DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

but has very little or no benefit in chronically exposed individuals.
Exchange transfusion to restore blood cells and remove arsenic often
is warranted following arsine gas exposure (Ibrahim et al., 2006).
Cadmium
Cadmium was discovered in 1817 and first used industrially
in the mid-20th century. Cadmium is resistant to
corrosion and exhibits useful electrochemical properties,
which has led to its use in electroplating, galvanization,
plastics, paint pigments, and nickel-cadmium
batteries.
Exposure. In the general population, the primary source of exposure
to cadmium is through food, with an estimated average daily intake
of 50 μg/day. Cadmium also is found in tobacco; a cigarette contains
1-2 μg of cadmium (Jarup and Akesson, 2009). Workers in smelters
and other metal-processing industries can be exposed to high levels
of cadmium, particularly by inhalation.
Chemistry and Mode of Action. Cadmium exists as a divalent cation
and does not undergo oxidation-reduction reactions. There are no
covalent organometallic complexes of cadmium of toxicological significance.
The mechanism of cadmium toxicity is not fully understood.
Like lead and other divalent metals, cadmium can replace zinc
in zinc-finger domains of proteins and disrupt them. Through an
unknown mechanism, cadmium induces formation of reactive oxygen
species, resulting in lipid peroxidation and glutathione depletion.
Cadmium also upregulates inflammatory cytokines and may
disrupt the beneficial effects of nitric oxide.
Absorption, Distribution, and Excretion. Cadmium is not well
absorbed from the GI tract (1.5-5%) but is better absorbed via inhalation
(~10%). Cadmium primarily distributes first to the liver and later
the kidney, with those two organs accounting for 50% of the
absorbed dose. Cadmium distributes fairly evenly to other tissues,
but unlike other heavy metals, little cadmium crosses the blood-brain
barrier or the placenta. Cadmium primarily is excreted in the urine
and exhibits a t 1/2
of 10-30 years (ATSDR, 2008a).
Toxicity. Acute cadmium toxicity primarily is due to local irritation
along the absorption route. Inhaled cadmium causes respiratory tract
irritation with severe, early pneumonitis accompanied by chest pains,
nausea, dizziness, and diarrhea. Toxicity may progress to fatal pulmonary
edema. Ingested cadmium induces nausea, vomiting, salivation,
diarrhea, and abdominal cramps; the vomitus and diarrhea
often are bloody.
Symptoms of chronic cadmium toxicity vary by exposure route.
The lung is an important target of inhaled cadmium, while the kidney
is a major target of cadmium from both inhalation and ingestion.
Cadmium bound to metallothionein is transported to the kidney,
where it can be released. The initial toxic effect of cadmium on
the kidney is increased excretion of small-molecular-weight proteins,
especially 2
microglobulin and retinol-binding protein. Cadmium
also causes glomerular injury, with a resulting decrease in filtration.
Chronic occupational exposure to cadmium is associated with an
increased risk of renal failure and death. There is no evidence for a
threshold level for cadmium’s effects on the kidney; cadmium levels
consistent with normal dietary exposure can cause renal toxicity,
including a reduction in glomerular filtration rate and creatinine
clearance (Jarup and Akesson, 2009).
Workers with long-term inhalation exposure to cadmium
exhibit decreased lung function. Symptoms initially include bronchitis
and fibrosis of the lung, leading to emphysema. The exact
cause of cadmium-induced lung toxicity is not known but may result
from inhibition of the synthesis of 1
antitrypsin. Chronic obstructive
pulmonary disease causes increased mortality in cadmiumexposed
workers.
When accompanied by vitamin D deficiency, cadmium exposure
increases the risks for fractures and osteoporosis. This may be
an effect of cadmium interfering with calcium and phosphate regulation
due to its renal toxicity.
Carcinogenicity. Chronic occupational exposure to inhaled cadmium
increases the risk of developing lung cancer (IARC, 1993; NTP,
2004). The mechanism of cadmium carcinogenesis is not fully understood.
Cadmium causes chromosomal aberrations in exposed workers
and treated animals and human cells. It also increases mutations
and impairs DNA repair in human cells (NTP, 2004). Cadmium substitutes
for zinc in DNA repair proteins and polymerases and may
inhibit nucleotide excision repair, base excision repair, and the DNA
polymerase responsible for repairing single-strand breaks (Hartwig et
al., 2002). There is evidence that cadmium also alters cell signaling
pathways and disrupts cellular controls of proliferation (Waisberg et
al., 2003). Thus, cadmium acts as a non-genotoxic carcinogen.
Treatment. Treatment of cadmium poisoning is symptomatic.
Patients suffering from inhaled cadmium may require respiratory
support. Patients suffering from kidney failure due to cadmium poisoning
may require a transplant. There is no evidence for clinical
benefit from chelation therapy following cadmium poisoning, and
chelation therapy may result in adverse effects (ATSDR, 2008a).
Chromium
Chromium is an industrially important metal used in a
number of alloys, particularly stainless steel, which
contains at least 11% chromium. Chromium can be oxidized
to multiple valence states, with trivalent (Cr III )
and hexavalent chromium (Cr VI ) being the two forms
of biological importance. Chromium exists almost
exclusively as the trivalent form in nature, and Cr III is an
essential metal involved in the regulation of glucose
metabolism. Cr VI is thought to be responsible for the
toxic effects of chromium exposure (ATSDR, 2008b).
Exposure. Exposure to chromium in the general population primarily
is through the ingestion of food, although there also is exposure
from drinking water and air. Workers are exposed to chromium during
chromate production, stainless steel production and welding,
chromium plating, ferrochrome alloy and chrome pigment production,
and in tanning industries (Ashley et al., 2003). Exposure usually
is to a mixture of Cr III and Cr VI , except in chromium plating, which
usually uses Cr VI , and tanning, where Cr III is used.
Chemistry and Mode of Action. Chromium occurs in its metallic state
or in any valence state between divalent and hexavalent. Cr III is the
most stable and common form. Cr VI is corrosive and is readily
reduced to lower valence states. The primary reason for the different
toxicological properties of Cr III and Cr VI is thought to be differences
in their absorption and distribution. Hexavalent chromate resembles
1871
CHAPTER 67
ENVIRONMENTAL TOXICOLOGY: CARCINOGENS AND HEAVY METALS