Acceptability of Risk From Radiation - Human Spaceflight

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The toxin has induced production of reactive oxygen species (ROS). This has increased the permeability of the mitochondria and a chain reaction of peroxidation within the cell membrane. 58 Pathophysiology of Selected Mechanisms Figure 3–7 Mechanism of calcium-mediated cell death. A toxin interacts with a cell and disrupts calcium homeostasis. Calcium may enter through a calcium channel or calcium-sodium exchanger. The cell attempts to adapt by accumulating calcium in the mitochondria and endoplasmic reticulum.

The iron in the heme portion of the hemoglobin molecule is oxidized from the ferrous (Fe++) to the ferric (Fe+++) state. • Exposure to a toxin or drug causes oxidation of hemoglobin to form methemoglobin, which is called methemoglobinemia. (A) (B) Figure 2–2 The pathophysiology of methemoglobin formation. (A) A normal red blood cell can carry a large amount of oxygen. Each hemoglobin molecule may bind as many as four oxygen molecules. Note iron is in the ferrous (Fe++) state. (B) After exposure to an oxidizing toxin, the tertiary structure of hemoglobin is altered.

The renal system is susceptible to the effects of toxins because of • blood flow (20% to 25% of cardiac output) Clinical Presentation and Diagnosis of Common Veterinary Toxicants 43 • metabolic activity of cells of the renal system energy demands drug-metabolizing ability • large surface area of the glomerular endothelial cells • secretory function of the kidneys • reabsorption by the kidneys reabsorb 99% of water concentration of some toxins Mechanisms of Renal Intoxication GLOMERULAR DYSFUNCTION (ALTERATION IN FILTRATION) • Decreased renal blood flow due to renin-angiotensin system–stimulated vasoconstriction, as by nonsteroidal antiinflammatory drugs • Blockage of tubular lumen • casts • increased pressure within the lumen, which decreases the net flux of filtration across the glomerular capillary bed • examples myoglobin hemoglobin TUBULAR DYSFUNCTION • Direct cytotoxicity • toxin may damage the tubular epithelial cells • Examples • amphotericin B • aminoglycosides Tests of Renal Function CLINICAL LABORATORY • Blood urea nitrogen • indicator of damage to renal tissue • occurs only after substantial nephron loss (>70%) • Serum creatinine also an indicator of renal damage 44 Clinical Presentation and Diagnosis of Common Veterinary Toxicants • Urinalysis • elevated sodium concentration • glycosuria • proteinuria • urine casts • enzymuria alkaline phosphatase lactate dehydrogenase CLEARANCE • Estimate of glomerular function (Figure 2–4) • Inulin • filtered by glomerulus • not bound by proteins • Creatinine • endogenous by-product of protein metabolism • not as accurate as inulin Clinical Presentation • Acute renal failure • nausea • vomiting • azotemia • dehydration • polyuria • bleeding in gastrointestinal tract • Chronic renal failure Cx = urine concentration (mg / mL) * urine volume (mL / min) plasma concentration (mg / mL) Figure 2–4 Clearance equation.

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