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 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 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)).