The Context for Nontherapeutic Research with Children
Risk of Harm and Nontherapeutic Research with Children
Beyond Risk: Other Dimensions of the Ethics of Nontherapeutic Research on Children
The Studies at the Fernald School
Chapter 7: Risk of Harm and Nontherapeutic Research with Children
The Twenty-One Case ExamplesDuring the 1944-1974 period, there was an explosion of interest in the use of radioisotopes in clinical medicine and medical research, including pediatrics. The twenty-one research projects we review here include only a small number of all those that were likely conducted. These twenty-one do include, however, every nontherapeutic study that was funded by the federal government and fell into our original group of eighty-one pediatric radiation experiments. The table that appears at the end of the chapter provides information about the number of children involved in each of the experiments, the radioisotopes used, and risk estimates for cancer incidence. These twenty-one represent a subset of eighty-one studies identified in documents of the Atomic Energy Commission and a review of the medical literature that met the criteria described above.
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. 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. 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. 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 RiskHow can the risks posed to children in these types of experiments be estimated? The primary risk posed by the administration of radioisotopes is the potential development of cancer years, even decades, after the exposure. As will be discussed further, the risk of cancer following external radiation exposure was not well documented until the late 1950s and the early 1960s. Thus, the published reports of research projects prior to that time rarely discuss the issue of long-term risks.
The principles of risk assessment for radioisotopes are laid out in "The Basics of Radiation Science" at the end of "Introduction: The Atomic Century." 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. 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; 11,000 children who were treated by x rays in Israel for ringworm under age ten; and Japanese atomic bomb survivors under age twenty. The risk estimates from these studies were divided by three to convert them to internal iodine 131 exposures. 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.
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