A Comparison Between the Late Effects of Thorotrast and a Non-Radioactive Zirconium Hydroxide Sol in Mice

Abstract

IN a previous communication (Guimaraes and Lamerton, 1956) upon the late effects of Thorotrast administration in mice, it was suggested that the apparent carcinogenic effect of Thorotrast might be related in some way to its physical properties rather than to its purely radioactive properties. The object of the present investigation was to follow up this suggestion by employing a colloidal contrast medium which was similar to Thorotrast in its distribution and other properties but which was at the same time entirely non-radioactive, and to compare the resulting tissue damage and tumour incidence.The ideal product for this purpose would be derived from a non-radioactive thorium isotope, but since no such isotope is known, attention was turned to the other elements in Group IV A of the Periodic Table, and in particular to hafnium, the closest analogue of thorium. Our attempts to produce a concentrated hafnium oxide sol were only partially successful. Owing to the relative scarcity and cost of hafnium salts further work was carried out using zirconium salts since these are virtually identical from the point of view of their chemical properties.A concentrated zirconium oxide sol was prepared (hereafter called Zirconotrast) and this material was well tolerated when given to mice by intravenous injection. This contrasts with a report (Shapiro, 1955) that whereas soluble zirconium salts are relatively non-toxic, a colloidal zirconium oxide preparation consistently caused death from pulmonary infarction when given intravenously to rabbits and guinea-pigs. In view of this finding we thought it worth while to include details of our method of preparing Zirconotrast.The present article concerns the results of a comparative study of the effects resulting from intravenous injection of Thorotrast and Zirconotrast into small groups of mice which were observed radiologically over a period of time and finally killed 8-17 months later for histological studies. METHODS ZirconotrastThe preparative scheme conisists essentially of three parts. First, formation of a dilute zirconium oxide sol by hydrolysis at the boiling point of a solution of zirconyl chloride (Robinson and Ayres, 1933). Second, neutralisation of the acid sol without the formation of locally high pHs which cause gelling, and third, concentration of the sol after the addition of dextrin as a stabilising agent. Dextrin was chosen since this is used in the preparation of Thorotrast (Zellmann, 1933).Twenty g. of z rconium oxychloride (ZrOCl2 . 8 H20) are dissolved in about