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1 Acrolein Shannon D. Langford, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas BACKGROUND Spacecraft maximum allowable concentrations (SMACs) for acrolein were documented in Volume 2 of Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants (Wong 1996). They were established for 1 and 24 h and for 7, 30, and 180 d. These time points were based on expected nomi- nal spacecraft mission timelines and potential exposure durations (nominal or emergency/contingency) of that era. Acrolein (2-propanal, molecular weight 56.06) is a volatile liquid with an extremely irritating vapor. As Wong (1996) pointed out, it is not a normal com- ponent used in the United States or International Partner spacecraft design or production, nor is it intentionally included in a spacecraft before launch. How- ever, this compound has been reported in off-gassing tests from Spacelab mis- sions (rates of 0.007 mg/d) (Geiger 1984). A limited number of studies pertaining to acrolein toxicity have been re- ported since the first SMACs were adopted for this compound. Key pertinent reports, including comprehensive examinations of acrolein toxicology by the U.S. Environmental Protection Agency (EPA) (EPA 2003) and the National Research Council (NRC) (NRC 2007) are examined. The information from re- ports since the initial release of acrolein SMACs is used here to confirm the ex- isting SMAC guidelines and to establish the new 1,000-d value. This report is intended as a companion document to complement and update the existing ac- rolein SMAC document. This document is organized as follows: â¢ The approach taken in developing existing acrolein SMACs is summa- rized, â¢ Recent data that may affect existing SMACs are examined and the 1,000-d acrolein SMAC is established, and 13
14 SMACs for Selected Airborne Contaminants â¢ A rationale for setting the 1,000-d acrolein SMAC and revising existing SMACs is provided. REVIEW OF EXISTING ACROLEIN SMACs NASA established the existing SMACs for acrolein in 1996 (Wong 1996). After the toxicologic information in the literature was assessed, one toxicologic end point was identified as being critical (mucosal irritation) and acceptable concentrations (ACs) were developed for this end point. Table 1-1 summarizes the SMACs established for acrolein using mucosal irritation as the toxicologic end point. SUMMARY OF ORIGINAL APPROACH USED TO SET SMACS Acrolein exposure produces mucosal irritation at concentrations lower than those that produce histopathologic changes in the respiratory tract (Lyon et al. 1970, Weber-Tschopp et al. 1977, Feron et al. 1978, Steinhagen and Barrow 1984). In addition, the eye is more susceptible than the nose to irritation pro- duced by acrolein (Weber-Tschopp et al. 1977). Therefore, both the 1- and 24-h SMACs were established based on minimizing irritation to the eye and nose and to preclude irreversible injury and significant crew performance decrements resulting from exposure. The 1-h acrolein SMAC was based on the report of Weber-Tschopp et al. (1977) describing moderate eye irritation in humans after 1 h of exposure to acrolein at 0.3 part per million (ppm) (0.68 milligram per cubic meter [mg/m3]). Further evidence from the studies of Weber-Tschopp et al. indicates no effect on the eyes after exposure to acrolein at 0.15 ppm (0.34 mg/m3) for 1.5 min. In ad- dition, Darley et al. (1960) reported decreased eye irritation at progressively lower acrolein exposure concentrations. They observed a reduction in reported eye irritancy (by half a grade, from moderate-to-severe to moderate) when ac- rolein concentration decreased by 35% to 40%. Weber-Tschopp et al. (1977) observed a reduction in reported eye irritation (from mildly irritating to no ef- fect) when the acrolein exposure concentration declined by a factor of 4 (from 0.6 to 0.15 ppm). Wong (1996) asserted that the sensitivity of the eyes and nose observed in humans toward irritation caused by acrolein depends on exposure concentration and duration. In longer exposures (1 h), irritation to the eyes prevails over irrita- tion to the nose, whereas short exposures show more irritation to the nose (expo- sures â¤ 0.3 ppm for 40-60 min) (Weber-Tschopp et al. 1977, Wong 1996). Addi- tionally, 1.5-min exposures to 0.6 ppm of acrolein caused similar irritation in the eyes and nose of human subjects, but 1.5-min exposures to 0.15 ppm of acrolein caused only slight nose irritation and no reported eye irritation (Weber-Tschopp et al. 1977). Wong (1996) proposed that acrolein exposure concentration is more influential than exposure duration in causing acute irritation in humans.
Acrolein 15 TABLE 1-1 SMACs for Acrolein, 1996 Duration ppm mg/m3 Toxic End Point to Avoid 1h 0.075 0.17 Mucosal irritation 24 h 0.035 0.08 Mucosal irritation 7d 0.015 0.034 Mucosal irritation 30 d 0.015 0.034 Mucosal irritation 180 d 0.015 0.034 Mucosal irritation Abbreviations: mg/m3, milligrams per cubic meter; ppm, part per million. As supporting evidence, a study by Sim and Pattle (1957) was cited, which reported that lacrimation was induced in 20 s in human subjects exposed to 0.8 ppm of acrolein but 1.2 ppm of acrolein caused the same response in 5 s. The report of Sim and Pattle (1957) suggests that irritation from acrolein in this study does not adhere to Haberâs rule. Wong (1996) applied a safety factor of 4 to the LOAEL observed by Weber-Tschopp, reasoning that a 4-fold reduction in acrolein concentration should provide a dose only mildly irritating to the eyes (an acceptable effect for short-term SMACs). Hence, the 1-h SMAC was established at 0.075 ppm (0.17 mg/m3), a con- centration expected to cause only mild eye irritation to spacecraft crew (Equa- tion 1). 1-h SMAC based on eye irritation 1-h AC(mucosal irritation) = 0.3 ppm (LOAEL) Ã 1/4 (safety factor) = 0.075 ppm (1) The 24-h acrolein SMAC was set at 0.035 ppm (0.08 mg/m3) (Equation 2). This value was established by further reducing the 1-h SMAC by a factor of 2. The rationale for this more stringent AC was based partly on the observations of Weber-Tschopp et al. (1977) showing a concomitant 2-fold lowering of reported eye irritation when exposure concentration decreased by half. Wong (1996) rea- soned that the 24-h acrolein SMAC could therefore be set at the same value as the 1-h SMAC but thought it was prudent to reduce the 24-h SMAC to lessen the degree of mucosal irritation that astronauts could experience. This factor was chosen based on data of Weber-Tschopp et al. (1977), leading Wong (1996) to surmise that reducing the mildly irritating 1-h SMAC by a factor of 2 would result in an acrolein AC that would cause only minimal eye irritation. Thus, the 24-h SMAC was set to decrease possible adverse effects to crew over a longer duration (24 h) resulting from exposure to acrolein (Equation 2). 24-h SMAC based on eye irritation 24-h AC(mucosal irritation) = 0.3 ppm (LOAEL) Ã 1/4 (safety factor) Ã 1/2 (safety factor) = 0.035 ppm (2)
16 SMACs for Selected Airborne Contaminants The acrolein SMACs for 7, 30, and 180 d (0.015 ppm, 0.034 mg/m3) were set based on extending the nonirritating 1-h acrolein SMAC adjusted for LOAEL to NOAEL extrapolation (factor of 4) and an additional safety factor of 10/ n for potential differences among individuals in a human population; ad- justment for small size of the study sample is applied to account for potential uncertainty relative to the results from a small number of study subjects (Equa- tion 3). The rationale for this AC estimate was predicated on the fact that muco- sal irritation is a surface-contact phenomenon that does not depend on exposure duration. The work of Lyon et al. was cited at the time as supportive of this ex- posure-duration independence. Specifically, these investigators reported dimin- ished evidence of mucosal irritation in dogs after 1 wk of continuous or repeated exposure to acrolein (Lyon et al. 1970). 7- , 30- , and 180-d SMACs based on eye irritation 7, 30, and 180-d AC(mucosal irritation) = 0.075 ppm (1-h AC) Ã 1/4 (LOAEL to NOAEL) Ã 53 / 100 (small n) = 0.015 ppm (3) SUMMARY OF NEW RELEVANT DATA FROM LITERATURE A review of recent scientific literature (1996 to present) regarding acrolein exposures suggests that mucosal irritation remains the toxicologic end point of concern for acute acrolein exposures (up to and including 30 d). Available hu- man studies, which were previously examined to establish the existing SMACs in 1996, are limited. These studies indicate that exposure to acrolein at concen- trations below 1 ppm can produce ocular and nasal irritation (moderate eye and nose irritation in humans after 1 h of exposure at 0.3 ppm) and can cause a de- crease in respiratory rate (approximately 25% decrease in respiratory rate in mice exposed for 10 min at 0.22 ppm) (Sim and Pattle 1957, Weber-Tschopp et al. 1977, Steinhagen and Barrow 1984). Most relevant studies pertaining to ac- rolein inhalation exposure were examined during initial SMAC development (Wong 1996). Some new data reporting reduced respiratory rate and alterations to the nasal epithelium of rats have become available since 1996. In work reported by Cassee et al. (1996), male Wistar rats, with five or six animals per exposure group, underwent nose-only exposure to acrolein or chemical mixtures including combinations of formaldehyde, acrolein, and acet- aldehyde. Animals were exposed to acrolein concentrations of 0, 0.25, 0.67, or 1.40 ppm for 6 h/d for three consecutive days. Slight histopathologic changes, including disarrangement and thickening of the respiratory epithelium, were reported at the lowest exposure concentration (0.25 ppm). Morris and co- workers exposed male and female C57Bl/6J mice to 0.3, 1.6, and 3.9 ppm of acrolein and measured changes in breathing frequency (Morris et al. 2003). C57Bl/6J mice without ovalbumin-induced allergic airway disease that were exposed to the lowest acrolein concentration of the study (0.3 ppm) demon- strated a 10% reduction in respiratory frequency compared with that observed
Acrolein 17 during preexposure baseline measurements (data reported as group mean Â± stan- dard deviation [SD] with three to six animals per group). The LOAEL reported in the Cassee et al. study (0.25 ppm) as well as the respiratory rate depression reported by Morris et al. at the lowest acrolein concentration tested (0.3 ppm) is complementary to the LOAEL of 0.3 ppm reported by Weber-Tschopp et al. in 1977 using human-derived data. The EPA completed a review of acrolein toxicity in 2003 in support of their information on the Integrated Risk Information System (EPA 2003). In this review, the EPA set an inhalation reference concentration (RfC) using the base study of Feron et al. (1978). The work of Feron et al. was also considered in setting the 1996 SMACs. A whole-body exposure system was used to expose sex- and weight-matched groups of hamsters, rats, and rabbits to 0, 0.4, 1.4, and 4.9 ppm of acrolein vapor for 6 h/d, 5 d/wk for 13 wk. The authors examined mortality, growth, food consumption, hematologic changes, blood chemistry, urinalyses, and organ weight and pathology in these animals. Of the species ex- amined, rats were the most sensitive to acrolein exposure, exhibiting slightly depressed growth and histopathologic changes of the nasal cavity at the lowest concentration (Feron et al. 1978). A LOAEL of 0.4 ppm (0.9 mg/m3) was de- rived from the data obtained in this study. The EPA considered three studies (Kutzman 1981, Kutzman et al. 1985, Costa et al. 1986) as supportive of the findings of Feron et al. (1978). The EPA modified the LOAEL reported by Feron et al. to obtain a LOAEL human equivalent concentration (LOAELHEC) of 0.02 mg/m3. Uncertainty factors totaling 1,000 were then applied to the LOAELHEC: 3 for animals to humans, 10 for intrahuman variability, 10 for ex- trapolation from subchronic to chronic effects, and 3 for extrapolation using a minimal LOAEL. Thus, the EPA set the RfC at 0.00001 ppm (2 Ã 10â5 mg/m3). The NRC, in conjunction with the U.S. Navy, proposed 1-h, 24-h, and 90- d exposure guidelines for acrolein in 2007 (NRC 2007). The NRC Committee on Toxicology recommended a 1- and 24-h emergency exposure guideline (EEGL) for submariners at 0.1 ppm (0.23 mg/m3) based on the work of Weber- Tschopp et al. The 90-d continuous exposure guidance level (CEGL) used as its basis the 90-d continuous exposure study of Lyon et al (1970), which found evi- dence of emphysema in dogs exposed to 0.22 ppm of acrolein for 24 h/d for 90 d. The NRC applied an interspecies uncertainty factor of 3 and a factor of 3 for extrapolation from a LOAEL to a NOAEL. This committee proposed a 90-d CEGL of 0.02 ppm (0.045 mg/m3). The Agency for Toxic Substances and Disease Registry (ATSDR) recently updated the toxicologic profile for acrolein, which has been submitted for public comment (ATSDR 2005). The ATSDR proposes both acute (â¤14 d) and inter- mediate (15 to 364 d) inhalation minimal risk levels (MRLs) for humans. The acute MRL of 0.003 ppm (0.007 mg/m3) was based on the LOAEL reported by Weber-Tschopp et al. (1977) (0.3 ppm for 60-min exposure resulting in irritation of nasal passages and throat and decreased respiratory rate). The ATSDR ap-
18 SMACs for Selected Airborne Contaminants plied uncertainty factors to account for extrapolation from a LOAEL (factor of 10) and for intrahuman variability (factor of 10). The ATSDR proposed an in- termediate MRL of 0.00004 ppm (0.00009 mg/m3). Uncertainty factors adjust- ing for using a LOAEL (factor of 10), for extrapolation from animals to humans (factor of 3), and to account for intrahuman variability (factor of 10) were ap- plied to a duration-adjusted, human equivalent LOAEL of 0.012 (derived from the LOAEL of 0.4 ppm reported by Feron et al. 1978). The ATSDR cited as the toxicologic end point was nasal epithelial metaplasia in rats, as reported by Feron et al. The ATSDR remarked that no human exposure data were available that could be used in setting their proposed intermediate MRL. Furthermore, the ATSDR found studies on chronic-duration exposure to acrolein inadequate for deriving a chronic MRL for this substance. Several studies (one originally reviewed by Wong  and others pub- lished in the intervening years) have examined the impact of acrolein exposure on antibacterial defenses of the lung. Jakab (1977) reported a significant in- crease in surviving bacteria (Staphylococcus aureus and Proteus mirabilis) in mice exposed to 1-2 ppm of acrolein for 24 h. A follow-on study demonstrated a significant increase in survival of S. aureus in mouse lungs after 8 h of exposure to acrolein at 3 ppm or greater (3, 6.2, 7.5, and 9 ppm) (Astry and Jakab 1983). Aranyi et al (1986) conducted a study in which mice exposed to 0.1 ppm of ac- rolein 3 h/d for 5 d showed a significant decrease in bacteriacidal activity (to Klebsiella pneumoniae). A more recent study by Jakab (1993) which used coex- posure of acrolein and carbon black showed less straightforward results with increased bacteriacidal activity toward P. mirabilis and decreased bacteriacidal activity toward Listeria monocytogenes. Bacteriacidal activity toward S. aureus at first decreased 1 d after acrolein exposure but returned to control concentra- tions 7 d postexposure (Jakab 1993). The effects reported by Jakab (1977, 1993), Astry and Jakab (1983), and Aranyi et al. (1986) may represent potential secondary effects of the direct irritation effects of acrolein. However, the sig- nificance of altered bacteriacidal activity was not clear to the U.S. Navy and the ATSDR (NRC 2007, ATSDR 2005) or was categorized as âother effectsâ by the EPA (EPA 2003). Although these groups acknowledge pulmonary defense ef- fects due to acrolein exposure, they do not apply a correction factor to account for these possible effects in deriving their respective acrolein ACs. The uncer- tainty on the part of the Navy, the ATSDR, the EPA, and NASA about the rele- vance or significance of the bacterial killing and clearance data leads us to choose not to modify our AC derivation based on these findings. Furthermore, protection against irritation, for which the ACs derived in the current review are set, presumably would address issues of altered bacteriacidal activity as well, specifically for longer-term exposures. The longer-term ACs presented here are well below concentrations associated with bacteriacidal effects in the litera- ture and therefore should address effects on the defense mechanisms of the lungs as well.
Acrolein 19 ADDITIONAL CONSIDERATION OF NONTOXIC ODOR THRESHOLD The possibility of detrimental effects (nontoxic) on job performance caused by aversion to noxious chemical smells such as that exhibited by acrolein should be considered. Acrolein has a noxious, choking odor with a reported odor threshold of 0.16 ppm (0.4 mg/m3) (Amoore and Hautala 1983). This odor thresholds is about 10 to 20 times higher than the 7-, 30-, 180-, and 1,000-d ac- rolein SMACs proposed in this review and about 2 times higher than the short- term 1-h SMAC. Thus, it is assumed that the lower SMACs (designed to protect against adverse health effects) will prevent spacecraft crew discomfort due to noxious odor. A footnote will be included with the revised acrolein SMAC table describing the concentrations at which the odor of the compound may become a concern. RATIONALE FOR 1,000-DAY SMAC AND REVISION OF 180-DAY SMAC The existing 7-, 30-, and 180-d acrolein SMACs (0.015 ppm, 0.034 mg/m3) used a departure concentration of 0.3 ppm (Weber-Tschopp et al. 1977, Wong 1996) modified by a safety factor of 4 (for extrapolation from a LOAEL to NOAEL) and an additional safety factor of 10/ n . The additional safety fac- tor was applied to adjust for uncertainties resulting from a study with fewer than 100 subjects (Wong 1996). Examination of relevant data pertaining to the poten- tial for chronic acrolein exposure to produce pathologic changes to the lungs warrants reevaluation of the long-term 180-d SMAC. The original rationale for adopting the same SMAC for 30- and 180-d ex- posures was based on data that indicated the toxic end point of mucosal irritation did not appear to depend on exposure duration. When the 180-d acrolein SMAC was established, the work of Lyon et al. was cited as supportive of this expo- sure-duration independence. They reported diminished signs of respiratory tract irritation (difficulty breathing and nasal discharge) in dogs after 1 wk of con- tinuous (1.0 Â± 0.2 ppm for 24 h/d, 90 d) or repeated (discontinuous at 3.7 Â± 0.8 ppm for 8 h/d, 5 d/wk for six consecutive weeks) acrolein exposure, suggesting reduced sensitivity to acrolein with increasing exposure duration (Lyon et al. 1970). However, these authors also reported evidence of emphysematous pul- monary changes in laboratory dogs who were continuously exposed for 90 d as well as acute congestion and vacuolization of bronchial epithelial cells, trou- bling pathologic findings. The authors characterized the pathologic findings reported in the 90-d continuous acrolein (1.0 Â± 0.2 ppm) exposures as âmoder- ateâ (Lyon et al. 1970). The Navy recognized the applicability and appropriateness of the 90-d continuous exposure study and considered the findings of emphysematous pul- monary changes in laboratory dogs as key in setting their LOAEL at 0.22 ppm
20 SMACs for Selected Airborne Contaminants (point of departure for the Navyâs 90-d CEGL, NRC 2007). The study of Lyon et al. has significant limitations that preclude it from being used as the basis for setting long-term exposure guidelines. Most notable among these limitations are the small number of animals per exposure group as well as the lack of reported controls, which complicates interpretation of the findings. Emphysematous changes occurred in the lungs of two dogs exposed to 0.22 ppm of acrolein but not in the lungs of dogs exposed to higher concentrations. However, in consid- eration of the emphysematous changes reported by Lyon et al., we propose that the existing 180-d acrolein SMAC be set lower. Using a LOAEL of 0.4 ppm (Feron et al. 1978) as a point of departure, we propose a revised 180-d acrolein SMAC of 0.008 ppm (0.0183 mg/m3). Expo- sure times used by Feron et al. were discontinuous with animals exposed 6 h/d, 5 d/wk for 13 wk (91 d). Extrapolation factors of 0.25 and 0.71 are proposed to adjust for continuous exposure conditions. Like the Navy, we propose that an uncertainty factor of 3 be applied to extrapolate from LOAEL to NOAEL. We agree with the NRC and the Navyâs previous assessment of an interspecies ex- trapolation factor of 3 and choose to adopt that value as well in our long-term SMAC derivations. Adoption of the interspecies correction factor of 3 is based on similarities in irritancy and a steep concentration-response relationship between species (rodents and humans). In addition, the resulting AC is below the reported effect level in human studies. Based on extension of the original argument for the exposure-duration independent nature of acrolein-induced mu- cosal irritation (Lyon et al. 1970, Wong 1996), no additional factor (Haberâs rule) was deemed necessary to adjust for exposure duration (from 91 to 180 d) (Equation 4). Revised 180-d SMAC 180-d AC(mucosal irritation) = 0.4 ppm (LOAEL) Ã [6/24 Ã 5/7] (time extrapolation) Ã 1/3 (LOAEL to NOAEL) Ã 1/3 (interspecies) = 0.008 ppm (4) By comparison, if the 0.22-ppm LOAEL from the study of Lyon et al. (1970) is modified by the same uncertainty factors of 3 (for the LOAEL to NOAEL and the interspecies factors) and application of the same adjustments for exposure duration, a 180-d SMAC of 0.004 ppm can be obtained. This value is similar to the 180-d SAMC of 0.008 ppm proposed here. The proposed 1,000-d SMAC uses the base study of Feron et al. (1978) and is derived similarly to the revised 180-d AC. Beginning with the LOAEL of 0.4 ppm, we propose that the same exposure extrapolation factors, LOAEL to NOAEL uncertainty factor, and interspecies extrapolation factor be applied. The risk due to low-level exposure to aldehydes, including acrolein, is not well un- derstood. Acrolein is an extremely reactive aldehyde (electrophilic) that reacts readily with sulfhydryl and thiol-containing compounds and can result in deple- tion of certain species such as reduced glutathione (McNulty et al. 1984, Lam et al. 1985, Grafstrom et al. 1990). Heck and co-workers (1986) reported that res- piratory and nasal mucosal nonprotein sulfhydryls, but not protein sulfhydryls,
Acrolein 21 were significantly depleted after 3 h of exposure to acrolein at 0.1 to 2.4 ppm. Overt toxicity to lung tissues may be attenuated by the reaction of acrolein with protein and nonprotein sulfhydryls, especially reduced glutathione. Although in situ defense mechanisms may afford protection for relatively acute exposures, it is unclear whether these mechanisms would remain effective under conditions of low-level continuous exposure to acrolein for more than 1,000 d. Application of Haberâs rule would result in an additional factor of 0.091 (extrapolating from 91 to 1,000 d of exposure). In light of the discussion above and the argument that acrolein-induced irritation is exposure-duration independent, it is likely that the application of Haberâs rule would result in an overly conservative AC. There- fore, no additional factor was applied to adjust for exposure duration (from 91 to 1,000 d). The proposed 1,000-d acrolein SMAC is 0.008 ppm (0.02 mg/m3) (Equation 5). Proposed 1000-d SMAC 1,000-d AC(mucosal irritation) = 0.4 ppm (LOAEL) Ã [6/24 Ã 5/7] (time extrapolation) Ã 1/3 (LOAEL to NOAEL) Ã 1/3 (interspecies) = 0.008 ppm (5) There is no evidence suggesting that the microgravity environment of planetary orbit or interplanetary travel will modify mechanisms associated with acrolein toxicity. Similarly, no foreseeable change in toxicity is expected as a result of space crews living in moon and Mars gravity conditions (accelerations of 1/6 and 1/3 gravity, respectively). Thus, no additional safety factors are war- ranted to compensate for possible gravity-induced physiological changes. Table 1-2 presents the proposed SMACs for acrolein for 2008. COMPARISON OF APPROACH OF ORIGINAL AND CURRENT NRC COMMITTEE ON TOXICOLOGY The current trend for risk assessment among many regulatory bodies, in- cluding the NRC Committee on Toxicology, is to apply a benchmark dose method (BMD) to set acceptable human exposure guidelines and limits. In par- ticular, this approach is recommended by the NRC for setting spacecraft water exposure guidelinesâand by inference SMACsâwhen sufficient and appropri- ate dose-response data are available (NRC 2000). Furthermore, the NOAEL- based method is recommended by the NRC in the absence of sufficient dose- response data or when special considerations are warranted. In the case of ac- rolein, few studies of either acute or chronic exposure are available. The U.S. Navy, the EPA, and the ATSDR have performed recent comprehensive exami- nation of the relevant acrolein inhalation toxicologic studies. On the basis of the available studies, these organizations chose to establish exposure guidelines predicated on reference concentrations. The same methodology was used in es- tablishing the existing (1996) acrolein SMACs. We have chosen to adhere to a
22 SMACs for Selected Airborne Contaminants TABLE 1-2 SMACs for Acrolein, 2008 Toxic End Point to Duration ppm mg/m3 Avoid Change from 1996 SMAC 1h 0.075 0.17 Mucosal irritation No change 24 h 0.035 0.08 Mucosal irritation No change 7d 0.015 0.034 Mucosal irritation No change 30 d 0.015 0.034 Mucosal irritation No change 180 d 0.008 0.02 Mucosal irritation ~1.9-fold reduction 1,000 d 0.008 0.02 Mucosal irritation New SMAC Note: The average odor threshold concentration is 0.16 ppm (Amoore and Hautala 1983). Although acrolein exhibits a noxious odor, the odor detection threshold is about 2 times higher than the 1-h SMAC. LOAEL-NOAEL methodology in confirming existing acrolein SMACs and for revising and establishing new SMACs. The following section presents an addi- tional explanation of our rationale for using each base and supporting study and provides BMD analysis of these studies when applicable. Short-Term SMACs Weber-Tschopp et al. 1977 The study of Weber-Tschopp et al. (1977) is considered the base study for establishing the original acrolein 1-h, 24-h, 7-d, and 30-d SMACs. The ATSDR also uses this studyâs corresponding LOAEL of 0.3 ppmâbased on nasal and throat irritation and reduction in respiratory rate in human subjectsâas the point of departure for setting the ATSDR acrolein MRL. We chose this study in set- ting a point of departure for our SMACs, as was chosen in setting the guidelines of the ATSDR, because it reports human-derived data. Using human- as op- posed to animal-derived data eliminates the need to include factors to adjust for uncertainties due to species differences in RfC derivations. The LOAEL ob- served by Weber-Tschopp et al. (1977) of 0.26 to 0.3 ppm is corroborated by the animal data presented by Cassee et al. (1996), who report a LOAEL of 0.25 ppm. Although the study reported by Weber-Tschopp et al. (1977) used an ap- preciable number of both male and female human subjects, it nevertheless relies on subjective self-reporting of effects by the study subjects. The results pre- sented by Weber-Tschopp et al. (1977) are presented as average scores for re- sponse categories. The unavailability of the raw data precludes modeling the findings of Weber-Tschopp et al. via BMD methodology for this review. Morris et al. 2003 The work of Morris et al. (2003) helps to validate the point of departure used to derive our acrolein SMACs based on NOAEL-LOAEL methodology.
Acrolein 23 This study is considered supportive of the base study of Weber-Tschopp et al. (1977) used in setting the original 1-h, 24-h, 7-d, 30-d, and 180-d acrolein SMACs. This study is also considered supportive in setting the revised 180-d and the new 1,000-d acrolein SMACs. Morris and co-workers exposed male and female mice to acrolein as part of their study to compare responses in healthy mice and in mice with allergic airway disease. Of concern to this review, these authors observed a 10% reduction from baseline in the respiratory rate of normal mice (C57Bl/6J mice without ovalbumin-induced allergic airway disease) at the lowest acrolein concentration of 0.3 ppm. As mentioned, the respiratory rate change noted in this study is considered supportive of the point of departure value and subsequent NOAEL-LOAEL extrapolations. Although applying BMD methodology to this respiratory rate data is problematic, it is nevertheless pre- sented here for comparison. Morris et al. give only a range of animals in each exposure groupâfour to six animals in control exposures (0 ppm of acrolein) and three to six animals exposed to 0.3 and 1.3 ppm of acrolein. For the BMD analysis presented here, the number of animals was estimated at five for controls and 4.5 for higher-dose groups. The SD for the low acrolein dose (0.3 ppm) was not reported numeri- cally in the text but had to be estimated from the reportâs graphic presentation (estimated at Â±five breaths/min based on interpretation of Figure 4 of Morris et al. ). A polynomial model with the dose-response data procedure for con- tinuous data in the EPA Benchmark Dose Software (BMDS) program was used to analyze the end point of interest (respiratory rate of control and acrolein- exposed mice). For normally distributed data, a shift of the mean from the base- line of 1 SD can be assumed to result in an excess risk of abnormal levels of about 10% (Crump 1995). Because the SD in the case of the breathing frequency data reported by Morris and co-workers is less than 10% of the baseline values, the SD in the benchmark concentration (BMC) calculation using these continu- ous data will approximate an increased risk of 10%. The BMC and lower 95% confidence limit of the benchmark concentration (BMCL) associated with an excess risk of 10% (e.g., a 10% incidence above background) were estimated to be 0.015 and 0.011 ppm, respectively. Using the BMD lower confidence limit (BMDL) as the point of departure, correction factors of 0.25 (interspecies vari- ability) and 0.17 (extrapolation from 10- to 60-min exposure) were applied, yielding an AC of 0.0005 ppm. Intermediate SMACs Cassee et al. 1996 The study of Cassee et al. (1996) used relatively high resolution analysis designed to elucidate the severity of effects from exposure to mixtures or single chemical irritants. Only the data from this study pertaining to histopathologic nasal changes and nasal epithelium biotransformation enzyme activities are pre-
24 SMACs for Selected Airborne Contaminants sented by the authors in enough detail to allow BMD analysis. In one part of the study of interest here, rats were exposed for 6 h/d for three consecutive days. For histopathologic analysis, 19 rats were used as controls (0 ppm of acrolein), 5 rats were exposed to 0.25 ppm of acrolein, and 6 rats were exposed to 0.67 ppm of acrolein. The data are reported as three levels of incidence (slight, moderate, and severe) for each histologic end point. One end point, âdisarrangement, necrosis, thickening and desquamation of respiratory/transitional epitheliumâ exhibited a 100% incidence at both doses tested (above 0 ppm) and therefore was not mod- eled. The other end points measured did not exhibit a significant biological re- sponse at either dose tested. The end point âbasal cell hyperplasia and/or increased number of mitotic figures in respiratory/transitional epitheliumâ from Cassee et al. (1996) showed a dose-dependent change amenable to BMD analysis. A multistage model for dichotomous data (EPA BMDS) was used to estimate the dose-response rela- tionship. For the purpose of this analysis, the three levels of incidence were summed to obtain a total incidence per end point per exposure. The BMC and lower BMCL associated with an excess risk of 10% were 0.08 and 0.012 ppm, respectively. The BMCL was then used as a point of departure for estimating a maximum allowable concentration for 24-h and 7-d exposures. A factor of 0.25, the same correction factor for interspecies variability as that used to derive the 24-h SMAC, was applied to this point of departure. No additional uncertainty factors for intraspecies variability or a potential risk at the point of departure (NOAEL or BMCL) were applied. The maximum AC for 24 h and 7 d was de- rived as 0.003 ppm. For nasal epithelium biotransformation enzyme activity determination, only three rats each were included in control (0 ppm of acrolein), medium- exposure (0.67 ppm of acrolein), and high-exposure (1.4 ppm of acrolein) groups. A polynomial model with the dose-response data procedure for a con- tinuous data (EPA BMDS) program was used to analyze the enzyme activity data. SDs for the dose-dependent nasal epithelium biotransformation enzyme activity of the Cassee et al. (1996) study were all less than 10% of their respec- tive baseline values. Therefore, using the SDs in the BMC calculations will ap- proximate an increased risk of 10% (Crump 1995). The most sensitive end points for severity were glutathione S-transferase and aldehyde dehydrogenase activities, both having BMC and lower BMCL associated with an excess risk of 10% of 0.045 and 0.028 ppm, respectively. Using the BMCL as the point of departure and applying the same correction factors as above for the histopathol- ogy end point, a maximum AC of 0.007 ppm was derived for the 24-h and 7-d exposures. The study of Cassee et al. (1996) is not ideal to derive a BMC as there are no âno-effectâ levels reported and a limited number of exposure con- centrations were tested. Importantly, there are a small number of animals in each exposure group (six animals per group for the histopathology assessment and three animals per group for the biotransforming enzyme assays), which can lead to derivation of wide confidence limits.
Acrolein 25 Long-Term SMACs Feron et al. 1978 The work of Feron et al. is selected as our base study for determining a point of departure for the revised 180-d SMAC as well as our new 1,000-d SMAC. The EPA in 2003 also chose to use this study as their base study. This study characterized several toxicologic end points by examining responses in three groups in three species as well as in both sexes. Of primary interest in the Feron et al. (1978) study is the extended exposure duration of 5 d/wk for 13 wk. Although not continuous, this exposure duration more closely approximates conditions that could be expected on long-duration space voyages and stays. Despite the positive aspects of this study, it has limitations with respect to BMD analysis. As with the report of Weber-Tschopp et al. (1977), results reported by Feron et al. for treatment-related effects (other than for body weight and organ weight ratios) are presented as summary scores averaged for all animals in each exposure group. The unavailability of the raw data precludes the BMD modeling of these histopathologic findings. BMD analysis was nevertheless applied to the body weight and organ weight ratio (g per 100 g of body weight) data reported by Feron et al. to estimate maximum allowable concentrations that could then be compared with the proposed SMACs, particularly the 180- and 1,000-d SMACs. Rats were the most sensitive of the species examined by Feron et al., ex- hibiting treatment-related effects at the lowest dose (0.4 ppm). Four groups of 12 rats each (divided by body weight and sex) were exposed to 0, 0.4, 1.4, and 4.9 ppm of acrolein for 6 h/d, 5 d/wk for 13 wk (91 d discontinuously). Body weight was measured as well as the organ weight ratios of multiple organs including heart, kidneys, liver, spleen, brain, testicles, ovaries, thymus, adrenals, and lungs. Statistically significant dose-related changes were reported for body weight and heart, lung, kidney, and adrenal organ weight ratios in rats. A poly- nomial model with the dose-response data procedure for a continuous data pro- gram (EPA BMDS) was applied to each of these data sets. The SDs reported by Feron et al. for body weight and organ weight changes were all either less than or in two midlevel doses of acrolein in the female rat adrenals, or equal to 10% of their respective baseline values. Therefore, using the SDs in the BMC calcu- lations will approximate an increased risk of 10% (Crump 1995). The BMC and BMCL associated with an excess risk of 10% were calculated for each end point of concern. The BMCL for each end point was used as a point of departure for estimating a maximum allowable concentration. Estimates of BMC and BMCL for 13-wk exposures reported by Feron et al. (1978) with estimated 180- and 1,000-d ACs are listed in Table 1-3. The most sensitive end points, lowest BMCL = 0.04 ppm, occurred for male rat body weight gain, which was decreased, and male rat adrenal weight ratio, which was also decreased. To derive an AC for 180-d exposures, factors of 0.25 and 0.71 were used to adjust for continuous exposure conditions. An inter-
26 SMACs for Selected Airborne Contaminants TABLE 1-3 Estimates of BMC and BMCL for 13-wk Exposures in Rats, Reported by Feron et al. (1978), with 180- and 1,000-d ACs BMD, BMDL, AC (180 d), AC (1,000 d), End Point ppm ppm ppm ppm Body weight Male 0.050 0.040 0.002 0.002 Female 0.080 0.070 0.004 0.004 Lung weight ratioa Male 0.060 0.050 0.003 0.003 Female 0.012 0.098 0.006 0.006 Heart weight ratio Male 0.130 0.100 0.006 0.006 Female 0.180 0.140 0.008 0.008 Kidney weight ratio Male 0.290 0.210 0.012 0.012 Female 0.130 0.110 0.007 0.007 Adrenal weight ratio Male 0.040 0.040 0.002 0.002 Female 0.100 0.090 0.005 0.005 a Organ weight ratio = g per 100 g of body weight. Abbreviations: AC, acceptable concentration; BMD, benchmark dose concentration; BMDL, lower 95% confidence limit of the benchmark concentration. species extrapolation factor of 3 was also applied. No uncertainty factors for intraspecies variability of a potential risk at the point of departure (NOAEL or BMCL) were applied. The resulting estimated 180-d AC is 0.002 ppm. To derive an AC for 1,000-d exposures, factors of 0.25 and 0.71 were used to adjust for continuous exposure conditions. An interspecies extrapolation fac- tor of 3 was also applied. No uncertainty factors for intraspecies variability or for a potential risk at the point of departure (NOAEL or BMCL) were applied. The resulting estimated 1,000-d AC is 0.002 ppm. Lyon et al. 1970 The emphysematous changes in laboratory dogs reported by Lyon et al. (1970) were carefully considered in setting the current revised 180-d and the new 1,000-d acrolein SMAC. However, limitations in the reporting detail and experimental design of this study preclude its choice as a base study and prohibit applying BMD methods to the data. As mentioned previously, this study used continuous exposure conditions (24 h/d) for 90 d. This exposure pro- tocol closely approximates the longer-duration SMAC intervals (especially 180 d). However, this study used small numbers of animals per exposure group and, most significantly, lacked reporting of control data; both factors exclude the
Acrolein 27 reported LOAEL as a valid point of departure and preclude application of BMD modeling. BMD analysis results for the base studies and supporting studies discussed above are summarized in Table 1-4. The ACs derived from BMDLs estimated from these studies fall below the current and proposed SMACs, which are based on LOAEL-NOAEL methods. BMD analysis of data from Morris et al. (2003) and the AC derived from this analysis falls well below (approximately 150 times below) the proposed 1-h SMAC. Because of the lack of available raw data and the need to estimate the number of animals in each exposure group, confidence in the derived 1-h AC resulting from this BMD analysis is low. We choose to rely solely on the NOAEL-LOAEL-derived 1-h SMAC based on Weber- Tschopp et al. (1977) and use the LOAEL of 0.3 ppm reported by Morris et al. (2003) as supportive data. BMD analysis of data presented by Cassee et al. (1996), although resulting in 24-h and 7-d ACs slightly below the current and proposed SMACs, are con- sidered supportive of the values already established. Confidence in the BMD analysis and derivation of subsequent ACs is medium. It is important to point out that the study design involved in producing the data used for the BMD analysis used a limited number of exposure concentrationsâcontrol, low, and medium acrolein for the âbasal cell hyperplasiaâ end point and control, medium, and high acrolein for the biotransformation enzyme activity end point. Also, the study for biotransformation enzyme activity involved only three animals per exposure group. Because of these limitations, we have chosen to use the base study of Weber-Tschopp et al. and consider the LOAEL of 0.3 ppm as the point- of-departure concentration for determining the intermediate 7- and 30-d SMACs. COMPARISON WITH OTHER AIR QUALITY LIMITS Exposure guidelines for acrolein exist with various public health and oc- cupational health entities as well as with industry and government advisory bod- ies. Table 1-5 presents a selected list of some of these guidelines and regulatory standards for comparison with the current and proposed NASA acrolein SMACs. The proposed NASA 180- and 1,000-d acrolein SMACs are more con- servative than the 90-d CEGL proposed by the Navy for submariners in 2007 (Table 1-5). These differences result from use of a different LOAEL point of departure (LOAEL of 0.4 ppm for NASA based on Feron et al. (1978) versus LOAEL of 0.22 ppm for the Navy based on Lyon et al. (1970) and the applica- tion of additional correction factors to account for differences between discon- tinuous and continuous exposure conditions. In contrast, both the revised 180-d and the proposed 1,000-d SMACs are approximately 900 times higher than the RfC set by the EPA. Explanation of this difference in ACs can be found in the inherent nature of the expected exposure conditions for which each guideline was established.
28 TABLE 1-4 Summation of Benchmark Dose Analysis Results BMD, BMDL, AC, BMD-Specific Study End Point ppm ppm ppm Limitations Comments Weber-Tschopp et al. 1977 Nasal and throat ND ND ND BMD analysis not Base study, LOAEL irritation, reduction in performed used as point of respiratory rate departure Morris et al. 2003 Respiratory rate 0.015 0.011 0.0005 Required estimation of 150 times lower (1 h) data, lack of reported than current or raw data. Required proposed SMAC estimation of n Cassee et al. 1996 âBasal cell hyperplasia 0.08 0.012 0.003 No âno-effectâ level 12 times lower and/or increased number (24 h) reported, limited number than current or of mitotic figures in of exposure proposed SMAC respiratory/transitional concentrations tested, epithelium.â small n in each exposure group Cassee et al. 1996 âBasal cell hyperplasia 0.08 0.012 0.003 No âno-effectâ level 12 times lower and/or increased number (7 d) reported, limited number than current or of mitotic figures in of exposure proposed SMAC respiratory/transitional concentrations tested, epithelium.â small n in each exposure group Cassee et al. 1996 Nasal epithelium 0.045 0.028 0.007 No âno-effectâ level 5 times lower biotransformation (24 h) reported, limited number than current or enzyme activity of exposure proposed SMAC concentrations tested, small n in each exposure group (Continued)
TABLE 1-4 Continued BMD-Specific Study End Point BMD, ppm BMDL, ppm AC, ppm Limitations Comments Cassee et al. 1996 Nasal epithelium 0.045 0.028 0.007 No âno-effectâ level 2 times lower biotransformation (7 d) reported, limited number than current or enzyme activity of exposure proposed SMAC concentrations tested, small n in each exposure group Feron et al. 1978 Body weight, adrenal 0.05 0.04 0.002 No BMD-specific 4 times lower weight ratio (180 d) limitations than current or proposed SMAC Feron et al. 1978 Body weight, adrenal 0.05 0.04 0.002 No BMD-specific 4 times lower than weight ratio (1,000 d) limitations proposed SMAC Lyon et al. 1970 Emphysematous changes ND ND ND BMD analysis Supporting study not performed Abbreviation: ND, not done. 29
30 SMACs for Selected Airborne Contaminants TABLE 1-5 Selected Inhalation Exposure Levels for Acrolein from Various Agencies Exposure Level, Organization ppm Reference OSHA PEL TWA 0.1 29 CFR 1910.1000  ACGIH TLV 0.1 ACGIH 2001 NIOSH REL TWA 0.1 NIOSH 2005 ATSDR ATSDR 2005 acute inhalation MRL (â¤14 d) 0.003 intermediate inhalation MRL 0.00004 (15-364 d) NAC/NRC AEGL-1a EPA 2005 1h 0.03 8h 0.03 NRC/Navy (submariner) NRC 2007 EEGL 1 h 0.1 EEGL 24 h 0.1 CEGL 90 d 0.02 EPA RfC 0.0000088 EPA 2003 NRC/NASA SMAC 1h 0.075 Wong 1996 24 h 0.035 Wong 1996 7d 0.015 Wong 1996 30 d 0.015 Wong 1996 180 d 0.008 Revised in current document 1,000 d 0.008 Proposed in current document a AEGL-1 is the airborne concentration of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discom- fort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; ATSDR, Agency for Toxic Substances and Dis- ease Registry; CEGL, Continuous Exposure Guideline Level; EEGL, Emergency Expo- sure Guideline Level; EPA, U.S. Environmental Protection Agency; MRL, minimal risk level; NAC, National Advisory Council; NASA, National Aeronautics and Space Ad- ministration; NIOSH, National Institute for Occupational Safety and Health; NRC, Na- tional Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; TLV, threshold limit value; TWA, time-weighted average; REL, recommended exposure limit; RfC, reference concentration; SMAC, Spacecraft Maximum Allowable Concentration. SMACs and the Navyâs analogous acute exposure guideline levels, EEGLs, and CEGLs differ from the usual public health and occupational health standards of exposure. Public and occupational health standards are aimed at
Acrolein 31 protecting sensitive subpopulations, including children, the elderly, and those with underlying chronic health conditions. SMACs are geared to protecting a healthy and relatively homogeneous population of adults. Occupational expo- sure standards are set for conditions of repeated exposure to the toxic agent throughout a workerâs lifetime (exposed 8 h/d Ã 5 d/wk Ã 52 wk/year Ã ap- proximately 30 years â 62,400 h). Whereas crew engaged in long-term space exploration as well as submariners potentially could be exposed to a toxicant such as acrolein for 24 h/d for up to 90 d (submariners) or 1,000 d (spacecraft crew), these resulting exposure durations are far shorter than those considered by occupational health standards (24 h/d Ã 90 d = 2,160 h for submariners or 24 h/d Ã 1,000 d = 24,000 h for space crews). Potential exposure conditions aboard spacecraft would preclude ârecovery periodsâ associated with nonwork- ing days that workers normally experience in a traditional workplace. If acrolein were present in confined living spaces such as those found in long-duration spaceflights and aboard modern submarines conducting extended submerged operations, circumstances of potentially similar acrolein exposure conditions could result. RECOMMENDATIONS FOR ADDITIONAL RESEARCH Establishing exposure limits for toxicants that cause sensory irritation is inherently difficult. In the case of acrolein, reports of ocular and respiratory tract irritation experienced by human subjects are subjective. The results of controlled human exposures to acrolein use descriptors such as âmildâ and âmild to moder- ate.â Furthermore, sensory irritation thresholds for acrolein and related materials can be highly variable from person to person. Current and proposed NASA ac- rolein SMACs are derived through use of a RfC âthreshold doseâ method with applicable safety factors applied. The supporting studies from which reference dosages were obtained are based in large part on subjective responses. Addi- tional studies that rely on less subjective subject responses about the effects of acrolein exposure are needed to better define exposure guidance levels. REFFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Acrolein in Documentation of Threshold Limit Values and Biological Exposure Indices, 7th Ed. American Conference of Government Industrial Hygienists, Cincinnati, OH. Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air water dilution. J. Appl. Toxicol. 3(6):272-290. Aranyi, C., W.J. OâShea, J.A. Graham, and F.J. Miller. 1986. The effects of inhalation of organic chemical air contaminants on murine lung host defenses. Fundam. Appl. Toxicol. 6(4):713-720. Astry, C.L., and G.J. Jakab. 1983. The effects of acrolein exposure on pulmonary anti- bacterial defenses. Toxicol. Appl. Pharmacol. 67(1):49-54.
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Acrolein 33 Lyon, J.P., L.J. Jenkins, Jr., R.A. Jones, R.A. Coon, and J. Siegel. 1970. Repeated and continuous exposure of laboratory animals to acrolein. Toxicol. Appl. Pharmacol. 17(3):726-732. McNulty, M.J., H.D. Heck, and M. Casanova-Schmitz. 1984. Depletion of glutathione in rat respiratory mucosa by inhaled acrolein. Fed. Proc. 43(3):575 [Abstr.1695]. Morris, J.B., P.T. Symanowicz, J.E. Olsen, R.S. Thrall, M.M. Cloutier, and A.K. Hub- bard. 2003. Immediate sensory nerve-mediated respiratory responses to irritants in healthy and allergic airway-diseased mice. J. Appl. Physiol. 94(4):1563-1571. NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) No. 2005-151. National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Cincinnati, OH. NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Ex- posure Guidelines. Washington, DC: National Academy Press. NRC (National Research Council). 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, Vol. 1. Washington, DC: The Na- tional Academies Press. Sim, V.M., and R.E. Pattle. 1957. Effect of possible smog irritants on human subjects. J. Am. Med. Assoc. 165(15):1908-1913. Steinhagen, W.H., and C.S. Barrow. 1984. Sensory irritation structure-activity study of inhaled aldehydes in B6C3F1 and Swiss-Webster mice. Toxicol. Appl. Pharmacol. 72(3):495-503. Weber-Tschopp, A., T. Fisher, R. Geier, and E. Grandjean. 1977. Experimentally induced irritating effects of acrolein on men [in German]. Int. Arch. Occup. Environ. Health 40(2):117-130. Wong, K.L. 1996. Acrolein. Pp. 19-38 in Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 2. Washington, DC: National Academy Press.