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Tracee A. Block

Dr. R. Jaeger

Spring 2000

Toxicology

Radiation as a carcinogen was first established in December 1895 after Roentgen’s discovery of X-rays. In 1902, the first radiation induced cancer was reported emerging from an ulcerated area of the skin. By 1911, a large number of these such skin cancers were reported as well as the first report of leukemia occurring in five radiation workers (Little 2000). Following these discoveries, large-scale tumor induction studies were carried out in animal models over the following 30 years. These studies elucidated many of the general characteristics of radiation carcinogenesis. With the explosion of the atom bomb in Hiroshima and Nagasaki in 1945, scientists were given the opportunity to examine the effects of radiation in a natural experiment that effected a broad range of subjects. The population of atom bomb survivors represents a wide range of ages as well as both sexes, a group comparable to that of the general population.

The Japanese atomic bomb survivor Life Span Study (LSS) cohort is the principal source of data used to estimate the risks of radiation-related cancer (Little et al 1999). In 1978, the original dose estimates were reassessed and now appear in a complete publication called the DS86-Dosimetry System 1986 ((Klaassen).

The four main types of radiation are alpha particles, beta particles and positrons, gamma rays and x-rays. These atoms can decay through the loss of a positively or negatively charged electron. The release of excess energy from the nucleus, usually after an alpha, beta or positron transition results in gamma radiation. X-ray radiation is released whenever an inner-shell orbital electron is removed and a rearrangement of the remaining atomic electrons takes place. This causes the release of the elements of x-ray energy (Klaassen).

Alpha particles are helium nuclei (two protons and two neutrons) with a charge of +2 that are ejected from the nucleus of an atom. When an alpha particle loses energy, it slows down and acquires 2 electrons. The particle then becomes a component of the helium background found in the environment. The energy that is lost is about 4-8 MeV. Alpha particles can penetrate distances over a range of 50-70um, approximately the width of human tissues. This type of radiation has the ability to penetrate and damage DNA and consequently cause genetic mutations and furthermore, cancer.

Beta particle decay occurs when a neutron is transformed into a proton and an electron in the nucleus of an element. Ejection of electrons subsequently occurs and the energy emitted is in the range of approximately 0.01-4 MeV. Beta particles rarely penetrate DNA. There have been no studies that have associated harmful physiological effects with beta emission.

Positron emission is similar to beta emission, however positron emission results in the transformation of a proton to a neutron and a positively charged electron. The maximum energy due to positron emission is approximately 1 MeV.

Gamma radiation is typically combined with alpha, beta or positron emission or electron capture. When an ejected particle is released and does not utilize all of the available energy for decay, the excess energy is released as a photon or gamma ray emission. Gamma radiation has an effective range of meters. The weapons used in the bombing of Hiroshima and Nagasaki released this type of radiation and were responsible for 64,000 deaths and over 72,000 cancer cases of 360 different types.

When assessing an amount of radiation exposure, we must quantify the level at which a subject is exposed. The standard unit of activity is the Ci, or the curie. One Ci represents 3.7 ´ 10 ¹⁰ disintegrations per second. Natural radiation activity is on the order of picocuries. The newer SI units of activity are the Bz, which is equivalent to one disintegration per second and the Hz, which is also equivalent to one disintegration per second. The units used to describe absorbed dose are the rad, which is equivalent to one hundred ergs per gram and the more recent standard of measurement, the gray, which is equal to one hundred rads or 1 J kg ^-1.

It is very important that we normalize the various types of radiation so that we can compare exposures of alpha, beta and gamma to each other. Therefore, a radiation weighting factor is used, W_r. The normalized dose is called the equivalent dose. The unit for the equivalent dose is the Sievert.

Radiation ionization has been shown to cause a variety of physiological effects. One of the most well studied consequences of radiation exposure is cancer. The type of cancer associated with radiation is dependent upon the type of radiation, dose and site of exposure. For example, the weapons that were used in the bombing of Hiroshima and Nagasaki released two different types of radiation. The first, being ²³⁵U and the second, ²³⁹Pu. According to the Atomic Bomb Casualty Committee (ABCC), many types of cancers were attributed to the mortality of atomic bomb survivors. These included colon, esophageal, stomach, bladder and among the most prevalent, leukemia, lung, breast and ovarian cancers.

In 1977 the term "effective dose" was introduced in order to allow scientists to directly compare the cancer and genetic risk of partial-body and full-body radiation doses.

The first important question that arises when investigating the effects of radiation on cancer development is "What is the mechanism by which radiation ionization causes cells to become cancerous"?

The cancers that are induced by radiation are of the same histological types that occur spontaneously. However, the frequency of certain types differs (Little 2000). Also, it is important to consider that carcinogenesis associated with radiation exposure may be modulated by non-carcinogenic factors.

Radiation can induce damage to DNA bases, DNA cross-linking and can cause DNA single stranded or double stranded breaks. These aberrations have the potential to induce cancers. The DNA repair mechanisms that are typically called upon to reverse

DNA damage can also be the source of genetic rearrangements that may result in more harmful effects than therapeutic ones.

Scientists have long investigated the initiation-promotion-progression paradigm of radiation induced cancers. However, currently there is no evidence of site specificity for mutations that are induced by radiation. Also, there have been no genetic alterations that have been identified that are unique to radiation-induced tumors.

This leads us to the possibility that the initial genetic events that result in tumor formation and cancer may not be a direct consequence of the radiation itself. There has been recent evidence that suggests that the genetic consequences of radiation may arise in cells that have not themselves received any direct nuclear exposure. For example, radiation has been shown to induce genomic instability. Ten percent of the clonal population derived from a single surviving radiated cell has shown a persistent increase in the rate at which mutations occur. This increased mutation rate can persist for up to thirty generation post-irradiation (Little 2000). Thus, the instability of one irradiated cell is transmissible across generations and any subsequent mutations may be indirectly related to the radiation exposure itself.

It has also been shown by Wu et al that cytoplasmic radiation can induce an increase in the frequency of mutations in mammalian cells. While it has been generally accepted that the nucleus of the cell is the target for the biological effects associated with radiation, this finding has further supported the hypothesis that indirect induction may play a role in the initiation of cancer in non-irradiated cells.

Finally, the bystander effect also implies that that genetic damage can be induced in a population of non-irradiated cells by transduction from a population of directly radiated cells.

In addition to the idea that damage to cells effected by radiation can be passed on to other cells that have not been directly effected by radiation, is the idea that nature may predispose individuals to be particularly sensitive to radiation. This predisposition may manifest itself as the sensitivity of an individual to developing cancer.

Now that we understand the properties of radiation, the units of activity and possible mechanisms of action, we can turn to a discussion of the factors that can influence the incidence of cancer in a population due to radiation exposure.

One important model that describes factors under consideration in radiation-related cancer places emphasis on the idea that an individuals attained age is a crucial factor in determining the risk of cancer and does not primarily depend on time since exposure or age at exposure (Pierce et al 1999).

This hypothesis was investigated using Armitage-Doll multistage formulation. The Armitage-Doll formulation holds that acute irradiation would increase cancer rates throughout life, since cells that are initiated by radiation-induced mutation would continue normal cell processes one step ahead of other normally dividing cells. The malignancy of such an irradiated cell would occur earlier than had it not been irradiated. Therefore, the older an individual and the higher that individuals natural risk of cancer formation, the higher the risk of an older individual attaining cancer due to a radiation event that would speed up these natural processes. However, cancers that are strongly influenced by hormones, such as breast and thyroid cancers involve additional considerations (Pierce 2000).

Under this model, there is the implication that an alternative mechanism for the effect of radiation induced cancer exists. This mechanism asserts that radiation itself causes the mutations that are required to induce cancer rather than simply increasing the factor by which cancer may be expressed. Following the traditionally accepted mechanism of cancer initiation by radiation, such time-age patterns of acute radiation could not be shown. If for example, individuals were exposed at a very early age, it would be expected that their risk for cancer would be increased throughout the rest of their life. Also, those exposed in middle age would have an increased risk for the rest of their lives after exposure. However, this data is not represented in the patterns found using the Armitage-Doll model.

Although cancer risk as a function of attained age is one view supported by scientific data, the subject is deeply divided. In a study by Cologne and colleagues, it was found that most of the excess risk of radiation exposure was elevated in those who were exposed between the ages of 10-30. However, there was little excess risk among those individuals exposed after age 30 and almost no excess risk among those exposed over the age of 45.

One other study that has investigated the primary factors involved in radiation associated cancer supports the idea that age at exposure is a major factor in determining cancer risk. In studies by Kai et al, the incidence of cancer of the lung, stomach and colon in atomic bomb survivors was investigated. According to this study, both the age at exposure and time since exposure play crucial roles in the initiation and progression of many types of radiation associated cancers. For young individuals, the excess exposure rate was initially high and then gradually reached an asymptotic limit. For older aged groups, the excess exposure rate remained constant. Therefore, time since exposure is a factor that is consistent with the results of previous studies.

Another factor, which needs to be considered, is the idea of sex differences among radiation-induced cancers. According to Pierce and colleagues, in adulthood males tend to have twice the background cancer rate of females for most types of solid cancers. This is also supported by results of the investigation of primary liver cancer among atomic bomb survivors (Cologne et al 1999). In a study by Cologne and colleagues, it was found that males and females had similar relative risk so that, given a three-fold higher background incidence in males, the radiation-related excess incidence was substantially higher in males. The incidence in males rose rapidly with age after age 40 but did not change substantially after age 60. However, there was a much slower rise in females that began around age 50. The explanation for these sex differences may be owed to biology or birth cohort.

It is also important to note that developing and surviving a first malignancy implies that the population is at risk for a second cancer (Little et al 1999). Much of the data on this subject comes from studies of patients treated with radiotherapy for cancer. Treatment with chemotherapy and radiation often results in the development of second neoplasms, most commonly acute myelogenous leukemia (Klassen). However, the risk of developing a second cancer is generally of a lower risk than first cancers developed in individuals due to the atomic bomb disaster. These results are not surprising because the objective of chemotherapeutic treatment is to deliver a sufficient dose of radiation that will eradicate all malignant cells. The majority of cells would have already received doses that would normally lead to cell death, which is why the treatment is effective in preventing reoccurring neoplasms.

As we can see, the data provided by the Japanese atomic bomb Life Span Study cohort has been our most important insight into radiation related cancer. Not only has it provided us with data that has been used to estimate cancer risk due to radiation, but has

also given us insight into the mechanism of action and biological and environmental factors that play a role in cancer development due to radiation. Through the data acquired in this study and further research in the field of radiation carcinogenesis, we are steps closer to identifying the detailed pathways that are involved in radiation associated cancer. Hopefully, one day we will be able to strictly regulate many of the factors that put the population at risk and have a clearer understanding of the therapeutic treatments that are involved in treating and eliminating radiation associated cancers.

Cologne, J.B., Tokuoka, S., Beebe, G.W., Fukuhara, T., Mabuchi Effects of Radiation on Incidence of Primary Liver Cancer among Atomic Bomb Survivors Radiation Research 1999 152:364-373

Kai, m., Luebeck, E.G., Moolgavkar, S.H. Analysis of the Incidence of Solid Cancer among Atomic Bomb Survivors Using a Two-Stage Model of Carcinogenesis Radiation Research 1997 148:348-358

Klaassen, Cutris D. Casarett & Doull’s Toxicology: The Basic Science of Poisons Fifth Edition 1999

Little, J.B. Radiation carcinogenesis Carcinogenesis 21(3):397

Little, M.P., Muirhead, C.R., Haylock, R.G.E., Thomas, J.M. Relative Risks of radiation-associated cancer: comparison of second cancer in therapeutically irradiated populations with the Japanese atomic bomb survivors Radiat Environ Biophys 1999 38:267-283

Pierce, D.A., Mendelsohn, M.L. A Model for Radiation-Related Cancer Suggested by Atomic Bomb Survivor Data Radiation Research 1999 152:642-654