Cancer Causes (XIIIb)

Excerpts (continued) from the book Preventing Breast Cancer: The Story of a Major, Proven, Preventable Cause of This Disease (John W. Gofman, M.D., Ph.D.), continued from part 1.

The "Master Table" referred to in the below extracts can be seen at www.ratical.org/radiation/CNR/PBC/chp39.html#MasterTblA-J.

What Is the "Story" of A, B, and C?

Curves A and B are nice, smooth curves suggesting nothing biologically EXOTIC. Nonetheless, their relationship generates a stunning PEAK in Relative Risk, and therefore in percent increase per rad, for early-onset cases diagnosed at an average age of 32. After its peak value of 20, Relative Risk declines dramatically --- down to 4.3 for diagnosis at age 38, down to 3.0 for diagnosis at age 44, and then remaining above 2.0 for diagnosis beyond age 44.

What is the meaning of this peak for early-onset cases?

When two curves (for irradiated and non-irradiated groups) have been near the zero-rate during a follow-up study, the addition of just a few cancer cases to one curve earlier than to the other curve has to cause very high Relative Risks --- even when the higher rates are not very high at all. Such events are illustrated for ages 30, 31, and 32 at diagnosis. At age 29 and younger, the breast cancer rates are shown as equal in the irradiated and non-irradiated groups. Curves A and B are right on top of each other, at the zero-rate. At age 30, both rates increase a LITTLE (see the tabulated values): Non-irradiated moves to 0.1 case per 10,000 women, and irradiated moves to 1 case per 10,000 women --- a very low rate compared with what is coming later. Nonetheless, this slight change means that the risk goes "overnight" from being equal in both groups, to being 10-fold higher in the irradiated group --- all because of 1 case per 10,000 women. At ages 31 and 32, additional small changes drive the Relative Risk to its peak at 20.

In computing Relative Risks, the spontaneous rates are the denominators of the fractions. As long as the spontaneous rates remain near zero, even modest growth in the exposed rates will generate enormous Relative Risks. The phenomenon does not happen when analysts look at the women exposed at older ages, because the spontaneous rate is already well above zero when analysts begin comparing the irradiated and non-irradiated groups.

The Key: A Baseline Rate Near Zero

For A-bomb survivors irradiated below age 20 and diagnosed with early-onset breast cancer before age 35, the exceedingly high Relative Risks (and percents increase per rad) are real --- but their initial magnitudes turn out to be temporary. Relative risks compute at a less spectacular level as soon as the spontaneous cancer-rates have their own rapid climb (away from zero) in the denominator of such ratios. We have been able to mirror these observations, in a generic way, with Curves A and B, which generate Curve C. The three curves also mirror the observation that the less spectacular Relative Risk (for cases diagnosed after age 40) persists at an approximately constant level through the 1985 follow-up (see Land's data in Part 2; confirmation in Tokunaga 1994, p.221).

In our opinion, "Three Curves with a Story" means this: Analysts of the A-Bomb Study need not invoke special concepts about the cancers or the hosts, in order to explain the much higher Relative Risk observed for early-onset cancer-cases than for the cases diagnosed at older ages. The observed difference in Relative Risk, due to radiation, can be explained by the fact that both curves rise from a baseline rate which is very close to zero.

True Meaning of "Less Spectacular"

The "less spectacular" Relative Risk really reflects a much greater number of radiation-induced breast cancers than the peak Relative Risk. In figures like ours, it is the AREA under a curve which reflects the aggregate number of cases observed. The area under Curve B minus the area under Curve A reflects the EXCESS number of cases induced by radiation. Clearly, the difference in the two areas for ages 30 through 35 is very small compared with the difference in the two areas beyond age 35. The "less spectacular" Relative Risk not only endures much longer, but it reflects the multiplication (by radiation exposure) of a much higher spontaneous cancer-rate.

Part 5. The Need for Action

How many women who have developed early-onset breast cancer over the past half-century KNOW whether or not they were irradiated in infancy?

We wonder. Readers of this book are going to learn about a very large number of female children who suffered the fate of such undesirable irradiation of the breasts --- even before they left the nursery of hospitals where they were born. Others suffered nearly the same fate in their first few years of life.

No one can alter the past. But from the past, we can learn the key to preventing many, many cases of early-onset and later breast cancer. Prevention.

Time Would Tell ... And Time Has Told

Once upon a time (1977), the United Nations Scientific Committee on the Effects of Atomic Radiation, known as UNSCEAR, speculated that breast-irradiation during infancy and childhood might have "minimal" cancer consequences because "only a few breast cells" exist to be irradiated before puberty (UNSCEAR 1977, p.389). Since these few cells must be the progenitors of all future breast-tissue cells, we rejected that line of reasoning (Gofman 1981, p.249-250).

In 1994, the issue seems settled. Tokunaga et al (1994, p.215, Table VI) report statistically significant excess breast cancer rates in the bomb-irradiated women who were ages 0-9 years old in 1945 --- as well as in the group which was 10-19 years old in 1945. Both groups, each analyzed separately for the period 1950-1985, show the excess. And both groups have much higher risks per rad than risks for women who were 20 years of age and older at the time of the bombings.

The Irradiation of Children Today

The era of irradiating children is far from past. The diagnostic use of x-rays can be extremely helpful in pediatric medicine. For example, we are aware that a high number of x-rays may be taken of premature infants and others in neonatal intensive care units (NCRP 1989). The use of x-rays is also high in association with birth defects (especially heart problems). The use of x-rays for children involved in automobile and other accidents can also be high, especially if there are insurance battles and lawsuits.

The task mandated by the evidence in this chapter is not to stop such examinations, but rather, it is to make sure that the frequency and doses are kept to the minimum really NEEDED. In Section 4 of this book, we have some suggestions about what concerned parents, physicians, and medical schools can do.

CHAPTER 9: Thymus Irradiation to Reduce Sudden Death in Children

Part 1. The Thymus and Sudden Death: A Pervasive Fear in Medicine
and in the Public

"A thymic death is one of the supreme tragedies of surgery. An apparently healthy child dies during the administration of an anesthetic, during or after an uncomplicated tonsil and adenoid operation, or, as recently happened, during a simple circumcision. Again, as reported by one of our medical examiners [coroners], a child was standing on the edge of the sidewalk. A runaway horse dashed by and the child dropped dead. At autopsy the condition known as status lymphaticus was found; that is, there was an enlarged thymus and a hypertrophy of all the lymphoid structures of the alimentary canal, these structures being the solitary follicles Peyer's Patches and the mesenteric glands. This slight pathology was all that was found to explain the unexpected death." This statement in 1926 is from Dr. Harris P. Mosher, Dr. Alexander S. MacMillan, Dr. Frederic E. Motley (Mosher 1926).

By no means was the concern about disorders of the thymus gland confined to infants under one year of age. Indeed, as we shall see in this chapter and the next, such concern was evident for all ages up through the 'teens. There were long-standing ideas concerning the thymus gland and sudden death; the availability of x-rays did not help to dismiss these long-standing worries, particularly in situations of stress, of which anesthesia and surgery were prime examples.

We continue with a quote from M.L. Janower and O.S. Miettenen, concerning policy at a major institution in Boston, Massachusetts (Janower 1971, p.753):

"From 1924 to 1946, it was the policy of the Massachusetts Eye and Ear Infirmary in Boston to apply prophylactic irradiation in every case in which an ‘enlarged’ thymus gland was diagnosed in infancy. The assessment of the size of the thymus gland was based upon an anteroposterior roentgenogram of the chest taken in expiration with the patient in the supine position. Whenever the width of the superior mediastinum was at least half the width of the heart the gland was characterized as `enlarged' or `suspicious,' and the child was given radiation treatment; if the gland was less than half the width of the heart the child was not given radiation. On the basis of these criteria, 1,131 children received thymus gland radiation in the 22-year period." Despite one use of the phrase "in infancy," the irradiated children were an average of 4.7 years of age at exposure.

At the end of this chapter, we will evaluate annual average breast-dose from such treatment of children, ages 1 through 9, for Column M of our Master Table.

Part 2. Enlarged Thymus, with and without Symptoms: Dr. O'Brien

The issues surrounding such treatments were succinctly and well stated by Dr. Frederick W. O'Brien in 1929, at the annual meeting of the American Roentgen Ray Society. We quote O'Brien (1929, p.271):

"For some years now, it has been the routine in certain hospitals to examine all children roentgenologically before submitting them to a general anesthetic. If there is found what is thought to be an enlarged thymus gland, a prophylactic roentgen treatment is given, because of the rather well-entrenched belief that an enlarged thymus gland is an integral factor of the syndrome of so-called status lymphaticus, a reputed cause of otherwise unexplained sudden death." He also described the controversy:

"An enlarged thymus as a symptom-producing organ, and the roentgenologist's ability to diagnose it, has not gone unchallenged. Status lymphaticus, indeed, as a pathologic entity is declared a misconception."

And the two propositions posed by Dr. O'Brien:

1. Is there a symptom-producing enlarged thymus in infants that can be diagnosed by the roentgen ray and relieved by irradiation?

2. Is there an enlarged thymus without symptoms in infants, children, and young adults, which represents objective evidence of status lymphaticus, and which can be diagnosed by the roentgen ray and should receive prophylactic radiation?"

Uncertainty about Where the Truth Lay

Dr. O'Brien appeared uncertain about where the truth lay. With respect to mortality, he divided the cases as follows (1929, p.273): "Cases of thymic death are readily referred to two distinct groups, those with and without symptoms." About cases with symptoms:

"Accepting the concept of the evolution of the thymus, I do not find any student of the subject who does not concede the existence of a symptom-producing thymus at least in infants. The groups with symptoms usually display the so-called syndrome of thymic asthma, characterized by attacks of inspiratory dyspnea, inspiratory stridor and the so-called Rehn's symptoms, the expiratory swelling of a tumor [meaning a fulness, not a real tumor], the cranial thymus-end in the jugulum." And about cases without symptoms (p.274):

"The other group of so-called thymic deaths occurring in older children in an apoplectiform manner without premonitory symptoms is the one responsible for the current hospital practice to which I have referred of roentgenographing all children before anesthesia." And:

"It has been suggested that these sudden deaths have been due to improper anesthetization and poor operative judgment and technique [see Part 3]. But they occur even without anesthesia and following minor or no surgical procedure at all. These are the cases that are the tragedies of practice and if personal, or under one's immediate authority, cause one to pause."

Prophylactic Irradiation: Claims of Success vs. the Skeptics

Dr. O'Brien continued (p.274):

"Mosher, well aware of the newer concepts, clings to the old idea that the thymus is involved in these sudden deaths, and he has the added argument of no sudden death in his great clinic since his study with MacMillan and Motley (Mosher 1926). They found out of a total of 2,344 children, a positive thymus shadow in 7.5 per cent. Of the positive cases treated by roentgen radiation all were successfully operated on and since employing the routine roentgen examination of the mediastinum, they have had no sudden unexplained death under anesthesia." And (p.274):

"This has been the practice for two years at the Boston City Hospital and the Cambridge Municipal Hospital with both of which I am connected. At the Boston City Hospital, out of a total of more than 2,000 children, there has been but one unexplained death under anesthesia, which occurred recently. There had been no prior roentgen examination and there was no autopsy. At the Cambridge Municipal Hospital, in 526 cases, there have been no deaths. A survey of the chests showed a ‘broadened mediastinal shadow' in +6 percent."

We will return to Dr. O'Brien's conclusions in Part 4.

Others were much more skeptical about the 1926 report by Dr. Mosher and colleagues, on the grounds that the absence of deaths was not proof that the roentgen treatment of ostensibly enlarged "silent" thymuses was the real reason for such absence.

Boston: "Nearly All Infants Are X-Rayed Promptly"

During the discussion of Dr. O'Brien's paper, Dr. R.D. Leonard of Boston commented as follows (in O'Brien 1929, pp.276-277):

"We have to construct some theory along which to work, and as our empirical results and our interest and enthusiasm in this theory develops we subconsciously forget that we are working simply on a hypothesis. I think this is something we need to bear in mind in relation to this thymus problem. As we see from these two papers, we know what is generally thought about the thymus gland, but very little has actually been proven." And:

"In Boston, as in various other places, the thymus gland is at the present time a popular subject for discussion. Our obstetricians are very much interested in the thymus gland. Nearly all infants are x-rayed promptly and if any sort of a shadow is seen in the mediastinum, treatment is instituted. In the sudden, unexplained deaths, we recognize the thymus gland as a probable cause. Therefore on account of the present popular interest in the thymus gland, I would add this word of caution that, as far as possible, we as roentgenologists should be sure we know what we are talking about."

The statement by Dr. Leonard strongly indicates that the practice of roentgenographing "nearly all infants" was not confined to research studies. One implication: Our estimate of breast-dose from the screening-process itself in Chapter 8, Part 2, Item 10 is almost certainly a serious underestimate.

Part 3. The 1914 Edition of "Anesthesia": Dr. Gwathmey

In his 1914 Edition of "Anesthesia," Dr. James Tayloe Gwathmey made some quite illuminating comments about the so-called Status Lymphaticus deaths which occurred in relation to anesthetic administration (p.331):

"Status Lymphaticus. Definition. Status lymphaticus or thymicus, or lymphatism, is a condition of infancy and childhood, marked by hyperplasia of the lymphatic structures, spleen and bone marrow, and persistence of the thymus gland (Stedman). It has also been defined as a condition of unstable equilibrium, coma, convulsions and vomiting accompanying hyperplasia of the persisting thymus (Gould); and as a morbid state due to excessive production or growth of lymphoid tissues, such as the thymus and thyroid glands, resulting in impaired development, lowered vitality, and sometimes death (Dorland)." And:

"History. As early as 1614 attention was called by Felix Plater to the fact that the thymus was enlarged in three cases of sudden death from dyspnea in one family. In 1823, and again in 1829, Kopp mentioned the association of the enlargement of the thymus gland with sudden death. Paltauf, in 1889 and 1890, collected, for the first time, a large number of cases of sudden death in adults, in which there was enlargement of the tonsils, lymphatic gland system, the follicles at the base of the tongue, the spleen, and the thymus gland, with narrowing of the aorta. Kundrat, in 1895, published ten cases of death immediately after anesthesia by chloroform or some mixture containing it, also one case in which ether was the anesthetic. Sudden deaths were noted after this time in many cases in which no anesthetics had been administered. Lymphatic hyperplasia had been found to occur in every chloroform fatality for the past twenty years in the children's clinic at Gratz. The first case recorded in England was reported by Wolff in 1905." And, in commenting on some features of such patients (p.332):

"Pasty complexion, a large amount of subcutaneous fat, and, in adults, a scant amount of axillary or pubic hair are usual; also the hair of the head has a peculiar dry brittle character ..." And (p.332):

"Most patients dying during or immediately after anesthesia have been young people or children, of flabby type, with enlarged adenoids, tonsils, thyroid (usually), and thymus; with narrow, high-arched palate, small mouth and throat, and weak heart sounds. During anesthesia a grayness of complexion or pallor is witnessed, with weak heart action and shallow breathing. Enlargement of the thyroid is said to exist in more than 50% of cases. Enlargement of the tongue is an important factor in diagnosis. The spleen has been found to be greatly enlarged in many cases, also the mesenteric, popliteal, axillary, and inguinal glands. Exophthalmic goiter may also be present, in which event heart failure under the anesthetic is probable. Congenital defects such as cleft palate and cleft kidney are sometimes associated with status lymphaticus. All patients have a pale, thin skin, pasty complexion, and usually subcutaneous fat. The glands of the neck are also sometimes enlarged. The above complex symptoms are noted when, given chloroform for any length of time, much of the anesthetic is absorbed and less secreted than is usual, with a consequent continual poisoning of the system until death occurs several days after the anesthetic. Sometimes delayed chloroform poisoning is mistaken for status lymphaticus. In status lymphaticus, especially in children, patients seem to dread the anesthetic more than is usually the case ..."

And Dr. Gwathmey offers a strong warning against using chloroform (p.333):

"From the study of a large number of statistics, the fact that chloroform is contraindicated cannot be questioned. Roberts concludes that ether is the safest anesthetic for all of these cases. Unquestionably, chloroform should be avoided in all suspected cases."

An Alternative Hypothesis about Deaths during Anesthesia

Dr. Gwathmey appeared skeptical about some of the cases alleged to be deaths due to status lymphaticus. At p.336, he cites Yandell Henderson (in Surgery, Obstetrics, and Gynecology, August 1911), who felt that unskillful anesthesia is more often the cause of death, and especially in adenoid and tonsil cases, than the status lymphaticus or heart disease. According to Dr. Gwathmey, Dr. Henderson wrote in 1911:

"Writers assume that status lymphaticus was the cause of death, although there may have been no autopsy. Even in those cases in which an autopsy was performed, the pathologist's report sometimes indicates that if he had not been told what to find, he would scarcely have found it."

And Dr. Henderson predicted as follows (according to Gwathmey):

"In many of the very best text books of pharmacology ... the practice of occasionally interrupting the administration of ether, and of allowing the patient to come for a few moments pretty well out of anesthesia, is expressly recommended. If anesthetists will only realize that this is a procedure which, above all others, should be shunned, the number of cases of so-called status lymphaticus fatalities, under anesthesia will, I believe, show a sudden and marked decrease."

We do not know how many anesthetists looked at Dr. Henderson's advice. But we do know that concern about sudden death in childhood, especially during anesthesia, caused decades of radiation screening and treatment for "Status Lymphaticus" and "enlarged thymus."

Differentiation of Thymus Disorders from Others ... with "Happy Results"

A number of writers (Dr. Henry Pancoast, 1930, in particular) have recorded their opinions that a variety of disorders in the thorax need differentiation from a possible enlarged thymus. Especially has this been true of bronchitis, bronchopneumonia, tuberculous adenitis, sinusitis with associated bronchitis, non-tuberculous lymphadenitis, and possibly other disorders.

Dr. C. Winfield Perkins is another who alluded to possible mis-identifications (1925, p.219): "Many sudden deaths of children FORMERLY SUPPOSED TO BE DUE TO BRONCHOPNEUMONIA [emphasis in original], congenital anomaly of the heart or acute intestinal indigestion, in which autopsies have given little information as to the cause of death, may have been due to unrecognized thymic hypertrophy. Such types of cases have recently been examined, considering the possibility of thymic enlargement, in spite of possible negative roentgen findings, [and have been] treated as such with the roentgen ray with happy results and the disappearance of the cyanosis and dyspnea."

Part 4. The Belief That the Radiation Did No Harm

In Part 2, we featured two pertinent questions of Dr. O'Brien. The second question concerned prophylactic use of radiation therapy for "enlarged thymus." In closing the discussion at the 1929 presentation, Dr. O'Brien made a very strong statement about the safety of thymus irradiation (p.280):

"As to the danger connected with treating the thymus, Hammar has studied the thymus for twenty years and should know something about it. He says there is absolutely no danger from roentgen treatment. The cases he has examined show an emigration of lymphocytes which return rather promptly after the treatment has ceased. That emigration of lymphocytes accounts for the decrease in the shadow" [when it does occur, of course].

This is not the first time we have reported assurances that such roentgen treatments appeared to be harmless (see Index: Safety assurances). And in an earlier paper than O'Brien's, Dr. Roy M. Greenthal was arguing as follows (1922, p.438):

"On the other hand, it seems reasonable to give these patients the benefit of a treatment which we know will reduce the size of the thymus gland. We are aware of the marked reduction in the size of the thymus that can be secured when patients with thymic symptoms are exposed to therapeutic roentgen rays or to radium emanations. We know of no reports of harmful effects following this form of treatment of the thymus and we have never observed any in this clinic."

Possible long latency in development of radiation-induced CANCER simply was not part of the discourse on the presumed harmlessness of roentgen-ray exposure in 1922. Nor did radiation-induction of cancer receive widespread attention for several additional decades.

Prophylactic Irradiation: "Not Only Desirable, but Requisite"

How did Dr. O'Brien answer his second question about screening for enlarged thymus and about prophylactic radiation therapy in symptom-free infants, children, and young adults?

"Since our second query concerns the enlarged thymus without symptoms in children, it is not necessary to consider here tracheobronchial adenitis or lymphosarcoma or thymoma except to say that any of these conditions sufficiently advanced to give a broadened mediastinal shadow would carry with them a very definite clinical as well as roentgenological picture." And Dr. O'Brien continued (p.276):

"I am therefore presuming that the 6 to 7 percent of cases of `broadened mediastinal shadow' seen in children without symptoms represent at least relatively enlarged thymus glands. No one who is informed thinks for a moment that all of this group represent pathological glands. This group comprises, undoubtedly, those which have not undergone accidental involution from disease, those in whom the rate of chest growth has not kept pace with the thymus, as well as those glands considered potentially a menace."

Dr. O'Brien's emphatic recommendation, about thymic irradiation prior to anesthesia, was tied to the presumed harmlessness of such irradiation (p.276):

"Since there is no evidence that the thymus is not an integral causative factor in the type of death under discussion, and since it is known that involution of the thymus takes place rapidly and without harm (Hammar) following roentgen or radium treatment, it would appear not only desirable but requisite, until such time as more exact knowledge or experience shall warrant a contrary opinion, to prescribe radiation therapy for those children presenting roentgen evidence of `broadened mediastinal shadow' without symptoms in whom general anesthesia or surgery is contemplated."

Part 5.
Quantitative Analysis of the Massachusetts Eye and Ear Infirmary Data

Here, we shall evaluate the breast-dose received by children of ages about 1 to 9 years old, from thymic irradiation administered due to the fear of sudden death when such children had a variety of chest problems. This will become the entry for Column M of our Master Table. While some of the children had surgical procedures, we shall treat the cases of tonsillectomy and adenoidectomy separately in the next chapter.

We begin with the 1971 study by Janower and Miettenen entitled "Neoplasms after Childhood Irradiation of the Thymus Gland." The average age of the children in their study was 4.7 years old at the time of irradiation, as mentioned already in Part 1. Thus, these children were considerably older than the children evaluated in the previous chapter, about 90 percent of whom were under 6 months of age. The children in the Janower/Miettenen Study represent children with a variety of chest problems plus some head and neck problems, including bronchitis, lymphadenitis, and other disorders which brought them into the Massachusetts Eye and Ear Infirmary.

We shall use almost the same checklist of "items" used in the previous chapter.

• Item 1: What was the place of study? The Massachusetts Eye and Ear Infirmary in Boston, Massachusetts which is SuffolkCounty. This is a single well-defined facility in a stable location in which essential population information will be available.

• Item 2: Can we regard the study's participants as representative of Suffolk County for the relevant period? Unfortunately, we have no basis whatever for assuming that all the hospitals and private practitioners referred their patients to this one Infirmary. Nonetheless, we shall make our dose-estimate as if ONLY the children in the Janower/Miettenen Study received such treatment in Suffolk County. For any children of this age-bracket who were treated in other institutions of Suffolk County, we assign ZERO dose.

This means that we shall definitely be underestimating the person-rads of breast-dose for Column M of our Master Table. But our intention is for doses in the Master Table to represent a credible LOWER limit of annual average breast-dose.

• Item 3: How many persons were treated? Over the 22 year period (1924-1946), there were 1,131 children treated for thymic enlargement.

• Item 4: What ages were represented in the treated group? Only the mean age was given in the report, a value of 4.7 years. We shall assume that the age-range of those irradiated was from 1 through 9 years of age. We shall assign equal numbers of children to each age-year of the 1-9 year age-range.

• Item 5: What was the period over which the treatments continued? The total period was about 22 years, starting in 1924 and ending in 1946.

Females of Each Age-Year Irradiated per Calendar-Year, Suffolk County.

• Item 6: We need to know how many children were present in each age-year for each year of the study. Since 1,131 children were irradiated in the course of 22 years, the number of children treated per year was (1,131 / 22), or 51.4 children per year. We shall make the approximation that one-half of the children were female, so there were 25.7 female children treated per year of the study.

If we divide this number equally into nine age-years, we arrive at (25.7 / 9), or 2.86 female children in each age-year who received therapeutic radiation at this Infirmary, in a calendar-year.

Total Females Ages 1-9, per Year, USA and Suffolk County

• Item 7: We need to know the total population of female children in each age-year (1-9) in SuffolkCounty for the average year in the period 1920-1960. We do this as we did it in Chapter 8 (Item 6).

In 1960, Suffolk County had 791,329 persons.
In 1960, the U.S. population was 179,333,000 persons.
The ratio, Suffolk / USA = (791,329 / 179,333,000).

In the Master Table, Column A, we have the number of females (age-year 1): (892,820 national) x (the ratio of 791,329 / 179,333,000) = 3,940 age-1 females.

And in this way, the full nine-year tabulation is built.

Age-Year Females, National:
Number in Age-Year
Females, Suffolk Cy.:
Number in Age-Year
1 892,820 3,940
2 892,097 3,936
3 891,518 3,934
4 890,657 3,930
5 890,332 3,929
6 890,051 3,927
7 889,806 3,926
8 889,589 3,925
9 889,390 3,925

Breast-Dose per Treated Child

• Item 8: We need to know the radiation dose absorbed in this "enlarged thymus" therapy. The treated children generally had a cumulative air dosage of 400 Roentgens (4 doses of 100 R each), but we cannot be sure what the distribution was to the breasts. A phantom study, as done by Dr. Rosenstein for the Hildreth Study in Rochester, would have been desirable. Absent that, we shall assume the same irradiation techniques were used in Boston as in Rochester, and that the absorbed breast-dose was the same: About 32.62 rads per child, after adjusting for supra-linear bending of the dose-response curve (see Chapter 8, Item 8). We will use 32.6 rads, below. If most of the Boston children received 400 R (air dosage), our use of 32.6 breast-rads may underestimate the true dose, but this is not provable within the data.

Conversion of Individual Dose to Population-Dose

• Item 9: We need the average population-dose from this irradiation, rather than the raw individual doses per treatment. We calculated in Item 6 that there were 2.86 female children in each age-year who received therapeutic radiation in SuffolkCounty, in a calendar-year. We use the same two-step process shown in Chapter 8, Item 9. First, we obtain "person-rads." So for each age-year:

(2.86 persons) x (32.6 rads) = 93.2 person-rads.

The second step is to distribute these person-rads, received by only 2.86 persons, into all the children of the same age-year in Suffolk County. We illustrate with the age-1 group:

  93.2 person-rads  
Population Exposure, rads = ----------------------------- = 0.02365 medical rads
per breast-pair.
  3,940 females  

And we must do this calculation for all nine age-groups.

Age-Year Females in Suffolk County Person-Rads Mean Population Dose,
medical rads per breast-pair
1 3,940 93.2 0.02365
2 3,936 93.2 0.02368
3 3,934 93.2 0.02369
4 3,930 93.2 0.02372
5 3,929 93.2 0.02372
6 3,927 93.2 0.02373
7 3,926 93.2 0.02374
8 3,925 93.2 0.02375
9 3,925 93.2 0.02375

• Item 10: We have considered, so far, only the dose received by those children chosen to get radiation therapy to the thymus gland. This does not tell us what dose was received for those who were roentgenographed, but who did not qualify for radiation therapy. The Janower paper indicates that the criterion used was a certain width of thymic shadow in an antero-posterior roentgenogram. If the Infirmary took just one film and never used diagnostic fluoroscopy, the diagnostic radiation dose to breasts distributed over the whole population of those ages could have been quite low.

We shall assign a ZERO dose for the "entrance exam" for this series. Of course, this underestimates the doses received, but we prefer an underestimate where there are no usable data.

• Item 11: Duration. Janower and Miettenen say explicitly that such treatments were given for the years 1924-1946. They do not explicitly say that no such therapy was given in any of the other years of 1920-1960. We are consistently trying to develop a credible LOWER limit of dose, so we will not assume treatments in all forty years. For the period before 1924, we will assume 2 years without activity. And for the period beyond 1924-1946, we will assume no activity during 7 years. So, we will approximate that treatment occurred for 31 years, and no treatment occurred at all for 9 years. Therefore, we adjust the average annual dose downwards, as follows:

((31 x 0.02368) + (9 x 0))/40 = 0.01835 medical rads for age-years 1 through 3, and
((31 x 0.02374) + (9 x 0))/40 = 0.01840 medical rads for age-years 4 through 9.

This completes the analytical work for this group, and we make nine entries for nine age-years into Column M in the Master Table.

Use of These Data As Typical for Nationwide Practice

There are sometimes regional differences in medical practice. In our study of the literature, we have looked for evidence of such differences with respect to all chapters of this work. So far, we have not found any reason to think that the Boston data used above were atypical. But if we just suppose that treatment for "enlarged thymus" was more popular in Boston than elsewhere, for age-years 1-9, we should still not worry about any OVERestimate of national breast-dose in Column M. Why not? Because of the undeniable UNDERestimate discussed in Item 2, above.

1922: No Surgery Planned? Reduce The Thymus Anyway.

In the debate as to whether infants and children with evidence of enlarged thymus should be irradiated, we have the following (at p. 438):

"Because some patients with thymic hyperplasia go through operations or severe illnesses without trouble, does not mean that all will do so. We have no means of knowing beforehand who will be the fortunate ones. It would seem, therefore, that the reduction of an enlarged thymus is indicated in all patients before operation."

As for those not being considered for surgery, Dr. Greenthal concluded that the following should occur:

"How shall we treat nonoperative cases which show thymic enlargement? We have given all these patients roentgen-ray treatments in order to reduce the size of the gland. It is our belief that this, too, is a beneficial procedure.

Why, we ask, did Dr. Greenthal think it was beneficial? The answer centered on one statement:

"It has long been known that some patients with enlargement thymus react to illnesses in a violent manner."

Roy M. Greenthal, "The Incidence of Thymic Enlargement Without Symptoms in Infants and Children," American Journal of Diseases of Children Vol.24: 433-440. 1922.

CHAPTER 12 Reaching into the Womb: Pre-Birth Breast Irradiation

Part 1. Cancer Production by Prenatal Exposure to Ionizing Radiation

In an important communication in Lancet, 1988, Yoshimoto, Kato, and Schull reported as follows (p.665):

"This study examines the risk of cancer (incidence) over 40 years among the in-utero exposed survivors of the atomic bombing of Hiroshima and Nagasaki, and adds eight years of follow-up to a previous report confined to mortality. Only two cases of childhood cancer were observed among these survivors in the first 14 years of life; both had been heavily exposed. Subsequent cancers have all been of the adult type. Not only did the observed cancers occur earlier in the 0.30+Gy [30+ rads] dose group than in the 0 Gy dose group but also the incidence continues to increase, and the crude cumulative incidence rate, 40 years after the A-bombing, is 3.9-fold greater in the 0.30+ Gy group."

This finding of a significant elevation in cancer rate in those irradiated in-utero is important. However, the total incidence of cancers is numerically small, 18 cases in all, with 16 of the 18 occurring in adults. This suggests, according to the authors, that:

"These results, when viewed in the perspective of fetus doses, suggest that susceptibility to radiation-induced cancers is higher in prenatally than in postnatally exposed survivors (at least those exposed as adults). However, definitive conclusions must await further follow-up studies" (p.665).

It is very early in this study. By 1984 (which was the closing date of the Yoshimoto study), those exposed in-utero were just about forty years old. The cancers are largely yet to come. There were three breast cancers in the series of 18 cancers in toto, and all three of them were in the ostensibly unexposed category. In view of the random fluctuations of small numbers (and three cases make a severe "small numbers problem"), and in view of what is already known about age-years 0-9 from larger parts of the same study (see Chapter 3, for example; also Gofman 1990), the distribution of the three breast cancer cases in Yoshimoto 1988 is almost certainly due to pure chance, with no biological meaning. We consider it highly reasonable to assume that breast cancer sensitivity is about the same for irradiation in utero as it is for irradiation at 0-9 years of age. Of course, we will continue to observe the on-going follow-up, of the in-utero cohort of A-bomb survivors, to ascertain whether the assumption is strenghthened or weakened by continued observation.

Part 2. Proportion of Infants Receiving X-Ray Doses in-Utero (USA)

The most common reason that pregnant women receive x-ray examinations which expose their infants, is to determine whether or not the women will be able to deliver the infants vaginally. The x-ray examinations sometimes take place during labor itself. According to Kevin Kelly and co-workers (1975):

"Roentgenographic evaluation of the relative sizes of the fetal head and maternal pelvis has been used clinically almost since the advent of medical radiography. The technique was considerably refined by Colcher and Sussman in 1944. Further refinements and variations have been instituted since that time."

Pelvimetry was a routine topic in medical textbooks of the 1930s and 1940s. For example, from Christopher's Textbook of Surgery, Third Edition (1942), we quote Dr. James T. Case, Professor of Radiology at NorthwesternUniversityMedicalSchool (p.1635):

"Roentgen measurements of the pelvic diameters can be taken without any special apparatus; the ordinary x-ray equipment of a hospital should be satisfactory. Space here does not permit description of the technic of pelvic and fetal mensuration (see the author's description in Curtis: Obstetrics and Gynecology, Phila., W.B. Saunders Co, 1932, vol.3, p.762)."

(a) Frequency of In-Utero Irradiation: MacMahon's Study

Dr. Brian MacMahon (1962) published a paper entitled "Prenatal X-Ray Exposure and Childhood Cancer." Our major interest here is in his evaluation of the frequency of prenatal exposure to x-rays.

The study-population consisted of 734,243 children born in, and discharged alive from, any of 37 large maternity hospitals in the northeast United States in the years 1947-1954. These hospitals were located in the nine states comprising the Northeast Region of the United States as defined by the U.S. Bureau of the Census. All but three of the hospitals were situated in Massachusetts, Rhode Island, Connecticut, or New York City. The frequency of intrauterine x-ray exposure in the population was estimated in MacMahon 1962 by review of the records of a 1 percent systematic sample.

MacMahon acknowledged that births in these hospitals were not representative of the general population of births in the area, since the included hospitals were not rigorously representative. For example, a special effort was made to obtain the collaboration of three hospitals in which the use of x-ray pelvimetry was believed to have been high, and in general, large hospitals were approached. We shall deal with the bias of this selection-process in a moment.

The MacMahon study concerns x-ray examinations of the maternal abdomen and pelvis in which the fetus received essentially direct whole-body exposure. The majority of such exams are pelvimetry examinations, but flat-plate examinations for twins, placentography and series-studies of the intestinal tract or urinary tract are also included.

The systematic sample comprised 7,346 live births, in which 104 occurred in multiple births and 7,242 in single pregnancies. X-ray of the maternal abdomen or pelvis was recorded in 32 (30.8%) of the multiple and 770 (10.6%) of the single pregnancies. In his Table 2, MacMahon lists 9.9% of all the female children as x-rayed, out of 3,570 cases observed. This is the percentage of special interest to us. For personal reasons, some readers may be interested in MacMahon's finding that first births showed a much higher rate of x-raying than did second and later births. Moreover, this finding has important implications for arranging proper control groups in health studies of in-utero radiation.

MacMahon obtained no estimates of in-utero doses in this series of cases. For doses, we must search elsewhere (Part 3).

(b) Frequency of In-Utero Irradiation: Kelly's Study

Kevin Kelly and colleagues (1975) addressed the question of "The Utilization and Efficacy of Pelvimetry." They reported the following (p.66):

"This study analyzed clinical information from 67,078 single deliveries of 1,000 grams or greater from 16 hospitals [in the years 1969 and 1970]. Pelvimetries were performed during 6.9 percent (4,599) of these deliveries ..." Later (p.68), they reported that pelvimetry accounted for 72% of the pelvic and abdominal x-ray procedures in their study. Thus, the rate of prenatal irradiation was (6.9% / 0.72), or 9.6% in remarkably close agreement with the MacMahon findings for a period some 20 years earlier. Like MacMahon, Kelly et al noted that their study-population was not a perfectly random sample, due to some geographic, economic, and racial factors. Also, all of the hospitals providing data were training institutions.

Our Adjustment Downward in the Frequency of X-Raying

For Dr. MacMahon's purposes (comparing frequency of prenatal X-raying in children having a malignancy, versus frequency in children having no malignancy), seeking out a few hospitals with a high frequency of pelvimetry is not a serious matter. For our purposes, such bias is undesirable. In order to avoid overestimating the frequency of prenatal irradiation, we shall simply reduce the total frequency of x-raying to 75% of the total observed by Dr. MacMahon. This should take care of the possible consequence of MacMahon's selection-process. So:

(9.9%) x (0.75) = 7.4 % of live births had pelvimetry or abdominal radiation.

Part 3. The Question of Radiation Dose to the Fetus in Such Studies

Robert Berman and Benjamin Sonnenblick (1957) have addressed the issue of doses received by the fetus and female pelvis (1957, p. 4):

"The purpose of this communication is to record actual measurements in roentgens of radiation dosage directed to the depths of the female pelvis during the exposure of films for x-ray pelvimetry and hysterosalpingography." Measurements were provided for a total of 28 women, 13 of whom had pelvimetry films taken at or near 38 weeks of gestation.

The total intrapelvic dose of x-ray radiation, as measured in the posterior vaginal fornix in 10 patients who were exposed for the full exam (4 pelvic views), had an average value of 2.9 R, with 6 patients receiving less than 3 R and only one receiving more than 4 R. The total range of doses was 2.1 to 4.4 R.

We shall use the Berman-Sonnenblick estimates for dose, and the MacMahon estimates (adjusted downward by us) for frequency of the examination.

Part 4. Preparation of the Dose Estimate for the Master Table

• Item 1: In the Master Table we have an entry (in Column A) of 905,213 female infants in the 0-1 age-year group, nationwide. This number is approximately the number of female live-births in the average year of 1920-1960.

• Item 2: We shall use the reduced value from the MacMahon studies as the frequency of examinations irradiating the fetus (pelvimetries plus abdominal examinations). That value is 7.4 % of live-births per year.

• Item 3: Number of infants who received the radiation in the 905,213 live-births = (905,213 births) x (0.074) = 67,000, rounded off, per year.

• Item 4: Person-rads per year = (67,000 persons) x (Radiation Dose). For dose, we shall evaluate the two extremes of Berman and Sonnenblick: 2.1 and 4.4 Roentgens. Since this is medical x-radiation, and since these are depth doses measured in Roentgens, we use the approximation here that person-Roentgens are equivalent to person-rads.

Person-rads = 67,000 persons x 2.1 rads = 140,700 person-rads. Person-rads = 67,000 persons x 4.4 rads = 294,800 person-rads.

The other approximation we make here is that the smaller component in the MacMahon frequency (the abdominal radiation) delivers about the same fetal dose as the dose delivered by pelvimetry.

• Item 5: We wish never to overestimate radiation dose, so we shall accept the lowest of the person-rad values obtained in Item 4, namely 140,700 person-rads.

• Item 6: For the Population Exposure in the Master Table, we need to distribute the person-rads into the entire 905,213 persons:

Thus, Population Exposure (in-utero) = 140,700 person-rads / 905,213 persons

= 0.16 rad per fetus.

This conservative value, reduced in Item 2 and reduced again in Item 5, is entered into Column K of the Master Table. For this singular entry, we can use the table's first row, because (as noted in Part 1) we will use the same conversion-factor, from dose to breast cancer, as we use for the year after birth until the first birthday.

In view of Kelly's comment (Part 2), we can assume pelvimetry was in common use for the entire 1920-1960 period.

CHAPTER 25 Weapons-Test Fallout, Pre-1960, and Breast Dose

For our considerations of the 1920-1960 breast-irradiation-doses, we wish to include only doses up to 1960 from weapons testing. For 1960 and beyond, such irradiation will be considered in further research on this topic. While we shall see in this discussion that weapons-test fallout contributes very little to the 1920-1960 breast-doses, the much larger fraction of the fallout in the years beyond 1960 implies that a larger contribution from weapons-test fallout can be anticipated in the post-1960 period.

Since there were no doses of any consequence before 1945, we have 62% of the 1920-1960 period without ANY contribution of fallout to dose. The period 1945-1960, or 38% of the total years, needs an estimate of dose contribution. Whatever that total dose-contribution is, it will be divided by 40 for the total years, 1920-1960.

Two Major Classes of Radionuclides

There are two major classes of radionuclides, those of very short half-lives, and those of relatively long half-lives. For those of relatively long half-lives (such as strontium-90 and cesium-137), the radiation dose PER YEAR is a small fraction of the ultimate dose-commitment. Since we are dealing with YEARLY radiation doses in this analysis of breast cancer, we need to consider nuclear test fallout doses on a per-year basis. For those radionuclides of very short half-lives, material injected into the stratosphere largely decays before returning to earth, and hence much of the potential dose does not occur.

The Time-Distribution of Fallout Deposition

UNSCEAR 1977 (Annex C) Table 2 (at p.122) provides some of the requisite information. We have there the annual deposition and cumulative deposition of strontium-90 up through January 1976. We shall, of course, use the data for the Northern Hemisphere, since pre-1960 fallout was largely there.

Strontium-90 Deposition fixme-u-g refer to original

Year Deposition in Mega-Curies
Pre-1958 1.80
1958 0.63
1959 1.05
1960 to Jan. 1976. 8.65
Grand total 12.13

Therefore, we have the approximation that before 1960, 3.48 mega-Curies out of a total of 12.13 mega-Curies, or about 28.7 % of the total, fell out. As a good approximation, we shall state that the cesium-137, the other prominent long-lived radionuclide, fell out quantitatively, before and after 1960, as did strontium-90.

The Short-Lived Radionuclides

The combination of Ce-144, Ru-106, Zr-95, Ru-103, Ce-141, and Ba-140 (plus their short-lived daughters) provide the major share of worldwide exposure in the very early years post-test.

At Table 26, p.153 of UNSCEAR 1977, external radiation from short-lived nuclides is given as 48 milli-rads. As a reasonable approximation for the pre-1960 period, we multiply this value by the same fraction, 0.287, as used for strontium-90. External dose from short-lived nuclides before 1960 is (0.287 x 48), or 13.8 milli-rads.

While we believe UNSCEAR has overestimated the correction for body shielding of the breast, we shall, as part of our conservative approach, utilize their values for organ doses directly, and we shall accept 13.8 milli-rads as dose to the breasts for the short-lived gamma-emitters during the 1945-1960 period.

The Long-Lived Radionuclides: Cesium-137 and Strontium-90

At Table 26, the dose contribution from external Cs-137 is given as 62 milli-rads (lifetime commitment). Using our 0.287 factor, we have 0.287 x 62, or 17.8 milli-rads. Gofman (1990, Ch.36, p.29) provides the datum that cesium-137 external dose during first 10 years is 20% of the all-time total. And since the pre-1960 period means less than 10 years since deposition, on the average, we can say external Cs-137 dose is less than 20% of total, or less than 20% of 17.8 milli-rads, or 3.6 milli-rads. Let us assign one-half of this value, or 1.8 milli-rads, for the shortness of the exposure period.

Total dose in the early period (before 1960) = 13.8 + 1.8, or 15.6 milli-rads delivered to breast from all external gamma-emitting sources.

For internal dose from Cs-137, it is estimated that 95% of the total effect is attained in a few years after deposition. The general rule is that internal / external dose, for Cs-137, is 3 / 7. But since the internal commitment is nearly over a few years after deposition, we must use the total external committed Cs-137 dose, which is 17.8 milli-rads, to be multiplied by (3/7), and this gives a value of 7.6 milli-rads for internal breast dose from Cs-137.

So, for the early period, total external dose to breast = 15.6 milli-rads. And for the same period, total internal dose to breast = 7.6 milli-rads. Combined total, internal plus external = 23.2 milli-rads to breast.

What about dose from strontium-90? Up to 1960, we can neglect it. This nuclide, having no gamma ray, delivers no breast-dose when it is external to the body. And the internally deposited strontium would add very little to the breast-dose during this short period of time (pre-1960). However, by also ignoring the external and internal dose from cesium-134 (radiological half-life of 2.06 years), we do underestimate dose here.

The Total Breast-Dose up to 1960

The 23.2 milli-rads must be divided by 40 to obtain the AVERAGE year's contribution to dose in the 1920 to 1960 period.

Therefore, final entry, for all ages, in the Master Table, for fallout from weapons testing is (23.2 / 40), or 0.58 milli-rads per year of high-energy radiation. And since all our entries in the Master Table are in MEDICAL RADS, we first convert to rads, and then divide by 2 to correct to medical rads. The final result in medical rads to transfer to the Master Table, Column "O," is 0.00029 medical rads per year for the average year of 1920-1960 period.

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