasal cavities of both species (Abdo et al. 1998). The authors attribute the lack of carcinogenicity of the larger aldehyde to the metabolic decomposition of isobutanal to propylene and formic acid, neither of which seem to be carcinogenic.

There is a report that attempts to associate worker exposure to various aldehydes with a possible increase in cancer incidence (Bittersohl 1975). Approximately 150 workers with >20 y experience participated in the study. They were exposed to concentrations giving a strong and sometimes irritating odor. In one sampling period, butanal concentrations were among the highest of the measured components at 5-70 mg/m³, but concomitant exposures to other aldehydes, acetaldol, and alcohols took place. Despite the finding of nine malignant neoplasms in a 5-y period among the workers, there were no matched controls, so the findings must remain inconclusive.

There is a single report that propanal and heptanal were weakly mutagenic to Drosophila (Rapoport 1948, as cited in Auerbach et al. 1977).

No data were found on the developmental toxicity of the aliphatic saturated aldehydes with three or more carbons.

One report suggests that a single intraperitoneal injection of butanal (30 mg/kg) into Q-strain mice interferes with spermatogenesis (Moutschen-Dahmen et al. 1976). Injections resulted in degeneration of spermatogenic cells, polyploidy, and an increased frequency of acrosomeless spermatozoa in the ductus deferens.

No data were found to suggest that aliphatic saturated aldehydes interact with other compounds to modify toxic effects.

Table 2-4 presents exposure limits for aliphatic saturated aldehydes set by other organizations and Table 2-5 presents the SMACs established by NASA.

Group SMACs for aliphatic saturated aldehydes depended on the completeness of the toxicity data base and whether the compounds exhibit similar toxicities. The toxicity of aldehydes has been reviewed previously by the National Research Council (NRC 1981). The toxicity data base is limited in many important respects; however, the toxicities of the C3-C8 aliphatic saturated aldehydes appear to be similar. Acceptable concentrations (ACs) for this group (Table 2-7) were set by selecting the AC for the most active compound for a given toxic effect. Where applicable, the guidelines from the Committee on Toxicology were used to set ACs (NRC 1992). The toxic effects that were considered include the following: mucosal irritation, nasal cavity injury, nausea and vomiting, and possible liver damage. This group of aldehydes appears to be much less toxic than unsaturated aldehydes or those with other functional groups, such as halogens or hydroxyl moieties.

Human irritancy data were available for three of the aldehydes in the series (Sim and Pattle 1957). Propanal was mildly irritating at 134 ppm, whereas butanal and isobutanal were not irritating at 230 and 207 ppm, respectively. The ACs for short-term exposure permit a risk of mild irritation; however, the mouse data (Table 2-2) suggest that some aliphatic aldehydes might be 2-3 times more irritating than propanal. Therefore, the short-term ACs for mucosal irritation were set at 50 ppm. For long-duration exposures (more than 24 h), even mild mucosal irritation would not be allowed. Because no concentration-response data were available, the no-observed-adverse-effect level (NOAEL) for irritation was estimated by the default approach of dividing the mildly irritating value of 134 ppm by 10. Hence, the AC (7 d, 30 d, and 180 d) was set at

134 ppm ÷ 10 = 13 ppm.

Another approach to the question of irritation is to directly apply the extensive rodent RD₅₀ data shown in Table 2-2. Except for two branched aldehydes, the RD₅₀'s were above 1000 ppm. A NOAEL for mucosal irritation in humans can be estimated from the 1000-ppm RD₅₀ by applying a factor of 10 to reach a rodent NOAEL and another factor of 10 for possible species differences. This conservative approach suggests that 10 ppm would be safely below concentrations that could induce irritation in humans even after prolonged exposure. It is also reasonably consistent with 13 ppm estimated above from the human data.

The 13-w and 2-y studies recently reported by Abdo et al. (1998) showed that the nasal cavities of both rats and mice are the target of isobutanal vapor. In the 13-w subchronic-toxicity study (cumulative exposure, 390 h), the NOAEL for the nasal-cavity effects in both species was 500 ppm. That value can be used to estimate an AC as follows:

7-d AC = 500 ppm × 1/10 (species) = 50 ppm.

(no time extrapolation needed)

30-d AC = 500 ppm × 1/10 (species) × 390 h/720 h = 27 ppm.

From the 2-y study (cumulative exposure, 3120 h), the 180-d AC was estimated

from the lowest-observed-adverse-effect level (LOAEL) of 500 ppm in female rats (500 ppm was a NOAEL in other sexes and species tested) as follows:

180-d AC = 500 ppm × 1/3 (LOAEL to NOAEL) × 1/10 (species) × 3120 h/4320 h = 12 ppm.

The LOAEL-to-NOAEL extrapolation factor of 3 was based on the steep dose response seen in the other species and sexes for nasal lesions (Table 2-6).

Liver-cell vacuolization was noted in rats exposed 6 times for 6 h to propanal at 1,300 ppm (Gage 1970). Liver-cell vacuolization itself is not an adverse effect; however, it suggests that prolonged exposure to aldehydes could lead to liver injury. To set ACs to prevent liver injury, it was noted that 20 exposures of 6-h durations (120 h total) to propanal at 90 ppm did not give detectable adverse effects in rats (Gage 1970). There are three possible ways to approach the problem of setting ACs for exposures that far exceed the 120-h duration of exposures in the data base. The approachs are as follows: (1) do not set an AC; (2) use the default approach, which calls for using Haber's rule; and (3) use metabolic arguments to support a threshold concentration below which no injury can occur. A combination of the last two approaches was used. The default approach was used to set the 7-d and 30-d ACs; however, the metabolic products of aldehyde metabolism (organic acids) would not be expected to accumulate or be harmful below a certain concentration. The 180-d AC was set

at the same value as the 30-d AC based on this expectation. The calculations were as follows:

7-d AC = 90 ppm × 1/10 (species) × 120/168 (time factor) = 6.4 ppm.

30- or 180-d AC = 90 ppm × 1/10 (species) × 120/720 (time factor) = 1.5 ppm.

A recent report on 2-y isobutanal exposures to rats and mice with no effects on the liver suggests that at least some of the large aldehydes cause no adverse effects on the liver (Abdo et al. 1998). In view of that recent report, the ACs to prevent potential liver injury based on hepatocyte vacuolization in rats by propanal are probably conservative.

There are major shortcomings in the toxicity data base. Short-term human exposures with measurement of various end points in addition to irritation, exposures to several of the aldehydes, and measurement at several concentrations would be useful. Additional long-term animal inhalation studies would be useful in defining whether any of these aldehydes can induce organ damage outside the respiratory system.

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