Nitrate and Nitrite Poisoning in Animals

Nitrates and nitrites are used in pickling and curing brines during meats preservation processes; as well as in certain machine oils, anti-corrosion tablets, gunpowders, explosives, and fertilizers. They may also serve as therapeutic agents for certain noninfectious diseases, (eg, cyanide poisoning). Toxicosis most often occurs in naive domestic species, most commonly due to ingestion of plants containing excess nitrates; particularly by hungry animals engorging themselves, thus ingesting an enormous volume of nitrate. Confounding metabolic interactions with nonprotein nitrogen, monensin, and other feed components may exacerbate effects of excessive nitrate content in animal diets, especially when coupled with management errors.

Nitrate toxicosis can also result from accidental ingestion of fertilizer or other chemicals. Nitrate concentrations may be hazardous in ponds with extensive feedlot or fertilizer runoff; these types of nitrate sources may also contaminate shallow, poorly cased wells. Although nitrate concentrations are increasing in groundwater in the US, well water is rarely the sole cause of nitrate toxicosis. Water with both high nitrate concentration and considerable coliform contamination has greater potential to adversely affect health and productivity than either presence of nitrates or bacteria alone.

Crops that readily concentrate nitrate include cereal grasses (especially oats, millet, and rye), corn (maize), sunflower, and sorghums. Weeds that commonly have high nitrate concentrations include pigweed, lamb’s-quarter, thistle, Jimson weed, fireweed (Kochia), smartweed, dock, and Johnson grass. Anhydrous ammonia and nitrate fertilizers and soils naturally high in nitrogen tend to increase nitrate content in forage.

Excess nitrate in plants is generally associated with damp weather conditions and cool temperatures (eg, ~55°F [13°C]), although high concentrations are also likely to develop when growth is rapid during hot, humid weather. Drought conditions, particularly if occurring when plants are immature, may result in vegetation with high nitrate content. Decreased light, cloudy weather, and shading associated with crowded planting can also cause increased concentrations of nitrates in plants. Well-aerated soil with a low pH, and low or deficient amounts of molybdenum, sulfur, or phosphorus in soil tend to enhance nitrate uptake; whereas soil deficiencies of copper, cobalt, or manganese tend to decrease nitrate uptake. Anything that stunts growth increases nitrate accumulation in the roots and lower stalks of plants. Phenoxy acid derivative herbicides (eg, 2,4-D), applied to nitrate-accumulating plants during early stages of growth causes increased growth and a high nitrate residual (10%–30%) in surviving plants, which tend to be lush and attractive to animals although previously avoided.

Nitrate does not selectively accumulate in fruits or grain and is found chiefly in the lower stalk, with lesser amounts in the upper stalk and leaves. Nitrate in plants can be converted to nitrite under favorable conditions of moisture, heat, and microbial activity after harvesting.

Clinical signs of nitrite poisoning usually appear acutely due to tissue hypoxia and hypotension resulting from vasodilation. Rapid, weak heartbeat with decreased body temperature, muscular tremors, weakness, and ataxia are early signs of toxicosis at methemoglobinemia levels of 30%–40%. Brown, cyanotic mucous membranes develop rapidly as methemoglobinemia exceeds 50%. Dyspnea, tachypnea, anxiety, and frequent urination are common. Some monogastric animals, usually because of excess nitrate exposure from nonplant sources, exhibit salivation, vomiting, diarrhea, abdominal pain, and gastric hemorrhage. Affected animals may die suddenly without appearing ill, with terminal anoxic convulsions within 1 hour; or after a clinical course of 12–24 hours or longer. Acute, lethal toxicoses almost always result from development of ≥80% methemoglobinemia.

In certain conditions, adverse effects may not be apparent until animals have been eating nitrate-containing forages for days to weeks. Some animals that develop marked dyspnea recover but then develop interstitial pulmonary emphysema and have continued signs of respiratory distress; most of these animals recover fully within 10–14 days. Abortion and stillbirths may be seen in some cattle 5–14 days after excessive nitrate/nitrite exposure; however, this is likely only in cows that have survived an initial acute ≥50% methemoglobinemia for 6–12 hours or longer.

• As the concentration of methemoglobin increases, affected animals develops dyspnea, cyanotic mucous membranes, weakness, ataxia, muscular tremors; and, often, frequent urination. Severely affected animals may collapse and die quickly from anoxia. Continued severe respiratory distress can lead to interstitial pulmonary emphysema. Abortions and stillbirths may be seen in some pregnant cattle 5–14 days after an exposure to excessive nitrates.

Nitrate toxicosis can be assessed by means of laboratory analysis for nitrate concentration in both ante- and postmortem specimens. Plasma is the preferred antemortem specimen, because some plasma protein–bound nitrite could be lost due to clotting if serum is collected. Ocular fluid is the preferred postmortem sample for nitrate testing. Additional postmortem specimens in cases of abortion include fetal pleural or thoracic fluids, fetal stomach contents, and maternal uterine fluid. All specimens should be frozen in clean plastic or glass containers before submission, except when whole blood is collected for methemoglobin analysis. Because the amount of nitrate in rumen contents is not representative of concentrations in the diet, evaluation of rumen contents is not indicated. Suspected sources of nitrate exposure should also be submitted for laboratory testing. 

Methemoglobin analysis alone is not a reliable indicator of nitrate toxicosis or nitrite exposure except in acute toxicosis. This is because 50% of methemoglobin is converted back to Hgb in ~2 hours, and alternative forms of nonoxygenated Hgb that may be formed by reaction with nitrite are not detected via methemoglobin testing. Nitrate and nitrite concentrations >20 ppm and >0.5 ppm, respectively, in maternal and perinatal serum, plasma, ocular fluid, and other similar biologic fluids are usually indicative of excessive nitrate or nitrite exposure in most domestic animal species. In acutely poisoned ruminant livestock, nitrate and nitrite concentrations as high as 300 ppm and 25–50 ppm, respectively, can be found in plasma or serum, with about one-third less in postmortem ocular fluid because of delayed equilibrium via diffusion. However, postmortem ocular fluid nitrate concentrations are relatively stable and remain diagnostically relevant for up to 60 hours after death. Once collected, plasma, serum, and ocular fluid specimens have stable nitrate concentration for testing at least 1 week if refrigerated and 1 month at –20°C.

Normally expected nitrate and nitrite concentrations in similar diagnostic specimens are usually < 10 ppm and < 0.2 ppm, respectively. Nitrate and nitrite concentrations >10 but < 20 ppm and >0.2 but < 0.5 ppm, respectively, are suspect and indicate nitrate or nitrite exposure of unknown duration, extent, or origin. It has been reported that the half-life of nitrate in beef cattle, sheep, and ponies was 7.7, 4.2, and 4.8 hours, respectively. Therefore, it would be at least five biologic half-lives (24–36 hours) before increased nitrate concentrations from excessive nitrate exposure diminish to normally expected values, allowing additional time for appropriate premortem specimen collection.

A latent period may exist between excessive maternal dietary nitrate exposure and equilibrium in perinatal ocular fluid. Aqueous humor is actively secreted into the anterior chamber at a rate of ~0.1 mL/hour, and nitrate and nitrite are thought to enter the globe of the eye via this mechanism. Equilibrium between aqueous and vitreous humor is by passive diffusion rather than by active secretion, so nitrate or nitrite may be present in comparatively lesser concentrations in vitreous humor after acute exposure.

Field tests for nitrate are presumptive and should be confirmed by means of standard analytical methods at a qualified laboratory. The diphenylamine blue test (1% in concentrated sulfuric acid) is more suitable to determine the presence or absence of nitrate in suspected forages. Nitrate test strips (dipsticks) are effective in determining nitrate values in water supplies and can be used to evaluate nitrate and nitrite concentrations in serum, plasma, ocular fluid, and urine.

Differential diagnoses include:

• toxicosis due to cyanide, urea, pesticides, toxic gases (eg, carbon monoxide, hydrogen sulfide), chlorates, aniline dyes, aminophenols, or drugs (eg, sulfonamides, phenacetin, and acetaminophen)

• various infectious or noninfectious diseases (eg, grain overload, hypocalcemia, hypomagnesemia, pulmonary adenomatosis, or emphysema)

• any other cause of sudden, unexplained deaths

• Slow IV injection of 1%–2% methylene blue at 4–15 mg/kg; retreatment may be necessary

• Affected animals should be handled such to minimize stress

• Any source of continued exposure to excess nitrates should be removed

Slow IV injection of 1%–2% methylene blue in distilled water or isotonic (0.9% NaCl) saline solution should be administered at 4–15 mg/kg or more, depending on severity of exposure. Lower dosages may be repeated in 20–30 minutes if the initial response is not satisfactory. Lower dosages of methylene blue can be used in all species; only ruminants can safely tolerate higher dosages. If additional exposure or absorption occurs during therapy, retreatment with methylene blue every 6–8 hours should be considered. Affected animals should be handled to minimize stress, which can exacerbate effects of hypoxia. Animals should be removed from the source of excess nitrates and given other supportive care as needed.

Animals may adapt to higher nitrate content in feeds, especially when grazing summer annuals such as sorghum-Sudan hybrids. Multiple, small feedings help animals adapt. Trace mineral supplements and a balanced diet may help prevent nutritional or metabolic disorders associated with long-term excess dietary nitrate consumption. Feeding grain with high-nitrate forages may reduce nitrite production. However, caution is advised when combining other feed additives/components, including non-protein nitrogen, ionophores (such as monensin) and other growth and performance enhancers, with high-nitrate diets in ruminants. Appropriate management practices, especially regarding acclimation, are critical. Forage nitrate concentrations >1% nitrate dry-weight basis (10,000 ppm) may cause acute toxicosis in unacclimated animals, and forage nitrate concentrations ≤5,000 ppm (dry-weight basis) are recommended for pregnant beef cows. However, even forage concentrations of 1,000 ppm dry-weight basis have been lethal to hungry cows engorging themselves in a single feeding within an hour, so the total dose of nitrate ingested is a key factor.

High-nitrate concentration forages may also be harvested and stored as ensilage rather than as dried hay or green chop; this may reduce the nitrate content in forages by up to 50%. Raising cutter heads of machinery during harvesting operations selectively leaves the more hazardous stalk bases in the field.

Hay appears to be more hazardous than fresh green chop or pasture with similar nitrate content. Heating may encourage bacterial conversion of nitrate to nitrite; therefore, feeding of hay, straw, or fodder that has been damp or wet for several days, or stockpiled, green-chopped forage should be avoided. Large, round bales with excess nitrates are especially dangerous if stored uncovered outside; rain or snow can leach and subsequently concentrate most of the total nitrate present into the lower third of these bales.

Water transported in improperly cleaned liquid fertilizer tanks may have an extremely high nitrate concentration. Young, unweaned livestock, especially neonatal pigs, can be more sensitive to nitrate in water.

• Hall JO. Nitrate- and Nitrite-Accumulating Plants. In: Gupta RC, ed. Veterinary Toxicology, 3rd Edition.  Academic Press, 2018:941–946.