In this review, we have examined the biochemical and toxic responses produced by halogenated aromatic hydrocarbons and have tried to develop a model for their mechanism of action. These compounds bind to a cellular receptor and evoke a sustained pleiotropic response. In many tissues this response consists of the expression of a battery of enzymes which are, for the most part, involved in drug metabolism, but in other tissues, those which develop toxicity, an additional set of genes is expressed which effects cellular involution, division, and/or differentiation. The toxicity of these compounds appears to be due to the sustained expression of a normal cellular regulatory system, of which we were previously unaware. In future investigations it is hoped that we will learn the nature and physiologic role of this regulatory system. Only then can we hope to understand the mechanism of toxicity of these compounds.

2,3,7,8-Tetrachlorodibenzo-p-Dioxin and Related Halogenated Aromatic Hydrocarbons: Examination of the Mechanism of Toxicity

Commercial polychlorinated biphenyls (PCBs) and environmental extracts contain complex mixtures of congeners that can be unequivocally identified and quantitated. Some PCB mixtures elicit a spectrum of biochemical and toxic responses in humans and laboratory animals and many of these effects resemble those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons, which act through the aryl hydrocarbon (Ah)-receptor signal transduction pathway. Structure-activity relationships developed for PCB congeners and metabolites have demonstrated that several structural classes of compounds exhibit diverse biochemical and toxic responses. Structure-toxicity studies suggest that the coplanar PCBs, namely, 3,3',4,4'-tetrachlorobiphenyl (tetraCB), 3,3',4,4',5-pentaCB, 3,3',4,4',5,5'-hexaCB, and their monoortho analogs are Ah-receptor agonists and contribute significantly to the toxicity of the PCB mixtures. Previous studies with TCDD and structurally related compounds ...

Polychlorinated Biphenyls (PCBs): Environmental Impact, Biochemical and Toxic Responses, and Implications for Risk Assessment

Endometriosis

Zebrafish as a model vertebrate for investigating chemical toxicity.

Publisher Summary This chapter discusses the role of glutathione (GSH) and glutathione s-transferases in metabolism of chemical carcinogens and other electrophilic agents. GSH is a tripeptide (I) that is present in nearly all living cells and is the most abundant sulfhydryl compound present in animal tissues, mainly in the cytosol. The chapter illustrates the wide range of electrophilic agents, including several known mutagens and carcinogens, which conjugate with GSH, a process usually catalyzed by the GSH S-transferases. This conjugation is probably a protective mechanism and is the initial stage in mercapturic acid biosynthesis for the elimination of foreign compounds from the body. GSH S-transferases provide protection not only by catalyzing the conjugation of a potential toxicant with GSH, but also by preferentially binding, even covalently, that toxicant. The reactive electrophiles that conjugate with GSH also bind to DNA, RNA, and protein and identification of GSH conjugates provide information on the nature of these biologically active intermediates or even their immediate precursors. Thus, the knowledge of the way in which mutagens and carcinogens are metabolized is essential to a better understanding of their mode of action and of the processes for their detoxication.

The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents.

Reproductive dysfunction in rhesus monkeys exposed to low levels of polychlorinated biphenyls (Aroclor 1248)

During the past several years experiments have been conducted in this laboratory to determine the toxicologic effects in animals exposed to three halogenated hydrocarbons-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs). TCDD and PCBs are considered to be worldwide environmental contaminants. PBBs have caused major environmental problems in the state of Michigan. The health implications of these compounds are further complicated by their extremely slow biodegradation and their ability to accumulate in body tissues and remain there for an indefinite period. As a result of their environmental and public health significance, a large amount of literature has been published on TCDD and PCB intoxication in humans and lower animals. There is also considerable research in progress to further clarify the toxicologic effects of the PBBs. However, there is a dearth of information on the effects of these halogenated hydrocarbons on reproduction in humans and closely related species, particularly when the exposure to these compounds is at low levels and occurs over an extended period. The rhesus monkey is a suitable animal model with which to study the effects of exposure to halogenated hydrocarbons. Many of the toxicologic signs produced by these halogenated hydrocarbons are similar to those observed in humans. Thus, the data obtained from research conducted on the nonhuman primate are helpful in postulating the injurious effects that may arise in the human population following exposure to these compounds. I n the presently reported research, the three compounds were evaluated for their toxicologic effects on nonhuman primates. Attempts have been made to simulate the levels to which humans may be exposed. Data are presented which indicate that low-level, long-term exposure to these compounds gives rise to reproductive abnormalities in the adult primate as well as fetal and neonatal toxicity.

James R. Allen

Papers

Reproductive dysfunction in rhesus monkeys exposed to low levels of polychlorinated biphenyls (Aroclor 1248)

Reproductive effects of halogenated aromatic hydrocarbons on nonhuman primates.

Increased incidence of neoplasms in rats exposed to low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Morphological changes in monkeys consuming a diet containing low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Hormonal alterations in female rhesus monkeys fed a diet containing 2, 3,7,8-tetrachlorodibenzo-p-dioxin.