Now, what I am drawing all the time is a triaxial element, why triaxial? You have the ground surface, you take any point over here and take out the sample, truly speaking the sample is getting exerted by the stressors in three directions, clear? So this is what is known as a triaxial state, three stressors acting on any element in the material, triaxial, very realistic situation but highly complicated to deal with because if you remember first of all we are dealing with a very complicated material like soils where we assume them as isotropic homogeneous, clear? We assumed isotropic homogeneous, you might be violating these situations, clear? So material is very complicated and then the complication comes in the form of the three dimensional analysis. So what I said is let us make life comfortable, let us try to understand 2D situations, we are dealing with the 2D situations by assuming that the effect of the stress which is perpendicular to the plane is ignored, these type of problems are known as plane strain problems, alright? So these are the plane strain problems, it is in a plane, alright? The reverse situation would be a plane stress problem, so right now we are going to deal with only plane strain problems. So if I take out this element and if I show here as sigma 1 and sigma 3, the statement of the problem is find out the state of stress at this plane which is inclined at an angle alpha of let us say 35 degree, sigma 1 is 52 kPa, sigma 3 is 12 kPa, find out the state of stress at this point which is nothing but sigma and tau, I hope you can solve this problem.  So try to solve this, the first thing you have to do is complete the Mohr's circle, you can do it very easily, sigma 1 is known, sigma 3 is known, radius is known, center is known, everything is known. Once this is known, 52, 0 is acting here, 12, 0 is acting over here, pole is known, clear? Second part of the problem, what it says is find out the state of stress at 35 degree angle, I have 2 ways to solve this problem, the state of stress is known, sigma 1, sigma 3, this point is 35 degree, what should I be doing now, where this plane is going to lie, can I project this plane on the Mohr's circle, do that and obtain the sigma and tau value. So the first stage is going to be MC, the second is going to be finding out sigma and tau, there are 2 ways of doing this now, I want you to do all these things and hence I am skipping steps, I can obtain sigma and tau by 2 methods, one is the graphical, this is what we have been doing, taking the help of the Mohr's circle, second is analytical, so this is analytical solution, sigma 1 is known, sigma 3 is known, alpha is known, sigma tau is known, clear? So if you do the analytical method which is nothing but your equations, try to match the answers and see whether you get the same answer or not, the answer you should be getting is, state of stress would be 39 kPa and 18.6 kPa, where is your guess, where the pole is, pole we have already identified, 35 degree line if I draw, this is the place where sigma and tau is acting, fine? So by definition, the state of stress has given me pole and pole is giving me a plane which is cutting the Mohr's circle where the state of stress is to be identified, this is part clear? Now most of the time in geomechanics, the problems are not going to be so simple, what is going to happen? Like in this case, if I consider this as the embankment, railway embankment and this happens to be the critical plane, you remember the definition of critical plane? At this plane, tau is getting or becoming higher than tau critical. So the failure has to happen, at this point the element looks like this, at this time this point the element looks like this, at this point the element looks like this, truly speaking what is happening is the axis is getting rotated, so we call this as the rotation of axis and what is going to happen if I am analyzing this type of situation from point 1 to 2 to 3 to n, how results are going to change? So second class of the problem which we normally talk about is, this is the first category of the problems. The second class of the problem would be if there is a complete rotation of the plane, that means this element rather than sitting horizontal, it might be sitting on a plane which is beta, rest of the things remain same, I might be having sigma 1, sigma 3 and again the statement of the problem is find out the state of stress at a plane which is let us say alpha equal to 35 degree, this is what is known as axis rotation. This plane 1, 1 has been rotated by an angle beta and the question is whether tau sigma or sigma tau is going to be same or changed when I do the same analysis for 35 degree angle. Do you think something substantial is going to change or everything remains same? I can still start with sigma 1, sigma 0, sigma 3 is 0, where these stress are going to act on the planes which are inclined to the horizontal plane now, try to solve this problem. Now let us take a situation where we call it as a generalized state of stress. So this is the C type of problem, the state of stress is defined as this is the element of the soil, you have a compressive stress acting over here, there is a tensile stress acting over here, this is a compressive stress, this is a tensile stress, so tensile stress is always negative, compressive stresses are always positive. The state of stress is you have shear stress acting at 2 MPa, the nomenclature is if I consider a point on this stress vector and if the direction of shear stress is clockwise, alright, if this is clockwise, we consider this as positive. If I consider a point over here and if I see the direction of the shear stress is anticlockwise, this becomes negative, alright. Solve the same problem and find out the state of stress, evaluate sigma and tau that is the state of stress at alpha equal to 30 degree, be evaluate sigma 1 sigma 3 when alpha equal to 30 degree, so this will come out to be take a graph paper and analyze this, this will be 6.4 minus 4.4, determine the orientation of major and minor principal stresses, in this case the orientation of the major and minor principal stresses was 0 because this happens to be the major principal stress and this happens to be the minor principal stress. The sign convention is the angles are always assumed to be positive when they are clockwise. Clockwise angles on the Mohr circle are positive, so you will be getting this as 11 degree and 101. I hope you will realize that the 2 planes are always inclined at 90 degree mutually, so 11 plus 90 would be 101, they are perpendicular planes, clear, sigma 1 sigma 3. The t problem is find the maximum shear stress, just to give you an idea the maximum shear stress acts at the point where you have this point and this point, clear, so these are the points of tau maximum, one is positive, another one is negative, the way we have shown over here, this is positive, this is negative, all right. Suppose if I ask you a question on which plane the maximum shear stress is acting, not difficult, once you have drawn the Mohr circle you get the sigma 1 sigma 3, identify the pole, you know the point at which the maximum shear is acting, this point when connected to the pole is going to give you a plane on which the state of stress is acting which is the maximum stress and its orientation would be this divided by 2 because we have been talking about 2 alpha, fine, so try to solve this. And this comes out to be 2 alpha equal to 90 degree, so alpha is 45 degree and the state of stress would be plus minus 5.4 MPa, this another class of problem which is more interesting, more practical but slightly difficult to assimilate, slightly trivial situation. So the triviality comes from the point that suppose on a tau sigma plane if I plot 2 points which are sitting very close like this that is a P1 and P2 point, all right, not very difficult but slightly trivial because you have to do something special to create a Mohr circle here what property you will be utilizing and you guess use the principle of quarts and perpendicular to the chord passing through the center, so try to solve this type of problem and the problem statement is 2 planes A and B are separated by an unknown angle, let us say this angle is theta on plane A the state of stress is sigma A equal to 10 kPa and this is 2 kPa, kPa is kilopascal, fine, 100 kilopascal is 1 kg per centimeter square, plane A lies 15 degree from the horizontal, the state of stress at point B sigma B is equal to 9 kPa and tau B equal to minus 3 kPa, the answers for this problem would be sigma 1 sigma 3 comes out to be 10.65 and 3.3 kPa and the value of theta comes out to be 46 degree, try to solve this problem, so what we have done in today's lecture is I have created a situation like this and try to explain to you what is the significance of state of stress in the material and then we have tried to answer this question by applying the concepts of Mohr's circle, alright, because as an engineer as a technologist most of the time you come across the question if this is a practical problem and if I have to construct something or provide some utility how I should be going ahead.


Section 34 of Final Report of the Advisory Committee on Human Radiation Experiments. For more information or to volunteer, please visit LibriVox.org. Final Report of the Advisory Committee on Human Radiation Experiments. Chapter 6 Part 3 From its inception, the AEC distribution system required each local institution to establish a local radioisotope committee, later termed a medical isotopes committee. Initially, the primary purpose was to simplify the allocation process by having local institutions establish their own priorities before applying to the AEC. Soon after the program began, supply increased and no dramatic new uses developed, so allocation was no longer a major issue. These local committees also took on responsibilities for physical safety, usually working closely with radiation safety offices. By October 1949, this requirement also applied to the AEC's national labs. When general authorizations were issued in 1951 granting broader discretion to qualifying local institutions, local isotope committees assumed greater responsibility. By 1956, the functions of the local radioisotope committees included reviewing applications, prescribing any special precautions, reviewing reports from their radiological safety officers, recommending remedial action when safety rules were not observed and keeping records of their own activities. The basic focus on radiological safety remained, although in reviewing applications a local medical isotopes committee could also consider other factors which the local medical isotopes committee may wish to establish for medical use of these materials. Exactly what these other factors might be was not specified. These local committees together reviewed thousands of applications over the next decades, although not federal agencies, they were required by the AEC and their proper functioning was an important part of the oversight system envisioned by the AEC. To fully assess whether this system fulfilled its goals would be an enormous task, requiring the retrieval and examination of thousands of local records. However, to make a preliminary assessment of whether the system as a whole generally appeared to function as planned, the advisory committee did examine the records of several public and private institutions, the Veterans Administration, VA, the University of Chicago, the University of Michigan, and Massachusetts General Hospital, MGH. Doing so provided us with an understanding of the techniques of risk management as used at the local level on a day-to-day basis. We specifically examined whether local radioisotope committees in fact were established as directed and what techniques they developed to monitor consent and ensure safety. Establishment of local isotope committees Overall the federal requirement seems to have been an effective means of instituting a reasonably uniform structure across the nation for local radioisotope committees. The AEC's requirements for local committees were followed in all of the institutions studied and there is no reason for believing they were exceptional. One local radioisotope committee, that of Massachusetts General Hospital, was established in May 1946, prior to the AEC requirement. The other institutions established a local radioisotope committee when required to do so by the AEC. Local committees also could have broader tasks than those required by the AEC. For example, the Radiation Policy Committee at the University of Michigan regulated all radioactive substances used on campus, not just those purchased from the AEC. These included reactor products, transuranic elements, and external sources of radiation. The Veterans Administration added another level of oversight in the form of a System-Wide Central Advisory Committee. In 1947 the VA embarked on a radioisotope research program that would take place within the newly established radiation units in the hospitals that would be the recipients of AEC-supplied isotopes. Among early research projects were the treatment of toxic goiter and hyperthyroidism with iodine-131, and treatment of polycythemia rubravera over production of red blood cells with phosphorus-32 at Los Angeles, radioactive iron tracers of erythrocytes at Framingham, and sodium-24 circulatory tracers in Minneapolis. By the end of 1948 radioisotope units had been established in eight VA hospitals. Each of the eight was asked to establish a radioisotope committee, as required by the AEC, to be appointed by the dean's committee of each hospital, while representatives from affiliated universities agreed to serve as consultants in the various units. Local Monitoring of Consent Generally, although local institutions created clear procedures to monitor safety, these local radioisotope committees did not establish procedures to monitor or require consent. See Part 1 for discussion of the broader historical context of consent in medical research. The standard application form to the Massachusetts General Hospital Committee as of 1953 had no place to describe an informed consent procedure. This does not, of course, resolve the question of whether consent was given. According to one prominent neurosurgeon interviewed by the advisory committee staff, William Sweet, at that time in the case of brain tumor patients oral consent was obtained from both the patient and, since mental competency could later be an issue, the next of kin. Similarly, no mention of the 1947 AEC requirements stated in General Manager Wilson's letters is contained in the advice Shields Warren gave in 1948 to the VA. Even though Warren, as director of the AEC's division of biology and medicine, must have known of discussions about consent requirements, an issue that arose before the VA Central Advisory Committee was whether patient subjects should sign release slips. This issue posed the question of whether the radioisotope units in the VA hospitals were treatment wards or clinical research laboratories. If wards, patients need not sign consent forms, for they were simply being treated in the normal course of an illness, Shields Warren agreed with this presumption and felt that there was no need for the patients to sign release slips. The proper use of radioisotopes in medical practice is encompassed in the normal responsibilities of the individual and of the institution or hospital. In addition, he felt that the practice would draw undue and unwholesome attention to the use of radioisotopes. Movement towards more formal consent requirements gradually arose at the local level. In 1956 the University of Michigan's own Human Use Subcommittee directed that in an experiment using Sodium-22 and Potassium-42, each volunteer would be required to sign a release indicating that he has full knowledge of his being subjected to a radiation exposure. Since the local committee was concerned about what it termed unnecessary radiation, the volunteers presumably were healthy subjects not otherwise receiving radiation for treatment or diagnosis. The committee appended a recommended release form to its minutes. I, the undersigned, hereby assert that I am voluntarily taking an injection of blank at a dose level which I understand to be considered within accepted permissible dose limits by the University of Michigan Radioisotope Human Use Subcommittee. By 1967 the Michigan Subcommittee also required that the subject explain the experiment to the researcher to clarify any doubts or misunderstandings. The following statement was incorporated into all applications to the University's Human Use Subcommittee. The opinion of the committee is that informed consent is the legal way of describing a meeting of minds in a contract. In this situation it means that the subject clearly understands what the experiment is, what the potential risks are, and has agreed, and without pressure of any kind, elected to participate. The best way to ascertain that the consent is informed is to have the subject explain back fully to the interviewer exactly what he thinks he is submitting to and what he believes the risks might be. This facilitates clarification of any doubts spoken or unspoken. The content of this discussion will be recorded in detail below. During the 1960s, as explained in Chapter 3, concern was growing over the adequacy of consent from subjects. Although not intended by the AEC to monitor the obtaining of consent from subjects, over the years the local radioisotope committees may have come to take on this task. By requiring such local committees the AEC had probably unwittingly provided an institutional structure that allowed the later concern for informed consent to be implemented at the local level. Local Monitoring of Risk This local and informal approach to consent is in sharp contrast to the detail and documentation with which risk was assessed. As discussed earlier, monitoring risk was the major task of the AEC's subcommittee on human applications. The local committees mirrored this task, examining in detail the various experiments presented to them. As with the AEC subcommittee, local committees developed a variety of methods, none especially surprising, to ensure what they believed was adequate safety. The basic dilemma facing local committees was to allow exploration of new territory while attempting to guard against hazards that, precisely because new territory was being explored, were not totally predictable. This dilemma was apparent at the local level, as well as at the level of the AEC's subcommittee on human applications. For example, in the minutes of the Massachusetts General Hospital Local Radioisotope Committee in 1955, during a discussion of new and experimental radiotherapies for patients, one member of the committee declared that the safety of the patient was of paramount importance. Yet other members suggested that a risk-benefit analysis needed to be an integral component of such a policy decision. The committee as a whole concluded merely that it was a complicated issue, and that it is not wise in any way to inhibit investigators with ideas, and yet the safety of the patient must come first. Requiring prior animal studies was a basic method of assessing risk. For example, the twenty-two studies reviewed by the University of Chicago's local committee in 1953 included multiple therapeutic and tracer studies involving brain tumors, the thyroid gland, metastatic masses, and tissue differentiation. Those the Chicago committee viewed as involving any risk to the patient were preceded by extensive animal studies. Animal studies were usually tailored to each project, and also raised the question of the differences between how humans and animals might respond to a particular radioisotope. A more uniform standard directly applicable to humans was the system of dose limits established by the National Committee on Radiation Protection for Occupational Purposes, the maximum permissible dose for each isotope. In addition, although no national system existed for reporting their decisions, local committees drew upon their knowledge of what had been approved at other institutions. At least one local committee issued its own dose limits. The Massachusetts General Hospital Local Committee in 1949 issued a seven-point policy on human use of beta and gamma emitting radioisotopes. By 1956 the Michigan Committee provided explicit limits for exposure of volunteers. At other times the condition of subjects who were patients was accepted as justification for higher doses. For example, in 1953 the Chicago committee approved a tracer study using Mercury 203 to study uptake by malignant renal tissue. Although admitted to be unusual, it was approved as potentially efficacious in patients suffering hypernefroma, a kidney cancer. Total dose would not exceed 10 milligrams of ionic mercury, a high dose for most tracer studies, which was approved as reasonable given the illness of the patients. Similarly, the Harvard Medical School Committee in 1956 stipulated that the risk of incurring any type of deleterious effect due to the radiation received should be comparable to the normal everyday risks of accidental injury. For seriously ill patients receiving experimental treatment, however, the committee stated the estimated deleterious effect from radiation should be offset by the expected beneficial effects of the procedure. In addition to setting limits, local committees encouraged the use of technical methods to reduce risk. Use of different detection techniques could reduce the dose required. In 1955, for example, the Michigan Committee considered an application to administer to normal volunteers up to 30 microcuries of sodium-22 and up to 350 microcuries of potassium-42, resulting in internal radiation doses of up to 300 milliram per week. The purpose was to study sodium-potassium exchanges. The committee asked itself, is it justifiable to subject the volunteers to an exposure in excess of the maximum permissible? This committee did not resolve this question, but came forward with the suggestion that more sensitive counting techniques might permit this investigation at lower dose levels. Another method of reducing risk was to restrict the type of subjects to those whose life expectancy was too short for any long term effects to appear. This has already been seen regarding terminal patients. Another variation of the same technique was to restrict the use of volunteers to those over a certain age. At Michigan, age restrictions on who would be acceptable as a volunteer began appearing in the 1960s. When a worthwhile experiment also involved novel risks, another method to control risk was to require additional monitoring by the local committee as the experiment proceeded. At times the Michigan Committee required preliminary reports before allowing experiments to proceed further. In another instance, the Michigan Committee required the researcher to obtain long term excretion data because of concern that the usual biologic half-life data might not be sufficient. Similar additional oversight was required at the University of Chicago in 1953. A proposal was made to use tritium-labeled cholesterol to study steroid estrogen metabolism in women. The question of the distribution of estrogenic hormones in humans was unexplored at that time and deemed worthy of research. While the risk appeared low, the committee ultimately approved the study for the first round of the experiment only for non-pregnant women who were sterile or pregnant women who planned to be sterilized post-abortion. If data from the first round suggested minimal risk to the women and the fetuses, the program could be expanded. Thus, in establishing a system of local radioisotope committees, the AEC effectively increased the detail with which each proposed experiment was reviewed. Often it appears experimental protocols were revised at the local level before being approved and sent on to the AEC. Thus the system created by the AEC did some of its most effective risk management out of sight of direct federal oversight. End of Section 34. Recording by Maria Casper. Section 35 of Final Report of the Advisory Committee on Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Final Report of the Advisory Committee on Human Radiation Experiments. Case Studies, Chapter 6, Part 4. General Benefits of Radioisotope Research. The system for distribution of radioisotopes worked well and encouraged researchers to explore new applications. There are two striking aspects of the application of radioisotopes to medicine since World War II. Rapid expansion and complexity. Practices that at the end of the war were limited to fewer than four dozen practitioners have now become mainstays of modern medicine. The second major aspect of the field is its complexity. Just as nature at times is best regarded as a seamless web, not unconnected scientific fields, knowledge nurtured in one field often provides unexpected benefits in another. A few examples can illustrate how some of the hopes at the dawn of the atomic age have actually been realized. Improved Instrumentation to Detect Radiation. Improved instruments, the basic tools for all biological research using radioisotopes, were developed through the interaction of biology and medicine with physics and engineering. Improvements not only provide greater precision, they also allow the same amount of information to be gathered with lower doses of radiation, thereby reducing the risk. Perhaps the best known example is the application of the whole body counter to biological problems. The device was originally developed as a tool for physics, enabling measurements of minute amounts of radiation by combining sensitive detectors with extensive shielding to eliminate extraneous radiation. The result was similar to placing a sensitive microphone in a soundproof room, allowing lower levels of radioactivity to be detected than was previously possible. For some research no radioisotope at all was administered, the counters could measure naturally occurring radioisotopes. Whole body counters also greatly simplified metabolic studies. In some studies subjects who previously would have had to reside continuously in a metabolic ward could now schedule visits to the whole body counter for their natural radioactivity to be measured on an outpatient basis. This device was later adapted for whole body counting after administration of tracer amounts of radioisotopes, and is the basis for a number of fundamental nuclear medicine tests. In the early 1970s computerized tomographic scanning CT was introduced. This technique was first applied to x-ray imaging by taking multiple x-ray slices through a region of the body, then programming a computer to construct a three-dimensional image from the information. Thus internal structures of the body may be imaged non-invasively. Newer types of tomographic scanning include positron emission tomography, PET, in which various metabolites or drugs are labeled with a very short half-life positron emitting radioisotope, such as fluorine-18, and the passage of the labeled material is tracked through the body by taking multiple images over several minutes or hours. Diagnostic Procedures The first medical application of any radiation was the use of x-rays for diagnostic purposes such as locating broken bones inside the patient. Radioisotopes later opened another window into the body. The natural tendency of certain organs to preferentially absorb specific radioisotopes, coupled with ever-improving detection techniques, allowed radioisotopes to be used to increase the contrast between different parts of the body. X-rays could distinguish between hard and soft tissues because of their different densities. Radioisotopes could go one step further and distinguish different kinds of tissues from one another based upon their metabolic function, not merely their physical density. Radioisotopes could also go beyond detecting different types of tissues. Since they were distributed throughout the body by the body's own metabolism, their location provided a picture not only of structure but also of processes. Tracing radioisotopes was a means of observing the body in action. The earliest success was using radioiodine to measure the activity of the thyroid. The gland cannot distinguish between radioactive and non-radioactive forms of iodine, and therefore preferentially absorbs all isotopes of iodine. Thus the activity of the gland can be assessed by observing its absorption of radioiodine. Largely as a result of these advances, the thyroid gland is arguably the best understood of all human endocrine organs, and its hormones the best understood of all endocrine secretions. Since the incidence of thyroid disease is second only to diabetes mellitus among human endocrine diseases, this understanding is basic to therapy in large numbers of patients.  In 1948 radioactive isotopes were applied to this task.  Similar scanning techniques were later developed for the liver, spleen, gastrointestinal system, gallbladder, lymphomas and bone. As mentioned a recently developed technique is PET scanning, which is especially helpful in studying the human brain in action. Glucose is the primary food for the brain. By tagging a glucose analog with fluorine-18, investigators can identify the actively metabolizing portions of the brain and relate that to function. This technique has opened a new era of studies of the brain. Outwardly observable functions such as language, object recognition and fine motor coordination can now be linked with increased activity in specific areas of the brain. Radioisotopes allow investigators to increase the sensitivity for analyzing biological samples, such as tissue and blood components, especially when separating out the material of interest using chemical processes would be difficult. Because instruments to measure radioactivity are so sensitive, radioisotopes are frequently used in tests to detect particular hormones, drugs, vitamins, enzymes, proteins or viruses. Therapeutic techniques Radioisotopes are energy sources that emit one or more types of radiation as they decay. If radioisotopes are deposited in body tissues, the radiation they emit can kill cells within their range. This may be harmful to the individual if the exposed cells are healthy. However, the same process may be beneficial if the exposed cells are abnormal, cancer cells, for example. The potential for radiation to treat cancer had been recognized in the early days of work with radiation, but after World War II the effort to develop radiation therapy for cancer increased. Iodine-131 treatment for thyroid cancer was recognized as an effective alternative to surgery, both at the primary and metastatic sites. Cancer is not the only malady susceptible to therapy using radioisotopes. The use of radioiodine to treat hyperthyroidism is perhaps the most widespread example. It illustrates the progression from using a radioisotope to measure a process, thyroid activity, to actually correcting an abnormal process, hyperthyroidism. Not all experimental applications of radioisotopes are successful. Some experiments end in blind alleys, an important result because this prevents widespread application of useless or even harmful treatments. Negative results also help researchers to redirect their efforts to more promising areas. The importance of negative results is sometimes not appreciated because they do not lead to effective treatments. Negative results may range from simply not obtaining an anticipated beneficial effect to the development of severe side effects. Such side effects may or may not have been anticipated. They may occur simultaneously with beneficial effects such as the killing of cancer cells. Occasionally negative results include earlier than anticipated deaths of severely ill subjects. An example is the experimental use of gallium-72 in the early 1950s on patients diagnosed with malignant bone tumors. Another radioisotope, cobalt-60, has been used successfully to irradiate malignant tumors, but in this case the radioisotope is not administered internally to the patient. Rather the cobalt-60 forms the core of an external irradiator and the gamma radiation emanating from the radioisotope source is focused on the patient's tumor. Although cobalt-60 irradiators have been largely replaced by linear accelerators, they were developed under AEC sponsorship and were responsible for many advances in radiation therapy. Recent efforts to utilize radioisotopes in cancer diagnosis and treatment are based on the ability of antibodies to recognize and bind to specific molecules on the surface of cancer cells and the ability of biomedical scientists to custom design and manufacture antibodies, thus improving their specificity. These fields are now contributing to a hybrid technique, cloning antibodies and tagging them with radioactive isotopes. As the antibody selectively binds to its target on the surface of the cancer cell, the radioactive isotopes attached to the antibody can either tag the cell for detection and diagnosis or deliver a fatal dose of radiation to the cancer cell. The Food and Drug Administration recently approved the first radio-labeled antibody to be used to diagnose colorectal and ovarian cancers. Even in the case of widespread metastases where cure is no longer possible, radiation treatments will often produce tumor regression and ease the pain caused by cancer. Phosphorus-32 has been used to ease, palliate the bone pain caused by metastatic prostate and breast cancers. Recently the FDA approved the use of Strontium-89 for similar uses. Metabolic studies Studies of the basic processes within the body may not have any immediate application in diagnosis or therapy, but they can indirectly lead to practical applications. One example is in the study of the metabolism of iron in the body. Iron is an important part of hemoglobin which carries oxygen from the lungs to all cells in the body. Studies using radioactive iron established the pathway iron takes from its ingestion in food to its use in the blood's hemoglobin and its eventual elimination from the body. These studies had practical applications in blood disease, nutrition and the importance of iron metabolism during pregnancy. Radioisotopes have also been used to study how the weightlessness of space travel affects the human body. Radioisotopes have allowed more precise observation of effects of space travel on blood plasma volume, total body water, extracellular fluid, red cell mass, red cell half-life and bone and muscle tissue turnover rates. Other uses of radioisotopes are in studies of the transport and metabolism of drugs through the body. New drugs for any clinical application, whether diagnostic or therapeutic, must be understood in detail before the FDA will approve them for general use. One method for readily determining how a drug moves through the blood to various tissues and is metabolically changed in structure is to incorporate a radioactive isotope into the structure of the drug. Unexpected results from an experiment can at times have widespread consequences. An example is how the work of Rosalind Yellow and Solomon Berson of the Bronx VA Medical Center opened up the field of radioimmunoassay. In the early 1950s it was discovered that adult diabetics had both pancreatic and circulating insulin. This appeared odd. Previously it had been believed that all diabetics lacked insulin. To explain the presence of diabetes in people with pancreatic insulin, Yellow and Berson decided to study how rapidly insulin disappeared from the blood of diabetics. To do this they synthesized radioiodine-labeled insulin. This would act as a radioactive tag, making it much easier to measure the presence of insulin in blood. To their surprise they found that insulin disappeared more slowly from diabetic patients than from non-diabetic people. Their work had an impact beyond the study of diabetes, however. In the process of studying the plasma of patients who had been injected with insulin, they discovered that the radioactively tagged insulin was bound to an antibody, a defensive molecule that had been produced by the patient's body and custom designed to attach itself to the foreign insulin molecule. This was a surprise, since prevalent doctrine held that the body did not produce antibodies to attack small molecules such as insulin. To study the maximum binding capacity of the antibodies, they did saturation tests, using fixed amounts of radio-labeled insulin and of antibody to measure graded concentrations of insulin. With this technique Yellow and Berson realized they could measure with great precision the quantities of insulin in unknown samples, thus they developed the first radioimmunoassay. This technique, for which Rosalind Yellow was awarded the Nobel Prize in Medicine in 1977, has become a basic tool in many areas of research. Radioimmunoassay revolutionized the ability of scientists to detect and quantify minute levels of tissue components, such as hormones, enzymes, or serum proteins, by measuring the components' ability to bind to an antibody or other protein in competition with a standard amount of the same component that had been radioactively tagged in the laboratory. This technique has permitted the diagnosis of many human conditions without directly exposing patients to radioactivity. No discussion of the impact of radioisotopes on biomedical science would be complete without a recognition of their fundamental importance in basic biological investigations. The ability of radioisotopically labeled metabolites to act like and therefore trace their non-radioactive counterparts has allowed scientists to follow virtually every aspect of metabolism in cells of bacteria, yeasts, insects, plants, and animals, including human cells. Among the benefits of such studies are A. an understanding of the similarities in metabolism of organisms throughout the evolutionary scale, B. identification of sometimes subtle differences in cell structure and function between organisms and thus the ability of drugs to kill bacteria, fungi, or insects without harming humans, and C. elucidation of the fundamental properties of genetic material, DNA. The last of these examples has important implications today, as the human genes controlling many important bodily functions are being identified and cloned and gene therapy is just beginning to find its way into clinical application. Many benefits of understanding the human genetic code have already been realized, and others will likely accrue in the next few years. These benefits are the result of fundamental advances in genetics and molecular biology of the past half-century, which in turn depended heavily on studies with lower organisms and with radioisotopically labeled materials. Thus human health is benefiting from both human and non-human research with radioisotopes. The grandest dream of the early pioneers, a simple and complete cure for cancer, remains unfulfilled. Promising paths at times proved to be dead ends. However the AEC's widespread provision of isotopes coupled with support for new techniques to apply them laid the foundation stones for much of modern medicine and biology. This section has only skimmed the field of nuclear medicine with its vast array of diagnostic and therapeutic techniques and the use of radioisotopes in many areas of basic research. An example of HOPE's unfulfilled, the Gallium-72 experiments. Human experiments with Gallium-72, as discussed in the section titled General Benefits of Radioisotope Research, were conducted at the Oak Ridge Institute of Nuclear Studies in the early 1950s. The experiments used Gallium-72 because of its short half-life, 14.3 hours, and because an earlier animal study indicated it concentrated in new bone making it useful as a tumor marker and possibly for therapy. The 1953 published report stated that the purpose of the study was to investigate the therapeutic possibilities in human tumors involving the skeletal system. In 1955 one of the original researchers stated to the advisory committee staff, a somewhat broader purpose, to exploit to the fullest possible extent any possible use of this isotope as a bone-seeking element rather than to seek a cure for a specific malignant bone tumor such as osteogenic sarcoma. While the Gallium-72 studies did include osteogenic sarcomas, they only represented less than half, 9 out of 21, 43%, of all the other primary and metastatic skeletal malignancies studied. Patients were chosen who had been diagnosed with ultimately fatal neoplasms not amenable to curative surgery or radiotherapy. The diagnosis later proved to be accurate in all but one of the 55 subjects. In one part of the study 34 patients were given trace amounts of gallium. Both external radiation measurements and a variety of excreta, blood, and tissue samples were analyzed to determine the localization of gallium. In another part of the study 21 other patients were given doses that the researchers hoped would be in the therapeutic range. Total doses ranged from 50 to 777 microcures. The gallium was administered in fractionated doses bi-weekly. According to the medical investigators these patients were in general in a more advanced stage of disease and were completely beyond even palliation from conventional forms of therapy. For these patients doses which were believed to be moderate were given and gradually increased to toxic level. The conclusion of the report notes that most of the patients in whom gallium therapy was attempted were given maximum amounts of the isotope. Only the hopelessness of their prognoses justified a trial of doses so damaging to the hematopoietic tissues. A major difficulty was lack of knowledge about both the chemical toxicity of stable that is non-radioactive gallium and the radiation toxicity of gallium 72. Calculations and small animal studies indicated that dosimetry techniques used for other radioisotopes would be of little value. During the study close monitoring was done of many bodily functions to observe toxic effects as soon as they began to appear. Blood tests revealed changes that were prominent and were usually of primary importance in determining when the treatments should be discontinued. Other effects included drowsiness, then anorexia, nausea, vomiting, and skin rash. One problem was determining whether these effects were due to chemical toxicity, radiation toxicity, or a combination. Due to technical difficulties in separating out pure gallium 72 the radioactive gallium was injected with larger amounts of stable gallium so both chemical and radiation effects could be present. To distinguish them one patient was administered an amount of stable gallium equal to a therapeutic dose but with only an insignificant amount of radioactive tracer to determine localization. Observed toxic effects in this patient did not include bone marrow depression. The researchers concluded therefore that the profound bone marrow depression is characteristic of radiation damage and is probably chiefly caused by radiation, though an element of stable metal toxicity may also be contributory. Bone marrow depression gradually ended after gallium injections were stopped. While it lasted bone marrow depression led to greater susceptibility to infection and bleeding. Two subjects died sooner than anticipated, one from infection and bleeding and the other from infection while their bone marrow was still depressed. These two patients died in spite of antibiotics, blood transfusions, and toluidine blue therapy. The researchers reported that in two patients our estimates of safe dosage limits were in error and radio gallium is believed to have hastened death. One researcher writing in 1995 stated that since safe dosage levels were only estimates and seven other patients had survived with even higher dosages, our choice of language, citing the preceding quotation, was unfortunate. It must be emphasized that this portion of the study must be likened to a current clinical phase one trial where in a limited fashion a broad range of toxicity levels may at best only be estimated. The major conclusion of the experiment was that hopes for gallium therapy were unfulfilled. Even though the maximum tolerated doses had been administered, the researchers reported that we were impressed with the almost complete lack of any clinical improvement following a gallium treatment, even in patients who showed evidence of striking differential localization of gallium in tumor tissue. Concerning patient consent, the published study says nothing, which was normal for scientific articles at that time. Near the end of the advisory committee's deliberations, Orens reportedly found consent forms signed by subjects in the gallium study. One of the researchers in 1995 did offer his recollections regarding consent to the committee. Forty-five years ago all of our patients and their families were given a booklet of information explaining how radioisotopes were used in medicine and more specific information about their own involvement including the possible known risks. Signed applications for admission and waiver and release forms were demanded for all patients. When, as in the ongoing gallium studies, toxicity or enhanced risks were encountered, these were immediately made clear to the patients and their families if they were known in that time frame. Very often toxicity is only apparent after review of the clinical data. In the gallium studies, when on review of the data it was determined that no therapeutic benefit had occurred, the study was immediately terminated. Conclusion. At the end of World War II radioisotopes were regarded as the most promising peacetime application of our new knowledge of the atom. Venturing into new fields carried with it substantial risks. Risks due to our ignorance of what lay ahead and risks due to the lack of training of many would-be explorers. The AEC consistently accepted and acted upon its responsibility to manage this risk. An extensive administrative system was created to oversee the safety of human radiation experiments that used radioisotopes supplied by the AEC. At the heart of the system was the AEC's subcommittee on human applications of the advisory committee on isotopes distribution policy. This system regulated the types of uses allowed according to their hazard and the extent of our knowledge of the risks. It required and provided training of those who would use radioisotopes. It required the establishment of local radioisotope committees, which not only reviewed proposals but suggested changes at the local level in experimental design to reduce risk. While extensive measures were taken to minimize risk, few measures were taken to ensure that all the explorers, subjects as well as researchers, were fully informed and willing members of the expedition. No evidence has yet been found that the standards for documented consent articulated by the AEC general manager Carol Wilson in 1947 were applied by the AEC isotopes distribution division. A limited consent requirement was instituted only for the administration of larger than usual doses to very sick patients. Only in the late 1950s did a consent requirement for normal volunteers appear in the AEC guidelines. Based on the records examined by the advisory committee, the adjunct system of local radioisotope committees appears to have functioned as planned. The records of local institutions indicate that they established their own local radioisotope committees, as required by the AEC, and that these local committees closely assessed the risks of experiments. At times this system went beyond what the AEC had planned. Some local committees had jurisdictions that extended to all radiation related work, not merely to radioisotopes supplied by the AEC. The local committees also provided, probably unintentionally, a ready-made vehicle for administering greater oversight of consent practices as concern developed in the 1960s. Requirements for consent on a federal level changed only in the late 1960s as part of a government-wide concern. End of Section 35. Recording by Maria Casper. Section 36 of Final Report of the Advisory Committee on Human Radiation Experiments. This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org. Final Report of the Advisory Committee on Human Radiation Experiments. Case Studies. Chapter 7, Part 1. Non-therapeutic research on children. In the late 1940s and again in the early 1950s, Massachusetts Institute of Technology scientists conducting research fed breakfast food containing minute amounts of radioactive iron and calcium to a number of students at Walter E. Fernald School, a Massachusetts institution for mentally retarded children. The National Institutes of Health, the Atomic Energy Commission, and the Quaker Oats Company funded the research, which was designed to determine how the body absorbed iron, calcium, and other minerals from dietary sources and to explore the effects of various compounds in cereal on mineral absorption.  With funding from the Division of Radiologic Health of the U.S. Public Health Service, the scientists conducting this experiment used Rentham students to test a proposed countermeasure to nuclear fallout. Specifically, the study was meant to determine the amount of non-radioactive iodine that would effectively block the uptake of radioactive iodine that would be released in a nuclear explosion. Recently, these two studies have received considerable media attention, and an official Massachusetts State Task Force has reported on both episodes in some detail. Although they represent special cases because they involve institutionalized children, the Fernald and Rentham experiments nonetheless are the most widely known examples of a category of research that raises particular concerns for the committee. Non-therapeutic experimentation on children. Experiments involving children are important to the committee for two reasons. First, children are more susceptible than adults to harm from low levels of radiation, and thus, as a group, they are more likely than adults to have been harmed as a consequence of their having been subjects of human radiation experiments. Second, an evaluation of research with children is critical to determining whether any former subjects of radiation experiments should be notified in order to protect their health, one of our specific charges. Subjects who were children at the time of their exposure are more likely than adults to be candidates for such notification, both because of their increased biological sensitivity and because they are more likely to still be alive. See Chapter 18 for the committee's recommendations with respect to notification and follow-up. We elected to focus on pediatric research that offered subjects no prospect of medical benefit, so-called non-therapeutic research, because it is this kind of research that has generated the most public concern and is the most ethically problematic. This is not to say, however, that experiments on children in which the children stand to benefit medically never raise ethical issues. Such research certainly can and does. But in deciding how to allocate our limited resources, we chose to concentrate where the issues are most sharply drawn. Also, because most non-therapeutic research with children involved tracer doses of radioisotopes, focusing on this work allowed us a window into radioisotope research generally. We begin the chapter by setting the context for non-therapeutic radiation experiments on children. We review those factors that make non-therapeutic research on children ethically problematic, and how such research has been viewed historically. We next consider what the practices and standards were for research on children in the 1940s, 1950s, and 1960s. This is a continuation of the discussion in Chapter 2, which focused on professional standards and practices for human research. The next three sections address human radiation experiments in terms of the central ethical issues raised by non-therapeutic research involving children. Level of risk, authorization for the involvement of children, and selection of subjects. To address the question of risk, we analyzed 21 non-therapeutic radiation experiments with children conducted during the 1944-1974 period. The focus of this analysis is whether it is likely that any of the subjects of these experiments was harmed or remains at risk of harm attributable to research exposures. A table summarizing these experiments and our risk estimates can be found at the end of this chapter. The 21 experiments were selected from 81 pediatric radiation research projects identified by the committee from government documents and the medical literature. Although these 81 by no means constitute all the pediatric radiation research conducted during this time, they include what are likely fairly typical examples of such research. Of the 81, 37 studies were judged to be non-therapeutic, and 21 of these were conducted or funded by the federal government, and thus fell under the charge of the committee. Included within these 21 studies were the two nutrition experiments conducted at the Fernald School and one fallout-related study conducted at the Rentham School, discussed in the introduction to this chapter. All 21 studies employed radioisotopes to explore human physiology and pathology. We turn next to a consideration of how authorization for the inclusion of these children in these experiments was obtained and who these children were. Unfortunately, for most of these experiments little is known about either of these issues. The last section of the chapter focuses specifically on the experiments at the Fernald School, where, thanks to the work of the Massachusetts Task Force on Human Subject Research, relevant information is available. Throughout the chapter we focus only on research in which children could not have benefited medically. The committee did not have the resources to pursue two related areas of research, non-therapeutic research on pregnant women and therapeutic research on children. We include two capsule descriptions of examples of these types of research at the end of this chapter. The context for non-therapeutic research with children. Children as mere means. In both law and medical ethics it has long been recognized that children may not authorize medical treatment for themselves except in special circumstances. Instead authorization must be sought from the parent. Historically the source of this respect for parental authority rested upon the view that children were the property of their parents and thus parents had the right to determine how their property was to be treated. Today we still speak of parental rights although the justification for these rights no longer rests on an analysis of children as property. Instead respect for the rights of parents is viewed as a mechanism for valuing and fostering the institution of the family and the freedom of adults to perpetuate family traditions and commitments. Another important line of justification for respecting the authority of parents relies not on a recognition of parental rights but on the view that the interests of the child are generally best served by ceding decisional authority to the parent. The parent is thought not only to be in the best position to determine what is in the interests of the child but is also thought to be generally motivated to act in the child's best interests. When research involving children offers a prospect of medical benefit to the child's subject the application of the above analysis is straightforward. Parents are generally thought to have the authority to determine whether their children should be made subjects of such research. Certainly today any use of a child in research would not be ethically acceptable or legally permissible without the parent's permission. Where the research does not offer any prospect of benefit to the child however the legitimacy of the parent as authorizer is less clear. Respect for the authority of parents to make decisions for their children and otherwise control their children's lives is not without bounds. The law recognizes several exceptions designed primarily to protect the child from what society at large considers to be unacceptable or unjustifiable harm or risk of harm. Laws against the physical abuse of children are perhaps the most obvious example of such limitations on parental authority. In the context of research the question arises of whether a parent has the authority to permit a child to be put at risk of harm in an experiment from which the child could not possibly benefit medically. In this case the child is to be used as a means to the ends of others. Children are not in a position to determine for themselves whether they wish to agree to such a use and thus cannot themselves render the use morally acceptable. Should parents have such authority? Should anyone? This question was resolved as a matter of public policy in the 1970s through the work of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. And the subsequent adoption, in 1983, of federal regulations governing research involving children that were guided by the recommendations of the National Commission. These regulations state that children can participate in federally funded research that poses greater than minimal risks to the subject if a local review committee, an institutional review board or IRB, finds that the potential risk is justified by the anticipated benefit to the subjects. The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by the available alternative approaches and adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians. The word consent is purposely avoided in these regulations to distinguish parental permission and minor assent from the autonomous, legally valid consent of a competent adult. Federal regulations do allow non-therapeutic research on children if an IRB determines that the research presents no greater than minimal risk to the children who would serve as subjects. Although no clear definition of what constitutes minimal risk is provided. As with therapeutic pediatric research, parents or guardians must grant permission and children who are deemed capable must offer assent. The regulations also allow for non-therapeutic research with children that does present more than minimal risk, again with parental permission and assent of the child as appropriate, 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 subject's disorder or condition. Research with children that is not otherwise approvable may be permitted, but only under special and presumably rare circumstances. In addition to local IRB review, such research must withstand the special scrutiny of the secretary of the agency sponsoring the research, who is to be advised by a special IRB. The secretary must also allow the opportunity for public review and comment on a proposed non-therapeutic research project that is not otherwise approvable. The regulations thus draw a sharp distinction between therapeutic and non-therapeutic research. Non-therapeutic research, while severely restricted, is not banned. The decision to permit parents to authorize the use of their children in non-therapeutic research reflects both the recognition that some important advances in pediatrics could only come from research with children that was of no benefit to them, and the recognition that we all, as parents, as potential future parents, and as members of society, share in the interest of advancing the health of the young. At the same time, however, parental authority to permit such use of a child is generally restricted to research judged to pose little risk, as important as it is to promote the welfare of children as a class. This interest justifies only minor infringements of the principle not to use people as mere means to the ends of others. These 1983 regulations, and the reasoning behind them, were the culmination of considerable public debate and scholarly analysis, much of which occurred in the 1970s. To situate properly the experiments of interest to the committee, it is necessary to examine the social and professional roots of the issues and arguments that ultimately led to the federal regulations. Public Attitudes, Professional Practices Attitudes and Practices, Prior to 1944 There was significant research interest in infants and children as early as the 18th century, as scientists began to experiment with vaccines and immunization. Children were particularly valuable subjects for this type of research, because in general they were less likely than adults to have been exposed to the disease being studied. A child's response to immunizations was also of great interest because most immunizations were performed during childhood. During the 19th century, the Industrial Revolution greatly increased the number of child laborers, and the public began to acknowledge the need for laws to protect children from abuse. Physicians started to specialize in pediatrics, studying specifically the health problems and diseases that afflicted children. Simultaneously, as social reformers were creating a wide range of institutions for children, such as orphanages, schools, foundling homes, and hospitals, scientists recognized the value of research conducted in these types of institutions. In the late 19th and early 20th centuries, Alfred F. Hess, the medical director of the Hebrew infant asylum in New York City, conducted pertussis vaccine trials and undertook extensive studies of the anatomy and physiology of digestion in infants at the asylum. According to advisory committee member and historian Susan Letterer, Hess sought to take advantage of the conditions in the asylum as they approximated those conditions which were insisted on in considering the course of experimental infection among laboratory animals, but which can rarely be controlled in a study of infestation in man. Although many shared Hess's laudable goal of improving the health of asylum children, many people drew the line at the pediatrician's investigations of scurvy and rickets. In order to study the disease, Hess and his colleagues withheld orange juice from infants at the asylum until they developed lesions characteristic of scurvy. Responding to the public discussion of the ethics of using children in such non-therapeutic experiments, the editors of one American medical journal insisted that such investigations gave the children an opportunity to repay their debt to society, even as they conceded that experimentation on human beings should be limited to children as may be utilized with parental consent. Hess's work was not the only case in which experiments involving children attracted negative public opinion. In 1896, for example, American anti-vivisectionists attacked a Boston pediatrician, Arthur Wentworth, who performed lumbar punctures on infants and children in order to establish the safety and utility of the procedure. The anti-vivisectionists were particularly alarmed because this procedure, which caused pain and discomfort, did not confer any benefits to the subjects. John B. Roberts, a physician from Philadelphia, labelled Wentworth's procedures human vivisection, saying that using the children in the hospital without explaining his plan to their mothers or gaining their permission intensified public fear of hospitals. The 20th century brought new drugs and advanced technologies, which allowed for increased research on children. The conduct of this experimentation, however, was largely left to the individual investigator. When his experimental gelatin injections provoked alarming symptoms of prostration and collapse in three normal children, including a feeble-minded four-year-old girl, the physician Isaac Abt stopped his pediatric experiments and began experimenting on rabbits. Meanwhile, legislation was being proposed throughout the country to protect children and pregnant women from experimenting physicians. Two proposals were introduced in the U.S. Senate in 1900 and 1902. Proposals to prohibit such terrible experiments on children, insane persons, and pregnant women, and to ensure that no experiment should be performed on any other human being without his intelligent written consent. Were introduced in the Illinois legislature in 1905 and 1907. In 1914 and 1923, the New York legislature considered bills that prohibited experimentation with children. Although these bills did not become law, it is clear that some unease concerning non-therapeutic research on children existed among the public and elected officials. Reaction to the polio vaccine trials conducted during the 1930s further demonstrated the growing discomfort over pediatric experimentation, as thousands of American children were involved in what some considered at the time to be premature trials of the polio vaccine. Although it appears that parental consent was obtained for a number of these studies, the controversy over these trials stalled polio vaccine research for almost two decades and generally made investigators ambivalent about the use of human subjects. Although there are no legal cases that bear directly on non-therapeutic research with children during this period, an appellate court ruling in 1941, Bonner v. Moran, involving the performance of a non-therapeutic medical procedure on a child without parental consent, suggests how such a case might have been decided. John Bonner, a 15-year-old African-American boy from Washington, D.C., had undergone an experimental skin graft for the benefit of Clara Howard, a cousin suffering from severe burns. When he discovered that John Bonner had the same blood type as the burn victim, Howard's plastic surgeon, Robert Moran, persuaded Bonner to allow him to fashion a tube of flesh by cutting from the boy's armpit to his waistline. This procedure, however, was conducted without the consent of a parent, as his mother, with whom he lived, was ill at the time and knew nothing about the arrangement. Moran then attached the free end of Bonner's flesh tube to Clara Howard, hoping that the flesh and blood link would bring benefit to the burned girl. Due to poor circulation in the tube, the procedure did not help the burn patient, and put the healthy boy, who was required to stay in the hospital for two months, at significant risk, and left him with permanent scars. Bonner's mother brought suit against Moran for assault and battery. The appellate court based its ruling against Moran on what it perceived as a disturbing combination of lack of direct benefit for John Bonner and a lack of permission from the boy's mother. Here we have a case of surgical operation, not for the benefit of the person operated on, but for another. We are constrained, therefore, to feel that the consent of the parent was necessary. The court did not refer to the episode as an instance of experimentation, but the parallels between this novel procedure performed for the benefit of another, and a non-therapeutic medical experiment are quite powerful. End of Section 36 Section 37 of Final Report of the Advisory Committee on Human Radiation Experiments This is a LibriVox recording. All LibriVox recordings are in the public domain. For more information or to volunteer, please visit LibriVox.org Final Report of the Advisory Committee on Human Radiation Experiments Case Studies Chapter 7 Part 2 Attitudes and Practices, 1944-1974 As best the committee can establish, there were no written rules of professional ethics for the conduct of research on children prior to 1964. Taken literally, the Nuremberg Code, which requires that all subjects of research have legal capacity to give consent, precludes all research with children. There is no reason to believe, however, that the judges at Nuremberg meant to impose such a prohibition, and the Nuremberg Code did not result in a ban on research with children. Pediatric research flourished after World War II, as did biomedical research in general. What is less clear is how this research was conducted, and on whom. One source of evidence about legal thinking on pediatric research, if not actual practice, is in the writings of Irving Latimer, a lawyer who, in 1958, was completing a doctoral degree in Juridical Science at the same time he was employed as an administrator at the National Institutes of Health. Latimer concluded his doctoral dissertation, Legal and Ethical Implications of Medical Research on Human Beings, with an appendix devoted to the issues surrounding experimentation on persons not competent to provide personal consent, whom he defined broadly as minors and mental incompetence. Latimer argued that it was permissible to employ minors and incompetence as subjects of medical investigations where there is informed consent by a parent or guardian, including the state, for procedures which also significantly benefit or may be expected to benefit the individual. Latimer was less sanguine, however, about non-therapeutic research with these populations. He expressed particular concern about the use of institutionalized children, even with proxy permission, in research that did not hold the possibility of personal benefit. Permission given by parents or the state to utilize institutionalized children without any suggestion of benefit to the children may well be beyond the ambit of parental or guardianship rights. Latimer did, however, leave open a window for the use of legally incompetent subjects in non-therapeutic research, but he clearly harbored great discomfort with his own suggestion. The availability of certain persons not able to consent personally may constitute a strategic resource in terms of time or location not otherwise obtainable. It must be remembered, however, that the Nazis hid behind this rationalization in explaining certain highly questionable or clandestine medical experiments. Such justification should not even be considered except in dire circumstances. If ever employed, it should not be assimilated into the concept of personal benefit, else there may be no legal or ethical control for the protection of both prospective subject and investigator and their individual integrity. As part of the committee's Ethics Oral History Project, we interviewed two pediatricians who were beginning their careers in academic medicine in the late 1940s. One of these respondents, Dr. Henry Seidel, had some research experience with institutionalized children. He noted that we got access to the children very easily, and although his research was merely observational, it was not hard to imagine that experimental research with these children could have been conducted. When asked about the studies conducted by Dr. Saul Krugman on institutionalized children at the Willowbrook State School, discussed later in this chapter, Seidel observed, I didn't have any problem imagining that possibility. In retrospect, I'm sure it could happen, you know. There was something about those reports that rang true. William Silverman, the other pediatrician interviewed, had clear recollections of how research was conducted in pediatrics at that time. He recalled that, in the late 1950s, many pediatricians, including himself, believed that it was not necessary to obtain the permission of parents before using a pediatric patient as a subject in research, even if the research was non-therapeutic. He has since become a strong proponent of the parental permission requirement in pediatric research. He also asserted that performing non-therapeutic experiments on children without authorization from parents was part of a broader ethos of the time in which everyone was a draftee in a national war on disease. Dr. Silverman's account squares with the picture that emerged in Chapter 2 of Practices in Research with Adults, in which it was not uncommon to use adult patients as subjects of research without their knowledge or consent. Silverman was among the researchers invited by Boston University's Law Medicine Research Institute, LMRI, to participate in a conference on Social Responsibility in Pediatric Research, held in May 1961. This meeting was one in a series of closed-door conferences organized by LMRI to investigate actual practices among clinical researchers. The transcripts of the conference provide an important window onto practices and attitudes of the time. In large measure they confirm Silverman's recollection of his own position some 35 years ago. Early in the meeting Silverman asserted that there is an unwritten consent by being a living person at this time to participate in this kind of advancement of knowledge, that is, non-therapeutic pediatric research. Some of the other participants employed the same analogy to the military draft that Silverman recently used to relate his recollections. However, there was by no means unanimity about the appropriateness of this view. Dr. A. Dr. B. says that this research without consent is like military conscription. Dr. C. Not comparable. We voted to do military conscription. The proceedings of the conference suggest that while it may not have been uncommon for pediatric patients to be used as subjects of non-therapeutic research without the permission of their parents, at least some physician investigators, including investigators who followed this practice, thought it was morally wrong to do so. Consider, for example, a story relayed by one pediatrician investigator at the conference who seemed to embrace with particular earnestness the desire of the conference organizers to learn the unvarnished reality of clinical research. In the opening minutes of the meeting this researcher reminded his colleagues that the question for us to discuss here today is how we operate on a daily basis. He offered for discussion a provocative case from his personal experience in which he and his associates wanted to do lumbar punctures on newborns. He explicitly noted that this study was not of benefit to the individual, it was an attempt to learn about normal physiology. One of the other conferees asked, did you ask parental permission? The researcher responded, no, we were afraid we would not get volunteers. The case prompted a great deal of discussion at the conference, but perhaps most tellingly this researcher frankly acknowledged toward the end of the discussion in a meeting that had begun with an assurance of confidentiality from the organizers that he had sinned in carrying out these lumbar punctures in normal infants without parental permission. The proceedings of the conference also suggest that at least some pediatrician investigators routinely obtained the permission of parents before embarking on research with their children. It is perhaps significant that the pediatric researcher who articulated this position at the conference was from Canada and the conference transcript seems to suggest that he was providing a general characterization of practices in his country. Dr. A. Let's ask Dr. B. from Canada. Dr. B. We have been quite sticky on consent. If we want a biopsy or a radioactive exposure and the parent says no, then we don't do it. The question of morals is too valuable. If this statement represents the sensitivity of Canadian pediatrician investigators to issues of parental permission, which this single quotation does not prove, there is no obvious explanation as to why many of their colleagues in the United States behave differently. The LMRI conference is noteworthy not only for what it reveals about the range of views and practices concerning parental permission for non-therapeutic research, but also for the unanimity expressed about the importance of obligations to prevent or minimize harm to pediatric subjects of research. Minimizing risk was recognized by those at the conference as the most important and for some participants the only moral duty of pediatric investigators. Three years after the LMRI conference in the summer of 1964, the World Medical Association ratified a Code of Ethics for Human Experimentation at a meeting in Helsinki. Unlike the Nuremberg Code, this statement, known as the Declaration of Helsinki, recognizes that research may be conducted on people with legal incapacity to consent. The declaration distinguishes between two kinds of research, clinical research combined with professional care and non-therapeutic clinical research. It permits the use of people with legal incapacity to consent as subjects in both kinds of research, provided that the consent of the subject's legal guardian is procured. Subjects of the first kind of research are referred to as patients. Disclosure to and consent from patient subjects are required by the declaration, consistent with patient psychology. The declaration does not specify whether considerations of patient psychology also could justify not obtaining the consent of the guardian where the subject does not have the legal capacity to consent. The subjects of non-therapeutic clinical research are not referred to as patients, but as human beings who must be fully informed and whose free consent must be obtained. The declaration also requires that non-therapeutic research be discontinued if, in the judgment of the investigators, to proceed would be harmful to the individual. Thus, although the declaration permits parents to authorize the use of their children as subjects in non-therapeutic research, such research is not intended to be harmful to the subjects. The language and reasoning of the declaration was unclear and confusing with regard to clinical research, both therapeutic and non-therapeutic, on legally incapacitated individuals. It was revised in 1975, at a time when the ethics of research with human subjects was receiving considerable public attention in the United States. Both in the 1960s and early 1970s, public controversies erupted about several cases of research involving human subjects, controversies that led to the establishment of the National Commission and publication of the Federal Regulations. One of the most well-known of these cases involved research on institutionalized children. During the 1950s and 1960s, Dr. Saul Krugman of New York University conducted studies of hepatitis at the Willowbrook State School, an institution for the severely mentally retarded. To study the natural history, effects, and progression of the disease, Krugman and his staff systematically infected newly arrived children with strains of the virus. Although the investigators did obtain the permission of the parents to involve their children in the research, critics of the Willowbrook experiments maintained that the parents were manipulated into consenting because, at least in the later years of the research, the institution was overcrowded and the long waits for admittance were allegedly shorter for children who were entering the research unit. Henry Beecher, a Harvard anesthesiologist whose impact on the history of research ethics is detailed in Chapter 3, condemned Krugman and his staff for not properly informing the parents about the risks involved in the experiment. Beecher also challenged the legal status of parental consent when no therapeutic benefit for the child was anticipated. A New York State senator, Seymour R. Thaler criticized the Willowbrook research on the pages of the New York Times in 1967, only to come to its defense later in 1971. Also in the early 1970s Willowbrook became the subject of a heated debate in the medical literature. Interestingly, Dr. Krugman was one of the participants at the LMRI Social Responsibility and Pediatric Research Conference, where he expressed pride that he routinely obtained permission from the parents of the children in his studies. In that group in 1961 Krugman was thus among those pediatric investigators most sympathetic to the position that children could not be used as mere means to the ends of the researcher without the authorization of the parent. AEC Requirements for Radiation Research with Children Although in the 1940s and 1950s there were apparently no written rules of professional ethics for pediatric research in general, there were guidelines for the investigational use of radioisotopes in children. In 1949 the Subcommittee on Human Applications of the Atomic Energy Commission's isotope division established a set of rules to judge proposals submitted by researchers for the use of radioisotopes in medical experiments with human subjects, including normal children. These standards appeared in the fall 1949 supplement to the AEC's isotope catalog and price list. Under the heading Normal Children, the isotope catalog offered the following statement. In general, the use of radioisotopes in normal children is discouraged. However, the Subcommittee on Human Applications will consider proposals for such use in important researches, provided the problem cannot be studied properly by other methods and provided the radiation dosage level in any tissue is low enough to be considered harmless. It should be noted that in general the amount of radioactive material per kilogram of body weight must be smaller in children than that required for similar studies in the adult. These guidelines did not mention consent of parents, guardians or children. Instead, this statement simply discouraged non-therapeutic experiments with children. The guidelines did not however suggest that the practice was completely inappropriate. The Subcommittee asserted that important research using harmless levels of radiation dosage with children was acceptable. The crucial terms important and harmless were left undefined. It seems reasonable to expect that important pediatric research would address a significant medical problem affecting children or would explore key aspects of normal human physiology relevant to health promotion or disease prevention for which research on children is indispensable. By these standards the 21 non-therapeutic radiation experiments with children whose risks we review in the next section of this chapter could all be said to address important questions relevant to pediatric health care. This judgment is not based on a determination of whether a given study proved important in the subsequent development of a particular field. Such retrospective analysis would place an unreasonable burden on investigators of the past as research is an inherently speculative enterprise. Many experiments that proved to be of little value in the advance of medical knowledge are, at the time they are implemented, well designed and appropriate attempts to address important research questions. It is easier to infer what the members of the AEC subcommittee on human applications would have considered important research than what the subcommittee would have considered harmless radioisotope research. Acute toxicity is not seen following the administration of non-therapeutic tracer doses of radioisotopes. Thus the principal potential harm from radiation exposure at lower doses is the subsequent development of cancer. In the 1940s and 1950s some in the field apparently discounted the risk while others were wary of a prevailing uncertainty. Dr. John Lawrence, an early radioisotope researcher at the University of California, described how some researchers conducted public demonstrations of tracers using unsuspecting physician out of the audience to act as the guinea pig, presumably to reassure the audience that tracers were innocuous. By contrast other investigators focused on the tragedy of the radium dial painters concerned that this might be repeated with man-made radionuclides. Evidence of how well the AEC enforced its 1949 guidelines with respect to research on children is elusive. AEC correspondents with researchers at the Fernald School suggest that in at least one case there was oversight of research in which children were administered radioisotopes.


Every time I try and get it to give me some power it just kills it, but so anyway I'll forget that for now. I want a little variable power supply, so I built one. This is my power coming in, if I clamp this down it makes a circuit, so I've got AC coming in to my little transformer here. This transformer is connected to my little retroactifier, so you can see that's where the connections are, so I've got one side of the transformer goes to this part of the retroactifier, this one goes to this part here, this junction, and then I come off here and here, and this is going to indicate the positive, indicate the negative, and it's in line with a couple of capacitors. This voltage then comes across here, it's only jumped to here so I can get into it easily. I suppose really I could take some of this out, but it's literally just jumped, this is the negative side which is the white wire here, positive is the yellow, and it's just jumped here so I can get another attachment to ground. From the input pin there, from there, my positive of the power supply goes to the input of the 317, I've got a little resistor here, 510 ohms between the output and the adjust, you can use, you know, 120, 180 or 1k in between on there, and then from the adjust pin to the centre of the pot, and then from the, well facing me it's the left, but if it was facing the other side it'd be the right, I don't even think it matters actually, it will matter because if I turn down it goes down, if I turn up, if I had this the other way around, if I turned up it would go down, if I turned down it would go up, so from here that just goes to ground, and all of them as well, I've just taken off from ground here to another little tiny smoothing capacitor there, I can't know what size that is, it's not very big, oh it's a thousand mic I think, yeah it is, and then I've got my outputs, so that little IC, that's just a little op amp, I'm going to have a little play around with that and see about doing some controlling of that, it's only because I've looked at the red that you can, and this wire here is absolutely nothing to do with it, so I've just got my two outputs then, negative side of the capacitor here, positive side of the capacitor here, and that's going off to the, you can't see that, it's going off to this zero multimeter, come here, I need to tidy up this bench, it wasn't like this earlier one, I've tidied it up twice today, but it's just got as messy again, so that's going to that multimeter, and I've also got this little clock timer kit thing connected, and I have my scope connected, so I just wanted to see how dirty the output was, and that's why I put the capacitor in, because there was a little bit and I've managed to clean it up just by checking that capacitor in, so yeah, pretty chuffed, so here we go then, I'm just going to flick down the power, oh well a natural patch, I thought I'd killed this because I wired it the wrong way around, I wired it the same as what I would do for just the 7809 regulator, which is here, and so I had that in, I thought I'd knackered it, so I kicked it out and put another one on the heatsink and put it in, and it works fine, so I've just checked it, let's just make sure that we're on the right pins, yep, and yeah the one that I thought I'd killed, because it wasn't working, it wasn't performing, let it cool down, and it all fixes again, so yeah, pretty chuffed, so what I'm going to do now then is I'm just going to flick down this, and as you'll see I'm just straight to the reference voltage 1.2, 1.26, and I'm going to turn it up there, and you should see as it comes up, four volts, well we haven't got this connected, I was expecting to see this come on, but if I just plug that in now, it doesn't normally make that noise, probably because it needs a little bit more than three and a half volts to work, and so there we go, let's come on, it's a bit annoying this thing is, because it's got no battery back up, and as soon as you just pull the power, it starts at 10, 10 every time as well, don't really know why, I'm sorry if I keep not seeing the video in the camera, it says I've got it in my hand, but it's the easiest way to see it, so I can use this little adjustment here, let's just see it, it'll go up, but don't turn it too quick, it'll go up, this little clock can only take up 12 volts, and we can turn it back down again, down it goes, and that clock should have gone out, there we go, so the clock's on, now the interesting thing about this is when I take this off, from this little power supply here, the AC comes in, if I use this green one in here, I've got seven volts, if I use this green one in this one, I've got seven volts, if I use these two, I've got 14 volts, and of course when you convert it into DC, you think you'd lose, you've voltage a bit, but no, because watch, I should have 14 volts tops, if I turn this up, oh yeah you think we should be stopping around about now, but oh no, let's just keep going, and there we go, all the way to 17.6 volts, awesome, let's take that back down again, there you go that's, I mean that's, I can't believe how easy that was, that's a real simple little circuit, and it works great, and in a minute I'm going to put another little circuit on it so I can charge a battery there, just for something to do, basically if you didn't have this little AC part here, you literally just have another power supply that you connect onto this, that's simple, the schematic's on the TI website, and it's just really simple to put forward, that's my first variable power supply, because I couldn't get this one to work, cheers watching guys, take care, bye


Hi everybody everybody did what did I say everybody I try to combine everybody and every one together We're doing a 2020 panini select football three box pick your team number 20 big. Thanks to everyone here For making this happen. Just build this up straight up the old-fashioned way There's Kevin with that last spot mojo buccaneers that's why is that star next to his name and These are our last three boxes of select I didn't see any more in the back unless they're hiding somewhere Don't have any more to post unfortunately, but I'm sure we are on the lookout For more we always are Yeah, I try to get I think I said every oney Everyone everybody I Decide to switch halfway in between and then just turn it to every oney. Oh wait. This is what am I doing? This is prism Where the select go? Sorry. All right. I had the video pause It's unpause we're gonna start a new video for it for a select these are gonna be Mark, what's the what's the last pick your team we have on the prisms on the basketball side here? this will be I Don't know if you even have any of this posted. Oh there is pick your team 20 All right, so all these are pick your team 20 and that'll be pick your team 20 as well All right, so there you go Set that up here We should probably do that next All right, and in a separate video will be the actual select break Jasper's case breaks calm