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

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-inammatory 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 inltration 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 difcult to dene because
the diagnosis of early injury and the documentation of the cascade of secondary
degenerative changes have not been adequately identied. Instead, most chemically
associated renal disease is only identied 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 inuence 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. Specic physiological
characteristics are localized to specic 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 signicantly 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-inammatory 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-specic receptor-like proteins seem to inuence 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 specic high-afnity 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 signicant 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 signicant 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 signicantly 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
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with exposure to chemicals. Environmental Health Criteria. IPCS, World Health Orga-
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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-
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2. Bennett, W. M. 1983. Aminoglycoside nephrotoxicity. Nephron 35: 73–77.
3. Bennett, W. M. 1985. Lead nephropathy. Kidney International 28: 212–220.
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© 2009 by Taylor & Francis Group, LLC