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LITERATURE SEARCH PRODUCT FOR

THE TOXICOLOGICAL REVIEW


OF
ACETALDEHYDE

(CAS No. 75-07-0)

In Support of Summary Information on the


Integrated Risk Information System (IRIS)

April 2012

CHEMICAL AND PHYSICAL INFORMATION


Badre, R; Guillern, R; Abran, N et al. (1978) Pollution atmospherique parlefumee de ta bac. Ann Pharm Fr 36:443 452. (French) Baez, A; Padilla, H; Garcia, R; Torres, MC; et al. (2003) Carbonyl levels in indoor and outdoor air in Mexico City and Xalapa, Mexico. Sci Total Environ 302:211226. Baez, AP; Padilla, HG; Garcia, RM; et al. (2004) Measurements of carbonyls in a 13-story building. Environ Sci Pollut Res Int 11:400404. Bakeas, EB; Argyris, DI; Siskos, PA. (2003) Carbonyl compounds in the urban environment of Athens, Greece. Chemosphere 52:805813. Baldauf, R; Fortune, C; Weinstein, J; et al. (2006) Air contaminant exposures during the operation of lawn and garden equipment. J Expo Sci Environ Epidemiol 16:362370. Ban-Weiss, GA; McLaughlin, JP; Harley, RA; et al. (2008) Carbonyl and nitrogen dioxide emissions from gasoline and diesel-powered motor vehicles. Environ Sci Technol 42:39443950. Boffetta, P., P. Kaihovaara, et al. (2011). Acetaldehyde level in spirits from central European countries. European Journal of Cancer Prevention 20(6): 526529. Brady, D; Pratt, GC. (2007) Volatile organic compound emissions from dry mill fuel ethanol production. J Air Waste Manag Assoc 57:10911102. Bruinen de, BY; Koistinen, K; Kephalopoulos, S; et al. (2008) Characterisation of urban inhalation exposures to benzene, formaldehyde and acetaldehyde in the European Union: comparison of measured and modelled exposure data. Environ Sci Pollut Res Int 15:417430. Buters, JT; Schober, W; Gutermuth, J; et al. (2007) Toxicity of parked motor vehicle indoor air. Environ Sci Technol 41:26222629. Clarisse, B; Laurent, AM; Seta, N; et al. (2003) Indoor aldehydes: measurement of contamination levels and identification of their determinants in Paris dwellings. Environ Res 92:245253. Correa, SM; Martins, EM; Arbilla, G. (2003) Formaldehyde and acetaldehyde in a high traffic street of Rio de Janeiro, Brazil. Atmos Environ 37:2329. Darowska, A; Borcz, A; Nawrocki J. (2003) Aldehyde contamination of mineral water stored in PET bottles. Food Addit Contam 20:11701177. Delcour, JA; Caers, JM; Dondeyne, P; Delvaux, F; Robberects, E. (1982) An enzymic assay for the determination of acetaldehyde in beers. J Inst Brew 88:384386. Feng, Y; Wen, S; Chen, Y; et al. (2005) Ambient levels of carbonyl compounds and their sources in Guangzhou, China. Atmos Environ 39:17891800. Filella, I; Peuelas, J. (2006) Daily, weekly, and seasonal time courses of VOC concentrations in a semi-urban area near Barcelona. Atmos Environt 40:77527769. Gilbert, NL; Guay, M; David, MJ; et al. (2005) Levels and determinants of formaldehyde, acetaldehyde, and acrolein in residential indoor air in Prince Edward Island, Canada. Environ Res 99:1117. Gillette, JW; Pohl, LR. (1977) A perspective on covalent binding and toxicity. J Toxicol Environ Health 2:24961. Grosjean, D; Grosjean, E. (2002) Airborne carbonyls from motor vehicle emissions in two highway tunnels. Res Rep Health Eff Inst:5778.

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Grosjean, D; Miguel, AH; Tavares, TM. (1990) Urban air pollution in Brazil: Acetaldehyde and other carbonyls. Atmos Environ 24B(1):101106. Guimaraes, CS; Custodio, D; de Oliveira, RC; et al. (2010) Comparative study of automotive, aircraft and biogenic emissions of aldehydes and aromatic compounds. Bull Environ Contam Toxicol 84:180184. Guo, H; Lee, SC; Louie, PK; et al. (2004) Characterization of hydrocarbons, halocarbons and carbonyls in the atmosphere of Hong Kong. Chemosphere 57:13631372. Gustafson, P; Barregard, L; Strandberg, B; et al. (2007) The impact of domestic wood burning on personal, indoor and outdoor levels of 1,3-butadiene, benzene, formaldehyde and acetaldehyde. J Environ Monit 9:2332. Hesterberg, TW; Lapin, CA; Bunn, WB. (2008) A comparison of emissions from vehicles fueled with diesel or compressed natural gas. Environ Sci Technol 42:64376445. Hoffman, D; Brunnenman, KD; Gori, GB; Wynder, EL. (1975) On the carcinogenicity of marijuana smoke. Recent Adv Phytochem 9:6381. Hugues, UJ; Hum, RW. (1960) A preliminary survey of hydrocarbon-derived oxygenated material in automobile exhaust gases. J Air Pollut Control Assoc 10:367371. Iovino, P; Salvestrini, S; Capasso, S. (2007) Background atmospheric levels of aldehydes, BTEX and PM10 pollutants in a medium-sized city of southern Italy. Ann Chim 97:597604. Jacobson, MZ. (2007) Effects of ethanol (E85) versus gasoline vehicles on cancer and mortality in the United States. Environ Sci Technol 41:41504157. Jia, LW; Shen, MQ; Wang, J; et al. (2005) Influence of ethanol-gasoline blended fuel on emission characteristics from a four-stroke motorcycle engine. J Hazard Mater 123:2934. Jo, WK; Lee, JW. (2002) In-vehicle exposure to aldehydes while commuting on real commuter routes in a Korean urban area. Environ Res 88:4451. Jurvelin, JA; Edwards, RD; Vartiainen; et al. (2003) Residential indoor, outdoor, and workplace concentrations of carbonyl compounds: relationships with personal exposure concentrations and correlation with sources. J Air Waste Manag Assoc 53:560573. Karavalakis, G; Stournas, S; Bakeas, E. (2009) Light vehicle regulated and unregulated emissions from different biodiesels. Sci Total Environ 407:33383346. Legreid, G; Reimann, S; Steinbacher, M; et al. (2007) Measurements of OVOCs and NMHCs in a Swiss highway tunnel for estimation of road transport emissions. Environ Sci Technol 41:70607066. Lovreglio, P; Carrus, A; Iavicoli, S; et al. (2009) Indoor formaldehyde and acetaldehyde levels in the province of Bari, South Italy, and estimated health risk. J Environ Monit 11:955961. Maarse, H; Visscher, CA. (1992) Volatile compounds in food. Qualitative and quantitative data. Suppl 3 and cumulative index. Zeist, Central Institute for Nutrition and Food Research, TNO, Biotechnology and Chemistry Institute, PP xxxiii - xli. Magnusson, R; Nilsson, C; Andersson, B. (2002) Emissions of aldehydes and ketones from a two-stroke engine using ethanol and ethanol-blended gasoline as fuel. Environ Sci Technol 36:16561664. Manning, DL; Maskarinec, MP; Jenkins, RA; et al. (1983) High performance liquid chromatographic determination of selected gas phase carbonyls in tobacco smoke. J Assoc Anal Chem 66(1):812. Margheri, G; Versini, G; Gianotti, I; et al. (1984) Acetaldehyde in beverages. Riv Society Ital Sci Aliment 5:401 406. Marchand C, Bulliot B, Le Calv S, Mirabel P. (2006) Aldehyde measurements in indoor environments in Strasbourg (France). Atmospheric Environment 40: 13361345.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Mohamed, MF; Kang, D; Aneja, VP. (2002) Volatile organic compounds in some urban locations in the United States. Chemosphere 47:853882. Moussa, SG; El-Fadel, M; Saliba, NA. (2006) Seasonal, diurnal and nocturnal behaviors of lower carbonyl compounds in the urban environment of Beirut, Lebanon. Atmospheric Environment 40:24592468. Okamato, M; Ohtsuka, K; Imai, J; et al. (1981) High performance liquid chromatographic determination of acetaldehyde in wine as its lutidine derivative. J Chromatogr 219:175178. Sax, SN; Bennett, DH; Chillrud, SN; et al. (2006) A cancer risk assessment of inner-city teenagers living in New York City and Los Angeles. Environ Health Perspect 114:15581566. Schupp, T; Bolt, HM; Hengstler, JG. (2005) Maximum exposure levels for xylene, formaldehyde and acetaldehyde in cars. Toxicology 206: 461470. TRI. (1993) Acetaldehyde: Toxic Release Inventory. U.S. Environmental Protection Agency. Available online at http://epa.gov/tri/. TRI. (2008) Acetaldehyde: Toxic Release Inventory. U.S. Environmental Protection Agency. Available online at http://epa.gov/tri/. Verschueren, U. (1983) Handbook of Environmental Data on Organic Chemicals, 2nd ed. New York: Van Nostrand Reinhold Co., pp. 139141.

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TOXICOKINETICS
Agarwal DP; Harada S; Goedde HW; et al. (1983) Cytosolic aldehyde dehydrogenase and alcoholism. Lancet 1:68. Aharonson, EF; Menkes, H; Gurtner, G; et al. (1974) Effect of respiratory flow rate on removal of soluble vapors by the nose. J Appl Physiol 37:654657. Andersen, ME; Jarabek, AM. (2001) Nasal tissue dosimetry issues and approaches for "Category 1" gases: a report on a meeting held in Research Triangle Park, NC, 1112 February, 1998. Inhal Toxicol 13:415436. Asgharian, B., O. T. Price, et al. (2012). A lung dosimetry model of vapor uptake and tissue disposition. Inhal Toxicol 24(3): 182193. Bardag-Gorce, F., J. Oliva, et al. (2010). S-adenosylmethionine decreases the peak blood alcohol levels 3 h after an acute bolus of ethanol by inducing alcohol metabolizing enzymes in the liver. Exp Mol Pathol 89(3): 217221. 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 72:364371. Bogdanffy MS; Randall HW; Morgan KT. (1986) Histochemical localization of aldehyde dehydrogenase in the respiratory tract of the Fischer-344 rat. Toxicol Appl Pharmacol 82:560567. Bogdanffy, MS; Sarangapani, R; Kimbell, JS; Frame, RS; Plowchalk, DR. (1998) Analysis of vinyl acetate metabolism in rat and human nasal tissues by an in vitro gas uptake technique. Toxicol Sci 46:235246. Boleda MD; Juli P; Moreno A; et al. (1989) Role of extrahepatic alcohol dehydrogenase in rat ethanol metabolism. Arch Biochem Biophys 274:7481. Booze TF; Oehme FW. (1986) An investigation of metaldehyde and acetaldehyde toxicities in dogs. Fundam Appl Toxicol 6:440446. Brecher, AS; Adamu MT. (2002) Short- and long-term effects of acetaldehyde on plasma. Alcohol 26:4953. Brooks, PJ; Goldman, D; Li, TK. (2009) Alleles of alcohol and acetaldehyde metabolism genes modulate susceptibility to oesophageal cancer from alcohol consumption. Hum Genomics 3:103105.

18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Brown, J; Fiatarone, R; Wood, P; et al. (1985) The effect of gastritis on human gastric alcohol dehydrogenase activity and ethanol metabolism. Alimentary Pharmacol Ther 9: 5761. Bunting KD; Townsend AJ. (1998) Dependence of aldehyde dehydrogenase-mediated oxazaphosphorine resistance on soluble thiols: Importance of thiol interactions with the secondary metabolite acrolein. Biochem Pharmacol 56:3139. Caballeria, J; Baraona, E; Leiber, CS. (1987) The contribution of the stomach to ethanol oxidation in the rat. Life Sci 41:10211027. Casanova-Schmitz M; David RM; Heck Hd'A. (1984) Oxidation of formaldehyde and acetaldehyde by NAD+ dependent dehydrogenases in rat nasal mucosal homogenates. Biochem Pharmacol, 33:11371142. Dalhamn, T; Edfors, M-L; Rylander, R. (1968a) Retention of cigarette smoke components in human lungs. Arch Environ Health 17:746748. Dalhamn, T; Edfors, M-L; Rylander, R. (1968b) Mouth absorption of various compounds in cigarette smoke. Arch Environ Health 16:831835. Dietrich, R. (1971) Genetic aspects of increase in rat liver aldehyde dehydrogenase induced by phenobarbital. Science (Washington, DC) 173:334337. Dietrich, RA; Collins, AC; Erwin, VA. (1972) Genetic influence upon phenobarbital-induced increase in rat liver supernatant aldehyde dehydrogenase activity. J Biol Chem 247:72327239. Deitrich, RA; Petersen, D; Vasiliou V. (2007) Removal of acetaldehyde from the body. Novartis Found Symp. 2007 285:2340; discussion 40-51, 1989. Di Padova C; Worner TM; Lieber CS. (1987) Effect of abstinence on the blood acetaldehyde response to a test dose of alcohol in alcoholics. Alcohol Clin Exp Res 11:559561. Dong YJ; Peng TK; Yin SJ. (1996) Expression and activities of class IV alcohol dehydrogenase and class III aldehyde dehydrogenase in human mouth. Alcohol 13:257262. Egle, JL Jr. (1970). Retention of inhaled acetaldehyde in man. J Pharmacol Exp Ther 174:1419. Egle, JL Jr. (1972) Retention of inhaled acetaldehyde in the dog. Arch Environ Occup Health, 24: 354357. Eriksson, CJ. (2007) Measurement of acetaldehyde: what levels occur naturally and in response to alcohol? Novartis Found Symp 285:24755; discussion 25660.: 247255. Fisher, SJ; Lee, IJ; Swaan, PW; et al. (2008) Evaluation of the effect of ethanol's toxic metabolite acetaldehyde on the gastrointestinal oligopeptide transporter, PEPT1: in vitro and in vivo studies. Alcohol Clin Exp Res 32:162 170. Frenzer A; Butler WJ; Norton ID; et al. (2002) Liver cirrhosis and hepatocellular carcinoma: Polymorphism in alcohol metabolizing enzymes, glutathione s-transferase and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis. J Gastroenterol Hepatol 17:177182. Freund, G. (1967) Serial determinations of acetaldehyde and acetone in alveolar air after standard amounts of ethanol. In Maickel, R. P. (Ed.). Biochemical factors in alcoholism. New York, NY: Pergamon Press. Fujimiya T; Yamaoka K; Ohbora Y; et al. (2002) Michaelis-Menten elimination kinetics of acetaldehyde during ethanol oxidation. Alcohol Clin Exp Res 26: 49S54S. Fujimiya T, Ohbora Y, Shinagawa H, et al. (2003) Pharmacokinetic study of ethanol and its metabolites during ethanol infusion. Leg Med (Tokyo) 5 Suppl 1:S126-8.: S126-S128. Gentry, RT; Baraona, E; Leiber, CS. (1994) Agonsit: Gastric first pass metabolism of alcohol. J Lab Clin Med 123:2126.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Ginsberg, G; Smolenski, S; Hattis, D; et al. (2002) Population distribution of aldehyde dehydrogenase-2 genetic polymorphism: Implications for risk assessment. Regul Toxicol Pharmacol 36:113. Goedde HW; Agarwal DP; Harada S. (1979) Alcohol metabolizing enzymes: Studies of isozymes in human biopsies and cultured fibroblasts. Clin Genet 16:2933. Goedde, HW; Agarwal, DP. (1987) Polymorphism of aldehyde dehydrogenase and alcohol sensitivity. Enzyme 37:2944. Guo, W. J., Q. Wang, et al. (2011). Gender-specific interactions between alcohol metabolism genes and severity of quantitative alcohol-related-traits in a Tibetan population. Neurosci Lett 495(1): 2225. Greenfield NJ; Pietruszko R. (1977) Two aldehyde dehydrogenases from human liver: isolation via affinity chromatography and characterization of the isozymes. Biochim Biophys Acta 483:3545. Greenfield, NJ; Pietruszko, R; Lin, G; et al. (1976) The effect of ethanol ingestion on the aldehyde dehydrogenases of rat liver. Biochim Biophys Acta 428:627639. 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 36:463468. Hald J; Jacobsen E; Larsen V. (1949). The rate of acetaldehyde metabolism in isolated livers and hind limbs of rabbits treated with antabuse (tetraethylthiuramdisulphide). Basic Clin Pharmacol Toxicol 5:298308. Hanna, LM; Lou, S-R; Su, S; Jarabek, AM. (2001) Mass transport analysis: Inhalation RfC methods framework for interspecies dosimetric adjustment. Inhal Toxicol 13(5):437463. Higuchi, S; Matsushita, S; Imazeki, H; et al. (1994) Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet 343:741742. Hinderliter PM; Thrall KD; Corley RA; et al. (2005) Validation of human physiologically based pharmacokinetic model for vinyl acetate against human nasal dosimetry data. Toxicol Sci 85:460467. Hobara N; Watanabe A; Kobayashi M; et al. (1985) Tissue distribution of acetaldehyde in rats following acetaldehyde inhalation and intragastric ethanol administration. Bull Environ Contam Toxicol 35:393396. Horton, AA. (1971) Induction of acetaldehyde in a mitochondrial fraction. Biochim Biophys Acta 253:514519. Horton, AA; Barrett, MC. (1976) Rates of induction of mitochondrial aldehyde dehydrogenase in rat liver. Biochem J 156:177183. Ibanes JD; Leininger JR; Jarabek AM; et al. (1996) Reexamination of respiratory tract responses in rats, mice, and rhesus monkeys chronically exposed to inhaled chlorine. Inhal Toxicol 8:859876. Ishikawa, H; Miyatsu, Y; Kurihara, K; et al. (2006) Gene-environmental interactions between alcohol-drinking behavior and ALDH2 and CYP2E1 polymorphisms and their impact on micronuclei frequency in human lymphocytes. Mutat Res 594:19. Isse, T; Oyama, 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 30:329337. Isse, T; Oyama, T; Matsuno, K; et al. (2005) Aldehyde dehydrogenase 2 activity affects symptoms produced by an intraperitoneal acetaldehyde injection, but not acetaldehyde lethality. J Toxicol Sci 30:315328. Jamal, M; Ameno, K; Ikuo, U; et al. (2007) Ethanol and acetaldehyde: in vivo quantitation and effects on cholinergic function in rat brain. Novartis Found Symp 285:13741; discussion 1414, 1989. Jones, AW. (1995) Measuring and reporting the concentration of acetaldehyde in human breath. Alcohol 30:271 85.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Julia, P; Farres, J; Pares, X. (1987) Characterization of three isoenzymes of rat alcohol dehydrogenase: Tissue distribution and physical and enzymatic properties. Eur J Biochem 162:179189. Julkunen, RJK; Tannenbaum, L; Baraona, E; et al. (1985) First pass metabolism of ethanol: An important determinant of blood levels after alcohol consumption. Alcohol 2:437441. Kallama S; Hemminki K. (1983) Urinary excretion products after the administration of 14C-acetaldehyde to rats. J Appl Toxicol 3:313316. Kayaalti, Z. and T. Soylemezoglu (2010). Distribution of ADH1B, ALDH2, CYP2E1 *6, and CYP2E1 *7B genotypes in Turkish population. Alcohol 44(5): 415423. Kimbell, JS; Subramaniam, RP; Gross, EA; Schlosser, PM; et al. (2001) Dosimetry modeling of inhaled formaldehyde: Comparisons of local flux predictions in the rat, monkey, and human nasal passages. Toxicol Sci 64:100110. Kimura, Y; Nishimura, FT; Abe, S; et al. (2009) A promoter polymorphism in the ALDH2 gene affects its basal and acetaldehyde/ethanol-induced gene expression in human peripheral blood leukocytes and HepG2 cells. Alcohol 44: 261266. Knowles, S; Jarrett, I; Filsell, O; Ballard, F. (1974) Production and utilization of acetate in mammals. Biochem J 142:401411. Koivula, T; Lindros, KO. (1975) Effects of long-term ethanol treatment on aldehydes and alcohol dehydrogenase activities in rat liver. Biochem Pharmacol 24:19371943. Larson, HN; Weiner, H; Hurley, TD. (2005) Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase "Asian" variant. J Biol Chem 280:3055030556. Levitt, MD. (1994) Agonsit: The case against first pass metabolism of ethanol in the stomach. J Lab Clin Med 123:2831. Lim, RT; Gentry, RT; Ito, D; Yokoyama, H; Baraona, E; Leiber, CS. (1993) First-pass metabolism of ethanol is predominantly gastric. Alcohol Clin Exp Res 17:13371344. Lindahl, R. (1992) Aldehyde dehydrogenases and their role in carcinogenesis. Crit Rev Biochem Mol Biol 27:283 335. Lindros KO. (1978) Acetaldehyde its metabolism and role in the actions of alcohol. In: Recent Adv. Alcohol Drug Problems, pp. 111176. Lubin M; Westerfeld WW. (1945). The metabolism of acetaldehyde. J Biol Chem 161:503512. Lutfullah, G., N. Q. Khan, et al. (2011). Structural modeling studies of aldehyde dehydrogenase X: insights into key interactions in the tetrameric assembly of the isoenzyme. Protein and Peptide Letters 18(1): 4157. Maly, I P; Sasse, D. (1987) Microquantitative determination of intra-acinar distribution profiles of low-Km and high-Km aldehyde dehydrogenase activity in rat liver. Eur J Biochem 170:173178. Matsumoto, M., I. Cyganek, et al. (2011). Ethanol metabolism by HeLa cells transduced with human alcohol dehydrogenase isoenzymes: control of the pathway by acetaldehyde concentration. Alcoholism: Clinical and Experimental Research 35(1): 2838. Morgan, KT; Kimbell, JS; Monticello, TM; et al. (1991) Studies of inspiratory airflow patterns in the nasal passages of the F344 rat and rhesus monkey using nasal molds: Relevance to formaldehyde toxicity. Toxicol Appl Pharmacol 110:223240. Morgan, KT. (1994) Nasal dosimetry, lesion distribution, and the toxicologic pathologist: A brief review. Inhal Toxicol 6(Suppl.):4157.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Morris, JB; Blanchard, KT. (1992) Upper respiratory tract deposition of inspired acetaldehyde. Toxicol Appl Pharmacol 114(1):140146. Morris, JB. (1997a) Uptake of acetaldehyde vapor and aldehyde dehygrogenase levels in the upper respiratory tracts of the mouse, rat, hamster and guinea pig. Fund Appl Toxicol 35:91100. Morris, JB. (1997b) Dosimetry, toxicity and carcinogenicity of inspired acetaldehyde in the rat. Mutat Res 380:113124. Morris, JB. (1998) Effect of acrolein vapor on upper respiratory tract uptake of acetaldehyde. Inhal Toxicol 10:843 856. Oyama, T; Isse, T; Kagawa, N; et al. (2005) Tissue-distribution of aldehyde dehydrogenase 2 and effects of the ALDH2 gene-disruption on the expression of enzymes involved in alcohol metabolism. Front Biosci 10:95160. Oyama, T; Isse, T; Ogawa, M; et al. (2007) Susceptibility to inhalation toxicity of acetaldehyde in Aldh2 knockout mice. Front Biosci 12:19271934. Peng, GS; Yin, SJ. (2009) Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH1B*2 on blood acetaldehyde concentrations. Hum Genomics 3:121127. Petersen, D; Lindahl, R. (1997) Aldehyde dehydrogenases. In: Guengerich, FP; ed. Comprehensive Toxicology, Vol. 3, Biotransformation. New York: Elsevier Science; pp. 97118. Plowchalk, DR; Andersen, ME; Bogdanffy, MS. (1997) Physiologically based modeling of vinyl acetate uptake, metabolism, and intracellular pH changes in the rat nasal cavity. Toxicol Appl Pharmacol 142:386400. Redmond, G; Cohen, G. (1971) Induction of liver acetaldehyde dehydrognase: Possible role in ethanol tolerance after exposure to barbiturates. Science 171:387391. Ren, S; Kalhorn, TF; Slattery, JT. (1999) Inhibition of human aldehyde dehydrogenase 1 by the 4-hydroxycyclophosphamide degradation product acrolein. Drug Metab Dispos 27:133137. Shiohara, E; Tsukada, M; Chiba, S; et al. (1984) Subcellular aldehyde dehydrogenase activity and acetaldehyde oxidation by isolated intact mitochondria of rat brain and liver after acetaldehyde treatment. Toxicology 30:2530. Sreerama, L; Hedge, M; Sladek, N. (1995) Identification of a class 3 aldehyde dehydrogenase in human saliva and increased levels of this enzyme, glutathione S-transferases, and DT-diaphorase in the saliva of subjects who continually ingest large quantities of coffee or broccoli. Clin Cancer Res 1:11531163. Stanek JJ; Morris JB. (1999) The effect of inhibition of aldehyde dehydrogenase on nasal uptake of inspired acetaldehyde. Toxicol Sci 49: 225231. 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: 375390. Thomasson HR; Edenberg HJ; Crabb DW; et al. (1991) Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet 48:677681. Wang, RS; Nakajima, T; Kawamoto, T; et al. (2002) Effects of aldehyde dehydrogenase-2 genetic polymorphisms on metabolism of structurally different aldehydes in human liver. Drug Metab Dispos 30:6973. Watanabe, A; Hobara, N; Nagashima, H. (1986) Blood and liver acetaldehyde concentration in rats following acetaldehyde inhalation and intravenous and intragastric ethanol administration. Bull Environ Contam Toxicol 37:513516. Westerfeld, WW; McKibben, JM; Roemmelt, JC; et al. (1949) Acetaldehyde metabolism and liver changes in dogs maintained on a purified diet. Am J Physiol 157:184192.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Wilkinson, PK; Sedman, AJ; Sakman, E; et al. (1976) Blood ethanol concentrations during and following constant rate intravenous infusion of alcohol. Clin Pharmacol Ther (St Louis) 19:213223. Woutersen, RA; Appelman, LM; van Garderen-Hoetmer, A; et al. (1986) Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology 41(2):213231. Yin, S-J; Agarwal, DP. (2001) Functional polymorphism of alcohol and aldehyde dehydrogenases: Alcohol metabolism, alcoholism, and alcohol-induced organ damage. In: Agarwal, DP; Seitz, H.; ed., Alcohol in Health and Disease. New York: Marcel Dekker. Yin, S-J; Liao, C-S; Wang, S-L; et al. (1989) Kinetic evidence for human liver and stomach aldehyde dehydrogenase-3 representing a unique class of isozymes. Biochem Genet 27:321-331. Yin SJ; Liao CS; Wu CW; et al. (1997) Human stomach alcohol and aldehyde dehydrogenases: comparison of expression pattern and activities in alimentary tract. Gastroenterology 112:766775. Yoshihara, E; Ameno, K; Nakamura, K; et al. (2000) The effects of the ALDH2*1/2, CYP2E1 C1/C2 and C/D genotypes on blood ethanol elimination. Drug Chem Toxicol 23(2):371379. Zorzano, A; Herrera, E. (1989) Disposition of ethanol and acetaldehyde in late pregnant rats and their fetuses. Paediatr Res 25(1):102106. Zuba D, Piekoszewski W, Pach J, Winnik L, Parczewski A. (2002) Concentration of ethanol and other volatile compounds in the blood of acutely poisoned alcoholics. Alcohol 26: 1722.

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Agarwal, DP; Goedde, HW. (1992). Pharmacogenetics of alcohol metabolism and alcoholism. Pharmacogenetics, 2: 4862. Andersen, ME; Jarabek, AM. (2001) Nasal tissue dosimetry Issues and approaches for Category 1 gases: A report on a meeting held in Research Triangle Park, NC, February 11-12, 1998. Inhal Toxicol 13:415435. Andersen, ME; Sarangapani, R; Frederick, CB; et al. (1999) Dosimetric adjustment factors for methylmethacrylate derived from a steady-state analysis of a physiologically based clearance-extraction model. Inhal Toxicol 11:899 9236. Bogdanffy, MS; Dreef-Van der Meulen, HC; Beens, RB; et al. (1994) Chronic toxicity and oncogenicity inhalation study with vinyl acetate in the rat and mouse. Fundam Appl Toxicol 23:25229. Bogdanffy, MS; Sarangapani, R; Kimbell, JS; et al. (1998) Analysis of vinyl acetate metabolism in rat and human nasal tissues by an in vitro gas uptake technique. Toxicol Sci 46:235246. Bogdanffy, MS; Sarangapani, R; Plowchalk, DR; et al. (1999b) A biologically-based risk assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity. Toxicol Sci 51:1935. Brenneman, KA; James, RA; Gross, EA; Dorman, DC. (2000) Olfactory neuron loss in adult male CD rats following subchronic inhalation exposure to hydrogen sulfide. Toxicol Pathol 28(2):326333. Brown, RP; Delp, MD; Lindstedt, SL; et al. (1997) Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13:407484. Cheng, K; Cheng, Y; Yeh, H; Swift, D. (1997) Measurements of airway dimensions and calculation of mass transfer characteristics of the human oral passage. J Biomech Eng 119:476482. Collins, L; Dawes, C. (1987) The surface area of the adult human mouth and thickness of the salivary film covering the teeth and oral mucosa. J Dental Res 66:13001302. Cussler, E. L. (1999) Diffusion: Mass Transfer in Fluid Systems. Cambridge University Press, Cambridge, UK.

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Frederick, CB; Bush, ML; Lomax, LG; et al. (1998) Application of a Hybrid Computational Fluid Dynamics and Physiologically Based Inhalation Model for Interspecies Dosimetry Extrapolation of Acidic Vapors in the Upper Airways. Toxicol Appl Pharmacol 152:211231. Hanna, LM; Lou, S-R; Su, S; et al. (2001) Mass transport analysis: Inhalation RfC methods framework for interspecies dosimetric adjustment. Inhal Toxicol 13(5):437463. Hebel, R; Stromberg, MW. (1986) Anatomy and Embryology of the Laboratory Rat. Biomed Verlag, Worthsee. Hinderliter, PM; Thrall, KD; Corley, RA; et al. (2005) Validation of human physiologically based pharmacokinetic model for vinyl acetate against human nasal dosimetry data. Toxicol Sci 85:460467. Kaneko, T; Wang, PY; Sato, A. (1994) Partition coefficients of some acetate esters and alcohols in water, Blood, olive oil and rat tissues. Occup Environ Med 51:6872. 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 145:388398. 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 64:100110. 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 102:229234. 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):140146. Morris JB; Hassett DN; Blanchard KT (1993). A physiologically based pharmacokinetic model for nasal uptake and metabolism of nonreactive vapors. Toxicol. Appl. Pharmacol. 123: 120129. Morris, JB; Robinson, DE; Vollmuth, TA; et al. (1996) A parallelogram approach for safety evaluation of ingested acetaldehyde. Reg Toxciol Pharmacol 24:251263. Pastino, G; Asgharian, B; Roberts, K; et al. (1997) A comparison of physiologically based pharmacokinetic model predictions and experimental data for inhaled ethanol in male and female B6C3F1 mice, F344 rats, and humans. Toxicol Appl Pharmacol 145:14757. Paulsson, B; Bende, M; Ohlin, P. (1985) Nasal mucosal blood flow at rest and during exercise. Acta Otolaryngol 99:140143. Plowchalk, DR; Andersen, ME; Bogdanffy, MS. (1997) Physiologically based modeling of vinyl acetate uptake, metabolism, and intracellular pH changes in the rat nasal cavity. Toxicol Appl Pharmacol 142:386400. Rudney, J; Ji, Z; Larson, C. (1995) The prediction of saliva swallowing frequency in humans from estimates of salivary flow rate and the volume of saliva swallowed. Arch Oral Biol 40: 507512 Sarangapani, R; Teeguarden, JG; Clewell, HJ; et al. (2000) Oral hazard identification and dose-response characterization for vinyl acetate. The K.S. Crump Group, Inc., ICF Consulting, Inc., Research Triangle Park, NC. Sarangapani, R; Teeguarden, JG; Clewell, HJ; et al. (In press) A biologically-based harmonized risk assessment for vinyl acetate from oral exposure. Stott, W; Dryzga, M.; Ramsey, J. (1983) Blood-flow distribution in the mouse. J Appl Toxicol 3:310312. Stott, WT; Ramsey, JC; McKenna, MJ. (1986) Absorption of Chemical Vapors by the Upper Respiratory Tract of Rats. In: CS Burrows; ed., Toxicology of the Nasal Passages. Washington, DC: Hemisphere, pp. 191210.

1 2 3 4 5 6 7 8 9

Subramaniam, R; Richardson, RB; Morgan, KT; et al. (1998) Computational fluid dynamics simulations of inspiratory airflow in the human nose and nasopharynx. Inhal Toxicol 10:91120. 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: 375390. Umulis, DM; Gurmen, NM; Singh, P; et al. (2005) A physiologically based model for ethanol and acetaldehyde metabolism in human beings. Alcohol 35:312. Wilkinson, PK; Sedman, AJ; Sakmar, E; Kay, KR; Wagner, JG. (1977) Pharmacokinetics of ethanol after oral administration in the fasting state. J Pharmacokinet Biopharm 5:207224.

10

HAZARD IDENTIFICATION: HUMAN


American Thoracic Society. (1987) Standard for diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am. Rev Respir Dis 136:225244. Bittersohl, G. (1974) Epidemiologic investigations on cancer incidence in workers contacted by acetaldol and other aliphatic aldehydes. Arch Geschwulstforsch 43:172176. 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 111:647656. Homann, N; Konig, IR; Marks, M; et al. (2009) Alcohol and colorectal cancer: the role of alcohol dehydrogenase 1C polymorphism. Alcohol Clin Exp Res 33:551556. Kim, JS; Kim, YJ; Kim, TY; et al. (2005) Association of ALDH2 polymorphism with sensitivity to acetaldehydeinduced micronuclei and facial flushing after alcohol intake. Toxicology 210:169174. Kim, S. W., K. Y. Bae, et al. (2010). The role of acetaldehyde in human psychomotor function: A double-blind placebo-controlled crossover study. Int J Neuropsychopharmacol 13(9): 5151. Lachenmeier, DW; Kanteres, F; Rehm, J. (2009) Carcinogenicity of acetaldehyde in alcoholic beverages: risk assessment outside ethanol metabolism. Addiction 104:533550. Li, DP; Dandara, C; Walther, G; et al. (2008) Genetic polymorphisms of alcohol metabolising enzymes: their role in susceptibility to oesophageal cancer. Clin Chem Lab Med 46:323328. Matsuse, H; Fukushima, C; Shimoda, T; et al. (2007) Effects of acetaldehyde on human airway constriction and inflammation. In Acetaldehyde-related pathology: Bridging the trans-disciplinary divide. Chichester, UK: John Wiley & Sons, Ltd; pp. 97106. Muttray, A; Gosepath, J; Brieger, J; et al. (2009) No acute effects of an exposure to 50 ppm acetaldehyde on the upper airways. Int Arch OccupEnviron Health 82:481488. 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):456460. Myou, S; Fujimura, M; Nishi, K; et al. (1993) Aerosolized acetaldehyde induces histamine-mediated bronchoconstriction in asthmatics. Am Rev Resp Dis 148:940943. Myou, S; Fujimura, M; Nishi, K; Ohka, T; Matsuda, T. (1994) Potentiating effect of inhaled acetaldehyde on bronchial responsiveness to methacholine in asthmatic subjects. Thorax 49(7):644648. Nelson, KW; Fox, JF Jr.; Morwick, R; et al. (1943) Sensory response to certain industrial solvent vapors. J Ind Hyg Tox 25(7):282285.

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

Ott, MG; Teta, MJ; Greenberg, HL. (1989a) Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment with attached tables and cover letter. U.S. EPA/OPTS Public Files, Fiche #OTS0513414-2. Ott, MG; Teta, MJ; Greenberg, HL. (1989b) Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment. Am J Ind Med 16(6):631643. Ott, MG; Teta, MF; Greenberg, HL. (1989c) Assessment of exposure to chemicals in a complex work environment. Am J Ind Med 16:617630. Prieto, L; Sanchez-Toril, F; Brontons, B; et al. (2000) Airway responsiveness to acetaldehyde in patients with asthma: relationship to methacholine responsiveness and peak expiratory flow variation. Clin Exptl 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 69:129135. Prieto L; Gutirrez 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 13:429438. Silverman, L; Schulte, HF; First, MW. (1946) Further studies on sensory response to certain industrial solvent vapors. J Ind Hyg Toxicol 28:262266. Sim,VM; Pattle, RE. (1957) Effect of possible smog irritants on human subjects. JAMA 163(13):19081913. Takigawa, T., Y. Saijo, et al. (2012). A longitudinal study of aldehydes and volatile organic compounds associated with subjective symptoms related to sick building syndrome in new dwellings in Japan. Sci Total Environ 417418: 6167. Visapaa, JP; Gotte, K; Benesova, M; et al. (2004) Increased cancer risk in heavy drinkers with the alcohol dehydrogenase 1C*1 allele, possibly due to salivary acetaldehyde. Gut 53:871876. 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 Prevention 6:256262. 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 98:12481253. Yokoyama, A; Omori, T. (2003) Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers. Jpn J Clin Oncol 33:111121. Yokoyama, A; Omori, T. (2005) Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers. Alcohol 35:175185.

35

HAZARD IDENTIFICATION: ANIMAL


Anderson, RA 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 34:685695. Anderson, RA; Reddy, JM; Joyce, C; Willis, BR; Van der Vend, H; Zaneveld, LJ. (1982) Inhibition of mouse sperm capacitation by ethanol. Biol Reprod 27:833840.

36 37 38 39 40

11

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

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):331336. 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 41:15661568. 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 79:143149. Badr, FM; Bartke, A; Dalterio, S; Bulger, W. (1977) Suppression of testosterone production by ethyl alcohol. Possible mode of action. Steroids 30:647655. Bankowski, E; Pawlicka, E; Sobolewski, K. (1993) Liver collagen of rats submitted to chronic intoxication with acetaldehyde. Mol Cell Biochem 121(1):3743. Bannigan, J; Burke, P. (1982) Ethanol teratogenicity in mice: A light microscopic study. Teratology 26:247254. Barilyak, IR; Kozachuk, SY. (1983) Embryotoxic and mutagenic activity of ethanol and acetaldehyde in intra amniotic exposure. Tsitol Genet (USSR) 17:5760. Beck, F. (1981) Comparative placental morphology and function. In: Developmental Toxicology (Kimmel, CA; Buelke-Sam, J, eds). New York: Raven Press, p. 3554. 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 72:355363. 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 72:364371. Boyden, TW; Silvert, MA; Pamenter, RW. (1981) Acetaldehyde acutely impairs canine testicular testosterone secretion. Eur J Clin Pharmacol 70:571576. Booze, TF; Oehme, FW (1986). An investigation of metaldehyde and acetaldehyde toxicities in dogs. Fundam Appl Toxicol 6:440446. Boulet, L-P. (1988) Increases in airway responsiveness following acute exposure to respiratory irritants: Reactive airway dysfunction syndrome or occupational asthma? Chest 94(3):476481. Campbell, MA; Fantel, AG. (1983) Teratogenicity of acetaldehyde in vitro: relevance to the fetal alcohol syndrome. Life Sci 32:26412647. 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 46:527536. 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) 30:175184. Cicero, TJ; Bell, RD; Badger, TM. (1980a) Acetaldehyde directly inhibits the conversion of androstenedione to testosterone in the testes. Adv Exp Med Biol 132:211217. Cicero, TJ; Bel,l RD; Meyer, ER; Badger, TM. (1980b). Ethanol and acetaldehyde directly inhibit testicular steroidogenesis. J Pharmacol Exp Ther 213:228233. Cicero, TJ; Bell, RD. (1980c) Effects of ethanol and acetaldehyde on the biosynthesis of testosterone in the rodent testes. Biochem Biophys Res Commun 94:814819.

12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Cobb, CF; Ennis, MF; Michael, F; et al. (1978) Acetaldehyde and ethanol are direct testicular toxins. Surg Forum 29:641644. 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 29:7179. 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 20:245256. 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 5:357362. Fadel, RAR; Persaud, TVN. (1991) Craniofacial ossification in the rat following prenatal exposure to alcohol, acetaldehyde and cafeine. , 12: 181184. 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: 5154. Feron, VJ. (1979) Effects of exposure to acetaldehyde in Syrian hamsters simultaneously treated with benzo(a)pyrene or diethylnitrosamine. Prog Exp Tumor Res 24:162176. Feron, VJ; Kruysse, A; Woutersen, RA. (1982) Respiratory tract tumours in hamsters exposed to acetaldehyde vapour alone or simultaneously to benzo(a)pyrene or diethylnitrosamine. Eur J Cancer 18:1331. 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: 229238. Fisher, SE; Atkinson, M; Holzman, I; David, R; et al. (1981a) Effects of ethanol upon placental uptake of amino acids. Prog Biochem Pharmacol 18:216223. 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 29:12831288. Fort, DJ; McLaughlin, DW; Rogers, RL; et al. (2003) Evaluation of the developmental toxicities of ethanol, acetaldehyde, and thioacetamide using FETAX. Drug Chem Toxicol 26:2334. 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 36:463468. Hartl, MW; Shibley, IA, Jr. (2002) Supraphysiological acetaldehyde levels suppress growth in chicken embryos. Alcohol 28:111115. 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. 299534. 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):465472. Henderson, GI; Patwardhan, RV; McLeroy, S; et al. (1982) Inhibition of placental amino acid uptake in rats following acute and chronic ethanol exposures. Alcoholism 6:495500. Higuchi, Y; Matsumoto, N. (1984) Embryotoxicity of ethanol and acetaldehyde: direct effects on mouse embryo in vitro. Congen Anom (Senten IJO) 24:928. 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 37:1823. Homann, N; Krkkinen, P; Koivisto, et al. (1997) Effects of acetaldehyde on cell regeneration and differentiation of the upper gastrointestinal tract mucosa. J Natl Cancer Inst 89:16921697.

13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Imai, T; Omoto, M. (1992) Effects of acetaldehyde exposure on maternal rats and their offspring. Jpn J Alcohol Stud Drug Depend 27(3):334354. Johnson, DE; Chiao, Y-B; Gavaler, JS; Van Thiel, DH. (1981) Inhibition of testosterone synthesis by ethanol and acetaldehyde. Biochem Pharmacol 36:18271831. Kawamoto, K. (1981) Effects of alcohol and its metabolites on the hatching process of chicken eggs. Nichidai Igaku Izasshi 40:249260. Kruysse, A; Feron, VJ; Til, HP. (1975) Repeated exposure to acetaldehyde vapor. Arch Environ Health 30:449452. Lhdetie, J. (1988) Effects of vinyl acetate and acetaldehyde on sperm morphology and meiotic micronuclei in mice. Mutat Res 202:171178. Lee, RD; An, SM; Kim, SS; et al. (2005) Neurotoxic effects of alcohol and acetaldehyde during embryonic development. J Toxicol Environ Health A 68:21472162. Messiha, FS. (1980) Testicular and epididymal aldehyde dehydrogenase in rodents: modulation by ethanol and disulfiram. Int J Androl 3:375382. Messiha, FS. (1981) Subcellular localization and biochemical properties of rat testicular alcohol- and aldehyde dehydrogenase. Sys Biol Reprod Med 7:329335. Messiha, FS. (1983) Subcellular distribution of oxidoreductases in genital organs of the male rat. Neurobehav Toxicol Teratol 5:241245. Milch, RA. (1964) Aqueous solution infrared spectra of collagen-reactive aldehydes. Biochem Biophys Acta 93:45 53. OShea, KS; Kaufman, MH. (1979) Teratogenic effects of acetaldehyde: implications for the study of fetal alcohol syndrome. J Anat 128:6576. OShea, KS; Kaufman, MH. (1981) Effects of acetaldehyde on neuroepithelium of early mouse embryos. J Anat 132:107118. Padmanabhan, R; Sreenathan, RN; Singh, S. (1983) Studies of the lethal and teratogenic effects of acetaldehyde in the rat. Congen Anom (Senten IJO) 23:1323. Pawlicka, E; Bankowski, E; Sobolewski, K. (1991) Chronic intoxication with acetaldehyde stimulates collagen biosynthesis in rat liver. Arch Toxicol 65(8):678680. 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) 92:17071710. Priscott, PK. (1985) The effect of acetaldehyde and 2,3-butanediol on rat embryos developing in vitro. Biochem Pharmacol 34:529532. 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):288292. 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 7:135139. Schauenstein, E; Estenbauer, H; Zollner, H. (1977) Aldehydes in biological systems. Pio Ltd., London. Soffritti, M; Belpoggi, F; Lambertin, L; et al. (2002) Results of long-term experimental studies on the carcinogenicity of formaldehyde and acetaldehyde in rats. Ann N Y Acad Sci 982:87105. Sreenathan, RN; Padmanabhan, R. (1984) Structural changes of placenta following maternal administration of acetaldehyde in the rat. Z Mikrosk Anat Forsch (E Germ) 98:597600.

14

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

Sreenathan, RN; Padmanabhan, R; Singh, S. (1982) Teratogenic effects of acetaldehyde in the rat. Drug Alcohol Depend 9:339350. Sreenathan, RN; Singh, S; Padmanabhan, R. (1984a) Implications of the placenta in the acetadehyde-induced intra uterine growth retardation. Drug Alcohol Depend 13:199204. Sreenathan, RN; Singh, S; Padmanabhan, R. (1984b) Effects of acetaldehyde on skeletogenesis in the rat. Drug Alcohol Depend 14:165174. Stanek, J; Symanowicz, PT; Olsen, JE; et al. (2001) Sensory-nerve mediated nasal vasodilatory response to inspired acetaldehyde and acetic acid vapors. Inhal Toxicol 13:807822. Steinhagen, WH; Barrow, CS. (1984) Sensory irritation structure-activity study of inhaled aldehydes in BC3F1 and Swiss-Webster mice. Toxicol Appl Pharmacol 72:495503. Thompson, PAC; Folb, PI. (1982) An in vitro model of alcohol and acetaldehyde teratogenicity. J Appl Toxicol 2:190195. 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):447452. 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 26:6573. Veghelyi, PF; Osztovics, M; Kardos, G; et al. (1978) The fetal alcohol syndrome: Symptoms and pathogenesis. Acta Paediatr Acad Sci Hung 19(3):171189. 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 27:231243. 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):295305. 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):213231. 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):295305.

33

MECHANISMS
Aeschbacher, HU; Wolleb, U; Lliger, J; Spadone, JC; Liardon, R (1989). Contribution of coffee aroma constituents to the mutagenicity of coffee. Food Chem Toxicol, 27: 227232. Andersen, ME; Krishnan, K; Conolly, RB; McClellan, RO. (1992) Mechanistic toxicology research and biologically-based modeling: Partners for improving quantitative risk assessments. CIIT Activities 12(1):17. 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 41:15661568.

34 35 36 37 38 39

15

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Bae, K. Y., S. W. Kim, et al. (2012). The acute effects of ethanol and acetaldehyde on physiological responses after ethanol ingestion in young healthy men with different ALDH2 genotypes. Clin Toxicol 50(4): 242249. Barnes, PJ. (1992) Neurogenic inflammation and asthma. J Asthma 29:165180. Beck, F. (1981) Comparative placental morphology and function. In: Developmental Toxicology (Kimmel, CA; Buelke-Sam, J, eds). New York: Raven Press, p. 3554. Bedford, P; Fox, BW. (1981) The role of formaldehyde in methylene dimethanesulphate-induced DNA cross-links and its relevance to cytotoxicity. Chem Biol Interact 38:119128. Bird, RP; Draper, HH; Basrur, PK. (1982) Effect of malondialdehyde and acetaldehyde on cultured mammalian cells: Production of micronuclei and chromosomal aberrations. Mutat Res 101:237246. Blasiak, J; Trzeciak, A; Malecka-Panas, E; Drzewoski, J; Wojewodzka, M. (2000) In vitro genotoxicity of ethanol and acetaldehyde in human lymphocytes and the gastrointestinal tract mucosa cells. Toxicology in vitro 14:287295. Bogdanffy, MS (2002). Vinyl acetate-induced intracellular acidification: Implications for risk assessment. Toxicol Sci, 66: 320326. Brodie, BB; Reid, WD; Cho, AK; Sipes, C; Kriskna, G; Gillette, JR. (1971) Possible mechanism of liver necrosis caused by aromatic organic compounds. Proc Natl Acad Sci USA 68:160169. Brooks, PJ; Theruvathu, JA. (2005) DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis. Alcohol 35:187193. Brooks, PJ; Goldman, D; Li TK. (2009) Alleles of alcohol and acetaldehyde metabolism genes modulate susceptibility to oesophageal cancer from alcohol consumption. Hum Genomics 3:103105. Boyden, TW; Silvert, MA; Pamenter, RW. (1981) Acetaldehyde acutely impairs canine testicular testosterone secretion. Eur J Clin Pharmacol 70:571576. Brocker, C., M. Cantore, et al. (2011). Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive aldehyde and oxidative stress induced cytotoxicity. Chemico-Biological Interactions 191(1-3): 269277. Cannizzaro, C., M. La Barbera, et al. (2010). Ethanol modulates corticotropin releasing hormone release from the rat hypothalamus: does acetaldehyde play a role? Alcoholism: Clinical and Experimental Research 34(4): 588593. Chandrasekaran, K., K. Swaminathan, et al. (2011). Elevated glutathione level does not protect against chronic alcohol mediated apoptosis in recombinant human hepatoma cell line VL-17A over-expressing alcohol metabolizing enzymes--alcohol dehydrogenase and Cytochrome P450 2E1. Toxicology In Vitro 25(4): 969978. 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. 211217. (Advances in experimental medicine and biology: v. 132). Commoner, B (1976) Reliability of bacterial mutagenesis techniques to distinguish carcinogenic and noncarcinogenic chemicals. U.S. EPA. EPA-600/1-76-022. Correa, M., J. D. Salamone, et al. (2012). Piecing together the puzzle of acetaldehyde as a neuroactive agent. Neuroscience and Biobehavioral Reviews 36(1): 404430. Costa, M; Zhitkovich, A; Harris, M; Paustenbach, D; Gargas, M. (1997) DNA-protein cross-links produced by various chemicals in cultured human lymphoma cells. J Toxicol Environ Health 50:433449. D'Addario, C., S. Johansson, et al. (2011). Ethanol and acetaldehyde exposure induces specific epigenetic modifications in the prodynorphin gene promoter in a human neuroblastoma cell line. FASEB Journal 25(3): 1069 1075. Dellarco, VL (1988). A mutagenicity assessment of acetaldehyde. DNA Repair (Amst), 195: 1-20.

16

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Dillon, D; Combes, R; Zeiger, E. (1998) The effectiveness of Salmonella strains TA100, TA102 and TA104 for detecting mutagenicity of some aldehydes and peroxides. Mutagenesis 13(1):1926. 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 20:245256. Duell, E. J., N. Sala, et al. (2012). Genetic variation in alcohol dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and aldehyde dehydrogenase (ALDH2), alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Carcinogenesis 33(2): 361367. Fanelli, S. L., M. E. Maciel, et al. (2011). Further studies on the potential contribution of acetaldehyde accumulation and oxidative stress in rat mammary tissue in the alcohol drinking promotion of breast cancer. J Appl Toxicol 31(1): 1119. 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 29:12831288. Fisher, SE; Atkinson, M; Holzman, I; David, R; et al. (1981a) Effects of ethanol upon placental uptake of amino acids. Prog Biochem Pharmacol 18:216223. 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: 229238. 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):104109. Gosepath, J; Brieger, J; Muttray, A; et al. (2006) mRNA induction and cytokine release of inflammatory mediators during in vitro exposure of human nasal respiratory epithelia to acetaldehyde. Inhal Toxicol 18:10831090. Graf, U; Frei, H; Kgi, A; Katz, AJ; Wrgler, FE. (1989) Thirty compounds tested in the Drosophila wing spot test. Mutat Res 222:359373. Grafstrom, RC; Curren, RD; Harris, CC. (1985) Genotoxicity of formaldehyde in cultured human bronchial fibroblasts. Science 228:8991. Grafstrom, RC; Dypbukt, JM; Sundqvist, K; et al. (1994) Pathobiological effects of acetaldehyde in cultured human epithelial cells and fibroblasts. Carcinogenesis 15:985990. 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. Greenwald, IS; Horvitz, HR (1980) Unc-93(e1500): A behavioral mutant of Caenorhabditis elegans that defines a gene witha wild-type null phenotype. Genetics 96:147164. Hall, JA; Saffhill, R; Green, T; et al. (1981) The induction of errors during in vitro DNA synthesis following chloroacetaldehyde-treatment of poly(da-dT) and poly(dC-dG) templates. Carcinogenesis 2:141146. He, S-M; Lambert, B. (1990) Acetaldehyde-induced mutation at the hprt locus in human lymphocytes in vitro. Environ Mol Mutagen 16(2):5763. Hecht, SS; McIntee, EJ; Wang, M. (2001) New DNA adducts of crotonaldehyde and acetaldehyde. Toxicology 166:3136. Helander, A; Lindahl-Kiessling, K. (1991) Increased frequency of acetaldehyde-induced sister-chromatid exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor. Mutat Res 264(3):103107. Hellmr, L; Bolcsfoldi, G. (1992) An evaluation of the E. coli K-12 uvrB/recA DNA repair host-mediated assay. I. In vitro sensitivity of the bacteria to 61 compounds. Mutat Res 72:145160.

17

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Hemminki, K; Falck, K; Vainio, H. (1980) Comparison of alkylation rate and mutagenicity of directly acting industrial and laboratory chemiclas. Arch Toxicol 46:277285. Hemminki, K; Suni, R (1984). Sites of reaction of glutaraldehyde and acetaldehyde with nucleosides. Arch Toxicol, 55: 186190. 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):465472. Henderson, GI; Patwardhan, RV; McLeroy, S; et al. (1982) Inhibition of placental amino acid uptake in rats following acute and chronic ethanol exposures. Alcoholism 6:495500. Hsiang, CY; Wu, SL; Chen; et al. (2007) Acetaldehyde induces matrix metalloproteinase-9 gene expression via nuclear factor-kappaB and activator protein 1 signaling pathways in human hepatocellular carcinoma cells: Association with the invasive potential. Toxicol Lett 171:7886. Ishikawa, H; Miyatsu, Y; Kurihara, K; et al. (2006) Gene-environmental interactions between alcohol-drinking behavior and ALDH2 and CYP2E1 polymorphisms and their impact on micronuclei frequency in human lymphocytes. Mutat Res 594:19. Ishikawa, H; Ishikawa, T; Yamamoto, H; et al. (2007) Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms. Mutat Res 615:134142. Ji, C. (2012). Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries. Biochemistry Research International 2012: 216450. Ji, Y. B., K. Tae, et al. (2011). ADH1B and ALDH2 polymorphisms and their associations with increased risk of squamous cell carcinoma of the head and neck in the Korean population. Oral Oncology 47(7): 583587. Johnston, DE; Chiao, Y-B; Gavaler, JS; Van Thiel, DH (1981). Inhibition of testosterone synthesis by ethanol and acetaldehyde. Biochem Pharmacol, 30: 18271831. Kato, F; Araki, A; Nozaki, K; Matsushima, T. (1989) Mutagenicity of aldehydes and diketones. Mutat Res 216:366 367. (abstract) 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 134:233239. Kayani, M. A. and J. M. Parry (2010). The in vitro genotoxicity of ethanol and acetaldehyde. Toxicology In Vitro 24(1): 5660. Kayani, MA; Parry, JM. (2009) The in vitro genotoxicity of ethanol and acetaldehyde. Toxicol In Vitro 24(1):5660. Kenney, WC. (1982) Acetaldehyde adducts of phospholipids. Alcohol Clin Exp Res, 6: 412416. Kenney, WC. (1984) Formation of Schiff base adduct between acetaldehyde and rat liver microsomal phosphatidylethanolaimine. Alcohol Clin Exp Res, 8: 551555. 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 210:169174. Klaunig, J. E., Z. Wang, et al. (2011). Oxidative stress and oxidative damage in chemical carcinogenesis. Toxicol Appl Pharmacol 254(2): 8699. Korte, A; Obe, G (1981). Influence of chronic ethanol uptake and acute acetaldehyde treatment on the chromosomes of bone-marrow cells and peripheral lymphocytes of Chinese hamsters. DNA Repair (Amst), 88: 389395. Kunugita, N; Isse, T; Oyama, T; et al. (2008) Increased frequencies of micronucleated reticulocytes and T-cell receptor mutation in Aldh2 knockout mice exposed to acetaldehyde. J Toxicol Sci 33:3136.

18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Kuykendall, JR; Bogdanffy, MS. (1992a) Efficiency of DNA-histone crosslinking induced by saturated and unsaturated aldehydes in vitro. Mutat Res 283:131136. Kuykendall, JR; Bogdanffy, MS. (1992b) Reaction kinetics of DNA-histone crosslinking by vinyl acetate and acetaldehyde. Carcinogenesis 13:20952100. Kuykendall, JR; Bogdanffy, MS (1994). Formation and stability of acetaldehyde-induced crosslinks between poly lysine and poly-deoxyguanosine. Mutat Res-Fundam Mol Mech Mutagen, 311: 4956. 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 65:9951012. Lhdetie, J. (1988) Effects of vinyl acetate and acetaldehyde on sperm morphology and meiotic micronuclei in mice. Mutat Res 202:171178. Lam, C-W; Casanova, M; Heck, Hd'A (1986). Decreased extractability of DNA from proteins in the rat nasal mucosa after acetaldehyde exposure. Toxicol Sci, 6: 541550. Lambert, B; Chen, Y; He, SM; Sten, M. (1985) DNA-crosslinks in human leucocytes treated with vinyl acetate and acetaldehyde in vitro. Mutat Res 146:301303. Lambert, B; Andersson, B; Bastlova, T; Hou, SM; Hellgren, D; Kolman, A (1994). Mutations induced in the hypoxanthine phosphoribosyl transferase gene by three urban air pollutants: Acetaldehyde, benzo[a]pyrene diolepoxide, and ethylene oxide. Environ Health Perspect Suppl, 102: 135138. Lamarche, F; Gonthier, B; Signorini, N; et al. (2004) Impact of ethanol and acetaldehyde on DNA and cell viability of cultured neurones. Cell Biol Toxicol 20:361374. Laumbach, AD; Lee, S; Wong, J; Streips, UN (1976) Studies on the mutagenicity of vinyl chloride metabolites and related chemicals. Proceedings of the 3rd International Symposium on the Prevention and Detection of Cancer. Vol. 1, p. 155169. Leikauf, GD. (2002) Hazardous air pollutants and asthma. Environ Health Perspect 110(Suppl. 4):505526. 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 and p38 mitogen activated protein kinase. J Biol Chem 279:1124411252. 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 40:283294. Li, DP; Dandara, C; Walther, G; et al. (2008) Genetic polymorphisms of alcohol metabolising enzymes: their role in susceptibility to oesophageal cancer. Clin Chem Lab Med 46:323328. Lin, Y-C; Ho, I-C; Lee, T-C. (1989) Ethanol and acetaldehyde potentiate the clastogenicity of ultraviolet light, methyl methanesulfonate, mitomycin C and bleomycin in Chinese hamster ovary cells. Mutat Res 216:9399. Litton Bionetics, Inc.. (1979) Mutagenicity evaluation of C-54 (acetaldehyde) in the Ames salmonella/microsome plate test (final report) with cover letter dated 11/22/91. Bridgewater, NJ: Hoechst Celanese Corporation. Liviac, D., A. Creus, et al. (2011). Mutagenic analysis of six disinfection by-products in the Tk gene of mouse lymphoma cells. Journal of Hazardous Materials 190(1-3): 10451052. Lorenti, GC; Mechilli, M; Proietti; et al. (2009) Relationship between DNA lesions, DNA repair and chromosomal damage induced by acetaldehyde. Mutat Res 662:39. Ma, H., R. Guo, et al. (2011). Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: role of autophagy paradox and toxic aldehyde. European Heart Journal (Online) 32(8): 10251038.

19

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Machida, I; Matsuse, H; Kondo, Y; et al. (2003) Acetaldehyde induces granulocyte macrophage colony-stimulating factor production in human bronchi through activation of nuclear factor-kappa B. Allergy Asthma Proc 24:367371. Madrigal-Bujaidar, E; Velazquez-Guadarrama, N; Morales-Ramirez, P; et al. (2002) Effect of disulfiram on the genotoxic potential of acetaldehyde in mouse spermatogonial cells. Teratog Carcinog Mutagen 22:8391. Marichalar-Mendia, X., A. Acha-Sagredo, et al. (2011). Alcohol-dehydrogenase (ADH1B) Arg48His Polymorphism in Basque Country Patients with Oral and Laryngeal Cancer: Preliminary Study. Anticancer Research 31(2): 677 680. Marichalar-Mendia, X; Rodriguez-Tojo, MJ; Acha-Sagredo, A; et al. (2009) Oral cancer and polymorphism of ethanol metabolising genes. Oral Oncol 46(1):913. Marichalar-Mendia, X., M. J. Rodriguez-Tojo, et al. (2010). Oral cancer and polymorphism of ethanol metabolising genes. Oral Oncology 46(1): 913. Marietta, C; Thompson, LH; Lamerdin, JE; et al. (2009) Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: implications for alcohol-related carcinogenesis. Mutat Res 664:7783. Marnett, LJ; Hurd, H; Hollstein, M; et al. (1985) Natural occurring carbonyl compunds are mutagens in Salmonella tester strain TA104. Mutat Res 148:2534. Masamune, A; Satoh, A; Watanabe, T; et al. (2010) Effects of ethanol and its metabolites on human pancreatic stellate cells. Dig Dis Sci 55:204211. Matsuda, T; Yabushita, H; Kanaly, RA; et al. (2006) Increased DNA damage in ALDH2-deficient alcoholics. Chem Res Toxicol 19:13741378. Matsuda, T; Matsumoto, A; Uchida, M; et al. (2007) Increased formation of hepatic N2-ethylidene-2' deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol. Carcinogenesis 28:23632366. Matsuse, H; Fukushima, C; Shimoda, T; et al. (2007) Effects of acetaldehyde on human airway constriction and inflammation. Novartis Found Symp 285:97106; discussion 1069, 1989. Mechilli, M; Schinoppi, A; Kobos, K; et al. (2008) DNA repair deficiency and acetaldehyde-induced chromosomal alterations in CHO cells. Mutagenesis 23:5156. Mello, T; Ceni, E; Surrenti, C; et al. (2008) Alcohol induced hepatic fibrosis: role of acetaldehyde. Mol Aspects Med 29:1721. Migliore, L; Nieri, M. (1991) Evaluation of twelve potential aneuploidogenic chemicals by the in vitro human lymphocyte micronucleus assay. Toxic. In Vitro 5(4):325336. Miyasaka, K., H. Hosoya, et al. (2010). Association of aldehyde dehydrogenase 2 gene polymorphism with pancreatic cancer but not colon cancer. Geriatr Gerontol Int 10 Suppl 1: S120-126. Morita, T. (1995) Low pH leads to sister-chromatid exchanges and chromosomal aberrations and its clastogenicity is S-dependent. Mutat Res 344:301308. Morita, T; Nagaki, T; Fukuda, I; et al. (1992) Clastogenicity of low pH to various cultured mammalian cells. Mutat Res 268:297305. Mortelmans, K; Haworth, S; Lawlor, T; et al. (1986) Salmonella mutagenicity tests. II. Results from the testing of 270 chemicals. Environ Mutagen 8(Suppl 17):1119. Myou, S; Fujimura, M; Nishi, K; et al. (1993) Aerosolized acetaldehyde induces histamine-mediated bronchoconstriction in asthmatics. Am Rev Resp Dis 148:940943.

20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

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 39:140147. Norppa, H; Tursi, F; Pfaeffli, P; et al. (1985) Chromosome damage induced by vinyl acetate through in vitro formation of acetaldehyde in human lymphocytes and Chinese hamster ovary cells. Cancer Res 45(10):48164821. Novitskiy, G; Traore, K; Wang, L; et al. (2006) Effects of ethanol and acetaldehyde on reactive oxygen species production in rat hepatic stellate cells. Alcohol Clin Exp Res 30:14291435. Oba, T; Maeno, Y; Nagao, M; et al. (2008) Cellular redox state protects acetaldehyde-induced alteration in cardiomyocyte function by modifying Ca2+ release from sarcoplasmic reticulum. Am J Physiol Heart Circ Physiol 294:H121H133. Obe, G; Natarajan, AT; Meyers, M; et al. (1979) Induction of chromosomal aberrations in peripheral lymphocytes of human blood in vitro, and of SCEs in bone-marrow cells of mice in vivo by ethanol and its metablite acetaldehyde. Mutat Res 68:291294. Ohba, Y; Morimitsu, Y; Watarai, A. (1979) Reaction of formaldehyde with calf-thymus nuclohistone. Eur J Biochem 100:285293. Ogawa, M; Isse, T; Oyama, T; et al. (2006) Urinary 8-hydoxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) levels in Aldh2 knock-out mice under acetaldehyde exposure. Ind Health 44:179183. Olin, KL; Cherr, GN; Rifkin, E; et al. (1996) The effects of some redox-active metals and reactive aldehydes on DNA-protein cross-links in vitro. Toxicology 110(1-3):18. Ott, MG; Teta, MJ; Greenberg, HL (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment. Carbide Corporation, Danbury, CT. Oyama, T., H. Nagayoshi, et al. (2010). Effects of acetaldehyde inhalation in mitochondrial aldehyde dehydrogenase deficient mice (Aldh2-/-). Frontiers in Bioscience (Elite Edition) 2: 13441354. Paget, V; Lechevrel, M, Sichel F. (2008) Acetaldehyde-induced mutational pattern in the tumour suppressor gene TP53 analysed by use of a functional assay, the FASAY (functional analysis of separated alleles in yeast). Mutat Res 652: 1219. Park, J. Y., K. Matsuo, et al. (2010). Impact of smoking on lung cancer risk is stronger in those with the homozygous aldehyde dehydrogenase 2 null allele in a Japanese population. Carcinogenesis 31(4): 660665. Pluskota-Karwatka, D; Pawlowicz, AJ; Kronberg, L. (2006) Formation of malonaldehyde-acetaldehyde conjugate adducts in calf thymus DNA. Chem Res Toxicol 19:921926. Pluskota-Karwatka, D; Pawlowicz, AJ; Kronberg L. (2007) Reactions of malonaldehyde and acetaldehyde with calf thymus DNA: formation of conjugate adducts. Nucleosides Nucleotides Nucleic Acids 26:567571. Pluskota-Karwatka, D; Le, CF; Munter, T; et al. (2002) Identification of conjugate adducts formed in the reactions of malonaldehyde-acetaldehyde and malonaldehyde-formaldehyde with cytidine. Chem Res Toxicol 15:110117. Pluskota-Karwatka, D; Le, CF; Munter, T; et al. (2005) Formation of conjugate adducts in the reactions of malonaldehyde-acetaldehyde and malonaldehyde-formaldehyde with guanosine. Chem Res Toxicol 18:300307. Poirier, M; Fournier, M; Brousseau, P; et al. (2002) Effects of volatile aromatics, aldehydes, and phenols in tobacco smoke on viability and proliferation of mouse lymphocytes. J Toxicol Environ Health A 65:14371451. Pool, BLK; Wiessler, M. (1981) Investigations on the mutagenicity of primary and secondary a-acetoxynitrosamines with Salmonella typhimurium: Activation and deactivation of structurally-related compunds by S-9. Carcinogeneiss 2:991997. Potter, J. J., A. Koteish, et al. (2011). Effects of acetaldehyde on hepatocyte glycerol uptake and cell size: implication of aquaporin 9. Alcoholism: Clinical and Experimental Research 35(5): 939945.

21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Reifferscheid, G; Heil, J. (1996) Validation of the SOS/umu test using test results of 486 chemicals and comparison with the Ames test and carcinogenicity data. Mutat Res 369:129145. Rey, M; Palermo, AM; Muoz, ER. (1994) Lack of effect of acute acetaldehyde treatment on X chromosome segregation in Drosophila melanogaster females. Mutat Res 320:17. Ristow, H; Obe, G. (1978) Acetaldehyde induces cross-links in DNA and causes sister-chromatid exchanges in human cells. Mutat Res 58:115119. Ristow, H; Seyfarth, A; Lochmann, ER. (1995) Chromosomal damages by ethanol and acetaldehyde in Saccharomyces cerevisiae as studied by pulsed field gel electrophoresis. Mutat Res 326:165170. Rosenkranz, HS. (1977) Mutagenicity of halogenated alkanes and their derivatives. Environ Health Perspect 21:79 84. Rossini, A; de Almeida, ST; Marques, CB; et al. (2009) TP53 mutation profile of esophageal squamous cell carcinomas of patients from Southeastern Brazil. Mutat Res 696(1):1015. Rossoni, G; Manfredi, B; Razzetti, R; et al. (2005) Positive interaction of the beta2-agonist CHF 4226.01 with budesonide in the control of bronchoconstriction induced by acetaldehyde in the guinea-pigs. Br J Pharmacol 144:422429. Ruben, Z; Rousseaux, CG. (1991) The limitations of toxicologic pathology. In: W.M. Haschek and C.G. Rousseaux; eds., Handbook of Toxicologic Pathology. New York: Academic Press, pp. 131142. Sako, M; Yaekura, I; Deyashiki, Y. (2002) Chemo- and regio-selective modifications of nucleic acids by acetaldehyde and crotonaldehyde. Nucleic Acids Res Suppl: 2122. Sako, M; Inagaki, S; Esaka, Y; et al. (2003) Oxidative hydrolysis of a cyclic 1,N2-propano-2-deoxyguanosine, an adduct of 2-deoxyguanosine with acetaldehyde or crotonaldehyde. Tetrahedron Letters 44:73037306. Saladino, AJ; Wiley, JC; Lechner, JF; et al. (1985) Effects of formaldehyde, acetaldehyde, benzoyl peroxide and hydrogen perioxide on cultured normal human bronchial epithelial cells. Cancer Res 45(6):25222526. Sanchez-Toril, F; Perez, JA; Brontons, B; Hernandez, J; Marin, J; Prieto, L. (1998) Differences in airway responsiveness to inhaled acetaldehyde between asthmatics and subjects with chronic bronchitis. Am J Respir Crit Care Med 167:A821. 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 7:135139. Sarc, L; Lipnik-Stangelj, M. (2009) Comparison of ethanol and acetaldehyde toxicity in rat astrocytes in primary culture. Arh Hig Rada Toksikol 60:297305. Sarc, L., B. Wraber, et al. (2011). Ethanol and acetaldehyde disturb TNF-alpha and IL-6 production in cultured astrocytes. Hum ExpToxicol 30(9): 12561265. Sasaki, Y; Endo, R. (1978) Mutagenicity of aldehydes in Salmonella. Mutat Res 54:251252. (abstract) Satoh, Y; Ide, Y; Sugano, T. (2008) Hypotensive and hypertensive effects of acetaldehyde on blood pressure in rats. Nihon Arukoru Yakubutsu Igakkai Zasshi 43:188193. Seitz, HK; Stickel, F. (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 7:599 612. Seitz, HK; Stickel, F. (2009) Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism. Genes Nutr. DOI 10.1007/s12263-009-0154-1. Setshedi, M., J. R. Wands, et al. (2010). Acetaldehyde adducts in alcoholic liver disease. Oxidative Medicine and Cellular Longevity 3(3): 178185.

22

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

Shimoda, T; Kohno, S; Takao, A. (1996) Investigation of the mechanism of alcohol induced bronchial asthma. J Allergy Clin Immunol 97(1 Pt 1):74 84. Shiraishi-Yokoyama, H; Yokoyama, H; Matsumoto, M; et al. (2006) Acetaldehyde inhibits the formation of retinoic acid from retinal in the rat esophagus. Scand J Gastroenterol 41:8086. Singh, NP; Khan, A. (1995) Acetaldehyde: Genotoxicity and cytotoxicity in human lymphocytes. Mutat Res 337:917. Sina, JF; Bean, CL; Dysart, GR; et al. (1983) Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of carcinogen/mutagenic potential. Mutat Res 113:357391. Soffritti, M; Belpoggi, F; Lambertin, L; et al. (2002) Results of long-term experimental studies on the carcinogenicity of formaldehyde and acetaldehyde in rats. Ann NY Acad Sci 982:87105. Stein, S; Lao, Y; Yang, IY; et al. (2006) Genotoxicity of acetaldehyde- and crotonaldehyde-induced 1,N2 propanodeoxyguanosine DNA adducts in human cells. Mutat Res 608:17. Stevens, G; Rank, K; Sauer, J; Stapleton, S; Ginsberg, LC. (1991) Evaluation of unscheduled DNA synthesis induced in acetaldehyde treated primary rat hepatocytes. Environ Mol Mutagen 17(Suppl 19):71. Takao, A; Shimoda, T; Kohno, S; Asai, S; Harda, S. (1998) Correlation between alcohol induced asthma and acetaldehyde dehydrogenase 2 genotype. J Allergy Clin Immunol 101(5):576 80. Timmons, SR; Nwankwo, JO; Domann, FE. (2002) Acetaldehyde activates Jun/AP-1 expression and DNA binding activity in human oral keratinocytes. Oral Oncol 38:281290. Tuma, DJ. (2002) Role of malondialdehyde-acetaldehyde adducts in liver injury. Free Radic Biol Med 32:303308. Tuma, DJ; Donohue, TM; Medina, VA; Sorrell. (1984) Enhancement of acetaldehyde - protein adduct formation by L-ascorbate. Arch Biochem Biophys 234:377381. Tuma, DJ; Sorrell, MF. (1985) Covalent binding of acetaldehyde to hepatic proteins: Role in alcoholic liver injury. In: Aldehyde Adducts in Alcoholism. Alan R. Liss, Inc., pp. 317. Vaca, CE; Nilsson, JA; Fang, J-L; et al. (1998) Formation of DNA adducts in human buccal epithelial cells exposed to acetaldehyde and methylglyoxal in vitro. Chem Biol Interact 108:197208. Vinci, S., F. Ibba, et al. (2010). Acetaldehyde elicits ERK phosphorylation in the rat nucleus accumbens and extended amygdala. Synapse 64(12): 916927. Wang, M; Yu, N; Chen, L; et al. (2006) Identification of an acetaldehyde adduct in human liver DNA and quantitation as N2-ethyldeoxyguanosine. Chem Res Toxicol 19:319324. Woodruff, RC; Mason, JM; Valencia, R; Zimmering, S. (1985) Chemical mutagenesis testing in Drosophila. V. Results of 53 coded compounds tested for the National Toxicology Program. Environ Mutagen 7(5):677702. Yang, M; Coles, BF; Delongchamp, R; et al. (2002) Effects of the ADH3, CYP2E1, and GSTP1 genetic polymorphisms on their expressions in Caucasian lung tissue. Lung Cancer 38:1521. Yu, H. S., T. Oyama, et al. (2010). Formation of acetaldehyde-derived DNA adducts due to alcohol exposure. Chemico-Biological Interactions 188(3): 367375. Zhang, L., L. Xu, et al. (2012). Comparison of DNA damage in human-derived hepatoma line (HepG2) exposed to the fifteen drinking water disinfection byproducts using the single cell gel electrophoresis assay. Mut Res 741(1-2): 8994. Zhong, L., J. Zhu, et al. (2010). Ethanol and its metabolites induce histone lysine 9 acetylation and an alteration of the expression of heart development-related genes in cardiac progenitor cells. Cardiovascular toxicology 10(4): 268 274.

23

SUSCEPTIBLE POPULATIONS AND LIFE STAGES


Agarwal, DP; Harada, S; Goedde, HW; Schrappe, O. (1983) Cytosolic aldehyde dehydrogenase and alcoholism. Lancet i:68. 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 46:527536. Di Padova C; Worner TM; Lieber CS. (1987) Effect of abstinence on the blood acetaldehyde response to a test dose of alcohol in alcoholics. Alcohol Clin Exp Res 11:559561. Druesne-Pecollo, N; Tehard, B; Mallet, Y; et al. (2009) Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncol 10: 173180. Fujimiya, T; Yamaoka, K; Ohbora, Y; et al. (2002) Michaelis-Menten elimination kinetics of acetaldehyde during ethanol oxidation. Alcohol Clin Exp Res 26:49S54S. Ginsberg, G; Smolenski, S; Hattis, D; Sonawane, B. (2002) Population distribution of aldehyde dehydrogenase-2 genetic polymorphism: Implications for risk assessment. Regul Toxicol Pharmacol 36:113. 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 36:463468. Homann, N; Konig, IR; Marks, M; et al. (2009) Alcohol and colorectal cancer: the role of alcohol dehydrogenase 1C polymorphism. Alcohol Clin Exp Res 33:551556. Ishikawa, H; Miyatsu, Y; Kurihara, K; et al. (2006) Gene-environmental interactions between alcohol-drinking behavior and ALDH2 and CYP2E1 polymorphisms and their impact on micronuclei frequency in human lymphocytes. Mutat Res 594:19. Isse, T; Oyama, 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 30:329337. Isse, T; Oyama, T; Matsuno, K; et al. (2005) Aldehyde dehydrogenase 2 activity affects symptoms produced by an intraperitoneal acetaldehyde injection, but not acetaldehyde lethality. J Toxicol Sci 30:315328. Jenkins, WJ; Cakebread, K; Palmer, KR. (1984) Effect of alcohol consumption on hepatic aldehyde dehydrogenase activity in alcoholic patients. Lancet 16:10481049. 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 210:169174. Kimura Y; Nishimura FT; Abe S; Fukunaga T; Tanii H; Saijoh K (2009). A promoter polymorphism in the ALDH2 gene affects its basal and acetaldehyde/ethanol-induced gene expression in human peripheral blood leukocytes and HepG2 cells. Alcohol Alcohol, 44: 261266. Kunugita, N; Isse, T; Oyama, T; et al. (2008) Increased frequencies of micronucleated reticulocytes and T-cell receptor mutation in Aldh2 knockout mice exposed to acetaldehyde. J Toxicol Sci 33:3136. Larson, HN; Weiner, H; Hurley, TD. (2005) Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase "Asian" variant. J Biol Chem 280:3055030556. Li, DP; Dandara, C; Walther, G; et al. (2008) Genetic polymorphisms of alcohol metabolising enzymes: their role in susceptibility to oesophageal cancer. Clin Chem Lab Med 46:323328. 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 and p38 mitogen activated protein kinase. J Biol Chem 279:1124411252.

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

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 40:283294. Lin, CC; Potter, JJ; Mezey, E. (1984) Erthyrocyte aldehyde dehydrogenase activity in alcoholism. Alcohol Clin Exp Res 8:539541. Matsuda, T; Yabushita, H; Kanaly, RA; et al. (2006) Increased DNA damage in ALDH2-deficient alcoholics. Chem Res Toxicol 19:13741378. Matsuda, T; Matsumoto, A; Uchida, M; et al. (2007) Increased formation of hepatic N2-ethylidene-2' deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol. Carcinogenesis 28:23632366. Matsuse, H; Fukushima, C; Shimoda, T; et al. (2007) Effects of acetaldehyde on human airway constriction and inflammation. In Acetaldehyde-related pathology: Bridging the trans-disciplinary divide. Chichester, UK: John Wiley & Sons, Ltd; pp. 97106. Ogawa, M; Isse, T; Oyama, T; et al. (2006) Urinary 8-hydoxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) levels in Aldh2 knock-out mice under acetaldehyde exposure. Ind Health 44:179183. Oyama, T; Isse, T; Kagawa, N; et al. (2005) Tissue-distribution of aldehyde dehydrogenase 2 and effects of the ALDH2 gene-disruption on the expression of enzymes involved in alcohol metabolism. Front Biosci 10:95160. Peng, GS, Wang, MF, Chen, CY, Luu, SU, Chou, HC, Li, TK, Yin, SJ. (1999) Involvement of acetaldehyde for full protection against alcoholism by homozygosity of the variant allele of mitochondrial aldehyde dehydrogenase gene in Asians. Pharmacogen 9(4):46376. Takada, A; Tsutsumi, M; Kobayashi, Y. (1994) Genotypes of ALDH2 related to liver and pulmonary diseases and other genetic factors related to alcoholic liver disease. Alcohol Alcoholism 29(6):719 27. Visap, J. (2004) Increased cancer risk in heavy drinkers with the alcohol dehydrogenase 1C*1 allele, possibly due to salivary acetaldehyde. Gut 53:871876. Yang, M; Coles, BF; Delongchamp, R; et al. (2002) Effects of the ADH3, CYP2E1, and GSTP1 genetic polymorphisms on their expressions in Caucasian lung tissue. Lung Cancer 38:1521. 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 Pac J Cancer Prev 6:256 262. 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 98:12481253. Yokoyama, A; Omori, T. (2005) Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers. Alcohol 35:175185. Yoshihara, E; Ameno, K; Nakamura, K; et al. (2000) The effects of the ALDH2*1/2, CYP2E1 C1/C2 and C/D genotypes on blood ethanol elimination. Drug Chem Toxicol 23(2):371379.

36

REPORTS FROM NATIONAL AND INTERNATIONAL HEALTH AGENCIES


ACGIH (American Conference Governmental Industrial Hygienists). (2002) Documentation of Threshold Limit Values and Biological Exposure Indices CD-ROM, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). (1999) Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices 1998. ACGIH, Cincinnati, OH.

37 38 39 40

25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Cal-OEHHA (California Office of Environmental Health Hazard Assessment). (2008) Acute toxicity of acetaldehyde. Available online at http://oehha.ca.gov/air/hot_spots/2008/AppendixD1_final.pdf#page=42 (accessed February 22, 2010). Cal-OEHHA (California Office of Environmental Health Hazard Assessment). (2002). Acetaldehyde as a toxic air contaminant. California EPA. Available online at http://www.oehha.org/air/toxic_contaminants/html/acetaldehyde.htm. Cal-OSHA. (2002) California Occupational Safety and Health Regulations, Subchapter 1. Regulations of the Director of Industrial Relations, Article 5. Hazardous Substances Information and Training 339. The Hazardous Substances List. Available online at http://www.dir.ca.gov/title8/339.html. Centers for Disease Control and Prevention (CDC). (2005) Acetaldehyde. RTECS no. AB1925000. Pocket Guide to Chemical Hazards. Available online at http://www.cdc.gov/niosh/npg/npgdrtec.html (accessed February 22, 2010). European Commission. (1998) Health and Consumer Protection, Committee on Food (Food Safety). Available online at http://europa.eu.int/comm/food/fs/sc/scf/out16_en.html. Hazardous Substances Data Bank (HSDB). (2010) Acetaldehyde. CASRN: 75-07-0. Available online at http://toxnet.nlm.nih.gov/. Accessed on 2/22/2010. International Agency for Research on Cancer (IARC). (1985) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. International Agency for Research on Cancer, World Health Organization, Geneva 71(2):319335. JECFA. (1995) International Programme on Chemical Safety, INCHEM, Joint FAO/WHO Expert Committee on Food Additives. Acetaldehyde (Environmental Health Criteria 167). Available online at www.inchem.org/documents/ehc/ehc/ehc167.htm. JECFA. (1997) International Programme on Chemical Safety, INCHEM, Joint FAO/WHO Expert Committee on Food Additives. TRS 884-JECFA 49/29. Available online at http://www.inchem.org/documents/jecfa/jeceval/jec_4.htm. National Institute for Occupational Health and Safety (NIOSH). (2009) Acetaldehyde: RTECS #: AB1925000. Registry of Toxic Effects of Chemical Substances (RTECS). Atlanta, GA: Centers for Disease Control (CDC). National Institute for Occupational Health and Safety (NIOSH). (2002) National Institute for Occupational Safety and Health, NIOSH Pocket Guide to Chemical Hazards and other Databases, Toxicological Review of Selected Chemicals, CD-ROM, publication No. 2001145, August, 2001. National Safety Council. (2002) Chemical Backgrounder: Acetaldehyde, National Safety Council Itasca, NY. NTP (National Toxicology Program). (1999) Chemical Health and Safety Data. NTP (National Toxicology Program). (2005) 11th Report on Carcinogens. Substance Profiles: Acetaldehyde. National Toxicology Program, Research Triangle Park, NC. OSHA (Occupational Safety and Health Administration). (1989a) Department of Labor, Occupational Safety and Health Administration, 29 CFR Part 1910, 54 FR 28154, July 5, 1989. OSHA (Occupational Safety and Health Administration). (1989b) OSHA comments from the January 19, 1989 Final Rule on Air Contaminants Project extracted from 54FR2332 et. seq. This rule was remanded by the U.S. Circuit Court of Appeals and the limits are not currently in force. OSHA (Occupational Safety and Health Administration). (1993) 29 CFR Part 1910. Air Contaminants; Rule. Federal Register 58(124):3533835351.

26

1 2 3 4 5

OSHA (Occupational Safety and Health Administration). (2002) U.S. Department of Labor, Occupational Safety and Health Administration, Limits for Air Contaminants, Occupational Safety and Health Standards, 29 CFR 1910.1000, Table Z-1. Available online at http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=STANDARDS&p_id=9992&p_text_version= FALSE

MISCELLANEOUS
Alarie, Y. (1966) Irritating properties of airborne materials to the upper respiratory tract. Arch Environ Health 13:433449. 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 23:293307. Babiuk, C; Steinhagen, WH; Barrow, CS. (1985). Sensory irritation response to inhaled aldehydes after formaldehyde pretreatment. Toxicol Appl Pharmacol 79:143149. Bam, TM; Neumann, CM. (2004) A human health assessment of hazardous air pollutants in Portland, OR. J Environ Manage 73:131145. Bascom, R. (1992) Differential responsiveness to irritant mixtures: Possible mechanisms. Ann N Y Acad Sci 641:225247. Bergh M; Karlberg AT. (1999) Sensitizing potential of acetaldehyde and formaldehyde using a modified cumulative contact enhancement test (CCET). Contact Dermatitis 40:139145. Bos, PMJ; Zwart, A; Reuzel, PGJ; et al. (1992) Evaluation of the sensory irritation test for the assessment of occupational health risk. Crit Rev Toxicol 21:423450. Boulet, L-P. (1988) Increases in airway responsiveness following acute exposure to respiratory irritants: Reactive airway dysfunction syndrome or occupational asthma? Chest 94:476481. Brooks, SM; Weiss, MA; Bernstein, IL. (1985) Reactive airways dysfunction syndrome (RADS: Persistent asthma syndrome after high level irritant exposures. Chest 88:376384. Burton, A. (2005) Acetaldehyde links alcohol consumption to cancer. Lancet Oncol 6:643. Carr, MJ; Undem, BJ. (2001) Inflammation-induced plasticity of the afferent innervation of the airways. Environ Health Perspect 4:567571. Cassee, FR; Arts, JHE; Groten, JP; et al. (1996) Sensory irritation to mixtures of formaldehyde, acrolein, and acetaldehyde in rats. Arch Toxicol 70:329337. Chang, JCF; Barrow, CS. (1984) Sensory irritation tolerance and cross-tolerance in F-344 rats exposed to chlorine or formaldehyde gas. Toxicol Appl Pharmacol 76:319327. 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 62:197202. Druesne-Pecollo, N; Tehard, B; Mallet, Y; et al. (2009) Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncol 10: 173180. Figuero, RE; Carretero Pelaez, MA; Cerero, LR; et al. (2004) Effects of the consumption of alcohol in the oral cavity: relationship with oral cancer. Med Oral 9:1423.

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39

27

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

Fisher, S. J., P. W. Swaan, et al. (2010). The ethanol metabolite acetaldehyde increases paracellular drug permeability in vitro and oral bioavailability in vivo. J Pharm Exp Ther 332(1): 326333. Fuchs, P., C. Loeseken, et al. (2010). Breath gas aldehydes as biomarkers of lung cancer. Int J Cancer 126(11): 26632670. Hoffmann, S., A. Kinsner-Ovaskainen, et al. (2010). Acute oral toxicity: variability, reliability, relevance and interspecies comparison of rodent LD50 data from literature surveyed for the ACuteTox project. Regul Toxicol Pharmacol 58(3): 395407. Isse, T; Oyama, 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 30:329337. Isse, T; Oyama, 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 30:315328. Jamal, M., K. Ameno, et al. (2012). High ethanol and acetaldehyde impair spatial memory in mouse models: Opposite effects of aldehyde dehydrogenase 2 and apolipoprotein E on memory. Pharmacology, Biochemistry and Behavior 101(3): 443449. Jamal, M; Ameno, K; Ikuo, U; et al. (2007) Ethanol and acetaldehyde: in vivo quantitation and effects on cholinergic function in rat brain. Novartis Found Symp, 285:137141; discussion 141-134, 198199. Jelski, W., E. Kutylowska, et al. (2011). Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with acute and chronic pancreatitis. Exp Mol Pathol 91(2): 631635. 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 40:207229. Kane, LE; Dombroske, R; Alarie, Y. (1980) Evaluation of sensory irritation from some common industrial solvents. Am Ind Hyg Assoc J 41:451455. Kocaelli, H; Apaydin, A; Karadeniz, A; et al. (2009) Increased salivary acetaldehyde levels in poor dental health status: a possible link to increased oral cancer risk. Int J Oral and Maxillofac Surg 38:535536. 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. Matsuse, H; Fukushima, C; Shimoda, T; et al. (2007) Effects of acetaldehyde on human airway constriction and inflammation. In Acetaldehyde-related pathology: Bridging the trans-disciplinary divide. Chichester, UK: John Wiley & Sons, Ltd., pp. 97106. 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 39:140147. Nielsen, GD. (1991) Mechanisms of activation of the sensory irritant receptor by airborne chemicals. Crit Rev Toxicol 21:183208. Oyama, T; Isse, T; Ogawa, M; et al. (2007) Susceptibility to inhalation toxicity of acetaldehyde in Aldh2 knockout mice. Front Biosci, 12:19271934. Saldiva, PHN; Caldeira, MPR; Massad, E; et al. (1985) Effects of formaldehyde and acetaldehyde inhalation on rat pulmonary mechanics. J Appl Toxicol 5:288292. 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) 204:641653. Schauenstein, E; Estenbauer, H; Zollner, H. (1977) Aldehydes in biological systems. Pio Ltd., London. Seitz, HK; Becker, P. (2007) Alcohol metabolism and cancer risk. Alcohol Res Health 30:3837.

28

1 2 3 4 5 6 7 8 9 10 11

Seitz, HK; Maurer, B; Stickel, F. (2005) Alcohol consumption and cancer of the gastrointestinal tract. Dig Dis 23:297303. Stanek, J; Symanowicz, PT; Olsen, JE; et al. (2001) Sensory-nerve mediated nasal vasodilatory response to inspired acetaldehyde and acetic acid vapors. Inhal Toxicol 13:807822. Steinhagen, WH; Barrow, CS. (1984) Sensory irritation structure-activity study of inhaled aldehydes in B6C3F1 and Swiss-Webster mice. Toxicol Appl Pharmacol 72:495503. Togias, A. (1999) Mechanisms of nose-lung interaction. Allergy 54:94105. Wang, W. L., C. T. Lee, et al. (2011). Risk factors for developing synchronous esophageal neoplasia in patients with head and neck cancer. Head Neck 33(1): 7781. Zhao, H., Y. Ge, et al. (2010). Carbonyl compound emissions from passenger cars fueled with methanol/gasoline blends. Sci Total Environ 408(17): 36073613.

12

REVIEWS
Clemens, DL. (2007) Effects of ethanol on hepatic cellular replication and cell cycle progression. World J Gastroenterol 13:49554959. Crabb, DW; Matsumoto, M; Chang, D; et al. (2004) Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology. Proc Nutr Soc 63: 4963. Feron, V; Til, H; deVrijer, F; Woutersen, R; Cassee, F; van Bladeren, P. (1991) Acetaldehyde: occurance, carcinogenic potential, mechanism of action and risk assessment. Mutat Res 259:363 385. Guo, R. and J. Ren (2010). Alcohol and acetaldehyde in public health: from marvel to menace. Int J Environ Res Public Health 7(4): 12851301. Hardman, JG; Limbird, LE; Molinoff, PB; Ruddon, RW; Gilman, AG. (1996) Goodman & Gilmans The Pharmacological Basis of Therapeutics. Ninth Edition. Lachenmeier, DW; Kanteres, F; Rehm, J. (2009) Carcinogenicity of acetaldehyde in alcoholic beverages: risk assessment outside ethanol metabolism. Addiction 104:533550. Luttrell, WE. (2009) Acetaldehyde. J. Chem. Health Saf 16(5):4344. Available online at http://www.sciencedirect.com/science/article/pii/S1871553209000826 Marichalar-Mendia, X; Rodriguez-Tojo, MJ; Acha-Sagredo, A; et al. (2009) Oral cancer and polymorphism of ethanol metabolising genes. Oral Oncol. Mello, T; Ceni, E; Surrenti, C; et al. (2008) Alcohol induced hepatic fibrosis: role of acetaldehyde. Mol Aspects Med 29:1721. Salaspuro, M. (2009) Acetaldehyde: a cumulative carcinogen in humans. Addiction 104:551553. Salaspuro, MP. (2003) Acetaldehyde, microbes, and cancer of the digestive tract. Crit Rev Clin Lab Sci 40:183 208. Salaspuro, M. (2011). Acetaldehyde and gastric cancer. J Dig Dis (Online) 12(2): 5159. Seitz, HK; Stickel, F. (2009) Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism. Genes Nutr. Skog, E. (1950) A toxicological investigation of lower aliphatic aldehydes. Toxicity of formaldehyde, acetaldehyde and butyraldehyde; as well as acrolein and crotonaldehyde. Acta Phrmacol Toxicol 6(4):299318.

13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

29

1 2 3 4

Voulgaridou, G. P., I. Anestopoulos, et al. (2011). DNA damage induced by endogenous aldehydes: current state of knowledge. Mutat Res 711(1-2): 1327. Xie, J., K. M. Marano, et al. (2012). A probabilistic risk assessment approach used to prioritize chemical constituents in mainstream smoke of cigarettes sold in China. Regul Toxicol Pharmacol 62(2): 355362.

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