Toxicological sciences : an official journal of the Society of Toxicology
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Chlorine gas is considered a chemical threat agent that can cause acute lung injury. Studies in the early 20th century on war gases led Haber to postulate that the dose of an inhaled chemical expressed as the product of gas concentration and exposure time leads to a constant toxicological effect (Haber's Law). In the present work, mice were exposed to a constant dose of chlorine (100 ppm-h) delivered using different combinations of concentration and time (800 ppm/7.5 min, 400 ppm/15 min, 200 ppm/30 min, and 100 ppm/60 min). ⋯ Most parameters (pulmonary edema, neutrophil influx, and levels of protein, immunoglobulin M, and the chemokine KC [Cxcl1] in lavage fluid) indicated that lung injury was most pronounced for the 15-min exposure and least for the 60-min exposure. In contrast, changes in pulmonary function at baseline and in response to inhaled methacholine were similar following the three exposure regimens. The results indicate that the extent of lung injury following chlorine inhalation depends not only on total dose but also on the specifics of exposure concentration and time, and they suggest that evaluation of countermeasures against chlorine-induced lung injury should be performed using multiple types of exposure scenarios.
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Liver disease is responsible for more than 42,000 deaths yearly. Elevated hepatic iron levels have been shown to play a role in chronic liver diseases including hereditary hemochromatosis, thalassemia, and chronic hepatitis C, whereas acetaminophen (APAP) is the leading cause of acute liver failure. The goal of this study was to determine whether increased hepatic iron affects APAP-induced cytotoxicity, reactive oxygen species (ROS) production, and/or mitochondrial dysfunction in primary mouse hepatocytes (PMHs) that are differentiated and have gap junctional intracellular integrity, properties associated with hepatocytes in vivo and important for conducting toxicant studies. ⋯ In addition, treatment with the iron chelator deferoxamine (DFO) protected from APAP and resulted in a higher threshold dose being needed to induce cell death. We also showed that after TMHF treatment, APAP induced ROS and mitochondrial dysfunction at earlier time points than treatment with APAP alone; treatment with DFO increased the length of time required for APAP to induce ROS and mitochondrial dysfunction; and treatment with DFO, subsequent to TMHF, partially protected against TMHF-potentiated APAP injury. We conclude that iron potentiates the effects of APAP on cytotoxicity, ROS production, and mitochondrial dysfunction in PMHs.
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Oxidative stress and mitochondrial dysfunction play an important role in acetaminophen (APAP)-induced hepatocyte cell death. However, exact mechanisms involved in the process are controversial, in part, because of the disparity in findings between in vitro and in vivo studies. A major difference in this context is the oxygen tension, with cells in culture being exposed to 21% oxygen, whereas those in the liver experience a gradient from 3 to 9% oxygen. ⋯ Furthermore, dihydrorhodamine fluorescence was significantly attenuated at 10% oxygen. Cells cultured at 5% oxygen were also protected but showed evidence of hypoxia (accumulation of lactate and nuclear translocation of hypoxia-inducing factor-1α). These results suggest that oxygen tension can modulate hepatocyte responses to APAP, with low physiological levels (10%) decreasing mitochondrial oxidant stress and delaying hepatocyte cell death.
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Transparency and documentation of the decision process are at the core of a credible risk assessment and, in addition, are essential in the presentation of a weight of evidence (WoE)-based approach. Lack of confidence in the risk assessment process (as the basis for a risk management decision), beginning with evaluation of raw data and continuing through the risk decision process, is largely because of issues surrounding transparency. There is a critical need to implement greater transparency throughout the risk assessment process, and although doing so will not guarantee the correctness of the risk assessment or that all risk assessors come up with the same conclusions, it will provide essential information on how a particular conclusion or decision was made, thereby increasing confidence in the conclusions. ⋯ The committee concluded that transparency is inextricably linked to credibility: credibility of the data, credibility of the risk assessment process, and credibility of the resulting decision making. To increase this credibility, existing guidance concerning criteria elements of transparency related to the risk assessment process must be more widely disseminated and applied, and raw data for studies used in human health and environmental risk assessment must be more widely available. Finally, the decision-making process in risk management must be better documented and a guidance framework established for both the process itself and its communication to the public.