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NYC 9/11 Public Portal Document

ASBESTOS MEDITEXT ® - Medical Management Page 1 of 3

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ASBESTOS MEDITEXT ® - Medical Management

9.0 PHARMACOLOGY/TOXICOLOGY 9.2 TOXICOLOGIC MECHANISM

A. CYTOTOXICITY - The actual toxic mechanisms of the different asbestos fibers is not well understood. 1. Experimental animal studies have suggested a role for lipid peroxidation, adsorption of red blood cells on asbestos fibers, decreased calcium- and magnesium-activated ATPase activities, stimulated phosphatidylinositol turnover, activation of protein kinase C, and increased cytochrome C oxidase activity (Bissonnette et al, 1990; Goodglick et al, 1989; Goodglick & Kane, 1990; Elferink et al, 1989; HSDB, 1995; Iguchi & Kojo, 1989; Roney & Holian, 1989). 2. In vitro studies found that more than 20 mcg/mL of chrysotile can increase prostaglandin E2 production by macrophages and target cells and inhibit the cytotoxicity of rat alveolar macrophages (Bissonnette et al, 1990). 3. In vitro studies found that crocidolite fibers induce lipid peroxidation and disrupt the mitochondrial membrane potential in mouse macrophages (Goodglick & Kane, 1990; Goodglick et al, 1989). Hemolysis of human erythrocytes was attributed to the same mechanism (Iguchi & Kojo, 1989). 4. With asbestos exposure, polymorphonuclear leukocytes can generate hydrogen peroxide which causes hemolysis and injury to human pulmonary epithelial cells (Iguchi & Kojo, 1989; Kamp et al, 1989). Superoxide anion production has also been noted in asbestos- exposed guinea pig and human alveolar macrophages (Rom et al, 1987; Roney & Holian, 1989). 5. Iron was required for hydroxyl radical production in alveolar epithelial cells cultured with asbestos. Both cytotoxicity and DNA damage were dependent on the production of hydroxyl radicals (Kamp et al, 1995). 6. Chrysotile asbestos induced release of lactic dehydrogenase from rabbit peritoneal polymorphonuclear leukocytes and caused membrane damage and cytotoxicity (Elferink et al, 1989). With extracellular calcium, asbestos activated exocytosis and release of lysozymes and glucuronidase. 7. Asbestos fibers exerted a dose-dependent functional suppressive, rather than cytotoxic, effect on the natural killer (NK) effector cells, thus rendering the NK cells "paralyzed" once bound to their targets (deShazo et al, 1988; Robinson, 1989). 8. Studies with human breast carcinoma cells and human laryngeal carcinoma cells suggest an interaction between asbestos fibers and the normal mitotic process. After fiber penetration of the cell cytoplasm, a rearrangement of the cytoskeletal apparatus appears to occur. Internalization of fibers appears to lead to formation of giant multinucleated cells (Malomi et al, 1990). B. FIBROGENESIS - The mechanisms that govern the fibrogenic effects of asbestos in the lungs

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