Radiation exposure to the gonads can cause changes in the genes of the irradiated person called

Ionizing Radiation

Ionizing radiation has its greatest effect on rapidly dividing cells in phases G2 through M of the cell cycle. Injury to keratinocytes and fibroblasts impairs epithelialization and formation of granulation tissue during wound healing. Radiation injury in endothelial cells results in endarteritis, atrophy, fibrosis, and delayed tissue repair. Repetitive radiation injury results in repetitive inflammatory responsesand ongoing cellular regeneration. Early side effects include erythema, dry desquamation, skin hyperpigmentation, and local hair loss. Late effects include skin atrophy, dryness, telangiectasia, dyschromia, dyspigmentation, fibrosis, and ulceration.12–14 The inflammatory and proliferative phases may be disrupted by the early effects of radiation. Affected factors include TGF-β, VEGF, TNF-α, IFN-γ, and cytokines such as IL-1 and IL-8. These cytokines are overexpressed after the radiation injury, leading to uncontrolled matrix accumulation and fibrosis. NO, which induces collagen deposition, is decreased in irradiated wounds; this may explain the impaired wound strength seen in irradiated wounds. Decreased MMP-1 may contribute to inadequate soft tissue reconstitution [Table 6.4].

Keratinocytes, which are crucial for wound epithelialization, demonstrate a shift in expression from the high molecular keratins 1 and 10 to the low molecular keratins 5 and 14 after radiation injury. In nonhealing ulcers, these cells display decreased expression of TGF-α, TGF-β1 FGF-1, FGF-2, KGF, VEGF, and hepatocyte growth factor [HGF]. Expression of MMP-2, MMP-12, and MMP-13 has been shown to be elevated in irradiated human keratinocytes and fibroblasts. Fibroblasts play a central role in wound healing through deposition and remodeling of collagen fibers. However, in irradiated tissue, fibroblasts generate disorganized collagen bundles from dysregulation of MMP and TIMP. Because TGF-β regulates MMPs and TIMP, it may be of particular relevance to radiogenic ulcers [seeTable 6.4].

Strategies for treating problematic radiogenic ulcers include standard wound care, negative pressure wound therapy, nutritional optimization, and optimized blood and oxygen delivery. Hyperbaric oxygen [HBO] therapy may improve tissue oxygen partial pressure in the treatment of osteoradionecrosis via increased capillary density and more complete neovascularization.12,15,16 HBO therapy is used clinically in patients with chronic diabetic ulcers and wound-healing complications after radiotherapy, and randomized clinical trials have demonstrated efficacy when HBO therapy was used in conjunction with standard wound care in cases of recalcitrant, diabetic, and potentially radiation-induced wounds.16,17 In recent years, we have seen further investigation in this area. For example, Wu and colleagues14 demonstrated improved wound healing with injection of adipose-derived stem cells, centrifuged adipose cells, and other products extracted from adipose matrix in an irradiated mouse model.

Abstract

Ionizing radiation [IR] is very damaging to the vital processes of life, inducing DNA damage that underlies a variety of human diseases, including cancer. On the cellular level, IR generates reactive oxygen species and ionizes DNA leading to single- and double-strand breaks, interstrand cross-linkages, and other oxidative lesions. Depending upon the type, quality, and dose of IR, the cellular-repair machinery may fail to accurately or completely repair DNA damage leading to cell death or transformation. As human technology has advanced, sources of IR exposure have multiplied increasing the incidence of radiation-induced human disease. In this chapter, the primary sources of human IR exposure and their health consequences, including nuclear attack, civilian nuclear disasters, aerospace travel, medical radiation [radiotherapy and computed tomography imaging], and radon gas inhalation are reviewed.

Ionizing Radiation: X-rays

In the past, exposure to radiation occurred mostly in the operating room with the use of portable fluoroscopy and x-ray machines. Advancements in endovascular surgery, hybrid cardiac surgery procedures, electrophysiology studies, and other imaging procedures significantly increase exposure of anesthesia personnel to ionizing radiation45 relative to traditional operating room cases. Radiation is undetectable with our normal senses, so a basic understanding of its features will minimize exposure.

One Sievert [Sv] is equal to 100 rem and is a measure of the biologic damage from radiation adjusted to apply to all tissues.46 Estimates of radiation exposure from natural sources vary, depending on geographic location. The average in the United States ranges from 0.8 to 2 mSv [80-200 millirem [mrem]] per year. Natural radiation comes primarily from cosmic rays [approximately 0.4 mSv at sea level, with an increase of 0.1 mSv/1000 feet], as well as from radioactive compounds found in soil, brick, and concrete. For most physicians, the additional radiation from occupational exposure is no greater than that from natural sources. OSHA sets limits of occupational exposure [expressed as rem] that vary by body area; allowable limits are higher for the hands than for the whole body, gonads, or blood-forming parts of the body.47 An easy rule of thumb is 5 rem [50 mSv] per year, with no more than 1.25 rem [12.5 mSv] in any given calendar quarter. In 2007 the International Commission on Radiological Protection, an international nonprofit, proposed more stringent limits than those proposed by OSHA [Table 88.1], and both agree that limits should be lower for personnel who are pregnant.48,49

Occupational exposure to radiation comes primarily from x-rays scattered by the patient and the surrounding equipment, rather than directly from the x-ray generator itself.50 One chest radiograph results in approximately 25 mrem of exposure to the patient; procedures requiring multiple films occasionally involve more than 1 rem. The amount of radiation generated during fluoroscopy depends on how long the x-ray beam is on; just as light is reflected from surfaces, x-rays are reflected from the surfaces on which they impinge. This scattering accounts for most occupational exposure. Research findings vary about the degree of exposure typical for anesthesia providers, but most studies show low levels of exposure.45,51-53 Recent studies have compared risk profiles of various positions of the anesthetist and the x-ray beam. A simulation-based study using phantom patient and anesthetist models with dosimeters demonstrated that exposure was greater near the head of the bed [vs. along the sides of the bed] or when the x-ray beam was in either of the lateral positions [e.g., shooting cross-table images].54 A real-time evaluation of exposure in personnel conducting transesophageal echocardiography [TEE] during transcatheter aortic valve replacement showed that the TEE operator receives 5 times as much radiation as otherclinicians involved in the procedure.55 Furthermore, this exposure is heightened by the use of oblique angles for imaging. Notably, by using additional shielding [e.g., a ceiling-mounted lead acrylic shield], this exposure was reduced by more than 80%.

Ionizing Radiation

Ionizing radiation is an abundant environmental human genotoxic carcinogen [IARC Group 1]. Additionally, there are a progressively rising number of people exposed to ionizing radiation either due to their occupation or due to medical diagnostic imaging and radiation treatments. It is well established that DNA damage is the main mechanism associated with ionizing radiation tumorigenicity; however, ionizing radiation also causes major aberrations in the cellular epigenome, including alterations in DNA methylation, histone modifications, and chromatin accessibility. Among these epigenetic abnormalities, a loss of global DNA methylation, driven by either demethylating mechanisms similar to those caused by ultraviolet radiation orionizing radiation-induced damage of 5-meC, and aberrant DNA damage-related histone modifications are the major epigenetic alterations.

Ionizing Radiation

The overwhelming concern related to diagnostic imaging is exposure of the developing fetus to ionizing radiation. The critical factors that determine the risk to the fetus are the dose of radiation to which the fetus is exposed and the gestational age at the time of exposure [Table 31.1; seeChapter 7]. Very early in gestation, within the first 2 weeks of conception, any significant cell damage caused by radiation is generally believed to result in miscarriage. This is believed to be an “all or none” phenomenon; that is, if the fetus remains viable after this early exposure, no adverse effects are expected.Radiation doses greater than 50 to 100 mGy [5 to 10 rad [1 mGy = 0.1 rad]] are likely necessary to cause embryonic death. Postconception weeks 2 through 8 are particularly sensitive to teratogenicity because this is the period of organogenesis. At this stage, the embryo is more resistant to radiation-induced death, and doses of more than 250 to 500 mGy [25 to 50 rad] are necessary to cause fetal demise.9,10

The fetal central nervous system is sensitive to radiation damage between 8 and 25 weeks and particularly during weeks 8 to 15 because this is a period of rapid neuronal development. However, increasingly high doses of radiation are necessary to result in any significant damage. Beyond 25 weeks, the fetus is fairly resistant to radiation-induced abnormalities.9,10

In addition to teratogenic risk, a concern remains for potential carcinogenic effects of ionizing radiation to the developing fetus. Some authors have estimated that the incidence of childhood leukemia and other cancers may increase by about 0.06% from baseline with each centigray of exposure.11 Given the low background risk, diagnostic doses of radiation do not appear to significantly increase the absolute risk to the fetus.9,12 Also, the causative link between fetal exposure to diagnostic radiation and childhood leukemia has been called into question.9

Table 31.2 shows the estimated doses of fetal radiation exposure from various commonly used diagnostic imaging examinations.12–14 It is important to note that the amount of radiation exposure from any of these diagnostic studies is well below the dose threshold for teratogenic risk.Therefore when evaluating a pregnant woman who presents with significant symptoms, the patient should be reassured that the radiation exposure to the fetus from diagnostic imaging does not confer a significant risk for fetal harm.15,16 It is important for the clinician to be familiar with the relative radiation doses delivered by commonly ordered tests because this information may aid in the decision to choose one modality over another. When clinically appropriate, consideration should be given to other diagnostic modalities, such as ultrasound or magnetic resonance imaging [MRI], that do not involve ionizing radiation. The general principle ofALARA [as low as reasonably achievable] applies to both mother and baby. Optimization of computed tomography [CT] scan protocols, appropriate shielding, and judicious use of radiation-based imaging remain important principles.

7.2 Ionizing radiation and metabolism

Ionizing radiation [IR] a known therapeutic strategy for treating patients with cancer that can cause several acute and delayed changes in metabolic flux, resulting in increased flux into glycolysis and pentose phosphate pathway for detoxification of ROS [Sertorio et al., 2018; Yazal, Dao, Dong, Dratver, & Vlashi, 2018]. Altered activity of the enzymes PKM2 and G6PDH control metabolic reprogramming as an acute response to radiation-generated oxidative stress [Yazal et al., 2018]. This helps re-balance the redox state of the surviving cancer cells. PKM2 activators can be used to prevent these protective metabolic rewirings and can significantly inhibit IR-induced cellular reprogramming of breast cancer cells [Yazal et al., 2018]. In addition to glycolysis, IR has been shown to affect other components of oncogenic metabolism. Such as enhanced PPP signaling, increased FA biosynthesis, along with decreased mitochondrial oxidative phosphorylation [Lee et al., 2017; Mims et al., 2015]. IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate [lactate and alanine]. IR also increases glycolysis by upregulating GAPDH [a glycolysis enzyme], along with increasing lactate production by activating LDHA, which is responsible for the conversion of pyruvate to lactate. LDHA inhibition prevents radiation-induced activation of TGF-β [Judge et al., 2015]. In addition, lactate induces cell migration and secretion of hyaluronan from cancer associated fibroblasts to support metastasis [Hirschhaeuser, Sattler, & Mueller-Klieser, 2011]. IR also increases MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumor microenvironment [Lee et al., 2017]. These changes result in IR-stimulated invasion of the non-irradiated, surrounding stromal tissues and normal endothelial cells [Liao, Hsu, et al., 2014; Liao, Qian, et al., 2014].

ROS plays a seminal role in the IR-induced glycolytic switch, possibly though the regulation of Akt [Lee et al., 2017; Zhong et al., 2013]. This is supported by studies utilizing antioxidant SOD mimic treatment, which suppresses IR-induced glucose uptake, prohibits the glycolytic switch, and inhibits invasiveness [Lee et al., 2017; Zhong et al., 2013]. IR-induced ROS generation assists in the development of EMT and CSC phenotypes through Snail, Dlx-2, HIF-1, and TGF-β. These molecules can regulate the enzymes involved in glycolysis and mitochondrial oxidative phosphorylation, causing the IR-induced glycolytic switch [Lee et al., 2017]. IR can also lead to elevated ROS generation via extracellular water radiolysis and intracellular metabolic alterations or damage to mitochondria [Lee et al., 2017]. ROS is implicated in IR-induced HIF-1 activation which stimulates vascular damage causing hypoxia that leads to stabilization by Nijmegen breakage syndrome protein 1 [NBS1], and nuclear accumulation [Harada, 2011; Harada et al., 2009; Kuo et al., 2015; Lee et al., 2017; Moeller, Cao, Li, & Dewhirst, 2004; Rankin & Giaccia, 2016]. IR-induced glucose availability also facilitates HIF-1α translation by activating the Akt/mTOR pathway [Harada et al., 2009]. HIF-1α stabilized by IR can dimerize with HIF-1β in the nucleus, regulating EMT molecules such as Snail, which also controls cancer cell migration, and invasion [Luo, Wang, Li, & Post, 2011; Rankin & Giaccia, 2016].

These studies predominantly document how radiation can upregulate cancer metabolism and thus contribute to resistance to radiotherapy. Targeting the mechanism by which radiation upregulates cancer metabolism could represent a potential way of ameliorating this phenomenon. Radiation can also lead to cytosolic nucleic acid sensing orchestrating tumor immunity during radiotherapy [Deng et al., 2016]. IR can thus use the host metabolism to result in the upregulation of “find-me” and “eat-me” signals from tumor cells [Fig. 7]. These signals can be augmented further by appropriate immunotherapy strategies to eradicate the tumor after radiation.

Radiation therapy

Ionizing radiation [IR] can damage cellular macromolecules, such as DNA, proteins, and membranes, primarily by generation of reactive oxygen species [ROS]. RT is based on the failure of the cell repair system to mend the DNA double strand breaks that are caused in effect by IR [directly or by radicals produced from water radiolysis], which triggers apoptosis in rapidly proliferating cells. In nonreplicative cells, IR can mediate structural changes in the proteins and in plasma membrane lipids that can affect cellular interactions with the ECM molecules and alter intracellular signaling [50]. Neuronal cell membrane damage can further exert physiologically detrimental effects, such as axonal demyelination, leading to inefficient neurotransmission, and neuronal cell death. Clinical challenges in RT have been reviewed by Chao et al. [2013] and others [66, 237, 238].

Ionizing Radiation

Ionizing radiation, such as ultraviolet and high-frequency rays like x-rays, causes damage to living cells and is capable of inducing changes in the genome. Immortalized human keratinocyte [HaCaT] cells exposed to UVB radiation for 24 h showed a dose-dependent increase in global 5-hmC content and increased RNA and protein levels of TET1, TET2, and TET3 [Wang et al., 2017]. Although the current research is limited, these data point toward the possibility of utilizing 5-hmC as a biosensor for skin UVB radiation exposure. Human fetal fibroblasts exposed to x-ray irradiation [2 and 4 Gy] showed no significant changes in global 5-hmC level [Wang et al., 2017], indicating that the effect of ionizing radiation on 5-hmC changes or TET protein expression may vary considerably among the types of ionizing radiation.

Biological effects

Ionizing radiation is more harmful than nonionizing radiation because it has enough energy to remove an electron from an atom and thereby directly damage biological material. The energy is enough to damage DNA, which can result in cell death or cancer. The study of ionizing radiation is a large area of classical toxicology, which has produced a tremendous understanding of the dose/response relationship of exposure. The primary effect of ionizing radiation is cancer. It can also affect the developing fetus of mothers exposed during pregnancy. Radiation exposure has a direct dose/response relationship: the more radiation one receives, the greater is the chance of developing cancer.

Radon is a radioactive gas that is present in uranium mines and can also be found in high concentrations in soil in some places. Radon exposure results in lung and esophagus cancer. The actual carcinogens are daughter products of radon that adhere to the internal tissue and emit alpha particles.

Radiation

Ionizing radiation is leukemogenic. An increased incidence of AML, ALL and chronic myelogenous leukemia [CML] was seen in survivors of the atomic bombings of Hiroshima and Nagasaki, which began approximately 1.5 years after exposure, peaked at 7 years, and returned to baseline 25 years later. The risk of leukemia was also increased in individuals treated with radiation for ankylosing spondylitis in the 1940s. Although most of the data from humans showing the leukemogenic potential of ionizing radiation come from individuals exposed to high dose rates, occupational exposure to low dose-rate radiation has more recently been associated with the development of leukemia.7