title: New parameter that supports speculation on the possible mechanism of hypothyroidism induced by chemical substances in repeated-dose toxicity studies.
abstract: Hypothyroidism induced by xenobiotic treatment was analyzed for possible underlying mechanism(s) on the basis of different responses of the thyroid gland and the liver, using a newly-created database of repeated-dose toxicity of 500 chemicals. Two mechanisms are proposed: direct inhibition of thyroid hormone biosynthesis in the thyroid gland, and stimulated degradation of thyroid hormone by induction of hepatic drug-metabolizing enzymes. In the database there were 10 chemicals inducing hypertrophy/hyperplasia of follicular cells in the thyroid gland and having data on thyroid glands. On the basis of the chemical structure and information available in the literature, we judged three chemicals to be typical thioamide derivatives that act directly on the thyroid gland, and the others as non-thioamide derivatives that were unlikely to have any direct action on the thyroid gland. All these chemicals were classified into two groups using the ratios of relative weight increase rate of thyroid gland versus that of the liver. These values were at least 1.7, but 3.2 or more in the most of the cases for thioamide derivatives, and 1.2 or less for non-thioamide derivatives. This background analysis suggests the feasibility of parameter-supported speculation on the possible underlying mechanism when new repeated-dose toxicity data on hypothyroidism becomes available.
authors.affiliation: Chemical Management Center, National Institute of Technology and Evaluation, Tokyo, Japan. yamada-takashi@nite.go.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Hasegawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sakuratani
authors.forename: Jun
authors.initials: J
authors.lastname: Yamada
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Koichi
authors.initials: K
authors.lastname: Yoshinari
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
authors.forename: Eiichi
authors.initials: E
authors.lastname: Kamata
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hirose
authors.forename: Makoto
authors.initials: M
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006965:Hyperplasia; D007037:Hypothyroidism / Q000139:chemically induced*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D013854:Thioamides / Q000008:administration & dosage / Q000633:toxicity*; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology
chemical_list: D013854:Thioamides