Arsenic is a known human carcinogen, but development of rodent models of inorganic
arsenic carcinogenesis has been problematic. Since gestation is often a period of
high sensitivity to chemical carcinogenesis, we performed a transplacental carcinogenicity
study in mice using inorganic arsenic. Groups (n = 10) of pregnant C3H mice were given
drinking water containing sodium arsenite (NaAsO(2)) at 0 (control), 42.5, and 85
ppm arsenite ad libitum from day 8 to 18 of gestation. These doses were well tolerated
and body weights of the dams during gestation and of the offspring subsequent to birth
were not reduced. Dams were allowed to give birth, and offspring were weaned at 4
weeks and then put into separate gender-based groups (n = 25) according to maternal
exposure level. The offspring received no additional arsenic treatment. The study
lasted 74 weeks in males and 90 weeks in females. A complete necropsy was performed
on all mice and tissues were examined by light microscopy in a blind fashion. In male
offspring, there was a marked increase in hepatocellular carcinoma incidence in a
dose- related fashion (control, 12%; 42.5 ppm, 38%; 85 ppm, 61%) and in liver tumor
multiplicity (tumors per liver; 5.6-fold over control at 85 ppm). In males, there
was also a dose-related increase in adrenal tumor incidence and multiplicity. In female
offspring, dose-related increases occurred in ovarian tumor incidence (control, 8%;
42.5 ppm, 26%; 85 ppm, 38%) and lung carcinoma incidence (control, 0%; 42.5 ppm, 4%;
85 ppm, 21%). Arsenic exposure also increased the incidence of proliferative lesions
of the uterus and oviduct. These results demonstrate that oral inorganic arsenic exposure,
as a single agent, can induce tumor formation in rodents and establishes inorganic
arsenic as a complete transplacental carcinogen in mice. The development of this rodent
model of inorganic arsenic carcinogenesis has important implications in defining the
mechanism of action for this common environmental carcinogen.
Copyright 2003 Elsevier Science (USA)