The history of radiation carcinogenesis goesback a long way.The harmful effects of X-rays were observed
soon after their discovery in 1895 by W. K. Ro¨ ntgen. The first observed effects were acute, such as reddening and blistering of the skin within hours or days after exposure. By 1902, it became apparent that cancer was one of the possible delayed effects of X-ray exposure. These cancers, which included leukemia, skin cancers, lymphomas, and brain tumors, were usually seen in radiologists only after long-term exposure before adequate safety measures were adopted, thus it was thought that there was a
safe threshold for radiation exposure. The hypothesis that small doses of radiation might also cause cancer was not adopted until the 1950s, when data from atomic bomb survivors in Japan and certain groups of patients treated with Xrays for noncancerous conditions, such as enlarged thyroids, were analyzed. These and other data led to the concept that the incidence of radiation-induced cancers might increase as a linear, nonthreshold function of dose. Thus the debate about whether there is a safe threshold pertains to radiation carcinogenesis, just as it does to chemical carcinogenesis.
In radiation carcinogenesis, the damage to DNA, and hence its mutagenic and carcinogenic effect, is due to the generation of free radicals as the radiation passes through tissues. The amount of radical formation and ensuing DNA damage depend on the energy of the radiation. In general, X-rays and gamma rays have a low rate of linear energy transfer, generate ions sparsely along their tracks, and penetrate deeply into tissue. This profile contrasts with that of charged particles, such as protons and a particles, which
have a high linear energy transfer, generate many more radical ions locally, and have low penetration through tissues. Thedamage toDNA can include single- and double-strand breaks, point mutations due to misrepair deletions, and chromosomal translocations.107–109 The molecular genetic events that follow radiation damage to cells include (1) induction of early-response genes such as c-jun and Egr-1; (2) induction of later-response genes such as tumor necrosis factor-a (TNF-a), fibroblast growth factor
(FGF), and platelet-derived growth factor-a (PDGF-a); (3) activation of interleukin-1 (IL-1) PKC110; and (4) activation of oncogenes such as c-myc and K-ras.111 Induction of these genes may be involved in the cellular responses to irradiation and in the longer-range effects that lead to carcinogenesis. At any rate, the production of clinically detectable cancers in humans after known exposures generally occurs after long latent periods. Estimates of these latent periods are 7 to 10 years for leukemia, 10– 15 years for bone, 27 years for brain, 20 years for thyroid, 22 years for breast, 25 years for lung, 26 years for intestinal, and 24 years for skin cancers.
A more recent example of nuclear fallout leading to environmental exposure to radiation is the Chernobyl accident, which happened onApril 26, 1986. A steam explosion blew the lid off the reactor. The graphite core caught fire and over 1019 becquerels (Bqs) of radioisotopes were released, producing a fallout that covered much of Belarus, Northern Ukraine, and part of the Russian Federation. Estimates are that
10–20 million people were exposed to significant fallout. There were some deaths due to acute
radiation sickness from high levels of exposure. However, the long-term effects are still being
recorded. So far, the reliable reports of increases in cancer incidences are mostly limited to thyroid
cancer.112 This finding is in contrast to cancer incidence among atomic bomb survivors in Japan, some of whom developed cancers of various types, including cancers of the thyroid, breast, lung, stomach, esophagus, bladder, leukemia, and lymphoma (although the incidence of cancers in Japanese atomic bomb survivors was less than would have been predicted by radiation exposure). The reason for this discrepancy is most likely that those exposed to the Chernobyl fallout received primarily dosage from
b-emitters, mostly isotopes of iodine, which concentrates in the thyroid. Atomic bomb survivors,
by contrast, received whole-body irradiation from neutrons and gamma rays.
Another interesting point about the Chernobyl survivors is that the type of thyroid cancer they developed, mostly among those under 2 years of age if they were exposed, were 98% papillary, many with an unusual morphology, whereas in non-exposed populations, only 67% of childhood thyroid cancers are papillary.112 Expression of two families of oncogenes, the c-ret and ras families, has been shown to be
involved in papillary thyroid cancers. The oncogene c-ret is a receptor tyrosine kinase activated
by gene rearrangement, and two of these, ret-ptc 1 and ret-ptc 3, are activated in papillary carcinomas. Since c-ret is activated by rearrangement, the high proportion of doublestrand DNA breaks seen in radiation-induced papillary carcinomas of the thyroid may explain its activation. Since the thyroid is not the only tissue that concentrates iodine, malignancies of other tissues that also concentrate iodine, such as the breast, salivary gland, and stomach, may appear in higher incidence as time goes on. Moreover,
other isotopes including cesium were present inthe fallout, and inhabitants of parts of the Ukraine and Belarus are still exposed to low levels of radioactive cesium. The long-term effects, if any, of such exposure is not yet clear.
