SAFE USE OF CHEMICALS: A Practical Guide - Chapter 10 pot

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.. Prolonged

and Nephrotoxicity

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 filtration 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

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:

therapeutic agents: analgesics, nonsteroidal anti-inflammatory 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 field 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, fitters 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

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

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 infiltration of mononu-clear cells, prominent interstitial fibrosis, and tubular atrophy A progressive fibrosis

of the interstitial tissue decreases the number of functional nephrons and also the rate of glomerular filtration 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 difficult to define because the diagnosis of early injury and the documentation of the cascade of secondary degenerative changes have not been adequately identified Instead, most chemically associated renal disease is only identified 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 financial burden to society.6 Indeed, there is some indication that chemical exposure could play a much greater influence 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 subsub-stances 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 Specific physiological characteristics are localized to specific 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

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 significantly 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 Bennett8 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-inflammatory agents Several chemical substances disturb the glomerular filtration rate (GFR) and related renal functions in animals and humans

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-specific receptor-like proteins seem to influence 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 specific high-affinity 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 fibrosis, 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

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 kidney11 with Pb remains a large environmental issue in North America because of its significant 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 insuffi-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 filtration 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 significant renal risk.5

Exposures to chemical substances such as carbon tetrachloride, 1,1-dichloroeth-ylene, paradichlorobenzene, ethylbenzene, monochlorobenzene, tetrachloroethyl-ene, tolutetrachloroethyl-ene, 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 filtering 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 significantly higher toxic actions in children and

on the developing central nervous system Similar is the global concern about metals like cobalt, lead, and mercury

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.