摘要:

Although there is an increasing awareness that drugs and chemicals can modulate the immune system by indirect mechanisms, few compounds have been thoroughly evaluated in this regard. Several environmentally relevant chemicals induce stresslike responses, as indicated by elevated glucocorticoid levels. Comparable glucocorticoid levels induced by physical or psychological stressors are consistently associated with suppression of one or more immunological parameters. Thus, it seems likely that stress‐related neuroendocrine mechanisms are important in immunosuppression by some environmental chemicals. Distinguishing direct and indirect (stress‐related) mechanisms of immunosuppression is generally possible, and this could be done as a routine part of immunotoxicity assessment. Although it is clear that glucocorticoids can contribute to such immunosuppression, it is also clear that several other neuroendocrine mediators associated with stress responses can be immunomodulatory. Thus, correlation between glucocorticoid levels and immunosuppression does not conclusively demonstrate a cause‐effect relationship. Demonstrating such relationships has been difficult, but it has been done in a few cases of drug‐induced thymic hypoplasia by monitoring several parameters known to be affected by glucocorticoids and by measuring the ability of a glucocorticoid antagonist (RU 486) or adrenalectomy to block changes in these parameters. A similar strategy might be useful for evaluation of the role of glucocorticoids in drug‐ or chemical‐induced suppression of a variety of immune functions, but the effects of RU 486 on neuroendocrine feedback circuits and the possibility of consequent immunological changes must be considered when the data are interpreted. This approach could also be applied to evaluation of the roles in chemical‐induced immunosuppression of other neuroendocrine mediators for which antagonists or agents that block the synthesis or release of the mediator are available. However, it is likely that a comprehensive (and perhaps predictive) understanding of the relationship between chemically induced stress responses and immunosuppression will require more detailed and quantitative elucidation of the mechanisms and regulation of neuroendocrine‐immune interactions.

ISSN:0098-4108    

DOI:10.1080/15287399309531744

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

Reactive oxygens are considered to be one of the mediators involved in inflammation. We investigated the constrictive effects of reactive oxygens generated by aerosolized xanthine/xanthine oxidase (XOD) on the airways of anesthetized guinea pigs. Airway resistance was measured with a modified Konzett‐Rössler method and expressed as a change in ventilation overflow (VO). Inhalation ofxanthine (1.0 M)/XOD (10, 15 U/ml) caused a significant increase in VO. This airway constriction tended to be enhanced by pretreatment with inhaled superoxide dismutase, but was suppressed by inhaled catalase. Inhalation of hydrogen peroxide caused an airway constriction in a concentration‐dependent manner (0.1–2.0 M). Xanthine/XOD significantly enhanced the maximal change in VO after inducing airway inflammation by SO2exposure. The pretreatment with inhalation of xanthine/XOD did not affect the airway constriction induced by inhaled histamine. However, in SO2‐exposed guinea pigs, the inhalation of xanthine/XOD significantly increased the sensitivity to histamine. These results indicate that hydrogen peroxide and other reactive oxygen intermediates produced by xanthine/XOD may cause an airway constriction and airway hyperresponsiveness.

ISSN:0098-4108    

DOI:10.1080/15287399309531745

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

The goal of this study was to determine whether chronic monoxide exposure in the developing heart produces long‐lasting coronary vasculature alterations. One‐day‐old male rat pups were exposed to 500 ppm CO continuously for 30 d, while littermate controls remained in room air (AIR). At 61 and 110 d of age hearts were removed, perfusion fixed, x‐rayed, and processed for analysis of coronary vessel architecture. Body weight (BW) and heart weight (HW) increased with age; the ratio of HW/BW decreased. There were no differences in HW and ventricular dimensions at either age due to prior CO exposure. Morphometric analysis of the fixed hearts from CO‐exposed and AIR rats revealed no significant individual group differences in the number of small (27–114 μm) or larger (>114 μm) vessels in any heart region. The septum (S) in CO rats was an exception: There were more small veins at 67 d of age and more larger veins at 110 d of age. There was a significant increase in the number of small arteries at both ages in the CO rats across all heart regions, and in the smaller veins at 61 d of age. The large vessels in the S at 61 d of age had a significantly greater diameter in CO compared to AIR rats. This was also true for the large arteries in the S and right ventricle (RV) of the 110‐d‐old rats. Taking all heart regions together, the large arteries in CO rats were larger than in AIR rats. Previous CO exposure significantly increased large artery and total cross‐sectional area in the S and RV at 61 d of age, and in RV at 110 d of age. Total cross‐sectional area of veins in the S was also increased. Taking all heart regions together, CO significantly increased small, artery cross‐sectional area at 61 d of age, and small, large, and total artery cross‐sectional area at 110 d of age. With one exception (small veins, 110 d of age), there was no effect of CO on vein cross‐sectional area. These changes resulted in the percentage of total cross‐sectional area contributed by the larger vessels being increased. Pathological examination showed nothing abnormal. The results suggest profound and persistent changes in coronary vessel architecture following chronic neonatal CO exposure.

ISSN:0098-4108    

DOI:10.1080/15287399309531746

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

The absorption, disposition, and metabolism of [14C]thiophene was investigated in rats following nose‐only inhalation exposure at 8000 ppm for 1 h. Under these exposure conditions, it was estimated that approximately 16.3% (493 μmol) of the inhaled thiophene was absorbed from the respiratory system. Within 72 h following exposure, a total of 488 μmol of thiophene equivalents (99% of that retained) was excreted, of which 360.4 μmol (73.9% of the total excreted radioactivity) was in expired air, 120.7 μmol (24.8%) was in urine, 3 μmol (0.6%) was in feces, and 3.7 μmol (0.8%) was in the cage wash. Excretion took place primarily within the first 8 h, during which 91% of the total radioactivity excreted was collected. The thiophene equivalents remaining in tissues at 72 h were estimated to total 5.1 μmol (1.0% of the retained radioactivity). Exhaled radioactivity was identified as thiophene. No14CO2was detected in the expired air. After 1 h following exposure, the elimination of thiophene equivalents from plasma was monophasic, with a half‐time of 3.6 h. The elimination of thiophene equivalents from blood cells was biphasic, with half‐times of 2.9 h and 9.1 d. The blood cells/plasma concentration ratios of thiophene equivalents ranged from 3 to 13, with the higher ratio observed at the 12‐h time interval. At 72 h after exposure, blood cells contained the highest concentration of thiophene equivalents, approximately fourfold higher than that of the liver, which contained the second highest concentration. Kidney, heart, and lung contained similar but lower concentrations than liver, while brain, fat, and skeletal muscles contained the lowest concentrations. In summary, this study demonstrates that thiophene was absorbed from the respiratory system, and the majority of the absorbed thiophene was eliminated unchanged in the exhaled air, while a smaller fraction was metabolized and eliminated in urine.

ISSN:0098-4108    

DOI:10.1080/15287399309531747

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

The teratogenicity of combined exposure to noise and cadmium was studied in mice. ICR mice were exposed to a wide octave‐band of noise at 100 dB(C) for 6 h on d 7 of pregnancy in one of two ways: continuous exposure or intermittent (15 min on/15 min off). Cadmium sulfate at 1 or 2 mg/kg was intraperitoneally injected on d 7 of pregnancy. Four groups were exposed to both cadmium and noise. On d 18 of pregnancy, fetuses were examined for external and skeletal malformations. Another experiment was performed with two other patterns of noise exposure: continuous exposure for 3 h, and intermittent exposure (5 min on/5 min off) for 6 h on d 7 of pregnancy.

ISSN:0098-4108    

DOI:10.1080/15287399309531748

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

Acute exposure to diisopropyl fluorophosphate (DFP) causes irreversible inhibition of acetylcholinesterase activity, leading to various behavioral and autonomic sequelae including hypothermia, reduced motor activity, and other neurological dysfunctions. To characterize the acute response and recovery of autonomic and behavioral processes to DFP exposure, rats of the Long‐Evans strain were implanted with radiotrans‐mitters that allowed the monitoring of core temperature, heart rate, and motor activity in unrestrained animals 24 h/d. These parameters were monitored for 96 h following subcutaneous injection of DFP at a dose of 0, 0.1, or 1.0 mg/kg. Rats given 0 and 0.1 mg/kg DFP displayed an increase in core temperature and motor activity during the first 24 h postinjection. The 1.0 mg/kg group showed a typical hypothermic response for the first 24 h following DFP administration. Core temperature decreased a maximum of 1.9°C by 5 h after DFP and then started to recover, reaching control levels by 17 h after DFP treatment Motor activity was also depressed during the first 24‐h period in the 1.0 mg/kg group. Heart rate was initially elevated above basal levels in all treatment groups for several hours after treatment, but the 1.0 mg/kg group showed a decrease in heart rate at the time when core temperature began its recovery from hypothermia. Core temperature was the only parameter significantly affected by DFP during the 24–96 h recovery phase. The 0.1 and 1.0 mg/kg groups showed a significant elevation in core temperature for the 3 d after DFP administration. The elevation in core temperature during the recovery from DFP treatment may represent an important facet of the acute cholinergic neurotoxicity of organophosphate compounds.

ISSN:0098-4108    

DOI:10.1080/15287399309531749

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

We investigated the concentration and time dependency of the effects of exposure to sulfuric acid (H2SO4) aerosol on airway responsiveness. Two hundred and sixteen male Hartley guinea pigs were used. The animals were divided into 3 groups (n ‐72/group), with 1 group being exposed to filtered air and the other 2 to 1.0 mg/m3or 3.2 mg/m3H2SO4aerosol. In each group, the animals were divided into 4 subgroups (n— 18/subgroup), with exposure terms of 3 d (24 h/d), 7 d, 14 d, and 30 d. Specific airway resistance (SRaw) under room air (SRaw0) and airway responsiveness were determined 1 wk before the beginning of exposure and on the day of termination of the exposure. Specific airway resistance values under room air (SRawr0) prior to and after exposure were compared. There was no significant change in SRaw0after the exposure to filtered air, 1.0 mg/m3, or 3.2 mg/m3H2SO4aerosol. Our results also showed that exposure to filtered air or 1 mg/m3H2SO4aerosol did not cause any significant change in airway responsiveness to inhaled histamine aerosol, expressed as the effective concentration of histamine (EC200His) that produced a doubling of SRawNaCl(SRaw after exposure to aerosol of 0.9% NaCI saline). On the contrary, exposure to 3.2 mg/m3H2SO4aerosol induced transient airway hyporesponsiveness after a 3‐d exposure [EC200His prior to and after exposure: 1.35 ± 0.28 and 2.23 ± 0.22 mM (p < .01), respectively] and then transient hyperresponsiveness after a 14‐d exposure [EC200His prior to and after exposure: 1.65 ± 0.27 and 0.95 ± 0.23 mM (p < .01), respectively]. Overall, the present results revealed that (1) 1.0 mg/m3or 3.2 mg/m3H2SO4aerosol had no significant effect on SRaw0during a 30‐d exposure period, (2) a high concentration (3.2 mg/m3) of H2SO4aerosol affected airway responsiveness during the 30‐d exposure, while a low concentration (1.0 mg/m3) of H2SO4aerosol did not, and (3) the effect of exposure to 3.2 mg/m3H2SO4aerosol on airway responsiveness was transient and stimulatory or inhibitory, depending on the duration of exposure.

ISSN:0098-4108    

DOI:10.1080/15287399309531750

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

Exposure to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) has been shown to decrease serum complement C3 levels in female B6C3F1 mice but failed to alter C3 production when added in vitro to either hepatoma cells (both human and mouse hepatoma cells) or mouse primary hepatocytes (Lin and White, 1993a). It has also been demonstrated that mouse liver intracellular C3 levels were not affected following TCDD exposure in vivo, while serum C3 levels were suppressed (Lin and White, 1993b). Therefore, further studies were undertaken to investigate the mechanism by which TCDD modulates newly synthesized serum C3 in vivo. Mouse serum C3 was depleted by an intravenous injection of 50 anti‐complement units (ACU)/kg cobra venom factor (CVF). This dose of CVF depleted serum C3 levels to 9% of control at 24 h after treatment. Subsequently, serum C3 levels returned to 19% and 75% of the control level on d 3 and d 5. The recovery of serum C3 was then monitored following an acute oral exposure to 20 μg/kg TCDD. In mice exposed to both TCDD and CVF, serum C3 levels reached 15% and 69% of control on d 3 and d 5 after treatment; these results were not significantly different from those of mice treated with CVF alone. Furthermore, when the radiolabeled amino acid [3H]leucine was injected intravenously into either vehicle‐ or TCDD‐treated mice, the incorporation of this labeled precursor into both C3 and other secreted plasma proteins was not inhibited by TCDD. These results demonstrated that TCDD did not decrease newly synthesized C3 in vivo. These studies provide additional support for the concept that TCDD does not act directly on hepatocytes to suppress C3 production. The lower serum C3 levels observed in vivo following TCDD exposure is not the result of a decrease in C3 production by hepatocytes.

ISSN:0098-4108    

DOI:10.1080/15287399309531751

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

摘要:

Two inhalation‐chamber studies were conducted to assess acute (2‐h out‐of‐chamber) and subacute (≤ 6 d postexposure) spontaneous activity effects of whole‐body phosphoric acids aerosol exposure(s) in black‐tailed prairie dogs (Cynomys ludovicianus) and rock doves (Columba livia). The aerosol was generated using a red phosphorus/ butyl rubber (RP/BR) mixture under development as a military obscurant. Each study involved (1) 3 RP/BR target concentration groups [0.0 (controls), 1.0, and 4.0 mg/L], (2) 24 prairie dogs or rock doves (8/group), with gender included as a factor, (3) a successive 3‐phase paradigm (2 d preexposure; 4 and 2 d of about 80 min/d exposures to RP/BR for prairie dogs and rock doves, respectively; and 6 d postexposure), and (4) infrared detection of the rodents'/birds’ home‐cage movements. In‐chamber atmospheres were uniform and acceptable for all exposures; median aerosol mass concentrations ranged from 0.76 to 0.89 mg/L and 3.46 to 3.74 mg/L for the 1.0 and 4.0 mg/L groups, respectively, with median phosphoric acid (H3PO4) readings of between 67.2 and 74.3%; median particles were ≤ 0.85 μm. Mortality was negligible; no prairie dogs died, but 1 male rock dove died on d 3 postexposure to two 4.0 mg/L target concentrations of RP/BR aerosol. Croup × session interactions were significant for the acute activity counts of both species. The acute mean ambulatory (e.g., walking) counts of prairie dogs and the acute mean ambulatory and horizontal (e.g., preening) counts of rock doves exposed to 4.0 mg/L RP/BR aerosol were relatively less than those of the other groups after the first 2 or 1 exposures, respectively. Nevertheless, acute session means for all groups approximated or exceeded the 23 h/d activity measured during the pre‐ and postexposure phases—data indicating that chamber confinement caused a temporary, sharp increase in activity for both species irrespective of RP/BR aerosol concentrations. No RP/BR concentration‐related, subacute shifts in the activity of the rodents/birds were observed.

ISSN:0098-4108    

DOI:10.1080/15287399309531752

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287399309531743

出版商:Taylor & Francis Group    

年代:1993

数据来源: Taylor