What are Nitrates and Nitrites?

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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)

Structures of Nitrate and Nitrite Ions
Structures of Nitrate and Nitrite Ions

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).

Environmental Nitrogen Cycle
Environmental Nitrogen Cycle

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.
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Where are Nitrates and Nitrites found?

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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.

Environmental Nitrogen Cycle
Environmental Nitrogen Cycle
  • 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.

Water Contamination
Water Contamination
  • 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.

Food Contamination Nitrate in Vegetables
Food Contamination Nitrate in Vegetables
  • 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

Vegetable Nitrate contentmg / 100g fresh weight
Celery, lettuce, red beetroot, spinach Very High (> 2500)
Parsley, leek, endive, Chinese cabbage, fennel High (100-250)
Cabbage, dill, turnip Medium (50-100)
Broccoli, carrot, cauliflower, cucumber, pumpkin Low (20-50)
Artichoke, asparagus, eggplant, garlic, onion, green bean, mushroom, pea, pepper, potato, summer squash, sweet potato, tomato, watermelon Very Low (<20)

Other Sources of Exposure

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

Nitrate or nitrite exposure from certain medications
Nitrate or nitrite exposure from certain medications

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.
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US Standards for Nitrates and Nitrites Exposure

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What are U.S. Standards and Regulations for Nitrates and Nitrites Exposure?

EPA has set an enforceable standard called a maximum contaminant level (MCL) in water for nitrates at 10 parts per million (ppm) (10 mg/L) and for nitrites at 1 ppm (1 mg/L).

  • EPA believes that exposure below this level is not expected to cause significant health problems.
  • All public water supplies must abide by these regulations.
  • Given present technology and resources, this MCL is also a level to which water systems can reasonably be required to remove this contaminant should it occur in drinking water.

Once a water source is contaminated, the costs of protecting consumers from nitrate exposure can be significant. This is because:

  • Nitrate is not removed by conventional drinking water treatment processes.
  • Its removal requires additional, relatively expensive treatment units.

Intake Nitrate Limits

The Joint Expert Committee on Food Additives (JECFA) of the Food and Agriculture Organization of the United Nations / World Health Organization and the European Commission’s Scientific Committee on Food have set an acceptable daily intake (ADI) for nitrate of 0–3.7 milligrams (mg) nitrate ion / kilogram (kg) body weight. This intake appears to be safe for healthy neonates, children, and adults. The same is also true of the EPA reference dose (RfD) for nitrate of 1.6 mg nitrate nitrogen / kg body weight per day (equivalent to about 7.0 mg nitrate ion / kg body weight per day).

JECFA has proposed an ADI for nitrite of 0–0.07 mg nitrite ion/kg body weight. EPA has set an RfD of 0.l mg nitrite nitrogen/kg body weight per day (equivalent to 0.33 mg nitrite ion/kg body weight per day).

Bottled Water and Food Additives Nitrate Limits

The FDA regulates allowable levels of inorganic nitrate and nitrite in bottled water [FDA 2005] as well as levels allowable in foodstuffs.

Bottled Water
Bottled Water

The FDA’s bottled water standard is based on the EPA standards for tap water. The bottled water industry must also follow FDA’s Current Good Manufacturing Practices (CGMPs) for processing and bottling drinking water. If these standards are met, water is considered safe for most healthy individuals. However, although not often reported, bottled water outbreaks do occur.

Allowable nitrite levels in bottled water:

  • Nitrate 10 mg/L (as nitrogen)
  • Nitrite 1 mg/L (as nitrogen)
  • Total nitrates, nitrites 10 mg/L (as nitrogen)

Allowable nitrite levels as an additive to foods:

  • As a preservative and color fixative, with or without sodium nitrite, in Smoked, cured sablefish; Smoked, cured salmon; Smoked, cured shad, so that the level of sodium nitrate does not exceed 500 parts per million (ppm) and the level of sodium nitrite does not exceed 200 ppm in the finished product.
  • As a preservative and color fixative, with or without sodium nitrite, in meat-curing preparations for the home curing of meat and meat products (including poultry and wild game), with directions for use which limit the amount of sodium nitrate to not more than 500 ppm in the finished meat product and the amount of sodium nitrite to not more than 200 ppm in the finished meat product.
  • The food additive potassium nitrate may be safely used as a curing agent in the processing of cod roe, in an amount not to exceed 200 ppm of the finished roe.

The U.S. Department of Agriculture’s (USDA’s) Food Safety and Inspection Service (FSIS) regulates food ingredients approved for use in the production of meat and poultry products. This includes inspection for required labeling of meat products when substances such as sodium nitrate are used in meat packaging.

Environmental Nitrate and Nitrite Standards

The current water standard for nitrate is based on levels considered low enough to protect infants from methemoglobinemia.

  • Some published results suggest a possible association between nitrate exposure during pregnancy and human malformations.
  • However, a review of the toxicology in relation to possible adverse effects on reproduction and development offers no evidence for teratogenic effects attributable to nitrate or nitrite ingestion.
  • The present maximum contaminant level appears to adequately protect even sensitive populations from nitrate-induced toxicity.
  • EPA concludes that the evidence in the literature showing an association between exposures to nitrate or nitrites and cancer in adults and children is conflicting.

Key Points of Nitrate and Nitrite Standards

  • The current water standard for nitrate is based on
    protection of infants from methemoglobinemia.
  • In vivo conversion of nitrates to nitrites significantly
    enhances nitrates’ toxic potency.
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Biologic Fate of Nitrates and Nitrites in the Body

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What Is the Biologic Fate of Nitrates and Nitrites in the Body?

Exposure to nitrates and nitrites may come from both internal nitrate production and external sources.

Intake of some amount of nitrates is a normal part of the nitrogen cycle in humans.

The mean intake of nitrate per person in the United States is about 40–100 milligrams per day (mg/day) (in Europe it is about 50–140 mg/day).

Nitrate can be synthesized endogenously from nitric oxide (especially in the case of inflammation), which reacts to form nitrite.

Figure 3 shows ways that nitrate, nitrite and nitric oxide can be produced and utilized from exogenous and endogenous sources.

A schematic diagram of the physiologic disposition of nitrate, nitrite
Figure 1
A schematic diagram of the physiologic disposition of nitrate, nitrite, and nitric oxide (NO) from exogenous (dietary) and endogenous sources. The action of bacterial nitrate reductases on the tongue and mammalian enzymes that have nitrate reductase activity in tissues are noted by the number 1. Bacterial nitrate reductases are noted by the number 2. Mammalian enzymes with nitrite reductase activity are noted by the number 3.

Absorption Nitrates and Nitrites

In the proximal small intestine, nitrate is rapidly and almost completely absorbed (bioavailability at least 92%).

  • Inorganic nitrate/nitrite can be absorbed via inhalation.
  • Inorganic nitrate/nitrite does not undergo first pass metabolism.

Distribution Nitrates and Nitrites

Inorganic nitrates/nitrites are distributed widely through the circulation with approximately 25% of absorbed nitrate concentrating in the salivary glands.

Salivary, plasma, and urinary levels of nitrate and then nitrite rise abruptly after ingestion.

An increase in inorganic nitrite levels peaks around 3 hours post ingestion and can be detected about an hour after ingestion.

Metabolism of Inorganic Nitrates and Nitrites

The two main metabolic pathways for inorganic nitrates / nitrites are

  • The nitrate-nitrite-NO pathway (Figure 1) and
  • Enterosalivary circulation pathway (nitrate reductase activity of bacteria on the tongue generates nitrite and nitrite which is metabolized to NO in the stomach and circulation).

Approximately 5%–10% of the total nitrate intake is converted to nitrite by bacteria in the saliva, stomach, and small intestine.

  • In vivo conversion of nitrates to nitrites significantly enhances nitrates’ toxic potency.
  • This reaction is pH dependent, with no nitrate reduction occurring below pH 4 or above pH 9.
  • The high pH of the infant gastrointestinal system makes them more susceptible to nitrite toxicity from elevated nitrate/nitrite ingestion.

The metabolic pathway of plasma and tissue nitrates depends on local conditions such as tissue oxygenation, and inflammatory state. In the skin, local conditions also include ultraviolet light exposure.

Nitrate can be reduced to nitrite and nitric oxide when needed physiologically or as part of pathological processes (see Figure 1).

Mammalian metalloproteins and enzymes that have nitrate reductase activity include aldehyde oxidase, heme proteins, mitochondria and xanthine reductase.

The reaction of nitrite with endogenous molecules to form N-nitroso compounds may have toxic or carcinogenic effects.

Excretion Nitrates and Nitrites

Approximately 60% to 70% of an ingested nitrate dose is excreted in urine within the first 24 hours.

About 25% is excreted in saliva through an active blood nitrate transport system and potentially is reabsorbed.

Half-lives of parent nitrate compounds are usually less than 1 hour; half-lives of metabolites range from 1 hour to 8 hours.

In the Fourth National Report on Human Exposure to Environmental Chemicals, urinary levels of nitrate were measured in a subsample of the National Health and Nutrition Examination Survey (NHANES) consisting of participants aged 6 years and older during 2007-2008. The geometric mean for urinary nitrate (in mg/g of creatinine) for the US population aged 6 years and older during 2007-2008 was 47.7, with a 95% confidence interval of 45.9-49.7. Note that these measurements are used in population based public health research and not intended for clinical decision making on individual patients.

Key Points the Biologic Fate of Nitrates and Nitrites in the Body

  • Exposure to nitrate and nitrites may come from both internal nitrate production and external sources.
  • Intake of some amount of nitrates is a normal part of the nitrogen cycle in humans.
  • Nitrate can be reduced to nitrite and nitric oxide when needed physiologically or as part of pathological processes depending on local conditions such as inflammation and tissue oxygenation.
  • In vivo conversion of nitrates to nitrites significantly enhances nitrates’ toxic potency.
  • Approximately 5%–10% of the total nitrate intake is converted to nitrite by bacteria in the saliva, stomach, and small intestine.
  • 60-70% of an ingested nitrate dose is excreted in urine within 24 hours.
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Risk from Overexposure to Nitrates and Nitrites

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Who is at most Risk of Adverse Health Effects from Overexposure to Nitrates and Nitrites?

Nitrate contaminated water
Nitrate contaminated water

Infants less than 4 months of age are most at risk of adverse health effects from over exposure to nitrates and nitrites through ingestion of formula diluted with nitrate contaminated water.

Although there is no nutritional indication to add complementary foods to the diet of a healthy term infant before 4 to 6 months of age, the American Academy of Pediatrics suggests that home-prepared infant foods from vegetables (i.e. spinach, beets, green beans, squash, carrots) should be avoided until infants are 3 months or older.

Gastroenteritis with vomiting and diarrhea can exacerbate nitrite formation in infants and has been reported to be a major contributor to methemoglobinemia risk in infants independent of nitrate / nitrite ingestion.

In addition, the pregnant woman and her fetus might be more sensitive to toxicity from nitrites or nitrates at or near the 30th week of pregnancy.

Individuals with glucose-6-phsphate dehydrogenase (G6PD) deficiency may have greater susceptibility to the oxidizing effects of methemoglobinemia inducers.

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What are Routes of Exposure to Nitrates and Nitrites?

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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, as well as
  • The chemical form of the nitrates and nitrites.

    Routes of Exposure to Nitrates and Nitrites
    Routes of Exposure to 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.
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