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Atoms in medicine The use of pharmaceutical products labelled with radionuclides for diagnosis/therapy is called nuclear medicine. Nuclear medicine includes methods and tools for both diagnosis and for treatment. The use of X-rays for examining patients is called diagnostic radiology. Radioisotopelabelled tracers are a powerful tool in medical science. When radiation beams are used to treat patients, the procedure is called radio-therapy. History In 1925, Herrman Blumgart and Soma Weiss performed the first application of radioactive tracers in medical research. They injected solutions of radon salt in the vein of one arm in a person and timed its appearance in the other arm. This allowed them to assess the time it took for blood to move in healthy blood vessels. This calculation gave them a base to compare the velocity of blood in people with problems of the blood vascular system. This was one of the first applications of nuclear medicine in diagnosing disease. DIAGNOSTIC TOOLS Principle Small amounts of radio-pharmaceuticals are introduced into the body by injection, ingestion or inhalation. The amount of the radio-pharmaceutical that is used is chosen to provide the lowest radiation exposure to a patient. These radio-pharmaceuticals are designed to go to specific organs such as the liver or the heart. The radioactive material gives off a small amount of energy. Special equipment such as a gamma camera, PET scanner, or probe detects this energy and with the help of a computer, creates pictures that give details of both the structure and function of the tissues. A gamma camera does not emit any radiation. Radio isotopes used in medical tests/treatments have a short half-life. Simply put, half life is the time it takes for the number of nuclei of the isotope in a sample to halve. A short half life means that the isotope decays quickly. Scintigraphy Scintigraphy is a form of diagnostic test used in nuclear medicine, in which radiopharmaceuticals are taken internally, and the emitted radiation is captured by gamma camera to form two-dimensional images. The term is derived from the Latin word meaning spark. It is different from techniques that can create 3-D images and also from imaging tests that use external sources of radiation such as X-rays. Computed tomography (CT- scan) Computed tomography (Computerized tomography or computerized axial tomography (CAT) scan), uses a computer to combine many X-ray images. This creates cross-sectional images of the internal organs and structures of the body. In a CT scan, the X--ray machine moves 1 around the body scanning the body part from many different angles. A computer creates separate images of the body area. These are called slices. The computer creates threedimensional models of the body area by stacking the slices together. The images so created provide extremely highly detailed body structures. Conventional CT scans take pictures of slices of the body that are a few millimetres apart. The newer spiral (helical) CT scan takes continuous pictures of the body in a rapid spiral motion, so that there are no gaps. A CT scan is quite quick and painless. The 1979 Nobel Prize in Physiology or Medicine was awarded jointly to Allan M. Cormack and Godfrey N. Hounsfield for the development of computer assisted tomography. Positron Emission Tomography (PET) A PET scan produces 3-dimensional, colour images of the processes taking place within the human body. Most molecular imaging procedures involve an imaging device and an imaging agent, or probe. The imaging agent is a radioactive atom tagged to a chemical called tracer. Hence it is also called radio-tracer. PET scans use a small amount of radioactive material tagged to a natural chemical. Radioactive fluorine tagged to a simple sugar gives fluoro-deoxy-glucose; a frequently used PET radiotracer. More of this material accumulates in areas that have higher levels of metabolism than it does in other areas. This difference provides the key to distinguish between normal/not-normal tissues. For example, cancer cells multiply more swiftly than normal cells and are more active too. Brain cells affected by dementia consume less energy than normal brain cells. Heart cells deprived of adequate blood flow begin to die. The cancer cells therefore will reveal themselves because of their high rate of metabolism unlike the brain cells affected by dementia or the dying heart cells which reveal themselves by their low energy requirement. The PET scan shows different levels of activity in different intensities of colour. Differences show up as brighter spots called hot-spots which are areas of high metabolic activity. Areas of low metabolic activity appear less bright and are sometimes referred to as cold spots. Basically, the radiotracer naturally gives out tiny particles called positrons. Positrons react with electrons in the body. This reaction, known as annihilation, produces energy in the form of a pair of photons. The imaging device detects the photons and creates pictures that show how it is distributed in the body. The images are displayed on a computer monitor for the medical expert to “read.” PET scans can be used to check brain function/disorders, diagnose cancer, monitor the spread of cancer or its response to therapy, heart problems such as poor blood flow and soon perhaps, even musculoskeletal problems such as soft tissue pain. PET-CT scan PET-CT is a combination of Positron Emission Tomography and Computed Tomography. It produces highly detailed views of the body. A mildly radioactive drug (tracer) is administered to the patient. This tends to accumulate in areas of increased activity in the body. The 2 scanner combines information about the body’s internal structure plus the areas where the activity is localized. This allows integration of the visualization of changes in the activity of cells with the exact areas where the changes are happening. Its uniqueness lies in its ability to precisely localize the anatomic area of interest and combine it with imaging of its functioning. The problem with this excellent diagnostic device is that the cost of producing the radiopharmaceuticals is high. In addition the radionuclides used decay very rapidly: (for example, fluorine18 used to trace glucose metabolism (using fluoro-deoxy-glucose) remains usable for only two hours; so the patient has to be brought to the facility where it is produced. The radionuclide cannot be transported very far or for very long. Single-Photon Emission Computed Tomography (SPECT) SPECT is similar to Computed Tomography but uses radionuclide emissions rather than Xrays. A rotating gamma camera takes images from many different angles (tomograms), each representing a slice of the body, and a computer is used to construct these into 2- and 3dimensional images. Organ function tests Thyroid gland Iodine is used to make thyroid hormones and thus it selectively accumulates in the thyroid gland. Thyroid function can be tested using radioactive iodine uptake (RAIU). It is a measurement of thyroid function, but does not involve imaging. How much of the isotope is taken up by the thyroid gland in a certain time period is monitored. Iodine 123 and iodine 131 are commonly used for clinical purposes; rarely iodine 124 and iodine 125 may also be used. The non‐ iodine radionuclides used for evaluating thyroid disorders include Technetium pertechnetate which mimics the action of iodine and needs a much lower radiation dose. Lungs (VQ scan) A lung ventilation/perfusion scan (VQ scan), is a test that measures air and blood flow in the lungs. It is usually used to diagnose a sudden blockage in an artery of the lung or poor blood supply in the organ. A VQ scan involves two types of scans: ventilation and perfusion. The ventilation scan shows air flows in the lungs. The perfusion scan shows the blood flows. Both scans use radioisotopes. • • 3 For the ventilation scan, the patient inhales xenon 133. Xenon does not accumulate in the areas where the lung is not expanding because of the problem and such areas remain light. Areas where the radioactive xenon is collecting show up as dark areas. For the perfusion scan, radioactive albumin is injected into an arm vein. The areas where the radioactivity does not show up are called cold areas.’ These areas indicate where the problem lies. A chest X-ray is usually done before or after a ventilation and perfusion scan. Biliary system This is called chole-scintigraphy. It is done to diagnose obstruction of the bile ducts and to detect diseases of the gallbladder. The injected radio pharmaceutical is taken up by the liver which treats it like bile. Thus it then passes via the bile ducts to the gallbladder and then, the intestines. The gamma camera is placed on the abdomen to capture images of these organs through which the radioactive tracer is travelling. The radiotracer shows up as regions of dark colour. The darker the colour in a given area; the greater is the amount of radioactive tracer present. Evenly present dark colour throughout the series of scan images means that there was no obstruction to the flow of the radioactive tracer through the biliary system and into the small intestine. If the radioactive tracer is missing from certain areas on a scan, it indicates a problem such as blockage. Other scintigraphic tests are done similarly for the other organs such as bone, brain, parathyroid and renal system etc., different radiotracers are used depending on the organ being studied. Myocardial Perfusion Imaging (MPI) Also called nuclear stress test, Myocardial Perfusion Imaging is a non-invasive imaging test that shows how well blood flows through (perfuses) the heart muscle. It examines blood flow through the heart while the person is exercising on a treadmill or exercise bicycle and while at rest. It reveals areas of the heart muscle that are not getting enough blood flow. It is used for the detection and prognosis of coronary artery disease. Thallium-201 chloride or technetium-99m is used for MPI. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are used for MPI. Further, PET cardiology viability imaging can determine how much heart muscle has been damaged by heart disease or a heart attack. In such a test radioactive sugar tracer is used. The test measures the way the heart uses glucose. Damaged or dead cells use little or no glucose. Healthy and recovering use more glucose. Radio-immunoassay Radioimmunoassay (RIA) is a method that combines immunologic and radio-labelling techniques to accurately measure minute quantities of a substance, for example hormones. It has many uses. In toxicology it is used to detect traces of the abused drugs in the body. It helps in blood banking by detecting the presence of infections in donated blood. For example, the hepatitis B surface antigen may be detected in donated blood by using RIA. It can be used to detect systemic lupus erythematosus by looking for the anti-DNA antibodies that are present in blood from such patients. SLE is known as one of “the great imitators” because it often mimics or is mistaken for other illnesses. RIA helps in accurate diagnosis. RIA is used 4 in the diagnosis of allergies and cancer and also in the field of virology, which is the study of virus. Radioimmunoassay usually uses radioactive iodine or tritium. Radio-immuno-scintigraphy Radio-immuno-scintigraphy is a bit like ordinary scintigraphy but it involves using a special type of radio-labelled antibodies (MAbs). MAbs or Monoclonal antibodies are directed against specific molecular targets. The labelled antibody-isotope conjugate is injected into the patient. This conjugate is allowed to reach the target and to collect there for 2 to 7-days. A gamma camera is used to image the results. The areas where the targeted antibodies end up show up as light areas because of the associated radioactivity. Indium 111, yttrium90 and samarium 153 are a few isotopes that are being explored in this process. Stable isotope studies Atoms of the same element have a fixed number of protons but can have different numbers of neutrons. The different ‘versions’ of each element with differing number of neutrons are called isotopes. Isotopes are of two types: stable and unstable or radioactive. Unstable isotopes decay spontaneously and disintegrate over time to form other isotopes. The difference in the number of neutrons between the various isotopes of an element means that the various isotopes have similar charges but different masses. A mass spectrometer can be used to measure this weight difference to trace the stable isotopes as they travel through the body and appear in blood, urine, breath, and stool samples. The first research paper that described the use of a stable isotope tracer in a human metabolic study was published in 1963. Today, there are four commonly studied isotopes used in nutrition studies: calcium, iron, magnesium and zinc. Stable isotopes do not appear to decay to other isotopes; at least on geologic timescales. These can be produced by the decay of radioactive isotopes. Stable isotopes have different atomic masses and react chemically in the same way but do so at different rates. Usually the term “stable isotopes” refers to isotopes of the same element. Stable isotopes of elements are present in small quantities but in constant proportions to the major form of the element. Since exposure to radioactivity, howsoever minimal, is avoided for groups, such as pregnant women and kids, stable isotope tracer studies are a viable alternative for them. Stable isotope studies have been used to determine obesity in kids, anaemia in women of child-bearing age, nutrition status in breast-fed infants, muscle mass in lactating mothers and bioavailability of iron in infants and young children and transport of dietary fat in human milketc. Isotopic techniques are also used to study the metabolism of protein, fat, vitamins and minerals. Results can provide invaluable information on the need/effectiveness of intervention programmes. TREATMENT TOOLS According to IAEA, by 2020, up to 15 million people worldwide will be diagnosed with cancer every year. 70% of these new cases are expected to occur in the developing world. 5 Rapidly dividing cells are particularly sensitive to radiation. Therefore, certain cancerous growths can be controlled or eliminated by irradiating the area where this malignant growth is taking place. More than 60% of cancer cases can be treated using radiation. Dosimetry (accurate measurement of radiation doses) is essential for safe and proper medical treatment for nuclear therapy/diagnostics. Accurate dose measurement and delivery are crucial for effectively treating patients. Proper attention to quality assures accurate image generation with minimal radiation dose to patients and medical personnel operating the device. Treatment for Thyroid cancer/Hyper-thyroidism. Radioactive iodine gets concentrated in the thyroid gland. The treatment thus destroys thyroid tissue but does not harm any other tissue in the body because no other tissue takes up iodine. Treatment using radioactive iodine for treating hyperthyroidism (overactive thyroid gland) does not lead to cancer of the thyroid gland. Actually, since the thyroid gland avidly takes up iodine, radioactive iodine sequestered by the thyroid gland is a way to kill cancerous thyroid cells. Thyroid cancer is usually treated by surgery. However, sometime radioactive iodine is recommended as a complementary treatment to get rid of any residual thyroid cancer cells. Radio-immunotherapy Radio-immunotherapy uses an antibody labelled with a radionuclide to deliver a lethal level of radiation to the cancer cell. This has been an active field of research spanning nearly 50 years and as science has progressed, this technology has increasingly become more sophisticated and efficient. An antibody with specificity for an antigen uniquely associated with the cancer cell (and NOT PRESENT in normal cells) is used to deliver death to the aberrant cells. For example, the ability for the antibody to specifically bind to a tumour-associated antigen increases the dose delivered to the tumour cells while bypassing the normal tissues. Another example would be the carcino-embryonic antigen (CEA) that is found in more than sixty per cent of colorectal, breast, and lung cancers. Thus radio-immunotherapy would mean using anti-CEA antibodies for targeted delivery. Radio-immuno therapy is being explored to kill not just cancer cells but cells infected with virus too. Lymphocytes are the most radiosensitive cells in the body. They are therefore suitable targets for destruction by radiation. Targetting the antigens uniquely expressed on the surface of infected lymphocytes using radio-labelled antibodies is a strategy that is being explored to destroy the lymphocytes in patients infected by Human Immunodeficiency Virus. Isotopes such as yttrium 90 and iodine 131 are used in radio-immunotherapy. Alpha particleemitting isotopes such as bismuth 213 or actinium225 are also being tested. Radioimmunotherapy finds application in prostate cancer, skin cancer melanoma, ovarian cancer, blood cancer leukaemia, brain glioma, and colorectal cancer. 6 Targeted Alpha Therapy (TAT) or alpha radio-immunotherapy, is an emerging therapy ideally suited for the control of cancers that have spread to other parts of the body(metastasis). Alpha particles release enormous amounts of energy over a very short distance. So, when directed accurately, these are more likely to more specifically kill the tumour cell without damaging the surrounding normal tissues as compared to β−-emitters. Actinium 225, astatine 211, bismuth 212, bismuth 213, lead 212, radium 223, and thorium 227 are suitable for the treatment of smaller tumours and micro-metastatics etc. Laboratory studies are encouraging and clinical trials for leukaemia, cystic glioma and melanoma are under way. TAT using lead-212 is reportedly a promising therapy for treating pancreatic, ovarian and melanoma cancers. Boron Neutron Capture Therapy is still in the experimental stage. This is a radiation therapy that brings together two components. Singly, these components have only minor effects on cells but together they can be deadly for the target cell. The first component is boron 10, a stable isotope of boron. The patient is given a dose of boron-10. This can be selectively concentrated in tumour cells by attaching it to compounds that seek out and concentrate in the tumourous cells. When the patient is irradiated with thermal neutrons, these are strongly absorbed by the boron, producing high-energy alpha particles which kill the cancer. However, the patient has to be brought to a nuclear reactor where such neutrons are produced, rather than the radioisotopes being taken to the patient. This therapy has potential for application in brain tumours. Teletherapy This is a non-invasive treatment for treating cancer. Linear accelerators use high energy electrons or high-energy X-rays for treatment of tumours. The Linear accelerator (Linac) is a device that uses high frequency electromagnetic waves to accelerate charged particles such as electrons to high energies through a Linear tube. The high energy electron itself can be used for treating superficial tumours or it can be made to strike a target to produce x-rays for treating deep seated tumours. Low, medium and high energy Linacs are now available which can generate X-rays and also, but also electrons for treatment. High energy gamma rayemitting radioisotopes, such as cobalt-60, cesium-137 and europium-152 are also used for cancer treatment. Radiation source is kept at a distance of 80-100 cm from the tumour to be treated. Brachytherapy The word Brachy is Greek for “near.” Brachytherapy is a treatment mode in which tiny radioactive sources are placed in/near the tumour. This exposes the tumour to high radiation but the radiation exposure in the surrounding healthy tissues is low. With High-Dose Rate (HDR) Brachytherapy, thin catheters are first placed in the tumour. The catheters are then connected to an HDR after-loader which contains a single highly radioactive iridium pellet at the end of a wire. A computer controls how long the pellet stays in each catheter. This is called the dwell time. It also calculates where it should pause to release its radiation. This is called dwell position(s). It takes just a few minutes to deliver a highly precise dose of 7 radiation to the cancer. Cancer of the prostate, breast, lung, esophagus, ano-rectal regions, head and neck as well as sarcomas are suitable candidates for this therapy. 3D conformal radiation This is a radiation therapy technique that sculpts radiation beams to the shape of a tumour. This is ideal for tumours that have irregular shapes or that lay close to healthy tissues and organs. This technique is usually a part of intensity modulated radiation therapy. CT scanners are used to obtain a 3D description of the patient’s internal anatomy. Then elaborate 3D models of the tumour and models of the organs to be protected during irradiation are made. The spatial distribution of the radiation dose is matched closely to the shape of the 3D target volume (cancerous cells). Gamma knife True to its name a gamma knife uses gamma radiation but despite being called a knife, it is not really one. It is a minimally –invasive neurosurgery device that uses radiation to target diseased brain tissue while leaving surrounding tissue intact. It contains cobalt-60 sources placed in a circular array in a heavily shielded unit. The Gamma knife works well for brain tumours, malformations in blood vessels, Parkinson’s disease, Trigeminal neuralgia , tremors etc. This is called radio-surgery. Radiation sterilization of medical products and instruments Bacteria, molds and yeasts often contaminate medical products and instruments. These health liabilities must be completely eradicated to ensure safety of medical devices and pharmaceutical products. A sterile product is one that is free from all viable microorganisms; sterility is essential in the healthcare sector. Gamma radiation and electron beams are used for radiation sterilization in this field. This radiation damages the DNA of the microbes; although the degree of radiation resistance of microbial species varies. Deinococcus radiodurans was discovered in 1956 by Arthur W. Anderson in USA when experiments were being performed to determine if canned food could be sterilized using high doses of gamma radiation. A tin of meat was exposed to a dose of radiation that was expected to kill all known forms of life. However, D. radiodurans was later isolated from the meat. INSTRUMENTS Advantages • • • 8 Destruction of contaminating microorganisms with an insignificant rise in the temperature of the irradiated materials. So the process can be used for heat-sensitive (thermolabile) drugs and plastic devices. The high penetrating power of radiation can be used on a large number of materials used in the manufacture and packaging of medical devices and pharmaceutical compounds. Products of any shape and size can be irradiated. Reliable and safe process. No toxic residue or radioactivity remain in the products. No environmental pollution. • • • Process can be automated. Direct human intervention can be almost eliminated. Process is simple and easy to control. Only either exposure time or dose needs to be controlled. In steam sterilization six variables need monitoring (temperature, time, pressure, vacuum, packaging and humidity). Since the Disadvantages • • The high cost is a limiting factor. Not suitable for all types of antibiotics and steroids. Radiation sterilization of human tissue Tissue transplants from one human being to another, is a medical marvel. So successful is this process that “tissue banks” have been set up in many parts of the world. Bone, cartilage, tendons, ligaments, dura mater, skin, amnion, pericardium, heart valves and corneas, are widely used for reconstructive surgery. These need to be sterilized prior to storage and use in orthopaedics, traumatology, neurosurgery, cardiosurgery, plastic surgery, laryngology and ophthalmology. For the first time in India, freeze-dried, irradiated amnion has been used in eye reconstruction to restore sight following injury and disease. Amnion is also finding use as a biological dressing that mimics skin. This has been made possible thanks to sterile amnion off-the-shelf packages that can be stored at room temperatures for long lengths of time. Radiation sterilization made this possible. The risk of infectious disease transmission to the recipient via the transplanted is a major risk. Such infections include tuberculosis, fungal, and viral infections, such as human immunodeficiency virus (HIV), hepatitis B, hepatitis C, cytomegalo virus, rabies virus and prion diseases. Besides, there is also the risk of microbial contamination during tissue procurement, processing, preservation and storage. Board of Radiation and Isotope Technology (BRIT) has developed a gamma irradiator for hygienisation of blood in hospitals and blood banks. India’s position In India research and development effort in the context of the use of radioisotopes in healthcare was initiated in 1958. Medically important radio-pharmaceuticals such as radioiodine, radio-chromium, radio-phosphate, radio labelled vitamin B12, radio-iodinated thyroxin etc. were developed in the 1960s. BARC introduced the country’s first radioimmunoassay kits in the 1970s, soon after these debuted in the global market. BRIT made Immuno-radiometric assay kit available in India in the 1980s. Today India has know-how for the production of over 100 radiopharmaceuticals and labelled compounds for medical including 99mTc generator, cold kits for the preparation of 99mTc- radiopharmaceuticals and radioimmunoassay kits. 9 BARC’s Radiation Medicine Centre in Mumbai, is a regional referral centre of the World Health Organisation for South East Asia in the area of radio-diagnosis and therapy. In 2013, the Centre celebrated 50 years of outstanding service to the people. India is conscious about the growing need of radioisotopes. According to a booklet published by the Department of Atomic Energy, India is one of the leading producers of radio isotopes in the world. The radioisotopes are produced in the research reactors at Trombay, accelerator at Kolkata and various nuclear power plants. Radio isotopes are produced by the research reactors APSARA, CIRUS and DHRUVA at Trombay. This includes: Molybdenum-99 and Iodine-131 constitute the bulk was processed and supplied through BRIT to different end users. Radionuclides such as Phosphorus-32, Samaraium-153, Mercury-203, Holmium-166, Bromine-82, and Gold-198 were regularly processed and supplied. Iodine-125 was produced by irradiating natural Xe gas for further preparation of Iodine-125 based radio-pharmaceuticals and sources. BARC has developed Holmium-166 labelled hydroxyapatite which seems to be a promising candidate for liver cancer therapy. It can also be used for rheumatoid arthritis. And India is consolidating its place. For example, the Regional Radiation Medicine Centre (VECC), Kolkata, was setup by the DAE in 1989 to cater to the need of the eastern part of the country. Today a BARC carries out active research with hospitals in other parts of the country. One such study has shown that lutetium-177, yttrium-90 and phosphorus-32 are effective therapeutic radionuclides for the treatment of liver cancer and skin cancer as well as for non-cancerous maladies such as rheumatic arthritis and haemophilia. Lu-177 has short range of tissue penetration which makes it ideally suitable for treating smaller and softer tumours (example non-operable neuro- endocrine tumours). In addition, it can be used for imaging studies too as it emits both gamma rays and beta rays. It is desirable that a developing country have at least one tele-therapy machine for every million citizen. So India needs to increase the number of available tele therapy machines. Rising to the need of the country, BARC created the Bhabhatron, a relatively inexpensive yet high performance tele-cobalt machine. The first unit found use at the Advanced Centre for Treatment, Research and Education in Cancer at Navi Mumbai in March 2005. The next year, BARC developed an improved version, named Bhabhatron-II. It has been installed across India. Bhabhatron-II has battery backup for six-hours which is an asset for operation in rural areas. Under the IAEA’s Program of Action for Cancer Therapy (PACT), India has signed agreements with IAEA, Sri Lanka and Namibia to donate Bhabhatron II to these two countries as a step towards affordable treatment of cancer. International Atomic Energy Agency and its global programme The IAEA maintains the NUMDAB or Nuclear Medicine Database, to gather and maintain updated information regarding the global status of nuclear medicine practice. 39 institutes from India are registered in this database. These are at Bangalore, Bhubaneshwar, 10 Chandigarh, Chennai, Cochin, Delhi, Gurgaon, Hyderabad, Lucknow, Mumbai, Prasanthinilayam , Pune, Secundrabad and Shimla. Of course many other facilities in India also provide the option of nuclear medicine. BRIT supplies radio isotopes to at least 120 nuclear medicine centres in India. The Tissue Bank at the Tata Memorial Hospital is the first such bank in India. It was set up to provide safe tissue for transplanted into recipients. It was established in collaboration with the IAEA in 1988 to “promote the use of radiation for the sterilisation of biological tissues...” At the Tissue Bank, tissues from suitably screened donors, are processed, freeze-dried, and sterilised using gamma irradiation. The IAEA website states that in 2004, the IAEA established the Programme of Action for Cancer Therapy (PACT) which serves as the IAEA’s umbrella programme for combating cancer and builds upon the experience in radiation medicine expertise and technology. The WHO-IAEA Joint Programme was established in 2009 to enable Low and Middle Income Member States to introduce, expand and improve their cancer treatment capacities and therapeutic effectiveness by integrating radiotherapy into a comprehensive national cancer control programme. Bibliography 1. http://www.iaea.org/Publications/Booklets/RadPeopleEnv/pdf/chapter_8.pdf 2. Trends in radiation sterilization of healthcare products : http://wwwpub.iaea.org/MTCD/publications/PDF/Pub1313_web.pdf 3. Application of Radioisotope in Healthcare – An Overview N.Sivaprasad http://www.britatom.gov.in/docs/pdf/radiopharm_article.pdf ( 31 October 2013) 4. Nuclear energy and societal development http://dae.nic.in/writereaddata/.pdf_42 (01 November 2013) 5. Role of BARC in quality assurance and safety in medical applications of Ionizing radiation; B. C. Bhatt http://mohfw.nic.in/WriteReadData/l892s/pg105to121-35190436.pdf (6 November 2013) 6. Tissue bank of Tata Memorial Hospital; http://dae.nic.in/writereaddata/.pdf_43 (6 November 2013) 11