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Recent epidemiological and experimental animal data, as well as reanalyses of data previously accumulated, indicate that the lens of the eye is more radiosensitive than was previously thought. This has resulted in a reduction of the occupational lens dose limit within the European Union countries, Japan and elsewhere. This Commentary introduces the work done by the LDLensRad Consortium contained within this Focus Issue, towards advancement of understanding of the mechanisms of low dose radiation cataract.
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RADIATION RESEARCH 197, 1–6 (2022)
0033-7587/22 $15.00
Ó2022 by Radiation Research Society.
All rights of reproduction in any form reserved.
DOI: 10.1667/RADE-21-00188.1
COMMENTARY
Introduction to the Special LDLensRad Focus Issue
Elizabeth A. Ainsbury,
a,1,2
Claudia Dalke,
b,2
Mariateresa Mancuso,
c,2
Munira Kadhim
d
, Roy A. Quinlan,
e
Tamara Azizova,
f
Lawrence T. Dauer,
g
Joseph R. Dynlacht,
h,2
Rick Tanner
a
and Nobuyuki Hamada
i,2
a
Public Health England (PHE) Centre for Radiation, Chemical and Environmental Hazards, Oxon, United Kingdom;
b
Institute of Developmental
Genetics, Helmholtz Zentrum Mu¨nchen GmbH - German Research Center for Environmental Health, Neuherberg, Germany;
c
Laboratory of Biomedical
Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy;
d
Department of
Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, OX30BP, United Kingdom;
e
Department of
Biosciences, Durham University, Durham DH1 3LE, United Kingdom;
f
Southern Urals Biophysics Institute, Ozyorsk, Russia;
g
Memorial Sloan Kettering
Cancer Center, New York, New York;
h
Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana; and
i
Radiation
Safety Unit, Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power
Industry (CRIEPI), Komae, Tokyo, Japan
Ainsbury EA, Dalke C, Mancuso M, Kadhim M, Quinlan
RA, T Azizova T, Dauer LT, Dynlacht JR, Tanner R, Hamada
N. Introduction to the Special LDLensRad Focus Issue. Radiat
Res. 197, 1–6 (2022).
Recent epidemiological and experimental animal data, as
well as reanalyses of data previously accumulated, indicate
that the lens of the eye is more radiosensitive than was
previously thought. This has resulted in a reduction of the
occupational lens dose limit within the European Union
countries, Japan and elsewhere. This Commentary introduc-
es the work done by the LDLensRad Consortium contained
within this Focus Issue, towards advancement of understand-
ing of the mechanisms of low dose radiation cataract. Ó2022
by Radiation Research Society
Recent epidemiological and experimental animal data, as
well as reanalyses of data previously accumulated, indicate
that the lens of the eye is more radiosensitive than was
previously thought. This has resulted in a reduction of the
occupational lens dose limit within the European Union
countries, Japan and elsewhere (1). For example, the
International Commission on Radiological Protection
(ICRP) recommended that the dose limit for workers should
be reduced from 150 mSv year
–1
to 20 mSv year
–1
averaged
over 5 years, with no single year exceeding 50 mSv (2). The
National Council on Radiation Protection and Measure-
ments (NCRP), which prefers to use absorbed dose when
addressing tissue-specific deterministic effects (also referred
to as tissue reactions) recently recommended a reduction in
the occupational annual lens limit to 50 mGy and advised
that members of the public should not exceed 15 mGy
annually (3, 4).
While the substantial reduction in dose limits was chiefly
driven by recent epidemiological data, both ICRP and
NCRP have concluded that the mechanism(s) of low dose
radiation cataract induction are still unclear, and that it is
currently not possible to identify a threshold dose for
cataract induction, or even to conclude whether a true dose
threshold is applicable (2, 3). This represents an important
current public health issue, especially for medical radiation
workers, since many have amended or will need to amend
their working practices in response to the new dose limits,
such as the EU Basic Safety Standards in EU countries (5).
The LDLensRad project was initiated in 2017 with
funding from the EU CONCERT European Joint Project,
with the objective to bring together experts from across
Europe to answer a number of key outstanding research
questions regarding radiation cataractogenesis. These ques-
tions included:
1. How does low dose radiation cause cataracts?
2. Is there a dose rate effect for cataract induction?
3. How do age at exposure and genetic background
influence cataract development after radiation exposure?
In addition, the project was designed to explore the shape
of the dose response more closely over time, the debate
regarding the nature of cataract (deterministic, stochastic or
both), the identification of biomarkers or bioindicators of
global radiosensitivity, and provide education and training
for early career scientists.
The overview of the LDLensRad project is described in
Fig. 1. The main focus of the experimental campaign was
the radiation response of mice of a variety of genetic
backgrounds for which radiation sensitivity in terms of
1
Address for correspondence: Cytogenetics Group Leader, Public
Health England Centre for Radiation, Chemical and Environmental
Hazards (PHE CRCE), Room C1.32, Chilton, Didcot, Oxon OX11
0RQ, UK; email: liz.ainsbury@phe.gov.uk.
2
Focus Issue guest editor.
1
cataract development was known or suspected. A range of
doses and two dose rates were chosen to assess the impact
of genetic background. A number of different short- and
long-term experimental endpoints hypothesized to be
involved in the action of radiation in the lens were chosen
for investigation. This work was supported by investigation
of additional endpoints using lens epithelial cell (LEC) lines
in vitro to complement the in vivo program. The project was
supported by an active Scientific Advisory Board.
This Focus Issue describes some of the key results of the
LDLensRad project. However, a number of articles were
published in advance of those presented herein, and a very
brief summary of those publications is warranted so as to
comprehensively describe the scope of the entire project.
Uwineza et al. (6) sought to re-design the concept of the
‘‘cataractogenic load’’ whereby ionizing radiation adds
to the burden of cataractogenic changes induced by
genetic, lifestyle and environmental factors.
Barnard et al. (7) found that there was an inverse dose-
rate effect for DNA damage repair in the mouse lens after
measuring residual 53BP1 foci induced by 0.5–2 Gy at 4
and 24 h postirradiation of mice at 10 weeks of age. This
observation was not seen in peripheral lymphocytes
obtained from the same mice.
Pawliczek et al. compared Spectral domain – optical
coherence tomography (OCT), histology and Scheimp-
flug imaging as monitoring tools in unexposed mice of
between 5 and 78 weeks of age, and highlighted the
value of OCT for anterior lens and eye imaging (8).
Pawliczek et al. found new evidence of vision impair-
ment in B6C3F1 mice, 8.5 months after 2 Gy exposure at
postnatal day 2 (9).
Quinlan and Hogg highlighted the role of c-crystallin as
an oxidoreductase and in aggregation of mutant crystal-
lins (10).
A lifetime study of radiation-induced catararactogenesis
was carried out in male and female Ptch1
þ
/–
,Ercc2
þ
/–
and
C57BL/6J mice (see Fig. 1) irradiated at 10 weeks of age
with doses of 0–2 Gy using dose rates of 0.063 and 0.3 Gy
min
–1
. The results, in terms of lens opacification as
monitored by Scheimpflug imaging over a period of up to
18 months postirradiation, are reported in McCarron et al. in
this issue (11). As expected, background opacification
increased with time and dose in most models. Mean lens
density increased with higher dose and dose rate in mice
FIG. 1. Overview of the LDLensRad Project. Short term investigations 4 h–12 months postirradiation;
lifetime studies 12–18 months postirradiation (full details of doses, dose rates, strains, age at exposure and post
exposure time points given in the individual publications).
2COMMENTARY
with Ercc2 and Ptch1 mutations, and overall, sex, dose,
dose rate and genetic background were all found to be
significant contributors to opacification, with strain being
the largest single contributor to percentage opacification.
Most importantly, significant interactions between these
experimental factors were identified for the first time,
clearly demonstrating the importance of testing or control-
ling for sex, genetic background and dose rate in studies
looking at the impact of ionizing radiation on cataract
formation. As different strains were housed in different
locations, further investigation of the husbandry conditions
must be carried out to ensure the ‘‘strain’’ differences
observed for lens opacification are not due to, at least in
part, differences in animal housing facilities. It is also
important to assess the data in the context of the previous
findings of Pawliczek et al., which indicate that Scheimp-
flug imaging may not be the most ideal method for tracking
early radiation-induced opacities, and particularly posterior
subcapsular cataracts (PSCs), due to a reported lack of
sensitivity for this type of opacity (8).
To further investigate the wider systemic effect of
ionizing radiation, De Stefano et al. (12) explored the
specific responses in both the lenses and brains of
neonatally exposed Ptch1
þ
/–
mice bred on CD1 and
C57BL/6J backgrounds that received whole-body irradia-
tion of 0.5–2 Gy with dose rates of 0.3 or 0.063 Gy min
–1
at
postnatal day 2. The authors identified an inverse
relationship between radiosensitivity to induction of lens
opacification and medulloblastoma up to 10 months
postirradiation, and also between lens opacification up to
6 months and neurogenesis at 6 weeks postirradiation, in the
Ptch1
þ
/–
mutants. Strain differences in cerebellum apoptosis
at 4 h postirradiation also highlighted the critical importance
of genetic background after exposure to low doses. In this
case, dose-rate related effects were not detected, perhaps
due to the dominance of the genetic effect. This work
further highlights the role of genetic background related
individual sensitivity in radiation response.
Pawliczek et al. (13) looked at the in vivo characteristics
of PSC induced in male and female B6C3F1 mice 70 days
after 0.5–2 Gy gamma irradiation was delivered at 10 weeks
of age. Spectral domain OCT was used to measure visual
acuity prior to histological sectioning for examination of
cataract phenotype; this was suggested as an improved
method over Scheimpflug imaging. The authors identified
three different anterior and posterior lesions, with no
significant increase in PSCs for doses ,1 Gy. Furthermore,
they found that PSCs identified using histology were not
necessarily vision impairing. Most importantly, the authors
found that early lesions formed in response to ionizing
radiation exposure were best characterized by a determin-
istic model, whereas later manifestation was better de-
scribed by a stochastic model. This key finding further
contributes to understanding of how the impact of ionizing
radiation on the lens might be best addressed for radiation
protection purposes.
Following a number of publications which have high-
lighted the potential role of DNA damage and repair within
the lens epithelium in cataractogenesis, and the recent
findings related to inverse dose rate response (7) in C57BL/
6J mice, Barnard et al. further explored DNA damage
responses in 10-week-old Ercc2
þ
/–
and Ptch1
þ
/–
mice
exposed to 0.5–2 Gy gamma radiation, at dose rates of
0.3 and 0.063 Gy min
–1
. Their observation of a definite,
direct dose rate effect for cataractogenesis in both wild-type
mice and mice with genetic backgrounds that confer
enhanced radiosensitivity further support the hypothesis
that the DNA repair response is different in the lens
epithelium compared to other tissues (14).
Barnard et al. (15) also looked at Ki67 responses as a
marker of proliferation at 30 min, 4, 24 and 48 h, and 3, 7,
10 and 14 days postirradiation in female C57BL/6J mice
exposed at 10 weeks of age to the same radiation conditions
as the genetic background studies. Radiation increased
proliferation of LEC at 2 and 24 h postirradiation, and while
dose rate was not identified as a singular significant factor,
there was a significant interaction between dose rate and the
lens epithelial region, with evidence of increased prolifer-
ation with increased dose rate in both the central and
peripheral regions (LEC start to differentiate into lens fiber
cells in the germinative zone which is found in the
peripheral region of the lens epithelium).
Tanno et al. (16) identified different miRNA signatures
induced 24 h after 2 Gy gamma irradiation in 10-week-old
Ptch1
þ
/–
mice with different genetic backgrounds using next
generation sequencing together with a sophisticated bio-
informatics analysis. In particular, the authors identified
contra-regulated expression in genes with key roles in
regulating Toll-like receptor (TLR) signaling pathways and
DNA damage responses involving p53. The interplay
between these mechanisms may explain the differences in
relative sensitivities of the CD1 and C57BL/6J back-
grounds.
Garrett et al. (17) analyzed the effects of 0.5–2 Gy gamma
radiation delivered at 0.3 Gy min
–1
on a range of different
animal behaviors in wild-type and Ercc2
S737P
mice. The
authors found clear dose-dependent effects, independent of
sex or genotype, for a number of endpoints, including
spontaneous locomotor and exploratory activity, anxiety-
related behavior, body weight and affiliative social
behavior. Some genotype, dose and sex-related effects were
identified in working memory. For example, locomotor
activity (as measured by total distance traveled and average
speed of movement) was found to be inversely related to
dose with the lower dose enhancing locomotor activity.
Most effects were present at 4 months postirradiation and
most observations did not persist to 12 or 18 months. It
should be noted that at 4 months, lenses in both strains of
mice were normal; hence, the observed effects were not
correlated with changes in visual acuity. When compared to
a previous study at 0.063 Gy min
–1
which produced
AINSBURY ET AL. 3
different behavioral outcomes (18), these data provide
further evidence that dose rate impacts radiation responses.
In order to further support the in vivo experimental
findings, Ahmedi et al., investigated mechanisms of cataract
induction in vitro using immortalized human LEC lines
exposed to
137
Cs gamma rays at doses of 0, 0.1, 0.25 and 0.5
Gy and at dose rates of 0.063 and 0.3 Gy min
–1
(19). Cell
viability decreased in a dose-dependent manner over 24 h
postirradiation as indicated by an increased permeability to
DNA staining dye, and reactive oxygen species (ROS) and
DNA damage were increased when measured at 1 h
postirradiation. Both ROS and DNA damage progressively
decreased with increased time after irradiation through 24
hr. Induction of senescence was also observed 15 days
postirradiation, but this was not attributed to telomere
erosion of the reduction in telomerase activity. The results
illustrate the potential for in vitro work to support the
investigation of low-dose effects in the lenses of living
animals. While it is difficult to draw firm conclusions in
such cellular models, the data demonstrate slight genetic
differences in the reduction in viability in response to
radiation exposure. There was also a small but statistically
significant indication that the lower dose rate was more
effective in reducing cellular viability for some but not all
experimental conditions. This mirrors the results of Barnard
et al. (4) for the DNA damage response, although others
failed to report such a response. Various hypotheses have
been suggested to explain these observations, including the
failure of LECs to arrest in the G2 phase of the cell cycle
phase in vivo. These aspects clearly require further
investigation. Ahmadi et al. also highlight the need for
further work looking at the potential involvement of
intracellular signaling (for example through microvesicles
and exosomes) and bystander effects as well as the
interruption of disassembly of the nuclear envelope in
differentiating LECs, as a consequence of radiation-induced
senescence (19).
The mechanisms of radiation cataract were reviewed by
Ainsbury and colleagues (20) just prior to the commence-
ment of the LDLensRad project. At the time there were
several open questions, particularly regarding the influence
of strain and dose rate. It is clear that the LDLensRad
project has advanced our understanding in this important
area of radiation protection. Each of the individual articles
in this Focus Issue comment, at least in brief, on the future
initiatives for radiobiological research on the lens, high-
lighting overall the need for continued research in this
important area, and in support of appropriate radiation
protection for the lens. However, as a direct result of the
work of the LDLensRad program, a number of important
conclusions can now be drawn. These include, in some of
the studies, the detection of measurable damage with very
low doses and at very low dose rates. The apparent inverse
dose rate effects for some endpoints are also of particular
note. These findings are clearly of relevance to occupational
exposures and, taken together with the finding of Pawliczek
and colleagues that phenotypic changes to the lens can be
both deterministic and stochastic, could imply that further
work is needed to ensure the system of radiation protection
is fit for purpose (21).
As others have noted (22, 23), there is a particularly
urgent need for a clearer understanding of how low dose,
high-linear energy transfer radiation affects the lens and
elicits wider, systemic, effects including those in the retina,
brain and other organs.
In conclusion, the authors of this Commentary now
strongly recommend the incorporation of cataract studies as
part of any larger scale programs focused on multiple
radiation health effects.
The authors would like to thank the LDLensRad
Consortium members, all of whom have been incredibly
active, as well as the large number of supporters – not least
Paul Schofield and Michael Gruenberger who helped
enormously with STORE, and the CONCERT coordinator
and colleagues too.
Finally, we would like to dedicate this Focus Issue to our
wonderful colleague Gabriele Babini who passed away
unexpectedly in November 2020. He was an integral part of
both the planning and the implementation of the project, and
we could not have done it without him. He will be sadly
missed by many.
IN MEMORIAM
On November 5, 2020, our young colleague Gabriele
Babini (top row of Fig. 2, second from left) unexpectedly
passed away in Rome, Italy. Gabriele was born in Lugo
(Ravenna) on November 20, 1987. In 2009 he obtained a
three-year degree in Physics from the University of Trieste,
and in 2011 a master’s degree in Physical Sciences from the
University of Pavia. He obtained his PhD in Physics from
the University of Pavia in January 2015 with a thesis
entitled ‘‘Systems radiation biology to unravel radiation-
induced dysregulation of cellular pathways’’ and continued
his research activities as a research fellow at the same
university until December 2018. Since January 2019 he was
hired as a research collaborator by the Fondazione
Policlinico Universitario Agostino Gemelli in Rome. He is
the author of 40 publications in international scientific
journals and of many conference presentations. His
professional competence, at the crossroads between biology
and radiation physics, strongly stimulated Gabriele’s
interest in the study of bioinformatics applications and
systems biology, and in this area he quickly established
himself as a point of reference in the Italian and
international radiobiological community, working and
making himself known and appreciated in various national
and European projects, and establishing fruitful collabora-
tions with important research institutions. Gabriele actively
participated in the LDLensRad project, making available to
the partnership his knowledge of bioinformatics and his
4COMMENTARY
brilliant skills of data analysis and interpretation. He co-
authors three of the manuscripts in this special issue.
We want to dedicate this volume to him, expressing deep
gratitude for having shared his innovative vision with us
and for having passed it on to the younger colleagues.
Besides his important scientific contributions, we wish to
remember his outstanding human qualities, his cheerfulness
and passion for sport and good food that allowed a deep
bond of friendship to grow over the years. The memory of
the moments spent together and his smile will remain etched
in our minds and hearts.
Arrivederci Gabriele!
The LDLensRad Consortium
Received: October 4, 2021; accepted: November 2, 2021; published
online: November 17, 2021
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FIG. 2. The LDLensRad Consortium members in Munich, Germany in 2018.
AINSBURY ET AL. 5
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6COMMENTARY
... Continued biological and epidemiological studies would be needed to justify (and modify if needed) these judgements. In this regard, the LDLensRad project (the European CONCERT project funded by European Union in 2017-2019) is the largestscale biology project about radiation effects on the lens, and published the special issue in January 2022 (Ainsbury et al. 2022). The special issue consists of 8 original papers, each of which reports on the results in in vitro or in vivo models. ...
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In the human eye, a transparent cornea and lens combine to form the “refracton” to focus images on the retina. This requires the refracton to have a high refractive index “n”, mediated largely by extracellular collagen fibrils in the corneal stroma and the highly concentrated crystallin proteins in the cytoplasm of the lens fiber cells. Transparency is a result of short-range order (SRO) in the spatial arrangement of corneal collagen fibrils and lens crystallins, generated in part by post-translational modifications (PTMs). However, while corneal collagen is remodeled continuously and replaced, lens crystallins are very long-lived and are not replaced, and so accumulate PTMs over a lifetime. Eventually, a tipping point is reached when protein aggregation results in increased light scatter, inevitably leading to the iconic protein condensation-based disease, age-related cataract (ARC). Cataracts account for 50% of vision impairment world-wide, affecting far more people than other well-known protein aggregation-based diseases. However, because accumulation of crystallin PTMs begins before birth and long before ARC presents, we postulate that the lens protein PTMs contribute to a “cataractogenic load” (CL) that increases with age but also has protective effects on optical function by stabilizing lens crystallins until a tipping point is reached. In this review, we highlight decades of experimental findings that support the potential for PTMs to be protective during normal development. We hypothesize that ARC is preventable by protecting the biochemical and biophysical properties of lens proteins needed to maintain transparency, refraction, and optical function.
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Purpose: Cataract (opacification of the ocular lens) is a typical tissue reaction (deterministic effect) following ionizing radiation exposure, for which prevention dose limits have been recommended in the radiation protection system. Manifestations of radiation cataracts can vary among individuals, but such potential individual responses remain uncharacterized. Here we review relevant literature and discuss implications for radiation protection. This review assesses evidence for significant modification of radiation-induced cataractogenesis by age at exposure, sex and genetic factors based on current scientific literature. Conclusions: In addition to obvious physical factors (e.g. dose, dose rate, radiation quality, irradiation volume), potential factors modifying individual responses for radiation cataracts include sex, age and genetics, with comorbidity and coexposures also having important roles. There are indications and preliminary data identifying such potential modifiers of radiation cataract incidence or risk, although no firm conclusions can yet be drawn. Further studies and a consensus on the evidence are needed to gain deeper insights into factors determining individual responses regarding radiation cataracts and the implications for radiation protection.
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One of the principal uncertainties when estimating population risk of late effects from epidemiological data is that few radiation-exposed cohorts have been followed up to extinction. Therefore, the relative risk model has often been used to estimate radiation-associated risk and to extrapolate risk to the end of life. Epidemiological studies provide evidence that children are generally at higher risk of cancer induction than adults for a given radiation dose. However, the strength of evidence varies by cancer site and questions remain about site-specific age at exposure patterns. For solid cancers, there is a large body of evidence that excess relative risk (ERR) diminishes with increasing age at exposure. This pattern of risk is observed in the Life Span Study (LSS) as well as in other radiation-exposed populations for overall solid cancer incidence and mortality and for most site-specific solid cancers. However, there are some disparities by endpoint in the degree of variation of ERR with exposure age, with some sites (e.g., colon, lung) in the LSS incidence data showing no variation, or even increasing ERR with increasing age at exposure. The pattern of variation of excess absolute risk (EAR) with age at exposure is often similar, with EAR for solid cancers or solid cancer mortality decreasing with increasing age at exposure in the LSS. We shall review the human data from the Japanese LSS cohort, and a variety of other epidemiological data sets, including a review of types of medical diagnostic exposures, also some radiobiological animal data, all bearing on the issue of variations of radiation late-effects risk with age at exposure and with attained age. The paper includes a summary of several oral presentations given in a Symposium on "Age effects on radiation response" as part of the 67th Annual Meeting of the Radiation Research Society, held virtually on 3-6 October 2021.
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Cataract is the leading cause of visual impairment which can result in blindness. Cataract formation has been associated with radiation exposure; however, the mechanistic understanding of this phenomenon is still lacking. The goal of this study was to investigate mechanisms of cataract induction in isolated lens epithelial cells (LEC) exposed to ionizing radiation. Human LECs from different genetic backgrounds (SV40 immortalized HLE-B3 and primary HLEC cells) were exposed to varying doses of 137Cs gamma rays (0, 0.1, 0.25 and 0.5 Gy), at low (0.065 Gy/min) and higher (0.3 Gy/min) dose rates. Different assays were used to measure LEC response for, e.g., viability, oxidative stress, DNA damage studies, senescence and changes to telomere length/telomerase activity at two time points (1 h and 24 h, or 24 h and 15 days, depending on the type of assay and expected response time). The viability of cells decreased in a dose-dependent manner within 24 h of irradiation. Measurement of reactive oxygen species showed an increase at 1 h postirradiation, which was alleviated within 24 h. This was consistent with DNA damage results showing high DNA damage after 1 h postirradiation which reduced significantly (but not completely) within 24 h. Induction of senescence was also observed 15 days postirradiation, but this was not attributed to telomere erosion or telomerase activity reduction. Overall, these findings provide a mechanistic understanding of low-dose radiation-induced cataractogenesis which will ultimately help to inform judgements on the magnitude of risk and improve existing radiation protection procedures.
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The International Commission on Radiological Protection (ICRP) has embarked on a review and revision of the System of Radiological Protection that will update the 2007 General Recommendations in ICRP Publication 103. This is the beginning of a process that will take several years, involving open and transparent engagement with organisations and individuals around the world. While the System is robust and has performed well, it must adapt to address changes in science and society to remain fit for purpose. The aim of this paper is to encourage discussions on which areas of the System might gain the greatest benefit from review, and to initiate collaborative efforts. Increased clarity and consistency are high priorities. The better the System is understood, the more effectively it can be applied, resulting in improved protection and increased harmonisation. Many areas are identified for potential review including: classification of effects, with particular focus on tissue reactions; reformulation of detriment, potentially including non-cancer diseases; re-evaluation of the relationship between detriment and effective dose, and the possibility of defining detriments for males and females of different ages; individual variation in the response to radiation exposure; heritable effects; and effects and risks in non-human biota and ecosystems. Some of the basic concepts are also being considered, including the framework for bringing together protection of people and the environment, incremental improvements to the fundamental principles of justification and optimisation, a broader approach to protection of individuals, and clarification of the exposure situations introduced in 2007. In addition, ICRP is considering identifying where explicit incorporation of the ethical basis of the System would be beneficial, how to better reflect the importance of communications and stakeholder involvement, and further advice on education and training. ICRP invites responses on these and other areas relating to the review of the System of Radiological Protection.
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Recent epidemiological findings and reanalysis of historical data suggest lens opacities resulting from ionizing radiation exposures are likely induced at lower doses than previously thought. These observations have led to ICRP recommendations for a reduction in the occupational dose limits for the eye lens, as well as subsequent implementation in EU member states. The EU CONCERT LDLensRad project was initiated to further understand the effects of ionizing radiation on the lens and identify the mechanism(s) involved in radiation-induced cataract, as well as the impact of dose and dose-rate. Here, we present the results of a long-term study of changes to lens opacity in male and female adult mice from a variety of different genetic (radiosensitive or radioresistant) backgrounds, including mutant strains Ercc2 and Ptch1, which were assumed to be susceptible to radiation-induced lens opacities. Mice received 0.5, 1 and 2 Gy 60Co gamma-ray irradiation at dose rates of 0.063 and 0.3 Gy min–1. Scheimpflug imaging was used to quantify lens opacification as an early indicator of cataract, with monthly observations taken post-irradiation for an 18-month period in all strains apart from 129S2, which were observed for 12 months. Opacification of the lens was found to increase with time post-irradiation (with age) for most mouse models, with ionizing radiation exposure increasing opacities further. Sex, dose, dose rate and genetic background were all found to be significant contributors to opacification; however, significant interactions were identified, which meant that the impact of these factors was strain dependent. Mean lens density increased with higher dose and dose rate in the presence of Ercc2 and Ptch1 mutations. This project was the first to focus on low (<1 Gy) dose, multiple dose rate, sex and strain effects in lens opacification, and clearly demonstrates the importance of these experimental factors in radiobiological investigations on the lens. The results provide insight into the effects of ionizing radiation on the lens as well as the need for further work in this area to underpin appropriate radiation protection legislation and guidance.
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Lens epithelial cell proliferation and differentiation are naturally well regulated and controlled, a characteristic essential for lens structure, symmetry and function. The effect of ionizing radiation on lens epithelial cell proliferation has been demonstrated in previous studies at high acute doses, but the effect of dose and dose rate on proliferation has not yet been considered. In this work, mice received single acute doses of 0.5, 1 and 2 Gy of radiation, at dose rates of 0.063 and 0.3 Gy/min. Eye lenses were isolated post-irradiation at 30 min up until 14 days and flat-mounted. Then, cell proliferation rates were determined using biomarker Ki67. As expected, radiation increased cell proliferation 2 and 24 h post-irradiation transiently (undetectable 14 days post-irradiation) and was dose dependent (changes were very significant at 2 Gy; P = 0.008). A dose-rate effect did not reach significance in this study (P = 0.054). However, dose rate and lens epithelial cell region showed significant interactions (P < 0.001). These observations further our mechanistic understanding of how the lens responds to radiation.
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Experimental mouse studies are important to gain a comprehensive, quantitative and mechanistic understanding of the biological factors that modify individual risk of radiation-induced health effects, including age at exposure, dose, dose rate, organ/tissue specificity and genetic factors. In this study, neonatal Ptch1+/- mice bred on CD1 and C57Bl/6 background received whole-body irradiation at postnatal day 2. This time point represents a critical phase in the development of the eye lens, cerebellum and dentate gyrus (DG), when they are also particularly susceptible to radiation effects. Irradiation was performed with g rays (60Co) at doses of 0.5, 1 and 2 Gy, delivered at 0.3 Gy/min or 0.063 Gy/min. Wild-type and mutant mice were monitored for survival, lens opacity, medulloblastoma (MB) and neurogenesis defects. We identified an inverse genetic background-driven relationship between the radiosensitivity to induction of lens opacity and MB and that to neurogenesis deficit in Ptch1+/- mutants. In fact, high incidence of radiation-induced cataract and MB were observed in Ptch1+/-/CD1 mutants that instead showed no consequence of radiation exposure on neurogenesis. On the contrary, no induction of radiogenic cataract and MB was reported in Ptch1+/-/C57Bl/6 mice that were instead susceptible to induction of neurogenesis defects. Compared to Ptch1+/-/CD1, the cerebellum of Ptch1+/-/C57Bl/6 mice showed increased radiosensitivity to apoptosis, suggesting that differences in processing radiation-induced DNA damage may underlie the opposite strain-related radiosensitivity to cancer and non-cancer pathologies. Altogether, our results showed lack of dose-rate-related effects and marked influence of genetic background on the radiosensitivity of Ptch1+/- mice, supporting a major contribution of individual sensitivity to radiation risk in the population.
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One harmful long-term effect of ionizing radiation is cataract development. Recent studies have been focused on elucidating the mechanistic pathways involved in this pathogenesis. Since accumulating evidence has established a role of microRNAs in ocular diseases, including cataract, the goal of this work was to determine the microRNA signature of the mouse lens, at short time periods postirradiation, to understand the mechanisms related to radio-induced cataractogenesis. To evaluate the differences in the microRNA profiles, 10-week-old Patched1 heterozygous (Ptch1+/-) mice, bred onto two different genetic backgrounds (CD1 and C57Bl/6J), received whole-body 2 Gy g-ray irradiation, and 24 h later lenses were collected. Next-generation sequencing and bioinformatics analysis revealed that genetic background markedly influenced the list of the deregulated microRNAs and the mainly predicted perturbed biological functions of 2 Gy irradiated Ptch1+/- mouse lenses. We identified a subset of microRNAs with a contra-regulated expression between strains, with a key role in regulating Toll-like receptor (TLR)-signaling pathways. Furthermore, a detailed analysis of miRNome data showed a completely different DNA damage response in mouse lenses 24 h postirradiation, mainly mediated by a marked upregulation of p53 signaling in Ptch1+/-/C57Bl/6J lenses that was not detected on a CD1 background. We propose a strict interplay between p53 and TLR signaling in Ptch1+/-/C57Bl/6J lenses shortly after irradiation that could explain both the resistance of this strain to developing lens opacities and the susceptibility of CD1 background to radiation-induced cataractogenesis through activation of epithelial-mesenchymal transition.
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Ionizing radiation is widely known to induce various kinds of lens cataracts, of which posterior subcapsular cataracts (PSCs) have the highest prevalence. Despite some studies regarding the epidemiology and biology of radiation-induced PSCs, the mechanism underscoring the formation of this type of lesions and their dose dependency remain uncertain. Within the current study, our team investigated the in vivo characteristics of PSCs in B6C3F1 mice (F1-hybrids of BL6 × C3H) that received 0.5-2 Gy γ-ray irradiation after postnatal day 70. For purposes of assessing lenticular damages, spectral domain optical coherence tomography was utilized, and the visual acuity of the mice was measured to analyze their levels of visual impairment, and histological sections were then prepared in to characterize in vivo phenotypes. Three varying in vivo phenotype anterior and posterior lesions were thus revealed and correlated with the applied doses to understand their marginal influence on the visual acuity of the studied mice. Histological data indicated no significantly increased odds ratios for PSCs below a dose of 1 Gy at the end of the observation time. Furthermore, our team demonstrated that when the frequencies of the posterior and anterior lesions were calculated at early time points, their responses were in accordance with a deterministic model, whereas at later time points, their responses were better described via a stochastic model. The current study will aid in honing the current understanding of radiation-induced cataract formation and contributes greatly to addressing the fundamental questions of lens dose response within the field of radiation biology.
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We have shown previously that a single radiation event (0.063, 0.125 or 0.5 Gy, 0.063 Gy/min) in adult mice (age 10 weeks) can have delayed dose-dependent effects on locomotor behavior 18 months postirradiation. The highest dose (0.5 Gy) reduced, whereas the lowest dose (0.063 Gy) increased locomotor activity at older age independent of sex or genotype. In the current study we investigated whether higher doses administered at a higher dose rate (0.5, 1 or 2 Gy, 0.3 Gy/min) at the same age (10 weeks) cause stronger or earlier effects on a range of behaviors, including locomotion, anxiety, sensorimotor and cognitive behavior. There were clear dose-dependent effects on spontaneous locomotor and exploratory activity, anxiety-related behavior, body weight and affiliative social behavior independent of sex or genotype of wild-type and Ercc2S737P heterozygous mice on a mixed C57BL/6JG and C3HeB/FeJ background. In addition, smaller genotype- and dose-dependent radiation effects on working memory were evident in males, but not in females. The strongest dose-dependent radiation effects were present 4 months postirradiation, but only effects on affiliative social behaviors persisted until 12 months postirradiation. The observed radiation-induced behavioral changes were not related to alterations in the eye lens, as 4 months postirradiation anterior and posterior parts of the lens were still normal. Overall, we did not find any sensitizing effect of the mutation towards radiation effects in vivo.
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Epidemiological studies suggest an increased incidence and risk of cataract after low-dose (,2 Gy) ionizing radiation exposures. However, the biological mechanism(s) of this process are not fully understood. DNA damage and repair are thought to have a contributing role in radiation-induced cataractogenesis. Recently we have reported an inverse doserate effect, as well as the low-dose response, of DNA damage and repair in lens epithelial cells (LECs). Here, we present further initial findings from two mutated strains (Ercc2+/– and Ptch1+/–) of mice, both reportedly susceptible to radiationinduced cataract, and their DNA damage and repair response to low-dose and low-dose-rate gamma rays. Our results support the hypothesis that the lens epithelium responds differently to radiation than other tissues, with reported radiation susceptibility to DNA damage not necessarily translating to the LECs. Genetic predisposition and strain(s) of mice have a significant role in radiation-induced cataract susceptibility.
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Ionising radiation interacts with lenses and retinae differently. In human lenses, posterior subcapsular cataracts are the predominant observation, whereas retinae of adults are comparably resistant to even relatively high doses. In this study, we demonstrate the effects of 2 Gy of low linear energy transfer ionising radiation on eyes of B6C3F1 mice aged postnatal day 2. Optical coherence tomography and Scheimpflug imaging were utilised for the first time to monitor murine lenses and retinae in vivo. The visual acuity of the mice was determined and histological analysis was conducted. Our results demonstrated that visual acuity was reduced by as much as 50 % approximately 9 months after irradiation in irradiated mice. Vision impairment was caused by retinal atrophy and inner cortical cataracts. These results help to further our understanding of the risk of ionising radiation for human foeti (∼ 8 mo), which follow the same eye development stages as neonatal mice.