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Background: An epidemiological investigation was undertaken in all age groups to assess the prevalence of methaemoglobinaemia in areas with high nitrate concentration in drinking water., Methods: Five areas were selected with an average nitrate concentration (as nitrate) of 26, 45, 95, 222 and 459 mg nitrate ions/litre in drinking water. These areas were visited and the house schedule (containing name, age, sex and weight of the family members) prepared in accordance with the statistically designed protocol. In all, 178 persons, matched for age and weight, were selected and arranged in five age groups. They constituted 10% of the total population of each of these areas. A detailed history of the selected population was taken, medical examination conducted and blood samples taken to ascertain the level of methaemoglobin. The collected data were subjected to statistical analysis to ascertain a relationship between nitrate concentration and methaemoglobinaemia., Results: High nitrate concentrations cause severe methaemoglobinaemia (7%-27% of Hb) in all age groups, especially in the age group of less than 1 year and above 18 years. The lower levels of methaemoglobin in the age group of 1-18 years is probably due to better reserve of cytochrome b5 reductase activity and its adaptation to increasing nitrate concentration in water to compensate for methaemoglobinaemia in this age group., Conclusion: We conclude that high nitrate ingestion causes methaemoglobinaemia in all age groups. Cytochrome b5 reductase activity and its adaptation with increasing water nitrate ingestion plays a role in compensating for the methaemoglobinaemia.

An epidemiological investigation was undertaken in India to assess the prevalence of methaemoglobinaemia in areas with high nitrate concentration in drinking-water and the possible association with an adaptation of cytochrome-b5 reductase. Five areas were selected, with average nitrate ion concentrations in drinking-water of 26, 45, 95, 222 and 459 mg/l. These areas were visited and house schedules were prepared in accordance with a statistically designed protocol. A sample of 10% of the total population was selected in each of the areas, matched for age and weight, giving a total of 178 persons in five age groups. For each subject, a detailed history was documented, a medical examination was conducted and blood samples were taken to determine methaemoglobin level and cytochrome-b5 reductase activity. Collected data were subjected to statistical analysis to test for a possible relationship between nitrate concentration, cytochrome-b5 reductase activity and methaemoglobinaemia. High nitrate concentrations caused methaemoglobinaemia in infants and adults. The reserve of cytochrome-b5 reductase activity (i.e. the enzyme activity not currently being used, but which is available when needed; for example, under conditions of increased nitrate ingestion) and its adaptation with increasing water nitrate concentration to reduce methaemoglobin were more pronounced in children and adolescents.

To obtain an indication of the nitrate-nitrogen levels in drinking water in rural areas of upstate New York and the number of infants at risk for methemoglobinemia, 419 wells supplying drinking water to farms were tested. Farmers were identified through two programs run by the New York State Department of Health. The farmers were asked to complete a short questionnaire about the type and size of their farm and their well and to collect the water sample. Overall, nitrates were detectable in 95% of the wells tested (concentration levels greater than 0.05 mg/L) and 15.7% had levels which exceeded 10 mg/L. Fifteen percent of the wells tested from farms where infants resided were also elevated. Wells which were shallow, dug or located on large farms, or springs were more likely to have elevated concentrations of nitrates., (Copyright 1999 Academic Press.)

NADH-cytochrome b5 reductase (b5R), present in various tissues of the body, is a redox enzyme of multiple functions. The deficiency of the enzyme leads to hereditary methemoglobinemia. With rabbit anti-b5R antibody for plate coating and enzyme-labeled anti-b5R monoclonal antibody as reporter, we have developed a sandwich ELISA procedure for the determination of b5R concentration. This procedure is sensitive to a wide range of linearity, and convenient in coping with large numbers of samples. Using this novel method, cytosolic b5R concentration in the erythrocytes of 30 normal Chinese adults was estimated to be 25.63+/-8.54 ng/mg Hb. It was found that the concentration of red cell soluble b5R of five newborns was significantly lower than that of normal adults and soluble b5R was undetectable in the erythrocytes of 4 patients with type I hereditary methemoglobinemia. Our results demonstrated that the reduced b5R activity in red cell cytosol of both neonates and type I hereditary methemoglobinemic patients results largely or mainly from the lowered b5R concentration. Our novel method might be further exploited for in-depth investigation of the relationship between the qualitative and quantitative changes of b5R with regard to physiological and pathological conditions.

Nitrite and nitrate ions are naturally occurring forms of nitrogen that can be present in ground and surface water and can be used as a food preservative because they inhibit the growth of Clostridium botulinum. Exposure to excessive levels of nitrite or nitrate may result in the acute syndrome of methemoglobinemia (MetHb), in which nitrite binds to hemoglobin. This report summarizes the findings of investigations of two incidents in which unintentional exposure to high doses of nitrite occurred through drinking potable water contaminated with additives to boiler conditioning fluids.

Infantile diarrhea is sometimes associated with methemoglobinemia. To determine the significance of intestinal bacterial infection or overgrowth and other predisposing factors in this entity, we evaluated prospectively 45 consecutive patients who were admitted for gastroenteritis and methemoglobinemia between March 1980 and September 1992. All the patients were younger than 3 months of age. In 95% of them, methemoglobinemia occurred between the ages of 15 days to 2 months. The peak mean methemoglobin concentration was 9.4% (range, 2.4-57%). Although stool cultures were positive in only 22% of the infants, the epidemiologic data strongly suggested a bacterial or viral etiology in our study population: for 12 years, there was a significant decrease in the annual incidence of methemoglobinemia associated with diarrhea in parallel to the decrease in infantile diarrhea due to known pathogens throughout the country in the same period. There was also a marked seasonal variation in the incidence of the disease, with two peaks in January and the summer months when viral and bacterial infections, respectively, are prevalent. Failure to thrive and low admission-weight percentiles were associated with methemoglobinemia in most of the patients and diarrhea lasting > or = 7 days in 22 (49%) patients. The blood pH and the degree of acidosis did not correlate with the severity of methemoglobinemia. All the patients were formula fed. In the etiology of methemoglobinemia in infants with enteritis, viral and bacterial pathogens appear to play an important role by altering intestinal flora. Breast feeding appears to protect against this entity.

In the study it was intended to evaluate the concentration of nitrates and nitrites in some food products and samples of potable water collected in Kraków region and compile these results with frequency of recognised toxic methemoglobinemia cases. In the years 1991-1993 91 food samples, 288 samples of tap water from the central waterworks of Kraków and 399 samples of well-water from the country side of Kraków region were collected. In the chemical laboratories the nitrates and nitrites concentration has been defined. The clinical material of inpatients from 2 hospitals of Kraków and the data from the Poison Information Centre in Kraków have been analysed. The examined food samples did not present, in general, raised levels of nitrates and nitrites. Also the tap water samples presented a low concentration of these substances. The well-water samples demonstrated in considerable percentage increased levels of nitrates and nitrites and exceed the level permitted by sanitary law. In the Provincial Childrens Hospital during recent 14 years 8 infants with recognised methemoglobinemia were treated. All cases were connected with environmental pollution. At the Department of Toxicology, where only adults are treated, no methemoglobinemia cases resulting from environmental pollution during recent 26 years were hospitalized. The Poison Information Centre during recent 14 years consulted 239 cases of methemoglobinemia; 90% of them concerned children intoxicated because of environmental pollution.

In the paper a thorough study of the influence of the methemoglobin levels and the occurrence of certain syndromes of clinical symptoms was made in the inhabitants living in the immediate vicinity of the large refuse dumps. During a 2.5-day clinical hospitalization the following examinations were done: general medical, specialistic and neuropsychological examinations, biochemical-analytical examination, EKG, chest X-ray, USG of the abdominal cave, spirometric tests, toxicological investigation of body fluids: carboxyhemoglobin, methemoglobin, lactates. The air pollution was measured and included: continuous measurement of the suspended particulate matter, carbon monoxide, sulfur dioxide, nitrogen oxide, nitrogen dioxide and the sum of nitrogen oxides. The evaluation of the refuse dumps gas showed that its main compounds were: carbon dioxide, methane in the amount of a few volume percent. Other pollutants were: carbon monoxide, hydrogen sulfide, methane homologues and aromatic hydrocarbons. The results of biochemical investigations were within normal limit. The elevated methemoglobin levels were found in 8 patients. The increased values of blood lactate concentration were found in 14 people and in 8 people the elevation of carboxyhemoglobin level was noted. The results of toxicological investigation do not unequivocally indicate the occurrence of toxic methemoglobinemia. However, the elevated levels of methemoglobin and lactates indicate a slight degree of oxygen deficiency in the body. In the examined people typical symptoms of methemoglobinemia were not observed, the only symptoms which may indicate their impact on the central nervous system were frequent headaches and neurovegetative disorders.

It was studies the content of nitrates and nitrites in water sources and vegetables from different geographical regions, resulting high values of nitrates in colinae and plain regions, and low values in mountain and submountain region. The high value of nitrates are related with methaemoglobinaemia. The nitrites from edible water studied and from vegetables presented very low values in the order of ppm.

After detection of a few clinical cases of methaemoglobinaemia (methb) in our NICU, a prospective clinical study was undertaken to determine the extent of the problem and to identify the causes. Consequently, during the following 8 months all haemoglobin tests included simultaneous measurements of methb on an OSM 3 hemoximeter (Radiometer): 8% (n = 33) of 415 neonates were found to be methb positive (defined as > or = 6% methb). Mean methb was 19% (range 6.5-45.5%). Maximum methb concentrations were found on day 4-31 postpartum (mean 12 days) and the number of days with a positive methb sample ranged from 1 to 18 days (mean 6 days). About 40% of the neonates born at 25-30 weeks of gestation and 60% with a birth weight < 1000 g were methb positive. Also, there was a negative correlation between the size of the methb positive concentration and gestational age (r = -0.38, p = 0.02). Measurements of C-reactive protein and leucocytes, NADH reductase, pH, Cl, nitrate and nitrite were carried out in methb positive patients. The tests were repeated 1 week after cessation of methb. The only significant difference was an increase in NADH reductase at the second measurement. Likewise, a wide range of clinical parameters were registered and they occurred with a higher frequency among the methb positive patients when compared with a methb negative control group matched with regard to gestational age and the closest possible birth weight. The mean birth weight of methb positive patients was 1170 g and that of negative controls 1380 g (p < 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

Background: On October 20, 1992, > 40 children from one elementary school visited the school nurse due to the acute onset of blue lips and hands, vomiting, and headache during and after the school lunch periods. Forty-nine children were seen by physicians that day and 14 were hospitalized. Laboratory analysis revealed methemoglobinemia in many of the children. All recovered in 36 hours., Objective: A case-control study was supplemented by environmental and laboratory investigations to determine the outbreak source., Methods: Cases were selected based on the laboratory diagnosis of methemoglobinemia (methemoglobin level > 2%). Children whose methemoglobin levels were missing or < 2% were excluded from analysis. Controls were obtained by selecting every third name from a school roster. The parents of 29 students who met the case definition and 52 controls were interviewed., Results: All 29 cases and 33% (17/52) of the controls ate soup during the school lunch (odds ratio undefined, lower 95% confidence limit 16.1). Two pots of soup were prepared from ready-to-serve cans, which were diluted with water and enriched with a commercially prepared flavor enhancer. The school's boiler, dormant during the previous 5 months, was restarted on the morning of the outbreak. The boiler also served as a tankless hot water heater. Laboratory analysis of the soup identified abnormally high quantities of nitrite (459 ppm) and sodium metaborate, major components of the boiler water treatment solution. Undiluted soup from the same lot had 2.0 ppm nitrites; the flavor enhancer had 2.2 ppm nitrites. Nitrites were present in the hot potable water system (4 to 10 ppm) and absent in the cold potable water system., Conclusions: This outbreak of methemoglobinemia due to nitrite poisoning was traced to soup contaminated by nitrites in a boiler additive. Nitrites are ubiquitous and potentially hazardous inorganic ions. Extreme caution should be used when the possibility for toxic human exposure to nitrites exists.

Objective: To identify commercial baby food varieties high in nitrate content using ion chromatography and compare the health risk associated with the consumption of high-nitrate water and high-nitrate commercial baby food., Design: Ion chromatographic determination of nitrate concentration in a variety of commercial baby foods., Setting: University Hygienic Laboratory, University of Iowa College of Medicine, Iowa City., Patients: None., Results: Commercial baby foods with nitrate levels higher than 45 ppm include mixed vegetables, bananas, carrots, garden vegetables, spinach, green beans, and beets. The amount of nitrate in one 113-g (4 oz) jar of beets, for example, is equivalent to the amount of nitrate in nearly 5.5 L of water at 45 ppm nitrate., Conclusions: A controlled clinical trial is needed to clarify how consuming high-nitrate foods correlates with methemoglobin levels in infants younger than 6 months.

In the production of cross-linked polyethylene in the air of the working environment above the norm concentrations of acetophenon, dicumyl peroxide and antioxidant are established, which create unfavourable working conditions. During clinical and laboratory examinations of 55 workers, engaged in the production of cross-linked polyethylene, are registered subjective complaints from the irritating effect of the chemical noxae on the mucous membranes and skin. Methaemoglobinaemia is found in 4 workers. There are deviations in the functional state of the liver (transaminase, APh, GGTP and triglycerides) in the group "maintaining staff". The same workers have also increased quantity of metabolite hippuric acid in the urine. On the grounds of the results, the group "maintaining staff" is determined as risk group. Recommendations are made for follow-up care and work in controlled parameters of the working environment.

Cases of unstable hemoglobin and hemoglobin M disease that have appeared as de novo mutants over a span of approximately 50 years were used to deriving minimal, direct estimates of mutation rates per nucleotide per generation in man. The estimates are based upon analysis of data related to 40 cases of unstable Hbs and 15 of Hbs M that arose in 13 countries. The estimated rate calculated using all de novo beta-gene mutants is 7.4 X 10(-9) per nucleotide per generation; that derived using de novo alpha-gene mutants is 10.0 X 10(-9). Subsequent calculations of mutation rates per alpha- and beta-chain gene and extrapolation of these rates to a hypothetical gene of 1000 nucleotides yield an estimated mutation rate of 8.6 X 10(-6) per 1000 nucleotides per generation. Even though some instances of false paternity may have biased these estimates in an upward direction, under-reporting of Hb M cases, and particularly of unstable hemoglobins, makes it likely that the cited values are minimal estimates of mutation rates at the molecular level.

Red blood cell activities of superoxide dismutase and glutathione peroxidase, two key enzymes responsible for the control of the concentrations of activated oxygen species, were approximately two-fold higher in residents of Vila Parisi (Cubatão, Brazil)--a higher polluted neighborhood--than in a population sample from São Paulo City. The catalase levels were the same in both samples. A concurrent high concentration of methemoglobinemia and sulfhemoglobinemia was encountered in the blood of Vila Parisi residents. These data raise the possibility that the increased rate of oxyhemoglobin oxidation yielding O-.2 and H2O2 may be relevant to mutagenesis induced by HO. radicals.

Several epidemiological studies in California have yielded data on percentage methaemoglobin in healthy individuals. The population groups represented include infants, elementary and high school children, and adults. The distributions of values in each group are described, as well as the differences between groups. Factors affecting the distributions are discussed. In the study of infants, the factors assessed include respiratory and gastrointestinal disease, and food and water intake. In schoolchildren, the effect of age and location of residence within Southern California are evaluated, and in adults, smoking, gender and time of day. Among infants in the 31 to 60 day age range, 33 per cent had methaemoglobin levels of 3 per cent or above, while 8 per cent had methaemoglobin levels of 4 per cent or above. Among adults, 15 per cent had levels of 3 per cent or above, while 2 per cent had levels of 4 per cent or above. Among both elementary and high school students, 3 per cent had methaemoglobin levels of 3 per cent or above, while less than 1 per cent had levels of 4 per cent or greater.