Mutation Research 770 (2016) 262291

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Cataractogenesis following high-LET radiation exposure

Nobuyuki Hamadaa,* , Tatsuhiko Satob
a
Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), 2-11-1 Iwado-kita,
Komae, Tokyo 201-8511, Japan
b
Research Group for Radiation Transport Analysis, Nuclear Science and Engineering Center, Japan Atomic Energy Agency (JAEA), 2-4 Shirakata, Tokai, Ibaraki
319-1195, Japan

A R T I C L E I N F O A B S T R A C T

Article history:
Received 15 June 2016 Biological effectiveness of ionizing radiation differs with its linear energy transfer (LET) such that high-
Received in revised form 4 August 2016 LET radiation is more effective for various biological endpoints than low-LET radiation. Human exposure
Accepted 17 August 2016 to high-LET radiation occurs in cancer patients, nuclear workers, aviators, astronauts and other space
Available online 20 August 2016 travellers. From the radiation protection viewpoint, the ocular lens is among the most radiosensitive
tissues in the body, and cataract (a clouding of the normally transparent lens) is classied as tissue
Keywords: reactions (formerly called nonstochastic or deterministic effects) with a threshold below which no effect
Crystalline lens would occur. To prevent radiation cataracts, the International Commission on Radiological Protection
Cataract
(ICRP) has recommended an equivalent dose limit for the lens according to the threshold for vision-
High-LET ionizing radiation
impairing cataracts. ICRP recommended the threshold of >8 Gy in 1984 and an occupational dose limit of
Relative biological effectiveness
Radiation weighting factor 150 mSv/year in 1980. These remained unchanged until 2011, when ICRP recommended lowering the
threshold to 0.5 Gy and the dose limit to 20 mSv/year (averaged over 5 years with no single year
exceeding 50 mSv). Although such reduction of the threshold was based on ndings from low-LET
radiation, the dose limit was recommended in Sv. Historically, the lens is the exceptional tissue for which
ICRP had assigned a special factor in addition to a general radiation weighting factor, predicated on a
belief that the lens is more vulnerable to high-LET radiation than other tissues. Considering such
radiosensitive nature of the lens, a deeper understanding of a cataractogenic potential of high-LET
radiation is indispensable. This review is thus designed to provide an update on the current knowledge as
to high-LET radiation cataractogenesis. To this end, changes in ICRP recommendations on lenticular
radiation protection, epidemiological and biological ndings on high-LET cataractogenesis are reviewed,
and future research needs are then discussed.
2016 Elsevier B.V. All rights reserved.

1. Introduction of its cancer and non-cancer effects. Take cataract (a clouding of the
normally transparent crystalline lens of the eye) for example the
The discovery of X-rays in 1895 was immediately followed not rst case of radiogenic cataracts in experimental animals and
merely by its use in medicine and industry but also by observations humans was reported in 1897 and 1903, respectively [1,2]. In 1928,

Abbreviations: A-bomb, atomic bomb; amu, atomic mass unit; ATM, ataxia telangiectasia mutated; BNCT, boron neutron capture therapy; BPA, boronophenylalanine; BSH,
sodium borocaptate; CDK1, cyclin dependent kinase 1; CDKN1A, cyclin dependent kinase inhibitor 1A; CHK2, checkpoint kinase 2; CI, condence interval; DSB, DNA double
strand break; DS86, dosimetry system 1986; DS02, dosimetry system 2002; Gy-Eq, gray-equivalents; ICRP, International Commission on Radiological Protection; ICRP-X, ICRP
Publication X; ISS, International Space Station; IXRPC, International X-ray and Radium Protection Committee; JAXA, Japan Aerospace Exploration Agency; LEC, lens epithelial
cell; LET, linear energy transfer; LQ, linear-quadratic; LFC, lens ber cell; LSAH, Longitudinal Study of Astronaut Health; MMP, matrix metalloproteinase; MN,
micronucleation; MPD, maximum permissible dose; MR, meridional row; NASA, National Aeronautics and Space Administration; NASCA, NASA Study of Cataract in
Astronauts: NZW New Zealand white; PSC, posterior subcapsular cataract; Q, quality factor; Q , effective quality factor; QF, quality factor; Q(L), quality factor as a
function of LET; RBE, relative biological effectiveness; RBEm, relative biological effectiveness maximum for nonstochastic/deterministic effects or tissue reactions;
RBEM, relative biological effectiveness maximum for stochastic effects; RBEs, relative biological effectiveness values; SD, Sprague-Dawley; SSB, DNA single strand
break; TIMP1, tissue inhibitor of matrix metalloproteinase 1; TG, Task Group; T65DR, tentative 1965 dose estimates revised; VIC, vision-impairing cataract; wR,
radiation weighting factor.
* Corresponding author.
E-mail addresses: hamada-n@criepi.denken.or.jp (N. Hamada), sato.tatsuhiko@jaea.go.jp (T. Sato).

http://dx.doi.org/10.1016/j.mrrev.2016.08.005
1383-5742/ 2016 Elsevier B.V. All rights reserved.
 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
the International X-ray and Radium Protection Committee (IXRPC)
issued the rst recommendations to avoid the dangers of
overexposure [3]. Its initial concern was protection against X-rays
and radium, but rapid developments in nuclear physics and its
applications in the 1930s and 1940s raised an issue of exposure to
neutrons and heavy ions. The terms relative biological effective-
ness (RBE) and linear energy transfer (LET) were coined in 1931
and 1952, respectively [4,5]. It was proposed in 1948 that the
mouse lens is especially sensitive to neutrons [6]. Two Science
papers published in 1949 attracted attention to radiation protec-
tion of the lens: one paper was on atomic bomb (A-bomb) cataracts
[7], and the other was on cyclotron cataracts [8], both of which
involved neutron exposures. In 1950, IXRPC was renamed the
International Commission on Radiological Protection (ICRP), which
issued its rst recommendations including those on the lens and
various types of radiation in addition to photons [9].
RBE varies with LET, dose, dose rates, tissues/organs and
endpoints, but it has widely been accepted that high-LET radiation
(e.g., neutrons and heavy ions) is more effective than low-LET
radiation (e.g., photons and protons) [10,11]. Hereinafter, helium
and heavier ions are referred to as heavy ions, and radiation with
LET of >10 keV/mm to as high-LET radiation. For radiation
protection purposes, a radiation weighting factor (wR) that is used
to reect RBE of high-LET radiation is largely predicated on RBE for
low dose clastogenic effects (i.e., stochastic effects with no
threshold). Cataract has been classied as a tissue reaction
(formerly called a nonstochastic or deterministic effect) with a
dose threshold below which no effect would occur [12]. ICRP has
recommended an equivalent dose limit for the lens for prevention
of cataract. To calculate equivalent dose to the lens in Sv, absorbed
dose in Gy is multiplied by wR, based on the judgment that RBE for
tissue reactions is generally smaller than that for stochastic effects
in corresponding tissues [13]. However, cataracts have not been
included in such analyses to judge this, and application of wR to
cataracts has yet to be justied. It is noteworthy that the lens is
historically the sole tissue for which ICRP recommended a special
factor in addition to a general radiation weighting factor in 1964
1977 [14,15]. This was due to the belief that the lens is more
sensitive to high-LET radiation (especially neutrons) than other
tissues. Taken together, ICRP Publication 92 (ICRP-92) issued in
2003 was unable to recommend wR or RBE for cataracts owing to
lack of human data and concern regarding how to apply the
experimental data [13]. Moreover, ICRP has recommended the
occupational dose limit for the lens of 150 mSv/year since 1980, but
in 2011, recommended reducing it to 20 mSv/year (averaged over
5 years with no single year exceeding 50 mSv) [12,16,17]. Such
Table 1
Changes in the dose limit for the lens recommended by the International Commission on Radiological Protection (ICRP).
Name Years (Publication)
Maximum permissible dose 1954a
1956a
1958 (ICRP 1)a
1964 (ICRP 6)a
1966 (ICRP 9)a
Dose limit 1966 (ICRP 9)a
1977 (ICRP 26)
1980 (Brighton Statement)
1990 (ICRP 60)
2011 (Seoul Statement)
Abbreviations: ICRP X, ICRP Publication X; N.A., not accounted.
a
Dose originally recommended in rem was converted to dose in mSv.
b
For public who reside in the neighborhood of controlled areas.
c
For adults who do non-radiation work in the vicinity of controlled areas or enter controlled areas occasionally.
d
For the population at large.
263
lowering was based on ndings from low-LET radiation [17],
although the dose limit was recommended in Sv. Altogether,
further analyses are warranted as human exposure to high-LET
radiation takes place, such as in cancer patients, nuclear workers,
cyclotron workers, aircraft crew and passengers, astronauts and
other space travellers [18,19].
This paper reviews changes in ICRP recommendations on
lenticular radiation protection, epidemiological and biological
ndings on high-LET cataractogenesis. The companion articles in
this issue review epidemiological and experimental ndings on
low-LET cataractogenesis [20,21].
2. Changes in ICRP recommendations for radiation protection
of the lens
Tables 1 and 2 summarize changes in dose limits for the lens
and radiation weighting factors for protons, neutrons and heavy
ions recommended by ICRP.
2.1. Changes in 1950s and 1960s
In 1950, ICRP rstly listed cataracts in the effects to be
considered [9]. The lens was assigned as one of the critical
organs because the lens was empirically shown to be particularly
vulnerable and thus considered critical from the viewpoint of
radiation protection. Various types of radiation were considered
besides X- and g-rays, and the relative biological efciency was
dened. In 1954, maximum permissible dose (MPD) was set for
workers and public assuming no threshold, and rem (1 rem =
10 mSv) was dened as the absorbed dose in rad (1 rad = 10 mGy)
multiplied by RBE. RBE values (RBEs) for protons, fast neutrons and
heavy recoil nuclei were given considering cataract [22]. In 1958,
ICRP-1 [23] recommended ophthalmological examinations with
particular reference to lenticular changes following exposure to
neutrons and heavy particles. In 1959, the use of eye shields or other
suitable shielding was advised to keep lens dose within MPD [24].
In 1964, ICRP-6 [14] abandoned RBE due to misgivings over its
use in both radiobiology and radiation protection. The dose
equivalent in rem was thus dened as the absorbed dose in rad
multiplied by the quality factor (QF) and other modifying factors.
On one hand, because the lens seems not to assume a greater
importance than other tissues when X-, g-, and b-radiations only
are concerned, the lens was no longer designated as a critical
organ. On the other hand, because the lens may be specically
radiosensitive only to particulate radiation of high-LET, a special
QF of 30 was recommended for cataractogenic effects of high-LET
Recommended values
Workers Public
3 mSv/week 0.3 mSv/week
3 mSv/week or 30 mSv/13 weeks 0.3 mSv/week or 3 mSv/13 weeks
50 mSv/year or 600 mSv up to age 30 (age <18) 5 mSv/yearb or 15 mSv/yearc
30 mSv/13 weeks or 50(age18) mSv (age 18)
40 mSv/13 weeks or 150 mSv/year 5 mSv/yeard or 15 mSv/yearc
150 mSv/year N.A.
N.A. 15 mSv/year
300 mSv/year 50 mSv/year
150 mSv/year Ditto
Ditto 15 mSv/year
100 mSv/5 years, 50 mSv/year Ditto
264 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

Table 2
Changes in radiation weighting factors for external exposure to protons, neutrons and heavy ions.

Factors Year (Publication) Radiation types Note

Protons Neutrons Heavy ions or

heavy recoil
nuclei
Relative biological efciency 1950 10 10 (<20 MeV) 20
Relative biological effectiveness 1954 10 (<10 MeV) 10 Ditto These values were assigned consideting cataract.
(RBE)a
Quality factor (QF)a 1964 (ICRP 6) N.A. Ditto Ditto A special QF of 30 for the lens in the case of high-LET
particulate radiation with the general QF value of 10.
1966 (ICRP 9) 10 Ditto Ditto An additional factor of 13 for the lens as a function
of QF: (2QF + 7)/9 for 1 QF <10 or 3 for QF 10.
Effective quality factor (Q)b 1973 (ICRP 21) 1.42.2 211 N.A.
1977 (ICRP 26) 10 10 10, 20e An additional factor of 13 for the lens was abandonedf .
1985 (Paris 10 20 Ditto
Statement)
Radiation weighting factor (wR) 1990 (ICRP 60) 5 (>2 MeV) 5, 10, 20c Ditto
2007 (ICRP 103) 2 2.520.7d 20

Abbreviations: ICRP X, International Commission on Radiological Protection Publication X; N.A., not accounted.
a
RBE and QF were given as a function of LET in water: 1 (3.5 keV/mm), 12 (3.57 keV/mm), 25 (723 keV/mm), 510 (2353 keV/mm) and 1020 (53175 keV/mm).
b
Q was given as a function of LET: 1 (3.5 keV/mm), 12 (3.57 keV/mm), 25 (723 keV/mm), 510 (2353 keV/mm), 1020 (53175 keV/mm) and 20 (175 keV/mm).
c
Given as a step function of energy. 5 for >0.01 MeV, >20 MeV. 10 for 0.01 0.1 MeV, 220 MeV. 20 for 0.12 MeV.
d
Given as a continuous function of energy (En). 2.5 + 18.2exp{ [ln(En)]2/6} for <1 MeV. 5.0 + 17.0exp{ [ln(2En)]2/6} for 150 MeV. 2.5 + 3.25exp{ [ln(0.04En)]2/6} for
>50 MeV.
e
10 for singly charged particles. 20 for multiply charged particles.
f
Its abandonment was proposed in 1969 (ICRP 14) and recommended in 1977 (ICRP 26).

particulate radiation instead of the general QF value of 10 for other
effects. This number 30 came from the 1953 Ham paper [25,26],
which appears to be calculated as the minimum cataractogenic
dose of X- or g-rays (500 r = 5 Gy) divided by that of fast neutrons
(15 rep = 0.15 Gy) [12]. In 1966, ICRP-9 [27] replaced a special QF
of 30 with an additional modifying factor of which numerical value
ranges between 1 and 3 and is a function of QF for the lens. ICRP-9
recommended MPD of 150 mSv/year for workers, but replaced
MPD with dose limits for public.
In 1969, ICRP-14 [26] reviewed literature on low- and high-LET
cataractogenesis. A threshold-type dose-response relationship for
opacication was dened irrespective of radiation quality,
predicated on the human data. ICRP-14 questioned the previous
belief that the human lens was unusually sensitive to high-LET
radiation. On one hand, the 1960 Ham paper [28] increased the
minimum cataractogenic dose of fast neutrons from 0.15 Gy
previously recommended in the 1953 Ham paper [25] to 0.75 Gy, so
that 15 mGy/year (i.e., 0.75 Gy accumulated in a working lifetime of
50 years) multiplied by 10 (QF for neutrons) yields 150 mSv/year
without an additional factor for high-LET radiation. On the other
hand, 5.5 Gy was regarded as the minimum dose of X- or g-rays
for opacication following exposure over periods varying between
3 months and 9 years [29], and 7.5 Gy (50 years at 150 mGy/year)
was considered prudent for low-LET radiation given a reduced
effectiveness by protraction over 50 years and a larger dose
required to produce vision-impairing cataracts (VICs). Taken
together, it was described that the results obtained in mice and
rabbits seemed to conrm the extreme sensitivity of the lens to
high-LET radiation, but that since there seems to be no a priori
reason for assuming that man should have the same sensitivity as
small laboratory animals, it can no longer be asserted that
experimental results conrm the special sensitivity of the human
lens to high-LET radiation. Altogether, abolition of an additional
modifying factor to QF was proposed.
2.2. Changes in 1970s and 1980s
In 1977, ICRP-26 [15] renamed QF as Q (and its effective value
named Q), and withdrew an additional modifying factor for QF.
MPD was replaced with dose limits for workers, and Gy and
Sv superseded rad and rem, respectively. Nonstochastic effects
were dened as effects for which the severity varies with dose and
no detrimental effects seem to occur below a clear threshold.
Nonstochastic was employed to mean of a nonrandom or
nonstatistical nature. Cataracts were classied as nonstochastic
effects, and an occupational dose limit for the lens of 300 mSv/year
was recommended to prevent VICs, given that protracted exposure
to 15 Sv of low- or high-LET radiation over 50 years does not
produce opacities that interfere with vision [16]. This raised
several objections that the new limit is too high. The 1980 Brighton
Statement [16] thus recommended returning it to 150 mSv/year,
which remained unchanged until 2011.
In 1984, ICRP-41 [30] regarded the lens as one of the most
radiosensitive tissues of the body. Nonstochastic effects were
dened as damage resulting from the collective injury of
substantial numbers or proportions of cells in affected tissues.
Threshold dose was dened as the amount of radiation required to
cause a particular effect in at least 15% of exposed individuals,
and was separately set each for detectable opacities and VICs, and
for highly fractionated/protracted exposures and single brief
exposure. Of these, the threshold dose of low-LET radiation for
VICs in highly fractionated/protracted exposures was judged
as >8 Sv based on three papers [3133], and it was inferred that
exposure at 150 mSv/year for 50 years would not cause a VIC but
might give rise to detectable opacity in some exposed individuals.
For high-LET radiation, the threshold dose of fast neutrons for VICs
was judged as 35 Gy according to the 1976 Roth paper [34]. This
implies an RBE of 23, leading to a conclusion that Q for neutrons in
excess of 10 is not warranted. However, the possibility cannot be
ruled out that such RBE was an underestimate, as a follow-up
period of 31 months in the 1976 Roth paper [34] was considerably
shorter than that of 35 years in three papers used to judge low-
LET threshold [3133]. It should also be noted that the 1976 Roth
paper documented that cataracts occurred in 31% of patients
exposed to 3.015 Gy and 44% of those to >10 Gy, but in none of 8
patients exposed to 5.0110 Gy [34]. The 1985 Paris Statement [35]
increased Q from 10 to 20 for fast neutrons (c.f., this change was
not specic to the lens).
In 1989, ICRP-58 [36] denoted maximal RBEs derived by
extrapolation to very low doses for stochastic effects and
 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
nonstochastic effects as RBEM (upon which Q has been based) and
RBEm, respectively, considering that RBE generally increases with
decreasing dose, dose per fraction and dose rate to a presumed
maximum value. It was assumed that the only cause of non-
stochastic effects is cell killing and that behavior of the underlying
lesions below the threshold follows the linear-quadratic (LQ)
model upon which parameters a and b can be based. RBEm was
thus calculated as aH/aL (a for high-LET radiation divided by a for
low-LET radiation) in skin, gastrointestinal tract, hematopoietic
system, vascular system, respiratory system, reproductive system
and urinary system, revealing that such RBEm is generally smaller
than RBEM in corresponding tissues. It was then concluded that the
application of Q in cases where nonstochastic effects are overriding
would result in an overestimate of contribution to the risk from
high-LET radiation, but cataracts were not considered to draw this
conclusion. The cataract data for high-LET radiation were
reviewed, and the development of cataracts was found to depend
on radiation quality quantitatively but not qualitatively. However,
it was judged that there were insufcient data to derive
parameters of the LQ model, so that RBEm for cataracts was not
calculated.
2.3. Changes in 1990s and 2000s
In 1990, ICRP-60 [37] replaced Q with wR. Radiation-induced
cell killing is a stochastic process and the initial cellular changes
are random; nonetheless, the large number of cells involved in the
initiation of a clinically observable nonstochastic effect was
thought to give the effect a deterministic character. Thus,
nonstochastic effects were considered unsuitable for injury
resulting from the death of a large number of cells, and renamed
deterministic effects, where deterministic was employed to
mean causally determined by preceding events. The acute
absorbed dose threshold for lens opacities was considered 2 or
3 times less for high-LET radiation than that for low-LET radiation.
It was also described that equivalent dose is not always the
appropriate quantity for deterministic effects because wR has been
chosen to reect RBE for stochastic effects, and that the use of
equivalent dose to predict deterministic effects for high-LET
radiation will lead to overestimates.
In 2003, ICRP-92 [13] wrote that the assumption used in ICRP-
58 that cell killing is the sole mechanism for induction of
deterministic effects is obviously not applicable to lens opaci-
cation as an important exception. Minor opacities evolving from
abnormal differentiation were regarded as a stochastic response,
but cataracts attributable to accumulation of minor opacities were
regarded as a deterministic effect. Nevertheless, a question was
raised as to whether lens opacication should be classied as a
deterministic effect. It was mentioned that there may be no
threshold or one too small to be detected, and that if there is a
threshold, it may be as low as 0.5 Gy [38]. It was also mentioned
that dose fractionation and a decrease in dose rate reduced the
induction of cataracts [38], but that if the damage to the lens is
cumulative, 150 mSv/year appears too high. The cataract data for
high-LET radiation were reviewed, and lens opacication due to
abnormal differentiation was considered to exhibit much higher
RBEs than other deterministic effects due to cell killing do.
However, it was concluded that the lack of the human data for
high-LET radiations and concern as to how the experimental data
should be applied, make it difcult to recommend wR in setting
limits for the lens. It was also documented that whilst equivalent
dose limits expressed in Sv are usually sufcient for low-LET
radiation, the use of the weighted dose in gray-equivalents (Gy-Eq)
is appropriate in situations where high-LET effects on the lens or
skin are critical. Uncertainties in ascribing appropriate wR for high-
energy neutrons (>20 MeV) and heavy ions at LET >200300 keV/
265
mm were recognized as a signicant issue in exposure at high
altitude.
ICRP-92 suggested the establishment of a new ICRP task group
to examine all the recent data on the lens and make proposals to
the ICRP Main Commission (MC) on dose limits for low- and high-
LET radiation. MC conrmed the importance of task group on
tissue injury and other non-cancer effects of radiation at its
October 2004 meeting in Beijing and Suzhou, China, and then
approved creation of task group at its September 2005 meeting in
Geneva and Bern, Switzerland. In 2006, Task Group 63 (TG63) on
tissue reactions and non-cancer effects was formed, and initiated
a review of available scientic information on tissue reactions to
low-LET radiation to prepare the report.
In 2007, ICRP-103 [39] used the term harmful tissue reactions
together with deterministic effects, and mentioned that these
effects are largely due to the killing or malfunction of cells
following high doses. ICRP-103 considered that it is more accurate
to refer to deterministic effects as early or late tissue or organ
reactions, because these effects are not necessarily predetermined
but are modiable by postirradiation procedures with the use of
various biological response modiers. However, considering its
rmly embedded use, the synonymous use of the generic terms
deterministic effects and stochastic effects and its correspond-
ing descriptive terms tissue reactions and cancer/heritable
effects was decided. The threshold dose was dened as dose
estimated to result in only 1% incidence of tissue reactions (c.f., at
least 15% in ICRP-41). On one hand, the scientic basis and
threshold for detectable lens opacities and VICs as well as
occupational and public equivalent dose limits for the lens
recommended in ICRP-60 remained unchanged, except that the
dose unit for thresholds was changed from Sv to Gy. It was also
documented by citing ICRP-41 and Edwards and Lloyd in 1996 [40]
that the threshold for 1% incidence of VIC that develops several
years after acute whole-body exposure to g-rays was estimated to
be 1.5 Gy. On the other hand, in the absorbed dose range up to
around 100 mGy (both low- and high-LET radiation, single acute
doses, and situations where these low doses are experienced in a
protracted form as repeated annual exposures), no tissues were
judged to express clinically relevant functional impairment. Dose
responses for tissue reactions in adults and children were in
general judged to have true dose thresholds resulting in the
absence of risk at low doses. However, further consideration of the
extent of the dose threshold for VIC induction was recommended,
and optimization in situations of exposure of the eyes was
emphasized. It was described by citing two papers [41,42] that
there is recent evidence for excesses of both cortical cataract and
posterior subcapsular cataract (PSC) at doses somewhat lower than
expected, suggesting that the lens may be more radiosensitive than
previously thought. Uncertainties in assigning a dose threshold
were recognized not only on the mechanisms of cataract
development but also on the relationship between the detection
of lens opacity and the expression of visual impairment. It was thus
decided that a newly formed task group (i.e., TG63) will address
such highlighted need for a detailed reappraisal of the radiosensi-
tivity of the lens, and that MC considers its possible signicance for
the equivalent dose limit for the lens when available. It was
documented that as the operational quantity for individual
monitoring for the assessment of the lens dose posed by external
exposure, the personal dose equivalent at a depth of 3 mm, Hp(3),
has rarely been used, but that at a depth of 70 mm, Hp(0.07), can be
used. Gonads (ovary and testes), bone marrow and the lens were
considered to be among the most radiosensitive tissues in the
body. It was noted that the occurrence and severity of any tissue
reaction are overestimated if wR is used to assess the exposure and
damage at high doses in comparison with photon irradiation,
because wR for high-LET radiation is derived for stochastic effects
266 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
at low doses. Instead, the use of an RBE-weighted dose (RBED) in
Gy (the mean absorbed dose to the organ or tissue, weighted by an
appropriate value of RBE for the biological endpoint of concern, of
which value may differ for different biological endpoints and
different tissues or organs) was recommended to assess radiation
exposure for determining the potential for tissue reactions (c.f., Gy-
Eq suggested in ICRP-92). Thus, ICRP-103 recognized uncertainties
in assigning a dose threshold for cataracts and mentioned the need
for a reappraisal of the equivalent dose limit for the lens.
2.4. Changes in 2010s
At its October 2010 meeting in Cape Town, South Africa, MC
approved the TG63 draft report for public consultation, and
concluded that the draft report will be accompanied by an ICRP
statement that will include, among other things, recommenda-
tions on revised equivalent dose limits for the lens [43]. Public
consultation began on 20 January 2011 and ended on 1 April 2011
[44]. A statement on tissue reactions was approved by MC at its
April 2011 meeting in Seoul, Korea, and was released on 21 April
2011. This so-called Seoul Statement recommended that (1) the
absorbed dose threshold for the lens is considered to be 0.5 Gy, (2)
an equivalent dose limit for the lens in planned exposure situations
is 20 mSv in a year, averaged over dened periods of 5 years, with
no single year exceeding 50 mSv, and (3) optimization of protection
should be applied in all exposure situations and for all categories of
exposure, and protection should be optimized not merely for
whole body exposures but also for exposures to specic tissues,
particularly the lens (and to the heart and the cerebrovascular
system because the absorbed dose threshold of 0.5 Gy was also
recommended for circulatory disease) [17]. This new limit built on
prevention of VICs, with the underlying assumption of a nominal
threshold of 0.5 Gy for acute or protracted exposure. However, the
recommended limit was 20 mSv/year but not 10 mSv/year (i.e.,
0.5 Sv  50 years), not only because a higher limit would not be
protective given the substantially lower threshold, but also
because alignment with the effective dose limit (100 mSv/5 years,
50 mSv/year) facilitates implementation [45]. Taken together,
optimization of protection for exposures of specic tissues (e.g.,
lens) was explicitly recommended to: (1) reect uncertainties in
applying a nominal threshold to the entire population; (2) aid in
keeping lifetime doses below the nominal threshold as the annual
limit alone does not guarantee this; and (3) account for the
possible lack of a threshold [17,45]. No change was recommended
to the public equivalent dose limit for the lens, not only because
MC judged that the existing limit (i.e., 15 mSv/year) remains
adequately protective and therefore reduction of the limit could
impose unnecessary restrictions, but also because any member of
the public seems highly improbable to receive a dose to the lens
over a lifetime in excess of the nominal threshold of 0.5 Gy in
planned exposure situations, considering application of the
effective dose limit of 1 mSv/year, the low likelihood of protracted
preferential exposure of the lens for any signicant period, and
optimization of protection below the equivalent dose limit for the
lens [17]. Although many options were considered, a change was
not justied based on improvements to protection [45].
MC approved the TG63 report for production at its October 2011
meeting in Bethesda, USA, of which the nal form was published as
ICRP-118 in August 2012 [17]. ICRP-118 preferably referred to
deterministic effects as tissue reactions because it was increasingly
recognized that these effects are not predetermined solely at the
time of irradiation and can be altered by the use of various
biological response modiers. Tissue reactions were dened as
injury in populations of cells characterized by a threshold dose and
an increase in the severity of the reaction as the dose is increased
further. Cell killing was considered unable to explain all tissue
reactions, especially late effects for which the paradigm has shifted
from one based mainly on killing of target cells to one based on an
orchestrated tissue response involving release of cytokines and
other mediators from damaged cells, leading to alterations in cell
function as well as cell killing. ICRP-118 arrived at the following six
major conclusions in relation to the lens: (1) radiation cataract is
still considered a tissue reaction with a dose threshold, albeit
small; (2) it is prudent to recommend changes to the threshold
doses in view of various problems in early studies and reports in
the past few years of markedly lower threshold doses deduced
from various radiation exposure scenarios; (3) acute dose
threshold should be lowered to a nominal value of 0.5 Gy, but
this is subject to the caveats that the progressive nature of assessed
opacities into cataracts and the likely greater sensitivity of the lens
in children compared with postadolescents require further
characterization; (4) the threshold dose for cataract is assumed
to be 0.5 Gy for acute, fractionated/protracted and chronic
exposures; (5) the public annual threshold dose values would
be scaled down in proportion to relative lifespan minus latency
period of 20 years for the lens vs working life, though great
uncertainty is attached to these values; and (6) acute doses up to
around 0.1 Gy produce no functional impairment of tissues
including the lens, with the caveat that the use of a threshold
model remains uncertain for the lens. These served as the scientic
basis for the Seoul Statement. The threshold dose of 0.5 Gy was
deduced mainly from three epidemiological papers [4648].
In 2013, ICRP-123 [49] described the special approach that
bases radiation weighting on Q, instead of wR, for applications in
space where high-energy heavy ions contribute signicantly to
total dose. This is because a single wR value of 20 does not reect
considerable variations in RBE and the body-mean quality factor
with types and energies of heavy ions, and because the Q approach
is better correlated with the assumption of a general LET
dependence of RBE. Taken together, it was mentioned that tissue
reactions cannot be excluded in space because of high dose rate
and less shielding, and that RBED is the appropriate quantity for
assessing risks of tissue reactions at higher doses involving high-
LET radiation. Last, the need for the measurement of the dose from
low-penetrating radiation was underlined, which may contribute
signicantly to the lens dose, especially when astronauts work
outside the spacecraft or during large solar are events.
In 2016, ICRP-132 [50] considered that in aviation, exposure of
aircraft passengers is public exposure and that of aircraft crew is
occupational exposure, and reviewed recent epidemiological
studies of aircraft crew that include a study showing a slight
increase in nuclear cataract risk in commercial airline pilots [51].
Findings related to high-LET cataractogenesis have been
reviewed extensively in ICRP-14, 41 and 92, but not in the past
14 years. It would thus be worthwhile reviewing what is currently
known epidemiologically and biologically (Sections 3 and 4), and
discussing what is not known and how to better improve the
situation (Section 5).
3. Epidemiological ndings on high-LET radiation
cataractogenesis
Table 3 lists epidemiological studies on high-LET cataracts.
3.1. Beginning of high-LET cataract epidemiology
In December 1948, cataracts were discovered in nuclear
physicists working with cyclotrons. The US Atomic Energy
Commission thus established a Committee on Radiation Cataracts
to conduct ophthalmological surveys for cyclotron cataracts and A-
bomb cataracts in Hiroshima and Nagasaki [7,52], of which
preliminary results were published in the same issue of Science
 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291 267

Table 3
Epidemiological studies reporting the effects of high-LET radiation on lens opacication.

Subjects Types of Types of Dose Dose with Number Age at Endpoint Latency Follow up References
radiation exposure cataracts analyzed exposure period after
initial
exposure
Cyclotron workers
Nuclear physicists 020 MeV Acute or 4135 n 4135 n 10 cataract N.A. Cataract N.A. <9 years [8]
neutrons protracted cases
in 10250
weeks
Nuclear physicists Fast neutrons Acute or 0.3 0.4 Gya , 13 cataract 2147 Cataract 1 >6 years <16 years [53]
protracted 1.2 Gy 0.8 Gyb cases years
in 10250
weeks
Radiotherapy patients
Patients with tumors 7.5 MeV Fractionated 0.2 8.6 Gy 57 eyes N.A. Cataract 212 28 days2 [54]
of the head and neck neutrons 15.1 Gy months years
Patients with tumors 7.5 MeV 12 fractions in 16.2 Gy 1 Gyc 93 eyes 2682 Cataract 34 weeks 10 weeks31 [34]
of the head neutrons 2633 days years 19 months months
f
Patients with uveal Protons, helium Fractionated 5075 N.A. 8809 patients 60 years Cataract N.A. 5 years (0.517 [55]
melanomad or carbon ions GyEe years)
Astronauts or aviators
NASA's LASH Space radiation Protracted <200 mSv >8 mSvg 295 41.8 years Cataract N.A. >30 years [57]
participants astronautsh (average)
NASCA participants Space radiation Protracted 12.9 mSvi N.A. 171 N.A. Minor N.A. N.A. [58]
(Phase I) astronautsj opacity
NASCA participants Space radiation Protracted <300 mSv N.A. 171202 N.A. Minor N.A. >40 years [59]
(Phase II) astronautsk opacity
m
Astronauts/ Space radiation Protracted N.A. N.A. 20 astronauts/ 4069 Minor N.A. 329 years [60]
cosmonauts cosmonautsl opacity
Astronauts Space radiation Protracted N.A. N.A. 27 N.A. Cataract N.A. N.A. [61]
astronautsn
Commercial aviators Cosmic Protracted N.A. N.A. 79 pilotso N.A. Cataract N.A. N.A. [51]
radiation
p
A-bomb survirors
A-bomb survirors Neutrons Acute N.A.q N.A.q 10 catatact 1355 VIC 0.52.5 4 years [7]
+ g-rays cases years years
A-bomb survirors Neutrons Acute N.A. 17.06 Gy 76 cataract 054 Posterior N.A. 1819 years [65]
(T65DR) + g-rays casesr years opacityr
A-bomb survirors Neutrons Acute N.A. N.A. 76 cataract 054 Posterior N.A. 1819 years [66]
(DS86) + g-rays casesr years opacityr
A-bomb survirors Neutrons Acute N.A. N.A. 67 cataract 054 Posterior N.A. 1819 years [68]
(DS86) + g-rays casess years opacity

Abbreviations: A-bomb, atomic bomb; DS86, dosimetry system 1986; GyE, gray equivalent; LSAH, Longitudinal Study of Astronaut Health; N.A., not available; NASA, US
National Aeronautics and Space Administration; NASCA, NASA Study of Cataract in Astronauts; RBE, relative biological effectiveness; T65DR, tentative 1965 dose estimates
revised; VIC, vision-impairing cataract.
a
On average, protracted exposure to 0.4 Gy induced VICs that slightly reduced vision (not below 20/30) with a latent period of 4 years.
b
On average, following exposure to 0.8 Gy protracted in 42 weeks, VICs occurred with a latent period of 10 months, the eyes being ready for operation within the st year.
c
Cataract frequency was 4% at 1 Gy, 4% at 1.013 Gy, 31% at 3.015 Gy, and 44% at >10 Gy, but 0% at 5.0110 Gy.
d
Meta-analysis of 27 studies. Of these, 3 were randomized clinical trials, and 24 were observational studies.
e
GyE was calculated based on RBE relative to 125I. RBEs were 1.1 for protons, 1.3 for helium ions and 3 for carbon ions.
f
Of these, 6718 received proton therapy, 623 helium ion therapy, 116 carbon ion therapy and 1352 either enucleation or 125I brachytherapy.
g
Hazard ratio of astronauts with a space lens dose of >8 mSv (average 45 mSv) compared to those with <8 mSv (average 3.6 mSv) was signicant at age 60 or 65 for
cataracts.
h
US astronauts.
i
Median. 25.4 mSv in 75th percentile.
j
US astronauts who ew at least one mission in space. Comparison group consisted of 53 astronauts who did not ow in space, 95 military aircrew, and 99 non-aircrew
ground-based comparison subjects.
k
US astronauts who ew at least one mission in space. Comparison group consisted of <60 astronauts who did not ow in space, and 5696 military aircrew. Ground-based
subjects were not used.
l
One of 21 (9 were from Russia, 6 from US and 1 each from Austria, Bulgaria, Kazakhstan, Poland, Romania and Syria) had already experienced cataract surgery, so that only
20 were analyzed. Reference group consists of a cohort of 395 persons (307 were male German Air Force employees, and 88 were patients with minor refractive errors
exclusing patients referred to the clinic because of lens opacities).
m
Age at the time of examinations. 1481 years for reference group.
n
LSAH participants (US astronauts) with spaceight experience in 19602000 and with recorded cataracts diagnosed before age 65 years. Comparison group consisted of
179 military aviators with recorded cataracts diagnosed before age 65 years (active aviators in 19532000).
o
Icelandair male pilots at age 50 years. Nonpilot controls were 366 men at age 50 (randomly selected residents of Reykjavik, Iceland).
p
This table does not aim to provide the extensive overview of all epidemilogical papers related to A-bomb cataracts, but overviews only papers closely related to neutron
aspects.
q
What part neutron played in cataractogenesis is not evident. Dose was unknown, but all of these patients were within 550950 m of the hypocenter where both neutrons
and g-rays were present.
r
Five cases with cortical opacity or nuclear opacity but without posterior subcapsular opacity were excluded, because posterior subcapsular opacity was viewed as the sine
qua non of a radiogenic lesion. 76 is the number after such exclusion.
s
All with the known degree of epilation.
268 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
in December 1949 [7,8]. Since then, some epidemiological studies
on high-LET cataracts have been conducted, albeit still very limited.
3.2. Cyclotron cataracts
Neutrons were identied in 1932, and its dose was measured
with equipment originally designed for use with X-rays. The
resulting dose was expressed in n units when the 100-r
chamber of Victoreen condenser r-meter was used, and in N
units when its 25-r chamber was used. Stone mentioned that
tissue dose in 1 rep generally equals 1.5 n equals 2 N [52], whilst
Abelson mentioned that 1 n equals 2.5 rep [8]. Assuming that
both 100-r and 25-r chambers can properly measure the air
kerma (kinetic energy released per unit mass) in a neutron eld,
the relationship between n or N and rep can be roughly estimated
based on the ratio between the tissue kerma and air kerma in the
eld. This ratio varies with the energy spectrum of the neutron
eld (e.g., 8.4 and 2.8 for 1 and 10 MeV mono-energetic neutron
elds, respectively). Considering that rather high energy neutrons
were used in the studies employing the dose unit of n or N, the
relationship 1 n = 1 N = 2.5 rep may be appropriate, similarly to the
Abelsons estimate.
In 1949, cataracts in 10 cyclotron workers were reported that
occurred within 9 years after acute or protracted exposures to 4
135 n [8]. The further analysis of 13 cyclotron workers reported in
1959 suggested that protracted exposure to 0.8 Gy of cyclotron
radiation induces cataracts requiring surgical intervention, with a
latent period of 10 months (c.f., 0.4 Gy induces cataracts that
slightly reduce vision, with a latent period of 4 years) [53]. It
was suggested that cyclotron cataracts may be slightly poor
operative risks than senile cataracts, e.g., owing to an undue
adhesion between the posterior capsule and the hyaloid face of the
vitreous.
3.3. Radiotherapy patients
Neutron therapy started in 1938 [52]. Two studies evaluated
cataracts in patients with tumors of the head and neck who
received fractionated exposures to fast neutrons (7.5 MeV). One
study showed that within a year after exposure, patients who
received 8.5 Gy exhibited cataracts [54]. The other study showed
that the incidence of cataracts manifested in 219 months after
exposure was 4% at 1 Gy, 4% at 1.013 Gy, 31% at 3.015 Gy, and
44% at >10 Gy, but 0% at 5.0110 Gy [34], which was used in ICRP-41
to judge the fast neutron threshold for VICs as 35 Gy as mentioned
in Section 2.2. These two studies had a short follow-up period
of <3 years, and thereby lack the information on later manifes-
tations.
Various types of charged particles have been used clinically
over the past half century (e.g., protons and helium ions since 1954,
negative pions since 1961, neon ions since 1977 and carbon ions
since 1994). Uveal melanoma represents the most common
primary ocular tumor in adults, for which surgical treatments
are successful but often involve enucleation (i.e., loss of vision). In
this regard, charged particle therapy and brachytherapy (e.g.,
with 125I, 106Ru or 103Pd) are among less invasive options. The
meta-analysis of 27 studies enrolling 8809 patients with uveal
melanoma revealed that the pooled rate of cataract formation after
charged particle therapy (with protons, helium ions or carbon
ions) was 0.34 [95% condence interval (CI), 0.15-0.53], which
was signicantly lower than that after 125I brachytherapy [55].
The follow-up period after treatment was 0.5-17 years. In
charged particle therapy, the selection of beam paths that
do not traverse the lens can keep the lens dose <10% of the
prescribed dose, thereby signicantly reducing cataract forma-
tion [56].
3.4. Astronauts and aviators
In the Longitudinal Study of Astronaut Health (LSAH) by US
National Aeronautics and Space Administration (NASA) [57],
hazard ratio of US astronauts with a space lens dose of >8 mSv
(average 45 mSv) compared to those with <8 mSv (average
3.6 mSv) was signicant at age 60 or 65 for all cataracts. Of
these, signicant hazard ratio was observed for non-trace
cataracts, and the combined PSCs, nuclear or mixed cataracts,
but not for cortical cataracts. A signicant association between
cataract and high inclination (>50 ) or lunar missions suggests that
high-LET heavy ions and neutrons are causative rather than
trapped protons. Several thousand particles with LET of >30 keV/
mm traverse the lens on an average 10-day space mission.
Phase I (cross-sectional study) of the NASA Study of Cataract in
Astronauts (NASCA) revealed a signicant association between
space radiation US astronauts received and the incidence of
cortical cataracts and PSCs but not nuclear cataracts [58]. Phase II
(the longitudinal analysis based on 5 years of follow-up) of NASCA
found a signicant association between space radiation US
astronauts received and the progression rate of cortical cataracts,
but not that of PSCs nor nuclear cataracts [59]. No impact of space
radiation on visual acuity was apparent.
Twenty astronauts or cosmonauts from eight countries tended
to show increased lens opacities in posterior capsule and posterior
cortex, but a statistical signicance was not analyzed [60].
Cataracts in US astronauts were compared with those in US
military aviators [61]. Average age at onset of cataracts (i.e., at
diagnosis of a rst cataract) was older in astronauts with cataracts
(age 6070 years) than in aviators with cataracts (age 4045 years).
The incidence density of cataracts was higher in astronauts than in
aviators. The most commonly observed cataracts were cortical
cataracts in astronauts, but PSCs in aviators.
The odds ratio for nuclear cataract risk among cases and
controls was 3.02 (95% CI, 1.446.35) for commercial airline pilots
compared with nonpilots, adjusted for age, smoking status, and
sunbathing habits, whereas that for cortical cataracts, central
optical zone involvement and PSCs was 0.95 (0.481.85), 0.64
(0.261.60) and 0.46 (0.102.04), respectively [51]. The odds ratio
became highest when adjusted for cumulative dose sustained
before age 40 years.
For the International Space Station (ISS), the Flight Rules dene
an international joint exposure limit of 1 Sv/30 days and 2 Sv/year
for the lens, and the Japan Aerospace Exploration Agency (JAXA)
denes a target level of 0.5 Sv/week, 2 Sv/year and 5 Sv/career for
the lens. For these, a quality factor as a function of LET, called Q(L),
is used to calculate an equivalent dose to the lens, instead of wR
[62]. NASA currently recommends a limit of 1 Gy-Eq/30 days, 2 Gy-
Eq/year and 4 Gy-Eq/career for the lens to prevent early severe
cataracts (<5 years), e.g., from a solar particle event [63]. NASA
considers that an additional cataract risk for subclinical cataracts
exists at lower doses from cosmic rays, which may progress to
severe types after long latency (>5 years) and are not preventable
by existing mitigation measures, but they are deemed an
acceptable risk to the program. RBEs recommended for Gy-
Eq calculation, instead of wR, are 6.0 (range 48) for 15 MeV
neutrons, 3.5 (25) for 550 MeV neutrons, 2.5 (14) for heavy ions
and 1.5 for >2 MeV protons.
3.5. A-bomb survivors
In 1949, 10 cases of cataracts were reported. These A-bomb
survivors were all within 550950 m of the hypocenter where both
neutrons and g-rays were present, but dose was unknown [7].
Later studies showed that the greatest distance from the
hypocenter that lens damage could be denitely established was
 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
2 km where neutron dose is negligible: thus, neutrons were not
incriminated in A-bomb cataracts [53].
In 1967, cataract cases in 84 A-bomb survivors were reported as
a result of an ophthalmological survey conducted in 19631964
(i.e., 1819 years after exposure), where the tentative dose
estimates developed in 1957 were used [64]. Of these, 76 cases
with posterior opacities were then reanalyzed with the tentative
1965 dose estimates revised (T65DR) [65] (n.b., cases with cortical
or nuclear cataracts but without PSCs were excluded from the
analysis). The most suitable model for posterior opacities under
T65DR appeared to be a model that assumes a linear g effect, a g
threshold and no demonstrable neutron effect, suggesting a small
dose contribution of neutrons. The data of 76 cases analyzed with
the T65DR [65] were reanalyzed with the dosimetry system 1986
(DS86) [66]. The best t was a linear g linear neutron relationship
assuming different thresholds each for g-rays and neutrons. RBEs
were estimated based on such a linearlinear model with two
thresholds. For T65DR, mean RBE was described as {4.1 + [1.35/
(Dn 0.56)]}, a lower bound of 95% CI as {2.1 + [0.53/(Dn 0.56)]},
and an upper bound of 95% CI as {8.0 + [2.01/(Dn 0.56)]}, where Dn
is neutron dose (Gy). For DS86 eye organ dose, mean RBE was
described as {32.4 + [0.73/(Dn 0.06)]}, a lower bound of 95% CI as
11.8 (i.e., constant, not as a function of Dn), and an upper bound of
95% CI as {88.8 + [1.39/(Dn 0.06)]}. For example, at 1 Gy, RBE was
33 (1290) for DS86 eye organ dose but 7 (313) for T65DR. RBE
increased with decreasing dose: e.g., 51 (12124) at 0.1 Gy and 105
(12228) at 0.07 Gy for DS86 eye organ dose. Then, a constant RBE
of 12.2 was derived because a threshold of 0.73 Gy for g-rays gave
the same safety zone as that of 0.06 Gy for neutrons. The risk
estimates associated with neutron exposures are 6.4 (95% CI, 2.2
19.2) fold higher for the DS86 kerma than T65DR, and 1.6 (0.52.3)
fold higher for the DS86 eye organ dose than the DS86 kerma.
T65DR, DS86 kerma and DS86 eye organ dose all suggested two
thresholds in the range of 0.71.4 Gy for g-rays and 0.06 0.6 Gy for
neutrons [67].
The subsequent analysis that employed a constant neutron RBE
of 10 to calculate lens dose (i.e., a total dose being the sum of the
g-ray dose and 10 times the neutron dose) showed that compared
with cataract cases without epilation, those with epilation had a
trend toward a lower threshold and a steeper slope estimate under
a linearlinear threshold model, albeit statistically insignicant
[68]. Since then (to date), the neutron RBE of 10 has been used in A-
bomb cataract studies [41,46,47], although the dosimetry system
2002 (DS02) has been used in papers published from 2006 [46]
onwards.
Whilst early studies used to look at posterior opacities only [65
68], later studies have also looked at other types of cataracts [41,46]
and cataract removal surgery [47,69,70].
4. Experimental ndings on the high-LET radiation response of
the lens
Table 4 summarizes experimental studies on high-LET lens
opacication, and Table 5 summarizes those on other lenticular
responses to high-LET radiation. This section also briey deals with
some low-LET radiations (i.e., photons, pions, protons and
deuterons) from the viewpoint of the RBE for the lenticular
response.
4.1. The lens response to acute, single exposure
4.1.1. Photons
Outcome selection and measurement are critical to determine
RBE because RBE differs with endpoints (e.g., severity of cataracts).
RBE also depends on a reference radiation for which photons are
generally used. It is therefore important to know RBEs for different
269
types of photons. In this regard, two studies have analyzed RBE of
60
Co g-rays for lens opacication in rodents [71,72]. In RF mice, RBE
relative to 250 kV X-rays was 0.8 at 6.5 or 8 Gy with a follow up
period of <15 months postirradiation, and 1 at 0.333.33 Gy with
a follow up period of >20 months [71]. In LAF1 mice, RBE relative to
250 kV X-rays was 0.8 at 4.9 or 6.5 Gy with a follow up period of
<40 months [71]. In white Sherman rats, RBE relative to 200 kV X-
rays was 1 at 15 Gy with a follow up period of >70 weeks [72]. In
these studies, mice received whole body irradiation, whilst rats
received eye irradiation.
4.1.2. Negative pions
In Bts/SAS/4 mice, RBE of 70 MeV p mesons relative to 60Co
g-rays or to 14 MeV electrons was 1 at 0.42 Gy with a follow up
period of 1 year [73].
4.1.3. Protons
In vivo lens effects have been studied in rabbits, rodents and
monkeys. In Dutch rabbits, RBEs relative to 1 MeV X-rays (LET =
0.4 keV/mm) for lens opacication were 23 for 100 MeV protons
(0.75 keV/mm) and 2.6 6 for 20 MeV protons (3.4 keV/mm) at 1
2.5 Gy with a follow up period of 2 years, but these proton RBEs
relative to 250 kVp X-rays (3 keV/mm) were considered to be 1
[74]. RBEs of 160 MeV protons relative to 60Co g-rays for 7 normal
tissues in C3Hf/Sed mice fell between 1.09 and 1.32 among which
the lens had the smallest RBE [75]. In Fischer 344 rats (Rattus
norvegicus), RBE of 55 MeV protons relative to X-rays for lens
opacication was 1.5 at 2 and 4 Gy and 1.3 at 8.5 Gy with a follow up
period of 1 year [76]. In CBA  C57BL6 F1 mice, RBE relative to 60Co
g-rays for lens opacication was 1 for 645 MeV protons (0.25 keV/
mm) and 50 MeV protons (1.25 keV/mm) at 16 Gy with a follow up
period of 2 years, but RBEs of 9 GeV protons (0.23 keV/mm) were 2
4 and 48 at 0.25 Gy and 12 and 1 at 5 Gy with a follow up period
of 25 and 67 weeks, respectively: thus, RBEs for high energy
protons are much higher than those for low energy protons despite
at similar LET [77]. In B6CF1/Anl mice, RBEs of 250 MeV protons
(0.42 keV/mm) relative to 60Co g-rays were 1.01 for meridional row
(MR) disorganization and 1.11 for micronucleation (MN), at 64
weeks after irradiation with 0.13.2 Gy [78].
In vitro effects have been studied using human lens epithelial
cells (LECs) and lens ber cells (LFCs). The magnitude and time
course of cyclin dependent kinase inhibitor 1A (CDKN1A/p21) gene
expression following irradiation with 4 Gy of 150 kVp X-rays and
protons [kinetic energy = 55 MeV/atomic mass unit (amu),
1.18 keV/mm] were similar with its maximum induction at 3 or
4 h. There was no signicant difference in the distribution of the
relative in situ uorescence intensity of CDKN1A after irradiation
with protons and X-rays [79]. At 3 h postirradiation, cyclin
dependent kinase 1 (CDK1/CDC2), cyclin G1, and checkpoint
kinase 2 (CHK2) were downregulated, concurrent with CDKN1A
upregulation [79]. Expression of matrix metalloproteinase (MMP)
family members was analyzed, and found that at 8 h after
exposure to 4 Gy of protons (55 MeV/amu, 1.18 keV/mm), MMP-2, 3,
9 and tissue inhibitor of MMP 1 (TIMP1) were transiently
downregulated in human LECs, but expression of these genes
did not change in human LFCs [80].
4.1.4. Neutrons
In vivo effects on the lens have been studied in rabbits, rodents,
swine, dogs, goat, cattle, burros and monkeys. High RBEs have been
reported, which even exceed 200 [81,82]. One study used the rat
lens in vitro [83], but there have been no other reports on in vitro
studies using primary cultures or cell lines.
4.1.4.1. Dependence of RBE on dose and time. The dose response
relationship determines dose dependence of RBE. If the shape of
 270
Table 4
Biological studies reporting the effects of high-LET radiation on lens opacication.

Test radiation Reference radiation Irradiation Subjects and age at irradiation Follow up RBE References
after
irradiation
Type Dose rate Dose Type Dose rate

Photons
Co g-rays
60
0.57 Gy/min Single dose of 6.5 and 8 Gy 250 kV X-rays 0.7 Whole body 814 week old male/female RF mice <15 months 0.8 [71]
0.8 Gy/
min
Co g-rays
60
N.A. Single dose of 4.9 and 6.5 Gy 250 kV X-rays 0.14 Gy/ Whole body 612 week old male/female LAF1 mice <40 months 0.8 [71]
min
Co g-rays
60
0.03 Gy/min Single or divided dose of 250 kV X-rays 0.03 Gy/ Whole body 1218 week old RF mice >20 months 1 [71]
0.333.33 Gy min
Co g-rays
60
0.13 Gy/min Single or divided dose of 200 kV X-rays 0.18 Gy/ Eye 4 month old female white Sherman >70 weeks 1 [72]
15 Gy (1.8 keV/mm) min rats
Pions
70 MeV p mesons 0.010.1 Gy/hour Single dose of 0.42 Gy 60
Co g-rays 0.01 Gy/ Head 1 day old male/female Bts/SAS/4 mice 12 months 1 [73]
min

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

70 MeV p mesons 0.010.1 Gy/hour Single dose of 0.42 Gy 14 MeV 4 Gy/sec Head 1 day old male/female Bts/SAS/4 mice 12 months 1 [73]
electrons
Protons
100 MeV protons (0.75 keV/mm) 0.25 Gy/min Single dose of 0.255 Gy 1 MeV X-rays N.A. Eye 810 week old Dutch rabbits 48 months 23 [74]
(0.4 keV/mm)
20 MeV protons (Bragg peak, 3.4 keV/ 0.25 Gy/min Single dose of 0.255 Gy 1 MeV X-rays N.A. Eye 810 week old Dutch rabbits 48 months 2.66 [74]
mm) (0.4 keV/mm)
100 MeV protons (0.75 keV/mm) 0.25 Gy/min Single dose of 0.52.5 Gy 1 MeV X-rays N.A. Eye 810 week old Dutch rabbits 24 months 2 [125]
(0.4 keV/mm)
20 MeV protons (Bragg peak, 3.4 keV/ 0.25 Gy/min Single dose of 0.52.5 Gy 1 MeV X-rays N.A. Eye 810 week old Dutch rabbits 24 months 3 [125]
mm) (0.4 keV/mm)
100 MeV protons (0.75 keV/mm) 0.25 Gy/min 0.55 Gy in 10 monthly 1 MeV X-rays N.A. Eye 810 week old Dutch rabbits 24 months N.A. [125]
fractions (0.4 keV/mm)
20 MeV protons (Bragg peak, 3.4 keV/ 0.25 Gy/min 0.55 Gy in 10 monthly 1 MeV X-rays N.A. Eye 810 week old Dutch rabbits 24 months N.A. [125]
mm) fractions (0.4 keV/mm)
160 MeV protons 1 Gy/min N.A. 60
Co g-rays 1 Gy/min Head 1012 week old C3Hf/Sed mice 210 days 1.09  0.07 [75]
55 MeV protons (spread Bragg peak) N.A. Single dose of 2 and 4 Gy X-rays N.A. Head 810 week old Fischer 344 rats 1 year 1.5 [76]
55 MeV protons (spread Bragg peak) N.A. Single dose of 8.5 Gy X-rays N.A. Head 810 week old Fischer 344 rats 1 year 1.3 [76]
32, 55, 138, 400 and 2300 MeV N.A. Single dose of 2.17.5 Gy N.A. N.A. Whole body 2 year old rhesus monkeys 2024 years N.A. [166]
protons
32, 55, 138, 400 and 2300 MeV N.A. Single dose of 0.57.5 Gy 2 MeV X-rays N.A. Partial or 2 year old rhesus monkeys 2024 years N.A. (<2) [76]
protons whole body
32, 55, 138, 400 and 2300 MeV N.A. Single dose of 1.257.5 Gy 2 MeV X-rays N.A. Partial or 2 year old rhesus monkeys 1625 years N.A. [167]
protons whole body
Mixed energy protons (10 and 0.28 Gy/min Single dose of 1.54.4 Gy 2 MeV X-rays N.A. Partial or 2 year old rhesus monkeys 1821 years N.A. [167]
110 MeV) whole body
50 MeV protons (1.25 keV/mm) 0.4 cGy/sec Single dose of 16 Gy 180 keV X-rays 1 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 <2 years 1 [77]
(0.25 keV/mm) mice
645 MeV protons (0.25 keV/mm) 6.3 cGy/sec Single dose of 16 Gy 60
Co g-rays 6 cGy/sec Whole body 1416 g male/female CBA  C57BL6 F1 <2 years 1 [77]
(0.25 keV/mm) mice
9 GeV protons (0.23 keV/mm) 2 cGy/sec Single dose of 0.25 Gy 60
Co g-rays 6 cGy/sec Whole body 1416 g male/female CBA  C57BL6 F1 25 weeks 24 [77]
(0.25 keV/mm) mice
9 GeV protons (0.23 keV/mm) 2 cGy/sec Single dose of 5 Gy 60
Co g-rays 6 cGy/sec Whole body 1416 g male/female CBA  C57BL6 F1 25 weeks 12 [77]
(0.25 keV/mm) mice
9 GeV protons (0.23 keV/mm) 2 cGy/sec Single dose of 0.25 Gy 60
Co g-rays 6 cGy/sec Whole body 1416 g male/female CBA  C57BL6 F1 67 weeks 48 [77]
(0.25 keV/mm) mice
9 GeV protons (0.23 keV/mm) 2 cGy/sec Single dose of 4 Gy 60
Co g-rays 6 cGy/sec Whole body 1416 g male/female CBA  C57BL6 F1 67 weeks 1 [77]
(0.25 keV/mm) mice

(continued on next page)

 645 MeV protons (0.25 keV/mm) 0.18, 1.8 or 18 Gy/ Single dose of 4 Gy N.A. N.A. Whole body 1416 g male/female CBA  C57BL6 F1 40 weeks N.A. [77]
min mice
645 MeV protons (0.25 keV/mm) 0.7 or 7 cGy/min Single dose of 0.52 Gy N.A. N.A. Whole body 1416 g male/female CBA  C57BL6 F1 40 weeks N.A. [77]
mice
50 MeV protons (1.25 keV/mm) 0.4 cGy/sec 6 Gy in 2 weekly fractions 180 keV X-rays 1 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 70 weeks N.A. [77]
(0.25 keV/mm) mice
645 MeV protons (0.25 keV/mm) 6.3 cGy/sec 2, 4 or 6 Gy in 2 weekly 180 keV X-rays 1 cGy/sec Whole body 1416 g male/female CBA  C57BL6 F1 70 weeks N.A. [77]
fractions (0.25 keV/mm) mice
55 MeV protons N.A. Single dose of 2.57.5 Gy 300 kV or 0.3 Gy/ Whole body 3 year old rhesus monkeys <30 years N.A. [168]
6 MV X-rays min
Protons (1 GeV/amu, 0.24 keV/mm) 0.2 Gy/min Single dose of 3 Gy N.A. N.A. Whole body Male CBA/JCR HSD mice 2 years N.A. [124]
Neutrons
Fast neutrons
Neutrons 0.0141.4 N/day Total daily dose of 6235 N 185 kVp X- 0.1 Gy/ Whole body 46 week old male/female Swiss 20 months 1213 [6]
rays min Rockland Farms or CF1 Carworth Farms
mice
0.43 MeV neutrons 0.108 Gy/min Single dose of 0.321.17 Gy 60
Co g-rays 0.2 Gy/ Eye 1218 week old BNL-Stoner white 11 months 7.3 or 8.9a [90]
min Swiss mice
1 MeV neutrons 0.108 Gy/min Single dose of 0.371.35 Gy 60
Co g-rays 0.2 Gy/ Eye 1218 week old BNL-Stoner white 11 months a
6.1 or 7.5 [90]
min Swiss mice

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

1.5 MeV neutrons 0.108 Gy/min Single dose of 0.421.55 Gy 60
Co g-rays 0.2 Gy/ Eye 1218 week old BNL-Stoner white 11 months 4.6 or 5.2 a
[90]
min Swiss mice
1.8 MeV neutrons 0.108 Gy/min Single dose of 0.361.33 Gy 60
Co g-rays 0.2 Gy/ Eye 1218 week old BNL-Stoner white 11 months 5.6 or 6.6a [90]
min Swiss mice
0.43 MeV neutrons 0.29 Gy/min Single dose of 0.010.3 Gy or 250 kVp X- 0.169 Gy/ Whole body 1518 week old female BNL-Stoner 32 weeks 10 [91]
0.15 Gy rays min white Swiss mice
1.8 MeV neutrons 0.25 Gy/min Single dose of 0.010.3 Gy or 250 kVp X- 0.169 Gy/ Whole body 1518 week old female BNL-Stoner 32 weeks 10 [91]
0.15 Gy rays min white Swiss mice
0.43 MeV neutrons 0.25 or 0.29 Gy/ Single dose of 0.0111.04 Gy 250 kVp X- 0.975 Gy/ Whole body 15 week old female BNL-Stoner white >65 weeks 10 [169]
min rays (25 keV/ min Swiss mice
mm)
1.8 MeV neutrons 0.25 Gy/min Single dose of 0.012 250 kVp X- 0.169 Gy/ Whole body 15 week old female BNL-Stoner white >65 weeks 10 [169]
0.362 Gy rays (25 keV/ min Swiss mice
mm)
0.43 MeV neutrons N.A. Single dose of 0.2 mGy 250 kVp X- 0.17 Whole body 6 or 13 week old female BNL-Stoner 10 months <6200< [81]
1.04 Gy rays 1.15 Gy/ white Swiss mice
min
1.8 MeV neutrons N.A. Single dose of 0.01 Gy 250 kVp X- 0.17 Whole body 6 or 13 week old female BNL-Stoner 10 months <550< [81]
0.36 Gy rays 1.15 Gy/ white Swiss mice
min
14 MeV neutrons N.A. Single dose of 5 mGy0.6 Gy 250 kVp X- 0.17 Whole body 6 or 13 week old female BNL-Stoner 10 months <340< [81]
rays 1.15 Gy/ white Swiss mice
min
12 MeV neutrons (515% g-rays) 0.61.25 Gy/min Single dose of 1.5<3 Gy 250 kV X-rays 0.7 Whole body 814 week old male/female RF mice 25 months 34 [71]
0.8 Gy/
min
12 MeV neutrons (515% g-rays) 0.61.25 Gy/min Single dose of 0.96.4 Gy 60
Co g-rays 0.57 Gy/ Whole body 814 week old male/female RF mice 25 months 5 [71]
min
12 MeV neutrons (515% g-rays) 0.61.25 Gy/min Single dose of 0.98 Gy 250 kV X-rays 0.7 Whole body 1518 week old Wistar rats 25 months 23 [71]
0.8 Gy/
min
12 MeV neutrons (515% g-rays) 0.61.25 Gy/min Single dose of 0.98 Gy 250 kV X-rays 0.7 Whole body 350450 g guinea-pigs 25 months 23 [71]
0.8 Gy/
min
23 MeV neutrons (<10% g-rays) 0.010.04 Gy/ Single dose of 0.12 and 60
Co g-rays or 0.03 Gy/ Whole body 1218 week old RF mice >20 months 9 [71]
hour 0.37 Gy 250 kV X-rays min
23 MeV neutrons (<10% g-rays) 0.010.04 Gy/ Single dose of 0.013 Gy 60
Co g-rays or 0.03 Gy/ Whole body 1218 week old RF mice >20 months 25 [71]
hour 250 kV X-rays min
23 MeV neutrons (<10% g-rays) Whole body 814 week old Wistar rats N.A. >9>28 [71]

271
(continued on next page)
 272
Table 4 (Continued)
Test radiation Reference radiation Irradiation Subjects and age at irradiation Follow up RBE References
after
irradiation
Type Dose rate Dose Type Dose rate

0.010.04 Gy/ Single dose of 0.0133 60

Co g-rays or 0.03 Gy/
hour 0.373 Gy 250 kV X-rays min
23 MeV neutrons (<10% g-rays) N.A. Single dose of 0.024 250 kV X-rays N.A. Whole body 2030 week old Dutch hybrid albino 3 years N.A. [71]
0.373 Gy rabbits
<4 MeV fast neurtons N.A. Single dose X-rays N.A. N.A. Mice N.A. 5 [128]
<4 MeV fast neurtons N.A. Divided dose X-rays N.A. N.A. Mice N.A. 8 [128]
4 MeV fast neutrons N.A. Single dose X-rays N.A. N.A. Mice N.A. 8 [128]
68 MeV neutrons (<0.1% g-rays) N.A. Single dose of 60150 N N.A. N.A. Eye 82 day, 56 month or 1 year old dogs 2 years N.A. [117]
68 MeV neutrons (<0.1% g-rays) N.A. Single dose of 810 or 900 N N.A. N.A. Eye 11 month or 3 year old dogs 2 years N.A. [117]
14 MeV neutrons 2  1091.5  1011 Single dose of 2  109 1.2 MeV X-rays N.A. Eye <10 week old French silver rabbits >9 months N.A. [161]
neutrons/cm2/ 9  1011 neutrons/cm2
hour
14 MeV neutrons N.A. Single dose of 8.4  109 1.2 MeV X-rays N.A. Head Pigmented rabbits <18 months 11 [170]
neutrons/cm2

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

14 MeV neutrons N.A. Single dose of 0.758.5 Gy 60
Co g-rays N.A. N.A. Monkeys >14 months 35 [28]
12 MeV neutrons (715% g-rays) N.A. Single dose of 1.81.9 Gy 200 kV or 0.33 or Whole body or 2.53.5 month old albino Swiss mice 1215 4.5 [139]
250 kV X-rays 0.5 Gy/ head months
min
56 MeV neutrons (511% g-rays), N.A. Single dose of 2.02.1 Gy 200 kV or 0.33 or Whole body or 2.53.5 month old albino Swiss mice 1215 4.0 [139]
180 250 kV X-rays 0.5 Gy/ head months
min
56 MeV neutrons (511% g-rays), N.A. Single dose of 3.23.3 Gy 200 kV or 0.33 or Whole body or 2.53.5 month old albino Swiss mice 1215 2.4 [139]
beam center 250 kV X-rays 0.5 Gy/ head months
min
Neutrons (p, n), 180 N.A. Single dose of 1.82.0 Gy 200 kV or 0.33 or Whole body or 2.53.5 month old albino Swiss mice 1215 4.0 [139]
250 kV X-rays 0.5 Gy/ head months
min
Neutrons (p, n), beam center N.A. Single dose of 1.92.0 Gy 200 kV or 0.33 or Whole body or 2.53.5 month old albino Swiss mice 1215 4.0 [139]
250 kV X-rays 0.5 Gy/ head months
min
15 MeV neutrons N.A. Single dose of 7.5 Gy 60
Co g-rays N.A. Head Rabbits 10 months 2 [162]
400 MeV neutrons 3.55 cGy/hour Single dose of 538 cGy 250 kVp X- 40.4 cGy/ Whole body 75 day old male C3H  C57Bl F1 hybrid 20 months 5.8b [86]
rays hour mice
400 MeV neutrons (attenuated with 9.75 cGy/hour Single dose of 758 cGy 250 kVp X- 40.4 cGy/ Whole body 75 day old male C3H  C57Bl F1 hybrid 20 months 2.2b [86]
polyethylene) rays hour mice
400 MeV neutrons 3.55 cGy/hour Single dose of 538 cGy 250 kVp X- 40.4 cGy/ Whole body 75 day old male C3H  C57Bl F1 hybrid 20 months 5.4c [86]
rays hour mice
c
400 MeV neutrons (attenuated with 9.75 cGy/hour Single dose of 758 cGy 250 kVp X- 40.4 cGy/ Whole body 75 day old male C3H  C57Bl F1 hybrid 20 months 1.9 [86]
polyethylene) rays hour mice
b
14 MeV neutrons 6.5 cGy/hour Single dose of 0.9538 cGy 250 kVp X- 45.8 cGy/ Whole body 75 day old male C57Bl  C3H hybrid 20 months 921 [87]
rays hour mice
14 MeV neutrons 6.5 cGy/hour Single dose of 0.9538 cGy 250 kVp X- 45.8 cGy/ Whole body 75 day old male C57Bl  C3H hybrd 25 months 8c [87]
rays hour mice
1 MeV neutrons N.A. Single dose of 0.935.6 cGy 250 kVp X- N.A. Whole body 67 week old male C3H  C57Bl F1 20 months 18.141.9b [88]
rays hybrid mice
b
5 MeV neutrons N.A. Single dose of 0.935.6 cGy 250 kVp X- N.A. Whole body 67 week old male C3H  C57Bl F1 20 months 10.924.5 [88]
rays hybrid mice
15 MeV neutrons 6.5 cGy/hour Single dose of 138 cGy 250 kVp X- 45.8 cGy/ Whole body 75 day old male C57Bl  C3H hybrid 20 months 9.033.6b [88]
rays hour mice
400 MeV neutrons 3.55 cGy/hour Single dose of 538 cGy 250 kVp X- 40.4 cGy/ Whole body 75 day old male C3H  C57Bl F1 hybrid 20 months 5.87.3b [88]
rays hour mice

(continued on next page)

 400 MeV neutrons (attenuated with 9.75 cGy/hour Single dose of 758 cGy 250 kVp X- 40.4 cGy/ Whole body 75 day old male C3H  C57Bl F1 hybrid 20 months 2.35.0b [88]
polyethylene) rays hour mice
600 MeV neutrons N.A. Single dose of 1.640.6 cGy 250 kVp X- N.A. Whole body 67 week old male C3H  C57Bl F1 20 months 5.825.7b [88]
rays hybrid mice
c
1 MeV neutrons N.A. Single dose of 0.935.6 cGy 250 kVp X- N.A. Whole body 67 week old male C3H  C57Bl F1 20 months 19 [88]
rays hybrid mice
c
5 MeV neutrons N.A. Single dose of 0.935.6 cGy 250 kVp X- N.A. Whole body 67 week old male C3H  C57Bl F1 20 months 9 [88]
rays hybrid mice
15 MeV neutrons 6.5 cGy/hour Single dose of 138 cGy 250 kVp X- 45.8 cGy/ Whole body 75 day old male C57Bl  C3H hybrid 20 months 6c [88]
rays hour mice
400 MeV neutrons 3.55 cGy/hour Single dose of 538 cGy 250 kVp X- 40.4 cGy/ Whole body 75 day old male C3H  C57Bl F1 hybrid 20 months 6c [88]
rays hour mice
d
0.44 MeV neutrons (106 keV/ 8 mGy/min Single dose of 2 mGy 250 kVp X- N.A. Whole body 28 day old Columbia-Sherman albino 102 weeks 250500 [82]
mm, <1.5% g-rays) rays rats
0.44 MeV neutrons (106 keV/ 8 mGy/min Single dose of 10 mGy 250 kVp X- N.A. Whole body 28 day old Columbia-Sherman albino 102 weeks 50100d [82]
mm, <1.5% g-rays) rays rats
0.44 MeV neutrons (106 keV/ 8 mGy/min Single dose of 50 mGy 250 kVp X- N.A. Whole body 28 day old Columbia-Sherman albino 102 weeks 1020d [82]
mm, <1.5% g-rays) rays rats
d
0.44 MeV neutrons (106 keV/ 8 mGy/min Single dose of 250 mGy 250 kVp X- N.A. Whole body 28 day old Columbia-Sherman albino 102 weeks 816 [82]
mm, <1.5% g-rays) rays rats

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

Slow neutrons
Thermal column (g-rays) 9  109 neutrons/ Single dose (2.580 min) 250 kV X-rays 0.064 Gy/ Whole body 810 week old Rf mice 19 months >2 [171]
cm2/sec min
Thermal column (g-rays) N.A. Single dose 250 kVp X- N.A. Whole body Swiss mice 30 weeks 9.73  3.11 [138]
rays
Thermal column (g-rays) N.A. Single dose 250 kVp X- N.A. Whole body Swiss mice 1 year 5.92  2.08 [138]
rays
Thermal neutrons
Neutrons (<1/3 g-rays) N.A. Single dose of 0.255 Sv 250 kV X-rays N.A. Whole body RF mice 16 months 36 [71]
Thermal column (<24% g-rays) N.A. Single dose of 0.032 250 kV X-rays N.A. Whole body Female white Swiss mice 30 weeks 8 [172]
0.257 Sv
Neutrons in thermal column N.A. Single dose of 0.032 250 kV X-rays N.A. Whole body Female white Swiss mice 30 weeks 15 [172]
0.257 Sv
Thermal column (g-rays) N.A. Single dose 250 kV X-rays 0.064 Gy/ Whole body 68 week old male/female RF mice 20 months 8 [173]
min
0.0250.05 eV thermal neutrons N.A. Single dose of 4.428.89 Gy N.A. N.A. Head 1012 week old male Fischer rats 1 year N.A. [96]
(+ g-rays, fast neutrons and heavy
ions)
Fission neutrons
0.3 MeV neutrons (1 cGy g-rays per 1 1081 1010 Single dose of 1 109 1.2 MeV X-rays N.A. Eye <10 week old French silver rabbits >9 months N.A. [161]
109 neutrons/cm2) neutrons/cm2/ 1 1012 neutrons/cm2
min
<0.3 MeV neutrons N.A. Single dose of 3.2  1010 1.2 MeV X-rays N.A. Head Pigmented rabbits <18 months 9 [170]
neutrons/cm2
Neutrons N.A. Single dose of 0.453.6 Gy 230 kV X-rays 0.14 Gy/ Whole body 612 week old male/female LAF1 mice <40 months 23 [71]
min
Neutrons N.A. Single dose of 0.453.6 Gy 60
Co g-rays N.A. Whole body 612 week old male/female LAF1 mice <40 months 2>4 [71]
Neutrons (<0.7 MeV at peak) N.A. Single dose of 1.75 Gy 200 kV or 0.33 or Whole body or 2.53.5 month old albino Swiss mice 1215 5.0 [139]
250 kV X-rays 0.5 Gy/ head months
min
Fission neutrons (Wilson shot) N.A. Single dose of 3.66 or 4.1 Gy N.A. N.A. Whole body Monkeys 669 days N.A. [174]
Fission neutrons (Fizeau shot) N.A. Single dose of 1.83 or N.A. N.A. Whole body Monkeys 580 days N.A. [174]
4.96 Gy
0.7 MeV neutrons N.A. Single dose of 16.33 Gy 2.5 MeV N.A. Whole body 23 year old goat 43 months N.A. [136]
g-rays
N.A. N.A. N.A. 60
Co g-rays N.A. Whole body 1620 month old female yearling 9 years N.A. [137]
Hereford cattle

273
(continued on next page)
 274
Table 4 (Continued)
Test radiation Reference radiation Irradiation Subjects and age at irradiation Follow up RBE References
after
irradiation
Type Dose rate Dose Type Dose rate

Fission neutrons and g-rays (8:1) N.A. Single dose of 2.14.5 Gy N.A. N.A. Whole body 3 year old Guernsey and Holstein- 3 years N.A. (2?) [137]
(3.5 Gy on average) Friesian cattle
Bomb radiation (neutrons and g-rays N.A. Single dose of 0.158.5 Gy N.A. N.A. Whole body 4 month old swine 11 years N.A. [137]
) (+ X-rays with a 4-month interval)
60 182
N.A. N.A. N.A. Co or Ta 0.25 Gy/ Whole body 4.5 month or 2.55 year old burros 19 years N.A. [137]
g-rays week
(60Co)
Bomb radiation (neutrons and N.A. Single dose of 2.35.1 Gy N.A. N.A. Whole body 4 year old burros 13 years N.A. [137]
g-rays)
Fission neutrons and g-rays N.A. Single dose of 0.15 Gy N.A. N.A. Whole body 7.5 year old burros 7.5 years N.A. [137]
0.85 MeV neutrons (72 keV/mm) N.A. Single dose of 1.252.25 Gy 250 kVp X- 0.7 Eye 6572 day old male Sprague-Dawley 5161 2.2 [85]
rays 0.8 Gy/ rats weeks (>0.31 Gy)
min
12

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

(<0.31 Gy)
Deuterons
22 MeV deuterons N.A. Single dose of 10330 Gy N.A. N.A. Eye Black mice N.A. N.A. [99]
(microbeams of 25, 75 or 1000 mm in
diameter)
Heavy ions
Oxygen ions (250 MeV/amu) N.A. Single dose of 10.9, 15.15 and N.A. N.A. N.A. Rhesus monkey 10 months N.A. [175]
15.5 Gy
570 MeV argon ions (400500 keV/ Several Gy/min Single dose of 3.510 Gy N.A. N.A. Whole body Male C57/bl6  CBA (LAF1) mice 46 months N.A. [129]
mm)
570 MeV argon ions (400500 keV/ Several Gy/min Single dose of 0.11 Gy N.A. N.A. Head Male C57/bl6  CBA (LAF1) mice 23 months N.A. [129]
mm)
600 MeV iron ions 0.11 cGy/min Single dose of 0.050.2 Gy N.A. N.A. Upper body 70140 day old female C57/bl6  BALB/ 340 5 [129]
c (B6CF1) mice 390 days
570 MeV argon ions (400500 keV/ Several Gy/min Single dose of 0.41.6 Gy N.A. N.A. Upper body 70140 day old female C57/bl6  BALB/ 340 N.A. [129]
mm) c (B6CF1) mice 390 days
470 MeV neon ions Several Gy/min Single dose of 0.20.8 Gy N.A. N.A. Upper body 70140 day old female C57/bl6  BALB/ 340 N.A. [129]
c (B6CF1) mice 390 days
920 MeV helium ions 1.5 Gy/min Single dose of 0.43.2 Gy N.A. N.A. Upper body 70140 day old female C57/bl6  BALB/ 340 N.A. [129]
c (B6CF1) mice 390 days
570 MeV argon ions (100 keV/mm) Several Gy/min Single dose of 0.050.9 Gy 220 keV X- N.A. Upper body or 100140 day old male BALB/c  C57/ 350 35 [129]
rays head bl6 (CB6F1) mice 400 days
470 MeV neon ions (30 keV/mm) Several Gy/min Single dose of 0.050.9 Gy 220 keV X- N.A. Upper body or 100140 day old male BALB/c  C57/ 350 <3<5 [129]
rays head bl6 (CB6F1) mice 400 days
400 MeV carbon ions (10 keV/mm) Several Gy/min Single dose of 0.050.9 Gy 220 keV X- N.A. Upper body or 100140 day old male BALB/c  C57/ 350 12 [129]
rays head bl6 (CB6F1) mice 400 days
225 MeV carbon ions Several Gy/min Single dose of 0.11.2 Gy 60
Co g-rays N.A. Upper body or 100140 day old male BALB/c  C57/ 13 months 3.5 [129]
or in 24 weekly fractions head bl6 (CB6F1) mice
Neon ions (365 MeV/amu, N.A. Single dose of 515 Gy 60
Co g-rays N.A. Eyes 6 week old NZW rabbits <5 years 2.072.22 [105]
35  3 keV/mm) (0.3 keV/mm)
Argon ions (530 MeV/amu, N.A. Single dose of 2.811.4 Gy 60
Co g-rays N.A. Eyes 6 week old NZW rabbits <5 years 3.283.61 [105]
90  5 keV/mm) (0.3 keV/mm)
Carbon ions (400 MeV/amu, 10 keV/ 0.52 cGy/min Single dose of 0.050.9 Gy 225 kVp X- 108 or Head and 1215 week old BALB/c  C57/bl6 21 months 12 [135]
mm) rays 997 cGy/ upper thorax (CB6F1) mice
min
Neon ions (425 MeV/amu, 30 keV/ 0.52 cGy/min Single dose of 0.050.9 Gy 225 kVp X- 108 or Head and 1215 week old BALB/c  C57/bl6 21 months 1.53 [135]
mm) rays 997 cGy/ upper thorax (CB6F1) mice
min

(continued on next page)

Argon ions (570 MeV/amu, 100 keV/ 0.52 cGy/min Single dose of 0.050.9 Gy 225 kVp X- 108 or Head and 1215 week old BALB/c  C57/bl6 21 months 35 [135]
mm) rays 997 cGy/ upper thorax (CB6F1) mice
min
Carbon ions (225 MeV/amu, 70 0.11 Gy/min Single dose of 0.41.2 Gy 60
Co g-rays N.A. Head and 80130 day old Balb/c  C57/BL6 560 days N.A. [118]
80 keV/mm) or in 24 weekly fractions (0.3 keV/mm) upper thorax (CB6F1) mice
Carbon ions (400 MeV/amu, 10 keV/ 0.52 Gy/min Single dose of 0.050.9 Gy 225 kVp X- 0.52 Gy/ Upper body 80130 day old Balb/c  C57/BL6 21 months 12 [118]
mm) rays min (CB6F1) mice
Neon ions (425 MeV/amu, 30 keV/ 0.52 Gy/min Single dose of 0.050.9 Gy 225 kVp X- 0.52 Gy/ Upper body 80130 day old Balb/c  C57/BL6 21 months 3 [118]
mm) rays min (CB6F1) mice
Argon ions (570 MeV/amu, 100 keV/ 0.52 Gy/min Single dose of 0.050.9 Gy 225 kVp X- 0.52 Gy/ Upper body 80130 day old Balb/c  C57/BL6 21 months 5 [118]
mm) rays min (CB6F1) mice
Neon ions (425 MeV/amu, 30 keV/ 310 Gy/min Single dose of 9 Gy N.A. N.A. Head and 8 week, 6 month, 3.9 year and 5.3 year 300 days N.A. [118]
mm) upper thorax old NZW rabbits
Neon ions (425 MeV/amu, 30 keV/ 310 Gy/min Single dose of 9 Gy N.A. N.A. Head and 8 week, 6 month, 3.9 year and 5.3 year 900 days N.A. [119]
mm) upper thorax old NZW rabbits
Neon ions (400 MeV/amu, 510 Gy/min Single dose of 9 Gy N.A. N.A. Head and 9 week, 6 month, 1.5 year, 3.9 year and 1400 days N.A. [120]
32  3 keV/mm) upper thorax 5.3 year old NZW rabbits
Neon ions (33  4 keV/mm) N.A. Single dose of 9 Gy N.A. N.A. Head and 8 week, 1 year, 4.5 year old NZW rabbits 1200 days N.A. [121]
upper thorax
Iron ions (460 MeV/amu, 1.53.5 Gy/min Single dose of 0.55 Gy N.A. N.A. Head and 9 week old NZW rabbits 9 months 46 [120]

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

223  31 keV/mm) upper thorax
Iron ions (460 MeV/amu, N.A. Single dose of 0.055 Gy N.A. N.A. N.A. 89 week old NZW rabbits <1500 days N.A. [166]
223  31 keV/mm)
Iron ions (460 MeV/amu, N.A. Single dose of 0.52 Gy X-rays N.A. Head 810 week old NZW rabbits 7 years 4.5 [76]
223  31 keV/mm)
Iron ions (460 MeV/amu, N.A. Single dose of 0.055 Gy 60
Co g-rays N.A. N.A. 810 week old NZW rabbits <6.5 years 5 [167]
223  31 keV/mm)
Argon ions (570 MeV/amu, 104 keV/ N.A. Single dose of 0.051 Gy 185 kVp X- N.A. Head 4 week old Columbia-Sherman albino 70 weeks 3.540 [102]
mm) rays rats
Argon ions (570 MeV/amu, 104 keV/ N.A. Single dose of 125 cGy 250 kVp X- N.A. Head 4 week old Columbia-Sherman albino 68 weeks N.A. [103]
mm) or in 4 fractions over 12 h rays rats
Iron ions (600 MeV/amu, 173 keV/ N.A. Single dose of 0.051.6 Gy N.A. N.A. Anterior 2/3 of 90110 day old C57-Black/6J  BALB/cJ 16 months >3>30 [103]
mm) the body ANL (B6CF1) mice
e
Argon ions (570 MeV/amu, 88 keV/ N.A. Single dose of 1 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 8 weeks 100200 [100]
mm) rays rats
Argon ions (570 MeV/amu, 88 keV/ N.A. Single dose of 5 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 8 weeks 2040e [100]
mm) rays rats
Argon ions (570 MeV/amu, 88 keV/ N.A. Single dose of 25 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 8 weeks 48e [100]
mm) rays rats
e
Argon ions (570 MeV/amu, 88 keV/ N.A. Single dose of 1 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 35 weeks 50200 [100]
mm) rays rats
e
Argon ions (570 MeV/amu, 88 keV/ N.A. Single dose of 5 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 35 weeks 1040 [100]
mm) rays rats
Argon ions (570 MeV/amu, 88 keV/ N.A. Single dose of 25 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 35 weeks 811e [100]
mm) rays rats
Argon ions (570 MeV/amu, 88 keV/ N.A. Single dose of 1 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 62 weeks 50100e [100]
mm) rays rats
e
Argon ions (570 MeV/amu, 88 keV/ N.A. Single dose of 5 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 62 weeks 1040 [100]
mm) rays rats
Argon ions (570 MeV/amu, 88 keV/ N.A. Single dose of 25 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 62 weeks 48e [100]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 2 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 109 weeks 50100e [131]
mm) rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 5 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 109 weeks 2040 [131]
mm) rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 25 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 109 weeks 48 [131]
mm) rays rats

275
(continued on next page)
 276
Table 4 (Continued)
Test radiation Reference radiation Irradiation Subjects and age at irradiation Follow up RBE References
after
irradiation
Type Dose rate Dose Type Dose rate

Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 50 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 109 weeks 24e [131]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. 250 cGy in 4 fractions over 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 117 weeks N.A. [131]
mm) 12 h rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 1 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 8 weeks 100200 [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 2 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 8 weeks 50100e [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 5 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 8 weeks 2040e [101]
mm) rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 25 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 8 weeks 830 [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 50 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 8 weeks 414e [101]
mm) rays rats

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 1 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 35 weeks 50200e [101]
mm) rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 2 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 35 weeks >20100 [101]
mm) rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 5 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 35 weeks 2040 [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 25 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 35 weeks 830e [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 50 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 35 weeks 414e [101]
mm) rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 1 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 62 weeks 50100 [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 2 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 62 weeks >2050e [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 5 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 62 weeks 2040e [101]
mm) rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 25 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 62 weeks 830 [101]
mm) rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 50 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 62 weeks 414 [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 1 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 117 weeks 100200e [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 2 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 117 weeks 50100e [101]
mm) rays rats
e
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 5 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 117 weeks 2040 [101]
mm) rays rats
Iron ions (450 MeV/amu, 190 keV/ N.A. Single dose of 50 cGy 250 kVp X- N.A. Head 28 day old Columbia-Sherman albino 117 weeks 214e [101]
mm) rays rats
Iron ions (600 MeV/amu, 175 keV/ N.A. Single dose of 5504 cGy or 60Co g-rays N.A. Whole body 1617 week old male CB6F1 mice 3 years N.A. [132]
mm) in 6 fractions over 12 weeks
+/+ +/ /
Iron ions (1 GeV/amu) N.A. Single dose of 32.5 cGy X-rays N.A. One eye ATM , ATM and ATM mice 18 months N.A. [112]
Iron ions (1 GeV/amu, 148 keV/mm) 0.5 Gy/min Single dose of 0.325 Gy 250 kVp X- 0.5 Gy/ Head (ions) or 28 day old ATM+/+ and ATM+/ 35 weeks N.A. [113]
rays min one eye (X- 129 Sv  Black Swiss mice
rays)
Iron ions (1 GeV/amu, 148 keV/mm) 0.5 Gy/min Single dose of 0.325 Gy 250 kVp X- 0.5 Gy/ Head (ions) or 28 day old ATM+/+ 129 Sv  Black Swiss 60 weeks 515 [114]
rays min one eye (X- mice
rays)

(continued on next page)

Iron ions (1 GeV/amu, 148 keV/mm) 0.5 Gy/min Single dose of 0.325 Gy 250 kVp X- 0.5 Gy/ Head (ions) or 28 day old ATM+/ 129 Sv  Black Swiss 60 weeks 524 [114]
rays min one eye (X- mice
rays)
Iron ions (600 MeV/amu, 181 keV/ N.A. Single dose of 1 Gy N.A. N.A. Eye 56 day old Sprague-Dawley rats <750 days N.A. [108]
mm)
Iron ions (600 MeV/amu, 181 keV/ N.A. Single dose of 2 Gy N.A. N.A. Eye 56 day or 1 year old Sprague-Dawley <650 days N.A. [122]
mm) rats
Iron ions (600 MeV/amu, 190 keV/ N.A. Single dose of 0.12 Gy 250 kVp X- 0.7 Eye 6572 day old male Sprague-Dawley 87 weeks 1.4 [85]
mm) rays 0.8 Gy/ rats ( > 0.74 Gy)
min 7.4
(<0.74 Gy)
Iron ions (1 GeV/amu, 150 keV/mm) 1 Gy/min Single dose of 0.5 Gy N.A. N.A. Whole body Male CBA/JCR HSD mice 2 years N.A. [124]
Helium ions (4 GeV/amu, 0.82 keV/ 1.5 cGy/sec Single dose of 0.54 Gy 60
Co g-rays 6 cGy/sec Whole body 1416 g male/female CBA  C57BL6 F1 67 weeks 1.42.6 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 3 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 31 weeks 16.733.3 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 5 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 31 weeks 1020 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 10 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 31 weeks 10 [77]
mm) (0.25 keV/mm) mice

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 15 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 31 weeks 13.3 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 20 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 31 weeks 2.510 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 25 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 31 weeks 8 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 50 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 31 weeks 24 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 5 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 43 weeks 1020 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 15 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 43 weeks 13.340 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 25 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 43 weeks 24 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 50 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 43 weeks 4 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 3 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 50 weeks 16.766.7 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 5 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 50 weeks 10 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 10 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 50 weeks 520 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 15 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 50 weeks 3.326.7 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 20 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 50 weeks 2.510 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 25 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 50 weeks 28 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 50 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 50 weeks 14 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 10 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 64 weeks 1020 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 15 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 64 weeks 6.713.3 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 20 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 64 weeks 510 [77]
mm) (0.25 keV/mm) mice
Carbon ions (300 MeV/amu, 12 keV/ 4 mGy/sec Single dose of 25 cGy 60
Co g-rays 6 cGy/sec Head 1416 g male/female CBA  C57BL6 F1 64 weeks 48 [77]
mm) (0.25 keV/mm) mice
4 mGy/sec Single dose of 50 cGy 6 cGy/sec Head 64 weeks 24 [77]

277
(continued on next page)
 278
Table 4 (Continued)
Test radiation Reference radiation Irradiation Subjects and age at irradiation Follow up RBE References
after
irradiation
Type Dose rate Dose Type Dose rate

Carbon ions (300 MeV/amu, 12 keV/ 60

Co g-rays 1416 g male/female CBA  C57BL6 F1
mm) (0.25 keV/mm) mice

Abbreaviations: amu, atomic mass unit; LET, linear energy transfer; N.A., not available; NZW, New Zealand white; RBE, relative biological effectiveness.
For simplicity, 1 rep and 1 r were treated as 0.01 Gy and 1 rem as 0.01 Sv. Kinetic energy is expressed in MeV/amu. LET is expressed in keV/mm.
a
The numer shown in the left hand side is RBE for stage 1 cataracts and that in the right is RBE for stage 2 cataracts.
b
Posterior opacity.
c
Anterior opacity.
d
RBE values at the 80% condence level (at 30 weeks postirradiation for 2 mGy and 10 mGy, at 62 weeks postirradiation for 50 mGy, and independently of postirradiation time for 250 mGy).
e
90% condence intervals.

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

Table 5
Biological studies reporting the effects of high-LET radiation on the lens with endpoints other than opacication.

Test radiation Reference radiation Irradiation Subjects and age at irradiation Endpoints Follow up RBE References
after
irradiation
Type Dose Dose Type Dose rate
rate
Protons
250 MeV protons (0.4 keV/ N.A. Single dose of N.A. N.A. Anterior 2/3 90110 day old female C57-Black/ Mitosis, FN, MN, MR 64 weeks N.A. [176]
mm) 0.13.2 Gy of the body 6J  BALB/cJ ANL (B6CF) mice disorganization, focal
stratication
250 MeV protons N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MN 64 weeks 1.11 [78]
(0.42 keV/mm) 0.13.2 Gy of the body cJ/Anl (B6CF1/Anl) mice
250 MeV protons N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MR disorganization 64 weeks 1.01 [78]
(0.42 keV/mm) 0.13.2 Gy of the body cJ/Anl (B6CF1/Anl) mice
Protons (55 MeV/amu, 14 Gy/ Single dose of 150 kVp X-rays 14 Gy/ Cell Nonimmportalized human diplod LEC CDKN1A, CDK1, Cyclin G1, 8 hours N.A. [79]
1.18 keV/mm) min 4 Gy min monolayer from 18 week prenatal lens and LFC CHK2
Protons (55 MeV/amu) N.A. Single dose of N.A. N.A. Cell Nonimmportalized human diplod LEC MMP-2, MMP-3, MMP-9, 12 hours N.A. [80]
0.54 Gy monolayer from 18 week prenatal lens and LFC TIMP1
Neutrons
Fast neutrons
4 MeV neutrons (Emax 4.87.2 Single dose of 200 kVp X-rays 31 cGy/ Head 2.53.5 month old male/female albino Histological change 15 months 5 [92]
13.5 MeV) (715% g-rays) cGy/min 2.5 Gy min Swiss mice
Neutrons (10% g-rays), 0.07 Gy/ Single dose of 250 kVp X-rays 0.8 Gy/ Head 2.53.5 month old albino Swiss mice Mitotic counts 13 months N.A. [127]
180 min 12 Gy min
14 MeV neutrons (15% 0.1 Gy/ Single dose of Co g-rays
60
8 cGy/min Whole body 67 week old female Wistar rats Morphological damage 24 hours N.A. [83]
g-rays) min 0.1 and 1 Gy

(continued on next page)

 Fission neutrons
0.8 MeV neutrons (4% N.A. Single dose of 250 kVp X-rays 1.6 Gy/min Head 23 month old female BCF1 mice DNA synthesis in PZ after 4 weeks 7.5 [93]
g-rays) 2 Gy wounding
0.8 MeV neutrons (4% N.A. 2 Gy in 4 250 kVp X-rays 1.6 Gy/min Head 23 month old female BCF1 mice DNA synthesis in PZ after 4 weeks 25 [93]
g-rays) weekly wounding
fractions
0.85 MeV neutrons N.A. Single dose of 250 kVp X-rays 0.7 Head 2.5 month old male Sprague-Dawley rats Mitotic abormality after 328 days 3.6 [89]
(70 keV/mm) 1.252.25 Gy 0.8 Gy/ wounding 16
min
Thermal neutrons
Thermal neutrons 0.3 Gy/ Single dose of N.A. N.A. N.A. Male C57BL/6 mice Histopathological changes 45 days N.A. [97]
min 10 or 33 Gy
Deuterons
190 MeV deuterons N.A. Single dose of 210 kV X-rays 5.90 or Right eye 23 month old male chinchilla rabbits Degenerate cell counts 21 days 3.87 [98]
(4 keV/mm) 1.2520 Gy (3 keV/mm) 2.02 Gy/
min
Heavy ions
380 MeV helium ions N.A. Single dose of 210 kV X-rays 5.90 or Right eye 23 month old male chinchilla rabbits Degenerate cell counts 21 days 4.08 [98]
(23 keV/mm) 1.2520 Gy (3 keV/mm) 2.02 Gy/
min

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

380 MeV helium ions N.A. Single dose of 210 kV X-rays 5.90 or Right eye 23 month old male chinchilla rabbits Mitotic counts 21 days 2.46 [98]
(23 keV/mm) 1.2520 Gy (3 keV/mm) 2.02 Gy/
min
380 MeV helium ions N.A. Single dose of 190 MeV N.A. Right eye 23 month old male chinchilla rabbits Mitotic counts 21 days 1 [98]
(23 keV/mm) 1.2520 Gy deuterons
(4 keV/mm)
Argon ions (570 MeV/amu, N.A. Single dose of 185 kVp X-rays N.A. Head 4 week old Columbia-Sherman albino FN in MR 7 days 3.5 [104]
104 keV/mm) 1 Gy rats
Argon ions (570 MeV/amu, N.A. Single dose of 185 kVp X-rays N.A. Head 4 week old Columbia-Sherman albino MR disorganization 67 weeks 8 [104]
104 keV/mm) 1 Gy rats
Iron ions (600 MeV/amu, N.A. Single dose of N.A. N.A. Anterior 2/3 90110 day old C57-Black/6J  BALB/cJ Mitosis, FN, MN, MR 16 months N.A. [103]
173 keV/mm) 0.051.6 Gy of the body ANL (B6CF1) mice disorganization, focal
stratication
Neon ions (670 MeV/amu, N.A. Single dose of N.A. N.A. Anterior 2/3 90110 day old female C57-Black/ Mitosis, FN, MN, MR 64 weeks N.A. [176]
25 keV/mm) 10160 cGy of the body 6J  BALB/cJ ANL (B6CF) mice disorganization, focal
stratication
Iron ions (600 MeV/amu, N.A. Single dose of N.A. N.A. Anterior 2/3 90110 day old female C57-Black/ Mitosis, FN, MN, MR 64 weeks N.A. [176]
193 keV/mm) 10160 cGy of the body 6J  BALB/cJ ANL (B6CF) mice disorganization, focal
stratication
Iron ions (350 MeV/amu, N.A. Single dose of N.A. N.A. Anterior 2/3 90110 day old female C57-Black/ Mitosis, FN, MN, MR 64 weeks N.A. [176]
219 keV/mm) 10160 cGy of the body 6J  BALB/cJ ANL (B6CF) mice disorganization, focal
stratication
Niobium ions (600 MeV/ N.A. Single dose of N.A. N.A. Anterior 2/3 90110 day old female C57-Black/ Mitosis, FN, MN, MR 64 weeks N.A. [176]
amu, 464 keV/mm) 10160 cGy of the body 6J  BALB/cJ ANL (B6CF) mice disorganization, focal
stratication
Lanthanum ions N.A. Single dose of N.A. N.A. Anterior 2/3 90110 day old female C57-Black/ Mitosis, FN, MN, MR 64 weeks N.A. [176]
(593 MeV/amu, 953 keV/ 10160 cGy of the body 6J  BALB/cJ ANL (B6CF) mice disorganization, focal
mm) stratication
Neon ions (670 MeV/amu, N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MN 64 weeks 2.00 [78]
25 keV/mm) 10320 cGy of the body cJ/Anl (B6CF1/Anl) mice
Iron ions (600 MeV/amu, N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MN 64 weeks 2.75 [78]
193 keV/mm) 10320 cGy of the body cJ/Anl (B6CF1/Anl) mice
Niobium ions (600 MeV/ N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MN 64 weeks 2.47 [78]
amu, 464 keV/mm) 10320 cGy of the body cJ/Anl (B6CF1/Anl) mice
Lanthanum ions N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MN 64 weeks 1.71 [78]
(593 MeV/amu, 953 keV/ 10320 cGy of the body cJ/Anl (B6CF1/Anl) mice
mm)

279
(continued on next page)
 280
Table 5 (Continued)
Test radiation Reference radiation Irradiation Subjects and age at irradiation Endpoints Follow up RBE References
after
irradiation
Type Dose Dose Type Dose rate
rate
Neon ions (670 MeV/amu, N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MR disorganization 64 weeks 2.36 [78]
25 keV/mm) 10320 cGy of the body cJ/Anl (B6CF1/Anl) mice
Iron ions (600 MeV/amu, N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MR disorganization 64 weeks 3.35 [78]
193 keV/mm) 10320 cGy of the body cJ/Anl (B6CF1/Anl) mice
Niobium ions (600 MeV/ N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MR disorganization 64 weeks 2.95 [78]
amu, 464 keV/mm) 10320 cGy of the body cJ/Anl (B6CF1/Anl) mice
Lanthanum ions N.A. Single dose of Co g-rays
60
N.A. Anterior 2/3 90110 day old female C57Bl/6J  BALB/ MR disorganization 64 weeks 2.00 [78]
(593 MeV/amu, 953 keV/ 10320 cGy of the body cJ/Anl (B6CF1/Anl) mice
mm)
Iron ions (600 MeV/amu, 0.5 Single dose of 250 kVp X-rays 0.7 Head and 2.5 month old male Sprague-Dawley rats Mitotic abormality after 328 days 210 [89]
190 keV/mm) 1 Gy/ 0.53 Gy 0.8 Gy/ neck wounding
min min
Oxygen ions (8.7 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound 1030 minb 0.106 [106]

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

mma, 285 keV/mm) monolayer from 10 year old donor DNA)
Oxygen ions (8.7 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DSB (measured by the neutral 1030 minb 0.5 [106]
mma, 285 keV/mm) monolayer from 10 year old donor elution)
Oxygen ions (3.5 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound 1030 minb 0.038 [106]
mma, 524 keV/mm) monolayer from 10 year old donor DNA)
b
Argon ions (19.3 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound 1030 min 0.2 [106]
mma, 790 keV/mm) monolayer from 10 year old donor DNA)
Krypton ions (18.0 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound 1030 minb 0.11 [106]
mma, 3040 keV/mm) monolayer from 10 year old donor DNA)
Xenon ions (16.5 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound 1030 minb 0.1 [106]
mma, 6200 keV/mm) monolayer from 10 year old donor DNA)
b
Xenon ions (10.1 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound 1030 min 0.05 [106]
mma, 7200 keV/mm) monolayer from 10 year old donor DNA)
Xenon ions (5.4 MeV/mma , N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound 1030 min b
0.023 [106]
8800 keV/mm) monolayer from 10 year old donor DNA)
Uranium ions (1.5 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound 1030 minb 0.008 [106]
mma, 14200 keV/mm) monolayer from 10 year old donor DNA)
Uranium ions (4.1 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound 1030 minb 0.016 [106]
mma, 16200 keV/mm) monolayer from 10 year old donor DNA)
c
Oxygen ions (8.7 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A. 0.124 [107]
amu, 285 keV/mm) monolayer from 10 year old donor DNA)
Oxygen ions (3.4 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.044 [107]
amu, 524 keV/mm) monolayer from 10 year old donor DNA)
Argon ions (19.3 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.221 [107]
amu, 790 keV/mm) monolayer from 10 year old donor DNA)
c
Argon ions (10.5 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A. 0.132 [107]
amu, 1150 keV/mm) monolayer from 10 year old donor DNA)
c
Argon ions (6.1 MeV/amu, N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A. 0.058 [107]
1620 keV/mm) monolayer from 10 year old donor DNA)
Argon ions (2.7 MeV/amu, N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.042 [107]
2200 keV/mm) monolayer from 10 year old donor DNA)
Titanium ions (14.3 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.139 [107]
amu, 1440 keV/mm) monolayer from 10 year old donor DNA)
c
Titanium ions (5.6 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A. 0.061 [107]
amu, 2360 keV/mm) monolayer from 10 year old donor DNA)
Titanium ions (4.8 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.048 [107]
amu, 2500 keV/mm) monolayer from 10 year old donor DNA)

(continued on next page)

 Germanium ions N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.111 [107]
(10.1 MeV/amu, 3400 keV/ monolayer from 10 year old donor DNA)
mm)
Krypton ions (18.0 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.117 [107]
amu, 3050 keV/mm) monolayer from 10 year old donor DNA)
Xenon ions (16.5 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.094 [107]
amu, 6200 keV/mm) monolayer from 10 year old donor DNA)
c
Xenon ions (10.1 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A. 0.054 [107]
amu, 7200 keV/mm) monolayer from 10 year old donor DNA)
c
Xenon ions (5.4 MeV/amu, N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A. 0.026 [107]
8800 keV/mm) monolayer from 10 year old donor DNA)
Lanthanum ions N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.071 [107]
(10.1 MeV/amu, 8400 keV/ monolayer from 10 year old donor DNA)
mm)
Lead ions (15.4 MeV/amu, N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.108 [107]

N. Hamada, T. Sato / Mutation Research 770 (2016) 262291

14100 keV/mm) monolayer from 10 year old donor DNA)
c
Lead ions (6.8 MeV/amu, N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A. 0.058 [107]
14300 keV/mm) monolayer from 10 year old donor DNA)
Lead ions (3.0 MeV/amu, N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.026 [107]
14500 keV/mm) monolayer from 10 year old donor DNA)
Uranium ions (1.5 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.011 [107]
amu, 14200 keV/mm) monolayer from 10 year old donor DNA)
c
Uranium ions (1.9 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A. 0.008 [107]
amu, 15000 keV/mm) monolayer from 10 year old donor DNA)
Uranium ions (2.6 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.012 [107]
amu, 15700 keV/mm) monolayer from 10 year old donor DNA)
Uranium ions (4.0 MeV/ N.A. N.A. 300 kV X-rays 5 Gy/min Cell B-26 nontransformed bovine diploid LEC DNA damage (alkali unwound N.A.c 0.020 [107]
amu, 16300 keV/mm) monolayer from 10 year old donor DNA)
Iron ions (1 GeV/amu, 14 Gy/ Single dose of 100 kVp X-rays 14 Gy/ Cell Nonimmportalized human diplod LEC CDKN1A 6 hours N.A. [79]
146 keV/mm) min 4 Gy min monolayer from 18 week prenatal lens and LFC
Iron ions (1 GeV/amu) N.A. Single dose of N.A. N.A. Cell Nonimmportalized human diplod LEC MMP-2, MMP-3, MMP-9, 12 hours N.A. [80]
4 Gy monolayer from 18 week prenatal lens and LFC TIMP1

Abbreviations: amu, atomic mass unit; CDK1, cyclin dependent kinase 1; CDKN1A, cyclin dependent kinase inhibitor 1A; CHK2, checkpoint kinase 2; DSB, DNA double strand break; Emax: maximum energy; FN, fragmented nuclei;
LEC, lens epithelial cell; LFC, lens ber cell; LET, linear energy transfer; MMP, matrix metalloproteinase; MN, micronucleation; MR, meridional row; N.A., not available; PZ, peripheral zone; RBE, relative biological effectiveness; TIMP1,
tissue inhibitor of matrix metalloproteinase 1.
For simplicity, 1 rep and 1 r were treated as 0.01 Gy and 1 rem as 0.01 Sv. Kinetic energy is expressed in MeV/amu. LET is expressed in keV/mm.
a
Specic energy was expressed in MeV/mm in the paper, of which unit is generally in Gy. So, it remains unclear whether this is a typo of MeV/amu for kinetic energy.
b
Cells were kept at 12 C from 15 to 45 min before irradiation until cells were lyzed at 1030 min after irradiation.
c
Cells were irradiated on ice.

281
282 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
the dose response curve of high-LET radiation is the same as that
for a low-LET reference radiation (e.g., linear vs linear), RBE is
independent of dose. If different, RBE depends on dose: for
example, RBE decreases with increasing dose if linear for high-LET
and superlinear for low-LET, but it increases with increasing dose if
linear for high-LET and supralinear for low-LET. The onset and
progressive nature of cataracts determine time dependence, such
that RBE is dependent on time for progressive cataracts but
independent of time for stationary cataracts.
Currently, a neutron RBE of 10 has been used in A-bomb studies,
as described in Section 3.5. The dose averaged LET of A-bomb
neutrons in Hiroshima was about 75 keV/mm [84]. Of interest in
this regard is the nding obtained in Sprague-Dawley (SD) rats
that RBE of ssion neutrons (0.85 MeV, 72 keV/mm) relative to 250
kVp X-rays for lens opacication at 5161 weeks postirradiation
was 12 at <0.31 Gy. Such RBE was dose dependent and 2.2 at
>0.31 Gy, because the shape of the dose response curve on a
semi-log plot was linear for neutrons but had two slopes for X-rays
[85].
In BNL-Stoner white Swiss mice, RBEs of fast neutrons (0.43, 1.8
and 14 MeV) relative to 250 kVp X-rays for lens opacication with a
follow up period of 11 months at 0.21040 mGy was found to be
proportional to (1/Dn)1/2, where Dn is the neutron dose [81], in
accordance with the theory of dual radiation action.
In C3H  C57Bl F1 hybrid mice, there was no dose dependence of
RBEs of fast neutrons (400 MeV) and its attenuated beam at 538
cGy relative to 250 kVp X-rays for lens opacication with a follow
up period of 20 months, although the possibility was not ruled out
that RBE might differ at lower dose [86]. It is of interest to note that
such 400 MeV neutron RBEs were 5.8 for the overall period, but 5.2,
5.9, 5.7, 5.3 and 5.2 at 8, 11, 13, 18 and 20 months postirradiation:
RBEs were thus constant as a function of time, suggesting time
independence.
In C57Bl  C3H hybrid mice, RBE of fast neutrons (14 MeV) for
lens opacication relative to 250 kVp X-rays with a follow up
period of 20 months at 0.9538 cGy was found to increase with
decreasing dose [87]. In C3H  C57Bl F1 hybrid mice, RBE of fast
neutrons (1, 5, 15, 400 and 600 MeV and attenuated 400 MeV
beams) at 0.9538 cGy relative to 250 kVp X-rays for lens
opacication with a follow up period of 20 months was also found
to increase with decreasing dose, but appeared to approach similar
values independent of neutron energy [88].
In Columbia-Sherman albino rats, RBE of fast neutrons
(0.44 MeV) at 0.225 cGy relative to 250 kVp X-rays for lens
opacication with a follow up period of 102 weeks was found to
increase with decreasing dose [82]. Such RBEs for 0.2, 1 and 5 cGy
decreased with increasing postirradiation time, but those for 25
cGy did not depend on time.
In SD rats, RBE of ssion neutrons (0.85 MeV, 70 keV/mm) at
1.252.5 Gy relative to 250 kVp X-rays for mitotic abnormality
increased with increasing time during 4 weeks postirradiation
[89].
4.1.4.2. Energy dependence of RBE. In BNL-Stoner white Swiss mice,
RBEs of fast neutrons (0.43, 1.0, 1.5 and 1.8 MeV) at 0.321.55 Gy
relative to 60Co g-rays with a follow up period of 11 months were
7.3, 6.1, 4.6 and 5.6 for stage 1 cataracts, and 8.9, 7.5, 5.2 and 6.6 for
stage 2 cataracts, respectively [90]. Likewise, in C3H  C57Bl F1
hybrid mice, RBEs relative to 250 kVp X-rays with a follow up
period of 20 months tended to decrease with increasing energy of
neutrons in a range between 1 and 600 MeV at 4 cGy, but were
similar (ranged between 24.0 and 41.9 for 1, 5, 15 and 600 MeV
neutrons) at 0.91.6 cGy [88]. These ndings, along with others
[87,91], highlight a tendency not only for general energy dependence
of neutron RBEs, but also for its energy independence at low
dose.
4.1.4.3. Effects on the lens other than opacication. For in vivo
experiments, Wistar rats were irradiated with 0.1 or 1 Gy of fast
neutrons (14 MeV). The lens was removed, which was immediately
xed (within 30 min postirradiation) or incubated until xation at
24 h postirradiation. For in vitro experiments, the lens removed
from Wistar rats was pretreated with 2.4 mM vitamin E, irradiated
with 0.1 or 1 Gy of fast neutrons (14 MeV), and xed immediately or
at 24 h postirradiation. Morphological damage (e.g., formation of
granular ber cells) was electron microscopically detectable in the
lens xed within 30 min postirradiation, which became greater
thereafter. Neutrons were more damaging to the lens than 60Co
g-rays (although RBEs were not estimated), and in vitro irradiation
appeared to be more damaging to the lens than in vivo irradiation.
[83].
In albino Swiss mice, RBE of fast neutrons (4 MeV) relative to
200 kVp X-rays for histological changes with a follow up period of
15 months was about 5 at 2.5 Gy. Histological changes observed
include derangement of the lens bow pattern, abnormal ber
elements in the cortex, undifferentiated cells migrating under the
capsule from the equator toward the posterior pole, and an
accumulation of abnormal cells and debris at the lens poles [92].
BCF1 mice were irradiated with 2 Gy of ssion neutrons
(0.8 MeV), and lenses were mitogenically stimulated from quies-
cence by mechanical wounding, followed by the analysis of DNA
synthesis in the peripheral zone of the lens epithelium. Following
irradiation, the wound response was suppressed at 1 h, and
recovery was evident at 1 week in both the mitogenically quiescent
and the slowly proliferating subpopulations. By 4 weeks, the
quiescent subpopulation showed signicant recovery, but the
slowly proliferating subpopulation had the decreased ability to
respond to neutrons. Fission neutron RBEs relative to 250 kVp X-
rays for such DNA synthesis was 7.5 at 4 weeks postirradiation [93].
Likewise, SD rats were irradiated with 1.252.5 Gy of ssion
neutrons (0.85 MeV, 70 keV/mm), and the lens was stimulated by
wounding, followed by the analysis of mitotic gures. No recovery
was found virtually during 4 weeks postirradiation. Fission
neutron RBEs relative to 250 kVp X-rays for mitotic abnormality
increased with increasing postirradiation time and ranged from 3.6
to 16 during 4 weeks [89].
4.1.4.4. Boron neutron capture therapy (BNCT). BNCT utilizes the
preferential uptake of boron compound in tumor and the 10B(n,
a)7Li reaction, where 10B capturing thermal neutrons produces a
and 7Li, both of which are high-LET and have a short range of about
one cell diameter. Clinically used typical 10B carriers are sodium
borocaptate (BSH) and boronophenylalanine (BPA). Boron uptake
by normal human ocular tissues was much lower than that by
ocular melanoma (e.g., the lens/melanoma ratio of boron
concentration was about 12%) [94]. BNCT should thus be able to
destroy a supercial ocular melanoma like iris melanoma, but a
typical brain tumor BNCT gives the human lens the average
absorbed dose of 1.07 Gy [95]. Thermal neutron (0.0250.05 eV)
irradiation of Fischer rats treated with saline, BSH, BPA and
BSH + BPA, leading to eye dose of 4.42, 7.84, 8.89 and 8.02 Gy
respectively, similarly induced lens opacication in about 80% of
irradiated animals within a year postirradiation [96]. Irradiation of
C57BL/6 mice with 33 Gy of thermal neutrons induced swelling,
vacuolation and granular changes in LECs and LFCs at 45 days
postirradiation, which were not affected by pretreatment with BSH
or BPA [97].
4.1.5. Deuterons
In chinchilla rabbits, the RBE of 190 MeV deuterons (4 keV/mm)
relative to 210 kV X-rays (3 keV/mm) for degenerate cell counts in
the lens epithelium was 3.87 (weighted average) at 1.2520 Gy at
 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
221 days postirradiation, during which time RBE ranged between
2.59 and 9.72 and peaked at 4 days postirradiation [98].
Eyes of black mice were targeted with 10330 Gy of 22 MeV
deuterons. At 10 Gy, many ne opacities induced with the 1 mm
diameter microbeam developed, but a very few point opacities
induced by the 25 or 75 mm diameter microbeams did not progress
[99]. The data for temporal kinetics were not reported, and a
comparison with photons was not made.
4.1.6. Heavy ions
The lens effects have been studied in rabbits, rodents and
monkeys in vivo as well as in human and bovine LECs in vitro. High
RBEs exceeding 100 have been reported [100,101].
4.1.6.1. Dependence of RBE on dose and time. In Columbia-Sherman
albino rats, RBE of argon ions (570 MeV/amu, 104 keV/mm) relative
to 185 kVp X-rays for lens opacication at 0.051 Gy with a follow
up of 70 weeks was described as (k/Dh)1/2, where k is constant and
Dh is the heavy ion dose in Gy, reminiscent of (1/Dn)1/2 for neutrons
(Section 4.1.4.1). Specically, k was 64 for argon ions [102].
Likewise, RBE of argon ions (570 MeV/amu, 88 keV/mm) at 0.01
0.25 Gy relative to 250 kVp X-rays for lens opacication with a
follow up of 62 weeks was described again as (k/Dh)1/2 where k was
25 [100], and was independent of postirradiation time (similar
RBEs observed at 8, 35 and 62 weeks). Interestingly, MR
disorganization presaged cataracts, and the dose response curve
for MR disorganization and MN, but not nuclear fragmentation,
resembled that for cataracts [103]. RBE for MR disorganization at
0.011 Gy with a follow up of 67 weeks increased with decreasing
dose, which was comparable to that for cataractogenesis [104].
In New Zealand white (NZW) rabbits (Oryctolagus cuniculus),
RBEs of neon ions (365 MeV/amu, 35 keV/mm) at 515 Gy or argon
ions (530 MeV/amu, 90 keV/mm) at 2.811.4 Gy relative to 60Co
g-rays with a follow up period of 5 years increased with
postirradiation time (e.g., RBE was 1530% higher at 3 years
postirradiation compared with 1 year postirradiation) [105].
In SD rats, RBE of iron ions (600 MeV/amu, 190 keV/mm) at 0.5
3 Gy relative to 250 kVp X-rays for mitotic abnormality increased
(almost linearly) with increasing postirradiation time, and ranged
from 2 to 10 during 4 weeks postirradiation [89]. This was because
the effect of a functional, slowly occurring recovery mechanism for
potential mitotic abnormality was demonstrated after X-irradia-
tion but not after iron ion irradiation.
In chinchilla rabbits, weighted average of RBE of 380 MeV
helium ions (23 keV/mm) at 1.2520 Gy relative to 210 kV X-rays
(3 keV/mm) for degenerate cell counts in the lens epithelium was
4.081 at 221 days postirradiation. Such RBE ranged between 2.34
and 15.12 and peaked at 4 days postirradiation. Interestingly, RBE
of 380 MeV helium ions (23 keV/mm) for mitotic counts was 2.46
relative to 210 kV X-rays (3 keV/mm), but was 1 relative to 190 MeV
deuterons (4 keV/mm) [98]. High RBE of low LET high energy
helium ions is also interesting: in CBA  C57BL6 F1 mice, RBE of
helium ions (4 GeV/amu, 0.82 keV/mm) at 0.54 Gy relative to 60Co
g-rays for lens opacication with a follow up period of 67 weeks
was 1.42.6 [77].
4.1.6.2. LET dependence of RBE. Only one study has provided the
systematic data for LET dependence of RBE. In B6CF1/Anl mice,
RBEs of neon (670 MeV/amu, 25 keV/mm), iron (600 MeV/amu,
193 keV/mm), niobium (600 MeV/amu, 464 keV/mm) and
lanthanum ions (593 MeV/amu, 953 keV/mm) relative to 60Co
g-rays at 0.13.2 Gy at 64 weeks postirradiation were 2.00, 2.75,
2.47 and 1.71 for MN, and 2.36, 3.35, 2.95 and 2.00 for MR
disorganization, respectively [78]. This suggests a trend toward
increased RBE until LET of 200 keV/mm and decreased RBE
thereafter.
283
4.1.6.3. Effects on the lens other than opacication. The rate of the
alkali unwinding was used as an endpoint to evaluate induction of
DNA strand breaks in bovine LECs by a variety of heavy ions
(oxygen, argon, krypton, xenon and uranium ions) with LET
ranging from 280 to 16,200 keV/mm. RBEs of heavy ions relative to
300 kV X-rays for such DNA strand break induction ranged
between 0.008 and 0.2 independent of LET. At >800 keV/mm, the
number of DNA strand breaks induced per particle increased with
increasing kinetic energy (i.e., which is expressed in MeV/amu) and
the atomic number of the projectile. The ratio of DNA single strand
breaks (SSBs) to DNA double strand breaks (DSBs) was <1.9 for
oxygen ions (285 keV/mm), but was 20 for X-rays, indicating that
oxygen ions produce >10 times more DSBs/SSB than X-rays. Most
DNA strand breaks (90%) induced by radiation with LET of
<10,000 keV/mm were repaired within a day postirradiation,
whilst repair of DNA damage induced by heavy ions was slower and
less complete than that by X-rays. No signicant repair was
observed at >10,000 keV/mm [106]. Later, similar experiments
were conducted in bovine LECs, but by using the greater number of
ion species (oxygen, argon, titanium, germanium, krypton, xenon,
lanthanum, lead and uranium) with LET ranging from 285 to
16,300 keV/mm. Again, RBEs of heavy ions relative to 300 kV X-rays
for such DNA strand break induction ranged between 0.011 and
0.221 independent of LET, and no signicant repair was observed at
LET of >10,000 keV/mm [107].
In human LECs and LFCs, CDKN1A was upregulated at 6 h after
irradiation with 4 Gy of iron ions (1 GeV/amu, 146 keV/mm), and its
distribution of relative in situ uorescence intensity was signi-
cantly different from that after irradiation with 4 Gy of X-rays [79].
In human LECs, TIMP1 was downregulated while expression of
MMP-2, 3 and 9 did not change at 8 h after irradiation with 4 Gy of
iron ions (1 GeV/amu, 146 keV/mm) [80].
4.1.6.4. Gender difference. The data for gender difference are also
limited. Following irradiation of SD rats with 1 Gy of high-LET iron
ions (600 MeV), males had lower incidence and slower progression
of lens opacication than females [108]. Following 10 Gy of 60Co
g-rays, males had higher incidence with no gender difference in
progression [109]. Estrogen enhanced iron ion cataractogenesis,
unlike the case for g-ray cataractogenesis [110].
4.1.6.5. Genetic susceptibility. There is mounting evidence for
genetic susceptibility to low-LET cataractogenesis [111], and the
enhanced sensitivity to high-LET cataractogenesis resulting from
haploinsufciency for ataxia telangiectasia mutated (ATM) has
been reported in mice. Following irradiation with 0.325 Gy of iron
ions (1 GeV/amu, 148 keV/mm), VICs appeared earlier in ATM
heterozygous mice than wild-type counterparts and both onset
and progression of cataracts were accelerated in ATM
heterozygotes [112,113], for which RBE may be higher than that
for wild-types (ranged form 524 for ATM heterozygotes vs 515
for wild-types depending on cataract grades) [114]. Intriguingly,
the preliminary analysis of A-bomb survivors participating in the
Adult Health Study has found a signicant increase in cataract
surgery prevalence in all minor homozygotes of three ATM
haplotypes [115]. The companion article in this issue further
deals with the genetic susceptibility issue [116].
4.1.7. Age dependence
Within 2 years after irradiation with 60150 N of fast neutrons
(68 MeV), no opacities were observed in adult dogs (aged 1 year at
the time of irradiation), but in puppies and young dogs (aged
82 days and 56 months at the time of irradiation, respectively),
transient vacuoles that started to appear 38 weeks postirradia-
tion all disappeared within 5 months [117].
284 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
At the age of 8 weeks, 6 months, 3.9 years and 5.3 years, NZW
rabbits were irradiated with 9 Gy of neon ions (425 MeV/amu,
30 keV/mm), at 1400 days after which lenses were assessed for
opacication [118121]. At 300 days postirradiation, the younger
the age at the time of irradiation, the earlier the onset of early and
intermediate levels of opacication, the lower the level of
stationary cataracts. At 800 days, however, the onset and
progression of late cataractogenesis and blindness were most
rapid in the oldest group.
At the age of 56 days or 1 year, SD rats were irradiated with 2 Gy
of iron ions (600 MeV/amu, 181 keV/mm) or 10 Gy of 60Co g-rays,
and observed for lens opacication up to 650 days thereafter
[122,123]. Older rats had faster progression, a shorter latent period
and higher incidence after iron ion irradiation, but had faster
progression, a longer latent period and lower incidence after
g-irradiation.
4.1.8. Radioprotective agents
Two papers have reported agents that potentially mitigate
damaging effects of high-LET radiation on the lens, when rodents
are treated before (along with or without treatment after)
irradiation [83,124].
For in vitro experiments, Wistar rats were pretreated for 4 days
with 100 units/day of vitamin E (D-a-tocopherol), and then
irradiated with 1 Gy of fast neutrons (14 MeV). Following irradia-
tion, the lens was removed, incubated for 24 h and xed. For in vitro
experiments, the lens removed from Wistar rats was pretreated
with 2.4 mM vitamin E, irradiated with 1 Gy of fast neutrons
(14 MeV), posttreated with 2.4 mM vitamin E and xed. Scanning
electron microscopy revealed that such vitamin E treatment
alleviates lenticular morphological damage, although its impact on
opacication was not characterized [83].
At 2 years after irradiation of male CBA/JCR HSD mice with 3 Gy
of protons (1 GeV/amu, 0.24 keV/mm) or 0.5 Gy of iron ions (1 GeV/
amu, 150 keV/mm), the lens was removed and assessed for
opacication. Mice were fed with diets supplemented either with
the Bowman-Bilk inhibitor concentrate (BBIC, soybean derived
protease inhibitor) or the antioxidant formation (L-selenomethio-
nine, N-acetyl cysteine, ascorbic acid, co-enzyme Q10, a-lipoic acid
and vitamin E succinate), which started from 3 days prior to
irradiation, and continued until enucleation. Intake of such diets
with BBIC or the antioxidant formation signicantly reduced the
prevalence and severity of iron ion-induced opacication. There
was a tendency toward protective effects of these supplements
against proton-induced opacication, but a difference did not
reach statistical signicance [124].
4.2. The lens response to fractionated or protracted exposures
In 1948, Evans reported the effects of fast neutrons on lens
opacication, who irradiated Swiss Rockland Farms or CF1
Carworth Farms mice at its total daily dose of 6196 N (at
0.0141.4 N/day, 5 days a week) [6]. He found that more than half of
mice exposed at 1.4 N/day have visible cataracts, and that
cataractous lens accompanies degeneration of the lens epithelium
and autolysis of lens bers with the lens nucleus reduced in size.
However, he did not perform the parallel experiments for single
acute exposure with which he could not compare such effects of
daily neutron doses. Following his report, several papers have been
reported as regards the fractionation or protraction effects of
particle radiation.
4.2.1. Protons
Irradiation of Dutch rabbits with 0.55 Gy of either 1 MeV X-
rays (0.4 keV/mm), 100 MeV protons (0.75 keV/mm) or 20 MeV
protons (3.5 keV/mm) in 10 monthly fractions decreased the
effectiveness for lens opacication by a factor of 1.52 (at 24
months postirradiation), compared with the same dose delivered
in a single, acute exposure. When fractionated, 20 MeV protons
were more effective than 100 MeV protons and 1 MeV X-rays, and
effectiveness of 100 MeV protons was similar to that of 1 MeV X-
rays [125].
When CBA  C57BL6 F1 mice were irradiated with 4 Gy of
645 MeV protons (0.25 keV/mm) at various dose rates, the lower
the dose rate, the lower the frequency of opacities (e.g., 1.1  0.2%/
week at 0.18 Gy/min vs 1.9  0.2%/week at 18 Gy/min), suggesting a
dose rate effect. Irradiation with 26 Gy of 645 MeV protons
(0.25 keV/mm) or 6 Gy of 50 MeV protons (1.25 keV/mm) reduced
the frequency of opacities by a factor of 1.52 (e.g., at 3045 weeks
postirradiation), as was the case for 180 keV X-rays (0.25 keV/mm),
but such difference disappeared later (e.g., at 50 weeks
postirradiation) [77]. However, it is important to note that all
mice irradiated with a single dose of 4 Gy exhibited opacities at
40 weeks, making intercomparisons between groups difcult.
4.2.2. Neutrons
Dutch hybrid albino rabbits were irradiated with 1 Gy of 60Co
g-rays or 0.373 Gy of 2.5 MeV neutrons, which was delivered as
either single, 10 fractions at 3 day intervals or 10 weekly fractions,
followed by observations of opacication up to 3 years. Such
fractionation slightly reduced the effectiveness, but did not have a
marked effect [71]. Little if any time dose relationship was
considered theoretically, because the lens has a lower metabolic
activity than many other tissues, is avascular, enclosed in a capsule,
and unable to eliminate injured cells [126].
Irradiation of white Sherman rats with 200 kVp X-rays in 3
fractions with an interval of 2 or 3 days reduced the effectiveness
for the lens, but such fractionation effect was less than that for
other tissues [126]. Consistent with this, irradiation of BNL-Stoner
white Swiss mice with 9.75 Gy of 250 kVp X-rays in 2 fractions split
with a 12-h interval reduced the effectiveness in production of
posterior opacities (observed 32 weeks postirradiation), but such
fractionation effect was not observed after irradiation with 0.3 Gy
of fast neutrons (0.43 MeV and 1.8 MeV) in 2 fractions split with a
22-h interval [91]. Likewise, irradiation of C57Bl  C3H hybrid mice
with 0.81.6 Gy of 250 kVp X-rays in 2 fractions split with a 12-h
interval reduced the effectiveness at producing opacities (observed
20 months postirradiation), but not with 0.15 Gy of fast neutrons
(14 MeV) [87].
Irradiation of albino Swiss mice with 1 Gy of fast neutrons or 8
9 Gy of 250 kVp X-rays (delivered as either singly, in 2 fractions
with a 3-week interval, or in 3 fractions with 10-day intervals)
decreased the mitotic activity in the lens followed by a
compensatory rise to levels above the normal range, but such
changes were not observed after 2.25 Gy of fast neutrons in 2
fractions with a 3-week interval [127].
Mice (strain not described) were irradiated with fast neutrons
(<4 MeV) either as a single dose or as divided doses. RBE of fast
neutrons relative to X-rays for lens opacication was 5 when
irradiated singly, which was increased to 8 when irradiated weekly
and monthly (dose, dose rates, follow up period not described)
[128]. It remains unclear, however, whether this is attributable to
fractionation effects only for neutrons or for both neutrons and X-
rays.
Irradiation of Columbia-Sherman albino rats with 2250 mGy
of fast neutrons (0.44 MeV, 106 keV/mm) delivered in 4 fractions
with 3-h intervals was more potent in inducing opacication
(observed 102 weeks postirradiation) than that delivered as a
single dose [82]. Likewise, in albino Swiss mice, fractionation
decreased the effectiveness of 200 kVp X-rays, but increased that of
fast neutrons (4 MeV) for induction of histological changes
observed over 15 months [92]. These ndings suggest an
 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
enhancing, inverse dose rate effect of neutrons, in contrast to a
sparing dose rate effect for low-LET radiation.
At various times after irradiation with 250 kVp X-rays or ssion
neutrons (0.8 MeV), lenses of BCF1 mice were mechanically
wounded to induce mitogenic stimulation of the subpopulations,
and DNA synthesis in two zones of the lens epithelium was then
analyzed up to 4 weeks afterward to know if irradiation suppresses
cellular response to mitogenic stimuli. In the central zone that
consists of G0 cells, fractionation (10 Gy of X-rays or 2 Gy of
neutrons in 4 weekly fractions) had a sparing effect for both X-rays
and neutrons initially (1 week postirradiation). Then, a sparing
effect continued for X-rays, whilst a slight enhancing effect was
observed for neutrons. In the peripheral zone consisting of cycling
and G0 cells, fractionation had an initial sparing effect (1 h
postirradiation) and a subsequent enhancing effect for both X-rays
and neutrons, where an enhancing effect was greater for neutrons.
This suggests a time-dependent shift from an initial sparing to a
nal enhancing effect of neutron fractionation for the slowly
proliferating subpopulation [93].
4.2.3. Heavy ions
In CB6F1 mice, cataract severity was reduced signicantly when
4.17 Gy of 60Co g-rays was given in 24 weekly fractions compared
to giving as a single dose. In contrast, cataract severity was
enhanced when 0.11.2 Gy of 225 MeV carbon ions (7080 keV/
mm) was given in 24 weekly fractions compared to when given as a
single dose [129]. Such fractionation effects were observed at 334
360 days, but was absent at 440 and 560 days postirradiation
[118]. This suggests an inverse dose rate effect or lack of tissue
sparing fractionation effect for heavy ion cataractogenesis.
In Columbia-Sherman albino rats, the cataractogenic effective-
ness of 210 Gy of 250 kVp X-rays, 125 cGy of argon ions
(570 MeV/amu, 88 keV/mm) or 250 cGy of iron ions (450 MeV/
amu, 190 keV/mm) delivered as a single dose was compared with
when delivered in 4 fractions over 12 h. The cataractogenic
effectiveness was reduced by fractionation of X-rays and enhanced
by that of argon ions, but such an enhancing effect was absent after
that of iron ions [130,131]. Likewise, in CB6F1 mice, the
cataractogenic effectiveness of 0.17 Gy of 60Co g-rays or 0.05
5.04 Gy of iron ions (600 MeV/amu, 175 keV/mm) delivered as a
single dose was compared with when delivered in 6 fractions over
12 weeks, revealing that the cataractogenic effectiveness (assessed
3 years) was reduced by fractionation of g-rays, but was not
affected by that of iron ions [132]. Although the cataractogenic
potential of an acute low dose of argon ions (88 keV/mm) or iron
ions (190 keV/mm) was indistinguishable statistically [101], it was
theoretically considered that any enhancing fractionation effect
will be most signicant at about 40140 keV/mm [133].
4.3. Species difference
Sensitivity to radiation cataractogenesis differs with species.
Mice appeared to be most sensitive, humans being most resistant
among mice, rats, guinea pigs, rabbits and humans [91]. Mice
seemed to be most sensitive, dogs being most resistant to radiation
cataractogenesis, among mice, rats, rabbits, dogs and monkeys
[28]. The order of the spontaneous mitotic index in the lens
epithelium from the highest to the lowest was mice, rats, rabbits,
dogs and monkeys, and an attempt was made to correlate the
lower mitotic index with lower sensitivity to radiation cataracto-
genesis in terms of species differences [134]. Rats and Dutch
rabbits seemed to be much more sensitive than NZW rabbits,
rhesus monkeys (Macaca mulatta) and humans, which all have
similar sensitivities [105].
One of the differences between mice and rabbits are anterior
changes. Anterior plaques are characteristic of the irradiated
285
mouse lens, and are not observed in the rabbit lenses. Anterior
plaques appear to be formed by a pile up of LECs [92,127]. Anterior
opacities in the mouse lens appear much later than posterior
opacities [135]. One of the differences between rodents and
humans is that the late degenerative phase of cataractogenesis is
difcult to differentiate in rodents [76].
Goats were assessed for lens opacication at up to 3 years after
irradiation each with 16.33 Gy of ssion neutrons (0.7 MeV) and
26 Gy of 2.5 MeV g-rays, for which the mean lethal dose within
30 days is 3.95 and 5.05 Gy, respectively. Within 3 years
postirradiation, cataracts were found in 2 out of 20 neutron
irradiated goats but none in g-irradiated ones [136].
Hereford cattle was irradiated with ssion neutrons (dose and
energy not described) or 26 Gy of 60Co g-rays, and observed for
opacication up to 9 years postirradiation. Guernsey and Holstein-
Friesian cattle was irradiated with 2.14.5 Gy of ssion neutrons
(energy not described), and observed up to 3 years thereafter.
Swine received 0.158.5 Gy of bomb radiation (mixed ssion
neutrons and g-rays) plus X-rays (delivered 4 months after bomb
radiation), and were observed up to 11 years thereafter. Burros
received bomb radiation or ssion neutrons (0.155.1 Gy), and
were observed up to 7.519 years thereafter. Opacication was
found in cattle, but not in swine and burros. The lens of swine and
burros appeared to be more resistant than that of small laboratory
animals, and the radiosensitivity of the bovine lens seemed to be
similar to that of the human lens [137].
5. Discussion
5.1. High RBE in the lens
It has long been known that RBE for lens opacication is much
higher than that for other endpoints like acute lethality
[6,71,138,139], leading to a belief that the lens is especially
sensitive to high-LET radiation. As summarized in Section 4.1 and
Tables 4 and 5, high RBEs of neutrons and heavy ions have been
reported, even exceeding 100 at <1 cGy. One of the reasons why
the lens has high RBE may be its low oxygen content [140]. The lens
is an avascular, relatively hypoxic tissue [138] (e.g., <20 mmHg in
the germinative zone of the lens epithelium [141]), where hypoxia
should reduce the effects of low-LET radiation but not much those
of high-LET radiation [142]. Interestingly, the fall of glutathione in
the rabbit lens was increased by 24  6% when oxygen was given at
1 atm pressure during irradiation with 190 kV X-rays, with a strong
impression that most opaque lenses had the greatest loss of
glutathione [141].
Another reason may be a difference in affected cell types. It has
long been accepted that high-LET radiation has less cell cycle
dependence than low-LET radiation [145,146]. It is therefore
tempting to speculate that low-LET radiation mainly acts on
dividing LECs around the germinative zone, but that high-LET
radiation also acts on resting LECs in other zones of the lens
epithelium and LFCs. In support of this, the primary damage to LFCs
with concomitant damage to LECs was thought to explain the
earlier onset of neutron cataracts [143], but convincing evidence is
unavailable hitherto.
The other reason may be its high nitrogen content. The mass
fraction of nitrogen in the elemental composition of the lens is
5.7%, which is highest among all bodily tissues [144]. Nitrogen has
a large capture cross section for low energy neutrons, and produces
protons with an energy of 626 keV. The RBE of such low energy
protons is generally high, and consequently, a higher RBE is
expected in the tissue with higher nitrogen content particularly for
low energy neutron irradiation. For example, the calculated mean
quality factor in spherical soft tissue with 30 cm diameter
irradiated by thermal neutron beam is 2.8, while the
286 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
corresponding data calculated replacing soft tissue by the lens is
4.6 (these values calculated by Particle and Heavy Ion Transport
code System PHITS [147] coupled with the Q(L) relationship
dened in ICRP-60).
5.2. Radiation weighting factor
In 2011, ICRP revised a threshold for the lens effects based on
low-LET data, but a revised dose limit was recommended in Sv,
without review of high-LET data and discussion of the suitability of
wR application [17].
As described in Section 2.2, ICRP-58 calculated RBEm and RBEM
in skin, gastrointestinal tract, hematopoietic system, vascular
system, respiratory system, reproductive system and urinary
system, and concluded that such RBEm is generally smaller than
RBEM in corresponding tissues. Based on this conclusion, wR has
been used for the lens, with the notion that the application of Q in
cases where tissue reactions are overriding would result in an
overestimate of contribution to the risk from high-LET radiation. To
draw this conclusion, the lens was not included, because there
were insufcient data to derive parameters for the LQ model (i.e.,
aH/aL): thus, RBEm for the lens could not be calculated. A quarter
century has passed since then, but this situation remains
unchanged, necessitating more human data. RBEm, when it
becomes available, needs to be compared with RBEM. RBEM is
generally calculated based on cancer induction, cell transformation
or chromosome aberrations. Humans and any other species except
for cats do not develop primary lens tumors [111,148,149].
Information on transformation and chromosome aberrations in
LECs is unavailable heretofore, necessitating development of in
vitro assays to examine the effects of stochastic nature.
ICRP TG79 on effective dose is proposing that the use of
equivalent dose continues as an intermediate step in effective dose
calculation, but discontinues as a radiation protection quantity,
and that a dose limit aiming at preventing tissue reactions (i.e., for
the lens, skin, hands and feet) is set in absorbed dose (Gy) [150].
This may necessitate a radiation weighting factor for various types
of high-LET radiation to calculate dose in Gy-Eq or RBED, and such
a factor may need to be a tissue specic. This would then reinforce
the need of further studies to characterize RBEs and its dependence
on energy, LET, postirradiation time, dose and dose rate. In addition
to LET, biological effects are known to differ among ion species at a
comparable LET [151,152], so that such ion species (or track
structure) dependence should also be studied.
5.3. Dose rate effects
Animal studies have documented an enhancing fractionation
effect of neutrons and heavy ions at some energy and LET [e.g.,
0.44 MeV (106 keV/mm) fast neutrons, 4 MeV fast neutrons,
0.8 MeV ssion neutrons, 7080 keV/mm carbon ions and
88 keV/mm argon ions, but not 175 or 190 keV/mm iron ions], as
discussed in Section 4.2. Such an inverse dose rate effect on the
lens differs from the current ICRP judgment.
Currently, ICRP recommends a nominal threshold of 0.5 Gy for
the lens effects, independent of rate of dose delivery and severity of
opacication, assuming that exposure to 0.5 Gy of low-LET
radiation induces minor opacities in 1% of exposed individuals
within 20 years after exposure, all of which progress to VICs [17].
Such a decision was made predicated on a series of epidemiological
evidence available by April 2011 (when Statement on tissue
reactions was released) that has suggested a threshold of 0.5 Gy for
a single, acute exposure (based on A-bomb data [46,47]), a
threshold not higher than 0.5 Gy for fractionated/protracted
exposures (based on Chernobyl data [48]: maximum likelihood
central estimates for a threshold ranging from 0.34 to 0.50 Gy), and
a threshold uncertain for chronic exposures [17]. Interestingly, the
recent epidemiological study analyzed lens opacities in residents
aged 45 years of the high natural background radiation area in
Yangjiang, Guangdong, China, reporting the signicant odds ratio
of 4.05 (95% CI, 1.5610.46) for posterior subcapsular opacities,
whilst the odds ratio of 1.45 (0.992.11) for cortical opacities, 0.82
(0.601.14) for nuclear opacities and 0.99 (0.721.37) for all types
of opacities was insignicant. The mean age was 64.5 years in
control area and 68.0 years in Yangjiang [153]. The estimated mean
indoor lens dose was 0.360.78 mGy/year in control area and 1.69
2.54 mGy/year in Yangjiang, depending on the type of house [154].
The outdoor dose of natural background radiation from ground is
3.24 mSv/year (c.f., 0.52 mSv/year on world average) [155]. Thus,
the lifetime lens dose should be of the order of a few hundred mSv
(c.f., a few ten mSv in control area). This may imply an inverse dose
rate effect in humans, rather than the lack of dose rate effect.
Proposed mechanisms behind the inverse dose rate effect at the
cellular level appear to involve the failure of ATM-dependent
repair processes to effectively arrest the progression of damaged
G2 cells containing unrepaired DNA breaks entering mitosis [156].
Such mechanism at the tissue level is unknown, but it is
nonetheless tempting to speculate on it. It has been proposed
that if radiation damage does not accumulate in the tissue due to
elimination of damaged tissue stem or progenitor cells through
tissue turnover or cell death, the irradiated tissue does not undergo
radiation carcinogenesis [157]. Namely, tissue turnover rate and
dose rate are postulated to determine the dose rate effect, where
irradiation may stimulate tissue stem cell turnover depending on
types of tissues [158]. In this regard, the lens is derived from a
single cell type, and continues to grow throughout life during
which time all live and dead cells stay inside the lens capsule that
encases the lens. The lens thus does not undergo tissue turnover, so
that damage should continue to accumulate (in the case of
radiation, not only dead LECs but also excessively proliferated LECs
may act as damage underlying cataractogenesis [159,160]).
Accordingly, a sparing dose rate effect may not be expected.
Although three plus decades have passed since the involvement of
stem cells in radiation cataractogenesis was proposed [105,118],
the radiation response of stem cells remains uncharacterized.
Currently, various questions are still unanswered, e.g., as to
whether (1) stem cells are target cells of radiation cataracto-
genesis, (2) irradiation modies a microenvironmental niche and
affects stem cell competition between undamaged and damaged
stem cells for residence in the niche, and (3) a single damaged stem
cell forms a cloudy lens (or lentoid). With increasing knowledge
and technological advances in lens stem cell research, such open
questions may be better answered, leading to elucidation of the
mechanisms underlying radiation cataractogenesis including its
inverse dose rate effects.
5.4. Lens response modiers
As described in Section 4.1.8, only two studies have thus far
reported agents that mitigate damaging effects of high-LET
radiation on the lens, when rodents were treated with such
agents before (along with or without treatment after) irradiation
[83,124]. Consequently, it remains unclear if treatment with these
agents only after irradiation (but without treatment before
irradiation) alleviates (or exacerbates) the lenticular response to
high-LET radiation. Further studies are warranted, especially to
develop radioprotective agents against high-LET cataractogenesis,
with which only postirradiation treatment has protective effects.
Such studies can also clarify if high-LET cataractogenesis is
predetermined at the time of irradiation (i.e., denition of
deterministic effects) or is modiable after irradiation (i.e.,
denition of tissue reactions).
 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
5.5. Potential qualitative difference in opacities induced by high- and
low-LET radiation
Most data have shown that high-LET radiation is quantitatively
more damaging to the lens than low-LET radiation, but that
resulting damage is qualitatively the same. However, several
papers have reported potential qualitative differences between
neutrons and photons. Fast neutrons (14 MeV) produced more of
the transient vacuoles than 1.2 MeV X-rays or ssion neutrons
(0.3 MeV) in French silver rabbits [161]. High dose (e.g., at >1.6 Gy)
of fast neutrons (12 MeV) produced mature cataracts, but not 250
kVp X-rays and 60Co g-rays even at lethal dose, in RF mice, Wistar
rats and guinea pigs [71]. Last, fast neutrons (15 MeV) produced
mature cataracts more rapidly than 60Co g-rays at dose giving the
same level of the initial opacities in rabbits [162]. Further studies
are encouraged to examine such potential qualitative differences in
opacities and other lenticular responses induced by high- and low-
LET radiation.
5.6. Uncertainty in neutron dosimetry
Evaluation of radiation dose in neutron elds is rather difcult
in comparison to that in photon or charged particle eld, because it
complicatedly depends not only on the characteristic of radiation
eld but also on the size of target. For example, contribution of
photon dose in a low-energy neutron eld becomes larger with an
increase in the target size because more g-rays are generated
inside the target via the 1H(n, g)d reaction [163]. Thus, RBE should
increase for smaller animals even if the real tissue response would
be the same. This makes it difcult to simply apply the high RBE
data obtained in mice to human.
Ideally, RBEs need to be based on dose of different types of
radiation that gives the same level of effect. However, this is
difcult for lens opacication because its severity is a function of
dose. Various studies used a relatively high dose of a reference low-
LET radiation, which often exceeds its minimum cataractogenic
dose. This leads to underestimation of RBE at low dose of high-LET
radiation as getting closer to its minimum cataractogenic dose
(e.g., RBE should be based on minimum cataractogenic doses of
high- and low-LET radiation, but not on the low-LET dose
exceeding its minimum cataractogenic dose and the high-LET
minimum cataratogenic dose). So, uncertainties in dosimetry and
choice of dose range should be kept in mind when looking at the
RBE data.
6. Conclusions
Here we have reviewed changes in ICRP recommendations on
the lens, and epidemiological and biological studies on high-LET
cataractogenesis. From the ICRP historical viewpoint, the lens was
the unique tissue for which a special factor of 13 was assigned in
addition to a general radiation quality factor (thus a maximum of
30 was recommended), predicated on the belief that the lens was
especially sensitive to high-LET radiation (Section 2). Epidemio-
logical data for high-LET cataractogenesis are available in cyclotron
workers, radiotherapy patients, astronauts, aviators and A-bomb
survivors, but evidence remains very limited (Section 3). As a
protection quantity for astronauts, Sv in combination with Q(L)
(instead of wR), or Gy-Eq (instead of Sv) in combination with RBE
(Section 3.4) has been used. In A-bomb cataract studies, a constant
neutron RBE of 10 has been used since the 1996 paper [68],
although RBE as a function of dose had been used for T65DR and
DS86 (Section 3.5). Biological studies have reported that RBEs for
single exposure for lens opacication or other lenticular changes
relative to photons were 1 for negative pions, 18 for protons, >200
287
for neutrons (80% CI includes 500), 3.9 for deuterons, and >100 for
heavy ions (90% CI includes 200) (Section 4.1). RBE of high energy
protons was higher than that of low energy protons at similar LET
(Section 4.1.3). Neutron RBEs tended to increase with decreasing
energy at high dose, but approached to similar values at low dose
independent of energy (section 4.1.4.2). As regards dose depen-
dence of RBE, several studies documented that RBEs of neutrons
and heavy ions are proportional to the inverse of the square root of
the high-LET dose, indicating that low-LET effectiveness increases
as the square of dose (Sections 4.1.4.1 and 4.1.6.1). Heavy ion RBE
for cataractogenesis was comparable to that for MR disorganiza-
tion, and depended on LET (Sections 4.1.6.1 and 4.1.6.2). Heavy ions
were suggested to induce more DSBs/SSB than X-rays. Most DNA
strand breaks induced by heavy ions at LET <10,000 keV/mm were
repaired, but there was no signicant repair of those induced at LET
>10,000 keV/mm (Section 4.1.6.3). Gender difference was sug-
gested in rats, but evidence is very limited (Section 4.1.6.4). ATM
haploinsufciency reported in mice, which may also contribute to
A-bomb cataracts, highlights the importance of genetic suscepti-
bility (Section 4.1.6.5). Evidence for age dependence is also very
limited, but the young lens and senile lens may be susceptible to
early and late cataractogenesis, respectively (Section 4.1.7). BBIC,
vitamin E and the antioxidant formation mitigated the damaging
effects of fast neutrons and heavy ions on the lens (Section 4.1.8).
Photon fractionation reduced the effectiveness in the lens to a
lesser extent than in other tissues. Proton fractionation had a
sparing effect reducing the effectiveness by a factor of 1.52, where
3.5 keV/mm protons were more effective than 0.75 keV/mm
protons (Section 4.2.1). Neutron fractionation had an enhancing
effect (including at 106 keV/mm) or no effect (Section 4.2.2). Heavy
ion fractionation had an enhancing effect at 7080 and 88 keV/mm
(carbon and argon ions, respectively), but no effect at 175 and
190 keV/mm (both iron ions) (Section 4.2.3). Whereas in vitro cell
culture studies employed only human and bovine cells, in vivo
studies employed various animal species. A premature conclusion
is that mice, rats and rabbits are sensitive, dogs, swine and burros
being resistant, between which humans, monkeys, guinea pigs,
cattle and goats lie, although this will also vary among strains
within species (e.g., Dutch rabbits are much more sensitive than
NZW rabbits) (Section 4.3).
The knowledge is available on high-LET cataractogenesis much
less than on low-LET cataractogenesis, although uncertainties still
exist for low-LET cataractogenesis [20,164]. Human lens effects of
high-LET radiation should be more epidemiologically studied with
a long follow up period, various confounding factors being taken
into account. Take astronaut cohorts for instance: potential
confounding factors include non-spaceight dose and space
acquired dose each from UV and ionizing radiation, aviation
frequency, military backgrounds, and microgravity are important
in addition to lifestyle factors (e.g., nutrition, smoking and alcohol
consumption) [57,61,165]. In addition to such human studies,
biological underpinnings need to be claried with in vivo animal
and in vitro culture models. More knowledge concerning depen-
dence of RBE on dose, dose rate, LET, ion species, energy, time, and
cataract severity/grading systems, for which the detailed informa-
tion on the shape of the dose response curve for various types of
high-LET radiation is indispensable. Then, a radiation weighting
factor for lens opacities can be discussed further. With better
mechanistic understanding, biological mitigation strategy can also
be developed.
Conict of interest statement
The authors declare that there are no conicts of interest.
288 N. Hamada, T. Sato / Mutation Research 770 (2016) 262291
Acknowledgements
This research did not receive any specic grant from funding
agencies in the public, commercial, or not-for-prot sectors.
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