This chapter focuses on bone cancer and cancer of the paranasal sinuses and mastoid air cells because these effects are known to be associated with 224Ra or 226,228Ra and are thought to be nonthreshold phenomena. The first is that of Rowland et al.67 in which estimated systemic intake (D) rather than average skeletal absorbed dose was used as the dose parameter and functions of the form (C + D + D2) exp(-D) were fitted to the data. D The intersection of the line with the appearance time axis provides an estimate of the minimum appearance time. Lyman et al.35 show a significant association between leukemia incidence and the extent of groundwater contamination with radium. The dose is delivered continuously over the balance of a person's lifetime, with ample opportunity for the remodeling of bone tissues and the development of biological damage to modulate the dose to critical cells. An analysis of the tumor appearance time data for carcinomas based on hazard plotting has been as employed by Groer and Marshall20 to analyze bone tumor rate in persons exposed to high doses from radium. This study examined a cohort of 634 women who had been identified by means of employment lists or equivalent documents. This population has now been followed for 34 yr; the average follow-up for the exposed group is about 16 yr. A total of 433 members of the exposed group have died, leaving more than 1,000 still alive. All five leukemias in the control group were acute forms, while three in the exposed group were chronic myeloid leukemia. Figure 4-5 shows the results of this analysis, and Table 4-3 gives the equations for the envelope boundaries. When the radiogenic risk functions (I The frequency distribution for appearance times shows a heavy concentration of paranasal sinus and mastoid carcinomas with appearance times of greater than 30 yr. For bone tumors there were approximately equal numbers with appearance times of less than or greater than 30 yr.67 Based on the most recent summary of data, 32 bone tumors occurred with appearance times of less than 30 yr among persons with known radiation dose and 29 tumors had occurred with appearance times of 30 yr or greater. The decay products of radium, except radon, are atoms of solid materials. why does radium accumulate in bones? For five subjects on whom he had autoradiographic data for the 226Ra specific activity in bone adjacent to the mastoid air cells, the dose rate at death from 222Rn and its daughters in the airspaces exceeded the dose rate from 226Ra and its daughters in bone. Evans et al. . Because of its short radioactive half-life, about 90% of the 224Ra atoms that decay in bone decay while on the surfaces.40. Marshall37 summarized results of limited studies on the rate of diminution of 226Ra specific activity in the hot-spot and diffuse components of beagle vertebral bodies that suggest that the rates of change with time are similar for the maximum hot-spot concentration, the average hot-spot concentration, and the average diffuse concentration. 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. 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. Rowland, R. E., A. F. Stehney, A. M. Brues, M. S. Littman, A. T. Keane, B. C. Patten, and M. M. Shanahan. This represents a nonquantifiable uncertainty in the application of the preceding equations to risk estimation. 228Ra intake was excluded because it was assumed that 228Ra is ineffective for the production of these carcinomas. In press. When one considers that endosteal doses from the diffuse component among persons exposed to 226,228Ra who developed bone cancer ranged between about 250 and 25,000 rad, it becomes clear that the chance for cell survival in the vicinity of the typical hot spot was infinitesimal. Later, similar effects were also found to be associated with internal exposure to 224Ra. 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. One tumor located in the left sacroiliac joint has been assigned half to the appendicular skeleton and half to the axial skeleton. Meaningful estimates of tissue and cellular dose obtained by these efforts will provide a quantitative linkage between human and animal studies and cell transformation in vitro. . With a lifetime natural tumor risk of 0.1%, the radiogenic risk would be -0.0977%. in the expiratory air . e is the endosteal dose. An additional three cases were found in the 19301949 cohort, yielding a standard mortality ratio of 221. Florida has substantial deposits of phosphate, and this ore contains 238U, which in turn produces 226Ra and 222Rn. It should be noted, however, that the early cases of Martland were all characterized by very high radium burdens. If this were substituted for the tumor rate caused by 224Ra exposure in Table 4-7 and the survival rate of those exposed to 224Ra were adjusted to the corresponding value (0.9998), survival in the presence of 224Ra exposure after 25 yr would be 777,293, with 3,272 deaths attributable to the 224Ra exposure. The most common types of fractures . As revealed by animal experiments and clearly detailed by metabolic models, alkaline earth elements deposit first on bone surfaces and then within the volume of bone. The importance of this work lies in the fact that it shows the maximum difference in radiosensitivity between juvenile and adult exposures for this study. 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. For female radium-dial workers first employed before 1930, the only acceptable fit to the data on bone sarcomas per person-year at risk was provided by the functional form (C + D2) exp(-D), which was obtained from the more general expression by setting = 0. There is a 95% probability that the expected number lies between the dashed boundaries. This argues for the interaction of doses and in the extreme case for squaring the cumulative dose. 1986. i). Mays, C. W., T. F. Dougherty, G. N. Taylor, R. D. Lloyd, B. J. Stover, W. S. S. Jee, W. R. Christensen, J. H. Dougherty, and D. R. Atherton. > 10 yr and 0 for t < 10 yr. If the tumors are nonradiogenic, then the linear extrapolation gives a substantial over prediction of the risk at low doses, just as a linear extrapolation of the 226,228Ra data overpredict the risk from these isotopes at low doses.17,44. However, at lower radium intakes, such as those experienced by the British luminizers and the bulk of the U.S. radium-dial workers, incorporated 226Ra does not appear to give rise to leukemia. The upper curve of the 68% envelope is nearly coincident with the upper boundary of the shaded envelope. 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. When radiogenic risk is determined by setting the natural tumor rate equal to 0 in the expressions for total risk and by eliminating the natural tumor rate (10-5/yr) from the denominator in Equation 4-14, the value of the ratio increases more slowly, reaching 470 at D Lyman, G. H., C. G. Lyman, and W. Johnson. 's analysis, the 228Ra dose was given a weight 1.5 times that of 226Ra. . 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. Radium-223 is a "calcium mimetic" that, like calcium, accumulates preferentially in areas of bone that are undergoing increased turnover, such as areas . These relationships have important dosimetric implications. 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. 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. They point out that there is no information on individual exposure to radium from drinking water, nor to other confounding factors. why does radium accumulate in bones? With environmental radiation, in which large populations are exposed, a spectrum of ages from newborn to elderly is represented. 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. In the analysis of radiation-effects data, the alpha particles emitted are considered to be the root cause of damage. Therefore, calculations of the uncertainty of risk estimates from the standard deviation will be accurate above 25 Ci but may be quite inaccurate and too small below 25 Ci. 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. A three- or four-inch pipe pulls radon from underneath the house and vents it outside. The half lives are 3.5 days for radium-224, 1,600 years for radium-226, and 6.7 years for radium-228, the most common isotopes of radium, after which each forms an isotope of radon. The rarity of naturally occurring mucoepidermoid carcinoma, contrasted with its frequency among 226,228Ra-exposed subjects, suggests that alpha-particle radiation is capable of significantly altering the distribution of histologic types. With the occasional accidental exposures that occur with occupational use of radium, both hot-spot and diffuse radioactivity are probably important to cancer induction, and the total average endosteal dose may be the most appropriate measure of carcinogenic dose. 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. The extreme thinness of the surface deposit has been verified in dog bone, but the degree of daughter product retention at bone surfaces is in question.76 Schlenker and Smith80 have reported that only 525% of 220Rn generated at bone surfaces by the decay of 224Ra is retained there 24 h after injection into beagles. The paranasal sinuses are cavities in the cranial bones that exchange air and mucus with the nasal cavity through a small ostium. 226Ra and 228Ra are also heavily concentrated on bone surfaces at short times after intake. 1986. 1966. Thereafter, tumors appear at the rate M(D,t). The case for a dose rate or dose-protraction effect rests on the observation of an association of the linear dose-response slope with dose rate in humans and the unequivocal appearance of a dose-protraction effect in mice and rats. Risk per person per gray versus mean skeletal dose. i is 226Ra intake, and D As of December 1982, the average followup time was 16 yr for patients injected after 1951 with lower doses of 224Ra for the treatment of ankylosing spondylitis.93 Of 1,426 patients who had been traced, the vital status for 1,095 of them was known. Schlenker and Smith80 also reported incomplete retention for 212Pb and concluded that the actual endosteal dose rate 24 h after injection varied between about one-third and one-half of the equilibrium dose rate for their experimental animals. Since then it has been used with adults as a clinically successful treatment for the debilitating pain of ankylosing spondylitis. 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. When the sinus becomes unventilated due to ostial closure, the gas composition of the sinus cavity changes and slight overpressure or underpressure may occur.13 When radioactive gases (radon) are present, as with persons exposed to 226,228Ra, there is the potential for a much higher concentration of those gases in the air of the sinus when unventilated than when ventilated. Radon is gaseous at room temperature and is not chemically reactive to any important degree. In the latter analysis,69 the only acceptable fit based on year of entry into the study is: where I and D . The points with their standard errors result from the proportional hazards analysis of Chemelevsky et al.9. The data for juveniles and adults was separated into different dose groups, a step not taken with the life-table analysis of Mays and Spiess.45 This, in effect, frees the analysis from the assumption of a linear dose-response relationship, implicit in the Mays and Spiess analysis. Thus, the absence of information on the tumor probability as a function of person-years at risk is not a major limitation on risk estimation, although a long-term objective for all internal-emitter analyses should be to reanalyze the data in terms of a consistent set of response variables and with the same dosimetry algorithm for both 224Ra and for 226Ra and 228Ra.
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