Comparative effects of single intraperitoneal or oral doses of sodium arsenate or arsenic trioxide during in utero development

Numerous studies have suggested that single-day intraperitoneal (IP) inject ion of inorganic arsenic results in failure of neural tube closure and othe r malformations in rats, hamsters, and mice. Most of these studies involved treatment of limited numbers of animals with maternally toxic doses of ars enic (generally As-V), without defining a dose-response relationship. In th e present Good Laboratory Practice-compliant study, sodium arsenate (AsV) w as administered IP and arsenic trioxide (As-III) was administered either IP or orally (by gavage) on gestational day 9 to groups of 25 mated Crl:CD(R) (SD)BR rats. Only at dose levels that caused severe maternal toxicity, incl uding lethality, did IP injection of arsenic trioxide produce neural tube a nd ocular defects; oral administration of higher doses of arsenic trioxide caused some maternal deaths but no treatment-related fetal malformations. i n contrast, IP injection of similar amounts of sodium arsenate (based on th e molar amount of arsenic) caused mild maternal toxicity but a targe increa se in malformations, including neural tube, eye, and jaw defects. In summar y, neural tube and craniofacial defects were observed after IP injection of both AsV and As-III; however, no increase in malformations was seen follow ing oral administration of As-III, even at maternally lethal doses. These r esults demonstrate that the frequently cited association between prenatal e xposure to inorganic arsenic and malformations in laboratory animals is dep endent on a route of administration that is not appropriate for human risk assessment. (C) 1999 Wiley-Liss,Inc.