title: Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard.
abstract: The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE.
authors: University of North Carolina, Chapel Hill, NC, USA. Electronic address: iir@unc.edu.
authors: Ivan
authors: I
authors: Rusyn
authors: U.S. Environmental Protection Agency, Washington, DC, USA.
authors: Weihsueh A
authors: WA
authors: Chiu
authors: Wayne State University School of Medicine, Detroit, MI, USA.
authors: Lawrence H
authors: LH
authors: Lash
authors: Utrecht University, Utrecht, The Netherlands.
authors: Hans
authors: H
authors: Kromhout
authors: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors: Johnni
authors: J
authors: Hansen
authors: U.S. Environmental Protection Agency, Washington, DC, USA.
authors: Kathryn Z
authors: KZ
authors: Guyton
mesh_terms: D000818:Animals; D002274:Carcinogens, Environmental / Q000493:pharmacokinetics / Q000506:poisoning / Q000633:toxicity*; D006801:Humans; D009153:Mutagens / Q000493:pharmacokinetics / Q000506:poisoning / Q000633:toxicity; D009369:Neoplasms / Q000139:chemically induced* / Q000453:epidemiology*; D012307:Risk Factors; D012997:Solvents / Q000493:pharmacokinetics / Q000506:poisoning / Q000633:toxicity*; D014241:Trichloroethylene / Q000493:pharmacokinetics / Q000506:poisoning / Q000633:toxicity*
chemical_list: D002274:Carcinogens, Environmental; D009153:Mutagens; D012997:Solvents; D014241:Trichloroethylene
keywords: Cancer; Human; Kidney; Mechanisms; Metabolism; Trichloroethylene
references: J Occup Med Toxicol. 2007 Nov 12;2:13
references: 17997830
references: Chem Res Toxicol. 1992 Mar-Apr;5(2):232-7
references: 1643252
references: Arch Toxicol. 1980 Feb;43(4):237-48
references: 7387385
references: Carcinogenesis. 1994 Oct;15(10):2255-61
references: 7955063
references: J Occup Environ Med. 1995 Jul;37(7):797-806
references: 7552463
references: Toxicol Lett. 2004 Jun 15;151(1):301-10
references: 15177666
references: Toxicol Appl Pharmacol. 1997 Nov;147(1):15-30
references: 9356303
references: Int J Hyg Environ Health. 2012 Apr;215(3):333-8
references: 21920816
references: Toxicol Appl Pharmacol. 2009 Jul 1;238(1):90-9
references: 19409406
references: Arthritis Rheum. 2001 Mar;44(3):662-5
references: 11263781
references: Toxicol Appl Pharmacol. 2008 Sep 15;231(3):300-7
references: 18565563
references: Toxicology. 2003 Sep 30;191(2-3):109-19
references: 12965114
references: Mol Pharmacol. 1995 Jan;47(1):74-81
references: 7838135
references: Toxicol Lett. 1980 Jan;5(1):89-93
references: 6892858
references: Br J Ind Med. 1991 May;48(5):342-7
references: 2039747
references: Chem Res Toxicol. 1998 May;11(5):464-70
references: 9585477
references: J Environ Sci Health A Tox Hazard Subst Environ Eng. 2006;41(3):249-71
references: 16484062
references: J Pharmacol Exp Ther. 2001 Apr;297(1):155-64
references: 11259540
references: Chem Res Toxicol. 1998 Sep;11(9):1082-8
references: 9760283
references: Expert Opin Drug Metab Toxicol. 2008 Oct;4(10):1321-31
references: 18798701
references: Toxicology. 2013 Apr 5;306:157-61
references: 23416178
references: Mutagenesis. 1997 Sep;12(5):321-8
references: 9379909
references: Carcinogenesis. 1995 Mar;16(3):495-500
references: 7697804
references: Mutat Res. 1989 Mar;222(3):279-82
references: 2922011
references: Chem Biol Interact. 1977 Feb;16(2):135-43
references: 849620
references: Toxicol Appl Pharmacol. 1987 Apr;88(2):225-33
references: 3564041
references: Ann N Y Acad Sci. 1988;534:316-42
references: 3389663
references: Biochem Pharmacol. 1984 Jul 1;33(13):2021-7
references: 6743352
references: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4156-61
references: 10725358
references: Clin Pharmacol Ther. 1972 Jan-Feb;13(1):37-49
references: 4550322
references: Reprod Toxicol. 2006 Feb;21(2):117-47
references: 16181768
references: Int Arch Occup Environ Health. 1976 Dec 15;38(2):87-102
references: 1002309
references: Toxicol Lett. 1993 Aug;69(2):129-37
references: 8212055
references: Toxicology. 1989 Apr;55(1-2):131-41
references: 2711399
references: Natl Cancer Inst Carcinog Tech Rep Ser. 1976 Feb;2:1-215
references: 12844147
references: Immunopharmacology. 2000 Feb;46(2):123-37
references: 10647871
references: Mutat Res. 1978 May;57(2):141-53
references: 351387
references: Am J Epidemiol. 2003 Dec 15;158(12):1182-92
references: 14652303
references: Res Commun Chem Pathol Pharmacol. 1992 May;76(2):192-208
references: 1376481
references: Environ Mol Mutagen. 1987;10 Suppl 10:1-175
references: 3319609
references: J Biol Chem. 1994 May 20;269(20):14546-52
references: 8182062
references: Toxicol Appl Pharmacol. 1998 Oct;152(2):339-59
references: 9853003
references: J Occup Med. 1994 May;36(5):556-62
references: 8027881
references: Mutagenesis. 2008 Jan;23(1):27-33
references: 18003627
references: J Immunotoxicol. 2007 Apr;4(2):129-41
references: 18958721
references: Pharmacogenomics. 2008 Jan;9(1):93-104
references: 18154451
references: Epidemiology. 1998 Jul;9(4):424-31
references: 9647907
references: Toxicol Appl Pharmacol. 1988 Nov;96(2):367-79
references: 2461605
references: Int Arch Occup Environ Health. 1990;62(2):171-6
references: 2323835
references: Toxicol Sci. 2000 Feb;53(2):458-66
references: 10696794
references: Toxicol Appl Pharmacol. 2002 Jul 1;182(1):55-65
references: 12127263
references: J Anal Toxicol. 2000 Jan-Feb;24(1):22-6
references: 10654565
references: Mutat Res. 2004 Dec 12;564(2):159-64
references: 15507380
references: Int Arch Occup Environ Health. 2004 Apr;77(3):186-90
references: 14986001
references: J Expo Anal Environ Epidemiol. 2003 Sep;13(5):325-40
references: 12973361
references: Toxicol Sci. 1998 Feb;41(2):157-65
references: 9520351
references: J Biol Chem. 1986 May 5;261(13):5930-5
references: 3700378
references: Water Res. 2010 Apr;44(8):2638-46
references: 20189624
references: J Occup Environ Med. 2011 Sep;53(9):992-1007
references: 21866047
references: Natl Toxicol Program Tech Rep Ser. 1990 May;243:1-174
references: 12750750
references: Toxicol Appl Pharmacol. 1993 Aug;121(2):291-5
references: 8346545
references: Carcinogenesis. 2012 Aug;33(8):1538-41
references: 22665366
references: J Natl Cancer Inst. 1999 May 19;91(10):854-61
references: 10340905
references: Toxic Rep Ser. 1999 Aug;(59):1-66, A1-E7
references: 11803702
references: Drugs Aging. 2001;18(11):837-51
references: 11772124
references: Mutat Res. 2010 Dec 21;703(2):174-9
references: 20801231
references: Chem Biol Interact. 1986 Oct 15;60(1):31-45
references: 3536138
references: IMS Ind Med Surg. 1970 Jan;39(1):46-9
references: 5263053
references: Environ Mutagen. 1983;5 Suppl 1:1-142
references: 6365529
references: Am J Ind Med. 1999 Jul;36(1):54-9
references: 10361587
references: Drug Metab Dispos. 2005 Oct;33(10):1429-37
references: 15987776
references: Mutagenesis. 2011 Nov;26(6):771-81
references: 21775299
references: Toxicol Appl Pharmacol. 1982 Jan;62(1):137-51
references: 7064149
references: Toxicol Appl Pharmacol. 2009 Nov 15;241(1):36-60
references: 19660485
references: Bull Environ Contam Toxicol. 1982 Mar;28(3):322-8
references: 7082873
references: Int Arch Occup Environ Health. 1993;65(1 Suppl):S61-7
references: 8406940
references: J Occup Environ Med. 2001 Feb;43(2):133-9
references: 11227631
references: J Pharmacol Exp Ther. 2006 Feb;316(2):520-9
references: 16269531
references: Carcinogenesis. 1997 Nov;18(11):2101-6
references: 9395208
references: Environ Health Perspect. 2009 May;117(5):696-702
references: 19479009
references: Am J Ind Med. 2003 Jun;43(6):618-29
references: 12768612
references: Toxicol Sci. 2011 Mar;120(1):206-17
references: 21135412
references: Occup Med (Lond). 1999 Jul;49(5):299-305
references: 10628055
references: J Toxicol Environ Health A. 2007 Oct;70(20):1745-51
references: 17885931
references: Biochem Pharmacol. 1987 Sep 1;36(17):2741-8
references: 3307787
references: Cell Biol Toxicol. 1988 Dec;4(4):393-403
references: 3228710
references: Occup Environ Med. 1998 Mar;55(3):161-71
references: 9624267
references: Cancer Treat Res. 2006;130:103-24
references: 16610705
references: Mutat Res. 2008 Mar 29;652(1):88-94
references: 18289923
references: Front Oncol. 2012 Jan 10;1:53
references: 22649769
references: Mutat Res. 2008 Jul 31;654(2):108-13
references: 18606566
references: Int J Epidemiol. 2000 Dec;29(6):1014-24
references: 11101542
references: J Occup Environ Med. 2005 May;47(5):453-7
references: 15891523
references: Toxicol Sci. 2002 Sep;69(1):3-15
references: 12215655
references: Environ Health Perspect. 2002 Feb;110 Suppl 1:61-74
references: 11834464
references: Lancet Oncol. 2007 Apr;8(4):292-3
references: 17431955
references: Toxicol Appl Pharmacol. 1991 Sep 1;110(2):303-14
references: 1891776
references: IARC Monogr Eval Carcinog Risks Hum. 1995;63:33-477
references: 9139128
references: Carcinogenesis. 2000 Apr;21(4):677-82
references: 10753203
references: Hum Exp Toxicol. 1996 Mar;15(3):254-8
references: 8839215
references: Mutat Res. 1988 Sep;206(1):83-90
references: 2901035
references: Arch Environ Health. 1974 Jul;29(1):1-5
references: 4276444
references: Ind Health. 2011;49(4):534-41
references: 21697614
references: Toxicol Appl Pharmacol. 1985 Jul;79(3):389-400
references: 4035686
references: Am J Ind Med. 2005 Oct;48(4):249-58
references: 16167347
references: Drug Metab Dispos. 2003 Mar;31(3):306-11
references: 12584157
references: Int Arch Occup Environ Health. 2007 Apr;80(5):357-70
references: 17106739
references: Biochem Pharmacol. 1992 Jan 22;43(2):251-7
references: 1739413
references: Am J Ind Med. 1997 Sep;32(3):217-22
references: 9219650
references: Toxicol Appl Pharmacol. 1999 Feb 1;154(3):264-78
references: 9931286
references: Genome Res. 2006 Feb;16(2):223-30
references: 16354753
references: Toxicology. 1996 Jun 17;110(1-3):103-11
references: 8658551
references: Chem Biol Interact. 2001 Aug 31;137(2):139-54
references: 11551530
references: Chem Biol Interact. 1997 Jul 11;105(2):99-117
references: 9251723
references: Hepatology. 2005 Feb;41(2):336-44
references: 15660387
references: J Biochem Mol Toxicol. 1999;13(5):231-7
references: 10402556
references: J Toxicol Environ Health. 1988;23(2):147-58
references: 3343692
references: Environ Health Perspect. 2000 May;108 Suppl 2:359-63
references: 10807565
references: Chem Res Toxicol. 1999 Oct;12(10):937-42
references: 10525269
references: Mutagenesis. 1994 Sep;9(5):429-37
references: 7837977
references: Biol Res Pregnancy Perinatol. 1985;6(2):79-88
references: 4016168
references: J Cancer Res Clin Oncol. 1998;124(7):374-82
references: 9719500
references: Toxicol Sci. 1998 Jun;43(2):139-44
references: 9710955
references: Environ Mol Mutagen. 2002;40(2):134-42
references: 12203407
references: Environ Health Perspect. 2000 May;108 Suppl 2:225-40
references: 10807554
references: Toxicol Appl Pharmacol. 2002 Aug 1;182(3):244-54
references: 12183104
references: Toxicol Appl Pharmacol. 1999 Dec 1;161(2):209-18
references: 10581215
references: Environ Toxicol Pharmacol. 2002 Jul;11(3-4):259-71
references: 21782610
references: Toxicology. 1985 Apr;35(1):25-33
references: 4002236
references: Toxicology. 1989 Oct 16;58(3):239-48
references: 2799828
references: Occup Environ Med. 2012 Dec;69(12):858-67
references: 23000822
references: Carcinogenesis. 2010 Sep;31(9):1592-6
references: 20530238
references: J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2009 Jul;27(3):178-96
references: 19657920
references: J Occup Environ Med. 2006 Oct;48(10):1070-92
references: 17033507
references: J Pharmacol Exp Ther. 1992 Jun;261(3):869-74
references: 1602390
references: Int J Occup Med Environ Health. 2011 Mar;24(1):67-77
references: 21468904
references: Arch Toxicol. 1997;71(5):332-5
references: 9137812
references: Toxicology. 2004 Nov 15;204(2-3):187-95
references: 15388244
references: AIHAJ. 2001 Jan-Feb;62(1):12-8
references: 11258863
references: Fundam Appl Toxicol. 1996 May;31(1):77-82
references: 8998956
references: Arch Toxicol. 2009 Sep;83(9):835-49
references: 19448997
references: Carcinogenesis. 2013 Apr;34(4):799-802
references: 23276795
references: Toxicol Sci. 2010 May;115(1):131-9
references: 20118189
references: Environ Health Perspect. 1998 Aug;106 Suppl 4:983-8
references: 9703482
references: Environ Health Perspect. 2006 Aug;114(8):1237-42
references: 16882532
references: Occup Environ Med. 2004 Apr;61(4):312-7
references: 15031388
references: Chem Biol Interact. 1992 Aug 14;83(2):183-99
references: 1505060
references: Occup Environ Med. 1999 Sep;56(9):581-97
references: 10615290
references: Carcinogenesis. 1995 May;16(5):1127-33
references: 7767975
references: Can J Physiol Pharmacol. 1994 Mar;72(3):205-10
references: 8069766
references: Fundam Appl Toxicol. 1996 Jul;32(1):87-95
references: 8812237
references: Toxicol Sci. 2007 Jan;95(1):23-36
references: 17032701
references: Am J Ind Med. 1988;13(6):683-93
references: 3389363
references: Natl Toxicol Program Tech Rep Ser. 1988 Apr;273:1-299
references: 12748681
references: Hum Exp Toxicol. 2001 Nov;20(11):585-9
references: 11926613
references: Toxicol Appl Pharmacol. 1988 Jun 15;94(1):45-54
references: 3376113
references: Mutat Res. 1994 Aug;322(2):111-6
references: 7519317
references: J Toxicol Environ Health A. 2006 Jul;69(13):1285-309
references: 16754541
references: Environ Mol Mutagen. 1992;20(4):277-88
references: 1330547
references: Hum Exp Toxicol. 2000 Feb;19(2):117-21
references: 10773841
references: Teratog Carcinog Mutagen. 2002;22(2):113-28
references: 11835289
references: Toxicol Sci. 1998 Jun;43(2):145-54
references: 9710956
references: Toxicol Lett. 1983 Jul;17(3-4):321-8
references: 6353674
references: Environ Health Perspect. 1998 Jan;106(1):41-4
references: 9417767
references: PLoS Genet. 2011 Oct;7(10):e1002312
references: 22022277
references: Res Commun Mol Pathol Pharmacol. 2000 Jul-Aug;108(1-2):116-32
references: 11758968
references: Environ Health Perspect. 1994 Nov;102 Suppl 9:31-4
references: 7698080
references: Int Arch Occup Environ Health. 2007 Nov;81(2):247-51
references: 17479278
references: Br J Ind Med. 1991 Aug;48(8):515-30
references: 1878308
references: Br J Cancer. 1983 Jul;48(1):1-15
references: 6191767
references: Cancer Res. 2010 Aug 15;70(16):6527-36
references: 20663906
references: Int J Environ Res Public Health. 2011 Nov;8(11):4238-72
references: 22163205
references: Mutat Res. 1998 Mar 30;413(3):265-76
references: 9651541
references: Curr Opin Immunol. 2007 Apr;19(2):209-16
references: 17276050
references: Mutat Res. 1995 Dec;348(4):147-52
references: 8544866
references: Environ Health Perspect. 2007 Nov;115(11):1553-6
references: 18007983
references: Adv Pharmacol. 2012;63:137-67
references: 22776641
references: Mutat Res. 1980 Jan;77(1):55-63
references: 6767185
references: Fundam Appl Toxicol. 1987 May;8(4):432-42
references: 3111923
references: J Toxicol Environ Health. 1997 Dec 12;52(5):425-45
references: 9388534
references: Arch Toxicol. 1995;69(5):291-9
references: 7654132
references: J Occup Environ Med. 2007 Aug;49(8):909-12
references: 17693789
references: Int Arch Occup Environ Health. 1994;66(1):49-54
references: 7927843
references: Ann Occup Hyg. 2006 Nov;50(8):777-87
references: 16840435
references: Arch Toxicol. 1997;71(9):596-9
references: 9285043
references: Fundam Appl Toxicol. 1997 Jun;37(2):125-30
references: 9242585
references: Environ Mol Mutagen. 1996;27(1):1-9
references: 8625942
references: Ind Health. 1983;21(4):243-54
references: 6654707
references: Biomed Environ Sci. 2002 Jun;15(2):113-8
references: 12244752
references: Sci Total Environ. 2012 Mar 1;419:225-32
references: 22285084
references: Xenobiotica. 1986 Feb;16(2):143-52
references: 3962335
references: J Environ Sci Health A Tox Hazard Subst Environ Eng. 2009 Apr;44(5):443-53
references: 19241258
references: Toxicology. 2000 May 5;146(2-3):123-36
references: 10814845
references: Toxicology. 2006 Jul 5;224(1-2):108-18
references: 16730402
references: Chem Biol Interact. 1992 Aug 14;83(2):135-53
references: 1505057
references: Mutat Res. 1989 Apr;222(4):329-35
references: 2704384
references: Drug Metab Dispos. 2006 Dec;34(12):2020-7
references: 16959879
references: J Biochem Mol Toxicol. 2001;15(2):100-6
references: 11284051
references: Ann Genet. 1981;24(2):105-6
references: 6977287
references: Environ Mol Mutagen. 1989;14(3):155-64
references: 2792091
references: Environ Health Perspect. 2000 May;108 Suppl 2:177-200
references: 10807551
references: Drug Discov Today. 2007 Aug;12(15-16):599-610
references: 17706541
references: J Environ Biol. 2009 Sep;30(5):685-91
references: 20136049
references: J Biol Chem. 1991 Oct 5;266(28):18415-8
references: 1917965
references: J Occup Environ Med. 2013 Feb;55(2):198-208
references: 23147555
references: J Biol Chem. 1986 Nov 25;261(33):15529-37
references: 3782077
references: Toxicology. 1999 Jan 1;132(1):9-18
references: 10199577
references: Arch Toxicol. 1999 Jun-Jul;73(4-5):246-54
references: 10463390
references: Arch Environ Occup Health. 2005 May-Jun;60(3):130-9
references: 17153085
references: Mutat Res. 2012 Jan 24;741(1-2):89-94
references: 22108252
references: J Toxicol Environ Health A. 1999 Jan 8;56(1):1-21
references: 9923751
references: Environ Health Perspect. 1993 Mar;99:281-4
references: 8319644
references: J Appl Toxicol. 1983 Oct;3(5):249-53
references: 6662999
references: Toxicol Appl Pharmacol. 2005 Aug 7;206(2):157-68
references: 15967204
references: Mutat Res. 1988 Oct;206(2):209-16
references: 3050501
references: Arch Toxicol. 1996;70(6):338-46
references: 8975632
references: Mutagenesis. 1990 Sep;5(5):453-9
references: 2263203
references: Cancer Res. 1990 Jul 1;50(13):4014-9
references: 2191770
references: Carcinogenesis. 1991 Sep;12(9):1715-9
references: 1893532
references: Toxicol Appl Pharmacol. 1987 Sep 15;90(2):183-9
references: 3629594
references: Exp Lung Res. 1991 May-Jun;17(3):601-14
references: 1860457
references: Adv Exp Med Biol. 2013;754:215-32
references: 22956504
references: Mutat Res. 1994 Aug;322(2):87-96
references: 7519326
references: J Immunotoxicol. 2010 Oct-Dec;7(4):350-6
references: 20925451
references: Respir Med. 2004 Jan;98(1):52-6
references: 14959814
references: J Occup Environ Med. 2008 Nov;50(11):1306-19
references: 19001957
references: Arch Toxicol Suppl. 1985;8:6-17
references: 3868383
references: Toxicol Appl Pharmacol. 2006 Oct 15;216(2):319-30
references: 16844155
references: Gastroenterology. 1982 Oct;83(4):926-9
references: 7106523
references: Int J Occup Environ Health. 2005 Jan-Mar;11(1):53-63
references: 15859192
references: Toxicology. 2004 Oct 15;203(1-3):83-98
references: 15363585
references: Forensic Sci Int. 2003 Jul 8;134(2-3):115-9
references: 12850404
references: Lancet Oncol. 2012 Dec;13(12):1192-3
references: 23323277