",isbn:"978-1-80355-829-5",printIsbn:"978-1-80355-828-8",pdfIsbn:"978-1-80355-830-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"b10af949acb1f5e774e9edd672b1833e",bookSignature:"Assistant Prof. Élvio Gouveia, Dr. Bruna Raquel Gouveia, Prof. Adilson Marques and Dr. Andreas Ihle",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11226.jpg",keywords:"Aging, Health, Determinants, Lifestyle, Geriatrics, Physical Activity, Exercise, Functional Abilities, Mobility, Cognitive Abilities, Quality of Life, Assisted Living",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 29th 2021",dateEndSecondStepPublish:"December 24th 2021",dateEndThirdStepPublish:"February 22nd 2022",dateEndFourthStepPublish:"May 13th 2022",dateEndFifthStepPublish:"July 12th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"5 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Sport Science researcher with the focus on the assessment and the implementation of strategies to promote physical activity, fitness, and quality of life, with the focus on the physiological assessment of human fitness and the promotion of healthy aging.",coeditorOneBiosketch:"A researcher in Health Sciences mainly focused on Epidemiology, Human Development, Rehabilitation, and Health-associated Technologies.",coeditorTwoBiosketch:"Sport Science researcher with the focus on the assessment and the implementation of strategies to promote physical activity, fitness, and quality of life.",coeditorThreeBiosketch:"Psychological and social sciences researchers with the focus on promoting cognitive and physical health across the lifespan.",coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"320525",title:"Assistant Prof.",name:"Élvio",middleName:null,surname:"Gouveia",slug:"elvio-gouveia",fullName:"Élvio Gouveia",profilePictureURL:"https://mts.intechopen.com/storage/users/320525/images/system/320525.jpg",biography:"Élvio Rúbio Gouveia has a degree in Physical Education, a master’s in Physical Education, and a Ph.D. in Sport Sciences. 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1. Introduction
Normal mammalian cells in culture have a limited life span and will eventually maintain a growth arrested state, referred to as replicative senescence. Usually induced by telomere shortening this form of arrest is irreversible in the sense that cells cannot be triggered to re-enter proliferation by physiological mitotic stimuli like growth factors. Senescence may also occur prematurely in response to various stress stimuli such as oxidative stress, DNA damage or active oncogenes. Thereby premature senescence acts as an important tumor suppressive mechanism and not surprisingly there is emerging evidence that senescence is indeed not only a result of tissue culture but markers of senescence have been identified in vivo in human and animal tissue.
The function of the retinoblastoma protein (pRb) is central to the onset of senescence. pRb, in its active hypophosphorylated form, is a potent repressor of genes that function during DNA replication and thereby pRb causes cell cycle arrest. The cell cycle inhibitors p16INK4a and p21Waf1 and their homologues work in concert with pRb by inhibiting cyclin dependent kinases (CDKs) from phosphorylating pRb and thus maintaining in its active growth inhibitory state.
Additionally to the transient role in growth inhibition active, hypophosphorylated pRb coordinates major changes in direct and epigenetic gene regulation leading to changes in chromatin structure, which are crucial to the onset and maintenance of senescence.
This chapter provides an insight in these molecular mechanisms of cellular senescence.
2. Senescence features and biomarkers
Senescent cells display several characteristic morphological and biochemical features. The detection of these markers has been used to identify senescent cells in vitro an in vivo. The typical senescence phenotype consist of enlarged cell with multiple or enlarged nuclei, prominent Golgi apparatus and sometimes a vacuolated cytoplasm (Figure1). Recently a novel method to measure protein levels with fluorescence microscopy confirmed that indeed senescent cells accumulate increased levels of protein in the cytoplasm and nucleus [1]. In addition to the detection of characteristic morphological changes the most common method used to identify senescent cells is measurement of the lysosomal beta-galactosidase activity with a simple biochemical assay [2]. Due to an expansion of the lysosomes senescent cells show an increased activity of this enzyme, which is therefore often referred to as senescence-associated beta-galactosidase (SA-beta-gal), [3, 4]. However, it should be noted, that an increased beta-gal activity is an unreliable marker of senescence since it is also detectable in vitro after prolonged cell culture, serum withdrawal, TGF-beta, heparin or TPA treatment [3, 5-8]. The tumour suppressors p16INK4a and p21Waf1 are mediators of cell cycle arrest and senescence and therefore often used as biomarkers. Since neither p16INK4a nor p21Waf1 is strictly required for the induction or maintenance of the senescence program their predictive value is limited if used individually. A specific feature of senescent cells are condensed heterochromatic regions, known as senescence-associated heterochromatic foci (SAHF). These heterochromatin spots are enriched with i) histone H3-methylated at lysine 9 (H3K9meth), its binding partner ii) heterochromatin protein-1γ (HP- 1γ) and iii) the non-histone chromatin protein, HMGA2, which all have been used as markers of SAHF [9, 10].
Figure 1.
Senescence characteristics
A) The typical senescence phenotype consist of enlarged cell with multiple or enlarged nuclei, and an increased SA-beta-gal activity is visible after N-RASQ61K induced senescence. Human diploid fibroblasts (HDF) were transduced with lentiviruses expressing N-RASQ61K or copGFP control. The efficiency of transduction was controlled with the co-expression of copGFP and was consistently above 90%. p16Ink4a expression, chromatin condensation (DAPI), and the appearance of increased SA-ß-Gal activity were analyzed and quantified 15 days after infection. Cells enlarged to show DAPI-stained chromatin foci are indicated with arrows. B, C) HDF induced to senesce with oncogenic N-RASQ61K were stained with DAPI and an antibody to H3K9meth or γH2AX to highlight senescence-associated heterochromatin foci or DNA damage foci respectively. H2AX is a member of the histone H2A family that gets instantly phosphorylated after DNA damage and forms foci at DNA break sites.
3. pRb in cell cycle regulation
The retinoblastoma protein (pRb) is often referred to as the “master brake” of the cell cycle because its main function is to inhibit E2F transcription factors from inducing a range of genes essential for DNA replication and thus proliferation [11]. Consequently active pRb causes cell cycle arrest. In contrast during proliferation when cells are promoted towards cell division, pRb is sequentially phosphorylated by a series of cyclin dependent kinases (CDKs) and this results in pRb inactivation and consequently derepression of proliferation genes.
Initiation of cell proliferation is normally triggered by growth factors. These external molecules function as ligands to a number of growth factor receptors expressed on the cell surface and thus activate signalling cascades, most prominently the mitogen activated protein kinase (MAPK) pathway, and ultimately lead to the expression of a number of genes including cyclin D [12]. CDK4 and 6 initiate phosphorylation of pRb in the presence of cyclin D and this leads to de-repression of early cell cycle genes including cyclin E and thus the entry into the cell cycle. Subsequently, CDK2 and CDK1, in co-operation with cyclins E, A and B, continue to stepwise further phosphorylate and inactivate pRb, which leads to cell cycle progression and finally cell division. As the “master brake” of the cell cycle pRb is an important tumor suppressor and alterations of its pathway have been associated with the childhood cancer retinoblastoma and are known to occur in over 90% of cancers [13]. There are two important types of cell cycle inhibitors represented most prominently by p16INK4a and p21Waf1. p16INK4a is at the forefront of cell cycle inhibition as it binds specifically to the cyclin D dependent kinases CDK4 and CDK6 and displaces cyclin D and thereby it prevents the entry into the cell cycle and arrests cells in G1 phase (Figure 2). p21Waf1 is more promiscuous and is able to inhibit all CDK molecules at any stage during the cell cycle. p21Waf1 molecules do not necessarily displace cyclin partners from their CDK target and importantly it may require several p21Waf1 molecules to effectively inhibit CDKs [14]. In normal cells p16INK4a and p21Waf1 are able to work hand in hand, the accumulation of p16INK4a and binding to CDK4 and 6 frees p21Waf1 molecules from these kinases to bind and inhibit CDK2 and 1 more efficiently [15]. These basic cell cycle regulatory functions of pRb, p16INK4a and p21Waf1 are essential to initiate and maintain senescence and it is not surprising that all three molecules are considered important tumor suppressors.
Figure 2.
The Cell Cycle
This simplified model, focusing on early cell cycle entry, illustrates that hypophosphorylated, active pRb represses E2F-mediated transcription. The action of CDKs, exemplified by the cyclin D dependent CDK4 and 6, phosphorylate pRb and thus release E2F to activate transcription of early DNA replication genes. p16INK4a and p21Waf1, the latter usually activated by p53, inhibit CDKs and retain pRb in its active cell cycle inhibitory state.
4. The role of the tumor suppressor p16INK4a in senescence
With regard to senescence, it is long known that p16INK4a levels accumulate and cause growth arrest and senescence when cells approach their replicative life span [16-23]. Moreover, in long term tissue culture studies cells that were able to overcome senescence commonly had lost p16INK4a and p53 expression [24]. Increased p16INK4a expression is also linked to oncogene induced and other forms of premature senescence [25-33].
Interestingly, despite this clear correlation of p16INK4a up-regulation with senescence there is some evidence from p16INK4a is not strictly required for senescence to occur. Evidence form mouse models show that mouse embryonic fibroblasts (MEFs) of p16-null mice undergo a comparable number of cell divisions as wild type MEFs before entering senescence [34] [35], while in primary melanocytes, which were lentivirally transduced to express oncogenic HRAS or NRAS, silencing of p16INK4a did not abolish most senescent features. Interestingly however, the formation of SAHF did only occur in the presence of p16INK4a [29, 36, 37]. These findings show two important points: first there are other redundant mechanisms able to compensate for p16INK4a loss and rescue senescence and second the p16INK4a-pRb pathway has a specific role in SAHF formation and, importantly, these heterochromatin foci have been suggested to abolish expression of proliferation associated genes and secure senescent features so senescence becomes irreversible [9] (see section 7 for more detail). This idea is supported by a report that senescence was only reversible, via p53 inactivation, in fibroblasts and mammary epithelial cells with low but not with high p16INK4a expression [38]. It is noteworthy that the importance of SAHF in securing senescence has been challenged recently and SAHF are thought dispensable for senescence by some investigators and/or only associated with oncogene-induced senescence [39, 40]. The fact that SAHF formation only occurs in the presence of increased p16INK4a levels remains undebated and it is therefore tempting to speculate a direct p16INK4a role in the formation of these structures.
Even though cells may be able to compensate for p16INK4a loss and still undergo a growth arrest characterised by most if not all senescent features, the importance of the tumor suppressor p16INK4a in senescence is clear as p16-null tumor cells can be driven into senescence by the sole re-expression of p16INK4a: Induced p16INK4a expression in glioma cells caused a typical senescent phenotype [41], reversing promoter hypermethylation allowed for the re-expression of endogenous p16INK4a in oral squamous cell carcinoma cells leading to senescence [42], inducible p16INK4a expression in osteosarcoma cells induced senescence after 3-6 days, potentially irreversible after 6 days [43] and inducible p16INK4a in human melanoma cells caused a senescent phenotype after 3-5 days in the absence of p53 [44, 45]. Moreover, even in normal early passage human fibroblasts the ectopic introduction of p16INK4a or functional peptides thereof initiated cell cycle arrest and senescent features [46, 47]. In line with this, melanoma associated germline mutations of p16INK4a are impaired in inducing a cellular senescence program in melanoma cells and this disability to promote senescence may contribute to the melanoma-risk of p16INK4a linked melanoma-prone families [45].
5. Timing of Senescence by repression and activation of p16INK4a
5.1. p16INK4a repression
In fact, the ability to induce senescence in response to accumulated or sudden genomic stress is probably the most important tumor suppressive function of p16INK4a. In line with this consideration it is not surprising that p16INK4a expression is tightly repressed at the chromatin and transcriptional level in “young” proliferating cells and in cells with extensive renewal capacities, such as stem cells. The polycomb protein Bmi1, which is also known as “stem cell factor” is facilitating repression of the INK4a locus at the chromatin level [48, 49]. Intriguingly, in a functional feedback loop, in human fibroblasts the Bmi1-mediated repression of p16INK4a requires active pRb and also H3K27 (histone 3/lysine 27] trimethylation facilitated by the histone methyltransferase EZH2 in concert with a second polycomb protein, SUZ12 [50]. Crucially, Bmi1 chromatin binding can be inhibited by its phosphorylation through the MAPK and p38 signalling pathways [51]. Hence these pathways are able to directly oppose p16INK4a repression and lead to its transcriptional activation via Ets and Sp-1 during oncogene-induced senescence.
In concert with Bmi-linked chromatin-remodelling events a number of transcription factors facilitate p16INK4a repression during the proliferative life-time of cells. The perhaps most important transcriptional repressors of p16INK4a are Id proteins, with the main representative Id1. Id proteins function by binding to E-box DNA sequences to repress the INK4a promoter and importantly by interfering with Ets transcriptional complex formation and thereby inhibiting the main INK4a transcriptional activator, Ets, in two ways [52, 53]. In line with this, high Id1 levels were associated with early stage melanoma whereas premalignant and interestingly also more advanced melanoma showed limited Id1 expression [54]. This suggests a role of the Id1/p16INK4a regulative connection during melanomagenesis and Id1 may be dispensable in later melanoma stages once p16INK4a is either more tightly repressed by engaging repressive histone modifications or inactivated by other mechanisms. Id1 down-regulation on the other hand is usually associated with cell differentiation and senescence [55]. Consequently, ectopic expression of Id1 delayed senescence in melanocytes [56] and keratinocytes [57], while MEFs lacking Id1 prematurely senesced due to increased p16INK4a levels [58, 59]. Another way to oppose Ets driven p16INK4a transcription was identified, when Cdh1, an adaptor protein of the anaphase promoting complex, was shown to bind to and promote degradation of Ets2 and thereby increased the replicative life span of MEFs [60], while the Epstein-Barr virus protein LMP1 represses p16INK4a by promoting the nuclear export of Ets2 [61, 62]
Interestingly, p16INK4a may also be repressed by the oncogene β-catenin, which has been linked to melanoma. β-catenin binds the INK4a promoter at a conservative β-catenin/Lef/Tcf binding site and thereby directly represses its transcription. Consequently β-catenin silencing increased p16INK4a levels in A375P human melanoma cells, while stabilization of β-catenin together with oncogenic N-RAS led to prevention of senescence and thus, immortalization [63]. Importantly, a role of β-catenin in melanocyte senescence is controversial as nuclear β-catenin was commonly found in benign melanocytic nevi [64-66] and these lesions were proposed to be senescent by some investigators [29, 67], this again is controversial, as benign nevi are not be distinguished from normal melanocytes or primary melanomas using a range of common senescence markers [68]. It would clearly be interesting to test whether nuclear β-catenin does overlap with the expression of p16INK4a in benign nevi as the latter is mosaic and not found in all cells [29] and co-localisation or lack of it could help clarify this debate. Another repressor of p16INK4a is the “T-box transcription factor” Tbx2, this transcription factor binds to corresponding T-box DNA sequence elements [69]. Tbx2 over-expression was identified in melanomas and associated with melanoma progression [70].
5.2. p16INK4a expression
When cells reach their finite life span the pendulum at the INK4a promoter swings from repression to activation and the SWI/SNF chromatin remodeling complex, replaces Bmi1 repressors and relaxes chromatin structures around the INK4 promoter region, which is strictly dependent on the SWI/SNF subunits BRG1 and hSnf5, and the relaxed chromatin structure allows transcription factor access [71] (Figure 3a). Alterations of hSnf5 are associated with early childhood rhabdoid cancer and re-expression of hSnf5 in rhabdoid cancer cells leads to p16INK4a accumulation, growth arrest and senescence [71, 72] and this requires functional p16INK4a [73].
The best understood transcription factors driving p16INK4a expression and thereby growth arrest and senescence are Ets1 and Ets2. They are effectors of MAPK signalling, often in response to oncogenic stress, such as activating N-RAS or B-RAF mutations, which induce an increase in p16INK4a levels [25, 29, 37, 52]. In line with this, human fibroblasts with biallelic mutations in p16INK4a did increase mutant p16INK4a expression in response to RAS signaling or expression of ectopic Ets, but failed to arrest or undergo senescence [74]. Interestingly increased p16INK4a expression has also been linked to loss of p53 and this appears to be correlated with increased Ets protein half-life [75]. Another member of the Ets transcription factor family, ESE-3, was independently identified as a down stream target of p38 signalling and caused senescence via p16INK4a up-regulation [76]. p38 signalling has been linked to enhanced p16INK4a expression before and this involved the downstream transcription factor Sp-1, which was proposed to be required for p16INK4a up-regulation during senescence in human fibroblasts [77]. Sp-1 was reported to engage the p300 enhancer leading to further p16INK4a upregulation [78] (Figure 3b).
Figure 3.
Schematic presentation of p16INK4a regulation
(A) During the proliferative cellular life-time, EZH2 in cooperation with SUZ12 trimethylates H3K27 at the genomic INK4a locus and these histone modifications attract the polycomb repressor BMI1, which maintains the p16INK4a promoter region inaccessible for transcriptional activation. Once cells reach their finite life span or during premature senescence the histone modifications at the INK4a locus change from repressive methylations to activating acetylations, which attract the SWI/SNF complex. The SWI/SNF subunits hSnf5 and BRG1 are instrumental in opening the chromatin structure and allowing access of the transcriptional machinery to the p16INK4a promoter. (B) Ets transcription factors are down stream targets of MAPK signalling, exemplified here by RAS, and bind to E-box p16INK4 promoter motifs to activate gene expression. Id transcription factors can compete with Ets for DNA binding and oppose transcriptional expression. The levels of Id proteins decline with onset of senescence and Ets are able to promote p16INK4a expression.
6. The role of the p53/p21 pathway in senescence
The transcription factor and tumor suppressor p53 is often referred to as “guardian of the genome” and inactivating mutations in p53 are observed in about half of all human cancer cases. The p53 protein is a critical regulator of cell survival in response to cellular stress signals including DNA damage, oncogene activation, hypoxia and viral infection (reviewed in [79]. In the absence of stress stimuli p53 gets rapidly ubiquitinated by one of several E3 ligases including MDM2, MDM4, TOPORS, COP1, and ARF-BP1 and subsequently degraded in the proteasome [80, 81]. Stress signals, on the other hand, induce covalent modification usually by disrupting the interaction between p53 and the E3 ubiquitin ligases which prevents its degradation. Oncogenic stress, for example, activates the alternative reading frame product of the INK4a locus (p14ARF) that stabilizes p53 by binding and thereby inhibiting its negative regulator MDM2.
Several lines of evidence show convincingly that the p53 and its downstream effector p21Waf1 play a crucial role in the regulation of cell cycle arrest and senescence. Overexpression of p53 [82] and p21Waf1 [83-86] autonomously induced senescence in human cells and activation of p53 by either overexpression of p14ARF [87] or nutlin-3 treatment [88] induced senescence in a p21Waf1 dependent manner in human diploid fibroblasts (HDF) and human glioblastoma cells respectively. Furthermore, inactivation of p53 or p19ARF (mouse homologue of human p14ARF) prevents senescence in mouse embryonic fibroblasts (MEF) [89-91] and human fibroblast lacking p21Waf1 can bypass the senescence growth arrest [83]. Further supporting evidence comes from studies that show that, inactivation of p53 using viral oncoproteins, anti-p53 antibodies or anti-sense oligonucleotides can extend the replicative lifespan or even reverse the senescence growth arrest in human cells [38, 92-94]. However, it should be noted that although inactivation of the p53 pathway can weaken or even reverse the senescence arrest in some cells, there is emerging evidence that it fails to do so in cells with an activated p16INK4a/pRb pathway [38, 95-97]. Despite the clear evidence of p53’s role in promoting senescence a study conducted by Demidenko and co-workers suggested that p53 can also act as an inhibitor of senescence [98]. Surprisingly, p53 was able to reverse a p16INK4a and p21Waf1 driven senescence response in human fibroblasts. Although the underlying mechanisms are not fully understood, inhibition of the mTor (mammalian target of rapamycin) pathway seems to be involved in the repression of cellular senescence [98-101].
6.1. DNA damage and senescence
The human genome is constantly exposed to genotoxic stress such as ultraviolet light, reactive oxygen species (ROS) as well as chemical and biological mutagens. To ensure the integrity of the genome cells have evolved a sophisticated safety system that can implement a cell cycle arrest to allow the repair of the incurred damage. The initial step in the complicated DNA damage repair process is the detection of DNA damage. The Mre11/Rad50/NBS1 (MRN) complex function as a DNA damage sensor is localized in nuclear foci at the sites of double strand breaks (DSBs) [102-104]. Here, the complex tethers DNA ends, processes and repairs free strands via endonuclease and exonuclease activities [105-107]. The MRN complex is also involved in the recruitment and activation of ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related) protein kinases, which in turn activate checkpoint-1/2 (CHK1/2) kinases leading to phosphorylation and thereby stabilization of a variety of target genes including p53 [108]. In the case of irreparable damage, the cell will be permanently retracted from the pool of dividing cells by the induction of apoptosis or senescence (Figure 4] [109, 110].
6.2. Drug induced senescence
Several sources of genotoxic stress including cisplatin, cyclophosphamide, doxorubicine, taxol, vincristine, cytarabine, etoposide, hydroxyurea, bromodeoxyuridine, adriamycin, bleomycin mitomycin D, interferon beta, radiation, ROS, H2O2 have been used to trigger senescence-like growth arrest in vitro and in vivo allowing a detailed analysis of the underlying signaling events [28, 111-122]. The crosslining agent cisplatin, for example, induced senescence in primary human fibroblasts and HCT116 colon carcinoma cells in a p53 and dose dependent manner [123, 124]). Interestingly, treatment of HCT116 cells with low cisplatin concentrations lead to DNA damage and senescence whereas high drug concentrations induced apoptosis via superoxide production. Furthermore, in human lung cancer cells induced p53 expression enhanced the cytotoxic effect of cisplatin whereas p21waf1 overexpression surprisingly lead to increased drug resistance [82]. Similarly, cisplatin-resistant human non-small cell lung cancer (NSCLC) cells could be sensitized to drug-induced senescence by re-expressing p16Ink4a [118]. Duale and co-workers compared changes in the gene expression profiles of a cisplatin treated human colon carcinoma cells (HCT116) and cell lines derived from testicular germ cell tumors (TGCTs). The systematic approach combining the acquired gene expression data and other publicly available microarray data identified 1794 genes that were differentially expressed including 29 senescence-related genes such as IGFBP 7, interleukin 1 and MAPK8 [125]. These findings highlight the notion that cellular response to chemotherapeutic agents is generally depending on the cellular context as well as the type and level of the stress signal.
6.3. Oncogene-induced senescence and DNA damage
In contrast to chemotherapeutic agents that directly damage the DNA, activated oncogenes do the harm by forcing the cell in uncontrolled, constitute replication cycles which leads to DNA replication stress and subsequent DNA damage [126, 127]. During this process DNA replication forks stall making the DNA more susceptible to single or double strand breaks. The subsequent activation of the DNA damage response (DDR) machinery delays cell-cycle progression by initiation of the ATM/ATR-CHK1/2 pathway and stable knockdown of any one of these DDR genes was sufficient to bypass RAS induced senescence in human fibroblasts. Specifically, in the absence of ATM, ATR, Chk1 or Chk2, human fibroblasts continued to proliferate despite Ras expression, and BrdU incorporation increased from approximately 5% in the control sample to 15% in cells deficient for a DNA damage protein. Interestingly, the inhibition of both the p16INK4a and DNA damage pathway enhanced the effect and enabled over 60% of the cells to replicate DNA [126]. In a similar study, Bartkova and co-workers showed that the suppression of ATM or p53 allowed the MRC5 and BJ human fibroblasts to bypass oncogene-induced senescence using overexpressed Mos (an activator of the MAPK pathway) or Cdc6 (a DNA replication licensing factor). However, in this report p16INK4a depletion alone did not weaken the senescence response [127].
Figure 4.
DNA damage pathway in senescence
To protect the integrity of their DNA, cells need to be able to sense DNA damage and activate response pathways that coordinate cell cycle progression and DNA repair. Ataxia telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) kinases are important DNA damage checkpoints proteins that transduce signals from the DNA damage sensors to the effector proteins that control cell cycle progression, chromatin restructuring, and DNA repair. ATM and ATR activate other kinases such as Chkl (activated by ATR) and Chk2 (activated by ATM) that phosphorylate and activate the tumour suppressor protein p53. ATM and ATR can additionally enhance p53 activity by directing p53 phosphorylation on Ser15. Activated p53 can halt progression of the cell cycle in the G1 phase, allowing DNA repair to occur and preventing the transmission of damaged DNA to the daughter cells.
7. pRb in senescence: maintaining a secure proliferative arrest
In the previous sections we have reviewed the pivotal role of the cell cycle inhibitors p16INK4a and p21Waf1 in keeping pRb in a hypophosphorylated, active state and explored the mechanisms of timing the expression of these tumor suppressors with the onset and maintenance of senescence. Here we explore the roles of active pRb in the senescence program, which go beyond the antiproliferative functions described in the cell cycle section 3.
There is longstanding evidence that pRb is required for an intact senescence program, for instance re-introduction of pRb into SAOS osteosarcoma cells that have lost its expression can cause senescence [128]. On the other hand inactivation of pRb with the viral oncoprotein E1A prevents senescence, while a mutant form of E1A that is impaired in pRb binding is unable to prevent senescence [9]. Interestingly, another mutant E1A, that is able to bind pRb but is unable to interact with the histone deacetylases p300 and p400 leads to less efficient development of senescence [9].
7.1. pRb and SAHFs
These data highlight that chromatin remodeling plays an important role in the cellular senescence program. Indeed, during senescence E2F responsive genomic promoter regions are stably repressed from transcription by the establishment of heterochromatin regions. As mentioned above (section 3) these regions are visible as microscopical “senescence associated heterochromatin foci” (SAHF) when cells are stained with certain DNA intercalating dyes such as DAPI. The term heterochromatin refers to a highly condensed protein-DNA structure, which is facilitated by modifications of the histone core molecules of chromatin and suppresses DNA access by the transcriptional machinery and thus gene expression of these regions is tightly suppressed (reviewed in [129]). The investigation of SAHF remains a progressing research field and is developing forward with improved microscopic imaging technology and the ability to isolate these complex structures and analyse them more precisely and we can expect to understand even more about their role and configuration in the future. To date we know that SAHF formation coincides with the recruitment of heterochromatin proteins by pRb when interacting with the histone deacetylase 1 (HDAC1] at E2F-responsive promoters [130]. A number of heterochromatin-associated histone modifications were characteristically found associated with SAHF. These include the reversion of histone 3/lysine 9 acetylation (H3K9Ac) and histone 3/lysine 4 trimethylation (H3K4me3) and significantly, since it is often used as a marker of senescence, the promotion of histone 3/lysine 9 trimethylation (H3K9me3) and H3K27me3. H3K9 trimethylation is a fundamental step during heterochromatin formation as it attracts HP1 proteins, which are pivotal for heterochromatin assembly [9]. It is important to highlight that senescence does not always lead to a net increase in overall H3K9me3, suggesting that SAHF formation is local and indeed targeted via pRb to E2F promoters [131]. H3K9me3 is thought to be very stable and is able to prevent histone acetylases (HATs) to catalyze histone acetylations. Histone acetylations are commonly associated with “euchromatin”, which describes actively transcribed chromatin regions. Accordingly, SAHF formation is thought to “lock” chromatin regions that encode proliferation genes and thus contributes to the very secure silencing of E2F responsive proliferation genes, which is not reversible by physiological stimuli [9]. H3K9 trimethylation associated with SAHF formation is thought to be catalyzed by either the SUV39H1 methyltransferase, which together with HP1 interacts with pRb during E2F promoter silencing in senescence [132] or the RIZ1/PRDM2 H3K9 methyltransferase, which was also shown to co-operate in pRb gene repression and is inactivated in colon, breast and gastric carcinoma [133]. Furthermore, a search for H3K9me3 interacting proteins to identify proteins involved in the senescence program identified JMJD2C, which is a H3K9 specific demethylase. Thereby it is the direct antagonist of the SUV39H1 H3K9 methyltransferase and its over-expression is not surprisingly associated with several forms of cancer [134].
Lately there is a different view about the importance of SAHF emerging and SAHF formation, may according to a recent study only be of major relevance in the oncogene induced senescence process that crucially involves DDR and the corresponding ATR signalling, as knock-down of ATR prevents SAHF formation during RAS induced senescence. The same study also found that SAHF resembling structures containing H3K9me3 do independently occur in proliferating oncogene expressing cells, however the investigators data show that these structures are not associated with E2F target promoters, which remain active. The authors concluded that SAHF structures might not be an essential feature of senescence [40].
More recently a groundbreaking study by the Narita group has combined microscopic, electron microscopic and genomic data analysis to shed more light on SAHF formation and structure. Their significant findings are that H3K9me3 and H3K27me3 may in fact not directly be involved in SAHF. Although these markers are usually associated with SAHF, the overall methylation status of histone tail lysines does not change within the genomic DNA during senescence. Moreover, the investigators found that SAHF formation was linked to pre-senescent replication timing and specific histone modifications were characteristic for early-, mid- and late replications genes. Significantly though, when they prevented SAHF formation by silencing of either pRb or the high mobility group AT-hook 1 (HMGA-1), which they and others had previously linked to SAHF formation, there was no change to H3K9me3 in proliferating cells [135] and this may explain the above-mentioned data by Micco et al [40]. Moreover, Chandra et al. reversed H3K9 and H3K27 trimethylation by either overexpressing the H3K9me3 favoring histone demethlyase JMJD2D or by silencing SUZ12, a polycomb protein involved in H3K9 and K27 methylation. Importantly, even without these methylated histone markers RAS induction still led to senescence with the occurrence of DAPI dense SAHF structures. The investigators concluded that SAHF formation is mediated through spatial rearrangement of pre-existing H3K9me3 and H3K27me3 regions but that these histone marks are not a prerequisite for the SAHF formation process [135]. Clearly, further studies are needed to fully define the combined roles of histone modifications, heterochromatin and SAHF in senescence.
Consistent with gene silencing and decreased acetylation during senescence is the down-regulation of the histone acetylases p300/CBP, which was observed in melanocytes reaching in their finitive lifespan [136].
With regard to the role of chromatin remodelling in senescence, there is also evidence that ATP dependent chromatin remodeling complexes, such as SWI/SNF are required for senescence onset in roles other than the timely expression of p16INK4a as described in section 5.1.2: The introduction of the ATPase active component of the SWI/SNF complex, BRG1, into various cell lines induced senescent features. This is attributed to the BRG1 ability to interact with pRb and participate in E2F target promopter repression [137]. However development of senescence in response to BRG1 introduction was only convincing in cells that also lack the BRG1 homologue ATPase BRM [138]. Interestingly we found that BRG1 is able to interact with p16INK4a, and since p16INK4a is required for SAHF formation it might directly be involved in this process in co-operation with BRG1. However, the absence of BRG1, by specific silencing, does neither prevent p16INK4a induced growth arrest nor senescence associated SAHF formation. It should be noted however, that the WMM1175 melanoma cells used in these experiments also express the BRG1 homologue BRM and therefore they still have functional SWI/SNF complexes even in the absence of BRG1. [139]. It still needs to be tested whether BRM also interacts with p16INK4a and whether the BRM-p16INK4a complex is involved in SAHF formation. This idea is in line with a suggested role for BRM in melanocyte senescence as it was demonstrated that BRM was recruited and required, albeit transiently, by the pRb-HDAC1 complex during the initiation of SAHF [140].
Importantly, although the p53-p21 pathway was demonstrated to be capable of inducing a number of senescent features and does so in response to DNA damage, telomere dysfunction and oncogene induced senescence [38, 97], E2F promoter silencing via SAHF formation requires an intact p16-pRb pathway [9, 141]. As expected, SAHF formation is prevented by cancer associated p16INK4a mutations [45]. Since p21Waf1 is capable of inhibiting all CDKs it remains unclear why it appears less effective in promoting a secure senescence program in involving heterochromatin formation (Figure5).
The current view is that pRb binds HDAC1 and attracts H3K9 and H3K27 methylating complexes (exemplified by SUV39H1 and EZH2/SUZ12) to promoters of E2F responsive proliferation genes leading to histone trimethylation and heterochromatin and thereby DAPI dense microscopic structures. Recent work indicates that H3K9 and H3K27, although usually associated with SAHF, may not be a strict requirement. Instead the formation of DAPI dense structures is linked to the timing of presenescent replication events [135]. This view would explain the fact that SWI/SNF including BRM has been associated in a transient manner with the build up of SAHF structures; BRM can also interact with pRb but strictly is associated with acetylated histones and replicating chromatin is acetylated [140]. The complete understanding of SAHF formation is still an evolving field. Regardless, it is widely accepted that functional p16INK4a and pRb as well as the HMGA, which accumulate at E2F target promoters during senescence, are critically required for SAHF arrangement. In regards to p16INK4a it is tempting to speculate that its specific role in SAHF formation goes beyond CDK inhibition and thus maintaining pRb in an active state.
Figure 5.
Chromatin remodeling and SAHF formation
8. Conclusion
Senescence is a potent means of tumor suppression. The mechanisms of senescence involve cell cycle regulatory protein functions in concert with the chromatin remodeling machinery to maintain a complex and secure withdrawal from proliferation. The understanding of these mechanisms is still evolving and is predicted to identify novel targets for cancer therapy.
Acknowledgments
We thank Dr Kavitha Gowrishankar for her assistance with the illustrations and Dr Roland Houben for the critical review of the manuscript.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/43112.pdf",chapterXML:"https://mts.intechopen.com/source/xml/43112.xml",downloadPdfUrl:"/chapter/pdf-download/43112",previewPdfUrl:"/chapter/pdf-preview/43112",totalDownloads:5183,totalViews:1132,totalCrossrefCites:3,totalDimensionsCites:7,totalAltmetricsMentions:0,impactScore:2,impactScorePercentile:76,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"May 25th 2012",dateReviewed:"October 4th 2012",datePrePublished:null,datePublished:"February 20th 2013",dateFinished:"February 16th 2013",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/43112",risUrl:"/chapter/ris/43112",book:{id:"3429",slug:"senescence-and-senescence-related-disorders"},signatures:"Therese Becker and Sebastian Haferkamp",authors:[{id:"89455",title:"Dr.",name:"Sebastian",middleName:null,surname:"Haferkamp",fullName:"Sebastian Haferkamp",slug:"sebastian-haferkamp",email:"Haferkamp_S@klinik.uni-wuerzburg.de",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Würzburg",institutionURL:null,country:{name:"Germany"}}},{id:"161435",title:"Dr.",name:"Therese",middleName:null,surname:"Becker",fullName:"Therese Becker",slug:"therese-becker",email:"t.becker@unsw.edu.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Senescence features and biomarkers",level:"1"},{id:"sec_3",title:"3. pRb in cell cycle regulation ",level:"1"},{id:"sec_4",title:"4. The role of the tumor suppressor p16INK4a in senescence",level:"1"},{id:"sec_5",title:"5. Timing of Senescence by repression and activation of p16INK4a",level:"1"},{id:"sec_5_2",title:"5.1. p16INK4a repression",level:"2"},{id:"sec_6_2",title:"5.2. p16INK4a expression",level:"2"},{id:"sec_8",title:"6. The role of the p53/p21 pathway in senescence",level:"1"},{id:"sec_8_2",title:"6.1. DNA damage and senescence",level:"2"},{id:"sec_9_2",title:"6.2. Drug induced senescence",level:"2"},{id:"sec_10_2",title:"6.3. Oncogene-induced senescence and DNA damage",level:"2"},{id:"sec_12",title:"7. pRb in senescence: maintaining a secure proliferative arrest",level:"1"},{id:"sec_12_2",title:"7.1. pRb and SAHFs",level:"2"},{id:"sec_14",title:"8. 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Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia
Department of Dermatology, Venereology und Allergology, University Hospital Würzburg, Germany
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1. Introduction
TLD method is considered an important technique as it can store radiation in trap centers for long period. Glow peaks of thermoluminescence dosimeters are later measured and discussed based on some models related to the physical changes in the band structure of dosimeter because of ionizing radiation exposure. A wide range of substances exhibits thermoluminescence (TL) phenomena after being exposed to nuclear radiation such as activated LiF and CaSO4. Thermoluminescent dosimeter (TLD) emits light when heated up after being irradiated. Due to this special property, TLD could be used as a radiation dosimeter. TLD has many advantages and sensitive to different types of radiation. A dosimeter of higher TL response to thermal neutrons is most commonly used in mixed radiation fields (neutron and gamma ray). The sensitivity of TLD to neutrons depends on the detector compound type, environment and neutron energy. For neutron dosimetry purposes, the neutron and gamma ray dose contribution must be separated by using two different detector types of TLD. The first one should be sensitive to gamma and the other should be sensitive to neutrons plus gamma (as LiF-700 and LiF-600) [1, 2].
The response of fast neutrons depends on the cross-section for the interaction in TLD material and the relative TL efficiency, which depends on the linear energy transfer (LET) of the reaction products in the first place. The response to intermediate-energy depends mainly on the cross-section of the reaction, which may take place with the composite material of the TLD.
1.1 TLD applications in neutron and gamma ray dosimetry
Generally, there are three types of TLD used for neutron dosimetry as follow:
1.1.1 Albedo neutron dosimeter
A considerable fraction of intermediate and fast neutrons can be slowed down to epithermal neutron energy and backscattered in the human body, interacting with the sensitive TL material. An albedo neutron dosimeter is a type of neutron monitor and is typically used in the neutron energy range of 0.2 eV to around 0.5 MeV. The slow neutrons interact with TL material, usually through 6Li (n,α) 3H reaction, and the resulting induced charged particles to stimulate the TL material. Recently, some of albedo TLD dosimeters depend on 10B (n, α) 7Li reactions. Because neutron TL sensitive material responds to gamma radiation, and neutrons are accompanied by this gamma radiation, another TLD is usually utilized in conjunction with TLD with a gamma ray.
The neutron albedo dosimeter measures (a) direct fast neutrons, (b) direct thermal neutrons, and (c) albedo neutrons reflected from the body. This type of dosimeter uses Lexan polycarbonate and/or CR-39 foils, as well as two 10B (n, γ) 7Li converters in a cadmium cover, to efficiently measure the three neutron dosage components independently [3, 4, 5]. Fast neutron dose is assessed in CR-39 by counting proton recoil tracks, while thermal neutron dose is determined by counting α particles created during the process. Because the albedo dosimeter has a sensitivity range of 0.3–30 mSv, it is advised that it be used as a backup dosimeter to assist in the assessment of high dose values in the event of accidents or patients receiving neutron therapy.
In another application, the 10B (n, α) 7Li reactions with the backscattered albedo neutrons employed with Electret’s ionization chamber proposed by Seifert et al. [6, 7]. In this chamber, induced 7Li from the ionization of the gas in the chamber worn on the body’s surface in the above reaction instance. Under saturation conditions, produced charge carriers with the corresponding polarity travel to the surface of the electret. As a result, the change in the electrets voltage is a direct measure of albedo neutron fluence and an indirect estimate of primary neutron fluence. In general, the advantages of albedo TLD dosimeter are: they are relatively inexpensive and can be reused, easily fabricated, lightweight to wear, Readout is simple and can be automated, Insensitive to humidity.
While their disadvantages are: Some of TLD exhibit fading, TLD is sensitive to gamma-ray, they must be worm properly or serious errors can be resulted, the measured values of TLD does not give permanent record as the track detectors, their sensitivity is highly dependent on the angle and energy of incidence radiation.
1.1.2 Hydrogenous radiator TLDs
In this type of dosimeters, the fast neutrons knock out protons from hydrogenous material mixed with the phosphor, and the protons dispel their energy in the dosimeter. In this method, the hydrogenous substances are called proton radiators [8]. This technique has demonstrated that TL materials mixed with hydrogenous material can detect fast neutrons, but the sensitivity needs to be improved by one order of magnitude before using in personnel neutron dosimetry.
1.1.3 LET-dependent deep trap TLD glow peaks
The fast neutron interacts directly with the TL material as calcium fluoride (CaF2:Tm) which is commercially called TLD-300. This type has a glow curve with two glow peaks and the peak temperature Tm centered 150 and 250°C, respectively. The higher temperature peak (250°C) has a greater response to the fast neutrons. TLD-300 dosimeter CaF2: Tm (0.35 Mol. %) showed a lower detection limit of about 0.3 mSv from 241Am-Be source.
2. Characteristic of TLD phosphors
2.1 The glow curve
The term “Glow curve” refers to the graph of TL as a function either of temperature or of time as shown in Figure 1.
Figure 1.
TLD glow curve and time–temperature profile (TTP).
Glow curves have the following features:-
The glow curve of a certain phosphor probably best characterizes that phosphor. For example, the appearance of glow peaks only at low temperatures implies that the phosphor loses its stored TL with time, and therefore would be unsuitable for long-term measurements.
A peak at very high temperatures indicates a phosphor that will produce infrared radiation at the temperature necessary to release the TL. This is a problem for the instrumentation.
A glow curve without well-defined peaks makes the selection of the appropriate end for integration difficult. Ideally then, a glow curve should reveal only a single thermoluminescent peak, which occurs at a temperature high enough to ensure room temperature stability but not so high as to present instrumental problems. However, the temperature at which a TL peak appears is quite affected by the heating rate.
The following factors may affect the shape of the glow curve:
2.2 TL sensitivity
The sensitivity of TLD should be evaluated for competitor’s materials to determine the dose linearity, sub linearity or supralinearity behavior of phosphors. The sensitivity and thermal stability of glass samples were found to be dependent on both the starting materials and the method of preparation in Refs. [9, 10, 11, 12, 13].
2.3 Dose rate dependence
TL dosimeters, in general, have demonstrated no dose rate effects over a wide range.
2.4 Stability
TL is the release, in the form of visible light, of energy absorbed from previous irradiation. The rate at which this energy is released is dependent upon the phosphor temperature and increases sharply at a higher temperature. Even though the concept of “glow peak temperature” that temperature at which the maximum of the glow peak occurs, is both useful and easily demonstrated. It should be remembered that a finite rate of loss of stored energy exists even for much lower temperatures. If a phosphor shows an insignificant loss of TL at room temperature, it is said to have good stability.
3. TL kinetics
The physical process leading to the emission of TL from a sample is related in most cases to the traffic of charge carriers, usually electrons and holes, between different imperfection states in the solid sample. Studying the kinetics of the TL process means the investigation of electron–hole transitions between energy states in cases of both the irradiation of the TL sample and the readout processes. Although, in most experimental situations the TL curve consists of several overlapping peaks, it is appropriate to start the discussion by dealing with a single peak to understand the basic process. For most purposes, it is not necessary to assume that the glow curve consists of only one peak. The analysis of a single peak may just be valid if a series of peaks occur, provided that the peak of interest is sufficiently separated from others, either because it appears separately or because we have an efficient method to isolate it from the rest of the curve.
3.1 First kinetics order
If n is the number of trapped electrons in the sample, which is maintained at constant temperature T, n decreases with time t as:
The rate of photon emission, and hence the rate of release of electrons from traps to their rate of arrival at luminescence centers, determine the strength of the TL glow peak [14].
Iα−dndt→I=−Cdndt=nCSexp−EKTE3
Where C is a luminescence efficiency constant.
When the dosimeter is heated with rate β =dT/dt. Then we may write dn/dt as:
It should be noted that I(T) in Eq. (6) dependents on two physical parameters, the activation energy E, and frequency factor S, and the heating rate β. The activation energy is the minimum energy required to release the electrons from their traps. Differentiation of Eq. (6) with respect to the temperature gives:
∂I∂T=noSCexp−EKTexpfT∂fT∂T+expfTexp−EKTEKT2
Where, fT=−Sβ∫Texp−EKTdT
At T=Tm→∂I∂T=o
→sβexp−EKTm=EKTm2E7
where Tm is peak position or the temperature at maximum intensity.
Equation (7) describes the condition of the occurrence of the maximum intensity and the determination of the corresponding temperature, which we call, Tm. The reduction in the second exponential function is faster than the growth in the first exponential function above this temperature, and the product function decreases until the traps are fully depopulated. This accounts for the end of the peak. A theoretical (calculated) glow peak plotted using Eq. (6) is shown in Figure 2. The main feature of the first-order peak is that the asymmetric, is such that at temperatures over Tm, the reduction is faster than the rise at low temperatures.
Figure 2.
Theoretical glow peak plotted using the first kinetics order equation.
The initial concentration no appears in the first kinetics order acts only as a constant multiplying the temperature-dependent factors. In this particular case of the first kinetics order, changing the initial concentration no has no effect on the curve’s form because adjusting the intensity at each temperature has the same proportional effect. Figure 3 shows several glow peaks with different no. One of the aspects of this fact is that Tm is independent of the initial concentration no.
Figure 3.
Glow curves plotted using the first-order kinetics equation for different no.
This appears well in the condition of the Tm described by Eq. (7), where no does not appear in the equation. This property of the independent of Tm on no is specified to the first-order case, and will not occur for most of the other kinetics possibilities [13]. Eq. (7) can be written in the following form:
βEK=STm2exp−EKTmE8
We see that changing the heating rate β must change Tm in a such way that equality still holds. The term Tm2exp−EKT is monotonically increasing with Tm, therefore increasing the rate β will immediately cause Tm to increase. Since Tm2exp−EKT is a very rapidly increasing function of Tm, only a small change of Tm may accompany a large variation in the heating rate β, this variation is usually rather easily observable.
3.1.1 Second kinetics order
One assumption made up by Randall and Wilkins [14] which led to the first kinetics order was that once a charge carrier is thermally elevated into the band, it is bound to recombine rather quickly with an opposite sign carrier trapped in a recombination center. Gralick and Gibson [15] considered another case in which the free carriers may re-trap with equal retrapping recombination probabilities with the further assumption that the concentration of electrons in traps and holes in recombination centers are equal during the entire process. Denoting the total number of traps of the given type (free electrons or holes) by N, they found the kinetics equation:
I=−dndt=SNn2exp−EKTE9
where (S/N) is a constant having units of m3s−1, which we may denote by S′. Then we have
I=−dndt=S′n2exp−EKTE10
where S′ is called “pre-exponential factor” which does not have the same meaning of “frequency factor” as was in the first kinetics order.
where Eq. (12) represents the intensity of a glow peak according to the second kinetics order model. At high temperature, the second decreasing function dominates so that the product function is decreasing. Somewhere between two regions the glow curve, therefore, reaches its maximum. Figure 4 Displays a hypothetical glow peak plotted using Eq. (12).
Figure 4.
Theoretical glow peak plotted using the second-order kinetics equation.
The condition of the maximum is found by setting the derivative of Eq. (12) to zero (dI/dT = zero) [16], then we may find:
Multiply by 1+S´βno∫Tmexp−EKTmdT3 and rearrange, one gets
1+S´βno∫Tmexp−EKTmdT=2KTm2S´noβEexp−EKTmE13
Then Eq. (13) represents the condition of the peak maximum according to the second kinetics order. As can see no appears in the equation and therefore we expect that Tm will depend on no. It can be shown numerically or analytically, that increasing no causes Tm to decrease. An exception to this rule of the shift of a second-order peak with no can be found by Wrzesinska [17], who writes Eq. (10) with S′=Sno. The resulting peak has all the regular features of a second-order peak (e.g., symmetry properties) except one can write S instead of noS’ and thus Eq. (10) turns out to be independent of no. The ensuring Tm is, therefore independent of no. It is not clear, however, what physical circumstances result in S′ being equal to S/no [17]. Other aspects of the dependence of the glow curve on the initial concentration no are paramount importance when we are interested in a TL as a dosimetric tool. In many cases, one associated the initial concentration with the imparted dose and then the dependence of different parts of the glow peak on no is important. In the first kinetics order, since the intensity at each point is multiplied by the same factor while changing no, the total area varies with the same amount so that the total area is proportional to no. Its occurrence in second-order peak can be illustrated by integrating Eq. (9) with respect to time from zero to infinity;
∫0∞Itdt=−∫nondn=no−n∞=noE14
Both in the first order and second order, as well as other cases, n∞ is zero and therefore the integral, which represents the area under the glow peak is equal (in appropriate units) to no.
Now we can consider the dependence of different portions of the second-order peak on no. First, we shall study the dependence of I on no for a given temperature T. In the initial rise range, Eq. (12) reduces to:
IT≅no2S′exp−EKTE15
This shows immediately that for a given temperature in this range the dependence of I on no is superlinear, namely I α no. It is to be emphasized that it is true only in the initial rise region; as already shown the total area is proportional to no and different dependencies are expected on other portions of the curve. Using the maximum condition equation and approximation to ∫Texp−E/KTdT, it can be shown that the two terms in the brackets in Eq. (12), namely unity and noS′βToexp−E/KTdT are more or less equal at T = Tm. At higher temperature, the latter term increases substantially and the unity can be neglected so that we obtain:
I≅S′no2exp−EKTS′βno∫Texp−EKTdT−2
yields→I≅S′exp−EKTS′β∫Texp−EKTdT−2E16
The main point in Eq. (18) is that the term includes no cancel. This means that at a higher temperature range the TL intensity is independent of no for any given temperature [17].
Figure 5 shows plotted glow peaks using Eq. (12) for different no. In the low-temperature range, the TL intensity appears to depend on no. As no increases, Tm decreases which makes the peaks appear to be shifted to the low-temperature side. As the temperature increases the effect of no on the peak starts to decrease which makes the peaks approach each other’s on the high-temperature side.
Figure 5.
Plotted glow peaks using the second-order kinetics equation for different no.
3.1.2 A single TL peak analysis
As seen in Figure 6, the concentration of the trapping state is denoted by N (m−3), with n(t) (m−3) being filled by electrons at time t(s). These electrons can be thermally elevated into the conduction band by crossing an energy barrier of E (eV) at a rate proportional to exp.(−E/kT), resulting in a concentration of free electrons nc(t) (m−3). Following that, these can be retrapped in a similar trap with a re-trapping probability An or recombined with a trapped hole in a center with a recombination center probability Am, generating a photon with the recombination center energy h. A set of three simultaneous differential equations governs this operation. The following factors influence the recombination process:
Iαncmyields→I=−dmdt=AmncmE17
where n, m, and nc are the trapped electron, hole in the center, and free-electron concentrations, respectively, and (dm/dt) is the recombination rate. This means that the amount of light emitted is proportional to the pace at which m decreases. The rate of recombination is proportional to both the instantaneous concentration of free electrons nc and the concentration of hole centers m, the proportional constant Am (m3 s−1). The product of cross-section recombination σ (m2) and thermal velocity is commonly used to calculate this value (m.s−1). The second equation is concerned with the movement of electrons that have been thermally liberated from the trapped condition. The rate of release of these electrons –dn/dt is proportional to the trapped electron concentration n (m−3) and the Boltzman constant exp.(−E/KT), with S serving as the proportional constant (s−1).
Figure 6.
A general treatment of the charge carriers’ transitions in the TL sample.
However, the actual rate of change of n is also related to the retraping term. The rate of retraping is proportional to the concentration of free electrons nc, and the unoccupied trapping states N-n, the proportional factor being the recombination probability An(m3s−1). Thus, the second combined equation is given by:
−dndt=Snexp−EKT−AnncN−nE18
The third equation is that of charge neutrality. In its simplest form, it should read m = n + nc. Taking the first derivative with respect to time, the charge neutrality condition can be written as:
dmdt=dndt+dncdtE19
yields→dncdt=Snexp−EKT−ncmAm+N−nAnE20
This equation has been given by Adirovitch [18] for phosphorescence and by Halperin and Braner [19].
Now let us discuss the kinetics of the process in more general terms and see how the simplified cases of first, second, and more general cases emerge from Eqs. (17)–(20). Two simplifying assumptions were first made by Adirovitch [18] and later by many other investigators [19, 20, 21, 22, 23]. These are related to the relation between the concentration of the electrons in the conduction band and in traps and to the rate of change of these concentrations, namely:
dddt≪dndt,nc≪nE21
Although, it seems to be the same connection between these two conditions, basically they are two separate relations and the occurrence of one does not necessarily imply the other. With these assumptions, Helperin and Braner [19] found the expression:
I=−dmdt=mAmmAm+AnN−nSnexp−EKTE22
Since this equation contains two unknown functions, n(t) and m(t), it cannot be solved without further assumption. As mentioned, Randall and Wilkins [14] wrote their first-order equation assuming strong recombination. This can be expressed in more specific terms. If we assume with relation to Eq. (22) that:
mAm≫N−nAn
The condition of Eq. (22) is the relation between functions rather than parameters. It is, therefore, possible that at the low-temperature range of a glow peak, the strong inequality holds, and at higher temperatures where m and n decreases, the inequality “weakens” may be inverted. This may result in a shift from first-order behavior to non-first-order behavior within the same peak [24].
Then we see that Eq. (23) takes the same form of Eq. (3). For linear heating rate function, the general solution of Eq. (23) is given by Eq. (24):
I=noSexp−EKTexp−Sβ∫Texp−EKTdTE24
Then from Eq. (22) with Randall and Wilkins [14] assumptions, we reached the first kinetics order equation.
The abovementioned second kinetics order, resulting from different assumptions associated with Eq. (22). In one set of assumptions, one can take n(t) = m(t) which is not very different from the parametric equality no = mo once the assumption nc≪n is made.
In addition, we have to assert the retraping dominates [15]
AnN−n≫mAmE25
We also suppose that the trap is far from being saturated, i.e., the retrapping duration.
Alternatively, one can assume, in addition to the concentration equality, that An = Am [18] which yields:
I=−dmdt=SNn2exp−EKTE31
Then Eq. (22) takes the same form of Eq. (8) which is found by Gralick and Gibson [15]. Where Eq. (30) sums up both these possibilities by employing the parameter S′ (m3s−1), the pre-exponential factor that replaces AmSAnN in one case and S/N in the other. The solution of Eq. (30) is given by Eq. (32)
I=S′no2exp−EKT1+S′βno∫Texp−EKTdT−2E32
It should be emphasized that two cases discussed so far, namely first and second kinetics order, are only special cases in a sense, extreme cases and the general case described by equations Eq. (17) through Eq. (19) may be neither first nor second order even if the simplifying conditions of Eq. (21) are assumed to be general. The resulting Eq. (20) consists of many intermediate cases that do not have a distinct kinetics order. Although, some researchers still attempt to determine for every TL peak a first or second kinetics order [25].
Several attempts [16, 26] have been made to add a third parameter to the two basic ones, the activation energy E and the pre-exponential constant S′ (or S), all the attempts extend the “order parameter” implied when talking about first or second-order peak. The order parameters considered so far as a discrete magnitude assuming the value of 1 and 2 can be extended to be a continuous parameter. It is to be noted, however, that the addition of a third parameter is in principle one step in the right direction since the general treatment should include eight parameters (E, S, Am, An, N, no, mo, nc). The best-known way of including the third parameter is that of general kinetics order, b, according to which one can assume that the glow peak is governed by [25].
I=−dndt=S′nbexp−EKTE33
The kinetics order, b, is normally considered to be between 1 and 2, but it can occasionally exceed this range [13]. The rationale behind writing Eq. (33) is as follows: it is readily seen that a first-order peak is asymmetric, where a second order peak is nearly symmetric. Following Halperin and Braner [19] and Chen [16] we can define the symmetry factor μg as:
μg=δωE34
where δ=T2−Tm,ω=T2−T1 as it is shown in Figure 7, and T1 and T2 are the low and high temperatures on half- maximum intensity, respectively. It has been shown [16] that for the first kinetics order, μg≅0.42 and the second kinetics order, μg≅0.52.
Figure 7.
Parameters used in the calculation of the symmetry factor.
Of course, intermediate symmetries represented by different values of μg are found and the simplest way to present them by taking 1<b<2 in Eq. (30). Chen [16] has shown that μg changes from 0.42 to 0.52 as b increasing from 1 to 2. The solution of Eq. (33) for linear heating rate β, is given by:
I=Snoexp−EKTb−1Sβ∫ToTexp−EKTdt+1−bb−1E35
where S=S′nob−1.Eq. (35) represents glow peak intensity according to the general kinetics order.
A few words of caution are in order with respect to this treatment. First, although Eq. (34) has been shown to quite accurately described measured TL peaks [27, 28], it is to be noted that in most cases it is only an empirical presentation and is not based on the three differential equations [Eqs. (17) up to (19)], seem to be more physically significant. However, the general order case is still important because it can handle intermediate circumstances and smooth the first and second-order cases as b1 and b2, respectively.
3.1.3 General-order kinetics
May and Partridge supposed the empirical equation that has been suggested to explain the thermoluminescence glow peak if the first or second-order kinetics do not describe the glow peak. The equation is namely the general- order kinetics and written by:
I=n0s′′exp−E/KT1+b−1s′′/β∫T0Texp−E/T′KdT′bb−1
Hence s′′=sNn0 is called the pre-exponential factor, b the order of kinetics and the rang supposed between 1 and 2 but sometimes this rang has able to be greater than those. The pre-exponential factor s′′ is constant for given the dose, however, it differs with changing the absorbed dose withn0.
3.1.4 Trap parameters evaluation techniques
3.1.4.1 Empirical methods
We can deduce that the higher the peak temperature Tm, the higher the activation energy Urbach [29], and Urbach [30] found empirically for KCl crystals:
EeV=TmK500E36
This can also be written as E = 23KTm and it differs according to the types of the sample. Halperin [19] deduced E = 38 KTm for NACL samples, and Miller and Bube [31] arrived at E = 39 KTm for LiF.
The maximum intensity of the peak, according to Randall and Wilkins [12, 13], occurs around the temperature where the electron escape probability is 1 s-1. As a result of Eq. (1), we have:
P=Sexp−EKTm=1yields→E=KTmlnSE37
3.1.4.2 Initial rise method
According to Eqs. (6), (12) and (3), we can say that at the start of the glow peak (initial rise region) the TL intensity is proportional to exp−E/kT, irrespective of whether the first kinetics order is obeyed or not [32]. This temperature relationship persists until the quantity of trapped electrons is drastically reduced. Hence, by plotting Log (I) versus 1/T, the value of E can be obtained from the slope of the straight line obtained. As a result, using the equation: it is possible to calculate E without knowing the frequency factor S:
E=−KlnI1TE38
From Eq. (6), we see that when T is slightly greater than Tm, the argument of the second exponential is very small and therefore the value of the exponential function is close to unity and varies very slowly with temperature. The temperature dependence of I(t) is therefore dominated by the first exponential function, however the second exponential function decreases with increasing temperature and at higher temperatures it decreases very rapidly [13].
Therefore, the range of the initial rise must be chosen in which the second exponential function has minimum influence on the TL intensity temperature dependence. Therefore, it is necessary to restrict the temperature range such that the TL intensity does not exceed one-tenth of the maximum intensity [32].
Between temperatures T1 and T2 (both < Tm) corresponding to values equal to a1Im and a2Im respectively as in Figure 8, where:
Figure 8.
Extracted parameters from “Christodoulides expression” are to correct the value of the activation energy evaluated by the initial rise method.
a2≤0.5,a2a1≥5E39
On the temperature scale, a series of points were taken at equal intervals and plotted as ln(I) versus (1/T). The value Ec can then be calculated from the slope of the straight line as the energy determined by the initial rise technique; this value is smaller than the real activation energy E by the amount that grows as a1 and a2 increase. Christodoulides [33] devised the following expression for the corrected energy E in terms of the measured values Ec, a1, and a2:
E=1+0.74a1+0.082a2Ec−2a1+0.22a2Tm11605E40
The range of applicability of this equation is restricted by:
10≪EKTm≪100E41
3.1.4.3 Peak shape method
Grossweiner [34] established the first peak shape approach for first-order peaks, writing:
E=1.41KTmT1τE42
Where: Tm is the temperature at the maximum intensity, T1 is the temperature at the half of the maximum intensity in low-temperature side, τ=Tm−T1 as in Figure 9. Grossweiner used the coefficient 1.51, which was later [20] amended to 1.41. Lushchik [35] developed a method for evaluating the activation energy by utilizing the high-temperature half width δ=T2−T1 for first peaks he suggested:
Figure 9.
Peak shape method used to calculate the activation energy.
E=KTm2δE43
and for second-order peak:
E=2KTm2δE44
Chen [16] improved these equations by adding a factor of 0.976 in front of the former and replacing the factor 2 by 1.71 in the latter.
Halperin and Braner [19] have derived their equations for both first [Eq. (45)] and second kinetics orders [Eq. (46)]:
E=1.51KTm2τ−3.16KTmE45
E=1.81KTm2τ−4KTmE46
Chen [16] managed to establish expressions for general kinetics order, which is dependent on the geometry factor of the glow peak which is defined by Eq. (35):
E=CφKTm2φ−bφ2KTmE47
Where φ stands for τ,δ,ω and the values of Cφ and bφ for the three methods are:
Cτ=3μg−0.42+1.51E48
Cδ=7.3μg−0.42+0.976E49
Cω=10.2μg−0.42+2.52E50
bτ=4.2μg−0.42+1.58E51
bω=1E52
bδ=0E53
whereμgis geometrical shape factor that equalδω.
3.1.4.4 Various heating rates method
As mentioned above about Eq. (7), Tm changes with the heating rateβ, writing Eq. (7) twice for heating rate β1 and β2 with maximum temperatures Tm1 and Tm2 we get [36]:
E=kTm1Tm2Tm2−Tm1lnβ1β2−lnTm12Tm22E54
The activation energy that will be evaluated from Eq. (54) will be of course in accord with the first kinetics order only. However, Chen and Winer [37], Chen and Kirsh [38] showed that it can be used as a very good approximation for nonfirst-order cases as well.
The maximum condition, Eq. (16), can also take the following form:
−lnβTm2=EK1Tm+lnESK
According to this equation, Hoogenstraaten [39] suggested using several heating rates, a plot of ln(β/T2m) vs. (1/Tm) should yield a straight line of slope E/K, so that the activation energy is evaluated. Extrapolation to 1/Tm → 0 gives the value of ln(E/SK) from which the frequency factor is immediately found. It was shown that a plot of ln(Im) versus 1/Tm for various heating rates usually yields a straight line too and the activation energy can be extracted similarly. It is to be noted from the theoretical point of view that β should be varied in as board a range as possible. However, this may cause various experimental difficulties. At very low heating rates, the maximum intensity will be low and in fact, the peak smeared, thus not allowing effective extraction of the experimental parameters. At high heating rates, a delay between the sample temperature and that of the measuring device impairs the temperature measurement. Moreover, temperature gradients within the sample usually occur at high heating rates which result in a smearing effect of a different kind. In practice, one should therefore compromise on a relatively narrow range of heating rates [10].
3.1.5 Three points method
A new technique was developed by Rasheedy [25], to evaluate the trap parameters from the measured glow curve according to the general kinetics order.
The behavior of a phosphor’s TL intensity is determined by the following equation, [40], for generic kinetics order.
I=−dndt=nbNb−1Sexp−EKTE55
Where I is the intensity of the TL, n (cm−3), is the electron concentration trapped at time t(s), N (cm−3) is the traps concentration and K (eV/oK) is the Boltzman constant. Eq. (55) is more general than the two equations describing the first and second kinetics orders.
Eq. (55) is a modification of Eq. (33) in which the pre-exponential factor is defined as: S′=SNb−1 instead of ′=Snob−1 .The solution of Eq. (55) is given by Rasheedy [40]:
I=noS"exp−EKT1+b−1S"β∫ToTexp−EKTdTbb−1E56
Where the pre-exponential factor S″ = S(no/N)b−1 which is constant for a given dose but it varies with changes in the absorbed dose, i.e., with n0.
This method is based on the proportional of the concentration of populated traps during the running of the TL to the area under the glow peak.
Ix is the TL intensity at temperature Tx at any portion of the glow peak as shown in Figure 10, then Eq. (55) becomes:
Figure 10.
Three points method used by Rasheedy [25] to investigate the equations used to calculate the trap parameters.
Ix=AxbNb−1Sexp−EKTxE57
Where Ax is the area under the glow peak between the temperatures Tx and Tf (the final temperature of glow peak). Similarly, we have:
Iy=Ixy=AybNb−1Sexp−EKTyE58
Iz=Ixz=AzbNb−1Sexp−EKTzE59
Where Iy and Iz are the TL intensities at temperatures Ty and Tz, respectively.
Then, the order of kinetics b can be obtained from Eq. (62). Once the order of kinetics b is determined, the activation energy E(eV) can be determined by using Eq. (60) or Eq. (61).
Since, at T=Tmyields→∂I∂T=0
From Eq. (56) and using Eq. (59) leads to the following expression [41]:
S"=βEexpEKTmbKTm2−b−1EexpEKTm∫ToTmexp−EKTdTE63
A simple analytical method has been developed to obtain the relative value of no in the case of general kinetics order [41]:
no=ImexpEKTmS´E64
where Tm, and Im can be obtained from the shape of the glow peak.
Thus, by calculating the kinetics order b, the activation energy E, and the initial trapped electrons number for many points that cover sufficient range on the glow peak, and taking the average value for each parameter, one can determine the trap parameters according to the general kinetics order.
3.1.6 Glow curve analysis (peak shape methods)
A review of the expression used in an intercomparison of glow curve analysis computer programs to evaluate TLD-100 glow curve is given in Ref. [42] where I(T) is written in the following form:
IT=ASexp−EKT1+Sb−1β∫ToTexp−EKTdtb1−bE65
where: A = area (counts); b = kinetics order; E = activation energy; I = intensity (counts per s, counts per K); S = frequency factor (s−1).
On the other hand, Eq. (66) is based on first order kinetics which was used by Puchalska, [43], to develop glow-curve analysis software, in the following form:-
where the constants a0, a1 … and b0, b1 … are listed in the followings: -
ao=0.26777bo=3.9584
a1=8.63476b1=21.099653
a2=18.05901b2=25.63295
a3=8.573328b3=9.573322
Equation (68) will be used throughout our results which give better fitting to the resultant deconvoluted peaks. Different software was developed by Ratovonjanahary et al. [32], which uses the first kinetics order with an approximation of the second kinetics order. In this software the following equation was used:
IT=Imexp1+EKTT−TmTm−T2Tm2expEKT−T−TmTm1−∆−∆mE68
where,
∆=2KTE,∆m=2KTmE
Such a technique was also developed to analyze the glow curve using Eq. (53) by Rasheedy [41], which used the value of the trap parameters obtained by the three points method.
4. Modern clinical applications of TLD
TLD is widely used in various clinical fields for different purposes. The key reasons are undoubtedly their widespread availability, well-studied dosimetric characteristics, and applicability across a broad dose range. Imaging and Radiation Oncology Core-Houston IROC-H conducts remote dosimetry audits on MV photon and electron beams. IROC-H usually used integration between TLD-100 and other dosimetry system like nanoDot or diode systems for achieving the dose commissioning and calibrating dosimetry systems in an acrylic mini-phantom [44]. The failure rate was recorded in dose curves after modeling of the TPS (RayStation-Elekta Inc.) using phantom tests, which was not observed by patient-specific IMRT QA. Such failure was related to little changes in the MLC leaf-tip offset rather than leaf-tip width. Koger and his team [45] in IROC-H prosed four labeled TLD distributed in an anthropomorphic head-and-neck phantom for correcting such failure, (see Figure 11). It was utilized a 3D diode array were used in addition to assess the detectability of modeling mistakes [45].
Figure 11.
TLDs were labeled in head-and-neck phantom at IROC-H [45].
Another crucial issue is to increase the staff’s awareness about radiation safety and enhance radiation protection against unnecessary radiation doses. For such purpose, TLD-100 was recently used to validate occupational doses both inside and outside the nuclear medicine department, radiation protection purposes as well as the dose rate distribution around the positron emission tomography or computed tomography (PET/CT) [46].
Some recent studies were envisaged to see how the department compared to reports from other centers across the world in terms of the annual number of procedures and exposure limits, and to see if there was an opportunity for further radiation protection enhancements. As an example, personal TLD was calibrated to estimate the personal equivalent dose Hp (10) and Hp (0.07) at PET/CT. It was used for assessing the employee’s exposure [47]. On the other hand, TLD rings personal dosimeters were worn by surgeons in their fingers through sentinel node biopsy procedure to measure personal doses Hp(10) and Hp(0.07), as well as ambiental dose for operating theater and during injection [48]. This will assure that personal equivalent doses are within the acceptable annual determined limits [49].
Other important recent TLD application in diagnostics is using an anthropomorphic phantom that modeled the reference person to get a conversion coefficient connecting dose area product (DAP) to effective patient dosage. They concluded that the effective dosage at the clinical dark-field radiography system, which generates both attenuation and dark-field pictures, is within the range of chest radiography standard dose values [50].
TLDs showed to be an excellent choice for skin dosimetry. Omojola et al. [51] used TLD in measurements of 3D skin dosimetry and verify their results using TPS planning verification at specific spots in the phantom. A full perspective of the dose distribution was achieved; however, they revealed that regions outside the PTV require special attention [52, 53, 54].
In addition, in the field of proton therapy, a novel tissue-equivalent TLD-sheet of manganese doped lithium triborate showed a valuable and effective dosimetry technique. It may also be a great in vivo skin dosimetry instrument for proton treatment due to its flexible and reusable properties. Despite the presence of significant energy dependences in the Bragg peak region, the response properties studied in this work, including as reproducibility, fading effects, dosage linearity and dose homogeneity are acceptable [55].
Monte Carlo (MC) simulation is considered a good tool to understand well the TLD [56]. Some algorithm methods based on MC as if pencil beam could be involved in accurate dose in MV radiotherapy calculations. It could be useful to calculate the spectrum inside the detector based on four categories primary photon and electrons and secondary photon and electrons [57].
On the other hand, Low-energy (100 keV) photons (x-rays and gamma) have been widely employed in biological research and medical applications for more than a century, including mammography, fluoroscopy, general radiography, computed tomography, and brachytherapy treatment, among others. The majority of electrons created by low photon energy beams have energies below 10 keV, according to research. The physical processes through which these low-energy electrons interact with matter, on the other hand, are still unknown. Furthermore, it is commonly thought that all energy put within a dosimeter-sensitive volume is converted into a response. However, this assumption could be inaccurate because some of the deposited energy could be utilized to build flaws or damages at the molecular and atomic levels [58].
The hybrid-functional density theory (H-DFT) has shown to be a promising tool for localizing secondary electrons within a dosimeter volume and calculating the energy spent on creating defects or colors centers, among other things, when it comes to the relationship between the energy deposited and the response of a dosimeter. Following that, the quantity of energy that can be truly turned into a dosimeter response following exposure to ionizing radiation would be more accurately determined.
5. Conclusion
The aim of this chapter is concerned with TLD materials, measurements and recent various applications in clinical and industrial fields. TL kinetics are also covered in details due to their importance in knowing traps parameters and band structure-related phenomena that are responsible for TL phenomena. Modern clinical applications of TLD are also covered like quality assurance purposes for proton, x-ray and gamma radiotherapy based on phantom tests. In addition, we shed spot on using TLD for recent accurate methods for skin dose evaluation under IMRT/VMAT radiotherapy. Special attention should be oriented to hybrid-functional density theory Monte Carlo simulation to model TL dosimeters. Recent studies proved a promising tool for localizing secondary electrons within a dosimeter volume and calculating the energy spent on creating defects or colors centers, among other things, when it comes to the relationship between the energy deposited and the response of a dosimeter. Such methods could give knowledge about misunderstanding behaviors of some TLD and could eliminate its disadvantages like missing TL signal or fading; angle and energy of incidence ionizing radiation. In general, the properties of TLD like its inexpensive cost and reusability; easily fabricated, lightweight to wear, readout is simple and can be automated, insensitive to humidity make it advantageous in different clinical and radiation safety applications.
\n',keywords:"TLD, TL kinetics, radiotherapy, hybrid-functional density theory, modern clinical applications",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80975.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80975.xml",downloadPdfUrl:"/chapter/pdf-download/80975",previewPdfUrl:"/chapter/pdf-preview/80975",totalDownloads:28,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 29th 2021",dateReviewed:"January 17th 2022",datePrePublished:"March 25th 2022",datePublished:null,dateFinished:"March 25th 2022",readingETA:"0",abstract:"Due to the risk of radiation exposure, radiation dosimetry is performed regularly to ensure the occupational safety of personnel and radiation workers. Therefore, various dosimeters are widely used to detect neutrons, gamma, X-ray, and proton irradiation fields. As an example, in medical applications, routine personal dosimetry is used to monitor and limit workers’ long-term occupational exposure. Radiation workers who undertake X-ray diagnostic, radiotherapy operations, in clinical and industrial application. Although, the overheads of running an in-house TLD (Thermoluminescent dosimetry) service for monitoring doses to eyes, pacemakers and so on seems rather high for the benefits conferred, however, it is still widely used for reporting doses accurately in various medical centers over the world. TLD also is widely used for measuring entrance doses on a handful of patients to validate a new LINAC/TPS combination. As well as in the industrial field as if petroleum, companies or nuclear reactor, RSO (radiation safety officer) used TLD badges to report delivered doses. In this chapter, we focus on the TLD technique for measuring doses of various ionizing radiation detection. Different methods for evaluations of TL Kinetics are covered. Modern TLD applications in the clinical field are also investigated. Some recommendations on advance dosimetry failure of TLD are concluded.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80975",risUrl:"/chapter/ris/80975",signatures:"Hossam Donya",book:{id:"11247",type:"book",title:"Dosimetry",subtitle:null,fullTitle:"Dosimetry",slug:null,publishedDate:null,bookSignature:"Dr. Thomas J. FitzGerald",coverURL:"https://cdn.intechopen.com/books/images_new/11247.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-460-0",printIsbn:"978-1-80355-459-4",pdfIsbn:"978-1-80355-461-7",isAvailableForWebshopOrdering:!0,editors:[{id:"241806",title:"Dr.",name:"Thomas J.",middleName:null,surname:"FitzGerald",slug:"thomas-j.-fitzgerald",fullName:"Thomas J. FitzGerald"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"297802",title:"Dr.",name:"Hossam",middleName:null,surname:"Donya",fullName:"Hossam Donya",slug:"hossam-donya",email:"hdunia@kau.edu.sa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297802/images/17391_n.jpg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 TLD applications in neutron and gamma ray dosimetry",level:"2"},{id:"sec_1_3",title:"1.1.1 Albedo neutron dosimeter",level:"3"},{id:"sec_2_3",title:"1.1.2 Hydrogenous radiator TLDs",level:"3"},{id:"sec_3_3",title:"1.1.3 LET-dependent deep trap TLD glow peaks",level:"3"},{id:"sec_6",title:"2. Characteristic of TLD phosphors",level:"1"},{id:"sec_6_2",title:"2.1 The glow curve",level:"2"},{id:"sec_7_2",title:"2.2 TL sensitivity",level:"2"},{id:"sec_8_2",title:"2.3 Dose rate dependence",level:"2"},{id:"sec_9_2",title:"2.4 Stability",level:"2"},{id:"sec_11",title:"3. TL kinetics",level:"1"},{id:"sec_11_2",title:"3.1 First kinetics order",level:"2"},{id:"sec_11_3",title:"3.1.1 Second kinetics order",level:"3"},{id:"sec_12_3",title:"3.1.2 A single TL peak analysis",level:"3"},{id:"sec_13_3",title:"3.1.3 General-order kinetics",level:"3"},{id:"sec_14_3",title:"3.1.4 Trap parameters evaluation techniques",level:"3"},{id:"sec_14_4",title:"3.1.4.1 Empirical methods",level:"4"},{id:"sec_15_4",title:"3.1.4.2 Initial rise method",level:"4"},{id:"sec_16_4",title:"3.1.4.3 Peak shape method",level:"4"},{id:"sec_17_4",title:"3.1.4.4 Various heating rates method",level:"4"},{id:"sec_19_3",title:"3.1.5 Three points method",level:"3"},{id:"sec_20_3",title:"3.1.6 Glow curve analysis (peak shape methods)",level:"3"},{id:"sec_23",title:"4. Modern clinical applications of TLD",level:"1"},{id:"sec_24",title:"5. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Furuta Y, Tanaka S. Response of 6LiF and 7LiF thermoluminescence dosimeters to fast neutrons. Nuclear Instruments and Methods. 1972;104:36-374'},{id:"B2",body:'Moreira Ribeiro R, Souza-Santos D. Monte Carlo characterization of an individual albedo neutron monitor. Brazilian Journal of Radiation Sciences. 2021;9(2C):1-8. DOI: 10.15392/bjrs.v9i2C.1657'},{id:"B3",body:'El-Faramawy N, Chopra V, Rawash S, El-Hafez AA, Dhoble SJ. Response of TLD-600/TLD-700 and CR-39 to neutrons for medical dosimetry. Luminescence. 2021;36(5):1257-1264'},{id:"B4",body:'Gibson AB, Piesch E. Technical Reports Series No. 252. Neutron Monitoring for Radiological Protection. Vienna: International Atomic Energy Agency. 1985'},{id:"B5",body:'ICRU. Determination of Dose Equivalents Resulting from External Radiation Sources. In: Report 39, International Commission on Radiation Protection and Measurements. Bethesda, MD. 1985'},{id:"B6",body:'Seifert H, Dörschel B, Pawelke J, Hahn T. Comparison of calculated and measured neutron sensitivities of an electret albedo dosemeter. Radiation Protection Dosimetry. 1991;37(1):13-18'},{id:"B7",body:'Seifert H, Dorschel B, Pawelke J. Neutron dosimetry using an electret albedo dosimeter. In: 1991 Proceedings 7th International Symposium on Electrets (ISE 7). London: IEEE; 1991. pp. 753–758'},{id:"B8",body:'Fellinger J, Hahn T, Henniger J, Hübner K, Schmidt P. Fast neutron sensitivity of TL detectors using proton radiator techniques. Isotopenpraxis Isotopes in Environmental and Health Studies. 1991;27(7):342-346. DOI: 10.1080/10256019108622562'},{id:"B9",body:'El-Adawy A, Khaled NE, El-Sersy AR, Hussein A, Donya H. TL dosimetric properties of Li2O–B2O3 glasses for gamma dosimetry. Applied Radiation and Isotopes. 2010;68(6):1132-1136'},{id:"B10",body:'Polymeris GS, Çoskun S, Tsoutsoumanos E, Konstantinidis P, Aşlar E, Şahiner E, et al. Dose response features of quenched and reconstructed, TL and deconvolved OSL signals in BeO. Results in Physics. 2021;25:104222'},{id:"B11",body:'Begum M, Rahman AM, Abdul-Rashid HA, Yusoff Z, Nawi SN, Khandaker MU, et al. Photonic crystal fibre as a potential medium for radiotherapy dosimetry. Applied Radiation and Isotopes. 2021;174:109771'},{id:"B12",body:'Saray AA, Kaviani P, Shahbazi-Gahrouei D. Dosimetric characteristics of lithium triborate (LiB3O5) nanophosphor for medical applications. Radiation Measurements. 2021;140:106502'},{id:"B13",body:'Horowitz YS, Yossian D. Computerised glow curve deconvolution: Application to thermoluminescence dosimetry. Radiation Protection Dosimetry. 1995;60(1):1-114'},{id:"B14",body:'Randall JT, Wilkins MHF. Phosphorescence and electron traps II. The interpretation of long-period phosphorescence. Proceedings of the Royal Society of London. Series A. Mathematical and Physical Sciences. 1945;184(999):390-407'},{id:"B15",body:'Garlick GFJ, Wilkins MHF. Short period phosphorescence and electron traps. Proceedings of the Royal Society of London. Series A. Mathematical and Physical Sciences. 1945;184(999):408-433'},{id:"B16",body:'Chen R. On the calculation of activation energies and frequency factors from glow curves. Journal of Applied Physics. 1969;40(2):570-585'},{id:"B17",body:'Wrzesińska A. Their production and thermoluminescence curves. Acta Physica Polonica. 1956;15:151'},{id:"B18",body:'Adirovitch EI. La formule de Becquerel et la loi élémentaire du déclin de la luminescence des phosphores cristallins. Journal de Physique et le Radium. 1956;17(8-9):705-707'},{id:"B19",body:'Halperin A, Braner AA, Ben-Zvi A, Kristianpoller N. Thermal activation energies in NaCl and KCl crystals. Physical Review. 1960;117(2):416'},{id:"B20",body:'Dussel GA, Bube RH. Theory of thermally stimulated conductivity in a previously photoexcited crystal. Physical Review. 1967;155(3):764'},{id:"B21",body:'Saunders IJ. The thermally stimulated luminescence and conductivity of insulators. Journal of Physics C: Solid State Physics. 1969;2(12):2181'},{id:"B22",body:'De Muer D. Development of a universal method for calculating the thermoluminescence parameters. Physica. 1970;48(1):1-12'},{id:"B23",body:'Bräunlich P, Kelly P, Fillard JP. Thermally stimulated luminescence and conductivity. In: Thermally Stimulated Relaxation in Solids. Berlin, Heidelberg: Springer; 1979. pp. 35-92'},{id:"B24",body:'Moharil SV. On the general‐order kinetics in thermoluminescence. Physica Status Solidi A: Applications and Materials Science. 1982;73(2):509-514'},{id:"B25",body:'Rasheedy MS. A new evaluation technique for analyzing the thermoluminescence glow curve and calculating the trap parameters. Thermochimica Acta. 2005;429(2):143-147'},{id:"B26",body:'May CE, Partridge JA. Thermoluminescent kinetics of alpha‐irradiated alkali halides. The Journal of Chemical Physics. 1964;40(5):1401-1409'},{id:"B27",body:'Prokić M. Analysis of the thermoluminescence glow curves of natural barite. Journal of Physics and Chemistry of Solids. 1977;38(6):617-622'},{id:"B28",body:'De Blasi C, Gallassini S, Manfredotti C, Micocci G, Ruggiero L, Tepore A. Trapping levels in PbI2. Solid State Communications. 1978;25(3):149-153'},{id:"B29",body:'Urbach R. Zur lumineszenz der alkalihalogenide. Sitzungsberichte Akad. der Wiss. Wien. 1930;139:363-372'},{id:"B30",body:'Urbach F. Storage and Release of Light by Phosphors. Vol. 115. New York: John Wiley and Sons; 1948'},{id:"B31",body:'Miller LD, Bube RH. Luminescence, trapping, and F centers in lithium fluoride crystals. Journal of Applied Physics. 1970;41(9):3687-3697'},{id:"B32",body:'Ratovonjanahary AJF, Raboanary R, Andriambololona R. Quartz Glow-Peaks Lifetime Analysis: TL Glow-Curve Deconvolution Functions for First Order of Kinetic Compared to Initial Rise Method. In: HEPMAD 04 Conference, Madagascar, 27 Sep-01 Oct. 2004'},{id:"B33",body:'Christodoulides C. Errors involved in the determination of activation energies in TL and TSDC by the initial rise method. Journal of Physics D: Applied Physics. 1985;18(8):1665'},{id:"B34",body:'Grossweiner LI. A note on the analysis of first‐order glow curves. Journal of Applied Physics. 1953;24(10):1306-1307'},{id:"B35",body:'Lushchik CB. The investigation of trapping centers in crystals by the method of thermal bleaching. Soviet Physics Jetp-USSR. 1956;3(3):390-399'},{id:"B36",body:'Booth AH. Calculation of electron trap depths from thermoluminescence maxima. Canadian Journal of Chemistry. 1954;32(2):214-215'},{id:"B37",body:'Chen R, Winer SAA. Effects of various heating rates on glow curves. Journal of Applied Physics. 1970;41(13):5227-5232'},{id:"B38",body:'Chen R, Kirsh Y. Analysis of Thermally Stimulated Process. Oxford: Pergamon Press; 1981'},{id:"B39",body:'Hoogenstraaten W. Electron traps in zinc sulphide phosphors. Philips Research Reports. 1958;13:515-693'},{id:"B40",body:'Rasheedy MS. On the general-order kinetics of the thermoluminescence glow peak. Journal of Physics: Condensed Matter. 1993;5(5):633'},{id:"B41",body:'Rasheedy MSRMS. A complete system for obtaining the trap parameters of thermoluminescence glow peak. Japanese Journal of Applied Physics. 1996;35(2R):634'},{id:"B42",body:'Bos AJJ, Piters TM, Gómez-Ros JM, Delgado A. An intercomparison of glow curve analysis computer programs: I. Synthetic glow curves. Radiation Protection Dosimetry. 1993;47(1-4):473-477'},{id:"B43",body:'Puchalska M, Bilski P. GlowFit—A new tool for thermoluminescence glow-curve deconvolution. Radiation Measurements. 2006;41(6):659-664'},{id:"B44",body:'Alvarez P, Kry SF, Stingo F, Followill D. TLD and OSLD dosimetry systems for remote audits of radiotherapy external beam calibration. Radiation Measurements. 2017;106:412-415'},{id:"B45",body:'Koger B, Price R, Wang D, Toomeh D, Geneser S, Ford E. Impact of the MLC leaf-tip model in a commercial TPS: Dose calculation limitations and IROC-H phantom failures. Journal of Applied Clinical Medical Physics. 2020;21(2):82-88'},{id:"B46",body:'Nilsson I, Himmelman J, Khan J, Dalmo J. The potential to use Tld measurements to validate the occupational radiation protection at the Department of Nuclear Medicine. Radiation Protection Dosimetry. 2021;195(3-4):355-362'},{id:"B47",body:'Pavičar B, Davidović J, Petrović B, Vuleta G, Trivić S, Šajinović V, et al. Nuclear medicine staff exposure to ionising radiation in 18F-FDG PET/CT practice: A preliminary retrospective study. Arhiv za Higijenu Rada i Toksikologiju. 2021;72(3):216-223'},{id:"B48",body:'Petrovic B, Vicko F, Radovanovic D, Samac J, Tot A, Radovanovic Z, et al. Occupational radiation dose of personnel involved in sentinel node biopsy procedure. Journal of Medical Physics. 2021;91:117-120'},{id:"B49",body:'Ali W, Sulieman A, Tamam N, Boshara N, Aldhebaib A, Alkhorayef M, et al. Estimation of patients organ doses and staff exposure during bone scan examination. Radiation Physics and Chemistry. 2021;188:109693'},{id:"B50",body:'Frank M, Urban T, Willer K, Noichl W, De Marco F, Schick R, et al. Dosimetry on first clinical dark-field chest radiography. Medical Physics. 2021;48(10):6152-6159'},{id:"B51",body:'Omojola AD, Akpochafor MO, Adeneye SO, Akala IO, Agboje AA. Chest X-rays of newborns in a medical facility: Variation between the entrance skin dose measurements using the indirect and direct methods for clinical dose audit. Japanese Journal of Radiology. 2021;40(2):1-7'},{id:"B52",body:'Moradi F, Khandaker MU, Mahdiraji GA, Ung NM, Bradley DA. Dose mapping inside a gamma irradiator measured with doped silica fibre dosimetry and Monte Carlo simulation. Radiation Physics and Chemistry. 2017;140:107-111'},{id:"B53",body:'Moradi F, Ung NM, Mahdiraji GA, Khandaker MU, Entezam A, See MH, et al. Angular dependence of optical fibre thermoluminescent dosimeters irradiated using kilo- and megavoltage X-rays. Radiation Physics and Chemistry. 2017;135:4-10'},{id:"B54",body:'Moradi F, Mahdiraji GA, Dermosesian E, Khandaker MU, Ung NM, Mahamd Adikan FR, et al. Influence of dose history on thermoluminescence response of Ge-doped silica optical fibre dosimeters. Radiation Physics and Chemistry. 2017;134:62-70'},{id:"B55",body:'Kato T, Sagara T, Komori S, Kato R, Takeuchi A, Narita Y. Dosimetric properties of a newly developed thermoluminescent sheet-type dosimeter for clinical proton beams. Journal of Applied Clinical Medical Physics. 2021;22(4):158-165'},{id:"B56",body:'Donya H, Seniwal B, Darwesh R, Fonseca TC. Prospective Monte Carlo simulation for choosing high efficient detectors for small-field dosimetry. In: Theory, Application, and Implementation of Monte Carlo Method in Science and Technology. London: IntechOpen; 2019'},{id:"B57",body:'Donya H. Pencil-beam fluence evaluation based on Monte Carlo simulations algorithm of high energetic treatment photons. Journal of Medical Signals and Sensors. 2018;8(2):81'},{id:"B58",body:'Massillon-JL G. Future directions on low-energy radiation dosimetry. Scientific Reports. 2021;11:10569. DOI: 10.1038/s41598-021-90152-3'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Hossam Donya",address:"hdunia@kau.edu.sa",affiliation:'
Faculty of Science, Department of Physics, King Abdulaziz University, Saudi Arabia
Faculty of Science, Physics Department, Menoufia University, Egypt
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IntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
",metaTitle:"Retraction and Correction Policy",metaDescription:"Retraction and Correction Policy",metaKeywords:null,canonicalURL:"/page/retraction-and-correction-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"
IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\\n\\n
1. RETRACTIONS
\\n\\n
A Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\\n\\n
A formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\\n\\n
\\n\\t
Data fabrication
\\n\\t
Data recycling in a purportedly original research article
\\n\\t
Severe plagiarism - whether or not the plagiarism is to be deemed severe will be determined by the Academic Editor and verified by plagiarism checking software
\\n\\t
Double publication
\\n\\t
Copyright infringement - for example, if a Chapter uses copyrighted figures without permission.
\\n\\t
Unreliable findings
\\n\\t
Unethical research practices
\\n\\t
Any other practice or act considered potentially harmful to the scientific community.
\\n
\\n\\n
Publishing of a Retraction Notice will adhere to the following guidelines:
\\n\\n\\n\\t
All relevant bibliographic information about a retracted Chapter will be given in the title.
\\n\\t
A Retraction Notice will be published as a regular book Chapter and will be given its own Chapter number.
\\n\\n\\n
\\n\\t
Authors shall be required to approve a proposed retraction of their Chapter. If Authors maintain that their Chapter should not be retracted, the Academic Editor may issue a Statement of Concern (see 2. below).
\\n
\\n\\n
1.2. REMOVALS AND CANCELLATIONS
\\n\\n
\\n\\t
Additionally, a Chapter retracted on grounds of copyright infringement (e.g. double publication) may be Removed by the publisher should the original copyright owner request such action. A Chapter retracted on grounds of its potential to harm the scientific community, for example, when a Chapter is defamatory in nature, may also be subject to removal.
\\n\\t
No formal Removal Notice will be published but a notice citing the reason for removal will be prominently displayed in place of a retracted and subsequently removed Chapter.
\\n\\t
Chapters published due to inadvertent production mistakes shall be canceled and the cancellation notice will be published.
\\n
\\n\\n
2. STATEMENTS OF CONCERN
\\n\\n
A Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\\n\\n
\\n\\t
Authors refuse to approve a retraction proposed by the Academic Editor
\\n\\t
There is inconclusive evidence of scientific misconduct
\\n\\t
Authors and their respective institutions fail or refuse to provide adequate assistance in an investigation
\\n\\t
The publication of a Statement of Concern will adhere to the Retraction Notice guidelines outlined above
\\n\\t
An article PDF for which a Statement of Concern is published will remain available online without being edited or watermarked
\\n
\\n\\n
IntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\\n\\n
3. CORRECTIONS
\\n\\n
A Correction will be issued by the Academic Editor when:
\\n\\n
\\n\\t
Only a small portion of a Chapter is flawed in a way that does not severely affect any findings.
\\n\\t
It is determined that the scientific community would be better served by a Correction rather than a Retraction.
\\n\\t
Corrections will be issued in one of two distinct forms -- ERRATUM or CORRIGENDUM, depending on the origin of a mistake.
\\n
\\n\\n
3.1. ERRATUM
\\n\\n
An Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\\n\\n
A published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n
3.2. CORRIGENDUM
\\n\\n
A Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n
4. FINAL REMARKS
\\n\\n
IntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\n
In the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\n
The general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n
1. RETRACTIONS
\n\n
A Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\n
A formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\n
\n\t
Data fabrication
\n\t
Data recycling in a purportedly original research article
\n\t
Severe plagiarism - whether or not the plagiarism is to be deemed severe will be determined by the Academic Editor and verified by plagiarism checking software
\n\t
Double publication
\n\t
Copyright infringement - for example, if a Chapter uses copyrighted figures without permission.
\n\t
Unreliable findings
\n\t
Unethical research practices
\n\t
Any other practice or act considered potentially harmful to the scientific community.
\n
\n\n
Publishing of a Retraction Notice will adhere to the following guidelines:
\n\n\n\t
All relevant bibliographic information about a retracted Chapter will be given in the title.
\n\t
A Retraction Notice will be published as a regular book Chapter and will be given its own Chapter number.
\n\n\n
\n\t
Authors shall be required to approve a proposed retraction of their Chapter. If Authors maintain that their Chapter should not be retracted, the Academic Editor may issue a Statement of Concern (see 2. below).
\n
\n\n
1.2. REMOVALS AND CANCELLATIONS
\n\n
\n\t
Additionally, a Chapter retracted on grounds of copyright infringement (e.g. double publication) may be Removed by the publisher should the original copyright owner request such action. A Chapter retracted on grounds of its potential to harm the scientific community, for example, when a Chapter is defamatory in nature, may also be subject to removal.
\n\t
No formal Removal Notice will be published but a notice citing the reason for removal will be prominently displayed in place of a retracted and subsequently removed Chapter.
\n\t
Chapters published due to inadvertent production mistakes shall be canceled and the cancellation notice will be published.
\n
\n\n
2. STATEMENTS OF CONCERN
\n\n
A Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\n
\n\t
Authors refuse to approve a retraction proposed by the Academic Editor
\n\t
There is inconclusive evidence of scientific misconduct
\n\t
Authors and their respective institutions fail or refuse to provide adequate assistance in an investigation
\n\t
The publication of a Statement of Concern will adhere to the Retraction Notice guidelines outlined above
\n\t
An article PDF for which a Statement of Concern is published will remain available online without being edited or watermarked
\n
\n\n
IntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n
3. CORRECTIONS
\n\n
A Correction will be issued by the Academic Editor when:
\n\n
\n\t
Only a small portion of a Chapter is flawed in a way that does not severely affect any findings.
\n\t
It is determined that the scientific community would be better served by a Correction rather than a Retraction.
\n\t
Corrections will be issued in one of two distinct forms -- ERRATUM or CORRIGENDUM, depending on the origin of a mistake.
\n
\n\n
3.1. ERRATUM
\n\n
An Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\n
A published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n
3.2. CORRIGENDUM
\n\n
A Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n
4. FINAL REMARKS
\n\n
IntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\n
In the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\n
The general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
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ASD is associated with deficiencies in communication and social interaction, as well as restricted and repetitive behavioural patterns, according to the fifth edition of the diagnostic and statistical manual of mental disorders (DSM-5). By using the ISI Web of Knowledge as the reference data basis, we perform a bibliometric study of the use of VR as an educational tool for high-functioning ASD children. By this study we can quantify, on the one hand, the up to day importance of the different types of VR applied to this field: immersive or non-immersive, as well as the use of human or agent avatars. On the other hand, we can also differentiate amongst those interventions that work on emotional and social competences. The analysis of periods of research scarce, research abundance and research trends provides a dynamic view of the strategies used in this field in the last 20 years and suggests future lines of research.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Jorge Fernández-Herrero, Gonzalo Lorenzo-Lledó and Asunción\nLledó Carreres",authors:[{id:"187920",title:"Prof.",name:"Gonzalo",middleName:null,surname:"Lorenzo",slug:"gonzalo-lorenzo",fullName:"Gonzalo Lorenzo"},{id:"189580",title:"Prof.",name:"Asunción",middleName:null,surname:"Lledó",slug:"asuncion-lledo",fullName:"Asunción Lledó"},{id:"213024",title:"Mr.",name:"Jorge",middleName:null,surname:"Fernandez-Herrero",slug:"jorge-fernandez-herrero",fullName:"Jorge Fernandez-Herrero"}]},{id:"68639",doi:"10.5772/intechopen.88569",title:"Social Media and Young People’s Mental Health",slug:"social-media-and-young-people-s-mental-health",totalDownloads:2079,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Evidence suggests that social media can impact detrimentally on children and young people’s mental health. At the same time, social media use can be beneficial and have positive effects. This chapter outlines the detrimental and positive effects of social media use for young people. Schools play a critical role in educating young people about how to use social media safely and responsibly. However, schools cannot address all the issues and parents, social media and advertising companies also have a responsibility to protect children and young people from harm. This chapter outlines some of the potential solutions to the issues that are identified.",book:{id:"7927",slug:"selected-topics-in-child-and-adolescent-mental-health",title:"Selected Topics in Child and Adolescent Mental Health",fullTitle:"Selected Topics in Child and Adolescent Mental Health"},signatures:"Jonathan Glazzard and Samuel Stones",authors:[{id:"294281",title:"Prof.",name:"Jonathan",middleName:null,surname:"Glazzard",slug:"jonathan-glazzard",fullName:"Jonathan Glazzard"},{id:"309587",title:"Mr.",name:"Samuel",middleName:"Oliver James",surname:"Stones",slug:"samuel-stones",fullName:"Samuel Stones"}]},{id:"57269",doi:"10.5772/intechopen.71265",title:"Enhancing Young Children’s Access to Early Childhood Education and Care in Tanzania",slug:"enhancing-young-children-s-access-to-early-childhood-education-and-care-in-tanzania",totalDownloads:1478,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter draws on the current situation of limited access of young children to early childhood education and care (ECEC) settings in Tanzania. It offers information and evidence on early childhood education and care (ECEC) from an international perspective to those who are, directly or indirectly, involved with young children and their families. Basically, early childhood education and care in Tanzania is still unsatisfactory. Many children have no access to early childhood settings for various reasons including: lack of parents’ awareness on the importance of early investment in education, lack of support from the government, low socio-economic status of parents, gender discrimination, and traditional norms and cultural values. To improve the situation, there is need for a forging of partnership between the government, parents, and the community. Government policy-makers have to set clear policies regarding how quality early childhood education and care can be equitably funded and conducted throughout the country.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Ignasia Mligo",authors:[{id:"212055",title:"Dr.",name:"Ignasia",middleName:null,surname:"Mligo",slug:"ignasia-mligo",fullName:"Ignasia Mligo"}]},{id:"57391",doi:"10.5772/intechopen.71287",title:"Influence of Parental Divorce on Anxiety Level of Adolescents",slug:"influence-of-parental-divorce-on-anxiety-level-of-adolescents",totalDownloads:1864,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Family divorce might have an effect on some aspects of child development. Adolescence as a transitional stage is marked by process of seeking identity, the need for intimate relationship, as well as the struggle for psychological independence from family. Anxiety is defined as a state of extreme worry, fear, and uncertainty which results from the expectation of a threatening event or situation. The aims of study are: to explore the differences in anxiety levels among adolescents from divorced and intact families; to explore the level of anxiety of adolescents from divorced and intact families with respect to their genders. A demographic questionnaire was created and The Beck Anxiety Inventory was applied to measure anxiety. The scale was applied with 162 participants who were chosen randomly from 5 different high schools in Istanbul province. The study found out that there are statistically significant differences in anxiety level of adolescents between children from divorced and intact families. Descriptive measures are in range as follows: (17.67 ± 9.645). The adolescents from divorced families had a higher level of anxiety (t = 17.322; p < .05). The result related to the second study aim shows that there are no statistically significant differences in anxiety between male and female adolescents from divorced and intact families (p > .05).",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Senija Tahirović and Gokce Demir",authors:[{id:"214445",title:"Dr.",name:"Senija",middleName:null,surname:"Tahirovic",slug:"senija-tahirovic",fullName:"Senija Tahirovic"},{id:"214465",title:"MSc.",name:"Gokce",middleName:null,surname:"Demir",slug:"gokce-demir",fullName:"Gokce Demir"}]},{id:"57686",doi:"10.5772/intechopen.71672",title:"Children and Young People’s Vulnerabilities to Grooming",slug:"children-and-young-people-s-vulnerabilities-to-grooming",totalDownloads:2219,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Child abuse is evolving, pervasive and complex and children are vulnerable to its widespread reach in many aspects of their lives, from face-to-face interactions to those they have online. This chapter aims to review contemporary literature which outlines the vulnerabilities of children to face-to-face and online grooming as part of a process leading to child abuse and exploitation. The chapter will undertake a review of literature on two aspects of grooming: child sexual exploitation (CSE) and radicalisation. It will draw on contemporary case examples to illustrate grooming drawn from UK Serious Case Reviews (SCR) on CSE and, on radicalisation, the case of the three girls from Bethnal Green who were groomed for travel to Syria. It will then reflect on the push and pull factors of grooming to highlight the similarities between CSE and radicalisation. Moving on, the chapter will then consider how and if interactive social media simulations, linked to an innovative, preventative educational approach and designed with reference to Vygotsky’s social construction theory, have the potential to educate young people to help protect them from being groomed. The chapter will then make reference to the findings of a small pilot study which evaluated the use of this approach with young people.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Jane Reeves, Emma Soutar, Sally Green and Tracy Crowther",authors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"},{id:"211838",title:"Dr.",name:"Tracy",middleName:null,surname:"Crowther",slug:"tracy-crowther",fullName:"Tracy Crowther"},{id:"211839",title:"Mrs.",name:"Emma",middleName:null,surname:"Soutar",slug:"emma-soutar",fullName:"Emma Soutar"},{id:"211840",title:"Mrs.",name:"Sally",middleName:null,surname:"Green",slug:"sally-green",fullName:"Sally Green"}]}],mostDownloadedChaptersLast30Days:[{id:"57686",title:"Children and Young People’s Vulnerabilities to Grooming",slug:"children-and-young-people-s-vulnerabilities-to-grooming",totalDownloads:2219,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Child abuse is evolving, pervasive and complex and children are vulnerable to its widespread reach in many aspects of their lives, from face-to-face interactions to those they have online. This chapter aims to review contemporary literature which outlines the vulnerabilities of children to face-to-face and online grooming as part of a process leading to child abuse and exploitation. The chapter will undertake a review of literature on two aspects of grooming: child sexual exploitation (CSE) and radicalisation. It will draw on contemporary case examples to illustrate grooming drawn from UK Serious Case Reviews (SCR) on CSE and, on radicalisation, the case of the three girls from Bethnal Green who were groomed for travel to Syria. It will then reflect on the push and pull factors of grooming to highlight the similarities between CSE and radicalisation. Moving on, the chapter will then consider how and if interactive social media simulations, linked to an innovative, preventative educational approach and designed with reference to Vygotsky’s social construction theory, have the potential to educate young people to help protect them from being groomed. The chapter will then make reference to the findings of a small pilot study which evaluated the use of this approach with young people.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Jane Reeves, Emma Soutar, Sally Green and Tracy Crowther",authors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"},{id:"211838",title:"Dr.",name:"Tracy",middleName:null,surname:"Crowther",slug:"tracy-crowther",fullName:"Tracy Crowther"},{id:"211839",title:"Mrs.",name:"Emma",middleName:null,surname:"Soutar",slug:"emma-soutar",fullName:"Emma Soutar"},{id:"211840",title:"Mrs.",name:"Sally",middleName:null,surname:"Green",slug:"sally-green",fullName:"Sally Green"}]},{id:"68639",title:"Social Media and Young People’s Mental Health",slug:"social-media-and-young-people-s-mental-health",totalDownloads:2079,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Evidence suggests that social media can impact detrimentally on children and young people’s mental health. At the same time, social media use can be beneficial and have positive effects. This chapter outlines the detrimental and positive effects of social media use for young people. Schools play a critical role in educating young people about how to use social media safely and responsibly. However, schools cannot address all the issues and parents, social media and advertising companies also have a responsibility to protect children and young people from harm. This chapter outlines some of the potential solutions to the issues that are identified.",book:{id:"7927",slug:"selected-topics-in-child-and-adolescent-mental-health",title:"Selected Topics in Child and Adolescent Mental Health",fullTitle:"Selected Topics in Child and Adolescent Mental Health"},signatures:"Jonathan Glazzard and Samuel Stones",authors:[{id:"294281",title:"Prof.",name:"Jonathan",middleName:null,surname:"Glazzard",slug:"jonathan-glazzard",fullName:"Jonathan Glazzard"},{id:"309587",title:"Mr.",name:"Samuel",middleName:"Oliver James",surname:"Stones",slug:"samuel-stones",fullName:"Samuel Stones"}]},{id:"57391",title:"Influence of Parental Divorce on Anxiety Level of Adolescents",slug:"influence-of-parental-divorce-on-anxiety-level-of-adolescents",totalDownloads:1864,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Family divorce might have an effect on some aspects of child development. Adolescence as a transitional stage is marked by process of seeking identity, the need for intimate relationship, as well as the struggle for psychological independence from family. Anxiety is defined as a state of extreme worry, fear, and uncertainty which results from the expectation of a threatening event or situation. The aims of study are: to explore the differences in anxiety levels among adolescents from divorced and intact families; to explore the level of anxiety of adolescents from divorced and intact families with respect to their genders. A demographic questionnaire was created and The Beck Anxiety Inventory was applied to measure anxiety. The scale was applied with 162 participants who were chosen randomly from 5 different high schools in Istanbul province. The study found out that there are statistically significant differences in anxiety level of adolescents between children from divorced and intact families. Descriptive measures are in range as follows: (17.67 ± 9.645). The adolescents from divorced families had a higher level of anxiety (t = 17.322; p < .05). The result related to the second study aim shows that there are no statistically significant differences in anxiety between male and female adolescents from divorced and intact families (p > .05).",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Senija Tahirović and Gokce Demir",authors:[{id:"214445",title:"Dr.",name:"Senija",middleName:null,surname:"Tahirovic",slug:"senija-tahirovic",fullName:"Senija Tahirovic"},{id:"214465",title:"MSc.",name:"Gokce",middleName:null,surname:"Demir",slug:"gokce-demir",fullName:"Gokce Demir"}]},{id:"57167",title:"The Early Childhood Educators’ Attitudes Towards Innovative Instructional Applications about Digital Learning Activities for Young Children",slug:"the-early-childhood-educators-attitudes-towards-innovative-instructional-applications-about-digital-",totalDownloads:1182,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The innovative value and practices of digital learning activities assist early childhood educators in employing effective instruction to improve young children’s performance as well as advance their own professional autonomy to implement digital learning activities for young children. This study examined the factors and relationships about early childhood educators’ attitudes towards the integration and behavioral intention of digital learning tools into young children’s innovative pedagogical activities using a questionnaire survey. The questionnaire consisted of five factors, including digital innovative value (DIV), digital innovative practices (DIP), perception of instructional use (PIU), instructional professional autonomy (IPA), and behavioral intention to use (BIU). The researcher used structural equation modeling to analyze the survey data. The results showed that early childhood educators’ perceptions about innovative value and applications of digital learning activities play a key role in the success of young children’s performance and competence in preschool. The early childhood educators with positive attitudes towards the innovative consideration and practical instructional applications of digital learning activities had more behavioral intention to plan and design instructional activities with innovative applications of digital learning tools.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Ru-Si Chen",authors:[{id:"211677",title:"Prof.",name:"Ru-Si",middleName:null,surname:"Chen",slug:"ru-si-chen",fullName:"Ru-Si Chen"}]},{id:"57680",title:"Thinking and Learning Demands in Contemporary Childhood",slug:"thinking-and-learning-demands-in-contemporary-childhood",totalDownloads:1457,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Is today’s childhood is the same as the past’s? Frankly speaking, we cannot answer this question as a clear yes. It is obvious that children today are more into tablet computers, social networks and online games than traditional child games. Besides, our communication styles have been changed significantly for the past years. We, no longer need to meet others face to face to ask for help or to chat. Artificial intelligence, machine learning and robots are another story of the contemporary world. Robots capable of perceiving their surroundings and making decisions have started to deprive many people of their jobs. But what kind of jobs will human beings perform? The increasing emphasis on innovation, cooperation, critical thinking, being creative, problem solving, communication skills and project management is an indicator of what kind of a business world will today’s children meet in the future. This on-going trend also includes clues about how should children be educated. This study is focusing on thinking and learning demands expected contemporary children to meet. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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