bis(tri-n-butyltin)oxide and Abnormalities--Drug-Induced

The results of a series of screening tests to determine the potential teratogenicity and neurotoxicity of developmental exposure to TBTO in rats are presented in this paper. For prenatal exposure, pregnant Long Evans rats were intubated with 0-16 mg/kg/day bis(tri-n-butyltin)oxide TBTO from Days 6 to 20 of gestation (GD 6-20). For postnatal exposure, rat pups were intubated with 0-60 mg/kg TBTO on Postnatal Day 5 (PND 5). Following prenatal exposure, dams were allowed to litter and pups were evaluated using a postnatal teratology screen. Postnatal evaluation for both exposures included motor activity (PND 13-64), the acoustic startle response (PND 22-78), growth, and brain weight. The maximally tolerated dose (MTD) in pregnant rats was 5 mg/kg/day, which is one-third the MTD in nonpregnant rats. There were decreased numbers of live births, and decreased growth and viability at dosages greater than or equal to 10 mg/kg/day. Cleft palate was found in 3% of the 12 mg/kg/day group. There was mortality following postnatal exposure to 60 mg/kg and all prenatal dosages greater than or equal to 10 mg/kg/day. Preweaning body weight was significantly decreased for all postnatal dosages, and all prenatal dosages greater than 2.5 mg/kg/day. Body weight reductions persisted to the postweaning period only in the high dose groups (10 mg/kg/day and 60 mg/kg). Behavioral evaluation demonstrated transient alterations in motor activity development (prenatal exposure only) and the acoustic startle response (postnatal exposure only). Persistent behavioral effects were observed only at dosages that produced overt maternal toxicity and/or postnatal mortality. The demonstration of the teratogenic and neurotoxic potential of TBTO in rats is confounded by associated maternal toxicity and/or pup mortality.

Topics: Abnormalities, Drug-Induced; Animals; Behavior, Animal; Birth Weight; Body Weight; Dose-Response Relationship, Drug; Female; Litter Size; Maternal-Fetal Exchange; Motor Activity; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Reflex, Startle; Sexual Maturation; Trialkyltin Compounds

The genetic and embryotoxic effects of bis(tri-n-butyltin)oxide (TBTO) were evaluated in multiple in vivo and in vitro short-term tests preparatory to its potential wide use as a molluscicide in control of schistosomiasis. When tested in the rec assay in Bacillus subtilis, TBTO was not mutagenic and it did not induce reverse mutations in Klebsiella pneumoniae. Neither in the presence nor in the absecne of rat liver activation system did TBTO produce point mutations in Salmonella typhimurium strains TA1530, TA1535, TA1538, TA97, TA98 or TA100. TBTO was matagenic in strain TA100 in a fluctuation test, but only in the presence of rat liver S9 (Aroclor-induced). TBTO did not induce gene mutations in the yeast Schizosaccharomyces pombe, mitotic gene conversions in the yeast Saccharomyces cerevisiae, nor sister-chromatid exchange in Chinese hamster ovary cells in the presence or absence of rat or mouse liver S9. In the latter cells, structural chromosomal aberrations, endoreduplicated and polyploid cells were induced. TBTO did not induce gene mutations in V79 Chinese hamster cells (to 8-azaguanine-, ouabain- or 6-thioguanine-resistance) in the presence of a rat liver postmitochondrial fraction or in cell (hamster embryo cells and human and mouse epidermal keratinocyte)-mediated assays. In mouse lymphoma cells, TBTO did not induce 6-thioguanine- or BUdR-resistant mutations. As many tumour promoters inhibit metabolic cooperation between V79 Chinese hamster 6-thioguanine-resistant/-sensitive cells, TBTO was tested but showed no such activity. TBTO was examined for the induction of recessive lethal mutations in adult Berlin K male Drosophila melanogaster, either by feeding or by injection. Doses of 0.37 or 0.74 mM did not increase the number of X-linked recessive lethal mutations. An increased number of micronuclei was observed in the polychromatic erythrocytes of male BALB/c mice 48 h after a single oral dose of TBTO (60 mg/kg bw), while a lower dose (30 mg/kg bw) was ineffective. Neither of the two doses had induced micronuclei 30 h after treatment. The reproductive toxicity of TBTO was studied in NMRI mice. In a 10-day toxicity study, the LD50 and LD10 were 74 and 34 mg/kg bw, respectively. An increased frequency of cleft palates was seen in the fetuses of mice (compared with controls, 0.7%) treated orally during pregnancy with 11.7 mg/kg TBTO (7%), 23.4 mg/kg (24%) or 35 mg/kg (48%).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Abnormalities, Drug-Induced; Animals; Bacteria; Cell Line; Cell Nucleus; Chemical and Drug Induced Liver Injury; Chromosome Aberrations; Cricetinae; Cricetulus; Drosophila melanogaster; Embryonic and Fetal Development; Female; Fibroblasts; Gene Conversion; Genes, Lethal; Male; Mice; Microsomes, Liver; Molluscacides; Mutagenicity Tests; Pregnancy; Rats; Trialkyltin Compounds; Yeasts

Examples of a combined approach using in vivo as well as in vitro methods for the assessment of prenatal toxicity are presented. The topics discussed include the analysis of the possible embryotoxic potential of valproic acid (VPA), female sex hormones, bis(tri-n-butyltin) oxide (TBTO), and acyclovir and the problem of supplementing in vitro systems with drug-metabolizing activity.

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Disinfectants; Embryo, Mammalian; Estrogens; Mice; Mice, Inbred C57BL; Organ Culture Techniques; Progesterone; Rats; Teratogens; Trialkyltin Compounds; Valproic Acid

(Bis[tri-n-butyltin])oxide (TBTO) was studied for its toxic potential on prenatal development. The effect of this substance on limb differentiation (mouse embryos) in organ culture was evaluated. In the organ culture system using mouse limb buds, TBTO interfered with morphogenetic differentiation at doses as low as 0.03 microgram/ml (5 X 10(-8)M). This is one of the lowest concentrations of a substance ever found to be active in this in vitro system. The in vitro studies suggest a high embryotoxic potential of TBTO. The low embryotoxicity found in the in vivo studies may be due to limited exposure of the embryos by the original unmetabolized substance.

Topics: Abnormalities, Drug-Induced; Animals; Dose-Response Relationship, Drug; Extremities; Limb Deformities, Congenital; Mice; Organ Culture Techniques; Trialkyltin Compounds