Export file:

Format

  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text

Content

  • Citation Only
  • Citation and Abstract

Evaluating toxic endpoints of exposure to a commercial PCB mixture: an in vivo laboratory study

1 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3;
2 Merck & Co., Inc., Whitehouse Station, NJ 08889, USA;
3 Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada K1A 0K9

Special Issues: Pollution and Chemicals in the Environment

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that produce a wide range of toxic effects. To determine sensitive endpoints in various organ systems, the effects of Aroclor 1260 on immune, endocrine, and hepatic systems were evaluated in a dose-response study. Nine-week old male rats were treated with Aroclor 1260 by oral gavage at dosages ranging from 0.025 to 156 mg/kg/day for 10 consecutive days and killed two days after the last treatment. Eight days prior to sacrifice, rats were injected i.v. with sheep red blood cells (SRBC) for determination of humoral immunity. No observable adverse effect level (NOAEL) and lowest observable adverse effect level (LOAEL) were determined for liver, thymus and genital organ weights, body weight, serum luteinizing hormone (LH), testosterone, thyroxine and thyroid-stimulating hormone (TSH) concentrations, hepatic microsomal testosterone hydroxylase activities, and hepatic microsomal cytochrome P450 (CYP) 1A1, CYP1A2, CYP2B1 and CYP2B2 protein levels. Treatment with Aroclor 1260, at all dosages, had no effect on testis, seminal vesicle or ventral prostate weights, on thymus weight or on serum LH or testosterone levels. Among the endpoints altered by Aroclor 1260, the most sensitive, with a LOAEL of 1.25 mg/kg/day, were increased testosterone 16β-hydroxylase activity and androstenedione formation. The LOAEL for increased liver weight, testosterone 16α-hydroxylase activity and CYP2B1 protein content was 3.13 mg/kg/day, while the LOAEL for decreased serum thyroxine levels and anti-SRBC IgM titer was 6.25 mg/kg/day. Less sensitive responses, as reflected by larger LOAEL values, included CYP1A enzyme induction and decreased body weight. In summary, comparison of NOAEL and LOAEL values indicated that hepatic CYP2B-mediated activities were a more sensitive response to Aroclor 1260 exposure in male rats than immune or endocrine endpoints.
  Figure/Table
  Supplementary
  Article Metrics

References

1. Breivik K, Sweetman A, Pacyna JM, et al. (2002) Towards a global historical emission inventory for selected PCB congeners – a mass balance approach. 1. Global production and consumption. Sci Total Environ 290: 181-198.

2. Carpenter DO (2008) Polychlorinated biphenyls (PCBs): routes of exposure and effects on human health. Rev Environ Health 21: 1-23.

3. Diamond ML, Melymuk L, Csiszar SA, et al. (2010) Estimation of PCB stocks, emissions, and urban fate: Will our policies reduce concentrations and exposure? Environ Sci Technol 44: 2777-2783.    

4. Robson M, Melymuk L, Csiszar SA, et al. (2010) Continuing sources of PCBs: The significance of building sealants. Environ Int 36: 506-513.    

5. Government of Canada (2012) PCB Regulations. SOR/2008-273. Minister of Justice, Canada.

6. Kim M, Kim S, Yun S, et al. (2004) Comparison of seven indicator PCBs and three coplanar PCBs in beef, pork, and chicken fat. Chemosphere 54: 1533-1538.    

7. Sun P, Basu I, Blanchard P, et al. (2007) Temporal and spatial trends of atmospheric polychlorinated biphenyl concentrations near the Great Lakes. Environ Sci Technol 41: 1131-1136.    

8. Robinson SD, Landrum PF, Van Hoof PL, et al. (2008) Seasonal variation of polychlorinated biphenyl congeners in surficial sediment, trapped settling material, and suspended particulate material in Lake Michigan, USA. Environ Toxicol Chem 27: 313-322.    

9. Solomon GM, Weiss PM (2002) Chemical contaminants in breast milk: time trends and regional variability. Environ Health Perspect 110: A339-A347.    

10. Guvenius DM, Aronsson A, Ekman-Ordeberg G, et al. (2003) Human prenatal and postnatal exposure to polybrominated diphenyl ethers, polychlorinated biphenyls, polychlorobiphenylols, and pentachlorophenol. Environ Health Perspect 111: 1235-1241.    

11. Safe SH (1994) Polychlorinated biphenyls (PCBs): environmental impact, biochemical and toxic responses, and implications for risk assessment. CRC Crit Rev Toxicol 24: 87-149.    

12. Tilson HA, Kodavanti PR (1998) The neurotoxicity of polychlorinated biphenyls. Neurotoxicology 19: 517-525.

13. Ulbrich B, Stahlmann R (2004) Developmental toxicity of polychlorinated biphenyls (PCBs): A systematic review of experimental data. Arch Toxicol 78: 252-268.

14. Selgrade MK (2007) Immunotoxicity: The risk is real. Toxicol Sci 100: 328-332.    

15. International Agency for Research on Cancer (1978) Polychlorinated biphenyls and polybrominated biphenyls. In: Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. IARC Scientific Publications, Vol. 18, IARC, Lyon, France.

16. Jusko TA, Sisto R, Iosif AM, et al. (2014) Prenatal and postnatal serum PCB concentrations and cochlear function in children at 45 months of age. Environ Health Perspect 122: 1246-1252.

17. Longnecker MP, Hoffman HJ, Klebanoff MA, et al. (2004) In utero exposure to polychlorinated biphenyls and sensorineural hearing loss in 8-year-old children. Neurotoxicol Teratol 26: 629-637.    

18. Brouwer A, Morse DC, Lans MC, et al. (1998) Interactions of persistent environmental organohalides with the thyroid hormone system: mechanisms and possible consequences for animal and human health. Toxicol Ind Health 14: 59-84.    

19. Desaulniers D, Leingartner K, Wade M, et al. (1999) Effects of acute exposure to PCBs 126 and 153 on anterior pituitary and thyroid hormones and FSH isoforms in adult Sprague Dawley male rats. Toxicol Sci. 47: 158-169.    

20. Zoeller RT (2001) Polychlorinated biphenyls as disruptors of thyroid hormone action. In: PCBs: Recent advances in environmental toxicology and health effects, ed. L. W. Robertson and L. G. Hansen, The University Press of Kentucky, Lexington, KY, 256-271.

21. Colburn T, vom Saal FS, Soto AM (1993) Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect 101: 378-384.    

22. Khan MA, Lichtensteiger CA, Faroon O, et al. (2002) The hypothalamo-pituitary-thyroid (HPT) axis: a target of nonpersistent ortho-substituted PCB congeners. Toxicol Sci 65: 52-61.    

23. Zoeller RT (2007) Environmental chemicals impacting the thyroid: Targets and consequences. Thyroid 17: 811-817.    

24. Darras VM (2008) Endocrine disrupting polyhalogenated organic pollutants interfere with thyroid hormone signaling in the developing brain. Cerebellum 7: 26-37.    

25. Desaulniers D, Poon R, Phan W, et al. (1997) Reproductive and thyroid hormone levels in rats following 90-day dietary exposure to PCB 28 (2,4,4'-trichlorobiphenyl) or PCB 77 (3,3',4,4'-tetrachlorobiphenyl). Toxicol Ind Health 13: 627-638.    

26. Hany J, Lilienthal H, Sarasin A, et al. (1999) Developmental exposure of rats to a reconstituted PCB mixture or Aroclor 1254: effects on organ weights, aromatase activity, sex hormone levels, and sweet preference behavior. Toxicol Appl Pharmacol 158: 231-243.    

27. Kaya H, Hany J, Fastabend A, et al. (2002) Effects of maternal exposure to a reconstituted mixture of polychlorinated biphenyls on sex-dependent and steroid hormone concentrations in rats: Dose-response relationship. Toxicol Appl Pharmacol 178: 71-81.    

28. Layton AC, Sanseverino J, Gregory BW, et al. (2002) In vitro estrogen receptor binding of PCBs: Measured activity and detection of hydroxylated metabolites in a recombinant yeast assay. Toxicol Appl Pharmacol 180: 157-163.    

29. Smialowicz RJ (1989) Evaluation of the immunotoxicity of low level PCB exposure in the rat, Toxicology 56: 197-211.

30. Harper N, Connor K, Steinberg M, et al. (1995) Immunosuppressive activity of polychlorinated biphenyl mixtures and congeners: nonadditive (antagonistic) interactions. Fund Appl Toxicol 27: 131-139.    

31. Weisglas-Kuperus N, Patandin S, Berbers GA, et al. (2000) Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children. Environ Health Perspect 108: 1203-1207.    

32. Tryphonas H, Feeley M (2001) Polychlorinated biphenyl-induced immunomodulation and human health effects. In: PCBs: Recent advances in environmental toxicology and health effects, ed. L. W. Robertson and L. G. Hansen, The University Press of Kentucky, Lexington, KY, 193-209.

33. Heilmann C, Grandjean P, Weihe P, et al. (2006) Reduced antibody responses to vaccinations in children exposed to polychlorinated biphenyls. PLoS Med 3: e311.    

34. Tryphonas H, Luster MI, Schiffman G, et al. (1991) Effects of chronic exposure of PCB (Aroclor 1254) on specific and non-specific immune parameters in the rhesus (Macaca mulatta) monkey. Fund Appl Toxicol 16: 773-786.    

35. Bandiera SM (2001) Cytochrome P450 enzymes as biomarkers of PCB exposure and modulators of toxicity. In: PCBs: Recent advances in environmental toxicology and health effects, ed. L. W. Robertson and L. G. Hansen, The University Press of Kentucky, Lexington, KY, 185-192.

36. Ngui JS, Bandiera SM (1999) Induction of hepatic CYP2B is a more sensitive indicator of exposure to Aroclor 1260 than CYP 1A in male rats. Toxicol Appl Pharmacol 161: 160-170.    

37. Frame GM, Wagner RE, Carnahan JC, et al. (1996) Comprehensive, quantitative, congener-specific analyses of eight Aroclors and complete PCB congener assignments on DB-1 capillary GC columns. Chemosphere 33: 602-623.

38. Newman JW, Becker JS, Blodina G, et al. (1998) Quantitation of Aroclors using congener-specific results. Environ Toxicol Chem 11: 2159-2167.

39. Wong A, Bandiera SM (1996) Inductive effect of Telazol® on hepatic expression of cytochrome P450 2B in rats. Biochem Pharmacol 52: 735-742.    

40. Temple L, Kawabata TT, Munson AE, et al. (1993) Comparison of ELISA and plaque-forming cell assays for measuring the humoral immune response to SRBC in rats and mice treated with benzo[a]pyrene or cyclophosphamide. Fund Appl Toxicol 21: 412-419.    

41. Thomas PE, Reik LM, Ryan DE, et al. (1983) Induction of two immunochemically related rat liver cytochrome P450 isozymes, P450c and P450d, by structurally diverse xenobiotics. J Biol Chem 258: 4590-4598.

42. Omura T, Sato R (1964) The carbon monoxide binding pigment of liver microsomes: I. Evidence for its hemoprotein nature. J Biol Chem 239: 2370-2378.

43. Lowry OH, Rosebrough NJ, Farr AL, et al. (1951) Protein measurement with Folin reagent. J Biol Chem 193: 265-275.

44. Ladics GS (2007) Use of SRBC antibody responses for immunotoxicity testing. Methods 41: 9-19.    

45. Anderson MD, Bandiera SM, Chang TKH, et al. (1998) Effect of androgen administration during puberty on hepatic CYP2C11, CYP3A, and CYP2A1 expression in adult female rats. Drug Metab Disp 26: 1031-1038.

46. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 207: 680-685.

47. Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets, procedures and some applications. Proc Natl Acad Sci USA 76: 4350-4354.    

48. Golub MS, Donald JM, Reyes JA (1991) Reproductive toxicity of commercial PCB mixtures: LOAELs and NOAELs from animal studies. Environ Health Perspect 94: 245-253.    

49. McFarland VA, Clarke JU (1989) Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: considerations for a congener-specific analysis. Environ Health Perspect 81: 225-239.    

50. Mayes BA, McConnell EE, Neal BH, et al. (1998) Comparative carcinogenicity in Sprague-Dawley rats of the polychlorinated biphenyl mixtures Arolcors 1016, 1242, 1254, and 1260. Toxicol Sci 41: 62-76.

51. van der Plas SA, Sundberg H, van den Berg H, et al. (2000) Contribution of planar (0-1 ortho) and nonplanar (2-4 ortho) fractions of Arolcor 1260 to the induction of altered hepatic foci in female Sprague-Dawley rats. Toxicol Sci 169: 255-268.

52. Silkworth JB, Antrim LA (1985) Relationship between the Ah receptor-mediated polychlorinated biphenyl (PCB)-induced humoral immunosuppression and thymic atrophy. J Pharmacol Exptl Therap 235: 606-611.

53. Silkworth JB, Antrim LA, Sack G (1986) Ah receptor-mediated suppression of the antibody response in mice is primarily dependent on the Ah phenotype of lymphoid tissue. Toxicol Appl Pharmacol 86: 380-390.    

54. Duffy-Whritenour JE, Kurtzman R, Kennedy S, et al. (2010) Non-coplanar polychlorinated biphenyl (PCB)-induced immunotoxicity is coincident with alterations in the serotonergic system. J Immunotoxicol 7: 318-326.    

55. Harris T, Zacharewski T, Safe S (1993) Comparative potencies of Aroclors 1232, 1242, 1248, 1254, and 1260 in male Wistar rats - assessment of the toxic equivalency factor (TEF) approach for polychlorinated biphenyls (PCBs). Fund Appl Toxicol 20: 456-463.    

56. Vos JG, Beems RB (1971) Dermal toxicity studies of technical polychlorinated biphenyls and fractions thereof in rabbits. Toxicol Appl Pharmacol 19: 617-633.    

57. Vos JG, Notenboom-Ram E (1972) Comparative toxicity study of 2,4,5,2',4',5'-hexachlorobiphenyl and a polychlorinated biphenyl mixture in rabbits. Toxicol Appl Pharmacol 23: 563-578.    

58. Crofton KM (2008) Thyroid disrupting chemicals: Mechanisms and mixtures. Int J Andol 31: 209-223.    

59. Byrne JJ, Carbone JP, Hanson EA (1987) Hypothyroidism and abnormalities in the kinetics of thyroid hormone metabolism in rats treated chronically with polychlorinated biphenyls and polybrominated biphenyls. Endocrinology 121: 520-527.    

60. Hood A, Klaassen CD (2000) Differential effects of microsomal enzyme inducers on in vitro thyroxine (T4) and triiodothyronine (T3) glucuronidation. Toxicol Sci 55: 78-84.    

61. Vansell NR, Klaassen CD (2001) Increased biliary excretion of thyroxine by microsomal enzyme inducers. Toxicol Appl Pharmacol 176: 187-194.    

62. Chauhan KR, Kodavanti PRS, McKinney JD (2000) Assessing the role of ortho-substitution on polychlorinated biphenyl binding to transthyretin, a transport protein. Toxicol Appl Pharmacol 162: 10-21.    

63. Sonderfan AJ, Arlotto MP, Dutton DR, et al. (1987) Regulation of testosterone hydroxylation by rat liver microsomal cytochrome P-450. Arch Biochem Biophys 255: 27-41.    

64. Ryan DE, Levin W (1990) Purification and characterization of hepatic microsomal cytochrome P-450. Pharmacol Ther 45: 153-239.    

65. Carter JW (1985) Hypercholesterolemia induced by PCBs (Aroclor 1254) on serum levels of lipoprotein cholesterol in Fischer rats. Bull Environ Contam Toxicol 34: 427-431.    

66. Fischer LJ, Seegal RF, Ganey PE, et al. (1998) Symposium overview: toxicity of non-coplanar PCBs. Toxicol Sci 41: 49-61.

67. Pessah IN, Cherednichenko G, Lein PJ (2010) Minding the calcium store: ryanodine receptor activation as a convergent mechanism of PCB toxicity. Pharmacol Ther 125: 260-285.    

Copyright Info: © 2015, Stelvio M. Bandiera, et al., licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved