Learning Objectives Review of the Radiobiological Principles of 1. To understand the radiobiological basis Protection of standards. 2. To define the radiation protection magnitudes and units, their values and their practical measurement. Cari Borrás, D.Sc., FAAPM, FACR Radiological Physics and Health Services Consultant 3. To distinguish between and Washington DC, USA deterministic effects.

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Interaction of with Radiation Effects DNA, the critical target

Ionizing radiation cell nucleus interacts at the cellular level:

• ionization • chemical changes incident • biological effect radiation

chromosomes DIRECT ACTION INDIRECT ACTION http://rpop.iaea.org/ 3 http://rpop.iaea.org/ 4 Indirect action of radiation Direct action of radiation Consider

+ H2O  H2O + e • Predominant for high LET radiation, particulates Water molecule becomes ionized to a free (unpaired ) and an ion (loss of an electron). These are highly reactive, short lifetime • High LET interact predominately with nuclei H O+ + H O  H O+ + OH 2 2 3 • setting in motion more and other heavier nuclear particles • diffusion distance twice diameter of DNA helix • estimated 2/3 of x-ray damage in mammalian cells from • smaller particles () are produced which cause indirect damage but this is less significant c.f. direct action hydroxyl radicals • less indirect action for high LET radiation • chemical sensitizers exploit indirect damage • Not modified by sensitizers or protectors • protectors act against radicals

http://rpop.iaea.org/ 5 http://rpop.iaea.org/ 6

Outcomes after Cell Exposure DNA Damage Radiation hits cell Unviable Cell There are qualitative and quantitative nucleus! Cell dies differences in initial DNA damage caused by radiation

Cell mutates  DNA damage caused by radiation exhibits multiply damaged but mutation Viable Cell sites and clustered legions is repaired

 Double strand breaks are more common in radiation-induced damage than single strand breaks, which are more common ? in normal endogenous DNA damage. Cell survives but mutated

http://rpop.iaea.org/ 7 http://lowdose.energy.gov/pdf/Powerpoint_WEBBystander.pdf 8 10-15 Energy deposition How does radiation interact Excitation/ionization PHYSICAL INTERACTIONS -12 with cells? 10 Initial particle tracks Radical formation 10-9 Diffusion, chemical reactions PHYSICO-CHEMICAL INTERACTIONS

10-6 Initial DNA damage )

Past Theory Present Theories c


s ( -3 DNA breaks / base damage

Hit theory Bystander effects E 10 1 ms


I T 100 1 Radiation causes free Radiation causes free Repair processes radicals to damage only radicals to trigger cell-cell Damage fixation Timing of communication and cell- 103 BIOLOGICAL RESPONSE the cell that is “hit” by 1 Cell killing matrix communication to events direct ionization 1 Mutations/transformations/aberrations cells other than those 6 10 Proliferation of "damaged" cells which are “hit” by the 1 year Promotion/completion leading to direct ionization. 109 Teratogenesis MEDICAL EFFECTS radiation Cancer effects. 100 years Hereditary defects http://lowdose.energy.gov/pdf/Powerpoint_WEBBystander.pdf 9 10

The 2007 (ICRP 103) Recommendations RP Dosimetric Quantities and Units

▲ ICRP reviewed new data since 1991 ▲ Incorporate Exposures ▲ Changed • External • Radiation-weighting factors (w ) R • Internal • Tissue-weighting factors (wT) • Risk of cancer induction rather than mortality ▲ Are Different For: ▲ Did not change • Low doses of (low-LET) radiation < 0.5 Gy • Radiation protection principles, (i.e. LNT) o Stochastic (probabilistic) effects, LNT is applicable • Dose limits • Cancer induction • Radiation quantities and units, accepting ICRU • Hereditary operational quantities for compliance with dose limits High doses of radiation ▲ Emphasized dose constraints • o Tissue reactions (deterministic effects), threshold exists 11 12 RP Dosimetric Quantities and Units RP Dosimetric Quantities and Units Stochastic Effects Tissue Reactions Evolution of Terminology

Dose to Tissue = * RBE (Gy) ICRP 26 (1977) ICRP 60 (1991) ICRP 103 (2007)

# RBE : radiobiological effectiveness * Equivalent Dose differs for Effective Dose Effective Dose Effective Dose Equivalent • different biological endpoints and • different tissues or organs * No specific term # Radiation Weighted Dose proposed but not accepted The SI unit is J kg-1 and the special name is (Sv) 13 14

RP Dosimetric Quantities and Units Radiation Weighting Factors (ICRP 103) Stochastic Effects (Sv) Equivalent Dose, H , in a tissue T: Radiation type and energy range wR T 1 Electrons and 1 HT = ΣR wR D T,R Protons (1991, 2007), (2007) 2 wR is the radiation weighting factor, which accounts for Alpha particles, fission fragments, heavy ions 20 the detriment caused by different types of radiation

Neutrons, energy < 10 keV Continuous Function relative to 10 keV to 100 keV D T,R is the absorbed dose averaged over the tissue > 100 keV to 2 MeV T due to radiation R > 2 MeV to 20 MeV wR values are derived from in vivo and in vitro RBE studies > 20 MeV They are independent of dose and dose rate in the low dose region 15 16 RP Dosimetric Quantities and Units Stochastic Effects (Sv) Effective Dose, E

E = ΣT wT H T = ΣT ΣR wT wR D R,T

wT represents the relative contribution of that tissue or organ to the total detriment resulting from uniform irradiation of the body

ΣT wT = 1 A uniform dose distribution in the whole body gives an effective dose numerically equal to the radiation- weighted dose in each organ and tissue of the body 17 18

Tissue Weighting Factors RP Dosimetric Quantities and Units (ICRP 103) Tissue w ∑ w T T ▲ Incorporate Exposures -marrow (red), Colon, , , Breast, 0.12 0.72 • External Remainder Tissues* • Internal Gonads 0.08 0.08 Bladder, Oesophagus, , 0.04 0.16 Bone surface, Brain, Salivary glands, Skin 0.01 0.04 So far we have discussed external exposures

Total 1.00 Let´s see about exposures from * Remainder Tissues: Adrenals, Extrathoracic region, Gall bladder, Heart, Kidneys, Lymphatic nodes, Muscle, Oral mucosa, Pancreas, Prostate, Small intestine, Spleen, Thymus and Uterus/cervix

19 20 RP Dosimetric Quantities and Units RP Dosimetric Quantities and Units Activity, A Stochastic Effects (Sv) The activity A of an amount of a Committed Equivalent Dose in particular energy state at a given time t is For radionuclides A = d N / d t incorporated in the body

where d N is the expectation value of the where τ is the integration time following the intake at time t0 number of spontaneous nuclear transitions from that energy state in the time interval d t Committed Effective Dose τ The SI unit of activity is the (Bq) Adults: 50 y Children: 70 y 1 Bq = 1 s-1 21 22

Limitations of RP Operational Quantities - ICRU Equivalent and Effective Doses Dose Equivalent, H ▲ Are not directly measurable H = Q * D (Sv) ▲ Point quantities needed for area monitoring (in Where: D = Absorbed Dose a non-isotropic radiation field, effective dose Q = Quality Factor, function of L (LET) depends on the body’s orientation in that field) ∞ ▲ Instruments for need to be calibrated in terms of a measurable quantity for which calibration standards exist At a point in tissue:

Where: DL is the distribution of D in L for the charged Operational protection quantities are needed! particles contributing to D

23 24 Assessment of Effective Dose from Individual Monitoring Data

• Hp (10) personal dose equivalent from external exposure H*(10) and H (10) – photons > 12 keV and P • ej,inh(τ) is the committed effective dose coefficient for activity intakes by inhalation of radionuclide j HP (0.07) – α and β particles and doses to extremities • Ij,inh is the activity intake of radionuclide j by inhalation • ej,ing(τ) is the committed effective dose coefficient for Ω in RP usually not specified. Instead, activity intakes of radionuclide j by ingestion

Maximum H’(0.07, Ω) is obtained • Ij,ing is the activity intake of radionuclide j by ingestion by rotating meter seeking maximum reading

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RP Dosimetric Quantities and Units System of Quantities for Radiological Protection Stochastic Effects Absorbed dose, D Collective Effective Dose, S Dose Quantities Operational (due to Individual Effective Doses E and E ) 1 2 defined in the body Quantities For external exposure Equivalent dose, HT, in an organ or tissue T Dose quantities for area monitoring individual monitoring Effective dose, E • d N / d E : number of individuals who experience For internal exposure an effective dose between E and E + d E Committed doses, Activity quantities in • ΔT specifies the time period within which the HT (τ) and E(τ) combination with effective doses are summed Collective effective dose, S biokinetic models and 27 computations 28 RP Dosimetric Quantities and Units E is calculated averaging gender, age and individual sensitivity Caveats Effective Dose should not be used for

▲ Retrospective dose assessments ▲ Estimation of specific individual human exposures and risks ▲ Epidemiological studies without careful consideration of the uncertainties and limitations of the models and values used ICRP 29 30

RP Dosimetric Quantities and Units Effective Dose vs Organ Doses Caveats in Medical Exposures Dose to Individuals Effective Dose is an adequate parameter Absorbed doses to organs or tissues should be used with the most appropriate biokinetic to intercompare doses from different parameters, biological effectiveness of the ionizing radiation and risk factor data, taking radiological techniques into consideration the associated uncertainties. However, to assess individual risks it is Medical exposures fall in this category! necessary to determine organ doses

31 32 Methods for Determining Organ and Tissue Doses (ICRU 74, 2005)

▲ Measurements in physical phantoms ▲ Monte Carlo radiation transport calculations • Mathematical phantoms • Special features of the active • Voxel phantoms • Anthropometric phantoms

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▲ To prevent (deterministic) detrimental tissue effects

▲ To limit the probability of stochastic effects to levels deemed to be acceptable

BEIR VII, 2005 35 36 Deterministic Effects Effects of

Radiation effects for which generally a threshold Probability of Death level of dose exists above which the severity of the effect is greater for a higher dose. 100%

Stochastic Effects

Radiation effects, generally occurring without a Dose threshold level of dose, whose probability is proportional (mGy) Co-60 Radiotherapy to the dose and whose severity is independent of the dose. D Overexposure Panama 2000-2001

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Radiation Syndromes (Whole Body Exposures) Radiation-induced Acute Chronic Cardiovascular Annual Threshold: 0.5 Gy (3-7 days) ▲ Radiotherapy – well documented side Death: 1 Gy, 2-3 Gy with medical care radiation exposures effect of irradiation for , 6 Gy (6-9 days) exceeding Hodgkin’s disease, and peptic ulcer. 0.7 - 1.0 Gy and > 50 Gy cumulative ▲ A-bomb data – statistically significant doses > 2-3 Gy dose-related incidence. BMS over 2-3 years (hemato- poyetic ▲ – some evidence in the GIS system) LD50/60 (Acute) (gastro CNS Russian study on emergency workers for intestinal (central 3.3 to 4.5 Gy no medical management system) nervous a dose-related increase. system) 6 to 7 Gy with medical management

Dose 39 40 Excess Relative Risk of Heart Disease CVD vs Radiation Dose

▲ The Adult Health Study (AHS) of A-bomb survivors 0,6 showed a linear relationship between radiation dose and Peptic ulcer mortality from myocardial infarction more than 40 years 0,5 after exposure, with an excess relative risk (ERR) of 0.17 0,4 Preston et al 2003: (90% CI = 0.01 to 0.36) per Sievert. heart disease ERRsv 0.17 Preston et al 2003 ▲ 90% cl 0.08; 0.26 The Life Span Study (LSS) of A-bomb survivors revealed 0,3 p=0.001 data from Carr et a 2005 an ERR for death from heart disease of 0.14 (90% CI = A-bombs 0.05 to 0.22) per Sievert. 0,2 ▲ For patients with peptic ulcer given local radiotherapy to 0,1

the stomach including partial irradiation of the heart, the disease ERRheart of ERR increased from 0 to nearly 0.5 as the average dose to 0 the heart increased from 1 Gy to nearly 2 Gy. 0 0,5 1 1,5 2 2,5 3 -0,1 ▲ For patients given adjuvant radiotherapy for breast dose (Sv) cancer leading to partial irradiation of the heart, the ERR (Preston et al 2003: colon dose; was about 0.3 after an average effective-single dose of 1.5 Carr et al: corrected mean heart dose) Gy to the heart.

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Irradiation of Gonads From current evidence, a judgement can be Threshold doses for approximately 1% made of a threshold acute dose of about 0.5 Gy incidence in morbidity (or 500 mSv) for both and cerebrovascular disease. On that basis, 0.5 Gy may to approximately 1% of exposed individuals developing the disease in question, more than 10 years after exposure. This is in addition to the high natural incidence (circulatory diseases account for 30-50% of all deaths in most developed countries).

Draft ICRP on Tissue Effects. http://www.icrp.org/page.asp?id=116 Draft ICRP on Tissue Effects. http://www.icrp.org/page.asp?id=116 43 44 Skin Injuries Threshold doses for approximately Multiple 1% incidence in morbidity Coronary Angiography & Angioplasty Procedures USA, 1991

Industrial Irradiator Accident Draft ICRP on Tissue Effects Spain, 1998 El Salvador, 1989 45 Draft ICRP on Tissue Effects. http://www.icrp.org/page.asp?id=116 46

Eye Injuries



Di Paola, Bianchi, Baarli: Res 73, 340 (1978) 47 48 Increased Risk of Cortical and Posterior among Chernobyl Clean-Up Workers Subcapsular Formation

▲ Reanalysis of Atomic Bomb Survivors ▲ A Cohort Of Patients With Chronic Exposure to Low-dose-rate Radiation ▲ From -60 Contaminated in their Residences ▲ Studies of Children Exposed to Low Doses from the Chernobyl (Ukraine) Accident ▲ Chernobyl Clean-up Workers ▲ Commercial Airline Pilots ▲ Space Radiation Research 167, 233-243 (2007) 49 50

Threshold doses for approximately Dose Limits – ICRP 1991, 2007 1% incidence in morbidity For occupational exposure of workers over the age of 18 years

 An effective dose of 20 mSv per year averaged over five consecutive years (100 mSv in 5 years), and of 50 mSv in any single year;

 An equivalent dose to the lens of the eye of 150 mSv in a year;

 An equivalent dose to the extremities (hands and feet) or the skin of 500 mSv in a year For apprentices (16-18 years of age)

 effective dose of 6mSv in a year. Draft ICRP on Tissue Effects. http://www.icrp.org/page.asp?id=116 51 52 Evolution of Limitation of Exposure Dose Limits – ICRP 2011 Tolerance Dose limits (avoid deterministic harm) (minimize stochastic harm) For occupational exposure of workers over the 1000 ? age of 18 years 100 ?  An effective dose of 20 mSv per year averaged over ? ? five consecutive years (100 mSv in 5 years), and of ? 50 mSv in any single year; 10 Workers  An equivalent dose to the lens of the eye of 20 mSv 1st propos.1922 in a year; 1 Population introduced 1977  An equivalent dose to the extremities (hands and feet) or the skin of 500 mSv in a year 0.1 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 Year

For apprentices (16-18 years of age) Annual Dose recommended of Log mSv/y in Note, for the times indicated by a ? no recommendations existed  effective dose of 6mSv in a year. Also units have been approximately converted from those used earlier.

53 Courtesy J. Hendry 54

Deterministic Effects

Radiation effects for which generally a threshold level of dose exists above which the severity of the effect is greater for a higher dose. Stochastic Effects of Stochastic Effects Ionizing

Radiation effects, generally occurring without a Radiation threshold level of dose, whose probability is proportional to the dose and whose severity is independent of the dose.

Cancer Heritable Effects

55 http://rpop.iaea.org/ 56 of leukemia (cases/1 million) Thyroid cancer diagnosed up to 1998 among children 0-17 years at the time of the Chernobyl accident



200 Belarus Russian Federation 150 Ukraine Number 100 Total 1800


0 1990 1991 1992 1993 1994 1995 1996 1997 1998 Year Equivalent dose (mSv) http://rpop.iaea.org/ 57 http://rpop.iaea.org/ 58

What happens at the low-dose end of the graph? Dose and Dose-Rate Effectiveness Factor (DDREF) a) Linear extrapolation

b) Threshold dose A judged factor that generalizes the usually lower biological effectiveness [per unit of dose] c) Lower risk per of radiation exposures at low doses and low dose for low doses dose rates as compared with exposures at high d) Higher risk per dose doses and high dose rates) for for low doses ICRP is taking a value of 2 for the DDREF For radiation protection purposes, ICRP has chosen a), acknowledging that below 100 mSv or 0.1 Gy no BEIR VII chose a value of 1.5 deleterious effects have been detected in humans. 59 60 ICRP Detriment-Adjusted Nominal Scale of Radiation Exposures Risk Coefficient for Cancer (10-2 Sv-1 – Percent per Sievert)

Exposed ICRP 103 (2007) ICRP 60 (1991) Typical Bone scan Radiotherapy Population Cancer Induction Cancer Fatality CT scan Fraction

Annual Background Whole 5.5 6.0

Adult 4.1 4.8

61 http://rpop.iaea.org/ 62

Genetic Susceptibility to Cancer Genetic (Heritable) Effects There is evidence of: (Mutations) Fruit Fly ▲ Single gene human genetic disorders, where Experiments excess spontaneous cancer is expressed in a 10 Frequency (%) high proportion of gene carriers – the so-called high penetrance genes which can be strongly 5 expressed as excess cancer ▲ Variant genes of lower penetrance through 0 gene-gene and gene-environment interactions 10 20 30 40 can result in a highly variable expression of Absorbed dose (Gy) cancer following

63 64 Genetic Effects HERITABLE EFFECTS

▲ Ionizing radiation is known to cause hereditary should not be confused with mutations in many plants and animals BUT EFFECTS FOLLOWING

▲ Intensive studies of 70,000 offspring of the atomic bomb survivors have failed to identify an increase IRRADIATION IN UTERO in congenital anomalies, cancer, chromosome aberrations in circulating lymphocytes or some of which are deterministic; mutational blood protein changes. some, stochastic

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IRRADIATION IN UTERO Principles of Radiation Protection ICRP 103 (2007) General Medical Exposure Justification of Practices Normal Dose benefit to the exposed End Point Period incidence in benefits and risks of available Threshold individuals or to society to live-born alternative techniques that do outweigh the radiation Pre- not involve ionizing radiation? Death 100 mGy --- detriment? Implantation Major Dose Limitation Malformations 100 mGy 1 in 17 Organogenesis for occupational and public not applicable to medical Severe Mental 8 - 15 Weeks exposure exposure 300 mGy 1 in 200 Retardations Post-Conception Optimization of Protection In Utero Cancer Risk None* 1 in 1000 dose minimum necessary to Exposure ALARA achieve the required diagnostic * Lifetime cancer risk ~ 3 times that of the population as whole or therapeutic objective 67 68