Subchronic toxicity study with ethylene-bis-(oxyethylene)-bis-(3-tert-butyl-4-hydroxy-5-methylhydro cin namate) in the cynomolgus monkey: lack of stimulation of the pituitary-thyroid-liver axis.
To evaluate the toxicological profile of the phenolic antioxidant ethylene-bis-(oxyethylene)-bis-(3-tert-butyl-4-hydroxy-5-methyl- hydrocinnamate) (EOC) in a non-human primate, male cynomolgus monkeys (Macaca fascicularis) were treated for 4 weeks by oral administration of 0, 200, or 1000 mg/kg body weight/day. Special attention was directed to parameters of the pituitary-thyroid-liver axis. Moderately increased liver weights and minimal to moderate hepatocellular hypertrophy were observed in treated animals. Otherwise, no treatment-related changes were detected in hematological, clinical chemistry, or urinalysis parameters or upon histopathological examination. Except for a slight induction of microsomal testosterone 16beta-hydroxylation, liver xenobiotic-metabolising enzyme activities and peroxisomal fatty acid beta-oxidation remained unchanged. Likewise, serum levels of thyroid stimulating hormone, thyroxine, 3,3',5-triiodothyronine and 3,3',5'-triiodothyronine as well as 5'-monodeiodinase type 1 mRNA levels in the liver, heart, cerebral cortex, and thyroid were found unchanged. The results demonstrate that, in the Cynomolgus monkey, EOC is only a very weak inducer of liver xenobiotic-metabolizing enzymes and has no effect on thyroid function. In contrast, upon feeding rats at dose levels up to 1000 ppm (equivalent to between 50 and 100 mg/kg body weight/day), EOC has been identified as a strong phenobarbital- and peroxisome proliferator-type inducer of hepatic xenobiotic-metabolizing enzymes, interfering with thyroid hormone homeostasis, causing thyroid follicular hypertrophy, and, upon chronic treatment, inducing thyroid gland follicular cell tumors (Thomas et al., 1995. In Toxicology of Industrial Compounds, pp. 319-339. Taylor and Francis). Thus, the results of this study with EOC in the cynomolgus monkey show that effects of xenobiotics on the pituitary-thyroid-liver axis as frequently observed in rodents can not necessarily be extrapolated to primates including man.
Waechter
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F
Novartis Crop Protection AG, Toxicology, Basel, Switzerland. felix.waechter@cp.novartis.com
Beilstein
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P
Burger
A G
AG
O'Connell
M
M
Fabreguettes
C
C
Forster
R
R
Weideli
H
H
D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013963:Thyroid Hormones / Q000097:blood; D013972:Thyrotropin / Q000097:blood; D018675:Toxicity Tests
D000975:Antioxidants; D012333:RNA, Messenger; D013963:Thyroid Hormones; C066840:TK 12627; D011092:Polyethylene Glycols; D013972:Thyrotropin; D003577:Cytochrome P-450 Enzyme System; D007453:Iodide Peroxidase; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster