Arsenic - Toxicology of Metals - page 366

compounds present in seafoods, 50-80% of the dose
was eliminated in the urine within 2 days (Tam et al .,
1982). A similar rate of excretion was seen in rabbits
exposed to arsenobetaine (Vahter et al ., 1983).
Elimination of organic arsenic compounds used as
drugs was noted by Hogan and Eagle (1944). They
found that trivalent organic arsenicals were eliminated
at a much slower rate than the pentavalent arsenicals
in the urine of rabbits. More recent studies by Lin et al .
(2005) reported that the tissue-specifi c distribution and
elimination rates for inorganic and methylated arsenic
species in rabbits after a single acute administration
of arsenic trioxide (AsIII) over a dose range of 0.2-
1.5 mgAs/kg for up to 30 and 60 days. The elimination
pattern was nonlinear, and the liver and lung showed
the highest concentrations of DMA, which was the
major metabolite measured, on day 30. Similar organ-
specifi c differences were observed in B6C3F1 mice after
acute oral administration of arsenate (AsV). As with
the rabbits, DMA was the predominant methylated
species at later time points (Kenyon et al ., 2005).

Studies in humans indicate that ingested MMA and
DMA are excreted mainly in the urine (75-85%), and
this occurs mostly within 1 day (Buchet et al ., 1981a).
The WHO/IPCS (2007) has examined a number of
issues related to the roles of elemental speciation in
human health risk assessment.

5.6 Mechanisms of Arsenical Toxicity
5.6.1 Mechanisms of Arsenical Metabolism and
Toxicity

Arsenical inhibition of cellular respiration as a
primary cause of cell death has been appreciated for
a number of decades (ATSDR, 2005; NRC, 1999; 2001),
and the methylation of inorganic arsenic to form meth-
ylated species such as methyl arsenic acid (MMA) and
dimethylarsinic acid (DMA) has also been studied for a
number of decades (Braman and Foreback, 1973; Chal-
lenger, 1945; 1951). In recent years, scientifi c attention
has been focused on understanding the relationships
that must exist between the in vivo methylation of inor-
ganic arsenic and mechanisms of arsenical toxicity. This
issue is of great practical importance, because the meth-
ylation of inorganic arsenic was originally thought to be
a detoxifi cation pathway, but more recent studies (NRC,
1999) have suggested that highly toxic reactive oxygen
species (ROS) generated by MMA (III) and DMA (III)
mitochondrial toxicity may also play an important role
in both cellular toxicity and carcinogenicity of this ele-
ment. The increased presence of MMA (III) in the urine
of a Mexican population exposed to inorganic arsenic
in drinking water on a chronic basis was found to be a
basis for identifying subpopulations at greater risk for
arsenic-induced toxicity and cancer (Steinmaus et al .,
2005a,b; Valenzuela et al ., 2005). These studies also
reported a strong linkage between dietary intakes of
protein and other nutrients and the ability to methylate
arsenicals such that persons with low dietary intakes of
these nutrients would be more susceptible than others
to arsenic-induced cancers. The central role of oxida-
tive stress induced by arsenic in cell death via apoptosis
or necrosis and carcinogenicity via oxidative damage
to cellular DNA cannot be underestimated, because it
may permit attenuation of these deleterious cellular
effects through nutritional interventions and stimula-
tion of cellular antioxidant systems.

5.5 Biological Half-Time
Animals exposed to arsenic through inhalation or
drinking water will have increased levels in tissue
during the fi rst weeks or months, but the levels will
decrease even if the exposure is prolonged (Bencko and
Symon, 1969; 1970; Hisanaga, 1982; Katsura, 1958).
It has been suggested that the decrease of arsenic con-
centrations in internal organs, such as the liver, after
long-term exposure may be due to a higher rate of excre-
tion. Changes in tissue retention in the case of chronic
exposure should be considered when evaluating
biological half-times for arsenic compounds.
The biological half-time of arsenic in rats after a single
exposure is long (approximately 60 days) because of the
accumulation of arsenic in the blood. In humans and in
other animals, the major part of the arsenic is eliminated
at a much higher rate. Generally, whole body clearance
is fairly rapid, with half-times of 40-60 hours in humans
(Buchet et al ., 1981b; Mappes, 1977). Three different
phases of urinary excretion have been demonstrated in
man after a single intravenous injection of radiolabeled
arsenite, having half-times of approximately 2 hours,
8 hours, and 8 days, respectively (Mealey et al ., 1959).
After oral intake of radiolabeled pentavalent arsenic,
66% was excreted with a half-time of 2.1 days, 30% with
a half-time of 9.5 days, and 3.7% with a half-time of 38
days in the three phases (Pomroy et al ., 1980).
As stated previously, the major part of arsenic in
ingested seafood is eliminated rapidly through the
kidneys. The biological half-time for these organic
compounds can be estimated to be less than 20 hours.

5.6.2 Metabolism

This section regarding arsenical metabolism is
focused on reviewing mechanistic linkages between
mechanisms of inorganic arsenical methylation and
mechanisms of toxicity at the cellular and molecular
levels of biological organization.