1969. Argonne, Ill.: 2]exp(-1.1 10-3 It has also been used for internal radiation therapy. Mays et al.47 showed that mean survival time increased with decreasing dose in beagles that had contracted osteosarcoma following radionuclide injection. In general, the data from humans suffice to establish radium retention in the bone volume compartment. Each group consisted of about 90% males. He used the same assumptions about linear energy transfer as Littman et al. Radiogenic tumors in the radium and mesothorium cases studied at M.I.T. Current efforts focus on the determination of risk, as a function of time and exposure, with emphasis on the low exposure levels where there is the greatest quantitative uncertainty. This large difference has prompted theoretical investigations of the time dependence of hotspot dose rate and speculations on the relative importance of hot-spot and diffuse components of the radioactivity distribution for tumor induction. For comparison with the values given previously for juveniles and adults separately, this is 2.0% incidence per 100 rad, which is somewhat higher than either of the previous values. i = 0.5 Ci. There is a 14% probability that the expected number of tumors lies within the shaded region, defined by allowing the parameter value in Equation 416 to vary by 2 standard errors about the mean, and a 68% probability that it lies between the solid line that is nearly coincident with the upper boundary of the shaded region and the lower solid curve. Platinum and eosin, once thought to focus the uptake of 224Ra at sites of disease development, have been proven ineffective and are no longer used. The error bars on each point are a greater fraction of the value for the point here than in Figure 4-6, because the subdivision into dose groups has substantially reduced the number of subjects that contributes to each datum point. The cumulative tumor rate for juveniles and adults at 25 yr after injection, a time after which, it is now thought, no more tumors will occur, were merged into a single data set and fitted with a linear-quadratic exponential relationship: where R is the probability that a tumor will occur per person-gray and D why did jasmine richardson kill her family. Thus, most data analyses have presented cancer-risk information in terms of dose-response graphs or functions in which the dependent variable represents some measure of risk and the independent variable represents some measure of insult. The first explicit description of the structure of the sinus and mastoid mucosa in the radium literature is probably that of Hasterlik,22 who described it as "thin wisps of connective tissue," overlying which "is a single layer of epithelial cells. In contrast, mean skeletal dose changes with time, causing a gradual shift of cases between dose bands and confusing the intercomparison of data analyses carried out over a period of years. Why does radium accumulate in bones?-Radium accumulates in bones because radium essentially masks itself as calcium. For 224Ra the dose-response relationship gives the lifetime risk of bone cancer following an exposure of up to a few years' duration. All of these cases occurred among 293 women employed in Illinois; none were recorded among the employees from radium-dial plants in other states. 2 for D Spiess, H., H. Poppe, and H. Schoen. For the Mays and Lloyd44 function, this consists of setting the radiogenic risk equal to the total risk rather than to the total risk minus the natural risk. analysis are closely parallel and, as might be expected, lead to the same general conclusion that the response at low doses [where exp(-D) 1] is best described by a function that varies with the square of the absorbed dose. There were 11 bone marrow failures in the exposed group, and only 4 in the control group. If cell survival is an exponential function of alpha-particle dose in vivo as it is in vitro, then the survival adjacent to the typical hot spot, assuming the hot-spot-to-diffuse ratio of 7 derived above, would be the 7th power of the survival adjacent to the typical diffuse concentration. Based on a suggestion by Muller drawn from his observations of mice, Speiss and Mays86 reanalyzed their 224Ra data in an effort to determine whether there was an association between dose protraction and tumor yield. The linear functions obtained by Rowland et al.67 were: where D why does radium accumulate in bones?coastal plains climate. The average skeletal doses were later calculated to be 23,000 and 9,600 rad, respectively, which are rather substantial values. With smooth curves, this analysis defined envelopes for which there was a 9, 68, or 95% chance that the true tumor rate summed over the seven intake groups fell between the envelope boundaries when no tumors were observed. The third analysis was carried out by Raabe et. The intense deposition in haversian systems and other units of bone formation (Figure 4-3) that were undergoing mineralization at times of high radium specific activity in blood are called hot spots and have been studied quantitatively by several authors.2528,65,77. in the expiratory air . In a similar study on bone from a man who had been exposed to radium for 34 yr, they found concentration ratios in the range of 116.25 Rowland and Marshall65 reported the maximum hot-spot and average concentrations for 12 subjects. The British patients that Loutit described34 also may have experienced high radiation exposures; two were radiation chemists whose radium levels were reported to fall in the range of 0.3 to 0.5 Ci, both of whom probably had many years of occupational exposure to external radiation. It should be noted, however, that the early cases of Martland were all characterized by very high radium burdens. The distribution of tumor types is not likely to undergo major changes in the future; the group of 226,228Ra-exposed patients at high risk is dwindling due to the natural mortality of old age and the rate of tumor appearance among 224Ra-exposed patients has dropped to zero in recent years.46. Both bones are important for proper motion of the elbow and wrist joints, and both bones serve as important attachments to muscles of the upper extremity. Regardless of the dose variable used, the scatter diagram indicated a nonlinear dose-response relationship, a qualitative judgment that was substantiated by chi-squared tests of the linear functional form against the data. In simple terms, the main issue has been linear or nonlinear, threshold or nonthreshold. An approximate approach would be to take the population as a function of age and exposure and apply the dose-response relationship to each age group, taking into account the projected survival for that age group in the coming years. Raabe et al. They conclude from their microscopic measurements that the average density of radium in the portions of the pubic bone studied was about 35 times as great as that in the femur shaft; this subject developed a sarcoma in the ascending and descending rami of the os pubis. In spite of these differences, 224Ra has been found to be an efficient inducer of bone cancer. 1973. The data have been normalized to the frequency for osteosarcoma and limited to the three principal radiogenic types: osteosarcoma, chondrosarcoma, and fibrosarcoma. The poorest fit, and one that is unacceptable according to a chi-squared criterion, was obtained for I = C + D2. The loss is more rapid from soft than hard tissues, so there is a gradual shift in the distribution of body radium toward hard tissue, and ultimately, bone becomes the principal repository for radium in the body. Rowland64 published linear and dose-squared exponential relationships that provided good visual fits to the data. Littman et al.31 report a single value of 17 m for the lamina propria in a person who had contracted mastoid carcinoma. Decay series for radium-228, a beta-particle emitter, and radium-224, an alpha-particle emitter, showing the principal isotopes present, the primary radiations emitted (, , or both), and the half-lives (s = second, m = minute, h (more). To supplement these investigations of high-level exposure, a second study was initiated in 1971 and now includes more than 1,400 individuals treated with small doses of 224Ra for ankylosing spondylitis and more than 1,500 additional patients with ankylosing spondylitis treated with other forms of therapy who serve as controls. In summary, there are three studies of radium in drinking water, one of which found elevated "deaths due in any way to malignant neoplasm involving bone," the second found elevated incidences of bladder and lung cancer in males and lung and breast cancer in females, and the third found elevated rates of leukemia. Summary of virtually all available data for adult man. There is no assurance that women exposed at a greater age or that men would have yielded the same results. The authors concluded that bone tumors most likely arise from cells that are separated from the bone surface by fibrotic tissue and that have invaded the area at long times after the radium was acquired. 1959. Carcinomas of the frontal sinus and the tympanic bulla, a portion of the skull comparable to the mastoid region in humans, have appeared in beagles injected with radium isotopes and actinides. A., P. Isaacson, R. M. Hahne, and J. Kohler. In an additional group of 37 patients who were treated with radium by their personal physicians, two blood dyscrasias were found. For male bladder cancer only, the highest radium level produced a higher cancer rate than was observed for those consuming surface water. For nonstochastic effects, apparent threshold doses vary with health endpoint. Included in the above summary are four cases of chronic lymphocytic or chronic lymphatic leukemia. . Being an -emitting radionuclide, the radium irradiates bone surface-lining cells and has resulted in an excess incidence of osteogenic sarcomas. u = 10-5 + 1.6 10-5 If the survival adjacent to the diffuse component were 37%, as might occur for endosteal doses of 50 to 150 rad, the hot-spot survival would be 0.09%. u and I Their induction, therefore, cannot be influenced by dose from the airspace as can the induction of carcinomas by 226Ra in humans. One tumor located in the left sacroiliac joint has been assigned half to the appendicular skeleton and half to the axial skeleton. These percentages contrast sharply with the results for beagles injected with 226Ra, in which osteosarcomas were about equally divided between the axial and appendicular skeletons and one-quarter of the tumors appeared in the vertebrae.90, Histologic type has been confirmed by microscopic examination of 45 tumors from 44 persons exposed to 226,228Ra for whom dose estimates are available; there were 27 osteosarcomas, 16 fibrosarcomas, 1 spindle cell sarcoma, and 1 pleomorphic sarcoma. s is 226Ra skeletal dose. It should be noted that if tumor rate were constant for a given dose, it could not be constant for a given intake because the dose produced by a given intake is itself a function of time; therefore, the tumor rate would be time dependent. > 10 yr and 0 for t < 10 yr. For 224Ra, 226Ra, and 228Ra the best-available relationships are based on different measures of exposure: absorbed skeletal dose for 224Ra and systemic intake for 226Ra and 228Ra. The quantitative impact of cell location on dosimetry was emphasized by Schlenker75 who focused attention on the relative importance of dose from radon and its daughters in the airspaces compared to dose from radium and its daughters in bone. The first widespread effort to control accidental radium exposure was the abandonment of the technique of using the mouth to tip the paint-laden brushes used for application of luminous material containing 226Ra and sometimes 228Ra to the often small numerals on watch dials. Spiers et al.83 note that this number from a total of 10 is not dissimilar from the 3.6 expected in the general population. Three-dimensional representation of health effects data, although less common, is more realistic and takes account simultaneously of incidence, exposure, and time. Here the available dose-response relationships are presented in terms of the number of microcuries that reach the blood. It does, however, deposit in soft tissue and there is a potential for radiation effects in these tissues. The fundamental reason for this is the chemical similarity between calcium and radium. They reported that about 50% of the Haversian systems in the os pubis were hot spots, while hot spots constituted only about 2% of the Haversian systems in the femur shaft. The most frequent clinical symptoms for paranasal sinus tumors were problems with vision, pain (not specified by location), nasal discharge, cranial nerve palsy, and hearing loss. The difference between mucosal and epithelial thickness gives the thickness of the lamina propria a quantity of importance for dosimetry. Evans, R. D., A. T. Keane, and M. M. Shanahan. Lyman, G. H., C. G. Lyman, and W. Johnson. In the subject with carcinoma, he observed a hot layer of bone beginning about 2 m from the surface and extending inward a distance greater than the alpha-particle range. These estimates are based on retention integrals74 and relative distribution factors40 that originate from retention and dosimetry models. The analysis shows that the minimum appearance time varies irregularly with intake (or dose) and that the rate of tumor occurrence increases sharply at about 38 yr after first exposure for intakes of greater than 470 Ci and may increase at about 48 yr after first exposure for intakes of less than 260 Ci. Roughly 900 persons who were treated with Peteosthor as children or adults during the period 19461951 have been followed by Spiess and colleagues8486 for more than 30 yr and have shown a variety of effects, the best known of which is bone cancer. Such negative values follow logically from the mathematical models used to fit the data and underscore the inaccuracy and uncertainty associated with evaluating the risk far below the range of exposures at which tumors have been observed. The standard deviation for each point is shown. Individuals may be exposed to higher levels of radium if they live in an area where there are higher levels of radium in rock and soil. Since then it has been used with adults as a clinically successful treatment for the debilitating pain of ankylosing spondylitis. Autoradiograph of bone from the distal left femur of a former radium-dial painter showing hotspots (black areas) and diffuse radioactivity (gray areas). In people with radium burdens of many years' duration, only 2% of the excreted radium exits through the kidneys. A similar situation exists for female breast cancer. The ratio of the 95% confidence interval range, for radiogenic risk, to the central value. 1958. A linear function was fitted to the data over the full range of doses, but the fit was rejected by a statistical test for goodness of fit that yielded a P value of 0.02. A total of almost 908,000 residents constituted the exposed population; the mean level of radium in their water was 4.7 pCi/liter. When the study was restricted to the 360 measured cases, one case of leukemia was found in a woman with a radium intake greater than 50 Ci. Marshall36 showed that bone apposition during the period of hot-spot formation, following a single intake of radium, would gradually reduce the dose rate to adjacent bone surface tissues far below the maximum for the hot spot and concluded that the accumulated dose from a hot spot would be no more than a few times the dose from the diffuse component.37 Later, Marshall and Groer38 stated that most hot spots are buried by continuing appositional bone growth and do not deliver much of their dose to endosteal cells that may lie within the alpha-particle range. ; Volume 35, Issue 1, of Health Physics; the Supplement to Volume 44 of Health Physics; and publications of the Center for Human Radiobiology at Argonne National Laboratory, the Radioactivity Center at the Massachusetts Institute of Technology, the New Jersey Radium Research Project, the Radiobiology Laboratory at the University of California, Davis, and the Radiobiology Division at the University of Utah. The time course for development of fibrosis and whether it is a threshold phenomenon that occurs only at higher doses are unknown. Animal data supplemented by models are required to estimate retention in the human bone surface, and human data combined with models of gas accumulation are applied to the pneumatized space compartment. The typical adult maxillary cavity has a volume of about 13 cm3; one frontal sinus has a volume of about 4.0 cm3, and one sphenoid sinus has a volume of about 3.5 cm3. 1978. Aub, J. C., R. D. Evans, L. H. Hempelmann, and H. S. Martland. Although this city draws its water from Lake Michigan, where the radium concentration is reported as 0.03 pCi/liter, the age- and sex-adjusted osteosarcoma mortality rate was 6.3/million/yr, which is larger than that found for the towns with elevated radium levels in their water. When the size of the study group was reduced by changing the criterion for acceptance into the group from year of first entry into the industry to year of first measurement of body radioactivity while living, the observed number of bone tumors dropped from 42 to 13, because radioactivity in many persons was first measured after death. It peaks about 5 yr after exposure following the passage of a minimum latent period. The found that the slope of the linear dose-response curve increased with increasing time period, suggesting that bone-cancer incidence increased with decreasing average skeletal dose rate, in accordance with results in mice. Radium is highly radioactive. In the Evans et al. 1972. The presentation and analysis of quantitative data vary from study to study, making precise intercomparisons difficult. The first attempts at quantitative dosimetry were those of Kolenkow30 who presented a detailed discussion of frontal sinus dosimetry for two subjects, one with and one without frontal sinus carcinoma. 2 Knowing the death rate as a function of time for each starting age then allows the impact of radiation exposure to be calculated for each age group and to be summed for the whole population. 1984. Three of the five tumors were induced by actinides that have no gaseous daughter products. In the data analyses that lead to these equations, a 10-yr latent period is assumed for carcinoma induction. In the context of radioactive poisoning by Radium and Strontium, it is known that they accumulate in the human skeleton and thus have a cumulative effect over time. Four isotopes of radium occur naturally and several more are man-made or are decay products of man-made isotopes. Mygind, N., M. Pedersen, and M. H. Nielsen. These high ratios emphasize, in quantitative terms, our ignorance of risk at low exposure levels. Human health studies have grown from a case report phase into epidemiological studies devoted to the discovery of all significant health endpoints, with an emphasis on cancer but always with the recognition that other endpoints might also be significant. Because bone cancer is an early-appearing tumor, the risk, so far as is now known, disappears within 25 yr after exposure. Some 87 bone sarcomas have occurred in 85 persons exposed to 226,228 Ra among the 4,775 persons for whom there has been at least one determination of vital status. The presence of radium does not mean that adverse health effects are occurring or could occur. For each of the seven intake groupings in this range (e.g., 0.51, 12.5, 2.55), there was about a 5% chance that the true tumor rate exceeded 10-3 bone sarcomas per person-year when no tumors were observed, and there was a 48% chance that the true tumor rate, summed over all seven intake groups exceeded the rate predicted by the best-fit function I = (10-5 + 6.8 10-8 If a dose-protraction effect were included in the analysis, there might be a reversal of the original situation, with adults having the greater radiosensitivity. The nonuniform deposition in bones and the skeleton is mirrored by a nonuniformity at the microscopic level first illustrated with high-resolution nuclear track methods by Hoecker and Roofe for rat27 and human28 bone. The data points in Figure 4-7 for juveniles and adults are not separable from one another, and the difference between juvenile and adult radiosensitivity has completely disappeared in this analysis. Radon is gaseous at room temperature and is not chemically reactive to any important degree. A plot of the bone sarcoma data for a population subgroup defined as female radium-dial workers first exposed before 1930 is shown in Figure 4-4. A cooperative research project conducted by the U.S. Public Health Service and the Argonne National Laboratory made a retrospective study of residents of 111 communities in Iowa and Illinois who were supplied water containing at least 3 pCi/liter by their public water supplies. The best-fit function, however, does contain a linear term, in contrast to the best-fit functions for the data on 226,228Ra. Raabe et al. With environmental radiation, in which large populations are exposed, a spectrum of ages from newborn to elderly is represented. This change occurred in 19251926 following reports and intensive discussion of short-term health effects such as ''radium jaw" in some dial painters. Direct observation in vivo of retention in these three compartments is not possible, and what has been learned about them has been inferred from postmortem observations and modeling studies. It emits alpha, beta, and gamma radiation. The data for persons exposed as juveniles (less than 21 yr of age) were analyzed separately from the data for persons exposed as adults, and different linear dose-response functions that fit the data adequately over the full range of doses were obtained.85 The linear slope for juveniles, 1.4%/100 rad, was twice that for adults, 0.7%/100 rad. The radium might exist in ionic form, although it is known to form complexes with some compounds of biological interest under appropriate physiological conditions; it apparently does not form complexes with amino acids. Evans, R. D., A. T. Keane, R. J. Kolenkow, W. R. Neal, and M. M. Shanahan. The age structure of the population at risk and competing causes of death should be taken into account in risk estimation. Groer and Marshall20 estimated the minimum time for osteosarcoma appearance in persons exposed to high doses of 226Ra and 228Ra. In an earlier summary for 24 224Ra-induced osteosarcomas,90 21% occurred in the axial skeleton. The identities of these cells are uncertain, and their movements and life cycles are only partly understood. Research should continue on the cells at risk for bone-cancer induction, on cell behavior over time, including where the cells are located in the radiation field at various stages of their life cycles, on tissue modifications which may reduce the radiation dose to the cells, and on the time behavior and distribution of radioactivity in bone. i - 3.6 10-8 However, no mention of such cases appear in his report. Later, similar effects were also found to be associated with internal exposure to 224Ra. The linear relationship that provided the best fit to the data predicted a tumor rate lower than the rate that had been observed recently, and led the authors to suggest that the incidence at long times after first exposure may be greater than the average rate observed thus far. Thus, the spectrum of tumor types appears to be shifted from the naturally occurring spectrum when the tumors are induced by radium. Among these individuals the minimum observed time to osteosarcoma appearance was 7 yr from first exposure. With a lifetime natural tumor risk of 0.1%, the radiogenic risk would be -0.0977%. and Rowland et al., are from the use of person-years at risk in the definition of tumor incidence, from the inclusion of both groups of radium-induced tumor, and the use of different weighting factors in the summation of 226Ra and 228Ra dose.

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