Mercury, fish and heart disease

[Guest guest]

Hi All, This seems to be part of the ongoing controversy over whether

mercury is bad. For me, the upshot appears to be: mercury is there

variably, but the consequence seems small.

Cheers, Al.

P.M. Bolger New Engl J Med 347:1735-1736 Nov 28, 02 No. 22

Mercury and Health

Mercury, particularly methylmercury, is an established worldwide

environmental pollutant with known toxicity in humans. The toxic

effects of methylmercury in fish were first brought to light after several

episodes of poisoning in Japan that involved a spectrum of adverse

clinical outcomes. These ranged from paresthesias and blurred vision

to more specific signs of methylmercury intoxication, such as

concentric vision and deafness, and to coma and death in some

cases. Pronounced deficits in neurologic development were also

noted. These outcomes were associated with the ingestion of fish that

contained methylmercury at levels of 10 ppm or higher — levels

clearly linked to pronounced environmental contamination and well

above those normally found in fish (average level, 0.12 ppm).

More recent data suggest that fetal exposure to methylmercury at high

enough levels results in subtle decrements in several measures of

neurologic development. On the basis of this concern, the National

Academy of Sciences–National Research Council published a

congressionally mandated report on the developmental risks of

methylmercury, which led to several modifications of federal policy.

The Environmental Protection Agency revised its definition of a safe

level of exposure, specifying a lower level that was consistent with the

report. At the same time, the Food and Drug Administration (FDA)

issued a new consumer advisory on methylmercury and fish

consumption.

The most recent advisory was prompted not only by the National

Academy of Sciences–National Research Council report but also by

a body of evidence from large-scale prospective studies linking methylmercury

exposure to neurologic

toxicity in humans, along with estimates of methylmercury exposure from

consumption of fish. The potential

risks of methylmercury ingestion were weighed against the presumed health

benefits of fish consumption.

The current advisory recommends that pregnant women and women who may become

pregnant avoid fish

species with the highest average amounts of methylmercury: king mackerel,

tilefish, shark, and swordfish.

Particularly high methylmercury levels are found in these species because

methylmercury concentrates in

species that are long-lived and are at the top of the food chain. The Table

lists methylmercury levels in

these and other key commercial species consumed in the United States. (A more

comprehensive list is

available from the FDA at http://www.cfsan.fda.gov/~frf/sea-mehg.html.)

Methylmercury Levels in Selected Commercial Fish Species.

ND denotes not detectable. The mean for salmon is presented as

not

detectable because most of the samples did not have a

detectable value and

therefore the true mean is below the level of detection.

[Tilefish > swordfish > king mackerel > tuna ....]

The advice to avoid the four species with the highest methylmercury levels was

extended to women who

are breast-feeding and to young children. Although there is no direct evidence

of a link between the

consumption of contaminated fish and adverse effects in these two groups, they

were included in the

advisory as a matter of caution, on the basis of the susceptibility of the

developing nervous system to

mercury exposure.

What about other commercial fish? The range of methylmercury in other commercial

species is fairly

narrow, from trace levels to about 0.4 ppm. It is these low-methylmercury fish

that are most commonly

consumed in the United States. Accordingly, the FDA advisory recommends a

" balanced " diet of seafood

consumption that will keep methylmercury levels low. The recommendations reflect

not only the

methylmercury levels in individual fish species but also the amount of fish

consumed over time and the

frequency of consumption. Even among women who are pregnant or are likely to

become pregnant,

consumption of 12 oz (340 g) per week of a variety of cooked fish (excluding the

four species with the

highest mercury levels) is considered to be safe. If this advice is followed,

resulting exposures will be well

below that reported to be associated with subtle deficits in development. In

addition, this level of fish

consumption is consistent with the recommendations of the American Heart

Association and the Public

Health Service, which are based on the presumed cardiovascular benefit.

Although the current recommendations provide useful guidance, some questions

remain. For example,

how much canned tuna is safe to eat? What level of fish consumption is safe for

children? To begin to

address these questions, the FDA sought the advice of its Food Advisory

Committee, which provided

several recommendations. These include conducting a detailed assessment of the

level of canned-tuna

consumption and the associated level of methylmercury exposure, defining what is

meant by " a variety of

fish, " relating dietary recommendations to the age or size of a child, working

with other federal and state

agencies to include commercial and recreational fish under the same umbrella

advisory, and expanding the

monitoring of methylmercury levels to include measurement of levels in humans

(in blood, hair, or both).

The current estimate is that 8 percent of women who become pregnant exceed the

most conservative

definition of a safe level of methylmercury exposure. An ultimate goal is to

reduce methylmercury exposure

in all such women to safe levels.

Although the current advisory on methylmercury focuses on a subgroup of women of

reproductive age, a

large case–control study reported in this issue of the Journal (pages 1747–1754)

suggests that

methylmercury exposure may have a negative effect on cardiovascular health in

adult men. Guallar et al.

found a significant association between toenail mercury levels and the risk of

myocardial infarction, after

adjustment for levels of beneficial n–3 fatty acids. However, the findings of

another study reported in this

issue of the Journal underscore the controversy; Yoshizawa et al. (pages

1755–1760) found no

association between methylmercury exposure and coronary heart disease in a large

cohort of male health

professionals.

The notion that methylmercury contributes to cardiovascular disease is certainly

a testable hypothesis and

one that warrants further testing. Robust prospective studies are needed in

populations in which fish

constitutes a major staple in the diet. Data from such studies are essential if

major changes in dietary

recommendations for the U.S. and other populations are to be made.

Guallar, E.....and Kok, F. J., the Heavy Metals and Myocardial Infarction

Study G, (2002).

Mercury, Fish Oils, and the Risk of Myocardial Infarction.

N Engl J Med 347: 1747-1754.

ABSTRACT

Background It has been suggested that mercury, a highly

reactive heavy metal with no known physiologic activity,

increases the risk of cardiovascular disease. Because fish

intake is a major source of exposure to mercury, the mercury

content of fish may counteract the beneficial effects of its n–3

fatty acids.

Methods In a case–control study conducted in eight

European countries and Israel, we evaluated the joint

association of mercury levels in toenail clippings and

docosahexaenoic acid (C22:6n–3, or DHA) levels in

adipose tissue with the risk of a first myocardial infarction

among men. The patients were 684 men with a first

diagnosis of myocardial infarction. The controls were 724

men selected to be representative of the same populations.

Results The average toenail mercury level in controls was

0.25 µg per gram. After adjustment for the DHA level and

coronary risk factors, the mercury levels in the patients were

15 percent higher than those in controls (95 percent

confidence interval, 5 to 25 percent). The

risk-factor–adjusted odds ratio for myocardial infarction

associated with the highest as compared with the lowest

quintile of mercury was 2.16 (95 percent confidence interval, 1.09 to 4.29; P

for trend=0.006).

After adjustment for the mercury level, the DHA level was inversely associated

with the risk of

myocardial infarction (odds ratio for the highest vs. the lowest quintile, 0.59;

95 percent

confidence interval, 0.30 to 1.19; P for trend=0.02).

Conclusions The toenail mercury level was directly associated with the risk of

myocardial

infarction, and the adipose-tissue DHA level was inversely associated with the

risk. High

mercury content may diminish the cardioprotective effect of fish intake.

-------------------------------------------------

Mercury is a highly reactive heavy metal with no known physiologic activity.1,2

Exposure to toxic levels of

mercury results in neurologic and renal damage, but the consequences of

long-term exposure to low levels

of mercury are poorly understood.1,2 Mercury may predispose people to

atherosclerotic disease by

promoting the production of free radicals or by inactivating several antioxidant

mechanisms through binding

to thiol-containing molecules or to selenium.3,4,5 In 1995, Salonen et al.

reported an increased risk of

coronary heart disease among residents of the Kuopio area in Finland whose hair

samples had increased

levels of mercury.6,7 The participants in that study, however, had relatively

high levels of mercury, which

were derived largely from locally contaminated freshwater fish.

Fish intake is a major source of exposure to mercury, mainly in the form of

methylmercury.2 Intake of fish

or fish oils (long-chain n–3 polyunsaturated fatty acids) has long been

hypothesized to prevent

cardiovascular events.8 Two large, randomized clinical trials have shown reduced

mortality after

myocardial infarction among patients assigned to a diet rich in fatty fish9 or

to fish-oil supplements,10 but

the generalizability of these findings to subjects without coronary heart

disease is uncertain. The results of

epidemiologic studies relating fish intake or fish-oil levels to coronary events

have been contradictory,11

and it has been suggested that mercury may counteract the beneficial

cardiovascular effects of n–3 fatty

acids in fish.2,6,7

To evaluate the association of mercury with the risk of myocardial infarction,

and to test the hypothesis

that high mercury levels may offset the inverse association between fish oil

consumption and myocardial

infarction, we assessed the joint association of mercury levels in toenail

clippings and docosahexaenoic

acid (C22:6n–3, or DHA) levels in adipose tissue with the risk of a first

myocardial infarction among men

who were participants in the European Multicenter Case–Control Study on

Antioxidants, Myocardial

Infarction and Cancer of the Breast (EURAMIC).12,13

Methods

Design and Subjects

The target population consisted of men 70 years of age or younger who were

native residents of any of

eight European countries or Israel.12,13 Subjects were excluded if they had a

previous diagnosis of

myocardial infarction, drug or alcohol abuse, or a major psychiatric disorder;

if they were institutionalized;

or if they had modified their dietary pattern in the previous year.

The patients were men with a first acute myocardial infarction ......... The

controls were men without a history

of myocardial infarction.......... with disorders not known to be associated

with dietary

factors ......

Patients and controls were recruited concurrently during 1991 and 1992. The

participation rates among

potential subjects were 81 percent for patients and 64 percent for controls.

...........

Data Collection

Information on smoking, hypertension, and diabetes was collected .....history of

hypertension or diabetes ....

.......... Because the levels of eicosapentaenoic acid (C20:5n–3) in adipose

tissue were

below the detection limit .... fish-oil fatty acids were ....exclusively ....

DHA.18.....

Statistical Analysis

Because the distribution of mercury was right-skewed, logarithmic transformation

was used ....

Results

In comparison with the controls, the patients had significantly higher body-mass

index and lower

high-density lipoprotein cholesterol levels and were more likely to have

hypertension, to have diabetes, to

smoke, and to have a family history of myocardial infarction (Table 1).12 The

total cholesterol level was

lower among patients than among controls, almost certainly reflecting the effect

of acute myocardial

infarction. Therefore, total cholesterol was not further considered in

case–control comparisons.

Table 1. Cardiovascular Risk Factors in Patients with

Myocardial Infarction

and in Controls.

Controls from Zeist, the Netherlands, and Berlin, Germany, had the lowest

average levels of mercury

among controls (0.14 and 0.17 µg per gram, respectively), whereas those from the

two Spanish centers

had the highest (0.57 µg per gram in Granada and 0.51 µg per gram in Málaga) — a

4.1-fold range of

variation (Table 2). The level of DHA in adipose tissue was strongly correlated

with the toenail mercury

level (Table 3). The age- and center-adjusted correlation coefficient between

the levels of DHA and

mercury was 0.34 (P<0.001).

Table 2. Means and Patient: Control Ratios for Mercury Levels

in Toenails.

Table 3. Risk Factors According to Quintile of Toenail Mercury

Level among

Controls, Adjusted for Age and Center.

After adjustment for age, center, and DHA level, the patients had higher mercury

levels than the controls

(case–control ratio, 1.10; 95 percent confidence interval, 1.03 to 1.18) (Table

2). This association

persisted after the exclusion of the two Spanish centers, which were the centers

with the highest mercury

levels (DHA-adjusted case–control ratio, 1.09; 95 percent confidence interval,

1.02 to 1.17), and after

adjustment for multiple cardiovascular risk factors (case–control ratio, 1.15;

95 percent confidence

interval, 1.05 to 1.25).

Analysis with adjustment for age and center showed an increased risk of

myocardial infarction at high

mercury levels (P for trend=0.01) (Table 4). Adjustment for DHA markedly

increased the association and

elicited a graded, positive dose–response pattern. This trend was further

strengthened after adjustment for

traditional risk factors and levels of antioxidants, resulting in an odds ratio

of 2.16 for patients in the highest

quintile of mercury level, as compared with the lowest (95 percent confidence

interval, 1.09 to 4.29; P for

trend=0.006). When mercury was introduced as a continuous variable in the

regression models, the

multivariate odds ratio associated with a change from the 25th to the 75th

percentile of the mercury

distribution was 1.63 (95 percent confidence interval, 1.22 to 2.18; P=0.001).

Table 4. Odds Ratios for a First Myocardial Infarction,

According to Quintile

of Toenail Mercury Level or Adipose-Tissue Docosahexaenoic

Acid (DHA)

Level.

The dose–response curve for the relation between the mercury level and the risk

of myocardial infarction

was further examined by nonparametric logistic regression (Figure 1).19 There

was a positive, monotonic

increase in risk associated with mercury levels above 0.25 µg per gram, which

was steeper after

adjustment for DHA levels.

Figure 1. Nonparametric Estimates of the Risk of

Myocardial

Infarction According to the Levels of Mercury in the

Toenails

(Panel A) and of Docosahexaenoic Acid (DHA) in Adipose

Tissue

(Panel .

All curves have been adjusted for age and center. The

nonparametric regression models used a lowess smoother

with 40

percent span.19 The reference value (odds ratio = 1.0)

was set at

0.08 µg per gram for mercury and 0.08 percent of the

total

fatty-acid peak area for DHA, both values

corresponding to the 5th

percentile of their respective distributions among

controls. The bars

represent the frequency distribution of mercury and

DHA in the

study sample.

The average levels of DHA, expressed as a percentage of the total fatty-acid

peak area, were 0.24±0.13

percent in patients and 0.25±0.13 percent in controls. In analyses adjusted for

age and center, there was

no consistent relation between increasing DHA levels and the risk of myocardial

infarction (Table 4).17

After adjustment for the mercury level as well, there was a significant trend

toward a lower risk of

myocardial infarction with higher DHA levels (P for trend = 0.01). This trend

was confirmed in the

nonparametric analyses (Figure 1). There was no interaction between mercury and

DHA with respect to

their associations with the risk of myocardial infarction (P for the

interaction=0.61).

We performed several sensitivity analyses to assess the consistency of our

findings. First, we reanalyzed

the data while excluding the results from Málaga, the center with the strongest

effect of mercury. When we

did so, the association of mercury with the risk of myocardial infarction

persisted: the DHA-adjusted

case–control ratio of mercury levels was 1.08 (95 percent confidence interval,

1.01 to 1.15). In addition,

there were no significant differences in the association of mercury and

myocardial infarction among study

centers (P for the interaction between center and mercury level=0.20). Second,

we found similar results in

centers that used controls from the general population and in those that

selected other types of controls

(data not shown). Third, we confirmed that the participation rates in each

center, both for patients and for

controls, were not correlated with the association between mercury level and

myocardial infarction

(P=0.66 for the correlation in controls and P=0.97 for the correlation in

patients). Finally, we assessed the

association between mercury level and myocardial infarction, restricting our

analyses to the five centers

with the highest response rates among controls; the results were similar to our

overall results (the ratio of

the mercury level in patients relative to that in controls, after adjustment for

DHA levels, was 1.12;

P=0.005).

Discussion

In this international case–control study, we found an independent and graded

association between toenail

mercury levels and the risk of myocardial infarction. Furthermore, mercury

masked an inverse association

between DHA levels and the risk of myocardial infarction that became evident

only after adjustment for

the mercury level.

Several factors add to the strength of our findings. First, toenail and

adipose-tissue samples were collected

from patients shortly after they had had a myocardial infarction. These

measurements are therefore unlikely

to have been affected by the development of disease, a common limitation of

case–control studies.

Second, only patients with a first myocardial infarction were examined, so it is

unlikely that they had

changed their diet before the event. Finally, toenail mercury is a reliable

biologic marker of long-term

exposure to mercury.2,20,21 The validity of the mercury measurements in our

study is further reinforced by

the finding of a strong association between mercury and DHA, a biologic marker

of fatty-fish intake.18

Mercury exists in three forms: elemental mercury, inorganic mercury compounds,

and organic mercury,

primarily methylmercury.1,2 Exposure to inorganic mercury occurs occupationally;

people can also be

exposed to inorganic mercury from silver–mercury amalgam in dental fillings.

Exposure to methylmercury

results almost exclusively from the consumption of fish, shellfish, and marine

animals; these foods are a

major source of exposure to mercury for the general population.2 Large,

predatory fish, such as swordfish

and sharks, have the highest concentrations of mercury (around 1 µg per gram);

tuna, trout, pike, and bass

have intermediate concentrations (0.1 to 0.5 µg per gram); and most shellfish

have low concentrations.1,2

In populations eating large quantities of fish from locally contaminated lakes

or rivers, however, other

species may be the main contributors to the total intake of mercury.6

Mercury may promote atherosclerosis and hence increase the risk of myocardial

infarction in several

ways. Mercury promotes the production of free radicals in experimental

models,3,4,5 and it may bind

selenium to form mercury selenide, an insoluble complex that cannot serve as a

cofactor for glutathione

peroxidase.22 In addition, methylmercury has a very high affinity for thiol

groups, and it may inactivate the

antioxidant properties of glutathione, catalase, and superoxide dismutase.23

Mercury may induce lipid

peroxidation,24 and mercury levels were a strong predictor of oxidized

low-density lipoprotein levels in the

Kuopio Ischemic Heart Disease Study.6 Mercury compounds may also promote

platelet aggregability25

and blood coagulability,26 inhibit endothelial-cell formation and migration,27

and affect apoptosis and the

inflammatory response.28 Increased rates of cardiovascular disease were found

among mercury-exposed

workers,29,30 and mercury levels in hair predicted the progression of carotid

atherosclerosis in a

longitudinal study.31 Toenail mercury, however, did not predict the incidence of

coronary heart disease in a

nested case–control study in U.S. health professionals reported elsewhere in

this issue of the Journal.32

Some limitations also need to be considered in the interpretation of our

findings. Our analyses were based

on single measurements of mercury and DHA, and they are subject to random

measurement error. In

addition, the levels of mercury or DHA were low in many study participants, thus

increasing the likelihood

of analytical error. It is likely that the results of our analyses underestimate

the associations of both mercury

and DHA levels with myocardial infarction.

Another potential limitation of our study is that the participation rate was

higher for patients than for

controls. Although this raises the possibility of selection bias, the

association of mercury levels with

myocardial infarction was higher in centers with higher participation rates,

making selection bias an unlikely

explanation of our results. Furthermore, because both mercury and DHA are

derived primarily from fish in

the diet, selection bias would be expected to influence associations of the

levels of both of these

substances with myocardial infarction in the same direction, not in opposite

directions.

We did not have information on the sources of mercury or DHA or on the amount

and type of fish

consumed by the study participants. However, the high mercury levels in the two

Spanish centers are

consistent with the high consumption of fish in that country33 and the high

levels of mercury in fish caught in

the Mediterranean34,35 and consumed in those cities. The correlation between

mercury and DHA suggests

that fish is probably the main source of mercury in toenails in our populations,

although other sources of

exposure are possible. Finally, our patient population was restricted to

patients with myocardial infarction

who survived until hospitalization. The observed associations thus cannot be

generalized to patients with

acute cardiac events who die before hospitalization.

Fish intake is currently recommended to reduce the risk of cardiovascular

diseases36 and as part of a

Mediterranean-type diet.37 However, the findings of epidemiologic studies of

fish intake or fish-oil levels

and coronary heart disease are contradictory, ranging from clearly inverse

associations38,39,40 to virtually

null associations17,41,42,43,44,45 and to positive associations.6 Protective

effects of fatty fish9 and fish-oil

supplements10 have been found in two secondary-prevention trials. In both

trials, the protection was

largely limited to fatal coronary events, whereas we found an inverse

association between DHA levels and

nonfatal myocardial infarction. It is possible that, although the antiarrhythmic

effects of fish oils may prevail

in the prevention of recurrent events in patients who have had a myocardial

infarction or in the prevention

of sudden death from cardiac causes,46,47 the antiaggregant and other

antiatherogenic properties of fish

oils may also have a substantial preventive effect.

The risk of cardiovascular disease in a population may depend on the balance

between n–3 fatty acids and

methylmercury in the fish consumed. Exposure to methylmercury is already a

concern in specific high-risk

groups; the Food and Drug Administration has advised pregnant women and women

who may become

pregnant not to eat swordfish, king mackerel, tilefish, shark, or fish from

locally contaminated areas.48 Our

results raise the possibility that this advice should be extended to the general

adult population. However,

our findings do not imply that people should stop eating fish. Our

mercury-adjusted analysis is consistent

with a protective effect of dietary fish, provided it is not heavily

contaminated.

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This article has been cited by:

Yoshizawa, K., Rimm, E. B., , J. S., Spate, V. L.,

Hsieh, C.-c., Spiegelman, D., Stampfer, M. J., Willett, W. C.

(2002). Mercury and the Risk of Coronary Heart Disease in

Men. N Engl J Med 347: 1755-1760 [Abstract] [Full Text] >>>>>>>>>>

ABSTRACT

Background A high dietary intake of mercury from

consumption of fish has been hypothesized to increase the

risk of coronary heart disease.

Methods Using a nested case–control design, we

investigated the association between mercury levels in

toenails and the risk of coronary heart disease among male

health professionals with no previous history of

cardiovascular disease or cancer who were 40 to 75 years

of age in 1986. Toenail clippings were collected in 1987

from 33,737 cohort members, and during five years of

follow-up, we documented 470 cases of coronary heart

disease (coronary-artery surgery, nonfatal myocardial

infarction, and fatal coronary heart disease). Each patient

was matched according to age and smoking status with a

randomly selected control subject.

Results The mercury level was significantly correlated with

fish consumption (Spearman r=0.42, P<0.001), and the

mean mercury level was higher in dentists than in

nondentists (mean, 0.91 and 0.45 µg per gram, respectively;

P<0.001). After age, smoking, and other risk factors for

coronary heart disease had been controlled for, the mercury

level was not significantly associated with the risk of

coronary heart disease. When the highest and lowest quintiles of mercury level

were

compared, the relative risk of coronary heart disease was 0.97 in the highest

level (95

percent confidence interval, 0.63 to 1.50; P value for trend=0.78). Adjustment

for intake of

n–3 fatty acids from fish did not appreciably change these results.

Conclusions Our findings do not support an association between total mercury

exposure and

the risk of coronary heart disease, but a weak relation cannot be ruled out.

Several lines of evidence suggest that oxidation of low-density lipoprotein

(LDL) in the arterial intima has

an important role in atherogenesis.1,2,3 Mercuric chloride increased hydrogen

peroxide formation and

depleted glutathione in rats.4 In a prospective cohort study in eastern Finland,

fish consumption and the

levels of mercury in the hair were positively associated with the risk of

coronary heart disease and with

serum titers of immune complexes containing oxidized LDL. The authors

hypothesized that the

associations were due to catalysis of lipid peroxidation by mercury, with which

fish in the region are highly

contaminated.5

Cadmium is also postulated to increase the risk of hypertension and coronary

heart disease,6,7 but the

evidence is limited and inconsistent.8 In studies in animals, the administration

of mercury modifies the

distribution and retention of injected cadmium in various organs,9,10 a result

that suggests an interaction

between cadmium and mercury. Selenium is thought to antagonize some of the

adverse effects of

mercury.11,12,13,14,15,16

In this analysis, we assessed the association between base-line levels of

mercury in the toenails and the

subsequent risk of coronary heart disease among men in the Health Professionals

Follow-up Study.

Because the majority of participants are dentists, who have occupational as well

as dietary exposures to

mercury, the range of mercury burden was unusually wide. The assessment included

the evaluation of

possible interactions of mercury with cadmium and selenium.

Methods

Study Population

The Health Professionals Follow-up Study is a prospective cohort study of the

relation between diet and

coronary heart disease and cancer among 51,529 men who were 40 to 75 years old

in 1986. The

population includes 29,683 dentists, 10,098 veterinarians, 485 pharmacists, 3745

optometrists, 2218

osteopathic physicians, and 1600 podiatrists. The study began in 1986....... In

1987.....

excluded 1595 men whose reported daily energy intake according to the 1986

semiquantitative

food-frequency questionnaire was below 800 kcal per day or greater than 4200

kcal per day .....

.. The men who reported a diagnosis of cancer (other than

nonmelanoma skin cancer), myocardial infarction, angina, stroke, coronary-artery

bypass surgery, or

percutaneous transluminal coronary angioplasty on the 1986 questionnaire were

also excluded. ............

Ascertainment of Cases

..........Men who had fatal coronary heart disease, nonfatal myocardial

infarction, coronary-artery bypass surgery,

or percutaneous transluminal coronary angioplasty between the return of toenail

clippings in 1987 and

January 31, 1992, were considered case patients. ........

...... During five years of follow-up between 1987

and January 1992, coronary heart disease developed in 470 participants eligible

for this analysis (234 had

nonfatal myocardial infarctions; 109 died of coronary heart disease, including

45 who died suddenly; and

127 underwent coronary-artery bypass grafting or percutaneous transluminal

coronary angioplasty). ......

.. The patient and the control were matched according to age (within one calendar

year), smoking status (current smoker; former smoker, matched according to the

number of years since

stopping; or nonsmoker [i.e., never smoked]), and the date on which the

clippings were returned (within

one month). In this analysis we included 442 matched pairs, as well as an

additional 28 patients and 22 controls ..........

Statistical Analysis

Because the distribution of cadmium levels was skewed to the right, the values

were log-transformed to

improve normality. .......Mercury values were categorized into quintiles.......

.. Alcohol intake was grouped into four categories: 0.0, 0.1 to 5.0, 5.1 to 30.0,

and

30.1 or more grams per day. Age was grouped into six categories: less than or

equal to 50, 51 to 55, 56

to 60, 61 to 65, 66 to 70, and 71 or more years. Smoking status was grouped into

three categories (never

smoked, former smoker, and current smoker), and the current smokers were further

grouped into two

categories (1 to 24 and 25 or more cigarettes per day). ........................

Results

The range of mercury levels among the control participants was 0.03 to 14.56 µg

per gram. Table 1

shows the proportion of dentists, the level of fish consumption, and potential

confounding factors

according to the level of mercury in the toenails. The mean (±SD) mercury level

was 0.91±1.47 µg per

gram in dentists, as compared with 0.45±0.40 µg per gram among nondentists

(P<0.001 by

nonparametric unpaired test). Fish consumption among all participants was higher

with higher mercury

levels. The median toenail mercury levels were 0.29, 0.34, 0.44, 0.62, and 0.75

µg per gram for

increasing quintiles of fish consumption (median intake, 20.7, 26.1, 30.4, 37.2,

and 51.0 g per day)

(Spearman r=0.42, P<0.001).

Table 1. Base-Line (1986) Characteristics of the Controls

According to

Quintile of Mercury Level in the Toenails.

The mean mercury level was similar in the patients and the controls, both among

matched pairs (mean,

0.74±1.21 µg per gram for patients and 0.72±1.40 µg per gram for controls;

P=0.76 by the

nonparametric paired test) and among all patients and controls (mean, 0.72±1.40

µg per gram for the 470

patients and 0.74±1.21 µg per gram for the 464 controls; P=0.36 by the

nonparametric unpaired test).

The relative risks of coronary heart disease according to quintile of toenail

mercury level are shown in

Table 2. After adjusting for age, smoking, and other risk factors for coronary

heart disease, we found no

evidence of an increased risk of coronary heart disease with higher mercury

levels. Furthermore, inclusion

of n–3 fatty acid intake from fish in the multivariate model did not change the

relative risks appreciably.

Table 2. Relative Risk of Coronary Heart Disease during Three

Years of

Follow-up According to Toenail Mercury Levels in 934 Subjects.

Toenail cadmium levels were not associated with the risk of coronary heart

disease (P for trend=0.18)

after adjustment for age, smoking, alcohol intake, presence or absence of a

family history of coronary

heart disease, high blood pressure, hypercholesterolemia, and diabetes, and

body-mass index (the relative

risks [and 95 percent confidence intervals] for increasing quintiles of cadmium

were 1.00, 0.95 [0.62 to

1.45], 1.11 [0.72 to 1.71], 0.98 [0.64 to 1.52], and 1.31 [0.85 to 2.03]). For

men in the highest category

of both mercury and cadmium levels (in which the risk was hypothesized to be the

greatest), the relative

risk, as compared with those who were in the lowest categories of both, was 1.18

(95 percent confidence

interval, 0.68 to 2.04). The interaction was not significant (P=0.87).

Table 3 shows the relative risks of coronary heart disease according to toenail

mercury levels within three

roughly equal categories of toenail selenium level (low, medium, and high). The

toenail mercury levels

within the low and medium selenium categories were not significantly associated

with the risk of coronary

heart disease. Within the highest nail selenium category, men with the highest

mercury level had a higher

risk of coronary heart disease than those with the lowest mercury level;

however, the result of the test for

trend did not attain statistical significance. The subjects were also divided

into three groups according to

levels of mercury, as well as according to selenium levels. For men in the

highest category for mercury and

the lowest category for selenium, in which the risk was hypothesized to be the

greatest, the multivariate

relative risk, as compared with those in the lowest category for mercury and the

highest category for

selenium, was 0.99 (95 percent confidence interval, 0.57 to 1.72), after age and

other risk factors were

controlled for (P for interaction=0.89).

Table 3. Relative Risk of Coronary Heart Disease during Three

Years of

Follow-up According to Toenail Mercury and Selenium Levels

among

Patients and Controls. [Highest quintile Hg + Se(+) RR was

1.47 +/- 1.01-6.04).]

In separate multivariate analyses, the relative risk of nonfatal myocardial

infarction or fatal coronary heart

disease for men in the highest versus the lowest quintile of mercury level was

1.04 (95 percent confidence

interval, 0.65 to 1.68; P for trend=0.68), and for coronary-artery bypass

grafting or percutaneous

transluminal coronary angioplasty, the relative risk was 0.96 (95 percent

confidence interval, 0.48 to 1.90;

P for trend=0.65).

The form of mercury in fish is primarily methylmercury, and that to which

dentists are occupationally

exposed is elemental mercury. Because it is possible that different forms of

mercury may have different

effects on cardiovascular risk, we repeated our analyses after excluding

dentists. Although the statistical

power was substantially reduced (220 cases), we observed a nonsignificant

association with the toenail

mercury level. The multivariate relative risk for the highest (0.84 µg per gram)

versus the lowest (0.13 µg

per gram) quintile of mercury was 1.27 (95 percent confidence interval, 0.62 to

2.59; P for trend=0.43);

with additional control for intake of eicosapentaenoic acid plus docosahexaenoic

acid, the relative risk was

1.70 (95 percent confidence interval, 0.78 to 3.73; P for trend=0.41).

Discussion

Among the participants in this study, dentists and those who ate more fish had

significantly higher levels of

mercury in their toenails. However, our data do not support an association

between mercury levels and an

increased risk of coronary heart disease, as has been reported previously5 and

also in a study reported in

this issue of the Journal.25 The absence of any clear association is probably

not due to methodologic bias,

because this study used a nested case–control design within a large prospective

cohort, and because the

toenail specimens were collected prospectively before the coronary heart disease

events occurred. The

absence of an association between mercury levels and coronary heart disease

could be due to a limited

range of mercury exposure. It is also possible that mercury levels in nails are

not a good indicator of

long-term mercury intake. However, the strong relation between mercury levels in

nails and the intake of

fish, as measured by a food-frequency questionnaire, and the much higher levels

in dentists than

nondentists support the validity of mercury levels in nails as a measure of

exposure. Because of the

occupational exposure of dentists, the range of mercury levels was greater than

would be seen in the

general U.S. population. Toenail mercury levels have previously been

demonstrated to be a valid measure

of dietary mercury exposure.26 Nail mercury levels also provided an indicator of

the long-term body

burden of mercury among women in the Nurses' Health Study.21

We speculated that there might be some beneficial effects of n–3 fatty acids in

fish that could

counterbalance the effect of mercury. However, the multivariate analysis that

controlled for n–3 fatty acid

intake did not change the relative risks appreciably. Furthermore, in the same

Health Professionals

Follow-up Study cohort, increasing fish intake (from one to two servings per

week to five to six servings

per week) was not associated with the overall incidence of coronary heart

disease, although an inverse

trend was seen with the small number of sudden deaths.27 The positive

association between fish

consumption and the risk of coronary heart disease in the Finnish study5,28

could be due to differences in

the nutrient composition of the fish, unique contaminants, or different

risk-factor characteristics among fish

eaters. The concentrations of mercury in hair from subjects in the Finnish study

and in toenails from the

recent European study25 are similar to or lower than those reported in our

study.

The form of mercury consumed in fish is primarily methylmercury, and that due to

the occupational

exposure of dentists is primarily elemental mercury. As indicated by the strong

associations with toenail

mercury concentrations in our study, both forms of mercury are absorbed, and

both can have serious

neurologic toxic effects.29 However, there are some differences in the clinical

and pathological

manifestations of neurologic toxicity from these two forms of mercury, so the

possibility exists that they

might influence the risk of cardiovascular disease differently. We found a

positive but nonsignificant

association between mercury levels and the risk of coronary heart disease in an

analysis excluding dentists.

The marginally significant increased risk of coronary heart disease associated

with higher mercury levels

among men in the highest third of the group with respect to selenium level was

probably due to chance,

because the combination of high mercury and low selenium levels was not

associated with excess risk. The

higher proportion of current smokers in the lowest mercury-level category in

this study is probably due to

the participants' lifestyles, because health-oriented men may eat more fish in

addition to not smoking.

In conclusion, toenail mercury levels measured by neutron activation reflect

occupational exposure of

dentists and intake of fish. However, we found no evidence, over a wide range of

mercury exposures, that

the overall levels were associated with any substantial increase in the risk of

coronary heart disease.

Furthermore, we found no increase in risk of coronary heart disease associated

with higher mercury levels

in combination with low selenium or high cadmium levels. However, a weak

relation between mercury

exposure, particularly from fish consumption, and the risk of coronary heart

disease cannot be excluded.

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