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. 1993 Oct;101(Suppl 3):317–325. doi: 10.1289/ehp.93101s3317

Development of bioassays and approaches for the risk assessment of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds.

S Safe 1
PMCID: PMC1521135  PMID: 8143638

Abstract

Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related halogenated aromatic hydrocarbons (HAHs) are industrial compounds or by-products that have been identified as contaminants in almost every component of the global ecosystem. 2,3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic HAH, and studies in rodents have shown that this compound is a carcinogen. Analysis of environmental samples for HAHs has shown that these extracts contain complex mixtures of isomers and congeners, and this greatly complicates risk assessment due to the paucity of data available for most of the individual compounds. Extensive research has demonstrated a common receptor-mediated mechanism of action for TCDD and related toxic HAHs, and this has led to the development of a mechanism-based risk assessment approach for HAHs. Toxic equivalency factors (TEFs; relative potency compared to TCDD) have been developed for selected HAH congeners, and the TEF values can be used to determine "toxic equivalents" (TEQs) for HAH mixtures. In addition, several bioassays that use receptor-mediated end points have been developed and can be used directly to determine the TEQs for HAH mixtures. The applications of the TEF/TEQ approach for the risk assessment of HAHs are considerable, particularly with the conversion of complex analytical data into TEQs. However, there appear to be several limitations to this approach, particularly with PCBs because their potential nonadditive (antagonistic), interactive effects with "2,3,7,8-TCDD-like" compounds may invalidate the use of the risk assessment procedure for some environmental matrices.

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Selected References

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  1. Atlas E., Giam C. S. Global transport of organic pollutants: ambient concentrations in the remote marine atmosphere. Science. 1981 Jan 9;211(4478):163–165. doi: 10.1126/science.211.4478.163. [DOI] [PubMed] [Google Scholar]
  2. Bannister R., Davis D., Zacharewski T., Tizard I., Safe S. Aroclor 1254 as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist: effects on enzyme induction and immunotoxicity. Toxicology. 1987 Oct 12;46(1):29–42. doi: 10.1016/0300-483x(87)90135-1. [DOI] [PubMed] [Google Scholar]
  3. Bradlaw J. A., Casterline J. L., Jr Induction of enzyme activity in cell culture: a rapid screen for detection of planar polychlorinated organic compounds. J Assoc Off Anal Chem. 1979 Jul;62(4):904–916. [PubMed] [Google Scholar]
  4. Bradlaw J. A., Garthoff L. H., Hurley N. E., Firestone D. Comparative induction of aryl hydrocarbon hydroxylase activity in vitro by analogues of dibenzo-p-dioxin. Food Cosmet Toxicol. 1980 Dec;18(6):627–635. doi: 10.1016/s0015-6264(80)80011-3. [DOI] [PubMed] [Google Scholar]
  5. Buchmann A., Kunz W., Wolf C. R., Oesch F., Robertson L. W. Polychlorinated biphenyls, classified as either phenobarbital- or 3-methylcholanthrene-type inducers of cytochrome P-450, are both hepatic tumor promoters in diethylnitrosamine-initiated rats. Cancer Lett. 1986 Sep;32(3):243–253. doi: 10.1016/0304-3835(86)90176-x. [DOI] [PubMed] [Google Scholar]
  6. Czuczwa J. M., McVeety B. D., Hites R. A. Polychlorinated Dibenzo-p-dioxins and Dibenzofurans in Sediments from Siskiwit Lake, Isle Royale. Science. 1984 Nov 2;226(4674):568–569. doi: 10.1126/science.226.4674.568. [DOI] [PubMed] [Google Scholar]
  7. Davis D., Safe S. Dose-response immunotoxicities of commercial polychlorinated biphenyls (PCBs) and their interaction with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett. 1989 Jul;48(1):35–43. doi: 10.1016/0378-4274(89)90183-5. [DOI] [PubMed] [Google Scholar]
  8. Davis D., Safe S. Immunosuppressive activities of polychlorinated biphenyls in C57BL/6N mice: structure-activity relationships as Ah receptor agonists and partial antagonists. Toxicology. 1990 Jul;63(1):97–111. doi: 10.1016/0300-483x(90)90072-o. [DOI] [PubMed] [Google Scholar]
  9. Denison M. S., Fisher J. M., Whitlock J. P., Jr Inducible, receptor-dependent protein-DNA interactions at a dioxin-responsive transcriptional enhancer. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2528–2532. doi: 10.1073/pnas.85.8.2528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Denomme M. A., Bandiera S., Lambert I., Copp L., Safe L., Safe S. Polychlorinated biphenyls as phenobarbitone-type inducers of microsomal enzymes. Structure-activity relationships for a series of 2,4-dichloro-substituted congeners. Biochem Pharmacol. 1983 Oct 1;32(19):2955–2963. doi: 10.1016/0006-2952(83)90402-1. [DOI] [PubMed] [Google Scholar]
  11. Dewailly E., Weber J. P., Gingras S., Laliberté C. Coplanar PCBs in human milk in the province of Québec, Canada: are they more toxic than dioxin for breast fed infants? Bull Environ Contam Toxicol. 1991 Oct;47(4):491–498. doi: 10.1007/BF01700935. [DOI] [PubMed] [Google Scholar]
  12. Eadon G., Kaminsky L., Silkworth J., Aldous K., Hilker D., O'Keefe P., Smith R., Gierthy J., Hawley J., Kim N. Calculation of 2,3,7,8-TCDD equivalent concentrations of complex environmental contaminant mixtures. Environ Health Perspect. 1986 Dec;70:221–227. doi: 10.1289/ehp.8670221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gonzalez F. J., Nebert D. W. Autoregulation plus upstream positive and negative control regions associated with transcriptional activation of the mouse P1(450) gene. Nucleic Acids Res. 1985 Oct 25;13(20):7269–7288. doi: 10.1093/nar/13.20.7269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Haake J. M., Safe S., Mayura K., Phillips T. D. Aroclor 1254 as an antagonist of the teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett. 1987 Oct;38(3):299–306. doi: 10.1016/0378-4274(87)90012-9. [DOI] [PubMed] [Google Scholar]
  15. Harvey G. R., Steinhauer W. G. Atmospheric transport of polychlorobiphenyls to the North Atlantic. Atmos Environ. 1974 Aug;8(8):777–782. doi: 10.1016/0004-6981(74)90173-5. [DOI] [PubMed] [Google Scholar]
  16. Israel D. I., Whitlock J. P., Jr Induction of mRNA specific for cytochrome P1-450 in wild type and variant mouse hepatoma cells. J Biol Chem. 1983 Sep 10;258(17):10390–10394. [PubMed] [Google Scholar]
  17. Israel D. I., Whitlock J. P., Jr Regulation of cytochrome P1-450 gene transcription by 2,3,7, 8-tetrachlorodibenzo-p-dioxin in wild type and variant mouse hepatoma cells. J Biol Chem. 1984 May 10;259(9):5400–5402. [PubMed] [Google Scholar]
  18. Jones P. B., Durrin L. K., Galeazzi D. R., Whitlock J. P., Jr Control of cytochrome P1-450 gene expression: analysis of a dioxin-responsive enhancer system. Proc Natl Acad Sci U S A. 1986 May;83(9):2802–2806. doi: 10.1073/pnas.83.9.2802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jones P. B., Galeazzi D. R., Fisher J. M., Whitlock J. P., Jr Control of cytochrome P1-450 gene expression by dioxin. Science. 1985 Mar 22;227(4693):1499–1502. doi: 10.1126/science.3856321. [DOI] [PubMed] [Google Scholar]
  20. Kannan N., Tanabe S., Ono M., Tatsukawa R. Critical evaluation of polychlorinated biphenyl toxicity in terrestrial and marine mammals: increasing impact of non-ortho and mono-ortho coplanar polychlorinated biphenyls from land to ocean. Arch Environ Contam Toxicol. 1989 Nov;18(6):850–857. doi: 10.1007/BF01160300. [DOI] [PubMed] [Google Scholar]
  21. Kannan N., Tanabe S., Tatsukawa R. Potentially hazardous residues of non-ortho chlorine substituted coplanar PCBs in human adipose tissue. Arch Environ Health. 1988 Jan-Feb;43(1):11–14. doi: 10.1080/00039896.1988.9934366. [DOI] [PubMed] [Google Scholar]
  22. Kannan N., Tanabe S., Tatsukawa R. Toxic potential of non-ortho and mono-ortho coplanar PCBs in commercial PCB preparations: "2,3,7,8-T4 CDD toxicity equivalence factors approach. Bull Environ Contam Toxicol. 1988 Aug;41(2):267–276. doi: 10.1007/BF01705441. [DOI] [PubMed] [Google Scholar]
  23. Kannan N., Tanabe S., Wakimoto T., Tatsukawa R. Coplanar polychlorinated biphenyls in aroclor and kanechlor mixtures. J Assoc Off Anal Chem. 1987 May-Jun;70(3):451–454. [PubMed] [Google Scholar]
  24. Kimbrough R. D. Laboratory and human studies on polychlorinated biphenyls (PCBs) and related compounds. Environ Health Perspect. 1985 Feb;59:99–106. doi: 10.1289/ehp.59-1568093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kimbrough R. D. The toxicity of polychlorinated polycyclic compounds and related chemicals. CRC Crit Rev Toxicol. 1974 Jan;2(4):445–498. doi: 10.3109/10408447309025705. [DOI] [PubMed] [Google Scholar]
  26. Miyata H., Takayama K., Ogaki J., Kashimoto T., Fukushima S. Polychlorinated dibenzo-p-dioxins in blue mussel from marine coastal water in Japan. Bull Environ Contam Toxicol. 1987 Nov;39(5):877–883. doi: 10.1007/BF01855869. [DOI] [PubMed] [Google Scholar]
  27. Mowrer J., Calambokidis J., Musgrove N., Drager B., Beug M. W., Herman S. G. Polychlorinated biphenyls in cottids, mussels and sediment in Southern Puget Sound, Washington. Bull Environ Contam Toxicol. 1977 Nov;18(5):588–594. doi: 10.1007/BF01684005. [DOI] [PubMed] [Google Scholar]
  28. Norback D. H., Weltman R. H. Polychlorinated biphenyl induction of hepatocellular carcinoma in the Sprague-Dawley rat. Environ Health Perspect. 1985 May;60:97–105. doi: 10.1289/ehp.856097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Poland A. P., Glover E., Robinson J. R., Nebert D. W. Genetic expression of aryl hydrocarbon hydroxylase activity. Induction of monooxygenase activities and cytochrome P1-450 formation by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice genetically "nonresponsive" to other aromatic hydrocarbons. J Biol Chem. 1974 Sep 10;249(17):5599–5606. [PubMed] [Google Scholar]
  30. 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]
  31. 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]
  32. 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]
  33. 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]
  34. Quensen J. F., 3rd, Tiedje J. M., Boyd S. A. Reductive dechlorination of polychlorinated biphenyls by anaerobic microorganisms from sediments. Science. 1988 Nov 4;242(4879):752–754. doi: 10.1126/science.242.4879.752. [DOI] [PubMed] [Google Scholar]
  35. Risebrough R. W., Rieche P., Peakall D. B., Herman S. G., Kirven M. N. Polychlorinated biphenyls in the global ecosystem. Nature. 1968 Dec 14;220(5172):1098–1102. doi: 10.1038/2201098a0. [DOI] [PubMed] [Google Scholar]
  36. Rushmore T. H., Pickett C. B. Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J Biol Chem. 1990 Aug 25;265(24):14648–14653. [PubMed] [Google Scholar]
  37. Safe S. H. Comparative toxicology and mechanism of action of polychlorinated dibenzo-p-dioxins and dibenzofurans. Annu Rev Pharmacol Toxicol. 1986;26:371–399. doi: 10.1146/annurev.pa.26.040186.002103. [DOI] [PubMed] [Google Scholar]
  38. Safe S. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Crit Rev Toxicol. 1990;21(1):51–88. doi: 10.3109/10408449009089873. [DOI] [PubMed] [Google Scholar]
  39. Safe S. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Crit Rev Toxicol. 1990;21(1):51–88. doi: 10.3109/10408449009089873. [DOI] [PubMed] [Google Scholar]
  40. Safe S., Robertson L. W., Safe L., Parkinson A., Bandiera S., Sawyer T., Campbell M. A. Halogenated biphenyls: molecular toxicology. Can J Physiol Pharmacol. 1982 Jul;60(7):1057–1064. doi: 10.1139/y82-151. [DOI] [PubMed] [Google Scholar]
  41. Safe S. Toxicology, structure-function relationship, and human and environmental health impacts of polychlorinated biphenyls: progress and problems. Environ Health Perspect. 1993 Apr;100:259–268. doi: 10.1289/ehp.93100259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schaeffer E., Greim H., Goessner W. Pathology of chronic polychlorinated biphenyl (PCB) feeding in rats. Toxicol Appl Pharmacol. 1984 Sep 15;75(2):278–288. doi: 10.1016/0041-008x(84)90210-2. [DOI] [PubMed] [Google Scholar]
  43. Schuetz E. G., Wrighton S. A., Safe S. H., Guzelian P. S. Regulation of cytochrome P-450p by phenobarbital and phenobarbital-like inducers in adult rat hepatocytes in primary monolayer culture and in vivo. Biochemistry. 1986 Mar 11;25(5):1124–1133. doi: 10.1021/bi00353a027. [DOI] [PubMed] [Google Scholar]
  44. Seegal R. F., Bush B., Shain W. Lightly chlorinated ortho-substituted PCB congeners decrease dopamine in nonhuman primate brain and in tissue culture. Toxicol Appl Pharmacol. 1990 Oct;106(1):136–144. doi: 10.1016/0041-008x(90)90113-9. [DOI] [PubMed] [Google Scholar]
  45. Shain W., Bush B., Seegal R. Neurotoxicity of polychlorinated biphenyls: structure-activity relationship of individual congeners. Toxicol Appl Pharmacol. 1991 Oct;111(1):33–42. doi: 10.1016/0041-008x(91)90131-w. [DOI] [PubMed] [Google Scholar]
  46. Sogawa K., Fujisawa-Sehara A., Yamane M., Fujii-Kuriyama Y. Location of regulatory elements responsible for drug induction in the rat cytochrome P-450c gene. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8044–8048. doi: 10.1073/pnas.83.21.8044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Thomas P. E., Kouri R. E., Hutton J. J. The genetics of aryl hydrocarbon hydroxylase induction in mice: a single gene difference between C57BL-6J and DBA-2J. Biochem Genet. 1972 Apr;6(2):157–168. doi: 10.1007/BF00486400. [DOI] [PubMed] [Google Scholar]
  48. Wassermann M., Wassermann D., Cucos S., Miller H. J. World PCBs map: storage and effects in man and his biologic environment in the 1970s. Ann N Y Acad Sci. 1979 May 31;320:69–124. doi: 10.1111/j.1749-6632.1979.tb13137.x. [DOI] [PubMed] [Google Scholar]
  49. Whitlock J. P., Jr The regulation of cytochrome P-450 gene expression. Annu Rev Pharmacol Toxicol. 1986;26:333–369. doi: 10.1146/annurev.pa.26.040186.002001. [DOI] [PubMed] [Google Scholar]
  50. Whitlock J. P., Jr The regulation of gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Pharmacol Rev. 1987 Jun;39(2):147–161. [PubMed] [Google Scholar]

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