The Task Force to Review Human Subject Research Massachusetts Department of Mental Retardation January 24, 1994 UNREADABLE RE: Human Subjects Testing and Research on the Mentally Retarded Dear Philip Campbell, Commissioner of the Massachusetts Department of Mental Retardation, has established a Task Force to Review Human Subject Research. l am writing to you today on behalf of the Task Force to request certain information which may be in the possession of your institution. The Task Force is charged with the following: To review and report on any and all research projects which utilized radioactive and other potentially harmful material involving human subjects within the facilities for the mentally retarded operated by the Commonwealth of Massachusetts. To that end, we are asking your institution, along with several others in Massachusetts, and along with several divisions of the state government, to supply certain information on human subjects testing. We are asking for your cooperation, recognizing that collecting such information is a difficult and time-consuming task, especially given that some of the research in question took place decades ago. At the same time, we will need your promptest possible attention to our request for information, so we can proceed with our task as quickly and efficiently as possible. In order to limit the inquiry to a more manageable time period, we are seeking information on human subjects testing at all of the State School which conducted between 1943 and 1973. For the purposes of this inquiry, we are limiting the terms "testing" and "research" to include testing on human subjects which included the use of radioactive materials, and/or testing which included the introduction of any harmful or potentially harmful compound into a human subject. This inquiry specifically excludes non-invasive behavioral research at this time, although the Task Force may later extend its inquiry into this area. P.0. Box 9108, Belmont, Massachusetts 02179 Voice/Fax/TTY (617) 527-5576 TASK FORCE TO REVIEW HUMAN SUBJECT RESEARCH January 24, 1994 Page 2 We ask that your construe this definition broadly, and that you include in any answer projects funded by your institution, projects conducted under the auspices of your institution, and/or any projects of which you are aware which were conducted by any employee of your institution, under the supervision of any employee, and/or by or in connection with any faculty, student, fellow, or volunteer. Should you discover additional research projects conducted between 1943 and 1973 which do not fall within the definition above, but which involved individuals with mental retardation, please identify them for us in any case. "State Schools includes any one of (or any combination of) the following: Walter E. Fernald State School in Waltham; the former Belchertown State School, the Wrentham State School in Wrentham; the Glavin Regional Center in Shrewsbury; the Paul A. Dever State School in Taunton; the Hogan/Berry Regional Center in Hathorne; the Monson Developmental Center in Monson; and the Templeton Developmental Center in Baldwinville. In your initial inquiry, we ask you to focus on studies involving radioactive materials. We ask that you provide the Task Force with copies of documents in your institution's custody that appear to have been generated in connection with any of the following types of research believed to have taken place: -The actual or proposed use of radioactive iron in research involving residents of the Fernald State School; --The actual or proposed use or radioactive calcium in research involving residents of the FernaLd State School; -The actual or proposed use of radioactive iodine in research involving residents of the Fernald State School. We certainly understand that when reviewing records from this long ago. you will find that the data is often primitive and/or that the records may be scattered through a number of places or even intermingled in personal collections. However, in order to complete this inquiry in a way that truly allows accurate information to be given to potential subjects, we must ask that you undertake the same intensive and extensive review that all involved institutions and agencies are conducting. Specifically, the type of information we ask that you identify and provide includes the following: 1. Identify Research Projects. Please identify all research projects that were conducted by your institution at the State Schools for the period 1943 to 1973. Please include in your answer the name of the project, state the dates the project began and ended, and state the purpose(s) of the project. 2. Identify Researchers. For each project identified in your answer to Question 1, please identify each person who directed, conducted, and/or participated in the project. TASK FORCE TO REVIEW HUMAN SUBJECT RESEARCH January 24, 1994 Page 3 3. Identify Human Subjects. For each project identified in your answer to Question 1, please identify each human subject who participated in the project. If the names of the subjects are not known. which we have found to be common, please provide any other available identifying data. such as date of birth, social security number, or residence. 4. Describe the Research Methodology. Please describe in reasonable detail how each human subject was utilized in each project identified in your answer to Question 1. Please describe the data collected and the results of the study. 5. Identify Publications. If any of the projects identified in your answer to Question 1 was the subject of a scientific publication or was the subject of a thesis or dissertation, and the paper, please provide us with a copy of the document, regardless of whether it was published in the scientific literature. If you do not have a copy of the document, please provide an appropriate reference to the document, and identify any person known to be in possession of the document so we may retrieve a copy. 6. Consent. The Task Force is closely evaluating the question of informed consent in connection with human subjects research. With regard to each project identified in your answer to Question 1, please state whether consent was sought and/or obtained for the study, and if so, from whom. Please describe how consent was obtained, and identify any documents which reflect the consent obtained. If you locate consent forms, please send us copies of them. 7. Identify Funding Sources. It would greatly assist the Task Force if you would identify the source of any funding for the research you identify and describe. This will enable the Task Force to conduct follow-up investigation through additional sources. As you conduct this investigation into your archives, kindly copy materials for our task force which relate to your answers to the questions above. We would appreciate receiving all documents which describe any research conducted, and especially any documents which identify human subjects. We would also appreciate receiving copies of any other documents identified in response to any of the questions above. As the Task Force has been given a deadline of March 31, 1994 to complete its investigation, time is of the essence. We ask that your reply to these requests be delivered on or before February 9, 1994. To the extent that we are able to identify additional specific research projects which took place at the State Schools, we will notify you as quickly as possible. Also, it would greatly assist the Task Force if your institution would designate one person at your institution who will serve as our primary contact person for the purposes of this request for information. We understand that these requests may require considerable effort on the part of your institution. Be assured than we are not TASK FORCE TO REVIEW HUMAN SUBJECT RESEARCH January 24, 1994 Page 4 asking you to do anything we have not already asked certain State agencies to do as well. If you are unable to complete this investigation within the time allotted, please provide as much preliminary information as possible by February 9, 1994. The questions are set forth in order of the Task Force's priorities. Please be advised that your responses to these questions will be a matter of public record, except where your responses identify human subjects, in which case appropriate confidentiality will be maintained. If you would like advice or direction in undertaking this review, please call Doe West at (617) 894-3600 Extension 2582 for further instructions prior to the deadline of February 9, 1994. Finally we want to emphasize our desire to work cooperatively with your institution and others. We greatly appreciate your assistance in helping to bring relevant information to our attention in a timely and orderly way. Please direct all questions about this letter, as well as all responses, to: Doe West Project Coordinator Task Force to Review Human Subject Research c/o Fernald State School P.O. Box 9108 Belmont, MA 01278 Hand deliveries may be made as follows: Doe West Project Coordinator Task Force to Review Human Subject: Research Howe Library FernaId State School 200 Trapelo Road Waltham, MA Thank you very much for your anticipated cooperation. Very truly yours, (Signed) Frederick M. Misilo, Jr. Deputy Commissioner Chairman, Task Force to Review Human Subject Research cc: Philip Campbell, Commissioner Task Force Members INDIVIDUALS REQUESTED TO PROVIDE INFORMATION ON HUMAN SUBJECTS TESTING Each of the following persons was contacted in February, 1994, and asked to provide comprehensive information to the Task Force concerning human subjects testing at the State Schools between 1943 and 1973. The full text of the letter sent is appended hereto: Mitchell T. Rabkin, M.D. J. Robert Bauchanan, M.D. President General Director Beth Isreal Hospital Massachusetts General Hospital 330 Brookline Avenue 55 Fruit Street Boston, MA 02215 Boston, MA 02114 Lewis W. Pollack John H. Britt Superintendent Superintendent Boston City Hospital Massachusetts Hospital School 818 Harrison Avenue 3 Randolph Street Boston, MA 02118 Canton, MA 02021 H. Richard Nesson, M.D. Elizabeth Coniaris President Chief Executive Officer Brigham & Women's Hospital Massachusetts Mental Health Center 75 Francis Street 74 Fenwood Road Boston, MA 02115 Boston, MA 02115 David S. Wiener Steven M. Mirin, M.D. President General Director Children's Hospital McLean Hospital 300 Longwood Avenue 115 Mill Street Boston, MA 02115 Belmont, MA 02178 John W. Pettit Francis P. Lynch Administrator President Dana Faber Cancer Institute Mount Auborn Hospital 44 Binney Street 330 Mount Auburn Street Boston, MA 02115 Cambridge, MA 02238 Sister Mary A. Loughlin Raymond C. McAfoose President President Franciscan Children's Hospital New England Baptist Hospital 30 Warren street 125 Parker Hill Avenue Boston, MA 02135 Boston, MA 02120 Bruce W. Steinhouer, M.D. J. Richard Gaintner Chief Executive Officer President Lahey Clinic Medical Center New England Deaconess Hospital Mall Road 185 Pilgrim Rd. Burlington, MA 01805 Boston, MA 02215 Peter Chinetti Jerome H. Grossman, M.D. President President Massachusetts Eye & Ear Infirmary New England Medical Center 243 Charles Street Hospital, Inc. Boston, MA 02114 750 Washington Street Boston, MA 02111 John P. Bihdorff President Newton-Wellesley Hospital Institutions Contacted for Information On Human Subjects Testing Page 2 Newton Lower Falls, MA 02162 Theodore Druhot, M.D. Dr. Sumner M. Robinson President Massachusetts College of St. Elizabeth's Hospital of Boston Pharmacy and Allie 73 Cambridge Street 179 Longwood Avenue Boston, MA 02135 Boston, MA 02115 Salvatore Russo, Ph. D. Dr. John DiBiaggio Administrator President Shriners Hospital for Crippled Tufts University Children Medford, MA 02155 51 Blossom Street Boston, MA 02114 Manuel J. Lipson, M.D. Mr. Phillip Marineau Executive Director President Spaulding Rehabilitation Hospital Quaker Oats Company 125 Nashua Street P. O. Box 049001 Boston, MA 02114 Chicago, IL. 60604-9001 J. Scott Abercrombie, Jr., M.D. President The University Hospital 88 East Newton Street Boston, MA 02118 Dr. John R. Silber President Boston University 147 Bay State Road Boston, MA 02215 Neil Rudenstine President Massachusetts Hall Harvard University Cambridge, MA 02138 Samuel O. Their, M.D. President Brandeis University P. O. Box 9110 Waltham, MA 02254-9110 Michael Hooker, Ph. D. President University of Massachusetts 18 Tremont Street, Suite 800 Boston, MA 02108 Dr. Charles M. Vest President Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge, MA 02139 STATE FACILITY REVIEW REPORT FROM THE METHODOLOGY SUBCOMMITTEE File reviews and interviews were conducted by staff at State facilities to identify additional Studies or experiments which utilized radioactive materials during the 1943 to 1973 periods. No such experiments or studies were identified (As noted below, independent sources identified experiments at the Fernald and Wrentham State Schools). At the Walter E. Fernald State School, based on data received from outside sources and reported in scientific journals, identities of some resident participants were established At the Wrentham State School, again based on information from independent outside sources and scientific journals, experiments were identified, some positive identification of participants was made. The medical files of identified and possible participants of the Wrentham studies (1962) were examined and none contained data indicating participation or consent to participate. 8,000 to 10,000 medical files of former residents of Fernald State School alone are located in facility and state archives, No attempt was made by the Task Force to review all of these files as our experience had been that resident medical files do not (except in rare instances) contain data concerning radioactive material experiments. (This information was kept separately by researchers and not otherwise recorded at the state facilities). We consulted with two medical statisticians: Dr. Monroe G. Sirken, Associate Director for Research and Methodology National Center for Health Statistics, U.S. Dept of Health and Human Services Dr. Nancy Veeder Associate Professor, Graduate School of Social Work Boston College Both statistical experts suggested that a random sampling search of archival medical files would not be productive in view of our experience that files do not contain notations of radioactive experiments. Set forth below are synopses of searches conducted at the various facilities. Detailed reports of their efforts are contained in the appendix. 1. BELCHERTOWN STATE SCHOOL (now closed) Staff of the Monson Developmental Center contacted Dr. Aaron Kasparian, Medical Director 1964-1985. He advised that no experimental research was done at Belchertown during the period he was there. Dr. Kasparian noted that Dr. Bowser was the Superintendent in 1964 and had been there approximately 20 years. Dr. Bowser never mentioned any kind of experimentation or research to Dr. Kasparian. Dr. Kasparian never saw any rotations in medical records indicating experimental treatments. Annual reports also reviewed by staff: Board of Trustees (1923 to 1992) Board of Trustees minutes of meetings (1923 to 1992) Human Rights Committee files (1981 to 1992) Superintendent's files (1976 to 1993) 2. PAUL A. DEVER STATE SCHOOL Contacted former employees, searched archival material, reviewed minutes of Board of Trustees meetings and Board of Trustees 2 annual reports. Provided a list of present and past Superintendents and Medical Directors. Reviewed in detail medical records of current residents who were living at Dever when Fernald experiments were conducted. 3. WALTER E. FERNALD STATE SCHOOL Archival material housed in the Howe Library was searched by staff for any mention of research experiments or other accounts dealing with radioactive materials. Included were monthly reports from the Research Unit of Fernald, Superintendent's Reports, the correspondence of Superintendents and Clinical Directors, Annual Reports and boxes of miscellaneous material. The initial review of archival records (client records and medical records) began with the names found on the "Christmas Club" list identified in the press. Thereafter, every time a list of names was found in materials from Fernald's archives, or submitted in papers supplied by Harvard and MIT those records were retrieved and reviewed. Persons calling the "800" phone line or sending a letter that involved a male who was here in the correct time frame also triggered an archival review. The most extensive sources, submitted to us, were files and reports, which had been donated by individuals to universities. We also performed extensive reviews of medical literature of the day for further clues on studies and subjects. Reviews of the medical files of the 74 individuals identified by name as subjects of studies failed to disclose a single reference to radiation experiments. 4.GLAVIN REGIONAL CENTER Staff reviewed medical records for indications of any forms of medical experiments. Interviewed medical staff, reviewed Human Rights Committee files. Provided list of medical directors and Superintendents. 5.HOGAN/BERRY REGIONAL CENTER Staff reviewed facility records and archival material. Interviewed staff and concluded that there had been no active medical research at this facility. 6.MONSON DEVELOPMENTAL CENTER Staff reviewed historical files (that date back to the late 1800's). Interviewed nursing supervisor (1950's to 1980's). Provided list of medical directors and Superintendent 7.TEMPLETON DEVELOPMENTAL CENTER (formerly a unit of the Fernald State School) Staff interviewed: former Superintendent and wife (1952 to 1977) former unit supervisor (1957 to 1981) former recreation supervisor (1962 to 1991) another unit supervisor (1950 to 1982) former senior L.P.N. (1952 to 1983) 8. WRENTHAM STATE SCHOOL Staff reviewed Trustees minutes 1933 to 1965; located Wrentham State School Article List - with data re: 18 articles published 1910 to 1955 by staff members. Completed a 10% random sampling including records of 20 current and 20 deceased/discharged former residents. Reviewed 500 to 600 publications in record room. Using data from the same "Pediatrics" article identified 61 residents who were between ages 1 and 16 at any time between 1960 and 1965. Medical records of all of these persons were examined in archives and no evidence of "thyroid study" was locate. A second level of review was conducted by the Project Coordinator Doe West, Chairperson Frederick Misilo and Task Force Member Richard Robinson. They were able to match records with birthyears and gender to positively identify twelve persons. This will be ongoing as the working group now focuses on the Thyroid studies over the summer of 1994. 3 DMR Task Force on Human Subject Experimentation CONTACT WITH SUBJECTS & INQUIRIES SUBCOMMITTEE February 28, 1994 (Revised March 4, 1994) Subcommittee Report A meeting was held with members of the Fernald Social Work Department, as well as members of the Wrentham State School Social Work Department, to discuss the status of communication with experiment "subjects" and plan for further contact with these individuals. Doe West and Rich Robison also participated in the meeting. This report summarizes issues discussed at that meeting. Issues raised in subsequent conversations with Dr. Allen Crocker and Dr. Gunnar Dybwad have also been incorporated into this report Preliminary Subcommittee recommendations, discussed during all previous meetings, are also included. Status of Communications with Involved Individuals To this date, no communication has been initiated with the individuals believed to have been involved in "radiation experiments". Communication has been only with those who have self-identified through the "800 number" and with interested individuals who have called the 800 number. + There have been approximately 300 calls to the "800 number" at Fernald State School. + To date, it has been determined that approximately 74 "science club members" participated in experiments involving radiation. + Only 10 of these 74 participants have been located through the process of calling the "800 number". An additional two individuals have been identified, but 62 known participants have still not identified themselves to the Department. [Note: On 314, Rich Robison found that it may be possible to locate an additional 9 or 10 individuals as a result of their continuing involvement with DMR. The numbers in the remainder of this document do n~ reflect this new finding.] ISSUE: What efforts should be taken to find the 62 individuals from Fernald known to have participated in the radiation experiments? Doe outlined potential avenues for finding the involved individuals through public information channels. These include identification by the Department of Revenue, the Department of Corrections, and Social Security - In many cases, our efforts are hindered by the fact that we don't have Social Security numbers for the participants. A letter to Senator Kennedy's Office asking for assistance in obtaining Social Security numbers has not received a response. None of these individuals currently reside at Fernald, and two of them are believed to be dead, but this has not been confirmed. Contact Subcommittee - Page 2 The group discussed both formal and informal methods for finding the 62 known Science Club participants in the experiments: Formal Efforts - Options for formal efforts included the use of a state agency (e.g., Department of Revenue, Department of Public Safety), or retaining a private agency. (A Maryland based agency specializing in "detective work" associated with medical cases has been identified. The cost of using such an agency has not been determined. [Allen Crocker subsequently suggested that the current DMR client list be reviewed to determine if any of these individuals are known to DMR.] Informal Efforts - It was suggested that we request the 12 known participants (including Task Force Members Austin & Charlie) to assist the Department through "networking" to obtain the addresses of as many of the remaining 62 as possible. The possibility of bringing together known participants for a meeting was discussed. This type of gathering would facilitate peer support, allow contact with Feanald Social Services staff, and might facilitate the location of other participants. [Subsequently, Allen Crocker strongly endorsed this idea.] Other informal strategies mentioned included contacting potential past or present employers (e.g., Waltham Ladder), and contacting physicians and clergy in areas believed to be the most likely residence of experiment participants (e.g., Lowell, Waltham). Discussion - After considering these options for identifying experiment participants, the group began discussing the more critical issue of obligation to inform versus respecting participant's privacy. For example, if we recommended that a state or private agency be charged with "tracking down" these 62 participants, might we also run the risk of `making public" some information about these individuals that had been intentionally kept private? Austin and Charlie shared their experiences of having gone public with the fact that they once lived at Fernald State School. It was suggested that additional efforts be made to publicize the Task Force's and the Department's work on this issue so that additional participants might voluntarily identify themselves. (Gerry Ryan, DMR spokesperson, may be able to provide assistance in this area.) Fernald Social Service personnel explained the process being used to review records and document findings on an Archive Retrieval Form. The question was raised as to whether this process was yielding all of the information that would be useful in finding the individual. For example, one Social Worker reported that he was recording the names and birth dates of all known siblings. It was suggested that a public or private agency with experience locating "missing" individuals be asked, "what information would be most useful to obtain from This discussion led us to the more basic question of What benefit is there for the individual who chooses to come forward, or who is identified through formal or informal methods? If medical experts suggest that providing a medical examination and ongoing monitoring will have a high probability of preventing future health problems, Contact Subcommittee - Page 3 then the obligation to inform couLd override the concern for respecting an individual's privacy. On the other hand, if it is highly unlikely that medical examination or monitoring will result in significant benefit to the individual, then the individual's privacy should be a higher priority. The group meeting on 2/25 agreed that a "reasonable effort" should be made to locate experiment participants, but that each individual's privacy should be a prime consideration. Further, the extent of the efforts to find individuals should be impacted by the information provided by medical experts and legal opinion on this question. We were left with the question of What constitutes `reasonable effort' to locate experiment participants? The Task Force may need additional expert opinion to answer this question. ISSUE: Once an experiment participant has been located, through formal or informal methods, what is the best method of communicating with him about his participation in the experiments? Due to the sensitive nature of this information and the potential for misunderstanding written material, it was generally agreed that once additional experiment participants have been identified, initial communication should take place in person, or via telephone if face-to-face contact is not possible. Subsequent communication should be done by telephone. In all instances, written material should be sent concurrently for review by the individual and his family if desired. PRELIMINARY RECOMMENDATIONS (1) Former residents of Fernald State School (or their family members) who have called the 800 number, and who we now believe not to have participated in any of the major studies (n=approx. 300) should be contacted as soon as possible with this information. They should also be told that they will be contacted again if any new information pertaining to participation by them becomes available. This information should be communicated by telephone with a letter sent concurrently. (2) As soon as medical expert opinion has been received, all known experiment participants (n= 12) shouLd be invited to a "gathering" at the Fernald State School, or at another location preferred by the participants. The purposes of this gathering would be to facilitate communication in a supportive atmosphere, allow for peer support, allow contact with Fernald Social Work staff, and to aid in the location of other participants. Contact Subcommittee - Page 4 (3) Once additional experiment participants have been located, initial communication should take place in person, or if face-to-face contact is not possible, it shouLd be done via a "careful" telephone conversation. Written materials shouLd be provided concurrently. (4) To facilitate ongoing communication with experiment participants, a "sole correspondent" should be identified for each participant. This individual shouLd have ongoing access to up-to-date information about risks as well as available resources for health and mental health services. Toll-free access should be maintained. (5) For persons without access to mental health services, DMR shouLd explore options for counseling, including, but not be limited to, the Department of Mental Health. (6) If an experiment participant does not have health insurance, DMR should provide assistance to facilitate linkage with an existing resource for medical care coverage (e.g., Mass Health). If it is not possible to access financial coverage through traditional channels, DMR shouLd arrange for access to and payment for health care services. ***The scope of coverage for medical follow-up should be discussed by the Task Force after we have received the opinions of medical experts. Dr. Crocker also raised an important question about what is being done for persons without mental retardation who received "comparable" radiation exposure. If this information is not already available to the Task Force, it should be acquired. (7) A packet of information should be developed for experiment participants to share with their physicians. This material should include information pertaining to radiation exposure and potential implications for health care. Anne M. Howard MASSACHUSETTS INSTITUTE OF TECHNOLOGY April 9, 1994 To: Reverend Doe West From: J. David Litster Subject: Radiation and Radioactivity Here is a brief introduction to some of the terms and ideas used to discuss radioactivity and radiation, which I hope some readers of your report may find useful. What is Radiation? The kind of radiation we are concerned with is called "ionizing radiation", which interacts with matter to produce charged ions by separating electrons from the atoms. The ions can cause chemical changes in tissue, such as modifying the DNA in cells, which may result in long term health consequences. The radiation must have enough energy to make ions. Radio waves, microwaves, and light are forms of electromagnetic radiation which do not have enough energy to produce ions. X-rays and gamma-rays are higher energy forms of electromagnetic radiation which do produce ions. Commonly, ionizing radiation is produced by the decay of unstable (radioactive) nucleii. In addition to x-rays and gamma-rays, they can produce beta-rays (high energy electrons), alpha-particles (high energy helium nucleii), protons, and neutrons. How is Radioactivity Measured? The amount of radioactive material is measured in units of curies, abbreviated Ci. A curie is enough material to produce 370 billion (3.7 X 1010) radioactive decays per second: that is the number produced by one gram of radium. Another unit of activity is the becquerel, which is one decay per second. The amount of radiation absorbed by matter can be described by saying how much energy the matte has absorbed. A common unit is the rad, which means that one cubic centimeter has absorbed one erg of energy. An erg is a very small amount of energy. (It takes about 42 million ergs to increase the temperature of one cubic centimeter of water by one degrees centigrade.) The radiation dose received by an organ, such as the thyroid gland, is usually expressed in rads.1 {1 Modern writers may use the approved international unit called the gray. One gray equals 100 rads.} Reverend Doe West Page 2 April 9,1994 What is the Biological Effect of Radiation? If we want to compare the biological effect of exposure to different amounts and kinds of ionizing radiation, we need to know what is called the whole body effective dose equivalent. That is expressed in terms of a unit called the rem, which stands for "roentgen equivalent man"2. {2 Modern writers may use the approved international unit called the sievert. One sievert equal 100 rems.} To calculate the effective dose equivalent, the dose of radiation to different organs (bone marrow, lungs, thyroid, etc.) is multiplied by a factor corresponding to the biological effectiveness of the type of radiation. These effective doses for all the organs are multiplied by a weighing factor for each organ and added together. The resulting number, in rems or sieverts, is a measure of the risk of the radiation. All effective dose equivalents which have the same number of rems or sieverts are presumed to pose the same risk of harmful effects, no matter what the source of radiation or what organs received the radiation. As Dr. James Adelstein explains in his letter of March 24, 1994, high doses of radiation (hundreds of rems) can have two kinds of biological effects in humans and animals. These effects appear shortly after exposure to the radiation, and may be repaired with time. With the studies at the Massachusetts State Schools, we need be concerned only with low doses of radiation (measured in millirems3) {3 1 millrem is 1/1000 rem. or 1/100000 sievert.} which have, if any, only delayed effects. The delayed effects of low doses of radiation are of two kinds: increased incidence of cancer, and an increase in genetic defects. Dr. Adelstein's letter gives the current (conservative) estimates for what these delayed effects may be. In some cases, such as exposure of the thyroid to radiation from iodine-131, large scale epidemiological studies have been made4,{4 L.-E. Holm, K.E. Wiklund, G.E. Lundel, N.A. Bergman, G. Bjelkengren, U.C. Ericsson, E.S. Cederquist, R.S. Lidberg, H.V. Wicklund, and J.D. Boice, Jr., "Cancer Risk in Population Examined with Doses of131, J. Nat. Cancer Inst. 81, 302-306 (1889).} and we have a reasonably good idea of the delayed effects of low doses. Some scholars feel that where iodine-131 is concerned, the effective dose equivalent overestimates the risk by three times. In other situations, we can use the general risk factor proposed by the National Council on Radiation Protection and Measurements, which is that a 1000 millirem exposure carries an increased risk of 5 additional cancers per 10,000 individuals exposed. Reverend Doe West Page 3 April 9, 1994 The whole body effective dose equivalent for some common medical procedures is shown in the graph below, along side the annual 300 millirem natural background effective dose equivalent which is received by residents of the Boston area. FOR REFERENCE SEE (4bb12) News Office Room 5-111 Cambridge Telephone Massachusetts 77 Massachusetts Massachusetts 617/253-2700 Institute Avenue 02139-4307 of Technology For Immediate Release, Jan. 2, 1994 1800 words Contact: Kenneth D. Campbell, MIT (617) 253-2703 or 2700. Try office first: If no answer, call me at home, 617 277.3414. A PRIMER ON RADIATION Radiation Comes from Cosmos, Our Bodies; How Much Radiation Is Considered Safe? Editor's Note: The table below compares 1. the radiation exposures to the whole body which are the established Federal standard for various activities (Note: The First Federal standard for fetuses of pregnant radiation workers went into effect yesterday.): 2. amounts of natural background radiation: 3. common sources of additional radiation: 4. amounts from medical treatment (very high radiation to a limited part of the body): and 5. amounts from diagnostic research (low levels from radioactive tracer elements). The source of this information is Francis Masse, director of the Radiation Protection Office of the Massachusetts Institute of Technology. Masse is a past president of the Health Physics Society and served in 1987-89 as chairman of the National Academy of Sciences panel which reviewed the exposure of soldiers to radiation from atmospheric testing in the 194Os and 1950s. ASTRONAUTS: 25,000 MILLIREMS PER SHUTTLE MISSION The highest recommended limit for radiation exposures is for astronauts--25,000 milliRems per Space Shuttle mission, principally from cosmic rays. This amount is beyond the average 300+ milliRems of natural sources of radiation and any medical radiation a person has received. 25,000 milliRems per year was the Federal occupational limit during World War II and until about 1950 for radiation workers and soldiers exposed to radiation. The occupational limited became 15,000 milliRems per year around 1950. In 1957, the occupational limit was lowered to a maximum of 5,000 milliRems per year. AVERAGE NATURAL BACKGROUND: 300 MILLIREMS PER YEAR The average exposure in the United States, from natural sources of radiation (mostly cosmic radiation and radon), is 3OO MilliRems per year at sea level. Radiation exposure is slightly higher at higher elevations--thus the exposure in Denver averages 400 milliRems per year. (A milliRem is 1/1000th of a Rem. According to McGraw-Hill's Dictionary of Scientific and Technical Terms, a Rem is a unit of ionizing radiation equal to the amount that produces the same damage to humans as one roentgen of high-voltage x-rays. The name is derived from "Roentgen equivalent man." Wilhelm Roentgen discovered ionizing radiation in 1895 at about the same time that Pierre and Marie Curie discovered radium.) All of these limits are for the amount of radiation exposure in addition to background radiation and medical radiation. ADULT: 5,000 MILLIREMS PER YEAR The current Federal occupational limit of exposure per year for an adult (the limit for a worker using radiation) is "as low as reasonably achievable; however, not to exceed 5,000 milliRems" above the 300--milliRems of natural sources of radiation and any medical radiation. Radiation workers wear badges made of photographic film which indicate the exposure to radiation. Readings typically are taken monthly. A Federal advisory committee recommends that the 2-2-2 Primer on Radiation January 2. 1994 lifetime exposure be limited to a person's age multiplied by 1,000 millirems (example: for a 65-year-old person, 65,000 milliRems). MINOR: 500 MILLIREMS PER YEAR The maximum permissible exposure for a minor under 18 working with radiation is one-tenth the adult limit or not to exceed 500 milliRems per year above the 300+ milliRems of natural sources, plus medical radiation. This was established in 1957 and reviewed as recently as 1990. FETUS: 500 MILLIREMS OR 50 PER MONTH (NEW RULE JAN. 1) New federal regulations went into effect New Year's Day, establishing for the first time an exposure limit for the embryo or fetus of a pregnant woman exposed to radiation at work. The limit for the gestation period is 500 milliRems. with a recommendation that the exposure of a fetus be no more than 50 milliRems per month. WEIGHT VARIABLES Like alcohol intoxication levels, levels of exposure to radioactivity (due to radioactivity deposited in the body) depend on a person's weight. A diagnostic tracer of one micro Curie of radioactive calcium 45, given orally. would result in an exposure of 3.7 milliRems for a 100 pound person, and half of that, l.85 milliRems, for a 200 pound person. THERAPEUTIC RADIATION Therapeutic radiation treatment that is delivered by administering radioactive material via the mouth or by injection usually results in high, very localized doses to a small part of the body, which absorbs most of the radioactivity. The radioactivity concentrates and remains in the target organ (example: the thyroid) for a longer period of time than does the radioactivity that is distributed to the rest of the body. The radiation exposure for other parts of the body is a function of the amount of radioactivity per pound and the time the radioactivity is present in the tissue. GEORGE BUSH'S HYPERTHYROID PROBLEM For example, a hyperthyroid problem such as that experienced by former President George Bush is typically treated with a radioactive iodine drink designed to deliver about 10,000,000 milliRems of radioactive iodine to the thyroid. It would coincidentally deliver a dose to the rest of the body of about 20,000 milliRems. Another example, using a slightly lower dose of radioactivity, is used for cancerous tumors. A radiation dose to kill a cancerous tumor often sends a radiation beam delivering 6,000,000 milliRems to the cancerous tissue, but the whole body equivalent dose is much less, as it was in the thyroid example cited above. What is a lethal dose from a single instance of radioactivity? According to studies made after the atomic bomb explosions in 1945 at Hiroshima and Nagasaki, half of the people died whose entire bodes were exposed to 450,000 milliRems of radioactivity from the atomic bomb. All persons died whose bodies were exposed to 600,000 milliRems of radioactivity. See Table, Next Page. 3-3-3 Primer on Radiation January 2, 1994 Federal Standards, permissible Levels Of Radiation Exposure to Whole Body (1994 unless noted otherwise) MilliRems Above Natural Background Levels (Average 300)and Medical Radiation +25,000 Astronauts, per Space Shuttle mission. This also was the annual occupational limit for adults from World War II through 1950. + 15,000 1950 to 1957 Occupational limit per year for adults, including radiation workers and soldiers. Limit changed in 1957 to +5,000 milliRems. +5,000 (Since 1957) Occupational limit per year for adult radiation workers, including soldiers exposed to radiation. It is "as reasonably achievable, however, not to exceed 5,000 milliRems." It is recommended that lifetime cumulative exposure is not to exceed the age multiplied by 1,000 milliRems. +500 Occupational limit per year for a minor under 18 years of age exposed to radiation. An embryo or a fetus of a pregnant worker exposed to radiation (a new regulation as of January 1, 1994) is not to exceed more than 500 cumulated total milliRems before birth, and it is recommended that the exposure of a fetus be limited to no more than about +50 milliRems per month. Sources of Naturally-Occurring Radiation (Whole Body Equivalents) 25 to 35 Human body's own radiation dose per year from radioactive elements and minerals in the body. 300 Average annual natural background radiation, sea level (includes your own body radiation, cosmic radiation and radon). 400 The city of Denver's average annual natural background radiation (altitude 5,000 feet). Common Additional Sources of Radiation (Whole Body Equivalents) +12 Coast-to-coast U.S. round trip flight in airplane at 35,000 feet of altitude. +10 Annul increase due to daily use of salt substitute (potassium chloride) or eating a diet heavy in such potassium-rich foods as bananas and Brazil nuts. Potassium is an essential dietary element that is present mostly in the muscles. +2 Annual exposure due to watching four hours of television every day. Therapeutic Doses of Radiation to A Part of the Body (Whole Body Equivalents) +20,000 Therapeutic radioactive iodine treatment of thyroid gland. A localized dose delivers 10,000,000 milliRems to the thyroid, and about 20,000 milliRems to the rest of the body. A radiation dose to kill a cancerous tumor often sends a radiation beam delivering 6,000,000 milliRems to the cancerous tissue, but the whole body equivalent dose is much less as in the thyroid case. 4-4-4 Primer on Radiation January 2, 1994 Doses of Radiation for Medical Diagnosis or Research Purposes (Whole Body Equivalents) +500 to +200 Cardiac stress test. +245 Exposure of one 70 pound youth in Federal research at the Fernald School by MIT in the 194Os, using trace elements to track iron absorption while eating cereal. The research showed iron supplements should not be taken with meals. +172 Average exposure of 17 youths, ages 12 to 17, avg. weight 100 lbs., in the above research. +127 Exposure of heaviest youth, 135 lbs., in the above research. +2 to +7 Exposure received by 45 youths, ages 10 to 16, in Federal research in the 1950s by the Fernald School, with the assistance of MIT. The study used radioactive calcium 45 to trace calcium absorption. One adult (age 21) received a higher dose, resulting in an exposure equal to 11 milliRems for the whole body. +2 One Chest X-ray (the whole body equivalent). A typical x-ray exposes the chest to a dose equal to 20 millirems at the exit. Averaging this exposure over the whole body equivalent of about 2 milliRems. The U.S. Food & Drug Administration's current regulations state, "The amount of radioactive material to be administered shall be such that the subject receives the smallest radiation dose with which it is practical to perform the study without jeopardizing the benefits to be obtained by the study. Under no circumstances may the radiation dose to any adult research subject from a single study, or cumulatively from a number of studies conducted within one year, be generally recognized as safe if such doses exceed the following: Single dose for an adult 3,000 milliRems Annual total dose 5.000 milliRems For a research subject under 18 years of age at the last birthday, the radiation dose shall not exceed 10% of that set forth above. Therefore, the single exposure limit for a child is 300 milliRems (whole body equivalent) and the annual total exposure cannot exceed 500 milliRems. Since 1968, medical researcher at the institution doing the research have been required to follow informed consent procedures. These procedures require the assent (if feasible) of a child 7 years of age or older, and the consent of both parents if there is an perceived risk involved in the research. For research involving any perceived risk, there also has to be a relationship between the study and a child's disorder or disease. If there is direct benefit that is likely to accrue from participation in the study, then a researcher needs the assent of the child (age 7 or older) and the consent of at least one of the parents. In such direct benefit research situations, the permitted levels of radiation can be exceeded. END KDC/FM 1/2/94 Testimony on MIT Nutrition Research Involving Radioactive Tracers and Human Subjects J. David Litster MIT Fernald School January 13, 1994 My name is David Litster and I am a Professor of Physics and Vice President and Dean for Research at MIT. My own field of research is condensed matter physics, so I am not an expert on health physics. However, I have learned a lot about the subject in the past two weeks, and I am accompanied by our Radiation Protection Officer, Mr. Francis X. Masse, who will answer any questions that are too difficult for me. I am here to tell you how the Massachusetts Institute of Technology has responded to the recent series of newspaper stories. These stories concerned research with human subjects in the 1940s and 1950s in which radioactive materials were used and which involved MIT faculty, staff, or students. I first became aware of the research when an article appeared in the Boston Globe on December 26. The next day I began to make some phone calls -- determine what was behind the stories, and later that day MIT President Charles M. Vest asked me to supervise a review of the issues. The aims of that review have been to understand: ù The nature, purpose, and results of the research. ù The amount of radiation the subjects were exposed to, and the levels of risk that it presents according to both 1950s understanding and current knowledge. ù Any information which might help identify the subject, in order that it might be communicated to the Massachusetts DMR Task Force. J. David Litster, MIT January 13, 1994 . Institute policies regarding the use of human subjects in experiments which existed at the time, and a comparison with current Institute policies. President Vest has expressed his concern over the apparent lack of fully informed consent involved in nutritional research conducted by MIT at the Walter E. Fernald School, and issued the following statement to the press: "I was sorry to hear that at least some of the young people who participated in this research and their parents apparently were unaware that the study involved radioactive tracers. People should not unknowingly become the subjects of research studies of this type. We have had in place for more than two decades at MIT numerous safeguards and approval processes that assure informed consent of human subjects of any research. It is important to recognize that the purpose of these studies was to improve understanding of nutritional processes in order to promote health of young people, and that radiation exposure appears to have been well within even today's limits." We have started to examine the archival records at MIT in order to learn as much as we can about these matters. I have essentially completed a review of the nutrition research using Fernald School pupils which was conducted by MIT Professor of Nutrition Robert S. Harris in the late 194Os and early 1950s. This research required the addition of minute amounts (less than one billionth of an ounce) of radioactive iron or calcium to breakfast cereal eaten by the participants, in order to trace how iron and calcium were absorbed from their diet, and in particular to determine how chemicals naturally present in some cereals would affect the uptake of these minerals from the diet. The research was published in four scientific papers that are listed in the appendix to these notes. I would like to share a summary of my findings with you today. These findings are from the scientific publications based on this research: a reading of the Ph.D. Thesis of Felix Bronner, which was based on the calcium studies, a conversation with Dr. Bronner, and J. David Litster, MIT 2 January 13, 1994 several discussions with Dr. Constantine Maletskos, a co-investigator in the research. Frank Masse has instructed me on matters of the effective dose of radioactive materials and the risks involved. What was the Research About? The purpose of the research was to understand how the body obtained the minerals iron and calcium from dietary sources and to find out whether chemical compounds naturally present in certain cereals, such as rolled oats, affected their absorption. Use of Iron Tracer: One of the scientific articles contains the results of a series of studies using radioactive iron as a tracer carried out over a year in the late 1940s; 17 youths from the Fernald School were involved. Earlier studies on the nutritional value of bread had shown that certain chemicals, known as phytates, could inhibit the uptake of dietary iron. These investigations showed that rolled oats, which do contain phytates, did not reduce iron uptake from the diet when compared to farina (e.g., Cream of Wheat)--which does not contain phytates. Professor Harris' research also showed that adding phytates in soluble form to the diet reduced the iron absorption 15-fold, and that both the oatmeal and farina breakfasts alone reduced it about three-fold. The general conclusion was that iron supplements to the diet should not be given with meals. In addition, children living in institutions could continue to eat oatmeal--which many of them probably did in large amounts--without concern for negative dietary effects, so far as iron uptake was concerned. Use of Calcium Tracer: These studies were carried out in the 1950s to determine the effect of these same phytate chemicals on calcium absorption from the diet. This time subjects were fed oatmeal and farina breakfasts and the milk contained a minute amount of radioactive calcium (about two trillionths of an ounce as a tracer to monitor the absorption of calcium by the body. The subjects were 36 youths aged 10 to 17 from the Fernald School, and each received two breakfasts three weeks apart containing radioactive calcium tracer. The conclusion was that if the oatmeal were accompanied by sufficient milk, the phytates in oatmeal had no effect on the amount of calcium absorbed by the body. They also showed that if only about two ounces of milk were given, the farina breakfast permitted better J. David Litster, MIT 3 January 13, 1994 absorption of the calcium in the milk. Most American diets were found to contain enough calcium that the phytates in food do not pose a problem for calcium absorption. A third set of studies involved the direct injection of small amounts of radioactive calcium. The subjects were nine youths from the Fernald School, aged 11 to 15, and one adult. The purpose of these studies was to determine what happened to calcium once it entered the blood stream (they showed it goes quickly to the bones) and also to see if calcium present in the feces contributed to the body's calcium balance. That knowledge is essential for metabolic studies involving calcium. The conclusion was that the body excretes calcium mostly through the urine, with only about a third being excreted in the feces. The studies also showed that the body excretes injected calcium very slowly. This research using radioactive calcium tracers to understand calcium metabolism laid the foundation for much subsequent research on osteoporosis. How Much Radiation Did The Subjects Get? This discussion needs to be a bit technical, and the details are given in the appendix for those who wish to understand how I did them. I will try to summarize the salient points here. It is usually most helpful to determine what is called the whole body "effective dose" of the radiation. This dose is expressed in units called rem, which stands for "roentgen equivalent man". Most doses are expressed in millirems, which is 1/1000 of a rem. The dose determination is based on the results of many studies, and takes into account which organs are exposed to the radiation, as well as the nature of the radiation. If radioactive materials are ingested, the fraction of them absorbed and the time they remain in the body are also important variables to consider. When all of the factors have been properly considered, all effective doses with the same number of milliRems are supposed to have the same effects, no matter what the source of the radiation. For low doses of radiation the major detrimental effect may be the increased J. David Litster, MIT 4 January 13, 1994 risk of cancer.1 Tables are published which give the effective dose for most radioactive materials when ingested. The most recent tables I have seen, and the ones I used for my calculations, were published in the Federal Register in December, 1992. The impact of ingested radioactive material, like the impact of ingested alcohol, scales with body weight; the same amount of material will give a larger dose to a smaller person. The Iron Studies From data published in the paper, it seems each of the 17 youths received seven breakfasts with a minute amount of radioactive iron as a tracer, over a period of about 40 weeks. The first five breakfasts were given over a period of about 12 weeks, then there was a gap, with breakfast six given at 37 weeks and breakfast seven at 40 weeks. Calculating the dose is complicated, because different amounts of iron were absorbed from each breakfast, and two different kinds of radioactive iron were used. Details of the calculation are to be found in the appendix. The subjects whose ages ranged from 12 to 17 years, weighed from 70 to 135 lbs. I calculated that a 135 lb. youth received a total dose of 170 millirems. The largest dose was received by the smallest youth (70 lbs.), and I calculated that to be 330 millirems. To understand the significance of these figures, it is helpful to know that all of us who live in Boston receive an annual dose of 300 millirems from natural sources -- mostly from cosmic rays and radon in the soil. If we lived in Denver, with its 5,000 foot greater altitude, we would receive a higher background dose of 400 millirems. We all stand a l in 5 chance of J. David Litster, MIT 5 January 13, 1994 dying from cancer, from whatever cause. A child receiving the average dose of 230 millirems would have an additional chance of about 1 in 3,000 of dying from cancer. The Calcium Studies Each of the 36 participants in the oral calcium studies received two breakfasts, each breakfast containing 0.85 microcuries of 45Ca (about 2 trillionths of an ounce), the radioactive isotope used. The subjects weighed from 58 to 166 lbs., and I calculate the effective doses in the appendix. The largest youth received a dose of 4 millirems, and the smallest received 12 millirems. I have also calculated the dose for the nine youths who were injected. They also received one breakfast with 45Ca, and so their total dose ranged from 15 millirems (66 lbs.) to 10 millirems (98 lbs.). The adult received 12 millirems. To put this into perspective, I can tell you that 12 millirems is the radiation dose you receive on an airplane flight from Boston to California, and back. What Institutional Review Policies Were in Effect? Frank Masse says that to the best of his knowledge no formal MIT review policies existed in the late 1940s and early 1950s when these studies were done. Dr. Harriet Hardy, who is now deceased, was hired to organize the MIT Environmental Medical Service in 1948. She began an informal review process and selected members of the Medical Department to review proposed studies on an ad hoc basis. We have found no written record to indicate that Harris' work with the Fernald School was reviewed by MIT. Dr. Maletskos was not aware of the process that was followed to obtain approval for the involvement of the Fernald School pupils. Dr. Bronner recalls that the Fernald School was the custodian for the participants and granted permission for them to participate in the research and supervised their medical care. It was apparently customary for the physician who made possible access to the patients to assume the responsibility for securing appropriate informed consent. The 1964 Declaration of Helsinki assigned the responsibility for obtaining patient/subject consent to the physician. The published papers in which 45Ca was used as a tracer state clearly that authorization; "for the use of restricted quantities of 45Ca in patients institutionalized for mental inadequacy J. David Litster, MIT 6 January 13, 1994 was granted through the Subcommittee on Human Applications by the Isotope Division of the Atomic Energy Commission." That was approval from the highest authority in the nation. A search of MIT records by Frank Masse shows that the AEC authorization was not granted to MIT, so I assume it must have been granted to the Fernald School. The beginning of the iron studies involving Fernald subjects predates the organization of the AEC, and the isotopes came from the MIT cyclotron rather than the AEC. Apparently that is why we have not found any record to indicate these studies "were approved by the Atomic Energy Commission." What Institutional Review Policies Are Now in Effect? Although our existing committees had not yet been formed, by the early 1960s Dr. Hardy had in place a system for review of the risks posed by radioactive materials and for ensuring informed consent. One of the researchers involved in some research in which isotope old radium and thorium were given to elderly people2 described the process which was followed in the early 1960s. . First of all, the Radiation Protection Office (RPO) reviewed the proposed protocols with the researchers and assessed the risks involved. . Following RPO approval of the protocol, the informed consent process began. First Dr. Hardy scrutinized the protocol carefully. - Next, the researchers met in an assembly with potential participants in the research, explained what was involved, what the risks were, what the purpose of the research was, and asked for volunteers to participate in the research. - Each volunteer then had an individual meeting with two of the researchers to have the risks and procedures explained once again. J. David Litster, MIT 7 January 13, 1994 - Each volunteer then had an individual meeting with Dr. Hardy. - All volunteers were then given a three day "cooling off" period, during which they were encouraged to consult their personal physician, before signing a consent form. In 1964, the World Medical Association adopted the Declaration of Helsinki, a code of ethics in human experimentation. In 1966 the National Institutes of Health required that all research it funded be reviewed according to the standards of the Declaration of Helsinki. I have attached a statement of the ethical requirements of the ICRP for research involving radiation, which are based on the Helsinki Declaration. They are essentially the standards which MIT has followed for more than 20 years. Current MIT policies require the review of at least two committees, the Committee on Use of Human Experimental Subjects (COUHES) and the Committee on Radiation Exposure to Human Subjects (CORETHS). COUHES addresses the issue of the suitability of the subjects and the informed consent process, even when not required by any Federal or State agency, while CORETHS addresses the radiation risk involved. COUHES was formed in response to the NIH regulations adopted in 1966. Before 1973, and going back to the mid 1960s, MIT had a broad license for non-human use of radioactive materials; any human use was covered under amendments to MIT's license on a case-by-case basis. In 1973 MIT obtained a broad scope NRC license for human use of radioactive isotopes and CORETHS was formed at that time. J. David Litster, MIT 8 January 13, 1994 Who Were the Subjects? So far, we have found nothing in the MIT archives that identifies the participants. We have not yet been able to contact any surviving relatives of Professor Harris to see if they might have received and kept any useful documents. Dr. Maletskos is searching his records to see if he can find anything useful. Felix Bronner's thesis identifies the subjects in the 45Ca studies only by number, but he also gives the weight and date of birth for each; when cross checked with the School records that may be enough to identify them. Dr. Bronner says he does not know of any other way to identify the participants in his research. What Are We Doing Now? We are taking a close look at other research conducted by MIT faculty, staff, and students during the 1940s, 1950s, and-early 1960s which involved exposing humans to radiation. Whatever we learn will be freely shared. (Except for any information which might violate patient confidentiality. That information will be provided only to the appropriate institution.) We intend to use these recent events as an occasion to verify that our oversight committees, COUHES and CORETHS, are indeed fulfilling their proper role. J. David Litster, MIT 9 January 13, 1994 Appendix Where was the research published? The research was published in the following four scientific papers: . The Iron Work I. L.M. Share, W.C. Peacock, R. Cooke, and R.S. Harris, J. Nutrition 41, 433-446 (1950) . The Calcium Work II. F. Bronner, R.S. Harris, C.J. Maletskos, and C.E. Benda, "Studies in calcium metabolism. Effect of food phytates on Calcium45 uptake in children on low calcium breakfasts.", J. Nutrition 54, 523-542 (1954) III. F. Bronner, R.S. Harris, C.J. Maletskos, and C.E. Benda, "Studies in calcium metabolism. Effect of food phytates on Calcium45 uptake in children on moderate calcium breakfasts.", J. Nutrition 59, 393-406 (1956) IV. F. Bronner, R.S. Harris, C.J. Maletskos, and C.E. Benda, "Studies in calcium metabolism. The fate of intravenously injected radiocalcium in human beings", J. Clin. Invest 35, 78-88 (1956) What was the Research About? The purpose of the research was to understand how the body obtained the minerals iron and calcium from dietary sources and to find out whether compounds in cereals affected their absorption. It had been known from nutritional studies of bread that a class of chemical compounds, inositol hexaphosphates--commonly called phytates, could form insoluble compounds with iron to prevent its being absorbed from food. [E.M. Widdowson and R.A. McCance, "Iron exchanges of adults on white and brown bread diets", Lancet I, 588 (1942); R.A. McCance, C.N. Edgcombe, and E.M. Widdowson, "Phytic acid and iron absorption", Lancet 2, 126 (1943)] Some cereals, for example rolled oats, contained phytates. J. David Litster, MIT 10 January 13, 1994 Others, for example Cream of Wheat, did not. The immediate goal of the research was to understand if either of these cereals was preferable from a nutritional point of view. How Much Radiation Did The Subjects Get? What we want to calculate is the "effective dose" of the radiation received by the participants in the research. The answer will be expressed in units of rem. The rem, "roentgen equivalent man" is a unit which is used to estimate the probability of the occurrence of cancer and genetic effects. For low doses of radiation, the currently accepted probability of a lifetime cancer risk for the population as a whole is 5 x 10-4 rem-1 for a fatal cancer (i.e., a risk of 1 in 2,000 for 1,000 millirem dose), and 1 x 10-4 rem-1 for a nonfatal cancer (a risk of 1 in 10,000 for a 1,000 millirem dose). The International Commission on Radiological Protection (ICRP) states that children are about three times more likely to die of cancer from a given dose than is the general population. The rem doses of radiation are calculated so that rem values for different sources and kinds of radiation may be directly compared. The unit of radiation is the rad, which is the deposition of one erg of energy per gram of matter. One rem is the equivalent of one rad applied uniformly to the whole body. For those wishing to use Standard International units, the corresponding units are the Gray (100 rad), and the Sievert (100 rem). In order to calculate the rem effective dose of a particular exposure to radiation, a complicated weighing process is followed. . There is a "quality factor" applied to the radiation which takes into account its biological effect. For x-rays, rays, and á radiation, the quality factor is 1.0. For a particles, it is 20, for protons it is typically 2.0, and for neutrons it ranges between 5.0 and 20, depending on the energy of the neutron. . For radioactive material, one takes into account how much of the radioactive material ends up in various organs. Calcium, for example, tends to concentrate in the bones. In addition. materials ingested orally may not be entirely absorbed by the body. Then, J. David Litster, MIT 11 January 13, 1994 one must compute the number of rads each organ receives. That is all weighted by the probability that irradiation of that particular organ will result in a cancer. . Where radioactive materials are involved, the amount of material is usually measured in curies (Ci). One Ci is the amount of material that gives 3.7 x 1010 radioactive disintegrations per second. Tables are available which give the rem dose for various radioactive materials according to how the body is exposed to them. I used the tables of Part 20 "Standards for Protection Against Radiation", Title 10 from the December 31, 1992, Federal Register. The data are given in the table below. The table gives the ALI (Annual Limit of Ingestion): the amount of radioactive material which must be ingested to give a 5,000 millirem dose to a 160 lb. adult. I have also included in the table the fraction of ingested radioactive material which is assumed to be absorbed by the body. (5,000 millirems is the annual dose allowed a worker who is exposed to radiation in his or her occupation.) ISOTOPE Assumed Radioactivity Effective (Oral) Absorption Permitted Dose 55Fe 10% 9, 000 Ci 5,000 millirem 59Fe 10% 800 MCi 5,000 millirem 45Ca 60% 2, 000 ~Ci 5,000 millirem The permitted radioactivity scales with weight. That is, a person who weighed 80 lbs. would need to ingest only 1,000 Ci of 45Ca to get a dose of 5,000 millirems. The Iron Studies From data in the paper, it seems each of the 17 youths (whose ages ranged from 12 to 17 years) received seven breakfasts with a small amount of radioactive iron as a tracer, over a period of about 40 weeks. The first five breakfasts were given over a period of about 12 weeks, then there was a gap, with breakfast six given at 37 weeks and breakfast seven at 40 weeks. J. David Litster, MIT 12 January 13, 1994 The radiation dose from this study can be calculated from the data in the paper in the following way. The iron isotopes were made in the MIT cyclotron and the tracer consisted of either 55Fe or 59Fe, as indicated by the entry for each meal in the table on the next page. The detector efficiency was different for the two isotopes (3% for 55Fe emitting x-rays, 25% for 59Fe emitting á particles) and so I get a different number for each when converting from the data in the paper, in detector counts per minute (c.p.m), to radioactivity, in disintegrations per minute (d.p.m.). Then the radioactivity is converted to curies (1 Ci = 3.7 x 1010 disintegrations per second). Since the absorbed iron was actually measured, and differed in some cases from the 10% assumed in the standard tables, we should use the actual values. The last step is to use the absorption data from the paper to calculate the radioactivity absorbed and then to convert that to millirems. From the table above, I calculate that for a person weighing 100 lbs. the dose for 1.0 Ci, if the 55Fe is 100% absorbed, is: 55Fe: 5000 x 160 x 10 = 8.9 millirem 9000 100 1 While for 59Fe, I get: 59Fe: 5000 160 10 = 100 millirem 800 100 1 The weights of the subjects varied from about 70 to 135 lbs., so I calculated the dose for both of these weights, as well as the mean weight of 100 lbs. The dose calculations show that the maximum dose the smallest youth would have received was 330 millirems of radiation above the natural background (300 millirems per year). The average would have received 230 millirems, and the largest got 170 millirems. The results are given in the table below. J. David Litster, MIT 13 January 13, 1994 Quantity \ Breakfast No. I II III IV V VI VII Total Detector (106 c.p.m.) 2.0 1.2 2.0 2.0 2.0 3.0 1.3 55Fe activity (106 d.p.m.) 66 66 66 99 300 59Fe activity (106 d.p.m.) 4.8 8.0 5.2 18 Activity, (pCi) 30 2.2 30 3.6 30 45 2.8 Percent Fe absorbed 4.43 17.4 1.74 9.81 26.9 5.76 8.84 Activity absorbed, (~Ci) 1.33 0.38 0.52 0.35 8.07 2.59 0.25 Effective dose, mrem (70 lb.)17 54 6.6 74 103 33 36 324 Effective dose, mrem (100 lb.)12 38 4.6 52 72 23 25 227 Effective dose, mrem (135 lb.)9 28 3.4 39 53 17 19 168 It would seem that the corresponding lifetime risk of a fatal cancer could be calculated by multiplying the total dose (in millirem) by 5 x 10-7, so that a 100 lb. subject would have a lifetime risk of 1.1 x 10-4 of contracting a fatal cancer. However, it is suggested by the ICRP that children suffer from two to three times the detriment that adults do from radiation exposure. Thus we might expect 17 x 3 x 1.1 x 10-4 = 0.006 extra cancers in the group of 17 youths who participated in the study. To be more conservative, we might consider the smallest youth, who received an effective dose of 330 millirems. (The natural background radiation in Boston is 300 millirems per year, and in Denver it is 400 millirems per year.) Thus, I would calculate for the most vulnerable subject, the youth who weighed 70 lbs., an increased lifetime fatal cancer risk of 5 x 10-4 or 1 in 2,000 as a result of his participation in the study. Note that the normal lifetime risk for someone to contract cancer is 1 in 3, and the normal lifetime fatal cancer risk is 1 in 5. J. David Litster, MIT 14 January 13, 1994 The Calcium Studies These are described in the papers numbered "II" through "IV", above. These calculations are easier to do. First, the absorption of the calcium was found to be about 60% in the two studies where 45Ca was given orally, so we may use the data from the first table above. Each participant received two breakfasts, each with 0.85 uCi of 45Ca. For the third study, paper "IV", a single injection of calcium was given nine youths (0.75 uCi) and one adult (2.02 uCi); we should assume this is 100% absorbed. From the thesis of Felix Bronner, I learned that the nine youths who received the injections also were given, on another occasion, a single breakfast containing 0.85 uCi of 45Ca. I included that in the dose shown for paper IV in the table below, From these data, and the weights of the participants from the paper, I calculate the following effective doses, for the smallest and largest participants in each study. STUDY Radioactivity Weight of Dose of Weight of Dose of Given (45Ca) Smallest Smallest Largest Largest Paper II 1.7uCi 80 lbs. 8.5 millirem 166 lbs. 4.1 millirem Paper III 1.7uCi 58 lbs. 11.7 millirem 122 lbs. 5.6 millirem Paper IV 0.75uCi 66 lbs. 14.9 millirem 98 lbs. 9.8 millirem The adult in paper 4 weighed 113 lbs. and received a dose of 2.02 x 160 x 1 x 5000 = 12 millirem 2000 113 0.6 A passenger on a round trip airplane flight from Boston to California receives an extra dose of 12 millirems. For a child this imposes an increased risk of a fatal cancer of 1.8 x 10-5 or 1 in 55,000. Recall that the normal lifetime risk for someone to contract cancer is 1 in 3, and the normal lifetime fatal cancer risk is 1 in 5. How Much Radioactive Material Was Given? Several people have asked how much radioactive iron or calcium was given to the subjects. A uCi is a very small amount of material, as I shall now calculate. The amount of material in a curie can be calculated from the half life. For 1 uCi, the number of grams is J. David Litster, MIT 15 January 13, 1994 A 3.7x104 6.023 x 1023 0.693 x T1/2 where A is the gram atomic weight and T1/2 is the half life, in seconds. The results are: ISOTOPE: 55Fe 59Fe 45Ca T1/2, seconds: 1.3 x 108 3.8 x 106 1.4 x 107 Atoms per ~Ci: 6.7 x 1012 2.0 x 1011 7.5 x 1011 Grams per 1LCi: 6.2 x 10-10 2.0 x 10-11 5.6 x 10-11 A gram is about 1/28 of an ounce. The typical amounts of 55Fe in a breakfast were about 30uCi, or 1/1,500,000,000 ounce; 59Fe amounts were about 3uCi, or 1/500,000,000,000 ounce. The 45Ca amounts were all about 1uCi, or 1/500,000,000,000 ounce of radioactive calcium. Who Sponsored This Research? The research using radioactive iron was supported entirely by the Quaker Oats Company. The published articles using 45Ca acknowledge sponsorship from the Quaker Oats Company, the National Institutes of Health (NIH Contract A-81 and A-81[C]), and the Atomic Energy Commission (AEC Contract AT[30-1]952). The Quaker Oats and NIH contracts were to the Nutrition Department, while the AEC contract supported the Radioactivity Center, part of the MIT Laboratory for Nuclear Science. _________________________ 1According to the National Council on Radiation Protection and Measurements (NCRP), and effective dose of 1,000 millirems poses a lifetime increased risk cancer of 1 in 2,000. The general risk of dying from cancer is 1 in 5. The International Commission on Radiological Protection (ICRP) states that children are about three times more likely to die of cancer from a given dose than is the general population. 2These studies were mentioned in the 1986 Staff Report of Representative Markey's Subcommittee on Energy Conservation and Power J. David Litster, MIT 16 January 13, 1994 Department of Environmental Medicine Division of Epidemiology & Biostatistics 341 East 25th Street, New York, NY 10010-2598 (212) 263-6500 Fax (212)263-8570 March 5, 1994 MEMO TO: The Task Force to Review Human Subject Research Massachusetts Department of Mental Retardation FROM: Dr. Roy Shore Professor of Environmental Medicine SUBJECT: Review of the MIT--Fernald-School Nutrition Research Involving Radioactive Tracers and Human Subjects General Comments From the perspective of epidemiology and risk assessment, the report that I was sent for review was sound and prudent in its risk assessment. The risk assessment method was in accordance with the approach and numerical estimates of the National Council on Radiation Protection and of international bodies as well (International Commission on Radiological Protection (ICRP) and the United Nations Scientific Council on the Effects of Atomic Radiation (UNSCEAR)). If the dose-estimation procedures are approximately correct (and I am not expert enough in dosimetry to judge that), then the risks are unlikely to be any greater than those stated, and may well be several times less because of the conservative, worst cases assumptions used in the dose estimation. As the report points out, the doses incurred by these children are of a similar magnitude as variations in doses to people that occur by virtue of living in different geographic locations, flying in airplanes, having diagnostic medical or dental x-rays, etc. Hence, the risks were commensurate with many others that we accept, and far less than some voluntary risks such as those of smoking. All in all, the risk from the small exposures at the Fernald School are minor. It seems to me that the principal remaining issue is the bioethical one: whether there was adequate informed consent. Specific Comments On p. 3 of Dr. Litster's January 2 memo and p. 5 of the Jan. 13 memo, allusion is made to the natural background dose of 300 millirem per year, I find this terminology questionable and confusing, in that this is not actually a dose typically received by any organ of the body. Residential radon gives the lungs a very large dose (up to several rem) and the rest of the body typically receives only 80-100 millirems per year. When risk-related weights for different organs are applied according to a scheme of the ICRP, it produces an average risk for background radiation which is numerically equivalent to what would obtain if the entire body had in fact received 300 millirems. But that is a different matter than saying that the body actually receives 300 millirem per year of background radiation. It is noteworthy that the dose estimates were made high by assuming that 100% of the iron isotopes was absorbed by the body (p. 13), when the data-derived average was about 10%. This is therefore a conservative approach, but in view of the variation among individuals in absorption and retention it is better to err on the side of prudence. The Task Force might want to consider making a separate risk calculation regarding leukemia, since should a leukemia occur among these boys, there is a greater probability that it might be due to the radiation received than there is for other types of cancer. BRIAN MACMAHON, M.D. 89 Warren Street Needham, Mass. 02192 Tel. 617-444-2244 24 February 1994 Rev. Doe West Project Coordinator Task Force to Review Human Subject Research P.O. Box 9108 Belmont, MA O2178-91O8 Dear Rev. West, Thank you for your letter of 17 February 1994, and the accompanying material. I have read the internal Memorandum of Dr. David Litster dated 2 January 1994 and the transcript of his testimony dated 13 January 1994. I have glanced through the scientific reports which you also sent, but they are outside my area of expertise and I cannot claim to understand them. Let me first outline the background that may have led Dean Adelstein to suggest me as an outside reviewer of this matter. I am neither radiobiologist nor nutritionist. My work has been in epidemiology, specifically the epidemiology of cancer and of congenital malformations. I have conducted some original research on radiation effects in humans, particularly on the role of diagnostic x-rays on cancer risk in the fetus and on the long-term effects of radiotherapy for carcinoma of the cervix. I have served on a number of committees dealing with radiation matters - the NAS Committee on the Biologic Effects of Ionizing Radiation (BEIR I), the NAS Advisory Committee to the Federal Radiation Council, several other NAS ad hoc committees dealing with specific issues, an Expert Panel of the World Health Organization, the Science Advisory Committee of the Radiation Effects Research Foundation (which I chaired for one year), and the American College of Radiology Committee on Radiation Exposure of Women - but I have served on these committees as an epidemiologist, not as an expert on radiation. What little I know of the substance of the matters before the Task Force has rubbed off on me in the course of participation in these committees and councils. Perhaps relevant also, is an experience of 40 years of research using human subjects (although not experimentally) both before and after the marked change in attitudes towards and requirements for such research that took place in the late l96Os. With respect to your first question, Dr. Litster's report seems to me straight forward and accurate. I am not in a position to question the exposure levels estimated by Mr Harris, but given his expertise I think they are likely to be as accurate as can be achieved, and they are in a range that does not surprise me. I Page 1 agree with Dr. Litster's conclusions that the informed consent procedure used in these studies "would not pass muster today" (page 7) and that such studies would probably not be permitted today "even with the low radiation doses that were used and informed consent of parents or guardian (had been obtained)." (page 8) On the other hand there are a great many things that went on both in clinical practice and in research laboratories in general in those days that would not pass muster today. There were different expectations of investigators then, and even if an investigator had sought external review of his proposal the mechanisms were not in place to undertake it. With respect to your question about how the information should be phrased in a report to the medical care team, it should be noted, perhaps, that the cancer risks estimated by NCRP and ICRP for low-level exposures to radiation are speculative. They are based on extrapolation using mathematical models of curves derived from observations of the effects of radiation exposures many times higher than those that any of the subjects of these experiments received. The shape of the exposure--response curve at levels below, say, 50,000 mrem are quite controversial. The lowest radiation levels at which effects are thought by some to be observed are those associated with prenatal diagnostic x-rays, and here the causal nature of the exposure, as well as the levels of exposure, are subjects of debate. Of course, leukemia or some other cancer may occur by chance in some of these subjects (we can expect it in about a quarter of them eventually, as in any group of children), but it is inconceivable to me that any increased risk of leukemia or other cancer will be demonstrable among them. I know of no disease, sign or symptom that persons caring for these children should be on the lookout for. I have not seen recent data on radiation exposure in the general population, but I suspect that a large majority of Americans have received as much or more radiation from one source or another as did the children in these experiments. As for the offspring of these subjects, extensive studies of the children of Japanese A-bomb survivors, who received exposures many orders of magnitude larger than these study subjects, have revealed no evidence of genetic damage. It is gracious of you to offer an honorarium for this review, but it is not necessary. I hope I have been of service. You may make such use of this letter as you wish. Sincerely, Brian MacMahon, M.D., Ph.D. Henry Pickering Walcott Professor of Epidemiology, Emeritus Harvard School of Public health Page 2 REPORT TO THE TASK FORCE BY JOSEPH L. LYON, M.D., M.P.H. This report summarizes my observations and recommendations during my visit with the Task Force members at the Fernald School, Thursday, April 7, 1994. The release to the public of a large number of documents concerning human experiments involving radioactive materials by the Secretary of the U.S. Department of Energy on December 26, 1993, prompted the creation of this task force. The four experiments that prompted the creation of this task force here conducted at the Fernald and Wrentham Schools between l943-l973. Two experiments at Fernald examined the absorption by the human body of radioactive calcium and iron in the presence of other dietary chemicals which were believed to block their absorption. An additional study at Fernald School used iodine-131 to determine if Down's Syndrome (a genetic defect referred to as trisomy 18 because of an extra chromosome on chromosome l8) impaired the functioning of the thyroid gland. The fourth study was conducted at the Wrentham School to determine the dose of iodine necessary to stop the thyroid gland from absorbing iodine from the blood. Its purpose was to provide information on the amount of iodine that would have to be given in the event of an accidental contamination of a large area by radioactive iodine. SUMMARY OF MY COMMENTS AT THE TASK FORCE MEETING: General Comments The work done by the committee staff to locate the records of these studies and identify possible participants is commendable. The level of record keeping for such events is not unusual for studies of this time period, though the failure to find documentation in the records held by the two schools is a concern. Retention of records by a researcher that contained personal medical information is problematic. Both paper and electronically stored records have come into the possession of other researchers e.g., graduate students, and this can create serious problems for everyone. Because of this problem the State of Utah created a legal entity to store such records. I will forward copies of this legislation to you in the next few days. DIVISION OF NUCLEAR MEDICINE BRIGHAM & WOMEN'S HOSPITAL 75 FRANCIS STREET BOSTON MASSACHUSETTS 02115 (617) 732-5500 1/10th that of the cancer producing effects and probably less**. The late-appearance of cancers has been seen in humans as all are aware. Radium-dial painters, who licked their brushes, developed bone cancers; early radiologists who fluoroscoped with unshielded sources and feeble screens developed cancer on their fingers; patients who received high radiation doses to their spines to treat arthritis developed leukemia from the irradiated bone marrow included in the field of irradiation. The largest group of individuals exposed to a range of radiations are survivors of the atomic bombings of Hiroshima and Nagasaki in 1945. This group has been the subject of intensive study for the past forty-five years. The earliest cancers to appear were the leukemias but subsequently excess cancers were found at other sites including stomach, lung, breast, urinary tract and others. In 76,000 survivors, 5,936 cancers had appeared by 1985 of which 344 were in excess of those expected. It is from this group that the risks of developing cancer have been derived. The most comprehensive estimates of radiation risk from the atom- bomb survivors were performed by the U.S. National Research Council (NRC) in 1990 (BEIR V) and the United Nations Scientific Committee on the Effects of Atomic Radiation in 1988 (UNSCZAR). In extrapolating to low doses, the committee had to make some assumptions. Perhaps the most important was that effects were proportionate to dose even at the lowest levels and that there is no threshold below which cancers cannot be induced. In addition to trying to estimate the late effects of low-level radiation effects by extrapolation from high and moderate dose exposures, attempts have been made to do this directly from populations exposed to low levels such as individuals living in high background areas and those occupationally exposed. Because the numbers are small the results are generally statistically unreliable with some proponents claiming that they show the extrapolated risk-estimates either to be too high or too low. In my view, the prudent course is to accept the NRC and UNSCSAR recommendations. For this reason, I have used the NRC and UNSCAAR recommendations in estimating the medical risks for those to whom radio-iron and radio-calcium were administered. The method is that of the International Commission on Radiation Protection (ICRP) and the International Council on Radiation Protection and measurements (NCRP). They employ a quantity called an "effective dose", that is the _________________________ **Because hereditary effects have not been observed in humans they can only be estimated from animal experiments. However, they have been looked for carefully in the offspring of atom-bomb survivors without result and, thus, the sense is that humans are no more sensitive to these effects than mice, perhaps less. Children exposed to ionizing radiation generally manifest the excess risk of leukemia in the first 15 years after the exposure. The risk of excess leukemia for these two groups is extremely low and would be impossible to detect in any kind of an epidemiologic study. The two studies of absorption of radioactive iodine by the thyroid gland are of greater concern because the amount of radiation exposure was much larger than from the tracer studies. The study of greatest concern was the one done at the Fernald School on children with Down' s Syndrome. The radiation exposure was about ten times greater than in the study done at the Wrentham School. The risk from the increased radiation exposure was likely lessened by the known short life expectancy of children with Down's Syndrome. Thyroid cancers in men occur mostly after age 45. This is not the case for women where about half the expected cases occur between ages 20-40. The other group involved were the five parents of Down's Syndrome children who also received radioactive iodine. They would have a normal- life expectancy. The children who received radioactive iodine at the Wrentham School were younger in age than the children at the Fernald School, and the greater sensitivity of their thyroid gland to radiation needs to be considered. I will develop estimates of risk of both groups, but this task will not be finished for several weeks. absorbed dose to the several organs making up the body corrected for the relative radiation sensitivity of the various tissues. At low doses and dose-rates the NCRP proposes a risk factor of 5 cancers in 10,000 individuals per rem (1000 mrem) exposure. Based on this risk factor I estimate the additional cancer risk (i.e. that over the normal expectation) to be: 3 in 10,000 for those administered radio-iron; less than 1 in 100,000 for those administered radio-calcium. For comparison purposes, I provide the following: 1. The lifetime risk of developing cancer is 22% or 22 in 100, 2,200 in 10,000 or 22,000 in 100,000. In the United States, taken by state this varies from 16 to 25%, a variation considerably greater than the excess risks calculated for the students. 2. The lifetime risk of dying from electrocution is about 4 in 10,000. The lifetime risk of being struck by lightning is about 4 in 100,000 (assuming 70 years of life). 3. The absorbed radiation dose from the radio-calcium study was about that for a skull or spine x-ray, for the radio-iron study about that for a colon (barium enema) x-ray or brain scan. Given these estimates, I am in agreement with Drs. Litster, MacMahon and Shore. I hope this helps. Yours sincerely, S. James Adelstein, MD, PhD Paul C. Cabot Professor of Medical Biophysics P.S. The following brief bibliography contains most of the material: Radiation Dose to Patients from Radiopharmaceuticals. Addendum 1 to ICRP Publication 53, Pergamon Press, Oxford 1994. Risk Estimates for Radiation Protection. NCRP Report No. 115, Bethesda 1993. Cancer Statistics. CA Vol. 44, No. l, pages 7-26, 1994 (A journal of the American Cancer Society). HARVARD MEDICAL SCHOOL DEPARTMENT OF RADIOLOGY JOINT PROGRAM IN NUCLEAR MEDICINE BETH ISRAEL HOSPITAL * BRIGHAM & WOMEN'S HOSPITAL DANA-FARBER CANCER INSTITUTE * THE CHILDREN'S HOSPITAL 24 March 1994 Doe West Project Coordinator Task Force on Human Subject Experimentation Department of Mental Retardation Commonwealth of Massachusetts PO Box 9108 Belmont, MA 02178-9108 Dear Reverend West, You have asked me to review the report of J. David Litster and the critiques of Brian MacMahon and Roy Shore on the radiation doses and possible consequent risks to the former students at the Fernald School who were administered radio-iron and radio-calcium tracers in the 1940's and 1950's. In this letter, I will also try to convey something about how these risks are estimated and a quantitative estimate of their magnitude. We know that exposure to high doses of radiation (hundreds of rem*) leads to two kinds of biological effects in humans and animals. The early effects include bone marrow depression with consequent infection and bleeding when the whole body is irradiated, and specific tissue and organ diseases such as cataracts of the eye when parts of the body are irradiated. These effects have a threshold of dose below which they are not seen. This threshold is much higher then the doses to which the former students were exposed and thus we need not be concerned about them. Moreover, such effects appear shortly after exposure and, in some instances such as bone marrow depression, are repaired with time. The late effects fall into two categories: an increase in the incidence of cancers and an increase in hereditary defects. Hereditary defects have not been observed in humans, but we know that exposure of fruit-flies and mice to high and moderate doses of radiation produces inheritable changes and that their frequency increases with increasing dose and decreases with lowering dose-rate. Extrapolating from mice to humans, it has been estimated that the hereditary effects of radiation are about *Although the international community employs sieverts/Sv (=100 rem) as the unit of absorbed radiation, I will use rem (=1000 mrem or millirem) in this letter as these are the units used by Professor Litster. The Nuremberg Code 1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated so as to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involves as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment: the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except perhaps, in those experiments where the experimental physicians also serve as subjects. 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7. Proper preparation should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all states of the experiment of those who conduct or engage in the experiment. 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. U.S. v. Brandt, in 2 Trials of War Criminals Before Nuremberg Military Tribunals (Oct. 1946- Apr. 1949) 181-84 (1950), quoted in 24 Syracuse Law Rev. 1067 (1973). The Declaration of Helsinki It is the mission of the doctor to safeguard the health of the people. His knowledge and conscience are dedicated to the fulfillment of this mission. The Declaration of Geneva of The World Medical Association binds the doctor with the words: "The health of my patient will be my first considerations and the International Code of Medical Ethics which declares that "Any act or advice which could weaken physical or mental resistance of a human being may be used only in his interest." Because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, The World Medical Association has prepared the following recommendations as a guide to each doctor in clinical research. It must be stressed that the standards as drafted are only a guide to physicians all over the world. Doctors are not relieved from criminal, civil and ethical responsibilities under the laws of their own countries. In the files of clinical research a fundamental distinction must be recognized between clinical research in which the aim is essentially therapeutic for a patient, and the clinical research, the essential object of which is purely scientific and without therapeutic value to the person subjected to the research. I. BASIC PRINCIPLES 1. Clinical research must conform to the moral and scientific principles that justify medical research and should be based on laboratory and animal experiments or other scientifically established facts. 2. Clinical research should be conducted only by scientifically qualified persons and under the supervision of a qualified medical man. 3. Clinical research cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject. 4. Every clinical research project should be preceded by careful assessment of inherent risks in comparison to foreseeable benefits to the subject or to others. 5. Special caution should be exercised by the doctor in performing clinical research in which the personality of the subject is liable to be altered by drugs or experimental procedure. II. CLINICAL RESEARCH COMBINED WITH PROFESSIONAL CARE 1. In the treatment of the sick person, the doctor must be free to use a new therapeutic measure, if in his judgment it offers hope of saving life, reestablishing health, or alleviating suffering. If at all possible, consistent with patient psychology, the doctor should obtain the patient's freely given consent after the patient has been given a full explanation. In case of legal incapacity, counsel should also be procured from the legal guardian; in case of physical incapacity the permission of the legal guardian replaces that of the patient. 2. The doctor can combine clinical research with professional care, the objective being the acquisition of new medical knowledge, only to the Helsinki Declaration Page 2 only to the extent that clinical research is justified by its therapeutic value of the patient. III. NON-THERAPEUTIC CLINICAL RESEARCH 1. In the purely scientific application of clinical research carried out on a human being, it is the duty of the doctor to remain the protector of the life and health of that person on whom clinical research is being carried out. 2. The nature, the purpose and the risk of clinical research must be explained to the subject by the doctor. 3a. Clinical research on a human being cannot be undertaken without his free consent after he has been informed; if he is legally incompetent, the consent of the legal guardian should be procured. 3b. The subject of clinical research should be in such a mental, physical and legal state as to be able to exercise fully his power of choice. 3c. Consent should, as a rule, be obtained in writing. However, the responsibility for clinical research always remains with the research worker; it never falls on the subject even after consent is obtained. 4a. The investigator must respect the right of each individual to safeguard his personal integrity, especially if the subject is in a dependent relationship to the investigator. 4b. At any time during the course of clinical research the subject or his guardian should be free to withdraw permission for research to be continued. The investigator or the investigating team should discontinue the research if in his or their judgment, it may, if continued, be harmful to the individual. 67 Annals Internal Med., Supp. 7, at 74-75 (1967), reprinted in 24 Syracuse Law Rev. 1067 (1973). HOUSE . . . . . . . No. 4609 THE COMMONWEALTH OF MASSACHUSETTS THE COMMONWEALTH OF MASSACHUSETTS EXECUTIVE DEPARTMENT STATE HOUSE . BOSTON (617) 727-3600 WILLIAM F. WELD ARGEO PAUL CELLUCCI February 24, 1994 To The Honorable Senate and House of Representatives: We are filing for your consideration the attached legislative proposal entitled, "An Act to Require the Informed Consent of Human Subjects as a condition of Performing Research Involving the Commonwealth's Facilities, Services, or Funds." This legislation will ensure that no research or experimentation involving human subjects that relies on funding, services, or facilities of the Commonwealth, is conducted without the informed consent of the subjects involved. It is intended to prevent any repetition of undisclosed and unwanted experimentation on the disadvantaged, as has been Publicly reported. Although agencies of the Commonwealth ordinarily require informed consent before authorizing research and many agencies have Promulgated detailed regulations of this kind, this legislation ensures that informed consent will be obtained in all circumstances and establishes uniform standards of informed consent. Among other things, it requires research investigators to explain clearly to subjects the Purposes of the Proposed research, the Procedures involved in such research, the risks the research entails, how the research results will be used, and that Participation in the research is entirely voluntary. It also establishes a simple mechanism for ensuring that informed consent is properly obtained prior to the initiation of any research covered by the bill. It authorizes the promulgation and enforcement of more stringent standards governing informed consent. We urge your favorable action on this bill. Respectfully submitted, William F. Weld Governor Argeo Paul Cellucci Lieutenant Governor THE COMMONWEALTH OF MASSACHUSETTS IN THE YEAR ONE THOUSAND NINE HUNDRED AND NINETY- AN ACT TO REQUIRE THE INFORMED CONSENT OF HUMAN SUBJECTS AS A CONDITION OF PERFORMING RESEARCH INVOLVING THE COMMONWEALTH'S FACILITIES, SERVICES OR FUNDS Be it enacted by the Senate and House of Representatives in General Court assembled, and by the authority of the same as follows: SECTION 1 The General Laws are hereby amended by inserting after chapter 94D the following new chapter 94E. Section 1. No person or organization shall conduct research which involves human subjects and which uses facilities, services, or funding provided by the commonwealth or by private entities who contract with the commonwealth to provide services to individuals, without obtaining the informed consent of the subjects involved in accordance with the requirements of this section. As used in this chapter, "human subjects" is defined to be a living individual, "research" is defined to be any systematic investigation designed to develop or contribute to generalizable knowledge, and "research investigator" is defined to be any person or organization that conducts, or proposes to conduct, research. (a) To satisfy the requirements of this section, informed consent shall be obtained in writing on a form signed by the subject or his legally authorized representative prior to commencing any research. Such form shall contain at least the following information in language understandable to the subject or his legally authorized representative: 1) an explanation of the nature and purposes of the research; 2) a statement of the expected duration of the subject's participation; 3) a description of the procedures that will be used, including the identification of which procedures, if any, are experimental; 4) a description of any reasonably foreseeable risks or discomforts to the subject, or of any costs the subject may reasonably be expected to incur; 5) a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject; 6) a description of any benefits to the subject or others which may reasonably be expected from the research; 7) a statement of the use that will be made of any records identifying the subject, and whether the subject's confidentiality will be maintained; 8) the name of a person whom the subject may - contact with questions or concerns about the research; 9) a statement that participation in the research is voluntary and that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled; and 10) a statement that the subject may discontinue participation in the research and withdraw his consent at any time without penalty. (b) An investigator shall seek a subject's consent only under circumstances that provide the subject or his legally authorized representative sufficient time to consider whether or not to participate in the proposed research project and that minimize the possibility of coercion or undue influence. The consent form may not include any waiver of a subject's rights or any exculpatory language absolving the investigator, the sponsor, the commonwealth or its agents of liability for negligence. Further, the form shall be signed by the research investigator or his designee, who shall attest to the accuracy of the information contained therein. Section 2. No research investigator subject to the requirements of section 1 shall perform research involving human subjects without certifying to the head of the state agency that is providing funding, services, or access to facilities in relation to such research that he has complied fully with the requirements of section 1. Section 3. Notwithstanding the provisions of sections 1 and 2, certification of compliance with Part 46 of Title 45 of the Code of Federal Regulations governing the protection of human research subjects shall be sufficient evidence of compliance with the requirements of section l. Such certification shall be submitted in accordance with section 2. Section 4. Nothing contained in this section shall nullify the requirements or state or local laws or regulations that provide more stringent protections for human subjects. Section 5. State agencies may establish procedures for waiving or modifying informed consent requirements, provided that such waivers or modifications apply only to research which involves no personal interaction with human subjects and which does not identify or permit the identification of the subjects involved. Section 6. In addition to any other remedies available by law, including those contained in section 8 of chapter 94C and including any power to sue, any persor or organization violating the provisions of this chapter may be enjoined in an action commenced in superior or probate court from continuing to utilize state facilities, services or funding, or from continuing to gain access to agency records or facilities, or to human subjects who are receiving state services. Further, any person or organization violating the provisions of this chapter may be fined not more than one thousand dollars for each violation. It shall be a separate violation for each human subject whose consent is not obtained in compliance with the provisions of this chapter. FERNALD LEAGUE for RETARDED CHILDREN, INC The Fernald League is the family advocates' organization for the residents of the Walter E. Fernald State School located in Waltham and Templeton Development Center located in Baldwinville, Massachusetts. The Fernald League is a non-profit tax-exempt organization whose objective is to improve the quality of life for people with mental retardation at Fernald and Templeton and in the community. Founded in 1952, it has about 700 members and reaches about 2400 families and legislatures throughout Massachusetts and the United States through its monthly publication, the Fernald Flicker. During the last 42 years the Fernald League has: * Pioneered special work with low level Fernald residents, who in the 1950s received from the state only custodial care. * Initiated the Class Action Suit in U.S. District Court, resulting in the approval of massive improvements at Fernald, including $90 million of building renovations, $2 million of furnishings and equipment, and recruitment and training of over 1,000 new positions since 1976. * Accelerated through the Class Action Suite the opening at Fernald of The Tufts Dental Clinic the largest and best dental clinic in the world for treatment of the mentally retarded *Maintains A Buildings Representatives Committee whose members monitor their respective buildings for the quality of life of the residents: their living conditions, the maintenance of their clothing, the quality of food served and services in the buildings. Representatives also evaluate the programs available to residents, in their training, workshops and recreational activities. They tour, the buildings with the Division Directors and send monthly reports to the superintendents to share this information and discuss remedies to problems and praise successes. * Established volunteer programs to provide needed help at Fernald * Established the first sheltered workshops now expanded to 12+ units certified by the U.S. Department of Labor and Massachusetts Department of Labor and Industries. * Supported establishment of CARVE, a unique program wherein selected individuals from correctional institutions work directly with the severely retarded. ADVOCACY NETWORK INCORPORATED Advocacy Network is the largest, pure advocacy group in Massachusetts and perhaps in the eastern United States and possibly America. Advocacy Network has assisted the mentally retarded for more than six years, building upon three prior decades of effective service under its previous corporate name, The Belcherr Town Friends. Effective Advocacy is the only service they offer. Achievements: * Established John Burns Legal Fund in 1992 to provide financial and legal resources to combat abuse and ensure victim rights * Class Action Suite Ricci vs. Greenblatt in Federal Court to benefit retarded citizens * Achieved the adoption of the Individual Service Plan (ISP) to ensure the contract of appropriate services * Provide advice counsel and emotional support to thousands of individuals and families with direct impact on improving services with private vendors and state-run program * Maintains a Hotline (413-256-l313) for anyone seeking support regarding services for persons with mental retardation * Helped produce three documents depicting living conditions and civil rights abuses of the retarded in Massachusetts DEVER ASSOCIATION for the RETARDED. INC. The Dever Association is the family advocates organization for the residents of the Paul A. Dever State School located in Taunton, Massachusetts. The Dever Association has worked to enhance and to protect the lives of family members who reside at Dever. It has endeavored to support state and private efforts to provide a happy, healthy environment in a modern, well-maintained facility with an experienced professional and compassionate staff. It endorses and encourages and active program to develop skills, social involvement, recreational activities, good medical supervision and emotional support. The Dever Association encourages family involvement. They notify the superintendent of deficiencies and problems that he can rectify. The Dever Association insists that parents and guardians be included in decisions regarding the care, education and future plans for residents and resist interference in this area. It supports legislation that furthers the interest of the individuals with mental retardation and fights proposed legislation that is considered damaging to the individuals with mental retardation. The Dever Association was one of the plaintiffs who were forced to bring suite in Federal Court against the Commonwealth on behalf of the residents at the Dever State School. HOGAN/BERRY ASSOCIATION of ADVOCATES for RETARDED PERSONS, INC. Hogan/Berry Association of Advocates for Retarded Persons was organized in 1976 as a tax-exempt organization to serve all mentally retarded persons in residence at the Hogan Regional Center, Danvers and at its Berry Campus in North Reading. It also serves the residents of the various state operated homes which exist or may become operational as community living homes in the future. Hogan/Berry Association supports a continuum of life long services for each mentally retarded person as their individual needs dictate. This Association supports and promotes the general welfare of all mentally retarded persons of all ages living at home, in community based homes, and facilities. They are deeply concerned for and advocate on behalf of the great number of unserved and underserved persons with mental retardation in Massachusetts. PARENTS and FRIENDS of MONSON DEVELOPMENTAL CENTER Formed in 1969, Parents and Friends of Monson Developmental Center represents the needs and concerns of the residents at Monson Developmental Center located in Palmer, Massachusetts. They filed their class action suit in 1975 against the Commonwealth of Massachusetts to improve the living conditions and staffing. Through COFAR and VOR, Parents and Friends of Monson advocate on the state and federal levels. The Parents and Friends of Monson Developmental Center are guardians for 65 residents at Monson and the community. They look over the ward's personal and medical well being, as they would their own child. At one time they were guardians for 105 individuals. The Parents and Friends are on the New Hope Activities Committee, which employs approximately two hundred residents on and off the grounds at Monson. The workshop does contract work for various agencies and firms in the community, plus their own bottle and can redemption center. The Parents and Friends have representatives on the Monson Canteen Committee which distributes the proceeds from the Monson canteen. 75% of the proceeds are used for the residents and 25% may be used for the staff for various events. WRENTHAM ASSOCIATION for the RETARDED Since 1955 the Wrentham Association for the Retarded, a volunteer family group, has labored to improve conditions at the Wrentham State School and to seek an environment of dignity and hope for its residents. In December, 1975, the Association was forced to bring constitutionally unacceptable conditions existed at the school. Conditions over the years have improved dramatically and are continually monitored by state and federal agencies. The Federal government through Medicaid, reimburses the Commonwealth of Massachusetts 53% of all money spent at Wrentham and other state facilities. The Wrentham Association strongly advocates for the continuation of the state facility system. This ensures that choices are available for those retarded citizens who require the specialized care available in such a setting. The Wrentham Association works closely with state employees and their unions and urges the Commonwealth and the legislature to support the competent and conscientious people who provide a stable living environment for their family members. As a member of COFAR and VOR, the Wrentham Association advocates on the state and federal levels. Massachusetts Coalition of Families & Advocates for the Retarded Formed in 1982, Massachusetts Coalition of Families & Advocates for the Retarded (COFAR) to be a united 2 organization with clout to monitor the terms of the various consent decrees. COFAR is the only statewide, non-profit, non-governmental funded advocacy group made up of family volunteers. Its mission is "to promote" the general welfare of the retarded wherever thy may be". COFAR believes that mentally retarded individuals should live in the residential setting most appropriate for their particular needs; whether that be the family home, a staffed apartment, a supervised community residence, or for the more severely retarded or those with other behavioral or medical needs, a large facility. COFAR members Dever Association, Fernald League, Hogan/Berry Association, Parents and Friends of Monson, Wrentham Association and the Glavin Parent association advocate on behalf of all mentally retarded people on the local, state and federal levels; with the Department of Mental Retardation, the legislature, in Congress and in the media. COFAR is the Massachusetts representative for the Voice of the Retarded. VOICE of the RETARDED Voice of the Retarded (VOR), founded in 1983, this national not-for-profit organization strongly favors a variety of services to meet the long-term health care needs of persons with mental retardation. VOR members in 47 states include parents and family members of mentally disabled persons, as well as providers, professionals, friends and affiliated groups. VOR is dedicated to these principles: * Empowerment of families * Choice of residential and habilitative services and supports Inclusion of large facilities as part of a continuum of residential care options * Federal and state standards of quality assurances measurable in terms of consumer satisfaction, freedom from harm, training, programmatic continuity and quality of life. * Independent monitoring of all programs * Programs design based on individual need * Research into causes, prevention and treatment of mental retardation * Continuing education of federal and state officials and the general public to the diversity of the population of persons with mental retardation. ASSOCIATION for RETARDED CITIZENS MASSACHUSETTS Founded in 1955, Association for Retarded Citizens Massachusetts (MARC) is a voluntary, non-profit organization. The Arc was a pioneer in a number of projects and activities including: * Resource Parents Program - providing support to young parents whose child has a disability * Self-Advocacy Groups - allowing persons with mental retardation to have a role in the direction of associations activities* MARC Trust - insuring families and individuals plans for the long term financial needs of individuals with mental retardationPublic education and information referral were important goals of the organization. They have developed an enviable track record in the legislative and judicial arena. Some examples of achievement: Passage of Chapter 766, which assures free and appropriate education to persons with special needs. This law anticipated the entitlement at the federal level. * Passage of Respite Care Funding and Turning 22 Law - They were the first acknowledgement that adults with mental retardation and other disabilities had the right to some type of services and a separate Department of Mental Retardation and the Early Intervention Program * Sponsor of the Class Action Suites against the Commonwealth of Massachusetts to defend the Constitutional rights of persons with mental retardation living in the state schools. Arc Massachusetts mission is "To promote the general welfare, protect the interests and rights of and advocate 3 for the needed supports and services for individuals with mental retardation and their families; to clearly express the concerns of people with mental retardation to all citizens; to coordinate support and augment the advocacy efforts of the member Arcs on a statewide and national basis; to provide leadership in addressing public issues and in presenting the true value of people with mental retardation in our society." Four major goals have been identified which stem from the mission: * Protection of individuals rights * Inclusion of individuals with mental retardation and their families in the community as equal participants * Maintenance and expansion of quality services or supports to people with mental retardation * Lifelong supports to people with mental retardation In Massachusetts, there are 24 local Arcs which provide direct services to individuals and families in their communities. Although their membership and support totals 7,000, their combined strength is significantly larger given the number of families involved and supporters at local Arcs across the state. They represent the concerns and needs of 100,000 persons with mental retardation in the Commonwealth. 4 115 CMR DEPARTMENT OF MENTAL RETARDATION 115 CMR 10.00 RESEARCH Section 10.01: Authority Section 10.02: Definitions Section 10.03: Scope Section 10.04: Research Review Committee of the Department Section 10.05: Research Proposals Section 10.06: Research Review Section 10.07: Informed Consent Section 10.08: Research Approval Section 10.09: Expedited Review Section 10.10: Complaint Section 10.11: Funding for Research Section 10.12: Sanctions 10.01 Authority The Department is authorized by M.G.L. c.19B, SS 1, 14 and 18 and M.G.L. c.123B, S2 to regulate research activities concerning mental retardation in the Commonwealth. These regulations, 115 CMR 10.00, also are promulgated in conformity with Part 46 of Title 45 of the Code of Federal Regulations (45 C.F.R. 46). 10.02 Definitions As used in 115 CMR 10.00, the terms listed below have the following meanings: (1) "Committee" means the Research Review Committee of the Department of Mental Retardation. (2) "Informed Consent" means the knowing consent voluntarily given by a subject (or if the subject is legally incompetent, by his guardian) who can understand and weigh the risks and benefits of the proposed research for the subject. (3) Minimal risk" means that the risk of physical or psychological harm or discomfort anticipated in the proposed research are not greater, in terms of probability and magnitude, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. 12/1/92 115 CMR - 274 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.02 cont. (4) "Research" means a systematic investigation designed to develop or contribute to generalizable knowledge and involving access to human subjects or private information, but shall not include: (a) any activity, such as diagnosis, preventive treatment and therapy, designed solely to enhance the well being of a particular individual; (b) any collection of information by the Department or its designee, or by an authorized federal or state governmental entity for any purpose related to the operation, administration or management of the Department; (c) any compilation or study of information, including information obtained through interview of human subjects, specifically designed by the Department or its designee (or a provider) for the purpose of evaluating the quality or availability of services, or opportunities or needs of persons eligible to receive or receiving services from the Department (or receiving services from the provider) - (d) any survey procedures, except where responses are recorded in such a manner that the survey subjects or individuals receiving services from the Department can be identified, directly or through identifiers linked to the survey subjects or to the individuals; provided that all surveys shall be submitted to the Committee for a determination as to whether such surveys are exempt from Committee review. (5) "Research Subject" means a person, whether or not such person is served by the Department, about whom an investigator conducting research will obtain data through intervention or interaction with the person, or through access to private information. 1211/92 115 CMR - 275 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.02 cont. (6) "Private information" means any information concerning an individual which because of name, identifying number, mark, or description can be readily associated with a particular person, or information which has been provided for a specific purpose by an individual and which the individual can reasonably expect will not be made public, or which is about his/her behavior occurring in a context in which an individual can reasonably expect that no observation or recording is taking place. 10.03 Scope (1) The provisions of 115 CMR 10.00 apply to any research, regardless of the source of funding, which meets one or more of the following conditions: (a) any research activity will take place at an office of the Department, a facility or a program site; (b) a person eligible to receive or receiving services provided or purchased by the Department is a research subject, unless the research in no way involves the Department or any provider; (c) the research involves disclosure by the Department or provider of private information; (2) No research within the scope of 115 CMR 10.03 may be conducted without the prior review and approval as required by the provisions of 115 CMR 10.0O. (3) No research project may be conducted which has been disapproved or terminated by the facility director, regional director, or head of the provider, as appropriate, or by the Commissioner or the Research Review Committee. 12/1/92 115 CMR - 276 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.04 Research Review Committee of the Department. (1) Membership. (a) The Research Review Committee shall have at least five (5) members, appointed by the Commissioner, who have relevant expertise and experience. Membership should reflect a diversity in racial and cultural backgrounds and shall not consist entirely of men or entirely of women. (b) The membership shall include one (1) attorney, one (1) physician, one (1) Ph.D. level psychologist, and one (1) individual who is neither employed by nor receives funds directly or indirectly from the Department and who is not part of the immediate family of a person employed by or receiving funds directly or indirectly from the Department. (c) Additional members may be appointed from time to time for regular terms. (d) The members shall serve without compensation and shall be special state employees for the purposes of tort claims and conflicts of interest. (2) Term of Office. Members of the Research Review Committee shall be appointed to terms of office as follows: (a) Upon the initial establishment of the Committee, the Commissioner shall appoint at least three (3) members to two (2) year terms, and the remaining members to three (3) year terms; (b) Upon the expiration of the term of any member, the Commissioner shall appoint a successor for a term of three (3) years; 12/1/92 115 CMR - 277 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.04 cont. (c) In the event a vacancy occurs prior to the expiration of the applicable term, the Commissioner may appoint a person to serve the remainder of the unexpired term. (3) Removal. The Commissioner, after consultation with the other Committee members, may remove a person as a member. Grounds for removal shall include serious disregard or gross neglect of responsibilities or other actions which are in violation of the regulations or policies of the Department or the procedures of the Committee. (4) Powers and Duties - The Research Review Committee shall have the following powers and duties: (a) To hold regular meetings during each year at which a quorum consisting of a majority of the appointed members must be present to act on any research proposal requiring the Committee's attention; (b) To review research proposals and conduct continuing review of research projects; (c) To develop procedures and guidelines related to its duties and consistent with the Department's regulations and policies; (d) To approve, approve with conditions, defer discussion pending receipt of additional information, or disapprove by a majority vote of the members present at the meeting, research proposals and projects; (e) To suspend or terminate approval of research that is not being conducted in accordance with the Committee's requirements or approval, or that has been associated with unexpected harm to subjects; 12/1/92 115 CMR - 278 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.04 cont. (f) To maintain written minutes of every meeting of the Committee which will record the names of the members present, those absent, the names of non-members who are present and the numerical vote of the Committee members on each research proposal and research project reviewed. (g) To maintain a permanent record which will list, in chronological order, every research proposal submitted to the Committee and contain the following information on each proposal: name/title of the research project, name and address of the investigator, date of receipt, date of approval/disapproval and date of withdrawal or termination. (h) To invite, at its discretion, experts in special areas to assist in the review of a particular research project which requires expertise beyond or in addition to what is available on the Committee. These experts may not vote with the Committee. (i) To serve, subject to the approval of the U.S. Department of Health and Human Services, as the Institutional Review Board of the Massachusetts Department of Mental Retardation. 10.05 Research Proposals (l) A research proposal must be submitted to the Research Review Committee for any research covered by these regulations. Unless otherwise directed by the Committee, the research investigator must send ten (10) copies of the proposal to the Committee chairperson at least four (4) weeks in advance of the meeting that is scheduled for review of the proposal. (2) Each proposal must include, at a minimum, the following information about the proposed research: (a) identification of the investigators conducting the research and their credentials; 12/1/92 115 CMR - 279 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.05 cont. (b) objectives of the research; (c) location(s) where the project will be conducted; (d) the private information or research subjects for which access is sought, including a description of the type of private information or the manner of access to the research subjects and the number of subjects who will be involved in the study; (e) the direct benefits of the research to the research subjects, if any; (f) justification for persons with mental retardation to participate as subjects in the research, if applicable; (g) description of the research methods and procedures to be used; (h) duration of the project; (i) identification of all foreseeable risks (physical, psychological, social, economic, legal or other), and a full discussion of their likelihood and seriousness; (j) discussion of why risks to subjects are reasonable in relation to the anticipated benefits to subjects and in relation to the importance of the knowledge that may reasonably be expected to result. (k) procedures to be followed in the event there is any adverse effect to a research subject; (l) description of how the research may affect the care or treatment of the research subject during the research and after the research has ended; 12/1/92 115 CMR - 280 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.05 cont. (m) information to be provided to the research subjects or their guardians prior to obtaining informed consent and a copy of the informed consent form to be used, where applicable; (n) safeguards for confidentiality to be maintained; (o) manner of disposal of the private information at the termination of the project; (p) type of final product to be produced, its intended `use and the manner of dissemination or publication, where applicable; (q) where applicable, disclosure of intent to establish copyright, patents, or any other rights to the product and disclosure of the organization or persons in whom such rights are vested; (r) a budget showing the projected expenditures and sources and amounts of funding for the project; and, (s) the method to be used for the recruitment of research subjects and copies of any advertisement or written material to be employed; and (t) where applicable, the manner in which the investigators intend to rely on Department or provider resources for assistance in conducting the research, collecting data, or providing private information. 10.06 Research Review (l) The Research Review Committee shall review each research proposal for the primary purpose of protecting the rights and welfare of research subjects. 12/1/92 115 CMR - 281 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.06 cont. (2) The Committee must consider, as part of the review, the impact the proposed research may have on the research subjects in terms of health and physical safety, confidentiality and privacy, human dignity, self-determination and freedom of choice, care and treatment, fairness in selection of subjects, freedom from undue discomfort, distress and deprivation, and such other interests that may be implicated by the particular research project.' (3) The Committee must further consider, in determining whether the foreseeable risks to the research subjects are reasonable in relation to anticipated benefits, available relevant clinical experience and expertise, existing knowledge of relevant research findings, canons of professional conduct and professional ethics, applicable laws, policies and procedural guidelines, standards of scientific methodology in the conduct of such research, the scientific merit of the research, the potential value of the research in the advancement of knowledge and the necessity or importance that individuals eligible for or receiving services from the Department participate as subjects if the research involves human subjects. (4) The Committee may require the research investigator or other staff persons involved in the conduct of the research to appear before the Committee to address the proposal. The Committee may require also the submission of additional documentation and materials which it deems appropriate for consideration before reaching a decision on the proposal. (5) The Committee may appoint an advocate for the subjects of a research project. The advocate shall provide counseling, assistance, and advocacy to research subjects with respect to their participation in the research. No member of the Committee and no research investigator may be appointed as an advocate. The Committee shall be responsible for informing research subjects of the name and address of the advocate where one has been appointed. 12/1/92 115 CMR - 282 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.07 Informed Consent (1) The requirements for Written Informed consent set out in this section, 115 CMR 10.07, are applicable to all research except for projects with waivers granted pursuant to these regulations. The content of the written consent form and the manner in which such consent will be sought shall be part of the Committee's review of the research proposal. (2) The consent form must be written in language understandable to the subject or the guardian. The form may not include any waiver of a subject's rights or any exculpatory language absolving the investigator, the sponsor, the Department, the program or their agents from liability for negligence. The form must provide the following information to each prospective subject: (a) a statement that the study involves research, with an explanation of the purposes of the research; (b) the basis for selection of the subject and the expected duration of the subject's participation; (c) a description of the procedures to be followed and the identification of any procedures which are experimental; (d) a description of any reasonably foreseeable risks or discomforts to the subject; (e) a description of any benefits to the subject or others which may reasonably be expected from the research; (f) a statement describing the extent, to which the confidentiality of records and privacy of subjects will be maintained; (g) a disclosure of any appropriate alternative procedures or courses of treatment if any, that might be advantageous to the subject; (h) an offer to answer any questions concerning the procedures and the research subjects' rights and a statement of whom to contact and how for further information; 12/1/92 115 CMR - 283 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.07 cont. (i) a statement that participation is voluntary and the individual is free to withhold consent or to withdraw consent and to discontinue participation in the research at any time without penalty or loss of benefits which the individual is otherwise receiving; (j) if the prospective subject is an individual receiving services provided or purchased by the Department or a family member of such an individual, a statement that mental retardation services to the individual do not depend on participation by the individual or family member in the research; (k) where applicable, a description of any controlled substance as defined in the Massachusetts Department of Public Health regulations implementing G.L. c.94, and any other substances to be used, and their anticipated effects, side effects and interactions. The description must be in language understandable to the prospective subject or guardian. (3) A copy of the consent form, as approved by the Committee, must be given to each research subject or his or her guardian. The Committee may require a witness to be present at the time consent is sought. (4) Notwithstanding the consent of the guardian, a research subject's participation in a research project must nevertheless cease -if the subject objects by verbal or nonverbal means, to participation. (5) The Committee may waive the requirement of informed consent for a research project involving access to research subjects but only if it finds and documents that all of the conditions listed below are met. (a) The proposed research involves no manipulation of the physical or psychological state of the subjects; and, (b) The proposed research involves no more than minimal risk of social, psychological, or physical harm to the subject; and 12/1/92 115 CMR - 284 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.07 cont. (c) The proposed research cannot be carried out without the waiver; and, (d) The subject does not object, by verbal or nonverbal means, to participation in the research. (6) The Committee may waive the requirement of informed consent for a research project involving access to private information but only if it finds and documents that: (a) the research consists of the study of historical records, and to require the research investigator to obtain informed consent from large numbers of relatives or descendants would make the research impracticable to conduct; or, (b) the research consists of a review of records for the sole purpose of extracting information for a demographic or statistical study in which no person can be identified. (7) Where a research investigator wishes to request a waiver of the requirement to obtain informed consent, he or she must submit to the Committee specific and detailed reasons for seeking such waiver as part of the research proposal submission. Before granting a waiver, the Committee may impose such conditions as it deems appropriate to safeguard the rights and welfare of the research subjects. Such conditions may include the appointment of advocates and monitors. 10.08 Research Approval (1) Basic Requirements. Before any research covered by these regulations may be approved by the Research Review Committee, the research proposal must satisfy all of the requirements listed below: (a) selection of subjects is equitable to the extent practicable by the objectives of the research; 12/1/92 115 CMR - 285 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.08 cont. (b) risks to subjects are minimized by using procedures consistent with sound research design and which do not present unnecessary risks to the subjects; (c) risks to subjects are reasonable in relation to anticipated benefits to subjects and importance of the knowledge to be gained; (d) informed consent will be sought and documented in accordance with and to the extent required by 115 CMR 10.07; (e) where appropriate, the research provides for the protection of the research subject's privacy and the confidentiality of private information; (f) where appropriate, the research provides for the safety of subjects through monitoring procedures and corrective interventions. (2) Additional Requirements. For certain types of research as described in 115 CMR 10.08(2), the research must meet additional requirements before the Research Review Committee may approve the project. (a) If the research involves more than a minimal risk of physical or psychological injury to subjects, then: (i) the probability and magnitude of the anticipated benefit for each subject as a result of the research must equal or exceed such risk of injury; and, (ii) where applicable, there is specific authorization by a court of competent jurisdiction for any subject incapable of consent to participate in such research; and, (iii) the additional consent and review procedures set out in 115 CMR 10.08(3) and (4) are met. 12/1/92 115 CMR - 286 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.08 cont. (b) If the research involves the administration of a new drug to a research subject, then: (i) the use of the drug must be approved for trial in human beings by the Federal Food and Drug Administration; (ii) the additional consent and review - procedures set out in 115 CMR 10.08 (3) and (4) are met; and, (iii) the procedures and requirements of the Massachusetts Department of Public Health that are applicable to research involving new drugs are met. (c) For any research project which the Commissioner, in his or her discretion, determines additional safeguards are required, one or more of the following requirements must be met: (i) the additional review procedure set out in 115 CMR 10.08(3); or, (ii) the additional consent procedure set out in 115 CMR 10.08(4); or, (iii) such other measures as the Commissioner, or his or her designee, determines appropriate to protect research subjects. (3) Additional Review Procedure. The Commissioner shall designate a mental retardation professional to participate as a consultant to the Research Review Committee. This professional shall take such steps as he or she determines appropriate to review and monitor the risks and benefits to the research subjects. In addition, if the mental retardation professional determines that the risk-benefit requirements are not met for a particular research subject, participation of the subject in the research shall terminate. 12/1/92 115 CMR - 287 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.08 cont. (4) Additional Consent Procedure. A witness appointed by the Research Review Committee must be present when consent is obtained for each subject, and the witness must determine that the investigator has obtained informed consent for that subject. The witness must be a person whose training and experience are sufficient for him or her to determine whether the consent of the prospective subject is informed. The Committee may appoint more that one witness for the research project. (5) Notification. Within ten (10) days of approving a research project, the Research Review Committee shall notify and send a copy of the research proposal and Committee minutes to the Commissioner, and where applicable, to the facility director or regional director and head of the provider with jurisdiction over the facility or program where the research activity will be conducted. (6) Notwithstanding approval of the research by the Committee, the facility director, or the regional director or the head of the provider with jurisdiction over the site where the research is proposed to be conducted, or the Commissioner, may at any time take any of the following action with regard to the research: (a) terminate the research, if he or she determines that it is too disruptive or burdensome on the programs involved or is not in the interest of the Department or the provider; (b) impose additional conditions on the research; (c) delay the initiation of research until further review is completed; (d) suspend the research temporarily pending further investigation or other action. (7) A statement of the reason(s) for the action shall be furnished promptly to the investigator(s). Any action taken pursuant to paragraph (6) of 115 CMR 10.08 is final and not subject to further review, judicial or otherwise. 12/1/92 115 CMR - 288 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.09 Expedited Review (1) The expedited review procedure is a review of a research proposal by the chairperson or a subgroup of the Research Review Committee. The reviewer may exercise all of the authorities of the Committee except disapproval of the research. A research activity may be disapproved only after review by the full Committee in accordance with the applicable requirements set out in these regulations. (2) The expedited review procedure is permitted only for research which involves no more than minimal risk and, (a) only seeks access to private information; or, (b) represents only minor changes to previously approved research, to be implemented during the period for which approval is authorized. 10.10 Complaint (1) Any person may file a complaint with the chairperson of the Research Review Committee about a research project approved by the Committee. (2) Upon receipt of a complaint, the chairperson of the Committee shall notify promptly the investigator(s) of the research that a complaint has been filed. The chairperson also shall conduct a preliminary investigation and refer the complaint to the Committee for further review and action if he or she determines that such referral is warranted. (3) The Committee, as part of its investigation of a complaint, shall provide the complainant and the investigator(s) of the research the opportunity to present relevant information to the Committee. Within thirty (30) days of receiving the complaint, the Committee shall take such action as it determines appropriate, including, but not limited to: (a) termination of the research project; (b) imposition of additional conditions on the research; 12/1/92 115 CMR - 289 115 CMR DEPARTMENT OF MENTAL RETARDATION 10.10 cont. (c) temporary suspension of the research pending further investigation or other action; or (d) dismissal of the complaint; (4) The Committee shall give prompt notification to the complainant and the investigator(s) of its action. The committee shall keep written records of all complaints, investigation of complaints, action taken by the Committee and reasons for such action. (5) Any action taken by the Committee on a complaint is final and not subject to further review, judicial or otherwise. 10.11 Funding for Research. (1) A research project which provides for compensation of any research participant may not be approved unless: (a) the compensation is received from or passes through an organization which has agreed that all its fiscal records pertaining to such research shall be subject to audit by the Department of Mental Retardation at any time; or (b) the compensation is received from the Commonwealth of Massachusetts. (2) This section, 115 CMR 10.11, does not apply where the compensation consists solely of funds from a grant from a federal government agency or authority. 10.12 Sanctions. In the event of violation of the human rights of subjects, or in the event that the research is not being conducted in accordance with applicable statutes, regulations or the requirements of the Committee, the Commissioner may impose appropriate sanctions. These may include the immediate suspension or termination of the research project and taking or seeking disciplinary action against project personnel. REGULATORY AUTHORITY 115 CMR 10.00: M.G.L. c.l9B, SS 1, 14 and 18; M.G.L. c.123B, S 2. 12/1/92 115 CMR - 290 Informed Consent Third Draft April 26, 1994 Page 1 INFORMED CONSENT Article 1 of the Massachusetts Declaration of rights provides, in pertinent part: "All people are born free and equal and have certain natural, essential and unalienable rights; among which may be reckoned the right of enjoying and defending their lives and liberty; that of acquiring, possessing and protecting property; in fine, that of seeking and obtaining their safety and happiness. The law has long recognized "that a person has a strong interest in being free from noncosensual invasion of his bodily integrity." Superintendent of Belchertown v. Saikewicz, 373 Mass. 728, 739 (1977); Thibault v. Lalumiere, 318 Mass. 72 (1945). "In short, the law recognizes the individual interest in preserving the inviolability of his person Pratt v. Davis, 118 III.App. 161, 166(1905), aff'd 224III.300(1906)" Superintendent of Belchertown v. Saikewicz, 373 Mass. at 739. As a matter of common law, a citizen has a right to be free of harmful or offensive touching. A common law battery in any intentional touching for which consent was not given. The common law has long recognized that a minor is not capable of giving consent. Commonwealth v. Nickerson, 87 Mass. (5 Allen) 51 8 (1862). A mentally retarded minor, likewise, is incapable of giving consent to a touching. Thus, when a medical procedure is to involve a child, the long standing rule is that the consent of a parent is required, and absent such consent, the physician may be liable for battery. A parent, or one in loco parentis, may give consent to a procedure on a child or mentally retarded person under a theory of substituted judgment. However, the test for the consent would be, and historically has been, whether the procedure was in the "best interests" of the individual. Reported legal cases involving consent to experimentation do not exist in Massachusetts prior to the 1940s. However, the Michigan Supreme Court in 1935 recognized the two fundamental parameters of the justification of experimentation on human subjects: a balance of risk and benefit and valid consent. The case concerned therapeutic research, i.e. research likely to benefit the subject, and the court permitted research on consenting human subjects. Fortner v. Koch, 272 Mich. 273, 261 N.W. 762 (1935). In the case of Bonner v. Moran, 125 F.2d 121 (D.C. Cir. 1941), a Federal appellate court considered the question of consent in the following context: A fifteen year old boy agreed to donate skin grafts and blood to cousin, and required a two month hospitalization during the procedures. The Circuit Court affirmed the general rule that the consent, either express or implied, of a parent is necessary for any operation on a child. The court noted, In deference to common experience, there is general recognition of the fact that many persons by reason of their youth are incapable of intelligent dec:sion, as the result of which public policy demands legal protection of heir personal as well as their property rights. . . . Hence it is not at 311 surprising that, generally speaking, the rule has been considered to be that a surgeon has no legal right to operate on a child without the conset af his parents or guardian." ld. at 122. The court also noted that there were exceptions to the rule, for emergency, where the child is