Pathological findings in rabbits and sheep following the subacute administration of triphenyltin acetate.

Organotins are used worldwide in agricultural practice as fungicides and herbicides. In this study morphological and ultrastructural investigations related with the subacute administration of the fungicide triphenyltin acetate (TPTA) were carried out in rabbits and lambs. Twenty-eight New Zealand White male rabbits were fed diets containing 0, 15, 75 or 150 ppm TPTA for 70 d; comparable doses (1 or 7.5 mg/kg bw) were administered daily to immature male lambs. After 70 d of treatment dose-dependent decreases in body weight gain and thymus relative weights were seen in both species. In rabbits, the main histological lesions were found in the thymus and mesenteric and retropharyngeal lymph nodes, confirming the immunosuppressive activity reported by TPTA in other rodents. Lambs showed similar, but less severe lesions. However, the involvement of the immune system was noted in both species, but at doses much higher than those reported for rats and guinea pigs. This different immunotoxic activity of TPTA might be related to species differences in the toxicokinetics of the fungicide.

Inhibition of hepatic xenobiotic metabolism and of glutathione-dependent enzyme activities by zinc ethylene-bis-dithiocarbamate in the rabbit.

Effects of either a single (300 mg/kg) or a subchronic (0.3 and 0.6% for 70 days) oral administration of a dithiocarbamate fungicide (zinc ethylene-bis-dithiocarbamate, zineb) on hepatic drug metabolism and on the activity of several glutathione-dependent enzymes were investigated in male New Zealand White rabbits. While a pronounced reduction in the rate of oxidative biotransformations occurred after either single or repeated exposure, both cytochrome P450 and total haem content were lowered following acute challenge to zineb. None of the experimental protocols affected microsomal carboxylesterase but induced a marked increase in glutathione content and none of the examined glutathione-dependent enzymes was altered by the single administration of zineb, whereas the subchronically exposed rabbits showed a fall in the activities of both total glutathione S-transferase and selenium-independent glutathione peroxidase. In the 0.6% treated animals, a decrease in class mu glutathione S-transferase and glyoxalase I, and an increase in thiol-transferase activities were also recorded. It is concluded that (1) zineb is able to selectively impair oxidative drug metabolism with possible different mechanism(s) according to the duration of the exposure, (2) only the subchronic treatment affects glutathione-dependent enzymes, (3) the decrease in glutathione S-transferase activity would seem to be ascribed to a direct interaction with the fungicide.

Age- and sex-related effects on hepatic drug metabolism in rats chronically exposed to dietary atrazine.

Male and female Wistar rats were administered a diet containing 450 ppm atrazine as early as 60 days prior to the cohabitation period and the same diet was offered to their offspring. Hexobarbital sleeping time and further in vitro assays pointed to a monooxygenase induction which appeared to be more marked in males vs females and most significant in the offspring at weaning. At this age, induction involved also the cytosolic glutathione S-transferase, a phase II enzyme. Results would suggest that the inducing properties of the herbicide can be transferred to the offspring via the placental and/or the mammary route.

Pathogenesis of sodium selenite and dimethylselenide acute toxicosis in pigs: cardiovascular changes.

In pigs and other food producing animals, relatively little is known about the mode of action of excess selenium. This study reports the cardiovascular effects brought about in anaesthetised Landrace pigs by 2 mg selenium kg-1 bodyweight intravenously as either sodium selenite or dimethylselenide. Sodium selenite dosing was characterised by a dramatic fall in systemic blood pressure with an increase in cardiac output and heart frequency. The only significant change elicited by dimethylselenide was a linear rise of cardiac output. Neither of the tested compounds significantly affected pulmonary arterial pressure. These results suggest that under the experimental conditions in this study, sodium selenite induces a vasculogenic shock without primarily affecting cardiac performance. The lack of detrimental effects on cardiovascular parameters with dimethylselenide indicates the importance of methylation in detoxifying excess selenium.

Pathogenesis of sodium selenite and dimethylselenide acute toxicosis in swine: tissue and blood biochemical changes.

The present investigation was undertaken to examine the biochemical changes occurring in blood and tissues of Landrace pigs given intravenously 2 mg selenium/kg b.w. as either sodium selenite or dimethylselenide. NADP-isocitric dehydrogenase, lactic dehydrogenase and succinic dehydrogenase activities were evaluated in subcellular fractions from liver, heart (right and left ventricle) kidney and longissimus dorsi. Other tested parameters included plasma cations and proteins, blood urea nitrogen, hematocrit as well as selected serum enzymes. The marked inhibition of succinic dehydrogenase along with the rise of the two other dehydrogenases and the modification of the plasma cation profile suggest that in swine sodium selenite may act by determining a shift toward anaerobiosis accompanied by alterations in cell membrane permeability. Comparatively, dimethylselenide was found to affect the tissue enzymes to a similar but less severe extent and appeared devoid of significant effects on the remaining parameters. The possible relationships between the cardiovascular alterations brought about by sodium selenite (described elsewhere) and the observed biochemical changes in the present study are finally discussed.

Toxic effects of theobromine on mature and immature male rabbits.

Mature and immature male rabbits were fed for 120 and 20 days, respectively, a commercial diet containing theobromine in amounts of 0, 0.5, 1 and 1.5 per cent. Clinical, haematological, histopathological and histoenzymological examinations were performed. Mortality, which appeared dose- and time-related, was severe and rapid, mostly in the 1 and 1.5 per cent groups and was attributed to cardiac failure. Theobromine administration resulted in marked changes in thymus and testes and the severity of lesions appeared to be related to the amounts of the ingested methylxanthine. The earliest thymic alterations in immature rabbits consisted of a blurring of demarcation between cortex and medulla accompanied, in the more advanced stages, by a decreased lymphocyte density. Similar lesions were observed in mature animals which had died in the earlier phase of the study. Testicular alterations ranged from vacuolation of spermatids and spermatocytes to multinucleated cell formation and oligospermia or aspermia with extensive degeneration of tubule cells. Some necrotic and post-necrotic myocardial foci were also recorded. The increase in testicular activity of beta-glucuronidase in immature rabbits compared to the untreated animals provided further evidence of an early theobromine-induced damage of the testes.