Correspondence
Mercury and the Risk of Myocardial Infarction
N Engl J Med 2003; 348:2151-2154May 22, 2003
- Article
To the Editor:
Guallar et al. (Nov. 28 isssue)1 report that a toenail mercury level as low as 0.11 to 0.66 μg per gram (estimated hair level, 0.34 to 2.03 μg per gram) was directly associated with a doubling of the risk of myocardial infarction. We find it difficult to reconcile this finding with published data on the cardiovascular health of highly exposed populations.
Patients with Minamata disease and hair mercury levels above 100 μg per gram did not have a higher rate of death from heart disease than controls,2 nor did they have a higher degree of arteriosclerosis.3 In the Minamata region of Japan, a population of approximately 50,000 with an average hair mercury level of 50 μg per gram did not have a higher rate of death from heart disease than a reference population of 800,000 with an average level of 9 μg per gram.4 According to data from monitoring programs in Canada, Cree Indians with an average hair mercury concentration of 10 μg per gram have a lower risk of death from circulatory disease than the rest of the population in Quebec,5 in which the average hair mercury level is 0.5 μg per gram. If, as Guallar et al. suggest, mercury increases the risk of myocardial infarction by more than 100 percent when the hair mercury level reaches approximately 2 μg per gram, how can one explain the absence of significant effects at doses greater than 100 μg per gram?
The authors raise the possibility of modifying fish-intake recommendations on the basis of their findings. In our opinion, this suggestion is ill founded and may do more harm than good, considering the nutritional value of fish.
5 ReferencesMichel Plante, M.D.
Stéphane Babo, Ph.D.
Hydro-Québec, Montreal, QC H2Z 1A4, Canada
plante.michel@hydro. qc. ca 1
Guallar E ,Sanz-Gallardo MI ,van't Veer P , et al. Mercury, fish oils, and the risk of myocardial infarction. N Engl J Med 2002;347:1747-1754
Full Text | Web of Science | Medline2
Tamashiro H ,Akagi H ,Arakaki M ,Futatsuka M ,Roht LH . Causes of death in Minamata disease: analysis of death certificates. Int Arch Occup Environ Health 1984;54:135-146
CrossRef | Web of Science | Medline3
Oyanagi K ,Furuta A ,Ohama E ,Ikuta F . Does methylmercury intoxication induce arteriosclerosis in humans? A pathological investigation of 22 autopsy cases in Niigata, Japan. Acta Neuropathol (Berl) 1992;83:217-227
CrossRef | Web of Science | Medline4
Tamashiro H ,Fukutomi K ,Lee ES . Methylmercury exposure and mortality in Japan: a life table analysis. Arch Environ Health 1987;42:100-107
CrossRef | Medline5
Robinson E . The health of the James Bay Cree. Can Fam Physician 1988;34:1606-1613
Web of Science | Medline
To the Editor:
In their Perspective article, Bolger and Schwetz1 recommend limiting the intake of mercury by reducing the consumption of mercury-contaminated fish because of possible negative cardiovascular and neurologic effects. We were surprised that they do not mention dental amalgam. Dental amalgam consists of 50 percent elemental mercury, and it is well known that mercury vapor is released from amalgam. In 1991, a World Health Organization (WHO) panel2 identified dental amalgam as the most important source of mercury in humans. The mean daily intake of mercury was calculated as 3 to 17 μg from amalgam and 2.4 μg from food and fish.2 A National Institutes of Health study of 1127 members of the military found that those with an average number of amalgam fillings had about 4.5 times the urine and blood mercury levels measured in controls without amalgam.3 Up to two thirds of the mercury burden in humans originates from dental amalgam.4 In addition, the mercury level in the human placenta correlates with the number of maternal amalgam fillings, and a substantial amount of mercury from amalgam can reach the fetus.5
Mercury from amalgam also contributes indirectly to the intake of methylmercury in humans because amalgam is an important source of mercury pollution from dental offices, crematories, and urine and feces from persons with amalgam fillings. We therefore believe it appropriate not only to reduce the consumption of mercury-contaminated fish but also to reduce the use of dental amalgam.
5 ReferencesJoachim Mutter, M.D.
Johannes Naumann, M.D.
University Hospital, 79106 Freiburg, Germany
jmutter@iuk3.ukl. uni-freiburg. de 1
Bolger PM ,Schwetz BA . Mercury and health. N Engl J Med 2002;347:1735-1736
Full Text | Web of Science | Medline2
Environmental health criteria 118: inorganic mercury. Geneva: World Health Organization, 1991.
3
Kingman A ,Albertini T ,Brown LJ . Mercury concentrations in urine and whole blood associated with amalgam exposure in a US military population. J Dent Res 1998;77:461-471
CrossRef | Web of Science | Medline4
Lorscheider FL ,Vimy MJ ,Summers AO . Mercury exposure from “silver“ tooth fillings: emerging evidence questions a traditional dental paradigm. FASEB J 1995;9:504-508
Web of Science | Medline5
Ask K ,Akesson A ,Berglund M ,Vahter M . Inorganic mercury and methylmercury in placentas of Swedish women. Environ Health Perspect 2000;110:523-526
CrossRef | Web of Science
To the Editor:
The contrasting results reported by Yoshizawa et al.1 and Guallar et al. on the role of mercury in the risk of myocardial infarction are puzzling. Yoshizawa et al., whose study was conducted in a U.S. population, report that mercury levels did not correlate with the risk of myocardial infarction and that high selenium levels did not have a protective effect. Guallar et al., whose study was conducted in a European population, report that mercury levels were directly associated with the risk of myocardial infarction and that high selenium levels were inversely associated with that risk. Most populations in Europe have a selenium intake of 12 to 94 μg per day, a level below the daily recommended dietary allowance; some even have an intake below the WHO's normative selenium requirements. In the United States, the selenium intake (60 to 220 μg per day) is well above the daily recommended dietary allowance,2 as reflected by the selenium levels reported in both articles. It is possible that mercury toxicity is pronounced at a selenium intake below a certain threshold.
Selenium is not a cofactor for glutathione peroxidase, as Guallar et al. state. Selenium is an essential trace element that is cotranslationally inserted in the form of the 21st amino acid, selenocysteine, into selenoproteins.3 Selenocysteine usually serves as the catalytic center of important redox enzymes, such as glutathione peroxidase and thioredoxin reductase. Numerous studies have shown the protective effects of selenium against mercury toxicity.4 The molecular basis of this protective effect is unclear. Further studies are needed to elucidate the role of selenium in mercury toxicity. Such studies will also help determine whether increasing the selenium intake in populations with a low selenium intake (as has been the practice in Finland since 1981, by means of selenium-supplemented fertilizers) has a public health benefit.
4 ReferencesChristoph Buettner, M.D., Ph.D.
Albert Einstein College of Medicine, Bronx, NY 10467
buettner11@yahoo.com 1
Yoshizawa K ,Rimm EB ,Morris JS , et al. Mercury and the risk of coronary heart disease in men. N Engl J Med 2002;347:1755-1760
Full Text | Web of Science | Medline2
Combs GF Jr . Selenium in global food systems. Br J Nutr 2001;85:517-547
CrossRef | Web of Science | Medline3
Hatfield DL ,Gladyshev VN . How selenium has altered our understanding of the genetic code. Mol Cell Biol 2002;22:3565-3576
CrossRef | Web of Science | Medline4
Goyer RA . Toxic and essential metal interactions. Annu Rev Nutr 1997;17:37-50
CrossRef | Web of Science | Medline
Author/Editor Response
Drs. Plante and Babo find it difficult to accept that an increased toenail mercury level (resulting from the consumption of contaminated fish) increases the risk of acute myocardial infarction in European men. The findings of epidemiologic studies of fish intake and coronary heart disease are contradictory, and it has been suggested that mercury might oppose the beneficial effects of n–3 fatty acids from fish. Because the effects of chronic exposure to low doses of mercury are difficult to extrapolate from data on acute high-dose exposures, our study was specifically designed to test this hypothesis. Indeed, we agree that one should promote the consumption of fatty fish on the basis of the presumed cardiovascular benefit. However, the public can increase its intake of n–3 fatty acids by eating fish species likely to have low mercury levels.
The latter message is also conveyed by Drs. Mutter and Naumann, but they remind us that dental amalgam is another important source of mercury exposure. It will be worthwhile to investigate the risk of coronary heart disease in subjects with such fillings, independently of poor oral hygiene.
Dr. Buettner finds the contrast between the results of our study and those of Yoshizawa et al. puzzling. In our study, mercury did not appreciably interact with selenium, as suggested by Dr. Buettner; the differences may have less to do with selenium and more to do with the study populations. Almost 60 percent of the subjects in the U.S. study were dentists, occupationally exposed to metallic mercury and with much higher toenail mercury levels than other health professionals. In this study, the overall association of mercury with the risk of cardiovascular disease could be influenced by a differential risk of disease among dentists. After the dentists were excluded, the risk of coronary heart disease for the highest as compared with the lowest quintile of mercury was 1.27 (95 percent confidence interval, 0.62 to 2.59), and this risk, as observed in our study, increased to 1.70 (95 percent confidence interval, 0.78 to 3.73) after adjustment for fish intake (both nonsignificant). This is remarkably close to our adjusted odds ratio of 1.86 (95 percent confidence interval, 1.20 to 2.91; P for trend = 0.001), even though the number of patients after exclusion of the dentists was roughly one third the number in our study. The increase in the relative risk of coronary heart disease from mercury after adjustment for fish intake has been very consistent.1,2 Since assessments of fish intake and mercury levels are subject to similar types of biases, these results strongly suggest that the opposing effects of mercury and fish oils are real and deserve careful consideration.
2 ReferencesEliseo Guallar, M.D., Dr.P.H.
Johns Hopkins Medical Institutions, Baltimore, MD 21205
eguallar@jhsph.edu Rudolph A. Riemersma, Ph.D.
University of Edinburgh, Edinburgh EH8 9XF, United KingdomFrans J. Kok, Ph.D.
University of Wageningen, 6701 BH Wageningen, the Netherlands1
Salonen JT ,Seppanen K ,Nyyssonen K , et al. Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in eastern Finnish men. Circulation 1995;91:645-655
Web of Science | Medline2
Rissanen T ,Voutilainen S ,Nyyssonen K ,Lakka TA ,Salonen JT . Fish oil-derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Circulation 2000;102:2677-2679
Web of Science | Medline
Author/Editor Response
Dr. Buettner raises the interesting possibility that differences in selenium intake might have contributed to the differences between Europe and the United States in the relation between mercury exposure and the risk of coronary heart disease. Although we did not observe an interaction with selenium levels, this possibility deserves examination within European populations.
In response to Drs. Mutter and Naumann, our findings should provide reassurance about potential adverse effects of mercury from dental amalgam on the risk of coronary heart disease. The form of mercury in amalgam is the same form that led to the high nail mercury levels in dentists, and in our study, dentists did not have a higher risk of coronary heart disease than other health professionals. Also, we have recently reported that a person's number of dental amalgam fillings, in contrast to his or her level of fish consumption, is not associated with nail mercury levels.1
1 ReferencesKazuko Yoshizawa, Sc.D.
Eric B. Rimm, Sc.D.
Walter C. Willett, M.D.
Harvard School of Public Health, Boston, MA 021151
Joshi A ,Douglass CW ,Kim HD , et al. The relationship between amalgam restorations and mercury levels in male dentists and nondental health professionals. J Public Health Dent 2003;63:52-60
CrossRef | Web of Science | Medline
Author/Editor Response
Although we certainly appreciate the concern expressed by Mutter and Naumann about dental amalgam, we did not address this source or form of mercury (elemental) in our Perspective article, but rather dealt exclusively with another form and source of mercury — namely, methylmercury in fish. In addition, Mutter and Naumann's initial statement is not entirely correct. The Food and Drug Administration advisory was constructed on the basis of possible adverse neurologic effects in fetuses, not on the basis of possible negative cardiovascular effects. This is not to say that the latter is not a cause of concern, but at the time the advisory was issued, and even now, the significance of preliminary reports of methylmercury-induced adverse cardiovascular effects remains very uncertain.
P. Michael Bolger, Ph.D.
Bernard Schwetz, D.V.M., Ph.D.
Food and Drug Administration, College Park, MD 20740
philip.bolger@cfsan. fda. gov - Citing Articles (14)
Citing Articles
1
P. Xun, N. Hou, M. Daviglus, K. Liu, J. S. Morris, J. M. Shikany, S. Sidney, D. R. Jacobs, K. He. (2011) Fish oil, selenium and mercury in relation to incidence of hypertension: a 20-year follow-up study. Journal of Internal Medicine 270:2, 175-186
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Masaaki Uematsu. (2010) Is Right Ventricular Dysfunction in Obstructive Sleep Apnea a Potential Screening Tool?. Circulation Journal 74:2, 250-251
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Masahiko Kato, Taro Adachi, Yuki Koshino, Virend K. Somers. (2009) Obstructive Sleep Apnea and Cardiovascular Disease. Circulation Journal 73:8, 1363-1370
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Marie-Claire Bélanger, Marc-Edouard Mirault, Eric Dewailly, Michel Plante, Line Berthiaume, Micheline Noël, Pierre Julien. (2008) Seasonal mercury exposure and oxidant-antioxidant status of James Bay sport fishermen. Metabolism 57:5, 630-636
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Kunitoshi Iseki. (2008) Chronic Kidney Disease in Japan. Internal Medicine 47:8, 681-689
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Yoshihiko Seino. (2007) Central Sleep Apnea due to Chronic Heart Failure: Cheyne-Stokes Respiration. Nihon Ika Daigaku Igakkai Zasshi 3:1, 34-38
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Yoshihiko Seino, Hidehiko Imai, Takaaki Nakamoto, Yoshihiko Araki, Shigetake Sasayama. (2007) Clinical Efficacy and Cost-Benefit Analysis of Nocturnal Home Oxygen Therapy in Patients With Central Sleep Apnea Caused by Chronic Heart Failure. Circulation Journal 71:11, 1738-1743
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Shigetake Sasayama, Toru Izumi, Yoshihiko Seino, Kenji Ueshima, Hidetsugu Asanoi, for The CHF-HOT Study Group. (2006) Effects of Nocturnal Oxygen Therapy on Outcome Measures in Patients With Chronic Heart Failure and Cheyne-Stokes Respiration. Circulation Journal 70:1, 1-7
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Takatoshi Kasai, Koji Narui, Tomotaka Dohi, Hisashi Takaya, Naotake Yanagisawa, George Dungan, Sugao Ishiwata, Minoru Ohno, Tetsu Ymaguchi, Shin-ichi Momomura. (2006) First Experience of Using New Adaptive Servo-Ventilation Device for Cheyne-Stokes Respiration With Central Sleep Apnea Among Japanese Patients With Congestive Heart Failure. Circulation Journal 70:9, 1148-1154
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Zhi-Hui Zhao, Zhi-Hong Liu, Qin Luo, Chang-Ming Xiong, Xin-Hai Ni, Jian Zhang, Shu Zhang, Yue-Jin Yang. (2006) Positive Pressure Ventilation Treatment Reduces Plasma Levels of Amino Terminal-Pro Brain Natriuretic Peptide in Congestive Heart Failure Patients With Sleep Apnea. Circulation Journal 70:5, 572-574
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(2004) Fish Consumption, Mercury Exposure, and Heart Diseases. Nutrition Reviews 62:2, 68-72
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