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Relationship: 1982

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Energy Deposition leads to Increase, Chromosomal aberrations

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Deposition of energy leading to lung cancer non-adjacent High High Vinita Chauhan (send email) Open for citation & comment WPHA/WNT Endorsed
Deposition of energy leading to occurrence of cataracts non-adjacent High High Vinita Chauhan (send email) Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Energy can be deposited on biomolecules from various forms of radiation in a randomized manner. Radiation with high linear energy transfer (LET) tends to produce more complex, dense structural damage than low LET radiation; both, however, can lead to detrimental damage within a cell (Bauchinger and Schmid 1998; Evans et al., 2001; Hada and Georgakilas 2008; Okayasu 2012; Lorat et al. 2015; Nikitaki et al. 2016). The DNA is particularly susceptible to damage in the form of DNA strand breaks.  This damaged DNA can lead to aberrations/rearrangements in chromosomes and chromatids. Examples of chromosome-type aberrations include chromosome-type breaks, ring chromosomes, and dicentric chromosomes, while chromatid-type aberrations refer to chromatid-type breaks and chromatid exchanges (Hagmar et al. 2004; Bonassi et al. 2008). Other types of CAs that may occur in response to radiation include micronuclei (MN), nucleoplasmic bridges (NPBs), and copy number variants (CNVs). CAs may also be classified as stable aberrations (translocations, inversions, insertions and deletions) and unstable aberrations (dicentric chromosomes, acentric fragments, centric rings and MN) (Hunter and Muirhead 2009; Zölzer et al. 2013; Qian et al. 2016). 

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022.  Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall Weight of Evidence: High 

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The biological plausibility for this KER is strong, as there is a broad mechanistic understanding of the process CA induction from deposited energy in the form of radiation, which is widely accepted. This has especially been demonstrated in humans and adult mammals. Reviews have been published that provide details regarding the relationships between radiation of different LETs and the relative effectiveness of CA induction (Hunter and Muirhead 2009), ionizing radiation and genomic instability (Smith et al. 2003), and low dose ionizing radiation and chromosomal translocations (Tucker 2008). When ionizing radiation comes into contact with a cell, it is able to deposit energy through ionization and excitation of molecules, which results in the freeing of electrons. These electrons have enough energy to break chemical bonds; thus if the high-energy electrons come into contact with DNA, they may break DNA bonds and cause damage in the form of double-strand breaks, single-strand breaks, base damage, or the crosslinking of DNA to other molecules. Direct damage to DNA occurs when radiation directly interacts with the DNA molecule, causing structural alterations such as breaks or cross-links. In contrast, indirect damage results from radiation interacting with nearby molecules, producing reactive species like free radicals, which can then indirectly affect the DNA by causing chemical modifications and impairing its integrity (Chatterjee et al, 2017). This damage should trigger DNA repair. If the enzymatic repair, however, is incorrect or incomplete, this could push the cell towards apoptotic pathways. However, the repair processes may lead to asymmetrical exchanges in the chromosomes that are not removed from the cell and can propagate in the form of aberrations. Radiation-damaged cells display accumulated CAs in the form of chromosomal rearrangements, genetic amplifications and/or MN (Smith et al. 2003; Christensen 2014; Sage and Shikazono 2017).  

CNVs may also be generated through deposition of energy by ionizing radiation. Due to the structural similarities between CNVs that are radiation-induced, chemically-induced, and spontaneously-occurring, all CNVs are likely produced by a similar mechanism. The chemicals, aphidicolin and hydroxyurea, are known inducers of DNA replication stress. This suggests that radiation-induced CNVs are also formed through a similar replication-dependent mechanism(Arlt et al. 2014). Additionally, CNVs may affect germline cells. In fact, there was a significant 8-fold increase in de novo CNVs in the progeny of irradiated male mice, regardless of whether the radiation affected post-meiotic sperm or pre-meiotic sperm. The majority of these CNVs were found to be large deletions, often more than 1000 kB (Adewoye et al. 2015).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Uncertainties and inconsistencies in this KER are as follows:

  • An individual’s response to radiation can be affected by a large variety of factors. Many of them cannot be controlled in a study, therefore leading to inconsistencies in results (Bender et al., 1988). 
  • When an organism is exposed to an initial low radiation dose followed by a higher dose, it can initiate an adaptive response, therefore decreasing the resulting damage. Day et al. also found this to be applicable when a low radiation dose was followed by an even lower dose (2007). 

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Modulating Factor 

Details 

Effects on the KER 

References 

Sex 

Females 

Females were found to have increased aberrant cells and chromosome breaks relative to males. 

Maffei et al., 2004 

Age 

Increased or decreased age 

Increases in age were associated with increased CAs. However, it has also been found that young organisms are more sensitive to radiation. One possible explanation for this is that dividing cells are more radiosensitive than those that are quiescent. 

Blakely, 2012; Santovito et al., 2013; Vellingiri et al., 2014 

Smoking 

Smoking status 

Smoking was found to increase chromosomal damage. Chromosome breaks were found to be significantly increased in smokers relative to non-smokers. Likewise, blood samples from smokers that were exposed to radon gas had lymphocytes with significantly increased dicentric aberrations, acentric fragments, chromatid breaks, MN, and NPBs relative to lymphocytes from non-smokers also exposed to radon gas. 

Maffei et al., 2004; Meenakshi and Mohankumar 2013; Meenakshi et al., 2017 

Hyperthermia 

Increased temperature 

In cells exposed to hyperthermic conditions (41°C for 1 h) followed by radiation (4 Gy), there were significant increases in chromosomal translocations and chromosomal fragments at 1 and at 24 h post-exposure, respectively, as compared to cells exposed only to radiation. 

Bergs et al., 2016 

DNA ligase IV 

Presence 

DNA ligase IV helps prevent DNA degradation and increase accurate DNA rejoining, therefore decreasing chromosome breaks and radiation-induced MN. 

Smith et al., 2003; Foray et al., 2016 

Genetic syndromes 

Cockayne syndrome, AT-like disorder, Nijmegen breakage syndrome, Bloom’s syndrome, xeroderma pigmentosum, Fanconi anemia, and ataxia telangiectasia 

The presence of one of these conditions can increase the number of CAs. 

Bender et al., 1988; Foray et al., 2016 

Antioxidants or antigenotoxic agents 

Increased concentration, examples include dimethyl sulfoxide (DMSO) 

The compounds can help decrease the frequency of CAs after irradiation. 

Yang, 1999; Kim and Lee, 2007 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

There is evidence of a positive response-response relationship between the radiation dose and the frequency of CAs (Tao et al., 1993; Tao et al., 1994; Durante et al., 1998; Williams et al., 1999; Belkacémi et al., 2001; Evans et al., 2001; Schmid et al. 2002; Thomas et al. 2003;Tucker et al., 2004; Hande et al., 2005; Tucker et al. 2005a; Tucker et al. 2005b; Wolf et al., 2008; George et al. 2009; Arlt et al. 2014; Balajee et al. 2014; Suto et al. 2015; Mcmahon et al. 2016; Abe et al. 2018; Dalke et al., 2018; Bains et al., 2019; Jang et al. 2019; Udroiu et al., 2020). Most studies found that the response-response relationship was linear-quadratic (Schmid et al. 2002; Suto et al. 2015; Foray et al., 2016; Abe et al. 2018; Jang et al. 2019). One study, however, reported different results when CAs were examined across five cell lines that had been irradiated with either iron nuclei or γ-rays. For complex aberrations in three types of fibroblasts (two of which were deficient in DNA repair), the best fit was a quadratic relationship for both γ-rays and iron ions; for simple aberrations induced by iron ions in these cells, there was a linear relationship found. In two tumor cell lines, a linear response was defined for simple aberrations for both types of radiation, while the response for complex aberrations was not well-defined by the models that were evaluated (George et al. 2009).

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The time scale relationship between radiation exposure and the frequency of CAs has been examined. Most studies search for CAs hours, days, weeks, or even years after exposure to radiation (Loucas and Geard, 1994; Durante et al., 1998; Schmid et al. 2002; Thomas et al. 2003; Tucker et al., 2004; Tucker et al. 2005a; Tucker et al. 2005b; George et al. 2009; Meenakshi and Mohankumar 2013; Arlt et al. 2014; Balajee et al. 2014; Han et al. 2014; Suto et al. 2015; Cheki et al. 2016; Mcmahon et al. 2016; Basheerudeen et al. 2017; Meenakshi et al. 2017; Abe et al. 2018; Jang et al. 2019) ; this makes it particularly difficult to identify CA induction in relation to the deposition of energy by ionizing radiation. There is an account, however, of CAs appearing within 20 minutes of irradiation, with levels peaking at 40 min and plateauing for the remainder of the experiment (up to 100 min) (Mcmahon et al. 2016). CAs have also been documented 2 - 3 h after radiation exposure, with frequency being shown to increase slightly at 24 h (Basheerudeen et al. 2017). CA frequency begins to decrease after exposure, but not all aberrations are repaired (Loucas and Geard, 1994; Durante et al., 1998; Tucker et al., 2004). This process also appears to depend on LET, with strand breaks induced by radiation with a lower LET able to be repaired quicker than those induced by a higher LET (Durante et al., 1998). Furthermore, a study examining CAs in human blood samples for 2 - 7 days following irradiation with γ-rays found that CAs were present at the 2-day mark, but had declined by day 7 (Tucker et al. 2005a; Tucker et al. 2005b) to suspected asymptotic minimum levels  (Tucker et al. 2005b). For translocations specifically, the relationship between time and translocation frequency was found to be linear at low doses (0 - 0.5 Gy) and linear quadratic at higher doses (0.5 - 4 Gy) (Tucker et al. 2005b). The sharpest decline over the 7 days was found in dicentrics, acentric fragments, and ring chromosomes (Tucker et al. 2005a).

Interestingly, in vivo radiation exposure has been shown to induce long-lasting CAs in a relatively short time-frame. When lymphocytes from patients undergoing an interventional radiology procedure were compared pre-procedure and 2-3 h post-procedure, there were significant increases in chromatid-type aberrations, chromosome-type aberrations, dicentrics and MN in post-procedure lymphocytes)(Basheerudeen et al. 2017). Similarly, lymphocytes from subjects exposed to radiation 32-41 years prior to blood collection were found to have significantly increased chromosome-type aberrations (acentric fragments, dicentrics and translocations) and MN relative to unexposed controls (Han et al. 2014). Taken together, the results from these two studies suggest that CAs are not only induced within mere h of radiation exposure, but that these radiation-induced CAs may also endure for several decades.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not identified.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

This KER is plausible in all life stages, sexes, and organisms with chromosomes. The majority of the evidence is from in vivo adult mice and human, and bovine in vitro models. 

References

List of the literature that was cited for this KER description. More help

Abe, Y. et al. (2018), "Dose–response curves for analyzing of dicentric chromosomes and chromosome translocations following doses of 1000 mGy or less, based on irradiated peripheral blood samples from fi ve healthy individuals.", J. Radiat. Res., 59(1):35–42. doi:10.1093/jrr/rrx052.

Adewoye, A.B. et al. (2015),  "Mutation induction in the mammalian germline.", Nature Comm. 6:(6684), doi:10.1038/ncomms7684.

Arlt, M.F. et al. (2014), "Copy number variants are produced in response to low-dose ionizing radiation in cultured cells", Envrion. and Mol. Mutagen, 55(2):103–113. doi:10.1002/em.21840.

Bains, S. K. et al. (2019), “Effects of ionizing radiation on telomere length and telomerase activity in cultured human lens epithelium cells”, International journal of radiation biology, Vol. 95/1, Taylor & Francis, Abingdon, https://doi.org/10.1080/09553002.2018.1466066 

Balajee, A.S. et al. (2014), "Multicolour FISH analysis of ionising radiation induced micronucleus formation in human lymphocytes.", Mutagenesis, 29(6):447–455. doi:10.1093/mutage/geu041.

Barquinero JF, Stephan G and Schmid E. 2004. Effect of americium-241 alpha-particles on the dose-response of chromosome aberations in human lymphocytes analysed by fluorescence in situ hybridization. Int J Radiat Biol. 80(2):155-164.

Basheerudeen, S.S. et al. (2017), "Entrance surface dose and induced DNA damage in blood lymphocytes of patients exposed to low-dose and low-dose-rate X-irradiation during diagnostic and therapeutic interventional radiology procedures.", Mutat Res Gen Tox En. 818(April):1–6., doi:10.1016/j.mrgentox.2017.04.001.

Bauchinger, M. and E. Schmid, (1998), LET dependence of yield ratios of radiation-induced intra- and interchromosomal aberrations in human lymphocytes., Int J Radiat Biol., Jul;74(1):17-25. doi: 10.1080/095530098141681

Bauchinger, M. et al., (1994), Chromosome aberrations in peripheral lymphocytes from occupants of houses with elevated indoor radon concentrations., Mutat Res., Oct 1;310(1):135-42

Belkacémi, Y. et al. (2000), “Ionizing radiation-induced death in bovine lens epithelial cells: Mechanisms and influence of irradiation dose rate”, International journal of cancer, Vol. 90/3, John Wiley & Sons, Inc, New York, https://doi.org/10.1002/1097-0215(20000620)90:3<138::AID-IJC3>3.0.CO 

Belkacémi, Y. et al. (2001), “Lens epithelial cell protection by aminothiol WR-1065 and anetholedithiolethione from ionizing radiation”, International journal of cancer, Vol. 96/S1, Wiley, New York, https://doi.org/10.1002/ijc.10346 

Bender, M.A. et al. (1988), "Current status of cytogenetic procedures to detect and quantify previous exposures to radiation.", Mutat Res Genet Toxicol. 196(2):103–159. doi:10.1016/0165-1110(88)90017-6.

Bergs, J.W. et al. (2016), "Dynamics of chromosomal aberrations, induction of apoptosis, BRCA2 degradation and sensitization to radiation by hyperthermia.", Int. J. Mol. Med., 38(1):243–250. doi:10.3892/ijmm.2016.2611.

Bilbao A, Prosser JS, Edwards AA, Moody JC, Lloyd DC. 1989. The Induction of Micronuclei in Human Lymphocytes by in vitro Irradiation with Alpha Particles from Plutonium-239. Int J Radiat Biol. 56(3):287-292.

Blakely, E. A. (2012), “Lauriston S. Taylor lecture on radiation protection and measurements: what makes particle radiation so effective?”, Health physics, Vol. 103/5, Health Physics Society, United States, https://doi.org/10.1097/HP.0b013e31826a5b85 

Bonassi, S. et al. (2008), "Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: results from a pooled cohort study of 22,358 subjects in 11 countries.", Carcinogenesis, 29(6):1178–1183. doi:10.1093/carcin/bgn075.

Brooks AL. 1975. Chromosome damage in liver cells from low dose rate alpha, beta, and gamma irradiation: derivation of RBE. Sci. 190(4219):1090-1092.

Chatterjee, N., & Walker, G. C. (2017),. “Mechanisms of DNA damage, repair, and mutagenesis”,. Environmental and molecular mutagenesis, 58(5), 235–263,. https://doi.org/10.1002/em.22087  

Cheki, M. et al. (2016), "The radioprotective effect of metformin against cytotoxicity and genotoxicity induced by ionizing radiation in cultured human blood lymphocytes.", Mutat Res - Genet Toxicol Environ Mutagen. 809:24–32. doi:10.1016/j.mrgentox.2016.09.001.

Christensen, D.M. (2014), "Management of Ionizing Radiation Injuries and Illnesses, Part 3: Radiobiology and Health Effects of Ionizing Radiation.", J. Am. Osteopath Assoc., 114(7):556–565. doi:10.7556/jaoa.2014.109.

Cornforth MN, Bailey SM, Goodwin EH. 2002. Dose Responses for Chromsome Aberrations Produced in Noncycling Primary Human Fibroblasts by Alpha Particles, and by Gamma Rays Delivered at Sublimating Low Dose Rates. Radiat Res. 158:43-53.

Curwen GB, Tawn EJ, Cadwell KK, Guyatt L, Thompson J, Hill MA. 2012. mFISH Analysis of Chromsome Aberrations Induced In Vitro by Alpha-Particle Radiation: Examination of Dose-Response Relationships. Radiat Res. 178:414-424.

Dalke, C. et al. (2018), “Lifetime study in mice after acute low-dose ionizing radiation: a multifactorial study with special focus on cataract risk”, Radiation and environmental biophysics, Vol. 57/2, Springer, Berlin/Heidelberg, https://doi.org/10.1007/s00411-017-0728-z 

Day, T.K. et al. (2007), "Adaptive Response for Chromosomal Inversions in pKZ1 Mouse Prostate Induced by Low Doses of X Radiation Delivered after a High Dose.", Radiat Res. 167(6):682–692. doi:10.1667/rr0764.1.

Durante M, Grossi GF, Napolitano M, Pugliese M, Gialanella G. 1992. Chromsome damage induced by high-LET alpha-particles in plateau-phase C3H 10T1/2 cells. Int J Radiat Biol. 62(5):571-580.

Durante et al. (1998), “Rejoining and misrejoining of radiation-induced chromatin breaks. IV. Charged particles”, in Radiation Research, Radiation Research Society, Oak Brook. DOI: 10.2307/3579784 

Edwards AA, Purrott RJ, Prosser JS, Lloyd DC. 1980. The induction of chromosome aberrations in human lymphocytes by alpha-radiation. Int J Radiat Biol. 38(1):83-91.

Evans, H. H. et al. (2001), “Genotoxic effects of high-energy iron particles in human lymphoblasts differing in radiation sensitivity”, Radiation research, Vol. 156/2, Radiation Research Society, Oak Brook, https://doi.org/10.1667/0033-7587(2001)156[0186:GEOHEI]2.0.CO 

Foray, N. et al. (2016), “Individual response to ionizing radiation”, Mutation research, Elsevier B.V, Amsterdam, https://doi.org/10.1016/j.mrrev.2016.09.001 

duFrain RJ, Littlefield G, Joiner EE, Frome EL. 1979. Human Cytogenetic Dosimetry: A Dose-Response Relationship for Alpha Particle Radiation from 241Am. Health Phys. 37:279-289.

Franken NAP, Hovingh S, Cate RT, Krawczyk P, Stap J, Hoebe R, Aten J, Barendsen GW. 2012. Relative biological effectiveness of high linear energy transfer alpha-particles for the induction of DNA-double-strand breaks, chromosome aberrations and reproductive cell death in SW-1573 lung tumour cells. Oncol reports. 27:769-774.

George, A., R. Dey & V.B. Dqhumhh (2014), "Nuclear Anomalies, Chromosomal Aberrations and Proliferation Rates in Cultured Lymphocytes of Head and Neck Cancer Patients.", Asian Pacific journal of cancer prevention. 15(3):1119-1123. doi:10.7314/APJCP.2014.15.3.1119.

George, K.A. et al. (2009), "Dose Response of γ Rays and Iron Nuclei for Induction of Chromosomal Aberrations in Normal and Repair-Deficient Cell Lines Dose Response of c Rays and Iron Nuclei for Induction of Chromosomal Aberrations in Normal and Repair-Deficient Cell Lines.", Radiat. Res., 171(6):752–763.doi: 10.1667/RR1680.1.

George, K. et al. (2010), “Persistence of space radiation induced cytogenetic damage in the blood lymphocytes of astronauts”, Mutation Research, Vol. 701/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrgentox.2010.02.007 

Guerrero-Carbajal, C., A.A. Edwards & D.C. Lloyd (2003), "Induction of chromosome aberration in human lymphocytes and its dependence on X ray energy. Radiat Prot Dosimetry.", Radiat. Prot. Dosimetry 106(2):131–135. doi:10.1093/oxfordjournals.rpd.a006342.

Hada, M. & A.G. Georgakilas (2008), "Formation of Clustered DNA Damage after High-LET Irradiation: A Review.", J. Radiat. Res., 49(3):203–210. doi:10.1269/jrr.07123.

Hagmar, L. et al. (2004), "Impact of Types of Lymphocyte Chromosomal Aberrations on Human Cancer Risk : Results from Nordic and Italian Cohorts.", Cancer Res., 64(6):2258–2263. doi: 10.1158/0008-5472.CAN-03-3360.

Hamza VZ and Mohankumar MN. 2009. Cytogenetic damage in human blood lymphocytes exposed in vitro to radon. Mutat Res. 661(1-2):1-9.

Han. L. et al. (2014), "Cytogenetic analysis of peripheral blood lymphocytes, many years after exposure of workers to low-dose ionizing radiation.", Mutat. Res. Genet. Toxicol. Environ. Mutagen. 1(771):1–5, doi: 10.1016/j.mrgentox.2014.06.003

Hande, M.P. et al., (2003), Past Exposure to Densely Ionizing Radiation Leaves a Unique Permanent Signature in the Genome., Am J Hum Genet. 72:1162-1170. doi: 10.1086/375041.

Hande, M. P. et al. (2005), “Complex chromosome aberrations persist in individuals many years after occupational exposure to densely ionizing radiation: an mFISH study”, Genes chromosomes & cancer, Vol. 44/1, Wiley, Hoboken, https://doi.org/10.1002/gcc.20217 

Hunter, N. & C.R. Muirhead (2009), "Review of relative biological effectiveness dependence on linear energy transfer for low-LET radiations Review of relative biological effectiveness dependence.", J. Radiol. Prot. 29(1):5-21, doi:10.1088/0952-4746/29/1/R01.

Jang, M. et al. (2019), "Dose Estimation Curves Following In Vitro X-ray Irradiation Using Blood From Four Healthy Korean Individuals.", Ann. Lab. Med. 39(1):91–95, doi: 10.3343/alm.2019.39.1.91.

Karthik K, Rajan V, Pandey BN, Sivasubramanian K, Paul SFD, Venkatachalam P, 2019. Direct and bystander effects in human blood lymphocytes exposed to 241Am alpha particles and the relative biological effectiveness using chromosomal aberration and micronucleus assay. Int J Radiat Biol. 95(6):725-736.

Kim, Jeoum Nam and B. M. Lee (2007), “Risk factors, health risks, and risk management for aircraft personnel and frequent flyers”, Journal of toxicology and environmental health, Taylor & Francis Group, England, https://doi.org/10.1080/10937400600882103 

Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, 1–12. https://doi.org/10.1080/09553002.2022.2110306 

Li, W. A. Lee & P.K. Gregersen (2009), "Copy-number-variation and copy-number-alteration region detection by cumulative plots.", BMC Bioinformatics, 10(Suppl. 1):S67, doi:10.1186/1471-2105-10-S1-S67.

Lorat. Y. et al. (2015), "Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy – The heavy burden to repair.", DNA Repair (Amst). 28:93–106. doi:10.1016/j.dnarep.2015.01.007.

Loucas BD, Durante M, Bailey SM, Cornforth MN. 2013. Chromosome Damage in Human Cells by Gamma Rays, Alpha Particles and Heavy Ions: Track Interactions in Basic Dose-Response Relationships. Radiat Res. 179(1):9-20.

Loucas, B. D and C. R. Geard (1994), “Kinetics of chromosome rejoining in normal human fibroblasts after exposure to low- and high-LET radiations”, Radiation research, Vol. 138/3, Radiation Research Society, Oak Brook, https://doi.org/10.2307/3578683 

Maffei, F. et al. (2004), "Spectrum of chromosomal aberrations in peripheral lymphocytes of hospital workers occupationally exposed to low doses of ionizing radiation.", Mutat Res., 547(1-2):91–99. doi:10.1016/j.mrfmmm.2003.12.003.

McMahon, S.J. et al. (2016), "Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage.", Nat. Publ. Gr.(April):1–14. doi:10.1038/srep33290.

Meenakshi, C. & M.N. Mohankumar (2013), "Synergistic effect of radon in blood cells of smokers - An in vitro study.", Mutat. Res., 757(1):79–82. doi: 10.1016/j.mrgentox.2013.06.018.

Meenakshi, C., K. Sivasubramanian & B. Venkatraman (2017), "Nucleoplasmic bridges as a biomarker of DNA damage exposed to radon.", Mutat Res - Genet Toxicol Environ Mutagen. 814:22–28. doi:10.1016/j.mrgentox.2016.12.004.

Mestres M, Caballin MR, Schmid E, Stephan E, Stephan G, Sachs R, Barrios L, Barquinero JF. 2004. Analysis of alpha-particle induced chromosome aberrations in human lymphocytes, using pan-centromeric and pan-telomeric probes. 80(10):737-744.

Mill AJ, Wells J, Hall SC, Butler A. 1996. Micronucleus Induction in Human Lymphocytes: Comparative Effects of X Rays, Alpha Particles, Beta Particles and Neutrons and Implications for Biological Dosimetry. Radiat Res. 145:575-585.

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