Ethylene dibromide: evidence of systemic and immunologic toxicity without impairment of in vivo host defenses.

Ethylene dibromide was administered intragastrically on 14 consecutive days to B6C3F1 female mice. Host resistance was not altered after challenge with B16F10 tumor cells, Listeria monocytogenes, influenza, or Herpes simplex viruses. In contrast, decreases were seen in relative thymus and spleen weights, red blood cells, hemoglobin, hematocrit, and in alveolar macrophage, natural killer cell, T-cell, and mixed lymphocyte culture responses. Increases occurred in relative kidney and liver weights, cholesterol, peripheral neutrophils, resident peritoneal exudate cells (with increased phagocytosis) and plaque-forming cells. There was little difference between the dose that caused immune modulation and that which produced significant toxicity.

Effects of inhaled hexachlorobenzene aerosols on rat pulmonary host defenses.

Pulmonary bactericidal activity, macrophage phagocytic activity, alveolar macrophage (AM) enzyme activity, and T- and B-cell mitogenesis of lymphocytes from lung associated lymph nodes (LALN) or mesenteric lymph nodes (MESLN) were assessed in Sprague-Dawley rats exposed 4 hr/d, 4 days/wk for 1, 4, or 16 days to hexachlorobenzene (HCB) aerosols. Pulmonary bactericidal activity was depressed after 1 or 4 but not 16 exposures to 35 mg/m3 of HCB. AM phagocytosis of 51Cr-RBC in vitro was increased after 4 but not 1 or 16 exposures to HCB, and no effect was observed in peritoneal macrophages. HCB significantly enhanced mitogenesis in MESLN to the B-cell mitogen Salmonella typhimurium lipopolysaccharide (STM) after 4 exposures; LALN STM mitogenesis and LALN and MESLN mitogenesis to phytohemagglutinin (PHA) were not affected. After 16 exposures, however, the PHA responses in LALN and MESLN were significantly increased and decreased, respectively.

Effects of inhalation of red phosphorus/butyl rubber combustion products on aveolar macrophage responses in rats.

The effects of inhalation of red phosphorus/butyl rubber (RP/BR) used as an obscurant smoke in tactical environments was examined. Sprague-Dawley male rats were exposed to 1000 mg/m3 of RP/BR for 3.5 h in single exposures, while in subsequent intermediate and subchronic studies the animals were exposed to concentrations ranging from 300 to 1200 mg/m3 for 2.25 h/day, 4 consecutive days/week for 4 and 13 weeks, respectively. Pulmonary bactericidal activity to inhaled [35S]-Klebsiella pneumoniae was depressed after the acute and the 13-week subchronic exposures but was unchanged after the 4-week exposures. The pulmonary free cells collected by lavage showed decreasing trends in total numbers, increased ATP levels and decreased ectoenzyme activity for 5'-nucleotidase after most of the exposures. Mild-to-moderate-to-severe terminal broncheolar fibrosis was observed in all rats after 4- and 13-week exposures to greater than or equal to 750 mg/m3 of RP/BR. The severity of the lesions increased with the severity of the exposure conditions. Except for the fibrosis, most changes were reversible.

Effects of arsenic trioxide inhalation exposure on pulmonary antibacterial defenses in mice.

The effects of single and multiple (5 and 20) 3-h inhalation exposures to aerosols of arsenic trioxide on the pulmonary defense system of mice were investigated. Arsenic trioxide mist was generated from an aqueous solution and dried to produce particulate aerosols of 0.4 micron mass median aerodynamic diameter. Aerosol mass concentration ranged from 125 to 1000 micrograms As/m3. Effects of the exposures were evaluated by determination of changes in susceptibility to experimentally induced streptococcal aerosol infection and in pulmonary bactericidal activity to 35S-labeled Klebsiella pneumoniae. Significant increases in mortality due to the infectious challenge and decreases in bactericidal activity were seen after single 3-h exposures to 270, 500, and 940 micrograms As/m3. Similarly, 5 or 20 multiple 3-h exposures to 500 micrograms As/m3 produced consistently significant increases in mortality and decreases in pulmonary bactericidal activity. At 125 or 250 micrograms As/m3, a decrease in bactericidal activity was seen only after 20 exposures to 250 micrograms/m3. Results from earlier studies with an arsenic-containing copper smelter dust were compared to these data. The possibility of the development of adaptation during multiple exposures to arsenic trioxide is also considered.

Effects of subchronic exposure to a mixture of O3, SO2, and (NH4)2SO4 on host defenses of mice.

Mice exposed 5 h/d, 5 d/wk up to 103 d, to 0.2 mg O3/m3 or to a mixture of O3, 13.2 mg SO2/m3, and 1.04 mg (NH4)2SO4 aerosol/m3 showed significantly greater susceptibility to group C streptococcal aerosol infection relative to filtered air controls. Pulmonary bactericidal activity by alveolar macrophages was significantly enhanced in the lungs of mice exposed to the mixture relative to those inhaling filtered air or O3 alone. The total number and distribution of the free cells lavaged from the lungs, as well as cellular ATP levels, did not change due to the pollutant exposures. In vitro cytostasis in tumor target cells cocultured with peritoneal macrophages from the exposed mice was significantly enhanced in the O3-exposed and in the mixture-exposed treatment groups relative to controls and also in the mixture-exposed relative to the O3-exposed group when a target-to-effector-cell ratio of 1:10 was used; no such effects were observed when this ratio was 1:20. Splenic T-lymphocyte function, as measured by blastogenesis to mitogens and alloantigens, was affected by exposure to O3 and/or the mixture, although the patterns of effects were qualitatively different. Splenic B-cell function and macrophage antigen processing, as measured by the generation of antibody plaque-forming cells, was unaffected by exposure.

The effect of diethylstilbestrol as measured by host resistance and tumor susceptibility assays in mice.

As part of a program to develop and validate methodology to measure chemically induced immunotoxicity, the effect of DES on resistance of adult B6C3F1 female mice to various microorganisms and to challenge with syngeneic tumor cells was evaluated. The mice received sc injections of 50 microliter corn oil alone or of corn oil containing the equivalent of 0.2, 1, and 4 mg DES/kg X d for 14 d. Three days later they were challenged with Listeria monocytogenes, Streptococcus sp. influenza virus, herpes virus, Trichinella spiralis, or B16-F10 tumor cells. Host resistance parameters were mortality for the bacterial and viral systems, expulsion of adult parasites from the gut for T. spiralis, and lung weights for the B16-F10 tumor-cell model. Host resistance to L. monocytogenes, herpes virus, and T. spiralis was significantly decreased following DES exposure. Resistance to Streptococcus sp. was decreased, but not at a statistically significant level following these doses of DES. However a dose of DES at 8 mg/kg X d resulted in a highly significant decrease in resistance to the organism. Resistance to influenza virus was unaffected by the DES. In contrast to the above, host resistance to iv-administered B16-F10 tumor cells was significantly increased as a consequence of DES exposure. These model systems for measuring alterations in host resistance have been indicated to hold potential for the routine screening of drugs, chemicals, and environmental agents for their possible immune effects, both adverse and potentiating. The results indicate the importance of selecting the appropriate assay for evaluating a particular agent. They also stress the necessity for including host resistance assays along with assays to measure specific immune aspects, in order to assess in the intact animal the overall effect of complex immune interactions following exposure to a test agent.