Neurotoxicity of 1-methoxycycloheptatriene--a Purkinje cell toxicant.

The toxicity of 1-methoxycycloheptatriene (1-MCHT), a sensory irritant, has been investigated in beagles. It was found to produce gross inco-ordination of the limbs at intravenous doses greater than 10 mg kg-1. The main histological abnormalities were in the cerebellum and consisted of Purkinje cell death and subsequent reactive gliosis. A few necrotic neurons were seen in the diencephalon, pons and medulla. Haematological abnormalities, e.g. leucocytosis with relative lymphopenia, were seen, while biochemical changes included hyperglycaemia and a rise in plasma aminotransferases. The no-effect dose for the histological and biochemical changes was the same. These abnormalities are compared with cerebellar changes observed in acrylamide and other toxic states.

The repeated dose toxicity of a zinc oxide/hexachloroethane smoke.

Mice, rats and guinea pigs were exposed to the smoke produced by ignition of a zinc oxide/hexachloroethane pyrotechnic composition, 1 h/day, 5 days/week, at three different dose levels, together with controls. The animals received 100 exposures except for the high dose guinea pigs, which underwent 15 exposures, because of high death rate during the first few days of exposure. The test material had very little effect on weight gain, but there was a high rate of early deaths in the top dose of mice. A variety of incidental findings was seen in both decedents and survivors, but organ specific toxicity was, with one exception, confined to the respiratory tract. The most important of these findings was a statistically significant increase in the frequency of alveologenic carcinoma in the high dose group mice (p less than 0.01) and a statistically significant trend in the prevalence of the same tumour over all dose groups and the controls. A variety of inflammatory changes was seen in the lungs of all species and some appeared to be treatment-related. Fatty change in the mouse liver was more common in the middle and high dose groups than the controls. The aetiology of the tumour incidence is discussed and it is pointed out that hexachloroethane and zinc, as well as carbon tetrachloride, which may be present in the smoke, may be animal carcinogens in appropriate circumstances. Carbon tetrachloride is a known human carcinogen.

Inhalation toxicity of a smoke containing Solvent Yellow 33, Disperse Red 9 and Solvent Green 3 in laboratory animals.

The repeated-dose inhalation toxicity of a smoke containing a mixture of three dyes was tested in female mice, rats and guinea pigs. The green component dye (Solvent Green 3) was retained in the lungs. Particularly in the rats marked collections of alveolar macrophages were found. In the same species several other adverse findings were noted: these included adenocarcinomas of the breast in the high-dose group and a dose-related incidence of biliary hyperplasia. Fatty change was noted in the livers of the test-group mice. A large proportion of the high-dose guinea pigs died during the exposure period, for which reason exposure was stopped early in that group, otherwise the guinea pigs were little affected. However, all test groups of all species showed reductions in growth during the exposure period.

Pathological changes produced by exposure of rabbits and rats to smokes from mixtures of hexachloroethane and zinc oxide.

Rabbits and rats were exposed to single doses of hexachloroethane zinc smoke and observed for up to 14 days. Changes in the respiratory tract included acute inflammation and in some cases necrosis of the laryngeal and tracheal mucosa. Pulmonary oedema and pneumonitis were observed in decedent animals. Animals that survived to the end of the experiment, showed similar but much less florid changes in the respiratory tract.

A repeated dose study of the toxicity of technical grade dibenz-(b.f.)-1,4 oxazepine in mice and hamsters.

The repeated dose inhalation toxicology of technical grade dibenz-(b.f.)-1,4 oxazepine (CR) was studied in mice and hamsters. The animals were exposed 5 days/week for 18 weeks and retained until 1 year after the start of exposure. CR, at high doses, affected survival of both species, nevertheless the material produced little specific organ-directed toxicity.

A repeated dose study of the toxicity of inhaled 2-chlorobenzylidene malononitrile (CS) aerosol in three species of laboratory animal.

The repeated dose inhalation toxicity of 2-chlorobenzylidene maloninitrile (CS) was investigated in male mice, rats, and guinea-pigs. Exposure was 1 h X day-1 for 120 days surviving animals being killed approximately 1 year after the start of exposure. Excess mortality was noted in the high dose groups of all three species but at exposure concentrations below 30 micrograms X 1(-1) mortality varied little between the control and test groups. Death during the experiment was related to concentration of exposure rather than total dose (Ct). No case of a dose-response relationship between tumours in a particular site, and total dose of CS was noted.

A repeated dose study of the toxicity of CR applied to the skin of mice.

Dibenz (b,f)-1-4 oxazepine (CR) was applied to the skin of C3H and Porton-strain mice, daily for 12 weeks. After a further 80 weeks the animals were sacrificed and examined grossly and histologically. The results were compared with appropriate solvent and untreated controls. No abnormalities were found that could be ascribed to CR, but a high incidence of fatty infiltration of the liver in 1 strain of mice might have been due to the solvent in which CR was dissolved, namely acetone. There were marked differences in the incidence of several lesions in the 2 strains of mice, alveologenic carcinoma being much more common in the Porton mice. CR appeared to have little effect on the skin but both the test and solvent groups of male Porton mice shared an increased incidence of acanthosis.

Cutaneous histamine-releasing activity of dimethylsulphoxide (DMSO) in guinea pigs.

Dimethylsulphoxide (DMSO) induced swelling in guinea pig ears was found to be abolished by H1- and H2-receptor blocking agents. On histological examination of the ears some degranulation of mast cells was seen. It was concluded that the swelling was mediated by histamine release.

Ultrastructure of rat lungs following exposure to aerosols of dibenzoxazepine (CR).

Three groups of 18 animals were exposed respectively to the following large doses of dibenz (b.f)-1:4 oxazepine (CR) aerosols, 78,200,140,900 and 161,300 mg/min/m3. Animals were killed at intervals from 15 min to 2 days, and the lungs examined macroscopically, by electron microscopy and conventional histology. There were no deaths during or after exposure. Macroscopically the lungs from all rats appeared normal. Microscopically there were a few areas of mild congestion, haemorrhage and emphysema, but there was little variation between the different groups. Electron micrographs revealed some morphological alteration of the epithelium and endothelium but only occasional changes in the interstitium. The alterations took the form of "ballooning" of the endothelium with isolated foci of swelling and thickening of the epithelium. Interstitial oedema was observed in one animal only which was exposed to the highest concentration. The effects appeared similar in all groups, and are thought to be transient. The results of this investigation suggest that even high doses of CR aerosols cause minimal damage to the lung, and the structural alterations which do occur are believed to be due to the stress to which the animals were subjected during the exposure period.