Chronic toxicity and carcinogenicity of bis(tri- n-butyltin)oxide (TBTO) in the rat

• Published in: Food and chemical toxicology Vol. 28; no. 3; pp. 179 - 196
• Main Authors: Wester, P.W., Krajnc, E.I., van Leeuwen, F.X.R., Loeber, J.G., van der Heijden, C.A., Vaessen, H.A.M.G., Helleman, P.W.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 1990; New York, NY Elsevier Science
• Subjects: Adrenal Cortex Neoplasms - chemically induced; Adrenal Cortex Neoplasms - pathology; Adrenal Gland Diseases - chemically induced; Adrenal Gland Diseases - pathology; Adrenal Medulla - drug effects; Adrenal Medulla - pathology; Animals; Biological and medical sciences; Carcinogenicity Tests; Carcinogens - toxicity; Female; Male; Medical sciences; Neoplasms - chemically induced; Neoplasms - pathology; Parathyroid Neoplasms - chemically induced; Parathyroid Neoplasms - pathology; Pesticides, fertilizers and other agrochemicals toxicology; Pituitary Neoplasms - chemically induced; Pituitary Neoplasms - pathology; Rats; Rats, Inbred Strains; Toxicology; Trialkyltin Compounds - toxicity; FSH = follicle stimulating hormone; CK = creatinine kinase; ICDH = isocitrate dehydrogenase; T4 = thyroxin; TBTO = bis(tri- n-butyltin)oxide; LH = luteinizing hormone; ANOVA = analysis of variance; PAS = Periodic acid-Schiff; ASAT = aspartate aminotransferase; TSH = thyrotropin; FT4 = free thyroxin; LDH = lactate dehydrogenase; ALAT = alanine aminotransferase; PCV = packed cell volume; AP = alkaline phosphatase; Carcinogen; Vertebrata; Chronic; Mammalia; Molluscicide; Rat; Toxicity; Animal; Rodentia; Pesticides; Tin Organic compounds
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/0278-6915(90)90006-9

In a 106-wk toxicity and carcinogenicity study, groups of 60 male and 60 female weanling Wistar rats were fed 0, 0.5, 5 or 50 mg bis(tri- n-butyltin)oxide (TBTO)/kg diet. In males, feed consumption was increased in all treated groups and increased water consumption occurred at 5 and 50 mg/kg. During the second year, body weight decreased in the 50-mg/kg males, while the females in that group showed no weight gain. Excess mortality was confined to the 50-mg/kg group towards the end of the study. Haematological changes, comprising anaemia, lymphocytopenia and thrombocytosis were noted mainly at the high-dose level. Also, signs of decreased kidney function and increased plasma enzyme activities (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) were noted. No effects on serum hormone concentrations (thyrotropin, follicle stimulating hormone, luteinizing hormone or insulin) were observed, except for a decrease in the free thyroxin:thyroxin ratio in both sexes at the high-dose level. Higher serum IgM and IgA levels were present at 50 mg/kg, while, in females, IgG was decreased. At 50 mg/kg, the ovaries, adrenals, spleen (females), heart (males), pituitary, liver and kidneys were increased in weight, but the thyroid weight was decreased in females. The total tin concentrations in liver and kidneys showed a dose relationship and, in general, the concentrations were similar after 1 and 2 yr. Non-neoplastic histological alterations after 1 yr consisted of a decrease in the cell height of the thyroid follicles in all dose groups, with a reduced number of psammoma bodies at 50 mg/kg, a decrease in splenic iron content at 5 (females only) and 50 mg/kg, and a slight bile-duct activation. After 2 yr, only the thyroid changes were still present. In addition, at 2 yr, vacuolation and pigmentation of the proximal tubular epithelium and nephrosis were enhanced at 50 mg/kg. The incidence of benign tumours of the pituitary was significantly elevated and enhanced at 0.5 and 50 mg/kg. At 50 mg/kg increases in pheochromocytomas in the adrenal medulla and in parathyroid adenomas (males) were noted, while adrenal cortical tumours were decreased (males). There was a low, non-dose-related incidence of pancreatic carcinoma. Other tumour rates were in line with control data. It is concluded that lifetime feeding of 50 mg TBTO/kg diet induces toxicity in various organ systems. An increase in some common tumours was found at the high dose, probably due to hormonal or immunological changes. Effects on the incidence of some of these tumours were observed also in the low-dose groups, but not at the intermediate dose. Because of the high spontaneous incidence of the tumours in this strain of rats, the variable incidence in the treated groups, and the absence of a dose-effect relationship, the significance of the increased incidence of these tumours is questionable. On the basis of the marginal effects at 5 mg/kg, a no-adverse-effect level of 0.5 mg TBTO/kg can be established.