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Structure-activity relationships of the polyhalogenated aromatic hydrocarbons
Abstract
The H-4-II E cell enzyme induction and Ah receptor bioassays were utilized to examine the biochemical potencies of environmental samples, and the structure-activity relationships of polyhalogenated aromatic hydrocarbons (PAHs). Rank order comparisons between the two bioassays with environmental samples were comparable, although the H-4-II E cells were found to be a more sensitive and reliable indicator of potential in vivo toxicity, particularly with those samples having little biochemical activity. The H-4-II E cell enzyme induction EC(,50) values of environmentally significant reconstituted polychlorinated biphenyl (PCB) and dibenzofuran (PCDF) mixtures were found to be an additive response to the enzyme inducing potencies of their constituents. Structure-activity studies with PCDFs demonstrated that the most toxic congeners in vivo were also the most potent AHH and EROD inducers (in vivo and in vitro), and bound with the highest affinity to the cytosolic receptor. The in vitro data also suggested that chloro substitution of PCDFs at C-4 and C-6 may result in congeners which are more active than isomers with C-1 or C-9 chloro groups. Structure-activity studies with a series of chlorinated and brominated tetrahalobiphenyls demonstrated that the biologic activity of these compounds was enhanced with increasing bromine substitution. Quantitative structure-activity relationship analysis of four series of PAHs was carried out. For the 7-substituted 2,3-dichlorodibenzo-p-dioxins and the 8-substituted 2,3-di and 2,3,4-trichlorodibenzofurans, only the lipophilicity of the lateral substituent influenced the relative binding affinities. This was in sharp constrast to the 4'-substituted 2,3,4,5-tetrachlorobiphenyls, where the lipophilic, electronic and hydrogen bonding parameters of the 4'-substituent determined the binding constants. In all four series, the enzyme induction was not found to be a linear function of binding. With the exception of the dibenzo-p-dioxins, EROD and AHH induction were linearly related. The relationship between EROD and AHH induction by the 7-substituted 2,3-dichlorodibenzo-p-dioxins was dependent on the lipophilicity of the substituent. Enzyme induction studies with White Leghorn cockerels using classical enzyme inducers, and selected PCB congeners and commercial mixtures suggested that the coordinate enzyme induction and toxicity responses noted in rats was not observed in the avian due to a unique mixed-function oxidase enzyme induction response.
Description
Typescript (photocopy).Collections
Citation
Sawyer, Thomas Willia (1984). Structure-activity relationships of the polyhalogenated aromatic hydrocarbons. Texas A&M University. Texas A&M University. Libraries. Available electronically from https : / /hdl .handle .net /1969 .1 /DISSERTATIONS -436178.
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