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

Toxicity to the nervous system is the primary concern
with chronic exposure to mercury vapor. Mercury
vapor induces characteristic CNS symptoms that are
consistent across patients exposed to mercury over short
or long periods. These symptoms include tremors (particularly
of the hands), emotional lability (irritability,
shyness, loss of confidence, and nervousness), insomnia,
memory loss, muscular atrophy, weakness, paresthesia,
and cognitive deficits. These symptoms intensify
and become irreversible, with increases in duration and
concentration of exposure. Other common symptoms of
chronic mercury exposure include tachycardia, labile
pulse, severe salivation, and gingivitis. Prolonged exposure
to mercury also causes kidney damage.
Inorganic Salts of Mercury. Ingestion of Hg 2+ salts is
intensely irritating to the GI tract, leading to vomiting,
diarrhea, and abdominal pain. The kidney is the primary
target of both valence states of inorganic mercury.
Acute exposure to mercury salts (typically in suicide
attempts) leads to tubular necrosis, resulting in
decreased urine output and often acute renal failure.
Chronic exposures also target the kidney, with glomerular
injury predominating.
Organic Mercury. The CNS is the primary target of
methyl mercury toxicity. Two incidents of high-dose
exposure to methyl mercury provide much of our
knowledge regarding methyl mercury poisoning. One
was in fishing villages surrounding the heavily polluted
Minamata Bay in Japan, and the other was in Iraq,
where grains treated with methyl mercury were accidentally
consumed. Symptoms of methyl mercury
exposure include visual disturbances, ataxia, paresthesia,
fatigue, hearing loss, slurring of speech, cognitive
deficits, muscle tremor, movement disorders, and, following
severe exposure, paralysis and death. The developing
nervous system exhibits increased sensitivity to
methyl mercury. Children exposed in utero can develop
severe symptoms, including mental retardation and
neuromuscular deficits, even in the absence of symptoms
in the mother. In adults, methyl mercury causes
focused lesions in specific areas of the brain, while the
brains of children exposed in utero sustain widespread
damage (Clarkson, 2002).
The effects of low-dose methyl mercury exposure from routine
consumption of fish are difficult to assess due to the opposing
beneficial effects of -3 fatty acids found in fish oils, and studies
have produced discrepant results (Grandjean et al., 1999; Myers
et al., 2003; Myers et al., 2007).
Treatment. With exposure to metallic mercury, termination of exposure
is critical and respiratory support may be required. Emesis may
be used within 30-60 minutes of exposure to inorganic mercury, provided
the patient is awake and alert and there is no corrosive injury.
Maintenance of electrolyte balance and fluids is important for patients
exposed to inorganic mercury. Chelation therapy is beneficial in
patients with acute inorganic or metallic mercury exposure. There are
limited treatment options for methyl mercury. Chelation therapy does
not provide clinical benefits, and several chelators potentiate the toxic
effects of methyl mercury (Rush, 2008). Nonabsorbed thiol resins may
be beneficial by preventing reabsorption of methyl mercury from the
GI tract.
Because of the conflicting effects of mercury and -3 fatty
acids, there is considerable controversy regarding the restriction of
fish intake in women of reproductive age and children. The EPA recommends
limiting fish intake to 12 oz (two meals) per week. Many
experts feel this recommendation is too conservative, and the FDA
is considering revising their recommendation to state that the benefits
of fish consumption outweigh the risks. The recommendation
that women consume fish that is lower in mercury content (i.e.,
canned light tuna, salmon, pollock, catfish) and avoid top predators,
such as swordfish, shark, and tilefish, is not controversial.
Arsenic
Arsenic is a metalloid that is common in rocks and soil.
Arsenic compounds have been used for >2400 years as
both therapeutic agents and poisons. In the late 19th
century, Robert Ehrlich coined the terms “magic bullet”
and “chemotherapy” to describe his work using the
organic arsenic compound arsphenamine for the treatment
of syphilis. The use of arsenic in drugs has been
mostly phased out, but arsenic trioxide (ATO) is still
used as an effective chemotherapy agent for acute
promyelocytic leukemia (see Chapter 63).
Exposure. The primary source of exposure to arsenic is through drinking
water. Arsenic naturally leaches out of soil and rocks into well
and spring water (Mead, 2005). Levels of arsenic in drinking water
average 2 μg/L (ppb) in the U.S. but can be >50 μg/L (five times the
EPA standard) in private well water, particularly in California,
Nevada, and Arizona. Drinking water from other parts of the world
where well water has been promoted to prevent waterborne illness,
particularly Taiwan, China, Argentina, Chile, Bangladesh, and eastern
India, sometimes is contaminated with much higher levels of
arsenic (sometimes several hundred micrograms per liter), and
widespread poisonings have resulted (Figure 67–8). Studies in
Bangladesh found that ~40% of water samples from across the country
were contaminated with >50 μg/L of arsenic, and some samples
had far higher levels (Mead, 2005; Chowdhury et al., 1999; BGS and
DPHE, 2001). Arsenic also can enter the environment through human
activities such as the use of arsenic-containing pesticides, mining,
and burning of coal. Food, particularly seafood, often is contaminated
with arsenic. Arsenic in seafood exists primarily as organic compounds
(i.e., arsenobetaine) that are much less toxic than inorganic
arsenic. The average daily human intake of arsenic is 10 μg/day,
almost exclusively from food and water.
Before 2003, >90% of arsenic used in the U.S. was as a
preservative in pressure-treated wood, but the lumber industry has
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CHAPTER 67
ENVIRONMENTAL TOXICOLOGY: CARCINOGENS AND HEAVY METALS