Toxicology and applied pharmacology
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Toxicol. Appl. Pharmacol. · May 2000
The spontaneously hypertensive rat as a model of human cardiovascular disease: evidence of exacerbated cardiopulmonary injury and oxidative stress from inhaled emission particulate matter.
Cardiovascular disease is considered a probable risk factor of particulate matter (PM)-related mortality and morbidity. It was hypothesized that rats with hereditary systemic hypertension and underlying cardiac disease would be more susceptible than healthy normotensive rats to pulmonary injury from inhaled residual oil fly ash (ROFA) PM. Eight spontaneously hypertensive (SH) and eight normotensive Wistar-Kyoto (WKY) rats (12-13 weeks old) were implanted with radiotelemetry transmitters on Day -10 for measurement of electrocardiographic (ECG) waveforms. ⋯ Thus, SH rats have underlying cardiac and pulmonary complications. When exposed to ROFA, SH rats exhibited exacerbated pulmonary injury, an attenuated antioxidant response, and acute depression in ST segment area of ECG, which is consistent with a greater susceptibility to adverse health effects of fugitive combustion PM. This study shows that the SH rat is a potentially useful model of genetically determined susceptibility with pulmonary and cardiovascular complications.
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Toxicol. Appl. Pharmacol. · Sep 1999
Increased serum and urinary concentrations of lung clara cell protein in rats acutely exposed to ozone.
Clara cell protein (CC16) is a 16-17-kDa protein secreted by Clara cells in the bronchial lining fluid of the lung from which it passively diffuses into serum before being eliminated by the kidneys. The concentration of CC16 in serum has recently been proposed as a peripheral marker of the integrity of Clara cells and/or of the bronchoalveolar/blood barrier. To evaluate the sensitivity of this new lung marker to acute epithelial damage induced by ozone (O(3)), CC16 was determined in the serum of rats after a single 3-h exposure to 0.3, 0.6, or 1 ppm O(3). ⋯ This effect was most likely responsible for the concomitant marked reduction of CC16 concentrations in BALF and lung homogenate, since the CC16 mRNA levels in the lungs were unchanged and the absolute amounts of CC16 leaking into serum or lost from the respiratory tract were similar. These changes were paralleled by an elevation of the urinary excretion of CC16 resulting from an overloading of the tubular reabsorption process. These results demonstrate that the assay of CC16 in serum and even in urine represents a new noninvasive test to detect the increased lung epithelial permeability induced by O(3).
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Toxicol. Appl. Pharmacol. · Jun 1999
Comparative StudyComparison of aldicarb and methamidophos neurotoxicity at different ages in the rat: behavioral and biochemical parameters.
Young organisms are often more sensitive to the toxic effects of pesticides, and this finding has spurred research on further characterization of this susceptibility. The neurotoxic effects of cholinesterase (ChE)-inhibiting pesticides are of particular concern for human health risk assessment due to the widespread exposure potential in children. This study evaluated age-related differences in susceptibility for a carbamate (aldicarb) and an organophosphorus pesticide (methamidophos). ⋯ Aldicarb-induced ChE inhibition was readily reversible in all age groups, whereas with methamidophos, enzyme activity recovered more rapidly in the young. Most behavioral alterations had recovered by 24 h with either pesticide. The results of these studies indicate that (1) ChE-inhibiting pesticides are not all the same regarding relative sensitivity of the young; (2) age-related differences were reflected in both the MTDs and degree of ChE inhibition; and (3) age-related differences in neurobehavioral measures depended on the pesticide and on the end points examined.
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Toxicol. Appl. Pharmacol. · Jan 1999
The mitochondrial permeability transition mediates both necrotic and apoptotic death of hepatocytes exposed to Br-A23187.
A23187 and related Ca2+ ionophores are widely used to study Ca2+-dependent cell injury. Here, using laser scanning confocal microscopy and parameter-indicating fluorophores, we investigated the role of the mitochondrial permeability transition (MPT) in Br-A23187 toxicity to cultured rat hepatocytes. After 10 microM Br-A23187, over 60% of hepatocytes lost viability within 1 h. ⋯ Acutely, the MPT causes mitochondrial uncoupling and profound ATP depletion, which leads to necrotic cell death. However, when glycolytic ATP generation is available, the MPT induces apoptosis. CsA blocks the MPT and prevents both necrotic and apoptotic cell killing after Br-A23187.
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Toxicol. Appl. Pharmacol. · Dec 1997
Comparative StudyPentachlorophenol dermal absorption and disposition from soil in swine: effects of occlusion and skin microorganism inhibition.
Residue of the environmentally relevant biocide pentachlorophenol (PCP) is found mainly in soil, making dermal contact one of the primary routes for PCP exposure. To quantify exposure effects on dermal absorption and systemic disposition, [14C-UL]PCP was dosed nonocclusively or occlusively at 40 micrograms/cm2 in a soil-based mixture in an in vivo swine model. Additionally, antibiotics were also codosed with occlusive PCP in soil to examine the impacts of skin microbial PCP biodegradation on total dermal absorption. ⋯ This study demonstrated significant dermal absorption and extensive tissue persistence of PCP after soil exposure. Occlusion and skin microflora growth may greatly impact dermal absorption, cutaneous disposition, and systemic toxic input. Therefore, exposure-specific PCP absorption and disposition profiles must be taken into consideration in risk analysis.