ARTICLE IN PRESS

Progress in Retinal and Eye Research 23 (2004) 523–531

Do blue light filters confer protection against age-related

macular degeneration?
T.H. Margraina,*, M. Boultona, J. Marshallb, D.H. Slineyc
a
School of Optometry and Vision Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, UK
b
Department of Ophthalmology, The Rayne Institute, St. Thomas’ Hospital, London, UK
c
US Army Center for Health Promotion and Preventive Medicine, Aberdeen Proving Ground, Maryland, MD 21010-5403, USA

Abstract

Age-related macular degeneration (AMD) is a major health problem in the developed world accounting for approximately half of
all blind registrations. Current treatment options are unsuitable for the majority of patients and therefore the identification of
modifiable risk factors that may inform disease prevention programmes is a priority. This review evaluates the long-held belief that
blue light exposure has a role in the pathogenesis of AMD. Laboratory evidence has demonstrated that photochemical reactions in
the oxygen-rich environment of the outer retina lead to the liberation of cytotoxic reactive oxygen species (ROS). These ROS cause
oxidative stress which is known to contribute to the development of AMD. The precise chromopore that may be involved in the
pathogenesis of AMD is unclear but the age pigment lipofuscin is a likely candidate. Its aerobic photoreactivity and adverse effects
on antioxidant activity combined with its gradual accumulation over time suggests that its in vivo phototoxicity increases with age
despite changes in the absorption characteristics of the crystalline lens. Evidence from animal studies confirms blue light’s damaging
potential but the results are not directly applicable to macular degeneration in humans. Studies of human macular pigment density
and the risk of AMD progression following cataract surgery lend further weight to the hypothesis that blue light exposure has a role
in the pathogenesis of AMD but the epidemiological evidence is equivocal. On balance the evidences suggests but does not yet
confirm that blue light is a risk factor for AMD. Given the socio-economic impact of this disease and urgent need to identify
modifiable risk factors, future work should include a large-scale clinical trial to evaluate the effect of blue blocking filters on AMD
progression rates.
r 2004 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
2. Light and the pathogenesis of AMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
2.1. Acute light exposure studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
2.2. Chronic light exposure studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
3. Ageing, lipofuscin and the potential for chronic light damage in humans . . . . . . . . . . . . . . . . . 526
4. Clinical evidence for the role of light in the pathogenesis of AMD . . . . . . . . . . . . . . . . . . . . 527
5. Epidemiological evidence for the role of light in the pathogenesis of AMD . . . . . . . . . . . . . . . . 528
6. Blue light filters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
7. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529

*Corresponding author.
E-mail address: margrainth@cardiff.ac.uk (T.H. Margrain).

1350-9462/$ - see front matter r 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.preteyeres.2004.05.001
 ARTICLE IN PRESS
524 T.H. Margrain et al. / Progress in Retinal and Eye Research 23 (2004) 523–531
1. Introduction
Age-related macular degeneration (AMD) is the
leading cause of blindness in the developed world and
currently affects 12.7 million people in Europe and
North America (Klein et al., 1995; 1999). At present, the
term AMD is used generically to describe two distinct
pathologies: geographic atrophy (GA) and exudative
AMD. In the early stages, both conditions are asso-
ciated with pigmentary disturbances and the develop-
ment of drusen at the posterior pole. In GA, the early
changes lead to degeneration of the retinal pigment
epithelium and receptors and in exudative AMD they
lead to the growth of new vessels under the retina. GA
accounts for the majority of AMD cases and for these
people there is a gradual loss of central vision eventually
resulting in an absolute central scotoma. For those with
the exudative form of the disease the loss of central
vision is often acute.
Laser photocoagulation and photodynamic therapy
have been shown to reduce the risk of severe visual loss
for some people with the exudative form of the disease
but for the vast majority of people with AMD there is
no effective treatment. Low vision aids can ameliorate
some of the problems associated with visual loss but
they can do little to alleviate the substantial individual
and socio-economic costs of this disease (Margrain,
1999).
Ultimately, the key to reducing the number of people
with AMD is likely to be found in the axiom that
‘‘prevention is better than cure’’. In this paper, we
evaluate the evidence collected over the last three
decades implicating blue light damage in the pathogen-
esis of AMD. We show that blue light phototoxicity
increases substantially with age and suggest that there is
now a powerful case for the establishment of a large-
scale clinical trial to evaluate the ability of blue light
filters to confer protection against AMD.
2. Light and the pathogenesis of AMD
It is well established that ultraviolet (UV) and visible
radiation has the potential to damage the retina and
pigment epithelium (Noell et al., 1966). Fortunately, the
human retina is protected from short-wavelength radia-
tion, which is particularly damaging, by the cornea
which absorbs below 295 nm and the lens which absorbs
strongly below 400 nm.1 The human retina is therefore
only exposed to the ‘‘visible component’’ of the
electromagnetic spectrum from 400–760 nm and some
short-wavelength infra red (IR). This part of the
1
In childhood the retina is exposed to a small amount of UV
(320 nm) because the lens transmits about 4% of incident radiation at
this wavelength.
electromagnetic spectrum may result in chronic or acute
tissue damage when it is absorbed by any one of a
number of photosensitisers or chromophores e.g. the
visual pigments, melanin, melanopsin, lipofuscin, flavins
and flavoproteins. Evidence collected since the 1970s
suggests that light may damage the retina in a number of
ways involving different chromopores and cellular
events (Kremers and Van Noren, 1988). For example,
short-intense exposures (100 ms–10 s) may result in
thermal damage when incident energy is absorbed by a
tissue and there is a significant rise in temperature. The
action spectra for this type of damage is dependent on
the absorption characteristics of the chromopore but
typically peaks in the blue/green, green and red regions
of the visible spectrum (Boulton et al., 2001). Although
such exposures are used therapeutically by surgeons, to
produce retinal photocoagulation, they are not encoun-
tered in the natural world.
Longer exposures (typically quoted as being 10 s and
longer) to much less-intense light sources may cause
retinal damage by a photochemical mechanism and it is
this mechanism that is most likely to be of relevance to
the development of AMD.
Photochemical reactions take place in normal ambi-
ent conditions and involve a reaction between energetic
photons and an absorbing molecule. In the presence of
oxygen this reaction leads, via a number of intermediary
steps, to the production of reactive oxygen species
(ROS) including singlet oxygen, superoxide, hydrogen
peroxide and hydroxyl radicals. These ROS are highly
toxic and can cause lipid peroxidation, protein oxidation
and mutagenesis (Boulton et al., 2001). ROS production
is also a natural by-product of respiration and is
believed to have a major role in ageing (Barja, 2002).
To minimise the destructive potential of ROS, cells
have developed a number of defence mechanisms, for
example enzymic (e.g. superoxide dismutase, catalase,
haeme oxygenase and phospholipases) and non-enzymic
(e.g. vitamin E, A and C) antioxidants. The RPE is
further protected from the ravages of ROS damage by
melanin which is an ROS scavenger. In particular, it has
the capacity to minimise the production of hydroxyl,
one of the most potent oxidative moieties (Boulton et al.,
2001). However, it is the photoreceptors which have
perhaps developed the ultimate solution to oxidative
damage i.e. the continuous replacement of their cellular
constituents (Marshall, 1985).
Ideally the cellular defence mechanisms, such as those
described above, should be sufficient to combat the toxic
effects of ROS damage. In reality, however, the defence
mechanisms are imperfect systems and the resulting
lifetime accumulation of ROS damage may contribute
not just to age-related eye disease but to ageing itself
(Barja, 2002). Indeed it has been suggested that ROS
damage to mitochondrial DNA in the RPE is a primary
mechanism in the pathogensis of AMD (Liang and
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T.H. Margrain et al. / Progress in Retinal and Eye Research 23 (2004) 523–531
Godley, 2003). The rate at which ROS damage
accumulates is likely to accelerate over time because
cellular defence mechanisms are known to decline with
age (Boulton et al., 2001). For reasons to be outlined
later, we suggest that the RPE is particularly vulnerable
to age-related ROS injury because the decline in its
melanin content, associated with advancing years, is
accompanied by an increase in its lipofuscin content.
Lipofuscin is not just a potent generator of ROS but
also has an inhibitory effect on antioxidant activity
(Shamsi and Boulton, 2001).
2.1. Acute light exposure studies
Animal studies suggest that there are two distinct
types of photochemical damage, one associated with
short exposures operating at the level of the RPE and
the other associated with longer, relatively less-intense
exposures, at the level of the photoreceptor outerseg-
ments.
Short exposures, up to about 12 h, to relatively intense
short-wavelength light, sometimes referred to as the
‘‘blue light hazard’’, can produce damage at the level of
the RPE in primates (Ham et al., 1978). The dependence
of this type of light damage on oxygen concentration
(Ham et al., 1984; Jaffe et al., 1988; Ruffolo et al., 1984)
and the ability of various antioxidants to reduce light
damage (Dillon, 1991; Organisciak and Winkler, 1994)
confirm its oxidative origins. There are a number of
candidate chromopores for this type of damage most
notably, melanin and lipofuscin.
Although capable of producing reactive oxygen
species at high irradiance levels, melanin seems an
unlikely candidate for the mediation of light-induced
damage in AMD. According to Mellerio (1994) the
action spectra for ‘blue-light-damage’ does not coincide
with the absorption spectrum of melanin nor its action
spectrum for the uptake of oxygen (Mellerio, 1994).
Total melanin content of the retina reduces with age
(Schmidt and Peisch, 1986) and its spatial distribution
does not coincide with AMD. Indeed, melanin is
generally thought to be photoprotective and increased
pigmentation is generally associated with a reduced risk
of AMD (Klein et al., 1999).
Laboratory studies have shown lipofuscin to be a
potent generator of ROS including singlet oxygen,
superoxide anion and hydrogen peroxide (Rozanowska
et al., 1995). These products are cytotoxic and give rise,
directly or indirectly, to lipid peroxidation, protein
oxidation, loss of lysosomal integrity, cytoplasmic
vacuolation and cell death (Davies et al., 2001). Most
importantly the action spectra for photochemical
damage to the RPE in primate retina (Ham et al.,
1976, 1982) and the aerobic photoreactivity of lipofuscin
(Rozanowska et al., 1995) are coincident (see Fig. 1)
suggesting that lipofuscin is largely responsible for this
525
1
Normalised reactivity
0.1
0.01
0.001
300 350 400 450 500 550 600
Wavelength (nm)
Fig. 1. Action spectra for light damage to the primate retina (symbols)
and for the aerobic photoreactivity of ocular lipofuscin (solid line).
The solid line is taken directly from Fig. 1 in Rozanowska et al. (1995)
and describes the photoreactivity of lipofuscin in isolated RPE cells
from human donors. The symbols describe the action spectra for light
damage to the primate retina normalised to the reactivity of lipofuscin
at 460 nm (Ham et al., 1982). The similarity of the data is remarkable.
type of ‘‘blue light damage’’. A number of components
are likely to contribute to lipofuscin’s photoreactivity.
One of these components, known as A2E, has been
shown to produce ROS, trigger RPE cell apoptosis,
damage DNA and lead to RPE cell death (Sparrow and
Cai, 2001; Sparrow et al., 2000, 2002, 2003). However,
A2E is only weakly photoreactive and is unlikely to
explain the photoreactivity of lipofuscin (Boulton et al.,
2001).
Longer exposures (typically, 12–48 h) to less-intense
exposures produce damage at the level of the photo-
receptors. This type of damage was initially demon-
strated in the rat where rod photoreceptor degeneration
was noted after a period of constant illumination from
fluorescent lamps (Noell et al., 1966). Similar findings
were obtained in young primates with the notable
exception that cones were more vulnerable than rods
showing degeneration after a 12 h exposure when the
retinal irradiance was between 195 and 361 mW/cm2
(Sykes et al., 1981). However, the apparent susceptibility
of cones is unlikely to reflect a difference in damage
threshold but rather a difference in repair capacity i.e.
rod outersegments are replaced more rapidly than cone
outer segments (Marshall, 1985). A number of mechan-
isms may contribute to light-induced photoreceptor
damage. The photopigments themselves have long been
implicated in receptoral damage. Early studies have
shown that the degree of light-induced damage posi-
tively correlated with pre-exposure rhodopsin content
and that the action spectrum for photoreceptor damage
 ARTICLE IN PRESS
526 T.H. Margrain et al. / Progress in Retinal and Eye Research 23 (2004) 523–531
was similar to that of rhodopsin (Noell and Albrecht,
1971; Organisciak and Noell, 1977). However, more
recent evidence has shown that deep blue light is 50–80
times more efficient at causing receptoral damage than
green light despite the fact that it is less efficiently
absorbed (Rapp and Smith, 1992). This observation has
been explained on the basis of rhodopsin photoreversal
(Grimm et al., 2000). That is, blue light promotes the
photoisomerisation of all-trans-retinal which leads to
the regeneration of rhodopsin and an increase in
phototransduction signalling this in turn leads to
photoreceptor apoptosis. The exact sequence of events
remains unclear but in relatively dim light photoreceptor
apoptosis is mainly dependent on a transducin-depen-
dent pathway (Hao et al., 2002). Receptoral damage
may also result from the liberation of ROS by all-trans-
retinal which is a well-known photosensitiser and
capable of producing singlet oxygen and superoxide
anions after photoexcitation with blue light (Boulton
et al., 2001).
On a cautionary note it should be remembered that
the majority of the animal studies mentioned above have
used nocturnal rodents and it has not been established
that the same damage pathways have a significant role in
diurnal species.
Furthermore, all of these investigations described
above have used exposures that are shorter and more
intense than might normally be encountered in the
natural environment i.e. they are all ‘acute’ light
exposure studies where the damage inflicted by photo-
chemical reactions has outstripped, at least in the short
term, the capacity of the various defence and repair
mechanisms. Consequently, they are only indirectly
related to the effects of ‘chronic’ light exposure in
elderly humans. What these studies do show, however, is
that light and in particular blue light has the potential to
cause retinal damage via a photochemical mechanism
and that the nature of the damage is dependent not just
on the photoreactivity of a variety of chromopores but
on the capacity of the defence and repair systems.
2.2. Chronic light exposure studies
Chronic exposure to ambient lighting produces ROS
in the same way that acute exposures do because all
photochemical reactions demonstrate reciprocity be-
tween irradiance and exposure duration (Sliney, 1991).
That is, both are capable of producing damage. The
nature of that damage will reflect the capabilities of the
various defence and repair mechanisms, and the time at
which the damage is observed. For example, the acute
light exposure studies described above typically obtain
measures of threshold damage in young animals after
defence systems have been overwhelmed and repair
systems have had insufficient time to act. Damage from
chronic light exposure in elderly humans whose defence
and repair mechanisms are compromised is likely to be
quite different. On the basis that ROS damage has a
major role in ageing, it seems likely that the damage
caused by chronic light exposure will manifest as
accelerated ageing (Barja, 2002; Liang and Godley,
2003).
3. Ageing, lipofuscin and the potential for chronic light
damage in humans
The studies described above have shown that two
distinct retinal layers are susceptible to photochemical
injury i.e. the photoreceptor outer segments and the
RPE, and that this damage is likely to be mediated by
the visual pigments and lipofuscin, respectively.
Although both may contribute to the development of
AMD, and in particular geographic atrophy, there are
several reasons for believing that lipofuscin is of
particular importance. Firstly, RPE cells are retained
throughout life, their repair systems operate at a
molecular level and this type of ‘‘closed system’’ is more
likely to accumulate ROS damage than cells of the
‘‘open system’’ type in which there is abundant
component renewal e.g. photoreceptors (Marshall,
1985). Secondly, the chronology of lipofuscin accumula-
tion in the RPE is coincident with the development of
AMD (Feeneyburns et al., 1984). Thirdly, longitudinal
studies of in vivo autofluorescence (which has been
ascribed to the presence of lipofuscin) have shown that it
is areas of retina with the highest autofluorescence that
are most susceptible to degeneration (Holz et al., 2001).
Fortunately, the crystalline lens attenuates the shorter
wavelengths reducing the potential phototoxicity of
lipofuscin. This is exemplified in Fig. 2 which shows
30.00
25.00
Relative Phototoxicity
20.00
15.00
10.00
5.00
0.00
300 400 500 600 700
Wavelength (nm)
Fig. 2. Action spectra for lipofuscin-mediated ‘blue light damage’ in
the intact human eye. The curve is based on the action spectra of
lipofuscin adjusted for the transmission characteristics of the ocular
media for a person in their 80s.
 ARTICLE IN PRESS
T.H. Margrain et al. / Progress in Retinal and Eye Research 23 (2004) 523–531 527

30.00 10
9

Relative phototoxicity
25.00

Relative Phototoxicity
8
7
20.00
6
15.00 5
4
10.00 3
2
5.00
1
0.00 0
300 400 500 600 700 1st 4th 9th

(a) Wavelength (nm) (b) Decades of life

Fig. 3. Phototoxicity action spectra for three different age groups (a) and their relative phototoxicty (b). The curves are based on the aerobic
photoreactivity of lipofuscin, the age-related reduction in the transmission characteristics of the human crystalline lens and the increase in lipofuscin
content with age (Barker and Brainard, 1991; Delori et al., 2001; Rozanowska et al., 1995).

the predicted action spectra for lipofuscin-mediated 4. Clinical evidence for the role of light in the
oxidative damage in vivo. pathogenesis of AMD
Phototoxicity contributed by lipofuscin increases
substantially with age because the protective effects of The phototoxic effects of light from ophthalmic
lens senescence are offset by a substantial increase in the instruments are well documented (Davidson and Stern-
concentration of photoreactive elements in the retina berg, 1993; Jaffe et al., 1988; Michels et al., 1992;
(Delori et al., 2001). Fig. 3 describes the relative Michels and Sternberg, 1990). Although these exposures
phototoxicity of light for three age groups. Analysis of are acute, the oxygen-dependent nature of the resulting
the area under the curves shows that the potential for damage suggests an oxidative mechanism.
blue light damage increases nine fold over a life-span. Of more relevance to the pathogenesis of AMD,
This figure, which contradicts earlier suggestions that it several studies have reported the effects of an increase in
may be light exposure in childhood that is important in chronic short-wavelength light exposure. The use of
AMD, (Simons, 1993) is likely to underestimate the intraocular lenses without UV filters was found to
effect of age on lipofuscin mediated photodamage increase the incidence of cystic macular oedema follow-
because of lipofuscin’s inhibitory effect on antioxidant ing cataract surgery (Kraff et al., 1985) and epidemio-
activity (Shamsi and Boulton, 2001). logical evidence has shown that progression of AMD is
Although this phototoxicity increases steadily with approximately 2.7 times more likely following cataract
age the potential for blue light damage is likely to be extraction and intraocular lens implantation (Klein
many times greater for those developing AMD where et al., 1998; Pollack et al., 1996). The increased risk of
lipofuscin ‘hot spots’ may act as a focus for local AMD progression has been directly attributed to an
oxidative damage (Holz et al., 2001). Indeed, massive increase in blue light exposure (Cruickshanks et al.,
quantities of lipofuscin have been demonstrated in 1993; Klein et al., 1998). (Werner et al., 1989) showed a
the RPE of eyes with atrophic AMD (Sarks et al., loss of blue colour vision in pseudoaphakic eyes without
1988). The hypothesis, that lipofuscin-mediated photo- UV filtration.
chemical damage increases with age, and particularly so Additional evidence suggesting that blue light has a
for those developing AMD, may explain why antiox- role in the development of AMD comes from studies
idant therapy is beneficial in these groups (Kassoff et al., which indicate that macular pigment is protective
2001). (Beatty et al., 1999; Weiter et al., 1988). Macular
If light were to have a role in the pathogenesis of pigment has a broad band absorbance spectra peaking
AMD the evidence outlined above enables us to make at 460 nm. It is therefore, particularly effective at
several predictions. Firstly, increased exposure to short- reducing the potentially damaging effects of lipofuscin
wavelength radiation, both in terms of intensity and whose photoreactivity peaks at 450 nm in elderly adults
duration, should increase the risk of AMD. Secondly, (see Fig. 2). Estimates of macular pigment density in the
exposure to short-wavelength radiation in old age will human eye suggest that it typically absorbs about 70%
be a greater risk than exposure at other times of life. of incident light at this wavelength. Although, macular
Thirdly, antioxidants should reduce the risk of AMD pigment is found in all retinal layers it reaches its highest
and more specifically their protective effects should be concentration at the receptor axon and the inner
greatest for those with the greatest concentration of plexiform layers and it is therefore well placed to act
lipofuscin. The following paragraphs examine the as a light filter. Unfortunately, despite its name macular
evidence for these predictions. pigment only confers protection to the fovea because its
 ARTICLE IN PRESS
528 T.H. Margrain et al. / Progress in Retinal and Eye Research 23 (2004) 523–531
concentration drops precipitously from the foveal pit i.e.
the optical density of macular pigment drops to half its
value 1.5 from fixation (Kilbride et al., 1989). The
topographical distribution of macular pigment may
explain the pattern of cell loss observed in histological
studies of early AMD (Curcio, 2001; Curcio et al., 2000;
Kilbride et al., 1989). Of course, macular pigment also
has the potential to protect the retina by neutralising
reactive oxygen species (Schalch, 1992) but its location
in the receptor axon layer and the inner plexiform layer,
some distance from the site where reactive oxygen
species are produced does not facilitate this potential.
The potential for light to cause retinal damage may be
increased in people with a history of above-average light
exposure because macular pigment density is inversely
related to light exposure (Mellerio et al., 2002). That is,
the potentially damaging effects of light exposure are
compounded by a reduction in the optical density of MP
associated with chronic light exposure.
It is also of interest to note that the optical density of
macular pigment is significantly reduced in smokers
(Hammond et al., 1996). The reduction in optical
density would increase blue light exposure and this
would be consistent with a blue-light contribution to the
heightened risk of AMD in smokers (Smith et al., 1996).
5. Epidemiological evidence for the role of light in the
pathogenesis of AMD
There have been several population-based studies that
have evaluated the role of ultraviolet and visible light on
the development of AMD (Cruickshanks et al., 1993;
Darzins et al., 1997; Hyman et al., 1983; Taylor et al.,
1990, 1992; West et al., 1989).
An extensive survey of the watermen in the Chesa-
peake Bay area concluded that chronic exposure to blue
or visible light may be related to the development of
AMD (Taylor et al., 1992). Similarly, the authors of the
Beaver Dam Eye Study also suggest that their measures
indicate that visible light rather than UV might be
associated with AMD (Cruickshanks et al., 1993).
Conversely, Darzins et al. (1997) and the Eye Disease
Case Control Study Group (1992) found no such
relationship (Darzins et al., 1997; Eye Disease Case
Control Study Group, 1992).
The equivocal findings reported in the epidemiologi-
cal literature are quite unremarkable. Firstly, the
absence of a relationship with UV simply confirms that
the adult lens absorbs almost all radiation below
400 nm. Secondly, the assumption has been that it is
lifetime exposure to sunlight that is the relevant variable
but this is unlikely to be the case. As already stated the
phototoxicity of blue light increases with age and is
likely to be particularly great for those with lipofuscin
‘‘hot spots’’. Therefore, it is light exposure in old age
and particularly for those with the early signs of AMD
that is the quantity of interest. In support of the notion
that oxidative stress is likely to be most damaging for
those at high risk of developing AMD, a recent large-
scale clinical trial found that the therapeutic effects of
antioxidant therapy were greatest in those with estab-
lished disease (Kassoff et al., 2001).
6. Blue light filters
A number of investigators have proposed the use of
sunglasses which attenuate short-wavelength light to
reduce the phototoxic potential of light (Fishman, 1986;
Ham et al., 1976; Sliney, 2001; Werner and Schmidt,
1975). However, apart from two small scale trials on
three people with retinitis pigmentosa the possible
therapeutic effect of short-wavelength light deprivation
has not been evaluated (Berson, 1980; Werner and
Schmidt, 1975).
The ideal absorption characteristics of sunglasses or
intraocular lenses (IOL) have not yet been established
(Mainster and Sparrow, 2003). However, sunglasses or
intraocular lenses with the transmission characteristics
shown in Fig. 4 reduce the amount of short-wavelength
light reaching the retina and have a yellow/orange and
bronze appearance. Calculations indicate that these
filters would reduce the in vivo aerobic photoreactivity
of lipofuscin by approximately 90%. The notion that a
yellow filter can provide this level of protection is
supported by a recent laboratory study which has shown
that a ‘yellow’ IOL can produce an 80% reduction in
death of A2E laden RPE cells exposed to light (Sparrow
et al., 2004). For reasons given earlier the prophylactic
effect of such filters is likely to be greatest in the elderly
and those at high risk AMD. There may be an added
100
yellow /orange
80
Transmission %
60
bronze
40
20
0
350 400 450 500 550 600 650 700
Wavelength (nm)
Fig. 4. Transmission characteristics of two filters that have a yellow/
orange and bronze appearance. Both filters reduce in vivo lipofuscin-
mediated photoreactivity (see Fig. 3a) by approximately 90% in people
in their 80s.
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T.H. Margrain et al. / Progress in Retinal and Eye Research 23 (2004) 523–531
visual benefit for this group of people when using the
yellow/orange filter because blue light is selectively
scattered by the ocular media and its attenuation has
been associated with improvements in contrast sensitiv-
ity and a reduction in glare sensitivity (Frennesson and
Nilsson, 1993; Leat et al., 1990; Wolffsohn et al., 2000).
Indeed many people with low vision show a preference
for yellow spectacle lenses despite their adverse impact
on colour vision (Rosenblum et al., 2000). However, for
those with normal vision, and in particular for those
who drive, the bronze filter may be preferable because
although such a filter attenuates blue light is does not
block blue light altogether and therefore it would have a
less detrimental effect on colour vision.
Although, it seems likely that filters that attenuate
blue light will have a beneficial effect in terms of retinal
photoprotection there may be unwanted side effects. For
example, the action spectra for photosensitive ganglion
cells, that are thought to have a role in setting our
circadian clock, peaks at 484 nm (Berson et al., 2002).
Consequently, it is possible that blue light filters may
disrupt sleep cycles. However, although sleep disruption
has been reported in people who are ‘blind’ (Tabandeh
et al., 1998), the effect of the blue light filters proposed is
unlikely to be dramatic. This is because the action
spectra is only weakly tuned to short-wavelength light
and multiple types of receptors are thought to con-
tribute to photic entrainment (Berson et al., 2002; Ruby
et al., 2002).
7. Conclusion and future directions
On the basis of the evidence presented here we believe
that there is support for the long-held belief that light
has a role in the pathogenesis of AMD. That is, the
recent finding that antioxidant therapy has a protective
effect confirms that oxidative stress has a role in the
pathogenesis of AMD and laboratory studies have
demonstrated that light, and in particular blue light, is a
source of oxidative stress via its interaction with retinal
chromophores. Therefore, a reduction in blue light
exposure might reasonably be expected to reduce
progression in AMD.
The precise chromopore(s) that may be involved in
the pathogenesis of AMD remains unclear, but the age
pigment lipofuscin which has long been associated with
AMD is a likely candidate. Its aerobic photoreactivity
and adverse effects on antioxidant activity combined
with its gradual accumulation over time suggests that
retinal phototoxicity increases substantially with age
despite changes in the absorption characteristics of the
crystalline lens. This hypothesis suggests that the
potential for blue light to cause retinal damage is
greatest in the elderly and those at risk of AMD
progression.
529
However, it would be premature to recommend the
wide spread use of blue blocking lenses in the elderly
because although there is considerable circumstantial
evidence for such a measure there is no direct evidence
that environmental light causes retinal damage. How-
ever, we conclude that there are now three compelling
reasons for undertaking a large-scale clinical trial to
evaluate the prophylactic effects of blue light filtration
in AMD. Firstly, there are now sound reasons for
suspecting that blue light exposure in old age may
contribute to the development of AMD. Secondly, the
debate on the role of blue light exposure and AMD has
continued for almost three decades and only a large-
scale randomised clinical trial will have sufficient power
to provide conclusive evidence. Thirdly, even a modest
beneficial effect is likely to be associated with substantial
individual and socio-economic benefits because AMD is
reaching epidemic proportions (Evans and Wormald,
1996).
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