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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

Energy Deposition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Chromosomal aberrations

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	Brendan Ferreri-Hanberry (send email)	Open for citation & comment	WPHA/WNT Endorsed
Deposition of energy leading to occurrence of cataracts	non-adjacent	High	High	Arthur Author (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).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Evidence supporting the formation of CAs from the direct deposition of energy in the form of ionizing radiation is strong. Of this data, humans are the most common organisms, adults are the most common life stage, and α particles and X rays are the most common stressors studied. There is also more in vivo data compared to in vitro, however most of the human studies are in vitro (Worgul et al., 1989; Tao et al., 1993; Loucas and Geard, 1994; Tao et al., 1994; Bauchinger and Schmid 1998; Durante et al., 1998; Williams et al., 1999; Belkacémi et al., 2000; Belkacémi et al., 2001; Evans et al., 2001; Schmid et al. 2002; Hande et al., 2003; Thomas et al. 2003; Maffei et al. 2004; Tucker et al., 2004; Hande et al., 2005; Tucker et al. 2005a; Tucker et al. 2005b; Wolf et al., 2008; George et al. 2009; George et al., 2010; Blakely, 2012; Balajee et al. 2014; George et al. 2014; Han et al. 2014; Vellingiri et al. 2014; Suto et al. 2015; Adewoye et al. 2015; Cheki et al. 2016; Foray et al., 2016; McMahon et al. 2016; Morishita et al. 2016; Qian et al. 2016; Basheerudeen et al. 2017; Meenakshi et al. 2017; Abe et al. 2018; Dalke et al., 2018; Bains et al., 2019; Jang et al. 2019; Udroiu et al., 2020; Puig et al., 2016; Barquinero et al., 2004; Curwen et al., 2012; Testa et al., 2018; Franken et al., 2012; Cornforth et al., 2002; Loucas et al., 2013; Nagasawa et al., 1990a; Nagasawa et al., 1990b; Edwards et al., 1980; Themis et al., 2013; Schmid et al., 1996; Mestres et al., 2004; Bilbao et al., 1989; Mill et al., 1996; Brooks, 1975; Tawn and Thierens, 2009; Durante et al., 1992; Hamza and Mohankumar, 2009; Takatsuji and Sasaki, 1984; Moquet et al., 2001; Purrott et al., 1980; duFrain et al., 1979).

Figure 1: Plot of example studies (y-axis) against equivalent dose (Sv) used to determine the empircal link between direct deposition of energy and increased rates of chromosomal aberrations. The y-axis is ordered from low LET to high LET from top to bottom.

Figure 2: Plot of example studies (y-axis) against time over which studies were conducted for a temporal response used to determine the empircal link between direct deposition of energy and increased rates of chromosomal aberrations. The y-axis is ordered from low LET to high LET from top to bottom.

Human relevance

Several human epidemiological studies have provided evidence of both dose/incidence and temporal concordance in terms of deposition of energy by ionizing radiation and resultant CAs. In a study involving 34 health professionals occupationally exposed to radiation, there was a significant increase in the number of chromosome breaks and aberrant cells relative to a group of 35 unexposed professionals from the same hospital. Furthermore, when the exposed group was broken into two groups based on the levels of radiation exposure (those with an effective dose of ≤50 mSv and those with an effective dose of >50 mSv), there was a dose-dependent increase in aberrant cells, chromosome breaks and chromatid breaks such that the higher exposure group had significantly elevated aberrations relative to controls for all three parameters scored (Maffei et al. 2004). In a similar study involving 1,392 radiation healthcare workers in the city of Tangshan in 2010, there was a significant increase in CA and MN in exposed workers relative to unexposed healthy controls. Furthermore, there were significant, dose-dependent increases in the CA rate and the MN rate when the exposed workers were split into groups according to effective dose, ranging from <10 mSv up to >50 mSv. There was also a time-dependent increase in CA and MN rate, such that workers with longer exposure times had significantly increased CAs and MNs. Exposure times ranged from less than 10 years to greater than 20 years (Qian et al. 2016). A final study with 31 plutonium and reactor workers found that those exposed to high doses of Pu had a frequency of complex translocations that was 2.9% higher and a frequency of simple translocations that was 5.1% higher compared to unexposed workers. They also found that workers exposed to γ-rays had a frequency of complex translocations that was only 0.21% higher than that of controls, and a frequency of simple translocations that was 4% higher than controls (Hande et al., 2005).

Dose Concordance

There is a clear correlation between radiation dose (i.e., increasing amounts of energy deposition) and different clastogenic endpoints including dose-dependent increases in: dicentric aberrations(Schmid et al. 2002; Thomas et al. 2003; Tucker et al. 2005A; Suto et al. 2015; Mcmahon et al. 2016; Abe et al. 2018; Jang et al. 2019), centric rings (Tucker et al. 2005a) (Schmid et al. 2002; Thomas et al. 2003; Tucker et al. 2005A), acentric fragments (Loucas and Geard, 1994; Schmid et al. 2002; Thomas et al. 2003) , translocations (Hande et al., 2005; Tucker et al. 2005A; Tucker et al. 2005B; Suto et al. 2015; Abe et al. 2018; Jang et al. 2019), CNVs (Arlt et al. 2014), large deletions (Mcmahon et al. 2016), NPBs (Thomas et al. 2003), MNs (Tao et al., 1993; Tao et al., 1994; Thomas et al. 2003; Balajee et al. 2014), fragmented nuclei (Tao et al., 1993), strand breaks (Durante et al., 1998) and CAs in general (Williams et al., 1999; Evans et al., 2001; Hande et al., 2003; George et al., 2009; Mcmahon et al. 2016) (George et al. 2009).

Interestingly, MN structural complexity was likewise demonstrated to be dose-dependent between 1 and 10 Gy. MN were found to contain fragments from two or more different chromosomes at and above 2 Gy; between 5 and 10 Gy, MN contained material from 3 - 5 different chromosomes. These results suggest that MN formation appears to become increasingly more complex with higher doses of radiation due to the increasing number of acentric fragments and the resultant fusion of these fragments (Balajee et al. 2014). Of note, the photon energy of the radiation has an effect on the relationship between direct deposition of energy and the resulting CAs. Specifically, dicentric aberration frequency in human peripheral blood lymphocytes was observed to change with voltage of the ionizing radiation. As the X-ray voltage decreased from 60 kV to 10 kV, there was an increase in the number of dicentric aberrations (Schmid et al. 2002).

Time Concordance

Temporal concordance is well established. Energy deposition happens immediately upon radiation exposure, with an increased incidence of CAs documented minutes, hours or days after irradiation (Loucas and Geard, 1994; Durante et al., 1998; Schmid et al. 2002; Thomas et al. 2003; Tucker et al. 2005A; Tucker et al. 2005B; George et al. 2009; Meenakshi and Mohankumar 2013; Arlt et al. 2014; Balajee 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).

Essentiality

Radiation exposure has been found to increase levels of CAs above background levels and lead to more complex damage, highlighting the essentiality of deposition of energy (Tao et al., 1994; Durante et al., 1998; Williams et al., 1999; Evans et al., 2001; Schmid et al., 2002; Hande et al., 2005; Wolf et al., 2008; George et al., 2009; Suto et al., 2015; Abe et al., 2018; Dalke et al., 2018; Bains et al., 2019; Jang et al., 2019; Udroiu et al., 2020). In the absence of radiation, there are minimal amounts of CAs. For example, abnormal karyotypes are half as likely in non-irradiated cells compared to irradiated cells (Wolf et al., 2008). Since deposited energy initiates events immediately, the removal of deposited energy, a physical stressor, also supports the essentiality of the key event. Studies that do not deposit energy are observed to have no downstream effects.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Quantitative understanding of this linkage suggests that CA frequency can be predicted from the radiation, as per the representative examples provided below. When predicting this relationship, the characteristics of the radiation and the model system should be taken into account (Smith et al. 2003; Hunter and Muirhead 2009). It is widely accepted that the deposition of energy, at all doses, results in immediate ionization events, followed by downstream events. The following tables provide representative examples of the relationship, unless otherwise indicated, all data is significantly significant.

Dose Concordance

Reference	Experiment Description	Result
Suto et al., 2015	In vitro. Human peripheral blood lymphocytes were exposed to 60Co γ-rays at 0 – 300 mGy and 5 mGy/sec. The number of dicentrics and translocations in chromosomes 1, 2, and 4 were determined using three differentially colored chromosome painting probes.	Study of human peripheral blood lymphocytes from a healthy donor subjected to γ-ray radiation in the dose (D) range of 0 - 300 mGy found a calculated CA rate (y) of dicentrics, translocations and dicentrics+translocations (of the quadratic form, y = a + bD + bD^2) found - dicentrics + translocations (a,b,c := 0.0023 ± 0.0003, 0.0015 ± 0.0058, 0.0819 ± 0.0225), dicentrics (a,b,c := 0.0004 ± 0.0001, 0.0008 ± 0.0028, 0.0398 ± 0.0117), translocations (a,b,c := 0.0019 ± 0.0003, 0.0008 ± 0.0028, 0.0398 ± 0.0117).
Abe et al., 2018	In vitro. Human mononuclear blood cells from five donors (four males aged 23, 35, 44, and 55 years old, and a 33-year-old female) were exposed to 60Co γ-rays at 0 – 1000 mGy. The dose rate in the irradiator was 26.6 mGy/min with an additional 6.42 mGy to the sample while entering and leaving the irradiation source. None of the subjects had a history of radiotherapy, smoking, or chemotherapy. The number of dicentrics and translocations in chromosomes 1, 2, and 4 were determined using Giemsa staining and Centromere-FISH staining.	Study of human mononuclear blood cells from healthy donors; analyzed for dicentric chromosomes. Exposure to γ-ray doses (D) in the 0 - 1000 mGy range. Quadratic form fit for the CA rate in Giemsa staining and Centromere-FISH staining cases (y) (of the form y = a + bD + cD^2) found to be: Giemsa staining: (a,b,c := 0.0013 ± 0.0005, 0.0067 ± 0.0071, 0.0313 ± 0.0091), Centromere-FISH staining (a,b,c := 0.0010 ± 0.0004, 0.0186 ± 0.0081, 0.0329 ± 0.0104). Study of mononuclear blood cells from healthy donors; analyzed for translocations. Exposure to γ-ray doses (D) in the 0 - 1000 mGy range. Quadratic form fit for the CA rate (y) before and after donor age adjustment (of the form y = a + bD + cD^2) found to be: before donor age adjustment: (a,b,c := 0.0053 ± 0.0009, 0.259 ± 0.0127, 0.0826 ± 0.0161), after donor age adjustment (a,b,c := 0.0015 ± 0.0009, 0.0049 ± 0.0155, 0.1033 ± 0.0223).
Jang et al., 2019	In vitro. Human peripheral blood lymphocytes from four different donors (two males, 36 and 22 years old, and two females, 28 and 24 years old) were exposed to 6 MV X-rays at 0-5 Gy and 0.5 Gy/min. None of the subjects had a history of chemotherapy, smoking, or radiotherapy. The number of dicentrics and translocations in chromosomes 1, 2, and 4 were determined using Giemsa staining and chromosome painting, respectively.	Human peripheral blood lymphocytes studied from healthy donors. Lymphocytes irradiated with X-rays in a dose (D) range 0 - 5 Gy. Calculated CA rate from dicentrics or translocations (y) (of the form y = a + bD + cD^2). Dicentrics, (a,b,c := 0.0011 ± 0.0004, 0.0119 ± 0.0032, 0.0617 ± 0.0019). Translocations, (a,b,c := 0.0015 ± 0.0004, 0.0048 ± 0.0024, 0.0237 ± 0.0014).
Schmid et al., 2002	In vitro. Human peripheral blood lymphocytes from one male donor were exposed to 29 kV X-rays at 0.115 – 2.194 Gy and at 0.009 – 0.140 Gy/min. CAs were determined with fluorescence plus Giemsa staining.	Study of various X- and γ-ray types irradiating peripheral human blood lymphocytes, analyzed dicentrics and acentrics (10, 29, 60, 220 kV X-rays & Cs-137, Co-60 γ-rays). See Schmid et al. (2002) for details on equations.
George et al., 2009	In vitro. HF19 normal primary lung fibroblasts, AT primary fibroblasts, NSB1-deficient primary fibroblasts, M059K glioblastoma cells, and M059J glioblastoma cells were exposed to iron nuclei (1000 MeV/nucleon, 0.2 – 0.5 Gy/min, average LET of 151 keV/um), and 137Cs γ-rays (0.2 – 1 Gy/min) at 0 – 3 Gy. CAs in chromosomes 1, 2, 4, and 11 were determined using FISH staining.	γ-rays and iron nuclei irradiating HF19 normal primary lung fibroblasts; Ataxia telangiectasia (AT) primary fibroblasts; NSB1-deficient primary fibroblasts (Nijmegen breakage syndrome); M059K glioblastoma cells & M059J glioblastoma cells (lack DNA-dependent protein kinase activity). Dose range of 0 - 3 Gy. See Table 5 & 6 of George et al. (2009) for details on equations.
Wolf et al. 2008	In vivo. Female, C57BL/6 mice received head-only exposure to 11 Gy soft X-rays. Mice were either 2 or 26 months-old at irradiation. 6 were irradiated and 6 were non-irradiated controls. Chromosomal aberrations were detected using Wright-trypsin G-banding.	Irradiation of eight-week-old mice with 11 Gy of X-rays increased the number of abnormal chromosomes from 15 (control) to 27. Irradiation of 26-month-old mice with 11 Gy of X-rays increased the number of abnormal chromosomes from 0 (control) to 30). However, the significance of these results was not indicated.
Williams et al., 1999	In vitro. Human lymphocyte cells were exposed to Fe ions (0 – 1 Gy, 1 GeV incident energy), 137Cs photons (0 – 7.5 Gy, 83 cGy/min), and protons (5 Gy, 250 keV incident energy). Chromosomal aberrations were identified using Leishman’s stain.	CAs rose from 0 to 0.001, 0.004, 0.014, and 0.017 after exposure to 1 Gy 137Cs, 1 Gy Fe, 5 Gy 137Cs, and 5 Gy energetic photons respectively.
Evans et al., 2001	In vitro. TK6 and WTK1 human lymphoblastoid cells were exposed to 56Fe ions (0 – 2.25 Gy, 1087 MeV/nucleon) and 137Cs γ-rays (0 – 4 Gy, 0.87 – 0.92 Gy/min). CAs were assessed using Giemsa staining.	Exposure to higher doses resulted in increased amounts of aberrant cells. For example, in TK6 cells after 56Fe irradiation, 0% of cells were aberrant in the control, 19% were aberrant after 0.63 Gy, and 66% were aberrant after 2.25 Gy. Additionally, 56Fe ions induced increased numbers of aberrant cells when compared to 137Cs γ-rays.
Hande et al., 2005	In vivo. Lymphocytes from 31 Russian reactor and plutonium workers were exposed to plutonium ions and γ-rays. Highly exposed plutonium workers received 1.1 Gy of Pu and 1.5 Gy of γ-rays. Moderately exposed plutonium workers received 0.19 Gy of Pu and 0.19 Gy of γ-rays. Reactor workers received only 2.3 Gy of γ-rays. Values are averages. CAs were detected using the mFISH assay.	The amount of interchromosomal complex translocations were 2.9, 0.23, and 0.21% higher than controls in workers highly exposed, moderately exposed, and exposed to only γ-rays, respectively. The amount of interchromosomal simple translocations were 5.1, 1.5, and 4% higher than controls in workers highly exposed, moderately exposed, and exposed to only γ-rays, respectively.
Durante et al., 1998	In vitro. Human male lymphocyte cells were exposed to carbon ions (5 Gy, 290 meV/nucleon, 42 keV/μm), neon ions (7 Gy, 400 MeV/nucleon, 31 keV/μm), hydrogen ions (1, 3, 5, 7 Gy, 0.4 keV/μm), and iron ions (0.5, 0.75, 1, 2, Gy, 1000 MeV/nucleon, 140 keV/μm). Chromosomal aberrations were detected using DAPI-counterstaining the PAINT classification.	As the dose increased from 0 to 7 Gy, the number of DNA breaks per human male lymphocyte cell also increased from 0 to 1.2. This included data using iron ions, hydrogen ions, carbon, and neon.
Tao et al., 1994	In vivo. 90 – 110-day old B6CF1/Anl mice received irradiation to the anterior 2/3 of the body with 60Co γ-rays (10 – 40 cGy), 20Ne (670 MeV/amu, 25 keV/um), 56Fe (600 MeV/amu, 193 keV/um), 93Nb (600 MeV/amu, 464 keV/um), 139La (593 MeV/um, 953 keV/um). All stressors except 60Co delivered 10, 20, 40, 80, 160, and 320 cGy. Doses were delivered to the anterior 2/3 of the body. CAs were detected using a modified Feulgen method 64 weeks post-exposure.	Mouse lenses exposed to all radiation types showed increased MN number per whole mount at increasing doses from 10 to 160 cGy. For example, irradiation from 56Fe particles led to a MN number of 10 after 10 cGy and an MN number of 100 after 160 cGy.
Bains et al., 2019	In vitro. Human LECs were exposed to X-rays at 0, 0.001, 0.01, 0.02, 0.1, 1, and 2 Gy. Doses of 0.1, 1.0, and 2.0 had a dose rate of 0.58 Gy/min. 0.001, 0.01 and 0.02 Gy at 0.022 Gy/min. The γ-H2AX assay was used to determine the number of telomere dysfunction induced foci (TIF).	At 30 min after irradiation, the number of TIF/human lens epithelial cell remained almost 0 after exposure to 0, 0.001, and 0.01 Gy. It then rose quickly to 4.75 TIF/cell at 2 Gy.
Udroiu et al., 2020	In vitro. Human LECs were exposed to X-rays at 25, 51.25, 135, 235, and 300 mGy at 0.51, 0.15, and 0.228 Gy/min. The micronuclei frequency was measured with a cytokinesis-blocked micronucleus assay.	In human LECs exposed to 25 – 300 mGy the micronuclei frequency increased steadily, reaching 2.4x control at the maximum dose.
Dalke et al., 2018	In vivo. 10-week-old, mixed sex B6C3F1 and B6RCF1 hybrid mice received whole-body exposure to 0.063, 0.125, and 0.5 Gy 60Co γ-rays at 0.063 Gy/min. CAs were assessed using Giemsa staining.	In heterozygous Ercc2 mutants, 12 months after irradiation, the number of aberrations/cell rose from 0.1 (control) to 0.82 (0.5 Gy). There was also a slightly smaller increase after 18 months where the number of chromosomal aberrations/cell rose from 0.1 (control) to 0.3 (0.5 Gy). In wild type mice the largest increase occurred after 12 months where the number of aberrations/cell rose from 0.12 (control) to 0.32 (0.5 Gy).

Time Concordance

Reference	Experiment Description	Result
Tucker et al., 2004	In vivo. 7-week-old female C57BL/6 mice transgenic for lacZ received whole-body exposure to 1 Gy of 26Fe ions at 1 Gy/min. Aberrations on chromosomes 1, 2, 3, and 8 were determined with a FISH assay.	Lymphocytes from mice exposed immediately to 1 Gy of iron ions had 19 translocations per 100 cells, 14 acentric fragments per 100 cells, and 10 dicentric chromosomes per 100 cells at 1 week post-irradiation.
Tao et al., 1994	In vivo. 90 – 110-day old B6CF1/Anl mice received irradiation to the anterior 2/3 of the body with 60Co γ-rays (10 – 40 cGy), 20Ne (670 MeV/amu, 25 keV/um), 56Fe (600 MeV/amu, 193 keV/um), 93Nb (600 MeV/amu, 464 keV/um), 139La (593 MeV/um, 953 keV/um). All stressors except 60Co delivered 10, 20, 40, 80, 160, and 320 cGy. Doses were delivered to the anterior 2/3 of the body. CAs were detected using a modified Feulgen method.	Mouse lenses exposed immediately to all radiation types showed increased MN number per whole mount at increasing doses from 10 to 160 cGy at 64 weeks post-irradiation. For example, irradiation from 56Fe particles led to a MN number of 10 after 10 cGy and an MN number of 100 after 160 cGy at 64 weeks post-irradiation.
Tao et al., 1993	In vivo. 90 – 110-day old female B6CF mice received irradiation to the anterior 2/3 of the body with 10, 20, 40, 80, 160, and 320 cGy of protons: 250 MeV, LET 0.4 keV/um. 20Ne: 670 MeV/amu, LET 25 keV/um. 56Fe: 600 MeV/amu, LET 183 keV/um. 56Fe: 350 MeV/amu, LET 219 keV/um. 93Nb: 600 MeV/amu, LET 464 keV/um. 139La: 593 MeV/amu, 953 keV/amu. Fragmented nuclei (FN) and MN were detected using a modified Feulgen staining method or haematoxylin and eosin staining.	In mice immediately irradiated with iron ions, the number of FN in the whole mount of lens cells increased from 1.5 FN (control) to 11 FN at 160 cGy after 64 weeks. The number of FN in the meridional rows increased from 0 (control) to 6 FN at 160 cGy after 64 weeks as well. The number of MN on the whole mount also increased from 0 to 100 at 160 cGy after 64 weeks. Similar changes were also observed with the other radiation types.
Belkacémi et al., 2001	In vitro. Bovine lens cells were exposed to 10 Gy at 2 Gy/min from a linear accelerator. The Hoechst 33342 fluorescence was used to measure chromosomal aberrations.	In lens cells immediately irradiated with X-rays, Hoechst 33342 fluorescence increased 13%, 25%, and 32% above controls at 24, 72, and 96 h post-irradiation, respectively.
Bains et al., 2019	In vitro. Human LECs were exposed to X-rays at 0, 0.001, 0.01, 0.02, 0.1, 1, and 2 Gy. Doses of 0.1, 1.0, and 2.0 had a dose rate of 0.58 Gy/min. 0.001, 0.01 and 0.02 Gy at 0.022 Gy/min.	In human LECs immediately exposed in vitro to 0.02 Gy, the number of telomere dysfunction-induced foci (TIF)/cell increased to 3x control 30 min post-irradiation.
Dalke et al., 2018	In vivo. 10-week-old, mixed sex B6C3F1 and B6RCF1 hybrid mice received whole-body exposure to 0.063, 0.125, and 0.5 Gy 60Co γ-rays at 0.063 Gy/min. CAs were assessed using Giemsa staining.	In mice immediately exposed to 0.125-0.5 Gy of γ-rays, CAs were observed after 12 months, increasing to a maximum of 0.82 CAs/cell at 0.5 Gy.

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

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