3.8 Acute Effects:TBI and Radiation Induced Cancer Cheat Sheet (DRAFT) by Molly

Acute Radiation Syndrome (ARS) (sometimes known as radiation toxicity or radiation sickness) 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).

Examples of people who suffered from ARS are the survivors of the Hiroshima and Nagasaki atomic bombs, the firefi­ghters that first responded after the Chernobyl Nuclear Power Plant event in 1986, and some uninte­ntional exposures to steril­isation irradi­ators.

1. Prodromal stage (N-V-D stage): Symptoms appear soon after irradi­ation and last for a limited period of time. 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.

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

The time of onset, severity and duration of symptoms, and the survival time and ultimate mode of death depend on the total radiation dose. In mammals three distinct modes of death can be identified although overlap frequently occurs. The three classic ARS Syndromes:

At very high radiation doses, (>100 Gy), death occurs in a matter of hours and appears to result from neurol­ogical and cardio­vas­cular breakdown.

For doses >20 Gy, severe nausea and vomiting occur within minutes followed by disori­ent­ation, loss of coordi­nation, respir­atory distress, diarrhea, convul­sions, coma and finally death.

It is believed that death results from build- up of pressure within the skull as a result of an increase in fluid content of the brain due to leakage from small vessels.

At radiation doses between 5 and 12 Gy, death occurs in a matter of days (usually 3 to 10) and is associated with extensive bloody diarrhea and destru­ction of the gastro­int­estinal mucosa.

The cells at the top of the folds of villi are contin­uously sloughed off and cells that originate from mitosis in the crypts contin­uously replace the villi. The radiation kills large propor­tions of the dividing cells and eventually the surface lining of the intestine will be completely denuded of villi.

Actively dividing precursor cells in the bone marrow are sterilised by the radiation and the subsequent supply of mature red cells, white cells, and platelets is dimini­shed. The critical time when the number of circul­ating cells in the blood reaches a minimum value occurs some weeks after the radiation dose.

Humans develop signs of haemat­olo­gical damage and recover from it much more slowly than all other mammals.

Many attempts have been made to estimate LD50/60 for man based on the experience of Hiroshima and Nagasaki, the total-body irradi­ation of patients with malignant disease, and nuclear accidents.

Bone marrow transp­lan­tation techniques are used routinely to ‘rescue’ patients given supra-­lethal doses of radiation for the treatment of leukemia or in prepar­ation for organ transp­lants. In such cases, the dosimetry is accurate and the doses are just enough to suppress the immuno­logical response. Typically, doses are 12 Gy in six fractions over three days, the two daily fractions being given about eight hours apart.

This in turn makes it difficult to provide optimum treatment. Patient management is usually conser­vative and treatment is instituted only in response to specific symptoms, that is, antibi­otics for infection, intrav­enous fluids for dehydr­ation and platelet infusion for bleeding.

Late effects of radiation are due to damage to cells that survive but retain some legacy of the radiation exposure which remains unapparent for prolonged periods of time.

On the other hand, irradi­ation of a somatic cell (any cell that has the diploid number of chromo­somes) may result in leukemia or cancer in the exposed indivi­dual.

Following cellular damage, two different outcomes are possible. These are known as either stochastic effects or determ­inistic effects.

Genetic effects and carcin­oge­nesis are said to be stochastic effects. In this case, there is no dose threshold and the effect is all or nothing.

The effects include cataracts, organ atrophy and fibrosis. There is a dose threshold and above this the severity of the biological response in the individual increases as the dose increases.

Cancer induction is generally considered the most important effect of low to interm­ediate doses of radiation in human popula­tions.

Other examples include the Japanese survivors from Hiroshima and Nagasaki, and patients given radiot­herapy to the spine for ankylosing spondy­litis (a chronic inflam­matory disease affecting the spine with eventual fusion -ankyl­osis- of the involved joints).

Physicists and engineers who worked around linear accele­rators before radiation safety standards were introduced suffered horrendous damage to their skin. Children who were given radiot­herapy for scalp epilation so that ringworm could be treated with drugs also developed skin cancer. This arose only in white children and involved areas of the face and scalp which were also subjected to sunlight.

Pitchb­lende and uranium miners developed lung cancer from inhalation of radon gas (α- emitter, high LET radiation) which became perman­ently deposited in the lung.

The lumino­us-dial painters of the early 20th century ingested radium (α-emi­tter) by pointing their brushes with their lips. The radium substi­tuted for calcium in areas of growing bone and ultimately produced cancer in this site. Similarly, patients injected with radium salts for the treatment of either tuberc­ulosis (a chronic granul­omatous infection usually affecting the lungs) or ankylosing spondy­litis also developed bone cancer.

In the past, patients were given the contrast material ‘Thoro­trast’ which contained thorium (α-emi­tter) and deposited in the liver producing tumours in this organ.

In children given radiot­herapy for suspected enlarged thymus, the treatment field included the thyroid area and so thyroid cancer often resulted from these proced­ures. Both malignant and benign thyroid tumours were observed. Thyroid cancer also resulted from radiot­herapy of children for scalp epilation (see skin cancer above).

When tuberc­ulosis was widesp­read, patients often underwent fluoro­scopy many hundreds of times during artificial pneumo­thorax. Pneumo­thorax is a collection of air or gas in the pleural space causing the lung to collapse and past therap­eutic methods for TB. patients included induced pneumo­thorax in an attempt to kill the infection through lack of oxygen. An increase in breast cancer in female patients was observed as a result of this technique. Also, patients who received radiot­herapy for postpartum mastitis (breast infection after child-­birth) also showed an increase in breast cancer.

Cancer formation is believed to be initiated by a somatic mutation produced in a single cell by ionising radiation or chemical carcin­ogens.

Tissue typically contains 10^{9 cells per gram. Therefore, if the cells divide at regular intervals then it will take 30 ‘doubling times’ to produce a mass of one cubic centimetre containing approx­imately 1000 million cells (230 = 1.07 x 10}9). The doubling time is, as it implies, the time taken to double the number of cells present and takes into consid­eration the cell cycle time and the natural programmed death of cells.

After 40 doubling times, the mass would be about one kilogram and signif­icant clinical changes would be apparent.

Therefore, the time from one cell to one gram is at least twice the length of time from one gram to death. This means that the tumour may have spent two-thirds of its history before being detected.

The ‘One Cell’ Theory helps us to explain the existence of a ‘latent period’ which is the time between the irradi­ation and the appearance of a tumour.

In the survivors of Hiroshima and Nagasaki, leukemia cases appeared within a few years, peaked between 7-12 years and essent­ially disapp­eared after 20 years.

For example, if the doubling time for a tumour is 100 days, it will take over eight years to grow to a diagno­sable mass of one gram. The cancer can, of course, spread to a secondary site at any stage during this period. If this metastasis grows at a similar rate, it too would take over eight years to be detected, and this would also help to explain how second­aries sometimes appear many years after the apparently successful removal of a primary tumour.

Dose is an important factor in carcin­oge­nesis.

High doses: The doses used in radiot­herapy are a special case. There are confli­cting reports of cancer risk, compounded by the higher second cancer risk expected in the population due to their genetic and enviro­nmental factors.

There is some evidence that lower dose rates, or fracti­onated doses, may cause less carcin­oge­nesis than a single dose at a high dose rate. This effect­ively halves the risk for lower dose rates when compared with high dose rates.

Dose is an important factor in carcin­oge­nesis.

High doses: The doses used in radiot­herapy are a special case. There are confli­cting reports of cancer risk, compounded by the higher second cancer risk expected in the population due to their genetic and enviro­nmental factors.

There is some evidence that lower dose rates, or fracti­onated doses, may cause less carcin­oge­nesis than a single dose at a high dose rate. This effect­ively halves the risk for lower dose rates when compared with high dose rates.

Dose is an important factor in carcin­oge­nesis.

High doses: The doses used in radiot­herapy are a special case. There are confli­cting reports of cancer risk, compounded by the higher second cancer risk expected in the population due to their genetic and enviro­nmental factors.

There is some evidence that lower dose rates, or fracti­onated doses, may cause less carcin­oge­nesis than a single dose at a high dose rate. This effect­ively halves the risk for lower dose rates when compared with high dose rates.

Dose is an important factor in carcin­oge­nesis.

High doses: The doses used in radiot­herapy are a special case. There are confli­cting reports of cancer risk, compounded by the higher second cancer risk expected in the population due to their genetic and enviro­nmental factors.

There is some evidence that lower dose rates, or fracti­onated doses, may cause less carcin­oge­nesis than a single dose at a high dose rate. This effect­ively halves the risk for lower dose rates when compared with high dose rates.

Dose is an important factor in carcin­oge­nesis.

High doses: The doses used in radiot­herapy are a special case. There are confli­cting reports of cancer risk, compounded by the higher second cancer risk expected in the population due to their genetic and enviro­nmental factors.

There is some evidence that lower dose rates, or fracti­onated doses, may cause less carcin­oge­nesis than a single dose at a high dose rate. This effect­ively halves the risk for lower dose rates when compared with high dose rates.

Most data on carcin­oge­nesis in humans involve relatively small numbers of indivi­duals who received relatively large doses of radiation.

Various models can be used to extrap­olate high dose data on cancer incidence to the low dose region, so that risk estimates can be made.

In the altern­ative linear­-qu­adratic relati­onship, the excess cancer incidence is propor­tional to the dose and the dose squared. You can see that this implies a smaller risk at low doses compared to the linear relati­onship.

Estimates are usually expressed as the number of excess (radia­tio­n-i­nduced) cases of cancer in an exposed population per unit dose. The radiation dose can be the result of exposure to x-rays, neutrons, α-part­icles and as we have seen earlier, the relative biological effect­iveness (RBE) of various radiations are often quite different.

The term Radiation Weighting Factor (WR) has been introduced for this purpose and the equivalent dose is obtained by multip­lying the absorbed dose by WR. When the absorbed dose is in Grays (Gy), equivalent dose is in Sieverts (Sv).

For the purposes of radiation protection in radiot­herapy, diagnostic radiology and nuclear medicine, the radiation weighting factor WR is unity since the radiations involved are generally only x-rays, gamma-rays and electrons. In these circum­sta­nces, an absorbed dose of 10 mGy will result in an equivalent dose of 10 mSv.

For low dose radiation accumu­lated at low dose rate, the numerical risk is estimated to be:

5.0 × 10^{-2 Sv}-1 for the whole population