Arsenic - Toxicology of Metals - page 375

arseniasis in southwestern Taiwan, and there was a dose-
response relationship between cumulative arsenic expo-
sure and prevalence of diabetes mellitus (Lai et al ., 1994).
There was an excess mortality from diabetes mellitus
among residents who lived in arseniasis-endemic area
of southwestern Taiwan (Tsai et al ., 1999). Both arsenic-
exposed workers in copper smelter and glass-producing
plants were reported to have an increased risk of dia-
betes mellitus (Rahman and Axelson, 1995; Rahman
et al., 1996). A dose-response relationship was reported
between prevalence of diabetes mellitus and arsenic in
drinking water in Bangladesh (Rahman et al ., 1998; 1999)
and between incidence of diabetes mellitus and arsenic
in drinking water in southwestern Taiwan (Tseng et al .,
2000; 2002). Glycosylated hemoglobin was signifi cantly
higher among arsenic-exposed workers than unexposed
ones in Denmark (Jensen and Hansen, 1998). The pre-
vious epidemiological studies are consistent with prior
experimental animal studies (Ghafghazi et al ., 1980,
Schiller et al ., 1981) which demonstrated marked exac-
erbating interactive effects between arsenic exposure,
altered insulin responsiveness, and urinary markers of
diabetes in an alloxan-induced diabetes rodent model.
More recent studies (Diaz-Vilasenor et al ., 2006) have
reported impaired insulin secretion and transcription in
rat pancreatic cells treated in vitro with arsenite (AsIII)
over a concentration range of 0.5-10

regulatory systems to regulate carbohydrate metabo-
lism would eventually be overwhelmed, resulting in the
development and/or exacerbation of an arsenic-induced
insulin-resistant diabetic state for susceptible individu-
als. This would be of particular concern under chronic
exposure conditions.

7.3.8 Immunological Effects

The peripheral blood lymphocyte count of arsenic-
exposed subjects was slightly increased relative to
the unexposed controls, and the progression of lym-
phocytes from the S-phase to M-phase of cell cycle
after phytohemagglutinin incubation was decreased
(Gonsebatt et al ., 1994). The retardation in cell rep-
lication of lymphocytes was much more striking in
arsenic-induced skin cancer patients than matched
controls (Hsu et al ., 1997).

7.3.9 Ophthalmic Effects

Long-term exposure to arsenic was reported to
be associated with an increased prevalence of lens
opacity. There was a dose-response relationship bet-
ween cumulative arsenic exposure and prevalence of
posterior subcapsular opacity, but not with preva-
lence of nuclear opacity and cortical opacity, after
adjustment for age, gender, diabetes mellitus, and
sunlight exposure (See, 2000).

mol/L As for 72
or 144 hours. They observed both altered cellular insu-
lin secretion at 144 hours in response to glucose at the
5

µ

mol/L As concentration and decreased insulin mRNA
expression at 72 hours at the 5

µ

7.4 Chronic Cardiovascular Effects
Table 4 shows chronic cardiovascular effects of long-
term exposure to arsenic through ingestion or inhalation.
The cardiovascular effects included electromyographic
abnormalities, especially QT prolongation and increased
dispersion; peripheral, coronary, and cerebral artery dis-
eases; carotid atherosclerosis; hypertension; and micro-
circulation abnormality (Chen et al ., 1997a; IARC, 2004;
NRC, 1999; WHO, 1981; 2001).

mol/L As concentration.
Possible underlying mechanisms for arsenic-induced
diabetes have been recently reviewed by Tseng (2004).
In addition to these suggestions, which are centered on
altered molecular regulatory mechanisms, it should be
noted that the metabolic impairments of carbohydrate
metabolism at the level of mitochondrial respiration
noted in Section 5.6 might represent an important basic
aspect of altered glucose regulation by arsenic. This
is reasonable, because mitochondria actively take up
arsenic, thus concentrating this element at even low dose
levels. The mitochondrion is also known to be the major
intracellular source of reactive oxygen species (ROS) in
cells. The specifi c inhibition of NAD-linked substrate
respiration/loss of respiratory control by arsenic at low-
dose levels has been shown to increase the formation of
ROS, which will stimulate a number of the stress protein
and intracellular signaling mechanisms on a secondary
basis. The overall concept with regard to arsenic stimula-
tion of the diabetic response is that, even at low-dose lev-
els, arsenic inhibition of mitochondrial respiration will
tax the fi nite capacity of hormonal/intracellular carbo-
hydrate regulatory systems to compensate for this basic
derangement of cellular metabolism. The ability of these

µ

TABLE 4 Chronic Cardiovascular Toxicity of Arsenic

Organ system Symptoms and signs

Heart Arrythmias, pericarditis

Peripheral artery Blackfoot disease (gangrene with spontane-

ous amputation), Rayuand's syndrome,
acrocyanosis, intermittent

Coronary artery Ischemic heart disease

Cerebral artery Cerebral infarction

Atherosclerosis Carotid atherosclerosis

Blood pressure Hypertension

Microcirculation Microcirculation abnormalities

Source: WHO, 1981, 2001, 2004; ATSDR, 2005; Chen and Lin,
1994; Engel et al ., 1994; Huang, 1995; Tseng et al ., 1995; Chen et al .,
1997a; NRC, 1999; Chen et al ., 2005.