Role of time as a factor in the toxicity of chemical compounds in intermittent and continuous exposures. Part II. Effects of intermittent exposure.
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Biomedical subjects
Publications and source records attributed to D L Coffin.
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The concentration of NO2 in polluted atmosphere is subject to wide variation, according to peak traffic load, industrial productivity, intensity of sunlight and meteorological conditions. Normally NO2 has a low basal concentration with superimposed spikes when the above conditions are optimal for its production. Thus, it is important to determine the relative importance of a short-term, relatively high concentration of NO2 versus exposure for longer periods of minimal dose levels. This problem was approached experimentally by measuring the effect of NO2 on an animal's resistance to the induction of bacterial pneumonia. The data collected indicate that: (1) in short-term dose-response studies using the same Ct (concentration x time) product of 7, the actual concentration exerts a greater influence on NO2 effect than does the duration of exposure; (2) when concentration is held constant and the time increased, the average difference in mortality from controls can be seen after only 1 hr exposure to 3.5 ppm and after 3 weeks of exposure to 0.5 ppm; and (3) the relative mean survival time at 3.5 ppm for 1 hr was 18--36 hr less than that of the control animals.
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The effect of inhalation of sulfuric acid (H2SO4) aerosol on respiratory deposition of radiolabeled streptococcus aerosol was investigated in guinea pigs. A 60 minute exposure to 3020 mugm/m3 H2SO4 (1.8 mum CMD) resulted in a 60% greater total respiratory deposition rate than control animals and a proximal shift in the regional pattern of deposition to the nasopharynx. Dose-response experiments revelaed that a concentration of 30 mugm/m3 H2SO4 (0.25 mum CMD) also induced a proximal shift in the regional pattern of particle deposition but in this instance the shift was to the trachea. The interrelationship between mass concentration of H2SO4 and its particle size to the interpretation of these results is discussed. A hypothesis concerning the relationship of these data to previously reported respiratory physiologic effects of H2SO4 inhalation and to a pathophysiologic mechanism which may underlie effects attributed to sulfur oxides by epidemiologic studies is described.
Experiments were performed to measure the effect of trace metals on a vital function of the alveolar macrophage (AM), phagocytosis. Since certain trace metals were found to reduce the viability of AMs, a technique was developed to permit examination of live cells only for phagocytosis. Evidence is presented that Ni(2+) selectively altered the phagocytic activity of AMs at concentrations lower than those which caused cell death. It is further shown that a level of VO(3) (-) that caused extensive lysis and death did not reduce phagocytosis in surviving cells. The effects of Cd(2+), Cr(3+), and Mn(2+) on AMs were also examined.
Mice immunized intraperitoneally with sheep erythrocytes were treated with nickel chloride, a common particulate air pollutant. Primary antibody production in the spleen was examined using a hemolytic plaque technique. A negative linear dose-response relationship (p is less than 0.05) was observed between the logarithm of (plaques/10(6) cells) and the nickel concentration administered. Mice injected with 3.09 mug Ni2+/g body weight displayed lymphocyte function similar to that of control mice. However, injection of 9.26-12.34 mug Ni2+/g caused significant immunosupression (p is less than 0.05).
The acute toxicity of tetravalent platinum was studied in vitro by use of rabbit alveolar macrophages and human lung fibroblasts (strain WI-38). Alveolar macrophages were exposed in tissue culture for 20 hr to platinum dioxide (PtO2) or platinum tetrachloride (PtCl4). There was no evidence of dissolution of PtO2 and no decrease in viable cells at concentrations as high as 500 mug/ml. PtCl4 was soluble in the macrophage system and after a 20-hr exposure, resulted in loss of viability in 50% of the cells originally present at a concentration of 0.30mM (59 mug Pt/ml). After a 20-hr exposure, rapidly growing human lung fibroblasts were rendered nonviable by PtCl4 at comparable concentrations. A decrease in total cellular ATP was observed at lower concentrations in macrophages and fibroblasts along with a reduction in phagocytic activity of macrophages as compared to controls. With the fibroblasts, a 50% decrease in incorporation of 14C-thymidine was observed after a 22-hr exposure to PtCl4 at a concentration of 0.007mM; higher concentrations were required to inhibit the incorporation of 14C-uridine and 14C-leucine. Time-course studies indicated that the inhibition of 14C-thymidine incorporation was nearly complete (90%) after 7 hr in the presence of 0.06mM PtCl4. Under the same conditions, there was little inhibition (15%) of 14C-leucine incorporation and moderate inhibition (50%) of 14C-uridine incorporation. Higher concentrations of PtCl4 were required to inhibit 14C-thymidine incorporation into the acid-soluble fraction than were required to inhibit incorporation into the acid-precipitable fraction. Hence, the preferential inhibition of DNA synthesis by PtCl4 may result from an impairment of the incorporation process.
For environmental inhalation studies a motorized exercise wheel was designed for small laboratory animals. Mice or hamsters were separated in individual enclosures, and each animal was required to perform the same exercise. The wheel was driven by a common barbecue spit motor, the speed of which may be varied by a standard variable transformer, from 1-6 revolutions per min. This unit can be adapted for a variety of laboratory applications.
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Phagocytosis is a two-step process involving attachment and ingestion of particulate material. It is often difficult to determine under a light microscope whether the particles are actually ingested or are merely attached to the cell. A more accurate, easy to perform technique with the use of xylene has been developed for determining the difference between the attachment and ingestion of polystyrene latex spheres. The xylene treatment dissolves the extracellular spheres, leaving only the intracellular spheres to be counted by the experimenter to obtain a more accurate phagocytic index. This technique also allows an investigator to get an ingestion index, an attachment index, or both.
Beagle dogs exposed for 8 hours a day to 3 ppm O(3) for 18 months showed cytologic changes that indicate metabolic alterations. The endoplasmic reticulum of the type 2 alveolar epithelial cells in the proximal alveoli were frequently dilated and contained a moderately electron-dense substance having a periodicity of approximately 754 A. This condition was accompanied by a substantial reduction in the lamellar membranes in the characteristic lamellar bodies of the type 2 cells, suggesting a sequestering of protein in the endoplasmic reticulum. In addition, endothelial cells contained paracrystalline arrays of cytoplasmic membranes not observed in control animals.
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