Arsenic - Toxicology of Metals - page 365

are involved: (1) reduction/oxidation reactions that
intervert As(III) and As(V), and (2) methylation reac-
tions, which convert arsenite to MMA and DMA.
The resulting series or reactions result in the reduc-
tion of inorganic arsenate to arsenite (if necessary),
methylation to MMA(V), reduction to MMA(III), and
methylation to DMA(V). These processes seem to be
similar whether exposure is by the inhalation, oral, or
parenteral route.
That trivalent inorganic arsenic is oxidized in vivo
is indicated by the fi nding of pentavalent arsenic in
urine of both animals and humans exposed to arsen-
ite (Bencko et al ., 1976; Mealey et al ., 1959; Vahter and
Envall, 1983). Also, the opposite reaction (i.e., the
reduction of arsenate to arsenite) has been demon-
strated in mice and rabbits (Vahter and Envall, 1983).
Both arsenite and arsenate, after reduction to arsenite
(McBride et al ., 1978), are methylated in vivo . The major
metabolite in urine of experimental animals exposed
to inorganic arsenic is dimethylarsinic acid (Bertolero
et al ., 1981; Charbonneau et al ., 1979; Inamasu, 1983; Tam
et al ., 1978; Vahter, 1981). The guinea pig, marmoset, and
tamarin monkey do not methylate inorganic arsenic
(Healey et al ., 1998; Vahter and Marafante, 1985, Vahter
et al ., 1982; Zakharyan et al ., 1996). Exposure of humans
to either arsenites or arsenates results in increased lev-
els of inorganic As(III), As(V), MMA, and DMA in urine
(Aposhian et al ., 2000a, 2000b). In man, the urinary
excretion at low-dose levels consists of approximately
20-25% inorganic arsenic, 15-25% methylarsonic acid,
and 40-75% dimethylarsinic acid (Buchet et al ., 198la ;
Crecelius, 1977b; Hopenhayn et al ., 2003; Loffredo
et al ., 2003; Mandal et al ., 2001; Smith et al ., 1977; Tam
et al ., 1979; Yamauchi and Yamamura, 1979a,b). Meth-
ylation effi ciency decreases with increasing dose lev-
els (Mahieu et al ., 1981; Vahter, 1981 ). The substrate
for methylation is As(III), and As(V) is not methylated
unless it is fi rst reduced to As(III) (Buchet and Lauw-
erys 1985, 1988; Lerman et al ., 1983). Reduction of arse-
nate to arsenite can be mediated by glutathione (Menzel
et al ., 1994). The main site of methylation seems to be
the liver, where the methylation process is mediated
by methyltransferases that use S-adenosylmethionine
as cosubstrate (Buchet and Lauwerys, 1985; 1988). The
relative proportions of As(III), As(V), MMA, and DMA
in urine can vary, depending on the chemical admin-
istered, time after exposure, dose level, and exposed
species. Arsenic derived from exposure to particles of
GaAs or InAs is methylated in manner similar to that
of As(III) (Yamauchi et al ., 1986; 1992).With relatively
constant exposure levels, these metabolic proportions
remain similar over time (Concha et al ., 2002) and seem
to be similar among family members (Chung et al .,
2002). It is expected that measurements of MMA and

DMA in urine will provide useful information for risk
assessment purposes once the relationships between in
vivo formation of these major metabolites of inorganic
arsenic and risk of toxicity or cancer are more fully
delineated.
Arsenobetaine is apparently not biotransformed in
vivo but excreted as such mainly in urine (Cannon et al .,
1981; Vahter et al ., 1983). Arsenocholine is, to a great
extent, oxidized to arsenobetaine (Marafante et al .,
1984).
Cacodylic acid and arsanilic acid are not converted
to inorganic arsenic in vivo (Buchet et al ., 1981a; Mara-
fante et al ., 1987; Stevens et al ., 1977; Vahter et al ., 1984;
Yoshida et al ., 2001).

5.4 Excretion
The major route of excretion after exposure to
inorganic arsenic is through the kidneys. Only a
low percent is excreted in feces (Apostoli et al ., 1999;
Bertolero et al ., 1981; Ducoff et al ., 1948; Hunter et al .,
1942; Mealey et al ., 1959). The rate of excretion in urine
varies, depending on the chemical form of arsenic and
the species exposed. The primary forms of arsenic
found in the urine of inhalation-exposed humans
are DMA and MMA, with inorganic arsenic mak-
ing up <25% of the total urinary arsenic (Apostoli et
al ., 1999). In humans exposed to a single low dose of
arsenite, approximately 35% was excreted in the urine
over a period of 48 hours (Buchet et al ., 1980; 1981a ).
At low exposure levels, urinary arsenic levels gener-
ally increase linearly with increasing arsenic intake
(Calderon et al ., 1999). Rabbits exposed to a similar
low dose excrete approximately 80% (Bertolero et al.,
1981), mice as much as 90% (Vahter, 1981), and mar-
moset monkeys as little as 15% within the same period
of time (Vahter et al ., 1982). In the case of continuous
human intake over a few days, 60-70% of the daily
dose is excreted in urine (Buchet et al ., 1981b; Mappes,
1977). After exposure to arsenate, the limited human
data available indicate a rate of excretion similar to that
for arsenite (Pomroy et al ., 1980; Yamauchi and Yama-
mura, 1979b). Animal data indicate a somewhat faster
excretion for arsenate than for arsenite (Charboneau et
al ., 1978; Hollins et al ., 1979; Vahter, 1981).
During lactation, a very small percent of ingested
arsenic may also be excreted in the breast milk (Concha
et al ., 1998a). Other routes of elimination of inorganic
arsenic, although of less importance, include skin, hair,
nails, and sweat (Molin and Wester, 1976).
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). After ingestion, by humans, of organic arsenic