Mortality after Cerebral Angiography with or without Radioactive Thorotrast: An International Cohort of 3,143 Two-Year Survivors

Abstract

There are few studies on the long-term sequelae of radionuclides ingested or injected into the human body. Patients exposed to radioactive Thorotrast in the 1930s through the early 1950s provide a singular opportunity, since the administration of this radiographic contrast agent resulted in continuous exposure to alpha particles throughout life at a low dose rate. We evaluated cause-specific mortality among an international cohort of 3,143 patients injected during cerebral angiography with either Thorotrast (n = 1,736) or a similar but nonradioactive agent (n = 1,407) and who survived 2 or more years. Standardized mortality ratios (SMRs) for Thorotrast and comparison patients were calculated, and relative risks (RR), adjusted for population, age and sex, were obtained by multivariate statistical modeling. Most patients were followed until death, with only 94 (5.4%) of the Thorotrast patients known to be alive at the closure of the study. All-cause mortality (n = 1,599 deaths) was significantly elevated among Thorotrast subjects [RR 1.7; 95% confidence interval (CI) 1.5-1.8]. Significantly increased relative risks were found for several categories, including cancer (RR 2.8), benign and unspecified tumors (RR 1.5), benign blood diseases (RR 7.1), and benign liver disorders (RR 6.5). Nonsignificant increases were seen for respiratory disease (RR 1.4) and other types of digestive disease (RR 1.6). The relative risk due to all causes increased steadily after angiography to reach a threefold RR at 40 or more years (P < 0.001). Excess cancer deaths were observed for each decade after Thorotrast injection, even after 50 years (SMR 8.6; P < 0.05). Increasing cumulative dose of radiation was directly associated with death due to all causes combined, cancer, respiratory disease, benign liver disease, and other types of digestive disease. Our study confirms the relationship between Thorotrast and increased mortality due to cancer, benign liver disease, and benign hematological disease, and suggests a possible relationship with respiratory disorders and other types of digestive disease. The cumulative excess risk of cancer death remained high up to 50 years after injection with >20 ml Thorotrast and approached 50%.

Radiation and circulatory disease

“…Among the largest of these is a cohort of US, Danish and Swedish patients [52] which reported marginally significant elevations in risk from cardiac disease [for males RR = 1.0 (95% CI 0.8, 1.2), for females RR =1.2 (95% CI 1.0, 1.6), total RR = 1.1 (95% CI 0.9, 1.3)) although for CeVD there was more substantial (and statistically significant) elevations (for males RR = 1.4 (95% CI 1.0, 2.0), for females RR =1.8 (95% CI 1.3, 2.5), total RR = 1.6 (95% CI 1.2, 2.0)]. In a somewhat smaller Portuguese series risks of circulatory disease were not significantly elevated (for males RR = 1.11 (95% CI 0.76, 1.62), for females RR =0.97 (95% CI 0.53, 7.70), total RR = 1.08 (95% CI 0.79, 1.46)) [53].…”

“…In a somewhat smaller Portuguese series risks of circulatory disease were not significantly elevated (for males RR = 1.11 (95% CI 0.76, 1.62), for females RR =0.97 (95% CI 0.53, 7.70), total RR = 1.08 (95% CI 0.79, 1.46)) [53]. The findings in relation to CeVD in the international series should be treated with caution, since a frequent reason for use of Thorotrast was investigation of cerebral vascular anomalies, as pointed out by Travis et al [52]. Thorotrast deposits α-particle dose primarily to the liver.…”

Ionizing radiation: a risk factor for mesothelioma

“…The bronchial epithelium is also exposed to a-particles from a 232 Th decay-product gaseous radionuclide ( 220 Rn) [21]. Thorotrast exposure has been noted to increase the risk of malignant mesothelioma (mostly of the pleura and peritoneum) in cohorts of Thorotrast-exposed patients in Denmark, Sweden, Japan, Germany, and the US (Table 2) [21][22][23][24][25].…”

The cancer epidemiology of radiation

“…About 5500 patients, mostly from Germany, have been followed and over 90% of them have died. A dramatic elevation (up to 100-fold or more) of liver cancer has been found and leukaemia is also in excess (IARC, 2001;NCRP, 2001a), and the excesses persist half a century after administration (Travis et al, 2001(Travis et al, , 2003a.…”