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

Guidelines for Canadian Drinking Water Quality

The effects of polycyclic aromatic hydrocarbons on the immune system of fish: a review.

Among the environmental chemicals that may be able to disrupt the endocrine systems of animals and humans, the polychlorinated biphenyls (PCBs) are a chemical class of considerable concern. One possible mechanism by which PCBs may interfere with endocrine function is their ability to mimic natural hormones. These actions reflect a close relationship between the physicochemical properties encoded in the PCB molecular structure and the responses they evoke in biological systems. These physicochemical properties determine the molecular reactivities of PCBs and are responsible for their recognition at biological acceptors and receptors, as well as for triggering molecular mechanisms that lead to tissue response. "Coplanarity" of PCB phenyl rings and "laterality" of chlorine atoms are important structural features determining specific binding behavior with proteins and certain toxic responses in biological systems. We compare qualitative structure-activity relationships for PCBs with the limited information on the related non-coplanar chlorinated diphenyl ethers, providing further insights into the nature of the molecular recognition processes and support for the structural relationship of PCBs to thyroid hormones. Steroidlike activity requires conformational restriction and possibly hydroxylation. We offer some simple molecular recognition models to account for the importance of these different structural features in the structure-activity relationships that permit one to express PCB reactivities in terms of dioxin, thyroxine, and estradiol equivalents. The available data support the involvement of PCBs as mimics of thyroid and other steroidal hormones. The potential for reproductive and developmental toxicity associated with human exposure to PCBs is of particular concern.(ABSTRACT TRUNCATED AT 250 WORDS)

Polychlorinated biphenyls as hormonally active structural analogues.

It was not very long ago that free radical biology was a rather arcane subject, regarded with disinterest (or even disbelief) by most biologists-a sea of speculation, but few islands of solid fact. Three striking and seminal discoveries have drastically changed this field. The first was the elucidation by McCord and Fridovich of the nature, function, and role of superoxide dismutase (SOD].’ In fact, SOD is now the world’s most studied enzyme; journal articles, conference proceedings, and books on superoxide chemistry and biology are appearing at a very rapid pace, but we probably are still just seeing the tip of the iceberg. The second discovery involves the biosynthesis of peroxidic compounds from arachidonic acid-products of what is called the “arachidonate cascade.”‘ Not more than 10 years ago, it was thought that lipoxygenase activity was limited to plants and that lipid hydroperoxides were not formed in animal cells. In fact, there was even concern that lipid hydroperoxides in plants might be in vitro artifacts and play no role in metabolism. Now it is clear that an array of cyclic and bicyclic peroxides as well as acyclic lipid hydroperoxides not only occur in all animal cells, but play a very critical role in bioregulation and in many vital normal and pathological processes. The third discovery, although perhaps more distant from traditional biochemical interests, also is having a major impact on current research. It is becoming clear that many important environmental toxins exert their effects through radical-mediated reaction^.^.^ In fact, a majority of the compounds that are positive in the Ames test may involve radical-mediated reactions. In this article, I will summarize current thinking on the in vivo sources of radicals. I will cover both exogenous sources-xenobiotics, pollutants, carcinogens, etc.-and endogenous sources-superoxide systems and the arachidonic cascade. And I will close by making some remarks about the effects of antioxidants on carcinogenesis and on the retardation of aging. Thus, I intend to skate from thick ice to thinner and thinner ice: with good timing, I should fall into the refreshingly cool water just at the end of my talk.

Free radical biology: xenobiotics, cancer, and aging.

B6C3F1 mice were exposed to two congeners of benzopyrene, either the carcinogen benzo(a)pyrene (B(a)P) or the non-carcinogen benzo(e)pyrene (B(e)P. Exposure of mice to B(a)P resulted in a reduced number of IgM and IgG antibody plaque forming cells (PFC) to the T-dependent (TD) antigen SRBC and IgM PFC's to the T-independent (TI) antigen LPS. The IgM response to hapten conjugated TI antigens was examined using TNP-LPS for reactivity of less mature B cells (B1) and TNP-Ficoll for more mature B cells (B2). Exposure to B(a)P severely depressed the TNP-Ficoll PFC response by up to 77% without altering the TNP-LPS response. These data indicated that exposure to B(a)P alters differentiation and antibody production in mature B cells to both TD and B2 TI antigens. No change in PFC was observed following exposure to B(e)P. Mishell-Dutton co-cultures confirmed that B cells were affected and that T helper cells or suppressor Mphi were not involved. Parameters of cell-mediated immunocompetence including delayed cutaneous hypersensitivity to KLH, allograft or tumour cell rejection and susceptibility to Listeria monocytogens were unaltered in B(a)P treated mice.

Lela D. Lawson

Papers

Selective immunosuppression resulting from exposure to the carcinogenic congener of benzopyrene in B6C3F1 mice.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on lipid profiles in tissue of the Fischer rat.

The effect of adult exposure to diethylstilbestrol in the mouse: alterations in immunological functions.

Radioimmunoassay for quantitation of 2,3,7,8-tetrachlorodibenzofuran

Production and characterization of antisera specific for chlorinated biphenyl species: Initiation of a radioimmunoassay for aroclors