Cadmium Neoplasia: Sarcomata at the Site of Injection of Cadmium Sulphate in Rats and Mice

Abstract

IN the course of a series of tests of iroii-containing compounds and irolicomplexes for carcinogenicity, it was found that a preparation of rat-ferritin induced not only a high incidence of sarcomata at the site of repeated subcutaneous injection, but also testicular atrophy, Leydig-cell hyperplasia and benign Leydigcell tumours (Haddow, Dukes and Mitchley, 1961 In this paper the induction of sarcomata at the site of subcutaneous injectiol-i of " rat-ferritin " or cadmium sulphate in rats is described and the failure to induce similar tumours in mice bv injection of the same agents, reported. In an accompanying paper (Roe et al., 1964) the testicular and pituitary changes following the injection of eadmi-Lun sulphate, or ferritin. are described and discussed.MATERIALS AND ',,%IETHODS Rats : Male albino rats of the Chester Beatty straiii were used. In the first experiment courses of injection were begun when the rats were 3-4 weeks old (80-1 00 g.), and in the third experiment when they were 6-7 weeks old (I 70-200 g.).(Rats of this strain are exceptionally large.) The rats were housed in metal cages in groups of 10, fed cubed Diet 86 on 2 days of each week and white bread plus milk, cod liver oil, margarine, or marmite on the 5 other davs. Water was provided ad libitum,

Non-carcinogenicity of cadmium-free ferritin

“…The total dose of cadmium-free ferritin given to the rats in the present investigation (126 mg.) was more than double that of cadmium-precipitated ferritin (56 mg.) used in the previous studies by Haddow and his colleagues (Haddow et al, 1964;Roe et al, 1964). But despite the use of this larger dose, no sarcomas appeared at the site of injection and the testes remained normal.…”

“…The failure to induce local sarcomas must, however, be interpreted with caution because the survival of many of the rats in the test group was short in relation to the induction-time of sarcomas produced in the earlier experiments with cadmium-precipitated ferritin. Haddow et al (1964), observed the first injection-site sarcoma at 14 months and the average time of appearance of the 7 sarcomas which subsequently developed was over 21 months. On the other hand, the cadmium-free ferritin produced significant fibrosis at the injection-site in only 1 animal; whereas in the earlier experiments, intense proliferation of fibrous tissue was seen in all the test animals, and was palpable in them long before they developed local sarcomas.…”

“…Previous and parallel observations demonstrated that simple inorganic cadmium salts were carcinogenic-both at the site of injection (Kazantzis, 1963;Haddow et al, 1964) and in the testis (Parizek and Zahor, 1956; Meek, 1959;Kar and Das, 1960;Gunn, Gould and Anderson, 1963)-and it thus seemed likely that some or all of the effects of cadmium-precipitated ferritin were due to its content of cadmium. To confirm this hypothesis, cadmium-free ferritin was tested for carcinogenic activity in rats and mice.…”

“…Received for publication April 16, 1968 IT was reported in 1964 that rats which received repeated subcutaneous injections of cadmium-precipitated ferritin developed sarcomas at the site of injection, interstitial cell (Leydig cell) tumours of the testes and testicular atrophy (Haddow, Roe, Dukes and Mitchley, 1964;Roe, Dukes, Cameron, Pugh and Mitchley, 1964). Previous and parallel observations demonstrated that simple inorganic cadmium salts were carcinogenic-both at the site of injection (Kazantzis, 1963;Haddow et al, 1964) and in the testis (Parizek and Zahor, 1956;Meek, 1959;Kar and Das, 1960;Gunn, Gould and Anderson, 1963)-and it thus seemed likely that some or all of the effects of cadmium-precipitated ferritin were due to its content of cadmium.…”

Test of an iron sorbitol-citric acid complex (Jectofer) for carcinogenicity in rats

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THE induction of sarcomas at the site of injection of iron-dextran, of otlher preparations of iron, and of other metal-carbohydrate complexes in rats, mice, hamsters and rabbits is well documented (Richmond, 1957(Richmond, , 1959(Richmond, , 1960Haddow and Horning, 1960; Golberg, Martin and Smith, 1960 ; Lundin, 1961 ;Haddow. Dukes and Mitchley, 1961;Haddow, Roe and Mitchley, 1964;Haddow and Roe, 1964; Roe, Haddow, Dukes and Mitchley, 1964) and has been considered in recent review articles (Roe and Lancaster, 1964;Roe, 1965).

The iron sorbitol-citric acid complex marketed under the name of " Jectofer' has hitherto received less attention from the point of view of carcinogenicitv.

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