Who is at most Risk of Adverse Health Effects from Overexposure to Nitrates and Nitrites?
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.
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
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.
During deep sleep, cerebrum cleans what it doesn’t need, study finds
During deep sleep, the brain may be tidying up the detritus that accumulates during a hard day of thinking, a recent study suggests.
A study suggests the brain wipes out detritus with fluid as we sleep
Researchers have found that during slow-wave sleep in particular – the type of slumber sandwiched between periods of dreaming – a sort of cleaning fluid pulses into the brain, taking out the trash as it recedes, according to a report published in Science.
Using high-speed brain imaging, the researchers were able to map out a series of events that occur as the brain enters deep sleep and brain waves start to slow and synchronize.
They found that the blood flow to the brain diminishes, allowing for an influx of clear, colourless cerebrospinal fluid (CSF). That fluid surges in and sloshes around, washing away the day’s detritus of proteins and other waste substances that might harm the brain if they aren’t cleared out.
“We haven’t ever seen CSF waves on this scale in the awake brain, suggesting that sleep involves a unique pattern of fluid flow in the brain,” said Laura Lewis, an assistant professor of biomedical engineering at Boston University and the study’s senior author.
“Previous studies in animals from other labs have shown that during sleep, proteins such as beta-amyloid (one of two hallmark proteins implicated in Alzheimer’s disease) are cleared more rapidly from the brain,” Lewis said. “Based on these studies; we wondered why this might occur and we wanted to ask whether CSF changes during sleep because CSF is thought to be important for waste removal.”
Lewis and her colleagues suspect that poor sleep in patients with neurological disorders might impact the tidying up process, leaving waste materials to accumulate, eventually leading to degeneration.
“We’re running new studies to test how these CSF waves may change in healthy aging and in neurological disorders,” she said. “We’re also going to test whether this would be associated with less waste removal from the brain during sleep in these patients.”
The new research shows how the rhythmic flow of fluid during deep sleep could be the way the brain washes away waste, Danish researchers write in a commentary that accompanied the new study.
Understanding that process might shed a light on how disturbed sleep could be linked to certain neurologic disorders, write Soren Grubb, an assistant professor in the department of neuroscience at the University of Copenhagen, and Martin Lauritzen, a professor of clinical neurophysiology at Rigshospitalet.
“Disturbances of (slow wave sleep) commonly accompany aging, major depressive disorders and dementia,” they note.
“It will be interesting to assess whether the CSF dynamics linked to SWS can be used as a biomarker for disease states and whether strategies to restore SWS can rescue brain function in neurodegeneration.”
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
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
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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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.
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.
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
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
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
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 or nitrite exposure can occur from certain medications and volatile nitrite inhalants.
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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