Radiation dose to patients from radiopharmaceuticals

RADIATION ADDENDUM

PROTECTION

1 TO ICRP PUBLICATION

53

Radiation Dose to Patients from Radiopharmaceuticals

A report of a Task Group of Committees 2 and 3 of the International Commission on Radiological Protection

ADOPTED

BY THE

COMMISSION

IN NOVEMBER

1992

PUBLISHED FOR The International

Commission on Radiological

Protection

by

PERGAMON PRESS OXFORD

* NEW YORK - SEOUL * TOKYO

CONTENTS Page Preface 1. Introduction 2. Ethical Aspects 3. The Nature, Types and Magnitude of Radiation Risks 4. Methodology of Risk Assessment-The Required Information 4.1. External irradiation 4.2. Internal irradiation 5. Principles of Research Design Involving Use of Ionising Radiation 6. Factors Related to Project Evaluation 7. Recommended Procedures for Project Evaluation and Responsibilities References Appendix A. Declaration of Helsinki Introduction A. Basic principles B. Medical research combined with professional care (clinical research) C. Non-therapeutic biomedical research involving human subjects (nonclinical biomedical research)

.. .

111

V

1 2 3 7 7 9 10 11 13 14 16 16 17 18

PREFACE In 1991 a Working Party of Committee 3 was established by the Commission to develop a report on criteria and the implementation of radiological protection principles for patients and volunteers exposed to ionising radiation in the course of research. The report is intended to be of use to individuals, regulatory bodies and ethical committees concerned with the design, assessment (justification), evaluation and oversight of such research. The Working Party was composed of: J. Liniecki (Chairman) A. Laugier G. A. M. Webb

J. J. Conway F. Mettler G. P. Hanson (corresponding member).

During the preparation of this report, the composition J. Liniecki (Chairman) C. F. Arias J. J. Conway J. E. Gray J. Jankowski S. Koga E. I. Komarov A. Laugier

of Committee 3 was:

S. Mattsson M . Rosenstein J. G. B. Russell S. Somasundaram L. B. Sztanyik J. Valentin G. A. M. Webb

1. INTRODUCTION (I) Investigations involving radiation exposure of humans form an important part of biomedical research. Such investigations are a necessary step in a multi-stage process of introduction of new diagnostic and therapeutical means and procedures. They also form a necessary link in applied physiology and related sciences, where projection to man of mechanisms and relationships that have been established in animals is difficult both qualitatively and quantitatively. Moreover, the application and interpretation of basic and clinical knowledge to patients, requires, as a rule, knowledge of similar data in healthy individuals, which can only be obtained from observation and measurements. Investigations involving humans form a valuable, often unavoidable step in the development off basic and mostly applied knowledge in biology and medicine. (2) It is well known however, that collection of such information sometimes involves a risk of health impairment or injury. To protect patients and individuals volunteering for such research from excessive or unacceptable risk, the World Medical Assembly issued the Declaration of Helsinki, augmented later in Tokyo in 1975 (World Medical Assembly, 1975). In that, principles were established for design, justification, evaluation and oversight of biomedical research involving humans. (3) The effects of exposure of humans to numerous physiological stresses as well as physical and chemical factors can be linked to the magnitude of the exposure by a threshold-type dose-response relationship. In such a case, below a certain level of exposure, understood as a threshold for an effect of defined nature and severity, the probability of health impairment, or any injury, is essentially zero, so that intentional exposure of a patient, or volunteer, carries essentially no risk. (4) Protection of humans against ionising radiation, however, requires consideration of the probability of induction of stochastic effects. These, if they occur, will be seriously ddrimental, and their likelihood cannot be linked to the amount of radiation (absorbed dose to a Kissueor an organ, or effective dose to the whole body) by the above mentioned sigmoid, threshold-type dose-response relationship. The assumption has to be that there is some risk of harm, even at low doses. (5) Therefore, intentional exposure of humans to ionising radiation at any dose, for purposes of diagnosis or treatment, but also for those of biomedical research, carries a risk of detrimental consequences. Whereas diagnostic or therapeutic irradiation, when competently administered by a qualified physician, carries an actual or potential health benefit to the patient, almost always exceeding the potential detriment, this may not necessarily be so in the case of an exposure for research purposes with volunteers. In the latter situation the potentia1 benefit to society, by increase of knowledge, must be weighed against the potential harm to t!he exposed individual. The Declaration of Helsinki, and the 1990 Recommendations of the International Commission on Radiological Protection (ICRP, 1991a) require that in such a case exposure to ionising radiation of individuals participating in research may take place only on a voluntary basis. (6) The use of ionising radiation, including the use of radionuclides, on human beings for medical research has been the subject of specific recommendations particularly from the World Health Organisation who published a Technical Report in 1977 (WHO, 1977). Since then, progress has been made in radiological methods, in dosimetry, and in the knowledge of radiation effects. The International Commission on Radiological Protection (hereafter 1

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abbreviated to the Commission) has increased its risk estimates from those on which the recommendations of 1977 (ICRP, 1977) had been based. In addition, more extensive information has become available on the effect of age at exposure, on gender differences, on the magnitude of the risk (Land and Sinclair, 1991), and on the consequences of in utero irradiation (Schull, 1991). It is therefore timely to review the risks and benefits of research involving the exposure of humans to radiation. (7) The objectives of the present document are to provide advice to individuals planning such research, those involved in issuing general rules of conduct (regulatory bodies and authorities), and those engaged in evaluation of specific research projects (design, assessment, justification, and oversight). In addition, the considerations in this document should be available to those who may become the subject of investigations (patients, volunteers), to assist them in making appropriate decisions related to their participation in such projects.

2. ETHICAL ASPECTS (8) The general principles stated in the context of biomedical research on human subjects by the World Medical Assembly are still a firm ethical basis for decisions on this and related aspects. They are reproduced as Appendix A. These principles were used and extended by the World Health Organisation in their specific advice related to the use of ionising radiation or radionuclides (WHO, 1977). They are restated here with some minor amendments. (9) Medical progress demands that in research the “benefit for the patient” should not be interpreted in a narrow sense, since this could hamper progress and deprive future patients of benefits. When a research project is of direct diagnostic or therapeutic relevance to the individual patient, the ethical problems involved tend to be simple ones. When, however, a research project is intended to extend medical and scientific knowledge in general, without specific benefit to the subject, the principles of medical ethics need to be applied in a broad sense, in relation to the benefit expected to accrue in the future to patients or others in general. (10) Whether the benefit is specific or general, no-one should be subjected to medical or scientific investigations without giving free and informed consent. This means that the risks and likely benefits of the proposed research should be explained in advance. The subject has the right to accept the risk voluntarily, and has an equal right to refuse to accept. By free and informed consent is meant genuine consent, freely given, with a proper understanding of the nature and consequence of what is proposed, obtained from adults who are of sound mind. This intentionally makes it difficult to carry out such investigations on children or those who are mentally ill or defective, as they cannot give free and informed consent in this sense. In exceptional circumstances, such as when proposed investigations are likely to benefit children or mental defectives and the risks are sufficiently small, those responsible for such individuals might be able to agree to their participation. This might also apply for example when the proposed societal benefit of the investigation is obviously advantageous and substantially exceeds the risk. (11) Pregnant women should not be asked to take part in research projects involving irradiation of the fetus unless the pregnancy itself is central to the research, and then only if other techniques involving less risk cannot be used. The proposed benefit of the study should be clear and substantially exceed the possible detriment. In this case the full and informed consent of the pregnant patient must be obtained and it would usually be appropriate to seek the same from the father. In some investigations it would be prudent to consider the possibility that a woman may be pregnant but not know it. If so the protocol involved in the investigation should recognise this possibility. (12) If the subject is in a position of obligation towards the investigators, for example as an

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employee, a student or even a patient, or can expect some non-health benefit such as promotion, special privileges or payment, a difficult situation arises. It is particularly important in such circumstances that consent should not be influenced unduly and should be given as freely as possible. Monetary payments for out-of-pocket expenses are not to be regarded as inducements ih the sense referred to here. (13) Even though a subject may have given consent to the investigation at the start, this consent can be withdrawn at any time by the subject. If the subject withdraws consent the investigator must at once terminate the subject’s involvement in the study. Similarly, if the subject is a patient receiving medical care and it becomes clear at any time that treatment would be improved by withdrawal from the investigation, then the investigator must do so forthwith. (14) All research involving human subjects must be carefully planned so as to gain the maximum medical or scientific knowledge with the minimum risk and inconvenience to the subject. This planning must encompass a statistical overview to ensure the utilisation of the minimum exposure to radiation by the smallest number of subjects needed to achieve the desired result. If, in the course of the investigation, it becomes clear that less exposure or fewer subjects will suffice, then the investigation must-be curtailed to what is necessary. (15) To ensure an impartial and independent view of the need for the investigation and the balance between the likely benefits and the risks, proposals should in general be vetted by a body such as an “Ethics Committee”. This is most important where the benefit is nolt likely to accrue directly to the subject. The Ethics Committee should be composed of persons not engaged in the research project under scrutiny and independent of the investigator, even though they may be known to each other.

3. THE NATURE, TYPES AND MAGNITUDE

OF RADIATION RISKS

(16) Broadly, biological effects of ionising radiation may be classified in two categories: “deterministic” and “stochastic”. A full description of these two types of effects can be found in the publications of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR, 1982,1986,1988) and the International Commission on Radiological Protection (ICRP, 1984) and a briefer treatment is given in the latest recommendations of the Commission (ICRP, 1991a). (17) In many organs and tissues of the body there is a continuous process of loss and replacement of cells. An increase in the rate of loss, for example following exposure to radiation, may be compensated for by an increase in the replacement rate, but there will be a transient, and sometimes permanent, net reduction in the number of cells available to maintain the functions of the organ or tissue. Many organs and tissues are unaffected by small reductions in the number of available cells, but if the decrease is large enough, there will be clinically observable pathological conditions such as a loss of tissue function or a consequential reaction as the body attempts to repair the damage. If the tissue is vital and is damaged sufficiently, the end result will be death. If some individuals in the exposed group are already in a state of health approaching the pathological condition, they will reach that condition as a result of exposure to radiation after a smaller loss of cells than would usually be the case. For healthy individuals, the probability of causing harm will be zero at doses up to some hundreds, or sometimes thousands, of millisieverts, depending on the tissue, and will increase steeply to unity (100%) above some level of dose called the threshold, more strictly, the threshold for clinical effect. The plot on linear axes of the probability of harm against dose is sigmoid. Above the appropriate threshold, the severity of the harm will increase with dose, reflecting the number of cells damaged, and

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usually with dose rate because a protracted dose will cause the damage to cells to be spread out in time, allowing for more effective repair or repopulation. This type of effect, characterised by a severity that increases with dose above some clinical threshold, was previously called “nonstochastic”. Although the initial cellular changes are essentially random, the large number of cells involved in the initiation of a clinically observable, non-stochastic effect gives the effect a deterministic character. For this reason, the Commission now calls such effects “deterministic” effects. In addition to the loss of functional cells in a tissue or organ, damage to supporting blood vessels may also occur, leading to secondary tissue damage. There may also be some replacement of functional cells by fibrous tissue causing a reduction in organ function. The clinical findings depend on the specific function of the irradiated tissue. For example, opacities may occur in the lens of the eye, sometimes leading to visual impairment (cataract), and, if the gonads are irradiated, there may be a temporary or permanent loss of fertility. (18) The important feature of a deterministic effect, is the presence of a dose threshold below which the effect, as specifically defined in any given case, does not manifest itself. Therefore, if the exposure falls below the threshold, these effects can be wholly avoided. Values of threshold doses for several typical deterministic effects in the most sensitive organs (gonads, lens, bone marrow) are presented in Table 1. The data in the first column refer to single exposures to lowLET radiations (x, gamma rays), at so called high dose rates (exceeding 0.1 Gy per minute). As can be seen from the data in column 2 and 3 prolongation of exposure in such a way that the dose rate falls below 0.1 Gy per hour increases, usually by a substantial factor, the values of the threshold doses. For other tissues and organs the threshold doses for deterministic effects are substantially higher than those given in Table 1, in most cases by more than an order of magnitude (UNCSCEAR, 1988; ICRP, 1991a). (19) An imperative requirement for all investigational procedures involving human subjects (except for therapeutical investigations), is that they must not approach the values of threshold dose. This condition will generally be easy to satisfy because the need to minimise stochastic effects predominates. (20) Stochastic e&cts are those which result from radiation induced changes in cells, which retain, however, the ability to divide (somatic cells), or to form a zygote (germ cells). It is commonly accepted that in both cases the relevant modifications affect the cell nucleus by changes in the chromatin and the DNA it contains. In the case of modified somatic cells an initial change may involve a multitude of possible modifications of the cells’ genome (including point mutations, deletions, translocations of chromatin to other sites (chromosomes), inactivation of controlling genes, activation of an oncogene). These may initiate a lengthy process, leading to malignant transformation of a cell, to development of a malignant clone, and eventually to a clinically overt cancer. The period between the initiation of the changes and manifest somatic disease in man may extend from a few years to several decades, and depends both on the irradiated tissue, or organ, and other individual characteristics such as age, sex, and perhaps to some extent individual sensitivity. The influence of the latter factor, however, is poorly understood. The relevant epidemiological data have been reviewed recently (UNSCEAR, 1988) and by this Commission in the main text and Annex B of the 1990 Recommendations (ICRP, 1991a); and in a Commission document on risk prepared by a Task Group of ICRP Committee 1 on Biological Effects (Land and Sinclair, 1991; Schull, 1991; Upton, 1991). (21) Irradiation of the gonads and germ cells may lead to the formation of mutations of the structure of the DNA they contain (point mutations, chromosomal aberrations). Possible transmission of the elements of the mutated genome to the progeny of irradiated individuals may lead to hereditary disorders, mostly of a deleterious nature. These inherited disorders have

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Table 1. Estimates of the threshold for deterministic effects in the adult human testes, ovaries, lens and bone marrow’ Threshold

Tissue and effect Testes Temporary sterility Permanent sterility Ovaries Sterility Lens Detectable opacities Visual impairment (cataract) Bone marrow Depression of haematopoiesis

Annual dose rate if Total dose received yearly in equivalent received highly fractionated in highly Total dose or protracted equivalent received fractionated or exposures for many in a single brief protracted years exposures (Sv) exposure (Sv) (Sv Y-‘1 0.15 3.56.0’

NAb NA

2.5-6.0

6.0

0.4 2.0 >0.2

OS-2.0d 5.0’

5 >8

r0.1 >0.15

0.5

NA

>0.4

’ From ZCRP Publication 60, Annex B. Biological effects of ionising radiations, Table B-l (ICRP, 1991a). For further details consult ICRP Publication 41 (ICRP, 1984). bNA denotes Not Applicable, since the threshold is dependent on dose rate rather than on total dose. ‘See (UNSCEAR, 1988). %ee (Otake and Schull, 1990). “Given as 2-10 Sv (NCRP, 1989). Except as noted in footnotes (c, d, e) the values in Table 1 represent current threshold values expressed as equivalent dose.

been discussed extensively in the recent UNSCEAR and Commission documents (UNSCEAR, 1988; ICRP, 1991a; Sankaranarayanan, 1991). (22) An important feature of stochastic effects is the absence of a dose threshold for their occurrence. In its 1990 recommendations (ICRP, 1991a) having reviewed in de:pth and discussed the relevant available knowledge on the subject, the Commission stated: “In short, for low LET radiations, the most characteristic form of the relationship between the equivalent dose in an organ and the probability of a resultant cancer is that of an initial proportional response at low values of equivalent dose, followed by a steeper rate of increase (slope) that can be represented by a quadratic term, followed finally by a decreasing slope due to cell killing. There are no adequate grounds for assuming a real threshold in the relationship. This form of response, while typical, is not necessarily the definitive form for all human cancers. Taken together with the linear approximation for increments over the dose due to natural background, it provides a suitable basis for the Commissions’ use of a simple proportional relationship at all levels of equivalent dose and effective dose below the dose limits recommended in this report.” (23) In other words, exposure of humans to ionising radiation at any dose confers on them a probability of induction of harm, i.e. later occurrence of a cancer, or inherited disease-if procreation follows-or both. From detailed discussions of possible dose-response relationships the Commission concluded that at low equivalent doses (defined for present purposes as those below 0.1-0.2 Sv), irrespective of the dose rate, the probability of a cancer-related death may be of the order of 4 to 5 x lo-’ Sv-’ (ICRP, 1991a). It must be stated that these prolbability

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coefficients are age and sex averaged (typical or nominal) values; at young ages (O-19 years) the probability of induction of cancer by irradiation is a few times higher. Following exposure at ages above about 50 years the risk decreases reaching values of 1/5th to l/lOth the nominal value at ages of 70-80 years following exposure. (24) Some radiation-induced cancers are curable. The curable fraction varies considerably according to the tumour type, its location and its ability to spread to other parts of the body. The level of health care in a country is also variable and an important consideration. Many tumours, even if treated successfully, are still a reason for anxiety, stress and suffering. However, counting such cancers for assessment of the total detriment as equal in severity to a fatal cancer, would be to overweight them. The Commission developed a system of weighting, based on the assumption that attributed weight to the non-fatal tumours of a given organ should vary inversely with the fraction that is cured. Details of this approach are presented in paragraphs B117-B119 of Annex B of ICRP Publication 60 (ICRP, 1991a). On such a conceptual basis, the estimate of detriment from fatal radiation-induced cancers should be augmented by that due to the non-fatal cancers taking into account the mean life time lost due to cancers of individual organs. On the average, for whole body irradiation the increase of the detriment from non-fatal cancers is equivalent to about 1/5th of that due to fatal cancers. (25) Hereditary ejkts. Irradiation of the gonads may result in hereditary changes in descendants of irradiated individuals. The total probability of severe hereditary damage in all succeeding generations has been estimated by the Commission (ICRP, 1991a) at about 1 x lo-’ per Sv for the whole population. In individual cases this figure must be corrected for probability of childbearing and would therefore decline to a low value after the age of 40 years, on the basis of the genetically significant dose. (26) Irradiation of the conceptus. The effects on the conceptus and developing fetus of exposure to radiation depends on the time of exposure relative to conception. In the first few weeks when the number of cells is small and their nature is not yet specialised, the effect of damage to these cells is most likely to be failure to implant or another form of undetectable death of the conceptus. For this reason the Commission concluded that exposure in the first 3 weeks was not likely to result in either deterministic or stochastic effects in the live-born child. A more recent review (Muirhead et al., 1993) has found some indirect evidence that supports a conclusion that, even though the risk of cancer induction in this period is lower than later phases of development, it may not be zero. During the rest of the period of major organogenesis, malformations may be induced but this will be a deterministic process with a threshold in man of at least 0.1 Gy. A recent paper (Mole, 1992) indicates that the threshold could be much greater. (27) There will be a probability of induction of stochastic effects in the live-born following irradiation throughout the remainder of pregnancy after the first 3 weeks. The data are sparse but the nominal probability coefficient is estimated by ICRP to be, at most, a few times that for the population as a whole. (28) The other effect that has been reported from studies on children exposed in utero during the atomic bombings at Hiroshima and Nagasaki is a change in intelligence quotient (IQ) (Schull, 1991). The period of greatest, in utero sensitivity is between 8 and 15 weeks after conception with a dose-related reduction of 30 IQ points Sv-’ . A lower risk is associated with the period from 16 to 25 weeks and there is no evidence for the effect outside these periods. Although this effect was first identified as an increase in the number of children classified as severely mentally retarded, this finding is now seen to be consistent with a general shift in the IQ distribution rather than a large change in the IQ of individual children following a small dose of radiation. This means that there is a practical threshold corresponding to the lowest measurable shift in IQ of about 0.1 Sv.

RADIOLOGICAL

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OF RISK ASSESSMENT-THE INFORMATION

REQUIR:ED

(29) An estimate of the risk resulting from irradiation of individuals who am being considered for participation in a voluntary investigation can be made on the basis of the information in Section 3. To use it however a reliable assessment of the dose is necessary. The first dosimetric quantity is the absorbed dose averaged over the mass of the exposed organ. The probability of stochastic effects is found to depend not only on the absorbed dose, but also on the type and energy of the radiation. This is taken into account by weighting the absorbed dose by a factor related to the quality of the radiation. The weighting factor for this purpose is called the radiation weighting factor wR, and is selected for the type and energy of the radiation incident on the body, or in the case of sources in the body, emitted by the source. The values of the radiation weighting factor to be used are those recommended by the Commission (ICRP, 1991a) and the weighted dose is called the equivalent dose. For the types of radiation used in the vast majority of investigations in medicine (i.e. x and gamma ray photons and electrons) this weighting factor is assumed to be unity. This tissue or organ averaged value may be used for risk estimation by applying the probability coefficients for cancer mortality for all irradiated organs supplemented by the detriment resulting from non-fatal cancers, weighted according to the procedures recommended by the Commission (ICRP, 1991a) and summing the risks. In the case of gonad irradiation in adults of reproductive capacity, the component of hereditary risk can also be estimated as given in paragraphs BlM-B159 and Tables B-23 of Annex B to ICRP Publication 60 (ICRP, 1991a). (30) Alternatively, a further quantity may be useful. The relationship between the probability of stochastic effects and equivalent dose depends on the organ or tissue irradiated. It is therefore appropriate to define a further quantity, based upon equivalent dose in several different tissues in a way which is likely to correlate with the total probability of stochastic effects. The factor by which the equivalent dose in tissue or organ T is weighted is called the tissue weighting factor, wT which represents the relative contribution of that tissue or organ to the total detriment due to these effects. For this doubly weighted dose, the Commission is now using the name effective dose and symbol E (ICRP, 1991a). The unit is the joule per kilogram with the special name sievert. The choice of values of the tissue weighting factors is discussed in paragraphs 27 lto 29 of ZCRP Publication 60 (ICRP, 1991a) and the recommended values are given in Table 2 of that report. (31) The effective dose as formulated in ZCRP Publication 60 is a measure of the radiation detriment to the general population, averaged over the full age distribution and for equal numbers of both sexes. Therefore, the effective dose can only be an approximate indicator of radiation detriment to individuals of specific sex and/or age groups from various diagnostic medical procedures using radiation sources. In many cases where similar groups and irradiation procedures are concerned the effective dose can be a useful comparator, however in other circumstances it may be necessary to take into account the age and sex specific risk factors by organ to obtain a good estimate of the risk involved (Land and Sinclair, 1991). In the latter case, an expert assessment by dosimetry specialists will generally be needed.

4.1. External Irradiation (32) Whole body irradiation. The physical characteristics of the radiation field (quanta or particles, their flux and energy) must be known as well as direction of the exposure. When this information is provided, absorbed doses to organs and the effective dose can be calculated, as

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specified in ZCRP Publication 51 (ICRP, 1989b). Whole body exposure will rarely be encountered in the planned investigation. (33) Partial body irradiation. All diagnostic and most therapeutic radiological procedures fall within this category. For x-ray diagnosis (radiography) advice is given in ZCRP Publication 34 (ICRP, 1980) as to the use of dose minimising devices and procedures (including rare earth screens, low attenuation materials, optimum temperature of film development, use of fresh developer). For a particular diagnostic procedure absorbed doses in various organs can and have been calculated utilising Monte Carlo computations and mathematical phantoms of the human body (both for adults and children of various age groups), if direction and cross section of the beam, and characteristics of x-rays are known (for example the applied potential, the time characteristics of the potential, the total filtration, the current and the duration of emission). Relevant results in terms of organ absorbed dose and/or the effective dose may be found in ZCRP Publication 34 (ICRP, 1980) and in numerous other publications (e.g. Drexler et al., 1984; Jones and Wall, 1985; Rosenstein and Warner, 1985; Rosenstein, 1988; Rosenstein et al., 1979, 1992). For x-ray equipment, subjected to regular quality assurance testing and technical control, and in recently proven good condition, the high voltage, mAs and filtration values may be taken from the indication on the console of the apparatus. Should there be any doubt as to the reliability of these data, a recommended alternative procedure for final evaluation and acceptance of the dose estimation is a direct check (measurement) of the characteristics of the xray beam. Measurements should be performed by a qualified expert, using properly calibrated instruments. The parameters to be measured should include the spectral characteristics of the beam, current time product (mAs), and the entrance skin dose. From the latter it may be checked whether they are within the range expected on basis of good practice using, for example, reference values of entrance skin dose such as those recommended in the UK (NRPB, 1992). Under conditions of uncertainty these measurements appear indispensable, because numerous surveys have demonstrated (FDA, 1982; Harrison et al., 1983; Indovina et al., 1985; Canadian Radiation Protection Bureau, 1988) that even for simple, routinely performed x-ray procedures, the entrance doses between hospitals and single installations vary by one, or sometimes even two orders of magnitude. Reliance on typical text-book values for doses delivered in x-ray diagnosis may be, therefore, a profoundly erroneous procedure and real doses can by far exceed optimal values sufficient for the proposed task. (34) X-ray diagnosis-jluoroscopy. If fluoroscopy is proposed as a technique it should be remembered that resulting effective doses can be substantial, if examination time is not limited to the acceptable minimum. The procedure should only be considered if compelling justification for its application is presented, and the risk and benefit are convincingly balanced. In such a case, working parameters of the imaging system have to be checked to see whether they fall in the range of acceptable values; this will vary according to the advice given by national authorities. Moreover, a device limiting the time (or exposure) during performance of fluoroscopy should be used, to prevent doses in excess of those justified. (35) X-ray computerised tomography (CT). Estimation of organ-averaged absorbed doses depends on the location and number of sections taken, but also upon characteristics of the equipment used. The axial dose measurements can be performed according to the methodology specified in a series of the UK National Radiological Protection Board (NRPB) reports (Jones and Shrimpton, 1991; Shrimpton et al., 1991a,b), yielding values of CT-dose index normalised to the unit of radiographic exposure setting (mAs). These values should be compared with a nominal value for a given type of CT scanner, and their acceptability assessed.The distribution of the dose across the width of the beam can also be determined from results of these measurements. Effective dose can then be obtained from the reports cited if the region of the

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body studied and number of cross sections taken are known. It should be noted that typically with modern equipment, the effective dose per CT examination is roughly an order of magnitude higher than the dose resulting from conventional radiographic examination of the same organ or region of the body. (36) Narrow beam procedures. Sometimes, typical narrow beam procedures are used for bone density measurements in adults (heel, forearm, hand). In such a case the absorbed dose can be easily measured using an adequate phantom, or calculated from the entrance kerma.. Mean organ dose will usually be very low when absorbed dose in the exposed part (skin and Ibone) is averaged over the entire mass of the organs. (37) Other radioanalytical techniques. In viva neutron activation is used for total or partial body determination of main body elements and trace elements. Proper measurements of the fluence rate of neutrons of various energies as well as of accompanying photons should be carried out using appropriate phantoms to estimate the equivalent dose to the relevant organs or tissues. These investigations can give quite high effective doses. X-ray fluorescence analysis is used for measurements of heavy metals in the body. Dose estimates should be carried out as for the photon-absorptiometric techniques. Organ and effective doses are normally very low. (38) Therapeutic doses. These must be calculated using contemporary methods (calmputer codes for the target and surrounding organs). The accuracy and precision of doses to be delivered should conform with the commonly accepted high standards (IAEA, 1987; Brahme, 1988). The demand appears particularly stringent in situations when high dose whole body irradiations and therapeutic procedures utilising high LET radiation are planned. 4.2. Internal Irradiation (39) Internal irradiation results from introduction into the body of radioactive substances, which by emission of particles (alpha, beta-, beta+, Auger electrons) and quanta of gamma or x rays, cause irradiation of various organs, and usually to some extent of the whole body. Estimation of the dose, in most cases of the effective dose, will vary with the available knowledge of metabolic and kinetic behaviour of the radioactive substance to be administered. Methods of dose calculation, including absorbed doses to individual organs and calculation of the effective dose are complex and involve Monte Carlo calculations based on a mathematical phantom proposed originally by the Medical Internal Radiation Dose (MIRD) Committee of the U.S. Society ofNuclear Medicine and used by the Commission in ZCRP Publication 30 (ICRP, 1981). (40) Radiopharmaceuticals with known dosimetry. There are many radiopharmaceuticals in use with thoroughly studied metabolism and kinetics for which typical absorbed doses per unit administered activity to all organs, relevant for effective dose calculation, are known for normal adults with sufficient accuracy. These data have been assembled in ZCRP Publication 53 (ICRP, 1988). Data on age-related doses and relevant disease states upon the magnitude of effective dose are also provided. Similar data are being collected and evaluated for radiopharmaceuticals introduced into regular clinical use since publication of ZCRP Publication 53 (ICRP, 1991b). (41) New diagnostic radiopharmaceuticals. Research and development of new radiopharmaceuticals must be supplemented by animal experiments (preferably based on studies of more than one species, one of which is a primate), to quantify the changes in activity in the relevant organs as a function of time. For the respiratory system (if relevant), excretory organs (urinary tract, gastrointestinal tract), and several other organs models of dose calculation should be used as specified in ZCRP Publication 53. A tentative assumption may be made, that partition of ,activity among various tissues, organs and excretory routes is broadly similar in investigational animals and man. However, the validity of this assumption must be tested in preliminary investigations on

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a small number of volunteers, and any necessary corrections introduced before further investigations. (42) New radiopharmaceuticals for therapy. Whereas no serious deterministic effects are expected after administration of radiopharmaceuticals for diagnostic purposes, such effects form the basis of therapeutic uses in the target tissue or organ, and effects may also occur in tissues surrounding the target tissue or organ. Experiments in animals must be checked against human data obtained from volunteers, collected at low administered activity (i.e. in the diagnostic range). Only then can doses to the target tissue and other organs at therapeutical activities be estimated with reasonable confidence. The probability of deterministic and stochastic (if relevant) damage can then be assessed. (43) Other biomedical research. There are a variety of research objectives for which radioactive tracers find application in human studies. The principles of dose calculation are basically the same as those stated earlier, but specific difficulties may arise with specification of models of the behaviour of the substance in the body (metabolism, kinetics). Extensive information on behaviour of elements and their radioactive nuclides in three solubility groups of compounds, can be found in ICRP Publication 30 (ICRP, 1981). Revised calculations on dose per unit intake for various radionuclides at various ages are also available in ICRP Publication 56, Parts 1 and 2 (ICRP, 1989a, 1992a). If details of metabolism and kinetics are not available from human studies and cannot be reliably obtained from animal investigations, dose calculations may proceed on simplified assumptions with the basic requirement that the latter should be conservative, i.e. leading to an over-estimate rather than under-estimate of the doses per unit administered activity.

5. PRINCIPLES OF RESEARCH DESIGN INVOLVING IONISING RADIATION

USE OF

(44) As part of the input to a decision whether to use sources of ionising radiation in biomedical research on humans, it is necessary to consider whether it would be possible to obtain similar, or equivalent information by other methods. These may include chemical and physicochemical instead of radiochemical methods, and imaging utilising ultrasound and magnetic resonance instead of x rays or radiopharmaceuticals. In this consideration the possibility of harm from the alternative methods must not be overlooked. (45) In therapy studies, the absorbed doses must conform to the purpose of the procedure: when radically treating a malignant disease the dose must be sufficiently high to destroy the tumours i.e. reduce survival probability of malignant cells to the lowest attainable level, while avoiding non-repairable damage to normal tissues. Therefore, selection of the dose and its delivery pattern will be a compromise between these conflicting requirements. Optimisation of radiological protection in these studies becomes the achievement of the best compromise, leading to the minimum effective dose to the normal tissues. (46) In all other investigations, optimisation requires that the dose should be kept as low as reasonably achievable. This condition may be fulfilled by a number of practical means, for example selecting from among alternative methods utilising radiation the procedure delivering the lowest effective dose and attaining for the latter the lowest value of the dose consistent with the current state of the art, but not below the level at which the required information can be secured. The latter should be understood as that providing an unequivocal answer to the basic question of the investigation. Lowering the dose (or administered activity) still further becomes contrary to the optimisation principle, as the dose and therefore the risk are not accompanied by the expected benefit,

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(47) In diagnostic investigations the design should satisfy the above requirement by selection of lowest x-ray doses (combination of kVp, filtration, mAs) at which images of diagnostically satisfying quality may be obtained, and selection of the lowest activity of radioactive substances that will provide images, or quantitative indices, of satisfying statistical stability. Conditions to achieve the latter must be specified case by case for each procedure. (48) An important demand on those responsible for the research project is that all equipment and procedures applied should be subject to conscientious quality assurance requirements. These latter can be found in the literature for conventional diagnostic radiology, CT scanning and nuclear medicine (Gray et al., 1993; NCRP, 1988). (49) Statistical considerations are also relevant. The number of individuals studied should be the lowest compatible with obtaining an unequivocal answer with regard to the tested hypothesis. This number can be estimated in advance if an approximate frequency distribution of the tested parameter(s) is known; if this information is not available the progress of investigations should be followed, and they should be terminated once statistically reliable information has been obtained.

6. FACTORS

RELATED

TO PROJECT

EVALUATION

(50) The information that should- be prepared and submitted to the Ethics Committee or whoever is responsible for deciding whether a particular proposed investigation should proceed has to cover the matters identified earlier in Section 2. On the one hand it will be necessary to explain why the investigation is needed, the benefit that will result if it is successful, the extent to which that benefit is to the volunteer or to society at large, the type of benefit, e.g. potentially life-saving, reducing disease and suffering or increasing knowledge that will give rise to other benefits. On the other hand the investigator must present an assessment of the likely harm to the volunteers from the investigation, based primarily on the best quantification of doses available, but modified to take account of any particular characteristics of the group of volunteers that might affect the risk resulting from the radiation, e.g. their age, sex and state of health. (51) To assist Ethics Committees in their evaluation of proposals, the WHO divided projects into categories depending on the amount of radiation dose to be received by the subject in each project. This categorisation is still regarded as a helpful procedure, and has been modified in this report to take into account the changes in the assessment of the risk from radiation that have occurred since 1977, especially those identified in the latest recommendations. To the categorisation in terms of dose or risk of harm has been added a more explicit corresponding categorisation in terms of benefit. This was implicit in the earlier recommendations from WHO and in the way they have been used in practice. (52) The basic criterion for the definition of categories is the level of risk. The boundaries between categories may for normal average adults be transformed to a level of dose, which is helpful in putting the doses directly in perspective with other doses. It should be noted that the risk is the total detriment from the exposure; namely the sum of the probability of fatal cancers, the weighted probability of non-fatal cancers and the probability over all succeeding generations of serious hereditary disease resulting from the dose. For investigations involving children the detriment per unit dose is 2 to 3 times larger than for adults; for people aged 50 years or over when exposed to the radiation sources it is only about 1/5th to l/lOth of that for younger adults. Clearly if those to be exposed are suffering from serious, possibly terminal disease then the likely expressed radiation-induced risk will be even lower. (53) The risk categories and associated information are shown in Table 2. The lowest risk category is of the order of one in a million and is in the region in which people are usually Icw22:3-n

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content to dismiss the risk as approaching the trivial. The corresponding dose region is lessthan 100 ~SV which is the amount of dose delivered by natural background radiation in a few weeks. It is considerably less than the variations in annual dose from natural background to persons living in different locations. It is therefore concluded that, given the requirement in Section 2 for all investigations to be fully justified, the level of benefit needed as the basis for approval of investigations with risks or doses in Category I will be minor and would include those investigations expected only to increase knowledge. Table 2. Categories of risk and corresponding levels of benefit

Level of risk Trivial Minor to intermediate Moderate

Risk category (total risk-see text) Category I (- low6 or less) Category II IIa (- 10ms) IIb (- 10-4) Category III (- 10V3 or more)

Corresponding effective dose range (adults) WV)

Level of societal benefit


Minor

0.1-l l-10 >lo”

Intermediate to moderate Substantial

‘To be kept below deterministic thresholds except for therapeutic experiments.

(54) At the other extreme the highest risk category includes risks of the order of one in a thousand or greater. This is a moderate risk for a single exposure but is in the region which people tend to regard as verging on the unacceptable for continued or repeated exposure. The corresponding dose region is tens of mSv or more which is greater than the current annual dose limit for occupational exposure. It covers the higher part of the range of annual doses from natural background radiation (including radon), a region in which remedial measures to reduce dose are usually recommended. To justify investigations involving doses or risks in Category III, the benefit would have to be substantial and usually directly related to the saving of life or the prevention or mitigation of serious disease. There may be other circumstances in which the potential benefit is directly to the participant in which case an investigation in this Category may be appropriate. Even in that case, and irrespective of the benefit, the doses should be kept below the thresholds at which deterministic effects would be induced (see Table 1); apart of course from therapeutic investigations. (55) Between these two there is a category in which the risks, although neither trivial nor approaching the unacceptable cannot readily be either accepted or used as the basis for refusal. These risks, of the order of one in ten thousand to one in a hundred thousand, cover most of the range of risks about which people express concern but that they are nevertheless willing to accept in a wide range of circumstances for many different types of benefit. In dose terms it includes the annual doses received by essentially all radiation workers in the course of their normal jobs and the annual doses received by members of the public from the totality of sources to which they are exposed, apart from some of the extreme doses from radon. Category II is that within which the balance between benefit and risk is probably the most difficult to make as neither is overwhelming. It may be felt helpful to make some distinction between Category IIb, the upper, intermediate level of risk, covering doses typically received by workers each year, for which a moderate benefit is needed; and Category IIa, a minor level of risk covering dose to the public from controlled sources, for which an intermediate benefit is nonetheless required. As further guidance, to justify risks in Category IIa the benefit will probably be related to increases

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in knowledge leading to health benefit. For risks in Category IIb the benefit will be moire directly aimed at the cure or prevention of disease. (56) In many of the dose comparisons used above, a contrast has been drawn between the dose from the proposed experiment and the annual dose from other causes. These comparisons are only valid provided the same individual volunteer is not subject to multiple or repeated exposures from the investigation. In general it is undesirable for the same individual to repeatedly take part in investigations involving exposure to radiation and ethical colmmittees should ascertain that this is not occurring inadvertently. Investigators should address this aspect as part of their submission for approval of a proposed study.

7. RECOMMENDED

PROCEDURES FOR PROJECT AND RESPONSIBILITIES

EVALUALTION

(57) The most important principle in evaluation of projects involving participation of humans in biomedical research with exposure of the volunteers to ionising radiation is to separate the responsibilities for proposing and approving the project. (58) The responsibility for designing and proposing the project rests with the research team, specifically with the principal investigator. The team should include people with appropriate academic education, and in clinical research, with the appropriate medical speciality. In a project of more biological than clinical orientation, medical supervision ofindividuals’ health as well as consistency of the methods and procedures with the requirements of good medical practice, must be secured. In addition to the chief investigator, who is responsible for formulation of aims and working hypotheses as well as justification of the project, the team will usually include a qualified medical physicist, who is able to perform the necessary dosimetric calculations and measurements. In some cases a person with specialised dosimetric expertise may need to be associated with the team. Clinical specialists, taking daily care of research protocols and securing evidence of informed consent for participation may be necessary for projects of a clinical nature. Qualified radiopharmacists, or their services, will be required for projects involving administration of radiopharmaceuticals, or radioactive labelled substances in general. Competence for statistical evaluation of acquired data, and the ability to judge when to discontinue their accumulation should also be secured within the research team. (59) Before the project is started, its aims, outline, methods, justification (benefit vs risk evaluation) and detailed plans should be evaluated by an independent body, referred Ito in this report as the “Ethics Committee”. Legal systems and traditions vary among individual countries and therefore, giving specific and detailed recommendations on how to ensure proper evaluation of the research projects would not be useful. It is the responsibility of the competent authorities of a country to create a framework to ensure the existence and proper functioning of independent advisory bodies dealing with the evaluation of proposals for research involving humans. However, the basic requirements can be specified. (60) The Ethics Committee should be formally independent of the individual investigators proposing the project. It should include people of the highest professional and scientific competence, and those competent in the appropriate specialty (e.g. diagnostic radiology, radiotherapy, nuclear medicine, the experimental use of radioactive compounds) and of course in radiological protection. Local professional medical organisations or boards could be represented in the committee, and in many countries it is customary that local communities are represented. Legal advice should be available. A substantial proportion of the membership of the Ethics Committee should be from outside the Institute or Organisation proposing the project. (61) The Ethics Committee should be entitled to receive and issue opinions on :research

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proposals in their preparatory phase, to request additional information and, if necessary, to require alterations in the design and methodology. A negative opinion of the committee should be binding unless there is an agreed procedure providing for appeal to another body of higher standing. The committee should work according to a formally established procedure, should keep records of its activities, deliberations and conclusions, and should be entitled to receive reports, including the published results of the projects approved. It should use the latter to check that the project was carried out according to the proposals approved and that the actual benefits were not unreasonable in comparison with those expected. In all these processes the confidentiality of medical information acquired and kept both by investigators and ethical committees must be observed.

REFERENCES Brahme, A. (1988). Accuracy requirements and quality assurance ofexternal beam therapy with photons and electrons. Acta

Oncol.

Suppl.

1.

Canadian Radiation Protection Bureau (1988). Canadian nation wide evaluation of x-ray trends (NEXT). Frequency distribution tables, 1975-1985. Referenced in UNSCEAR (1988), p. 278 (Table 17), p. 292 (Table 39). Drexler, G., Panzer, W., Widenmann, L., Williams, G. and Zankl, M. (1984). The calculation of dose from external photon exposures using reference human phantoms and Monte Carlo methods, Part III: Organ doses in x-ray diagnosis. GSF-Bericht 91026. Institut fiir Strahlenschutz, Munich. FDA (1982). Nation wide evaluation of X-ray trends (NEXT). Medical X-ray data HHS (FDA) 82-8056. Center for Devices and Radiological Health, Rockville, Maryland. Gray, J. E., Winkler, N. T., Stears, J. G. and Frank, E. D. (1983). Quality Control in Diagnostic Imaging. Aspen Publishers Inc., Rockville, MD, U.S.A. Harrison, R. M., Clayton, C. B., Day, M. J., et al. (1983). A survey of radiation doses to patients in five common diagnostic examinations. Br. J. Radial. 56, 83-395. IAEA (1987). International Atomic Energy Agency, Absorbed dose determination in photon and electron beams, an international code of practice. Technical Report Series No. 277, IAEA Publication, Vienna. ICRP (1977). Recommendations of the International Commission on Radiological Protection. ICRP Publication 26. Annals of the ZCRP l(3). Pergamon Press, Oxford. ICRP (1980). Protection of the Patient in Diagnostic Radiology. ICRP Publication 34. Annals of the ZCRP 9(2/3). Pergamon Press, Oxford. ICRP (1981). Limitsfor Intakes of Radionuclides by Workers. Indexed in Annals of the ZCRP8(4). ICRP Publication 30 Parts 1-4. Pergamon Press, Oxford. ICRP (1984). Nonstochastic E&cts of Ionizing Radiation. ICRP Publication 41. Annals of the ZCRP 14(3). Pergamon Press, Oxford. ICRP (1988). Radiation Dose to Patientsfrom Radiopharmaceuticals. ICRP Publication 53. Annals of the ZCRP 18(1-4). Pergamon Press, Oxford. ICRP (1989a). Age-Dependent Doses to Members ofthe Publicfrom Intakes of Radionuclides. ICRP Publication 56 Part 1. Annals of the ZCRP 20(2). Pergamon Press, Oxford. ICRP (1989b). Datafor Use in Protection against External Radiation. ICRP Publication 51. Annals of the ICRP 17(2/3). Pergamon Press, Oxford. ICRP (1991a). Recommendations of the International Commission on Radiological Protection. ICRP Publication 60. Annals of the ZCRP 21(1-3). Pergamon Press, Oxford. ICRP (1991b). Addendum 1 to Publication 53: Radiation Dose to PatientsJiom Radiopharmaceuticals. Annals of the ICRP

22(3).

ICRP (1992). Age-dependent Doses to Members of the Publicfrom Intake of Radionuclides. ICRP Publication 56 Part 2. Annals of the ZCRP 23(2-3) (in preparation). Indovina, P. L., Caliechia, A., Marchetti, A., et al. (1985). Preliminary results of the Italian NEXT programme. Br. J. Radiol. 18 (Suppl.) 87-89. Jones, D. G. and Wall, B. F. (1985). Organ doses from medical x-ray examinations calculated using Monte Carlo techniques, National Radiological Protection Board, NRPB Report R186, Chilton, Didcot. Jones, D. G. and Shrimpton, P. C. (1991). Survey of CT practice in the UK. Part 3: Normal&d organ doses calculated using Monte Carlo techniques, NRPB Report R 250, Chilton, Didcot. Land,C. E. and Sinclair, W. K. (1991). The Relative Contributions ofDi@rent Organ Sites to the Total Cancer Mortality Associated with Low-dose Radiation Exposures. Risks associated with ionising radiations. Annals of the ICRP 22(l), 31-57. Pergamon Press, Oxford. Mole, R. H. (1992). Expectation of malformations after irradiation of the developing human in utero: the experimental basis for predictions. Advances in Radiation Biology, Vol. 15, pp. 217-299 (Eds Altman and Lett). Academic Press, San Diego.

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Muirhead, C. R., Cox, R., Stather, J. W., MacGibbon, B. H., Edwards, A. A. and Haylock, R. G. E. (1993). Estimates of late radiation risks to the UK population. NRPB Report (in preparation). NCRP (1988). Quality assurance for diagnostic imaging. NCRP Report No. 99. National Council oni Radiation Protection and Measurements, Bethesda, MD, U.S.A. NCRP (1989). Guidance on radiation received in space activities. NCRP Report No. 90. National Council on Radiation Protection and Measurements, Bethesda, MD, U.S.A. NRPB (1992). Dosimetry working party of the Institute of Physical Sciences in Medicine. National Protoco,lfor Patient Dose Measurements in Diagnostic Radiology. Published by NRPB, Chilton, Didcot. Otake, M. and Schull, W. J. (1990). Radiation-related posterior lenticular opacities in Hiroshima and Nagasaki atomic bomb survivors based on the DS86 dosimetry system. Radiat. Res. 121,343. Rosenstein, M., Beck, T. J. and Warner, G. C. (1979). Handbook of selected organ doses for projections common in paediatric radiology. FDA 798079. Center for Devices and Radiological Health, Rockville, MD, U.S.A. Rosenstein, M. and Warner, G. (1985). Handbook of glandular tissue doses in mammography. FDA 85-8239. Center for Devices and Radiological Health, Rockville, MD, U.S.A. Rosenstein, M. (1988). Handbook of selected tissue doses for projections common in diagnostic radiology. FDA 898031. Center for Devices and Radiological Health, Rockville, MD, U.S.A. Rosenstein, M., Suleiman, 0. H., Burkhart, R. L., Stem, S. H. and Williams, G. (1992). Handbook of selected tissue doses for the upper gastrointestinal fluoroscopic examination. FDA 92-8282. Center for Devices and Radiological Health, Rockville, MD, U.S.A. Sankaranarayanan, K. (1991). Genetic E&cts oflontsing Radiation. Risks associated with ionising radiations. Annals of the ICRP 22(l), 75-94, Pergamon Press, Oxford. Schull, W. K. (1991). Ionising Radiation and the Developing Human Brain. Risks associated with ionising radiations. Annals of the ICRP 22(1),95-118, Pergamon Press, &ford. Shrimoton. P. C.. Hart. D.. Hillier. M. C.. Wall. B. F. and Faulkner. K. (1991a). Survev of CT nractice in the UK. Part 1: Aspects of examination frequency and quality assurance. NRPB Report’R248 Clnlton, bidcot. Shrimpton, P. C., Jones, D. G., Hillier, M. C., Wall, B. F., Le Heron, J. C. and Faulkner, K. (1991b). Sulrvey of CT practice in the UK. Part 2: Dosimetric aspects. NRPB Report R 249 Chilton, Didcot. UNSCEAR (1982). Ionizing Radiation: Sources and Biological Eficts. Report to the General Assembly, with annexes. United Nations, New York. UNSCEAR (1986). Genetic and Somatic Effects oflonizing Radiation. Report to the General Assembly, with annexes. United Nations, New York. UNSCEAR (1988). Sources, E&cts and Risks oflonizing Radiation. Report to the General Assembly, with annexes. United Nations, New York. Upton, A. C. (1991). Risk Estimatesfir Carcinogenic Effects of Radiation. Risks associated with ionising radiations. Annals of the ZCRP 22(l), l-29, Pergamon Press, Oxford. WHO (1977). Use of ionizing radiation and radionuclides on human beings for medical research, training and nonmedical purposes. Technical Report Series 61 I. WHO, Geneva. World Medical Assembly (1975). Declaration of Helsinki. Recommendations guiding medical doctors in biomedical research involving human subjects. Adopted by the 18th World Medical Assembly, Helsinki, Finland ((1964); and revised by the 29th World Medical Assembly, Tokyo, Japan.

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APPENDIX A DECLARATION OF HELSINKI Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects. Adopted by the Eighteenth World Medical Assembly, Helsinki, Finland, 1964; and revised by the Twenty-ninth World Medical Assembly, Tokyo, Japan, 1975.

INTRODUCTION It is the mission of the medical doctor to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfilment 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 consideration”, and the International Code of Medical Ethics declares that, “Any act of advice which would weaken physical or mental resistance of a human being may be used only in his interest”. The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis of disease. In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies afortiori to biomedical research. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. In a field of biomedical research, a fundamental distinction must be recognised between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and without direct diagnostic or therapeutic value to the person subjected to the research. Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected. 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 every doctor in biomedical research involving human subjects. 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.

A. BASIC PRINCIPLES (Al) Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature. (A2) The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted to a specifically appointed independent committee for consideration, comment and guidance. (A3) Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified

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person and never rest on the subject of the research, even though the subject has given his or her consent. (A4) Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject. (A5) Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interest of the subject must always prevail over the interest of science and society. (A6) The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subje:ct and to minimize the impact of the study on the subject’s physical and mental integrity and on the personality of the subject. (A7) Doctors should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable. Doctors should cease any investigation if the hazards are found to outweigh the potential benefits. (A8) In publication of the results of his or her research, the doctor is obliged to preserve the accuracy of the results. Reports on experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication. (A9) In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The doctor should then obtain the subject’s freely-given informed consent, preferably in writing. (AlO) When obtaining informed consent for the research project, the doctor should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress. In that case, the informed consent should be obtained by a doctor who is not engaged in the investigation and who is completely independent of this official relationship. (Al 1) In the case of a legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces that of the subject in accordance with national legislation. (A12) The research protocol should always contain a statement of the ethical consideration involved and should indicate that the principles enunciated in the present Declaration are complied with.

B. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (CLINICAL RESEARCH) (Bl) In the treatment of the sick person, the doctor must be free to use a new diagnostic and therapeutic measure, if in his or her judgement it offers hope of saving life, re-establishing health or alleviating suffering. (B2) The potential benefits, hazards and discomfort of a new method should be weighed against the advantages of the best current diagnostic and therapeutic methods. (B3) In any medical study, every patient-including those of a control group, if any-should be assured of the best proven diagnostic and therapeutic method. (B4) The refusal of the patient to participate in a study must never interfere with the doctor-patient relationship. (B5) If the doctor considers it essential not to obtain informed consent, the specific reasons for

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this proposal should be stated in the experimental protocol for transmission to the independent committee. (B6) The doctor can combine research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient.

C. NON-THERAPEUTIC BIOMEDICAL HUMAN SUBJECTS (NON-CLINICAL

RESEARCH BIOMEDICAL

INVOLVING RESEARCH)

(Cl) In the purely scientific application of medical research carried out on a human being, it is the duty of the doctor to remain the protector of life and health of that person on whom biomedical research is being carried out. (C2) The subjects should be volunteers--either healthy persons or patients for whom the experimental design is not related to the patient’s illness. (C3) The investigator of the investigating team should discontinue the research if in his/her or their judgement it may, if continued, be harmful to the individual. (C4) In research on man, the interest of science and society should never take precedence over consideration related to the well-being of the subject.