Health Risks of Radon and Other Internally Deposited Alpha-Emitters BEIR IV (1988) / Chapter Skim
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4 Radium
4 Radium
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From page 176... ...
It has also been used for internal radiation therapy. The primary sources of information on the health effects and dosimetry of radium isotopes come from extensive studies of 224 Ra, 226Ra, and 228Ra in humans and experimental animals.
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From page 177... ...
The question remained open, however, whether the health effects were threshold phenomena that would not occur below certain exposure or dose levels, or whether the risk would continue at some nonzero level until the exposure was removed altogether. The issue remains unresolved, but as a matter of philosophy, it is now commonly assumed that the so-called stochastic effects, cancer and genetic effects, are nonthreshold phenomena and that the so-called nonstochastic effects are threshold phenomena.
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From page 178... ...
W Mays et al.; Volume 35, Issue 1, of Health Physics; the Supplement to Volume 44 of Neatth 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 I,aboratory at the University of California, Davis, and the Ra~liobiology Division at the University of Utah.
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From page 179... ...
Two compartments are usually identified in the skeleton, a bone surface compartment in which the Helium is retained for short periods and a bone volume compartment in which it is retained for long periods. A third compartment, which is not a repository for radium itself but which is relevant to the induction of health effects, consists of the pneumatized portions of the skull bones, that is, the paranasal sinuses and the air cells of the temporal bone (primarily the mastoid air cells)
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From page 180... ...
STABLE FIGURE 4-1 a. 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 (a, if, or both)
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From page 181... ...
During life, four quantities that can be monitored include wholebody content of radium, blood concentration, urinary excretion rate, and fecal excretion rate. These are supplemented by postmortem measurements of skeletal and soft-tissue content, observations of radium distribution within bone on a microscale, and measurements of radon gas content in the mastoid air cells.
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From page 182... ...
At high radiation doses, whole-body retention is dose dependent. This observation was originally made on animals given high doses where retention, at a given time after injection, was found to increase with injection level.
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From page 183... ...
for alkaline earth metabolism29 was developed by the ICRP to describe the retention of calcium, strontium, barium, and radium in the human body and in human soft tissue, bone volume, bone surfaces, and blood. Separate retention functions
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From page 184... ...
~ ~~~ ~ ~ ~~ ~~ O~ as # ~ FICORE 4-3 Autor~dlogr~ph of bone Tom the data lea Tour of ~ krmer radlum-dl~1 paster strong hotspots unlock areas] and Valise r~dloact~hy (gray bread.
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From page 185... ...
BONE CANCER F REQUENCY AND C ELL TYPE Radium deposited in bone irradiates the cells of that tissue, eventually causing sarcomas in a large fraction of subjects exposed to high doses. The first case of bone sarcoma associated with 226 228 Ra exposure was a tumor of the scapula reported in 1929, 2 yr after diagnosis in a woman who had earlier worked as a radium-dial painter.42 Bone tumors among children injected with 224 Ra for therapeutic purposes were reported in 1962 among persons treated between 1946 and .87 Spontaneously occurring bone tumors are rare.
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From page 186... ...
program.52 The chance of contracting bone sarcoma during a lifetime is less than 0.1%o. Some 87 bone sarcomas have occurred in 85 persons exposed to 226 228Ra among the 4,775 persons for whom there has been at least one determination of vital status.
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From page 187... ...
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 The distribution of histologic types for radium-induced tumors is compared in Table 4-2 with that reported for naturally occurring bone tumors. The data have been divided into two groups according to age of record for the tumor.
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From page 188... ...
DOSIMETRY The weight of available evidence suggests that bone sarcomas arise from ceils that accumulate their dose while within an alphaparticle range. These cells are within 3~80 Am of endosteal bone surfaces, defined here as the surfaces bordering the bone-bone marrow interface and the surfaces of the forming and resting haversian canals.
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From page 189... ...
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 as pubis. In a study of microscopic volumes of bone from a radium-dial painter, Hindmarsh et al.26 found the ratio of radium concentrations in hot spots to the average concentration that would have occurred if the entire body burden had been uniformly distributed throughout
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From page 190... ...
This is not a trivial point since rate of loss could be greatly affected by the high radiation doses associated with hot spots. According to Hindmarsh et al.26 the most frequent ratio of hotspot to average concentration in bone from a radium-dial painter was 3.5.
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From page 191... ...
If cell survival is an exponential function of alph~particle dose in viva 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. If the survival adjacent to the diffuse component were 37%, as might occur for endosteal doses of 50 to 150 red, the hot-spot survival would be O.O9%o.
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From page 192... ...
The picture that emerges from considerations of cell survival is that hot spots may not have played a role in the induction of bone cancers among the 226 228Ra-exposed subjects, but they would probably play a role in the induction of any bone cancer that might occur at significantly lower doses, for example, following an accidental occupational exposure. With life-Ion" continuous intake of dietary radium, the distinction between hot spot and diffuse activity concentrations is diminished; if dietary intake maintains a constant radium specific activity in the blood, the distinction should disappear altogether because blood and bone will always be in equilibrium with one another, yielding a uniform radium specific activity throughout the entire mineralized skeleton.
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From page 193... ...
Therefore, no judgment can be made as to whether such a layer would develop in response to a single injection of 224Ra or whether the layer could develop fast enough to modify the endosteal cell dosimetry for multiple 224 Ra fractions delivered over an extended period of time. TIME TO TUMOR APPEARANCE AND TUMOR RATE The times to tumor appearance for bone sarcomas induced by 224 Ra and 226 228 Ra differ markedly.
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From page 194... ...
In addition, they reported a tumor rate of 1.8%o/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. DOSE-RESPONSE RELATIONSHIPS Cancer induction by radiation is a multifactorial process that involves biological and physical variables whose importance can vary with time and with age of the subject.
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From page 195... ...
In contrast, 226Ra delivers most of its dose while residing in bone volume, from which dose delivery is much less efficient. 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 226 Ra decay series, allowing 228 Ra to go deeper into the bone marrow and, possibly, to irradiate a larger number of target cells.
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From page 196... ...
For radium-dial painters, however, the number of persons estunated to have worked in the industry is not too much greater than the number of subjects that have been located and identified by name.67 This fact implies that coverage of the radium-dial painter segment of the population is reasonably good, thus reducing concerns over selection bias. The first comprehensive graphical presentations of the doseresponse data were made by Evans.~5 In that study both tumor types (bone sarcoma and head carcinoma)
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From page 197... ...
Following consolidation of U.S. radium research at a single center in October 1969, the data from both studies were combined and analyzed in a series of papers by Rowland and colleagues.66~69 Bone tumors and carcinomas of the paranasal sinuses and mastoid air cells were dealt with separately, epidemiological suitability classifications were dropped, incidence was redefined to account for years at risk, and dose was usually quantified in terms of a weighted sum of the total systemic intakes of 226 Ra and 228Ra, although there were analyses in which mean skeletal dose was used.
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From page 198... ...
: ,'""'T - 0.0046% PER RAD I 1 1 1 4000 8000 12,000 16,000 AVERAGE SKELETAL DOSE IN RADS O I ·1 1 10 + ~ 1 1 ~ _, 100 1 k 10k 100k AVERAGE SKELETAL DOSE7 red FIGURE 4-4 1) ose-response relationships of Evans et al.l7 (a)
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From page 199... ...
The findings were similar to those described above. For female radiumdial 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 + ,BD2)
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From page 200... ...
In the model, this dose is directly proportional to the average skeletal dose, and tumor rate is an analog of the response parameter, which is bone sarcomas per person-year at risk. Thus, the mode} and the Rowland et al.
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From page 201... ...
It is clear, therefore, that a nonzero function could be fitted to these data but would have numerical values substantially less than 28~o. For the percent of exposed persons with bone sarcomas, Mays and [loy344 give 0.0046~o Da' where Do is the sum of the average skeletal doses for 226Ra and 228Ra in red In the analysis by Rowland et al.
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From page 202... ...
(~8) With attention now focused on exposure levels well below those at which tumors have been observed, it is natural to exploit functions such as those presented above for radiogenic risk estimation.
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From page 203... ...
, there was about a Do 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 X 10-8Di2) expt—1.l x 1o-3Di)
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From page 204... ...
10-3 cr: he o in cr LLI c,n in LL he o m 10 5 Envelopes I\\\\\\\\\\\ RSL.9% 68% _ _ _ _ 95% _ ~ , 204 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS a,!
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From page 205... ...
increases with decreasing intake from 1.7 at Di = 100 psi to 700 at Di = 0.5 psi, the lower boundary of the lowest intake cohort used when fitting functions to the data. 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)
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From page 206... ...
As a response parameter, the number of bone sarcomas that have appeared divided by the number of persons known to have been exposed within a dose group was used. The data for persons exposed as juveniles (less than 21 yr of age)
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From page 207... ...
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. Although the change of tumor incidence with exposure duration was not statistically significant, an increase did occur both for juveniles and adults.
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From page 208... ...
is 1.4 times the risk to adults (133 it 36 bone sarcomas/106 person-red)
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From page 209... ...
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
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From page 210... ...
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 results of this series of studies of bone sarcoma incidence among 224 Ra-exposed subjects extending over a period of 15 yr underscore the importance of repeated scrutiny of unique sets of data.
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From page 211... ...
However, Solo of the bone tumors in the this series, for which histologic type Is known, are osteosarcomas, while fibrosarcomas and reticulum cell sarcomas each represent only about 2%o of the total, and multiple myeloma was not observed at all. Based on this, the chance of randomly selecting three tumors from the this distribution and coming up with no osteosarcomas ~ about (0.2~3 = 0.008, throwing the weight of evidence in favor of a nonradiogenic origin for the three bone cancers found in this study.93 94 However, this could occur if there were a dramatic change in the distribution of histologic types for tumors induced by 224 Ra at doses below about 90 red, which is approximately the lower limit for tumor induction In the Spiess et al.~8 series.
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From page 212... ...
2 12 HEALTH RISKS OF RAD ON AND O TNER ALPHA-EMT TTERS of the 226 228Ra data overpredict the risk from these isotopes at low doses.~7 44 SchIenker74 has provided a confidence interval analysis of the Spiess et al.~8 data in the region of zero observed tumor incidence to parallel that for 226 228Ra. The results are shown in Figure 4-8.
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From page 213... ...
PRACTICAL THRESHOLD The term practical threshold was introduced into the radium literature by Evans,~5 who perceived an increase of the minimum tumor appearance time with decreasing residual radium body burden and later with decreasing average skeletal dosed A plot showing tumor appearance time versus average skeletal dose conveys the impression that the minimum tumor appearance time increases with decreasing dose. The practical threshold would be the dose at which the minimum appearance time exceeded the maximum human life span, about 50 red.
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From page 214... ...
Raabe et al. demonstrated an increase of median tumor appearance time with decreasing average skeletal dose rate for a subset of radium-~nduced bone tumors in humans6t and for bone tumors induced in experimental animate by a variety of radionuclides.60 The validity of the analysis of mouse data has been challenged,62 but not the analysis of human and dog data.
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From page 215... ...
Therefore, the minimum observed tumor appearance time is not an absolute lower bound, and there is a small nonzero chance for tumors to occur at doses less than the practical threshold. CARCINOMA OF THE PARANASAL SINUSES AND MASTOID AIR CELLS The paranasal sinuses are cavities in the cranial bones that exchange air and mucus with the nasal cavity through a small ostium.
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From page 216... ...
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. Ventilation of the mastoid air cells occurs through the eustachian tube which normally allows little air to move.
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From page 217... ...
Some 35 carcinomas of the paranasal sinuses and mastoid air cells have occurred among the 4,775 226 228Ra-exposed patients for whom there has been at least one determination of vital status. For 31 of the tumors, estimates of skeletal dose can and have been made.
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From page 218... ...
in the expiratory air...." In 1952, Aub et al.3 stated that the origin of these neoplasms in mucosal cells that were well beyond the range of the alpha particles emitted by radium, mesothorium, and their bone-fixed disintegration products is also interesting. Only the beta and gamma rays, which were of low intensity compared to the alpha rays, emitted by these radioactive materials in the adjacent bone could have reached these cells.
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From page 219... ...
Hasterlik22 and Hasterlik et al.23 further elucidated the role of radon by postulating that it can diffuse from bone into the essentially closed airspaces of the mastoid air cells and paranasal sinuses and decay there with its daughters, adding an additional dose to the epithelial cells. A significant role for free radon and the possibly insignificant role for bone volume seekers is not universally acknowledged; the ICRP lumps the sinus and mastoid mucosal tissues together with the endosteal bone tissues and considers that the dose to the first 10 ,um of tissue from radionuclides deposited in or on bone is the carcinogenically significant dose, thus ignoring trapped radon altogether and taking no account of the epithelial cell locations which are known to be farther from bone than 10 ~m.
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From page 220... ...
A clear implication of these data is that the connective tissue in the mastoid is thinner than the connective tissue in the paranasal sinuses. In a dos~metric study, Schienker73 confirmed this by determining the frequency with which the epithelium lay nearer to or farther from the bone surface than 75 ,um, at which level more than 75~o of the epithelial layer in the mastoids would be irradiated.
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From page 221... ...
Working from various radium-exposed patient data bases, several authors have observed that carcinomas of the paranasal sinuses and mastoid air cells begin to occur later than bone tumors. i~ 66 7\ In the latest tabulation of tumor cases,1 the first bone tumor appeared 5 yr after first exposure, and the first carcinoma of the paranasal sinuses or mastoid air cells appeared 19 yr after first exposure; among persons for whom there was an estimate of skeletal radiation dose, the first tumors appeared at 7 and 19 yr, respectively.
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From page 222... ...
and that the rate of tumor occurrence increases sharply at about 38 yr after first exposure for intakes of greater than 470 psi and may increase at about 48 yr after first exposure for intakes of less than 260 psi. As of the 1980 follow-up, no carcinomas of the paranasal sinuses and mastoid air cells had occurred in persons injected with 224 Ra, although Mays and Spiess46 estimated that five carcinomas would have occurred if the distribution of tumor appearance times were the same for 224 Ra as for 226 228Ra 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.
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From page 223... ...
As the response variable, they used carcinomas per person-year at risk and regressed it against a measure of systemic intake of 226Ra and against average skeletal dose. They fit mathematical functions of the general form: I= (C+aD+~BD2)
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From page 224... ...
The analysis of Rowland et al.67 assumes that tumor rate is constant with time for a given intake DS, and when based on skeletal dose assumes that tumor rate Is constant for a given dose De. The analysis also yields good fits to the data.
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From page 225... ...
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 ,uCi, respectively. The average skeletal doses were later calculated to be 23,000 and 9,600 red, respectively, which are rather substantial values.
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From page 226... ...
This cohort was derived from a total of about 1,400 pre1930 radium-dial workers who had been identified as being part of the radium-dial industry of whom 1,260 had been located and were being followed up at Argonne. By 1954, when large-scale studies of the U.S.
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From page 227... ...
The most inclusive and definitive study of leukemia in the U.S. radium-dial workers was published by Spiers et al.83 By including all the dial workers, male and female, who entered the industry before 1970, a total of 2,940 persons who could be located, they were able to document a total of 10 cases of leukemia.
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From page 228... ...
In summary, the evidence indicates that acquisition of very high levels of radium, leading to long-term body contents of the order of 5 psi or more, equivalent to systemic intakes of the order of several hundred microcuries, resulted in severe anemias and aleukemias. However, at lower radium intakes, such as those experienced by the British Juminizers and the bulk of the U.S.
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From page 229... ...
While five cases of leukemia were observed among 681 adults who received an average skeletal dose of 206 red, none were observed among 218 1 - to 2~yr-olds at an average skeletal dose of 1,062 red. The expected number of leukemia for the adult group was two, but the authors point out that the drugs often taken to suppress the pain associated with ankylosing spondylitis are suspected of inducing the acute forms of leukemia.
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From page 230... ...
Thus, while leukemia and diseases of the blood-forming organs have been seen following treatment with 224Ra, it is not clear that these are consequences of the radiation insult or of other treatments experienced by these patients. 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.
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From page 231... ...
There is no doubt that male and female lung cancers appear to increase with an increase in the radium content of the water, but in the case of female lung cancers the levels were never as great as observed for those who drank surface water. A sirn~lar situation exists for female breast cancer.
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From page 232... ...
In summary, there are three studies of radium in drinking water, one of which found elevated Sheaths due in any way to malignant neoplasm involving bone," the second found elevated incidences of blailder and lung cancer in males and Jung and breast cancer in females, and the third found elevated rates of leukemia. None of these findings are in agreement with the long-term studies of higher levels of radium in the radium-dial workers.
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From page 233... ...
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 224 Ra and for 226 Ra and 228Ra. When the time dependence of bone tumor appearance following 224 Ra 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: M(D,t`)
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From page 234... ...
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. At the low exposures that occur environmentally and occupationally, exposure to radium isotopes causes only a small contribution to overall mortality and would not be expected to perturb mortality sufficiently to distort the normal mortality statistics.
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From page 235... ...
For 226 Ra and 228 Ra the constant tumor rates given by Rowland et al.68 as functions of systemic intake are computed for the intake of interest, and the results are worked out with a table such as Table 4-7. For continuous intake with the dose-squared exponential function for bone sarcoma induction, it is necessary to decide whether to add the cumulative dose
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From page 236... ...
On the microscale the chance of a single cell being hit more than once diminishes with dose; this would argue for the independent action of separate dose increments and the squaring of separate dose increments before the addition of risks. In the mode} of bone tumor induction proposed by Marshall and Groer,38 however, two hits are required to cause transformation.
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From page 237... ...
Further efforts to refine dose estimates as a function of time in both man and animals will facilitate the interpretation of animal data in terms of the risks observed in humans. As indicated in Annex 7A, the radium-dial painter data can be a useful source of information for extrapolating to man the risks from transuranic elements that have been observed in animal studies.
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From page 238... ...
carcinomas in persons exposed to 226 Ra and 228 Ra are produced largely by the action of 222Rn and its progeny; continued study may offer insights into the ejects of occupational and environmental radon. The dosimetry of the mastoid air cell system is much simpler than the dosimetry of the bronchial tree; the mastoid mucosa may be the respiratory tissue for which the epithelial structure may permit accurate target cell dose estimates so that the risk to epithelial tissues per unit dose and the specific energy that has an impact on cells can be determined; this may improve our estimation of the carcinogenic risk in the epithelium of the respiratory tract.
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From page 239... ...
1906. Uber die Beziehungen der Grossenvariationen der Highmorshohlen zum individuellen Schadelbau und deren praktische Bedeutung fur die Therapie der Kieferhohleneiterungen.
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From page 240... ...
1959. A note on the distribution of radium and a calculation of the radiation dose non-uniformity factor for radium-226 and strontium-90 in the femur of a luminous dial painter.
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From page 241... ...
1986. Bone sarcoma cumulative tumor rater in patients injected with 224 Ra.
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From page 242... ...
1978. Bone cancer among female radium dial workers.
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From page 243... ...
1973. Protraction effect on bone sarcoma induction Of 224Ra in children and adults.
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From page 244... ...
1984. Mortality from cancers of major sites in female radium dial workers.
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