Four-Week Inhalation Toxicity Study of 2, 2-Dichloro-1, 1, 1trifluoroethane (HCFC-123) in Guinea Pigs

Isamu KABE; Toru TAKEBAYASHI; Yuji NISHIWAKI; Tamie NAKAJIMA; Eiji IKEDA; Takehito SAITO; Shigeru TANAKA; Hiroyuki MIYAUCHI; Yuichi ENDO; Kazuyuki OMAE

doi:10.1539/joh.43.314

Isamu KABE, Toru TAKEBAYASHI, Yuji NISHIWAKI, Tamie NAKAJIMA, Eiji IKEDA, Takehito SAITO, Shigeru TANAKA, Hiroyuki MIYAUCHI, Yuichi ENDO, Kazuyuki OMAE

著者情報

Isamu KABE
Department of Preventive Medicine and Public Health, School of Medicine, Keio University
Department of Health Administration, Furukawa Electric Co. Ltd.
Toru TAKEBAYASHI
Department of Preventive Medicine and Public Health, School of Medicine, Keio University
Yuji NISHIWAKI
Department of Preventive Medicine and Public Health, School of Medicine, Keio University
Tamie NAKAJIMA
Department of Hygiene, School of Medicine, Shinshu University
Eiji IKEDA
Department of Pathology, School of Medicine, Keio University
Takehito SAITO
Department of Preventive Medicine and Public Health, School of Medicine, Keio University
Shigeru TANAKA
Faculty of Hygienic Technology, School of Allied Health Science, Kitasato University
Hiroyuki MIYAUCHI
The Association of Industrial Health
Yuichi ENDO
Department of Health Administration, Furukawa Electric Co. Ltd.
Kazuyuki OMAE
Department of Preventive Medicine and Public Health, School of Medicine, Keio University

キーワード: 2,2-Dichloro-1,1,1-trifluoroethane (HCFC123), Liver toxicity, Chlorofluorocarbon substitute, Trifluoroacetic acid, Guinea pig, Inhalation, Fatty change, Peroxisome

ジャーナルフリー

2001 年 43 巻 6 号 p. 314-320

DOI https://doi.org/10.1539/joh.43.314

詳細

Published: 2001 Received: 2001/03/23 Available on J-STAGE: 2006/04/07 Accepted: 2001/07/26 Advance online publication: - Revised: -
訂正情報
訂正日: 2006/04/07 訂正理由: - 訂正箇所: 所属機関情報訂正内容: 訂正前 :
1) Department of Preventive Medicine and Public Health, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
2) Department of Health Administration, Furukawa Electric Co. Ltd.
3) Department of Hygiene, School of Medicine, Shinshu University
4) Department of Pathology, School of Medicine, Keio University
5) Faculty of Hygienic Technology, School of Allied Health Science, Kitasato University
6) The Association of Industrial Health

訂正後 :
1) Department of Preventive Medicine and Public Health, School of Medicine, Keio University
2) Department of Health Administration, Furukawa Electric Co. Ltd.
3) Department of Hygiene, School of Medicine, Shinshu University
4) Department of Pathology, School of Medicine, Keio University
5) Faculty of Hygienic Technology, School of Allied Health Science, Kitasato University
6) The Association of Industrial Health

訂正日: 2006/04/07 訂正理由: - 訂正箇所: 引用文献情報訂正内容: Wrong : 1) Fisher DA, Hales CH, Filkin DL, et al. Model calculations of the relative effects of CFCs and their replacements on stratospheric ozon. Nature 1990; 344: 508-512.
2) McFarland M, Kaye J. Chlorofluorocarbons and ozone. Photochem Photobiol 1992; 55: 911-929.
3) Moline MJ, Rowland FS. Stratospheric sink for chlorofluoromethanes: Chlorine atom-catalysed destruction of ozone. Nature 1994; 249: 810-812.
4) Rusch GM, Trochimowicz HJ, Malley LJ, et al. Subchronic inhalation toxicity studies with hydrochlorofluorocarbon 123 (HCFC 123). Fundam Appl Toxicol 1994; 23: 169-178.
5) Malley LA, Carakostas M, Hansen JF, Rusch GM, Kelly DP, Trochimowicz HJ. Two-year inhalation toxicity study in rats with hydrochlorofluorocarbon 123. Fundam Appl Toxicol 1995; 25: 101-114.
6) Malinverno G, Rusch GM, Millischer RJ, Hughes EW, Schroeder RE, Coombs DW. Inhalation teratology and reproduction studies with 1,1-Dichloro-2,2,2 trifluoroethane (HCFC 123). Fundam Appl Toxicol 1996;34:276-287.
7) Hoet P, Graf ML, Bourdi M, et al. Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons. Lancet 1997; 40: 556-559.
8) Takebayashi T, Kabe I, Endo Y, et al. Acute liver dysfunction among workers exposed to 2,2-dichloro 1,1,1-trifluoroethane (HCFC-123): a case report. J Occup Health 1998; 40: 169-170.
9) Takebayashi T, Kabe I, Endo Y, et al. Exposure to 2,2-dichloro-1, 1, 1-trifluoroethane (HCFC-123) and acute liver dysfunction: a causal inference. J Occup Healt 1998;40:334-338.
10) Omae K, Takebayashi T, Tanaka S, et al. Acute and recurrent hepatitis induced by 2,2-dichloro-1,1,1 trifluoroethane (HCFC-123). J Occup Health 2000; 42: 235-238.
11) Yoshinami N, Shintani H, Katsuma Y. Liver dysfunction caused by hydrochlorofluorocarbon. Liver, Gall and Spleen 2000; 40: 913-920 (in Japanease).
12) Marit GB, Dodd DE, George ME, Vinegar A. Hepatotoxicity in guinea pigs following acute inhalation exposure to 1,1-dichloro-2,2,2 trifluoroethane. Toxicol Pathol 1994; 22: 404-414.
13) Tanaka S, Kabe I, Takebayashi T, et al. Environmental and biological monitoring of 2,2-dichloro-1,1,1 trifluoroethane (HCFC 123). J Occup Health 1998; 40: 348-349.
14) Osumi T, Hashimoto T, Ui N. Purification and properties of acyl-CoA oxidase from rat liver. J Biochem 1980; 87: 1735-1746.
15) Furuta S, Miyazawa S, Osumi T, Hashimoto T, Ui N. Properties of mitochondrial and peroxisomal enoyl CoA hydratases from rat liver. J Biochem 1980; 88: 1059-1070.
16) Furuta S, Hayashi H, Hijikata M, Miyazawa S, Osumi T, Hashimoto T. Complete nucleotide sequence of cDNA and deduced amino acid sequence of rat liver catalase. Proc Natl Acad Sci USA 1986; 83: 313-317.
17) Zimmerman HT, Ishk KG. Hepatic injury due to drugs and toxins. In: MacSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portmann BC, eds. Pathology of the liver, 3rd ed.: Churchill Livingstone, 1994: 563-633.
18) Lind RC, Gandolfi AJ, Hall PD. Biotransformation and hepatotoxicity of HCFC-123 in the guinea pigs: potentiation of hepatic injury by prior glutathione depletion. Toxicol Appl Pharmacol 1995; 134: 175-181.
19) Lind RC, Gandolfi AJ, Brown BR, Jr., Hall PM. Halothane hepatotoxicity in guinea pigs. Anesth Analg 1987;66:222-228.
20) Clarke JB, Lind RC, Gandolfi AJ. Mechanisms of anesthetic hepatotoxicity. Advances in Anesthesia 1993;10:219-246.
21) Parkinson A. Biotransformation of xenobiotics. In: Klaassen CD ed. Casarett and Doull''s toxicology. New York: McGraw-Hill, 1996: 125-126.
22) Spracklin DK, Hankins DC, Fisher JM, Thummel KE, Kharasch. Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro. J Pharmacol Exp Ther 1997; 281: 400-411.
23) Lunam CA, Hall PM, Cousins MJ. The pathology of halothane hepatoxicity in a guinea pig model: A comparison with human halothane hepatitis. Br J Exp Pathol 1989; 70: 533-541.
24) Hursh D, Gelman S, Bradley EL. Hepatic oxygen supply during halothane or isoflurane anesthesia in guinea pigs. Anesthesiology 1987; 67: 701-706.
25) Urban G, Speerschneider P, Dekant W. Metabolism of the chlorofluorocarben substitute 1,1-dichloro-2,2,2 trifluoroethane by rat and human liver microsomes: the role of cytochrome P450 2E1. Chem Res Toxicol 1994;7:170-176.
26) Dekant W, Assmann M, Urban G. The role of cytochrome P450 2E1 in the species-dependent biotransformation of 1,2-dichloro-1,1,2-trifluoroethane in rats and mice. Toxicol Appl Pharmacol 1995; 134: 200-207.
27) Roberts RA. Peroxisome proliferators: mechanisms of adverse effects in rodents and molecular basis for species differences. Arch Toxicol 1999; 73: 413-418.
28) International Agency for Research on Cancer. IARC Technical Report No. 24. Peroxisome proliferatoion and its role in carcinogenesis. Lyon: IARC, 1995.
29) Lake BG, Evans JG, Gray TB, Korosi SA, North CJ. Comparative studies on nafenopin-induced hepatic peroxisome proliferation in the rats, syrian hamster, guinea pig and marmoset. Toxicol Appl Pharmacol 1989;99:148-160.
30) Hasmall SC, James NH, Soames A, Roberts RA. The peroxisome proliferator nafenopin does not suppress hepatocyte apoptosis in guinea pig liver in vivo nor in human hepatocytes in vitro. Arch Toxicol 1998; 71: 777-783.
31) Wang R, Nakajima T, Honma T. Trichloroethylene inhibits aldehyde dehydrogenase only for aliphatic aldehydes of short chains in rats. Toxicol 1999; 132: 9-18.
32) Krey G, Braissant 0, L''Horset F, et al. Fatty acids, eicosanoids and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 1997; 11: 779-791.
33) Kersten S, Desvergne B, Wahll W. Roles of PPARs in health and disease. Nature 2000; 405: 421-424.

Right : 1) Fisher DA, Hales CH, Filkin DL, et al. Model calculations of the relative effects of CFCs and their replacements on stratospheric ozon. Nature 1990; 344: 508-512.
2) McFarland M, Kaye J. Chlorofluorocarbons and ozone. Photochem Photobiol 1992; 55: 911-929.
3) Moline MJ, Rowland FS. Stratospheric sink for chlorofluoromethanes: Chlorine atom-catalysed destruction of ozone. Nature 1994; 249: 810-812.
4) Rusch GM, Trochimowicz HJ, Malley LJ, et al. Subchronic inhalation toxicity studies with hydrochlorofluorocarbon 123 (HCFC 123). Fundam Appl Toxicol 1994; 23: 169-178.
5) Malley LA, Carakostas M, Hansen JF, Rusch GM, Kelly DP, Trochimowicz HJ. Two-year inhalation toxicity study in rats with hydrochlorofluorocarbon 123. Fundam Appl Toxicol 1995; 25: 101-114.
6) Malinverno G, Rusch GM, Millischer RJ, Hughes EW, Schroeder RE, Coombs DW. Inhalation teratology and reproduction studies with 1,1-Dichloro-2,2,2 trifluoroethane (HCFC 123). Fundam Appl Toxicol 1996;34:276-287.
7) Hoet P, Graf ML, Bourdi M, et al. Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons. Lancet 1997; 40: 556-559.
8) Takebayashi T, Kabe I, Endo Y, et al. Acute liver dysfunction among workers exposed to 2,2-dichloro 1,1,1-trifluoroethane (HCFC-123): a case report. J Occup Health 1998; 40: 169-170.
9) Takebayashi T, Kabe I, Endo Y, et al. Exposure to 2,2-dichloro-1, 1, 1-trifluoroethane (HCFC-123) and acute liver dysfunction: a causal inference. J Occup Healt 1998;40:334-338.
10) Omae K, Takebayashi T, Tanaka S, et al. Acute and recurrent hepatitis induced by 2,2-dichloro-1,1,1 trifluoroethane (HCFC-123). J Occup Health 2000; 42: 235-238.
11) Yoshinami N, Shintani H, Katsuma Y. Liver dysfunction caused by hydrochlorofluorocarbon. Liver, Gall and Spleen 2000; 40: 913-920 (in Japanease).
12) Marit GB, Dodd DE, George ME, Vinegar A. Hepatotoxicity in guinea pigs following acute inhalation exposure to 1,1-dichloro-2,2,2 trifluoroethane. Toxicol Pathol 1994; 22: 404-414.
13) Tanaka S, Kabe I, Takebayashi T, et al. Environmental and biological monitoring of 2,2-dichloro-1,1,1 trifluoroethane (HCFC 123). J Occup Health 1998; 40: 348-349.
14) Osumi T, Hashimoto T, Ui N. Purification and properties of acyl-CoA oxidase from rat liver. J Biochem 1980; 87: 1735-1746.
15) Furuta S, Miyazawa S, Osumi T, Hashimoto T, Ui N. Properties of mitochondrial and peroxisomal enoyl CoA hydratases from rat liver. J Biochem 1980; 88: 1059-1070.
16) Furuta S, Hayashi H, Hijikata M, Miyazawa S, Osumi T, Hashimoto T. Complete nucleotide sequence of cDNA and deduced amino acid sequence of rat liver catalase. Proc Natl Acad Sci USA 1986; 83: 313-317.
17) Zimmerman HT, Ishk KG. Hepatic injury due to drugs and toxins. In: MacSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portmann BC, eds. Pathology of the liver, 3rd ed.: Churchill Livingstone, 1994: 563-633.
18) Lind RC, Gandolfi AJ, Hall PD. Biotransformation and hepatotoxicity of HCFC-123 in the guinea pigs: potentiation of hepatic injury by prior glutathione depletion. Toxicol Appl Pharmacol 1995; 134: 175-181.
19) Lind RC, Gandolfi AJ, Brown BR, Jr., Hall PM. Halothane hepatotoxicity in guinea pigs. Anesth Analg 1987;66:222-228.
20) Clarke JB, Lind RC, Gandolfi AJ. Mechanisms of anesthetic hepatotoxicity. Advances in Anesthesia 1993;10:219-246.
21) Parkinson A. Biotransformation of xenobiotics. In: Klaassen CD ed. Casarett and Doull's toxicology. New York: McGraw-Hill, 1996: 125-126.
22) Spracklin DK, Hankins DC, Fisher JM, Thummel KE, Kharasch. Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro. J Pharmacol Exp Ther 1997; 281: 400-411.
23) Lunam CA, Hall PM, Cousins MJ. The pathology of halothane hepatoxicity in a guinea pig model: A comparison with human halothane hepatitis. Br J Exp Pathol 1989; 70: 533-541.
24) Hursh D, Gelman S, Bradley EL. Hepatic oxygen supply during halothane or isoflurane anesthesia in guinea pigs. Anesthesiology 1987; 67: 701-706.
25) Urban G, Speerschneider P, Dekant W. Metabolism of the chlorofluorocarben substitute 1,1-dichloro-2,2,2 trifluoroethane by rat and human liver microsomes: the role of cytochrome P450 2E1. Chem Res Toxicol 1994;7:170-176.
26) Dekant W, Assmann M, Urban G. The role of cytochrome P450 2E1 in the species-dependent biotransformation of 1,2-dichloro-1,1,2-trifluoroethane in rats and mice. Toxicol Appl Pharmacol 1995; 134: 200-207.
27) Roberts RA. Peroxisome proliferators: mechanisms of adverse effects in rodents and molecular basis for species differences. Arch Toxicol 1999; 73: 413-418.
28) International Agency for Research on Cancer. IARC Technical Report No. 24. Peroxisome proliferatoion and its role in carcinogenesis. Lyon: IARC, 1995.
29) Lake BG, Evans JG, Gray TB, Korosi SA, North CJ. Comparative studies on nafenopin-induced hepatic peroxisome proliferation in the rats, syrian hamster, guinea pig and marmoset. Toxicol Appl Pharmacol 1989;99:148-160.
30) Hasmall SC, James NH, Soames A, Roberts RA. The peroxisome proliferator nafenopin does not suppress hepatocyte apoptosis in guinea pig liver in vivo nor in human hepatocytes in vitro. Arch Toxicol 1998; 71: 777-783.
31) Wang R, Nakajima T, Honma T. Trichloroethylene inhibits aldehyde dehydrogenase only for aliphatic aldehydes of short chains in rats. Toxicol 1999; 132: 9-18.
32) Krey G, Braissant 0, L'Horset F, et al. Fatty acids, eicosanoids and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 1997; 11: 779-791.
33) Kersten S, Desvergne B, Wahll W. Roles of PPARs in health and disease. Nature 2000; 405: 421-424.

訂正日: 2006/04/07 訂正理由: - 訂正箇所: PDFファイル訂正内容: -

抄録

Four—Week Inhalation Toxicity Study of 2, 2—Dichloro—1, 1, 1—trifluoroethane (HCFC-123) in Guinea Pigs: Isamu KABE, et al. Department of Preventive Medicine and Public Health, School of Medicine, Keio University—Groups of eight male Hartley guinea pigs were exposed to 30, 100 or 300 ppm 2, 2—dichloro—1, 1, 1—trifluoroethane (HCFC—123) by inhalation for 6 hours a day for 4 wk. All the animals were sacrificed 48 h postexposure. Guinea pigs exposed to 300 ppm HCFC—123 had significantly lower body weight and the weight gain than controls, but there was no significant difference and no tendency in absolute and relative organ weight. ICDH, ALT and AST, which were the most sensitive indicators of halothane-induced liver injury, did not differ significantly between exposed groups and controls. In the 100 ppm group, a few vacuolar fatty changes in the portal area (zone I) were identified. In the 300 ppm group, severe fatty degeneration was observed in the portal and intermediate areas, partly centrilobule, and the incidence increased significantly compared to the controls. On the other hand, there was no histopathological change in the control or 30 ppm groups. No increase in any of the liver peroxisomal enzymes (AOX, PT, catalase) was seen in male guinea pigs exposed to HCFC—123. The activity of hepatic ALDH was significantly decreased in the 300 ppm exposed group, suggesting that HCFC—123 or its metabolite inhibited ALDH activity. In conclusion, inhalation exposure to 100 ppm or more of HCFC—123 for 4 wk produced nonfatal liver change in guinea pigs, namely hepatic fatty changes predominantly in the portal area (zone I) without any increase in AST, ALT or ICDH. The o—observed—adverse—effect level (NOAEL) of HCFC—1 23 for four wk in guinea pigs may be 30 ppm. Peroxisome proliferation, which may result in hepatocellular tumor induction, was not observed in guinea pigs exposed to HCFC—123. (J Occup Health 2001; 43: 314-320)

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