Hexachlorobenzene-induced

Michielsen, C.C. et al., The role of the immune system in hexachlorobenzene-induced toxicity, Environ. Health Perspect., 107, 783, 1999. 

Ezendam, J. et al., Hexachlorobenzene-induced Immunopathology in Brown Norway rats is partly mediated by T cells. Toxicol. Sci., 78, 88, 2004. 

Ezendam, J., Vos, J., and Pieters, R., Mechanisms of Hexachlorobenzene-induced adverse immune effects in Brown Norway rats. J. Immunotoxicol., 1, 167, 2004. 

Michielsen, C.P., Bloksma, N., Ultee, A., van Mil, F., and Vos, J.G. (1997) Hexachlorobenzene-induced immunomodulation and skin and lung lesions A comparison between brown Norway, Lewis, and Wistar rats. Toxicol. Appl. Pharmacol., 144, 12, 1997. 

Ezendam, J. et al., Macrophages are involved in hexachlorobenzene-induced adverse immune effects. Toxicol. Appl. Pharmacol., 209, 19, 2005. 

Andrews JE et al Hexachlorobenzene-induced hyper-parathyroidism and osteosclerosis in rats. Fundam Appl Toxicol 12 242-251, 1989... 

Loose LD, Pittman KA, Benitz KF, et al. 1977. Polychlorinated biphenyl and hexachlorobenzene induced humoral immunosuppression. J Reticuloendothel Soc 22(3) 253-267. 

In conclusion, although hexachlorobenzene induces an auto-immune-like disorder in humans and rats, neoantigen formation and direct elicitation of autoreactive T cells are probably not involved. Rather, hexachlorobenzene, by activation of inflammatory cells such as macrophages, exacerbates autoimmunity above a level at which autoimmune phenomena and systemic inflammatory responses become apparent. This cascade of reactions is depicted in Figure 2 and illustrates the complexity of the etiology of immune derangements induced by hexachlorobenzene. 

Fig. 2. Proposed mode of action of hexachlorobenzene-induced adverse immune effects (HCB = hexachlorobenzene ROS = reactive oxygen species NO = nitric oxide DC = dendritic cells) (from Ezendam, 2004).

Ezendam J (2004) Mechanisms of hexachlorobenzene-induced adverse immune effects [thesis], Utrecht, Utrecht University. 

Gocmen A, Peters HA, Cripps DJ, Morris CR, Dogramaci I (1986) Porphyria turcica hexachlorobenzene-induced porphyria. In Morris C Cabral JR eds. Hexachloroben-zene Proceedings of an international symposium. Lyon, International Agency for Research on Cancer, pp 567-573 (IARC Scientific Publications No. 77). 

Michielsen C, Bloksma N, Klatter FA, Rozing J, Vos JG, van Dijk JE (1999b) The role of thymus-dependent T cells in hexachlorobenzene-induced inflammatory skin and lung lesions. Toxicol Appl Pharmacol, 161 180-191. 

Michielsen C, Leusink-Muis A, Vos JG, Bloksma N (2001) Hexachlorobenzene-induced eosinophilic and granulomatous lung inflammation is associated with in vivo airways hyperresponsiveness in the Brown Norway rat. Toxicol Appl Pharmacol, 172 11-20. 

Vos JG, van Logten MJ, Kreeftenberg JG, Kruizinga W (1979a) Hexachlorobenzene-induced stimulation of the humoral response in rats. Ann NY Acad Sci, 320 535-550. 

Many commercial lots of technical PCP are known to contain small — but possibly biologically significant — amounts of highly toxic dioxins, dibenzofurans, and hexachlorobenzene. These contaminants may be responsible for most of the toxicity of technical PCP preparations (McConnell et al. 1980 Parker et al. 1980 Wollesen et al. 1986 Holsapple et al. 1987). However, both technical-and analytical-grade PCP can induce hepatic mixed-function oxidases in intoxicated rats and cattle. In cattle, this effect was observed in both calves and adults, and in hepatic as well as pulmonary microsomes, and seemed to be dose related (Shull et al. 1986). 

Of all rat strains, the Brown Norway (BN) rat is used most frequently in relation to chemical-induced autoimmunity. This strain displays clinically manifested autoimmune disease following exposure to a number of chemicals. HgCl2 is the most scrutinized compound in the BN rat but D-penicillamine [6-8], gold-salts [9,10],hexachlorobenzene (HCB) [11-14] and recently, nevirapine [15], have all been shown to induce clinical effects. Captopril [7] and felbamate [16] appeared not to induce autoimmune effects in BN rats. 

Simon GS, Kipps BR, Tarcliff RG, et al. 1978. Failure of Kepone and hexachlorobenzene to induce dominant lethal mutations in the rat. Toxicol Appl Pharmacol 45 330-331. 

Canonero R, Campart GB, Mattioli F, et al. 1997. Testing of p-dichlorobenzene and hexachlorobenzene for their ability to induce DNA damage and micronucleus formation in primary cultures of rat and human hepatocytes. Mutagenesis 12(l) 35-9. 

Smith AG et al Goitre and wasting induced in hamsters by hexachlorobenzene. Arch Toxicol 60 343-349, 1987... 

Hexachlorobenzene acted like a weak Ah receptor agonist and caused an up to 40% decrease in specific hepatic cytosol binding of 2,3,7,8-TCDD in rat cells (Hahn et al. 1989b). Similarly, 2,3,7,8-TCDD-induced myelotoxicity and enzyme induction was antagonized by 1-amino-3,7,8-trichlorodibenzo-p-dioxin in B6C3Fj mice presumably by competitive binding to the cytosolic Ah receptor (Luster et al. 1986). Comparable effects were observed in vitro in murine bone-marrow-cells cultures. Treatment of Fischer 344 rats orally with di(2-ethylhexyl)phthalate (DEHP) before or after oral administration of... 

The porphyrias are a heterogeneous group of diseases, all of which involve disorders of heme biosynthesis, which result in accumulation and increased excretion of porphyrins or porphyrin precursors. The porphyrias can be divided into two kinds the hereditary porphyrias, some of which can be exacerbated by exposure to certain chemicals, and the toxic porphyrias, which can be produced by exposure to certain chemicals alone. The pattern of excretion of porphyrins and porphyrin precursors is characteristic for each type. Clinical symptoms consist mainly of cutaneous photosensitivity and/or neurological disturbances. Hexachlorobenzene is a chemical inducer of porphyria. 

The formation of benzyne via o-FC6H4MgBr from o-bromofluorobenzene and magnesium is closely related in mechanism to the base-induced eliminations, but the reaction conditions for the Grignard method (in refluxing tetrahydrofuran) are often more convenient. Benzyne is also produced from o-bromofluorobenzene and butyllithium, and hexachlorobenzene is the usual precursor for generation of tetrachlorobenzyne (Eq. 1). 

The Brown Norway rat has long been considered to be a valuable model (Donker et al., 1984 Balazs, 1987), as a number of chemicals have been shown to induce clinically manifested auto-immune-like disease in this particular strain of rats. This model has been used extensively in studies of mercury(II) chloride. D-Penicil-lamine (Tournade et al., 1990), gold salts (Toumade et al., 1991 Qasim et al., 1997), and hexachlorobenzene (Vos et al., 1979a Michielsen et al., 1999a, 1999b Ezendam et al., 2004a, 2004b) have been shown to induce clinical effects in the Brown Norway rat model. Captopril (Donker et al., 1984) and also felbamate (Popovic et al., 2004) were tested in Brown Norway rats as well, but effects were not seen with these exposures. 

ZACHEIS, G. A., GRAY, K. A., KAMAT, P. V., Radiation-Induced Catalysis on Oxide Surfaces Degradation of Hexachlorobenzene on y-Irradiated Alumina Nanoparticles , J. Phys. Chem. B 1999,103, 2142-2150. 

Uroporphyrinogen decarboxylase (EC 4.1.1.37). The enzyme is unstable. Increased fecal excretion of uroporphyrin, porphyrins possessing 7 carboxylic add groups, copropoiphyrin and isocoproporphyrin. Phot ennatosis. Hepatic siderosis. Risk of primary hepatocellular carcinoma greatly increased. Treatment by phlebotomy. Autosomal dominant. The condition may also be induced by exposure to halogena-ted aromatic hydrocarbons (e.g. polychlorinated biphenyls, hexachlorobenzene). 

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