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ANNOTATED REFERENCE OUTLINE
FOR THE TOXICOLOGICAL REVIEW
OF
Acetaldehyde
(CAS No. 75-07-0)
In Support of Summary Information on the
Integrated Risk Information System (IRIS)
6/1/10
NOTICE
This document is an [author: insert Agency Review, Interagency Review or
External Review] draft. It has not been formally released by the U.S.
Environmental Protection Agency and should not at this stage be construed to
represent Agency position on this chemical. It is being circulated for review of its
technical accuracy and science policy implications.
U.S. Environmental Protection Agency
Washington, DC

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3.4. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS
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Brown, RP; Delp, MD; Lindstedt, SL; et al. (1997) Physiological parameter values for physiologically based
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Cheng, K; Cheng, Y; Yeh, H; Swift, D. (1997) Measurements of airway dimensions and calculation of mass transfer
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Collins, L; Dawes, C. (1987) The surface area of the adult human mouth and thickness of the salivary film covering
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model for vinyl acetate against human nasal dosimetry data. Toxicol Sci 85:460-467.
Kaneko, T; Wang, PY; Sato, A. (1994) Partition coefficients of some acetate esters and alcohols in water, Blood,
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Kimbell, JS; Godo, MN; Gross, EA; et al. (1997) Computer simulation of inspiratory airflow in all regions of the
F344 rat nasal passages. Toxicol Appl Pharmacol 145:388-398.
Kimbell, JS; Subramaniam, RP; Gross, EA; et al. (2001) Dosimetry modeling of inhaled formaldehyde: Comparisons
of local flux predictions in the rat, monkey, and human nasal passages. Toxicol Sci 64:100-110.
Meurman, J; Rantonen, P. (1994) Salivary flow rate, buffering capacity, and yeast counts in 187 consecutive adult
patients from Kuopio, Finland. Scand J Dental Res 102:229-234.
Morris, JB. (1997b) Dosimetry, toxicity and carcinogenicity of inspired acetaldehyde in the rat. Mutat Res 380:113—
124.
Morris, JB; Blanchard, KT. (1992) Upper respiratory tract deposition of inspired acetaldehyde. Toxicol Appl
Pharmacol 114(1): 140-146.
Morris JB; Hassett DN; Blanchard KT (1993). A physiologically based pharmacokinetic model for nasal uptake and
metabolism of nonreactive vapors. Toxicol. Appl. Pharmacol. 123: 120-129.
Morris, JB; Robinson, DE; Vollmuth, TA; et al. (1996) A parallelogram approach for safety evaluation of ingested
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inspiratory airflow in the human nose and nasopharynx. Inhal Toxicol 10:91-120.
Teeguarden, JG; Bogdanffy, MS; Covington, TR; et al. (2008) A PBPK model for evaluating the impact of aldehyde
dehydrogenase polymorphisms on comparative rat and human nasal tissue acetaldehyde dosimetry. Inhal Toxicol 20:
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administration in the fasting state. J Pharmacokinet Biopharm 5:207-224.
4. HAZARD IDENTIFICATION
4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS
American Thoracic Society. (1987) Standard for diagnosis and care of patients with chronic obstructive pulmonary
disease (COPD) and asthma. Am. Rev Respir Dis 136:225-244.
Bittersohl, G. (1974) Epidemiologic investigations on cancer incidence in workers contacted by acetaldol and other
aliphatic aldehydes. Arch Geschwulstforsch 43:172-176.
Delfino, RJ; Gong, H, Jr; Linn, WS; et al. (2003) Asthma symptoms in Hispanic children and daily ambient
exposures to toxic and criteria air pollutants. Environ Health Perspect 111 :647-656.
Homann, N; Konig, IR; Marks, M; et al. (2009) Alcohol and colorectal cancer: the role of alcohol dehydrogenase 1C
polymorphism. Alcohol Clin Exp Res 33:551-556.
Kim, JS; Kim, YJ; Kim, TY; et al. (2005) Association of ALDH2 polymorphism with sensitivity to acetaldehyde-
induced micronuclei and facial flushing after alcohol intake. Toxicology 210:169-174.
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Lachenmeier, DW; Kanteres, F; Rehm, J. (2009) Carcinogenicity of acetaldehyde in alcoholic beverages: risk
assessment outside ethanol metabolism. Addiction 104:533-550.
Li. DP; Dandara. C; Walther. G; et al. (2008) Genetic polymorphisms of alcohol metabolising enzymes: their role in
susceptibility to oesophageal cancer. Clin ChemLab Med 46:323-328.
Matsu.se. H; Fukushima. C; Shimoda. T; et al. (2007) Effects of acetaldehyde on human airway constriction and
inflammation In Acetaldehy de-related pathology: Bridging the trans-disciplinary divide. Chichester, UK: John
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Muttray, A; Gosepath, J; Brieger, J; et al. (2009) No acute effects of an exposure to 50 ppm acetaldehyde on the
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Myou, S; Fujimura, M; Kamio, Y; et al. (1995) Repeated inhalation challenge with exogenous and endogenous
histamine released by acetaldehyde inhalation in asthmatic patients. Am J Resp Crit Care Med 152(2):456-460.
Myou, S; Fujimura, M; Nishi, K; et al. (1993) Aerosolized acetaldehyde induces histamine-mediated
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Myou, S; Fujimura, M; Nishi, K; Ohka, T; Matsuda, T. (1994) Potentiating effect of inhaled acetaldehyde on
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Nelson, KW; Fox, JF Jr.; Morwick, R; et al. (1943) Sensory response to certain industrial solvent vapors. J Ind Hyg
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Ott, MG; Teta, MJ; Greenberg, HL. (1989a) Lymphatic and hematopoietic tissue cancer in a chemical manufacturing
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Ott, MG; Teta, MJ; Greenberg, HL. (1989b) Lymphatic and hematopoietic tissue cancer in a chemical manufacturing
environment. Am J Ind Med 16(6):631-643.
Ott, MG; Teta, MF; Greenberg, HL. (1989c) Assessment of exposure to chemicals in a complex work environment.
Am J Ind Med 16:617-630.
Prieto, L; Sanchez-Toril, F; Brontons, B; et al. (2000) Airway responsiveness to acetaldehyde inpatients with
asthma: relationship to methacholine responsiveness and peak expiratory flow variation. ClinExptl Allergy 30:71-
78.
Prieto, L; Sanchez-Toril, F; Gutierrez, V; et al. (2002) Airway responsiveness to inhaled acetaldehyde in subjects
with allergic rhinitis: relationship to methacholine responsiveness. Respiration 69:129-135.
Prieto L; Gutierrez V; Cervera A; et al. (2002) Airway obstruction induced by inhaled acetaldehyde in asthma:
Repeatability relationship to adenosine 5'-monophosphate responsiveness. J Investig Allergol Clin Immunol 12:91—
98.
Rinsky, RA; Ott, MG; Ward, E; et al. (1988) Study of mortality among chemical workers in the Kanawha Valley of
West Virginia. Am J Ind Med 13:429-438.
Silverman, L; Schulte, HF; First, MW. (1946) Further studies on sensory response to certain industrial solvent
vapors. J Ind Hyg Toxicol 28:262-266.
Sim,VM; Pattle, RE. (1957) Effect of possible smog irritants on human subjects. JAMA 163(13): 1908—1913.
Visapaa, JP; Gotte, K; Benesova, M; et al. (2004) Increased cancer risk in heavy drinkers with the alcohol
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Yang. CX; Matsuo. K; Ito. H; et al. (2005) Esophageal cancer risk by ALDH2 and ADH2 polymorphisms and
alcohol consumption: Exploration of gene-environment and gene-gene interactions. Asian Pacific Journal of Cancer
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Yin, G; Kono, S; Toyomura, K; et al. (2007) Alcohol dehydrogenase and aldehyde dehydrogenase polymorphisms
and colorectal cancer: the Fukuoka Colorectal Cancer Study. Cancer Sci 98:1248-1253.
Yokoyama, A; Omori, T. (2003) Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for
esophageal and head and neck cancers. JpnJ Clin Oncol 33:111-121.
Yokoyama, A; Omori, T. (2005) Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for
esophageal and head and neck cancers. Alcohol 35:175-185.
4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIO ASSAYS IN ANIMALS—ORAL AND
INHALATION
Appelman, LM; Woutersen, RA; Feron, VJ; Hooftman, RN; Notten, WRF. (1986) Effect of variable versus fixed
exposure levels on the toxicity of acetaldehyde in rats. J Appl Toxicol 6(5):331-336.
ASTM. (1984) Standard test method for estimating sensory irritancy of airborne chemicals. Designation E981.
American Society for Testing and Materials, Philadelphia.
Babiuk, C; Steinhagen, WH; Barrow, CS. (1985) Sensory irritation response to inhaled aldehydes after formaldehyde
pretreatment. Toxicol Appl Pharmacol 79:143-149.
Bankowski, E; Pawlicka, E; Sobolewski, K. (1993) Liver collagen of rats submitted to chronic intoxication with
acetaldehyde. Mol Cell Biochem 121(1):37—43.
Boo/e. TF; Oehme. FW (1986). An investigation of metaldehvde and acetaldehyde toxicities in dogs. Fundam Appl
Toxicol 6:440-446.
Boulet, L-P. (1988) Increases in airway responsiveness following acute exposure to respiratory irritants: Reactive
airway dysfunction syndrome or occupational asthma? Chest 94(3):476-481.
Cassee, FR; de Burbure, CY; Rambali, B; et al. (2008) Subchronic inhalation of mixtures of cigarette smoke
constituents in Xpa-/-p53+/- knock-out mice: a comparison of intermittent with semi-continuous exposure to
acetaldehyde, formaldehyde, and acrolein. Food Chem Toxicol 46:527-536.
Dorman, DC; Struve, MF; Wong, BA; et al. (2008) Derivation of an inhalation reference concentration based upon
olfactory neuronal loss in male rats following subchronic acetaldehyde inhalation. Inhal Toxicol 20:245-256.
Feron, VJ. (1979) Effects of exposure to acetaldehyde in Syrian hamsters simultaneously treated with
ben/o(aIpyrene or diethvlnitrosamine. Prog Exp Tumor Res 24:162-176.
Feron. VJ; Kruysse, A; Woutersen. RA. (1982) Respiratory tract tumours in hamsters exposed to acetaldehyde
vapour alone or simultaneously to benzo(a)pyrene or diethvlnitrosamine. Eur J Cancer 18:13-31.
Guo, R; Zhong, L; Ren, J. (2009) Overexpression of aldehyde dehydrogenase-2 attenuates chronic alcohol exposure-
induced apoptosis, change in Akt and Pim signalling in liver. Clin Exp Pharmacol Physiol 36:463-468.
HoLownia, A; Chwiecko, M; PawLowska, D; et al. (1992) The diminution of liver glutathione content and changes
in activities of antioxidant enzymes in long-term acetaldehyde poisoning. Rocz Akad Med Bialystok 37:18-23.
Homann, N; Karkkainen, P; Koivisto, et al. (1997) Effects of acetaldehyde on cell regeneration and differentiation of
the upper gastrointestinal tract mucosa. J Natl Cancer Inst 89:1692-1697.
Kruysse, A; Feron, VJ; Til, HP. (1975) Repeated exposure to acetaldehyde vapor. Arch Environ Health 30:449-452.
Milch, RA. (1964) Aqueous solution infrared spectra of collagen-reactive aldehydes. Biochem Biophys Acta 93:45-
53.
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Pawlicka, E; Bankowski, E; Sobolewski, K. (1991) Chronic intoxication with acetaldehyde stimulates collagen
biosynthesis in rat liver. Arch Toxicol 65(8):678-680.
Saldiva, PHN; Do Rio Caldeira, MP; Massad, CW; et al. (1985) Effects of formaldehyde and acetaldehyde
inhalation on rat pulmonary mechanics. J Appl Toxicol 5(5):288-292.
Schauenstein, E; Estenbauer, H; Zollner, H. (1977) Aldehydes in biological systems. Pio Ltd., London.
SolTritti. M; Belpoggi, F; Lambert in. L; et al. (2002) Results of long-term experimental studies on the
carcinogenicity of formaldehyde and acetaldehyde in rats. Ann N Y Acad Sci 982:87-105.
Stanek, J; Symanowicz, PT; Olsen, JE; et al. (2001) Sensory-nerve mediated nasal vasodilatory response to inspired
acetaldehyde and acetic acid vapors. Inhal Toxicol 13:807-822.
Steinhagen, WH; Barrow, CS. (1984) Sensory irritation structure-activity study of inhaled aldehydes inBC3Fl and
Swiss-Webster mice. Toxicol Appl Pharmacol 72:495-503.
Til, HP; Woutersen, RA; Feron, VJ; Clary, JJ. (1988) Evaluation of the oral toxicity of acetaldehyde and
formaldehyde in a 4-week drinking-water study in rats. Food Chem Toxicol 26(5):447-452.
Woutersen, RA; Ferron, VJ. (1987) Inhalation toxicity of acetaldehyde in rats. IV. Progression and regression of
nasal lesions after discontinuation of exposure. Toxicology 47(3):295-305.
Woutersen, R; van Garderen-Hoetmer, A; Appelman, LM. (1985) Lifespan (27 months) inhalation carcinogenicity
study of acetaldehyde in rats. Report No. V85.145/190172. CIVO-Institutes TNO, The Netherlands.
Woutersen, RA; Appelman, LM. (1984) Lifespan inhalation carcinogenicity study of acetaldehyde in rats. III.
Recovery after 52 weeks of exposure. Report No. V84.288/190172. CIVO-Institutes TNO, The Netherlands.
Woutersen, RA; Appelman, LM; Feron, VJ, van der Heijden, CA. (1984) Inhalation toxicity of acetaldehyde in
rats. II. Carcinogenicity study: interim results after 15 months. Toxicology 31:123 133.
Woutersen, RA; Appelman, LM; van Garderen-Hoetmer, A; et al. (1986) Inhalation toxicity of acetaldehyde in rats.
III. Carcinogenicity study. Toxicology 41(2):213—231.
Woutersen, RA; Ferron, VJ. (1987) Inhalation toxicity of acetaldehyde in rats. IV. Progression and regression of
nasal lesions after discontinuation of exposure. Toxicology 47(3):295-305.
4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION
Anderson, R A Jr; Quigg, JM; Oswald, C; et al. (1985) Demonstration of a functional blood-testis barrier to
acetaldehyde: evidence for lack of acetaldehyde effect on ethanol-induced depression of testosterone in vivo.
Biochem Pharmacol 34:685-695.
Anderson, RA; Reddy, JM; Joyce, C; Willis, BR; Van der Vend, H; Zaneveld, LJ. (1982) Inhibition of mouse sperm
capacitationby ethanol. Biol Reprod 27:833-840.
Asai, M; Narita, O; Kashiwamatu, S. (1985) Effect of acetaldehyde and/or ethanol on neutral amino acid transport
systems in microvillous brush border membrane vesicles prepared from human placenta. Experientia 41:1566-1568.
Badr, FM; Bartke, A; Dalterio, S; Bulger, W. (1977) Suppression of testosterone production by ethyl alcohol.
Possible mode of action. Steroids 30:647-655.
Bannigan, J; Burke, P. (1982) Ethanol teratogenicity in mice: A light microscopic study. Teratology 26:247-254.
Barilyak, IR; Kozachuk, SY. (1983) Embryotoxic and mutagenic activity of ethanol and acetaldehyde in intra-
amniotic exposure. Tsitol Genet (USSR) 17:57-60.
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Beck, F. (1981) Comparative placental morphology and function. In: Developmental Toxicology (Kimmel, CA;
Buelke-Sam, J, eds). New York: Raven Press, p. 35-54.
Blakley, PM; Scott, WJ. (1984a) Determination of the proximate teratogen of the mouse fetal alcohol syndrome.1.
Teratogenicity of ethanol and acetaldehyde. Tox Appl Pharmacol 72:355-363.
Blakley, PM; Scott, WJ. (1984b) Determination of the proximate teratogen of the mouse fetal alcohol syndrome. 2.
Pharmacokinetics of the placental transfer of ethanol and acetaldehyde. Tox Appl Pharmacol 72:364-371.
Boyden, TW; Silvert. MA; Pamenter. RW. (1981) Acetaldehyde acutely impairs canine testicular testosterone
secretion. Eur J Clin Pharmacol 70:571-576.
Campbell. MA; Fantel. AG. (1983) Teratogenicity of acetaldehyde in vitro: relevance to the fetal alcohol syndrome.
Life Sci 32:2641-2647.
Checiu. M; Sandor. S; Garban. Z. (1984) The effect of ethanol upon early development in mice and rats VI In vivo
effect of acetaldehyde upon preimplantation stages in rats. Morphol Embryol (Bucur) 30:175-184.
Cicero, TJ; Bell, RD; Badger, TM. (1980a) Acetaldehyde directly inhibits the conversion of androstenedione to
testosterone in the testes. Adv Exp Med Biol 132:211-217.
Cicero, TJ; Bel.l RD; Meyer. ER; Badger, TM. (1980b). Ethanol and acetaldehyde directly inhibit testicular
steroidogenesis. J Pharmacol Exp Ther 213:228-233.
Cicero, TJ; Bell, RD. (1980c) Effects of ethanol and acetaldehyde on the biosynthesis of testosterone in the rodent
testes. Biochem Biophys Res Commun 94:814-819.
Dreosti. IE; Ballard. FJ; Belling. GB; et al. (1981) The effect of ethanol and acetaldehyde on DNA synthesis in
growing cells and on fetal development in the rat. Alcohol Clin Exp Res 5:357-362.
Cobb. CF; Ennis. MF; Michael. F; et al. (1978) Acetaldehyde and ethanol are direct testicular toxins. Surg Forum
29:641-644.
Cobb. CF; Ennis. MF; Van Thiel. DH; et al. (1980) Isolated testes perfusion: a method using a cell- and protein-free
perfusate useful for the evaluation of potential drug injury. Metabolism 29:71-79.
Fadel, RAR; Persaud, TVN. (1991) Craniofacial ossification in the rat following prenatal exposure to alcohol,
acetaldehyde and cafeine., 12: 181-184.
Fadel, RAR; Persaud, TVN. (1993) Ossification of the vertebral column in the offspring of rats exposed to alcohol,
acetaldehyde and caffeine. Exp Toxicol Pathol, 45: 51-54.
Fisher. SE; Atkinson, M; Van Thiel. DH (1984). Selective fetal malnutrition: the effect of nicotine, ethanol. and
acetaldehyde upon in vitro uptake of alpha-aminoisobutyric acid by human term placental villous slices. Dev
Pharmacol Therapeut, 7: 229-238.
Fisher, SE; Atkinson, M; Holzman, I; David, R; et al. (1981a) Effects of ethanol upon placental uptake of amino
acids. Prog Biochem Pharmacol 18:216-223.
Fisher, SE; Atkinson. M; Van Thiel. DH; et al. (1981) Selective fetal malnutrition: the effect of ethanol and
acetaldehyde upon in vitro uptake of alpha amino isobutyric acid by human placenta. Life Sci 29:1283-1288.
Fort, DJ; McLaughlin, DW; Rogers, RL; et al. (2003) Evaluation of the developmental toxicities of ethanol,
acetaldehyde, and thioacetamide using FETAX. Drug Chem Toxicol 26:23-34.
Hartl, MW; Shibley, IA, Jr. (2002) Supraphysiological acetaldehyde levels suppress growth in chicken embryos.
Alcohol 28:111-115.
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Hazelton Laboratories America, Inc. (1983). Teratology screen in rats using C-180, C-181, C-236, C-254, C-255, C-
256, C-257, C-258, and C-259: Revised final report. Hazeleton Laboratories America Inc., Vienna, VA. Project No.
299-534.
Henderson, GI; Turner, D; Patwardhan, RV; et al. (1981) Inhibition of placental valine uptake after acute and
chronic maternal ethanol consumption. J Pharmacol Exp Therap 216(3):465-472.
Henderson, GI; Patwardhan, RV; McLeroy, S; et al. (1982) Inhibition of placental amino acid uptake in rats
following acute and chronic ethanol exposures. Alcoholism 6:495-500.
Higuchi, Y; Matsumoto, N. (1984) Embryotoxicity of ethanol and acetaldehyde: direct effects on mouse embryo in
vitro. Congen Anom (Senten IJO) 24:9-28.
Imai, T; Omoto, M. (1992) Effects of acetaldehyde exposure on maternal rats and their offspring. Jpn J Alcohol
Stud Drug Depend 27(3):334-354.
Kawamoto, K. (1981) Effects of alcohol and its metabolites on the hatching process of chicken eggs. Nichidai Igaku
Izasshi 40:249-260.
Johnson, DE; Chiao, Y-B; Gavaler, JS; Van Thiel, DH. (1981) Inhibition of testosterone synthesis by ethanol and
acetaldehyde. Biochem Pharmacol 36:1827-1831.
Lahdetie, J. (1988) Effects of vinyl acetate and acetaldehyde on sperm morphology and meiotic micronuclei in mice.
MutatRes 202:171-178.
Lee, RD; An, SM; Kim, SS; et al. (2005) Neurotoxic effects of alcohol and acetaldehyde during embryonic
development. J Toxicol Environ Health A 68:2147-2162.
Messiha, FS. (1980) Testicular and epididymal aldehyde dehydrogenase in rodents: modulation by ethanol and
disulfiram. Int J Androl 3:375-382.
Messiha, FS. (1981) Subcellular localization and biochemical properties of rat testicular alcohol- and aldehvde-
dehydrogenase. Sys Biol Reprod Med 7:329-335.
Messiha, FS. (1983) Subcellular distribution of oxidoreductases in genital organs of the male rat. Neurobehav
Toxicol Teratol 5:241-245.
O'Shea, KS; Kaufman, MH. (1979) Teratogenic effects of acetaldehyde: implications for the study of fetal alcohol
syndrome. J Anat 128:65-76.
O'Shea, KS; Kaufman, MH. (1981) Effects of acetaldehyde on neuroepithelium of early mouse embryos. J Anat
132:107-118.
Padmanabhan, R; Sreenathan, RN; Singh, S. (1983) Studies of the lethal and teratogenic effects of acetaldehyde in
the rat. Congen Anom (Senten IJO) 23:13-23.
Popov, VB; Vaisman, BL; Puchkov, VP; et al. (1982) Toxic effects of ethanol and its biotransformation products on
post-implantation embryos in culture. Bull Exp Biol Med (Rus) 92:1707-1710.
Priscott, PK. (1985) The effect of acetaldehyde and 2,3-butanediol on rat embryos developing in vitro. Biochem
Pharmacol 34:529-532.
Santucci, L; Graham, TJ; Van Thiel, DH. (1983) Inhibition of testosterone production by rat Leydig cells with
ethanol and acetaldehyde: prevention of ethanol toxicity with 4-methylpyrazole. Alcoholism 7:135-139.
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Sreenathan, RN; Padmanabhan, R. (1984) Structural changes of placenta following maternal administration of
acetaldehyde in the rat. Z Mikrosk Anat Forsch (E Germ) 98:597-600.
Sreenathan, RN; Padmanabhan, R; Singh, S. (1982) Teratogenic effects of acetaldehyde in the rat. Drug Alcohol
Depend 9:339-350.
Sreenathan, RN; Singh, S; Padmanabhan, R. (1984a) Implications of the placenta in the acetadehyde-induced intra-
uterine growth retardation. Drug Alcohol Depend 13:199-204.
Sreenathan, RN; Singh, S; Padmanabhan, R. (1984b) Effects of acetaldehyde on skeletogenesis in the rat. Drug
Alcohol Depend 14:165-174.
Thompson, P AC; Folb, PI. (1982) An in vitro model of alcohol and acetaldehyde teratogenicity. J Appl Toxicol
2:190-195.
Varma, P; Persaud, T. (1979) Influence of pyrazole, an inhibitor of alcohol dehydrogenase, on the prenatal toxicity
of ethanol in the rat. Res Commun Chem Pathol Pharmacol 26:65-73.
Veghelyi, PF; Osztovics, M; Kardos, G; et al. (1978) The fetal alcohol syndrome: Symptoms and pathogenesis. Acta
Paediatr Acad SciHung 19(3): 171—189.
Webster, WS; Walsh, DA; McEwen, SE; et al. (1983) Some teratogenic properties of ethanol and acetaldehyde in
C57BL/6J mice; implications for the study of fetal alcohol syndrome. Teratol 27:231-243.
4.4 OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES
Alarie, Y. (1966) Irritating properties of airborne materials to the upper respiratory tract. Arch Environ Health
13:433-449.
Alarie, Y. (1973) Sensory irritation of the upper airways by airborne chemicals. Toxicol Appl Pharmacol 24:279-
297.
Appelman. LM; Woutersen. RA; et al. (1982). Inhalation toxicity of acetaldehyde in rats I Acute and subacute
studies. Toxicology 23:293-307.
Babiuk. C; Steinhagen. WH; Barrow, CS. (1985). Sensory irritation response to inhaled aldehydes after
formaldehyde pretreatment. Toxicol Appl Pharmacol 79:143-149.
Bascom. R. (1992) Differential responsiveness to irritant mixtures: Possible mechanisms. Ann N Y Acad Sci
641:225-247.
Bergh M; Karlberg AT. (1999) Sensitizing potential of acetaldehyde and formaldehyde using a modified cumulative
contact enhancement test (CCET). Contact Dermatitis 40:139-145.
Bos, PMJ; Zwart, A; Reu/el. PGJ; et al. (1992) Evaluation of the sensory irritation test for the assessment of
occupational health risk. Grit Rev Toxicol 21:423-450.
Boulet. L-P. (1988) Increases in airway responsiveness following acute exposure to respiratory irritants: Reactive
airway dysfunction syndrome or occupational asthma? Chest 94:476-481.
Brooks. SM; Weiss, MA; Bernstein, IL. (1985) Reactive airways dysfunction syndrome (RADS: Persistent asthma
syndrome after high level irritant exposures. Chest 88:376-384.
Carr, MJ; Undem, BJ. (2001) Inflammation-induced plasticity of the afferent innervation of the airways. Environ
Health Perspect 4:567-571.
Cassee. FR; Arts, JHE; Groten. JP; et al. (1996) Sensory irritation to mixtures of formaldehyde, acrolein, and
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acetaldehyde in rats. Arch Toxicol 70:329-337.
Chang, JCF; Barrow, CS. (1984) Sensory irritation tolerance and cross-tolerance inF-344 rats exposed to chlorine or
formaldehyde gas. Toxicol Appl Pharmacol 76:319-327.
Correa, M; Arizzi, MN; Betz, A; et al. (2003) Open field locomotor effects in rats after intraventricular injections of
ethanol and the ethanol metabolites acetaldehyde and acetate. Brain Res Bull 62:197-202.
Isse. T; Ovama. T; Matsuno. K; et al. (2005) Paired acute inhalation test reveals that acetaldehyde toxicity is higher
in aldehyde dehydrogenase 2 knockout mice than in wild-type mice. J Toxicol Sci 30:329-337.
Isse. T; Ovama. T; Matsuno. K; Uchiyama I; et al. (2005) Aldehyde dehydrogenase 2 activity affects symptoms
produced by an intraperitoneal acetaldehyde injection, but not acetaldehyde lethality. J Toxicol Sci 30:315-328.
Jamal. M; A me no. K; Ikuo. U; et al. (2007) Ethanol and acetaldehyde: in vivo quantitation and effects on cholinergic
function in rat brain. Novartis Found Symp. 285:137-141; discussion 141-134. 198-199.
Kane. LE; Barrow, CS; Alarie. Y. (1979) A short-term test to predict acceptable levels of exposure to airborne
sensory irritants. Am Ind Hyg Assoc J 40:207-229.
Kane, LE; Dombroske, R; Alarie, Y. (1980) Evaluation of sensory irritation from some common industrial solvents.
Am Ind Hyg Assoc J 41:451-455.
Lacroix, G; Tissot. S; Rogerieux. F; et al. (2002) Decrease in ovalbumin-induced pulmonary allergic response by
benzaldehyde but not acetaldehyde exposure in a Guinea pig model. J Toxicol Environ Health A Curr Iss 65:995-
1012.
Matsu.se. H; Fukushima, C; Shimoda. T; et al. (2007) Effects of acetaldehyde on human airway constriction and
inflammation. In Acetaldehy de-related pathology: Bridging the trans-disciplinary divide. Chichester, UK: John
Wiley & Sons. Ltd., pp. 97-106.
Nakamura. Y; Yokoyama. H; Higuchi. S; et al. (2004) Acetaldehyde accumulation suppresses Kupffer cell release of
TNF-Alpha and modifies acute hepatic inflammation in rats. J Gastroenterol 39:140-147.
Nielsen. GD. (1991) Mechanisms of activation of the sensory irritant receptor by airborne chemicals. Crit Rev
Toxicol 21:183-208.
Ovama. T; Isse, T; Ogawa, M; et al. (2007) Susceptibility to inhalation toxicity of acetaldehyde in Aldh2 knockout
mice. Front Biosci. 12:1927-1934.
Saldiva. PHN; Caldeira. MPR; Massad. E; et al. (1985) Effects of formaldehyde and acetaldehyde inhalation on rat
pulmonary mechanics. J Appl Toxicol 5:288-292.
Sanchez-Catalan, MJ; Hipolito, L; Zornoza, T. (2009) Motor stimulant effects of ethanol and acetaldehyde injected
into the posterior ventral tegmental area of rats: role of opioid receptors. Psychopharmacology (Berl) 204:641-653.
Schauenstein, E; Estenbauer, H; Zollner, H. (1977) Aldehydes in biological systems. Pio Ltd., London.
Stanek, J; Symanowicz, PT; Olsen, JE; et al. (2001) Sensory-nerve mediated nasal vasodilatory response to inspired
acetaldehyde and acetic acid vapors. Inhal Toxicol 13:807-822.
Steinhagen. WH; Barrow. CS. (1984) Sensory irritation structure-activity study of inhaled aldehydes in B6C3F1 and
Swiss-Webster mice. Toxicol Appl Pharmacol 72:495-503.
Togias, A. (1999) Mechanisms of nose-lung interaction. Allergy 54:94-105.
4.5 MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION
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4.5.1
MECHANISMS OF NONCANCER EFFECTS
Asai, M; Narita, O; Kashiwamatu, S. (1985) Effect of acetaldehyde and/or ethanol on neutral amino acid transport
systems in microvillous brush border membrane vesicles prepared from human placenta. Experientia 41:1566-1568.
Barnes, PJ. (1992) Neurogenic inflammation and asthma. J Asthma 29:165-180.
Beck, F. (1981) Comparative placental morphology and function. In: Developmental Toxicology (Kimmel, CA;
Buelke-Sam, J, eds). New York: Raven Press, p. 35-54.
Boyden, TW; Silvert. MA; Pamenter. RW. (1981) Acetaldehyde acutely impairs canine testicular testosterone
secretion. Eur J Clin Pharmacol 70:571-576.
Cicero, TJ; Bell. RD; Badger, TM (1980). Acetaldehyde directly inhibits the conversion of androstenedione to
testosterone in the testes. Presented at In: Thurman, R. G., ed. Alcohol and aldehyde metabolizing systems - IV:
proceedings of the third international symposium; July 1979; Toronto, ON. Canada. New York. NY: Plenum Press;
pp. 211-217. (Advances in experimental medicine and biology: v. 132).
Fisher, SE; Atkinson. M; Van Thiel. DH; et al. (1981) Selective fetal malnutrition: the effect of ethanol and
acetaldehyde upon in vitro uptake of alpha amino isobutyric acid by human placenta. Life Sci 29:1283-1288.
Fisher, SE; Atkinson, M; Holzman, I; David, R; et al. (1981a) Effects of ethanol upon placental uptake of amino
acids. Prog BiochemPharmacol 18:216-223.
Fisher, SE; Atkinson. M; Van Thiel, DH (1984). Selective fetal malnutrition: the effect of nicotine, ethanol, and
acetaldehyde upon in vitro uptake of alpha-aminoisobutyric acid by human term placental villous slices. Dev
Pharmacol Therapeut, 7: 229-238.
Fujimura, M; Myou, S; Amemiya, T; Tachibana, H; Kita, T; Matsuda, T. (1997) Peptide leukotrienes mediate
acetaldehyde-induced bronchial hyper-responsiveness in guinea-pigs. Clin Exp Allergy 27(1): 104-109.
Green, MA; Egle, JL Jr. (1983) Effects of intravenous acetaldehyde, acrolein, formaldehyde and propionaldehyde
on arterial blood pressure following acute guanethidine treatment. Res Commun Mol Pathol Pharmacol, 40: 337-340.
Henderson, GI; Turner, D; Patwardhan, RV; et al. (1981) Inhibition of placental valine uptake after acute and
chronic maternal ethanol consumption. J Pharmacol Exp Therap 216(3):465-472.
Henderson, GI; Patwardhan, RV; McLeroy, S; et al. (1982) Inhibition of placental amino acid uptake in rats
following acute and chronic ethanol exposures. Alcoholism 6:495-500.
Johnston, DE; Chiao, Y-B; Gavaler, JS; Van Thiel, DH (1981). Inhibition of testosterone synthesis by ethanol and
acetaldehyde. Biochem Pharmacol, 30: 1827-1831.
Kawano, T; Matsuse, H; Kondo, Y; et al. (2004) Acetaldehyde induces histamine release from human airway mast
cells to cause bronchoconstriction. Int Arch Allergy Immunol 134:233-239.
Lacroix, G; Tissot, S, Rogerieux, F; et al. (2002) Decrease in ovalbumin-induced pulmonary allergic response by
benzaldehyde but not acetaldehyde exposure in a Guinea pig model. J Toxicol Environ Health A 65:995-1012.
Leikauf, GD. (2002) Hazardous air pollutants and asthma. Environ Health Perspect 110(Suppl. 4):505-526.
Li, SY; Gomelsky, M; Duan, J; et al. (2004) Overexpression of aldehyde dehydrogenase-2 (ALDH2) transgene
prevents acetaldehyde-induced cell injury in human umbilical vein endothelial cells: role of ERK andp38 mitogen-
activated protein kinase. J Biol Chem 279:11244-11252.
Li, SY; Li, Q; Shen, JJ; et al. (2006) Attenuation of acetaldehyde-induced cell injury by overexpression of aldehyde
dehydrogenase-2 (ALDH2) transgene in human cardiac myocytes: role of MAP kinase signaling. J Mol Cell Cardiol
40:283-294.
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4.6 SYNTHESIS OF MAJOR NONCANCER EFFECTS
4.6.1.	Oral
4.6.2.	Inhalation
4.6.3.	Mode-of-Action Information
4.7.	EVALUATION OF CARCINOGENICITY
4.7.1.	Summary of Overall Weight of Evidence
4.7.2.	Synthesis of Human, Animal, and Other Supporting Evidence
4.7.3.	Mode-of-Action Information
4.8.	SUSCEPTIBLE POPULATIONS AND LIFE STAGES
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6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE
6.1.	HUMAN HAZARD POTENTIAL
6.2.	DOSE RESPONSE
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