VOL.: 79 (2001) (p. 493)
Chem. Abstr. Name: Hexachlorobenzene
5.1 Exposure data
Hexachlorobenzene is a chlorinated hydrocarbon which may contain some higher polychlorinated dibenzofurans and dioxins as impurities. It has been used in the manufacture of industrial chemicals, including chlorinated pesticides, and as a fungicide and seed dressing in agriculture. The production and use of hexachlorobenzene have decreased since the 1970s owing to bans and restrictions on its use in many countries, but it still occurs as a by-product of the production of a number of chlorinated solvents and other industrial chemicals. Occupational exposure to hexachlorobenzene has occurred during its production and use in industry and agriculture. Hexachlorobenzene has been detected in many foodstuffs, but dietary intake has probably decreased in recent years.
5.2 Human carcinogenicity data
The risk for breast cancer has been investigated in relation to life-long, accumulated exposure to hexachlorobenzene in nine studies.
Five small case–control studies that included fewer than 50 cases of breast cancer each showed no overall association with the concentration of hexachlorobenzene in contemporary samples of adipose breast tissue. A secondary subgroup analysis in one of the studies revealed a significant association in postmenopausal women with estrogen receptor-positive cancer, based, however, on a small number of cases.
Four large case–control studies of exposure to hexachlorobenzene have been reported, one from Canada and three from the USA. In three of these, the concentration of hexachlorobenzene was measured in biological samples (serum fat or breast fat) from the study subjects, obtained close to the time of breast cancer diagnosis. No consistent increase in the risk for breast cancer was found in women with elevated concentrations of hexachlorobenzene. In the fourth case–control study (from the USA), banked serum samples obtained before the breast cancer diagnosis were used to assess the body burden of hexachlorobenzene. The risk for breast cancer of women whose concentration of hexachlorobenzene was in the upper three quartiles was twice that of those whose samples were in the lower quartile. However, there was no evidence of a dose–response relationship, and the association was limited to women whose blood was collected close to the time of diagnosis of their breast cancer.
One case–control study each of endometrial cancer, pancreatic cancer and hairy-cell leukaemia yielded no notable results with respect to exposure to hexachlorobenzene.
5.3 Animal carcinogenicity data
Hexachlorobenzene was tested for carcinogenicity by oral administration in one study in mice, four studies in rats and one in hamsters. It produced liver-cell tumours in all three species and renal tubular tumours in rats of each sex in one study. After perinatal administration to rats, it increased the incidences of parathyroid adenomas in males and adrenal phaeochromocytomas in females. In hamsters, it also produced liver haemangioendotheliomas and thyroid follicular-cell adenomas. In several studies in which it was given with other compounds, hexachlorobenzene promoted liver carcinogenesis in mice and rats.
5.4 Other relevant data
Hexachlorobenzene is lipophilic, accumulates in humans and is excreted as a cysteine conjugate of pentachlorobenzene. In rats, hexachlorobenzene has been shown to follow several metabolic pathways, which include the formation of pentachlorobenzene, tetrachlorobenzene and tri- and tetrachlorophenol.
Accidental consumption by humans of a large quantity of hexachlorobenzene resulted in porphyria cutanea tarda, liver toxicity, neurological effects and skin changes, which were persistent.
In experimental animals, the effects of treatment with hexachlorobenzene on the thyroid include decreased thyroid hormone concentrations due to increased glucuronidation and inhibition of type-1 deiodinase, interference with serum carrier binding of the thyroid hormones and increased thyroid-stimulating hormone concentrations. In the livers of experimental animals, hexachlorobenzene induced cytochrome P450 enzymes and inhibited uroporphyrinogen decarboxylase, iron accumulation and oxidative damage. These effects are believed to be involved in the production of hepatic tumours.
In a poisoning epidemic in Turkey, exposure to hexachlorobenzene via breast milk caused a very high rate of lethality among infants. An increased frequency of pregnancy loss was reported among women exposed to hexachlorobenzene as children. The presence of this compound in breast milk has been associated with altered immune function in Inuits. Hexachlorobenzene was teratogenic in mice, and increased mortality rates were observed among rats and monkeys exposed in utero. Effects on steroid hormones have also been reported in exposed female mice.
In a single study of workers exposed to a number of chlorinated solvents, including hexachlorobenzene, an increased frequency of micronucleated lymphocytes was found; there was no association with the concentrations of hexachlorobenzene in blood. Micronuclei were induced by hexachlorobenzene in human and rat primary hepatocytes in vitro. Otherwise, there was little evidence that hexachlorobenzene has genetic activity.
There is inadequate evidence in humans for the carcinogenicity of hexachlorobenzene.
There is sufficient evidence in experimental animals for the carcinogenicity of hexachlorobenzene.
Hexachlorobenzene is possibly carcinogenic to humans (Group 2B).
Previous evaluations: Vol. 20 (1979); Suppl. 7 (1987)For definition of the italicized terms, see Preamble Evaluation.
See Also: Toxicological Abbreviations Hexachlorobenzene (EHC 195, 1997) Hexachlorobenzene (HSG 107, 1998) Hexachlorobenzene (ICSC) Hexachlorobenzene (PIM 256) Hexachlorobenzene (FAO/PL:1969/M/17/1) Hexachlorobenzene (WHO Pesticide Residues Series 4) Hexachlorobenzene (IARC Summary & Evaluation, Supplement7, 1987) Hexachlorobenzene (IARC Summary & Evaluation, Volume 20, 1979)