Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants Volume 3 (2009) / Chapter Skim
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2 Acetaldehyde
2 Acetaldehyde
Pages 20-45
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The committee considered all that information in its evaluation of the U.S. Navy's 1-h, 24-h, and 90-day exposure guidance levels for acetaldehyde.
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. Several studies have measured acetaldehyde concentrations in ambient air in the United States; results range from nondetectable to 69 ppb (IARC 1985)
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Repeated subchronic exposure of rats at higher concentrations (such as those greater than 500 ppm) has also resulted in inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium; moderate to severe lesions of the olfactory epithelium with neuronal loss and hyperplasia result at 1,500 ppm (Dorman et al.
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Subjects reported no increase in irritating symptoms after exposure to acetaldehyde as measured by questionnaire. There was a nonsignificant increase in mucociliary transport time, but no change in olfactory threshold.
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. Bronchoconstriction was noted in 21 of 46 asthmatics and corresponded with increased blood histamine and acetaldehyde concentrations and decreased enzymatic activity of acetaldehyde dehydrogenase 2 (ALDH2)
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. The acetaldehyde concentration resulting in a 50% reduction in respiratory rate (RD50)
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At 400 ppm, degeneration of the nasal olfactory epithelium was slight to moderate in most animals, without hyperplasia or metaplasia but with loss of microvilli, thinning and disarrangement of epithelial cells, and occasional loss of sensory cells. Thus, increasing acetaldehyde concentrations were associated with more severe epithelial lesions and effects deeper into the respiratory tract, going beyond the nasal cavity at 2,200 ppm.
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The investigators concluded that the fixed, variable, or peak exposure regimens tested had little effect on the toxicity of acetaldehyde to nasal epithelial cells. Another 4-week study examined pulmonary effects in nonsensitized or ovalbumin-sensitized guinea pigs that were challenged with an ovalbumin aerosol at the end of 4 weeks of exposure to acetaldehyde 6 h/day, 5 days/week (Lacroix et al.
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and ALDH2-/knockout mice to acetaldehyde at 0, 125, and 500 ppm 24 h/day for 14 days. ALDH2-/- mice, particularly at the highest concentration, showed greater erosion of the nasal respiratory epithelium; hemorrhage of the nasal subepithelium; hemorrhage of the nasal cavity; degeneration of the respiratory epithelium in larynx, pharynx, and trachea; erosion of the dorsal skin; and higher acetaldehyde blood concentration than the wild-type mice.
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Various in vitro tests have indicated effects on immune-system cells, but concentrations used in the cell cultures are much higher than what would result in the body from air concentrations causing initial upper respiratory system effects (reviewed by WHO 1995)
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has also classified acetaldehyde as a B2 or probable human carcinogen by inhalation on the basis of sufficient animal data (nasal tumors in rats and laryngeal tumors in hamsters)
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. Squamous cell carcinomas of the nasal respiratory epithelium showed clear concentration-related increases, whereas adenocarcinomas of the olfactory epithelium were highest in the middle-concentration group, possibly because of high mortality and competing squamous cell carcinomas in the high-concentration group.
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. Humans with the inactive variant of ALDH2 may have a lower critical concentration for saturation of acetaldehyde removal, which results in increased tissue concentrations in the upper respiratory tract, greater potential for systemic absorption, and deeper penetration at lower concentrations than in those with the active form of this enzyme.
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INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS A number of organizations have established or proposed acceptable exposure limits or guidelines for inhaled acetaldehyde. Selected values are shown in Table 2-2.
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Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; NAC, National Advisory Committee; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; SMAC, spacecraft maximum allowable concentration; TLV, Threshold Limit Value; TWA, time-weighted average. TABLE 2-3 Emergency and Continuous Exposure Guidance Levels for Acetaldehyde Current U.S.
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The uncertainty factor is based on the difference between blood acetaldehyde concentrations in ALDH2-deficient and wild-type mice at low air concentrations (a factor of about 1.4 at 125 ppm; Oyama et al.
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(2008) also calculated the reference concentration by converting the rat nasal tissue concentration to a human-equivalent air concentration by using the PBPK model in humans and then applying the uncertainty factor of 30 (see Figure 2-1)
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FIGURE 2-1 Calculation of the acetaldehyde reference concentration by Dorman et al.
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Differences in human sensitivity to acetaldehyde are expected to be less variable at low air concentrations because it is associated with direct tissue effects at the site of entry rather than systemic effects. The combined uncertainty factor is 6 on the basis of a factor of 3 for pharmacodynamic differences between rats and humans and a factor of 2 for intraindividual variation.
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Lower doses would not have cell proliferation to amplify the genotoxic effects and therefore would be associated with a substantially lower risk of tumor formation. The toxicokinetic and mechanistic evidence suggests that the dose-response relationship for acetaldehyde toxicity may also be nonlinear as the activity of ALDH becomes saturated; this would allow tissue concentrations to increase more rapidly.
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1986. Histochemical localization of aldehyde dehydrogenase in the respiratory tracts of the Fisher 344 rat.
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2008. Derivation of an inhalation reference concentration based upon olfactory neuronal loss in male rats following subchronic acetaldehyde inhalation.
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Presentation to the First Meeting on Emergency and Continuous Ex posure Guidance Levels for Selected Submarine Contaminants, June 17, 2008, Washington, DC.
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1997b. Uptake of acetaldehyde vapor and aldehyde dehydrogenase levels in the upper respiratory tracts of the mouse, rat, hamster, and guinea pig.
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Pp. 103-138 in Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, Vol.
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Inhalation Carcinogenicity Study of Acetaldehyde in Rats: Final Report. Report No.
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