Chronic exposure of animals and humans to benzene causes aplastic anemia, a complete absence of the formed elements in blood, and in humans also causes several forms of acute leukemia. The formation of the formed elements of the blood, hemopoiesis, results from an interaction of hemopoietic stem cells with the bone marrow stroma which provides a microenvironment for regulated proliferation and differentiation of the blood cell precursors. Benzene may be toxic to the stromal microenviroment but the target cell and the identity of the toxic metabolite are unknown. Methods are now available for studying hemopoiesis in liquid culture, a system which requires the development of a marrow adherent layer which closely resembles in composition and function, the narrow stroma in vivo. This represents an ideal system for studing the effects of benzene and its metabolites on the ability of the cells of thestroma to support hemopoiesis. One such cell, the macrophage, is a major biosynthetic source of granulacyte/macrophage colony-stimulating activity (CSF-GM) and we have previously shown that macromolecular synthesis in the macrophage is inhibited by benzene. Therefore, the aims are to determine whether: o The site of benzene toxicity is the marrow adherent layer. o The target cell in the adherent layer is the macrophage. o Toxicity results from an inability of the benzene-poisoned macrophage to produce growth factors such as GM-CSF required for granulopoiesis. o The quinone metabolites of benzene, hydroquinone and p-benzoquinone represent the toxic species. These experiments should provide information on the target of benzene toxicity and the toxic species and thus pave the way for futher studies on the mechanisms whereby benzene causes aplastic anemia and may provide an insight as to how benzene acts as a leukemogen.
