Conclusion

Chapter 7: Risk of Harm and Nontherapeutic Research with Children

The Twenty-One Case Examples

All twenty-one projects analyzed in detail involve the administration of radioisotopes to children in order to better understand child physiology or to develop better diagnostic tools for pediatric disease. In this respect, the studies supported by the federal government do not differ from those reviewed that had other funding sources. With the exception of the study at the Wrentham school to evaluate protective measures for fallout, none of the twenty-one experiments reviewed was related to national defense concerns. Seventeen of the twenty-one experiments involved the use of iodine 131 for the evaluation of thyroid function.

Three examples of research reviewed by the Committee will help illustrate the nature of the experiments and the risks posed to children. In the first example, investigators at Johns Hopkins in 1953 injected iodine 131 into thirty-four children from ages two months to fifteen years with hypothyroidism and an unknown number of healthy "control" children in order to better understand the cause of this disease.[59] Iodine is normally taken up and used by the thyroid gland for hormone production. In this experiment, a radiation detector was placed over the thyroid to detect the amount of iodine 131 taken up. Most children with hypothyroidism have an underdeveloped thyroid gland, in which case only very low levels of iodine 131 uptake will occur. Indeed, this is what the investigators found in this experiment, which was one of the first projects to use iodine 131 uptake as a measure of thyroid function in children. Hypothyroidism is a relatively common condition (1 per 4,000 births) that can cause profound mental retardation if untreated. Today, better diagnostic tests for thyroid function including radioimmunoassay and effective thyroid hormone replacement have virtually eliminated hypothyroidism as a cause of mental retardation in the developed world.

A second example of research reviewed by the Committee is an experiment by investigators at the University of Minnesota in 1951 in which four children with nephrotic syndrome were injected with an amino acid labeled with sulfur 35, along with two "control" children hospitalized for other conditions.[60] Nephrotic syndrome is a serious pediatric condition in which protein is excreted by the kidneys in large quantities. There was controversy at the time over whether children with nephrotic syndrome have low blood protein levels solely because of renal losses or whether they also have impaired protein production. This experiment looked at the incorporation of the radioisotope-labeled amino acid into protein, and the results suggested that the protein production in children with nephrotic syndrome is normal.

A third example of research reviewed by the Committee is a study of iodine 125 and iodine 131 uptake by eight healthy children performed at the Los Alamos Laboratory in 1963.[61] The purpose of the study was to evaluate the use of radioisotopes in very small doses (nanocurie levels) as a measure of thyroid function. The study demonstrated that the technique was scientifically valid and exposed the children to smaller radiation doses than earlier methods.

Estimating Risk

The principles of risk assessment for radioisotopes are laid out in "The Basics of Radiation Science" at the end of "Introduction: The Atomic Century."[62] To review: the increased risk of cancer is generally assumed to be proportional to the dose of radiation delivered to the various organs of the body. This dose depends upon a number of factors, including the amount of radioactivity administered, its chemical form (which determines which organs will be exposed), and how long it stays in the body, which in turn depends upon the radioactive decay rate and the body's normal excretion rate for that substance. For many radioisotopes, the overall personal dose can be derived by the "effective-dose method," in which the doses to the ten most sensitive organs are computed and added together, weighting the various organs in proportion to their radiosensitivity. Thus, this effective dose can be thought of as producing the same excess risk of cancer (all sites combined) as if the whole body had received that amount as a uniform dose. This risk is then computed by multiplying the effective dose by established risk estimates per unit dose for various ages. For this chapter, the Advisory Committee has adopted the effective doses and risk estimates tabulated by the International Commission on Radiation Protection and the National Council on Radiation Protection.[63] The lifetime-risk estimate used in this chapter is 1/1,000 excess cancers per rem of effective dose for children and fetuses exposed to slowly delivered radiation doses, like those from radioactive tracers.

The risks of thyroid cancer following exposure to radioactive iodine (generally I-131) represent a special case for three reasons. First, use of the effective-dose method is inappropriate because the dose is much greater to the thyroid than for other organs, and the lifetime risk is therefore dominated by the thyroid cancer risk. Therefore, risk is best calculated using only the thyroid dose and its associated risk. Second, the thyroid cancer risk varies even more by age than for other cancers. Third, the risk for iodine 131 has not been measured directly, but several lines of evidence suggest that it may be substantially lower than for external radiation. For this chapter, the Advisory Committee has adopted estimates provided by three follow-up studies of external irradiation of the thyroid by x rays or gamma rays in childhood: 2,600 children who received x-ray treatment for enlarged thymus glands in the first year of life;[64] 11,000 children who were treated by x rays in Israel for ringworm under age ten;[65] and Japanese atomic bomb survivors under age twenty.[66] The risk estimates from these studies were divided by three to convert them to internal iodine 131 exposures.[67] The estimates from these studies are for cancer incidence; for mortality we have divided them by 10, since 90 percent of thyroid cancers are curable. The resulting estimates are summarized in table 1. These are the same estimates used by the Massachusetts Task Force, which investigated the Fernald and Wrentham experiments.[68]

We can use data from the previously described Johns Hopkins iodine 131 study as an example. In this study, the amount of radioactivity administered was 1.75 microcuries per kilogram body weight; equivalent to 44 microcuries in a seven-year-old child weighing 25 kilograms. Based on interpolation of the tables in ICRP 53, and assuming a 13 percent thyroid uptake, this would produce a thyroid dose of 115 rem to a child aged seven. In this age range (5-9), the lifetime risk of developing thyroid cancer would be calculated by multiplying this dose by 20 per million person rems to produce an estimate of 2.3 cases per 1,000 exposed individuals, or 0.23 percent for a particular child. The risk of dying of thyroid cancer would be one-tenth of this, or 0.023 percent.

The twenty-one experiments subjected to the Committee's detailed risk analysis included approximately 800 children. Eleven of the studies produced estimates of average risk of cancer incidence within the range of 1 and 0.1 percent; eight studies ranged within 0.09 and 0.01 percent, and the remaining two studies produced average risk estimates of 0.001 percent. The maximum potential risk estimate was 2.3 percent in a few children aged one to two years at the time of exposure. The average risk of cancer incidence for the Fernald radioiron and radiocalcium studies were 0.03 percent and 0.001 percent respectively, and for the Wrentham fallout (iodine 131) study, 0.10 percent. All of the highest-risk experiments involved iodine 131, and hence the risks of dying of cancer would be about ten times smaller. (See table 2 at the end of this chapter for further details.)

Table 1. Summary of Risk Estimates for Thyroid Cancer from Iodine 131

e. Based on an assumed forty-year period at risk from five to forty-five years after exposure and assuming females have twice the excess risk of males.

Based on the average risk estimate for each of the twenty-one experiments, we would estimate an excess cancer incidence of 1.4 cases for the entire group of 792 subjects. However, given the uncertainties built into the risk analysis, it is also possible that no excess cases resulted. Furthermore, since most of that excess would have been thyroid cancer, it is particularly unlikely that any cancer deaths would have been caused. Finally, as thyroid cancer does occur in the general population, it would be difficult to attribute these cases to an individual's involvement in research. In addition, any cases of thyroid cancer among former subjects attributable to their participation in research conducted in the 1940s and 1950s are likely to have occurred already, although there is little long-term follow-up data to know for certain what the ultimate lifetime risk might be.

How do these risk figures compare with what is acceptable in nontherapeutic research today? As noted earlier in this chapter, the contemporary regulatory standard permits children to be involved in nontherapeutic research if the research poses no more than "minimal risk" to the subjects. "Minimal risk" is defined by analogy only: "A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological tests."[69] The regulations also allow for nontherapeutic research with children that does present more than minimal risk, but only if the risk represents a minor increase over minimal risk, the procedures involved are commensurate with the general life experiences of subjects, and the research is likely to yield knowledge of "vital importance" about the subjects' disorder or condition.[70] The regulations do not specify what would count as a minor increase over minimal risk. With this general guidance, it is the obligation of individual institutional review boards (IRBs) to determine whether a nontherapeutic study involving children is acceptable.[71] It is likely that a cancer risk of greater than 1 per 1,000 subjects would be considered by most, if not all IRBs to be unacceptable by a minimal-risk standard, even for nonfatal cancers. It is less clear whether this risk would be considered unacceptable by the "minor increase over minimal risk" standard (assuming the research satisfied the "vital importance" condition). The difficulty of establishing an acceptable level of risk in nontherapeutic radiation research with children is currently being debated in the medical literature,[72] a debate that will likely continue at least until federal guidelines become more specific.

What Was Known at the Time About Risk in Children

It is clear that the medical community's understanding of the nature and magnitude of risks posed to children by radiation exposure is not what it is today. Researchers did not positively associate prior exposure to external radiation with an increased risk of cancer until the mid to late 1950s. In 1950, Duffy and Fitzgerald raised the question as to whether there might be cause to investigate a possible association between therapeutic thymic irradiation during childhood and subsequent development of thyroid or thymic cancers:

To pose a cause and effect relationship between thymic irradiation and the development of cancer would be quite unjustified on the basis of data at hand when one considers the large number of children who have had irradiation of an "enlarged thymus." However, the potential carcinogenic effects of irradiation are becoming increasingly apparent, and such relationships as those of thymic irradiation in early life and the subsequent development of thyroid or thymic tumors might be profitably explored.[73]

By 1959, several studies had reported an association between radiation exposure and the subsequent development of leukemia.[74] Saenger et al. performed an epidemiologic study of several thousand children in 1960 to evaluate the association between radiation exposure and cancer.[75] They stated:

The question of whether or not radiation can be indicted as the principal causative factor in the induction of neoplasia following radiation exposure for either diagnostic or therapeutic purposes has been of increased interest over the past several years.[76]

In completing their analysis, they concluded: "It remains a fact, indisputable in all respects, that the rate of thyroid cancers in the irradiated group is disproportionately high."[77]

In 1961, Beach and Dolphin prepared a detailed analysis of the literature on the relationship between radiation and thyroid cancer in children.[78] They reported:

The thyroid has always been considered to be an organ comparatively radio-resistant to alteration and subsequent tumor development. Although no definite development of radiogenic tumor has been reported in adults after therapeutic administration of iodine-131, Jelliffe and Jones (1960) discuss a total of 10 cases of thyroid cancer reported in the literature in persons treated early in life by x-ray irradiation in the neck region. [T]he total of malignant thyroid tumors which develop in children given a dose of x-radiation to the thyroid that is of the same order of magnitude as the incidence estimated for other tumors if a linear dose-response relationship is assumed. No biologic significance is attached to this point, apart from noting the fact that the child's thyroid appears to be more radio-sensitive than an adult's but not more sensitive than some adult tissues.[79]

This lack of appreciation for the potential long-term effects of radiation in children is further reflected in institutional policy development for use of radioisotopes at the time. The Massachusetts General Hospital developed standards for tracer doses of radioisotopes in May 1949. Dr. Shields Warren, director of the AEC Division of Biology and Medicine, assisted in the development of the MGH standard:

Tracer doses in humans will always be kept to the absolute minimum required to make the observation.

Adult humans who are ill and who are expected to benefit from the procedure, shall not receive tracer doses of radioactive material giving off radiation in excess of a total of 4 rep. Children (all patients below 15 years of age) shall not receive more than a total of 0.8 rep.[80]

In any other cases, tracer doses will be limited to radioactive material giving off radiation in an amount less than a total of 1 rep.

In the case of iodine, the thyroid, which retains most of the radioactivity, is radioresistant. In this case, the permitted dosage may be increased by a factor of 100.[81]

Despite the cautious tone of this document, the policy illustrates the complete lack of understanding of the true radiosensitivity of the thyroid gland, especially in the pediatric population. Further allowances must be made with regard to what was known about the distribution of radioisotopes in children at the time. It is evident that investigators using radioisotopes in children were not employing available information on organ weights in children to calculate tissue exposures at least until the mid-1960s. When "standard man" assumptions were used to calculate pediatric exposures before pediatric standards were developed, investigators may have significantly and systematically underestimated effective tissue dosages in children. It is notable that the highest levels of risk posed in the experiments reviewed were to infants administered iodine 131.

Iodine 131 was routinely used for diagnostic procedures in the pediatric population until the 1980s, when it was replaced by I-123, a newly available radioisotope with a significantly shorter half-life, which reduced the thyroid dose markedly. The Wrentham fallout study, performed in 1961, employed doses of iodine 131 that resulted in an average dose of 44 rad to the gland, slightly less than the dose that would have been received for a diagnostic thyroid scan during this time.

Although the doses of radioisotopes subsequently declined during these years for both therapeutic medicine and nontherapeutic research, these guidelines were not based on long-term outcome studies of exposed individuals but rather on conservative extrapolations from high-dose studies and on the dosages necessary to enable detection with the available equipment.

The debate over the potential risks of low-dose exposure continues today, as epidemiological studies of thyroid cancer incidence subsequent to iodine 131 administration in both the diagnostic as well as therapeutic dose range have been largely negative. Risks as a result of iodine 131 exposure are still unclear, and risk analyses for exposure to radioisotopes are thus based on extrapolations from studies involving external irradiation.

In summary, during the period in which children were exposed to the highest levels of risk from nontherapeutic research involving radioisotopes, investigators had a limited understanding of the potential long-term risks of low-dose radiation and of methods to accurately calculate the tissue doses in children. Today, we cautiously assume that any exposure to radiation likely produces some small increase in cancer risk, so that no exposure is absolutely harmless. Instead, the concept of minimal or acceptable risk is commonly used, as discussed earlier. Some of the studies during this period involved risks that would be judged as minimal even today, whereas others would be clearly viewed as unacceptable today. Should the investigators then have viewed any of these studies as harmless? Though an understanding of the association between exposure to external radiation and subsequent development of cancer was emerging during this time, a similar association had not been made for exposure to low dose levels of radioisotopes. In addition, the relative radiosensitivity of many pediatric tissues, including thyroid, had not been established, and most researchers during this period subscribed to the "threshold" theory of risk, which assumed that sufficiently low doses were probably harmless. In the face of such widespread factual ignorance, it is difficult to hold these investigators culpable for imposing risks on their subjects that were not appreciated at the time.