Åke Bergman

Accumulation of methylsulfonyl derivatives of some bronchial-seeking polychlorinated biphenyls in the respiratory tract of mice

Abstract Seventeen polychlorobiphenyls (PCBs), 14 C-labeled and/or unlabeled, were studied with regard to their deposition as such or as metabolites in the lung tissues after iv or ip injection in mice. Four of these compounds were known by autoradiography to possess affinity for bronchial tissues. Lung extracts of mice treated with the 11 labeled PCBs were analyzed in a partition scheme to indicate the presence of hydroxylated and/or methylsulfonyl metabolites. Extracts of lungs from mice treated with the unlabeled compounds were analyzed by gas chromatography. The extracts that appeared to contain methylsulfonyl metabolites were further analyzed by mass fragmentography. Five of the biphenyls studied were each found to appear in the lungs as two isomeric methylsulfonyl PCBs. The structures of the major metabolites were confirmed by comparison with synthetic reference compounds. One of the biphenyls previously known to accumulate in the bronchi was found not to occur in the lung as methylsulfonyl derivatives, but most probably only as the unchanged compound. None of the remaining 11 PCBs studied was found to occur as methylsulfonyl derivatives in the lung.

Convulsive properties of lindane, lindane metabolites, and the lindane isomer α-hexachlorocyclohexane: Effects on the convulsive threshold for pentylenetetrazol and the brain content of γ-aminobutyric acid (GABA) in the mouse

Abstract The threshold for pentylenetetrazol-induced convulsions in the mouse is affected by lindane in two opposite ways. Following the administration of a single dose of lindane, the threshold first decreases and then, after 2 days, increases above the normal level. None of the tested metabolites of lindane altered the convulsive threshold. When lindane elevates the convulsive threshold it also elevates the content of γ-aminobutyric acid (GABA) in the brain. The lindane isomer α-hexachlorocyclohexane elevates both convulsive threshold and the GABA content. The smallest single oral dose of lindane lowering the convulsive threshold for pentylenetetrazol in the mouse, 3 hr after administration, corresponds to a lindane concentration of 56 ppb in whole blood.

Target cells for methylsulphonyl-2,6-dichlorobenzene in the olfactory mucosa in mice

Previously we reported that methylsulphonyl-2,6-dichlorobenzene, 2, 6-(diCl-MeSO(2)-B), was irreversibly bound to the olfactory mucosa of mice and induced necrosis of the Bowmans glands with subsequent neuroepithelial degeneration and detachment. In this study, autoradiography and histopathology were used to determine tissue-localization and toxicity of 2,6-(diCl-MeSO(2)-B) in the olfactory mucosa of control mice and animals pretreated with cytochrome P450 (CYP) and glutathione (GSH) modulators. The Bowmans glands of the olfactory mucosa were the major target sites of non-extractable binding of 2,6-(diCl-(14)C-MeSO(2)-B), whereas the olfactory neuroepithelium and nerve bundles showed only background levels of silver grains. Metyrapone pretreatment slightly decreased binding in the Bowmans glands and markedly decreased toxicity in the olfactory mucosa after 2,6-(diCl-MeSO(2)-B) administration. These results support that a CYP-mediated activation of 2, 6-(diCl-MeSO(2)-B) takes place in the Bowmans glands giving rise to toxic reactive intermediates. In mice pretreated with the GSH-depleting agent phorone, a marked increase of irreversible binding of 2,6-(diCl-(14)C-MeSO(2)-B) in the Bowmans glands was observed. Tape-section autoradiograms also revealed a significant increase of uptake of radioactivity in the olfactory bulb. As determined by histopathology, GSH-depletion increased both the extent and severity of the lesion in the mucosa. These results imply that 2,6-(diCl-MeSO(2)-B)-reactive intermediates are conjugated with GSH. The amount of irreversible binding and toxicity in the olfactory mucosa seems to be associated with the level of 2, 6-(diCl-MeSO(2)-B)-reactive intermediates.