Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue11.2000:

Bright Light Exposure of a Large Skin Area Does Not
Affect Melatonin or Bilirubin Levels in Humans
Niki Lindblom, Taina Hätönen, Maija-Liisa Laakso, Aino Alila-Johansson,
Marja-Leena Laipio, and Ursula Turpeinen
Background: Light treatment through the eyes is effective
in alleviating the symptoms of some psychiatric disorders.
A recent report suggested that skin light exposure can
affect human circadian rhythms. Bilirubin can serve as a
hypothetical blood-borne mediator of skin illumination
into the brain. We studied whether bright light directed to
a large body area could suppress the pineal melatonin
secretion or decrease serum total bilirubin in conditions
that could be used for therapeutic purposes.
Methods: Seven healthy volunteers participated in two
consecutive overnight sessions that were identical except
for a light exposure on the chest and abdomen in the
second night from 12:00 AM to 6:00 AM (10,000-lux, 32
W/m2 cool white for six subjects and 3000-lux, 15 W/m2
blue light for one subject). Hourly blood samples were
collected from 7:00 PM to 7:00 AM for melatonin radioimmunoassays. Bilirubin was measured by a modified diazo
method in blood samples taken at 12:00 AM and 6:00 AM

and in urine samples collected from 7:00 PM to 11:00 PM
and from 11:00 PM to 7:00 AM.
Results: The skin light exposure did not cause any
significant changes in serum melatonin or bilirubin levels.
The excretion of bilirubin in urine was also the same in
both sessions.
Conclusions: Significant melatonin suppression by extraocular light does not occur in humans. Robust concentration changes of serum total bilirubin do not have a role
in mediating light information from the skin to the central
nervous system. Biol Psychiatry 2000;48:1098 –1104
© 2000 Society of Biological Psychiatry
Key Words: Extraocular phototransduction, skin light
exposure, light treatment, pineal gland, melatonin suppression, bilirubin

From Pediatric Neurology, Hospital for Children and Adolescents (NL) and
Institute of Biomedicine, Department of Physiology (TH, M-LLaa, AA-J),
University of Helsinki, Helsinki; Neural Networks Research Centre, Helsinki
University of Technology, Espoo (M-LLaa); the Department of Clinical
Chemistry (M-LLai) and Laboratory (UT), Helsinki University Central Hospital, Helsinki, Finland.
Address reprint requests to Niki Lindblom, M.D., Rinnekoti Foundation, Kumputie
1, FIN-02980 Espoo, Finland.

Received January 3, 2000; revised April 14, 2000; accepted April 20, 2000.

© 2000 Society of Biological Psychiatry

Introduction

T

he mechanisms by which light affects the regulation
of sleep, circadian rhythms, and mood are poorly
understood. Nevertheless, since the 1980s numerous studies have shown that light therapy has beneficial effects
when applied in certain types of sleep and mood disorders
(e.g., Eastman et al 1998; Lewy et al 1982; Rosenthal et al
1984; Terman et al 1995, 1998). Today, research is in
progress for defining the optimum quality and quantity of
light, and the proper timing of exposure in various
disorders (e.g., Chesson et al 1999; Lewy et al 1998).
To date, it was thought that in adult mammals light can
affect brain functions only through the eyes (Nelson and
Zucker 1981; Underwood and Groos 1982); however, this

concept has to be re-evaluated, since it was reported that
the human body temperature rhythm and melatonin onset
time were shifted by bright light directed to the skin
behind the knee (Campbell and Murphy 1998). The
finding is theoretically interesting, and in addition, it
might have practical applications.
The level of effective illuminance in light treatment
directed to the eyes is highly dependent on the subject’s
behavior. For example, the threshold illuminance needed
to suppress melatonin varies greatly according to the
experimental conditions. Illuminances as low as 6 –17
photopic lux have been reported to suppress melatonin in
strictly controlled conditions (monochromatic light of 509
nm, light beam directed uniformly on the retina, dilated
pupils, and subject’s head kept motionless; Brainard et al
1988). In another study, when the subjects were sitting in
front of a light source and gazed at the source for 10 sec
every 2 min, a significant suppression was produced by
500-lux but not by 200-lux illuminance (Hashimoto et al
1996). This variability does not cause problems if the

patient participating in the light therapy is well motivated
and able to follow the instructions; however, sleep disorders are extremely common and harmful in, for example,
mentally retarded people and in patients with Alzheimer’s
disease, and some of them can benefit from light therapy
(Guilleminault et al 1993; Van Someren et al 1997). In
their case, it would be useful if the light treatment could be
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Skin Light, Melatonin, and Bilirubin

delivered without worrying about the gaze direction or
openness of the eyes.
In attempts to determine the effectiveness of light, the
melatonin suppression test is often used. Although it is
quite possible that light affects the brain functions without
changing the secretion of the pineal hormone, the suppression of nocturnal melatonin synthesis can be a sign of the
light stimulus reaching the hypothalamus, the site of the
main body clock. This assumption is valid at least if the
light stimulus is directed to the eyes and mediated through

the retinohypothalamic pathways. Two independent studies have shown that bright light directed to the small skin
area behind the knee for 3 hours does not suppress
melatonin secretion in humans (Hébert et al 1999; Lockley
et al 1998). It is possible, however, that the efficacy of skin
light exposure depends on the size of the exposed area and
the duration of the exposure. Therefore, we decided to
study whether extraocular light exposure delivered to a
larger body area and for a longer period would produce
melatonin suppression.
The mechanisms involved in the possible humoral
phototransduction are completely unknown; however, an
attractive hypothesis has been presented. According to the
original model, some light-sensitive molecules, such as
bilirubin or hemoglobin, circulating in retinal blood vessels could mediate the effects of light to the circadian
regulatory machinery (Oren 1996). Later this hypothesis
was further developed to include the concept of extraocular phototransduction through the skin (Oren and Terman
1998).
Bilirubin is formed mainly in the cells of the reticuloendothelial system as a product of heme catabolism. Despite
seemingly only a waste product, it has been shown to
posses strong antioxidant activity (Stocker et al 1987).

This and its well-known sensitivity to light may be in
favor of the assumption that it might function as a
blood-borne mediator of extraocular phototransduction. In
hyperbilirubinemic newborns the renal excretion of bilirubin can be substantially increased by skin phototherapy
(McDonagh and Lightener 1985). The effect of phototherapy is based on the light-induced formation of hydrophilic
molecules from the lipophilic bilirubin.
There is minimal information available about the effects
of light on normobilirubinemic adults. According to a case
study, molecular changes similar to those in newborns
occurred in the structure of bilirubin in an adult subject
wearing only shorts and exposed to natural sunlight for 90
min (McDonagh 1986); however, no changes in the serum
level of total bilirubin could be found. This may be due to
the short exposure time and the fact that the bilirubin
concentration changes caused by the excretion of photodegradation products may be detectable only after a longer
period. Therefore, we studied whether a 6-hour skin light

BIOL PSYCHIATRY
2000;48:1098 –1104

1099

exposure might cause changes in total serum bilirubin
levels or in the amounts of bilirubin excreted in urine of
healthy adult volunteers.

Methods and Materials
Seven healthy unmedicated subjects (two female and five male,
all white, age range 19 – 43 years) gave informed consent after
the nature of the study had been explained. The study protocol
was accepted by the ethical committee of the institute. During the
5 days preceding the study the subjects were told to avoid bright
lights at night, strenuous physical excercise, and beverages
containing alcohol.
For the sham light laboratory session the subjects arrived
between 5:00 PM and 6:30 PM and were asked to empty their
bladders, after which a venous cannula for hourly blood samples
was inserted in the antecubital vein. Thereafter the subjects were
in a dimly lit room (,10 lux, Chroma Meter CL-100, Minolta,
Osaka, Japan). During the period from 7:00 PM to 11:00 PM the

subjects were allowed to play games and listen to music but not
to lie down. A standard snack was served from 10:00 PM to 11:00
PM. Urine was collected at 11:00 PM (not at 12:00 AM) for
practical reasons.
At 11:00 PM the subjects lay down under the light sources and
their eyes were covered with black cloth (tied four times around
the head and extending from the upper forehead to cheeks)
impermeable to the illuminance of 10,000 lux (tested by the
authors). The subjects were also specifically asked to report
immediately if any light entered their eyes during the light
exposure. No such report was given by any one of the subjects.
In addition, the light sources were covered with multiple dark
blankets to prevent light from escaping to the surroundings.
During the sham light session, the lights of the panels were off,
but fans were on from 12:00 AM to 6:00 AM to make the sound
conditions similar to those during the light exposure session. At
7:00 AM the last blood sample was drawn, the eyes were
uncovered, and the urine was collected.
On the same day between 5:00 PM and 6:30 PM the subjects
returned to the laboratory for the skin light session, which was

carried out in a manner similar to that of the sham light session
except that from 12:00 AM to 6:00 AM the lights were on and the
fans were directed under the panels to cool the air. The
temperature under the panels was continuously monitored by the
researchers during both sessions. Most of the time it was
24 –26°C, but rose transiently to 29°C during the light exposure
session. The subjects were allowed to sleep from 11:00 PM to
7:00 AM while lying, but their sleep was disturbed when the
researchers monitored the posture, eye covers, and temperature
under the light panels and collected the hourly blood samples.
The sleep was similarily disturbed during both nights.
Three light sources, each suitable for the light exposure of two
subjects lying side by side, consisted of two fluorescent broadspectrum (Figure 1A) white light tubes (Philips TLD 18/950,
Rosendahl, Holland; 5300 K, 58 W, length 152 cm) assembled in
a wooden structure (length 168 cm, height 60 cm, width 48 cm),
giving an illuminance of approximately 10,000 lux and an
integrated irradiance of 32 W/m2 (measured spectroradiometri-

1100

N. Lindblom et al

BIOL PSYCHIATRY
2000;48:1098 –1104

The assay used for the analysis of total bilirubin was a
modified diazo method (Doumas et al 1982; Jendrassik and Gróf
1938). Total bilirubin was measured in both sessions from serum
samples taken at 12:00 AM and 6:00 AM and from urinary
specimens taken as described above. The intra-assay variability
was ,7%. All bilirubin samples were placed in dark tubes,
protected from light during all procedures, and measured in the
same assay.
Two-way analysis of variance (ANOVA) for repeated measures was used in statistical evaluations of the serum melatonin
and bilirubin levels, the excretion rate of urine, and the excretion
of bilirubin in urine. In addition, the secretion of melatonin
during the 2 nights was compared by applying the area under the
curve (AUC) analysis. The “prelight” and “during light” AUCs
and the peak and postlight levels of melatonin were expressed as
percentages of the corresponding values in the sham light session

and evaluated by two-tailed one-sample t test (deviation from
100%). The minimum detectable deviation from 100% was
calculated by a method described previously (Rosner 1986). The
same method was used for the calculations of the minimum
detectable difference in serum total bilirubin levels between the
samples taken at 12:00 AM and 6:00 AM.

Results

Figure 1. Spectral power distributions of the light sources used
in the experiment. (A) White light. (B) Blue light.
cally—Bentham Instruments, Reading, UK) to the subjects’
naked skin between the neck and hip levels (the size of the
illuminated body area was estimated to be approximately 50
cm 3 40 cm, distance from the lamps ca. 20 cm). For one subject
a commercial fluorescent blue light device (Figure 1B) was used
as the light source (Phototherapy lamp Medela Ag, Baar,
Switzerland, 90 W, 3000 lux, 15 W/m2, distance 40 cm from the
subject). The other conditions and protocol for this subject were
similar to those of the other subjects. All calculations and
statistical evaluations were performed both by including and by
excluding the subject exposed to blue light. Because the results
and interpretations were the same for both sets of subjects, only
the results from all seven subjects are presented.
The blood samples were centrifuged and the serum stored at
224°C. Melatonin was extracted from 1.0 mL of serum with
chloroform and measured in duplicate by radioimmunoassay
(Vakkuri et al 1984). The nonspecific binding of the tracer was
5– 6%. The least detectable concentration, defined as apparent
concentration at 2 SDs from the counts at maximum binding
(n 5 6 in each assay), was smaller than the lowest standard (1.95
ng/L). Intra-assay variability was ,10%. The interassay variability during 24 months in 16 assays including the assays of this
study was 15–18%, depending on the concentration. All samples
of each pattern were measured in the same assay.

All seven subjects had a clear melatonin rhythm with peak
values during the night (Figure 2, B–H). The average
serum level profiles did not differ significantly between
the sham light and skin light sessions (two-way ANOVA;
Figure 2A). In most subjects the profiles were very similar
during both nights. However, two of the seven subjects
(Figure 2, B and C) had somewhat lower serum melatonin
concentrations during the light exposure than during the
sham light, one from the beginning of the treatment for
3– 4 hours and the other during the latter part of the light
exposure from 3:00 AM to the end of the experiment.
In AUC analysis it was found that subject B had
similarily decreased melatonin levels before and during
the light treatment as compared with the corresponding
intervals in the sham light night (85% vs. 86%; Table 1).
The decrease of serum melatonin in subject C during light
exposure seemed more pronounced (AUC during light
78% of sham light vs. AUC prelight 102% of sham light;
Table 1); however, statistical evaluation of the mean
AUCs of all seven subjects did not disclose any differences between the sessions. Furthermore, the melatonin
peak level, found at any time from 12:00 AM to 6:00 AM,
did not differ between the sessions, nor did the postlight
melatonin concentration (Table 1).
The mean serum bilirubin levels were equal in both
sessions at 12:00 AM and of the same magnitude at 6:00 AM
(Table 2). The standard deviation of the individual differences between the values at 12:00 AM and 6:00 AM was
63.4 mmol/L. Thus, the minimum detectable difference
was 3.7 mmol/L (n 5 7, p 5 .05, power 80%). Bilirubin

Skin Light, Melatonin, and Bilirubin

BIOL PSYCHIATRY
2000;48:1098 –1104

1101

Figure 2. Serum melatonin concentrations in 7
healthy subjects during the sham light session (■)
and the skin light session (E). (A) Means with
SEMs (two-way analysis of variance: session, ns;
time, p , .001; interaction, ns). (B–H) Individual
curves. Light was directed to the chest and abdomen of the subjects with the eyes covered for 6
hours, with 10,000-lux, 32 W/m2 cool white light
for six subjects (B–D and F–H) and 3000-lux, 15
W/m2 blue light for one subject (E). The period of
the light exposure is indicated by the rectangle
above the abscissa.

excretion in urine was equally low during both sampling
intervals and similar in both sessions. Thus, no effect of
skin light exposure was found on serum total bilirubin
concentration or excretion rate in urine. There were no
significant correlations between the individual serum bilirubin levels and the excretion rates in urine, probably due
to the large variation of urine bilirubin excretion rates.

Discussion
The 6-hour bright light exposure on a large skin area had
no significant influence on the average melatonin secre-

tion profile in our subjects. The result is in line with the
findings that illumination of the popliteal skin with bright
white light (Lockley et al 1998) or blue light (400 –550
nm; Hébert et al 1999) for 3 hours did not suppress
melatonin in healthy adults. The illuminated skin areas in
the previous studies were 10 and 50 –100 cm2, respectively. In our study, a rough estimation for the skin area
illuminated effectively was about 50 cm 3 40 cm. Thus,
prolonging the exposure period twofold and extending the
illuminated area at least 20-fold did not make the treatment more effective.
Furthermore, the conclusion that melatonin suppression

1102

N. Lindblom et al

BIOL PSYCHIATRY
2000;48:1098 –1104

Table 1. Characteristics of Serum Melatonin Profiles in Seven Healthy Subjects during the Skin Light Session
Area under the curve
Subject
E
B
C
D
F
G
H
Mean 6 SD
MDD

Prelight
(7:00 PM–12:00

AM)

During light
(12:00 AM– 6:00 AM)

Peak level
(any time)

Postlight level
(6:00 AM)

97
86
78
110
103
103
97
96 6 11
14

90
93
74
90
114
107
96
95 6 13
16

117
103
65
135
119
99
100
105 6 22
27

93
85
102
130
92
96
83
97 6 16
20

Light was directed for 6 hours (12:00 AM– 6:00 AM) to the chest and abdomen of the subjects lying under the light sources with their eyes covered. Subjects B–D and
F–H: fluorescent white light, illuminance 10,000 lux, integrated irradiance 32 W/m2. Subject E: blue light, 3000 lux, 15 W/m2. All values are given as percentages of the
corresponding values of the control profiles determined in the sham light session without turning the lights on. None of the mean percentages was different from 100%
(two-tailed one-sample t test). MDD, minimum detectable deviation from 100% (n 5 7, p 5 .05, power 90%).

in humans does not occur through skin illumination is
supported by the finding that in hyperbilirubinemic newborns exposed to phototherapy with the eyes covered, the
serum melatonin levels were elevated rather than suppressed (Jaldo-Alba et al 1993). In addition, there is
evidence for the inefficacy of facial illumination to suppress melatonin in completely blind people (Czeisler et al
1995) and for its relative inefficiency to suppress melatonin in sighted people with the eyes closed (Hätönen et al
1999); however, the lack of melatonin suppression by
extraocular light does not exclude the possibility that other
brain functions can be influenced by extraocular light.
The decreased serum melatonin concentrations in two
of the seven subjects during the light exposure session
raises the question of whether there might be interindividual differences in the sensitivity to extraocular light and
whether melatonin suppression might be seen in a subpopulation. Usually, the individual melatonin profiles are
very similar from night to night (Arato et al 1985; Arendt
1988; Laakso et al 1990), as they were in the other five
subjects in this study. Because the low melatonin levels in
the two subjects were not found evenly during the light
exposure and the decrease occurred during different times

within the light exposure period, it seems improbable that
the suppressions were caused by light.
When we tried to find the explanation for the suppression, we noticed that these two persons deviated from the
other five subjects in having an exceptionally high urine
flow during the light exposure session from 11:00 PM to
7:00 AM (B sham light/light 36/64 mL/hour, C 22/69
mL/hour; other five subjects 29/22, 30/29, 24/25, 21/26,
and 58/69 mL/hour). Thus, although the mean urine flows
did not differ significantly between the sessions, the two
persons with the decreased serum melatonin levels excreted urine during the light exposure approximately two
or three times the amount they excreted during the sham
light exposure. When interviewed afterwards, subject B
said that she felt thirsty in the evening preceding the light
exposure and drank a lot of water, which was freely
available during the sessions. Subject C was given water to
drink several times during the light exposure because he
complained of “unbearable thirst.”
Thus, the water balance of the two subjects most
probably differed between the two sessions. It has been
shown that changes in hemodynamics by posture alterations can result in significant changes in serum melatonin

Table 2. Concentration of Serum Total Bilirubin, Excretion of Urine, and Excretion Rate of Urine Bilirubin (mean 6 SEM) in
Seven Healthy Subjects during the Sham Light and the Skin Light Sessions
Urine

Sham light
Skin light
Two-way
analysis of variance

Time

Serum bilirubin
(mmol/L)

12:00 AM
6:00 AM
12:00 AM
6:00 AM
Session
Time
Interaction

12.6 6 3.0
13.4 6 3.5
12.9 6 3.0
13.8 6 2.6
ns
ns
ns

Period
6:00 PM–11:00
11:00 PM–7:00
6:00 PM–11:00
11:00 PM–7:00

PM
AM
PM
AM

Volume
(mL/hour)

Bilirubin
(nmol/hour)

65 6 17
31 6 5
61 6 7
43 6 9
ns
p , .05
ns

284 6 70
233 6 23
316 6 84
204 6 56
ns
ns
ns

Light exposure (10,000-lux, 32 W/m2 cool white in six subjects and 3000-lux, 15 W/m2 blue light in one) of chest and abdomen from 12:00

AM

to 6:00

AM.

Skin Light, Melatonin, and Bilirubin

concentrations (Deacon and Arendt 1994). It is possible
that alterations in fluid balance for other reasons also
cause changes in serum melatonin concentrations. In
addition, an increased urine flow has been reported to
increase the rate of melatonin excretion in sheep, probably
due to decreased tubular reabsorbtion (Valtonen et al
1993). In the sheep study, the serum melatonin concentration did not decrease within 90 min; however, a decrease
can appear if the abundant urine flow continues for a long
time and the loss of melatonin is not compensated for by
increased melatonin synthesis. We consider the variations
in fluid balance the most probable reason for the decreased
serum melatonin levels in subjects B and C.
The 6-hour bright light exposure on the chest and
abdomen did not change the serum total bilirubin concentrations or the urinary excretion rate of bilirubin in our
subjects. When bilirubin absorbs a photon, three types of
chemical reactions can occur: slow photo-oxidation (e.g.,
to monopyrroles and dipyrroles), structural isomerization
to lumirubin, or configurational isomerization by conversion from double to single bonding of one of the bridges
joining the pyrrole rings (Ennever 1990; McDonagh and
Lightner 1985). The reaction products are more water
soluble than the original substrate and can be excreted in
bile and urine.
The diazo method used in the measurements does not
detect the oxidation products or lumirubin, but it does
detect all the configurational isomers (Ennever 1990). Our
results suggest that significant skin light–induced photooxidation or structural isomerization of bilirubin does not
occur in normobilirubinemic adults during a 6-hour skin
light exposure. As in the previous case study (McDonagh
1986), the configurational isomerization could have occurred in our subjects, but the reactions did not lead to any
detectable decrease of total bilirubin levels. The possibility
remains that different isomers can have different effects in
the central nervous system. In addition to the heme-related
compounds, other molecules such as vitamin D, known to
be sensitive to ultraviolet radiation (Holick 1995), may
serve as messengers from the skin to the brain (Stumpf and
Privette 1991).
In summary, the secretion of the pineal hormone melatonin, known to be very sensitive to ocular light, was not
significantly affected by skin light exposure on a larger
body area (chest and abdomen) and for a longer period (6
hours) than previously tested; however, possible effects of
extraocular light on other hypothalamic functions cannot
be excluded by this study. Moreover, the present results do
not support a role for short-term fluctuations of serum total
bilirubin levels in mediating the light information from the
skin to the central nervous system. The possibility remains
that more subtle changes in the structure of bilirubin are
involved in extraocular phototransduction.

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1103

This study was financially supported by the Rinnekoti Research Foundation, Espoo, Finland.

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