Transplacental and Lactational Carcinogenesis by Safrole1

The carcinogenicity of safrole following transplacental ex posure of the mouse fetus and exposure of the neonatal mouse via the mother's milk was investigated in C57BL/6J x CSHeB/ FeJ F, (hereafter called B6C3F,) mice by intragastric admin istration of the agent to pregnant and lactating C57BL/6J females. Safrole (120 ftg/g body weight per treatment) was administered to (a) pregnant mice (4 times on Days 12,14,16, and 18 of gestation); (b) lactating mothers (12 times every second day following parturition); or (c) 4-week-old offspring (180 times twice weekly for 90 weeks). Two additional groups of offspring received a, b, and a, b, and c combination treat ments. All survivors were killed at 94 weeks of age. Renal epithelial tumors were observed in 7% of female offspring exposed to safrole in utero', none of the other experimental and control animals developed these tumors. Only male offspring nursed during the preweaning period by mothers treated with safrole developed hepatocellular tumors (34%). In contrast, direct administration of safrole, beginning at the time of wean ing and continuing for the duration of experiment, led to a significantly high incidence of hepatocellular tumors in females (48%), but not in males (8%). Eighty-six % of the liver tumors observed in females were hepatocellular carcinomas with a high rate of pulmonary métastases(42%). The data suggest that safrole or its metabolites came into contact with fetuses by crossing the placenta and with infants through its excretion in milk to exert the perinatal carcinogenicity.