Lic. En Biología

Teratogenesis, Carcinogenesis, and Mutagenesis 20:219–227 (2000)

Comparative Developmental Toxicity Study of Indium in Rats and Mice
Mikio Nakajima,1* Hiroki Takahashi,1 Masanori Sasaki,1 Youshiro Kobayashi,1 Yasuo Ohno,2 and Makoto Usami2
1

Laboratory for Toxicological Research, Institute for Life Science Research, Asahi Chemical Industry Co., Ltd., Shizuoka, Japan 2 Division ofPharmacology, National Institute of Health Sciences, Tokyo, Japan
The developmental toxicity of indium was examined in both rats and mice using comparable experimental protocols. Pregnant rats received a single intravenous administration of indium trichloride (InCl3) at 0.4 mg In/kg, on day 9, 10, or 11 of pregnancy and their fetuses were examined on day 20. Pregnant mice were treated in the same mannerat 0.8 or 1.6 mg In/kg on day 7, 8, or 9 of pregnancy and their fetuses were examined on day 18. In rats, indium caused fetal weight decrease and fetal gross malformations, such as brachyury, kinked tail, cleft palate, and oligodactyly, most severely by the administration on day 10. In mice, however, indium did not cause fetal gross malformations, although it caused fetal weight decrease at 0.8 mgIn/kg or more and fetal death at 1.6 mg In/kg, most severely by the administration on day 8. It was concluded from these results that rats and mice were susceptible to the embryotoxicity of indium at similar developmental stages in the early organogenetic period, but mice were less susceptible to the teratogenicity of indium than rats in terms of gross malformation. Toxicokinetic factors may beinvolved in this different susceptibility. Teratogenesis Carcinog. Mutagen. 20:219–227, 2000. © 2000 Wiley-Liss, Inc.
Key words: rat; mouse; indium trichloride; developmental toxicity; teratogenicity

INTRODUCTION

It has been shown that indium (In), a metal commonly used for semiconductors in industry and for scintigraphy in medicine, is teratogenic in hamsters and rats. In hamsters, a singlei.v. administration of indium nitrite to pregnant hamsters around 0.5 mg/kg on day 8 of pregnancy induced fetal death and malformations of the digit [1]. In rats, a single i.v. administration of 0.4 mg In/kg of indium trichloride to preg-

*Correspondence to: Mikio Nakajima, Laboratory for Toxicological Research Institute for Life Science Research, Asahi Chemical Industry Co., Ltd. 632-1,Mifuku, Ohito-cho, Tagata-gun, Shizuoka 410-2321, Japan. E-mail: a8586381@ut.asahi-kasei.co.jp

© 2000 Wiley-Liss, Inc.

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nant rats on day 9 of pregnancy caused malformations such as kinked tail, brachyury, and oligodactyly in 65% of the term fetuses, but single oral administration caused malformations only in 12% of the fetuses even at 300 mg In/kg [2]. This differencebetween the routes of administration was considered to be due to the low bioavailability of indium by oral administration, because a toxicokinetic experiment showed that the peak serum concentration of indium in pregnant rats by oral administration at 300 mg In/kg (1.5 µg/ml) was about four times lower than that by i.v. administration at 0.4 mg In/kg (6.3 µg/ml) [2]. In mice, on the other hand, theteratogenicity of indium is not evident. Repeated oral administration of indium trichloride (InCl3) to pregnant mice from days 6 through 15 of pregnancy at 250 mg/kg/day caused fetal weight decrease and fetal death, but no increase in fetal malformations [3]. However, indium caused malformations or growth inhibition in cultured mouse embryos [3]. A disposition study in male mice showed that thepeak plasma indium concentration by oral administration of 250 mg/ kg was only 1.6 µg/ml [3], which is comparable to the serum concentration in the pregnant rat by single oral administration [2]. It is therefore suggested that low-level exposure to indium for a long period by repeated administration might result in embryofetal death without fetal malformation in mice and that indium could cause...