Br J Ind Med: first published as 10.1136/oem.17.1.69 on 1 January 1960. Downloaded from Brit. J. industr. Med., 1960, 17, 69. RENAL LESIONS IN EXPERIMENTAL CADMIUM POISONING BY J. A. BONNELL, J. H. ROSS, and E. KING From the Department for Research in Industrial Medicine, Medical Research Council, The London Hospital (RECEIVED FOR PUBLICATION MARCH 12, 1959) A series of controlled experiments was carried out on rats to study the effects on the kidneys of the repeated administration of small doses of cadmium for periods of up to 12 months. Renal lesions consisting essentially of tubular atrophy and interstitial fibrosis were produced, and the evidence that these lesions were due solely to cadmium is discussed. No similar lesions occurred in a series of control animals, litter mates of the experimental animals. The lesions were shown to be reproducible in two prolonged experiments on two strains of rats. The relationship between the lesions and the concentration of cadmium in the tissues of the rats is discussed and a com- parison is made with tissues from human cases of chronic cadmium poisoning. It is of interest that the cadmium concentration of human tissues and rat experimental tissue is of the same order of magnitude. Animals in which the administration of cadmium was discontinued after five months of the experiment had developed as severe lesions seven months later as those animals which had received cadmium for 12 months. It has been shown previously that the first sign of chronic copyright. cadmium poisoning can occur in man for the first time many years after the last exposure, and that the disease once established in man is progressive despite the absence of further exposure. Emphysema and proteinuria have been described but the actual doses were not mentioned. At in men exposed to cadmium oxide as either dust or necropsy these animals were found to have in- freshly formed fume (Friberg, 1948; Bonnell, 1955). farction of the lungs with subpleural haemorrhages, The significance of the proteinuria and its relation- fatty degeneration of the liver and heart, and a ship to progressive renal damage has been discussed diffuse inflammation of the kidneys. The excretion http://oem.bmj.com/ by Bonnell, Kazantzis, and King (1959). of cadmium was found to be slow and to occur Because the evidence that progressive renal mainly in the urine. damage occurred in men suffering from chronic The effect of cadmium on the kidneys was studied cadmium poisoning was incomplete, experiments by Severi in 1896. Ten milligrammes of cadmium were carried out to study the effect of repeated as a 1 % solution of cadmium chloride were injected small doses of cadmium on the kidneys of rats. subcutaneously in rabbits and dogs first daily and These experiments are described here, together with then on alternate days. The macroscopic and micro- a review of the literature involving animal scopic appearances of the kidneys were said to on September 30, 2021 by guest. Protected experiments with cadmium. resemble closely the kidneys in mercuric chloride poisoning. There was an intense necrosis of the Review of the Literature convoluted tubules, the cells were poorly defined, The earliest work on the toxic effects of cadmium pale and with irregular granulations. There were in animals was published by Marme in 1867. He tubular casts which appeared to be formed from the determined the lethal dose of 14 cadmium com- desquamating cells, and some calcified casts. pounds on dogs, cats, rabbits, and pigeons. The Alsberg and Schwartze (1919), using cats, dogs, cadmium was administered intravenously, sub- rabbits, and rats as experimental animals, reported cutaneously, and orally. He found that the lethal renal changes after parenteral administration but dose for dogs was 30 mg. intravenously and no histological details were given. No other patho- 60-90 mg. subcutaneously. The lethal dose for logical changes were noticed and no cumulative rabbits was 300-600 mg. by mouth. Small doses of effects were noted with small doses. cadmium salts were found to produce chronic effects Johns, Finks, and Alsberg (1923) showed that the 6 469 Br J Ind Med: first published as 10.1136/oem.17.1.69 on 1 January 1960. Downloaded from 70 BRITISH JOURNAL OF INDUSTRIAL MEDICINE growth of young rats was completely retarded by a most sensitive criterion of chronic absorption of diet containing 250 p.p.m. of cadmium. The cadmium discovered in this work was the effect on initial growth rate was normal on diets containing the teeth. The normally yellow incisor teeth were 125 p.p.m. but all the male rats died within 56 days. bleached by cadmium, the effect being almost Diets containing 62-5 p.p.m. produced no noticeable identical with that produced by fluorine poisoning. effects. Similar effects on growth were noted by Statistically significant increases in weight were Schwarz and Otto (1925) but they also reported a found for the heart, adrenals, and kidneys of these reduction in the haemoglobin content of the blood. animals at necropsy. The mean weight of the hearts Haemoglobin estimations in rats fed 1-11 mg./kg. of of rats on a diet containing 0-0125 % cadmium was cadmium demonstrated a fall of 10 to 20% in the almost double that of the control animals. Micro- haemoglobin (Sahli scale). scopic examination of the heart showed hypertrophy Prodan (1932) devised a series of inhalation ex- of the cardiac muscle, which was claimed to be due periments on cats using cadmium fume, cadmium to the anaemia and not to renal damage. Histo- oxide, and cadmium sulphide. Two cats were logical examination of the other organs showed a exposed to a high concentration of cadmium fume subacute pancreatitis, particularly in the rats for 30 minutes. One cat was killed five hours later absorbing 0-025 % cadmium. There were focal and the other died 12 hours after exposure. Both areas of centrilobular necrosis with lymphocytic had acute pneumonia. Three other cats were ex- infiltration in the liver. There was swelling and posed for 24 hours to a lower concentration of granulation of the epithelium of the convoluted cadmium fume (the settling curve showed an initial tubules of the kidneys with formation of both concentration of 16 mg./m.3 which fell to 4 mg./m.3 hyaline and granular casts. All these effects were after 24 hours). All three cats developed acute more marked in the rats taking a diet containing pulmonary lesions. The first cat was killed imme- 0-025 and 0 05 % cadmium. diately after exposure; the other two cats were Princi and Geever (1950) described experiments killed five and nine days later. The lungs showed in which dogs were exposed to cadmium sulphide areas of acute inflammation, collapse, and acute and cadmium oxide dusts in specially constructed emphysema. There were haemorrhages in the tanks. The dogs were exposed to cadmium bronchioles and acute inflammatory changes in the oxide dust for six hours daily for five days each copyright. liver and kidneys. Prodan estimated that the cats week at a mean concentration of 4 mg./m.3. retained only 3 to 6 mg. of cadmium. In another Ninety-eight per cent. of the dust particles were experiment two cats were exposed to cadmium oxide less than 3,t in diameter and no particle greater dust at a concentration of 400 mg./m.3. The than 5,t was seen. The dogs were exposed for necropsy findings were similar to those in the periods which averaged 1,102 hours. animals exposed to cadmium fume. Cats exposed Complete necropsies on all 30 dogs showed no to cadmium sulphide showed changes in the lungs significant abnormalities. The lungs, liver, and http://oem.bmj.com/ similar to those seen in animals exposed to cadmium kidneys were carefully examined, but even though fume and cadmium oxide dust. appreciable quantities of cadmium were found in Wilson, DeEds, and Cox (1941) studied the effect the organs, there were no structural changes. Blood of adding cadmium to the diet of rats. Male albino cadmium levels varied between 0 3 ,ug./g. blood rats were fed on diets containing 0, 0-0031, 0 0062, after one week and 2-2 ,ug./g. after 12 months' 0-0125, 0 025, and 0-05% cadmium as cadmium exposure. The cadmium excreted in the urine was chloride. Three effects were noticeable: (a) The c. 6 ,tg./litre after one week and c. 387 ,tg./litre after effect on the growth of the animals; (b) the pro- 12 months' exposure. The blood and urine cadmium on September 30, 2021 by guest. Protected duction of anaemia; and (c) the effects on the teeth. levels after exposure to cadmium sulphide were The growth of the animals was retarded in direct much lower. The cadmium concentration in the relation to the concentration of cadmium in the liver and kidney was 20-6 to 133 ,ug./g. of kidney and diet. The rats taking 0-0125% cadmium in the diet 12-4 to 4 70 ,g./g. of liver. Princi suggested as a were markedly affected after 84 days. When their result of these experiments that the maximum allow- diet was replaced with a normal diet, they rapidly able concentration of cadmium in the atmosphere attained a normal rate of growth with no apparent of workshops should be increased. ill effects. Feeding on a diet containing as little as Friberg (1950a and b) described experiments in 0-0031 % cadmium produced an anaemia which was which rabbits were exposed to cadmium dust in two sufficiently severe to alter the normally pink eyes groups of 13 and 12 for seven and nine months of the albino rats.