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Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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2
Acrolein

This chapter summarizes the relevant epidemiologic and toxicologic studies on acrolein. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure limits from the National Research Council (NRC) and other agencies are also presented. The subcommittee considered all of that information in its evaluation of the Navy’s current and proposed 1-hour (h), 24-h, and 90-day exposure guidance levels for acrolein. The subcommittee’s recommendations for acrolein exposure levels are provided at the conclusion of this chapter along with a discussion of the adequacy of the data for defining those levels and the research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Acrolein is a reactive, flammable liquid at room temperature that has a pungent odor (Budavari et al. 1989). Amoore and Hautala (1983) reported an odor threshold of 0.16 parts per million (ppm), and Leonardos et al. (1969) reported an odor threshold of 0.21 ppm. Ruth (1986) tabulated odor thresholds ranging from 0.023 to 16.36 ppm and reported a threshold for irritation at 0.55 ppm. Selected physical and chemical properties are summarized in Table 2-1.

OCCURRENCE AND USE

Acrolein primarily is used in the chemical industry as an intermediate in the synthesis of acrylic acid and the synthesis of D,L-methionine, an

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

animal feed supplement (Etzkorn et al. 1991). Acrolein also exhibits antimicrobial activity and is used as a biocide in a number of process streams, including liquid fuel lines and recirculating process water systems.

Acrolein has been measured in ambient and indoor air (IARC 1995). Ambient air measurements in the United States have detected acrolein at concentrations ranging from 2 parts per billion (ppb) to 7 ppb. Acrolein is a component of tobacco smoke (IARC 1995; EPA 2003). Jones (1999) reported that the acrolein emission factor for mainstream smoke ranges from 10 to 140 micrograms (g) per cigarette, and the emission factor for sidestream smoke ranges from 100 to 1,700 g per cigarette. In smoky indoor environments, acrolein concentrations have been reported to range from 1 to 120 ppb (IARC 1995). Acrolein has also been detected in exhaust from gasoline and diesel engines and from the heating of animal fats and vegetable oils, and it is present in a variety of foods (IARC 1995).

Sources of acrolein on submarines include high-temperature paints, motor varnishes, diesel generators, and cigarette smoke (Crawl 2003). ATSDR (1990) noted that acrolein concentrations at 57-85 ppb were measured during system testing conducted on a submarine being overhauled. No other details were provided. Raymer et al. (1994) reported the

TABLE 2-1 Physical and Chemical Properties of Acroleina

Synonyms and trade names

Acraldehyde, acrylaldehyde, acrylic aldehyde, allyl aldehyde, crolean, propenal, 2-propenal, prop-2-en-1-al, 2-propen-1-one

CAS registry number

107-02-08

Molecular formula

CH2CHCHO

Molecular weight

56.06

Boiling point

52.5°C

Melting point

−88°C

Flash point

−18°C (open cup)

Explosive limits

2.8% to 31% (by volume in air)

Specific gravity

0.8389 at 20°C/4°C

Vapor pressure

210 mmHg at 20°C

Solubility

Soluble in alcohol, ether, and 2 to 3 parts water

Conversion factors

1 ppm = 2.29 mg/m3; 1 mg/m3 = 0.44 ppm

aData on explosive limits are from ACGIH (2001); all other data are from Budavari et al. (1989).

Abbreviations: mg/m3, milligrams per cubic meter; mmHg, millimeters of mercury; ppm, parts per million.

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

results of air sampling conducted during the missions of two submarines. The fan room, galley, and engine room on each submarine were sampled over 6 h. Sampling indicated acrolein concentrations of 0.39 ppb and 0.14 ppb in the engine rooms of the submarines; no acrolein or “small” concentrations were noted for the other locations. A similar sampling exercise (two submarines, three locations, and a sampling duration of 6 h) was reported by Holdren et al. (1995). Acrolein concentrations ranged from <0.10 to 0.7 ppb on the two submarines. The subcommittee notes that the results presented by Raymer et al. (1994) and Holdren et al. (1995) represent one-time sampling events on four submarines. Whether the reported concentrations are representative of the submarine fleet is not known, particularly as few details were provided about the conditions on the submarines when the samples were taken.

SUMMARY OF TOXICITY

Several reviews of the toxicology of acrolein are available (Beauchamp et al. 1985; ATSDR 1990; IARC 1995; NRC 1996; ACGIH 2001; EPA 2002; EPA 2003). Only data that were directly relevant for deriving the submarine EEGL and CEGL values are discussed.

The adverse health effects of acrolein exposures are defined by the chemical’s cytotoxicity at the site of initial contact. Acrolein is a potent lacrimator and respiratory tract irritant. Exposures to airborne concentrations as low as 0.09 ppm for 5 minutes (min) have produced eye irritation. As concentration increases, eye and upper respiratory tract irritation increases. Liquid acrolein is absorbed through intact skin in amounts capable of producing systemic intoxication, and direct contact with the liquid can produce chemical burns.

Effects in Humans

Accidental Exposures

At least three fatalities have been associated with accidental exposure to airborne acrolein. Gosselin et al. (1979) recounted the case of a 4-year-old boy who died after a 2-h exposure to acrolein-containing smoke from an overheated fryer. Autopsy found multiple pulmonary infarcts, desquamation of the bronchial lining, and debris in the bronchiole lumen. A younger

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

brother was found dead and apparently died of asphyxiation. Prentiss (1937) reported a death that occurred 10 min after a man was exposed to acrolein at 150 ppm. No further details were available.

Mahut et al. (1993) described the case of a 27-month-old boy who was exposed to smoke from burning vegetable oil for 1 h. Acute respiratory failure and respiratory acidosis regressed within a few hours of treatment, but diffuse bronchiectasis developed over the months following the exposure. Bauer et al. (1977) described a similar incident involving a 21-year-old man exposed to kitchen smoke for 6 h. He developed chronic pneumopathy, bronchitis, and emphysema.

Champeix et al. (1966) described the onset of fever, coughing, dyspnea, cyanosis, and acute pulmonary edema with foamy expectoration in a 39-year-old male worker who was accidentally exposed to acrolein vapor. The victim suffered from chronic bronchitis and emphysema 18 months after the accident.

Experimental Studies

Controlled inhalation investigations have demonstrated that even brief exposures to acrolein at concentrations <1 ppm are associated with increased complaints of eye and nose irritation. Those complaints are accompanied by prompt reductions in ventilation rates (Sim and Pattle 1957; Weber-Tschopp et al. 1977).

Lacrimation and evidence of marked eye, nose, and throat irritation developed in 12 adult male volunteers within 20 seconds (s) of exposure to acrolein at 0.8 ppm (Sim and Pattle 1957). Exposure at 0.8 ppm for 10 min was considered “only just tolerable.” The subcommittee notes that in this study the description of the method of acrolein administration (mask or chamber) was not clear. When 12 adult male volunteers were exposed at 1.2 ppm, lacrimation and evidence of marked eye, nose, and throat irritation developed within 5 s. Exposure at 1.2 ppm for more than 5 min was considered intolerable.

Stephens et al. (1961) found that 10-35% of humans exposed to acrolein at 0.5 ppm complained of eye irritation within 5 min of initial contact with the chemical. As the duration of exposure increased to 12 min, nearly all of the subjects (91%) complained of eye irritation. Darley et al. (1960) considered the eye irritation associated with a 5-min exposure at 1.3-1.6 ppm to be moderate and the eye irritation associated with a 5-min exposure at 2.0-2.3 ppm to be moderate to severe.

Weber-Tschopp et al. (1977) conducted three controlled acrolein

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

inhalation trials in healthy young adult male and female volunteers. The first trial studied effects of increasing concentrations, the second studied effects of brief exposures (1.5 min) to progressively increasing concentrations, and the third studied effects of constant exposure. In the first trial, 31 males and 22 females were exposed to acrolein at concentrations that increased gradually from 0 to 0.6 ± 0.02 ppm over a 35-min period. Volunteers were exposed in a chamber. For the final 5 min, the volunteers were exposed at 0.6 ppm. Eye, nose, and throat irritation increased significantly compared with unexposed volunteers at concentrations as low as 0.09, 0.26, and 0.43 ppm, respectively.

In the second trial, 25 female and 17 male volunteers were intermittently exposed to airborne acrolein for up to 1.5 min at increasing concentrations—0, 0.15, 0.3, 0.45, and 0.6 ppm. Questionnaires were provided to volunteers after 1 min of exposure. The volunteers were allowed 8 min of recovery in a well-ventilated room between successive exposures. Discomfort, which was described as a wish to leave the room, was significantly increased at 0.15 ppm. Eye irritation scores increased significantly at 0.3 ppm and higher, and nasal irritation scores increased significantly at 0.6 ppm.

In the third trial, 21 males and 25 females were divided into groups of three and exposed at 0.3 ppm for 1 h. Significant reductions in respiratory rates were noted. Respiratory rates were decreased by 10% in 47% of volunteers after 10 min and in 60% of volunteers after 20 min. Doubling of eye-blink rate was reported in 66% and 70% of volunteers after 10 min and 20 min, respectively. Moderate eye irritation was reported in 18% and 35% of volunteers after 10 min and 20 min, respectively, and severe to very severe eye irritation was reported in 3% and 18% of volunteers after 10 min and 20 min, respectively.

Weber-Tschopp et al. (1977) found that increased complaints of “annoyance” and eye irritation began at concentrations as low as 0.09 ppm. Complaints of nasal irritation increased as acrolein concentrations reached 0.15 ppm or more. A 10% reduction in respiration was evident at 0.3 ppm within 10-20 min of exposure. Complaints of throat irritation increased at acrolein concentrations of 0.43 ppm or more. Thus, the eyes were most sensitive to airborne acrolein exposure.

Occupational and Epidemiologic Studies

Ott et al. (1989) described six male employees who had been exposed to acrolein in workplace air and were later afflicted with multiple myeloma,

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

non-Hodgkins lymphoma, or nonlymphocytic leukemia. The odds ratios for the three cancers (1.7-2.6) were elevated in workers exposed to acrolein. However, because none of the lower confidence bounds significantly exceeded 1, the number of affected individuals was small, and the workers were concomitantly exposed to other workplace chemicals, no rigorous conclusions or causal inference could be made regarding the carcinogenic potential of inhaled acrolein.

Effects in Animals

Acute Toxicity

The marked irritant effects of inhalation exposures to acrolein result from its chemical reactivity. Ballantyne et al. (1989) calculated the combined LC50 values (concentrations lethal to 50% of subjects) in male and female Sprague-Dawley rats for 1 and 4 h to be 26 and 8.3 ppm, respectively. Catalina et al. (1966) found a 10-min LC50 of 375 ppm, and Skog (1950) found a 30-min LC50 of 131 ppm. The 6-h LC50 in mice was 66 ppm (Philippin et al. 1970).

Steinhagen and Barrow (1984) found that even brief exposures (10 min) to acrolein inhibited respiratory rates in mice. The authors calculated RD50 (50% reduction in respiratory rate) concentrations at 1.41 and 1.03 ppm for male B6C3F1 and Swiss-Webster mice, respectively. The authors also found that acrolein was the most potent respiratory tract irritant out of 14 aldehydes evaluated under identical conditions in the mice. RD50 concentrations of other aldehydes ranged from 3.53 to 4,167 ppm. Kane and Alarie (1979) reported a slightly higher 10-min RD50 value (1.7 ppm) for Swiss-Webster mice than did Steinhagen and Barrow (1984).

Although acrolein is a less potent respiratory tract irritant in rats than in mice, similar reductions in the respiratory rates of rats were evident after exposures at 6 ppm (Babiuk et al. 1985). Acrolein is 5 times more potent a respiratory tract irritant (RD50 = 6.0 ppm) than formaldehyde (RD50 = 31.7 ppm) in Fischer 344 rats (Babiuk et al. 1985).

Several studies have investigated the effects associated with acrolein exposures in rats. Cassee et al. (1996) exposed male Wistar rats to acrolein at 0.67 ppm for 6 h per day for 3 days and found that acrolein exposure produced respiratory thickening and disarrangement similar to that seen in rats that inhaled formaldehyde at 3.2 ppm over the same duration, although the acrolein-induced changes were more pronounced. Springhall et al.

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

(1990) exposed Porton strain Wistar rats to acrolein at 22, 81, or 249 ppm for 10 min. The animals exposed at 81 or 249 ppm developed slight pulmonary edema and hemorrhage into the lung parenchyma, which was more commonly observed in those exposed at the highest concentration. Immunohistochemical evaluation of the respiratory tract demonstrated concentration-dependent reductions in tracheal nerve fibers reactive for calcitonin gene-related peptide (CGRP) and substance P. A decrease of substance P-reactive nerve fibers in the lung was observed in rats exposed to 249 ppm. The authors considered the reductions to be reflections of acrolein-induced damage to sensory nerve fibers, in contrast to autonomic nerve fibers, because CGRP and substance P are the primary neuropeptides found in the sensory nerves of the rodent respiratory tract.

When male Sprague-Dawley rats inhaled 0.2 or 0.6 ppm acrolein for 6 h, there was a prompt increase in respiratory tract epithelial cell proliferation (Roemer et al. 1993). In hamsters, similar 4-h exposures to acrolein at 6 ppm resulted in a >50% exfoliation rate in bronchial ciliated cells, and by 96 h after acrolein exposure, there was evidence of irregular epithelia with early stratification, hyperplasia, and loss of cilia (Kilburn and McKenzie 1978).

Kaplan (1987) conducted inhalation studies in juvenile baboons exposed to acrolein for 5 min. The animals were trained to perform an escape and avoidance procedure. When baboons were exposed to acrolein at 12, 25, 100, 250, 505, 1,025, or 2,780 ppm, all of the animals completed the avoidance procedure. Baboons exposed at 1,025 and 2,780 ppm developed severe pulmonary edema and died 24 or 1.5 h after acrolein exposure, respectively.

Murphy et al. (1963) found reduced respiratory rates, increased tidal volume, and increased respiratory flow resistance in guinea pigs within 30-60 min of their initial contact with acrolein at 0.6 ppm. Turner et al. (1993) exposed male Dunkin-Hartley guinea pigs to acrolein at 0 or 1.6 ppm for 7.5 h per day for 2 consecutive days. Pulmonary edema (as assessed by wet-to-dry lung weight ratio and protein levels in bronchoalveolar lavage fluid) was present 1 day after acrolein exposure. Evaluation of pulmonary lavage fluid also revealed increased epithelial cells, inflammatory cells (neutrophils and monocytes), and erythrocytes. Those changes were consistent with pulmonary inflammation and hemorrhage.

Leikauf et al. (1989a,b) evaluated inflammatory cells and inflammatory mediators in bronchial lavage fluid and bronchial airway responsiveness in guinea pigs (5-7 per group) administered an intravenous acetylcholine challenge before and 1, 2, 6, and 24 h after exposures to acrolein at

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

≤0.01 (control), 0.31, 0.67, 0.94, or 1.26 ppm for 2 h. A 2-h exposure at ≥0.94 ppm produced a doubling in bronchial airway resistance to intravenous acetylcholine that persisted for at least 24 h. In a second set of experiments, guinea pigs were exposed to 1.2-1.4 ppm acrolein for 2 h. Pulmonary neutrophil, thromboxane B2, prostaglandin F2α, and leukotriene C4 concentrations were increased in lavage fluid during the first day post-exposure. Pretreatment with either leukotriene antagonists or 5-lipooxygenase activity inhibitors reduced the hyperresponsive acetylcholine response induced by inhaled acrolein. Because of the increased sensitivity of guinea pigs to irritant gases compared with other rodent models, these data might suggest that asthmatic individuals would be more sensitive to inhaled acrolein (Leikauf 2002).

Repeated Exposures and Subchronic Toxicity

Buckley et al. (1984) found that male Swiss-Webster mice exposed to acrolein at 1.67-1.73 ppm for 6 h per day for 5 consecutive days developed moderate erosion and exfoliation of the respiratory epithelium. The changes were accompanied by epithelial squamous metaplasia and focal blebbing, vacuolization, cell separation, and early exfoliation in the nasal turbinates. The olfactory epithelium was also damaged. The injury was considered minimal to moderate and was characterized by ulceration, necrosis, squamous metaplasia, and serous exudates. Most of the epithelial sensory cells in the dorsal meatus were destroyed, and early transformation to a squamous epithelium was evident. Minimal to moderate recovery was observed in the epithelium 72 h post-exposure.

Costa et al. (1986) reported the results of inhalation studies in male Fischer 344 rats exposed to acrolein at 0, 0.4, 1.4, or 4.0 ppm for 6 h per day, 5 days per week for 62 days. Exposure to 4.0 ppm acrolein was associated with severe peribronchiolar and bronchiolar damage. The associated lesions were noted in only 10% of rats exposed to 1.4 ppm. No adverse changes in pulmonary histology were found among rats exposed at 0.4 ppm. Changes in pulmonary function were observed in rats exposed to 4.0 ppm. Changes in maximal expiratory flow-volume curves were observed in rats exposed to 0.4 and 4.0 ppm but not to 1.4 ppm.

Feron et al. (1978) exposed Syrian golden hamsters, Wistar rats, and Dutch rabbits to acrolein at 0, 0.4, 1.4, or 4.9 ppm for 6 h per day, 5 days per week for 13 weeks. Respiratory tract pathology was observed in acrolein-exposed animals. Nasal injury was the most sensitive end point.

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

Rats, rabbits, and hamsters exposed to 4.9 ppm developed nasal epithelial injury. The normal nasal epithelium was replaced by stratified squamous epithelium with occasional keratinization. Neutrophilic infiltration was observed in the nasal mucosa. At 1.4 ppm, rats displayed nasal metaplasia and inflammation, hamsters showed only a local inflammatory response in the nose, and rabbits were unaffected. One of 12 rats exposed to 0.4 ppm exhibited metaplastic and inflammatory changes in nasal epithelium. Hamsters and rabbits exposed to 0.4 ppm were unaffected.

In a 90-day continuous (24 h per day) inhalation study, Lyon et al. (1970) exposed Sprague-Dawley rats, Princeton or Hartley-derived guinea pigs, squirrel monkeys (Saimiri sciurea), and beagle dogs to acrolein at 0, 0.22, 1.0, or 1.8 ppm. Dogs and monkeys were the most sensitive species. Two of four dogs exposed to 0.22 ppm developed moderate emphysema, bronchiolar pathology, and subcapsular splenic hemorrhage. Dogs and monkeys exposed to 1.0 ppm developed signs compatible with ocular and nasal irritation. Rats and guinea pigs exposed to 1.0 ppm and greater displayed focal liver necrosis, and the guinea pigs developed pulmonary inflammation at concentrations at or above 1.0 ppm.

Chronic Toxicity

When groups of Syrian golden hamsters (18 per gender) inhaled acrolein at 0 or 4 ppm for 7 h per day, 5 days per week for 52 weeks, nasal inflammation and epithelial metaplasia were observed in acrolein-exposed hamsters (Feron and Kruysse 1977). Those lesions primarily were observed in the dorsomedial region and nasomaxillary turbinates. The changes persisted for up to 6 months post-exposure in 20% of treated hamsters. There was only one tumor (tracheal papilloma) found in the respiratory tract of one treated female. When Le Bouffant et al. (1980) exposed 20 female Sprague-Dawley rats to acrolein at 8 ppm for 1 h per day, 5 days per week for 10 or 18 months, no respiratory tract metaplasia or neoplasia was observed.

Reproductive Toxicity in Males

When male SPF OFA rats that had been exposed continuously to acrolein at 0.55 ppm for 4 days were mated to females that were then exposed to acrolein at 0.55 ppm throughout gestation, no adverse effects

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

were observed on the number of pregnant animals, litter size, or fetal weight (Bouley et al. 1976).

Kutzman (1981) was unable to detect any treatment-related changes to reproductive parameters in male Fischer 344 rats that were exposed to acrolein by inhalation at 0, 0.4, 1.4, or 4.0 ppm for 6 h per day, 5 days per week for 62 days of exposure.

Immunotoxicity

Topical acrolein (0.01%, 0.5%, and 2.5%, volume-by-volume in distilled water) applied to the shaved skin of 15 female guinea pigs failed to elicit any signs of sensitization (Susten and Breitenstein 1990).

Astry and Jakab (1983) found a concentration-dependent increase in Staphylococcus aureus survival in Swiss mice that inhaled acrolein at 3.0 or 6.0 ppm for 8 h. When male rats inhaled acrolein at 0, 0.1, 1.0, or 3.0 ppm for 6 h per day, 5 days per week for 3 weeks, no significant changes were observed in the responses of pulmonary or spleen lymph node cells to T-cell mitogen or B-cell mitogen, and no significant changes were observed in resistance to Listeria monocytogenes infection (Leach et al. 1987). After male Sprague-Dawley rats inhaled acrolein at 0.1, 1.0, or 3.0 ppm for 6 h per day, 5 days per week for 3 weeks, alveolar macrophage lysozyme activity was increased at 1.0 and 3.0 ppm, but there were no effects on macrophage killing or clearance of inhaled 35S-Klebsiella pneumoniae (Sherwood et al. 1986).

When CD-1 mice were inoculated with S. aureus and Proteus mirabilis 30 min prior to a 4- or 24-h inhalation exposure to acrolein at 1-2 ppm, greater numbers of bacteria survived in the lungs of acrolein-treated mice than in the lungs of control mice (Jakab 1977). Jakab (1993) extended these studies using female Swiss mice in nose-only acrolein exposures for 4 h per day over 4 days at an acrolein concentration of 2.5 ppm to determine pulmonary survival of S. aureus, P. mirabilis, influenza A virus, and L. monocytogenes. Inhaled acrolein failed to alter alveolar macrophage immune response or T-cell mediated immunity against those pathogens.

The percentage of inhaled K. pneumoniae that survived in the lungs of female CD-1 mice exposed to acrolein at 0.1 ppm (nominal concentration) for 3 h per day for 1 day was no different from the percentage of bacteria that survived in control mice (Aranyi et al. 1986). However, a 5-day exposure produced a decrease in bactericidal activity in the treated animals versus the air-exposed controls. Thus, available data show that

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

exposures to airborne acrolein at high concentrations can interfere with the in vivo bactericidal activity of murine alveolar macrophages.

Genotoxicity

No studies of the potential genotoxicity of inhaled acrolein in mammals were available (EPA 2003). The International Agency for Research on Cancer (IARC) (1995) and EPA (2003) tabulated the published data on the effects of acrolein in prokaryotic and eukaryotic systems designed to assess mutagenic activity. Acrolein’s potent cytotoxicity was considered to be responsible for the conflicting or equivocal results that provide a mixed picture of its genotoxic potential (IARC 1995).

Acrolein induced DNA-protein cross-links and was clastogenic in cultured human lymphoma cells when administered at near cytotoxic concentrations (Costa et al. 1997), and it induced sister chromatid exchange and increased chromosomal aberrations in cultured Chinese hamster ovary cells (IARC 1995). There was no evidence of dominant lethal mutations in mice after a single parenteral dose (IARC 1995).

Acrolein was mutagenic without metabolic activation in Salmonella typhimurium TA104 (EPA 2003). Acrolein was not mutagenic with or without metabolic activation in strains TA1535, TA1537, and TA1538 (EPA 2003). Equivocal results were observed in frameshift tester strain TA98 and base repair tester strain TA100 (EPA 2003). Acrolein induced somatic mutations in Drosophilia melanogaster exposed at 500-2,000 ppm in air (Vogel and Nivard 1993), and there was a similar response after feeding acrolein at 5-20 millimolar (mM) (Sierra et al. 1991).

Carcinogenicity

At least two laboratories have conducted oral carcinogenicity bioassays of acrolein in rodents. Lijinsky and Reuber (1987) administered acrolein at 0, 100, 250, or 625 ppm in drinking water for 5 days per week to groups of Fischer 344 rats (20 per gender) starting at 7-8 weeks of age. Exposures lasted up to 124 weeks. Survival was comparable in the treated and control groups, and there was no significant treatment-related increase in tumors at any site. Parent et al. (1991) conducted a study in which groups of CD-1 mice (70-75 per gender) were given acrolein at 0, 0.5, 2.0, or 4.5 milligrams per kilogram of body weight (mg/kg) per day in water by gavage

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

for 18 months. There were no increases in numbers of tumors in the treated animals at any site. In a companion study, Parent et al. (1992) gave groups of Sprague-Dawley rats (70 per gender) 0, 0.05, 0.5, or 2.5 mg/kg per day in water by gavage for up to 102 weeks. There were no indications of carcinogenic response in any tissues, regardless of dose.

As noted above, Feron and Kruysse (1977) conducted a study in which groups of Syrian golden hamsters (18 per gender) inhaled acrolein at 0 or 4 ppm for 7 h per day, 5 days per week for 52 weeks. Six hamsters (six per gender) were sacrificed at 52 weeks, and the remaining hamsters were sacrificed after 81 weeks. One tumor was observed in the respiratory tract of one acrolein-treated females. The study evaluated the effects of benzo[a]-pyrene and diethylnitrosamine treatment on acrolein-induced tumor formation, and the authors combined the results of animals exposed to acrolein with and without saline treatment in their data analysis.

On the basis of the published studies described above, IARC (1995) concluded that there was inadequate evidence to determine the carcinogenicity of acrolein in humans and animals. IARC (1995) assigned acrolein to its Group 3 category—not classifiable as to its carcinogenicity to humans. EPA (2003) also concluded that the carcinogenicity of inhaled acrolein could not be determined.

TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS

Mechanisms of acrolein toxicity have been reviewed (EPA 2003). Acrolein reacts with plasma membranes, produces oxygen radicals, and depletes the respiratory tract neuropeptides associated with vasodilation and bronchoconstriction. Depletion of reduced glutathoine (GSH) is an important initial event because it leaves cellular thiol groups vulnerable to oxidation. Acrolein exposures also cause reduced pulmonary compliance and increased pulmonary resistance.

Because of acrolein’s marked chemical reactivity, distribution to tissues other than the site of initial contact is very limited (EPA 2003). Acrolein reacts with respiratory tract tissues (Egle 1972). The respiratory tract retention of very high concentrations of inhaled acrolein (>170 ppm) approaches about 80% in dogs (Egle 1972). Studies with anesthetized male Fischer 344 rats exposed to lower acrolein concentrations (0.9-9.1 ppm) showed that nasal absorption of acrolein is significantly dependent on the concentration and ranged from 28% to 62% depending upon acrolein concentrations and inspiratory flow rates used (Morris 1996).

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

Acrolein reacts with thiols and sulfhydryl groups, and it quickly reacts with protein and nucleic acid primary and secondary amines (EPA 2003). Acrolein depletes rat nasal epithelial GSH (McNulty et al. 1984) and human bronchial epithelial GSH (Grafstrom et al. 1990), and it initiates cell proliferation in the rat respiratory tract (Roemer et al. 1993). When male Wistar rats inhaled acrolein at 1 or 2 ppm, pulmonary lipid peroxidation was extensive (Arumugam et al.1999).

INHALATION EXPOSURE LEVELS FROM THE NRC AND OTHER ORGANIZATIONS

A number of organizations have established or proposed inhalation exposure limits or guidelines for acrolein. Selected values are summarized in Table 2-2.

SUBCOMMITTEE RECOMMENDATIONS

The subcommittee’s recommendations for EEGL and CEGL values for acrolein are summarized in Table 2-3. The current and proposed U.S. Navy values are provided for comparison.

1-Hour EEGL

Sufficiently high concentrations of acrolein in air can induce pronounced eye and upper respiratory tract irritation. Acrolein-induced sensory irritation is prompt (Steinhagen and Barrow 1984; Babiuk et al. 1985) and is characterized by a steep concentration-response relationship (Babiuk et al. 1985). Healthy adult volunteers (18%) complained that exposures to airborne acrolein at 0.3 ppm for 20 min produced “severe to very severe” ocular irritation (Weber-Tschopp et al. 1977). Those complaints were corroborated by a doubling of the eye-blink rate in 66% of subjects after exposure at 0.3 ppm for 10 min and in 70% of subjects after exposure at 0.3 ppm for 20 min. Eye irritation was classified as “moderate” in 35% of the volunteers after 20 min of exposure at 0.3 ppm. Complaints of “a little” eye irritation began after exposure at 0.09 ppm. Complaints of “a little” nasal irritation were reported after exposure at 0.3 ppm for 20-30 min. WeberTschopp et al. (1977) identified ocular and nasal irritation thresholds of 0.09 and 0.15 ppm, respectively.

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

TABLE 2-2 Selected Inhalation Exposure Levels for Acrolein from NRC and Other Agenciesa

Organization

Type of Level

Exposure Level (ppm)

Reference

Occupational

 

 

 

ACGIH

TLV-Ceiling

0.1 (skin)

ACGIH 2000

NIOSH

REL-TWA

0.1

NIOSH 2004

 

REL-STEL

0.3

 

OSHA

PEL-TWA

0.1

29 CFR 1910.1000

Spacecraft

 

 

 

NASA

SMAC

 

NRC 1996

 

1 h

0.075

 

 

24 h

0.035

 

 

30 days

0.015

 

 

180 days

0.015

 

Submarine

 

 

 

NRC

EEGL

 

NRC 1984

 

1 h

0.05b

 

 

24 h

0.01b

 

 

CEGL

 

 

 

90 days

0.01

 

General Public

 

 

 

ATSDR

Acute MRL

0.00005

ATSDR 1990

 

Intermediate MRL

0.000009

 

NAC/NRC

AEGL-1 (1 h)

0.03

EPA 2004

 

AEGL-2 (1 h)

0.1

 

 

AEGL-1 (8 h)

0.03

 

 

AEGL-2 (8 h)

0.1

 

aThe comparability of EEGLs and CEGLs with occupational and public health standards or guidance levels is discussed in Chapter 1, section “Comparison to Other Regulatory Standards or Guidance Levels.”

bThe 1984 NRC subcommittee designated the value as “tentative” on the basis of its review of the data. The 2004 NRC subcommittee provides a qualitative description of uncertainties and identifies data gaps in the final section of this profile rather than qualifying a recommendation with terms, such as “tentative.”

Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; ATSDR, Agency for Toxic Substances and Disease Registry; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; h, hour; MRL, minimal risk level; NAC, National Advisory Committee; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; ppm, parts per million; REL, recommended exposure limit; SMAC, spacecraft maximum allowable concentration; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average.

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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TABLE 2-3 Emergency and Continuous Exposure Guidance Levels for Acrolein

Exposure Level

U.S. Navy Values (ppm)

NRC Recommended Values (ppm)

Current

Proposed

EEGL

 

 

 

 

 

1 h

0.05

0.07

0.1

 

24 h

0.01

0.03

0.1

CEGL

 

 

 

 

 

90 days

0.01

0.01

0.02

Abbreviations: CEGL, continuous exposure guidance levels; EEGL, emergency exposure guidance level; h, hour; NRC, National Research Council; ppm, parts per million.

On the basis of controlled human exposure studies (Weber-Tschopp et al. 1977), complaints of “a little” eye irritation—the most sensitive acute effect—begin at about 0.09 ppm, which is effectively 0.1 ppm. Therefore, the subcommittee recommends 0.1 ppm as the 1-h EEGL. That level can be considered a minimal lowest-observed-adverse-effect level (LOAEL) and is one-third the concentration at which a doubling of eye-blink rate was noted in about 70% of subjects after exposure for 20 min.

24-Hour EEGL

A concentration-dependent increase in eye-blink rate was observed at concentrations ≥0.17 ppm when human subjects were exposed continuously to increasing concentrations of acrolein over 35 min (Weber-Tschopp et al. 1977). The increase became significant at 0.26 ppm with the rate doubled at 0.3 ppm. Exposures to airborne acrolein described as irritating by most volunteers ranged from 0.3 ppm for 20-30 min (Weber-Tschopp et al. 1977) to 0.5 ppm for 5 min (Stephens et al. 1961). Anecdotal accounts of human inurement to sensory irritants are common, and some degree of adaptation to airborne acrolein can be expected (Bouley et al. 1976). A threshold of 0.09 ppm for ocular irritation in humans has been identified, and the degree of ocular and mucous membrane irritation associated with exposure to acrolein at 0.1 ppm for 1 h is not anticipated to increase over a 24-h period. Therefore, the 1-h EEGL of 0.1 ppm was considered appropriate for use as the 24-h EEGL.

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×
90-Day CEGL

No human studies appropriate for use in deriving the 90-day CEGL were identified. Acute pulmonary inflammation was a consistent consequence of inhalation exposures to acrolein in animals; exposure durations as brief as 5 min (Kaplan 1987) or 10 min (Springhall et al. 1990) have induced concentration-dependent pulmonary edema. Subchronic whole-body inhalation studies in rodents, rabbits, dogs, and nonhuman primates demonstrated excessive salivation, ocular and nasal irritation, nasal inflammation, nasal or tracheal squamous metaplasia, basal cell hyperplasia, and acute pulmonary congestion (Lyon et al. 1970; Feron et al. 1978). Subchronic LOAELs of 0.4 ppm in rats and 1.4 ppm in hamsters were identified on the basis of nasal inflammation observed after exposures lasting 6 h per day, 5 days per week (Feron et al. 1978). Two of four beagles that inhaled acrolein at 0.22 ppm for 24 h per day for 90 days developed emphysema (Lyon et al. 1970). Recognizing the irreversible nature of emphysema and the appropriateness of the 90-day continuous-exposure inhalation protocol of Lyon et al. (1970), the subcommittee selected the beagle LOAEL of 0.22 ppm as the basis for the 90-day CEGL. An interspecies uncertainty factor of 3 was applied on the basis of acrolein’s similar irritant action in rodent and human target tissues and the steep acrolein concentration-response relationships seen in both laboratory animals and human volunteers. An uncertainty factor of 3 for extrapolation from a LOAEL to a no-observed-adverse-effect level (NOAEL) was also applied to yield a 90-day CEGL of 0.02 ppm. The subcommittee concludes that application of a total uncertainty factor of 10 is appropriate as the resulting 90-day CEGL is below the exposure concentrations at which any irritation was reported in human volunteers.

DATA ADEQUACY AND RESEARCH NEEDS

Although responses to airborne acrolein are well documented, there remain considerable difficulties and uncertainties associated with the quantification of sensory irritation. Several animal systems, such as rat and mouse RD50 calculations, have been designed to predict and quantify sensory irritation (ASTM 1991). Some investigators have designed assays to separate perception of chemical odor from nasal pungency using anosmic and normosmic volunteers (Cometto-Muniz and Cain 1993, 1994). Others (Abraham et al. 1996, 1998; Hau et al. 1999) have devised algorithms for

Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

nasal pungency to rank volatile organic materials. However, none of those methods have received the review and critical evaluation necessary to achieve the level of confidence required for regulatory acceptance.

Derivation of quantitative environmental and occupational exposure limits for sensory irritants is fraught with difficulty, because the reports of ocular and respiratory tract irritation experienced are considered by some to be subjective. That view can lead to points of considerable contention (Paustenbach 2001). The results of controlled human exposures to acrolein use typical descriptors, such as “mild” or “mild to moderate,” and the databases of sensory irritation thresholds for acrolein and related materials can be highly variable. Considerable research should be done to quantify the diverse sensory irritation methods for use in public- and occupational-health risk assessment (Dalton 2001). Thus, the subcommittee concludes that additional studies on the irritant effects of acrolein are needed to better define the exposure guidance levels for the short-term durations.

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40(2):117-130. Translated by R.A. Faust, Toxicology and Hazard Assessment Group, Life Sciences Division, Oak Ridge National Laboratory).

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Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Suggested Citation:"2 Acrolein." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1 Get This Book
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U.S. Navy personnel who work on submarines are in an enclosed and isolated environment for days or weeks at a time when at sea. Unlike a typical work environment, they are potentially exposed to air contaminants 24 hours a day. To protect workers from potential adverse health effects due to those conditions, the U.S. Navy has established exposure guidance levels for a number of contaminants. The Navy asked a subcommittee of the National Research Council (NRC) to review, and develop when necessary, exposure guidance levels for 10 contaminants.

Overall, the subcommittee found the values proposed by the Navy to be suitable for protecting human health. For a few chemicals, the committee proposed levels that were lower than those proposed by the Navy. In conducting its evaluation, the subcommittee found that there is little exposure data available on the submarine environment and echoed a previous recommendation from an earlier NRC report to conduct monitoring that would provide a complete analysis of submarine air and data on exposure of personnel to contaminants.

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