10.3.2.1 Polychlorinated biphenyls The polychlorinated biphenyl (PCB) content of animal food is decreasing in recent years. This is due to the ban on the use of PCBs. Notwithstanding, the levels of PCBs can still be high because of their low biodegradability.
PCBs are known to cause:
- induction of phase I (i.e., oxidases, reductases) as well as of phase II (i.e., conjugases) xenobiotic-metabolizing enzymes
- teratogenic effects
- neurotoxic effects
The most prominent effect in humans is persistent chloracne on the skin of the head and chest. This skin disease is believed to result from acanthosis and hyperkeratosis of the skin. Hair follicles are ultimately plugged by keratinaceous material and the glands around the follicles become cystic. The majority of studies on enzyme induction by PCBs concerned the cytochrome P-450-dependent monooxygenase. Evidence has been obtained that the mechanism underlying the induction of cytochrome P-450 isoenzymes consists of a sequence of events, the first of which is binding to a receptor protein, the so-called Ah (aromatic hydrocarbon) receptor. The ligand-Ah receptor complex is transferred to the nucleus. Interactions of the complex with structural genes result in stimulation of the transcription of those genes. This leads to an increasing synthesis of the enzymes coded for by the genes.
The mechanism of the carcinogenicity of PCBs involves promotion rather than initiation. They stimulate the growth of tumors (induced) in liver, skin and lungs. Although PCBs have been reported to be carcinogenic in animals, there are only a few reports suggesting that these compounds are also carcinogenic in man. Tumors were found in 8 of 22 people involved in a rice oil accident in Japan, and in 7 of 92 industrial workers exposed to arochlor.
Several of the toxic effects are similar to those of pesticides like dieldrin and aldrin: teratogenicity and neurotoxic effects. In both cases, the underlying mechanisms are not yet exactly known.
10.3.2.2 Polychlorinated dibenzodioxins and dibenzofurans Polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) originate from several sources.
PCDD/PCDF emission can result from the incineration of domestic waste containing low-molecular chlorinated hydrocarbons and PCBs. PCDDs and PCDFs are also formed during the production of organochlorine compounds such as polychlorobenzenes, polychlorophenols, and PCBs. The most toxic polyhalogenated aromatic hydrocarbon is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a well-known contaminant of the herbicide 2,4,5-trichlorophenoxyacetic acid(2,4,5-T). TCDD has an oral LD50 of 22 to 45 |g/kg in rats.
Many TCDD-induced effects are similar to effects caused by PCBs and other structurally-related compounds. Hepatic monooxygenase activity is elevated. PCDDs and PCDFs are also highly teratogenic (0.25 |g/kg). Further, immunosuppression and thymic atrophy have been reported in experimental animals (after 10 |g/kg).
Enzyme induction, immunosuppression, and thymic atrophy by TCDD and structurally-related compounds are believed to be mediated via stereospecific and irreversible binding to the Ah receptor (see Section 10.3.2.1). An essential structural requirement is coplanarity. The structures of the halogenated aromatic hydrocarbons involved should be as planar as that of TCDD.
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