**6. Radiobiology in nuclear medicine and molecular imaging**

Paediatric patients are referred to nuclear medicine from nearly all paediatric specialities including urology, oncology, cardiology, gastroenterology or orthopaedics. Radiation exposure is associated with a potential small risk of inducing cancer in the patient, later in life; this danger is higher in younger patients.

In the field of *nuclear medicine imaging*, which uses very small amounts of radioactive substances (*radiopharmaceuticals)* to diagnose and treat disease, the radiopharmaceuticals injected into the patient's body are detected in very precise images of the part of the body being imaged.

#### **6.1 The role of radiobiology in nuclear medicine**

In 2021, the EANM published a position paper on the role of radiobiology in nuclear medicine [14]. For that paper, a group of EANM radiobiology, physics and dosimetry experts summarized the main issues concerning radiobiology in nuclear medicine. The position of the EANM is that radiobiology will contribute to the *optimization* of radiotherapy to ensure that they are effective and safe for each individual patient, considering age and weight.

#### *Nuclear Medicine Dosimetry in Paediatric Population DOI: http://dx.doi.org/10.5772/intechopen.105346*

There is a need to generate and apply more radiobiologic knowledge specific to nuclear medicine diagnostic and therapeutic procedures, as DNA damage induction and repair strongly because of the comparatively low dose rates varying over time with physical decay and kinetic clearance.

While the role of radiobiology for diagnostics remains to be clarified, its role in the benefits of radiopharmaceuticals in therapy is clear.

It is expected that a better understanding of radiobiological parameters can contribute to fully exploiting the abilities of new and existing nuclear medicine applications; how can be effective and safe for each individual patient, child or adult. Radiobiology plays an important role in supporting *optimizations*, in an increase of the use of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine.

A better understanding of radiobiologic parameters will enhance the capabilities of new and existing nuclear medicine applications in adults and paediatric patients. There is a need to better define the dose-effect relationships of radiopharmaceutical radiation in tumours and normal tissue. To reach this target, the EANM recommends a strong link between all scientists involved (Radiobiologists, radiochemists, radiopharmacists, medical physicists, and physicians). So, an improved understanding of the biological processes, with special regard to the effects of ionizing radiation to normal tissues and tumours, for any living matter, will be gained.

When ionizing radiation interrupts living matter, it deposits energy along its path leading to atomic ionization, thereby damaging biological molecular structures (**Figure 6**).

DNA damage induced by radiation is considered critical. DNA, as well as proteins, lipids and metabolites can potentially be modified by ionizing radiation. As first action, absorption of ionizing radiation will occur at the site of the atoms of the cellular molecules. Following ionization events may cause the breakage of chemical bonds. It may also convert atoms and molecules into free radicals with very sensitive unpaired electrons that can further interact with close molecules, after which a damaging sequence may occur.

#### **Figure 6.**

*Interaction of ionizing radiation with cellular matter- DNA and others. DNA and other cell elements are potential targets for ionizing radiation damage. Ionizing radiation also influences cell signalling pathways like oxidative stress, cell death and survival pathways, premature ageing and inflammation [14].*

#### **6.2 Molecular imaging: how it works**

Molecular imaging provides detailed images at the molecular and cellular levels. Molecular imaging indicates how the body is functioning and gives the prospect to measure its chemical and biological processes. It offers exclusive insights into the human body that patients can obtain *personalized* care. In diagnostic molecular imaging, diseases are identified in the earliest stages and the exact location can be determined, avoiding more invasive procedures such as biopsy or surgery.

When disease occurs, the biochemical activity of cells begins to change. Cancer cells may multiply at a much faster rate and are more energetic than normal cells. As the disease progresses, this abnormal cellular activity begins to affect body tissue and structures, causing anatomical changes; Cancer cells may form a mass or tumour. Molecular imaging detects cellular changes early in the course of the disease. A variety of imaging agents are used to visualize cellular activity, such as the chemical processes involved in metabolism, oxygen use or blood flow. The imaging agent in the body accumulates in a target organ or attaches to specific cells. The distribution pattern of the agent helps to distinguish how well organs and tissues are functioning.

#### **6.3 Radiosensitivity of children**

Children are more radiosensitive as the organs and cells in children are undergoing constant self-renewal, therefore are more sensitive to radiation. Measurement of DNA synthesis by PET Radiopharmaceuticals that identify increased DNA synthesis can be used to identify increased cellular proliferation in tumours.

Children, due to increased mitotic activity and longer life expectancy, are more radiosensitive than middle-aged adult by a factor of up to 10 and girls are considered more radiosensitive than boys [12].

Radiosensitivity decreases with age, exhibiting lifetime attributable cancer mortality risks per unit dose as a function of age at a single acute exposure. This was estimated by the Committee on the Biological Effects of Ionizing Radiations (BEIR) [15, 16] and the International Commission on Radiological Protection (ICRP) [17].

Children are two to three times more susceptible to radiation for the development of leukaemia. Adults exposed to radiation during childhood have an increased likelihood of emerging breast or thyroid cancer.

The National Academy of Sciences BEIR V committee and the ICRP report 60 have estimated the lifetime cancer mortality risks per unit dose at a single acute exposure as a function of age. They have shown a rapid increase in lifetime risk with decreasing age at exposure (**Figure 7**).

This indicates that radiosensitivity decreases with age. Neonates are more radiosensitive than infants, infants are more radiosensitive than children and children are more radiosensitive than adolescents.

#### **6.4 Radiation life-time risk**

Radiation-induced cancers tend to appear at the same age as spontaneous cancers of the same type. So, it takes half a century or more to judge the impact of radiation exposure, especially when children are included in the exposed individuals.

Exposed to radiation individuals in their first decade of life, the risk is approximately 15% per Sv, while for adults in their late middle age, the risk drops to 1 or 2%/Sv. *Nuclear Medicine Dosimetry in Paediatric Population DOI: http://dx.doi.org/10.5772/intechopen.105346*

#### **Figure 7.**

*The above risk estimate is an average for a population comprised of all ages. It is apparent that the risk varies dramatically with age (from Eric J. Hall, 2002), [15].*

There is also a clear gender difference, especially at early ages, with girls being more radiosensitive than boys (**Figure 7**).

### **7. Paediatric patient-specific dosimetry**

#### **7.1 Individualized dosimetry**

Paediatric Dose Reference Levels (PDRLs) must be established, especially in a national level and then effective dose estimations from images data can be obtained. The calculated PDRLs may help in the standardization of the appropriate activity in paediatric nuclear medicine.

Individualized dosimetry and iterative algorithms may reduce further the administered dose resulting in safer children's examinations.

To limit radiation exposure to children from diagnostic nuclear medicine procedures to the lowest levels consistent with quality imaging, a study has been established [18] to correlate administered activity/weight- to an effective dose in paediatric nuclear medicine imaging.

In radiopharmaceutical schedules for children, fractions of adult administered amounts and formulae based on the child's body parameters are used. Recommended activities could also be obtained by EANM dosage-card or North American Guidelines.

The paediatric administered activities are determined by the formula that reduces adult administered activity as:

Paediatric dosage [MBq] = (Child Weight [Kg] x Adult Reference Activity [MBq])/70.

Radiopharmaceutical dosages for five diagnostic radiopharmaceuticals (Tc99m-DMSA, Tc99m-DTPA, Tc99m-MAG3, Tc99m-MDP & I123-MIBG) were calculated for 100 paediatric imaging procedures and administered in terms of activity/kg.

Knowledge of physical and biological parameters is required for the calculation of the absorbed dose.

Absorbed dose is the average deposition of energy in the tissue from the administered radiopharmaceutical.

The radioactive elements, used in the diagnosis, are distributed to the human body following the rules of pharmacokinetics & pathophysiology (**Figure 8**)*.*

The RADAR dosimetry program was used by Plousi et al [18] in order to estimate the effective dose per child per weight/age for various radioisotopes, with reduced reference adult activity being incorporated, **Figure 9**.

Weighting Factor of administered activities per weight (kg) were varied from (0.1–0.86%) for 3Kg weight of a neonate to 40Kg weight of an adult.

#### **Figure 8.**

*The absorbed dose depends on: The administered activity. The active time of its stay in an organ. The parameters fixed in time, that is: radioisotope characteristics, shape and size of the radiating organ (source), the irradiated organ (target) and the distance and mass of the target) [18].*


#### **Figure 9.**

*The absorbed dose in neonates is extremely higher (because the activity is distributed over smaller volumes). Significant differences -about a factor of two and sometimes three in activity and effective dose were measured between underweight, average weight and corpulent children of the same age [18].*

For neonates and infants' cases, a minimum administered activity is applied considering that the use of a fraction of the administered activity of adults would result in an uncompleted study. Planar whole-body and SPECT imaging studies were performed on a γ-camera equipped with a high-resolution collimator.

Regarding I123-MIBG, the lower limit [30 MBq for neonatal] and upper limit [110 MBq] was established to give the least effective dose with the best quality imaging.

For newborn cases, it is necessary to apply a minimum activity, as the activity calculated according to weight is less than the recommended minimum activity. When the suggested weight-based administered activities are used, the resulting effective doses range in ages 1–10 years old are, **Figure 10**.

Activities for Tc99m-DMSA for planar and 3D imaging are lowering as filtering and iterative reconstruction methods were used. In dynamic studies of paediatric patients, the SNMMI/EANM Guidelines for Diuresis Renography in infants and children were followed [19]. The lowest burden is estimated for Tc99m-MAG3.

Optimal protocols, with improved image reconstruction methods and advanced instrumentation, facilitate the dosage reduction and provide the maximum image quality at a minimum of effective dose [20].

A graphic relation of Administered Activity versus weight of all patient groups, from neonates to adolescents, is presented in **Figure 11A**.

In **Figure 11B**, a positive correlation of the effective dose (mSv) with patient ages (0–26years) is shown. No differences were observed between boys and girls of the same age [18].
