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. 1985 May;60:41–46. doi: 10.1289/ehp.856041

Mechanisms of the biological effects of PCBs, polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in experimental animals.

R A Neal
PMCID: PMC1568561  PMID: 2992926

Abstract

Polychlorinated biphenyls, certain polychlorinated dibenzo-p-dioxins and certain polychlorinated dibenzofurans cause a variety of biological effects in experimental animals. The mechanism of the induction of certain enzymes is perhaps best understood. That is, there is binding of certain chlorinated biphenyls, dibenzo-p-dioxins and dibenzofurans to a receptor, translocation of the compound-receptor complex into the nucleus followed by an increased activity of a number of enzymes in the cell. Although the concentration of this receptor in various tissues of some mouse strains correlates well with the intensity of some of the biological effects observed in the mouse strains exposed to these compounds, this correlation apparently does not extend across various species. The current evidence suggests that the acute toxic effects of TCDD in various species is in some way associated with binding of TCDD to the receptor. However, biological effects of TCDD in addition to those resulting from binding to the receptor may be required to produce acute toxicity and, perhaps, other effects. The acute toxic effects of TCDD are probably caused by the parent compound rather than metabolites; however, this conclusion must be viewed as tentative. Also, it cannot be excluded at this time that biological effects other than acute toxicity may be caused by metabolites of TCDD. Finally, the acute toxic effects of TCDD appear not to be related, at least not directly, to the rate of metabolism of TCDD in experimental animals nor to the half-life of excretion.

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Selected References

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  1. Barsotti D. A., Marlar R. J., Allen J. R. Reproductive dysfunction in rhesus monkeys exposed to low levels of polychlorinated biphenyls (Aoroclor 1248). Food Cosmet Toxicol. 1976 Apr;14(2):99–103. doi: 10.1016/s0015-6264(76)80251-9. [DOI] [PubMed] [Google Scholar]
  2. Beatty P. W., Lembach K. J., Holscher M. A., Neal R. A. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on mammalian cells in tissue cultures. Toxicol Appl Pharmacol. 1975 Feb;31(2):309–312. doi: 10.1016/0041-008x(75)90166-0. [DOI] [PubMed] [Google Scholar]
  3. Beatty P. W., Vaughn W. K., Neal R. A. Effect of alteration of rat hepatic mixed-function oxidase (MFO) activity on the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Appl Pharmacol. 1978 Aug;45(2):513–519. doi: 10.1016/0041-008x(78)90113-8. [DOI] [PubMed] [Google Scholar]
  4. Elder G. H., Sheppard D. M. Immunoreactive uroporphyrinogen decarboxylase is unchanged in porphyria caused by TCDD and hexachlorobenzene. Biochem Biophys Res Commun. 1982 Nov 16;109(1):113–120. doi: 10.1016/0006-291x(82)91573-x. [DOI] [PubMed] [Google Scholar]
  5. Gasiewicz T. A., Geiger L. E., Rucci G., Neal R. A. Distribution, excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J, DBA/2J, and B6D2F1/J mice. Drug Metab Dispos. 1983 Sep-Oct;11(5):397–403. [PubMed] [Google Scholar]
  6. Gasiewicz T. A., Neal R. A. The examination and quantitation of tissue cytosolic receptors for 2,3,7,8-tetrachlorodibenzo-p-dioxin using hydroxylapatite. Anal Biochem. 1982 Jul 15;124(1):1–11. doi: 10.1016/0003-2697(82)90212-3. [DOI] [PubMed] [Google Scholar]
  7. Goldstein J. A., Hickman P., Bergman H., McKinney J. D., Walker M. P. Separation of pure polychlorinated biphenyl isomers into two types of inducers on the basis of induction of cytochrome P-450 or P-448. Chem Biol Interact. 1977 Apr;17(1):69–87. doi: 10.1016/0009-2797(77)90073-4. [DOI] [PubMed] [Google Scholar]
  8. Henck J. M., New M. A., Kociba R. J., Rao K. S. 2,3,7,8-tetrachlorodibenzo-p-dioxin: acute oral toxicity in hamsters. Toxicol Appl Pharmacol. 1981 Jun 30;59(2):405–407. doi: 10.1016/0041-008x(81)90212-x. [DOI] [PubMed] [Google Scholar]
  9. Jones K. G., Sweeney G. D. Dependence of the porphyrogenic effect of 2,3,7,8-tetrachlorodibenzo(p)dioxin upon inheritance of aryl hydrocarbon hydroxylase responsiveness. Toxicol Appl Pharmacol. 1980 Mar 30;53(1):42–49. doi: 10.1016/0041-008x(80)90379-8. [DOI] [PubMed] [Google Scholar]
  10. Kimbrough R. D., Squire R. A., Linder R. E., Strandberg J. D., Montalli R. J., Burse V. W. Induction of liver tumor in Sherman strain female rats by polychlorinated biphenyl aroclor 1260. J Natl Cancer Inst. 1975 Dec;55(6):1453–1459. doi: 10.1093/jnci/55.6.1453. [DOI] [PubMed] [Google Scholar]
  11. Kimura N. T., Kanematsu T., Baba T. Polychlorinated biphenyl(s) as a promotor in experimental hepatocarcinogenesis in rats. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol. 1976 Dec 9;87(3):257–266. doi: 10.1007/BF00506498. [DOI] [PubMed] [Google Scholar]
  12. Knutson J. C., Poland A. 2,3,7,8-Tetrachlorodibenzo-p-dioxin: failure to demonstrate toxicity in twenty-three cultured cell types. Toxicol Appl Pharmacol. 1980 Jul;54(3):377–383. doi: 10.1016/0041-008x(80)90163-5. [DOI] [PubMed] [Google Scholar]
  13. Kouri R. R., Ratrie H., 3rd, Atlas S. A., Niwa A., Nebert D. W. Aryl hydrocarbon hydroxylase induction in human lymphocyte cultures by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Life Sci. 1974 Nov 1;15(9):1585–1595. doi: 10.1016/0024-3205(74)90324-5. [DOI] [PubMed] [Google Scholar]
  14. Lambrecht L. K., Barsotti D. A., Allen J. R. Responses of nonhuman primates to a polybrominated biphenyl mixture. Environ Health Perspect. 1978 Apr;23:139–145. doi: 10.1289/ehp.7823139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. McConnell E. E., Hass J. R., Altman N., Moore J. A. A spontaneous outbreak of polycholorinated biphenyl (PCB) toxicity in rhesus monkeys (Macaca mulatta): toxicopathology. Lab Anim Sci. 1979 Oct;29(5):666–673. [PubMed] [Google Scholar]
  16. McConnell E. E., Moore J. A., Haseman J. K., Harris M. W. The comparative toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs. Toxicol Appl Pharmacol. 1978 May;44(2):335–356. doi: 10.1016/0041-008x(78)90195-3. [DOI] [PubMed] [Google Scholar]
  17. Neal R. A., Beatty P. W., Gasiewicz T. A. Studies of the mechanisms of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Ann N Y Acad Sci. 1979 May 31;320:204–213. doi: 10.1111/j.1749-6632.1979.tb56602.x. [DOI] [PubMed] [Google Scholar]
  18. Neal R. A., Olson J. R., Gasiewicz T. A., Geiger L. E. The toxicokinetics of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin in mammalian systems. Drug Metab Rev. 1982;13(3):355–385. doi: 10.3109/03602538209029985. [DOI] [PubMed] [Google Scholar]
  19. Nebert D. W., Gielen J. E. Genetic regulation of aryl hydrocarbon hydroxylase induction in the mouse. Fed Proc. 1972 Jul-Aug;31(4):1315–1325. [PubMed] [Google Scholar]
  20. Oesterle D., Deml E. Promoting effect of polychlorinated biphenyls on development of enzyme-altered islands in livers of weanling and adult rats. J Cancer Res Clin Oncol. 1983;105(2):141–147. doi: 10.1007/BF00406924. [DOI] [PubMed] [Google Scholar]
  21. Olson J. R., Gasiewicz T. A., Neal R. A. Tissue distribution, excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Golden Syrian hamster. Toxicol Appl Pharmacol. 1980 Oct;56(1):78–85. doi: 10.1016/0041-008x(80)90132-5. [DOI] [PubMed] [Google Scholar]
  22. Olson J. R., Holscher M. A., Neal R. A. Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the golden Syrian hamster. Toxicol Appl Pharmacol. 1980 Aug;55(1):67–78. doi: 10.1016/0041-008x(80)90221-5. [DOI] [PubMed] [Google Scholar]
  23. Poiger H., Schlatter C. Biological degradation of TCDD in rats. Nature. 1979 Oct 25;281(5733):706–707. doi: 10.1038/281706a0. [DOI] [PubMed] [Google Scholar]
  24. Poland A., Glover E. Chlorinated biphenyl induction of aryl hydrocarbon hydroxylase activity: a study of the structure-activity relationship. Mol Pharmacol. 1977 Sep;13(5):924–938. [PubMed] [Google Scholar]
  25. Poland A., Glover E., Kende A. S. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem. 1976 Aug 25;251(16):4936–4946. [PubMed] [Google Scholar]
  26. Poland A., Greenlee W. F., Kende A. S. Studies on the mechanism of action of the chlorinated dibenzo-p-dioxins and related compounds. Ann N Y Acad Sci. 1979 May 31;320:214–230. doi: 10.1111/j.1749-6632.1979.tb56603.x. [DOI] [PubMed] [Google Scholar]
  27. Poland A., Knutson J. C. 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol. 1982;22:517–554. doi: 10.1146/annurev.pa.22.040182.002505. [DOI] [PubMed] [Google Scholar]
  28. Preston B. D., Van Miller J. P., Moore R. W., Allen J. R. Promoting effects of polychlorinated biphenyls (Aroclor 1254) and polychlorinated dibenzofuran-free Aroclor 1254 on diethylnitrosamine-induced tumorigenesis in the rat. J Natl Cancer Inst. 1981 Mar;66(3):509–515. [PubMed] [Google Scholar]
  29. Rose J. Q., Ramsey J. C., Wentzler T. H., Hummel R. A., Gehring P. J. The fate of 2,3,7,8-tetrachlorodibenzo-p-dioxin following single and repeated oral doses to the rat. Toxicol Appl Pharmacol. 1976 May;36(2):209–226. doi: 10.1016/0041-008x(76)90001-6. [DOI] [PubMed] [Google Scholar]
  30. Sawahata T., Olson J. R., Neal R. A. Identification of metabolites of 2, 3, 7, 8-tetrachlorodibenzo-P-dioxin (TCDD) formed on incubation with isolated rat hepatocytes. Biochem Biophys Res Commun. 1982 Mar 15;105(1):341–346. doi: 10.1016/s0006-291x(82)80050-8. [DOI] [PubMed] [Google Scholar]
  31. Schwetz B. A., Norris J. M., Sparschu G. L., Rowe U. K., Gehring P. J., Emerson J. L., Gerbig C. G. Toxicology of chlorinated dibenzo-p-dioxins. Environ Health Perspect. 1973 Sep;5:87–99. doi: 10.1289/ehp.730587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Vos J. G., Beems R. B. Dermal toxicity studies of technical polychlorinated biphenyls and fractions thereof in rabbits. Toxicol Appl Pharmacol. 1971 Aug;19(4):617–633. doi: 10.1016/0041-008x(71)90294-8. [DOI] [PubMed] [Google Scholar]
  33. Vos J. G., de Roij T. Immunosuppressive activity of a polychlorinated diphenyl preparation on the humoral immune response in guinea pigs. Toxicol Appl Pharmacol. 1972 Apr;21(4):549–555. doi: 10.1016/0041-008x(72)90011-7. [DOI] [PubMed] [Google Scholar]

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