The Production of Malignant Primary Hepatic Tumours in the Rat by Feeding Dimethylnitrosamine

Abstract

IN a previous paper (Barnes and Magee, 1954) some toxic properties of dimethylnitrosamine (DMN) were described. It was found that rats and other animals suffer severe liver damage after the administration of DMN in doses of the order of 25 mg. per kilogram body weight, either orally or parenterally. The liver lesion was an extensive centrilobular type of necrosis, involving all lobules; followed by evidence of regeneration in surviving animals. An outstanding feature of the necrosis was its very haemorrhagic character and the liver lesion was frequently accompanied by massive haemorrhagic ascites and bleeding into the gastro intestinal tract.These features of the acute liver necrosis were similar to those produced by the senecio alkaloids in rats (Davidson, 1935). A recent paper (Schoental, Head and Peacock, 1954) showed that senecio alkaloids also produced liver tumours if they were administered over longer periods. It seemed possible, therefore, that the chemically much simpler molecule DMN might also produce liver tumours in rats. The present paper describes the results of a long-term feeding experiment in which the compound was added to the diet of rats. A smaller and shorter experiment on rabbits was also performed. In the rats a very high incidence of hepatic tumours occurred, many with metastatic spread, but in the rabbits no tumours were observed. In no instance were primary tumours found in organs other than the liver.MATERIAL AND METHODS Male and female albino rats and cross-bred male rabbits were used. The basal diets were M.R.C. Diet 41 (Bruce and Parkes, 1949) for the rats and M.R.C. Diet 18 (Bruce, 1947) for the rabbits. The diet was given in powder form. DMN was made up as a solution in arachis oil so that 10 ml. added to 1 kg. of powder gave the required concentration.The food intake of the rats was measured for each cage of 5 animals by filling the container each day and measuring the unconsumed residue.The animals were weighed weekly and observed each day when their food was being measured. Post mortems were carried out on all animals that were either found dead or killed by coal gas when seriously ill. Tissues were fixed in Helly's fluid and formol-saline, embedded in paraffin and sectioned at 5,s. All sections were stained with haematoxylin and eosin as a routine and selected material was stained by Mallory's connective tissue method, Gomori's silver impregnation, and

Comparative Studies of the Hepatocarcinogen N,N-Dimethylnitrosamine in vivo: Reaction Sites in Rat Liver DNA and the Significance of their Relative Stabilities

“…On the other hand, exposure of adult rats to a chronic treatment (50 parts/] 06 in the diet; equivalent to about 4 mg/kg/day) does produce liver tumours (Magee and Barnes, 1956). Adult rats given this chronic exposure to the carcinogen showed an increased rate of turnover of liver DNA which was detected by the incorporation of ['4C]labelled adenine into the DNA of these animals (Craddock, 1 97 a).…”

Geonotoxicity study of illegal drug MDMA and its nitroso derivative N-MDMA by micronucleus and chromosomal aberration tests using Chinese hamsger lung fibroblast cell line

“…The neurotoxicity of MDMA has been widely reported (10)(11)(12), but the genotoxicity of this drug has not yet been previously studied. We investigated the risk of carcinogenesis induced by MDMA in this study.…”

Differential Patterns of Vasculature to Liver Tumours

“…In our experiments using the C57BL/6 mouse the male bladder tumour incidence falls from 80% in animals given 30 mg./kg./day to 36% at 7-5 mg./kg./day, as the dosage to the ICR mouse was only 5-24 mg./kg./day (Takayama, 1969, personal communication), this may have been below the threshold for bladder tumour induction. The mechanism by which the bladder is spared could be analogous to the situation in rats treated with dimethylnitrosamine which, although predominantly a liver carcinogen, induces kidney tumours when given in acute near toxic doses, probably by overriding the ability of the liver to metabolize the carcinogen and allowing a greater quantity to reach the kidneys (Magee and Barnes, 1962;Swann and McLean, 1969). The only other published reference to the action of DBN in the mouse is a limited study of the short term administration to C57 x IF mice at a dose level of 1 mg./mouse/day (approximately 30 mg./kg./ day) which induced hyperplasia of the bladder epithelium.…”

“…In addition 5 carcinomas of the fore-stomach in the low dose group and a total in both groups of 13 tumours of the soft palate and tongue were found. The mean cumulative doses and respective induction times for the high and low dose groups were 7*4 and 2-0 g./kg., and 240 and 260 days.N-NITROSO compounds were first shown to be carcinogenic by Magee and Barnes (1956) and have since been the subject of extensive research to determine both their mode of action and their structure-activity relationship. The review by Magee and Barnes (1967) gives a comprehensive coverage of this topic.…”

“…N-NITROSO compounds were first shown to be carcinogenic by Magee and Barnes (1956) and have since been the subject of extensive research to determine both their mode of action and their structure-activity relationship. The review by Magee and Barnes (1967) gives a comprehensive coverage of this topic.…”