Characterization of liver toxicity in F344/N rats and B6C3F1 mice after exposure to a flame retardant containing lower molecular weight polybrominated diphenyl ethers.
Lower molecular weight polybrominated diphenyl ethers (PBDEs), components of flame retardants, are found in the environment and in human and animal tissues. Toxicity studies were conducted in F344/N rats and B6C3F1 mice by administering a flame retardant containing these lower molecular weight PBDEs (BDE-47, BDE-99, BDE-100, and BDE153) by oral gavage 5 days/week for 13 weeks at doses of 0.01, 5, 50, 100 or 500mg/kg/day. Liver was the primary target organ in rats and mice. Treatment-related increases in liver weights, liver cytochrome P450 (1A1, 1A2, 2B) and UDPGT (rats only) levels, and liver lesions were seen in both rats and mice. Hepatocyte hypertrophy and vacuolization increased in incidence and severity with treatment, and occurred at levels of 50mg/kg and above in rats, and at 100mg/kg and above in mice. Liver Cyp 1A1, 1A2, and 2B levels were increased at exposure levels of 50mg/kg and above in rats and mice. In addition, treatment-related thyroid lesions occurred particularly in rats. The most sensitive parameter for PBDE toxicity was the increase in liver weights which occurred at 5mg/kg above in rats and 50mg/kg and above in mice. These results suggest that liver may be a target organ for carcinogenesis processes after long-term administration of PBDEs. A chronic PBDE study is currently being conducted by the National Toxicology Program.
Dunnick
June K
JK
National Institute of Environmental Health Sciences, Research Triangle Park, P.O. Box 12233, NC 27709, USA. dunnickj@niehs.nih.gov
Nyska
Abraham
A
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005411:Flame Retardants / Q000032:analysis / Q000633:toxicity*; D055768:Halogenated Diphenyl Ethers / Q000032:analysis / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011916:Rats, Inbred F344; D013959:Thyroid Diseases / Q000139:chemically induced / Q000473:pathology; D014018:Tissue Distribution
D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D003577:Cytochrome P-450 Enzyme System
Arch Biochem Biophys. 1985 Apr;238(1):43-8
3985627
Biochem J. 1992 Feb 1;281 ( Pt 3):577-92
1536639
Toxicol Pathol. 1997 Nov-Dec;25(6):541-8
9437797
Toxicology. 2007 Feb 12;230(2-3):126-36
17157429
Environ Health Perspect. 2003 Nov;111(14):1723-9
14594622
Environ Int. 2003 Sep;29(6):879-85
12850103
Food Chem Toxicol. 1998 Sep-Oct;36(9-10):831-9
9737431
Environ Health Perspect. 2003 Jul;111(9):1175-9
12842770
Xenobiotica. 2006 Jan;36(1):103-17
16507516
Nature. 2001 Jul 12;412(6843):140-1
11449259
Chemosphere. 2003 Jul;52(2):299-312
12738254
J Natl Cancer Inst. 1979 Apr;62(4):957-74
285297
Xenobiotica. 2006 Jun;36(6):515-34
16769647
Environ Health Perspect. 2004 May;112(6):654-8
15121506
Toxicol Sci. 2005 Nov;88(1):127-33
16107549
J Pharmacol Exp Ther. 1995 May;273(2):977-85
7752103
Chemosphere. 2002 Feb;46(5):729-35
11999796
Toxicol Sci. 2006 Jul;92(1):157-73
16601080
Environ Health Perspect. 2001 Apr;109(4):399-407
11335189
Biochim Biophys Acta. 1969 Nov 4;191(2):279-91
5354263
Drug Metab Dispos. 2007 Jul;35(7):1009-16
17431034
Toxicol Sci. 2001 May;61(1):76-82
11294977
Chemosphere. 2000 May-Jun;40(9-11):937-41
10739029
Environ Health Perspect. 2006 Nov;114(11):1770-5
17107866
J Expo Sci Environ Epidemiol. 2008 Jan;18(1):2-19
17426733
Biochem Pharmacol. 1998 Dec 15;56(12):1657-60
9973187
Environ Int. 2003 Sep;29(6):771-9
12850095
Integr Environ Assess Manag. 2005 Nov;1(4):343-54
16639901
Ciba Found Symp. 1980;76:261-74
6906264
Environ Sci Technol. 2004 Jan 1;38(1):112-9
14740725
Chemosphere. 2007 Apr;67(9):S386-92
17257644
Environ Sci Technol. 2004 Jan 1;38(1):127-32
14740727
Toxicol Sci. 2002 Mar;66(1):105-16
11861977
Toxicol Appl Pharmacol. 2006 Sep 1;215(2):135-45
16580039
Environ Sci Technol. 2001 Dec 1;35(23):4585-91
11770759
Xenobiotica. 2006 Sep;36(9):824-37
16971346