Radiation Biology

Radiation Biology Robert Metzger, Ph.D.

Biologic Effects • Many factors determine the biologic response to radiation exposure • Radiosensitivity and complexity of the biologic system determine the type of response from a given exposure • Usually complex organisms exhibit more sophisticated repair mechanisms • Some responses appear instantaneously, others weeks to decades c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 814.

Classification of Bio Effects • Biologic effects of radiation exposure can be classified as either stochastic or deterministic (non-stochastic) • Stochastic Effect • The probability of the effect, rather than its severity, ↑ with dose • Radiation-induced cancer and genetic effects • Basic assumption: risk ↑ with dose and no threshold • Injury to a few cells or even a single cell can theoretically result in manifestation of disease • The principal health risk from low-dose radiation

Classification of Bio Effects • Deterministic or Non-stochastic Effect • Predominant biologic effect is cell killing resulting in degenerative changes to the exposed tissue • Severity of the effect, rather than its probability, ↑ with dose • Require much higher dose to produce an effect • Threshold dose below which the effect is not seen • Cataracts, erythyma, fibrosis, and hematopoietic damage are some deterministic effects • Dx radiology: only observed in some lengthy, fluoroscopically guided interventional procedures

Interaction of Radiation with Tissue • Ionizing radiation energy deposited randomly and rapidly (< 10-10 sec) via excitation, ionization & thermal heating • Interactions producing biologic changes classified as either direct or indirect • Direct • Critical targets (e.g., DNA, RNA or protein) directly ionized or excited • Indirect • Radiation interacts within the medium (e.g., cytoplasm) creating reactive chemical species (free radicals) which in turn interact with the a critical target macromolecule

Interaction of Radiation with Tissue • Vast majority of interactions are indirect (body 70% - 85% water) • Results in an unstable ion pair, H2O+, H2O- • Dissociate into another ion and a free radical (lifetime is less than 10-5) • H2O+ H+ + OH• • H2O-  H• + OH- • Combine w/ other free radicals to form molecules such as hydrogen peroxide (H2O2) → highly toxic to cell • Oxygen enhances free radical damage via production of reactive oxygen species (e.g., H• + O2 → HO2•)

Interaction of Radiation with Tissue c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 816.

Linear Energy Transfer • Biological effect dependent on the dose, dose rate, environmental conditions, radiosensitivity and the spatial distribution of energy deposition • Linear Energy Transfer (LET) • Amount of energy deposited per unit length (eV/cm) • LET  q2/KE • Describes the energy deposition density which largely determines the biologic consequence of radiation exposure • High LET radiation: α2+, p+, and other heavy ions • Low LET radiation: • Electrons (e-, β- and β+) • EM radiation (x-rays or g-rays) • High LET >> damaging than low LET radiation

Relative Biological Effectiveness (RBE) • Although all ionizing radiation capable of producing a specific biological effect, the magnitude/dose differs • Compare dose required to produce the same specific biologic response as a reference radiation dose (typically 250 kVp x-rays): Relative Biological Effectiveness (RBE) • Essential in establishing radiation weighting factors (wR) • X-rays/gamma rays/electrons: LET ≈ 2 keV/μm; wR = 1 • Protons (< 2MeV): LET ≈ 20 keV/μm; wR = 5-10 • Neutrons (E dep.): LET ≈ 4-20 keV/μm; wR = 5-20 • Alpha Particle: LET ≈ 40 keV/μm; wR = 20 • H (equivalent dose, Sv) = D (absorbed dose, Gy) ∙ wR

LET vs. RBE c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 817.

Cellular Targets • Radiation-sensitive targets are located in the nucleus and not the cytoplasm of the cell • Cell death may occur if key macromolecules (e.g., DNA) which have no replacement are damaged or destroyed • Considerable evidence that damage to DNA is the primary cause of radiation-induced cell death • Concept of key or critical targets has led to a model of radiation-induced cellular damage termed target theory in which critical targets may be inactivated by one or more ionization events (hits)

Radiation Effects on DNA c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 819.

Cellular Radiosensitivity • Studied through radiation-induced cell death (loss of reproductive integrity) • Useful in assessing the relative biologic impact of various types of radiation and exposure conditions • Cellular inability to form colonies as a function of radiation exposure → cell survival curves • Three parameters defining response to radiation: n, Dq and D0 c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 822.

Cell Survival Cures: n • n: Extrapolation number - found by extrapolating the linear portion of the curve back through the y-axis Represents either the number of targets in a cell that must be “hit” once by a radiation event to inactivate the cell or the number of “hits” required on a single critical target to inactivate the cell • For mammalian cells: [2,10] c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 822.

Cell Survival Curves: D0 • D0: Mean lethal dose • Radiosensitivity of the cell population under study • Dose producing a 63% (1-e-1) reduction in viable cell number: slope = Δy/Δx = .63/D0 (e ≈ 2.72; e-1 = 0.37) •  reciprocal linear region slope • Radioresistant cell D0 > radiosensitive cell D0 • ↓ D0 → lesser survival/dose • Mammalian cells: [1Gy,2Gy] c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 822.

Cell Survival Curves: Dq • Dq: Quasithreshold dose (Dq = D0 · logen) • Width of the shoulder region and a measure of sublethal damage • Irradiated cells remain viable until enough hits received to inactivate the critical target or targets • Clear evidence that for low-LET radiation, damage produced by a single radiation interaction with cellular critical target(s) is insufficient to produce reproductive death c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 822.

Factors Affecting Cellular Radiosensitivity • Conditional factors - physical or chemicals factors that exist previous to and/or at irradiation • Dose rate • LET • Fractionation • Presence of oxygen • Inherent factors - biologic factors characteristic of the cell • Mitotic rate • Degree of differentiation • Cell cycle phase

Conditional Factors-Dose Rate Which has highest D0? Which has highest n? Which has highest Dq? c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 823.

Conditional Factors-LET c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 824.

Conditional Factors-Fractionation c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 825.

Conditional Factors-Presence of Oxygen • Increases cell damage by inhibiting • Free radical recombination to form harmless chemical species • Repair of damage caused by free radicals • Oxygen enhancement ratio (OER): ratio of dose producing a given biologic response in the absence of oxygen to that in the presence of oxygen • Mammalian cells • Low-LET: [2,3] • High-LET: [1,2]

Conditional Factors - Oxygen Conditional Factors- Oxygen c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p.

Inherent Factors: Law of Bergonie & Tribondeau • Radiosensitivity greatest for cells with • High mitotic rate • Long mitotic future • Undifferentiated c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 826.

Inherent Factors-Cell Cycle Phase • Cells are most sensitive to radiation during mitosis (M phase) and RNA synthesis (G2 phase) • Less sensitive during the preparatory period for DNA synthesis (G1 phase) • Least sensitive during DNA synthesis (S phase) • During mitosis (M), the metaphase is the most sensitive c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 827.

Davis Notes-Radiation Biology • 4. The quasi-threshold dose (Dq) for cell line C is: • A. 500 • B. 700 • C. 1,000 • D. 1,500 • E. impossible to determine from this data

Huda 2nd Edition-Chapter 10-Radiation Biology • 1. Radiological LD50 is the radiation dose that kills: • (A) 50% of exposed cells • (B) 50 exposed cells • (C) All exposed cells within 50 days • (D) e-50 of exposed cells • (E) e/50 of exposed cells

Huda 2nd Edition-Chapter 10-Radiation Biology • 10. Stochastic effects of radiation • (A) Can be recognized as caused by radiation • (B) Have a dose-dependent severity • (C) Have a threshold of 50 mSv/year • (D) Include carcinogenesis • (E) Involve cell killing

Huda 2nd Edition-Chapter 10-Radiation Biology • 5. The LET of x-rays is: • (A) Between 0.3 and 3 keV/μm • (B) Cannot be defined for energies greater than 2 MeV • (C) Greater than the LET for alpha particles • (E) Low energy threshold • (D) Independent of relative biological effectiveness (RBE)

Huda 2nd Edition-Chapter 10-Radiation Biology • 4. Which is not true of the interaction of ionizing radiation with tissues? • (A) Cellular DNA is a key target • (B) Direct action is more frequent than indirect action • (D) Ions can dissociate into free radicals • (E) It can produce chromosome aberrations • (C) Indirect action causes most of the biological damage

Huda 2nd Edition-Chapter 10-Radiation Biology • 3. Which cells are considered to be the least radiosensitive? • (A) Bone marrow cells • (B) Lymphoid tissues • (C) Neuronal cells • (D) Skin cells • (E) Spermatids

Huda 2nd Edition-Chapter 10-Radiation Biology • 2. The cell division stage most sensitive to radiation is: • (A) Anaphase • (B) Interphase • (C) Metaphase • (D) Prophase • (E) Telophase

Organ Systems Response: Regenerization and Repair c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 828.

Organ Systems Response: Skin c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 830.

Organ Systems Response: Reproductive System • Gonads are very radiosensitive • Females • Temporary sterility: 1.5 Gy (150 rad) acute dose • Permanent sterility: 6.0 Gy (600 rad) acute dose* • *reported for doses as low as 3.2 Gy • Males • Temporary sterility: 2.5 Gy (250 rad) acute dose* • *reported for doses as low as 1.5 Gy • Permanent sterility: 5.0 Gy (500 rad) acute dose • Reduced fertility 20-50 mGy/wk (2-5 rad/wk) when total dose > 2.5 Gy

Organ Systems Response: Ocular Effects • Eye lens contains a population of radiosensitive cells • Cataract magnitude and probability of occurrence  to the dose • Acute doses • = 2 Gy (200 rad) cataracts in a small percentage of people exposed • > 7 Gy (700 rad = 700 cGy) always produce cataracts • Protracted exposure • 2 months: 4 Gy threshold • 4 months: 5.5 Gy threshold • Unlike senile cataracts that typically develop in the anterior pole of the lens radiation-induced cataracts begin with a small opacity in the posterior pole and migrate anteriorly

Acute Radiation Syndrome • Characteristic clinical response when whole body (or large part thereof) is subjected to a large acute external radiation exposure • Organism response quite distinct from isolated local radiation injuries such as epilation or skin ulcerations • Combination of subsyndromes occurring in stages over hours to weeks as the injury to various tissues and organs is expressed • In order of their occurrence with increasing radiation dose: • Hematopoietic syndrome • Gastrointestinal syndrome • Neurovascular syndrome

ARS Sequence of Events • Prodromal symptoms typically begin within 6 hours of exposure • No symptoms during the latent period, which may last up to 6 weeks for dose < 1 Gy • Manifest illness stage: onset of organ system damage clinical expression which can last 2-3 wks • Most difficult to manage from a therapeutic standpoint • Treatment during the first 6-8 wks essential to optimize recovery • Higher risk of cancer and genetic abnormalities in future progeny if patient survives c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., pp. 832-3.

Acute Radiation Syndrome Interrelationships c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 836.

Epidemiologic Investigations of Radiation Induced Cancer • Dose-response relationships for cancer induction at high dose and dose rate have been well established • Not so for low dose exposures like those resulting from diagnostic and occupational exposures • Very difficult to detect a small increase in the cancer rate due to radiation • Natural incidence of many forms of cancer is high • Latent period for most cancers is long • To rule out simple statistical fluctuations, a very large irradiated population is required

Difficulties in Quantifying Low Dose Risk • If excess risk proportional to dose, then large studies are required for low absorbed dose to maintain statistical precision and power; the necessary sample power increases approximately as the inverse square of dose • This relationship reflects a decline in the signal (radiation risk) to noise (natural background risk) ratio as dose decreases. • 500 persons needed to quantify the effect of a 1,000 mSv dose • 50,000 for a 100 mSv dose • 5 million for a 10 mSv dose (a single body CT = 7.5 mSv) SS = c/D2 National Research Council (1995) Radiation Dose Reconstruction for Epidemiologic Uses. Natl. Acad. Press

What is the Evidence? • Major epidemiological investigations that form the basis of current cancer dose-response estimates in human populations: • Atomic-bomb survivors (Japan) life span study (LSS) • Anklyosing spondylitis (UK) • Postpartum mastitis study (New York) • Radium dial painters (Tritium) • Thorotrast (radioactive Thorium x-ray contrast agent) • Massachusetts tuberculosis patients (multiple chest fluoroscopy) • Stanford University Hodgkin’s disease patients (x-ray therapy)

Risk Estimation Models Dose-Response Curves • Dose-response models predict cancer risk from exposure to low levels of ionizing radiation → dose-response curves • Linear, non-threshold (LNT) • Effect = α∙Dose • Linear-quadratic, non-threshold • Effect = α∙Dose + β∙Dose2 • α/β: [1Gy-10Gy] • appears linear for low dose • appears quadratic (non-linear) for higher dose c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 844.

Risk Estimation Models-Risk Models • Multiplicative risk model: after a latent period, the excess risk is a multiple of the natural age-specific cancer risk for the population in question • Additive risk model: fixed or constant increase in risk unrelated to the spontaneous age-specific cancer risk at the time of exposure • Latency periods: • Leukemia 10 yrs average • Solid tumors 25 yrs average c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 845.

Risk Estimation Models-Risk Expression • Relative Risk • Ratio of the cancer incidence in the exposed population to that in the general (unexposed) population • RR of 1.2 would indicate 20% increase over the spontaneous rate • Excess relative risk is simply RR - 1 • Absolute Risk • Expressed as the number of excess radiation-induced cancers per 104 people/Sv-yr • For a cancer with a radiation-induced risk of 4 per 10,000 person/Sv-yr and a latency period of 20 years, the risk of developing cancer from a dose of 0.1 Sv (~13x body CT dose) within the next 40 years would be: • (40-20) or 20 years x 0.1 Sv x 4 per 10,000 person/Sv-yr • = 8 per 10,000 or 0.08%

Radiation Standards Organizations • Independent bodies of experts evaluate information on radiation health effects • BIER - National Academy of Sciences/National Research Council Committee on the Biological Effects of Ionizing Radiation • UNSCEAR - United Nations Scientific Committee on the Effects of Radiation • RERF - Radiation Effects Research Foundation • Experts draw upon this collective knowledge to develop recommendations for systems of radiation protection • NCRP – National Council on Radiation Protection and Measurements • ICRP – International Commission on Radiological Protection • Radiation protection regulatory framework • NRC – Nuclear Regulatory Commission • EPA - Environmental Protection Agency

BEIR V Risk Estimates • BEIR published a report in 1990 entitled, “The Health Effects of Exposure to Low Levels of Ionizing Radiation” or the BEIR V report • Single best estimate of radiation-induced mortality at low exposure levels is 4% per Sv (0.04% per rem) for a working population (ICRP - 5% per Sv for the whole population - takes children into account) • The single best estimate of radiation-induced mortality at high doses applied at high dose rate is 8% per Sv (0.08% per rem) • The BEIR V Committee believed that the LNT dose-response model was best for all cancers except leukemia and bone cancer; for those malignancies, a linear-quadratic model was recommended • According to the LNT model, an exposure of 10,000 people to 10 mSv would result in approximately 4 cancer deaths in addition to the 2,200 (22%) normally expected in the general population

ACRP 60 Risk Estimates c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 847.

Specific Cancer Risk Estimates: Leukemia • Natural incidence in US population: 1 in 104 (0.01%) • 17% of total mortality from radiocarcinogenesis • The incidence of leukemia greatly influenced by age at the time of exposure • BEIR V: nonlinear dose-response model predicting excess life-time risk of 10 in 104 (0.1%) after exposure to 0.1 Gy (10 rad) • Average latent period = 10 yrs c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2nd ed., p. 849.

Specific Cancer Risk Estimates: Thyroid Cancer • 6-12% of total mortality from radiocarcinogenesis • Females 3-5x greater risk than males • Latency period • Benign nodules: 5-35 yrs • Thyroid malignancies: 10-35 yrs • Dose-response curve: LNT • Associated mortality rate: 5% • However, other responses such as hypothyroidism and thyroiditis with thresholds: • 2 Gy for external irradiation • 50 Gy for internal radiation (radioactive materials like 131I)

Specific Cancer Risk Estimates: Breast Cancer • One of 8 US women at risk of developing breast cancer • 180,000 new cases/yr • 1 in 30 women die of breast cancer • Low LET radiation risk age dependent, ≈ 50 times greater for the 15 yo age group (≈ 0.3% per year) after exposure of 0.1 Gy than those > 55 yo • The risk estimates for women in the 25, 35 and 45 yo age groups are 0.05%, 0.04% to 0.02% respectively (BEIR V) • Dose-response curve: LNT w/ dose of ≈ 0.8 Gy doubling the natural incidence • Latent period [10yrs,40yrs]; longer latencies with younger women

Radiation Biology