Developmental toxicity potential of grayanotoxin I (GTX I), a toxic diterpenoid contained in plants of the family Ericaceae, with sodium ionophore activity, was studied in mice and chicks. In mice, intraperitoneal injections of 1.5 mg GTX I/kg body weight of mouse for three consecutive days during the organogenetic period caused some dams to die, but neither embryotoxicity nor teratogenicity was detected. In chicks, a single injection of 0.1-1.0 μg GTX I per egg into the extraembryonic coelom on day 1.5 or 2 of incubation, or into the amnionic cavity on day 3 or 4 of incubation induced neither embryotoxic nor teratogenic signs, but 10μg GTX I per egg showed lethal effects when applied on eath of those days.

View full abstract

Cisplatin is an effective antineoplastic agent that causes severe vomiting due to unknown mechanism. The ferret, an animal model useful in the determination of emetic activity, was used to clarify the emesis-related biochemical and histopathological changes that were induced by cisplatin. Cisplatin (5 to 10 mg/kg) was administered intraperitoneally and a 7-10 mg/kg i. p. dose evoked dose-dependent emesis in the ferret. Almost all cisplatin-vomiting episodes occurred within a 6 hour observation period. All ferrets receiving cisplatin in this study died within 3-5 days. Significant increases in ileal mucosal levels of serotonin and norepinephrine were observed in cisplatin-treated ferrets. There were no significant changes in the levels of serotonin and dopamine in the gastric mucosa. Also, karyorrhexis was observed in the epithelial cel1s of the ileum and in the lymph follicles of the spleen of cisplatin-treated ferrets. These significant biochemical and pathological changes in the ileum may play an important role in cisplatin-induced emesis.

View full abstract

A quantitative structure-activity relationship (QSAR) approach has been applied to the analysis of the relation between the structural features of chemicals and the primary eye irritation in rabbits. One hundred thirty one heterogeneous chemicals including medicals, pesticides, detergents and organic solvents were used in this study. The eye irritation ratings were made in three classes on the basis of the recovery time of corneal and conjunctival damages. Thirty six descriptors were used to describe the molecules. To correlate eye irritation ratings with the descriptors, a QSAR model was formulated by the adaptive least-squares method. A three-class discrimination was made as follows ; class I included 23 chemicals which induced the damages recovering within 24 hr, class II included 64 chemicals which induced the damages persisting for more than 24 hr but recovering within 21 days, class III included 44 chemicals which induced the damages not recovering within 21 days. The discriminant function included 18 descriptors. The accuracy in classifying the chemicals was 86.3% in the recognition and 74.0% in the leave-one-out prediction. These results suggest that QSAR analysis is valuable to predict the primary eye irritation of chemicals.

View full abstract

A procedure for recording the electroretinogram (ERG) and the visual evoked potential (VEP) in freely moving cats was developed and used to test the visual toxicity of nalidixic acid. The electrodes for recording the ERG and VEP were implanted chronically in the sclera of the eye and on the surface of the visual cortex, respectively. Both the ERG and VEP were simultaneously recorded in freely moving cats using a slip ring that allows the cat to move freely without twisting the cables. After a 15-min dark-adaptation period, 20 responses to repetitive photic stimulation with an intensity of 2 joules and a 10-sec interstimu1s interval were averaged by means of a minicomputer. The waveform of the ERG consisted of a negative wave (a-wave) followed by a positive wave (b-wave) with 2 to 3 oscillatory potentials on the rising slope. The VEP consisted of initial positive wave (P1 wave) followed by a negative wave (N1 wave) and late positive and negative deflections. The amplitude of the components of the ERG and VEP varied considerably from animal to animal, whereas within the same animal they were very stable. Using this technique, the effects of nalidixic acid, a retinotoxic compound, on the ERG and VEP were studied. Nalidixic acid produced a marked, but transient, decrease in the amplitude of the ERG b-wave after a single intravenous injection at a dose of 10 mg/kg. After repeated doses at 40 mg/kg/day for 2 weeks, the reduction in the amplitude of the b-wave was stronger, but remained transient. Upon ophthalmologic and histopathologic examination of the retina, no abnormalities indicating visual toxicity were observed. These results indicate that this procedure for recording the ERG and VEP is useful for evaluating the visual toxicity of drugs in freely moving cats.

View full abstract