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Nitrate as a cause of methemoglobinemia

Nitrate itself is relatively non-toxic, but through the activity of bacteria in the gastrointestinal tract, it is converted to the more toxic nitrite ( 7). Nitrite then enters the bloodstream, where it reacts with hemoglobin to form methemoglobin ( 7). Unlike hemoglobin, methemoglobin cannot transport oxygen. The primary health concern due to nitrate (or nitrite) exposure is methemoglobinemia. Methemoglobin in concentrations above 10% of the total hemoglobin can produce cyanosis, characterized by bluish lips and skin color. Higher concentrations (25% and above) are associated with hypotension, rapid pulse, and rapid breathing; concentrations above 50% can be fatal ( 4). Low concentrations of methemoglobin may normally occur, and concentrations of up to 10% may occur without clinical signs ( 4).

The bacteria which convert nitrate to nitrite are normally present in the mouth and stomach. The level of toxicity of nitrate depends on how much of it is converted to nitrite, which depends on the concentration and type of bacteria present. The risk of methemoglobinemia is most acute in infants in the first 6 months of life ( 8). One reason for this is the greater total fluid intake per unit body weight ( 8). The infant stomach has low acidity, which allows for the growth of bacteria that can convert nitrate to nitrite ( 7). Also, the type of hemoglobin in the infant's blood is more easily changed to methemoglobin than in an adult ( 7), and the enzyme systems that change methemoglobin back to hemoglobin are not developed fully yet, either ( 9). Once the intestinal tract is adequately developed and other physiological changes have occurred, methemoglobinemia from nitrate found in drinking water is no longer a risk.

Infants are at risk if they are fed nitrate- or nitrite-contaminated water, most likely mixed with powdered formula. This risk is increased if the water is boiled, as the nitrate becomes more concentrated. Other factors such as bacterial count and vitamin C deficiency may affect toxicity ( 7). Unfortunately, high bacterial content is often found in water with high nitrate levels, and this bacteria may also function to convert nitrate ( 7). Vitamin C is also known to reduce methemoglobin, and may be used in treatment of mild cases. Although methemoglobinemia from drinking water is generally thought to affect only infants, there are reportedly some data from the Soviet Union that suggest increased methemoglobinemia concentrations in school children drinking nitrate-contaminated water ( 10).

It appears that most cases of infant methemoglobinemia have involved water nitrate concentrations over twice the MCL. This is based on several reviews that found most cases in which the levels were known have occurred at levels greater than 100 mg/L, which is equivalent to 22.2 mg/L nitrate as nitrogen ( 8). Thus this is slightly over twice the MCL of 10 mg/L. However, the data suggest that a small percentage of cases may occur at levels closer to, or even below, the MCL ( 8-10). One review in 1971 of cases from 14 countries found that 3% occurred at concentrations of less than 8.9 mg/L nitrate as nitrogen, vs. MCL=10 ( 8). However, often the exposure levels are not known. Also, the true incidence is probably underestimated, as morbidity and mortality among infants from nitrate-induced methemoglobinemia may be misdiagnosed, perhaps as sudden infant death syndrome ( 10).

Sensitive subpopulations

Sensitive subpopulations have been identified for methemoglobinemia. These include African Americans, Alaskan Eskimos, and Native Americans, some of whom lack a hereditary enzyme that helps reduce methemoglobin levels in the blood and are thus at greater risk ( 11). Also, dialysis patients are uniquely susceptible to methemoglobinemia, and it has been recommended that water for dialysis treatments not exceed 2 mg/L nitrate as nitrogen ( 8).

Infections and inflammatory conditions increase the process of methemoglobinemia production ( 4). Infants who are experiencing such illnesses are thus at greater risk for developing methemoglobinemia when exposed to nitrate sources. Any individuals who suffer from stomach conditions such as gastric ulcers, pernicious anemia, adrenal insufficiency, gastritis, or gastric carcinoma are likewise at risk because these conditions reduce stomach acidity and cause more nitrate to be converted to hazardous nitrite ( 9).

ATSDR Child Health Initiative

ATSDR recognizes that infants and children, in general, may be more sensitive to exposures than adults who encounter contamination of their water, air, or food. Because children depend completely on adults for risk identification and management decisions, ATSDR, as part of their Child Health Initiative, is committed to evaluating the special interests of children at all sites.

In the case of nitrate and methemoglobinemia, as the health consultation discusses, infants represent a special population that is more sensitive to nitrate. According to the 1990 census, nearly 1,100 infants under the age of 1 reside near the LEHR site (approximately the area represented in the map in Figure 1) ( 12). As the focus of this health consultation in its entirety primarily addresses this sensitive population, their special conditions and needs will not be additionally discussed in this section.

Causes of methemoglobinemia other than nitrate

Although nitrate is one of the most commonly reported causes of methemoglobinemia, other substances and circumstances are also capable of causing this condition, including: organic nitrate (e.g. room deodorizer propellants and certain pharmaceutical agents), sulfonamides, topical and injected anesthetics (e.g. benzocaine and lidocaine), aniline dyes, wax crayons, laundry ink, industrial solvents, mothballs, fungicides, and diarrhea with acidosis ( 7, 13).

Exposure to nitrate in combination with other chemicals

It is also possible that simultaneous exposure to nitrate in combination with another substance could produce methemoglobinemia. A recent well-water methemoglobinemia case was reorted in Wisconsin in which a 6-week old infant consumed formula mixed with well water ( 14). Water used for drinking and food preparation was filtered through a reverse osmosis unit. A water sample from this source found nitrate at a level near the MCL (9.9 mg/L nitrate as nitrogen), and copper dissolved from pipes at levels above the copper MCL of 1.3 ppm ( 14). Copper is an emetic and a gastrointestinal irritant, and the child's methemoglobinemia was thought to have been induced by the combined exposure to nitrate and copper ( 14).

Search for cases of methemoglobinemia

We sought to identify any cases of methemoglobinemia in infants that could have been caused by nitrate exposure via drinking water in the vicinity of the LEHR site. We searched 7 zip codes in the area, defined broadly to include 95695, 95776, 95616, 95618, 95605, 95691, and 95620. ( Figure 1).

To find methemoglobinemia cases, we selected hospital discharge records available through the Office of Statewide Health Planning and Development (OSHPD). OSHPD data contain a record for every hospital discharge in the state of California, with the exception of federal hospitals. Data tapes from the 13 years 1983 through 1995 were searched for any hospital discharges which contained the diagnosis code for methemoglobinemia (289.7), based on the International Classification of diseases, 9th Revision (ICD-9). Records include codes for the principal diagnosis (the main reason for hospitalization) and up to 24 additional diagnoses; all were searched.

In addition to diagnosis codes, data on age, race, sex, year of diagnosis, zip code, county of hospital, and county (this was only available for years 1994 and later) were retrieved. Also, supplementary classification information of external causes of injury and poisoning, called e-codes in the ICD-9 system, were searched as to clues to the origin of the methemoglobinemia condition. Unfortunately, nitrate-related methemoglobinemia is not a reportable illness, nor is there a code specific enough to identify ingestion of nitrate-contaminated water as a cause of methemoglobinemia. The code e-866 may be the most likely: accidental poisoning by other and unspecified solid and liquid substances.

Cases in the LEHR zip codes

Two cases of methemoglobinemia were noted in the LEHR vicinity zip codes during the years searched, but neither of these were infants.

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