241Am removal by DTPA vs. occurrence of skeletal malignancy.

Beagle dogs injected with 241Am and treated subsequently with DTPA exhibited a reduced occurrence of skeletal malignancies and increased lifespans when compared to corresponding untreated animals also given 241Am. Whereas 92% of dogs given about 11 kBq 241Am kg(-1) and not treated with DTPA developed bone cancer (skeletal dose about 5.9 Gy), skeletal malignancy was seen in only 40% and 27%, respectively, among two groups of DTPA-treated animals injected with 11 kBq kg(-1) (doses of 5.7 and 1.7 Gy). The median lifespan among the untreated dogs was 1,728 d, but the median lifespans in the DTPA-treated groups were 2,478 and 3,654 d, respectively. Untreated dogs with a skeletal dose averaging about 2 Gy had 53% bone cancer occurrence and a median lifespan of 3,227 d. These data did not enable us to address the question of whether the reduction in cancer occurrence was proportional to, greater than, or less than the reduction in skeletal dose, but the third possibility seems unlikely.

Relationship of natural incidence and radiosensitivity for bone cancer in dogs.

A comparison of the risk coefficients for 239Pu- or 226Ra-induced bone cancer in two canine breeds, one with a relatively low (beagle) and the other with a very high (St. Bernard) natural incidence, indicated only slightly higher risk in the giant breed. The differences in risk for skeletal malignancy in 239Pu and 226Ra dogs were nonsignificant (p > 0.05). Likewise, the values of the 239Pu:226Ra "toxicity ratios" for these respective breeds, using bone cancer as the endpoint, were not significantly different at the 0.05 level. The anatomical distribution of the radiation-induced bone tumors tended to be a function of both the bone mass and the skeletal distribution of the radionuclide, not the site of predilection for naturally occurring bone neoplasia. Although the etiology of the higher natural incidence of bone cancer in the St. Bernard was not determined, several possible factors, including a higher osteoblastic activity level in the St. Bernards, are presented. These data suggest that making extrapolations of radiation-induced bone cancer risk from animals to humans is valid.

Fission fragment relative biological effectiveness for liver tumor induction.

The risk coefficients for liver tumors as derived from 60 beagles with body burdens of 249Cf or 252Cf were used to determine the relative biological effectiveness of fission fragments relative to alpha particles. For liver malignancies the relative biological effectiveness was calculated to be about 2 +/- 3. The estimate based on the combined benign and malignant liver tumors was about 7, with a proportionately larger standard deviation of about +/- 14. Although the confidence intervals were wide, it is possible that the relative biological effectiveness of fission fragments relative to alpha particles, using liver neoplasia as the endpoint, is greater than 1.0 as compared to a value only slightly above zero when bone cancer was the lesion of interest.

Liver cancer induction by 239Pu, 241Am, and thorotrast in the grasshopper mouse, Onychomys leukogaster.

Forty young adult grasshopper mice (Onychomys leukogaster) of both genders were injected with either 129 or 44 kBq kg-1 of monomeric 239Pu and were maintained for lifetime observation. Average liver doses to death (mean times +/- standard deviation (SD) from injection to death = 405 +/- 133 and 756 +/- 189 d) were calculated as approximately 16 and 9 Gy, respectively. These animals developed a total of 18 primary liver tumors (neoplasms, malignant, and benign). Comparison of these mice to a previously published study involving 49 control animals of the same species, 70 mice given 241Am, and 73 given Thorotrast, indicated that the liver cancer induction of Thorotrast can be attributed almost exclusively to the effects of the radioactivity and not to its nonradiation properties. This suggests that projected risks of liver cancer induction from 239Pu, 241Am, or other liver-seeking actinides in humans probably can be estimated from the liver cancer experience in Thorotrast patients using the calculated radiation doses to liver. For this species, the linear risk coefficient for induction of liver neoplasia (percent of mice with liver tumor) by 241Am or Thorotrast was estimated to be about 14.6 +/- 5.4 times the average liver dose (in Gy) for groups of animals with average liver doses of 5 Gy or less. The lowest average liver dose among groups of these mice given 239Pu was about 9 Gy, the dose was not in the linear range, and it was too high to yield reliable results for determining a risk coefficient for low dose irradiation. However, the estimates for a risk coefficient were similar for the plutonium and americium mice with liver doses of approximately 9 Gy or 16 Gy.

Comprehensive evaluation of a Thorotrast patient: an overview.

For several decades, thousands of people received Thorotrast during the course of angiography and other radiologic procedures. Eventually, as the hazards of this radioactive, radiographic contrast agent became apparent, research was initiated to further evaluate its associated adverse effects. In 1988 and 1989, Charles W. Mays, together with colleagues at a variety of sites, developed a detailed protocol for the comprehensive postmortem evaluation of one subject who had been administered Thorotrast 36 y previously. This case represents the first holistic approach to the analysis of Thorotrast in a whole body, simultaneously assembling clinical and autopsy findings with dosimetric, radiochemical, autoradiographic, and molecular evaluations.

External gamma-ray counting of selected tissues from a Thorotrast patient.

Results of gamma-ray measurements of selected tissues from a patient who was injected with Thorotrast almost 36 y ago are reported. The purposes of this study were: 1) to determine the relative tissue distribution and activities of specific radionuclides in the 232Th decay chain, specifically 228Ra (as measured by 228Ac), 212Pb, and 224Ra (measured directly and as measured by 212Pb), and 2) to evaluate the level of radioactive disequilibrium among the daughter products. The spleen and liver had the highest concentrations of radioactivity. Bone also appears to be a long-term sink for 232Th daughter products based on estimates from a small portion of one rib. Larynx and esophagus contained measurable activity, which may have been due to their proximity to the "Thorotrastoma." Radioactivity in the remaining measured tissues were low, as expected. Secular equilibrium could be demonstrated in bone, pancreas, larynx, esophagus, and breast. Significant disequilibrium was observed for spleen, liver, kidney, and red blood cells. Radioactivity measurements reported here will be useful in estimating radiation doses to selected tissues. Such dose estimates are valuable in refining current risk estimates (e.g., liver) and in identifying tissues at risk for further epidemiologic studies. These results, while consistent with other published studies, should be interpreted with caution since measurements were made on only one patient.

The distribution of Thorotrast in human bone marrow: a case report.

Samples of bone containing cellular and fatty bone marrow were removed at autopsy from the body of a woman who, following an automobile accident, had been injected with approximately 25 mL of the radiographic contrast medium Thorotrast. The woman survived for 36 y after the accident and died at age 72 y following bone marrow failure. The samples were analyzed to determine their thorium content by x-ray fluorescence and by image analysis. In addition, Thorotrast was visualized in the different bones examined by light microscopy and by backscattered electron imaging with a scanning electron microscope. The results showed Thorotrast to be largely restricted to areas of cellular bone marrow. In such regions, Thorotrast was present throughout the marrow tissue and was also concentrated within cells that were commonly aggregated within focalized areas of the marrow. Overall the results suggest a rather uniform pattern of Thorotrast uptake by the red bone marrow at different skeletal sites. Significant deposits of Thorotrast were not found in fatty yellow marrow. We conclude that Thorotrast-derived risk estimates for human leukemia following high LET, alpha irradiation may be used for calculating the risks of alpha exposure, but with caution.

Promotion of radiation-induced liver neoplasia by ethanol.

The risk of americium-induced liver cancer in beagle dogs that received long-term dietary ethanol was two to three times that of their nonalcoholic cohorts, even though the radionuclide retention time in hepatic tissue was shortened by the alcohol treatment. Liver malignancies did not occur in the ethanol-treated, nonirradiated controls. An ethanol-induced tumor-promoting effect was not observed in organs or tissues other than the liver.

Plutonium- or americium-induced liver tumors and lesions in beagles.

Plutonium-239 or 241Am administered intravenously in the monomeric citrate form was initially deposited in beagle livers principally in the hepatocytes and to a much lesser extent in the sinusoidal macrophages and connective tissues. The initial distribution was quite uniform throughout the hepatic parenchyma; however, at later postinjection intervals, depending on the amount of injected activity, the liver burden became increasingly more focal due to: (1) a progressive shift of the radionuclide from the hepatic epithelium to the macrophages; (2) the movement of such macrophages toward the portal or central regions of the lobule; and (3) the displacement of the older more radioactive tissue by regenerating hepatocytes, which generally have a much lower radionuclide content. The hepatic lesions produced by Pu or Am included: (1) necrosis and degenerative changes that were clinically serious or fatal in some of the animals injected with approximately 107 kBq kg-1; (2) marked structural and circulatory changes resulting from necrosis and focal hepatocyte hyperplasia; (3) a significant incidence of both benign and malignant primary liver tumors. In both Pu- and Am-treated dogs, the most frequently appearing neoplasm was the bile duct adenoma, followed by the cholangiocarcinoma. The most obvious difference between Pu- and Am-induced liver neoplasia was the greater frequency of fibrosarcomas and mast cell sarcomas in the Am-treated groups. Hepatomas were of relatively low frequency in animals with Pu or Am burdens. Although the incidence of bone neoplasia was high among the dogs in these studies, the risk of liver tumors, especially in the Am-treated animals, exceeded that of the skeleton in some of the lower dosage levels where the survival times were long. A risk coefficient of approximately 1200 fatal liver malignancies (10(4) beagle Gy)-1, derived from the dosage groups with long survival times, was calculated for combined Pu and Am animals. The prominence of the liver syndromes in beagles with burdens of Pu or Am indicates that humans with body burdens of 239Pu, 241Am, or other actinide elements may be at risk from radiation effects in the liver, including neoplasia development.

Radium-226 dose to a boy from playing on mill tailings.

Two boys born in September 1949 played on uranium mill tailings from about ages 8 to 12. One of these boys was diagnosed as having leukemia at age 15.5. The 226Ra body burden of the survivor was measured at age 38. The whole-body 226Ra content measured by counting in vivo was 0 +/- 17 Bq and independently by Rn breath analysis as 4.3 +/- 2.1 Bq. At the same time, a control subject with no known exposure to 226Ra, matched in age, height, and weight, was also measured. The whole-body content was estimated as 4 +/- 15 Bq and independently by Rn breath analysis as 5.5 +/- 3.7 Bq. The body burden of the control subject was not significantly different from that of the exposed person. The radiation dose to the marrow-free skeleton assuming a constant 226Ra:Ca ratio since birth was 0.49 and 1.33 mGy at ages 14 and 38, respectively. The radiation dose to the marrow-free skeleton assuming 226Ra intake only between ages 8 to 12 was 1.4 and 2.8 mGy at ages 14 and 38, respectively. The best estimate is the mean of these two estimates: 0.9 and 2.1 mGy at ages 14 and 38, respectively. The alpha-particle dose to the red marrow from 226Ra and its decay products was 0.05 mGy at age 14 and 0.10 mGy at age 38. Since no excess was found for the radium dial painters whose doses were much higher, the induction of leukemia by doses of this magnitude would seem quite unlikely.

The reverse protraction factor in the induction of bone sarcomas in radium-224 patients.

More than 50 bone sarcomas have occurred among a collective of about 800 patients who had been injected in Germany after World War II with large activities of radium-224 for the intended treatment of bone tuberculosis and ankylosing spondylitis. In an earlier analysis [H. Spiess and C. W. Mays, in Radiation Carcinogenesis. (C. L. Sanders et al., Eds.) pp. 437-450. USAEC Symposium Series 29, CONF-720505, 1973] it was concluded that, at equal mean absorbed doses in the skeleton, patients with longer exposure time had a higher incidence of bone sarcomas. The previous analysis was based on approximations; in particular, it did not account for the varying times at risk of the individual patients. In view of the implications of a reverse protraction factor for basic considerations in radiation protection, the need was therefore felt to reevaluate the data from the continued follow-up by more rigorous statistical methods. A first step of the analysis demonstrates the existence of the reverse dose-rate effect in terms of a suitably constructed rank-order test. In a second step of the analysis it is concluded that the data are consistent with a linear no-threshold dose dependence under the condition of constant exposure time, while there is a steeper than linear dependence on dose when the exposure times increase proportionally to dose. A maximum likelihood fit of the data is then performed in terms of a proportional hazards model that includes the individual parameters, dose, treatment duration, and age at treatment. The fit indicates proportionality of the tumor rates to mean skeletal dose with an added factor (1 + 0.18.tau), where tau is the treatment time in months. This indicates that a protraction of the injections over 15 months instead of 5 months doubles the risk of bone sarcoma.

Kidney disease in beagles injected with polonium-210.

An unusually high incidence of kidney disease (tubular degeneration and necrosis with fibrous replacement) was observed among 24 beagles injected at about 5 years of age with 116 or 329 kBq 226Ra kg-1 but not among an additional 10 beagles given about 39 kBq 226Ra kg-1. This 226Ra solution also contained 210Pb, 210Bi, and 210Po. To determine whether the kidney disease was related to the radiation from 226Ra and its short-lived progeny or to the alpha radiation from 210Po, 2 beagles about 7 years of age were injected with 451 kBq 226Ra kg-1 of 210Po citrate. Measurements of polonium retention in the kidneys of 4 additional beagles given 210Bi citrate enabled us to model the retention of these emitters in the dog kidney and to estimate the kidney dose from the alpha radiation of 210Po following injection of either 226Ra + 210Bi + 210Po or 210Po only. Autoradiography revealed that almost equal concentrations of 210Po were in the tubular epithelium and/or its basement membrane and in the glomeruli, but very little of the 210Bi deposited in kidney tissue was present in the glomeruli. Radiation damage to the kidneys similar to that observed previously in beagles given 226Ra solutions that also contained 210Bi and 210Po was seen among the beagles given 210Po but not in the dogs given purified 226Ra. The analysis of these data indicated that the relatively high incidence of kidney disease among the mature beagles injected with 226Ra and its accompanying 210Bi and 210Po resulted from alpha irradiation of the kidneys by the substantial amount of 210Po that was in the injection solution.

Fission fragment RBE for bone sarcoma induction.

Thirty beagles and 277 mice were injected with 249Cf, and 30 beagles and 274 mice were injected with 252Cf. The skeletal dose (in Gy) from 252Cf was about half from fission fragments and half from alpha particles, whereas 249Cf emits alpha particles in 100% of its transformations. Bone sarcomas (mostly osteosarcomas) were the main radiation-induced cancer. The relative biological effectiveness (RBE) of fission fragment dose relative to alpha-particle dose for bone sarcoma induction was calculated from the ratio of 249Cf/252Cf doses at equal times to bone sarcoma in (a) beagles and (b) mice, and (c) from the ratio 252Cf/249Cf risk coefficients in mice. The average RBE +/- standard deviation of the three evaluations was 0.1 +/- 0.1. The very low RBE for bone sarcomas is supported by the data of A. L. Batchelor, T. J. Jenner, and L. M. Cobb [Phys. Med. Biol. 28, 475-483 (1983)] for lung cancer induction in rats and by that of A. L. Brooks, J. A. Mewhinney, and R. O. McClellan [Health Phys. 22, 701-706 (1972)] for producing chromosome aberrations in the liver cells of Chinese hamsters. The low effectiveness of fission fragments relative to alpha particles, per gray of absorbed dose, is ascribed primarily to the much larger number of cells traversed by the alpha particles. Consideration might be given to decreasing the quality factor of fission fragments by an order of magnitude below that for alpha particles.

[Radiation cataract following injection of radium 224]. / Strahlenkatarakt nach Injektion von Radium-224.

The Spiess Ra-224 series ist presented. It consists of 900 patients who were repeatedly injected intravenously with known dosages (microCi/kg) of the alpha-particle emitter Ra-224 for the intended treatment of tuberculosis and ankylosing spondylitis between 1943 and 1952/1965. 682 patients had been treated as adults after the age of 20 years, and 218 hat been injected as "juveniles" aged 20 years or younger. All 218 "juvenile" patients except one who had suffered from ankylosing spondylitis, had been injected for tuberculosis. Among the 218 patients 91 have died leaving 127 alive. Of the "juvenile" patients 9 were examined at the Eye Hospital of the Universität München including histopathology of an autopsy eye in one case. Of the 9 patients 8 proved to have some cataracts and 2 appeared morphologically similar to age-related cataract. In 6 patients there was a posterior subcapsular cataract which was a dense round plaque with a clear subcapsular zone of about 0.5 to 0.6 mm. This clear zone corresponds well to newly deposited lens fibres during the period of about 40 years from treatment to examination.

Alpha-particle-induced cancer in humans.

Updated information is given on alpha-particle-induced cancer in persons internally exposed to 222Rn progeny, Thorotrast, long-lived 226Ra and 228Ra, and short-lived 224Ra. The lung cancer risk to persons breathing 222Rn progeny in the indoor air of offices, schools, and homes is of increasing concern. About half of the recent deaths among the German Thorotrast patients have been from liver cancer. Animal studies indicate that the liver cancer risk from Thorotrast is mainly from its radioactivity and that the risk coefficient for the Thorotrast patients can be used provisionally for other alpha emitters in the human liver. Six skeletal cancers have occurred in persons with average skeletal doses between 0.85 and 11.8 Gy from 226Ra and 228Ra. In the low-dose German 224Ra patients, two skeletal sarcomas have occurred at about 0.7 Gy compared to about six cases predicted by results from 224Ra patients at higher doses. The minimal appearance time for radiation-induced bone sarcomas in humans is about 4 y. Following brief irradiation, the vast majority of induced bone sarcomas are expressed by about 30 y. Recent evidence against the "practical threshold" hypothesis is given. With the downward revision of neutron doses to the atomic-bomb survivors, the follow-up of persons exposed to alpha particles may be the best opportunity to evaluate directly the effects of high LET radiation on humans.

Stochastic and nonstochastic concepts: is revision needed?

Stochastic effects of radiation, specifically cancers and hereditary defects, were defined in ICRP Publication 26 as having two constraints: No threshold in dose and no change in the severity of the induced effect with increasing dose. Nonstochastic effects were narrowly restricted to be the exact opposite, namely having a threshold and changing in severity with dose. Initially, these definitions seemed logical. It now appears, however, that no threshold may exist for the reduction of intelligence by irradiation of the fetal brain at critical ages. Otake et al. (in press) have shown, for Japanese A-bomb survivors irradiated at all fetal ages, that the average intelligence quotients decreased approximately linearly without threshold at 11 +/- 2 IQ points per Gy of fetal dose, based on either the T65D or the DS86 dosimetry systems. The decrease in intelligence quotient (IQ) was most severe in those irradiated at fetal ages of 8-25 wk. There is good reason to suspect that additional "nonstochastic" effects, such as cataracts, impaired fertility, and growth retardation might have a nonthreshold component to their dose-response at least in highly susceptible individuals. It was formerly believed that stochastic effects could be limited to acceptable levels, while nonstochastic effects could be completely prevented. However, to prevent entirely the special class of nonstochastic effects that have no true threshold, zero dose would be required. Zero dose is an unrealistic limit that would prevent most of the beneficial uses of radiation. Therefore, the realistic goal of radiation protection should be to limit all radiation effects to acceptable levels.

An epidemiological assessment of lens opacifications that impaired vision in patients injected with radium-224.

The incidence of lens opacifications that impaired vision (cataract) was analyzed among 831 patients who were injected with known dosages of 224Ra in Germany shortly after World War II. The dependence of the incidence on dosage, i.e., injected activity per unit body weight, and on time after treatment was determined. The observations are equally consistent with proportionality of the incidence of cataract to the square of dosage or with a linear dependence beyond a threshold of 0.5 MBq/kg. The possibility of a linear dependence without threshold was strongly rejected (P less than 0.001). The analysis of temporal dependences yielded a component that was correlated with the injected amount of 224Ra and a component that was uncorrelated. The former was inferred by a maximum likelihood analysis to increase approximately as the square of the time after treatment. The component unrelated to the treatment was found to increase steeply with age and to become dominant within the collective of patients between age 50 and 60. The relative magnitudes of the two components were such that a fraction of 55 to 60% of the total of 58 cataracts had to be ascribed to the dose-related incidence. Impaired vision due to cataract was diagnosed before age 54 in 25 cases. In terms of injected activity per unit body weight no dependence of the sensitivity on age was found; specifically there was no indication of a faster occurrence of the treatment-related cataracts in patients treated at older ages.

Time and dose dependency of bone-sarcomas in patients injected with radium-224.

The time course and dose dependency of the incidence of bone-sarcomas among 900 German patients treated with high doses of radium-224 is analysed in terms of a proportional hazards model with a log-normal dependency of time to tumor and a linear-quadratic dose relation. The deduced dose dependency agrees well with a previous analysis in terms of a non-parametric proportional hazards model, and confirms the temporal distribution which has been used in the Radioepidemiological Tables of NIH. However, the linear-quadratic dose-response model gives a risk estimate for low doses which is somewhat less than half that obtained under the assumption of linearity.

Cancer incidence and lifespan vs. alpha-particle dose in beagles.

Young adult beagles were injected with graded activities of 239Pu, 241Am, 228Th, 228Ra or 226Ra and observed throughout their lifespans. The vast majority of the dose was from alpha particles. The lifetime incidence of bone sarcoma increased with average skeletal dose, more or less linearly up to high incidence for 239Pu, 241Am, 228Th and 226Ra, but sigmoid fashion for 228Ra. Based on average skeletal dose, the toxicity of the emitters relative to 226Ra = 1.0 was 239Pu = 16.6 +/- 4.5, 241Am = 5.4 +/- 1.6, 228Th = 8.5 +/- 2.3 and 228Ra = 2.0 +/- 0.5. At the lowest doses, the average lifespans were 97% +/- 3% of that in the controls. If beneficial effects occurred, they may have been overwhelmed by the destructiveness of the densely ionizing alpha particles. A cell nucleus 5 micron in diameter receives a mean dose of about 1 Gy (100 rad) when traversed by a single alpha particle. We found no evidence that alpha-particle doses suppressed cancer or lengthened lifespan in beagles.