The peculiar characteristics of radiopharmaceuticals make it possible to treat some diseases with the same molecule used for diagnosis but labeled with a different radionuclide: this possibility, recently called "theragnostics", has been known in Nuclear Medicine since the dawn when Iodine131 was used both for diagnostic and therapeutic purposes in the thyroid field.

The discipline evolves rapidly also thanks to the progress of two related fields: one is that of molecular biology, radiochemistry and radiopharmacy, which deal with the development of new radiopharmaceuticals that today are applied above all for "Molecular Imaging" purposes (a term that has become almost synonymous with Nuclear Medicine), the other is that of electronic engineering, clinical engineering and applied physics, who deal with the development of new diagnostic equipment, an area that is now particularly interested in the enthusiasm shown by nuclear doctors and clinicians for "Hybrid Imaging".

For cultural, scientific, professional and continuing education aspects, Italian Nuclear Medicine refers, at European level, to the EANM (European Association of Nuclear Medicine and Molecular Imaging) Scientific Society and to the IAEA (International Atomic Energy Agency), at national level to the AIMN (Italian Association of Nuclear Medicine) which brings together over 700 specialists in the field. The latter association carried out a census in 2016 from which it appears that there are over 250 centers in Italy (about 1 center for every 250,000 inhabitants); there are about 400 gamma cameras and over 170 PET tomographs (1).

There are two Italian scientific journals: the Quarterly Journal of Nuclear Medicine (Minerva Medica), born as Minerva Nucleare, the oldest journal of Nuclear Medicine in the world and the Clinical and Translational Imaging (Springer) owned by the same AIMN. The European scientific society EANM in collaboration with the UEMS (Union Européenne des Médecins Specialistes) have produced and periodically update a European training curriculum for the training of the specialist in Nuclear Medicine (Nuclear Medicine Training in the European Union), known as the European Syllabus, whose last update was in 2016 (2).

1)       https://www.aimn.it/documenti/notiziario/2017_2.pdf 

(2)       Eur J Nucl Med Mol Imaging (2016) 43:583–596

The specialization course in Nuclear Medicine aims to train a specialist ready to take on the role of medical director of a hospital or hospital/university structure of Nuclear Medicine both in Italy and abroad. He must therefore be able not only to perform or supervise all the assistance activities of nuclear medical competence both in the diagnostic field (conventional, SPECT and PET), and in the therapeutic field, but, in relation to the typicality of many UOS or UOC of this discipline, made up of 2 or 3 professionals, to immediately assume managerial responsibilities.

The School also trains the student in :

• supervise the application of health and radiation protection regulations relating to nuclear medicine departments and its periodic revisions
• write and review operational care and clinical research protocols,
• supervise the training and updating of other colleagues and students/postgraduates,
• to establish and strengthen joint working relationships in care and research with related disciplines:

1) in the field of specialist areas (such as radiology and radiotherapy),

2) in the clinical area (such as oncology, cardiology and neurology),

3) with other related disciplines that offer complementary skills, sometimes even in accordance with the law, for the exercise of the profession at the highest level of quality and safety (such as health physics, clinical engineering and hospital pharmacy), also ensuring the professional and cultural development of all the teams with which it collaborates (doctors and non-doctors).

• possess and demonstrate strong interdisciplinary skills and competencies in the fields of management and interdisciplinary and intersectoral communication, interfacing proactively with medical colleagues, physicists, chemists/pharmacists, technicians, nurses and other non-medical professionals.
• be able to perform and interpret (preferably in collaboration with specialists in the field but, in case of impossibility, also independently) some "hybrid" diagnostic investigations such as ultrasound, CT and MRI (equipment that is increasingly structurally integrated with the more traditionally medical-nuclear ones) or complementary to the exercise of scintigraphic activities, such as stress/pharmacological ECG. 
• be able to manage all foreseeable clinical emergencies following the administration of radiopharmaceuticals and contrast media or cardiological provocative tests.
• know and teach radiobiology and radiation protection (the discipline requires professional practice in whole or in part within the "controlled areas"), in order not only to collaborate in the optimization of safety in the wards but also to provide answers to anyone (from institutional interlocutors to the individual patient) about the risks deriving from ionizing radiation with reference not only to individual diagnostic investigations or therapeutic treatments but also to the nuclear accidents that require medical figures with clinical, radiopharmaceutical and physical skills.
• to be able to conduct clinical research in English both as a speaker and as a moderator/reviewer (conference communications and scientific works) and to be able to maintain and promote updating with all the modern means of continuing education in medicine.

The attitude of public opinion towards radiation is truly curious. Starting from the early years of the last century and for several decades, the prevailing opinion was that they were good for health: and so  - it now seems incredible - syrups based on radioactive Thorium, creams of beauties containing Uranium, devices to introduce Radon into soda water siphons and Radium tablets to be hung from the ceiling to be comfortably irradiated in bed or reading the newspaper in the living room were quietly sold as "restoratives". On the other hand, I remember that my mother before the war gave me as a child ("Drink Guido it's good for you!") a mineral water defined by the label as "powerfully radioactive". The owner of a Fonte who printed that label today would be sure not to sell a single bottle.

But then came Hiroshima, Nagasaki, Chernobyl, science fiction films with the horrors produced by atomic radiation and everything changed: today even a solitary X-ray or gamma photon arouses terror. For a package found a few years ago in a dumpster in Rome and containing radioimmunology reagents with infinitesimal traces of radioactivity, the reporter of an important Italian newspaper concluded his piece as follows: "Fortunately the package was sealed, otherwise the very powerful radiation would have poisoned all the inhabitants of the surrounding buildings."! This is an incomprehensible attitude of the public, especially if we consider that, since electromagnetic radiation is a continuous spectrum, not only those with short wavelengths (X-rays and gamma rays, in fact), but also those with high wavelengths such as radio frequencies (the deadly transmitters of Vatican radio!) are feared; welcome, on the other hand, those of light, which are in the middle, with an extension of sympathy to ultraviolet rays: who does not run to the sea to get a nice tan?

But what is the truth about radiation damage? I specify that here I will talk about those used in Medicine (X-rays in radiodiagnostics; gamma rays and electrons in Nuclear Medicine) which represent for an Italian the only practical opportunity to be exposed: nuclear power plants are closed and hopefully there will be no atomic wars or nuclear attacks.

To understand what follows, we need to introduce the concept of "dose". Radiation acts for the energy it deposits in the tissues (which gives rise to ionization phenomena, with damage to biological structures) and is measured in relation to the amount of energy deposited. The unit of measurement is the Gray (Gy) which corresponds to the transfer of energy of one Joule per kilogram. It is a very large unit, because we are usually exposed to doses that are measured in thousandths of Gray (mGy): an X-ray examination gives, on average, about 1 mGy (the CT scan even 6-8 mGy), a nuclear medical examination, on average, 4-5 mGy; we all receive an average of 2.4 mGy per year from natural radiation (cosmic rays, radioisotopes in soil and food, Radon in buildings, etc.).

It is certainly ascertained, especially thanks (!) to the explosions of Hiroshima and Nagasaki, that at high doses radiation is harmful. There are two types of damage: the "deterministic" ones are due to the killing of cells, especially radiosensitive tissues such as the hematopoietic marrow (with the fall of figurative elements in the blood, especially lymphocytes): doses of 3-5 Gy can lead to death of the person by destruction of the marrow; with higher doses, death also occurs due to lesions of the intestinal epithelium (diarrhea, infections) or the CNS (convulsions, coma). This is what happened, unfortunately, for about thirty people who worked in Chernobyl or rushed to the rescue at the time of the disaster. Deterministic damage occurs, however, only from a certain dose upwards: there is, that is, a "dose threshold". The first alterations in the blood series are observed, for example, only from about 0.5 Gy; for doses below 0.15 Gy (150 mGy) no damage has ever been observed even for the most radiosensitive tissues (among which, in addition to the hematopoietic marrow, embryonic and fetal tissues, spermatogonia, and the lens should also be mentioned).

Also at high doses, another type of damage has certainly been ascertained, the "stochastic" (meaning: "random") due to DNA alterations produced by radiation (mutations; chromosomal aberrations, etc.) with the consequence of hereditary diseases, if they occur in germ cells, and radioinduced cancers, if in the DNA of  somatic cells.

The crucial problem in practice is as follows. Both if you are exposed for professional reasons (radiologists, rangers on construction sites, etc.), and if you are exposed for medical reasons, you usually do not receive (except in the case of radiotherapy) doses higher than  30-50 mGy. So there are no deterministic effects; but can there be, or not, stochastic damage for these "small doses"?  (those less than 0.2 Gy, 200 mGy are defined as such).

There are, in this regard, three doctrines.

1)      The most widespread and "official" doctrine is the one supported by the authoritative International Commission on Radiological Protection (ICRP), which inspires protectionist legislation all over the world. A "threshold" does not exist: even a single event (for example a photon or a particle that causes a break of both strands that form the DNA helix) can be sufficient to start a malignant tumor or a hereditary genetic alteration. Furthermore, in an irradiated population, the frequency of effects (which turns into "probability" for the individual) is linearly correlated with dose: if out of 100 individuals receiving 1 Gy there are 10 radio-induced cancers (during their entire life), they will be 5 for 0.5 Gy and 2 for 0.2 Gy. This doctrine, called LNT (Linear No-threshold Theory), however, has an attenuation for "small doses": in fact, the ICRP admits that they have a less biological effect than can be expected and introduces a "reduction factor" (DREF) of 2: so a dose of 0.2 Gy (200 mGy) in those 100 people will not cause two malignant tumors, but only one.

The ICRP does not at all claim that the LNT is indubitably true: it says that it is precautionarily useful, for protectionist purposes, to consider it as such. But it has been taken up as the Gospel by many; And the concept of the "cumulative collective dose effect", which is its derivation, is the one that has caused the most alarm in the mass media. Let's continue with the example, going down with the doses and remembering that, according to the LNT, there is no threshold. If 200 mGy causes, according to the DREF, 1 fatal tumor in 100 people, 20 mGy will cause one in 1000 people and 1 mGy will give rise to a malignant tumor if it is received by 20000 people. Even a tenth of mGy (infinitesimal dose, twenty-four times lower than the average dose that each of us receives from environmental radiation) can cause a malignant tumor if administered to 200000 people; So 10 malignant tumors out of 2 million people, 100 out of 20 million, 1000 out of 200 million. With calculations like these, tens of thousands of malignant tumors have been prophesied all over the world as a result of the radioactive fallout from Chernobyl: which, however, almost 20 years later, no one has seen. The only cancers that can be linked to Chernobyl are a few hundred papillary thyroid carcinomas in children in Belarus, who had received large thyroid doses from isotopes of radioiodine. The concept of "collective dose" has unfortunately also been applied to medical exposures. Just this year Berrington and Darby, multiplying the very small doses due to radiological examinations by the millions of patients examined, published that the exercise of radiology causes every year 7587 fatal cancers in Japan, 5695 in the USA, 2049 in Germany, 700 in England and so on for 14 countries, among which Italy does not appear (perhaps disliked by the authors). With the consequence that a German periodical, whose political orientation is not difficult to glimpse, wrote that radiologists know very well that they are killing their patients, but are forced to do so to support the market of the multinational manufacturers of radiological equipment!

2)      A doctrine that has fewer supporters (but some very authoritative, such as the Académie des Sciences de France) maintains that stochastic effects are indeed proportional to dose, but that when small doses are reached there is  a "threshold", or at least a "practical threshold". It is emphasized that the cell has very efficient DNA repair systems (mostly enzymatic). which daily face myriads of lesions produced by oxidative metabolism and environmental genotoxics: it seems strange that they cannot dominate the few additional lesions due to a small dose of radiation, while it is understandable that the repair mechanisms can be overwhelmed by a large dose. Even the breaking of both strands of DNA, particularly feared in the case of radiation, can be repaired, albeit with some difficulty. Even more important is the consideration that tumor development is a multi-stage process: "initiation" is followed by "promotion", "conversion" and "progression". In each of these stages, the body knows how to defend itself, with various mechanisms: mitotic arrest, apoptosis (programmed cellular suicide), differentiation, immune reactions. Even if one or a few cells were started, because there was a defect in DNA repair, how is it possible that in the later stages they escape these protective mechanisms?

This doctrine, not devoid of common sense, receives indirect support from observations on tens of thousands of workers exposed (especially in countries where the nuclear industry is most active) to small doses of radiation and who have so far not provided evidence of radioinduced carcinogenesis.

3)      A doctrine that is spoken of in a whisper, because it is not "politically correct", but which has fanatical supporters, even among distinguished scientists, is Hormesis. Hormesis believes that small doses of radiation can not only be harmless, but even have favorable effects. Small doses would evoke an "adaptive response" that makes the body better able to resist not only high doses received later, but also to oppose many other harmful and genotoxic agents and even aging. The doctrine makes use of: general considerations (almost everything that is toxic in nature is toxic at a high dose, while it is harmless or beneficial at a small dose; the adaptive response is very effective because life has developed it in the course of a phylogenetic evolution that for the most part took place when the natural background of radiation was higher than today, etc.), epidemiological observations and also experimental data, which tend to prove the adaptive response. The best experimental evidence comes from studies on human lymphocytes (but also from studies on other biological systems). Lymphocytes chronically irradiated by small doses of tritium introduced into cultures (resulting in incorporation of thymidine tritiate) show, when exposed to doses of 1.5 Gy of radiation, only about half of the chromosomal aberrations found in controls. The same happens if the lymphocytes are previously irradiated with small doses of X-rays (10 mGy). Recently it has been seen that even lymphocytes taken from subjects undergoing hyperthyroidism therapy with 131I resist irradiation with 0.5 and 1 Gy of  gamma rays better than lymphocytes taken from normal subjects.

But, perhaps because it is a minority subjected to persecution, there is often excess, which can annoy, in the writings of the Ormeticists. One of them said that the adaptive mechanisms were developed in the early days when the background of environmental radiation was much higher and that they risk weakening today as we are "in debt" compared to then of about 4 mGy per month. Hence the opportunity to carry out a skeletal scintigraphy per month, without medical indication, but only to "fill up" with radiation! Frankly, it seems too much to me.

In conclusion,  let us return to Pilate's question "Quid est veritas?". We will probably learn this, for small doses, only from the progress of radiobiology: there are in fact great statistical difficulties in significantly ascertaining, with direct epidemiological observation, a small excess of radioinduced tumors compared to the great mass of spontaneous tumors that are in no way distinguished from them. However, if molecular biology were able to offer us a specific marker of radioinduction, the situation would become completely different. But advances in genetics are also important. It has already been seen that some mutated genes (ATM, BRCA1, BRCA2, etc.) predispose not only to spontaneous tumors, but also to radioinduced ones because DNA repair systems are compromised; And we are beginning to think that the stochastic effects are not random, but that they may concern, for not high doses, only genetically predisposed individuals, even in a multifactorial way by multiple genes with low penetrance. If it were possible to identify, through genetic tests, who is predisposed and who is not, this would, of course, be of extreme practical importance.

In the meantime, I think that as far as medical diagnostic exposures are concerned, we can rest assured. Which does not always happen: I know well a mother who did not want to take a chest X-ray on her feverish and drug-addicted daughter because "The rays hurt", then finding it very natural that she  was glued a few centimeters from the television to absorb the X-rays coming from the cathode ray tube for hours.

 It is already known that the very cautious ICRP in the forthcoming Recommendations will greatly reduce the risk coefficient for hereditary genetic effects (which have never been observed in humans, not even in the first generations of the survivors of Hiroshima and Nagasaki) and also, to a lesser extent, that for radioinduced carcinogenesis. Furthermore, as we have seen, there are good reasons to think that small doses of radiation (X-rays, gamma rays or electrons: because for alpha particles, neutrons and protons the situation would be different) may not cause harm, or, if we want to be bold, even have a beneficial effect. And finally: if despite my mother's radioactive water and my past as a radiologist and nuclear doctor I have reached the age of 78 in excellent health, there must be a reason! .   

G.Galli

Director Emeritus Institute of Nuclear Medicine Catholic University of the Sacred Heart - Rome