Arsenic - Toxicology of Metals - page 381

developing cancers of the skin, lung, liver, bladder, and
kidney from ingested inorganic arsenic were within a
sevenfold range of magnitude. The risks were practi-
cally identical for both men and women within a twofold
range of magnitude, indicating no gender difference in
arsenic-induced carcinogenic responses.
Epidemiological studies on arsenic-induced devel-
opment and reproductive effects have been reviewed
periodically (Chen et al ., 1997b; NRC, 1999; WHO,
1981; 2001). Babies born to female employees of a cop-
per smelter, who were exposed to inorganic arsenic
through inhalation during pregnancy, were reported
to have an increased incidence of congenital malfor-
mation, low birth weight, and spontaneous abortion
(Nordstrom et al ., 1979ab). Low birth weight was also
observed among newborns in smelter areas than in
nonsmelter areas (Tabacova et al ., 1994).
An increased, but not statistically signifi cant, risk
of coarctation of the aorta was found to be associated
with elevated arsenic level in drinking water (Zierler et
al ., 1988). Arsenic in drinking water has been reported
to increase the mortality from congenital anomalies
of the heart in females, and the mortality from con-
genital anomalies of the circulatory system for both
sexes in the United States (Engel and Smith, 1994).
Arsenic in drinking water was reported to be associ-
ated with an increased risk of spontaneous abortion in
two studies (Aschengrau et al ., 1989; Borzsonyi et al .,
1992), and with a signifi cantly increased risk of still-
births in two studies (Borzsonyi et al ., 1992; Ihrig et al .,
1998). Arsenic in drinking water was also reported to
be associated with an increased neonatal mortality in
Chile (Hopenhayn-Rich et al ., 1999). Similar fi ndings
of increased rates of spontaneous abortions, stillbirths,
and infant mortality have been reported among popu-
lations consuming arsenic-contaminated well water in
Bangladesh (Milton et al ., 2005) and West Bengal (von
Ehrenstein et al ., 2006).

sters (Inamasu et al ., 1982; Pershagen et al ., 1984) were
also positive, particularly in combination with other
organic carcinogens (see Section 7.7). Arnold et al .
(2003) exposed male and female rats to 0, 50, 400, or
800 ppm MMA (monoarsonic acid) and male and
female B6C3F1 mice to 0, 10, 50, 200, or 400 ppm MMA
in the diet for 104 weeks; estimated average daily
doses were up to 47.3 mg arsenic/kg/day for female
rats and up to 48.5 mg arsenic/kg/day for female mice.
No treatment-related neoplastic changes were seen in
either sex of either species. A similar lack of carcino-
genicity of MMA was reported by Shen et al . (2003a),
who exposed male F344 rats to 0, 50, or 200 ppm of
MMAA(V) in the drinking water for 104 weeks. Wei
et al . (1999; 2002) exposed male F344 rats to 0, 12.5,
50, or 200 ppm DMAA (dimethylarsinic acid) for 104
weeks in the diet, the average daily doses were 0,
0.03, 0.14, or 0.53 mg arsenic/kg/day. Increases in the
number of animals with bladder tumors were seen in
the two highest dosed groups. No increases in tumor
incidence were seen in other organs. Hayashi et al .
(1998) reported that mice exposed to 400 ppm of DMA
for 50 weeks, but not those exposed to 50 or 200 ppm,
showed an increased incidence of papillary adeno-
mas and an elevated number of average lung tumors
per mouse. Dimethylarsinic acid (DMAA), which is a
major methylated metabolite of inorganic arsenic, has
been reported by Hayashi et al . (1998) to exhibit tum-
origenicity and to stimulate tumor progression in mice
after drinking water exposure at 400 ppm for up to 50
weeks. These data are in concert with epidemiological
studies of humans who developed lung cancer from
drinking water exposures noted above.

7.6.1 Developmental and Reproductive Effects

7.6.1.1 Teratogenic Effects
Until recently, there were very few reports on the
teratogenicity of inorganic arsenic in humans. Con-
genital malformations were observed in children
whose mothers worked, during pregnancy, at a Swed-
ish copper smelter and were exposed to arsenic, other
heavy metals, and sulfur dioxide. The observed inci-
dence was fi ve times greater than that in children born
to other mothers from the same region (Nordstrom et
al ., 1979ab). No conclusion can be drawn as to whether
arsenic is responsible for these malformations. Tera-
togenic effects have been shown to occur after a sin-
gle administration of high doses (6-10 mg As/kg
body weight) of sodium arsenate to pregnant golden
hamsters (Ferm, 1977). The compound was given intra-
venously to the hamsters on the 8th day of gestation.
Both the reabsorption and malformation rates in the
fetus increased with increasing doses of the arsenate.

7.6 Experimental System Cancer Studies
No studies on cancer in humans after oral exposure
to organic arsenicals have been located, but there are
some animal studies on the carcinogenicity of organic
arsenicals. In an early 2-year study of roxarsone
(3-nitro-4-hydroxyphenylarsonic acid) toxicity in ani-
mals, no increase in tumor frequency was detected in
dogs, rats, or mice given 1.5, 2.9, and 3.8 mg arsenic/
kg/day, respectively (Prier et al ., 1963). Lifetime stud-
ies of roxarsone at doses up to 1.4 mg arsenic/kg/
day yielded no evidence of carcinogenicity in male
or female mice or female rats, but a slight increase in
pancreatic tumors was noted in male rats (NTP, 1980).
Carcinogenesis studies with inorganic arsenic in ham-