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Thymus Irradiation before Age One:   Start of Our Master Table

          Now we begin the task of estimating the average levels of breast irradiation for a typical year during the 1920-1960 period. At the start, a few reminders from Chapter 5, Part 2, may be helpful."

          o - Our Master Table considers 65 different age-years (age at irradiation) for a single, typical calendar year.

          o - Because our method is based on a typical year, ideally the population-size and the dose-level would be the same in every year (1920, 1921 ... 1958, 1959). In the real world, no year is just like the years before or after it, with respect to population-size and dose-level. But it is valid to "even out" the differences mathematically, and we do so, to produce one "synthetic" year which can be treated as typical.

          Except for some general considerations in Part 4, this chapter deals only with radiation received before age one, and only from diagnosis and treatment of "enlarged thymus" and "status lymphaticus." Thus, this chapter provides the entries for Column C of the Master Table (Chapter 39). Additionally, Part 1 of this chapter describes the origin of the entries for population in Column A of the Master Table, and Part 4 of this chapter provides the entries for natural background radiation in Column B of the Master Table.

Part 1.   Average Annual Breast-Dose from the Therapy

          We will begin with the 1985 study by Hildreth and co-workers of 2,856 infants who received such treatments in Monroe County, New York between 1926 and 1957. Data from Hildreth 1985 carry over to Hildreth 1989 (which is the next follow-up report).

          Actually, however, we must add approximately 375 additional children who were treated with radiation to the thymus during the period under study, but for whom the records were destroyed, so that follow-up could not be conducted on these. Whether followed or not, these additional children must, of course, be included, if we are to approximate that "all" children treated in Monroe County have been taken into account. See Item 3, below.

          o - Item 1:   What was the place of study? Five hospitals and four private radiologists in Rochester, New York, were engaged in the practice of thymus examination and subsequent therapy when deemed necessary. All of these facilities are in Monroe County, in "upstate" New York. The county is a single well-defined geographic location for which some essential population data are readily available.

          o - Item 2:   Can we regard the listed participants as truly representative of Monroe County for the relevant period? The answer is "Yes." The authors are quite explicit on this point. They tell us that the initial roster of subjects was developed by searching radiation therapy records maintained by five Rochester hospitals and four private radiologists to identify individuals who were irradiated for this condition in Monroe County between 1926 and 1957. And the report assures us that this series represents nearly all the individuals who received x-ray treatment for this condition. In Item 3, we point out that the key word here is "almost," since there are some 375 additional children who were treated, but not followed.

          o - Item 3:   How many persons were treated? 2,856 were treated, with "nearly" half females. Therefore, we use 1,428 as the number of female infants treated. But Hildreth (1989 at p.1281) states:   "...As a result, this series includes almost everyone who received x-ray treatment for an enlarged thymus in Monroe County. The only records not reviewed were those of a private radiologist who had destroyed his records on retirement in 1944. It is estimated that he treated fewer than 400 children for this condition..."

          Since our analysis seeks to know how many children were actually treated, and not necessarily who were followed, we can not exclude the "fewer than 400" additional treated children. We can simply make the best approximation of how many were treated in this group. We shall use a value of 375 additional children treated, to interpret "fewer than 400."

          Since approximately half the treated children were female, we should add (375/2), or 187 female children with thymus irradiation. The total number of female children treated in Monroe County becomes (1428 + 187), or 1,615 female children as the total treated group.

          o - Item 4:   What ages are represented in the treated group? All the infants were under 1 year of age, with most of them under 6 months of age at treatment. The age between birth and the first birthday is called "age-year 0" in our Master Table.

          o - Item 5:   What was the total period over which the treatments continued? We are told that the treatments were between 1926 and 1957. We shall return to the duration of the study in Items 7 and 12.

Total Female Infants below Age One, per Year, USA and Monroe County

          o - Item 6:   We need to know the total population of female children below age one in Monroe County for the average year in the period 1920-1960. We shall get this value in an indirect fashion. The Master Table (Chapter 39) gives the number of female persons in each age-year in the entire USA from age-0 through age-64, in its Column A. Now we must ask how the numbers in Column A were derived.

          From the World Almanac, we obtain the female population of the United States for each decennial year, 1920 through 1960. The average for this period is 69,037,400 females, all ages combined. Now we need to distribute the population by ages. In Table 24 of Radiation and Human Health (Gofman 1981), we have the life-table values for the number of female persons in each age-year for a total population of 131,000,000 females (out of a total population of 250,000,000). So for the mid-period of 1920-1960, the entries for Column A of the Master Table are obtained by the following relations:

          The entry for Col.A of the Master Table for age-0 is 905,213 females.

          Next, we find out how the population of Monroe County compares with the population of the United States. For this comparison, the year chosen is not crucial, provided the composition by age or other features did not change materially with time. We shall use 1960 data from the 1962 County and City Data Book for this purpose.

          So, the number of female infants, age-0 in Monroe County in a typical year between 1920-1960, was:   (The ratio Monroe / USA) times (the entry for the entire USA from Col. A):
((586,309) / (179,333,000)) x (905,213 from Col.A) = 2,959 female children, age-0, per year.

Total Age-0 Females irradiated per Year, Monroe County

          o - Item 7:   How many female infants in the age-0 group were irradiated per average year in the Hildreth Study? For 1,615 irradiated in-toto (Item 3), and a 31-year period over which such irradiations occurred, the average per year = 1,615 / 31 , or 52.1 .

Breast-Dose per Treated Child, and Its Adjustment for Supra-Linearity

          o - Item 8:   We need the average dose to the breast-pairs for the irradiated children. Dr. Marvin Rosenstein (in Hildreth 1985, p.386) has estimated the average breast-pair dose to be 69 rads for the irradiated children. He provided the distribution of absorbed dose by percentiles, shown in the following tabulation. In the righthand column, we show our downward adjustment for supra-linearity, to be discussed below.

%         Dose Range        Mean Dose         Each Dose,
              to               to            Adjusted for
            Breasts          Breasts      Supra-Linearity
25%        0 to 3 rads       1.5 rads           1.5 rads
25%      3 to 9.5 rads      6.25 rads          5.75 rads
25%     9.5 to 95 rads     52.25 rads         29.78 rads
15%     95 to 212 rads     153.5 rads         65.39 rads
 5%    212 to 287 rads     249.5 rads         99.30 rads
 4%    287 to 491 rads       389 rads        154.82 rads
 1%    499 to 705 rads       602 rads        239.60 rads

          From the tabulated data, we calculate that the Mean Dose (weighted) for the entire group = 72.08 rads, before our supra-linearity adjustment. Given that Rosenstein had the actual raw numbers at his disposal, the agreement with his 69 rads is excellent.

          Except for 1.5 rads, each of the individual Hildreth/Rosenstein Mean Doses in the tabulation needs a downward adjustment for use in our analysis. The reason for this was first mentioned in Chapter 5, Part 5, when we defined "conversion-factor" as any formula which says how many radiation-induced cancers result from each rad of dose. Then we mentioned that the number of radiation-induced cases per rad varies with the size of the dose. As the dose per exposure rises, the effect per rad declines. The shape of this supra-linear "dose-response" relationship is depicted and discussed in Chapter 40, Part 2, Discussion of Box 3.


O - Adjustments For Use Of Low-Dose Conversion-Factors.

Whenever a dose per medical procedure is above 5 rads, we adjust the stated dose downward by the appropriate factor in Column C. The adjustment factors in Column C prevent an exaggeration of cancer-effect when we use low-dose conversion-factors in the Master Table. The adjustment is based on the supra-linear curvature of the dose-response, which is shown by the figure in Chapter 40.

          Col.B:   These entries are for average increase in cancer-rate per rad (cSv) among 10,000 people. They come directly from Gofman 1990, Table 14-A, Column F --- which matches the figure shown in Chapter 40 of this breast-cancer book. The entries apply to the combined observations for all ages, both sexes, all cancer-sites. However, we are not interested in the absolute values here. We are interested in the ratio of each entry to the low-dose entry at 5 rads, because the ratio reflects the declining carcinogenic potency of the average rad, as dose increases.

          Col.C:   These entries are each entry in Col.B divided by 4.716, which is the 5-rad reference value in Col.B. Factors for other specific doses can be calculated from Gofman 1990, Table 14-A.

    Col.A                Col.B                      Col.C
                 Avg. Increase in Cancer-   Adjustment Factor of Dose,
 Dose per         Rate per 10,000 People      for Use of Low-Dose
 Exposure            per Rad (cSv)             Conversion-Factors

   5 rads & below        4.716                      1.000
  10 rads                3.966                      0.841
  20 rads                3.335                      0.707
  30 rads                3.014                      0.639
  50 rads                2.652                      0.562
  70 rads                2.438                      0.517
 100 rads                2.230                      0.473
 150 rads                2.015                      0.427
 200 rads & up           1.875                      0.398

          Due to the supra-linear bend in the dose-response, we can not use the same conversion-factor for different dose-levels. A great variety of dose-levels occurred, not only in the Hildreth Study but also in other sources of breast-irradiation examined in subsequent chapters. So we had to make a choice in constructing our Master Table. We could (1) use a great variety of conversion-factors adjusted in the Master Table for both dose-level and age, or we could (2) adjust the dose downward as needed in various chapters and then use a single low-dose conversion-factor adjusted only for age in the Master-Table. Both approaches are equivalent, and we chose the latter one so that each adjustment (dose-level, then age) would be clear.

          The box above, "Adjustments for Use of Low-Dose Conversion-Factors," provides examples of the way in which the carcinogenic potency or "effectiveness" of the average rad declines, as total dose increases.

          We can use the box to make an approximate adjustment for the 69-rad average breast-dose in the Hildreth Study. If we use the Adjustment Factor of 0.517 (for 70 rads), the Adjusted Dose would be (69 rads x 0.517), or 35.67 rads. This is the same as saying that 35.67 rads --- at the same per-rad potency as the per-rad potency of 5 rads --- is equivalent to 69 rads at reduced per-rad potency.

          Because Rosenstein (in Hildreth 1985) provided us with the input to the average dose of 69 rads, we could adjust each dose-level separately. The separate adjustments were already shown in the righthand column of the earlier tabulation. From those entries, the average weighted dose is 32.62 rads, adjusted for use with low-dose conversion-factors. So:

          Final Adjusted Mean Dose = 32.62 medical rads, adjusted for supra-linearity.

Conversion of Individual Dose to Population-Dose

          o - Item 9:   Population Exposure. We need now to go through the steps to get the average population exposure from this irradiation, rather than the raw individual doses per treatment. In Item 6, above, we calculated that there were 2,959 female children in the age-0 group during a typical year. In effect, we must now distribute the dose received by only 52.1 infants per typical year into the whole population of age-0. There are two steps:

                    (a) the calculation of person-rads, and
                    (b) the calculation of average dose taking the whole population into account.

          Let us start with person-rads. When we have a group of people who each receive a radiation dose, we can calculate a measure which describes the overall harm for the group. Two rads each to 10 persons is twice as harmful as two rads each to 5 persons. We formalize this by writing:

          Person-rads = (c number of persons) x (d number of rads) = cd person-rads.

          In our case of infant breast-irradiation in Monroe County, we have in a typical year:   52.1 persons x 32.62 rads = 1699.5 person-rads.

          And now the second step produces the average exposure in the entire population of Monroe-County infants in the age-0 group:

                              1699.5 person-rads
Population Exposure, rads, = -------------------- = 0.574 rad per year.
                                 2959 persons

Why There Are No High Doses in Our Master Table

          We stop to call the readers' attention to the fact that high doses like 69 rads to individual infants (Item 8) become low doses like 0.574 rads to the average infant, after the adjustment for supra-linearity has been made and after the infants who received no dose at all have been included. So there is no contradiction between high doses reported in the narrative parts of this book, and the low doses which characterize the entries in our Master Table.

Part 2.   Average Annual Breast-Dose from the Diagnosis

          Thus far, we have considered breast-dose received by the infants who received therapy for enlarged thymus, but now we must ask about breast-doses received by the treated children and by additional children in the process of selecting specific infants for the treatment, not only in Monroe County, but nationwide. The decision almost always was based upon diagnostic roentgenology.

          But the number of age-0 infants irradiated in the diagnostic phase of thymus disorders is uncertain. It makes a very big difference whether it was routine practice in many hospitals to examine every newborn with x-rays, or to examine only the heavy newborns (see Chapter 7, Part 6), or to give prophylactic treatment to asymptomatic infants if the parents were fearful of sudden infant death, or to use x-ray examination only on age-0 infants who were already having overt problems.

          We have tried to pin down the pre-therapy facts for the Hildreth Study, in vain. This is not a criticism of the study. Far from it. Sometimes the past just can not be reconstructed in detail. There is another source, much earlier than Hildreth, which describes the pre-therapy "facts" (and lack thereof) quite well, and we shall quote that discussion here. The reference is the paper by James W. Pifer and his co-workers (1963, pp.1338-1339) concerning an earlier follow-up of this Rochester study-group:

          "The degree of heterogeneity cannot be determined because the symptoms were diagnosed, and the children treated in nine radiology departments and private offices over the 31-year period. The various diagnostic criteria used to select the cases are unknown and probably varied considerably since each practicing radiologist in the early period had been trained in a different medical center. The diagnosis for one subgroup of children, for example, was based on fluoroscopic examination, while that for another was made by examination of routine roentgenograms of all newborn infants. Also, the indications for treatment differed with each radiologist, pediatrician, or general practitioner. Frequently parents insisted that their child be treated. Some pediatricians fluoroscoped all infants routinely, but probably most children treated in private offices had symptoms at presentation which prompted a radiologic examination. In hospitals, also, indications for treatment varied greatly. In one hospital, only very sick infants were treated, whereas in another hospital, all newborn babies with thymic enlargement, determined by routine roentgenographic examinations, were given therapy, even if asymptomatic. Because of these heterogenic factors, it was impossible to select a control group comparable in all respects except for radiation exposure."

          It is clear, for the Hildreth Study, that not all of the treated infants were newborns. Hildreth and co-workers state that "Approximately 90% of the irradiated persons were less than 6 months old at the time of treatment." Also it is unlikely that all newborns were screened in Monroe County, as we will see.

          We have estimated (Item 6) that 2,959 female children were born per year in Monroe County, and that 52.1 received therapeutic thymus irradiation during their first year of life. That is a rate of 1.76 %. If every consecutive newborn had been screened by x-ray examination for enlarged thymus, the number receiving therapeutic treatment would have been higher than 52.1 infants per year. Why do we say this? The percentage of newborn infants with "definitely enlarged" thymus was reported to be 11.2 % in Dr. Donaldson's radiologic study of 2,000 consecutively born infants in Michigan (Donaldson 1938). The percentage was reported to be 3 % to 4 % in the Conti-Patton radiologic study of 7,400 consecutive newborns in Pennsylvania (Conti + Patton 1948, Tables 3 and 5). The difference in these two studies may reflect judgments about what qualified as "enlarged," or may reflect different examination technics. In both studies, however, the rate of treatment for newborns alone was higher than our estimated rate for Monroe County even when infants up to the first birthday were included there.

          In any case, we are interested in the typical situation nationwide. Except for research studies like Donaldson 1938 and Conti-Patton 1948, we will assume that radiologic screening of every newborn was not typical. But then, what was the typical way in which infants, age-0, came to receive x-ray therapy for enlarged thymus? We know of no documents which answer this question. We are going to lean toward assumptions which may produce a great underestimate of total breast-dose from the radiologic screening-process of infants at age-0, prior to therapeutic irradiation.

          o - Item 10:   We consider that Donaldson's earlier studies of 1930 are of consequence in making an estimate. He studied one group of 165 infants recently born and in hospital but referred to the roentgenology department for thymus exam because someone felt that there might be a problem of enlarged thymus. Donaldson's finding was that 41% of these infants were positive for definitely enlarged thymus gland.

          He studied a separate group of infants, ranging in age from newborn to six months of age, who were referred to roentgenology from the outpatient department based upon some suspicion about the thymus. In this group he found 40.7 % who received a diagnosis of definitely enlarged thymus gland.

          We can round off these results to 40% of both groups. Therefore, we estimate that 2.5 infants were subjected to diagnostic examination by x-ray for each infant subjected to thymus therapy by irradiation. We recognize the likelihood that this may be a serious underestimate of the number subjected to diagnostic examination.

          o - Item 11:   We are not provided with a dose-value for those undergoing thymus evaluation by x-ray. We shall assume that only half of the diagnostic examinations used any fluoroscopy, and that when fluoroscopy was used, the breast-dose was only 5.0 rads. In other words, we will assume that the extensive fluoroscopic observations recommended by Dr. Pancoast (Chapter 7, Part 1) were not in general practice. We will assign an average breast-dose of only 2.5 rads per diagnostic thymus examination. Again, this may well be a significant underestimate. But using these approximations for the diagnostic work-up, we have for Monroe County, per year:

          Persons examined = (52.1) x (2.5) = 130.3
          Person-rads (diagnostic) = (130.3 persons) x (2.5 rads)
                                                                = 325.8 person-rads to breasts.

          These 325.8 person-rads were delivered among 2,959 persons. So population exposure would have been (325.8 person-rads) / (2,959 persons), which means an average dose of 0.110 rads. (In the low-dose range of 5 rads or less, no adjustment for supra-linearity is needed.)

          Final average dose (diagnostic) per year, age-0 = 0.110 rads.

Part 3.   Average Annual Breast-Dose from Therapy plus Diagnosis

          Our total average annual dose is now 0.574 rads from therapy + 0.110 rads from diagnosis, or 0.684 rads per year.

          o - Item 12:   Did this occur in every year, 1920 to 1960? The Hildreth Study tells us about the experience in Monroe County over a 31-year period between 1926 and 1957. No one states or suggests that such irradiations were not going on there before 1926. Knowing as we do that the "enlarged thymus" story was growing, not declining, in the early 1920s, we think it highly unlikely that no radiation therapy for it was done in Rochester, New York, until 1926. We think it would be a mistake to deduct for the period 1920-1926.

          At the other end of the time period, the Rochester study does not state that the practice was entirely discontinued precisely in 1957 either in Rochester or nationally. But we do believe that the practice of thymus radiation was declining in those years. We consider it appropriate to make a correction for the decline, and we shall do so in the most radical manner, namely by assuming zero dose for the last 3 years (between 1957 and 1960). So we reduce our dose to breasts as follows:

          Rads, total = ((37 years at 0.684 rads) + (3 years at 0 rads)) / 40 years.
          Rads, total = 0.633 rads per year, to be entered into the Master Table.

          This entry, 0.633 rads, goes into Column C of the Master Table. There is only one entry in Column C because the age-0 group is the only age-group involved in the Hildreth Study.

Use of the Hildreth Data As Typical for Nationwide Practice

          Is generalization nationally from the Rochester experience a reasonable action? In our opinion it is. We have reviewed many other papers and many comments in discussions of papers. Some of these involve studies of thousands of infants tested and treated within a month of their birth in the hospital. And a number of these studies put every child consecutively born in the hospital through the "enlarged thymus" screening. We know of no reason to believe that the Rochester experience was abnormal in radiation dose or in frequency of therapy. On the contrary, what we have read is consistent with regarding the Rochester experience as typical for the nation.

Did Thymus Irradiation Really Induce Cases of Breast-Cancer?

          The Hildreth papers are flagged in our Reference list as papers which confirm the radiation-induction of breast-cancer. And Hildreth 1989 is mentioned in Chapter 2, Part 2, when we addressed the question:   "Can breast-irradiation during infancy and childhood really cause radiation-induced breast-cancer in adulthood?" Yes. The Hildreth finding is confirmed also by study of atomic-bomb survivors who were infants in 1945, at the time of the bombings.

Part 4.   Some General Comments about the Master Table

          In subsequent chapters, we will be re-using many of the same steps required to develop the entry for Column C of the Master Table. But in one aspect, the entry in Column C is unusual:   It is solitary. There is only one age-year filled in. For this reason, we wish to contrast it immediately with a column which will have every age-year filled in:   Column B.

Developing the Entry for Column B of the Master Table

          Column B describes the radiation received by everyone over the total body from natural radiation, exclusive of radiation from radon and its daughter products. The general estimate is that, in the USA, such radiation occurs at a level of about 0.1 rad per year, with some regions receiving nearly double that level. These are rads calculated for radiation more energetic than medical x-rays. Therefore, we have reduced the natural radiation dose to 0.05 medical rads per year (see Chapter 3, Part 1).

          Readers will see the identical entry of 0.05 medical rads from the very top of the Master Table to the bottom (from zero years of age through 64 years of age). Of course, there is nothing one can do to remove this source of radiation. Its effects deserve entry into our calculation of total radiation effects. And, of course, natural radiation has not varied from the 1920 period to now.

Developing Entries for the Other Sources of Breast Irradiation

          Most of the other entries into the Master Table, which the reader will come to understand, require going through an item-by-item checklist of issues very similar to, but not identical with, those shown here for the enlarged thymus problem in age-0 infants, as reported from Rochester. There are other thymus studies for different age groups (Columns D and M). And there are other totally different reasons for breast irradiation. We shall be going through each of these additional sources in the coming chapters.

The Master Table:   Understanding the "Horizontals" and the "Verticals"

          All of the entries in the Master Table are for one "synthetic" year --- that year which is the typical year for the entire 1920-1960 period. We feel it is important to repeat this, lest someone be asking "Which year?" and seeking in vain for a particular calendar-year in the Master Table.

          We have just illustrated how two columns (B and C) of the Master Table were constructed. Now let's consider the construction of rows. Each row must accommodate all the entries for all types of breast irradiation for a particular age-year. Thus, the row which pertains to entries for age-15 has no entries for any age other than for age-15. There may be similar entries for a given source of breast irradiation in other rows, but each row pertains uniquely for one age-year.

          Horizontal addition in a particular row is an essential final step after all the entries for breast-dose have been made. The sum of all the horizontal entries tells us, for a typical year in the 1920-1960 period, what the total breast-dose of radiation is from all the measurable sources, for one specific age-year in the range from 0 through 64 years of age.

          Each horizontal row, with all entries of dose summed, provides that information for one age-year at a time. There is no requirement that any particular row have numerical entries in each box along the horizontal row. If there are no available data for a specific source of breast irradiation for a specific age-year, then there will be a blank entry in that horizontal row for that radiation source. We do not put zero into such rows. We do not know what the entry might be if all knowledge were available to us. So, for now, we leave such a row blank, with the possibility that some positive entries will be added at some later date, from new information. There are no possible negative entries in any such row.

          Since each horizontal row finally gives us a sum of all the breast-doses for a particular age-year, it follows that these 65 sums are the annual radiation doses which cause a year's production of radiation-induced breast-cancers, which are put "on the shelf" to be delivered later. And we know from the "Law of Equality" in Chapter 4 that the number produced per year will be the same as the number clinically observed (delivered) each year, if the annual average radiation dose (in person-rads) is maintained indefinitely.

# # # # #

The "Take No Chances" Approach with Suspicious Thymuses

1926     "In any suspected case, therefore, even if the radiologist can find no positive evidence of enlargement, therapeutic application of the x-rays or radium should be made until the shadow is reduced to normal proportions or until clinical symptoms have entirely disappeared." And:

          "A `suspected' case may be defined as one which has shown any evidence of respiratory difficulty not clearly due to causes other than enlargement of the thymus. I do not believe that the so-called status lymphaticus can often be diagnosed with certainty antemortem. Suspicion should attach to the child, especially if under 3 years of age, who exhibits widespread lymphatic hyperplasia with or without splenic enlargement. No operative interference on such a child should be attempted without x-ray studies, whether the thymus area is enlarged to percussion or not."

          "If all borderline cases are to be suspected, it is inevitable that there will be unnecessary use of the x-rays, both in diagnosis and in treatment. Until diagnostic criteria are available for differentiating the harmless from the harmful thymus, there seems to be no choice, since we are dealing on the one hand with a potentially fatal disease and on the other with a harmless but most efficient preventive and curative measure [emphasis added]."

          "In some clinics, the routine preoperative technic for the tonsil and adenoid operation includes a radiographic study. With the criticism that this seems to be an unnecessary precaution, the surgeon who has lost an operative case from thymus asthma probably will not agree."

          "Finally, it may be permitted to point out that the very nature of thymus death is calculated to destroy a physician's professional poise. The death of any patient is a cause for more or less self-reproach, but an unexpected and possibly avoidable death is not only a reproach to the physician, but in these days, an excuse for the laity to interpret it as due to professional neglect. From this standpoint, it may be admitted that preoperative study of all patients under 4 years of age by x-rays is justifiable technic."

From J.C. Gittings, M.D. "Thymus Death in Early Life:   Its Clinical Differentiation," The Atlantic Medical Journal pp.853-857. September 1926.

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