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Exposure to benzene can induce a number of hematotoxicities and decrease host resistance to microorganisms and tumors. Several studies have shown that metabolism of benzene to reactive intermediates is required for myelotoxicity. Since receptor-mediated phagocytosis by macrophages is an important host defense, we have examined the effects of benzene metabolites on receptor-mediated phagocytosis in cultured murine peritoneal macrophages. 1,4-Benzoquinone (BQ) was the most potent of the metabolites examined. Ten-minute exposures to a 12.5 microM concentration inhibited Fc and complement receptor-mediated phagocytosis by > or = 90%. Macrophage viability was largely unaffected by BQ treatment. Exposure to 50 and 100 microM 1,2,4-benzenetriol (BT) inhibited Fc receptor-mediated phagocytosis by 70 and 95%, respectively. Hydroquinone (HQ) elicited a major decrease (50%) only at 100 microM. The comparative inhibitory potencies of BT and HQ correlate with previously published data on their relative facility for autooxidation to quinones at physiological pH. Catechol had no effect at the concentrations employed. Macrophages treated with BQ and BT failed to recover their Fc receptor-mediated phagocytic capacity when incubated overnight in the absence of the xenobiotics. Only small differences in the inhibition of Fc receptor-mediated phagocytosis were observed between macrophages exposed to BQ at 4 versus 37 degrees C. BQ also had little effect on the Fc receptor binding of target cells. Fluorescent digital imaging microscopy demonstrated that BQ treatment markedly decreased the filamentous actin content of macrophages. However, BQ bound in low amounts to purified actin and did not affect its assembly. Our findings suggest that a mechanism for inhibition of Fc receptor-mediated phagocytosis by BQ is disruption of filamentous actin via an effect(s) other than the direct alkylation of actin by BQ.

Exposure to benzene has been shown to decrease resistance to challenges by Listeria monocytogenes or tumor cells in mice. Alterations of T-lymphocytes have been suggested as one probable cause. Macrophages are also critical participants in resistance to Listeria and to tumor cells. We have previously shown that exposure of macrophages in vitro to benzene metabolites, but not to benzene, inhibited several functions of macrophages that are critical for host resistance. The present studies were conducted to determine the effects of exposure to benzene in vivo on the murine mononuclear phagocyte system. Treated animals received daily subcutaneous injections of benzene (800 mg/kg) for 5 days. Macrophages were obtained by lavage from the peritoneal cavity after ip injection of sterile eliciting agents. Enumeration, peroxidase histochemistry, and a series of functional assays were performed. Animals exposed to benzene displayed a decreased number of macrophages elicited by peptone injection. Specific alterations of macrophage functions included a 50% decrease of Fc-receptor-mediated phagocytosis and 70% inhibition of tumor cell cytolysis but an enhancement of TPA-stimulated H2O2 release. There was no effect on interferon-gamma stimulated expression of Ia antigen. The observations that the elicited macrophage populations were composed of newly immigrated cells and that benzene treatment was terminated 3 days before the functional analyses were performed suggest that benzene was affecting monocytes in the blood and precursor cells in the bone marrow. Alterations of macrophage functions in injection controls suggested that determining the primary effect of exposure to benzene may be complicated by the inflammation induced by treatment at the site of injection.(ABSTRACT TRUNCATED AT 250 WORDS)

The vapors of formaldehyde have been reported to represent a potential health hazard, resulting in an increased incidence of carcinomas of the nasal turbinates in experimental animals. To determine the potential role of alterations in the mononuclear phagocyte system (MPS) induced by inhalation of formaldehyde, we studied the systemic effects of exposure upon macrophages. Specifically, we examined the effects of formaldehyde exposure upon development of the MPS by use of an established system of quantitative objective markers, which characterizes and classifies populations of murine macrophages into several developmental stages. Exposure of mice to 15 ppm of formaldehyde for 6 hr daily for 3 weeks did not alter the number or impair the function of resident peritoneal macrophages, although this exposure increased (approximately twofold) competence for release of H2O2 from the macrophages. Furthermore, formaldehyde exposure did not alter the tumoricidal activation or differentiation of macrophages produced by the defined stimulant MVE-2. The data thus indicate that exposure of mice to formaldehyde can induce selective systemic alterations in the function of the MPS for H2O2 production, a change which has been shown in other studies to increase the frequency of mutagenesis.

A series of immune function and host resistance parameters were examined in female B6C3F1 mice following a 21-day (6 hr/day) inhalation exposure to 15 ppm of formaldehyde (HCHO). Immune parameters examined included delayed hypersensitivity to keyhole limpet hemocyanin, antibody plaque-forming cell response to sheep erythrocytes (T-lymphocyte-dependent antigen) and TNP-Ficoll (T-lymphocyte-independent antigen), lymphoid organ weights and histopathology, routine hematology, bone marrow cellularity and CFU progenitor cell enumeration, lymphocyte subpopulation quantitation by cell surface markers, mitogen-induced lymphocyte blastogenesis, macrophage function parameters, and host resistance to challenge with the bacterium Listeria monocytogenes and transplantable tumor cells. Lymphoid organ weight, bone marrow cellularity, and hematology parameters were unchanged in HCHO exposed mice. Similarly, the percentage of T and B lymphocytes and their proliferative responses to mitogens were not significantly altered. Antibody (IgM) plaque-forming cell response following antigen challenge was unchanged. Macrophage function was normal although some evidence of enhanced H2O2 production associated with elevated bactericidal activity was observed in resident macrophages. Resistance to challenge with the bacteria Listeria monocytogenes was significantly enhanced, while resistance to tumor challenge remained unchanged. No evidence of immunosuppression following short-term exposure to HCHO was observed.

Benzene is a potent bone marrow toxin in animals and man. Animal studies have shown that exposure to benzene can alter T lymphocyte functions and decrease the resistance of animals to Listeria monocytogenes and transplanted tumor cells. Mononuclear phagocytes participate in host resistance to Listeria and tumor cells. The purpose of the studies presented here was to determine the effects of benzene and benzene metabolites on macrophage functions and the ability of macrophages to be activated for functions which are important in host defense. Benzene had no effects on macrophage function or activation for any of the functions tested. Conversely, metabolites of benzene, catechol (CAT), hydroquinone (HQ), benzquinone (BQ), and 1,2,4-benzenetriol (BT) had potent and varied effects on macrophage function and activation. BQ inhibited the broadest range of functions including release of H2O2, Fc receptor-mediated phagocytosis, interferon gamma priming for tumor cell cytolysis, and bacterial lipopolysaccharide (LPS) triggering of cytolysis. BQ was also the most potent metabolite causing inhibition at lower concentrations than the other metabolites. HQ inhibited H2O2 release and priming for cytolysis and BT inhibited phagocytosis and priming for cytolysis. CAT only inhibited the release of H2O2. None of the compounds tested inhibited the induction of class II histocompatibility antigens on the cell surface. All of the effects measured occurred using concentrations of compounds which did not disrupt the cell integrity or inhibit general functions such as protein synthesis. Taken together these data suggest that benzene metabolites alter macrophage function through several mechanisms including inhibition of output enzymes and disruption of signal transduction systems.