© 2002 by CRC Press LLC HALOGENATED HYDROCARBONS These molecules are likely to damage kidney tissue in the same manner in which they affect the liver. They are thought to be activated by cytochrome P 450 oxidases producing free radicals which can then attack cell organelles such as cell membranes. Halogenated hydrocarbons like chloroform may covalently bind renal tubular cell proteins and thereby disrupt the normal activity of those proteins. ANALGESICS Aspirin and phenacetin damage the medulla, the inner structure of the kidney where many of the loops and collecting ducts are located. They also affect the blood vessels, which may be the reason the medulla is secondarily affected. In other words, aspirin inhibits prostaglandin synthesis, thus reducing vasodilation with an eventual effect on kidney function. ASSESSMENT OF KIDNEY INJURY BY BIOCHEMICAL TESTING The kidney’s ability to filter blood depends primarily on the health of the nephron and, within the nephron, on the integrity of the glomerulus. Glomerular filtration, therefore, is the best index of filtering ability. The best measure of filtration, in turn, is clearance, i.e., the removal of waste chemicals from blood per unit time. Good renal function equals the ability to clear waste chemicals effectively from the blood. Clearance is expressed in units of milliliters per minute and equals the volume of blood that is cleared per minute. A normal result in humans is approximately 120 mL/min. Individuals with serious impairment may have clearances of only 20 mL/min or less. These figures are based on the clearance of creatinine, a waste product of muscle metabolism. Of various chemicals that have been tested as can - didates for determining the glomerular filtration rate, creatinine is regarded as the best chemical to measure. It is not perfect because some creatinine is transferred to the urine by tubular secretion and, therefore, it is not strictly accurate to regard all urinary creatinine as being due to glomerular filtration. Nevertheless, creatinine clearance is very close to an exact estimate of the true glomerular filtration rate. The formula for creatinine clearance is where: Urinary creatinine is in mg/dL.* Serum creatinine is in mg/dL.* Urine volume is in mL. * Any concentration unit is acceptable as long as it is the same for both urinary and serum creatinine. Creatinine clearance = urinary creatinine concentration urine volume serum creatinine collection time× ( ) × ( ) © 2002 by CRC Press LLC HALOGENATED HYDROCARBONS These molecules are likely to damage kidney tissue in the same manner in which they affect the liver. They are thought to be activated by cytochrome P 450 oxidases producing free radicals which can then attack cell organelles such as cell membranes. Halogenated hydrocarbons like chloroform may covalently bind renal tubular cell proteins and thereby disrupt the normal activity of those proteins. ANALGESICS Aspirin and phenacetin damage the medulla, the inner structure of the kidney where many of the loops and collecting ducts are located. They also affect the blood vessels, which may be the reason the medulla is secondarily affected. In other words, aspirin inhibits prostaglandin synthesis, thus reducing vasodilation with an eventual effect on kidney function. ASSESSMENT OF KIDNEY INJURY BY BIOCHEMICAL TESTING The kidney’s ability to filter blood depends primarily on the health of the nephron and, within the nephron, on the integrity of the glomerulus. Glomerular filtration, therefore, is the best index of filtering ability. The best measure of filtration, in turn, is clearance, i.e., the removal of waste chemicals from blood per unit time. Good renal function equals the ability to clear waste chemicals effectively from the blood. Clearance is expressed in units of milliliters per minute and equals the volume of blood that is cleared per minute. A normal result in humans is approximately 120 mL/min. Individuals with serious impairment may have clearances of only 20 mL/min or less. These figures are based on the clearance of creatinine, a waste product of muscle metabolism. Of various chemicals that have been tested as can - didates for determining the glomerular filtration rate, creatinine is regarded as the best chemical to measure. It is not perfect because some creatinine is transferred to the urine by tubular secretion and, therefore, it is not strictly accurate to regard all urinary creatinine as being due to glomerular filtration. Nevertheless, creatinine clearance is very close to an exact estimate of the true glomerular filtration rate. The formula for creatinine clearance is where: Urinary creatinine is in mg/dL.* Serum creatinine is in mg/dL.* Urine volume is in mL. * Any concentration unit is acceptable as long as it is the same for both urinary and serum creatinine. Creatinine clearance = urinary creatinine concentration urine volume serum creatinine collection time× ( ) × ( ) © 2002 by CRC Press LLC Cardiac Toxicity CONTENTS Conduction System Overall Cardiac Activity Cardiac Function and Toxicity: General Principles Biochemical Mechanisms Ionic Changes Energy Changes Membrane Changes Free Radical Formation Classification of Cardiotoxins Specific Cardiotoxins Catecholamines Cancer Chemotherapy Oxidative Stress Calcium Changes Energy Fluxes Alcohols Emetine Metals Carbon Monoxide Questions The cardiovascular system delivers oxygen and other nutrients to the 300 billion cells that make up the human body. It also removes waste materials to lungs, kidneys, and other destinations for disposal from the body. Other functions such as a role in neuroendocrine control are also part of its activities. In an approximate sense, it has two components: a hollow, muscular pump, the heart, and a system of large and small elastic vessels. Some knowledge of cardiac anatomy and physiology is needed to understand the nature of toxic activity by especially cardiotoxic chemicals. The heart is found between the lungs in the middle of the chest somewhat skewed (2/3) toward the left of the breastbone. The bottom left corner of the heart is tilted forward and comes close to the surface of the body. A normal heart weighs approximately 200 to 400 grams and equals two clenched fists in volume. Cardiac anatomy includes four chambers whose walls are composed of muscle, the myocardium. The chambers are separated from each other by structures called septa. Blood flows between the chambers through openings that are controlled by valves. 9 © 2002 by CRC Press LLC Neurological Toxicity CONTENTS Anatomy and Physiology of the Nervous System Cells in the Nervous System Neurons Glial Cells The Nervous System and Susceptibility to Toxins Protection for the Nervous System Manifestations of Neurotoxicity Specific Interference with Normal Neurological Activity Toxins and Electrical Conduction Toxins That Attack the Nerve Cell Body Toxins That Attack Myelin Toxins That Attack Axons Toxins That Attack Synaptic Function Acetylcholine Botulinum Toxin Nicotine Muscarine Curare Atropine Scopolamine Biogenic Amines GABA Glycine Tetanus Toxin Questions The nervous system is very vulnerable to many toxins because of its central and delicate role in the overall control of bodily activities. Within the nervous system a number of actions contribute to coordinated control. First, sensory organs evaluate the environment and relay the collected information to other parts of the nervous system. The motor system responds to external and internal stimuli. Integration of information is a third part of the nervous system’s activity and involves thinking, learning, and memory. 1 0 . radicals which can then attack cell organelles such as cell membranes. Halogenated hydrocarbons like chloroform may covalently bind renal tubular cell proteins and thereby disrupt the normal. serious impairment may have clearances of only 20 mL/min or less. These figures are based on the clearance of creatinine, a waste product of muscle metabolism. Of various chemicals that have been. radicals which can then attack cell organelles such as cell membranes. Halogenated hydrocarbons like chloroform may covalently bind renal tubular cell proteins and thereby disrupt the normal