Toxic effect of nitrate and nitrite
on the blood
• Nitrate and nitrite are compounds
that contain a nitrogen atom joined
to oxygen atoms.
• In nature, nitrates are readily
converted to nitrites and vice versa.
(NO3 / NO2)
• Drugs: Amyl, butyl, Isobutyl nitrite
(recreational drugs)
Uses
• Nitrate is used in the treatment of myocardial ischemia.
• Nitrates are used primarily to make fertilizer, heavily
used in farming communities to grow vegetable crops.
• They are also used to make glass and explosives.
• These compounds also are used in various chemical
production and separation processes.
• Nitrites are manufactured mainly for use as a food
preservative(meat preservatives). both nitrates and
nitrites are used extensively to enhance the color and
extend the shelf life of processed meats.
Exposure to nitrate
• The main exposure route to
nitrates is by eating vegetables
and preserved meats.
• Vegetables account for more than
70% of the nitrates in a typical
human diet. Cauliflower, broccoli,
spinach and root vegetables
(potatoes, beets, turnips, etc)
contain higher amounts of nitrates
than other plant foods.
• About 6% of the exposure
comes from meat and meat
products.
• The remainder of the nitrate in
a typical diet comes from
drinking nitrate-contaminated
water (about 21%).
• In agricultural (farming) areas,
nitrates are a major source of
contamination for shallow
ground water aquifers that
provide drinking water.
The risk of nitrate depend on
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The route of exposure (eating or drinking)
The dose.
The duration.
The frequency.
General Health, Age, Lifestyle Young children,
the elderly and people with chronic (on-going)
health problems are more at risk to chemical
exposure
The risk of nitrate depend on
• Diets low in vitamin C
• People with reduced stomach acidity, such as
those being treated for ulcers Gastroenteritis, an
inflammation of the stomach and intestines (gut)
• Diets high in preserved meats such as bacon or
sausage
• Cancer patients with compromised hemoglobin
• Smoking, drinking alcohol or taking certain
medicines or drugs
Mechanism of toxicity
• Their common mechanism is the release of
nitric oxide (NO), which lead to excessive
vasodilatation.
• The majority of nitrates, such as nitroglycerine
(NTG) or isosorbide-5-dinitrate (ISDN),
additionally stimulate production of reactive
oxygen species (ROS).
• This may counteract the beneficial effects of
NO on the endothelium.
Mechanism of toxicity
• Nitrates themselves are relatively nontoxic.
However, when swallowed, they are converted to
nitrites that can react with hemoglobin in the
blood, oxidizing its divalent iron to the trivalent
form and creating methemoglobin. This
methemoglobin cannot bind oxygen,which
decreases the capacity of the blood to transport
oxygen so less oxygen is transported from the
lungs to the body tissues, thus causing a
condition known as methemoglobinemia often
called “blue baby syndrome”.
Normal levels of nitrate and nitrite
• The environmental protection agency(EPA) primary
drinking water standards for nitrate and nitrite are
10 and 1 parts per million (ppm), respectively.
• The Food and Drug Administration allows these
compounds to be used as food additives as long as
they are of food grade and are added only in the
amount needed. The maximum amount of nitrite
allowed in smoked and cured fish and meat is 200
ppm.
Signs and symptoms of methemoglobinemia
• The two major toxicologic concerns resulting from nitrate
poisoning are Cardiovascular collapes and
methemoglobinemia
• Normal individuals have low levels (0.5 to 2%) of
methemoglobin in their blood
• 10-20% Cyanosis (turning blue) of limbs/trunk; usually
asymptomatic
• 20-45% Nervous system problems such as headache and
dizziness
• 45-55% Shock, convulsions, arrhythmias (irregular heart
rate) and coma
• Over 70% High risk of mortality (death)
Antioxidant enzymes of RBC
• The normal erythrocyte has metabolic mechanisms for
reducing heme iron back to the ferrous state.(these
mechanisms are normally capable of maintaining the
concentration of methemoglobin at less than 1-2% of
the total hemoglobin).
• The predominant pathway is cytochrome b5
methemoglobin reductase, which is dependent on
(NADH) and is also known as NADH-diaphorase.
• An alternate pathway involves a reduced (NADPH)
diaphorase that reduces a reduces methemoglobin.
This pathway usually accounts for less than 5% of the
reduction of methemoglobin, but its activity can be
greatly enhanced by methylene blue.
Chemicals cause methemoglobinemia
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Dapsone
Amylnitrite
Primaquine
Metoclopromide
Nitroglycerine
Quinones
Methylene blue
Treatment for Nitrate exposure
• People with blood methemoglobin levels less than 20%,
with no symptoms, do not require treatment. People
having moderate to severe symptoms should receive
100% oxygen immediately.
• Other therapies for severe symptoms include receiving
intravenous (IV) of methylene blue and a blood
transfusion. Methylene blue acts as an electron donor
for the nonenyzmatic reduction of methemoglobin. A
distinct enzyme, NADPH methemoglobin reductase,
converts methylene blue ,the oxidized form of the dye
to the reduced form, using NADPH . The reduced form
then chemically reduces methemoglobin (Hgb(Fe(III)))
to hemoglobin Hgb(Fe(II)).