Nitrate and methemoglobinemia. (Correspondence).

After they had collected extensive particulars in the Transylvania Region of Romania for an epidemiologic cohort study exploring a hypothetical relationship between high nitrate infant exposure and later neuropsychologic development, Zeman et al. (2002) tried to take advantage of these data in order to settle the question of whether infant methemoglobinemia is correlated with mean daily nitrate intakes or with diarrheal disease in the first months of life. However, we have serious reservations about their paper, especially their methodology.

In the study, proxy interviews of primary caregivers were used to reconstruct mean daily dietary nitrate exposures, but these interviews took place nearly 5 years after the clinical events. Although such data may be accurate enough for the study of a chronic disease, their reliability and accuracy are questionable in the study of an acute condition such as methemoglobinemia.

Well-water samplings were intended to evaluate water nitrate levels and reconstruct mean daily dietary nitrate exposures; they too were taken nearly 5 years after the clinical incidents. Nitrate levels in well water vary with time and season, which again opens the method to criticism.

Infant methemoglobinemia is an acute event. Usually the only clinical symptom (i.e., cyanosis) spontaneously disappears in several minutes, at the most in a few hours. We wonder what good it serves to try to correlate such an acute and transitory infant disease with mean daily nitrate intake during the first months of life. Moreover, why did interviewers (Zeman et al. 2002) ask primary caregivers to recall dietary habits of the child at both 2 and 6 months of life, when all clinical incidents regarded as methemoglobinemias appeared before (in their Table 1) or around (noted in text) 2 months of life?

Our primary criticism of the paper (Zeman et al. 2002) refers to the recruitment criteria of the infant methemoglobinemia cases: in all the cases, diagnoses are merely clinical. It is commonly known that cyanosis appears when methemoglobin levels exceed 10% (not 3% as might by construed from the comments of the authors). Of course, methemoglobinemia is not the only cause of infant cyanosis. Other pathologic conditions are quite possible. The only way to diagnose a case of infant methemoglobinemia with assurance is to measure the methemoglobin level in the blood at the time of the clinical incident. The physician will be justified in recognizing the case as infant methemoglobinemia if, and only if, the methemoglobin level exceeds 10%.

These important reservations having been stated, it is not at all surprising that Zeman et al. (2002) found the strongest association with estimated nitrate exposure, given that the infants were exposed to extremely high nitrate levels. The mean nitrate content of the drinking water in the cases was estimated at over 25 times the current U.S. drinking water maximum contaminant level (MCL) of 10 ppm nitrate nitrogen (U.S. Environmental Protection Agency 1991). In all of the cases, the nitrate content of the drinking water was at least 5 times higher than the MCL, and one case was 120 times the U.S. official limit.

Despite these extreme water nitrate concentrations, it is possible to note, as Zeman et al. (2002) did, that at lower estimated nitrate exposures diarrhea seems to be able to favor the appearance of infant methemoglobinemia. We are not sure that their work really succeeds in demonstrating such a link, but a number of papers published in the last few years [cited by Avery (1999) and L'hirondel and L'hirondel (2001)] had already convinced us of it.

Alex Avery
Hudson Institute
Center for Global Food Issues
Churchville, Virginia
E-mail: [e-mail]

Jean-Louis L'hirondel
Service de Rhumatologie
Centre Hospitalier Universitaire de Caen
Caen, France
E-mail: [e-mail]

REFERENCES

Avery AA. 1999. Infantile methomoglebinemia: reexamining the role of drinking water nitrates. Environ Health Perspect 107:583-586.

L'hirondel J, L'hirondel J-L 2001. Nitrate and Man: Toxic, Harmless or Beneficial? Wallingford, UK:CABI.

U.S. Environmental Protection Agency. 1991. National primary drinking regulations; final rule. 40CFR141-143. Fed Reg 56(20):3526-3597.

Zeman CL, Kross B, Vlad M. 2002. A nested case-control study of methemoglobinemia risk factors in children of Transylvania, Romania. Environ Health Perspect 110:817-822.