Phenylamino-1,2 propanediol (PAP) and its mono-oleoyl ester have been identified in samples of the cooking oil thought to be responsible for the Toxic Oil Syndrome (TOS) which occurred in Spain in 1981. The acute toxicity of PAP and its mono-oleoyl ester have been examined in rats and mice, after daily administration for periods of up to 14 days to determine whether these compounds could produce any of the pathologies of TOS. Even at the highest dose, the 1-mono-oleoyl ester of 3-phenylamino-1,2 propanediol did not cause any toxicity in rats or mice when given intraperitoneally. 3-Phenylamino-1,2 propane diol, however, was toxic when administered to rats by this route. After 6-10 consecutive daily doses of PAP, at the highest dose administered (350 mg kg -1 ), all of the rats became unwell. Postmortem examination showed that the major pathology present was massive pulmonary throm boembolism. Further investigations of the toxicity of PAP after intravenous administration showed that it was not directly vasotoxic. The pulmonary thromboembolism seen with intraperitoneally administered PAP was due to the toxic effect of PAP on the mesenteric tissue and blood ves sels, causing thrombosis which subsequently embolised the blood vessels in the lung. Intra-gastric administration of PAP caused no toxicity in rats. Comparatively, the pathology seen after intraperitoneal administration of PAP was not thought to be representative of the pathology of the toxic oil syndrome in man.

Tamoxifen administered in the diet (420 ppm) to Wistar rats (TOX:P) for only 3 months caused cumulative hepatic DNA damage as assessed by 32P-postlabeling, consistent with the proposal that tamoxifen is a genotoxic carcinogen in this species. Promotion of tumor development with phenobarbital after discontinuation of dietary tamoxifen resulted in the formation of liver carcinomas after 9 months. At 12 and 20 months in this study, the majority of these rats had liver carcinomas. Rats treated with tamoxifen for 3 months but not promoted with phenobarbital also developed liver tumors over a longer period of time. These tumors were predominantly adenomas, with one carcinoma, and occurred at a lower incidence than the tumors produced by promotion with phenobarbital. Rats treated with phenobarbital alone did not develop tumors after 20 months. Tamoxifen-induced DNA adducts were relatively persistent, with only a 38% decrease 3 months after tamoxifen treatment had been discontinued. This demonstrates that, in a susceptible species (the rat), tamoxifen can cause initiation of liver cancer after only 3 months exposure. It is proposed that the persistence of such DNA adducts may account for the ability of phenobarbital to promote a high incidence of liver carcinoma, even after discontinuation of tamoxifen treatment. These data are relevant to the concern for women given prophylactic tamoxifen for long periods in that even if there is a relatively small amount of cumulative tamoxifen-induced liver DNA damage, liver tumors could be promoted by other agents, even after the cessation of tamoxifen treatment.

In order to determine whether they are potentially carcinogenic to the pleural mesothelium, three samples of ceramic fibre have been administered to rats by the intrapleural route, These samples were a high-duty grade refractory ceramic fibre (manufactured by Thermal Ceramics Ltd) in the as-manufactured vitreous state and two devitrified samples produced by heating the same fibre for 2 weeks at 1200 degrees C and for two weeks at 1400 degrees C. The mean lifespans of the groups of rats treated with vitrified and devitrified ceramic fibres were not significantly different from that of the control rats. In these studies none of the treated or control rats developed pleural mesothelioma, making it unlikely that ceramic fibres of this type, whether vitreous or devitrified, are potentially carcinogenic to the pleural mesothelium.

BACKGROUND:Hemochromatosis is a disease of excessive iron storage leading to tissue damage and fibrosis. Both genetic hemochromatosis, which can affect 1 in 500 of some populations, and the form of this disease which occurs as a secondary consequence of the hemoglobinopathy, homozygous beta-thalassemia, with 40 million carriers worldwide, have a common pathology. The cardiotoxicity and hepatotoxicity, which occurs with this disease, have never been produced experimentally in other species.EXPERIMENTAL DESIGN:Using a regimen of iron dextran administered subcutaneously to gerbils on a weekly basis for 7 weeks, we have produced severe hemosiderosis, especially of the liver and heart. By examining gerbils at 1, 2 and 3 months after the final iron injections we followed the subsequent development of hemochromatosis in the hearts and livers of iron overloaded animals.RESULTS:Hemochromatosis of the liver was evident as a scarring fibrosis in all cases between 1 and 3 months after iron dextran administration to gerbils. The iron burden in the cardiac myocytes of gerbils gradually increased between 1 and 3 months, resulting in hemochromatosis of the heart 2 and 3 months after the final iron dextran injections.CONCLUSIONS:Repeated parenteral injections of iron dextran to gerbils resulted in hemochromatosis affecting the liver and heart with a pathology which is the same as occurs in the end-stage disease in man. This model will allow the detailed study of the mechanism of iron induced, free radical tissue damage, which is though to be the cause of these lesions and will also be useful in the evaluation of iron chelating therapies to determine whether the hepatic and cardiac pathology of iron overload can be modulated over a long period.

A previous study using intrapleural administration of surface-modified amosite asbestos showed a difference in the number of pleural mesotheliomas induced with C18-hydrocarbon derivatised fibres compared to native amosite asbestos. The study has been repeated with larger groups of animals (30) under specific pathogen free conditions, resulting in an increase in the mean animal survival time for both fibre-treated groups. Under these conditions there was no significant difference between the numbers of pleural mesotheliomas induced by C18 hydrocarbon-modified amosite asbestos and native amosite asbestos. The major difference between the two studies was the mean time to death from tumour of rats exposed to fibres. The C18 amosite treated rats in the first study may not have had a mean survival time long enough to allow mesotheliomas to develop.

1 The dietary exposure of rats to tributyltin oxide at a concentration of 150 ppm for 6 weeks is known to lead to a significant reduction in relative thymic weight. 2 To determine whether this reduction in thymic weight also leads to an impairment of function sufficient to alter the host response to micro-organisms, we have examined the development of virus- and mycoplasma-induced pneumonia in TBTO-exposed rats. 3 Using a quantitative histopathological method for measuring both the extent and duration of lung lesions in TBTO-exposed rats, no statistically significant increase in the extent or persistence of virus-induced lung lesions was found in rats exposed chronically to TBTO. 4 The susceptibility of rats to Mycoplasma pulmonis infection, alone, or in conjunction with viral pneumonia, was also not increased by dietary exposure to TBTO.

This study reports the findings of hepatic fibrosis and the accumulation of iron in the livers of 12 gerbils. The primary lesion was a haemorrhagic necrosis of the liver that was identical to that produced experimentally in the gerbil by administration of E. coli endotoxin lipopolysaccharide. The resulting extravasation of blood caused focal histiocytic reactions. The number of lesions increased with age, eventually resulting in a micronodular cirrhosis after 9 to 12 months owing to repeated episodes of endotoxin-induced haemorrhages in the liver. The accumulation of iron occurred in perisinusoidal cells, Kupffer cells and hepatocytes. The perisinusoidal cells were responsible for the subsequent hepatic fibrosis. The fibrosis associated with this condition appears to result from iron accumulation in the liver, following haemorrhage caused by endotoxin lipopolysaccharide. The gerbil is the first recorded rodent species to develop hepatic fibrosis in response to hepatic iron overload.

Ageing rats are known to have an increased incidence of myocardial fibrosis and dyspnoea caused by pulmonary intravascular coagulation. In order to determine whether endotoxin can be responsible for such responses in ageing rats we have exposed rats of differing ages (2 months, 16 months and 24 months) to single or repeated (two doses 24 h apart; generalized Shwartzman regime) intravenous doses of endotoxin (E. coli 0111 B4). Only the 2-year-old rats reacted adversely. Two doses of endotoxin produced death, with focal myocardial necrosis, haemorrhage and pulmonary and hepatic intravascular coagulation. The increased susceptibility of aged rats to the toxic effects of endotoxin explains some of the changes found in the tissues of old rats. The sporadic nature of both cardiac failure and dyspnoea as a cause of morbidity and mortality in ageing rats may be related to the need for two endotoxin episodes in a period of 24 h to provoke a generalized Shwartzman reaction, an occurrence likely to be relatively uncommon under natural conditions.