why does radium accumulate in bones?

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. Autoradiograph of bone from the distal left femur of a former radium-dial painter showing hotspots (black areas) and diffuse radioactivity (gray areas). There have been two systematic investigations of the 226,228Ra data related to the uncertainty in risk at low doses. In addition to the primary radiationalpha, beta, or bothindicated in the figures, most isotopes emit other radiation such as x rays, gamma rays, internal conversion electrons, and Auger electrons. For example, the central value of total risk, including that from natural causes, is I = (10-5 + 6.8 10-8 The probability of survival for cells adjacent to the endosteal surface and subjected to the estimated average endosteal dose for this former radium-dial painter was extremely small. Twenty-eight towns met the three criteria for the second study: a population between 1,000 and 10,000, water is obtained solely from wells greater than 500 ft (152 m) deep, and no water softening. When the model is used for radium, careful attention should be paid to the constraints placed on the model by data on radium retention in human soft tissues.74 Because of the mathematical complexity of the retention functions, some investigators have fitted simpler functions to the ICRP model. The two bones of the forearm are the radius and the ulna. Higher doses of radium have been shown to cause effects on the blood (anemia), eyes (cataracts), teeth (broken teeth), and bones (reduced bone growth). For the atomic-bomb survivors and the 224Ra-exposed patients, the exposure periods were relatively brief. The heavy curve represents the new model. Data on tumor locations and histologic type are presented in Table 4-4. When the time dependence of bone tumor appearance following 224Ra exposure is considered an essential component of the analysis, then an approximate modification of the dose-response relationship can be made by taking the product of the dose-response equation and an exponential function of time to represent the rate of tumor appearance: where F(D) is the lifetime risk, as specified by the analyses of Spiess and Mays85 and r is a coefficient based on the time of tumor appearance for juveniles and adults in the 224Ra data analyses. In the case of the longer-half-life radium isotopes, the interpretation of the cancer response in terms of estimated dose is less clear. 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 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. The data on human soft-tissue retention were recently reviewed.74 The rate of release from soft tissue exceeds that for the body as a whole, which is another way of stating that the proportion of total body radium that eventually resides in the skeleton increases with time. 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. A common reaction to intense radiation is the development of fibrotic tissue. Rowland, R. E., A. T. Keane, and P. M. Failla. The analysis took into account tumors appearing between 14 and 21 yr after the start of exposure in 43 subjects that received a known dose. as result of the local effects of the radon . Control cities where the radium content of the public water supply contained less than 1 pCi/liter were matched for size with the study cities. 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. This is an instance in which an extrapolation of animal data to humans has played an important role. 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. The work by Raabe et al.61,62 permits the determination of a practical threshold dose and dose rate. Annual Report No. Otherwise, clearance half-times are about 100 rain and are determined by the blood flow through mucosal tissues.73 The radioactive half-lives of the radon isotopes55 s for 220Rn and 3.8 days for 222Rnare quite different from their clearance half-times. Tumor frequencies for axial and appendicular skeleton are shown in Table 4-1. The distance across a typical air cell is 0.2 cm,73 equivalent to a volume of about 0.004 cm3 if the cell were spherical. Thus, the model and the Rowland et al. The excess death rate due to bone cancer for t > 5 yr is computed from: Effect of Single Skeletal Dose of 1 rad from 224Ra Received by 1,000,000 U.S. White Males at Age 40. For example, if a person is exposed to 226Ra at time zero, the person is not considered to be at risk for 10 yr; the total number of carcinomas expected to occur among N people with identical systemic intakes D The analysis of response as a function of 226Ra dose was conducted with exhumed cases included. With the analyses presently available, only part of this prescription can be achieved. An additional three cases were found in the 19301949 cohort, yielding a standard mortality ratio of 221. 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. Later, similar effects were also found to be associated with internal exposure to 224Ra. i There were 1,501 exposed cases and 1,556 ankylosing spondylitis controls. D With 228Ra, dose delivery is practically all from bone volume, but the ranges of the alpha particles from this decay series exceed those from the 226Ra decay series, allowing 228Ra to go deeper into the bone marrow and, possibly, to irradiate a larger number of target cells. 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. Spiers, F. W., H. F. Lucas, J. Rundo, and G. A. Anast. The mobility of populations in this country, the inability to document actual radium intakes, and the fact that water-softening devices remove radium from water all tend to make studies of this nature very difficult to evaluate. These authors concluded that there was no relationship between radium level and the occurrence of leukemia. If forms with negative coefficients are eliminated, as postulated by the model, then only (C + D) exp(-D) from this latter group provided an acceptable fit, but it had a chi-squared probability (0.06) close to the rejection level (0.05). In later work, juvenile-adult differences have not been reported. All towns, 1,000 to 10,000 population, with surface water supplies. For the 27 subjects for whom radium body burden information was available, they estimated that, for airspace thicknesses of 0.5 to 2 cm, the dose from radon and its daughters averaged over a 50-m-thick mucous membrane would be 2 to 5% of the average dose from 226Ra in bone. The late effects of internally deposited radioactive materials in man, The U.K. radium luminiser survey: Significance of a lack of excess leukemia, The Radiobiology of Radium and Thorotrast, Drinking water and cancer incidence in Iowa, Drinking water and cancer incidence in lowa, Zur Anatomie der Stirnhohlen, Koniglichen Anatomischen Institut za Konigsberg Nr. The increase of diffuse activity relative to hot-spot activity, which is suggested by Marshall and Groer38 to occur during prolonged intake, has a strong theoretical justification. 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. For humans and some species of animals, an abundance of data is available on some of the observable quantities, but in no case have all the necessary data been collected. The other 98% passes out through the bowel. They found that, for the period 19501962, the age- and sex-adjusted rate for the radium-exposed group was 1.41/100,000/yr. National Research Council, In addition, they reported a tumor rate of 1.8%/yr for these subjects exposed to high doses and suggested that the sample of tumor appearance times investigated had been drawn from an exponential distribution. The best fit of response against systemic intake was obtained for the functional form I = C + D, obtained from Equation 4-21 by setting = = 0. A necessary first step for the estimation of risk from any route of intake other than injection is therefore to apply these models. This emphasizes that there is no unique way to specify the uncertainty in risk at low exposures when the shape of the dose-response curve is unknown. The functional form in the analysis of Rowland et al. The excretion rate of radium can be determined by direct mea measurement in urine and feces or by determining the rate of change in whole-body retention with time. A total of 9.2 cases would be expected to occur naturally in such a population. The layer was 8- to 50-m thick, was sometimes a cellular, and sometimes contained cells or cell remnants within it. To circumvent this problem, two strategies have been developed: (1) classification of the cases according to their epidemiological suitability, on a scale of 1 to 5, with 5 representing the least suitable and therefore the most likely to cause bias and 1 representing the most suitable and therefore the least likely to cause bias; and (2) definition of subgroups of the whole population according to objective criteria presumably unrelated to tumor risk, for example, by year of first exposure and type of exposure. Otherwise, the retention in bone is estimated by models. The high-exposure group was further divided into three graded groups. At this time, it is clear that it is not a primary consequence of radium deposited in human bones. Raabe, O. G., S. A. i, redefinition is not required to avoid negative expected values, and radiogenic risk is set equal to the difference between total risk and natural risk. Raabe, O. G., S. A. The results are shown in Figure 4-8. The extremely high radiation doses experienced by a few of the radium-dial workers were not repeated with 224Ra, so clear-cut examples of anemias following massive doses to bone marrow are lacking. The heavy curve represents the new model. Mays, C. W., H. Spiess, D. Chmelevsky, and A. Kellerer. The cumulative tumor risk (bone sarcomas/106 person-rad) was similar in the juvenile and adult patients under the dosimetric assumptions used. It later appears in the urine and feces, with the majority of excretion occurring by the fecal route. One of these was panmyelosis, and the other was aplastic anemia; the radium measurements for these two cases showed body contents of 10.5 and 10.7 Ci, respectively. For 224Ra the dose-response relationship gives the lifetime risk of bone cancer following an exposure of up to a few years' duration. The analysis is most relevant to the question of practical threshold and will be discussed again in that context. Therefore, estimates of the cumulative average skeletal dose may not be adequate to quantitate the biological insult. l That Define the Dose-Response Envelopes in Figure 4-5. The radium, once ingested, behaves chemically like calcium and, therefore, deposits in significant quantities in bone mineral, where it is retained for a very long time. 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. Following entry into the circulatory system from the gut or lungs, radium is quickly distributed to body tissues, and a rapid decrease in its content in blood occurs. D Fact Sheet #29 Radium-226 ( 226Ra) Page 3 of 3 Its use with children came to an end in 1951, following the realization that growth retardation could result and that it was ineffective in the treatment of tuberculosis. ." Radium has been used commercially in luminous paints for watch and instrument dials and for other luminized objects. Data points fall along a straight line when the tumor rate is constant. The ratios of maximum to average lay in the range 837. i = 0.5 Ci. When injected into humans for therapeutic purposes or into experimental animals, radium is normally in the form of a solution of radium chloride or some other readily soluble ionic compound. 2)exp(-1.1 10-3 The type of dose used is stated for each set of data discussed. For continuous intake with the dose-squared exponential function for bone sarcoma induction, it is necessary to decide whether to add the cumulative dose and then take the square or to take the square for each annual increment of dose. employed a log-normal dose-rate, time-response model that was fitted to the data and that could be used to determine bone-cancer incidence, measured as a percentage of those at risk, versus absorbed skeletal radiation dose. Evans, Mays, and Rowland and their colleagues presented explicit numerical values or functions based on their fits to the radium tumor data. The same observation can be made for the function 1 - exp(-0.00003D) for the probability of tumor induction developed from the life-table analysis of Schlenker.74. In a review of the papers published in the United States on radium toxicity, and including three cases of radium exposure in Great Britain, Loutit34 made a strong case "that malignant transformation in the lymphomyeloid complex should be added to the accepted malignancies of bone and cranial epithelium as limiting hazards from retention of radium." The final report of this study by Petersen et al.56 reported on the number of ''deaths due in any way to malignant neoplasm involving bone." Equations for the Functions I In 1977 it was estimated that only 15 people died in the United States from cancers of the auditory tube, middle ear, and mastoid air cells.53 Comparable statistics are lacking for cancers of the ethmoid, frontal, and sphenoid sinuses; but mortality, if scaled from the incidence data, would not be much greater than that caused by cancers of the auditory tube, middle ear, and mastoid air cells. . The identities of these cells are uncertain, and their movements and life cycles are only partly understood. The take and release of activity into and out of the surface compartment was studied quantitatively in animals and was found to be closely related to the time dependence of activity in the blood.65 Mathematical analysis of the relationship showed that bone surfaces behaved as a single compartment in constant exchange with the blood.37 This model for the kinetics of bone surface retention in animals was adopted for man and integrated into the ICRP model for alkaline earth metabolism, in which it became the basis for distinguishing between retention in bone volume and at bone surfaces. With the present state of knowledge, a single dose-response relationship for the whole population according to isotope provides as much accuracy as possible. 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. Raabe et al. 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. Since it is not yet possible to realistically estimate a target cell dose, it has become common practice to estimate the dose to a 10-m-thick layer of tissue bordering the endosteal surface as an index of cellular dose. In effect, essentially all the 220 Rn that diffuses into the pneumatized air space decays there Before it can be cleared, but essentially all the 222Rn that reaches the pneumatized air space is cleared before it can decay. When persons that had entered the study after exhumation were excluded from the analysis, in an effort to control selection bias, all six forms of the general function gave acceptable fits to the data. Whether the practical threshold represents a dose below which the tumor risk is zero, or merely tiny, depends on whether the minimum tumor appearance time is an absolute boundary below which no tumors can occur or merely an apparent boundary below which no tumors have been observed to occur in the population of about 2,500 people for whom radium doses are known. that contains an exponential factor. Radium-226 adheres quickly to solids and does not migrate far from its place of release. Most of the 220Rn (half-life, 55 s) that escapes bone surfaces decay nearby, as will 216Po (half-life 0.2 sec). If it is inhaled or swallowed, radium is dangerous because there is no shielding inside the body. 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. Investigation of other dosimetric approaches is warranted. It peaks about 5 yr after exposure following the passage of a minimum latent period. 226Ra and 228Ra are also heavily concentrated on bone surfaces at short times after intake. 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. The cause of paranasal sinus and mastoid air cell carcinomas has been the subject of comment since the first published report,43 when it was postulated that they arise ''. The above results, based on observations of several thousand individuals over periods now ranging well over 50 yr, make the recent report by Lyman et al.35 on an association between radium in the groundwater of Florida and the occurrence of leukemia very difficult to evaluate. 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. 's analysis, the 228Ra dose was given a weight 1.5 times that of 226Ra. Evans et al. i - 3.6 10-8 Evans, R. D., A. T. Keane, R. J. Kolenkow, W. R. Neal, and M. M. Shanahan. 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 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. In the case of leukemia, the issue is not as clear. Rowland, R. E., A. F. Stehney, and H. F. Lucas, Jr. For example, when the risk coefficient is: For functions that lack an exponential factor, such as I = 1.75 10-5 + (2.0 0.6) 10-5 1983. Such cells could accumulate average doses in the range of 100300 rad, which is known to induce transformation in cell systems in vitro. He also estimated dose rates for situations where there were no available autoradiographic data. No maxillary sinus carcinomas have occurred, but 69% of the tumors have occurred in the mastoids. Florida has substantial deposits of phosphate, and this ore contains 238U, which in turn produces 226Ra and 222Rn. 1984. 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. A similar issue exists for 226Ra and 228Ra. On average, the dose rate from airspaces was about 4 times that from bone. Rowland et al.67 have reported the only separate analyses of paranasal sinus and mastoid carcinoma incidence. Risk per person per gray versus mean skeletal dose. He placed the total thickness of connective tissue plus epithelium at between 5 and 20 m. Lyman et al.35 show a significant association between leukemia incidence and the extent of groundwater contamination with radium. The removal of the difference came in two steps associated with analyses of the influence of dose protraction on tumor induction. Four of the five leukemias occurred in patients with ankylosing spondylitis; two were known to be acute; it is not known whether the other three were acute or chronic. 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. There is a 95% probability that the expected number lies between the dashed boundaries. The most common types of fractures . The frequencies for different bone groups are axial skeleton-skull (3), mandible (1), ribs (2), sternebrae (1), vertebrae (1), appendicular skeleton-scapulae (2), humeri (6), radii (2), ulnae (1), pelvis (10), femora (22), tibiae (7), fibulae (1), legs (2; bones unspecified), feet and hands (5; bones unspecified). 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. 1976. There is no assurance that women exposed at a greater age or that men would have yielded the same results. Incident Leukemia in Located Radium Workers. Concurrently, Mays and Lloyd44 analyzed the data on bone tumor induction by using Evans' measures of tumor incidence and dosage without correction for selection bias and presented the results in a graphic form that leaves a strong visual impression of linearity, but which, when subjected to statistical analysis, is shown to be nonlinear with high probability. Were it not for the fact that these cancers were not seen at radium intakes hundreds to thousands of times greater in the radium-dial painter studies, they might throw suspicion on radium. 2]exp(-1.1 10-3 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 In the analysis by Rowland et al. There is more information available on the dosimetry of the long-term volume deposit.

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