Radiation Biology Q & A

Radiation Biology Q & A Robert L. Metzger, Ph.D.

Radiobiology Q&A • How far does the average photon in an x-ray beam go before experiencing a collision?

Radiobiology Q&A • One Mean Free Path. • MFP= 1/ • The mean free path is the distance the average photon travels before making a collision.

Radiobiology Q&A • Does the spacing between collisions of monochromatic photons increase as a beam with good geometry penetrates tissue?

Radiobiology Q&A • Yes. The linear attenuation coefficient does not change appreciably with tissue depth, but the number of available photons does. If fewer photons survive, then the spacing between collisions must increase.

Radiobiology Q&A • What is the range of a beam of 100 keV electrons in soft tissue, give that the average LET is 1 keV/m?

Radiobiology Q&A • 100 keV = maximum range x 1 keV/m. • So the max range is 0.1 mm.

Radiobiology Q&A • Nine Gray of 250 kVp x-rays will kill 99% of the hamster fibroblast cellsin a petri dish. A 0.45 Gy dose of another radiation will do the same. What is the RBE of the second radiation?

Radiobiology Q&A • RBE is the energy required to produce a given effect (e.g.cell killing), as compared to 250 kVp x-rays. • So 9 Gy/0.45 = 20 • It must be an alpha particle.

Radiobiology Q&A X-ray produced chromosomal aberrations, such as dicentrics and rings, are generated as a consequence of: A. A single chromosomal break interacting with itself. B. Interaction of two separate chromosomal breaks. C. Two single strand breaks on the same chromosome. D. Misreplication events

Radiobiology Q&A This option is correct. The justification for this answer is a follows: Chromosomal aberrations that are generally lethal to the cell, result from the illegitimate recombination of double strand breaks in two chromosomes. A dicentric, as its name implies, has two centromeres, one from each of two separate chromosomes. It is impossible to get a complex aberration such as a dicentric or a ring from one chromosome break (hence option A is incorrect) as a result of misreplication events (hence option D is incorrect). Single strand breaks are readily repaired, unless there are breaks on opposite strands close together. Even when it would result only in one double strand break, it is not enough to produce an exchange type aberration

Radiobiology Q&A For how long after a total body exposure of 1 Gy do detectable chromosomal aberrations persist in peripheral lymphocytes? A.Days B.Weeks C.Months D.Years

Radiobiology Q&A You answered D: After a total body exposure of 1 Gy detectable chromosomal aberrations persist in peripheral lymphocytes for years. This option is correct. The justification for this answer is as follows: Some chromosomal aberrations are potentially lethal, causing the cell to die when the cell attempts to divide (so called “unstable aberrations”). This includes, for example, a dicentric. Consequently, these aberrations are removed slowly over a long period of time, but it takes many years for them to disappear from human peripheral lymphocytes. Other chromosomal aberrations are commensurate with cell viability (so called stable aberrations). This includes symmetrical translocations, which are not removed over time since they do not cause a cell to die in attempting to divide. These aberrations can be detected by chromosome painting, i.e., fluorescent in situ hybridization, or FISH. Both dicentrics and translocations can still be detected in the A-bomb survivors who were exposed over 50 years ago, though the number of dicentrics has now decreased.

Radiobiology Q&A • A cell is considered to have retained its reproductive integrity following exposure to radiation, if: • DNA replication has occurred • It has undergone two mitoses • It is intact and functioning • It has produced a colony of 60 cells.

Radiobiology Q&A • For a given total dose of x rays, a protracted exposure at low dose rate is less effective in killing mammalian cells than an acute exposure at high dose rate, primarily because • Fewer free radicals are produced • The mitotic cell cycle is shortened • Ion pairs recombine during extended exposure • Repair of sublethal damage occurs during exposure

Radiobiology Q&A A protracted exposure allows more opportunity for the repair of sub-lethal damage, leading to a reduction in the number of cells killed by a given total dose. As for the other options: The number of free radicals produced depends on the dose, not in the time over which it is delivered (dose rate), so that option A is incorrect. Radiation tends to lengthen, rather than shorten the cell cycle, so option B is also incorrect.

Radiobiology Q&A • A cell is considered to have retained its reproductive integrity following exposure to radiation, if: • It has undergone two mitoses • DNA replication has occurred • It is intact and functioning • It has produced a colony of 60 cells.

Radiobiology Q&A A cell is said to have retained its reproductive integrity if it is capable of sustained proliferation, i.e. if it can grow into a macroscopic colony of perhaps 60 cells or more. Option A is incorrect, since after two divisions the colony would be tiny, consisting of only 4 cells. Exposure to radiation may cause chromosomal damage in a cell, which would cause it to die in attempting the next or a subsequent division; damaged cells can often go through a few divisions before they peter out. Cells doomed to die can synthesize DNA and become a giant cell; consequently option B is incorrect. Cells that are out of cycle can still function after substantial doses of radiation. If called upon to divide days or months later, they may die because their chromosomes are damaged. The ability to function is not, therefore, an indication that the cell has retained its reproductive integrity; consequently option C is incorrect.

Radiobiology Q&A • The most radiosensitive portion of the GI tract to cell killing is the: • Esophagus. • Stomach. • Small intestine. • Large intestine. • Oropharynx.

Radiobiology Q&A All of the G.I. tract is sensitive to both cell killing and to the induction of carcinomas by exposure to radiation. However, radiation sensitivity varies markedly between the midpoint and the ends: the esophagus, oropharynx, and rectum are relatively radiation-resistant, and the midpoints, including the stomach and small intestine, are more sensitive. The small intestine is the most sensitive portion of the GI tract to cell killing because of the rapidly proliferating cells of the mucosal epithelium in the crypts. These cells divide approximately once every 24 hours, making this the most rapidly proliferating tissue and one of the most radiosensitive tissues in the body. The relatively high sensitivity of the of the mucosal lining compared with the underlying components means that acute changes are of the most clinical significance and that late changes rarely occur.

Radiobiology Q&A • A radiologist develops a pronounced erythema of the hands 2 weeks after exposure. Which of the following is true? • The threshold dose for an erythema is 10 Gy • Thick lead gloves (0.5 mm Pb equivalent) would have prevented 90% of the dose. • The erythema is unlikely to be accompanied by a temporary epilation • Late erythema is usually followed by necrosis

Radiobiology Q&A Lead gloves, if they are thick, and contain a lead equivalent of 0.5 mm, do indeed stop 90% of the dose of diagnostic quality x rays. This answer is therefore a true statement. Thin flexible gloves would not be as protective. As for the other options... The threshold dose for a transient erythema is about 2 Gy, and for a main erythema reaction is about 6 Gy; consequently option A is incorrect. The threshold dose for a temporary epilation is only 3 Gy, lower than that for the main erythema reaction which appears at one and a half weeks post irradiation. Thus, the pronounced main erythema seen here is likely to be accompanied by a temporary epilation which makes option C incorrect. On the other hand, delayed necrosis requires a dose of about 12 Gy, much higher than that for a late erythema, so that option D is incorrect.

Radiobiology Q&A • What determines the time delay between exposure to radiation and death in the gastrointestinal and hematopoietic syndromes? • The proportion of stem cells sterilized • The lifetime of the mature functioning cells • The duration of the cell cycle of the stem cells • The mitotic delay in the stem cells

Radiobiology Q&A Both the gastrointestinal and hematopoietic syndromes result from the failure of a self-renewal system, the intestinal epithelium and the circulating blood elements respectively. In a classical self-renewal system, cells produced by cell division in the stem cell compartment then pass through a series of steps to differentiate before becoming functioning cells. Radiation kills some or all of the stem cells, cutting off the supply of cells to differentiate. This does not immediately compromise the well-being of the organism since the functioning cells are still in place. The problem arises sometime later when the differentiated functioning cells reach the end of their useful life and are removed; it then becomes evident that replacements are not available because of the damage to the stem cell compartment. Option B is correct; the life-time of the mature functioning cells determines the interval between exposure to radiation and the crisis that may result in death.

Radiobiology Q&A • Which of the following statements is true concerning total body irradiation of humans with an acute exposure to x rays? • The LD50/60 is between 3 and 5 Gy. • Seizures are likely if the dose exceeds 3 Gy. • The nadir in white cell count following a dose of 2 Gy will occur within 6 days. • Bone marrow transplants are likely to save individuals exposed to more than 15 Gy.

Radiobiology Q&A The LD50 is the lethal dose, 50%, i.e., the dose that would be lethal to half of an irradiated population. The subscript 60, refers to death within 60 days of exposure, indicating that it is death due to failure of the hematopoietic system. For a dose between 3 and 5 Gy this mode of death, also known as bone-marrow death is expected, so option A is correct. It is not clear that any dose will result in seizures, certainly not below doses commensurate with the cerebrovascular syndrome (100 Gy), so option B is incorrect.

Radiobiology Q&A • Transient erythema is seen as a consequence of exposure to a radiation dose of: • 0.25 Gy • 0.5 Gy • 1 Gy • 2 Gy

Radiobiology Q&A You answered D: Transient erythema is seen as a consequence of exposure to a radiation dose of 2 Gy. This answer is correct. The justification for is as follows: Erythema is an early reaction, similar to sunburn, caused by vasodilation, edema and loss of plasma constituents from capillaries. The approximate threshold dose is 2 Gy; consequently option D is correct.

Radiobiology Q&A • Following an acute x-ray exposure of 8 Gy, which appears first? • Main Erythema reaction • Permanent epilation • Dry desquamation • Telangiectasia

Radiobiology Q&A There is an ordered hierarchy in time and dose for the skin changes that occur following irradiation. Early transient erythema (2 to 24 hours) is followed by the main erythema reaction (1 ½ weeks) followed by epilation (3 weeks), desquamation (4 weeks), necrosis (>10 weeks), and telangiectasia (> 52 weeks). Option A is correct; erythema is the first observable reaction of the skin.

Radiobiology Q&A • Concerning radiation induced heritable effects, which of the following statements is true? • Radiation induced heritable changes are different from those that occur spontaneously. • Humans are much more sensitive than mice. • 10-20% of heritable changes in the population can be attributed to diagnostic radiation. • The double dose in the human is estimated to be 0.5 to 2.5 Sv (acute exposure).

Radiobiology Q&A The best quantitative data on heritable effects of radiation come from experiments with mice. The doubling dose, i.e. the radiation dose required to double the spontaneous mutation rate, was estimated by the BEIR V committee to be in the range 0.5 to 2.5 Sv, and by the UNSCEAR (1988) committee to be 1 Sv. Option D is therefore the correct answer. As for the other choices: Option A is incorrect because the heritable changes induced by radiation are indistinguishable from those that occur spontaneously; radiation simply increases the incidence. Data from the first generation offspring of the A-bomb survivors allow an estimate to be made of the doubling dose for the human, although it is not statistically significant. The estimated value is 1.58 Sv for an acute dose in humans, compared with the 1 Sv (or 0.5 to 2.5 Sv) for a protracted exposure in mice, i.e. humans appear to be rather more resistant than mice. Option B is therefore incorrect. This option is incorrect because the ICRP estimate for the risk of hereditary disorders is 0.6 x 10-2 per Sv. The GSD from diagnostic radiation is of the order of 300 mSv per annum, which corresponds to be a hereditary risk of only (0.6 x 10-2 Sv-1) x (3 x 10-4) Sv, or 0.00018%.

Radiobiology Q&A • Which statement is true concerning radiation-induced sterility? • 0.5 Gy acute dose of gamma rays can induce temporary sterility in males. • 1 Gy acute dose of gamma rays or more can induce permanent sterility in females. • Radiation induced permanent sterility in males leads to loss of libido. • Radiation induced sterility in females does not produce hormonal changes. • An acute dose of 2 Gy gamma rays will cause immediate sterility in males (i.e. no latent period).

Radiobiology Q&A The threshold for temporary sterility in males exposed to a single absorbed dose in the testes is about 0.15 Gy. Option A is therefore a true statement. As for the other options: As mentioned in the review, the threshold for permanent sterility in women is an acute absorbed dose in the range of 2.5 to 6 Gy. Option B is therefore incorrect. The induction of sterility by radiation in human males does not produce significant changes in hormone balance, libido, or physical capability. By contrast, pronounced hormonal changes, comparable to those associated with the natural menopause, accompany radiation-induced sterilization in females. Consequently, options C & D are incorrect. The effect of radiation on fertility is not apparent immediately, i.e. there is a latent period, because the postspermatogonial cells are relatively resistant compared with the sensitive stem cells. After exposure to a moderate dose of radiation, the individual remains fertile as long as mature sperm cells are available, but decreased fertility or even temporary sterility follows if these are used up. Option E is therefore incorrect.

Radiobiology Q&A • Which of the following statements is true concerning radiation oncogenesis? • Generally, the mean latent period for radiation-induced leukemia is about 20 years. • Children are less sensitive than adults to the induction of leukemia. • Benign neoplasms are not induced after irradiation. • Solid tumors induced by radiation may appear 50 years or more after exposure. • A whole-body dose of 0.1 Gy would be expected to increase the incidence of cancer from approximately 20% (the natural incidence) to approximately 30%.

Radiobiology Q&A Following exposure to whole body irradiation, an excess incidence of leukemia shows up within a few years, reaching a peak at 5 to 7 years; option A is therefore incorrect. By contrast to leukemia, solid tumors take longer to show up. However, as stated in the text, the excess risk for carcinogenesis apparently manifests itself as a lifelong elevation of the natural age-specific cancer risk. In the A-bomb survivors, for example, there is still an excess incidence of solid tumors today, more than 50 years after the exposure to radiation; option D is therefore correct. As for the other options, children and teenagers are much more sensitive than adults to radiation carcinogenesis. See figure 7 in the review material. Option B is therefore incorrect. Radiation induces benign as well as malignant tumors; the thyroid in children is the best example, where benign nodules as well as malignant tumors are common following an exposure to radiation. Option C is also incorrect. The risk estimate for radiation induced cancer, for the general population (which includes children), exposed to a single acute dose of low LET radiation, is 10% per Sv, (or Gy). A dose of 0.1 Gy would result in a 1% incidence of cancer, not to 10% as indicated in option E, which is therefore incorrect.

Radiobiology Q&A • Which of the following organs in a child is most sensitive to the induction of both benign and malignant tumors from low doses of x rays? • Bone • Brain • Thyroid • Extremities

Radiobiology Q&A You answered C: In a child the thyroid is the most sensitive organ to the induction of both benign and malignant tumors from low doses of x rays. This option is correct. The justification is as follows: Organs which contain larger proportions of cycling cells are generally the more radiogenic. Option C is therefore correct.

Radiobiology Q&A • The dose response relationship for solid tumors in the Japanese survivors used by the BEIR V and UNSCEAR committees has the form _____________. • linear no threshold • linear with threshold • quadratic no threshold • exponential • quadratic with threshold

Radiobiology Q&A The dose response relationship for solid tumors in the Atomic-bomb survivors, used by the national and international committees, is linear no threshold, i.e., the cancer incidence up to about 2.5 Sv increases in proportion to dose. There is no apparent threshold, i.e., there is no dose below which the risk is zero. This, of course, is an assumption since there are no data at very low doses. Adding a quadratic term in dose does not improve the fit to the data for solid tumors, though it does for leukemia

Radiobiology Q&A • In which age range are women least susceptible to radiation-induced breast cancer? • < 20 years • 20-29 years • 20-39 years • 40-49 years • > 49 years

Radiobiology Q&A For most malignancies, sensitivity to radiation-induced cancer is greatest in children and decreases with age. This age dependence for radiation-induced cancer is particularly striking for breast cancer. Young girls before the age of 10 years, and teenagers are most susceptible, with the incidence of radiation-induced cancer falling with age at the time of exposure.

Radiobiology Q&A • The ICRP estimate of the total number of cases of cancer of all types produced by a total body exposure of a working population to 1 Sv of low LET radiation at low dose-rate is closest to: • 4 in 102 • 4 in 103 • 4 in 104 • 4 in 105

Radiobiology Q&A The ICRP suggest risk estimates for fatal radiation induced cancer, which vary for the general population (including children) versus a working population (no children below 18 years of age), and for high dose-rate versus low dose-rate. For the situation in this question, a working population exposed at low dose-rate, the risk is 4% / Sv. Option A is therefore correct.

Radiobiology Q&A • Which of the following is considered to be a deterministic effect of radiation? • Leukemia • Opacification of the ocular lens • Carcinoma of the prostate • Mutation in a second generation offspring

Radiobiology Q&A A stochastic effect is an all-or-nothing effect, i.e., the severity of the effect does not vary with dose, though the probability of it occurring is dose dependent. A stochastic effect is believed to be due to damage to one or a few cells, and there is no threshold in dose. Radiation induced leukemia, cancer, and hereditary effects fall into this category. By contrast a deterministic effect has a threshold in dose, and above this threshold the severity of the effect increases with dose. It is believed to be due to damage to many cells. A Cataract, i.e. an opacity of the ocular lens, falls into this category. Option B is therefore correct

Radiobiology Q&A • The minimum single acute dose of x rays that will result in a cataract is closest to: • 0.5 Gy • 1.0 Gy • 2.0 Gy • 4.0 Gy

Radiobiology Q&A • An acute exposure of 1 Gy to the embryo/fetus at 1 week gestation age is most likely to result in: • Congenital anomalies • Microcephaly • Embryonic death • Mental retardation

Radiobiology Q&A Gestation is divided into preimplantation, organogenesis, and the fetal period. In humans, these periods correspond to about 0 through 9 days, 10 days through 6 weeks, and 6 weeks through term, respectively. Irradiation during preimplantation leads to death of the embryo. Growth retardation or malformations are generally not seen in animals at this time. The human data are consistent with this conclusion. In humans, mental retardation is one of the most important endpoints observed, but this is typically not observed before 7 weeks gestation, and reaches a peak at 8 to 15 weeks. Consequently, option C is correct.

Radiobiology Q&A • The most likely consequence of an acute radiation dose of 0.5 Gy during the 8 to 15 week gestation period is: • Fetal death • Mental retardation • Childhood malignancy • Congenital heart disease

Radiation Biology Q & A