C H A P T E R
16
Cardiovascular Disease
BENGT SJÖGREN, CAROLINA BIGERT, AND PER GUSTAVSSON
ABSTRACT
There is strong epidemiological and mechanistic
evidence for a causal association between exposure to
arsenic and lead and development of cardiovascular
disease. There is relatively strong but less conclusive
evidence for a causal relationship between cadmium
and mercury exposure and cardiovascular disease. All
of these metals are suspected of inducing pathophysi-
ological changes relevant to atherogenic disorders,
including increased oxidative stress, inflammatory
response, and coagulation activity.
Cardiomyopathy has been associated with exces-
sive intake of arsenic, cobalt, and iron. Deficiency of
selenium has been related to dilated cardiomyopathy.
Airborne beryllium exposure has been associated
with heart disease, including both ischemic heart
disease and cor pulmonale. Signs of cor pulmo-
nale have also been observed after cobalt exposure
among hard-metal workers. Pulmonary fibrosis with
increased blood pressure in the pulmonary circula-
tion is a likely mechanism in the development of cor
pulmonale.
Ionizing irradiation may explain the suggested rela-
tion between uranium exposure and cerebrovascular
disease.
1 INTRODUCTION
Cardiovascular disease (CVD) is the leading cause
of death in the developed as well as in the develop-
ing world. The annual mortality of CVD is expected
to reach 23.6 million by 2030 (Alissa and Ferns, 2011).
Handbook on the Toxicology of Metals 4E
http://dx.doi.org/10.1016/B978-0-444-59453-2.00016-0
CVD is a group of diseases that includes coronary
heart disease (CHD), cerebrovascular disease, periph-
eral arterial disease, rheumatic heart disease, deep
vein thrombosis, and pulmonary embolism (WHO,
2012). Sometimes the term circulatory diseases is used
to encompass all of these diseases. CHD is a disease of
the blood vessels supplying the heart muscle. This con-
dition is often called ischemic heart disease (IHD) and
acute myocardial infarction belongs to this entity. Cere-
brovascular diseases are subdivided into ischemic and
hemorrhagic diseases. Stroke is a widely used unspe-
cific term for a group of cerebrovascular diseases of
abrupt onset that cause neurological damage. Approx-
imately 85% of strokes are caused by inadequate blood
flow to the brain, i.e. ischemic stroke. Hemorrhagic
strokes are subdivided into hemorrhage into the brain
tissue and hemorrhage into the subarachnoid space
(Zivin, 2004). The main representative of peripheral
arterial disease is hypertension. Terminology used in
the different studies was retained in the following text.
The most common cause of CVD is atherosclerosis.
Atherosclerosis has an inflammatory nature, which
was described by the Austrian pathologist Carl von
Rokitansky in the 1840s and by Rudolf Virchow some-
what later. Rokitansky believed that inflammation
was secondary to other disease processes and Virchow
promoted atherosclerosis as a primary inflammatory
disease (Frostegård, 2010; Mayerl et al., 2006). The
response-to-injury hypothesis was summarized by
Ross (1993). This theory postulates alteration to the
endothelium and intima, due to for example mechani-
cal injury, toxins, and oxygen radicals, as the initiating
event leading to endothelial dysfunction. During the
last two decades more data has linked inflammation
313 Copyright © 2015 Elsevier B.V. All rights reserved.
314 Bengt Sjögren, Carolina Bigert, and Per Gustavsson
to the occurrence of atherosclerosis and thrombosis
(Epstein et al., 1999; Libby et al., 2002; Ridker, 1999;
Ross, 1999). Several markers of inflammation such
as interleukin-6 (IL-6), fibrinogen, C-reactive protein
(CRP), serum amyloid A protein, and increased leu-
kocyte cell count are established risk factors for IHD
(Danesh et al., 1998, 2000, 2005, 2008).
Environmental studies focus on the general popula-
tion, and the exposure route is almost always ingestion
of metals or metal-containing compounds. Prospective
studies are more conclusive because the exposure by
definition occurs prior to the effect or disease outcome.
Consequently, cross-sectional studies are regarded as
less conclusive. Occupational studies focus on a spe-
cific occupational group or a specific metal exposure,
and the exposure route is inhalation as a rule. In many
studies of occupational exposures, the CVD mortal-
ity for one specific occupational group is compared
with the national mortality. Such comparisons may be
biased because the general population includes sick
and disabled people who are unable to work.
This is a condensed review, mainly focusing on epi-
demiological studies of environmental as well as occu-
pational exposures to metals and metal-containing
compounds and their relations with CVD.
2 ALUMINUM
Aluminum is ubiquitous in the environment and
comprises about 8% of the Earth’s crust. Aluminum
can be absorbed by ingestion or inhalation. Accumula-
tion in the human body relates to the presence of alu-
minum in dialysis fluids and the concomitant intake of
aluminum-containing drugs. The highest occupational
exposures occur among aluminum welders and pow-
der production workers.
Australian gold miners who inhaled aluminum
powder in order to prevent silicosis had a slightly
increased cardiovascular mortality compared to other
gold miners [hazard ratio (HR) 1.02 per year of expo-
sure, 95% confidence interval (CI) 1.00-1.04] (Peters
et al., 2013).
Several studies of primary aluminum smelter work-
ers reported an increased risk of ischemic heart and
cerebrovascular diseases (Rønneberg, 1995; Thériault
et al., 1988). Increased risks were also found among
potroom workers at the old Söderberg pots, as well as
among workers using prebaked electrodes (Thériault
et al., 1988). Slightly higher levels of fibrinogen were
observed among smelter workers at Söderberg pots
exposed to high levels of air pollutants compared to
those working with prebaked electrodes and exposed
to lower levels of air pollutants (Sjögren et al., 2002).
A total of 7026 Canadian aluminum primary pro-
duction workers using Söderberg pots were followed
between 1957 and 1999 and compared with the
province’s population. Smoking-adjusted internal
­
comparisons were conducted using Cox regression
for the male subjects (n = 6423). Cumulative benzo[a]
pyrene exposure was associated with IHD mortality
(HR 1.62, 95% CI 1.06-2.46) in the highest exposure cat-
egory (Friesen et al., 2010).
In summary, studies of aluminum exposure and
CVD are scarce and consequently no firm conclusions
can be drawn.
3 ARSENIC
The most common sources of exposure to arsenic
are contaminated drinking water and occupational
exposure among primary copper smelter workers.
CVD is one of several important outcomes of arsenic
exposure. These diseases comprise peripheral vascular
disease including blackfoot disease, IHD, stroke, and
hypertension. These effects are mentioned in Chapter
28 on arsenic.
In 1900 in the Manchester area in England an epi-
demic of a multisystem disease occurred, with over
6000 cases and more than 70 deaths. This epidemic has
been described as the first metal-induced cardiotoxic
syndrome, and was produced by the intake of beer
contaminated with arsenic (Alexander, 1969). The syn-
drome included the usual signs and symptoms of arse-
nic poisoning, and an unusual but prominent aspect of
this epidemic was heart failure. The source of arsenic
was contaminated sulfuric acid, which was used to treat
cane sugar. It was observed that some persons seemed
to have a “peculiar idiosyncracy” and “that many per-
sons became ill who drank less beer than others who
were not affected” (Klatsky, 2006). The authors drew
the conclusion that arsenic predisposed susceptible
persons to develop alcoholic cardiomyopathy. Arsenic
intoxication has been associated with atypical ven-
tricular tachycardia (Goldsmith and From, 1980). Mice
treated orally with NaAsO2 for 2 days developed lipid
peroxidation and abnormal ultrastructural changes in
the cardiac tissue (Manna et al., 2008). These authors
summarized that arsenic exposure is associated with
direct myocardial injury, cardiac arrhythmias, and car-
diomyopathy (Manna et al., 2008).
A review of 11 cross-sectional studies identified an
association between arsenic exposure and the preva-
lence of hypertension. The association was evident in
studies conducted both in areas with arsenic drink-
ing water concentrations above 50 μg/L and in those
with drinking water concentrations below 50 μg/L.
 16  Cardiovascular Disease
The evidence is suggestive of an association but is
insufficient to infer a causal relationship because the
number of studies was small and no prospective stud-
ies were done (Abhyankar et al., 2012).
A Spanish ecological investigation in a population
of 24.8 million people related arsenic concentrations
in drinking water during 1998-2002 to mortality for
the period 1999-2003 to allow for a 1-year delay with
respect to arsenic determinations. An arsenic concen-
tration above 10 μg/L was associated with an increased
risk of CVD and CHD mortality in men as well as
women (Medrano et al., 2010). In the United States,
millions of persons are exposed to arsenic concentra-
tions above 10 μg/L and populations in many coun-
tries (e.g. Bangladesh, China, India, Cambodia, Ghana,
Argentina, and Mexico) are exposed to arsenic levels in
drinking water above 10 μg/L (Abhyankar et al., 2012).
A pooled analysis included groups exposed to
arsenic concentrations above 50 μg/L in drinking
water. The pooled relative risks (RRs) for CVD, CHD,
stroke, and peripheral arterial disease were 1.32 (95%
CI 1.05-1.67), 1.89 (95% CI 1.33-2.69), 1.08 (95% CI
0.98-1.19), and 2.17 (95% CI 1.47-3.20), respectively
(Moon et al., 2012).
Low levels of arsenic are common in copper ore all
over the world, and primary copper smelter work-
ers are exposed to arsenic, as well as to several other
compounds such as silica dust, and sulfur dioxide.
A cohort of 8047 white male workers from copper
smelters in Montana exposed to arsenic trioxide was
followed until 1963; increased mortality from heart
disease was observed [standardized mortality ratio
(SMR) 1.18, P < 0.01]. However, these smelter work-
ers were also exposed to sulfur dioxide and silica, and
some also to lead (Lee and Fraumeni, 1969). A subco-
hort of 1800 men from the same smelter was followed
until 1978. In the group heavily exposed to arsenic
(> 0.5 mg/m3), increased IHD mortality was observed
(SMR 1.77, P < 0.01). A tentative dose-response was
observed when exposure to the highest level of arsenic
for at least 30 days was related to IHD mortality (Welch
et al., 1982). The total cohort of 8045 arsenic-exposed
copper smelter workers in Montana followed until
1977 also had increased mortality from heart disease
(Lee-Feldstein, 1983).
A total of 2802 white males were included in a
cohort of copper smelter workers in Tacoma, Washing-
ton. After adjustment for the healthy worker survivor
effect, significantly increased mortality from CVD was
observed after high cumulative exposure to arsenic
(Hertz-Picciotto et al., 2000).
A case-referent study from a Swedish primary cop-
per smelter showed significantly increased mortality
from CVD. There was also a significant dose-response
315
relationship for increasing categories of arsenic expo-
sure (Axelson et al., 1978). In a cohort study of 3916
male smelter workers from the same smelter, slightly
increased mortality from IHD was found (SMR 1.07,
95% CI 0.97-1.17) but there was no dose-response rela-
tionship (Järup et al., 1989).
In summary, the consumption of beer contaminated
with arsenic was associated with cardiomyopathy. A
high concentration of arsenic in drinking water is asso-
ciated with cardiovascular, including peripheral vas-
cular, disease. Some studies of occupationally exposed
primary smelter workers suggest a relationship
between arsenic exposure and CVD, although con-
founding exposures may contribute to the observed
excess risk.
4 BERYLLIUM
The worldwide use of beryllium is increasing and
occupational beryllium exposure occurs in the aero-
space, nuclear, automotive, electronics, and telecommu-
nication industries. Prolonged inhalation of beryllium
may stimulate the acquired immune response to
release mediators of chronic inflammation in the lung,
involving cellular and molecular components of innate
immunity, and it is this vicious cycle driven by beryl-
lium that results in the progressive impairment of lung
function, granuloma formation, and progression to
lung fibrosis (Sawyer and Maier, 2011). Absorption of
beryllium from ingestion is very low (see Chapter 30
“Beryllium”).
Several U.S. cohort studies of beryllium-exposed
workers have reported increased mortality from heart
diseases. A cohort of 3055 white male beryllium-
exposed workers employed between 1942 and 1968
was followed until 1975. An increased risk of heart dis-
ease was observed among workers employed before
1950 (SMR 1.16, P < 0.05). The risk of death from heart
disease was higher for workers exposed for more than
5 years (SMR 1.29) than among workers exposed for
less than 5 years (SMR 1.10) (Wagoner et al., 1980). The
estimated air concentrations of beryllium in the 1940s
frequently exceeded 1000 μg/m3 in some of the indus-
tries included (Ward et al., 1992).
A U.S. cohort comprising 9225 males who had
worked between 1940 and 1969 was followed until
1988. The cohort members had worked in plants
engaged in beryllium processing, including the extrac-
tion of beryllium hydroxide from beryl ore, the pro-
duction of beryllium oxide, pure beryllium metal, and
beryllium copper alloy, and the machining of beryl-
lium-containing products. Mortality from IHD was
significantly increased in the total cohort (SMR 1.08,
316 Bengt Sjögren, Carolina Bigert, and Per Gustavsson
95% CI 1.01-1.14). Mortality from diseases of the arter-
ies, veins, and pulmonary circulation, which includes
cor pulmonale, was increased in one plant (Lorain)
(SMR 1.78, P < 0.05). Cor pulmonale is a heart disease
characterized by enlargement and hypertrophy of the
right ventricle secondary to increased resistance and
high blood pressure in the pulmonary circulation.
Beryllium pneumoconiosis causes such an increased
resistance in the pulmonary circulation (Ward et al.,
1992). The cohort was updated with quantitative expo-
sure estimates, expanded to 9199 workers, and fol-
lowed until December 2005. Increased mortality from
cor pulmonale was reported (SMR 1.17, 95% CI 1.08-
1.26). No risk estimate for mortality from IHD was
reported (Schubauer-Berigan et al., 2011).
To summarize, an increased risk of IHD was
observed in one study and increased risks of cor pul-
monale were reported in two studies. A suggestive
dose-response relationship was found for heart disease
including both IHD and cor pulmonale. The increased
risk may have been caused by the very high exposure
levels (around 1000 μg/m3) prevalent before 1950.
5 CADMIUM
Cadmium is widely spread in the environment.
Exposure to humans occurs by ingestion of food con-
taminated with cadmium, by smoking, and in certain
industrial settings. Smokers have approximately twice
the body burden of cadmium compared to nonsmok-
ers. In nonsmokers, the primary source of exposure
is food (Gallagher & Meliker, 2010). Exposure to cad-
mium has been associated with diseases of the cardio-
vascular system, bone, kidneys, and lungs. Cadmium
and cadmium compounds are classified as carcinogens
(see also Chapter 18 “Carcinogenicity of Metal Com-
pounds” and Chapter 32 “Cadmium” of this book).
The effects of cadmium on the cardiovascular system
have been suggested to be a result of its action on
the cardiovascular endothelium and smooth muscle,
mediated by the generation of a proinflammatory
state, endothelium dysfunction, increased oxidative
stress, and downregulation of nitric oxide production
(Agarwal et al., 2011). This chapter describes investiga-
tions in the general population and also occupational
mortality studies.
Blood levels of cadmium were associated with an
increased prevalence of peripheral arterial disease
(defined as a blood pressure ankle-brachial index < 0.9
in at least one leg) in a representative sample (cross-
sectional analysis) of the general U.S. population
(Navas-Acien et al., 2004). The results were similar to
a study in the same population in which urinary levels
of cadmium were strongly positively associated with
peripheral arterial disease. After multivariate adjust-
ment (age, sex, race, education level, and smoking
status), subjects with peripheral arterial disease had
36% higher levels of cadmium in urine than subjects
without peripheral arterial disease (Navas-Acien et al.,
2005). The results support a possible role for cadmium
in atherosclerosis.
A 15-year follow-up study of urinary cadmium and
mortality among inhabitants of a cadmium-polluted
area (Kakehashi River Basin) in Japan showed that the
mortality risk of subjects with high urinary cadmium
(≥ 10 μg/g creatinine) after adjustment for age was
higher than that of subjects with moderate urinary
cadmium (< 10 μg/g creatinine) in both sexes. When
the subjects were divided into five groups accord-
ing to the amount of urinary cadmium (< 3, 3-5, 5-10,
10-20, and ≥ 20 μg/g creatinine), the mortality risk was
significantly increased among women with urinary
cadmium ≥ 3 μg/g creatinine. The results suggested
that mortality risk ratio is increased in proportion to
increases in the urinary cadmium concentration after
adjustment for age. When special causes of death
among subjects with high and moderate urinary cad-
mium were investigated, the mortality risk ratio for
heart failure was significantly increased in both sexes
compared with those with moderate urinary cadmium
(Nakagawa et al., 2006).
Another follow-up study among the inhabitants of
the cadmium-polluted Kakehashi River Basin area in
Japan showed excess mortality due to heart failure and
cerebral infarction in both sexes, as well as nephritis
and nephrosis in men, among subjects with renal tubu-
lar dysfunction (urinary β2-microglobulin > 1000 μg/g
creatinine) induced by cadmium in the environment.
A significant increase in mortality risk for cerebral
infarction in men was observed during the first five-
year observation period. The mortality risk for heart
failure and cerebral infarction increased in proportion
to increased urinary β2-microglobulin in both sexes
(Nishijo et al., 2006).
In a Belgian study, subjects were randomly
recruited from an area contaminated with cadmium
and a reference area with lower exposure to cadmium,
and blood cadmium, urinary cadmium, and mortal-
ity were followed. At baseline, blood cadmium (14.6
versus 10.2 nmol/L) and urinary cadmium (14.1 ver-
sus 8.6 nmol/24 hr) were higher in subjects who died
than in survivors. However, there was no relationship
between cadmium levels and cardiovascular mortality
(Nawrot et al., 2008).
In a cross-sectional study of U.S. adults, the cad-
mium level in blood, but not in urine, was associ-
ated with a modest elevation in blood pressure. The
 16  Cardiovascular Disease
average difference in systolic and diastolic blood pres-
sure between participants in the 90th versus the 10th
percentile of the blood cadmium distribution were
1.36 mm Hg (95% CI −0.28 to 3.00) and 1.68 mm Hg
(95% CI 0.57-2.78), respectively. There was no associa-
tion between cadmium levels and the prevalence of
hypertension (Tellez-Plaza et al., 2008).
Cadmium in the blood and urine in the general U.S.
population was positively associated with the risk of
having a history of stroke or heart failure. After adjust-
ing for demographic and cardiovascular risk factors,
a 50% increase in blood cadmium corresponded to a
35% increased odds of a history of stroke (OR 1.35, 95%
CI 1.12-1.65) and a 48% increased odds for a history of
heart failure (OR 1.48, 95% CI 1.17-1.87). A 50% increase
in urinary cadmium corresponded to a 9% increase in
odds for a history of stroke (OR 1.09, 95% CI 1.00-1.19)
and a 12% increase in odds for a history of hyperten-
sion (OR 1.12, 95% CI 1.03-1.20) (Peters et al., 2010).
In a review by Alissa and Ferns (2011), the authors
discuss a possible association between cadmium expo-
sure and hypertension, diabetes, myocardial infarc-
tion, early atherosclerotic vessel wall thickening, and
CVD, although there may be confounding exposures,
for example coexposure to other metals and residual
confounding from smoking habits.
Cadmium levels in blood and urine were associated
with the prevalence and future growth of atheroscle-
rotic plaques in the carotid arteries (Fagerberg et al.,
2012), and with low ankle-brachial index as a measure
of peripheral artery disease (Fagerberg et al., 2013), in a
cohort of 64-year-old Swedish women, after adjusting
for smoking and other cardiovascular risk factors.
A prospective study in the general U.S. population
(8989 participants who were ≥ 20 years of age) showed
that cadmium levels in the blood and urine were asso-
ciated with future CVD mortality, heart disease mor-
tality, and for cadmium levels in urine also with CHD
mortality, after adjusting for sociodemographic and
CVD risk factors, including smoking status, recent
smoking dose, and cumulative smoking dose. The
adjusted HRs for blood and urine cadmium, compar-
ing the 80th to the 20th percentiles of cadmium distri-
butions, were 1.69 (95% CI 1.03-2.77) and 1.74 (95% CI
1.07-2.83) respectively, for CVD mortality; 1.98 (95% CI
1.11- 3.54) and 2.53 (95% CI 1.54-4.16) for heart disease
mortality; and 1.73 (95% CI 0.88-3.40) and 2.09 (95%
CI 1.06-4.13) for CHD mortality. The population attrib-
utable risks associated with the 80th percentile of the
blood (0.80 μg/L) and urine (0.57 μg/g creatinine) cad-
mium distributions were 7.5% and 9.2%, respectively,
for CVD mortality (Tellez-Plaza et al., 2012).
A prospective cohort study of 3348 American Indian
adults 45-74 years of age showed that urine cadmium
317
was associated with increased cardiovascular mortal-
ity and increased incidence of CVD. After adjusting for
sociodemographic and cardiovascular risk factors, the
HRs (comparing the 80th to the 20th percentile of urine
cadmium concentrations) were 1.43 for cardiovascular
mortality (95% CI 1.21-1.70) and 1.34 for CHD mor-
tality (95% CI 1.10-1.63). The corresponding HRs for
incident CVD, CHD, stroke, and heart failure were 1.24
(95% CI 1.11-1.38), 1.22 (95% CI 1.08-1.38), 1.75 (95%
CI 1.17-2.59), and 1.39 (95% CI 1.01-1.94), respectively
(Tellez-Plaza et al., 2013a).
In a systematic review by Tellez-Plaza et al. (2013b),
the authors state that, together with experimental evi-
dence, their review (12 studies were included) sup-
ports an association between cadmium exposure and
CVD, especially for CHD. The number of studies with
stroke, heart failure, and peripheral artery disease end-
points was small. Overall, the pooled RRs for CVD,
CHD, stroke, and peripheral artery disease were 1.36
(95% CI 1.11-1.66), 1.30 (95% CI 1.12-1.52), 1.18 (95% CI
0.86-1.59), and 1.49 (95% CI 1.15-1.92), respectively. The
pooled RRs for CVD in men, women, and never smok-
ers were 1.29 (95% CI 1.12-1.48), 1.20 (95% CI 0.92-1.56)
and 1.27 (95% CI 0.97-1.67), respectively.
In a cohort mortality study in Great Britain almost
7000 male cadmium-exposed workers from five indus-
tries (primary production, copper-cadmium alloys,
silver-cadmium alloys, pigments and oxide, and stabi-
lizers), who were exposed for more than 1 year between
1942 and 1970, were followed with regard to mortality
to the end of 1984. Compared with the general popu-
lation, there was no significant excess of death due to
hypertensive disease (SMR 1.19, 95% CI 0.85-1.52) and
the SMR for deaths from cerebrovascular disease was
significantly lower than expected (SMR 0.77, 95% CI
0.66-0.89) (Kazantzis et al., 1988).
In a mortality study of 347 male copper-cadmium
alloy workers in Great Britain (all subjects first
employed in the period 1922-1978 and for a minimum
period of 1 year) were investigated for the period 1946-
1992. Compared with the general population, there
was no excess of mortality from diseases of the circu-
latory system (SMR 1.03, 95% CI 0.83-1.27) (Sorahan
et al., 1995).
In a mortality study of 869 Swedish battery work-
ers exposed to nickel hydroxide and cadmium oxide
(employed for at least 1 year between 1940 and 1980),
the workers were followed up until 1992. Compared
with the general population, the SMRs for IHD were
1.16 (95% CI 0.96-1.40) in males and 0.75 (95% CI 0.25-
1.76) in females, and the SMRs for cerebrovascular
disease were 0.78 (95% CI 0.47-1.21) in males and 1.34
(95% CI 0.37-3.43) in females, after adjusting for smok-
ing habits (Järup et al., 1998).
318 Bengt Sjögren, Carolina Bigert, and Per Gustavsson
A cohort of 1462 male workers at a UK tin smelter
(who had been employed for at least 1 year between
1967 and 1995) were followed up until 2001. Mortality
from IHD showed a deficit compared with the national
population (SMR 0.96, 95% CI 0.82-1.11) and with
the regional population (SMR 0.94, 95% CI 0.80-1.09)
(Binks et al., 2005).
A cohort of 2422 male workers (employed for three
or more years between 1946 and 1996) exposed to arse-
nic, cadmium, and other substances at a copper mine
and smelter in Copperhill, Tennessee, were followed
up until 2000. Based on national and local county
comparisons, there was no evidence of an increased
mortality risk from cerebrovascular disease, all heart
disease, or hypertension (Marsh et al., 2009).
In summary, the data support an association of
cadmium exposure with the occurrence of CVD and
CHD. There is also a possible association with periph-
eral artery disease, stroke, and heart failure. Several
occupational mortality studies showed no association
between cadmium exposure and CVD compared with
the general population.
6 CHROMIUM
The diet is the main source of chromium among
humans who are not occupationally exposed. Occupa-
tional chromium exposure occurs in the manufactur-
ing of chromates and ferrochromium, in chromium
plating, and in stainless steel welding.
In the early 1960s, the University of Pittsburgh was
contracted to study mortality in males born in 1890
or later and employed in three chromate-producing
plants between 1937 and 1940; they were followed
for mortality until 1961. Arteriosclerotic heart dis-
ease mortality was 1.93 in 1941-45 and 0.64 in 1956-60
(Table 1). During the initial period (1941-1945) death
rates were very high for some causes. The decline in
TABLE 1  Mortality among Chromate Workers, Working
between 1937 and 1940, Followed until 1960
1941–1945 1946–1950 1951–1955 1956–1960
Cause of
death Obs SMR Obs SMR Obs SMR Obs SMR
All 59 1.58 55 1.26 75 1.35 57
Respiratory 16 29.1 19 15.7 19 7.92 15
cancer
Arterioscle- 11 1.93 12 1.13 18 1.03 13
rotic heart
disease
Obs, observed; SMR, standardized mortality ratio.
Source: Enterline, 1974.
mortality due to respiratory cancer indicates decreased
exposure to a very potent carcinogen. The author sus-
pects calcium chromate to be the carcinogenic agent in
these old chromate-producing plants. However, it was
unknown whether all of the excess deaths were related
to exposures to chromate production (Enterline, 1974).
A total of 1737 male workers were studied in a
New Jersey chromium pigment factory. The pigments
contained both lead and zinc chromates. IHD mor-
tality was 0.85 (95% CI 0.71-1.00) (Hayes et al., 1989).
Another cohort originating from New Jersey com-
prised 3408 workers who had worked between 1937
and 1971 in former chromate-producing plants in the
northern part of the state. The proportionate mortality
ratios regarding arteriosclerotic heart disease was 0.97
for white men, 0.90 for black men, and 1.19 (95% CI
0.73-1.83) for white women. However, a weakness of
the study is the inability to distinguish between pro-
duction workers and management staff (Rosenman
and Stanbury, 1996).
A cohort of 482 former chromate production work-
ers from Painesville, Ohio, USA, was followed until
1997. Forty-one percent started working at the chro-
mate plant during the 1940s, and 59% started before
1955. The average airborne concentration of hexava-
lent chromium in the indoor operating areas of the
plant from 1943 to 1948 was 720 μg/m3, from 1957
to 1964 was 270 μg/m3, and from 1965 through 1972
was 39 μg/m3. SMR for diseases of the heart was 1.13
(95% CI 0.93-1.36) based on Ohio reference rates and
1.21 (95% CI 0.99-1.46) based on U.S. reference rates.
The corresponding SMRs for other circulatory dis-
eases were 1.43 (95% CI 0.96-2.04) and 1.51 (95% CI
1.02-2.16), respectively (Crump et al., 2003; Luippold
et al., 2003).
A chromate chemicals manufacturing facility in
Castle Hayne, North Carolina, was built in 1971 and
designed to reduce the high levels of chromium expo-
sure found at most older facilities. A cohort comprised
398 workers employed between 1971 and 1989. More
than 99% of the measurements of hexavalent chromium
based on personal sampling were below 50 μg/m3. Forty-
five employees had previously worked at the plant in
Painesville, Ohio. The SMR for all heart diseases was
0.65 (90% CI 0.26-1.37) based on only five cases and the
mortality experience of the surrounding eight North
1.00 Carolina counties (Pastides et al., 1994).
4.75 A cohort study of employees was formed from two
different U.S. plants. Exposure levels to hexavalent
0.64
chromium at both plants were very low after major
process changes from high-lime to no-lime processes.
The geometric mean of personal air concentrations of
Cr(VI) remained much less than 1.5 μg/m3 for most
years at both plants. The range of annual means was
 16  Cardiovascular Disease
0.36 to 4.36 μg/m3 and the highest personal air sam-
pling values were generally less than 10 μg/m3. This
study examines the mortality experience of two post-
change cohorts of chromate production employees
constituting the current U.S. chromium chemical
industry. The SMR for IHD was 0.55 (95% CI 0.18-1.28)
based on five cases (Luippold et al., 2005.)
A total of 2298 chromate-producing workers were
identified from three different factories (Bolton, Ruther-
glen and Eaglescliffe) in the United Kingdom. They
had worked for at least 1 year between 1950 and 1976
and were followed until 1988. During this follow-up
no significant increases were observed in the different
factories regarding IHD (SMR 1.03-1.12) or cerebrovas-
cular disease (SMR 1.06-1.30) (Davies et al., 1991).
Two cohorts from two German chromate-producing
factories comprised 1417 workers; they were fol-
lowed until 1988. Both factories were originally high-
lime facilities. The plant in Leverkusen completed
the changeover to a no-lime process in 1958 and the
plant in Uerdingen completed the changeover in 1964.
Mortality due to CVD was 1.16 (95% CI 0.97-1.39) in
Leverkusen and 0.96 (95% CI 0.78-1.15) in Uerdin-
­ number of animals with arteritis in the renal arteries
gen (Korallus et al., 1993). In a later study, 901 work-
ers exposed only after the changeover formed a new
cohort, which was followed until 1998. Exposure
declined from the mid-1970s based on chromium lev-
els in urine samples. The SMR for diseases of the heart
was 0.66 (95% CI 0.45-0.93) and for other diseases of
the circulatory system was 1.00 (95% CI 0.57-1.63) (Birk
et al., 2006), thus suggesting a reduced risk.
A Japanese cohort study of 896 male workers
manufacturing chromium compounds observed an
increased SMR for lung cancer (9.5) but no increases
for heart disease (SMR 0.6) and cerebrovascular dis-
ease (SMR 1.0) (Satoh et al., 1981).
In summary, one study of chromate-producing
workers from the USA has shown decreasing trends
of cardiovascular mortality that may be associated
with improvements in the working environment and
decreasing exposures. These observations may indi-
cate a relationship between hexavalent chromium
exposure and CVD. Hexavalent chromium exposures
below 50 μg/m3 were not associated with heart disease.
7 COBALT
In the early 1960s cobalt salts, chloride or sulfate,
were added to some brands of beer in order to stabi-
lize the foam; as a result of this intervention, heavy
beer drinkers developed cardiomyopathy, which led
to a high mortality rate (Morin et al., 1971). It is likely
that poor nutrition and ethanol played a synergistic
319
role with cobalt in the development of this disease
(Lauwerys and Lison, 1994; Seghizzi et al., 1994).
Cardiomyopathy was also described in two workers
exposed to heavy dust concentrations from cobalt-
containing ores for 2 months and 2 years, respectively
(Jarvis et al., 1992). Cardiomyopathy was also reported
after exposure to hard-metal dust in a man responsible
for weighing and mixing tungsten carbide and cobalt
powder (Kennedy et al., 1981).
The bioavailability of cobalt increases in the pres-
ence of tungsten carbide. Endotracheal instillation of
tungsten carbide-cobalt mixture in rats causes severe
alveolitis and fatal pulmonary edema, whereas the
corresponding dose of cobalt powder alone causes
a moderate inflammatory response (Lauwerys and
Lison, 1994).
Mice exposed to 30 mg/m3 cobalt sulfate heptahy-
drate for 90 days developed arteritis in the main cor-
onary artery (2/17 compared to controls 0/18). In a
long-term inhalation study of exposure to 3.0 mg/m3
cobalt for 24 months, 2/48 animals developed arte-
ritis in coronary arteries versus 0/46 in controls. The
was 5/48 versus 1/46. Thus, there was a significantly
increased risk when all groups were taken into account
(Moyer et al., 2002).
In a cross-sectional study of 30 cemented tungsten
carbide workers with a mean exposure duration of 9.9
years, a weak but significant inverse correlation was
found between duration of exposure and resting left
ventricular function. Nine workers with abnormal
chest X-ray findings had relatively lower exercise right
ventricular ejection fractions. Diminished right ven-
tricular reserve was probably due to fibrotic lung dis-
ease and early cor pulmonale. The authors concluded
that although overt left ventricular dysfunction was
not present, prolonged exposure to industrial cobalt
may have a weak cardiomyopathic effect (Horowitz
et al., 1988).
No increased mortality risk of all circulatory dis-
ease or IHD were observed in the largest cohort of
French hard-metal workers comprising totally 7459
men and women. The SMRs were 0.88 (95% CI 0.75-
1.03) and 0.93 (95% CI 0.71-1.19), respectively (Moulin
et al., 1998).
A cohort of 3163 male Swedish hard-metal workers
was followed from 1951 to 1982. In the total cohort,
the SMR for IHD was 0.99 (95% CI 0.80-1.21). In a sub-
group with estimated high cobalt exposure and long-
term (> 10 years) exposed workers, a higher SMR was
observed (SMR 1.69, 95% CI 0.96-2.75) (Hogstedt and
Alexandersson, 1990).
Thus, cardiomyopathy has been induced by the
intake of cobalt-containing beer and after inhalation
320 Bengt Sjögren, Carolina Bigert, and Per Gustavsson
of high concentrations of dust from cobalt-containing
ores. Signs of cor pulmonale have been observed as a
result of fibrotic lung disease induced by inhalation of
hard-metal dust. The majority of cohorts comprising
cobalt-exposed hard-metal workers do not report an
increased risk of IHD. However, one study suggests an
excess in long-term exposed workers.
8 IRON
Iron is an essential metal for the human body.
Almost all cells employ iron as a cofactor for funda-
mental biochemical activities, such as oxygen trans-
port, energy metabolism, and DNA synthesis. The vast
majority of body iron is distributed in the hemoglo-
bin of red blood cells and developing erythroid cells.
Iron is absorbed from the diet mainly in two forms of
iron; heme and nonheme (inorganic) iron. Humans are
unable to excrete iron actively, and the concentration
in the body is regulated at the site of iron absorption in
the proximal small intestine (Wang and Pantopoulos,
2011; Zimmermann and Hurrell, 2007). Welders inhale
iron oxide and the lungs of welders exposed continu-
ously for 18 years may contain between 30 and 2000 mg
(Kalliomäki et al., 1978).
Iron overload is the accumulation of excess iron
in different organs as a result of increased intestinal
absorption, parenteral administration, or increased
dietary intake. During iron overload, transferrin, the
carrier of iron in the circulation, which is normally
around 30% saturated, becomes fully saturated, and
toxic non-transferrin-bound iron species appear in the
blood. The heart is one of the main organs affected by
excess iron accumulation. The term iron overload car-
diomyopathy refers to cardiomyopathy resulting from
iron accumulation in the myocardium. This condition
may be caused by genetically determined disorders
of iron metabolism or by multiple blood transfu-
sions. This myopathy comprises different forms of
cardiac dysfunction secondary to the iron deposition.
Iron overload cardiomyopathy accounts for one-third
of the deaths in hereditary hemochromatosis and is
the leading cause of mortality in thalassemia major
(­Kremastinos and Farmakis, 2011).
The total iron-binding capacity (TIBC) represents
the level of transferrin, which is usually inversely
correlated to iron stores. In a meta-analysis compris-
ing seven studies, high TIBC levels were associated
with a decreased risk of coronary artery disease. The
association persisted when only prospective studies
were included in the analysis (Kang et al., 2012). Thus,
increased iron stores seem to be associated with an
increased risk of CHD.
Dietary intake of iron was assessed at baseline by
a questionnaire in a cohort study comprising 58,615
healthy Japanese. Dietary intake of total iron was posi-
tively associated with mortality from total and isch-
emic stroke and total CVD in men but not in women
(Zhang et al., 2012a).
Several occupations are associated with exposure
of airborne iron-containing particles e.g. welders and
iron foundry workers. However, these workers are
exposed to other metals and gaseous air pollutants in
addition to iron, which may confound possible asso-
ciations between iron exposure and outcomes.
8.1 Welders
Welding processes generate both respirable particles
and gases. Iron is the major particulate component in
most steel-welding operations (Flynn and Susi, 2010).
An increase in the inflammatory marker CRP was
observed among welders from an apprentice weld-
ing school who mainly worked in low-alloy steel for 1
day, with a mean exposure of 1.7 mg/m3 measured as
particulate matter with an aerodynamic mass median
diameter of 2.5 μm (PM2.5) (Kim et al., 2005).
Increased mortality from IHD was observed
among welders, despite the fact that the death rates
of these welders were compared with those of the
general population (which also includes sick and dis-
abled people unable to work); consequently, the risk
estimates may underestimate the true risk (Moulin
et al., 1993; Newhouse et al., 1985). Some cohort stud-
ies of welders did not observe any significant differ-
ences in diseases of the circulatory system (Becker,
1999; Simonato et al., 1991); in one study a signifi-
cantly decreased risk was observed (Beaumont and
Weiss, 1980). Later studies were better designed and
included both fatal and nonfatal cases of disease. In
a Danish study, 8376 male metal workers answered
a questionnaire about their welding experience and
lifestyle. A cohort of 5866 welders was followed from
the start of 1987 until the end of 2006. Information
of CVD was retrieved from the Danish National
Patient Registry. Increased risks were observed for
acute myocardial infarction [standardized incidence
ratio (SIR) 1.1, 95% CI 1.0-1.2], chronic IHD (SIR 1.2,
95% CI 1.1-1.3), and cerebral infarction (SIR 1.2, 95%
CI 1.1-1.4) (Ibfelt et al., 2010). A Swedish record-
linkage study found an increased risk of acute myo-
cardial infarction both among male (HR 1.2, 95% CI
1.1-1.3) and female (HR 1.3, 95% CI 1.1-1.6) welders.
An increased risk was also observed for other IHDs
among males (HR 1.2, 95% CI 1.1-1.2) but the risk was
not as pronounced among females (HR 1.1, 95% CI
0.98-1.3) (Wiebert et al., 2012).
 16  Cardiovascular Disease
In a cross-sectional study, 97 welders were com-
pared with 91 nonwelding controls (mean ages 35.7
and 35.4 years, respectively). Male welders had signifi-
cantly higher serum concentrations of iron than con-
trols, but this association was not found among female
welders (Lu et al., 2005).
In summary, iron overload can cause cardiomyopa-
thy. Several studies have also observed an association
between iron stores and an increased risk of CHD.
Welders are generally exposed to small particles of iron
but also to many other particles of metal or nonmetal
origin. Several studies of welders support the associa-
tion between airborne particle exposure and the occur-
rence of CVD, and one study observed an increase in
an inflammatory marker.
9 LEAD
The general population may be exposed to lead from
leaded gasoline, lead in paint, and industrial emis-
sions. Occupational exposures originate mainly from
smelters, refineries, and battery and paint production.
Several mechanisms have been reported to explain the
observed increases of blood pressure associated with
lead exposure, including impaired renal function, the
induction of oxidative stress and inflammation, and
endothelial dysfunction (Navas-Acien et al., 2007).
A meta-analysis focusing on blood lead and blood
pressure comprised a total of 31 studies. An association
between blood lead and blood pressure was found in
both men and women. A twofold increase in blood lead
concentration was associated with a 1.0-mm Hg rise in
systolic blood pressure (95% CI 0.5-1.4 mm Hg) and a
0.6-mm Hg rise in diastolic blood pressure (95% CI 0.4-
0.8 mm Hg) (Nawrot et al., 2002). An increase in tibia lead
by 10 μg/g bone was associated with a 0.26 mm Hg rise in
systolic blood pressure (95% CI 0.02-0.5 mm Hg) and the
summary odds ratio per 10 μg/g bone for hypertension
was 1.04 (95% CI 1.01-1.07) (Navas-Acien et al., 2008a).
Navas-Acien and coworkers (2007) reviewed the
literature on the relation between lead exposure and
CVD. The review included 12 studies of the general
population: five prospective cohort studies, one cross-
sectional study, and six case-control studies. Lead
exposure was positively associated with clinical car-
diovascular endpoints in all studies. The evaluation
included 18 studies with occupational exposures from
different industrial settings: battery, ceramic, refin-
ery, and smelter industries. Most were cohort studies
and used external comparisons to the general popu-
lation to derive SMRs. Relative risk estimates varied
widely. In two of the three studies that reported asso-
ciations by duration of employment, cerebrovascular
321
disease mortality was related to increasing duration of
exposure (Michaels et al., 1991; Steenland et al., 1992).
Navas-Acien and coworkers (2007) concluded that the
evidence was sufficient to infer a causal relationship
between lead exposure and hypertension. They also
concluded that the evidence was suggestive of, but not
sufficient to infer, a causal relationship between lead
exposure and clinical cardiovascular outcomes.
After the review by Navas-Acien and coworkers
(2007), some further studies have been published. A
Russian study in printing workers comprised 1423 men
and 3102 women. An increased risk of IHD was found
for male typecasting machine operators (SMR 1.29, 95%
CI 1.08-1.56). Information on exposure was based on
an industrial hygiene survey and exposure duration
in years. However, no dose-response relationship was
observed. In male or female manual typesetters and
linotype operators no increased risks of cerebrovascu-
lar disease were observed (Ilychova and Zaridze, 2012).
Among 868 totally environmentally exposed men,
lead levels in bone (patella and tibia) were measured
and the average follow up was 8.9 years. The highest
tertile of lead bone levels was compared with the low-
est. This comparison resulted in significantly increased
mortalities for both CVD (HR 2.5, 95% CI 1.1-5.6) and
IHD (HR 8.4, 95% CI 1.3-54.4) (Weisskopf et al., 2009).
In 2012 the U.S. National Toxicology Program (NTP)
reviewed the health effects of low-level lead expo-
sure. The NTP evaluation declared that there is suffi-
cient evidence that blood lead levels below 10 μg/dL
(0.5 μmol/L) are associated with small but detectable
increases in blood pressure and risk of hypertension.
The NTP concluded that there is limited evidence of
CVD mortality at blood levels below (0.5 μmol/L).
Lead levels in bone reflect long-term lead exposure,
and these levels were more consistently associated
with hypertension, CVD and mortality (NTP, 2012).
In summary, there is strong evidence for an asso-
ciation between lead exposure and both hypertension
and CVD. Some studies in occupationally exposed
workers showed a relationship between lead exposure
and cerebrovascular diseases after long-term exposure.
It has been estimated that 4% of the total global bur-
den of IHD is due to lead exposure (annually, 674,000
deaths and 13.9 million disability-adjusted life-years,
which is the sum of years of life lost due to death and
years of life with disability) (Lim et al., 2012).
10 MAGNESIUM
Magnesium is the fourth most common cation in the
body and the second most abundant intracellular cat-
ion after potassium. Magnesium plays an essential role
322 Bengt Sjögren, Carolina Bigert, and Per Gustavsson
as an enzymatic cofactor in a number of biochemical
pathways, including energy production from adenos-
ine triphosphate (ATP). This cation has a direct effect
on the Na+, K+-ATPase pump in both cardiac and
nerve tissues. Magnesium is a cofactor in more than
300 enzyme systems in human cells and has a piv-
otal position in normal myocardial physiology. Pos-
sible sites of action include vascular smooth muscle,
thrombocytes, and myocardial cells (Elin, 1987; Marx
and Neutra, 1997). Oral magnesium acts as a natural
channel blocker, increases nitric oxide, improves endo-
thelial dysfunction, and induces direct and indirect
vasodilation (Houston, 2011). Investigations of animal
and cellular responses to magnesium deficiency have
found evidence of complex proinflammatory path-
ways that may lead to better understanding of inflam-
matory processes (Weglicki, 2012).
The largest proportion of magnesium intake origi-
nates from food; the estimated intake from drinking
water is less than 5-10% (Rosenlund et al., 2005). A
low correlation was observed between dietary mag-
nesium intake and serum levels of magnesium (Ohira
et al., 2009). The serum magnesium concentration cor-
relates with the intracellular magnesium level in red
blood cells (Ryzen et al., 1989), but serum magnesium
accounts for less than 1% of the whole body burden of
magnesium (Elin, 1987).
Rodríguez-Móran and coworkers (2011) reviewed
epidemiological studies and clinical trials regarding
type 2 diabetes mellitus (T2DM). The body of evidence
from epidemiological studies showed a strong inverse
relationship between dietary magnesium intake and
the occurrence of T2DM. Magnesium is an important
component of unprocessed foods such as whole grains,
nuts, and green leafy vegetables. Randomized clinical
trials evaluating the benefits of magnesium supple-
mentation on glucose levels in individuals with T2DM
are scarce and controversial.
The intake of dietary magnesium was assessed
in 58,615 Japanese men and women. Dietary magne-
sium intake was inversely associated with mortality
from hemorrhagic stroke in men and with mortality
from total and ischemic strokes, CHD, heart failure,
and total CVD in women (Zhang et al., 2012b). Previ-
ous studies of magnesium dietary intake and ischemic
stroke have observed the same inverse relation among
women in the Nurses’ Health Study (Iso et al., 1999)
and among men from the USA (Ascherio et al., 1998).
The Atherosclerosis Risk in Communities (ARIC)
study comprised around 13,000 participants between
1987 and 1989 in four U.S. communities. The partici-
pants were reexamined between 1990 and 1995. Low
serum magnesium values were associated with an
increased incidence of CHD. This association was
stronger for women than for men. Further adjustment
for diabetes status and systolic blood pressure elimi-
nated the relation for men. However, the authors dis-
cuss whether this was an appropriate way to adjust
for two confounders or whether an overadjustment
had been made for factors within a causal pathway if
low magnesium concentrations had contributed to the
development of diabetes and hypertension (Liao et al.,
1998). The cohort was followed further until 2004.
Serum magnesium was inversely associated with isch-
emic stroke incidence (Ohira et al., 2009). In a separate
analysis, 7731 participants free of hypertension were
followed for 6 years. The results from this study sug-
gest that low magnesium may play a modest role in
the development of hypertension (Peacock et al., 1999).
In 2002, a meta-analysis of 20 studies detected
dose-dependent blood pressure reductions following
magnesium supplementation. However, the authors
recommended further adequately powered trials with
sufficiently high doses of magnesium supplementa-
tions to confirm this relationship (Jee et al., 2002).
Within the Cochrane Collaboration, magnesium
supplementation was reviewed for the management
of primary hypertension in adults. A total of 12 trials
enrolling 545 persons compared magnesium with pla-
cebo and measured blood pressure 8 weeks to 6 months
later. On average, people receiving extra magnesium
achieved slightly lower diastolic blood pressure at the
end of the trials. However, most trials included were
of poor quality, so the results may not be reliable. The
review did not find robust evidence that oral magne-
sium supplementation reduces high blood pressure in
adults (Dickinson et al., 2006, 2009).
The Cochrane Heart Group (Li et al., 2007, 2009)
evaluated the effect of intravenous magnesium on lim-
iting damage to the heart muscle, preventing serious
arrhythmias, and reducing the risk of death in heart
attack patients. A large well-designed trial with 58,050
participants did not demonstrate any beneficial effect
of intravenous magnesium, contradicting earlier meta-
analyses of smaller trials (ISIS-4, 1995). This review
included 26 clinical trials that had randomly assigned
heart attack patients to receive either intravenous mag-
nesium or an inactive substance (placebo). This review
did not support the continued use of intravenous mag-
nesium (Li et al., 2007, 2009).
Magnesium sulfate is a neuroprotective agent that
may hypothetically improve the outcome of aneurys-
mal subarachnoid hemorrhage by reducing the occur-
rence or improving the outcome of delayed cerebral
ischemia. In a clinical trial, 606 patients were assigned
to the magnesium group and 597 patients were
assigned to the placebo group. Intravenous magne-
sium sulfate did not improve the clinical outcome after
 16  Cardiovascular Disease
aneurysmal subarachnoid hemorrhage. In a meta-
analysis of six previous studies the same pattern was
observed (Dorhout Mees et al., 2012).
Inhalation exposure of magnesium has been studied
much less than magnesium exposure through drink-
ing water and dietary intake. The use of hydrated
magnesium carbonate hydroxide (magnesia alba) for
drying the hands is an important source of airborne
particulate matter in indoor climbing halls. Mean val-
ues for PM10 in these halls were generally in the order
of 0.2-0.5 mg/m3. Periods of high activity were associ-
ated with levels of between 1 and 4 mg/m3 (Weinbruch
et al., 2008).
Metal fume fever is an acute disability that occurs
after inhalation of fumes from a metal heated to a
temperature above its melting point. Zinc, copper,
and magnesium are the most common of these metals
(Hunter, 1978). Adding magnesium to molten iron has
induced fever in foundry workers (Hartmann et al.,
1983). Investigations have not identified a relationship
between occupational magnesium exposure and CVD.
In summary, an inverse relationship has been
observed between dietary magnesium intake and the
occurrence of diabetes and stroke. There is a low cor-
relation between dietary magnesium intake and serum
levels of magnesium. Low serum magnesium may be
associated with an increased risk of hypertension and
CHD. Clinical studies into intravenous magnesium
treatment after a heart attack or aneurysmal subarach-
noid hemorrhage did not support beneficial effects of
this regimen.
11 MANGANESE
Manganese is absorbed by ingestion and inhalation
after occupational exposure. Manganese ions may also
be injected intravenously in order to use their strongly
paramagnetic properties in magnetic resonance imag-
ing. Cardiovascular magnetic resonance is an impor-
tant diagnostic tool in cardiology. Manganese ions
accumulate inside myocytes and enable better imag-
ing. Fifteen healthy volunteers were given manganese
(MnCl2) intravenously. There was a slight increase in
systolic pressure and heart rate after 3 and 4 minutes
of the infusion, with normalization of these parameters
thereafter. On follow-up 6 months after investigation,
no volunteer reported any neurological or cardio-
logical adverse events or symptoms (Fernandes et al.,
2011).
In a Korean National Health and Nutrition Exami-
nation Survey (KNHANES), a total of 1991 partici-
pants were included in cross-sectional design. Blood
manganese concentration was positively associated
323
with hypertension in this representative sample of the
Korean adult population (Lee and Kim, 2011). A simi-
lar result was found in males from India (Taneja and
Mandal, 2007). A U.S. cross-sectional study comprised
639 older men in the Normative Aging Study (NAS).
Toenail concentrations of several metals including
manganese were assessed. Manganese was negatively
but not significantly associated with blood pressure.
After adjusting for other metals, an increase in man-
ganese was more strongly associated with decreased
blood pressure (Mordukhovich et al., 2012).
Manganese-exposed ferroalloy workers had
decreased systolic blood pressure (Saric and Hrustic,
1975); in another investigation, ferroalloy manufactur-
ers had higher systolic and diastolic blood pressure
than nonexposed referents (Cowan et al., 2009).
Manganese superoxide dismutase (MnSOD;
encoded by SOD2) is a member of the superoxide
dismutase family, the members of which have anti-
oxidant capacity. MnSOD may be the most important
member of the SOD family, as it resides in mitochon-
dria, where cellular respiration takes place. One study
demonstrated that a SOD2 polymorphism (Ala16Val)
may be associated with the development of T2DM in
Japanese-Americans (Nakanishi et al., 2008). However,
manganese per se is not necessarily involved in this
observed effect.
Rodier (1955) made an interesting observation when
studying manganese-exposed Moroccan miners. The
ore was very rich in manganese, neurological symp-
toms were common among the underground miners,
and 150 cases of poisoning were reported. Each year
approximately 3.7% of the workers were affected by
pneumonia. Death from heart failure was observed
to occur after a week with pneumonia or occurred
suddenly in patients regarded as cured. Manganese
pneumonia was associated with a marked rise in the
erythrocyte sedimentation rate among the miners.
The sedimentation rate can be influenced by several
serum proteins, for example, fibrinogen, haptoglobin,
immunoglobins, and ceruloplasmin. Increased fibrino-
gen concentration is an established risk factor for IHD
(Danesh et al., 2005) and has also been associated with
sudden death (Kucharska-Newton et al., 2009). In
another study of workers producing oxides and salts
of manganese, the white blood cell count was higher
among exposed workers than among referents when
smoking habits were taken into account (Roels et al.,
1987). An increased white blood cell count is associated
with an increased risk of CHD (Wheeler et al., 2004).
In a study of Norwegian ferromanganese-silico-
manganese furnace workers, three deaths due to
pneumonia occurred during active occupational expo-
sure (Hobbesland et al., 1997a); increased mortality
324 Bengt Sjögren, Carolina Bigert, and Per Gustavsson
from sudden death was also observed (Hobbesland
et al., 1997b). However, the furnace workers were also
exposed to other agents such as carbon monoxide
and heat.
In summary, studies addressing the relation between
manganese exposure and blood pressure revealed con-
flicting results and studies of other CVDs were very
scarce.
12 MERCURY
Vapor inhalation is the most important occupational
exposure route for mercury, typically occurring in mer-
cury mining and in chloralkali factories. In the general
public, fish consumption is an important source of
methylmercury exposure.
Inhalation of large doses of elemental mercury
vapor results in an influenza-like illness (Gerstner and
Huff, 1977).
Increased cardiovascular mortality was found
among 1190 male workers exposed to inorganic mer-
cury from eight Swedish chloralkali plants (when this
cohort was compared with national mortality rates);
the latency time was 10 years or more (SMR 1.3, 95%
CI 1.0-1.5) (Barregård et al., 1990). A similar study from
Norway comprising 674 male workers from two chlo-
ralkali plants did not observe increased cardiovascular
mortality (Ellingsen et al., 1993). An American study of
2133 male workers exposed to mercury vapor during
the production of nuclear weapons did not experience
increased mortality due to vascular lesions of the cen-
tral nervous system (Cragle et al., 1984). Other vascu-
lar diseases were not reported.
No increase in cardiovascular mortality was
observed among workers compensated for mercury
intoxication following exposure in the Italian fur hat
industry. The number of compensated women and
men was 820 and 326, respectively (Merler et al., 1994).
Mortality was studied in 6784 male workers from
four mercury mines and mills in Italy, Slovenia, Spain,
and the Ukraine. Increased mortality was found from
hypertension (SMR 1.46, 95% CI 1.08-1.93), heart dis-
ease other than ischemic (SMR 1.36, 95% CI 1.20-1.53),
and pneumoconiosis (SMR 27.1, 95% CI 23.1-31.6)
(­Boffetta et al., 2001). Workers in the mines had the high-
est SMR for diseases of the heart other than ischemic
and they were probably exposed to the highest levels
of silica. Cor pulmonale is one of the diagnoses under
the category “other diseases of the heart,” and this
disease may develop as a consequence of pneumoco-
niosis. There were no significant trends between dura-
tion of employment or estimated cumulative exposure
based on mercury urine levels and hypertension and
other diseases of the heart, respectively (Boffetta et al.,
2001). No conclusion can be drawn regarding mercury
exposure and circulatory diseases.
In 2002 the first results were presented from the
Health Professionals Follow-Up Study (HPFS), a cohort
study comprising 33,737 men who supplied toenail
clippings. The cohort was followed from 1987 to 1992.
Dentists had higher levels of mercury in their toenails
(0.91 μg/g) compared with nondentists (0.45  μg/g).
The mercury levels were not significantly associated
with the risk of CHD after adjustment for age, smok-
ing, and other risk factors (Yoshizawa et al., 2002). The
U.S. HPFS cohort was followed further and a female
cohort from the Nurses’ Health Study was added. Mer-
cury levels were derived from toenail clippings from
both studies. No increased risk of CHD, stroke, or
total CVD was observed at higher mercury levels. The
median mercury concentration was 0.23 μg/g among
cases with CVD and 0.25 μg/g among control partici-
pants (Mozaffarian et al., 2011).
In population-based investigations, mercury expo-
sure originates mainly from fish consumption. In
a population-based nested case-control study from
northern Sweden, 78 cases of first-ever myocardial
infarction were compared with 156 controls. High
erythrocyte mercury levels or high plasma polyunsat-
urated fatty acids were associated with a low risk of
myocardial infarction (Hallgren et al., 2001).
A case-control study from northern Sweden com-
prised 431 cases with myocardial infarction and 499
controls. Mercury was measured in erythrocytes: the
median level was 3.54 μg/L. An increased level of mer-
cury in erythrocytes was associated with a lower risk
of myocardial infarction. The authors propose that
mercury levels are a biomarker of fish intake and con-
sider the results to indicate a protective effect of fish
consumption (Wennberg et al., 2011).
In 1995 the first results were presented from the
Kuopio Ischaemic Heart Disease Risk Factor Study
(KIHD) regarding a possible relation between mer-
cury and heart disease. A total of 1833 men were fol-
lowed from 1984 to 1991. Mercury was measured in
hair, and men in the highest tertile (> 2.0 μg/g) had
an increased risk of acute myocardial infarction (RR
2.0, 95% CI 1.2-3.1) and cardiovascular deaths (RR
2.9, 95% CI% 1.2-6.6) compared to those with a lower
mercury content (Salonen et al., 1995). The study in
eastern Finland was slightly enlarged to comprise
1871 men who were followed from 1984 to 1997. A
44% reduction of acute coronary events was observed
when the highest fifth of the serum n-3 end-product
fatty acids docosahexaenoic acid (DHA) and docosa-
pentaenoic acid (DPA) was compared with the lowest
fifth of these fatty acids. Men in the highest fifth of
 16  Cardiovascular Disease
the DHA + DPA who had a low hair content of mer-
cury had a 67% reduced risk of acute coronary events
(Rissanen et al., 2000). This cohort was followed fur-
ther until 2002, and now men in the highest third of
hair mercury content (> 2.03 μg/g) had an increased
risk of acute coronary events (RR 1.60, 95% CI 1.24-
2.06), CVD (RR 1.68, 95% CI 1.15-2.44) and CHD (RR
1.56, 95% CI 0.99-2.46). A high mercury content in hair
attenuated the protective effects of high serum levels
of DHA and DPA (Virtanen et al., 2005). A concentra-
tion of 2 μg mercury per gram hair corresponds to
an erythrocyte concentration of 15 ng/g erythrocyte.
This level was exceeded by only two subjects in the
Swedish study by Hallgren et al. (2001). The discrep-
ancy between the results of the Finnish and Swedish
studies may be explained by the higher dose in the
Finnish study.
A case-control study conducted in eight European
countries and Israel comprised 684 men with first
myocardial infarction and 724 referents. Toenail mer-
cury levels were 0.27 μg/g among cases and 0.25 μg/g
among referents. The risk-factor-adjusted odds ratio
for myocardial infarction was 2.16 (95% CI 1.09-4.29)
when the highest quintile of toenail mercury level
(0.66 μg/g) was compared with lowest quintile. DHA
levels in adipose tissue were also included in this
adjustment (Guallar et al., 2002).
Three out of four studies supported a link between
methylmercury exposure and intima-media thicken-
ing of the carotid artery (Roman et al., 2011). In one
of the studies, comprising men from eastern Finland,
there was a linear relationship between their hair mer-
cury concentration and plasma fibrinogen (Salonen
et al., 2000), indicating a possible weak inflammatory
response.
Blood pressure was studied among Nunavik Inuit
adults from northern Quebec, Canada. The mean age of
the 732 participants was 34.4 years and the mean blood
mercury level was 50.2 nmol/L (10 μg/L). Mercury was
significantly associated with systolic blood pressure
(Valera et al., 2009). Blood pressure was also investi-
gated in a cross-sectional study of 1240 U.S. women in
the National Health and Nutrition Examination Sur-
vey (NHANES) 1999-2000. The mean concentration of
mercury in blood was 1.8 μg/L. Fish consumers had
a higher mean concentration compared with nonfish
consumers: 2.3 and 0.8 μg/L, respectively. A significant
relationship was found between blood mercury levels
and systolic blood pressure among nonfish consum-
ers but not among fish consumers. The intake of fish
oils may counteract the harmful effects of mercury on
blood pressure (Vupputuri et al., 2005).
Methylmercury exposure can cause oxidative stress,
an early biological response that can produce vascular
325
endothelial cell damage by promoting inflamma-
tion and vasoconstriction as well as lipid peroxida-
tion via generation of reactive oxygen species (Grotto
et al., 2009). Rats were exposed to 100 μg/kg of meth-
ylmercury chloride per day for 100 days. The long-
term treatment increased the systolic blood pressure.
The treated group also had a decreased level of glu-
tathione in the erythrocytes and an increased level of
malondialdehyde (MDA) in plasma. There was a nega-
tive correlation between plasma nitrite/nitrate levels
and systolic blood pressure and a positive correlation
between MDA and systolic blood pressure, suggest-
ing increased inhibition of NO formation with increase
of hypertension (Grotto et al., 2009). This study sug-
gests that long-term exposure to methylmercury
increases systolic blood pressure, associated at least in
part with increased production of radical oxygen spe-
cies as judged by increased production of MDA and
depressed NO availability (Grotto et al., 2009).
Mercury exposure and oxidative stress were stud-
ied among fish-eating riparians living in the Brazilian
Amazon. Both mercury in whole blood and in hair
were significantly inversely related with several bio-
markers of oxidative stress such as glutathione peroxi-
dase, glutathione, catalase, and δ-aminolevulinic acid
dehydratase (ALADH). These results further support
a relation between mercury exposure and oxidative
stress (Grotto et al., 2010).
In summary, the results from studies of workers
occupationally exposed to mercury are not consistent
regarding the risk of CVD. Several studies indicate a
positive association between methylmercury exposure
from fish consumption and myocardial infarction. The
adverse effect of methylmercury fish intake may be
counteracted by the intake of fish-derived fatty acids
with a protective effect on heart disease.
13 NICKEL
Humans may be exposed to both metallic nickel
and nickel compounds. Nickel is a strong skin sensi-
tizer (see Chapter 48 “Nickel” of this book), and nickel
compounds have been classified as human carcinogen
by the International Agency for Research on Cancer
(IARC, 2012). The IARC noted that the carcinogenic
action of nickel compounds may involve an inflam-
matory process, and a specific chronic inflammation
mechanism at the cellular level has been identified
after inhalation of nickel compounds in experimental
animals (Goodman et al., 2011).
Most studies of nickel-exposed workers focus on
skin sensitization and cancer, and only a few have
reported mortality from CVD.
326 Bengt Sjögren, Carolina Bigert, and Per Gustavsson
No increase in circulatory diseases was reported
in 812 nickel carbonyl refinery workers in Wales, fol-
lowed for mortality between 1958 and 2000. There were
85 deaths from circulatory diseases (SMR 0.94, 95% CI
0.75-1.16) (Sorahan and Williams, 2005). There was a
deficit in deaths from circulatory diseases in a cohort
of 1649 male workers at a nickel refinery and fertilizer
plant in Fort Saskatchewan, Alberta, Canada. During
follow-up (1954-1995), the SMR for circulatory dis-
eases was 0.57 (95% CI 0.36-0.87), based on 22 deaths
(Egedahl et al., 2001). Lightfoot et al. (2010) reported
mortality findings in a large cohort of 10253 male nickel
and copper production workers in Sudbury, Ontario,
Canada. The number of deaths from circulatory dis-
eases during 1964-2001 was close to the expected num-
ber for both the first 15 years after employment (SMR
0.96, 95% CI 0.72-1.24) and after 15 years or more (SMR
0.99, 95% CI 0.92-1.06).
Enterline and Marsh (1982) reported mortality
among nickel refinery workers in West Virginina, USA.
The cohort comprised 1865 workers hired before 1947
and 1354 workers hired after 1946. A statistically insig-
nificant excess incidence of stroke was noted among
those employed before 1947 (SMR 1.62, 12 cases).
No excess stroke incidence was noted among those
employed after 1946, and there was a deficit of deaths
due to heart disease in both subcohorts.
In summary, only a few studies of nickel-exposed
workers have reported mortality from CVD. There
is very little evidence of an increased risk of CVD in
these studies. It should be noted, though, that the stud-
ies have mainly focused on evaluating cancer risks and
there has been less emphasis on exploring a potential
association with CVD.
14 SELENIUM
Selenium is an essential trace element (although
toxic in large doses) necessary for the activity of many
enzymes and proteins; it is derived mainly from plant
foods, animal proteins, and seafood. Occupational
exposure may occur in metal industries, selenium-
recovery processes, and painting and special trades.
It has been hypothesized that the antioxidant prop-
erties of selenium, especially on the glutathione-­
peroxidase-system, and decreased lipid peroxidation
may play an important role in the prevention of
atherosclerotic CVD.
Keshan disease (dilated cardiomyopathy) has been
linked to selenium deficiency, mainly in children and
young women from the Keshan region of China; it
is often reversible after selenium supplementation.
However, a role for an infectious agent has also been
suspected as part of the etiology, and selenium defi-
ciency is currently considered to be a conditioning pre-
disposing (rather than a causative) factor for Keshan
disease (Tanguy et al., 2012). Cardiomyopathy has also
been described in selenium deficiency resulting from
prolonged parenteral alimentation (Johnson et al.,
1981). In a prospective cohort study conducted in Fin-
land, a country with a low selenium intake, Salonen
and coworkers (1982) found a strong inverse associa-
tion between selenium and cardiovascular death and
myocardial infarction in a matched-pair longitudinal
study. Since then, several cohort studies have evalu-
ated the association between selenium biomarkers and
coronary risk, with inconsistent findings (Navas-Acien
et al., 2008b). Randomized controlled trials have not
detected any major effects of selenium supplementa-
tion on CVD incidence (Hercberg et al., 2004; Stranges
et al., 2006). Selenium was not significantly associated
with any of the CVD endpoints (all CVD, myocardial
infarction, stroke, all-CVD mortality) during 7.6 years
of follow-up, even after analyses were further stratified
by tertiles of baseline plasma selenium concentrations
(Stranges et al., 2006). In a meta-analysis of six stud-
ies, the pooled RR for CHD endpoints of supplements
containing selenium compared with placebo was 0.89
(95% CI 0.68-1.17). The authors concluded that the
evidence was inadequate to establish a protective role
for selenium supplements against CHD (Flores-Mateo
et al., 2006).
A meta-analysis of observational (14 prospective
cohort studies and 11 case-control, most of them con-
ducted in Europe) studies on serum or plasma sele-
nium levels and CHD was performed by Flores-Mateo
and coworkers (2006). The pooled RR, when compar-
ing the highest to the lowest category of selenium con-
centration, was 0.85 in cohort studies (95% CI 0.74-0.99)
and 0.43 in case-control studies (95% CI 0.29-0.66). The
authors conclude that the validity of the association
is, however, uncertain because observational studies
have been unreliable in determining the cardiovascu-
lar effects of other antioxidants and vitamins, and that,
overall, the evidence is still inadequate to establish a
protective role for selenium in CHD.
Navas-Acien and coworkers (2008b) reviewed the
role of selenium in the prevention of atherosclerotic
CVD. The authors concluded that current evidence is
insufficient to support a protective role for selenium in
CVD prevention. They also stated that data from trials
of selenium-containing supplements and from epide-
miological studies suggest that chronically increased
selenium intake in selenium-replete populations can
induce diabetes and maybe also hypercholesterolemia.
A recent review by Tanguy and coworkers (2012) pres-
ents the current knowledge on the role of selenium in
 16  Cardiovascular Disease
cardiac health and describes growing epidemiologi-
cal evidence of several side effects of high selenium
intake that may negatively influence cardiovascular
health. Recent studies have shown that very moder-
ate increases in selenium status, far below doses that
induce intoxication symptoms (nausea, vomiting, nail
discoloration, hair loss, fatigue, and orthostatic hypo-
tension), can increase cardiometabolic risk factors such
as T2DM or dyslipidemia in populations with a nor-
mal selenium intake (Tanguy et al., 2012).
In summary, selenium deficiency has been related
to dilated cardiomyopathy. Selenium may have a pro-
tective role against CVD, but the evidence is insuf-
ficient. There are also data suggesting that increased
selenium intake may increase the risk of diabetes and
dyslipidemia.
15 URANIUM
Natural uranium is composed of several isotopes
and may exert negative health effects both from tox-
icity of the metal and from the associated ionizing
irradiation.
It is well known that high exposure to ionizing irra-
diation causes an increased risk of developing CVDs.
Irradiation therapy for cancer of the thorax is associ-
ated with an increased risk of myocardial infarction,
and patients treated with irradiation for tumors of
the head and neck are at an increased risk of cere-
brovascular diseases (Travis et al., 2012). Studies of
atomic bomb survivors have shown an elevated risk
of both CVDs and cerebrovascular diseases (Preston
et al., 2012).
Studies of occupational exposure to ionizing irra-
diation show diverging results. Excess mortality from
stroke has been reported among nuclear power plant
workers (Azizova et al., 2011; Laurent et al., 2010),
Chernobyl emergency workers (Ivanov, 2007), and
medical X-ray technicians (Hauptmann et al., 2003).
No excess of stroke or circulatory diseases was found
in a multicenter study of nuclear power plant workers,
although statistical power may have been low among
highly exposed workers (Vrijheid et al., 2007).
There are a few studies in workers specifically
exposed to uranium. Nusinovici et al. (2010) reported
a study of mortality (during 1946-1999) in a cohort of
5085 male French uranium miners. Exposure was char-
acterized based on dosimetry. The RR of stroke among
exposed versus unexposed subjects in the cohort was
1.39 (95% CI 0.81-2.38), and there was a positive dose-
response relationship (P = 0.03). There was no indica-
tion of an association between exposure to uranium
and IHD.
327
Kreuzer et al. (2010) reported a cohort study of 58,987
male German uranium miners who were followed for
mortality from 1946 to 2003. A cohort-internal analy-
sis relating radiation dose in terms of working level
months (WLM) to cause-specific mortality showed no
evidence of an association with CHD or cerebrovascu-
lar disease.
Canu et al. (2012) reported a cohort mortality study
of workers at a French uranium-enrichment plant.
A total of 2897 workers (of which 188 were women)
employed between 1960 and 2006 were followed for
mortality from 1968 to 2007. Exposure was classified in
terms of exposure to natural and reprocessed uranium,
and in terms of solubility (fast, medium, or slow), by
a job exposure matrix. An increased risk of death from
CVD in general was observed, particularly in associa-
tion with slow solubility reprocessed uranium, which
is thought to be associated with a higher internal irra-
diation dose. The number of deaths from myocardial
infarction and cerebrovascular disease was small, pre-
cluding conclusions regarding the relation to uranium
exposure.
No statistically significant association was found
between urinary levels of uranium and CHD or stroke
in a cross-sectional study of 1857 U.S. adults in the
NHANES (Mendy et al., 2012).
In summary, high exposure to ionizing irradiation
such as in patients treated with radiotherapy and in
atomic bomb survivors is causally linked to an excess
of CVD. Studies in uranium miners and uranium pro-
cessing workers show less consistent evidence but sug-
gest an excess of stroke (in particular) in association
with exposure to ionizing irradiation from uranium.
16 ZINC
Zinc was established to be an essential trace metal
in 1961 following the discovery of zinc deficiency in
humans. Zinc is normally absorbed from ingested
food. It is one of the most abundant elements within
cells and is necessary for a broad range of physiologi-
cal processes. An initial consequence of zinc deficiency
is impaired immunological functions. Zinc deficiency
is reported to contribute significantly to the global bur-
den of disease (Foster and Samman, 2012). Zinc fume
fever is a well-known effect of inhalation of newly gen-
erated fumes (Hunter’s diseases of occupation, 2010).
A meta-analysis of 33 controlled clinical trials and
14,238 subjects was conducted to determine the effect
of zinc supplementation on plasma cholesterol and
triglyceride concentrations in humans. Plasma zinc
concentrations increased significantly. No effect of zinc
supplementation on plasma lipoprotein was detected
328 Bengt Sjögren, Carolina Bigert, and Per Gustavsson
in the overall analysis. In individuals classified as
healthy, zinc supplementation was associated with a
decrease in high-density lipoprotein cholesterol levels,
thus contributing to an increased risk of CHD (Foster
et al., 2010). However, in a study of patients with T2DM
a higher serum concentration of zinc was associated
with a decreased risk of myocardial infarction (Soinio
et al., 2007). Oral zinc sulfate does not appear to aid the
healing of arterial and venous ulcers (Wilkinson, 2012).
Inhalation of 2.5 or 5 mg/m3 zinc oxide fume for 2 h in
human volunteers increased the plasma concentration
of IL-6. This level of exposure also resulted in mild fever
(Fine et al., 1997). In a later study, sheet-metal workers
occupationally exposed to low levels of zinc oxide were
exposed to 5 mg/m3. Despite a mild clinical response,
the mean plasma IL-6 levels increased significantly after
exposure. The inflammatory response decreased in naive
subjects exposed on three successive days (Fine et al.,
2000). These experiments indicate adaptation, with a
milder inflammatory response after repeated exposures.
Welders are sometimes exposed to zinc oxide fumes
when welding galvanized steel. In a survey, 31% of
welders aged between 20 and 59 years had experi-
enced metal fume fever on at least one occasion (Ross,
1974). However, not all metal fume fevers are caused
by zinc oxide.
The California Teachers Study comprised approxi-
mately 45,000 women. Long-term airborne exposure
to PM2.5 doubled mortality from IHD. Airborne zinc
exposure correlated with PM2.5 exposure and had an
effect which was much weaker (Ostro et al., 2010).
In summary, the impact of zinc supplementation or
serum levels of zinc on the occurrence of CVD cannot
be evaluated because long-term occupational cohort
studies have not been done.
17  CONCLUDING REMARKS
There is strong epidemiological and mechanistic
evidence for an association between exposure to arse-
nic and lead and the development of CVD. There is rel-
atively strong but less conclusive evidence for a causal
relationship between cadmium and mercury exposure
and CVD. All of these metals are suspected of inducing
pathophysiological changes relevant to atherogenic
disorders, including increased oxidative stress, inflam-
matory response, and coagulation activity (Alissa and
Ferns, 2011).
It is quite well established that high exposure to
ionizing irradiation increases the risk for both CVDs
and cerebrovascular diseases. Irradiation may explain
the suggested relation between uranium exposure and
cerebrovascular disease.
Cardiomyopathy has been associated with exces-
sive intake of arsenic, as well as cobalt, in beer. Iron
overload cardiomyopathy is a consequence of iron
accumulation in the myocardium, mainly caused by
genetically determined disorders of iron metabolism
or multiple transfusions. Deficiency of selenium has
been linked to dilated cardiomyopathy in children and
young women from the Keshan region of China.
Cor pulmonale has been associated with airborne
exposure to beryllium, and signs of this disease have
also been observed after cobalt exposure among hard-
metal workers. Pulmonary fibrosis with increased
blood pressure in the pulmonary circulation is a likely
mechanism in the development of cor pulmonale.
Various types of systematic errors may introduce
bias in epidemiological studies. One type of systemic
error is inadequate comparability between exposed
workers and nonexposed referents. In many historical
occupational cohort studies, disease or death rates of
exposed workers are compared with those of the gen-
eral national or regional population. Such comparisons
are likely to result in underestimation of the true risk
as the general population includes sick and disabled
people who are unable to work. This underestimation
is known as the healthy worker effect (McMichael, 1976;
Baillargeon, 2001). This bias may explain the decreased
risk reported in many occupational cohort studies
focusing on CVDs. Consequently, results may have
been incorrectly interpreted as showing that no rela-
tionship exists between a specific exposure and CVD.
Since the late twentieth century, particulate envi-
ronmental air pollutants have attracted increasing
interest. In 2010 the American Heart Association
summarized the epidemiological evidence for the
cardiovascular effects of PM2.5, traffic-related or com-
bustion-related, air pollution exposure at ambient
levels. There was strong overall epidemiological evi-
dence for an association between short-term exposure
(days) or longer-term exposure (months to years) and
IHD (Brook et al., 2010). The American Heart Asso-
ciation also stated strong overall mechanistic evidence
of a relation between a systemic proinflammatory
response and cardiovascular effects in humans as well
as in animals (Brook et al., 2010). The theory linking
environmental and occupational air pollutants with
IHD via low-grade inflammation was launched in the
mid-1990s (Seaton et al., 1995; Sjögren, 1997). There is
some evidence that inhalation of metal particles may
induce an inflammatory response associated with an
increased blood coagulation. Inhalation of zinc or
copper may cause metal fume fever (Hunter’s dis-
eases of occupation, 2010). Experimental exposure to
zinc oxide increased the serum level of IL-6, which is
a marker of inflammation (Fine et al., 1997) and a risk
 16  Cardiovascular Disease
factor for CHD (Danesh et al., 2008). Welding fume
exposure increased another inflammatory marker,
CRP, which is also a risk factor for CHD (Danesh et al.,
1998). In some studies focusing on environmental par-
ticulate air pollutants, some single metals (e.g. nickel)
have shown relations with CVD (Lippmann et al.,
2006; Mostofsky et al., 2012; Ostro et al., 2010; WHO,
2013). These studies must be interpreted with caution
as these results are based on multiple comparisons
with a significant result for only one or two metals.
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