Revisions to Spacecraft Maximum Allowable Concentrations for Acetaldehyde

Acetaldehyde is a volatile liquid with an odor that is fruity at low concentrations (with an odor threshold of 0.05 ppm) and becomes more pungent as concentrations increase. It is used as a chemical intermediate in the production of pesticides, pharmaceuticals, fragrances, flavors, and plastics. It is also produced naturally as a by-product of fermentation and combustion.¹ Acetaldehyde is frequently detected on the International Space Station at levels as high as 1 ppm (1.8 mg · m⁻³). Historically, the concentration has averaged on the order of 0.1 ppm (0.2 mg · m⁻³), but lower levels have been observed over the last several years. NASA uses Spaceflight Maximum Allowable Concentrations (SMACs) as environmental safety guideline values for crew exposures during spaceflight. The previous SMACs for acetaldehyde were set in 1994.² For durations of 1 h and 24 h during an off-nominal event, such as an unexpected hardware leak, concentrations of 12.5 ppm and 5 ppm, respectively, were deemed acceptable, as these levels were unlikely to cause more than minor, reversible effects over that period. Longer-term SMACs (7-d, 30-d, 180-d) were set at 2 ppm, which is not expected to cause any symptoms. A SMAC for 1000-d was not set.

METHODS

A comprehensive search of the peer-reviewed literature was conducted using principles of systematic review to identify toxicological data on acetaldehyde published since 1994. This search was supplemented by the review and assimilation of summary sources that describe the development of other safety values [i.e., U.S. Environmental Protection Agency’s (EPA’s) interim Acute Emergency Guideline Levels (AEGLs) and Integrated Risk Information System (IRIS) assessment, occupational limits, etc.].

RESULTS

The systemic toxicity of acetaldehyde is understood best as a metabolite of ethanol.^1,3,4 Ingested ethanol is metabolized to acetaldehyde, which is then converted to acetate (acetic acid) by aldehyde dehydrogenase (ALDH), which is then further metabolized to acetyl CoA by acetyl coenzyme A synthetase.⁵ A genetic polymorphism of ALDH2 creates a well-characterized sensitivity to acetaldehyde; humans with this polymorphism may experience flushing, tachycardia, headache, nausea, and other effects after consuming even small amounts of alcohol. This polymorphism is much more frequent among persons of Asian heritage, appearing in as much as 50% of the population.¹

Acetaldehyde is very volatile and highly reactive in the environment, and as such the most sensitive toxicological endpoint for acetaldehyde vapor is irritation of the eyes and upper respiratory tract followed by damage to olfactory epithelium.¹ These effects are likely mediated by a combination of general reactivity and mechanosensory effects, macromolecular cross-linking, and the increase in intracellular H+ (proton) levels as a result of ALDH-mediated detoxification of acetaldehyde.^5,6 At lower concentrations, effects are isolated to the upper respiratory areas, but as concentrations rise, effects will begin to occur deeper in the respiratory tract (including bronchiolitis obliterans and bronchoconstriction secondary to the release of histamine).³ This threshold may be attributable to the capacity of ALDH to detoxify acetaldehyde, which can be saturated in laboratory animals at concentrations somewhere between 100–1000 ppm.⁷ The relationship between the irritation effects and the effects on olfactory epithelium is unclear, but it is possible that irritation is a function of H + generation (generated by ALDH), while degeneration of olfactory epithelium is more a function of macromolecular binding by acetaldehyde as ALDH activity is saturated under higher doses.^5–7 A PBPK model for acetaldehyde indicates that the susceptible phenotype should not affect the local/irritation responses that arise after exposure to lower concentrations of acetaldehyde.⁵ Interestingly, the model seems to predict that rats are more sensitive to the effects of acetaldehyde than humans, as the human equivalent concentration (HEC) of 50 ppm in rats is 67 ppm in humans. This, however, is contradicted by the analysis described in Dorman et al.⁶ in which 50 ppm exposures in rats is projected to have an HEC of 12.5 ppm (using the same PBPK model).

In a study conducted by Silverman et al.,⁸ groups of 12 volunteers (both male and female, but numbers not specified) were exposed to acetaldehyde vapor for 15 min at nominal concentrations of 25, 50, and 200 ppm. Several volunteers “strenuously objected” to the vapor at 25 ppm due to eye irritation, and the majority developed eye irritation at 50 ppm (though exposure concentrations were not analytically confirmed). Subjects reported nose or throat irritation at 200 ppm, and some experienced erythematous eyelids and bloodshot eyes at that concentration. However, a majority of the subjects declared that they would be willing to work an 8-h shift at 200 ppm acetaldehyde.

In a separate study, 14 healthy male volunteers were exposed to a series of irritating components of smog, including acetaldehyde.⁹ The volunteers did not report eye irritation at 134 ppm acetaldehyde after 30 min, though it was reported after exposure to other aldehydes. Mild respiratory tract irritation was reported, however.

Muttray et al.¹⁰ exposed 20 healthy male volunteers (age 20–35) to 50 ppm acetaldehyde for 4 h. The subjects were monitored for numerous clinical parameters and asked to provide subjective levels of irritation via questionnaire. On a scale of 0–5, the median score for subjective symptoms of irritation was 0. The study also did not detect any changes in expression of inflammatory markers or physiological functions of the upper respiratory tract.

Cassee et al. examined the irritation effects of three aldehydes (formaldehyde, acrolein, and acetaldehyde) individually and as mixtures.^11,12 Male Wistar rats were exposed to these aldehydes for 30 min to establish an irritation potency via decreases in breathing frequency,¹¹ and for 1 or 3 d to determine the effects on nasal epithelium.¹² Formaldehyde and acrolein were determined to be approximately 300 times more potent as irritants,¹¹ as measured by RD50 (i.e., 50% reduction in breathing frequency). Acetaldehyde caused minimal changes in nasal epithelium after up to 1500 ppm and 18 h of cumulative exposure; there is some dispute as to whether the effects were more significant after 18 h vs. 6 h. The authors note that the toxicological relevance of the observed effects at 18 h is “somewhat doubtful,” as similar effects are observed in control animals.¹² When developing their interim AEGL-2 (acute emergency guideline level above which health effects are expected to occur in the general population), the EPA judged that these findings indicated that olfactory degradation is duration-dependent and not solely concentration-dependent. As a result, the AEGL-2 values were time-scaled from 6 h, with 1500 ppm as the point of departure.¹

To determine the toxicological importance of the ADLH2 polymorphism, Oyama et al.¹³ exposed wild-type and ALDH2 knockout mice to 125 and 500 ppm acetaldehyde for 14 d (24 h · d⁻¹). As expected, the ALDH2 knockout mice exhibited increased sensitivity to acetaldehyde exposure, with more frequent and more severe damage to the respiratory tract at both dose levels. This study served as the basis for the 24-h Emergency Exposure Guideline Level (EEGL) set by the U.S. Navy [125 ppm as the point of departure, including two uncertainty factors of 3 to account for extrapolation from LOAEL to NOAEL (lowest and no observed adverse effects level) and from mice to humans; final value 12.5 ppm].³

In a subacute study (6 h · d⁻¹, 5 d · wk⁻¹, 4 wk), groups of 20 rats were exposed to 401, 941, 2217, or 4975 ppm acetaldehyde.⁴ Growth retardation was noted in the 941 ppm exposure group and above, as well as histopathological changes in the nose. Tracheal and lung lesions were observed in the two highest exposure groups. A follow-up study used concentrations of 110, 150, or 500 ppm for 4 wk, with damage to olfactory epithelium noted at the 500 ppm dose level.⁴ In a similar study, rats exposed to 243 ppm for 5 wk (8 h · d⁻¹, 5 d · wk⁻¹) showed inflammatory reaction in the nasal cavity and perturbations of the olfactory epithelium.¹⁴ A NOAEL of 390 ppm was identified in a 90-d study in hamsters exposed to 390, 1340, and 4560 ppm (390 h of cumulative exposure),¹⁵ with similar findings of growth retardation, ocular and nasal irritation, and damage to nasal epithelium.

In rats exposed for up to 65 d (6 h · d⁻¹, 5 d · wk⁻¹) to concentrations up to 1500 ppm, no effects were seen on weight gain and there were no other signs of systemic toxicity.⁶ However, the study did observe inflammation, growth perturbations in respiratory epithelium, and loss of olfactory neurons at concentrations greater than 150 ppm, with an identified NOAEL of 50 ppm.

Woutersen et al.¹⁶ exposed rats for 28 mo (6 h · d⁻¹, 5 d · wk⁻¹) to acetaldehyde at 750, 1500, or 3000 ppm. Growth retardation and degeneration of the olfactory nasal epithelium was observed, along with nasal carcinomas and adenocarcinomas. The EPA has designated acetaldehyde as a probable human carcinogen, with sufficient evidence in animals based on this study and others.⁴ The International Agency for Research on Cancer (IARC) concluded that acetaldehyde contributed to esophageal cancers observed in humans who were deficient in ALDH2, and its likely mode of genotoxicity is via sister chromatid exchange and/or the formation of stable DNA-protein crosslinks.²

Most safety values for acetaldehyde were developed before the 1994 SMAC was established (Table I). The EPA developed a reference concentration (RfC) using the Appleman et al. studies in rats.⁴ This value included an overall uncertainty factor of 1000 to account for inter- and intraspecies differences, as well as extrapolation from subchronic data to a chronic application.⁴ The EPA classifies acetaldehyde as a probable human carcinogen (B2) and developed an inhalation unit risk of 2.2 × 10⁻⁶ per ug · m⁻³. As a result of this designation, the U.S. National Institute of Occupational Safety and Health (NIOSH) requires that concentrations of acetaldehyde be kept to the lowest feasible concentration (LFC). In 1968, the U.S. Occupational Safety and Health Administration (OSHA) promulgated a Permissible Exposure Limit (PEL) of 200 ppm (360 mg · m⁻³). A revised PEL of 100 ppm with a Short-Term Exposure Limit (STEL) of 150 ppm was proposed in 1989 but was never adopted. The American Conference of Government Industrial Hygienists’ (ACGIH’s) Threshold Limit Value (TLV) is currently set at 25 ppm (45 mg · m⁻³).

Table I. Terrestrial Safety Values for Acetaldehyde.

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DISCUSSION

The prior 1-h SMAC for acetaldehyde was set in 1994 based on the study in human volunteers conducted by Silverman et al.^2,8 To account for the sensitive individuals and duration of exposure, the 1-h SMAC (10 ppm) was based on the LOAEL of 25 ppm reduced by half to reduce the level of overall irritation expected. For the 24-h SMAC (6 ppm), the LOAEL of 25 ppm was divided by an additional factor of 2 for the uncertainty of extrapolating a 15-min exposure value to 24 h. The longer-duration SMACs (7-d, 30-d, and 180-d) were further adjusted by a factor to account for the small number of volunteers, yielding a final value of 2 ppm. A change in the irritancy potential of this level was not expected to change over any of these durations.² This study was disregarded by the EPA when setting their AEGLs, as the concentrations were not confirmed analytically and because of a lack of detail regarding protocol and results.¹

The key study for setting the current 1-h SMAC is Sim and Pattle,⁹ the highest NOAEL in humans (Table II). After a 30-min exposure to 134 ppm, the volunteers reported no eye irritation and only mild respiratory tract irritation. As noted in the interim AEGL, this study is superior to that of Silverman et al.⁸ as the exposure concentration was measured analytically and the exposure methods were better described.¹ Though the exposure duration was only 30 min, extrapolation to an hour is appropriate as respiratory irritation would be driven more by the concentration than by the duration in this scenario (AEGL). Despite its limitations, Silverman et al.⁸ does mention that the majority of volunteers in their study felt they would be able to work an 8-h shift at a nominal concentration of 200 ppm, higher than the proposed 1-h SMAC. This is consistent with the paradigm for short-term SMACs for off-nominal situations, in which minor, reversible symptoms are considered acceptable as the crew responds to the event.

Table II. Spaceflight Maximum Allowable Concentrations for Acetaldehyde.

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In considering a SMAC for 24-h, it is possible that 134 ppm remains appropriate for this duration. However, given a lack of data in human subjects for this duration, the 24-h SMAC is predicated on Muttray et al.,¹⁰ in which human volunteers reported no irritation after 4 h of exposure to 50 ppm acetaldehyde. In the same study, no detectable changes in molecular markers for inflammation were observed. A duration adjustment is not considered necessary, as irritation effects would not be expected to vary greatly at this level between 4–24 h of exposure. This approach is similar to that taken by EPA in developing their interim AEGL-1 values, which they set at 45 ppm at durations from 10 min to 8 h, and which are considered protective of sensitive subpopulations after division of the NOAEL from Sim and Pattle (134 ppm)⁹ by 3 to address variability among humans.¹

Because there are no subchronic human exposure studies, the proposed 7-d SMAC of 12.5 ppm is predicated on the findings of Dorman et al.⁶ (Table II). Rats exposed to 50 ppm for up to 65 d (approximately 390 cumulative hours of exposure) displayed no olfactory degeneration, the most sensitive endpoint in the study.^5,6 Relatively minor effects were observed at 150 ppm. The authors estimated that an HEC of 12.5 ppm under continuous exposures would achieve the local concentrations corresponding to a NOAEL in rats (though Teeguarden et al.,⁵ using the same model, suggested that the HEC would be 67 ppm). Dorman et al.⁶ applied an aggregate uncertainty factor of 30 (presumably 3 for toxicodynamic differences between rats and humans and 10 for differences in sensitivity among human receptors) in proposing a reference concentration (RfC) of 0.42 ppm. This additional uncertainty factor for interspecies variation is deemed not necessary for the astronaut population. The work of Oyama et al.¹³ demonstrates that a deficiency in ALDH2 could lead to slightly increased rates and severity of damage at 500 ppm in mice. The difference at 125 ppm is markedly less clear, and the proposed 7-d SMAC is 10-fold lower than that concentration. Further, it appears that mice have a significantly lower baseline capability to metabolize acetaldehyde compared with hamsters, rats, or guinea pigs.⁷

In considering the longer-term SMACs, no studies provide insight into safe levels of exposure beyond 390 h. The only chronic studies available used high concentrations (>750 ppm) as their lowest dose level, and significant increases in hyperplasia/neoplasia were observed in rats (750 ppm) and hamsters (1650 ppm),^4,16 but not observed in hamsters at 1500 ppm.⁴ No increases in DNA-protein crosslinking were observed in rats at 50 ppm after 65 d of exposure.⁶ This is consistent with the observation that detoxification capacity of ALDH is not saturated at this level.⁷ No data is available to characterize the prevalence of ALDH2 polymorphisms in the astronaut community. Thus, the possibility of an ALDH2 polymorphism among Asian astronauts (i.e., from the Japanese Space Agency, JAXA) cannot be discounted. As such, an uncertainty factor of 3 is applied to the NOAEL_HEC provided in Dorman et al.⁶ for longer durations. This establishes a SMAC of 4 ppm for 30, 180, and 1000 d. The NOAEL_HEC developed in Dorman et al.⁶ was developed by averaging the tissue concentration over time, in effect correcting for continuous, longer-term exposures. The authors used this HEC to propose an RfC for the general population (with uncertainty factors appropriate to that population, indicating that they viewed further extrapolation for time-dependent effects to be unnecessary). This proposed set of SMAC values is expected to produce no symptoms and no increased risk of carcinogenesis, even with continuous exposure out to 1000 d.