Methemoglobinemia: Response to Avery.

In his letter, Avery expressed concern about the accuracy and completeness of our case reports (1). Because his letter is quite long and touches on many different subjects, we have attempted to address his major points individually below.

Avery states that it seemed ill considered "to include this case [case 1] in a serious discussion of the causes of methemoglobinemia." Although case 1 was not confirmed by laboratory testing, the infant was seen by an experienced public health nurse. We discussed and acknowledged the presumptive nature of this infant's diagnosis in our paper (1). We included this case, in part, because we believe the way in which it was handled is typical of the manner in which the majority of nitrate-induced infant illnesses are handled in Wisconsin and, perhaps, throughout the United States.

As reported by Avery, the infant in case 2 experienced diarrhea during her hospital stay. However, this symptom was not mentioned on the infant's emergency room or medflight records and appears to have onset sometime after she was admitted to the pediatric intensive care unit. It should be noted that diarrhea is a common side effect of methylene blue therapy (2) and ceftriaxone (3). Both of these drugs were administered to this infant by emergency room staff. Severe hypoxia may also have contributed to this infant's gastrointestinal symptoms. Thus, although diarrhea has been implicated as a risk factor for infant methemoglobinemia, it does not appear to have contributed to the onset of this infant's illness.

We disagree with Avery's contention that diarrhea has not been reported in cases of anoxia and oxidant chemical exposure. Diarrhea, nausea, and vomiting are common symptoms associated with hypoxia caused by carbon monoxide and nitrite exposures (4). In a recent outbreak of methemoglobinemia among New Jersey school children, symptoms of cyanosis, nausea, abdominal pain, vomiting, headache, and dizziness onset within 1 hr of their exposure to nitrite-contaminated soup (5).

Avery states that "It is worth noting that the well water in case 2 tested positive for Escherichia coli." Although many private drinking water wells in Wisconsin test positive for E. coli, this contamination has not been associated with infant methemoglobinemia. The parents of this infant indicated that they boiled the well water for several minutes before using it to prepare infant formula because they were concerned about possible contamination of the well. This practice is effective in eliminating the risk of E. coli infection, but it could slightly increase the nitrate level. Stool cultures for this infant were negative for pathogenic E. coli, Shigella sp., Salmonella sp., and Campylobacter sp.

Avery also commented on our failure "to discuss the lengthy hospitalization of case 2." In our paper (1), we indicated that the infant (case 2) was discharged 17 days after admission. The length of a patient's hospitalization is a matter of the physician's professional judgment. The length of this infant's hospital stay was undoubtedly influenced by several factors, including the seriousness of her condition on admission, young age, prematurity, body weight of only 5 lbs, and rural residence.

Regarding our discussion of other published cases of infant methemoglobinemia, Avery states that

   Contrary to the claims of Knobeloch et al. (1), secondary risk factors ...
   were ruled out in all of these cases, as well as in dozens of additional
   cases caused by diarrhea.

Although we have not had an opportunity to review some of the papers cited by Avery, none of the case summaries that we have reviewed to date included detailed information on potential exposures to methemoglobin-inducing agents. The list of possible agents is extensive, including strained fruits and vegetables, vegetable broths, water that may have been contaminated by nitrite-containing boiler treatments, lidocaine, prilocaine, analine dyes, and oxides of nitrogen.

Avery believes that our conclusion from the work of Hegesh and Shiloah (6)--that "as little as 12 mg of nitrate-N per day can significantly increase an infant's methemoglobin level"--is erroneous. Hegesh and Shiloah (6) measured urinary nitrate levels, which is the measurement referenced in our paper. Because ammonia, nitrate, nitrite, and nitric oxide exist in a dynamic equilibrium in the body, it is not possible to accurately predict blood nitrite levels from a urinary nitrate measurement.

Avery also suggested that the

   emphasis in the APHA survey ... has created an inherent bias: any
   methemoglobinemia case with elevated nitrates in the water is assumed to be
   caused by the nitrates, even though it is now clear that additional factors
   are critical for methemoglobinemia to occur.

We believe that infant exposure to nitrate and/or nitrite has the potential to cause methemoglobinemia in the absence of other risk factors. Secondary risk factors, such as diarrhea or inherited enzyme deficiencies, can exacerbate the effects of exposure to nitrate or nitrite. However, these factors are not critical to the occurrence of methemoglobinemia.

We disagree with Avery's statement that

   ... there is no plausible mechanism whereby the relatively small
   contribution of nitrates from drinking water contributes to cancer or other
   adverse health conditions while the considerably larger nitrate exposure
   through vegetables and endogenous production does not.

Several researchers have described mechanisms whereby ingested nitrate/nitrite might induce birth defects, cancer, diabetes, and thyroid disease. Although additional research is needed in this area, we believe the proposed mechanisms are scientifically plausible.

We also disagree with Avery's assertion that nitrate from vegetables and endogenous nitrite production is "considerably larger" than exposures related to water-borne nitrate. According to Table 4-1 of the National Research Council's (NRC) report on Nitrate and Nitrite in Drinking Water (7), dietary nitrate intake for an adult averages 76 mg/day. This is equivalent to 17 mg nitrate-N per day. Endogenous nitrate production was estimated to be 62 mg nitrate/day (7), which is equivalent to 14 mg nitrate-N per day. In comparison, ingestion of 2 L water that contains 10 mg nitrate-N per liter would provide a nitrate-N dose of 20 mg/day. Thus, at the level of the current standard, drinking water provides more than one-third of an adult's daily nitrate intake. Ingestion of water that contains 20 mg nitrate-N per liter, the level proposed by Avery as safe, would increase an adult's daily nitrate-N exposure from about 30 mg/day to more than 70 mg/day.

Several studies cited in our paper have reported associations between nitrate-contaminated water and a variety of health problems, including cancer, thyroid disease, and diabetes. The U.S. Environmental Protection Agency (8) and NRC reports (7) cited by Avery were constrained to evaluating exposures to nitrate in municipal water supplies. Thus, both reports assumed a maximum nitrate concentration of 10 mg/L and did not address risks that might be posed by higher nitrate levels.

Lynda Knobeloch Henry A. Anderson Wisconsin Division of Public Health Madison, Wisconsin Email: [e-mail]

REFERENCES AND NOTES

(1.) Knobeloch L, Salna B, Hogan A, Postle J, Anderson H. Blue babies and nitrate-contaminated well water. Environ Health Perspect 108:675-678 (2000).

(2.) National Library of Medicine. Medline Plus: Methylene Blue (Systemic). Available: http://www.nlm.nih.gov /medlineplus/druginfo/methylenebluesystemic202703.html [cited 23 August 2000].

(3.) National Library of Medicine. Medline Plus: Cephalosporins (Systemic). Available: http://www.nlm.nih.gov/medlineplus/ druginfo/cephalosporinssystemic202119.html [cited 23 August 2000].

(4.) Gosselin RE, Smith RP, Hodge HC. Clinical Toxicology of Commercial Products. 5th ed. Baltimore, MD:Williams & Wilkins, 1984.

(5.) MMWR. Methemoglobinemia attributable to nitrite contamination of potable water through boiler fluid additives--New Jersey, 1992 and 1996. MMWR Morb Mortal Wkly Rep 46(9):202-204 (1997).

(6.) Hegesh E, Shiloah J. Blood nitrates and infantile methemoglobinemia. Clin Chim Acta 125:107-115 (1982).

(7.) National Research Council. Nitrate and Nitrite in Drinking Water. Washington, DC:National Academy Press, 1995.

(8.) US Environmental Protection Agency. Final Drinking Water Criteria Document on Nitrate/Nitrite. NTIS PB91-142836. Springfield, VA:National Technical Information Service, 1990.