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Nitrates and nitrites can be categorized into inorganic and organic forms based on their chemical structure.
There are similarities and differences between these two chemical forms that affect their pharmacokinetic and pharmacodynamic properties and their subsequent biologic effects in humans. This artical  will focus on inorganic nitrates.

Inorganic Nitrates and Nitrites

Inorganic nitrate (NO3–) and nitrite (NO2–) are water soluble (as a result of their interaction with the positively charged portions of polar water molecules)

and commonly exist as salts of nitric acid and nitrous acid, respectively. They are often bound to a metal cation such as Na+ or K+ and occur naturally through the fixation of atmospheric nitrogen and oxygen as part of the environmental nitrogen cycle (the cyclic movement of nitrogen in different chemical forms from the environment, to organisms, and then back to the environment as illustrated).

Inorganic nitrites are also produced endogenously through oxidation of nitrous oxide (NO) formed from the enzymatic degradation of L-arginine and through the reduction of nitrate with xanthine oxidoreductase.

Organic Nitrates and Nitrites

The organic forms of nitrates and nitrites are more complex and most are synthesized medicinal products (except ethyl nitrite). Organic nitrates are small non-polar hydrocarbon chains attached to a nitrooxy-radical (-ONO2; -ONO for amyl and ethyl nitrite). The addition of aliphatic or aromatic groups of variable length and volume affect the lipophilic properties of these molecules. It has been suggested that for some molecules, the greater the number of –ONO2 groups, the greater its potency; (the potency being dependent on the molecule’s lipophilicity).

Key Points

• Nitrates and Nitrites exist in organic and inorganic
  forms.
• The chemical form affects the pharmacokinetic and
  pharmacodynamic properties of nitrates and
  nitrates.
• Inorganic nitrates and nitrites are generally more
  water soluble than organic nitrates and nitrates.
• Inorganic nitrates and nitrites are produced
  endogenously and exogenously.
• Organic nitrates and nitrites are mostly synthesized
  medicinal products.
• Organic nitrates and nitrites are generally more
  complex and lipophilic than inorganic nitrates and nitrites.

(5 votes, average: 5.00 out of 5)

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The primary routes of exposure to nitrates and nitrites may differ depending on occupational and non­ occupational factors. Non-occupational factors may include:

• Age,
• Diet,
• Medications,
• Hobbies (such as gardening, arc welding, etc.),
• History of inhalational drug use,
• Source of drinking/cooking water and how it is supplied,
• Outdoor activities,
• The chemical form of the nitrates and nitrites.

Occupational and Paraoccupational Exposures

Occupational exposure occurs primarily through the inhalation and dermal routes. Explosive and fertilizer industry workers may be exposed to nitrate through inhalation of dusts containing nitrate salts. Dusts can also dissolve in sweat exposing skin to concentrated solutions of the salts. Farmers may experience periodic exposures depending on their activities, especially with regard to the handling of fertilizers. Exposure of family members to nitrates from dusts brought home on work clothes has been reported.

Non­-occupational Exposures

The primary route of non-occupational exposure is ingestion of water or foodstuffs that contain high levels of nitrates or nitrites. Inhalation exposures may occur from inhalant drug use and dermal exposures may occur from some topical medications. These would be special instances and not the primary routes of exposure for the general population.

Key Points

• Primary occupational routes of exposure to nitrates and nitrites include inhalation and dermal routes.
• The primary route of exposure to nitrates and nitrites for the general population is ingestion.
• Inhalation and dermal exposures have been reported in non-occupational settings under certain circumstances, but are not the primary routes of exposure for the general population.

(3 votes, average: 5.00 out of 5)

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Understanding the environmental fate of nitrates and nitrites may help pinpoint potential sources of exposure. This would be important in assessment of patient exposure risk, prevention and mitigation of nitrate / nitrite overexposure and in the prevention of adverse health effects from exposure.

Environmental Nitrogen Cycle

In general, the following describes the activity of nitrates and nitrites in the environment. Microbial action in soil or water decomposes wastes containing organic nitrogen into ammonia, which is then oxidized to nitrite and nitrate.

• Because nitrite is easily oxidized to nitrate, nitrate is the compound predominantly found in groundwater and surface waters.
• Contamination with nitrogen-containing fertilizers (e.g. potassium nitrate and ammonium nitrate), or animal or human organic wastes, can raise the concentration of nitrate in water.
• Nitrate-containing compounds in the soil are generally water soluble and readily migrate with groundwater.

Water Contamination

Shallow, rural domestic wells are those most likely to be contaminated with nitrates, especially in areas where nitrogen-based fertilizers are widely used.

• Approximately 15 percent of Americans rely on their own private drinking water supplies which are not subject to U.S. Environmental Protection Agency (EPA) standards, although some state and local governments do set guidelines to protect users of these wells.
• In agricultural areas, nitrogen-based fertilizers are a major source of contamination for shallow groundwater aquifers that provide drinking water.
• A recent United States Geological Survey study showed that 7 percent of 2,388 domestic wells and about 3 percent of 384 public-supply wells nationwide were contaminated with nitrate levels above the EPA drinking water standard of 10 parts per million (ppm) or 10 mg/L.
• Elevated concentrations were most common in domestic wells that were shallow (less than 100 feet deep) and located in agricultural areas because of relatively large nitrogen sources, including septic systems, fertilizer use, and livestock.
• Although suppliers of public water sources are required to monitor nitrate concentrations regularly, few private rural wells are routinely tested for nitrates.
• During spring melt or drought conditions, both domestic wells and public water systems using surface water can show increased nitrate levels.
• Drinking water contaminated by boiler fluid additives may also contain increased levels of nitrites.
• Mixtures of nitrates / nitrites with other well contaminants such as pesticides and VOCs have been reported.

Food Contamination

Nitrate and nitrite overexposure has been reported via
ingestion of foods containing high levels of nitrates and nitrites. Inorganic nitrates and nitrites present in contaminated soil and water can be taken up by plants, especially green leafy vegetables and beet root.

• Contaminated foodstuffs, prepared baby foods, and sausage / meats preserved with nitrates and nitrites have caused overexposure in children.
• Although vegetables are seldom a source of acute toxicity in adults, they account for about 80% of the nitrates in a typical human diet.
• Celery, spinach lettuce, red beetroot and other vegetables have naturally greater nitrate content than other plant foods do.
• The remainder of the nitrate in a typical diet comes from drinking water (about 21%) and from meat and meat products (about 6%) in which sodium nitrate is used as a preservative and color- enhancing agent.
• For infants who are bottle-fed, however, the major source of nitrate exposure is from contaminated drinking water used to dilute formula.
• Bottled water is regulated by the U.S. Food and Drug Administration (FDA) as a food. It is monitored for nitrates, nitrites and total nitrates / nitrites.

Nitrate Content of Selected Vegetables

Other Sources of Exposure

Nitrate or nitrite exposure can occur from certain medications and volatile nitrite inhalants.

Accidental and inadvertent exposures to nitrites as well as ingestion in suicide attempts have been reported.

Deliberate abuse of volatile nitrites (amyl, butyl, and isobutyl nitrites) frequently occurs. Amyl nitrite (nicknamed by some as “poppers”) is used commercially as a vasodilator and butyl / isobutyl nitrites can be found in products such as room air fresheners.

Fatalities have been reported in adults exposed to nitrates in burn therapy; however infants and children are especially susceptible to adverse health effects from exposure to topical silver nitrate used in burn therapy.

Other medications implicated in methemoglobinemia include:

• Quinone derivatives (antimalarials),
• Nitroglycerine,
• Bismuth subnitrite (antidiarrheal),
• Ammonium nitrate (diuretic),
• Amyl and sodium nitrites (antidotes for cyanide and hydrogen sulfide poisoning),
• Isosorbide dinitrate/tetranitrates (vasodilators used in coronary artery disease therapy),
• Benzocaine (local anesthetic), and
• Dapsone (antibiotic).

Other possible sources of exposure include ammonium nitrate found in cold packs and nitrous gases used in arc welding.

An ethyl nitrite folk remedy called “sweet spirits of nitre” has caused fatalities.

Key Points

• Shallow, rural domestic wells are those most likely to be contaminated with nitrates, especially in areas where nitrogen based fertilizers are in widespread use.
• Other nitrate sources in well water include seepage from septic sewer systems and animal wastes.
• Foodstuffs high in nitrates, home prepared baby foods, and sausage/meats preserved with nitrates and nitrites have caused overexposure in children.
• Nitrate or nitrite exposure can occur from certain medications and volatile nitrite inhalants.

(4 votes, average: 5.00 out of 5)

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