Biological effects of radiation

INTRODUCTION

• Radiation is all around us. It is naturally present in our environment & comes from outer space (cosmic), the ground (terrestrial), and even from within our own bodies.

• Certain foods such as bananas and brazil nuts naturally contain higher levels of radiation than other foods.

• Levels of natural or background radiation can vary greatly from one location to the next.

Typical Effective Radiation Dose from Diagnostic X Ray—Single Exposure

Typical Effective Radiation Dose from Nuclear Medicine Examination

• Radiation is of 2 types:– Ionizing (α, β, γ & x-rays)– Nonionizing (visible light, infrared, radiowaves)

• Ionizing radiation is subdivided into:– electromagnetic radiation (X-rays and γ rays) – particulate radiation (neutrons, alpha and beta

particles).

Radiation Biology History• 1895-Roentgen announces discovery of X-rays• 1896-(4 months later) Reports of skin effects

in x-ray researchers• 1902-First cases of radiation induced skin

cancer reported• 1906-Pattern for differential radiosensitivity of

tissues was discovered.

• Biological effects of ionizing radiation depend on several factors that make them variable and inconsistent.

• The effects are classified based on their nature and timing after exposure into– early or delayed, – somatic or hereditary, – stochastic or deterministic

Prompt Effects• High doses delivered to the whole body of healthy adults within short

periods of time can produce effects such as blood component changes, fatigue, diarrhea, nausea and death. These effects will develop within hours, days or weeks, depending on the size of the dose. The larger the dose, the sooner a given effect will occur.

Effect Dose

Blood count changes 50 rem

Vomiting (threshold) 100 rem

Mortality (threshold) 150 rem

LD50/60* (with minimal supportive care) 320 – 360 rem

LD50/60 (with supportive medical treatment) 480 – 540 rem

100% mortality (with best available treatment) 800 rem 

Delayed effects: • effects such as cataract formation and cancer

induction that may appear months or years after a radiation exposure

*average lifetime risk of death from cancer following an acute dose equivalent to all body organs of 0.1 Sv (10 rem) is estimated to be 0.8%. baseline risk of cancer induction in the United States is approximately 25%.

Another way of stating this risk is by considering the Relative Risk of a 1 in a million chance of death from some common activities:

· Smoking 1.4 cigarettes in a lifetime (lung cancer)· Eating 40 tablespoons of peanut butter (aflatoxin)· Spending two days in New York City (air pollution)· Driving 40 miles in a car (accident)· Flying 2500 miles in a jet (accident)· Canoeing for 6 minutes (drowning)· Receiving a dose of 10 mrem of radiation (cancer)

• Stochastic effects refer to random and unpredictable effects usually following chronic exposure to low dose radiation. E.g. Hereditary effects and carcinogenesis

Schematic development of the events leading to stochastic radiation effects

• Deterministic (non-stochastic) effects are non-random and have a highly predictable response to radiation. There is a threshold of radiation dose after which the response is dose-related. E.g. radiation-induced lung fibrosis and cataract

MECHANISMS OF RADIATION EFFECTS

Ionizing radiation exerts its effects on biological targets through two major mechanism:

Direct effect

• ionizing radiation acts by direct hits on target atoms.

• All atoms or molecules within the cells, such as enzymatic and structural proteins and RNA, are vulnerable to radiation injury but DNA is the principal target, in which ionizing radiation produces single or double-stranded chromosomal breaks.

• It is estimated that about one third of biological damage by γ radiation is caused by direct effects.

• This process becomes more dominant with high LET radiation, such as neutrons or α particles

Indirect Effect

• two-thirds of biological damage caused by low linear energy transfer (LET) radiation is due to indirect action

• Water Radiolysis absorption of energy depends on the abundance

of material in the path of the radiation. Water is the most predominant molecule in living organisms, therefore, a major proportion of radiation energy deposited will be absorbed in cellular water.

A complex series of chemical changes occurs in water after exposure to ionizing radiation. This process is called water radiolysis

• These primary water radicals have high reactivity towards molecules of cells, DNA, lipids and other subcellular constituents. In oxygenated solutions, hydrogen atoms can react with oxygen to give hydroperoxyl free radicals(HO2•)

• The relative yields of the water radiolysis products depend on the pH and LET of the radiation.

• The concentration of these radicals are expressed in terms of a G value which is defined as the number of radicals or molecules produced per 100 eV of energy absorbed in the medium

FACTORS AFFECTING RADIATION HAZARD

Factors Related to Ionizing Radiation

• Type of Radiation: – Various types of radiation differ in penetrability

based on LET. – This value is high for alpha particles, lower for

beta particles, and even less for gamma rays and X-rays. Thus alpha particles penetrate a short distance but induce heavy damage,

• Mode of Administration:– a single dose of radiation causes more damage

than the same dose being divided (fractionated)• Dose Rate: – The longer the duration for the same total dose,

the better the chance of cellular repair and the smaller the damage

Factors Related to Biological Target

• Radiosensitivity:– Radiosensitivity varies with the rate of mitosis and cellular

maturity. Blood-forming cells are very sensitive to radiation, while neurons, muscle and parathyroid cells are highly radioresistant. With in a given cell, the nucleus in general is relatively more radiosensitive than the cytoplasm.

– When cells in G0/G1phase of the cell cycle are exposed to radiation they tend to halt their progression into G2/M phase. G2 synchronization produces a cluster of radiosensitive cells. A second hit within a time frame of 5–12 h leads to a higher proportion of deleterious effects.

• Repair Capacity of Cells:

• Cell-Cycle Phase:– All phases of the cell cycle can be affected by ionizing radiation. Overall,

sensitivity appears to be greatest in G2 phase.– Recovery from sublethal damage occurs in all phases of the cell cycle.

However, this is most pronounced in the S phase, which is also the most radio-resistant phase

• Degree of Tissue Oxygenation:– Molecular oxygen is known to have the ability to potentiate the response

to radiation

MOLECULAR AND CELLULAR RADIOBIOLOGY

Radiation lesions in DNA

• Radiation causes a wide range of lesions in DNA such as – single strand breaks in the phosphodiester linkage, – double strand breaks on opposing sites or – base damage, – protein-DNA crosslinks and protein-protein

crosslinks involving nuclear proteins such as histones and non-histone proteins.

• The number of DNA lesions generated by irradiation is large, but the number giving rise to cell kill is extremely small. The numbers of lesions induced in the DNA of a cell by a dose of1-2 Gy are approximately: – base damages > 1000; – single strand breaks (ssb) ~1000; – double strand breaks (dsb) ~40.

• Dsb play a critical role in cell killing

Fate of Irradiated Cells

• No effect.• Division Delay• Apoptosis: cell death before it can divide.• Reproductive Failure: cell death when attempting MITOSIS.• Genomic Instability: delayed reproductive failure.• Mutation: cells contains mutation in genome.• Transformation: mutation leads to carcinogenesis.• Bystander Effects: damaged cell induces damage in

surrounding ones.• Adaptative Response: increased resistance to radiation.

• Genomic Instability:– Maximal radiation-induced genetic damage is

formed shortly (minutes to hours) after radiation exposure. Nevertheless, it has been observed that not only the irradiated cells but also descendents may show delayed effects.

– Cells that sustain non-lethal DNA damage show increased mutation rate in descendent cells several generations after the initial exposure

• Bystander Effect. – The cells in the vicinity of irradiated cells show effects

that cannot be attributed to targeting by ionizing radiation tracks. The mechanism is not clearly understood; however, gap junctional intercellular communication or release of soluble factors (such as cytokines) from irradiated cells has been proposed. Through cell-to-cell interaction, the directly irradiated cells communicate with adjacent cells and spread the effect of radiation to a larger number of cells.

Acute effects of radiation

• Acute Radiation Syndrome (ARS) is an acute illness caused by irradiation of the entire body (or most of the body) by a high dose of penetrating radiation in a very short period of time (usually a matter of minutes)

• conditions for Acute Radiation Syndrome (ARS) are:

• The radiation dose must be large (i.e., greater than 0.7 Gray (Gy)).– Mild symptoms may be observed with doses as low as 0.3 Gy or 30 rads.

• The dose usually must be external ( i.e., the source of radiation is outside of the patient’s body).– Radioactive materials deposited inside the body have produced some ARS

effects only in extremely rare cases.• The radiation must be penetrating (i.e., able to reach the internal organs).

– High energy X-rays, gamma rays, and neutrons are penetrating radiations.• The entire body (or a significant portion of it) must have received the

dose.– Most radiation injuries are local, frequently involving the hands, and these local

injuries seldom cause classical signs of ARS.• The dose must have been delivered in a short time (usually a matter of

minutes).– Fractionated doses are often used in radiation therapy. These are large total

doses delivered in small daily amounts over a period of time. Fractionated doses are less effective at inducing ARS than a single dose of the same magnitude.

stages of ARS

• Prodromal stage (N-V-D stage): The classic symptoms for this stage are nausea, vomiting, as well as anorexia and possibly diarrhea (depending on dose), which occur from minutes to days following exposure. The symptoms may last (episodically) for minutes up to several days.

• Latent stage: In this stage, the patient looks and feels generally healthy for a few hours or even up to a few weeks.

• Manifest illness stage: In this stage the symptoms depend on the specific syndrome and last from hours up to several months.

• Recovery or death: Most patients who do not recover will die within several months of exposure. The recovery process lasts from several weeks up to two years

three classic ARS Syndromes• Bone marrow syndrome (aka: hematopoietic syndrome) occur with a dose

between 0.7 and 10 Gy (70 – 1000 rads) though mild symptoms may occur as low as 0.3 Gy or 30 rads.– The survival rate of patients with this syndrome decreases with increasing dose.

The primary cause of death is the destruction of the bone marrow, resulting in infection and hemorrhage.

• Gastrointestinal (GI) syndrome: occur with a dose greater than approximately 10 Gy (1000 rads) although some symptoms may occur as low as 6 Gy or 600 rads.– Survival is extremely unlikely with this syndrome. Destructive and irreparable

changes in the GI tract and bone marrow usually cause infection, dehydration, and electrolyte imbalance. Death usually occurs within 2 weeks.

• Cardiovascular (CV)/ Central Nervous System (CNS) syndrome: occur with a dose greater than approximately 50 Gy (5000 rads) although some symptoms may occur as low as 20 Gy or 2000 rads.– Death occurs within 3 days. Death likely is due to collapse of the circulatory

system as well as increased pressure in the confining cranial vault as the result of increased fluid content caused by edema, vasculitis, and meningitis

Cutaneus radiation syndrome• It is possible to receive a damaging dose to the skin without

symptoms of ARS, especially with acute exposures to beta radiation or X-rays. Sometimes this occurs when radioactive materials contaminate a patient’s skin or clothes.

• When the basal cell layer of the skin is damaged by radiation, within a few hours after irradiation, a transient and inconsistent erythema (associated with itching) can occur. Then, a latent phase may occur and last from a few days up to several weeks, when intense reddening, blistering, and ulceration of the irradiated site are visible.

• In most cases, healing occurs by regenerative means; however, very large skin doses can cause permanent hair loss, damaged sebaceous and sweat glands, atrophy, fibrosis, decreased or increased skin pigmentation, and ulceration or necrosis of the exposed tissue.

Initial Treatment and Diagnostic Evaluation

• Treat vomiting, and repeat CBC analysis, with special attention to the lymphocyte count, every 2 to 3 hours for the first 8 to 12 hours following exposure (and every 4 to 6 hours for the following 2 or 3 days).

• Sequential changes in absolute lymphocyte counts over time are demonstrated in the Andrews Lymphocyte Nomogram

From Andrews GA, Auxier JA, Lushbaugh CC. The Importance of Dosimetry to the Medical Management of Persons Exposed to High Levels of Radiation. In Personal Dosimetry for Radiation Accidents. Vienna : International Atomic Energy Agency; 1965

• Patients with a minimal lymphocyte count (MLC) of 1000-1499/mm3 have an approximate absorbed dose of 0.5-1.9 Gy. prognosis is good because the absorbed dose is usually nonlethal.

• Patients with MLC of 500-999/mm3 have an approximate absorbed dose of 2.0-3.9 Gy. fair prognosis.

• MLC of 100-499/mm3 coincides with an approximate absorbed dose of 4.0-7.9 Gy. poor prognosis,

• MLC less than 100/mm3 have an estimated absorbed dose of greater than 8 Gy. high incidence of death despite bone marrow stimulation.

• Survival has not been documented for those exposed to greater than 10 Gy.

• Time to emesis:– Time to emesis (TE) correlates with exposure

dose, decreasing as exposure dose increases. – For TE less than 1 hour, whole-body dose

estimates are greater than 4 Gy. – For TE between 1 and 2 hours, whole-body dose is

estimated to be greater than 3 Gy. – for TE greater than 4 hours, whole-body dose is

estimated to be around 1 Gy.

Pharmacologic Therapy for Radiation Injury

• Enteral binding agents– Barium sulfate: Adult dose: 200 mL PO x 1 dose

Binds with strontium and radium– Aluminum and magnesium salts: Adult dose: 100

mL PO x 1 dose. Binds with strontium, radium, and phosphorous

– Activated charcoal

• Blockade of end-organ uptake– Potassium iodide: Adult dose: 130 mg PO daily (maximum: 1 dose in

24h) Duration of therapy: Continue daily dose until exposure risk has

passed and/or until other measures (eg, evacuation, sheltering, control of the food and milk supply) have been successfully implementedBlocks thyroid uptake of iodine and technetium

– Calcium gluconate: Adult dose: 3 g IV x 1 dose Blockade into bone by increasing urinary excretion of radioactive

strontium and calcium– Calcium chloride: Adult dose: 1 g IV x 1 dose Blockade into bone by increasing urinary excretion of radioactive

strontium and calcium

• Dilution– Oral fluids: Adult dose: 5-10 L PO/IV daily x 1wk

Excretion of tritium– Neutra Phos: Adult dose: 1 packet (diluted) PO

QID x 3d. Excretion of phosphorus– K Phos: Adult dose: 2 tablets PO QID x 3d.

Excretion of phosphorus

• Chelation– Pentetate trisodium salts(DTPA; Ca-DTPA within

24h, Zn-DTPA after 24h): Adult dose: 1 g IV in 250 mL saline/D5W daily. Chelates americium, uranium, plutonium, heavy metals

– Penicillamine: Adult dose: 250-500 mg PO QID. Chelates cobalt

– Prussian blue: Adult dose: 3 g PO TID; minimum 30-day treatment. Chelates cesium and thallium

• Decrease organ damage– Sodium bicarbonate: Adult dose: 2 mEq/kg IV x 1

dose. Nephroprotective for uranium

RADIATION AND PREGNANCY

Acute RadiationDose* to theEmbryo/Fetus

Time Post ConceptionBlastogenesis(up to 2 wks)

Organogenesis(2 –7 wks)

Fetogenesis(8–15 wks) (16 –25 wks) (26 –38 wks)

< 0.05 Gy (5 rads)† Noncancer health effects NOT detectable0.05–0.50 Gy (5–50 rads) Incidence of failure to

implant may increase slightly, but surviving embryos will probably have no significant (noncancer) health effects

• Incidence of major malformations may increase slightly

• Growth retardation possible

• Growth retardation possible

• Reduction in IQ possible (up to 15 points, depending on dose)

• Incidence of severe mental retardation up to 20%, depending on dose

Noncancer healtheffects unlikely

> 0.50 Gy (50 rads)

The expectant mother may be experiencing acute radiation syndrome in this range, depending on her whole-body dose.

Incidence of failure to implant will likely be large,‡depending on dose, but surviving embryos will probably have no significant (noncancer) health effects

• Incidence of miscarriage may increase, depending on dose

• Substantial risk of major malformations such as neurological and motor deficiencies

• Growth retardation likely

• Incidence of miscarriage probably will increase, depending on dose

• Growth retardation likely

• Reduction in IQ possible (> 15 points, depending on dose)

• Incidence of severe mental retardation > 20%, depending on dose

• Incidence of major malformations will probably increase

• Incidence of miscarriage may increase, depending on dose

• Growth retardation possible, depending on dose

• Reduction in IQ possible, depending on dose

• Severe mental retardation possible, depending on dose

• Incidence of major malformations may increase

Incidence of miscarriage and neonatal death will probably increase depending o

Radiation Dose Estimated Childhood Cancer Incidence* †

Estimated Lifetime‡ Cancer Incidence§(exposure at age 10)

No radiation exposure above background

0.3% 38%

0.00–0.05 Gy (0–5 rads) 0.3%–1% 38%–40%0.05–0.50 Gy (5–50 rads)

1%–6% 40%–55%

> 0.50 Gy (50 rads) > 6% > 55%

* Data published by the International Commission on Radiation Protection.

† Childhood cancer mortality is roughly half of childhood cancer incidence.

‡ The lifetime cancer risks from prenatal radiation exposure are not yet known. The lifetime risk estimates given are for Japanese males exposed at age 10 years from models published by the United Nations Scientific Committee on the Effects of Atomic Radiation.§ Lifetime cancer mortality is roughly one third of lifetime cancer incidence.

Estimated Risk for Cancer from Prenatal Radiation Exposure

RADIATION HORMESIS:

introduction

• There are threevmodels predicting relationships between the radiation dose and the effect of such an expo-sure to a biological target.

• The differences between these models arise from different underlying assumptions

• Linear-No Threshold Model: It assumes that any level of radiation is harmful and that the risk increases linearly with increments of dose. It is applied for radiation protection purposes and is meant to limit the risk to workers in radiation fields.

• ThresholdModel: It assumes that the risk of radiation is linearly related to the dose; however, this occurs only after a certain threshold level is exceeded. Below the threshold level no risk is to be expected. The theory behind the threshold level is that some degree of cellular damage should

accumulate and produce cell damage.

• Hormesis Model: In this model there is a bimodal effect of radiation, where below a certain threshold level radiation is protective, and harmful effects are seen only when this threshold is exceeded. The rationale is that radiation at low levels induces protective cellular mechanisms which prevent DNA damage occurring spontaneously or due to other stresses

definition

• Hormesis is a concept that describes the nature of dose-response relationships in biological systems as displaying a stimulatory response at low doses and an inhibitory response at higher doses.

• The probability of radiation induced adaptive protection measurably outweighs that of damage from doses well below 200 mGy low-LET radiation.

Note that mechanisms of DNA damage prevention and repair and the immune stimulation decrease after a maximum at doses between 0.1 Gy and 0.2 Gy, in contrast to apoptosis incidence that increases with dose

Single low-dose induced adaptive responses have dif-ferent times of duration depending on protective mechanisms that begin with a delay of several hours and may last for daysto weeks – and even up to months for immune response. Note that repair in response to radiation damage begins immediately after damage has occurred.