185 10 Chemical Substances and Nephrotoxicity 10.1 INTRODUCTION Nephrotoxicity is a renal health disorder due to direct or indirect effects of chemi- cal substances. One of the most common kidney problems, nephrotoxicity has been traced to exposures to drugs and toxic chemical substances. The disorder eventu- ally causes kidney damage and disturbs the body functions and elimination of urine and wastes. Reports have indicated that prolonged periods of exposure to metals causes neurotoxicity among workers. Also, cadmium, other environmental heavy metals and the organometallic compounds used as therapeutic agents, anticancer drugs, cyclosporin, analgesic abuse, and antibiotics have been implicated in kidney disorder diseases. The kidney is the ltration mechanism for the blood. As is well known, the kidney has to perform three major functions to maintain normal health. It helps in removing wastes, prevents leakage of essential elements and chemical compounds from the body, and provides homeostasis. However, prolonged exposure to chemical substances causes adverse health effects and damage of the renal system in animals and humans—a health disorder termed nephrotoxicity. This disorder has been found among workers and members of the public exposed to toxic chemicals, and because of improper medication. The chemical substances that cause damage to the renal system are called nephrotoxins. Reports have indicated that the nephrotoxic effect of chemical substances, including drugs, has become more profound in workers and patients who have a history of renal impairment. Also, some drugs are known to affect renal function in more than one way. Chemical substances such as toxic met- als, organic compounds, and pesticides have caused global concern as nephrotoxi- cants. Prolonged occupational exposure to metals like cadmium, lead, and mercury has also caused renal disorders. 1–5 10.2 CHEMICAL SUBSTANCES AND RENAL INJURY It is well established that toxic nephropathies are not restricted to a single type of renal injury. Some chemicals target one discrete anatomical region of the kidney and may affect only one cell type. Chemical insult to the kidney may result in a spectrum of nephropathies that are indistinguishable from those that do not have a chemical etiology. Nephrotoxicity and neural disorders in animals and humans have occurred due to prolonged exposure to chemical substances. These may be broadly categorized as: © 2009 by Taylor & Francis Group, LLC 186 Safe Use of Chemicals: A Practical Guide therapeutic agents: analgesics, nonsteroidal anti-inammatory drugs (NSAIDs), antibiotics, aminoglycosides, cephalosporins, amphotericin B, tetracyclines, penicillamine, lithium, and anticancer drugs; chemical substances: ethylene glycol, organic chemicals and solvents, vola- tile hydrocarbons, chloroform, halogenated alkenes, bipyridyl herbicides, mycotoxins, and silicon; and metals: arsenic, bismuth, cadmium, chromium, germanium, gold, lead, mer- cury, and uranium. For purposes of users’ understanding, the chemical substances may be listed as follows: adhesives, agent orange, aspartame, ammonia, arsenic, benzene, carbonless copy paper, carbon monoxide, carpet cleaning agents, copper-chromium-arsenate, (CCA), chemical warfare agents, chlorine, combustion products, dioxin, drugs, formaldehyde, gamma butyrolactone, gasoline, glues, heavy metals, herbicides, lead, lithium, methyl diisocyanate (MDI), methyl-ethyl-ketone (MEK), manga- nese, mercury, metals, methylene chloride, mixed toxic waste, mold, municipal sludge, mycotoxins, naphthalene, n-hexane, oil and gas eld emissions, opiates, organic metals, paint, paint remover, Paxil, pentachlorophenol, pesticides (organo- chlorines, organophosphates, etc.), phenolic resins, polluted air, polychlorinated biphenyl (PCB), Prozac, psychiatric drugs (such as antidepressants, antipsychotics, tranquilizers, and sleep drugs), radiation injuries, solvents, styrene, toluene diisocya- nate (TDI), toluene, toxic waste, trichloroethane, trichloroethylene, welding fumes, wood preservatives, and xylene. 1 Thus, the commonest nephrotoxic chemicals are hydrocarbons—present, for instance, in organic solvents, glues, fuels, paints, and motor exhausts. Exposure is common among groups of workers such as painters, printers, cabinet makers, tters and mechanics, and electricians; in manufacturing; and in many other occupations. Hydrocarbon exposure through paint spraying may result in active proximal tubular damage, which may be reduced by improvement of protection at the worksite. However, renal impairment independent of tubular injury may result from chronic paint exposure, even with improved protection. 1a 10.3 SYMPTOMS OF NEPHROPATHY Nephrotoxic chemical substances cause adverse health effects. The vulnerability of kidney tubules and the nephrotoxic chemicals are known to be related to the nature of normal tubular function. The common symptoms of nephrotoxicity include memory disorders, concentration problems, slowed reaction time, sleep disorders, depression, confusion, personality changes, fatigue, numbness of the hands and feet, numer- ous neurological and psychiatric disorders, irrational behavior, and violent behavior. It has become increasingly evident during the last two decades that the kidney is adversely affected by prolonged periods of exposure to an array of environmental chemicals. Man is exposed to medicines, industrial and environmental chemicals, and a variety of naturally occurring substances. The level of exposure varies from minute quantities to very high concentrations. Exposure may be over a long period © 2009 by Taylor & Francis Group, LLC Chemical Substances and Nephrotoxicity 187 of time or limited to a single event, and it may be due to a single substance or several chemical substances. Lead and cadmium have been known to cause the kidney disorder chronic inter- stitial nephritis (CIN). Morphological studies indicate the inltration of mononu- clear cells, prominent interstitial brosis, and tubular atrophy. A progressive brosis of the interstitial tissue decreases the number of functional nephrons and also the rate of glomerular ltration and eventually leads to renal failure. Some of the chlo- rinated compounds—for instance, carbon tetrachloride and trichloroethylene—are also known to cause glomerular lesions leading to nephrotic syndrome and renal failure. Some chemical substances cause acute injury, while others produce chronic renal damage leading to end-stage renal failure and renal malignancies. The extent and cost of clinically relevant nephrotoxicity has only started to become apparent during the last decade. However, the full extent of the economic impact of chemically induced or associated nephropathy is difcult to dene because the diagnosis of early injury and the documentation of the cascade of secondary degenerative changes have not been adequately identied. Instead, most chemically associated renal disease is only identied as acute renal failure or chronic renal fail- ure at a very late stage, when therapeutic intervention is impossible. More importantly, at this stage the etiology may be obscured by lack of reli- able information on the likely causative agents, the levels and duration of exposure, and other possible contributing and exacerbating factors. At present, epidemiological evidence indicates that nephrotoxicity leading to acute and/or chronic renal failure represents a substantial nancial burden to society. 6 Indeed, there is some indication that chemical exposure could play a much greater inuence in the very high inci- dence of end-stage renal disease. Also, the nephropathies caused by chemical sub- stances are not restricted to a single type of renal injury. Some chemical substances target one discrete anatomical region of the kidney and may affect only one cell type, while it may be different with another chemical substance. Chemical insult to the kidney presents a wide spectrum of nephropathies that are indistinguishable from those that do not have a chemical etiology, and the dis- eases associated with exposure to chemical substances have remained unrecognized. Examples include the nephropathies caused by cadmium, other environmental heavy metals, the organometallic compounds used as therapeutic agents, anticancer drugs, cyclosporin, analgesic abuse, and antibiotics. The nephron and its related cells perform diverse physiological functions. It is the major organ of excretion and homeostasis for water-soluble molecules; because it is a metabolically active organ, it can concentrate certain substances actively. In addition, its cells have the potential to bioconvert chemicals and metabolically acti- vate a variety of compounds. There are a number of other processes described in the following that establish the potential for cellular injury. Specic physiological characteristics are localized to specic cell types. This makes them susceptible to, and the target for, chemicals. The effect of chemical substances on cells may be pharmacological, in which case the effect is dose related and occurs only as long as the concentration of the chemical substance is high enough to be active. Alternatively, the chemical substance © 2009 by Taylor & Francis Group, LLC 188 Safe Use of Chemicals: A Practical Guide may cause damage to the cell. The cell responds to injury by repair and the kidney responds to cellular lesion by renal and extrarenal adaptation to compensate for loss of that cell function. Although there is a substantial capacity within the kidney for repair, there are also several conditions where damage becomes completely irrevers- ible. In general, the proximal and distal tubules and urothelia can be repaired, but the glomeruli and medulla may have a signicantly lower repair facility. It is there- fore possible to initiate a series of degenerative changes as a result of interfering with one or more of the normal physiological processes. The array of industrial chemicals, negligence during use, and the long-term health consequences need to be understood by workers. The rational understanding of the mechanism of nephrotoxicity in animals and man provides the basis for safe use. Reports of Kluwe et al. 7 and Porter and Bennett 8 indicate the type of adverse health effects vis-à-vis nephrotoxicity caused by aminoglycosides, halogenated hydrocarbons and aromatic amines produce chronic kidney injury in humans and species of mammals. However, there is still a wide gap in the understanding of the nephrotoxic effects caused by certain therapeutic agents such as cyclosporin, analgesics, and nonsteroi- dal anti-inammatory agents. Several chemical substances disturb the glomerular ltration rate (GFR) and related renal functions in animals and humans. 10.4 METALS AND NEPHROTOXICITY It is well known that a large number of chemical substances, including toxic metals and metalloids such as arsenic, cadmium, lead, and mercury, cause cell injury in the kidney. With metal-induced neurotoxicity, factors such as metal-binding proteins, inclusion bodies, and cell-specic receptor-like proteins seem to inuence renal injury in animals and humans. It is of interest to note that certain renal cell popula- tions become the targets for metal toxicity, while others do not. In fact, the target cell populations handle the organic and common inorganic nephrotoxicants differently. 9 Lead is known for its toxicity in several organ systems in animals and humans (especially children). Acute exposure to lead causes nephropathy, which is charac- terized by proximal tubular dysfunction. The affected tubules show alterations in mitochondrial structure and the development of cytosolic and nuclear inclusion bod- ies. Intracellular lead is associated with specic high-afnity proteins and can also bind to metallothionein. In contrast to acute exposures, lead nephropathy caused by chronic exposure is irreversible. The kidney damage includes interstitial brosis, hyperplasia, glomerulonephritis, and atrophy of the tubules, leading to renal failure. Exposure to lead for long periods causes renal neoplasm in animals. Studies have shown that lead interacts with renal membranes and enzymes and disrupts energy production, calcium metabolism, glucose homeostasis, ion transport processes, and the renin-angiotensin system, as well as other health disorders. 10 Metals have been associated with the regulation of the heme biosynthetic pathway in the kidney. Acute and chronic exposures to high concentrations of lead cause disturbances to renal heme biosynthesis. Chronic exposure to methyl mercury results in increased urinary excretion of uro- and coproporphyrins in rats, mediated via inhibition of ferrochelatase. Acute © 2009 by Taylor & Francis Group, LLC Chemical Substances and Nephrotoxicity 189 treatment of laboratory rats with other metals such as nickel, platinum, tin, antimony, bismuth, and cobalt has caused induction of heme oxygenase, followed by decreased microsomal heme content. The stimulation in the kidney 11 with Pb remains a large environmental issue in North America because of its signicant hematological actions in children, although its renal actions may be of greater importance than previously thought, underlining the need for vigilance. Similarly, prolonged periods of exposure to diquat and paraquat have caused acute renal failure. 11a Long-term exposure to heavy metals and some halogenated hydrocarbons causes progressive degenerative changes in the kidney, possibly leading to renal insuf- ciency. The screening tests most widely used to assess the integrity of the kidney are the estimation of serum creatinine, blood urea nitrogen (BUN), and the quantitative or semiquantitative measurement of total proteinuria lack sensitivity. They do not permit the detection of renal disturbances at a stage when removal from exposure may prevent progression of the disease and are not suitable to determine the no-effect levels of potentially nephrotoxic chemicals. During the last decades, new markers have been proposed for the early detection of structural and/or functional changes at various sites of the renal parenchyma. Some tests mainly attempt to assess the integrity of the glomerulus, the proximal tubule, the loop of Henle, and distal tubule. Workers exposed to cadmium develop a persistent low proteinuria. This has been linked with the age-related decline of the glomerular ltration rate (GFR). The study of dose effects and response relationships based on a large battery of renal markers has allowed better determination of the internal dose of cadmium that is not associ- ated with signicant renal risk. 5 Exposures to chemical substances such as carbon tetrachloride, 1,1-dichloroeth- ylene, paradichlorobenzene, ethylbenzene, monochlorobenzene, tetrachloroethyl- ene, toluene, 1,1,2-trichloroethane, xylenes, cadmium, and lead are known to cause adverse effects on the kidney. The kidney is unusually susceptible because of its role in ltering harmful substances from the blood. Some of these toxicants cause acute injury to the kidney, while others produce chronic changes that can lead to end-stage renal failure or cancer. Furthermore, evaluation of the nephrotoxicity of complex industrial waste mixtures with organic chemicals and metals requires more studies. It has become increasingly apparent that a number of chemical substances cause adverse effects on one or more of the anatomical elements of the kidney. These include the glomerulus; proximal, intermediate, and distal tubules; and medullary, endothelial, and urothelial cells. While the proximal tubular cells have self-repairing ability, the same is not true with glomerular epithelium and the medullary interstitial cells. Reports have indicated that cadmium and lead cause renal tubular dysfunction in animals and humans. 12,13 Cell culture studies show that cadmium increases cell death. The preceding reports unequivocally suggest the need for greater vigilance to avoid exposure to these toxic metals by all and, especially, children. Awareness about metal toxicity and children’s health is very important because certain metals, like cadmium, are known to cause signicantly higher toxic actions in children and on the developing central nervous system. Similar is the global concern about metals like cobalt, lead, and mercury. © 2009 by Taylor & Francis Group, LLC 190 Safe Use of Chemicals: A Practical Guide REFERENCES 1. International Program on Chemical Safety (IPCS). 1991. Nephrotoxicity associated with exposure to chemicals. Environmental Health Criteria. IPCS, World Health Orga- nization, Geneva, Switzerland. 1a. Pai, P., Stevenson, A., Mason, H., and Bell, G. M. 1998. Occupational hydrocarbon exposure and nephrotoxicity: A cohort study and literature review. Postgraduate Medi- cal Journal 74: 225–228. 2. Bennett, W. M. 1983. Aminoglycoside nephrotoxicity. Nephron 35: 73–77. 3. Bennett, W. M. 1985. Lead nephropathy. Kidney International 28: 212–220. 4. Bennett, W. M. 1986. Drugs and renal disease. New York: Churchill Livingstone. 5. Lauwerys, R., Bernard, A., and Cardenas, A. 1992. Monitoring of early nephrotoxic effect on industrial chemicals. Toxicology Letters, Dec Spec (33–42): 64–65. 6. Nuyts, G. D., Elseviers, M. M, and De Broe, M. E. 1989. Health impact of renal disease due to nephrotoxicity. Toxicology Letters 46: 31–44. 7. Kluwe, W. M., Abdo, K. M., and Huff, J. 1984. Chronic kidney disease and organic chemical exposures: Evaluations of causal relationships in humans and experimental animals. Fundamental Applications in Toxicology 4: 889–901. 8. Porter, G. A., and Bennett, W. M. 1989. Drug-induced renal effects of cyclosporine, aminoglycoside antibiotics and lithium: Extrapolation of animal data to man. In Neph- rotoxicity: Extrapolation from in vitro to in vivo, and animals to man, ed. Bach, P. H. and Lock, E. A., 147–170. New York, London: Plenum Press. 9. Fowler, B. A. 1993. Mechanisms of kidney cell injury from metals. Environmental Health Perspectives 100: 57–63. 10. Nolan, C. V., and Shaikh, Z. A. 1992. Lead nephrotoxicity and associated disorders: Biochemical mechanisms. Toxicology 73(2): 127–146. 11. Oskarsson, A., and Fowler, B. A. 1987. Alterations in renal heme biosynthesis during metal nephrotoxicity. Annals of the New York Academy of Sciences 514(1): 268–277. 11a. World Health Organization. 1984. Paraquat and diquat. Environmental Health Criteria 39: 181. International Program on Chemical Safety. World Health Organization, Geneva. 12. Zalups, R. K., and Diamond, G. L. 2003. Heavy metals. In The toxicology of the kidney, ed. Tarloff, J. and Lash, L. London: Taylor & Francis. 13. Diamond, G. L., and Zalups, R. K. 1998. Understanding renal toxicity of heavy metals. Toxicology and Pathology 26: 92–103. © 2009 by Taylor & Francis Group, LLC . chemical substances. These may be broadly categorized as: © 2009 by Taylor & Francis Group, LLC 186 Safe Use of Chemicals: A Practical Guide therapeutic agents: analgesics, nonsteroidal anti-inammatory. LLC 188 Safe Use of Chemicals: A Practical Guide may cause damage to the cell. The cell responds to injury by repair and the kidney responds to cellular lesion by renal and extrarenal adaptation. for vigilance. Similarly, prolonged periods of exposure to diquat and paraquat have caused acute renal failure. 1 1a Long-term exposure to heavy metals and some halogenated hydrocarbons causes progressive