Subject Rabbit

Haytliurii s next experiment ctjnsi ted in subjecting rabbits and guinea pigs to the fumes of heated TNT fur several hours a day for over a month. In this way the animals were under the same conditions as men in the plants who are forced to breathe fumes from washing or crystallizing appara.tus, or from any source where the TNT is subjected to heat. The animals used in this test showed no Webster reaction. 

Melamine ia a skin test on rabbits produced neither local irritation nor systemic toxicity. As a 10% solution ia methylceUulose, it caused no irritation ia the eyes of rabbits. Human subjects were given patch tests with melamine. No evidence of either primary irritation or sensitization was found. Such results suggest that melamine crystal may be handled ia ordinary iadustrial use without special hygienic precautions. 

Skin tolerance was tested on rabbits. A 1 % alkanesulfonate solution applied five times did not produce any irritation on the rabbits skin. The same results were obtained by the closed patch test carried out with human test subjects in a hospital. The good dermatological properties were also confirmed by the Polano test (arm immersion test). 

There are only two animals that are used in the search for criteria rat (intoxication by inhalation, skin and orally) and rabbit (by skin). The only means of penetration that can be used are inhalation, skin and orally. When a substance is not subjected to regulations, the absence of one or several animal/means of penetration combinations prevents the proposal of any level of danger for the substance labelling and also any suitable prevention measures. 

Green, C.J., HeaUng, G., Simpkin, S., Lunec, J. and FuUer, B.J. (1986c). Desferrioxamine reduces susceptibUity to lipid peroxidation in rabbit kidneys subjected to warm ischaemia and reperfusion. Comp. Biochem. Physiol. 85B, 113-117. 

Aminopeptidase A is another brush border membrane enzyme which has been the subject of various studies [79,81,83-86], It has been found in the intestinal brush border membrane of humans, rabbits, rats, and pigs and is active against peptides with acidic amino acids at the amino terminus. Its activity against dipeptides is more limited. Shoaf et al., isolated three rat brush border aminopeptidases with distinct but somewhat overlapping substrate specificities. These enzymes had preference for dipeptides containing methionine, arginine, or aspartic acid and glycine. The optimal pH for activity of aminopeptidase was reported to be 7-8. 

Lengthening of the side chain of DMT by a single methylene group produces N,N-dimethylhomotryptamine (DMHT 76, R = H, n = 3), which produced hyperthermia when administered to rabbits (7,232) but was found to be inactive in man (235). Intravenous administration of 5 and 10 mg and intramuscular injection of 20 to 70 mg DMHT was without psychologic effect in 10 human subjects (235). Additional studies on DMHT homologs (i.e., 76, n = 4-10) did not show any interesting activity (7,232). 

Psilocin has also been the object of considerable investigation using animals as subjects. Much of the initial work with psilocin, as well as other 4-hydroxy-tryptamine derivatives with alterations in the side chain and/or terminal amine, was performed at Sandoz Laboratories in Switzerland (29,245). Subsequent investigations have shown that psilocin produces hyperthermia in rabbits (113), induces the head-twitch in mice (43), disrupts acquisition of avoidance behavior in rats (240), increases startle response magnitudes in rats (68), increases limb-flick behavior in cats (120), and produces discriminative stimulus effects in rats similar to those of 5-OMeDMT (59) (93). 

Experimental studies with human subjects and several mammalian species (monkey, dog, rat, mouse, and rabbit) were located. Animal studies addressed neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitization and were conducted over acute, subchronic, and chronic exposure durations. 

Chronic and subchronic toxicity studies are conducted to define the dose level, when given repeatedly, that cause toxicity, and the dose level that does not lead to toxic findings. In Japan, such studies are referred to as repeated-dose toxicity studies. As with single-dose studies, at least two animal species should be used, one rodent and one nonrodent (rabbit not acceptable). In rodent studies, each group should consist of at least 10 males and 10 females in nonrodent species, 3 of each sex are deemed adequate. Where interim examinations are planned, however, the numbers of animals employed should be increased accordingly. The planned route of administration in human subjects is normally explored. The duration of the study will be dictated by the planned duration of clinical use (Table 2.14). 

Conquet, P., Durand, G., Lailler, J. and Plazonnet, B. (1977). Evaluation of ocular irritation in the rabbit Objective versus subjective assessment. Toxicol. Appl. Pharm. 39 129-139. 

When individuals were administered 800 mg. per day of phenylbutazone (Butazolidin) for 14 days or more, each developed a characteristic plasma level.39 For 60 subjects this level ranged from 60 to 150 mg. per liter and was constant from day to day for individuals. It was concluded that the rate at which the drug was metabolized under the conditions used varied from 17 to 35 per cent per day for different individuals. It is interesting that the "biological half-life" of this substance varies from species to species3 hours for rabbits, 6 hours for dogs and rats, 72 hours for man. It is also clear from the above that its rate of disappearance varies widely for individual human subjects. 

As discussed in detail by Dillard et al. and by Mittman et al. the possible relationship of lysosomal proteases to chronic lung disease has been inferred from the finding of an increased incidence of emphysema in subjects deficient in serum ai>antitrypsin factor, an -globulin that can inhibit lysosomal proteases. (No effect of ozone on serum aj-antitrypsin inhibitor was noted in rabbits chronically exposed to ozone. ) Thus, an ozone-induced increase in concentrations of such enzymes in the lung might produce excess proteolysis and result in eventual chronic lung disease. However, the available evidence is inadequate to support the belief that such a process occurs in humans intermittently exposed to ozone. Further studies of this potential hazard would be of value. 

In order to investigate the active sites of these proteins, laccases I and III were subjected to ESR (electron spin resonance) spectroscopic analysis. The ESR spectra shown in Figure 5 indicate clear differences in peaks 2 and 6 which support the concept that the copper atoms in laccases I and III have different conformations in each molecule. Furthermore, immunological similarity between laccases I and III was also investigated. Antibody specific for laccase III was prepared from rabbit serum by conventional methods. When applied to Ouchterlony diffusion plates containing laccase I, no precipitation lines developed (Figure 6). This result showed that there were no conserved epitopes on the surfaces laccases I and III. 

The finding that the administration of 6-mercaptopurine to rabbits following exposure to bovine serum albumin prevented antibody formation [374] formed the basis for a new area of chemotherapy for purine analogues and other antimetabolites and was soon followed by the use of these drugs for the therapy of autoimmune disease and the suppression of homograft rejection. This subject has been reviewed in depth [ 12, 375, 375a], has occasioned a symposium [376], and has received much recent publicity as a result of human heart transplants. 

---