Abstract
Pentachlorophenol (PCP), hexachlorocyclohexane-[alpha], -beta, and -[gamma] (HCH-[alpha], -beta, and -[gamma]), polychlorinated biphenyls (PCBs), and hexachlorobenzene (HCB) are widely distributed industrial chemicals. They are suspected to induce immunologic impairments in exposed individuals. We examined dose-response relationships of blood levels of these chemicals with cellular (numbers of lymphocyte subpopulations, in vitro lymphocyte response) or humoral (plasma cytokine levels, immunoglobulin autoantibodies) immunologic dysfunctions. We studied 146 patients who had been occupationally exposed primarily to PCBs for more than 6 months. Lymphocyte subpopulations, in vitro responses to mitogens and allogeneic stimulator cells, plasma neopterin, cytokines, soluble cytokine receptors, soluble adhesion molecules, anti-Ig autoantibodies, and liver transaminases were determined. Blood levels of the different compounds were strongly correlated with one another. There were only weak dose-response relationships between blood levels of PCBs with cellular immune parameters, and of HCHs and HCB with humoral immune parameters. An exception was the statistically significant negative association of HCB with interferon-[gamma] (IFN-[gamma]), indicating that HCB has a significant impact on Th1 lymphocytes. Patients with HCB blood levels above the mean of 1,109 ng/L more often had undetectable IFN-[gamma] blood levels than patients below the mean. Patients with increased PCB 138 (> 710 ng/L) had more frequently undetectable interleukin-4 blood levels than patients with PCB 138 below the mean, and patients with increased PCB 101 (> 31 ng/L) more often had low DR+ cell counts in the blood (< 190/microL) than patients with PCB 101 below the mean. To assess possible cumulative effects, we compared patients who had blood levels of all compounds below background with patients who had blood levels of all compounds above background. Patients with low or absent blood levels of the compounds studied had higher IFN-[gamma] plasma levels, providing some evidence for a cumulative effect of several weakly active compounds. In conclusion, exposure to PCBs, HCB, or HCHs is associated with weak immunologic abnormalities. These results contrast with those obtained in earlier studies of blood levels of PCP, which showed a strong dose-dependent relationship with immunologic impairments. Our data suggest that long-term exposure of patients to HCB suppresses IFN-[gamma] production.
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- Arkoosh M. R., Clemons E., Myers M., Casillas E. Suppression of B-cell mediated immunity in juvenile chinook salmon (Oncorhynchus tshawytscha) after exposure to either a polycyclic aromatic hydrocarbon or to polychlorinated biphenyls. Immunopharmacol Immunotoxicol. 1994 May;16(2):293–314. doi: 10.3109/08923979409007096. [DOI] [PubMed] [Google Scholar]
- Arnold D. L., Bryce F., McGuire P. F., Stapley R., Tanner J. R., Wrenshall E., Mes J., Fernie S., Tryphonas H., Hayward S. Toxicological consequences of aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys. Part 2. Reproduction and infant findings. Food Chem Toxicol. 1995 Jun;33(6):457–474. doi: 10.1016/0278-6915(95)00018-w. [DOI] [PubMed] [Google Scholar]
- Belpaeme K., Delbeke K., Zhu L., Kirsch-Volders M. PCBs do not induce DNA breakage in vitro in human lymphocytes. Mutagenesis. 1996 Jul;11(4):383–389. doi: 10.1093/mutage/11.4.383. [DOI] [PubMed] [Google Scholar]
- Blakley B. R., Yole M. J., Brousseau P., Boermans H., Fournier M. Effect of pentachlorophenol on immune function. Toxicology. 1998 Feb 6;125(2-3):141–148. doi: 10.1016/s0300-483x(97)00154-6. [DOI] [PubMed] [Google Scholar]
- Carthew P., Edwards R. E., Smith A. G. Immunotoxic effects of hexachlorobenzene on the pathogenesis of systemic, pneumonic and hepatic virus infections in the mouse. Hum Exp Toxicol. 1990 Nov;9(6):403–411. doi: 10.1177/096032719000900608. [DOI] [PubMed] [Google Scholar]
- Daniel V., Huber W., Bauer K., Opelz G. Impaired in-vitro lymphocyte responses in patients with elevated pentachlorophenol (PCP) blood levels. Arch Environ Health. 1995 Jul-Aug;50(4):287–292. doi: 10.1080/00039896.1995.9935956. [DOI] [PubMed] [Google Scholar]
- Das S. N., Paul B. N., Saxena A. K., Ray P. K. Effect of in utero exposure to hexachlorocyclohexane on the developing immune system of mice. Immunopharmacol Immunotoxicol. 1990;12(2):293–310. doi: 10.3109/08923979009019674. [DOI] [PubMed] [Google Scholar]
- De Krey G. K., Baecher-Steppan L., Deyo J. A., Smith B., Kerkvliet N. I. Polychlorinated biphenyl-induced immune suppression: castration, but not adrenalectomy or RU 38486 treatment, partially restores the suppressed cytotoxic T lymphocyte response to alloantigen. J Pharmacol Exp Ther. 1993 Oct;267(1):308–315. [PubMed] [Google Scholar]
- De Krey G. K., Baecher-Steppan L., Fowles J. R., Kerkvliet N. I. Polychlorinated biphenyl-induced suppression of cytotoxic T lymphocyte activity: role of prostaglandin-E2. Toxicol Lett. 1994 Dec;74(3):211–220. doi: 10.1016/0378-4274(94)90080-9. [DOI] [PubMed] [Google Scholar]
- De Krey G. K., Hollingshead N. C., Kerkvliet N. I., Smith B. B. Suppression of prolactin and cytotoxic T-lymphocyte activity in PCB-treated mice. Int J Immunopharmacol. 1994 Mar;16(3):251–257. doi: 10.1016/0192-0561(94)90020-5. [DOI] [PubMed] [Google Scholar]
- Dunstan R. H., Donohoe M., Taylor W., Roberts T. K., Murdoch R. N., Watkins J. A., McGregor N. R. A preliminary investigation of chlorinated hydrocarbons and chronic fatigue syndrome. Med J Aust. 1995 Sep 18;163(6):294–297. doi: 10.5694/j.1326-5377.1995.tb124593.x. [DOI] [PubMed] [Google Scholar]
- Esser C., Welzel M. Ontogenic development of murine fetal thymocytes is accelerated by 3,3',4,4'-tetrachlorobiphenyl. Int J Immunopharmacol. 1993 Nov;15(8):841–852. doi: 10.1016/0192-0561(93)90001-f. [DOI] [PubMed] [Google Scholar]
- Exon J. H., Koller L. D. Effects of chlorinated phenols on immunity in rats. Int J Immunopharmacol. 1983;5(2):131–136. doi: 10.1016/0192-0561(83)90004-8. [DOI] [PubMed] [Google Scholar]
- Fernlöf G., Gadhasson I., Pödra K., Darnerud P. O., Thuvander A. Lack of effects of some individual polybrominated diphenyl ether (PBDE) and polychlorinated biphenyl (PCB) congeners on human lymphocyte functions in vitro. Toxicol Lett. 1997 Feb 7;90(2-3):189–197. doi: 10.1016/s0378-4274(96)03848-9. [DOI] [PubMed] [Google Scholar]
- Fowles J. R., Fairbrother A., Trust K. A., Kerkvliet N. I. Effects of Aroclor 1254 on the thyroid gland, immune function, and hepatic cytochrome P450 activity in mallards. Environ Res. 1997 Nov;75(2):119–129. doi: 10.1006/enrs.1997.3776. [DOI] [PubMed] [Google Scholar]
- Harper N., Connor K., Safe S. Immunotoxic potencies of polychlorinated biphenyl (PCB), dibenzofuran (PCDF) and dibenzo-p-dioxin (PCDD) congeners in C57BL/6 and DBA/2 mice. Toxicology. 1993 Jun 11;80(2-3):217–227. doi: 10.1016/0300-483x(93)90183-s. [DOI] [PubMed] [Google Scholar]
- Harper N., Howie L., Connor K., Dickerson R., Safe S. Immunosuppressive effects of highly chlorinated biphenyls and diphenyl ethers on T-cell dependent and independent antigens in mice. Toxicology. 1993 Dec 31;85(2-3):123–135. doi: 10.1016/0300-483x(93)90037-s. [DOI] [PubMed] [Google Scholar]
- Hoffman D. J., Melancon M. J., Klein P. N., Rice C. P., Eisemann J. D., Hines R. K., Spann J. W., Pendleton G. W. Developmental toxicity of PCB 126 (3,3',4,4',5-pentachlorobiphenyl) in nestling American kestrels (Falco sparverius). Fundam Appl Toxicol. 1996 Dec;34(2):188–200. doi: 10.1006/faat.1996.0189. [DOI] [PubMed] [Google Scholar]
- Kerkvliet N. I., Baecher-Steppan L., Smith B. B., Youngberg J. A., Henderson M. C., Buhler D. R. Role of the Ah locus in suppression of cytotoxic T lymphocyte activity by halogenated aromatic hydrocarbons (PCBs and TCDD): structure-activity relationships and effects in C57Bl/6 mice congenic at the Ah locus. Fundam Appl Toxicol. 1990 Apr;14(3):532–541. doi: 10.1016/0272-0590(90)90257-k. [DOI] [PubMed] [Google Scholar]
- Kerkvliet N. I., Brauner J. A., Baecher-Steppan L. Effects of dietary technical pentachlorophenol exposure on T cell, macrophage and natural killer cell activity in C57Bl/6 mice. Int J Immunopharmacol. 1985;7(2):239–247. doi: 10.1016/0192-0561(85)90032-3. [DOI] [PubMed] [Google Scholar]
- Kerkvliet N. I., Brauner J. A., Matlock J. P. Humoral immunotoxicity of polychlorinated diphenyl ethers, phenoxyphenols, dioxins and furans present as contaminants of technical grade pentachlorophenol. Toxicology. 1985 Sep;36(4):307–324. doi: 10.1016/0300-483x(85)90033-2. [DOI] [PubMed] [Google Scholar]
- Kimbrough R. D. Human health effects of polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs). Annu Rev Pharmacol Toxicol. 1987;27:87–111. doi: 10.1146/annurev.pa.27.040187.000511. [DOI] [PubMed] [Google Scholar]
- Lahvis G. P., Wells R. S., Kuehl D. W., Stewart J. L., Rhinehart H. L., Via C. S. Decreased lymphocyte responses in free-ranging bottlenose dolphins (Tursiops truncatus) are associated with increased concentrations of PCBs and DDT in peripheral blood. Environ Health Perspect. 1995 May;103 (Suppl 4):67–72. doi: 10.1289/ehp.95103s467. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lai Z. W., Griem P., Gleichmann E., Esser C. CD8 thymocytes derived from 3,3',4,4'-tetrachlorobiphenyl-exposed fetal thymi possess killing activity. Toxicol Appl Pharmacol. 1995 Aug;133(2):223–232. doi: 10.1006/taap.1995.1145. [DOI] [PubMed] [Google Scholar]
- Lai Z. W., Kremer J., Gleichmann E., Esser C. 3,3',4,4'-Tetrachlorobiphenyl inhibits proliferation of immature thymocytes in fetal thymus organ culture. Scand J Immunol. 1994 May;39(5):480–488. doi: 10.1111/j.1365-3083.1994.tb03403.x. [DOI] [PubMed] [Google Scholar]
- Lang D., Mueller-Ruchholtz W. Human lymphocyte reactivity after in vitro exposure to technical and analytical grade pentachlorophenol. Toxicology. 1991;70(3):271–282. doi: 10.1016/0300-483x(91)90002-i. [DOI] [PubMed] [Google Scholar]
- Loose L. D., Pittman K. A., Benitz K. F., Silkworth J. B., Mueller W., Coulston F. Environmental chemical-induced immune dysfunction. Ecotoxicol Environ Saf. 1978 Sep;2(2):173–198. doi: 10.1016/0147-6513(78)90008-8. [DOI] [PubMed] [Google Scholar]
- Mandal A., Chakraborty S., Lahiri P. Hematological changes produced by lindane (gamma-HCH) in six species of birds. Toxicology. 1986 Jul;40(1):103–111. doi: 10.1016/0300-483x(86)90050-8. [DOI] [PubMed] [Google Scholar]
- McConnachie P. R., Zahalsky A. C. Immunological consequences of exposure to pentachlorophenol. Arch Environ Health. 1991 Jul-Aug;46(4):249–253. doi: 10.1080/00039896.1991.9937456. [DOI] [PubMed] [Google Scholar]
- Meera P., Rao P. R., Shanker R., Tripathi O. Immunomodulatory effects of gamma-HCH (Lindane) in mice. Immunopharmacol Immunotoxicol. 1992;14(1-2):261–282. doi: 10.3109/08923979209009224. [DOI] [PubMed] [Google Scholar]
- Nagayama J., Tsuji H., Iida T., Hirakawa H., Matsueda T., Okamura K., Hasegawa M., Sato K., Ma H. Y., Yanagawa T. Postnatal exposure to chlorinated dioxins and related chemicals on lymphocyte subsets in Japanese breast-fed infants. Chemosphere. 1998 Oct-Nov;37(9-12):1781–1787. doi: 10.1016/s0045-6535(98)00243-4. [DOI] [PubMed] [Google Scholar]
- Nakagawa R., Takahashi K. [Studies on the application of residual PCBs, PCQs and PCDFs concentrations to Yusho diagnosis]. Fukuoka Igaku Zasshi. 1991 May;82(5):280–294. [PubMed] [Google Scholar]
- Nakanishi Y., Nomoto Y., Matsuki A., Kunitake R., Hara N. Effect of polychlorinated biphenyls and polychlorinated dibenzofurans on leukocyte in peripheral blood and bronchoalveolar lavage fluid. Fukuoka Igaku Zasshi. 1995 May;86(5):261–266. [PubMed] [Google Scholar]
- Omara F. O., Flipo D., Brochu C., Denizeau F., Brousseau P., Potworowski E. F., Fournier M. Lack of suppressive effects of mixtures containing low levels of methylmercury (MeHg), polychlorinated dibenzo-p-dioxins (PCDDS), polychlorinated dibenzofurans (PCDFS), and aroclor biphenyls (PCBS) on mixed lymphocyte reaction, phagocytic, and natural killer cell activities of rat leukocytes in vitro. J Toxicol Environ Health A. 1998 Aug 7;54(7):561–577. doi: 10.1080/009841098158700. [DOI] [PubMed] [Google Scholar]
- Queiroz M. L., Bincoletto C., Perlingeiro R. C., Quadros M. R., Souza C. A. Immunoglobulin levels in workers exposed to hexachlorobenzene. Hum Exp Toxicol. 1998 Mar;17(3):172–175. doi: 10.1177/096032719801700308. [DOI] [PubMed] [Google Scholar]
- Queiroz M. L., Quadros M. R., Valadares M. C., Silveira J. P. Polymorphonuclear phagocytosis and killing in workers occupationally exposed to hexachlorobenzene. Immunopharmacol Immunotoxicol. 1998 Aug;20(3):447–454. doi: 10.3109/08923979809034826. [DOI] [PubMed] [Google Scholar]
- Rodriguez-Pichardo A., Camacho F., Rappe C., Hansson M., Smith A. G., Greig J. B. Chloracne caused by ingestion of olive oil contaminated with PCDDs and PCDFs. Hum Exp Toxicol. 1991 Sep;10(5):311–322. doi: 10.1177/096032719101000503. [DOI] [PubMed] [Google Scholar]
- Rogan W. J., Gladen B. C. Neurotoxicology of PCBs and related compounds. Neurotoxicology. 1992 Spring;13(1):27–35. [PubMed] [Google Scholar]
- Ross P. S., Van Loveren H., de Swart R. L., van der Vliet H., de Klerk A., Timmerman H. H., van Binnendijk R., Brouwer A., Vos J. G., Osterhaus A. D. Host resistance to rat cytomegalovirus (RCMV) and immune function in adult PVG rats fed herring from the contaminated Baltic Sea. Arch Toxicol. 1996;70(10):661–671. doi: 10.1007/s002040050326. [DOI] [PubMed] [Google Scholar]
- Schielen P., Den Besten C., Vos J. G., Van Bladeren P. J., Seinen W., Bloksma N. Immune effects of hexachlorobenzene in the rat: role of metabolism in a 13-week feeding study. Toxicol Appl Pharmacol. 1995 Mar;131(1):37–43. doi: 10.1006/taap.1995.1044. [DOI] [PubMed] [Google Scholar]
- Schielen P., Van Der Pijl A., Bleumink R., Pieters R. H., Seinen W. Local popliteal lymph node reactions to hexachlorobenzene and pentachlorobenzene: comparison with systemic effects. Immunopharmacology. 1996 Mar;31(2-3):171–181. doi: 10.1016/0162-3109(95)00045-3. [DOI] [PubMed] [Google Scholar]
- Schielen P., Van Rodijnen W., Pieters R. H., Seinen W. Hexachlorobenzene treatment increases the number of splenic B-1-like cells and serum autoantibody levels in the rat. Immunology. 1995 Dec;86(4):568–574. [PMC free article] [PubMed] [Google Scholar]
- Schäfer A. J., Daniel V., Dreikorn K., Opelz G. Assessment of plasma neopterin in clinical kidney transplantation. Transplantation. 1986 Apr;41(4):454–459. doi: 10.1097/00007890-198604000-00008. [DOI] [PubMed] [Google Scholar]
- Svensson B. G., Hallberg T., Nilsson A., Schütz A., Hagmar L. Parameters of immunological competence in subjects with high consumption of fish contaminated with persistent organochlorine compounds. Int Arch Occup Environ Health. 1994;65(6):351–358. doi: 10.1007/BF00383243. [DOI] [PubMed] [Google Scholar]
- Svensson B. G., Hallberg T., Nilsson A., Schütz A., Hagmar L. Parameters of immunological competence in subjects with high consumption of fish contaminated with persistent organochlorine compounds. Int Arch Occup Environ Health. 1994;65(6):351–358. doi: 10.1007/BF00383243. [DOI] [PubMed] [Google Scholar]
- Süsal C., Lewin I. V., Stanworth D. R., Terness P., Daniel V., Oberg H. H., Huth-Kühne A., Zimmermann R., Opelz G. Anti-IgG autoantibodies in HIV-infected hemophilia patients. Vox Sang. 1992;62(4):224–229. doi: 10.1111/j.1423-0410.1992.tb01203.x. [DOI] [PubMed] [Google Scholar]
- Tryphonas H., Luster M. I., White K. L., Jr, Naylor P. H., Erdos M. R., Burleson G. R., Germolec D., Hodgen M., Hayward S., Arnold D. L. Effects of PCB (Aroclor 1254) on non-specific immune parameters in rhesus (Macaca mulatta) monkeys. Int J Immunopharmacol. 1991;13(6):639–648. doi: 10.1016/0192-0561(91)90176-8. [DOI] [PubMed] [Google Scholar]
- Van Loveren H., Krajnc E. I., Rombout P. J., Blommaert F. A., Vos J. G. Effects of ozone, hexachlorobenzene, and bis(tri-n-butyltin)oxide on natural killer activity in the rat lung. Toxicol Appl Pharmacol. 1990 Jan;102(1):21–33. doi: 10.1016/0041-008x(90)90080-e. [DOI] [PubMed] [Google Scholar]
- Vos J. G. Immunotoxicity of hexachlorobenzene. IARC Sci Publ. 1986;(77):347–356. [PubMed] [Google Scholar]
- Weisglas-Kuperus N., Sas T. C., Koopman-Esseboom C., van der Zwan C. W., De Ridder M. A., Beishuizen A., Hooijkaas H., Sauer P. J. Immunologic effects of background prenatal and postnatal exposure to dioxins and polychlorinated biphenyls in Dutch infants. Pediatr Res. 1995 Sep;38(3):404–410. doi: 10.1203/00006450-199509000-00022. [DOI] [PubMed] [Google Scholar]
- Whiteside T. L., Friberg D. Natural killer cells and natural killer cell activity in chronic fatigue syndrome. Am J Med. 1998 Sep 28;105(3A):27S–34S. doi: 10.1016/s0002-9343(98)00155-7. [DOI] [PubMed] [Google Scholar]
- Yoo B. S., Jung K. H., Hana S. B., Kim H. M. Apoptosis-mediated immunotoxicity of polychlorinated biphenyls (PCBs) in murine splenocytes. Toxicol Lett. 1997 Apr 28;91(2):83–89. doi: 10.1016/s0378-4274(96)03861-1. [DOI] [PubMed] [Google Scholar]
- Yu M. L., Hsin J. W., Hsu C. C., Chan W. C., Guo Y. L. The immunologic evaluation of the Yucheng children. Chemosphere. 1998 Oct-Nov;37(9-12):1855–1865. doi: 10.1016/s0045-6535(98)00251-3. [DOI] [PubMed] [Google Scholar]
- Zheng T., Holford T. R., Mayne S. T., Tessari J., Owens P. H., Zahm S. H., Zhang B., Dubrow R., Ward B., Carter D. Environmental exposure to hexachlorobenzene (HCB) and risk of female breast cancer in Connecticut. Cancer Epidemiol Biomarkers Prev. 1999 May;8(5):407–411. [PubMed] [Google Scholar]
- de Swart R. L., Ross P. S., Vos J. G., Osterhaus A. D. Impaired immunity in harbour seals [Phoca vitulina] fed environmentally contaminated herring. Vet Q. 1996;18 (Suppl 3):S127–S128. [PubMed] [Google Scholar]