Toshiyuki Kumatori

Summary of entire Japanese thorotrast follow-up study: updated 1998.

Updated data from two series in a cancer mortality study for a total of 412 Japanese Thorotrast patients were combined. The rate ratio for all deaths of Thorotrast patients, compared to controls, started to increase after a latent period of 20 years after injection of Thorotrast. Rate ratios for liver cancer, liver cirrhosis, leukemia and lung cancer were 35.9, 6.9, 12.5 and 2.0 times higher, respectively, than those for controls.

1998 results of the first series of follow-up studies on Japanese thorotrast patients and their relationships to an autopsy series

The 1998 survey of the first series of epidemiological studies of Japanese Thorotrast patients revealed that 18 (6.9%) were alive and 244 (93.1%) had died among 262 war-wounded veterans to whom Thorotrast had been administered intravascularly. Of 1,630 age- and sex-matched controls, 525 (32.2%) were alive and 1,105 (67.8%) had died. These results indicated a shortening of the life span in patients who had received Thorotrast compared to their controls. Of the patients in the Thorotrast group, the main causes of death were liver malignancies (79, 30.2%), liver cirrhosis (20, 7.6%), blood diseases (9, 3.4%), and cancers of the extrahepatic bile duct (5, 1.9%). Statistical analyses by the chi(2) test and estimation of the relative risk (risk ratio) showed that the incidences of these disorders were significantly higher in the Thorotrast group than in the controls. In the 54-year period from 1945 to 1998, our autopsy series was enlarged to include 398 individuals: 386 injected with Thorotrast intravascularly and 12 injected by other routes. Results of analyses of the 386 autopsy cases given Thorotrast intravascularly were as follows: 263 cases (68.1%) of liver malignancies, 28 cases (7.3%) of liver cirrhosis, 29 cases (7.5%) of blood diseases, 16 cases (4.1%) of lung cancer, 4 cases (1.0%) of malignant peritoneal tumors, 2 cases (0.5%) of bone sarcomas, and 1 case (0.3%) of hemangiosarcoma of the spleen. The relative risks of liver malignancies, blood diseases, bone sarcomas, malignant peritoneal tumors, and hemangiosarcoma of the spleen manifested significantly higher ratios in the Thorotrast autopsy cases (ratio of proportion) than in the autopsy control cases. Histological studies of these autopsied cases revealed that Thorotrast-induced liver malignancies showed remarkable differences in the proportions of histological types of tumors from those of non-Thorotrast liver malignancies since 1975. However, in this survey, we noted a remarkable increase in the incidence of liver malignancy of multiple histological types compared to that in histological controls. Based on the results of our 1998 survey, we estimated attributable risks of Thorotrast-inducedliver malignancies and blood diseases in the life span. Results showed 523 liver malignancies per 10(4) person Gy and 150 blood diseases per 10(4) person Gy for Japanese male Thorotrast carriers (wasted dose 10 years).

Thorotrast dosimetric study in Japan

Abstract A dosimetric study of Thorotrast is described. Steady state activity ratios and self-absorptions of α-particles in the 232 ThO 2 aggregates were determined by α- and γ-ray spectrometry. By using these results, the absorbed doses in 39 autopsy cases were estimated and compared with German data. For hepatic malignant tumors, the mean absorbed dose in the liver was estimated to be 939 rad for 23 cases.

A nine-year cytogenetic follow-up of a patient injected with Thorotrast.

SummaryChromosomal abnormalities in the peripheral lymphocytes of a Thorotrast case were followed up for almost nine years during which four direct bone marrow observations were made. Chromosomal abnormalities, both Cu type (dicentrics, rings, and acentric fragments) and Cs type (reciprocal translocations, inversions, deletions, duplications, and others), were observed with an average frequency of about 7.5% and 8%, respectively. The frequency of chromosomal abnormalities showed no significant changes during the nine years. Formation of clones of cells with identical chromosomal abnormalities was observed both in bone marrow and peripheral lymphocytes. There were clones common to myeloid and lymphoid cell series, which may be regarded as evidence for the presence of pluripotent stem cells in man. One such common clone had a translocation involving chromosomes 2 and 22. Banding analysis revealed a break in chromosome 22 at the q12 or q12/13 band interface. The frequency of the clone remained fairly constant within 5% for several years and the patient showed no indication of leukemia or any other blood disease. The finding seems to suggest a genetic factor relating to the development of chronic myelocytic leukemia (CML), which generally shows the Ph1 chromosome resulting from a translocation of chromosome 22 with the break at the q11 or q11/12 band interface. The increase in the number of cells lacking the Y chromosome was observed in our final bone marrow sample, but the phenomenon may be attributed to the age of the patient rather than to the direct effect of radiation. Results of the cytogenetic follow-up study seem to indicate the importance of studies in this direction for a better understanding of radiation effects on human beings.

Chromosome aberrations in bone marrow cells from Japanese patients with thorotrastosis.

Exposure of bone marrow cells to alpha-particle radiation causes various types of chromosome abnormalities and hematological malignancies. We performed chromosome analysis of hematopoietic stem cells from the bone marrow of 52 Japanese patients with thorotrastosis and 21 age-matched controls. The frequency of cells with stable chromosome abnormalities was significantly higher in the patients with thorotrastosis. Further studies found 14 clonal chromosome aberrations in cells from 11 patients (21.2%); clones observed in the cells from 2 of these patients had high frequencies of chromosome abnormalities. In one case, 68 to 100% of the cells analyzed had a large partial loss in the short arm of chromosome 1 and a translocation between the short arms of chromosomes 2 and 3 [46,XY,1p-,t(2p+;3p-)]. The cells from the other patient contained a clone with partial loss of both the short and long arms of chromosome 5 (46,XX,5p-,5q-). The frequency of this clone has been constant for the last 15 years (6-24%). We also analyzed bone marrow mononuclear cells from 17 of the patients for mutations of the TP53 tumor suppressor gene (formerly known as p53). However, no mutation was found in any of the cells, including those from the 2 patients with abnormal clones. Moreover, repeated medical examinations showed no evidence of leukemia or myelodysplasia in these patients. Our study suggests that exposure of bone marrow cells to alpha-particle radiation may induce clonal chromosomal aberrations at a high frequency.