(Circulation. 1995;91:645-655.)
© 1995 American Heart Association, Inc.
Articles |
Intake of Mercury From Fish, Lipid Peroxidation, and the Risk of Myocardial Infarction and Coronary, Cardiovascular, and Any Death in Eastern Finnish Men
From the Research Institute of Public Health (J.T.S., K.S., K.N., J.K., R.S.) and Departments of Community Health and General Practice (H.K.) and Chemistry (M.K.), University of Kuopio, Finland; the Department of Epidemiology and Health Promotion (J.T.), the National Public Health Institute of Finland, Helsinki, Finland; and the Institute of Biochemistry (H.E., F.T.), University of Graz, Austria.
Correspondence to Prof Jukka T. Salonen, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Even though previous studies have suggested an association between high fish intake and reduced coronary heart disease (CHD) mortality, men in Eastern Finland, who have a high fish intake, have an exceptionally high CHD mortality. We hypothesized that this paradox could be in part explained by high mercury content in fish.
Methods and Results We studied the relation of the dietary intake
of fish and mercury, as well as hair content and urinary excretion of
mercury, to the risk of acute myocardial infarction (AMI) and death
from CHD, cardiovascular disease (CVD), and any cause in 1833 men aged
42 to 60 years who were free of clinical CHD, stroke, claudication, and
cancer. Of these, 73 experienced an AMI in 2 to 7 years. Of the 78
deceased men, 18 died of CHD and 24 died of CVD. Men who had consumed
local nonfatty fish species had elevated hair mercury contents. In Cox
models with the major cardiovascular risk factors as covariates,
dietary intakes of fish and mercury were associated with significantly
increased risk of AMI and death from CHD, CVD, and any death. Men in
the highest tertile (
2.0 µg/g) of hair mercury content had a
2.0-fold (95% confidence interval, 1.2 to 3.1; P=.005) age-
and CHD-adjusted risk of AMI and a 2.9-fold (95% CI, 1.2 to 6.6;
P=.014) adjusted risk of cardiovascular death compared with
those with a lower hair mercury content. In a nested case-control
subsample, the 24-hour urinary mercury excretion had a significant
(P=.042) independent association with the risk of AMI. Both
the hair and urinary mercury associated significantly with titers of
immune complexes containing oxidized LDL.
Conclusions These data suggest that a high intake of mercury from nonfatty freshwater fish and the consequent accumulation of mercury in the body are associated with an excess risk of AMI as well as death from CHD, CVD, and any cause in Eastern Finnish men and this increased risk may be due to the promotion of lipid peroxidation by mercury.
Key Words: lipids • oxygen • mortality • infarction
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
A high fish intake has been associated with a reduced mortality from coronary heart disease (CHD) in several prospective population studies.1 2 3 4 In at least three more recent studies in populations with high fish intakes, no such relation was, however, observed.5 6 7 Also, even though men in Eastern Finland consume a lot of fish,8 their mortality from CHD is one of the highest in the world.9 This is in controversy with the concept that a high fish intake would uniformly be healthy for the cardiovascular system. Studies that found an association could not establish the nutrient in fish that was protective, even though n-3 polyunsaturated fats were suggested to have a key role.1 4
Because in some populations a high intake of fish did not appear to be associated with reduced CHD mortality, differences have to exist in the nutrient composition of fish, or possibly some unmeasured harmful substances in fish might account for these inconsistencies. We hypothesized that mercury in fish could counteract the beneficial metabolic effects of other nutrients in fish.
We have earlier observed a relation between selenium deficiency and an excess risk of acute myocardial infarction (AMI) as well as death from CHD and CVD in Eastern Finland.10 The finding was subsequently confirmed in another prospective population study11 and in a case-control study.12 We also found an association of both low serum selenium levels13 and lipid peroxidation in vivo14 with accelerated progression of carotid atherosclerosis in Eastern Finnish men. In another prospective population study in men in Eastern Finland, the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD), we found a relation between high dietary intake and stored body levels of iron, a catalyst of lipid peroxidation, with increased risk of AMI.15
Because mercury is another transition metal that also can catalyze lipid peroxidation,16 17 and because mercury counteracts the antioxidative effect of selenium,18 we hypothesized that a high dietary intake of mercury from freshwater fish could be associated with an increased risk of AMI and death from CHD, cardiovascular disease (CVD), and any cause.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Subjects
The KIHD is a population study to investigate previously unestablished risk factors for AMI and carotid atherosclerosis19 in men in Eastern Finland, the population with the highest recorded CHD incidence and mortality.9 One of the main purposes of the study was to investigate the role of lipid peroxidation, pro-oxidative minerals, and antioxidants in atherosclerosis and CHD. Hair and urine samples were collected at the baseline examination for mercury determinations. The baseline examinations were carried out between March 1984 and December 1989.
The study sample was composed of 3235 men in Eastern Finland aged 42, 48, 54, or 60 years at the baseline examination. Of these, 2682 (82.9%) participated. Men with either prevalent CHD (n=677) or history of cerebrovascular stroke (n=60), claudication (n=108), or cancer (n=46) were excluded from the present analyses, as these diseases could have influenced the dietary habits. Prevalent CHD was defined as either a history of AMI or angina pectoris or positive angina pectoris on effort in Rose interview20 or the use of nitroglycerin tablets once a week or more frequently. The diagnosis of stroke, claudication, and cancer was based on an interview and examination by a physician. Of the remaining 1889 men, data on both fish intake and hair mercury content were available for 1833 men. For these men, data on systolic blood pressure were missing for 10 men, on cigarette-years for 36 men, on serum ferritin concentration for 47 men, on serum apolipoprotein B for 61 men, on serum HDL2 cholesterol for 72 men, and on maximal oxygen uptake for 183 men. For these men, the mean value of the variable in question in the entire cohort (n=1833) was used.
Urinary mercury excretion was determined in a subset of subjects consisting of those who had an AMI during the follow-up and a double number of control subjects who had no AMI during the follow-up. Two control subjects were matched to each patients according to age, municipality of residence, and date of baseline examination. A baseline 24-hour urine sample was available for 69 patients and 138 control subjects, totaling 207 men.
Laboratory Methods
Blood, Hair, and Urine Sampling
The examination protocol and measurements have been described in
detail
previously.8 13 14 15 19
Subjects came to give blood
and hair specimens between 8:00 and 10:00 AM on Tuesday,
Wednesday, or Thursday. They were instructed to abstain from ingesting
alcohol for 3 days, from smoking for 12 hours, and from eating for 12
hours. After the subject had rested in the supine position for 30
minutes, blood was drawn with Terumo Venoject vacuum tubes. No
tourniquet was used. For blood sampling, a hair sample averaging 40 mg
was cut from the scalp hair of the subjects for mercury measurements.
The subjects had a 24-hour urine sample collected during the 24 hours
preceding the study visit when blood samples were drawn.
Determination of Hair and Urine Mercury
Mercury in
hair and urine samples was determined between May
1992 and August 1993 by flow injection analysis–cold vapor atomic
absorption spectrometry and amalgamation. Hair samples were processed
in a random order at the Department of Chemistry of the University of
Kuopio. The chemist who did the measurements was blinded with regard to
all risk factor values and health outcomes.
All reagents were of
analytical grade unless indicated otherwise. All
solutions were prepared with ultrapure water with a specific
resistivity of 18 M
/cm (Millipore).
As the quality control materials for hair, we used a hair pool (UPPS85) with a certified mercury content of 1.11±0.10 µg/g, a flour with a mercury content of 5.60±0.40 µg/g (International Atomic Energy Agency), a BCR pig kidney reference material no. 186 with a mercury content of 1.97±0.04 µg/g (Commission of the European Communities, Community Bureau of Reference, Brussels, Belgium), and hair from a control subject. For urine, the quality control material was Seronorm Trace Elements Urine with an added mercury of 50.0 µg/L (Nycomed Pharma AS).
Sample mineralization was performed with a Microwave Digestion System (model MDS-81D, CEM Corp). Dry hair samples (3 to 50 mg) and concentrated urine samples (1.0 mL) were treated with a mixture of Suprapur nitric acid and hydrochloric acid. After mineralization, samples were stabilized with potassium permanganate. The mercury in the samples, standards diluted from a stock mercury solution (1000 mg/L, Merck), and quality control materials was determined with the FIAS-200 Flow Injection Analysis and Amalgam System (Bodenseewerk Perkin-Elmer GmbH). Mercury was reduced in the Chemifold of FIAS-200 to atomic mercury vapor with NaBH4. Atomic mercury vapor was first carried by a stream of 99.998% argon (AGA) into the Amalgam System and next into the quartz cell in the Perkin-Elmer Zeeman 5000 Spectrometer (Bodenseewerk Perkin-Elmer GmbH), where the quantity of mercury was measured at 253.7 nm.
The mean values of mercury content in the UPPS85 hair pool, in the flour, and in the BCR material were 1.10, 5.44, and 1.97 µg/g, and the coefficients of variation between sample batches were 7.3%, 3.9%, and 6.1%, respectively. The variation coefficients for a subject's hair were 8.6% (n=48), 7.8% (n=52), and 7.7% (n=92) in three periods, during each of which one batch was used. The mean value of mercury concentrations in the Seronorm Trace Elements Urine was 49.35 µg/L, and the coefficient of variation between sample series (including lyophilization, digestion, and measurement procedure) was 9.8%.
To study the tracking of hair mercury values over time, repeat hair samples were collected and the mercury contents were measured for 21 subjects 4 to 9 years (mean, 6 years) after the baseline examination. Pearson correlation coefficient between the original and the repeat measurements was .91.
Determination of Immune Complexes
Containing Oxidized LDL
Serum immune complexes containing oxidized LDL
were measured in
a subsample of 187 control subjects using an ELISA assay with
copper-oxidized LDL as the antigen. Serum samples had been kept frozen
at -20°C for 3 to 8 years and had not been thawed previously. The
assays were performed at the Institute of Biochemistry, University of
Graz, Austria, in 1992.
To derive oxidized human LDL antigen, LDL was isolated from healthy donors by density gradient ultracentrifugation and oxidized with copper ions as previously described.21
To prepare rabbit antisera to oxidized LDL, two rabbits were immunized five times with oxidized LDL at intervals of 2 weeks.21 Antisera derived from these two rabbits were used in parallel in the present study.
Microtiter plates (Nunc Maxisorp) were coated with 250 µL of 1:1000 diluted antiserum in CO3 buffer20 and kept overnight at +4°C. After washing (Dubecco's phosphate-buffered saline [PBS] with 21.2 g NaCl and 0.5 mL Tween-20 per liter), 200 µL of dilution buffer (PBS with 1% bovine serum albumin) was added into each well and incubated for 30 minutes at +20°C, followed by addition of 10 µL of serum sample and incubation for 2 hours at +37°C. After washing, the assay was developed with a goat anti-human IgG antibody labeled with peroxidase (Medac) and tetramethylbenzidine as substrate. The absorption was measured at 492 nm. For calibration, a human serum that gave a very high signal in this assay was used as the standard and was assayed on each plate in parallel with all other samples. The titer was expressed as a percent of the signal of the standard serum. All assays were done in duplicate, and the mean titer was used in the statistical analysis.
The entire series of immune
complex measurements was repeated using a
-globulin fraction of another rabbit antiserum against oxidized LDL
instead of the neat rabbit antiserum. This material was prepared by
adding ammonium sulfate (35% saturation) to the serum at +40°C. The
sediment obtained after centrifugation was redissolved in a volume of
PBS equal to the original volume of serum. For plate coating, the
-globulin fraction was diluted 1:1000. The nonspecific binding of
all 187 serum samples was measured in the same way except that plates
were not coated with the rabbit antiserum. The titer was expressed,
after subtraction of nonspecific binding, as a percent of the signal of
the standard serum.
Other Chemical Measurements
The
main lipoprotein fractions (VLDL, LDL, and HDL) were
separated from fresh serum samples using ultracentrifugation and
precipitation as described previously in detail.22 The
HDL2 and HDL3 subfractions were separated
during a second ultracentrifugal spin at 108 000g for 62
hours against a density of 1.125 g/cm3. The cholesterol
contents of all lipoprotein fractions were measured enzymatically
(CHOD-PAP method, Boehringer Mannheim) on the day after the last spin.
Apolipoprotein B was determined by an immunoturbidimetric method of
Kone Oy.15
Serum samples for ferritin assays were kept frozen at -20°C for 1 to 5 years.15 Ferritin concentrations were measured with a double antibody radioimmunoassay (Amersham International). Plasma fibrinogen concentration was measured based on clotting of diluted plasma with excess thrombin with the Coagulometer KC4 (Heinrich Amelung GmbH).23 Albumin concentrations were measured from frozen serum samples photometrically (Kone Oy). The between-batch coefficient of variation for albumin was 1.9% at the level of 32 g/L. Blood glucose was measured by glucose dehydrogenase method (Merck) after precipitation of proteins with trichloric acetic acid.
Serum selenium concentration was measured by an atomic absorption spectrometric method using graphite furnace, Zeeman background correction, and pyrolytically coated graphite tubes with a platform13 and serum copper with atomic absorption spectrometry with flame atomization.24
Plasma ascorbate concentrations were measured with a high-performance liquid chromatography method.25 Urinary nicotine metabolites were assayed by a colorimetric method in 24-hour urine samples.26 The nicotine metabolite concentration was multiplied by the 24-hour urine volume to derive the 24-hour excretion.
Assessment of Dietary Fish and Mercury Intake
The consumption
of foods was assessed at the time of blood
sampling with an instructed and interview-checked 4-day food recording
by household measures.8 15 The instructions were
given and
the completed food records were checked by a nutritionist. The intake
of nutrients, including mercury, was estimated using
NUTRICA software. The data bank of NUTRICA
is compiled using mainly Finnish values for the nutrient composition of
foods. The food recording was repeated approximately 12 months after
the baseline examination in a random subsample of 50 men. The
intraclass correlation coefficient between the original and
reassessment of dietary intake was .36 for fish and .38 for mercury
(Pearson coefficients, .36 and .37, respectively).
Other Risk Factor Measurements
The number of cigarettes,
cigars, and pipefuls of tobacco
currently smoked daily, duration of regular smoking in years, history
of myocardial infarction, angina pectoris and other ischemic heart
disease, presence of hypertension, and current antihypertensive
medication were recorded with a self-administered questionnaire, which
was checked by an interviewer. Repeat interviews to obtain medical
history were conducted by a physician. The family history of CHD was
defined as positive if either the biological father, mother, sister, or
brother of the subject had a history of CHD.
A subject was defined a smoker if he had ever smoked on a regular basis and had smoked cigarettes, cigars, or pipe within the past 30 days. The life-long exposure to smoking ("cigarette years") was estimated as the product of years smoked and the number of tobacco products smoked daily at the time of examination. Years smoked were defined the sum of years of smoking regardless of when smoking had started, whether the subject had stopped smoking, and whether smoking had occurred continuously or during several periods. The consumption of alcohol in the previous 12 months was assessed with the quantity-frequency method by using the Nordic Alcohol Consumption Inventory, which contains 15 items.27 The socioeconomic status was measured with a summary index that combined measures of income, education, occupation, occupational prestige, material standard of living, and housing conditions.28
Resting blood pressure was measured between 8:00 and 10:00 AM in the first examination day by one nurse with a random-zero mercury sphygmomanometer. The measuring protocol included, after a supine rest of 5 minutes, three measurements in the supine, one in the standing, and two in the sitting position with 5-minute intervals. The mean of all six systolic pressure measurements was used in the present analyses as the systolic blood pressure, and the mean of all six diastolic pressure measurements was used as the diastolic blood pressure.
The respiratory gas exchange was measured
during a symptom-limited
exercise test.23 29 The testing protocol included an
increase in work load by 20 W/min. The maximal oxygen uptake
(VO2max) was defined as the highest oxygen
uptake during the test. Exercise ECGs were coded manually by one
cardiologist. The criteria for ischemia were (1) ischemic ECG, defined
as horizontal or downsloping ST-segment depression 0.05 mV or
upsloping ST-segment depression 0.1 mV, (2) typical angina pectoris
pain leading to discontinuation of exercise, or (3) maximal heart rate
during exercise 
130 beats per minute. Diabetes was defined as
previous clinical diagnosis of diabetes or fasting blood glucose of
8.0 mmol/L.
Determination of Follow-up Events
As a part of the
multinational WHO MONICA project,9
an AMI registry was established in the province of Kuopio in
1982.30 The registry collects detailed diagnostic
information of all suspected nonfatal AMIs and fatal coronary events
that occurred in the population (including the present study
cohort) in a prospective manner. Heart attacks were classified either
as definite AMI, possible AMI, no AMI, or insufficient data according
to the explicitly defined, uniform diagnostic criteria, described
previously in detail.30 The coverage of the AMI registry
was checked against the national computerized death certificate
register. Information concerning all deaths was obtained from the
National Statistics Office. The underlying cause of death that had been
checked and coded by the statistics office was used in this study. We
obtained diagnostic information and the date of onset of all suspected
AMIs in our study cohort by record-linkage based on the uniform Finnish
personal identification code (social security number). No personal
identification codes were missing either in our study cohort or in the
AMI registry data. Therefore, the losses to follow-up were negligible,
if any.
Between March 1984 and December 1991, a definite or possible fatal or nonfatal AMI was registered in 73 of the 1833 men at risk. For 69 of these men, a 24-hour urinary sample had been collected in the baseline examination. Thus, analyses concerning the association of urinary mercury with AMI were based on 69 patients and 138 control subjects. In the case of multiple events during the follow-up, the first one for each subject was taken as the end point in the present analyses. By the end of 1992, of 78 deaths that had occurred, 18 deaths were due to CHD (International Classification of Diseases [ICD] 410-414) and 24 were due to CVD (ICD 390-458). The longest follow-up period for AMIs for individual subjects was 7.75 years, and the mean follow-up time was approximately 5 years. The follow-up period for deaths was as long as 8.75 years, averaging approximately 6 years.
Statistical Analysis
Associations between hair mercury
content and dietary intakes of
fish and mercury and risk factors for CHD were estimated with Pearson
correlation coefficients adjusted simultaneously for age and the year
of the baseline examination (1985 versus other, 1986 versus other, 1987
versus other, 1988 versus other, 1989 versus other). Partial
associations of hair and urinary mercury with titers of immune
complexes against oxidized LDL were estimated by SPSS stepup
least-squares regression analysis.31
The association of hair mercury and intakes of fish and mercury with the risk of AMI and death from CHD, CVD, and any cause was analyzed using the Cox proportional hazards model.32 To illustrate the relation, "survival" functions were plotted in two categories of the hair mercury content. To control for confounding by other risk factors, risk factors were entered in SAS Cox models33 uncategorized. Two different sets of fixed covariates were entered. The first analyses included only age, examination year (five dummy variables), ischemic exercise ECG (yes versus no), and maximal oxygen uptake. The second set of models included age, examination year (five dummies), ischemic exercise ECG, maximal oxygen uptake, family history of CHD, cigarette-years, mean systolic blood pressure, diabetes, socioeconomic status, place of residence (urban versus rural), dietary iron intake, plasma fibrinogen and serum apolipoprotein B, and HDL2 cholesterol and ferritin (above versus below 200 mg/L) concentrations.
AMIs or deaths from either CHD, CVD, or any cause were defined as events in separate models and deaths from other causes than CHD and CVD in models concerning those were defined as losses. The fit of the proportional hazards models was examined by analyzing changes in the proportionality of hazards with time and with risk factor levels. The results indicated that the application of the models was appropriate.
In the nested case-control subsample with urinary mercury data, the association with the risk of AMI was analyzed by SPSS logistic regression analysis. Risk factor–adjusted relative risks were estimated as antilogarithm of a coefficient. Their confidence intervals were computed based on the assumption of the asymptotic normality of estimates.
The differences in mean hair mercury content according to the use of specific fish species, the place of residence (urban versus rural), and smoking (yes versus no) were analyzed by SAS two- and three-way ANCOVA with linear covariate corrections. All tests of significance were two-sided.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The mean daily intake of fish was 46.5 g, ranging from 0 to 619.2 g (Table 1
). The mean estimated daily dietary
intake of mercury was 7.6 µg (range, 1.1 to 95.3 µg). The measured
content of mercury in the hair ranged from 0 to 15.67 µg/g of hair
(mean, 1.92 µg/g). In the subset of 207 subjects, the daily urinary
excretion of mercury varied from 0 to 4.95 µg with a mean of 1.18
µg and SD of 1.10 µg. There was no change over the years of
baseline examinations in the estimated daily intake of either fish
(P=.516 for linear trend) or mercury (P=1.000
for
linear trend). However, the hair mercury content declined over the
years of baseline examinations. The annual mean values in men examined
in 1984, 1985, 1986, 1987, 1988, and 1989 for hair mercury were 2.55,
2.47, 1.92, 1.51, 1.40, and 1.72 µg/g (P<.001 for linear
trend), and values for urinary mercury were 1.36, 1.02, 1.32, 0.91, and
0.88 µg/d (P=.315 for linear trend). Because of these
trends, the year of baseline examination was adjusted for in all
subsequent statistical analyses.
|
The hair mercury content correlated strongly with the daily urinary
excretion of mercury (r=.56, Table 2). Both
the hair mercury (r=.27) and the urinary mercury
(r=.47) correlated with the estimated fish intake. The hair
mercury content also correlated with low socioeconomic status
(r=.21), serum apolipoprotein B (r=.11),
selenium
(r=.12), and plasma fibrinogen (r=.09)
concentrations; the number of cigarettes smoked daily
(r=.07); and the urinary excretion of nicotine metabolites
(r=.05, P=NS). The urinary mercury excretion
also
correlated with serum selenium concentration (r=.26) but not
with any other risk factor.
|
Of the subjects, 29.2% were current smokers. These had an 18.0% higher mean hair mercury content compared with nonsmokers (2.20 versus 1.81 µg/g, P<.001 for difference). Twenty-three percent (n=427) of the subjects lived in the country. These rural men had a 39.9% higher mean hair mercury content compared with men living in population centers (2.46 µg/g versus 1.76 µg/g, P<.001 for difference). Forty-six percent of the subjects had a family history of CHD, and 17% had ischemic ST-segment depression on the maximal exercise test. Twenty-six percent had serum ferritin of >200 mg/L. The mean hair mercury content did not differ significantly between subgroups according to CHD family history, exercise ECG, or serum ferritin.
The unadjusted survival curves for men in the highest tertile (>2.0
µg/g) and in the two lowest tertiles (<2.0 µg/g) of hair mercury
content are shown in the Figure. The curves diverge
monotonically over the entire range of follow-up time, and the hazard
ratio was approximately constant over time. In separate Cox
proportional hazards models adjusting for age, examination year (five
indicator variables) and subclinical CHD (ischemic exercise ECG and
maximal oxygen uptake), both the hair content of mercury
(P=.037) and the estimated intakes of both fish
(P=.002) and mercury (P=.006) associated
statistically significantly with the risk of AMI (Table 3). On
the average, an increment of 1 µg Hg/g of hair
(6% increment) associated with an increment of 9% (95% confidence
interval [CI], 1% to 19%) in the 5-year risk of AMI. An increment
of 1 mg/d of dietary mercury intake was associated with a 3% (95% CI,
1% to 5%) average increment in the 5-year AMI risk (Table 3).
|
|
These associations were attenuated by the additional statistical
control for potential confounding factors (socioeconomic status, place
of residence [urban versus rural], and cigarette-years) and the
major
coronary risk factors (family history of CHD, mean systolic blood
pressure, diabetes, dietary iron intake, and serum apolipoprotein B,
HDL2 cholesterol, and ferritin [> versus <200
µg/L]
concentrations), and remained significant only for the intakes of fish
and mercury (Table 4). The hair mercury associated
significantly with the risk of death from CHD, CVD, and any cause, even
when we adjusted for all covariates (Table 4).
|
Men in the highest tertile (>2.0 µg/g) of the hair mercury content
had a 2.0-fold (95% CI, 1.2 to 3.1; P=.005) risk of AMI
compared with men in the two lowest tertiles when adjusting for age,
examination year, ischemic exercise ECG, and the maximal oxygen uptake
(Table 3
). This relative risk was 1.7 (95% CI, 1.03 to 2.8;
P=.038) in a model adjusting for all considered confounders
and risk factors (Table 4). The relative risk was similar for
coronary
deaths but not statistically significant due to the smaller number of
events. However, a high hair mercury content was significantly
associated with the risk of death from CVD (relative risk [RR], 2.9;
95% CI, 1.2 to 6.6; P=.014) and from any cause (RR, 2.3;
95% CI, 1.4 to 3.6; P<.001).
An average daily fish intake of 30 g was associated with 2.1-fold
age-, examination year–, and CHD-adjusted risk of AMI (95% CI, 1.3 to
3.4; P=.004) compared with men consuming less fish. For each
additional 10 g/d fish intake, there was an increment of 5% (95% CI,
2% to 8%) in the 5-year risk of AMI (Table 3).
In additional Cox models (not presented in the tables), we entered
a number of other variables that had been associated with the risk of
CHD in previous studies. These included dietary intakes of energy,
saturated fatty acids, dietary polyunsaturated fatty acids, and
carotene; the consumption of alcohol and coffee; leisure time physical
activity; body mass index (kg/m2); blood leukocyte count;
plasma ascorbate and 
-tocopherol, serum copper, albumin, and
triglyceride concentrations. The addition of any of these variables
alone or in combination had no appreciable effect on the relative risk
estimates for intake of either fish or mercury or hair mercury. All Cox
models were also fitted separately in men residing in urban and in
rural areas. The strength of association of hair mercury and fish
intake did not appreciably differ between these two strata.
The mercury content in 24-hour urine samples was determined in a
subsample of men who had an AMI during the follow-up and for 2:1
matched (for age, examination date, and place of residence) control
subjects. The mean daily mercury excretion was nonsignificantly higher
for the patients with AMI (mean, 1.29 µg/d; SD, 1.14) than for the
control subjects (mean, 1.13 µg/d; SD 1.08) (t=.97,
P=.334 for difference). In a multivariate logistic model
adjusting for the strongest risk factors—cigarette-years, serum
ferritin concentration, ischemic exercise ECG, serum apolipoprotein B,
family history of CHD, maximal oxygen uptake, and serum
HDL2 cholesterol—there was a statistically significant
residual association between the urinary mercury excretion and the risk
of AMI (Table 5). For each microgram of mercury excreted
daily, the risk of AMI increased by 36% (95% CI, 1% to 82%;
P=.042).
|
In a subsample of the subjects (n=187) for whom we had measurements
of
serum immune complexes containing oxidized LDL, both the hair mercury
content and the urinary mercury excretion associated with immune
complex titers measured with a neat rabbit antiserum against oxidized
LDL (titer 1, Table 6) and the -globulin fraction of
a rabbit antiserum against oxidized LDL (titer 2, Table 6). Of
all
variables tested in multivariate models, the hair mercury content was
the strongest predictor of both immune complex titers. Also, a high
daily excretion of nicotine metabolites, high serum copper, and low
serum albumin concentration associated significantly with a high immune
complex titer when adjusting for age and examination year. In
multivariate step-up regression models, the hair mercury content was,
however, the only statistically significant predictor of oxidized LDL
immune complex titers (Table 6). A high serum ferritin and a
low plasma
ascorbate concentration had nonsignificant associations with a high
immune complex titer. Serum LDL cholesterol concentration had no
association with the immune complex titers (age- and examination
year–adjusted r=.035 and .012 for the two titers), in
favor
of specificity of the assay to oxidized LDL.
|
Men who consumed 30 g/d of any fish had 56% higher mean hair mercury
content (P<.001 for difference) than those who had consumed
<30 g/d of fish. The most commonly used fish species were vendance
(Coregonus albula, a small local white fish) (17%), rainbow
trout (12%), and the Northern pike (10%).
To explore the dietary sources of mercury in more detail, the mean hair
mercury content was computed in subgroups of men who reported the use
of specific fish species during the four food-recording days preceding
hair sampling, separately for men residing in countryside and in towns
(Table 7). A linear covariance correction was applied
for age, socioeconomic status, and the year of examination. The highest
mercury hair contents were measured among men who had ingested either
burbot, vendace, Northern pike, or whitefish. Rural men who had
consumed Baltic herring had a higher hair mercury content than rural
men who had not. There was a similar but smaller difference for urban
men. Consumers of fatty fish species such as salmon, herring, domestic
rainbow trout, and tuna did not have a higher hair mercury content than
men who had not eaten these fish species during the four food-recording
days. All of these fatty fish species (except some of the rainbow
trout) are caught from the sea rather than the local lakes. In a
separate set of three-way covariance analyses, smoking (yes versus no)
was entered, in addition to each fish species and the place of
residence. The associations of the use of burbot (P=.002),
vendace (P<.001), Northern pike (P<.001), and
whitefish (P=.025) remained statistically significant. There
were no significant interactions with the use of any fish species with
smoking.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The human body (70 kg) contains on the average 13 mg Hg.34 No metabolic functions in the human body are known for which mercury is required. At high concentrations, mercury is known to cause liver and kidney damage as well as neurological symptoms.35 Also, interest has grown in the possible health effects of mercury liberated from dental amalgam fillings, which may be the principal source of exposure to mercury for a large segment of the US population.36 Clarkson36 has proposed that given the increasing consumption of fish in the United States and its important nutritional role, it is vital that the potential for prenatal damage from methyl mercury be assessed. There is, however, practically no previous research concerning the possible harmful effects of a usual intake of mercury with regard to the cardiovascular system.
There are at least three mechanisms through which mercury can promote lipid peroxidation. First, mercury is a transition metal, and it can thus act as a catalyst in Fenton-type reactions, resulting in the formation of free radicals. The notion that mercury promotes free radical generation was first presented by Ganther37 based on the observation that vitamin E and the antioxidant DPPD provided protection against methyl mercury poisoning in rats.38 In a recent in vitro study, Hg(II) ions in micromolar concentrations increased the production of superoxide anions in human neutrophils.39 In another in vitro study, mercuric ions (1 to 6 µmol/L) caused a concentration-dependent increase (up to fivefold) in mitochondrial H2O2 production.40 In addition to its direct catalytic effect, mercury has been found to enhance iron-stimulated lipid peroxidation in vitro.16
An in vivo study revealed a significant concentration-related depolarization of the inner mitochondrial membrane, increased H2O2 formation, glutathione depletion, and formation of thiobarbituric acid reactive substances after the addition of Hg(II) to mitochondria isolated from kidneys of untreated rats.41 Thus, although catalytic Fe(II) principally catalyzes the oxidation of H2O2 to the more reactive hydroxyl radical,42 mercury appears to act earlier in the Fenton reaction chain, catalyzing the production of H2O2.
Second, mercury has a very high affinity to sulfhydryl groups,35 which in plasma proteins have been estimated to account for as much as 10% to 50% of the antioxidative capacity of plasma.43 By binding to sulfhydryl groups, mercury inactivates antioxidative thiolic compounds such as the glutathione.44 Glutathione has a central role in the regeneration of the tocopheroxyl radical to tocopherol. Mercury poisoning, which is associated with increased lipid peroxidation in the liver and in the kidneys, also results in inactivation of superoxide dismutase and catalase,45 two important enzymes that scavenge H2O2. Thiol antidotes such as DMPS and D-penicillamine chelate mercury and protect against mercury-induced lipid peroxidation.45
Third, mercury forms an insoluble complex with selenium, the mercury selenide,46 thus binding selenium in an inactive form that cannot serve as a cofactor for glutathione peroxidase, an important scavenger of H2O2 and lipid peroxides. Before 1987, the dietary intake and blood concentrations of selenium were exceptionally low in Finland.10 47 48 The high mercury intake probably has reduced the bioavailability of selenium even further. Ganther and coworkers17 have demonstrated that selenium protects against methyl mercury toxicity. Selenium has been observed to protect against the peroxidative liver injury caused by mercury.49 Thus, there may have been insufficient selenium available to inactivate catalytic mercury in the Finnish population during most of the 1980s.
All of these pathways reduce the antioxidative capacity in both plasma and intracellularly and promote free radical stress and lipid peroxidation in cell membranes and lipoproteins. The theory that mercury would elevate the risk of AMI through the promotion of lipid peroxidation receives empirical support from our finding that both high hair mercury content and high urinary mercury excretion were associated with elevated titers of immune complexes containing oxidized LDL in a subsample of our study subjects. Also, as we have reported previously,14 serum selenium concentration associated inversely with autoantibodies against oxidized LDL.
An additional possible atherogenic effect of mercury would be the stimulatory effect on proliferation of arterial smooth muscle cells in a cell culture study.50 Mercury compounds have also potentiated ADP-induced platelet aggregation.51 Because oxidized lipids promote arterial smooth muscle cell proliferation52 and platelet activity,53 both of these atherogenic effects of mercury could be consequences of enhanced free radical stress and lipid peroxidation.
Mercury is a poisonous metallic element that is released by manufacturing and burning fuels and minerals as well as by industrial and household wastes.54 Eventually, it settles in waterways, where it joins naturally occurring mercury. There, bacteria and algae convert it to the toxic methyl mercury.55 According to the Harriss-Hohenemser comparative hazard index, mercury is by far the most dangerous environmental poison of all heavy metals.54
The mercury content in Finnish lakes is high.56 In the late 1970s, it was observed to be especially high in ground waters in Eastern Finland. There are several both geological and man-made reasons for this56 : The Finnish lakes are shallow and have large catchment areas. Both the soil and the lake waters are relatively acidic, which enhances the availability of soil mercury and increases the level of methyl mercury in the edible tissues of fish.35 The acidity of lake waters is most pronounced in Eastern Finland.57 Water levels in most Finnish water systems vary widely between seasons, and humic material and mercury from the soil surface are washed to the lake waters. Drying of swamps by ditching has lead to drainage of the high-mercury swamp water into lakes. Finally, some Finnish watercourses may still bear the consequences of discharges from chloralkali plants that used mercury electrodes and the use of phenyl mercury slimicides in paints and fungicides in agricultural seed dressings. In addition to the high acidity, a characteristic of the Finnish soil as well as lake and ground waters is the low selenium content.10 47 48
Fish and fish products are the dominant source of methyl mercury in food.35 Methyl mercury is rapidly accumulated by most aquatic biota and attains its highest concentration in fish at the top of the aquatic food chain.
The mercury concentrations in Northern pike (Esox lucius L) in Finland generally exceed the level of 0.5 µg/g (w/w) used in many countries as the highest acceptable level for edible fish.56 58 In a sample of pike, the selenium content in the tissue was inversely associated with the mercury content (r=-.45, P<.001, n=105).58 High mercury concentrations have also been measured in the burbot (Lota lota L).56 In the present study, the highest mercury hair content was measured in men who had ingested lean, locally caught fish.
In a market basket survey by the US Food and Drug Administration,35 the mean estimated daily mercury intake for a 70-kg adult in the United States was 3.5 µg. The mean daily intake in our subjects, 7.6 µg, was more than double the average US intake.
At least four prospective population studies have reported an inverse association between fish intake and coronary mortality.1 2 3 4 In the study by Kromhout and coworkers,1 mortality from CHD was >50% less among men who consumed at least 30 g/d of fish than among those who did not eat fish, as assessed in 1960. These findings provided persuasive evidence in favor of a CHD mortality–reducing effect of even moderate consumption of fatty sea water fish.
We retested the Dutch finding in our study by using the same cut point
for daily fish intake. In our study cohort, however, the daily intake
of fish of 30 g was associated with a 2.1-fold risk of AMI and a
2.4-fold risk of coronary mortality compared with men who consumed <30
g/d of fish. The mean daily fish intake in our subjects was 47 g, more
than double that in Zutphen men-20 g in 1960. The majority of fish
consumed in Eastern Finland in the 1980s was lean local freshwater
fish. The intake of these fish species was associated with elevated
hair mercury levels, whereas none of the fatty fishes consumed (rainbow
trout, salmon, herring, tuna) were associated with increased hair
mercury. Thus, in addition to increased n-3 polyunsaturated fatty
acids, these fatty fishes have a lower mercury content.
The role of mercury as a risk factor for CHD can explain a number of previous findings for which a plausible biological explanation has been lacking. First, the association of high fish intake with decreased CHD risk was not observed in two prospective studies in populations consuming high amounts of fish, in Hawaii5 and Norway,6 and in a large prospective US study, the Physicians' Health Study.7 Apart from measurement imprecision and threshold effect as possible explanations, the lack of association could be due to differences in the mean mercury intake. Alternatively, mercury from fish may affect lipid peroxidation and CHD risk only at intakes that exceed an unknown threshold.
Second, in a case-control study59 and in a prospective population study,60 an association was observed between dental disease and the risk of CHD. In the Finnish case-control study, the number of dental fillings was associated with the risk of AMI.59 The authors speculated that the increased risk would be due to bacteria that cause periodontitis.59 No mercury measurements were carried out in either of the two studies, and the possible role of mercury was not even discussed. Our findings provide an alternative and perhaps more likely explanation for the association of dental disease with CHD risk: the release of mercury from amalgam tooth fillings, associated with poor dental health.
Third, the association between low serum11 and toenail12 selenium and an increased risk of CHD has been observed at high selenium levels at which glutathione peroxidase activity is not expected to be lowered. An explanation for these findings could be the reduced bioavailability of selenium due to complexing with mercury. Also, in some prospective population studies no association was observed between serum selenium concentration and the risk of CHD; this was originally believed to be due to higher mean selenium levels.61 All these studies were, however, conducted in populations consuming high amounts of fish, and the strong association between intakes and body contents of selenium and mercury could account for the lack of association.
The present study may be the first one in which hair mercury contents have been measured in a representative population sample of healthy individuals. For this reason, the mean hair mercury content in our subjects (1.92 µg/g) cannot be directly compared with values reported earlier. In previous studies in selected groups of subjects, the mean hair mercury contents have varied between 0.50 and 3.4 µg/g in Europe and between 3.6 and 4.3 µg/g in Alaska.62
The likelihood of bias or confounding as an explanation for our findings is very small. First, the dietary intake of mercury and the hair mercury content did not covary with any other of the more than 60 nutrients measured, except selenium. Other than the interactions with selenium, there is no known metabolic regulation of either the absorption, accumulation, or excretion of mercury. The hair content of mercury is a direct measure of the accumulation of methyl mercury in the body over a period of several months.63 Urinary mercury excretion is considered an indicator of the amount of elemental mercury in the body, derived from both dental amalgams and the diet.35 Second, in extensive exploratory analyses, the only potential confounding factors that we found were a low socioeconomic status and living in rural areas. The socioeconomic status was assessed comprehensively covering six different aspects.28 Both of these factors were associated with high hair mercury content and an increased risk of AMI and death. However, the association between dietary intake, hair content, and urinary excretion of mercury with the risk of AMI and death persisted after a statistical control for these factors and in urban and rural subjects separately. Also, a low socioeconomic status and rural living should be considered in this context more as determinants of high fish intake than of confounding factors. The weak positive association between the amount of cigarette smoking and the hair mercury content was most likely due to the intake of mercury from cigarette smoke, and the statistical control for smoking in our analysis may represent overadjustment.
Theoretically, our findings could be specific only for men in Eastern Finland, who traditionally have a high intake of meat, fish, and saturated animal fat and a low intake of selenium and vitamin C8 10 47 53 and, most likely, other vegetable-derived antioxidants. Nevertheless, our findings in men in Eastern Finland provide new information about the etiology of CHD. Pathological mechanisms involved must apply to humans in general, even though the consequences of the high mercury intake for the cardiovascular system may vary among populations due to various effect modifying factors.
The results of the present study are significant in several ways. First, although consumption of fish may be healthy in general, some fish may contain agents that are not healthy for the human cardiovascular system. More important, our findings suggest that mercury, even in subtoxic amounts, is a risk factor for coronary and fatal CVD. Our observation in a subset of subjects provides evidence suggesting that high mercury intake would increase the risk of CHD by promoting lipid peroxidation. Because in many countries fish and seafood are contaminated with mercury and because fish is an important foodstuff all over the world, our findings could be of enormous public health importance. For that reason, they need to be retested urgently in other population studies in which hair, nail, blood cell, or urine samples have been collected and stored for mineral measurements. If our observations are confirmed in subsequent studies, the measurement and labeling of mercury content of various foods, the prevention of additional pollution of the environment by mercury, and, eventually, the elimination of environmental mercury could be considered new measures to advance the prevention of cardiovascular diseases.
|
Acknowledgments |
|---|
This work was supported by grants from the Academy of Finland and the Ministry of Education of Finland. We are grateful to George A. Kaplan, PhD, and Ossi V. Lindqvist, PhD, for reviewing the manuscript and to Rainer Rauramaa, MD, PhD, for the participation of the Kuopio Research Institute of Exercise Medicine in data collection. We also thank Merja Ihanainen, MSc, for food recordings; Dr Jaakko Eränen for coding the exercise ECGs; Dr Esko Taskinen, Dr Juha Venäläinen, and Dr Hannu Litmanen for their participation in the supervision of the maximal exercise tests; and Kimmo Ronkainen, MSc, for carrying out the data analyses.
Received June 1, 1994; accepted August 19, 1994.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Kromhout D, Bosschieter EB, De Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312:1205-1209. [Abstract]
2. Shekelle RB, Misell LU, Paul O, Shryock AM, Stamler J. Fish consumption and mortality from coronary heart disease. N Engl J Med. 1985;313:820. [Medline] [Order article via Infotrieve]
3. Norell SE, Ahlbom A, Feychting M, Pedersen NL. Fish consumption and mortality from coronary heart disease. Br Med J. 1986;293:426.
4. Dolecek TA, Grandits G. Dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial (MRFIT). In: Simopoulos AP, Kifer RR, Martin RE, Barlow SD, eds. Health Effects of Omega-3 Polyunsaturated Fatty Acids in Seafoods. World Rev Nutr Diet. Basel, Switzerland: S Karger; 1991;66:205-216.
5. Curb JD, Reed DM. Fish consumption and mortality from cardiovascular disease. N Engl J Med. 1985;313:821-822.
6. Vollset SE, Heuch I, Bjelke E. Fish consumption and mortality from cardiovascular disease. N Engl J Med. 1985;313:820-821.
7. Morris MC, Manson JE, Rosner B, Buring JE, Willett WC, Hennekens CH. A prospective study of fish consumption on cardiovascular disease. Circulation. 1992;86(suppl I):I-463. Abstract.
8. Ihanainen M, Salonen R, Seppänen R, Salonen JF. Nutrition data collection in the Kuopio Ischaemic Heart Disease Risk Factor Study: nutrient intake of middle-aged Eastern Finnish men. Nutr Res. 1989;9:597-604.
9. WHO Monica Project. WHO Monica Project: assessing CHD mortality and morbidity. Int J Epidemiol. 1989;18:S38-S45. [Abstract]
10. Salonen JT, Alfthan G, Huttunen JK, Pikkarainen J, Puska P. Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet. 1982;2:175-179. [Medline] [Order article via Infotrieve]
11. Suadicani P, Hein HO, Gyntelberg F. Serum selenium concentration and risk of ischaemic heart disease in a prospective cohort study of 3000 males. Atherosclerosis. 1992;96:33-42. [Medline] [Order article via Infotrieve]
12.
Kok FJ, Hofman A, Witteman JC, de Bruijn AM, Kruyssen DH, de
Bruin M, Valkenburg HA. Decreased selenium levels in acute myocardial
infarction. JAMA. 1989;261:1161-1164.
13. Salonen JT, Salonen R, Seppänen K, Kantola M, Suntioinen S, Korpela H. Interactions of serum copper, selenium, and low density lipoprotein cholesterol in atherogenesis. Br Med J. 1991;302:756-760.
14. Salonen JT, Ylä-Herttuala S, Yamamoto R, et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992;339:883-887. [Medline] [Order article via Infotrieve]
15.
Salonen JT, Nyyssönen K, Korpela H, Tuomilehto J,
Seppänen R, Salonen R. High stored iron levels are associated
with excess risk of myocardial infarction in Eastern Finnish men.
Circulation. 1992;86:803-811.
16. Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine, 2nd ed. Oxford, UK: Clarendon Press; 1989.
17. Sunderman FW Jr. Metals and lipid peroxidation. Acta Pharmacol Toxicol. 1986;59(suppl 7):248-255.
18.
Ganther HE, Goudie C, Sunde ML, Kopecky MJ, Wagner P.
Selenium: relation to decreased toxicity of methylmercury added to
diets containing tuna. Science. 1972;175:1122-1124.
19. Salonen JT. Is there a continuing need for longitudinal epidemiologic research? The Kuopio Ischaemic Heart Disease Risk Factor Study. Ann Clin Res. 1988;20:46-50. [Medline] [Order article via Infotrieve]
20. Rose GA, Blackburn H, Gillum RF, Prineas RJ. Cardiovascular Survey Methods. Geneva, Switzerland: World Health Organization; 1982:162-165.
21.
Winyard PG, Tatzber F, Esterbauer H, Kus ML, Blake DR, Morris
CJ. Presence of foam cells containing oxidised low density lipoprotein
in the synovial membrane from patients with rheumatoid arthritis.
Ann Rheum Dis. 1993;52:677-680.
22.
Salonen JT, Salonen R, Seppänen K, Rauramaa R,
Tuomilehto J. HDL, HDL2, and HDL3 subfractions,
and the risk of acute myocardial infarction: a prospective population
study in Eastern Finnish men. Circulation. 1991;84:129-139.
23. Lakka TA, Salonen JT. Moderate to high intensity conditioning leisure time physical activity and high cardiorespiratory fitness are associated with reduced plasma fibrinogen in Eastern Finnish men. J Clin Epidemiol. 1993;46:1119-1127. [Medline] [Order article via Infotrieve]
24.
Salonen JT, Salonen R, Korpela H, Suntioinen S, Tuomilehto J.
Serum copper and the risk of acute myocardial infarction: a prospective
population study in men in Eastern Finland. Am J Epidemiol. 1991;134:268-276.
25. Parviainen MT, Nyyssönen K, Penttilä IM, et al. A method for routine assay of plasma ascorbic acid using high-performance liquid chromatography. J Liq Chromatogr. 1986;9:2185-2197.
26. Puhakainen EVJ, Barlow RD, Salonen JT. An automated colorimetric assay for urine nicotine metabolites: a suitable alternative to cotinine assays for the assessment of smoking status. Clin Chim Acta. 1987;170:255-262. [Medline] [Order article via Infotrieve]
27. Kauhanen J, Julkunen J, Salonen JT. Coping with inner feelings and stress: heavy alcohol use in the context of alexithymia. Behav Med. 1992;18:121-126. [Medline] [Order article via Infotrieve]
28. Kaplan GA, Salonen JT. Socioeconomic conditions in childhood and ischaemic heart disease during middle-age. Br Med J. 1990;301:1121-1123.
29.
Lakka TA, Venäläinen JM, Ranramaa R, Salonen R,
Tuomilento J, Salonen JT. Relation of leisure-time physical activity
and cardiorespiratory fitness to the risk of acute myocardial
infarction in men. N Engl J Med. 1994;330:1549-1554.
30.
Tuomilehto J, Arstila M, Kaarsalo E, et al. Acute myocardial
infarction (AMI) in Finland: baseline data from the FINMONICA AMI
register in 1983-1985. Eur Heart J. 1992;13:577-587.
31. SPSS-X Users Guide, 3rd ed. Chicago, Ill: SPSS Inc; 1988.
32. Cox DR. Regression models and life-tables. J Roy Stat Soc. 1972;34:187-201.
33. SAS Technical Report P-217 SAS/STAT Software: The Phreg Procedure, Version 6. Cary, NC: SAS Institute Inc; 1990.
34. Linder MC. Nutrition and metabolism of the trace elements. In: Linder MC, ed. Nutritional Biochemistry and Metabolism, 2nd ed. New York, NY: Elsevier; 1991:215-276.
35. International Programme on Chemical Safety (IPCS). Environmental Health Criteria 101: Methylmercury. Geneva, Switzerland: World Health Organization; 1990.
36. Clarkson TW. Mercury-an element of mystery. N Engl J Med. 1990;323:1137-1139. [Medline] [Order article via Infotrieve]
37. Ganther HE. Interactions of vitamin E and selenium with mercury and silver. Ann N Y Acad Sci. 1980;355:1-372. [Medline] [Order article via Infotrieve]
38. Welsh SO. The protective effect of vitamin E and N,N'-diphenyl-p-phenylenediamine (DPPD) against methyl mercury toxicity in the rat. J Nutr. 1979;109:1673-1681.
39. Jansson G, Harms-Ringdahl M. Stimulating effects of mercuric and silver ions on the superoxide anion production in human polymorphonuclear leucocytes. Free Rad Res Commun. 1993;18:87-98. [Medline] [Order article via Infotrieve]
40. Miller OM, Lund BO, Woods JS. Reactivity of Hg(II) with superoxide: evidence for the catalytic dismutation of superoxide by Hg(II). J Biochem Toxicol. 1991;6:293-298. [Medline] [Order article via Infotrieve]
41. Lund BO, Miller DM, Woods JS. Studies on Hg(II)-induced H2O2 formation and oxidative stress in vivo and in vitro in rat kidney mitochondria. Biochem Pharmacol. 1993;45:2017-2024. [Medline] [Order article via Infotrieve]
42. Salonen JT. The role of iron as a cardiovascular risk factor. Curr Opin Lipid. 1993;4:277-282.
43. Wayner DDM, Burton GW, Ingold KU, Barclay LRC, Locke SJ. The relative contributions of vitamin E, urate, ascorbate and proteins to the total peroxyl radical-trapping antioxidant activity of human blood plasma. Biochim Biophys Acta. 1987;924:408-419. [Medline] [Order article via Infotrieve]
44. Naganuma A, Koyama Y, Imura N. Behavior of methylmercury in mammalian erythrocytes. Toxicol Appl Pharmacol. 1980;54:405-410. [Medline] [Order article via Infotrieve]
45. Benov LC, Benchev IC, Monovich OH. Thiol antidotes effect on lipid peroxidation in mercury-poisoned rats. Chem Biol Interact. 1990;76:321-332. [Medline] [Order article via Infotrieve]
46. Cuvin-Aralar ML, Furness RW. Mercury and selenium interaction: a review. Ecotoxicol Environ Safety. 1991;21:348-364. [Medline] [Order article via Infotrieve]
47. Salonen JT, Salonen R, Seppänen K, et al. Relationship of serum selenium and antioxidants to plasma lipoproteins, platelet aggregability and prevalent ischemic heart disease in Eastern Finnish men. Atherosclerosis. 1988;70:155-160. [Medline] [Order article via Infotrieve]
48. Alfthan G. Effects of selenium fertilization on the human selenium status and the environment. Norwegian J Agr Sci. 1993;(suppl 11):175-181.
49. Rana SV, Boora PR. Antiperoxidative mechanisms offered by selenium against liver injury caused by cadmium and mercury in rat. Bull Environ Contam Toxicol. 1992;48:120-124. [Medline] [Order article via Infotrieve]
50. Lu KP, Zhao SH, Wang DS. The stimulatory effect of heavy metal cations on proliferation of aortic smooth muscle cells. Schi China B. 1990;33:303-310.
51. Kostka B. Potentiation of ADP-induced platelet aggregation by mercury compounds. Thromb Res. 1990;57:795-801. [Medline] [Order article via Infotrieve]
52. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915-924.[Medline] [Order article via Infotrieve]
53.
Salonen JT, Salonen R, Seppänen K, et al. Effects of
antioxidant supplementation on platelet function: a randomized
pair-matched, placebo-controlled, double-blind trial in men with low
antioxidant status. Am J Clin Nutr. 1991;53:1222-1229.
54. Harriss RC, Hohenemser C. Mercury-measuring and managing the risk. Environment. 1978;20:25-36.
55. Wilkinson SC, Goulding KH, Robinson PK. Mercury accumulation and volatilization in immobilized algal cell systems. Biotechnol Lett. 1989;11:861-864.
56. Verta M. Mercury in Finnish Forest Lakes and Reservoirs: Anthropogenic Contribution to the Load and Accumulation in Fish. Helsinki, Finland: Government Printing Office; 1990, publication of the Water and Environment Research Institute, National Board of Waters and the Environment, Finland, No. 6.
57. Kämäri J, Forsius M, Kortelainen P, Mannio J, Verta M. Finnish lake survey: present status of acidification. Ambio. 1991;20:23-27.
58. Leskinen J, Lindqvist OV, Lehto J, Koivistoinen P. Selenium and Mercury Contents in Northern Pike (Esox Lucius, L) of Finnish Man-Made and Natural Lakes. Helsinki, Finland: Government Printing Office; 1986, publication of the Water Research Institute, National Board of Waters, Finland, No. 65.
59. Mattila KJ, Nieminen MS, Valtonen VV, et al. Association between dental health and acute myocardial infarction. Brt Med J. 1989;298:779-781.
60. DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell CM. Dental disease and risk of coronary heart disease and mortality. Br Med J. 1993;306:688-691.
61.
Salonen JT. Selenium in ischaemic heart disease. Int J
Epidemiol. 1987;16:323-328.
62. Iyengar GV. Concentrations of 15 Trace Elements in Some Selected Adult Human Tissues and Body Fluids of Clinical Interest From Several Countries: Results From a Pilot Study for the Establishment of Reference Values. Juelich, Germany: Institute of Medicine, Juelich Nuclear Research Center; 1985.
63. Airey D. Mercury in human hair due to environment and diet: a review. Env Health Perspectives. 1983;52:303-316.
This article has been cited by other articles:
 |
|
 |
|
  M. M. Rogge The Role of Impaired Mitochondrial Lipid Oxidation in Obesity Biol Res Nurs, April 1, 2009; 10(4): 356 - 373. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Aarsetoey, V. Ponitz, H. Grundt, H. Staines, W. S. Harris, and D. W. T. Nilsen (n-3) Fatty Acid Content of Red Blood Cells Does Not Predict Risk of Future Cardiovascular Events following an Acute Coronary Syndrome J. Nutr., March 1, 2009; 139(3): 507 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Nuttall Interpreting Hair Mercury Levels in Individual Patients Ann. Clin. Lab. Sci., January 1, 2006; 36(3): 248 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.A. Iestra, D. Kromhout, Y.T. van der Schouw, D.E. Grobbee, H.C. Boshuizen, and W.A. van Staveren Effect Size Estimates of Lifestyle and Dietary Changes on All-Cause Mortality in Coronary Artery Disease Patients: A Systematic Review Circulation, August 9, 2005; 112(6): 924 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Knobeloch and H. A. Anderson HUMAN BIOMONITORING TO OPTIMIZE FISH CONSUMPTION ADVICE Am J Public Health, August 1, 2005; 95(8): 1304 - 1304. [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Virtanen, S. Voutilainen, T. H. Rissanen, J. Mursu, T.-P. Tuomainen, M. J. Korhonen, V.-P. Valkonen, K. Seppanen, J. A. Laukkanen, and J. T. Salonen Mercury, Fish Oils, and Risk of Acute Coronary Events and Cardiovascular Disease, Coronary Heart Disease, and All-Cause Mortality in Men in Eastern Finland Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 228 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ip, V. Wong, M. Ho, J. Lee, and W. Wong Mercury Exposure in Children With Autistic Spectrum Disorder: Case-Control Study J Child Neurol, June 1, 2004; 19(6): 431 - 434. [Abstract] [PDF]
|
|
|
|
 |
|
 L. Jarup Hazards of heavy metal contamination Br. Med. Bull., December 1, 2003; 68(1): 167 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. W. Clarkson, L. Magos, and G. J. Myers The Toxicology of Mercury -- Current Exposures and Clinical Manifestations N. Engl. J. Med., October 30, 2003; 349(18): 1731 - 1737. [Full Text] [PDF]
|
|
|
|
|
|
M. Plante, S. Babo, J. Mutter, J. Naumann, C. Buettner, E. Guallar, R. A. Riemersma, F. J. Kok, K. Yoshizawa, E. B. Rimm, et al. Mercury and the Risk of Myocardial Infarction N. Engl. J. Med., May 22, 2003; 348(21): 2151 - 2154. [Full Text] [PDF]
|
|
|
|
|
|
D. Mozaffarian, R. N. Lemaitre, L. H. Kuller, G. L. Burke, R. P. Tracy, and D. S. Siscovick Cardiac Benefits of Fish Consumption May Depend on the Type of Fish Meal Consumed: The Cardiovascular Health Study Circulation, March 18, 2003; 107(10): 1372 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Yuan, R. K. Ross, and M. C. Yu THREE AUTHORS REPLY Am. J. Epidemiol., January 1, 2003; 157(1): 85 - 86. [Full Text] [PDF]
|
|
|
|
|
|
E. Guallar, M. I. Sanz-Gallardo, P. v.'t Veer, P. Bode, A. Aro, J. Gomez-Aracena, J. D. Kark, R. A. Riemersma, J. M. Martin-Moreno, F. J. Kok, et al. Mercury, Fish Oils, and the Risk of Myocardial Infarction N. Engl. J. Med., November 28, 2002; 347(22): 1747 - 1754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yoshizawa, E. B. Rimm, J. S. Morris, V. L. Spate, C.-c. Hsieh, D. Spiegelman, M. J. Stampfer, and W. C. Willett Mercury and the Risk of Coronary Heart Disease in Men N. Engl. J. Med., November 28, 2002; 347(22): 1755 - 1760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kurl, T.P. Tuomainen, J.A. Laukkanen, K. Nyyssonen, T. Lakka, J. Sivenius, and J.T. Salonen Plasma Vitamin C Modifies the Association Between Hypertension and Risk of Stroke Stroke, June 1, 2002; 33(6): 1568 - 1573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F Risher, H E. Murray, and G. R Prince Organic mercury compounds: human exposure and its relevance to public health Toxicology and Industrial Health, April 1, 2002; 18(3): 109 - 160. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Snapir, P. Heinonen, T.-P. Tuomainen, P. Alhopuro, M. K. Karvonen, T. A. Lakka, K. Nyyssonen, R. Salonen, J. Kauhanen, V.-P. Valkonen, et al. An insertion/deletion polymorphism in the {alpha}2b-adrenergic receptor gene is a novel genetic risk factor for acute coronary events J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1516 - 1522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Vrachatis, M. A. Alpert, V. P. Georgulas, D. J. Nikas, E. N. Petropoulou, G. I. Lazaros, N. A. Michelakakis, A. I. Karavidis, J. A. Lakoumentas, L. Stergiou, et al. Comparative Efficacy of Primary Angioplasty with Stent Implantation and Thrombolysis in Restoring Basal Coronary Artery Flow in Acute ST Segment Elevation Myocardial Infarction: Quantitative Assessment Using the Corrected TIMI Frame Count Angiology, March 1, 2001; 52(3): 161 - 166. [Abstract] [PDF]
|
|
|
|
 |
|
 T. A. Lakka, J. A. Laukkanen, R. Rauramaa, R. Salonen, H.-M. Lakka, G. A. Kaplan, and J. T. Salonen Cardiorespiratory Fitness and the Progression of Carotid Atherosclerosis in Middle-Aged Men Ann Intern Med, January 2, 2001; 134(1): 12 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Rissanen, S. Voutilainen, K. Nyyssonen, T. A. Lakka, and J. T. Salonen 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, November 28, 2000; 102(22): 2677 - 2679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kauhanen, G. A. Kaplan, D. E. Goldberg, R. Salonen, and J. T. Salonen Pattern of Alcohol Drinking and Progression of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 1999; 19(12): 3001 - 3006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-P. Tuomainen, K. Kontula, K. Nyyssonen, T. A. Lakka, T. Helio, and J. T. Salonen Increased Risk of Acute Myocardial Infarction in Carriers of the Hemochromatosis Gene Cys282Tyr Mutation : A Prospective Cohort Study in Men in Eastern Finland Circulation, September 21, 1999; 100(12): 1274 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Lakka, R. Salonen, G. A. Kaplan, and J. T. Salonen Blood Pressure and the Progression of Carotid Atherosclerosis in Middle-Aged Men Hypertension, July 1, 1999; 34(1): 51 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-P. Tuomainen, K. Punnonen, K. Nyyssonen, and J. T. Salonen Association Between Body Iron Stores and the Risk of Acute Myocardial Infarction in Men Circulation, April 21, 1998; 97(15): 1461 - 1466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kromhout Fish Consumption and Sudden Cardiac Death JAMA, January 7, 1998; 279(1): 65 - 66. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kauhanen, G. A Kaplan, D. E Goldberg, and J. T Salonen Beer binging and mortality: results from the kuopio ischaemic heart disease risk factor study, a prospective population based study BMJ, October 4, 1997; 315(7112): 846 - 851. [Abstract] [Full Text]
|
|
|
|
|
|
K. Nyyssonen, M. T Parviainen, R. Salonen, J. Tuomilehto, and J. T Salonen Vitamin C deficiency and risk of myocardial infarction: prospective population study of men from eastern Finland BMJ, March 1, 1997; 314(7081): 634 - 634. [Abstract] [Full Text]
|
|
|
|
|
|
J. T. Salonen, K. Nyyssonen, R. Salonen, E. Porkkala-Sarataho, T.-P. Tuomainen, U. Diczfalusy, and I. Bjorkhem Lipoprotein Oxidation and Progression of Carotid Atherosclerosis Circulation, February 18, 1997; 95(4): 840 - 845. [Abstract] [Full Text]
|
|
|
|
|
|
J. X. Kang and A. Leaf Antiarrhythmic Effects of Polyunsaturated Fatty Acids: Recent Studies Circulation, October 1, 1996; 94(7): 1774 - 1780. [Full Text]
|
|
|
|
|
|
J. T. Salonen, K. Nyyssonen, R. Salonen, A. Leaf, R. De Caterina, A. Ascherio, and W. C. Willett Fish Intake and the Risk of Coronary Disease N. Engl. J. Med., October 5, 1995; 333(14): 937 - 938. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||