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Relationship: 2849

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 Bone Loss

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

Bone Loss

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 occurrence of bone loss	non-adjacent	High	Moderate	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed

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	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	Moderate
Unspecific	Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult	High
Juvenile	Moderate

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 deposited onto an organism from ionizing radiation (IR) can result in an increase in bone loss. Bone loss refers to a decrease in bone mass or density as observed in a variety of conditions such as osteopenia and osteoporosis (Cummings, Bates, and Black, 2002). Energy deposition can interfere with overall bone integrity and the capacity to withstand mechanical load, leading to an increased risk of fractures (Cummings, Bates, and Black, 2002; Green and Rubin, 2014; Orwoll et al., 2013; Willey et al., 2011; Willey et al., 2013; Wright, 2018). Ionizing energy deposited into an organism is absorbed eliciting breakage of water molecules leading to free radical formation, if this overwhelms the antioxidant capacity, then oxidative stress ensues. If this occurs in bone tissue cells, including osteoblasts, osteoclasts, and osteocytes, it can dysregulate their activity. The subsequent increases in bone resorption and decreases in bone formation culminate in increased bone loss. Bone loss can be induced by a variety of radiation sources, including low linear energy transfer (LET) radiation, such as X-rays, gamma rays, and protons, and high LET radiation, such as heavy ions, at a wide range of doses and dose rates. IR-induced bone loss can be observed through microarchitectural measurements that show the structural deterioration of affected bones.

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 on radiation stressors 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

Extreme stresses, such as energy deposited by IR, can dysregulate bone resorption from osteoclasts and formation from osteoblasts, resulting in bone loss (Donaubauer et al., 2020). Numerous studies have shown that skeletally mature adults exposed to radiotherapy have a greater risk of bone fractures, reduced bone strength, and osteoporosis. Availability of human studies to support this relationship is extensive from both in a clinical and space setting. Bone loss in areas exposed to clinical radiotherapy have been associated with increased fracture risk (Green and Rubin, 2014; Orwoll et al., 2013; Willey et al., 2011, Willey et al., 2013; Wright, 2018). A substantial body of evidence from spaceflight missions demonstrates that the space environment, which consists of IR, induces an imbalance between bone production and resorption (Orwoll et al., 2013; Stavnichuk et al., 2020; Willey et al., 2011). Stavnichuk et al. (2020) performed a meta-analysis using 148 astronauts and found decreased bone density at a rate of 0.8% per month of spaceflight. Even when appropriate nutrition and enhanced physical activity training are implemented, the concentrations of bone resorption indicators increase in astronauts during flight (Farris et al., 2020; Yang et al., 2018).

Irradiated bone has a lower number of osteoblasts than non-irradiated bone. Fewer osteoblasts results in a decrease in the bone formation rate leading to bone loss. This may reduce the synthesis of a new matrix (e.g., collagen) and decrease bone density, which can increase bone loss and the risk of bone fracture (Costa and Reagan, 2019; Farris et al., 2020). Increased osteoclast and decreased osteoblast activity following irradiation results in increased bone resorption and trabecular bone turnover.

Bone marrow is among the most radiosensitive tissues in the body. Another outcome of irradiation on bones is the elimination of red (active, hematopoietic) marrow and the replacement with yellow (or white, inactive, fatty) marrow (ICRP, 2007; Pacheco and Stock, 2013). Yellow marrow is less vascular than red marrow and is therefore more vulnerable to repetitive physiologic skeletal loads (Pacheco and Stock, 2013).

One contributor to bone loss from deposited energy is an increase in reactive oxygen species (ROS), associated DNA damage, and related apoptosis. In bone marrow-derived skeletal cell progenitors, radiation reduced osteoblast development and promoted ROS generation (Willey et al., 2011; Yang et al., 2018). Total body irradiation in rodents increases the production of ROS in marrow cells and accelerates cell death. These findings suggested that irradiation could generate oxidative stress, inhibiting osteoblast development and differentiation while promoting bone resorption. As a result, radiation may influence key bone cell processes by promoting the generation of ROS and suppressing osteoblasts. After gamma irradiation, male C57BL/6 mice showed reduced cancellous BV/TV in the proximal tibia and lumbar vertebrae, higher osteoclast surface in the tibia, and increased ROS generation in marrow cells (Donaubauer et al., 2020; Tian et al., 2017; Willey et al., 2011; Yang et al., 2018).

The degree of bone mineralization and bone density are direct indicators of bone loss in the body that are depleted following irradiation (Farris et al., 2020; Green and Rubin, 2014; Slyfield et al., 2012). Changes to trabecular and cortical parameters also indicate bone loss due to the deposition of energy. Indirect measures of bone loss following radiation can include the incidence of fractures as well as the energy required to fracture the bone (Fonseca et al., 2014; Turner, 2002). In addition, stiffness and the elastic modulus have been shown to positively correlate with the degree of mineralization of bones (Fonseca et al., 2014; Turner, 2002).

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

The empirical data relevant to this KER provides support for the linkage between deposition of energy and bone loss. The majority of the evidence supporting this relationship comes from studies examining the effect of IR sources, including X-rays, gamma rays, protons, and heavy ions, on the skeletal system. Current literature on the subject explores the deterioration of bone structure under exposure to a wide range of doses (0.05-64 Gy), dose rates (0.1-4 Gy/min), and LET levels (0.23-175 keV/µm). IR exposure consistently resulted in increased bone loss, often in a dose- and time-dependent manner (Alwood et al., 2017; Alwood et al., 2010; Bandstra et al., 2009; Bandstra et al., 2008; Chandra et al., 2017; Chandra et al., 2014; Ghosh et al., 2016; Green et al., 2012; Hamilton et al., 2006; Hui et al., 2014; Lloyd et al., 2012; Nishiyama et al., 1992; Stavnichuk et al., 2020; Willey et al., 2010; Wright et al., 2015; Yumoto et al., 2010).

Dose Concordance

Current literature on the effects of IR on bone tissue provides strong evidence for a dose concordance relationship between energy deposition and bone loss. Once energy is deposited onto matter at all doses, follow-on downstream events are immediately initiated. The models used in these studies, mostly C57BL/6 mice, generally experienced some degree of degradation in one or more parameters of bone structure or quality, including bone mineral density (BMD), bone volume fraction (BV/TV), connectivity density (Conn.D), trabecular number (Tb.N), trabecular separation (Tb.Sp), trabecular thickness (Tb.Th), maximum load, stiffness, the elastic modulus, and the frequency of fractures after irradiation.

A few human studies show the response after a given dose of IR. Patients with uterine cervix carcinoma irradiated with photons (4 MV) showed similar reductions in CaCO₃ content by an average of 55 mg after both 22.4 and 45 Gy (Nishiyama et al., 1992). In astronauts exposed to space radiation, bone density is estimated to be reduced at 0.8% per month in lower limbs and 0.1% per month in upper limbs as longer duration flights lead to a higher dose of IR (Stavnichuk et al., 2020). Short duration flights (<30 days) led to decreased bone density up to 10%, which could be due to an early onset of increased resorption and late onset of increased formation (Stavnichuk et al., 2020). However, astronauts are also exposed to microgravity and not just radiation. A follow-up study of the Stockholm I and II Trials found a significantly increased incidence of femoral neck or pelvic fractures in rectal carcinoma patients receiving 25 Gy of radiotherapy compared to unexposed patients (Holm et al., 1996). Multiple clinical studies demonstrate that increasing fractionated doses of photons from ~40-60 Gy during radiotherapy lead to an increased incidence of bone fractures, likely due to lower bone mass after higher radiation doses (Dickie et al., 2009; Overgaard, 1988).

Of the studies that examined the effects of irradiation in animal models with low LET sources, such as X-rays, gamma rays, and protons, most found that low doses (<2 Gy) could result in bone loss (Alwood et al., 2017; Bandstra et al., 2008; Lloyd et al., 2012). Similarly, higher LET sources, such as heavy ions, could result in bone loss at doses as low as 0.1 Gy (Alwood et al., 2017; Alwood et al., 2010; Bandstra et al., 2009; Ghosh et al., 2016; Yumoto et al., 2010). However, changes at low doses were often non-significant.

Exposure to high doses (>2 Gy) of IR resulted in statistically significant bone loss in almost all cases, regardless of the radiation type, along with greater changes compared to lower doses (Alwood et al., 2017; Alwood et al., 2010; Bandstra et al., 2008; Chandra et al., 2017; Chandra et al., 2014; Green et al., 2012; Hamilton et al., 2006; Hui et al., 2014; Jia et al., 2011; Willey et al., 2010; Wright et al., 2015; Yumoto et al., 2010). While bone loss was generally significant in all high dose studies, Hamilton et al. (2006) and Alwood et al. (2017) compared the impact that exposure to the same dose of radiation has on bone structure when multiple sources with different LET levels are used. They found that changes in BV/TV and Tb.Th were generally LET-dependent, with higher LET sources consistently inducing greater loss of bone than lower LET sources. However, some measurements, including Tb.N, Tb.Sp, and Conn. D, did not always follow this trend.

Studies that examined the impact of a range of radiation doses on bone structure in the same model provide excellent evidence for a dose-dependent relationship between energy deposition and bone loss. These studies found that high dose radiation generally resulted in more pronounced bone loss than low dose radiation (Alwood et al., 2017; Alwood et al., 2010; Bandstra et al., 2008), except for the study by Yumoto et al. (2010), which observed significant dose-dependent decreases in BV/TV and Conn. D at 0.1 and 0.5 Gy compared to non-irradiated controls, but a non-significant decrease at 2 Gy. Bandstra et al. (2008) observed linear, dose-dependent decreases in BV/TV and volumetric BMD (vBMD) from 0.5-2 Gy, while Tb.Sp similarly increased in a linear, dose-dependent manner at 0.5-2 Gy. Alwood et al. (2017) observed proton and ⁵⁶Fe radiation both induced a decrease in BV/TV and Tb.N at 2 Gy, but not at 0.05 or 0.1 Gy. Alwood et al. (2010) observed significant changes to BV/TV, Tb.Sp, Tb.N, Conn. D, cancellous bone stress, and the elastic modulus after exposure to 2 Gy of ⁵⁶Fe heavy ions, while 0.5 Gy did not result in significant changes to any measures of bone structure. Jia et al. (2011) showed that BMD decreased almost 2-folds with each increasing dose (5, 10, 15, 20 Gy) from 0 Gy. A significant decrease in BV/TV was observed in mice exposed to 5Gy compared to the control group, while 1 Gy did not result in any significant changes (Pendleton et al., 2021). Mice exposed to 0.5 Gy in a single or fractionated dose (0.17 X3) of high-LET 28 SI ions showed significant reductions in bone volume, respectively, when compared to sham controls (Macias et al. 2017). Additionally, under spaceflight conditions mice were observed to exhibit a 6.23% decrease in BV/TV and a 11.91% decrease Tb.Th in the pelvis compared to the ground control group (Blaber et al., 2013).

Time Concordance

In the current literature, there is limited evidence of a time-concordance relationship between energy deposition and bone loss. When energy is deposited onto biological models it immediately causes ionization events which directly lead to downstream events occurring at later time points. In patients with uterine cervix carcinoma irradiated with protons (4 MV) at 22.5 and 45 Gy, bone CaCO₃ content decreased linearly from 140 mg to 84 mg after 3 months, plateauing at about 70 mg after 6 and 12 months (Nishiyama et al., 1992). A higher incidence of fractures was observed in patients receiving 25 Gy of photons compared to unexposed patients, measured 5 years after exposure (Holm et al., 1996). Current data in animal models suggests that most bone loss occurs in the first few months after exposure. In mice exposed to 5 Gy gamma radiation, significant decline was found in both mineral/bone matrix ratio and bone volume fraction 10 days following exposure (Green et al. 2013). The BV/TV of control mice after 12 weeks decreased 11.5% compared to the 0 Gy at 11 days. After exposure to 5 Gy, BV/TV in mice decreased 23% after 11 days and –21.6% after 12 weeks (Pendleton et al., 2021). At 12 weeks post-exposure to 20 Gy gamma rays, Tb.Sp and the ratio of bone surface to volume (BS/BV) were increased, while BV/TV, Tb.Th, Tb.N, and maximum loading were decreased (Zou et al., 2016). One week to 1 year after exposure resulted in significant decreases in BMD, BV/TV, Tb.N, Conn.D, bending strength, the elastic modulus, and stiffness (Alwood et al., 2017; Green et al., 2012; Hui et al., 2014; Oest et al., 2018; Zhang et al., 2019). Mandair et al. 2020 observed a significant decrease in mineral/matrix ratio in the endosteal and mid-cortical bone 2 weeks following 20 Gy (4 X 5Gy) radiation exposure, with a progressive decrease 4- and 8-weeks post exposure (Mandair et al. 2020). In mice exposed to 5 or 20 Gy of x-ray radiation, a significant decrease in bone volume was shown in irradiated mice with both 5 Gy and 20 Gy at 6-, 12- and 26-weeks post irradiation. A significant increase in Trabecular spacing (Tb sp) was also shown in the 20 Gy irradiated mice when compared with control groups up to 13 weeks post-irradiation (Wernle et al.2010).

Essentiality

In vivo studies show that bone loss mainly occurs in the bone tissue directly receiving radiation. In several experiments, malleable lead shielding was used to protect the contralateral limbs of mice from the effects of IR. Contralateral bone tissue was harvested and was compared to the bone tissue directly receiving radiation. Relative to baseline levels, shielding of contralateral limbs consistently attenuated the effects of IR on all markers of bone loss compared to non-shielded limbs. Shielding reduced the IR-induced changes to various bone loss measures including BV/TV, Conn.D, Tb.N, and Tb.Th (Oest et al., 2018; Wright et al., 2015). Furthermore, Baxter et al. (2005) found that the risk of osteoporotic fractures in humans exposed to radiotherapy increased only at the irradiated site. However, some studies still show bone loss in shielded limbs, possibly due to the abscopal effects of radiation (Zhang et al., 2019; Zou et al., 2016).

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

At 8 days post-16 Gy irradiation, there was a significant increase in trabecular BV/TV relative to the non-irradiated controls, contrary to the expected reduction in bone volume usually seen following energy deposition (Hui et al., 2014).
When exposed to 0.1, 0.5, and 2 Gy of ⁵⁶Fe heavy ions, mice did not follow the expected dose-dependent response. Compared to non-irradiated controls, 0.1 and 0.5 Gy irradiation resulted in significant 16% and 18% decreases in BV/TV, respectively. 2 Gy radiation did not have a significant effect on trabecular BV/TV. 0.1 and 0.5 Gy irradiation similarly decreased Tb.N by 7% and 5%, respectively, while changes following 2 Gy irradiation were non-significant (Yumoto et al., 2010).
Many clinical studies demonstrate that bone loss occurs following radiotherapy in humans (Willey et al., 2011). However, very few studies specify the dose of radiation used, reducing the availability of human studies and an understanding of dose-effects.
There was approximately a 2-fold increase in %BV/TV of the distal femur of mice following a 0.5 Gy of 56Fe compared to the sham-irradiated group (Bokhari et al., 2019)
There was a significant increase in trabecular BV/TV, Conn.D and Tb.N after mice were exposed to 4.4 cGy of ionizing radiation (Karim and Judex, 2014)
Exposure to 0.5 Gy 56Fe radiation in WB and 6/G mice improved cancellous bone microarchitecture 21 days after irradiation and continued to improve during recovery period. Additionally, in irradiated WB and G/6 mice, cancellous bone volume of the distal femur was 78% and 5% greater compared to their sham control groups (Bokhari et al. 2019).
Bone mineral to matrix ratio, which is correlated with mineral density, was significantly increased at 4 weeks post 20 Gy irradiation in mice tibia (Gong et al. 2013). However, at 12 weeks the parameters shifted in the opposite direction with the ratio significantly decreasing in the irradiated group. It is important to note that these findings were done using Raman spectroscopy, which is not a well-established technology for biochemical measurements. In another study, mineral crystallinity which also supports mineral density, was transiently increased from weeks 2 to 4 after irradiation (4x5Gy) (Oest et al., 2016).

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	MF details	Effects on the KER	References
Drug	Risedronate	Led to restored BV/TV and Conn. D levels after radiation.	Willey et al., 2010
Genotype	Loss of function mutations (like in sclerosteosis and van Buchem disease) in the SOST gene for sclerostin (sclerostin is a Wnt receptor antagonist that inhibits osteoclastogenesis).	Radiation did not affect BMD and BV/TV in sclerostin knockout mice.	Chandra et al., 2017
Drug	1–34 amino-terminal fragment of parathyroid hormone (osteoporosis treatment that attenuates osteoblast apoptosis).	Treatment with 60 µg/kg/day for 27 days led to increased BV/TV and BMD after radiation-induced decreases.	Chandra et al., 2014
Age	Old age	Lower estrogen at old age is thought to contribute to the detrimental effects of radiotherapy on bone loss in elderly patients.	Pacheco and Stock, 2013

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

The following are a few examples of quantitative understanding of the relationship. All reported findings are statistically significant at various alpha levels as listed in the original sources.

Response-response Relationship

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

Dose Concordance

Reference	Experiment Description	Result
Overgaard, 1988	In vivo. Patients receiving post-mastectomy photon radiation (8 MV) had the number of rib fractures evaluated with chest radiograms.	The frequency of fractures increased dose-dependently between 40 and 50 Gy (12 fractions) and between 50 and 55 Gy (22 fractions), resulting in a maximum of 48% of patients with rib fractures at 50 Gy.
Holm et al., 1996	In vivo. Rectal carcinoma patients received preoperative radiotherapy with photons at 25 Gy (500 irradiated, 527 control). The source of photons was either 60Co or a 6-21 MV linear accelerator. The incidence of hospitalizations for femoral neck or pelvic fracture was determined at a 5-year follow-up.	Patients irradiated with 25 Gy had an incidence of pelvic fracture of 5.3%, while significantly fewer non-irradiated patients were admitted for fracture (2.4%).
Dickie et al., 2009	In vivo. Lower extremity soft tissue sarcoma patients receiving radiotherapy were divided into patients with lower extremity fractures (n=21) and patients without fractures (n=53). The average dose received was compared between the two groups.	Radiotherapy patients that had a bone fracture received an average dose of 45 Gy. Patients without a fracture had a lower average dose of 37 Gy. In addition, the maximum dose received by patients with a fracture was 64 Gy, while the maximum dose received by non-fractured patients was 59 Gy.
Nishiyama et al., 1992	In vivo. Patients with uterine cervix carcinoma from 1989 to 1990 with or without 4 MV photon irradiation to lumbar vertebrae had bone mineral content (measured in mg CaCO3 eq/cm3) determined. Radiation was given in 1.8 Gy fractions over 5 weeks for a total dose of either 22.5 or 45 Gy to the vertebrae (radiation plan dependent).	The control group did not show a change in bone mineral content. Both 22.5 and 45 Gy reduced bone mineral content by about 55 mg.
Stavnichuk et al., 2020	In vivo. A meta-analysis that extracted the percent change in bone density in 148 astronauts from articles from 1971 to 2019. The longer the spaceflight, the higher dose of IR the astronauts received, although IR was not the only stressor that the astronauts would have received.	In missions from 30 to 250 days, the estimated reduction in bone density was 0.1% per month in upper limbs and 0.8% per month in lower limbs.
Bandstra et al., 2008	In vivo. 58-day-old, female, juvenile, C57BL/6J mice were exposed to whole-body irradiation with 0.5, 1, and 2 Gy of 250 MeV protons at a rate of 0.7 Gy/min. Microarchitecture measurements, including trabecular BV/TV, Tb.Sp, and vBMD, were measured in the proximal tibiae. Three-point bending tests on the left femora were performed to assess mechanical parameters.	Following exposure to 2 Gy of proton radiation, mice showed significant changes in bone structure compared to the non-irradiated controls, including a 20% loss of trabecular BV/TV, an 11% increase in Tb.Sp, and a 19% decrease in trabecular vBMD. BV/TV also decreased by 13% at 1 Gy. 0.5 Gy irradiation did not result in significant changes to trabecular bone structure. BV/TV and vBMD followed a decreasing trend at 1 and 2 Gy, and Tb.Sp similarly showed a linear, dose-dependent increase. No significant changes to mechanical strength were observed at any dose.
Hamilton et al., 2006	In vivo. 9-week-old, juvenile, female, C57BL/6 mice were exposed to 2 Gy whole-body irradiation from different sources, including LET=0.23 keV/µm 60Co gamma rays, LET=0.4 keV/µm protons, LET=13 keV/µm 12C, and LET=148 keV/µm 56Fe. 4 months post-exposure, microarchitectural parameters, including trabecular BV/TV, Tb.Sp, Tb.Th, Tb.N, cortical porosity (Ct.Po), cortical volume (Ct.V), and Conn.D (integrity), were measured in the proximal tibiae.	Compared to non-irradiated controls, mice from all radiation groups experienced significant decreases in trabecular BV/TV following exposure to 2 Gy of IR, including decreases of 29% for gamma rays, 35% for protons, 39% for 12C, and 34% for 56Fe. Tb.Th showed a LET-dependent difference in IR-induced bone loss, with high LET sources (12C and 56Fe) showing significant decreases of 10% and 11%, respectively, while changes caused by low LET sources (gamma rays and protons) were non-significant. Only proton-irradiated mice experienced significant changes in Tb.N, and Tb.Sp, with a 20% decrease in Tb.N and a 22% increase in Tb.Sp. Trabecular Conn.D declined significantly in all radiation groups following exposure, with decreases of 54% for gamma rays, 64% for protons, 54% for 12C, and 46% for 56Fe. Ct.Po and Ct.V did not change significantly compared to the control after exposure to gamma, proton, 12C, or 56Fe radiation.
Willey et al., 2010	In vivo. 20-week-old, adult, female, C57BL/6 mice were exposed to whole body irradiation with 2 Gy of 140 kVp X-rays at a rate of 1.36 Gy/min. Microarchitectural parameters, including BV/TV, Conn.D, Tb.N, Tb.Th, Tb.Sp, Ct.V, Ct.Po, polar moment of inertia (pMOI), the percent eroded surface at the endocortical surface (Ec.ES/Ec.BS), vBMD, and marrow volume (Ma.V) were measured in the tibiae.	The irradiated group experienced a 30% decrease in BV/TV and a 53% decrease in Conn.D in the proximal tibia after 3 weeks. Similar changes occurred in the distal femur and the fifth lumbar vertebrae. Decreases in vBMD and Tb.N and increases in Tb.Sp were observed from 1-3 weeks in the proximal tibia, distal femur, and the fifth lumbar vertebrae. vBMD decreased a maximum of 44%, Tb.N decreased a maximum of 13%, and Tb.Sp increased a maximum of 15%. There was no significant change in Tb.Th. Neither endocortical or periosteal Ct.V, Ct.Po, Ma.V, or pMOI changed significantly after exposure to X-rays. Ec.ES/Ec.BS increased by 68% at week 3.
Ghosh et al., 2016	In vivo. 16-week-old, adult, male C57BL/6 mice were exposed to whole body irradiation with 1 Gy of LET=150 MeV/µm 56Fe heavy ion radiation at a rate of 0.1 Gy/min. Microarchitectural measurements, including BV/TV, Tb.Th, Tb.Sp, and Tb.N, were measured in the cancellous bone of the tibia.	Compared to non-irradiated controls, mice that underwent total body irradiation experienced a 14% decrease in BV/TV, an 11% increase in Tb.Sp, and a 14% decrease in Tb.N. The resulting change in Tb.Th after irradiation was not significant.
Alwood et al., 2010	In vivo. 4-month-old, adult, male, C57BL/6 mice were exposed to irradiation with 0.5 Gy (low dose) and 2 Gy (high dose) of 1 GeV/nucleon 56Fe heavy ions at a rate of 0.45 Gy/min and 0.9 Gy/min, respectively. 1-month post-irradiation, microarchitectural parameters, including BV/TV, Tb.Sp, Tb.N, cortical thickness (Ct.Th), cortical bone area (Ct.BA), and Conn.D, were measured in the mineralized cancellous bone tissue of the fourth lumbar vertebra. Stress transfer was assessed within the fourth lumbar vertebra. The elastic modulus of the cancellous centrum compartment and whole-vertebral body were determined with an axial compression test.	Compared to non-irradiated controls, mice that were exposed to 2 Gy of heavy ions showed a 14% decrease in cancellous BV/TV, a 9% decrease in Tb.N, and an 18% decrease in Conn.D, as well as a 12% increase in Tb.Sp. The average cancellous tissue stress increased by 27% within the centrum following 2 Gy. The centrum elastic modulus (30%) and whole-vertebral body elastic modulus (10%) were decreased at 2 Gy. Mice that received a 0.5 Gy dose did not exhibit a significant degradation in bone structure or mechanical properties. Ct.Th and Ct.BA were not significantly affected.
Green et al., 2012	In vivo. 8- and 16-week-old (young and mature adult) C57BL/6J mice were irradiated with 5 Gy of 137Cs gamma rays at a rate of 0.6 Gy/min. 8 weeks post-irradiation, microarchitectural parameters, including BV/TV, Tb.N, Tb.Sp, and Conn.D, were measured in the proximal tibial bones of the mice.	Compared to non-irradiated controls, mice showed decreases of 45% and 51% for BV/TV, 34% and 21% for Tb.N, and 81% and 85% for Conn.D, as well as a 56% and 28% increase in Tb.Sp, in young and mature adults, respectively.
Bandstra et al., 2009	In vivo. 16-week-old, adult, male, C57BL/6 mice were irradiated with 0.47 Gy of LET=151.4 keV/µm 56Fe heavy ions at a rate of 4 Gy/min. Nine weeks after irradiation, microarchitectural parameters, including BV/TV, Conn. D, Tb.Sp, Tb.Th, Tb.N, Ct.V (excluding marrow volume), cortical total volume (Ct.TV, including marrow volume), Ct.Po, pMOI and vBMD, were measured in the trabecular bone of the proximal humerus.	Compared to non-irradiated controls, mice saw a 17% decrease in BV/TV and a 4% decrease in Tb.Th in the trabecular bone of their proximal humerus. While the changes to BV/TV and Tb.Th were statistically significant, the changes to the other microarchitecture parameters were not significant. After exposure to 0.47 Gy radiation, the proximal humerus experienced a significant decrease in BV (4%), TV (3%), and pMOI (6%), as well as a significant increase in Ct.Po (6%), compared to the control. After exposure to 0.18 Gy radiation, the proximal tibia experienced non-significant changes to all endpoints.
Yumoto et al., 2010	In vivo. 16-week-old, adult, male, C57BL/6 mice were exposed to whole-body irradiation with 0.1, 0.5, and 2 Gy of LET=150 keV/µm 56Fe heavy ions at a rate of 0.2-1 Gy/min. 3 days after irradiation, BV/TV, Tb.Th, Tb.N, and Conn. D were measured in the proximal tibiae of the mice.	Compared to non-irradiated controls, 0.1 and 0.5 Gy irradiation resulted in significant 16% and 18% decreases in BV/TV, respectively. 2 Gy radiation did not have a significant effect on trabecular BV/TV. 0.1 and 0.5 Gy irradiation similarly decreased Tb.N by 7% and 5%, respectively, while changes following 2 Gy irradiation were non-significant. Following 0.1 and 0.5 Gy irradiation, Conn. D decreased by 21% and 24%, respectively. Tb.Th was not affected by IR at any of the measured doses.
Alwood et al., 2017	In vivo. 16-week-old, adult, male, C57BL/6J mice were irradiated with 0.05, 0.1, 0.5, or 2 Gy of either LET»0.52 keV/µm protons or LET»175 keV/µm 56Fe heavy ions. At 5 weeks and 1 year after exposure, microarchitectural parameters, including BV/TV, Tb.N, Tb.Th, Tb.Sp, Ct.BV, and Ct.Th, were measured in the proximal tibial metaphysis of the mice.	At 5 weeks post-exposure, IR affected BV/TV and Tb.N in an identical manner. High doses of 56Fe radiation (0.5 and 2 Gy) resulted in a 16% and 31% decrease, respectively, in both parameters compared to non-irradiated controls, while 2 Gy of protons similarly caused a 22% reduction in both. 0.5 Gy of protons caused non-significant decreases in BV/TV and Tb.N (11 and 13%, respectively). 2 Gy of proton irradiation also resulted in an increase in Tb.Sp, but it did not affect Tb.Th. Low doses (0.05 and 0.1 Gy) did not have an effect on bone loss after exposure to either protons or 56Fe heavy ions. Ct.BV and Ct.Th were not significantly affected in the femur midshaft.
Lloyd et al., 2012	In vivo. 16-week-old, adult, female, C57BL/6 mice were exposed to whole body irradiation with 1 Gy of low LET protons at a rate of ~0.6 Gy/min. Microarchitectural parameters, including BV/TV, Conn. D, Tb.N, Tb.Sp, Ct.BV, Ct.TV, Ct.Po, and pMOI were measured in the proximal tibia and distal femur of the mice. Three-point bending tests on the left femur were performed to assess mechanical parameters.	Compared to non-irradiated controls, BV/TV, Conn. D, and Tb.N in the proximal tibiae of the mice decreased significantly by 16%, 28%, and 7.7%, respectively, while Tb.Sp increased significantly by 9%. Microarchitectural parameters of the distal femur were not as affected, with BV/TV and Conn. D decreasing significantly by 22% and 37%, respectively, while Tb.N and Tb.Sp were unchanged. Ct.BV, Ct.TV, Ct.Po, and pMOI were not significantly affected by radiotherapy in the femur or tibiae. Mechanical strength was not significantly changed by radiation.
Chandra et al., 2017	In vivo. The distal metaphyseal region of right femurs of 8- to 10-week-old male mice were irradiated with 8 Gy of focal SARRP (small animal radiation research platform) X-ray radiation at a rate of 1.65 Gy/min. vBMD, BV/TV, Tb.N, and Tb.Sp were measured from the femurs of the mice. Linear elastic analysis was performed to assess stiffness.	Compared to non-irradiated controls, irradiated mice experienced a 30% decrease in vBMD, a 31% decrease in BV/TV, a 13% decrease in Tb.N, and a 19% increase in Tb.Sp. Trabecular bone stiffness decreased 56%.
Chandra et al., 2014	In vivo. Three-month-old female Sprague-Dawley rats were irradiated at the proximal metaphyseal region of the right tibiae with 16 Gy of SARRP X-rays, fractionated into two 8 Gy doses at a rate of 1.65 Gy/min. Stiffness, BMD, BV/TV, Tb.N, and Tb.Sp were measured from the tibiae of the rats.	Compared to non-irradiated controls, IR exposure resulted in a 14.3% decrease in BMD, a 17.7% decrease in BV/TV, a 17.7% decrease Tb.N, and a ~25% increase in Tb.Sp at 28 days post-exposure. Trabecular stiffness was decreased 51%.
Hui et al., 2014	In vivo. 16-week-old adult female BALB/c mice were exposed to a single 16 Gy dose of 250 kVp X-rays. The BV/TV and Ct.Th of the distal femurs of irradiated mice were measured.	Compared to non-irradiated controls, irradiation resulted in the mice experiencing a ~55% decrease in trabecular BV/TV at 30 days post-exposure. Ct.Th increased significantly by ~12% at day 8 post-exposure.
Wright et al., 2015	In vivo. The hindlimbs of 20-week-old adult male mice were irradiated with 2 Gy of 320 kV X-rays at a rate of 1.6 Gy/min to the right hindlimb. 7 days post-irradiation, microarchitectural measurements, including BV/TV, Conn. D, Tb.N, Tb.Th, and Tb.Sp, were measured in the tibia and femur of the affected hindlimb.	Compared to baseline levels, 2 Gy of IR resulted in a 22% and 14% (significant only against controls) decrease in BV/TV, a 50% and 45% (significant only against baseline) decrease in Conn. D, a 16% (significant only against baseline) and 13% decrease in Tb.N, and a 20% (significant only against baseline) and 16% increase in Tb.Sp in the proximal tibia and distal femur, respectively.
Oest et al., 2018	In vivo. An experiment was done on 6-week-old female BALB/cj mice exposed to 5 Gy X-ray radiation (225 kV beam at 17 mA) to the femur. Changes in BV/TV, Conn.D, Tb.Th, Tb.N, Ct.BA and Ct.Th were measured up to 26 weeks after exposure. Three-point bending tests were used to assess the mechanical properties of the whole bone and of cortical bone at the mid-diaphysis of the femur.	In metaphyseal trabecular bone at 12 weeks, BV/TV was decreased by 69%, Tb.N by 79%, and Conn.D by 93% compared to the sham group. Tb.Th was increased compared to controls until 8 weeks. In the epiphyseal compartment, similar trends were seen. BV/TV decreased by 21%, Tb.N decreased by 30%, connectivity density decreased by 51%, and Tb.Th increased by 12%. Ct.Th decreased 8.1% and Ct.BA decreased 8.3% in the mid-diaphysis after 12 weeks compared to controls. In the metaphyseal region, cortical parameters increased. By 12 weeks, bending strength was reduced by 14.1% and bending stiffness was reduced by 13.3%. For cortical bone at 12 weeks, flexural strength decreased 5.7% and the flexural modulus decreased 4.9%.
Zou et al., 2016	In vivo. Male Sprague-Dawley rats were exposed to 20 Gy radiation (0.8 Gy/min) using 137Cs gamma ray irradiation chamber for tibia and distal femur. Non-irradiation body parts were shielded, and contralateral sides of the femur and tibia were also harvested. BMD, BV/TV, Ct.Po, Tb.Th, and Tb.N of the irradiated femur were determined 12 weeks after exposure. Three-point bending tests were performed on the femur to assess mechanical parameters.	Trabecular BMD of the irradiated femur was reduced by 21.2% in comparison with the control group. Trabecular BV/TV was reduced by 30.8% at the irradiated femur. Compared to the control group, BS/BV was increased by 32.9% at the irradiated femur. Both Tb.Th and Tb.N decreased after irradiation 17.5% and 18.1%, respectively. Tb.Sp increased after irradiation by 39% in the irradiated femur. Ct.Po was increased by 13.8% and 17.9%. Regarding tibia, BMD decreased 8.5%, and trabecular bone volume did not change significantly at 2 weeks post irradiation but decreased significantly in both irradiated and contralateral tibia at 12 weeks. The maximum loading of the femur was decreased 32.6% after 12 weeks.
Zhang et al., 2019	In vivo. An experiment was done on 4-week-old male C57BL/6J mice exposed to 2 Gy X-ray radiation at the mid-shaft of the left femur. Changes in BMD, BV/TV, Tb.Th, Tb.N were measured 7 and 28 days after exposure.	7 days after irradiation, substantial degeneration of trabecular microarchitecture, with losses of 19% for BMD, 17% for BV/TV, 16% for Tb.Th, and an increase of 31% for Tb.Sp. Irradiated femurs showed further degeneration after 28 days. BMD decreased 15%, BV/TV decreased 42%, Tb.Th decreased 17%, Tb.N decreased 30%, and Tb.Sp increased 62%.
Blaber et al., 2013	In vivo. 16-week-old female mice were subjected to 15-days of spaceflight. Changes in BV/TV and Tb.Th were anazlyed with micro-computed tomography (μCT).	Spaceflight resulted in a 6.23% decrease in BV/TV and a 11.91% decrease Tb.Th in the pelvis compared to the ground control.
Jia et al., 2011	In vivo. 10 to 12-weeks-old male mice were exposed to 0, 5, 10, 15 and 20 Gy of X-ray. BMD was determined at day 7 to 14 after irradiation and using the standard DEXA technique.	Decreases in BMD in the femur, tibia and lumbar vertebrae were approximately 2-fold with each increasing dose (5, 10, 15, 20 Gy) from 0 Gy.
Macias et al., 2016	In vivo, four-month-old female BALB/cByJ were exposed to a fractionated dose of 0.5 Gy (3X 0.17), single dose of 0.17 or 0.5 Gy high-LET 28Si ions. Bone volume was assessed using microcomputed tomography (micro-CT)	Mice exposed to 0.5 Gy in an acute or fractionated dose produced a –14 and –18% bone volume reductions, respectively, when compared to sham controls.
Pendleton et al., 2021	In vivo. 17-week-old male mice were exposed to 0, 1, 5 Gy of 137Cs gamma rays at 0.76 Gy/min. BV/TV, were measured 11 days and 12 weeks post radiation using micro-computed tomography.	BV/TV decreased for 0 Gy by 11.5% after 12 weeks compared to the control at 11 days. For 5 Gy, BV/TV decreased by 23% after 11 days and by 21,6% after 12 weeks compared to the control group. Results for 1 Gy were not significant.

Time-scale

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Time Concordance

Reference	Experiment Description	Result
Holm et al., 1996	In vivo. Rectal carcinoma patients received preoperative radiotherapy with photons at 25 Gy (500 irradiated, 527 control). The source of photons was either 60Co or a 6-21 MV linear accelerator. The incidence of hospitalizations for femoral neck or pelvic fracture was determined at a 5-year follow-up.	By 5 years post-radiotherapy, 5.3% of irradiated patients were admitted for a fracture, while 2.4% of non-irradiated patients were admitted for a fracture.
Nishiyama et al., 1992	In vivo. Patients with uterine cervix carcinoma from 1989 to 1990 with or without 4 MV photon irradiation to lumbar vertebrae had bone mineral content (measured in mg CaCO3 eq/cm3) determined. Radiation was given in 1.8 Gy fractions over 5 weeks for a total dose of either 22.5 or 45 Gy to the vertebrae.	The control group did not show a change in bone mineral content over time. Bone mineral content was 140 mg in the pre-treatment for the irradiated group. Bone mineral content was 95 mg after irradiation (5 weeks), 84 mg after 3 months, 74 mg after 6 months, and 71 mg after 12 months.
Hui et al., 2014	In vivo. 16-week-old adult female BALB/c mice were exposed to a single 16 Gy dose of 250 kVp X-ray radiation. The BV/TV of the distal femurs of irradiated mice were measured.	Trabecular BV/TV initially increased relative to the non-irradiated control on day 3, but gradually declined to day 8 until it was ~55% lower relative to controls on day 30. Ct.Th increased significantly by ~12% at day 8 post-exposure.
Zou et al., 2016	In vivo. Male Sprague-Dawley rats were exposed to 20 Gy radiation (0.8 Gy/min) using 137Cs gamma ray irradiation chamber for tibia and distal femur. Non-irradiation body parts were shielded, and contralateral sides of the femur and tibia were also harvested. BMD, BV/TV, Ct.Po, Tb.Th, and Tb.N of the irradiated femur were determined 12 weeks after exposure. Three-point bending tests were performed on the femur to assess mechanical parameters.	Trabecular BMD of the irradiated femur was reduced by 21.2% after 12 weeks. Trabecular BV/TV was reduced by 30.8% after 12 weeks. Compared to the control group, BS/BV was increased by 32.9% after 12 weeks. Both Tb.Th and Tb.N decreased after 12 weeks 17.5% and 18.1%, respectively. Tb.Sp increased after 12 weeks by 39% in the irradiated femur. Ct.Po was increased by 13.8% and 17.9% after 12 weeks. Regarding tibia, BMD decreased 8.5% after 12 weeks, and trabecular bone volume did not change significantly at 2 weeks post irradiation but decreased significantly in both irradiated and contralateral tibia at 12 weeks. The maximum loading of the femur was decreased 32.6% after 12 weeks.
Oest et al., 2018	In vivo. An experiment was done on 6-weeks old female BALB/Cj mice exposed to 5 Gy X-ray radiation to the femur. Changes in BV/TV, Conn.D, Tb.Th, Tb.N, Ct.BA and Ct.Th were measured up to 26 weeks after exposure. Three-point bending tests were used to assess the mechanical properties of the whole bone and of cortical bone at the mid-diaphysis of the femur.	In metaphyseal trabecular bone BV/TV, Tb.N, and Conn.D increased slightly during the radiation period but declined almost linearly between 1 and 26 weeks, reaching 69%, 79%, and 93% below the initial values, respectively, by 12 weeks. Tb.Th was increased. In the epiphyseal compartment, similar trends can be seen. By 12 weeks, BV/TV, Tb.N, and Conn.D declined linearly after exposure reaching 21%, 30%, and 51% below the control group, respectively. Tb.Th was increased. All mechanical parameters increased over time up to 26 weeks, but the parameters of irradiated mice were lower than those for control mice. Both cortical parameters were decreased about 8% in the mid-diaphysis by 12 weeks. By 12 weeks, bending strength was reduced by 14.1% and bending stiffness was reduced by 13.3%. For cortical bone at 12 weeks, flexural strength decreased 5.7% and the flexural modulus decreased 4.9%.
Alwood et al., 2017	In vivo. 16-week-old, male, C57BL6/J mice were subjected to low LET protons or high-LET 56Fe ions using either low (5 or 10 cGy) or high (50 or 200 cGy) doses. Trabecular microarchitectural parameters such as BV/TV, and Tb.N were measured in the in the proximal tibial metaphysis.	In the proximal tibia, 50 and 200 cGy 56Fe induced a reduction in BV/TV (16 percent and 31%, respectively) and Tb.N (16 percent, and 31%, respectively) at 5 weeks after irradiation, compared to the control group. For protons, 200 cGy resulted in a 22% reduction in BV/TV and Tb.N, while 50 cGy resulted in a trend toward lower BV/TV and Tb.N. After 1 year, no changes in any endpoints were observed other than a 25% decrease in both BV/TV and Tb.N at 200 cGy (non-significant).
Zhang et al., 2019	In vivo. An experiment was done on 4-week-old male C57BL/6J mice exposed to 2 Gy X-ray radiation at the mid-shaft of the left femur. Changes in BMD, BV/TV, Tb.Th, Tb.N were measured 7 and 28 days after exposure.	7 days after irradiation, substantial degeneration of trabecular microarchitecture occurred, with losses of 19% for BMD, 17% for BV/TV, 16% for Tb.Th, and an increase of 31% for Tb.Sp. Irradiated femurs showed further degeneration after 28 days. BMD decreased 15%, BV/TV decreased 42%, Tb.Th decreased 17%, Tb.N decreased 30%, and Tb.Sp increased 62%.
Green et al., 2012	In vivo. Eight-week-old and 16-week-old mice were irradiated with 5 Gy of 137Cs gamma rays. BV/TV, Conn.D, Tb.Sp, and Tb.N were measured 2 days, 10 days, and 8 weeks post radiation in the proximal tibia.	None of the microarchitecture parameters indicated significant bone loss at 2 days post-irradiation. BV/TV, Tb.N, Tb.Sp, and Conn.D all demonstrated significant bone loss at 10 days and 8 weeks post-irradiation. By 8 weeks, mice showed decreases of 45% and 51% for BV/TV, 34% and 21% for Tb.N, and 81% and 85% for Conn. D, as well as a 56% and 28% increase in Tb.Sp, in young and mature mice, respectively.
Green et al., 2013	In vivo. eight-week old male C57BL/6 mice were irradiated with gamma irradiation at a total dose of 5 Gy. Mineral composition was assessed using Fourier transform infrared imaging (FTRI). Trabecular bone volume was measured using micro-computed tomography (micro-CT)	10 days post-irradiation, significant decline was observed in the mineral/matrix ratio when compared to control groups. 10 days post-irradiation, a significant -41±12% and –33+4% decrease was also shown in bone volume fraction, with no improvement by 8 weeks post-irradiation.
Pendleton et al., 2021	In vivo. 17-week-old male mice were exposed to 0, 1, 5 Gy of 137Cs gamma rays at 0.76 Gy/min. BV/TV, were measured 11 days and 12 weeks post radiation using micro-computed tomography.	BV/TV decreased for 0 Gy by 11.5% after 12 weeks compared to the control at 11 days. For 5 Gy, BV/TV decreased by 23% after 11 days and by 21,6% after 12 weeks compared to the control group. Results for 1 Gy were not significant.
Mandair et al., 2020	In vivo. 12-week-old female BALB/cJ mice aged 12-weeks were exposed to 5 Gy radiation doses for four consecutive days, for a final dose of 20 Gy. Cortical mineral matrix ratio was evaluated by Raman spectroscopy.	Cortical mineral matrix ratio showed significant decrease by –16.9% in the endosteal bone and –7.5% in the mid cortical bone 2 weeks post-irradiation when compared to controls. Mineral matrix ratio progressively decreased continually 4- and 8-weeks post radiation.
Wernle et al. 2010	In vivo, female mice aged 12-14 weeks were exposed to 5 Gy or 20 Gy of X-ray irradiation. Trabecular bone volume and trabecular spacing were measured via micro-computed tomography up to 26 weeks post-irradiation.	A significant decrease in BV/TV was shown in irradiated mice with both 5 Gy and 20 Gy at 6-, 12- and 26-weeks post irradiation. A significant increase in Trabecular spacing (Tb sp) was also shown in the 20 Gy irradiated mice when compared with control groups up to 13 weeks post-irradiation.

Known Feedforward/Feedback loops influencing this KER

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Not Identified

Domain of Applicability

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Evidence for this relationship is from human, mice, and rat models, with considerable available evidence in mice and humans. The relationship is well supported in both males and females using in vivo models. There is in vivo evidence from studies conducted using preadolescent, adolescent, and adult rodent models.

References

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

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