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PubMed1992

Clinical consequences of Thorotrast in a long-term survivor.

Thorotrast, a colloidal suspension of 252Th dioxide, was widely used as a radiographic contrast medium for more than 25 y after its clinical practice introduction in 1930. Its excellence as a contrast medium was ultimately eclipsed by its long-term associated morbidities, and its use essentially ended by 1954. This case history presents the clinical events in the last 10 y of life in a patient injected with Thorotrast in 1953. This patient developed three previously described Thorotrast-associated morbidities: pneumococcus sepsis due to functional asplenia and reticuloendothelial system blockade, an enlarging Thorotrastoma (inflammatory mass) at the injection site, and a fatal blood dyscrasia. In addition, she developed three clinical syndromes where a Thorotrast association may exist. She suffered from severe spinal column osteoarthritis and vertebral collapse. An abnormal bone-density measurement implies the presence of radiodense radioactive thorium or its degradation products as potentially responsible. She had evidence of chronic immune system disregulation with immunoglobulin excess, auto antibodies, and cell-mediated immunity deficiency. This condition is similar to that found in patients infected with human immunodeficiency virus and may suggest a shared etiology in reticuloendothelial system damage. Lastly, she developed dense bilateral cataracts. This case history illustrates the temporal relationship of a variety of symptoms. Discussion is directed at review of previous data and support for new associations.

Aged↗
PubMed1983

Recent results of the German Thorotrast study--dose relevant physical and biological properties of Thorotrast equivalent colloids.

As a prerequisite for quantifying the non-radiation effect of Thorotrast, nonradioactive and radioactive aquasols with identical physicochemical properties and with biophysical behavior comparable to that of Thorotrast were developed and produced for a second long-term animal experiment. Comparative investigations with hafnium and zirconium (zirconotrast) dioxide aquasols showed the latter to be most appropriate considering the size of both the dispersoids and the aggregates in the liver tissue. The average particle diameters of ThO2, ZrO2 and HfO2 proved to be values of 9.3 nm, 15 nm and 45 nm, respectively. The size of the aggregates shows a slight dependence on the applied amount but no dependence on the duration of body burden of the colloid. The aggregate diameters in the 600 microliters group turned out to be 9.6 microns, 14.4 microns and 5.3 microns, respectively. Radioactive zirconotrast was prepared by radiochemical incorporation of 230Th and 228Th at dose rates which produce accumulated doses in the liver of rats equivalent to those of commercial 230Th enriched Thorotrast after 1.5 yr. Five different colloids were prepared with alpha-energy emission rates increased by factors of 1, 2.5, 5, 10 and 25 compared to Thorotrast and then injected into rats.

Animals↗
PubMed2000

Ras gene mutations in vinyl chloride-induced liver tumours are carcinogen-specific but vary with cell type and species.

Previous studies have shown that a high proportion (5/6) of human liver angiosarcomas (ASL) associated with exposure to vinyl chloride (VC) contains a GC-->AT mutation at the Ki-ras codon 13. This mutation, however, has not been found in 5 ASL or 2 hepatocellular carcinomas (HCC) induced in rats by VC. These 2 HCC did contain a mutation at codon 61 of the Ha-ras gene. In order to extend this study and further explore the mechanisms of tumour induction, an additional 6 ASL and 6 HCC induced in rats by VC were analysed for ras gene point mutations, as well as 10 rat and 10 murine ASL induced by vinyl fluoride (VF), and 5 ASL, 6 Kupffer cell sarcomas, 4 HCC and 2 cholangiocellular carcinomas induced by Thorotrast in rats. Tumour DNA was analysed by PCR-SSCP and direct sequencing. None of the rodent ASL contained a mutation at codon 13 of the Ki-ras gene showing that the ras gene mutational pattern is species-specific. The CAA-->CTA mutation, previously found at codon 61 of the Ha-ras gene in rat HCC, was observed in 5 further VC-induced HCC but was not detected in the Thorotrast-induced HCC, suggesting carcinogen-specificity. This mutation was also absent in VC-induced ASL, which supports the cell-specificity of the ras mutational pattern in chemically induced tumours. No predominant mutation was detected in VF- and Thorotrast-induced tumours. Thus, a given mutation in a tumour may be carcinogen-specific but also depend on the species and the cell type.

Animals↗
PubMed2000

Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene.

Gap junctional intercellular communication is often impaired in cancers, and the genes which encode the connexin gap junction proteins are considered to be tumor-suppressor genes. In this study, we analyzed the presence of mutations in the connexin 37 (Cx37) gene in 22 human hepatic angiosarcomas, 6 and 4 of which were associated with exposure to vinyl chloride and Thorotrast, respectively. The other 12 samples were from patients with no history of exposure to these 2 agents. In 9 samples, a proline (ACC) to serine (ACT) amino acid change in codon 319 was detected. However, DNA from non-tumorigenic tissue of the same patients also showed this amino acid change, suggesting that this is a polymorphism rather than a mutation. Subsequent analysis of 84 DNA samples from normal donors revealed the frequencies of Pro/Pro, Pro/Ser and Ser/Ser alleles to be 65.5%, 23.8% and 10.7%, respectively, while among the group of angiosarcoma patients the corresponding figures were 59.1%, 31.8% and 9. 1%, respectively. Thus, there was no correlation between the polymorphism at codon 319 and hepatic angiosarcoma occurrence. However, among the 6 cases of vinyl chloride-associated angiosarcoma, the percentages of the polymorphic alleles were 33.3%, 66.7% and 0%, respectively. While the number of samples was too small to allow us to conclude that the Ser319 allele in Cx37 predisposes to this rare type of human cancer, it may be noted that codon 319 is located at the cytoplasmic tail of Cx37, where most regulatory sequences reside, and that it could be a site of phosphorylation for some protein kinases, which may in turn affect the function of Cx37, including intercellular communication.

Carcinogens↗