Shift work: Coping with the Biological Clock
Professor Emeritus, Endocrinology
Director Emeritus, Centre for Chronobiology
Faculty of Health and Medical Sciences
University of Surrey
Email email@example.com (preferred), or firstname.lastname@example.org
Key words: shift work, circadian rhythm, body clock, melatonin, light, metabolism,
heart disease, cancer
This review concerns the importance of circadian rhythms to the health of shift
Background: A basic description of the circadian system is provided to further
understanding of the phenomena resulting from the misaligned or desynchronised
rhythms which occur in shift work. The use of the circadian marker rhythm melatonin
for determination of body clock time is described.
Effects of circadian desynchrony: Suboptimal functioning of physiological systems
with marked circadian rhythms especially sleep, alertness and performance is related
to the state of desynchrony and its occurrence in different shift schedules. The links
between shift work and major disease risk (heart disease, cancer) are considered
together with the possible mechanisms leading to increased risk.
Possible mechanisms related to long term disease risk: Abnormal metabolism is
invoked as a contributory factor to increased risk of heart disease. Particular emphasis
is put on recent evidence for an increased risk of certain cancers and the hypothesised
roles of light at night, melatonin suppression and circadian desynchrony. The possible
influence of a clock gene variant in tolerance of sleep deprivation is mentioned.
Strategies to alleviate problems of circadian desynchrony: Finally various
strategies for coping with circadian desynchrony and for hastening circadian
realignment are presented.
Many reviews have been published regarding the subjective perceptions, health,
performance and psychosocial aspects of shift work, for example (1-11). There is little
doubt that shift work is associated with a number of health problems such as poor
sleep, gastro-intestinal disorders, abnormal metabolic responses and increased risk of
accidents. A longer term risk of major disease such as heart disease and cancer is
beginning to be appreciated. This review will concentrate on shift work in relation to
biological rhythms since disturbed rhythms appear to underly many of the short and
long term health problems of shift workers (12-14). To this end an introduction to the
subject is provided.
A literature search with the keywords ‘shift work’ and ‘circadian’ gave 1034
references in PubMed. Since the primary output of the internal clock currently used as
a marker of circadian timing, is the pineal hormone melatonin (as well as its actions as
a chronobiotic), the search was then restricted to ((shift work) and (circadian) and
(melatonin)). This provided 189 references, which together with the author’s personal
collection formed the basis of this revue.
Importance of biological rhythms to health
Biological rhythms serve to align our physiological functions with the environment.
We are a diurnal species and thus we normally sleep at night and are active during the
day time. The timing of functions with prominent rhythms such as sleep, sleepiness,
metabolism, alertness and performance in a normal environment is such that they are
optimal during the most suitable phase of the day (Fig 1). Abrupt deviations from
‘normal’ timing of work and sleep can lead to problems, for example sleep taken
during the day is usually shorter and of worse quality than when taken at night (6, 15).
Alertness and performance reach their nadir at night during peak sleep propensity and
fatigue (13, 16, 17), close to the low point of core body temperature and the peak of
melatonin secretion. The health problems and increased risk of major disease in long
term shift workers are ascribed largely to working out of phase with the internal
biological clock. It is likely that many perceptions of the detrimental effects of clock
disruption or abnormal timing derive from observations in shift workers.
Figure 1. Diagrammatic examples of circadian rhythms, from Rajaratnam and Arendt,
Lancet 2001, by permission.
Characteristics of circadian rhythms
Everything is rhythmic unless proved otherwise (18). Biological rhythms of various
periodicity are ubiquitious. The frequency displayed varies from fractions of a second (for
example the firing of neurones) to years (for example population variations). By far the most
information is available concerning daily rhythms (18, 19). They are either externally
imposed, internally generated, or more frequently a combination of these two factors.
Internally generated rhythms with approximately a 24h period are known as circadian, from
the Latin ‘circa diem’, 'about a day'). Circadian rhythms serve to temporally programme the
daily sequence of metabolic and behavioural changes. By definition they persist in the
absence of time cues such as alternating light and darkness and are coordinated by an internal
biological clock (pacemaker, oscillator) situated in the suprachiasmatic nuclei (SCN) of the
brain hypothalamus (20). The basis of circadian rhythm generation is a negative feedback
loop of clock gene expression (21, 22).
Individuals kept in a time free environment (or at least with very weak time cues), manifest
their own endogenous periodicity referred to as ‘free-running’. The free-running period is
individually variable and is an inherited characteristic. On average human endogenous period
(or tau) is about 24.2-3h although this does depend on previous experience of time cues (18,
23). Synchronisation or entrainment of the circadian clock to 24h is dependent on suitable
time cues, also known as ‘zeitgebers’. In circadian literature, synchronisation means that
rhythms display a 24h period but may not necessarily be in the right phase, for example,
12 16 20 24 04 08 12 h
Clock time h
Used as an index of
body clock time
adapt slowly to a
abnormally delayed or advanced. Entrainment means the rhythms are synchronised with the
appropriate phase. When entrained to the 24h day a short endogenous tau is associated with
morning diurnal preference (larks) and a long tau with evening preference (owls)(18).
Circadian response to time cues:
Because the circadian clock period is not exactly 24h it must be reset regularly (phase shifted)
to maintain a 24h period. The most important time cue for maintaining a 24h period is the
light dark cycle acting partly via a novel retinal photoreceptor system and a novel
photopigment melanopsin (circadian photoreception) (24). Recent evidence indicates that
short wavelengths of light (460-480 nm, blue) have the most powerful resetting effects (25).
Blind people with no conscious or unconscious light perception frequently display free-
running rhythms, underlining the importance of light. The timing of sleep also has an
influence together with minor ‘non-photic’ zeitgebers such as exercise, social cues, clock time
and food ingestion. Specific manipulation of food timing in animals influences a so-called
food entrainable oscillator which is independent of the SCN (26). The content of meals in
humans may also have a minor influence.
The circadian response (change in timing or phase shift) to light exposure, and indeed to other
time cues, is dependent on the strength and timing of the stimulus. It can be described by a
‘phase response’ curve (Fig 2) (27, 28). The central clock adapts slowly, and with
considerable individual variability, to a rapid shift in work time or time zone. After a time
zone change the average rate often approximates to one hour of adaptive shift per day. After
an abrupt shift in work time the change is very variable as discussed later (29-31). During the
process of adaptation endogenous rhythms are out of phase with the external environment
(external desynchronisation). They may also be out phase with each other, i.e. assume a
transitory abnormal phase relationship (internal desynchronisation). This condition is often
referred to as ‘circadian desynchrony’. Time cues or ‘zeitgebers’ are all important in
controlling the circadian response to such changes. In general it is easier to delay the clock
than to advance it in view of the longer than 24h period of most people. During a period of
desynchrony, for example a single night of night shift in a sequence of days, workers are
attempting to sleep at a time of maximum alertness and to work at the nadir of alertness and
performance. If adaptation of the clock to a new work schedule occurs, the problems of
desynchrony resolve (32-35).
Figure 2. Circadian response (‘phase response curve’, shift of the melatonin rhythm, advances
are positive, delays are negative) to a 1-2h light pulse, ca 300 lux, 500 nm, at different times
of night. DLMO = dim light melatonin onset, on average at approximately 2100h, thus 8h
after DLMO = 0500h clock time. From Paul et al., 2009, by permission.
Genetic basis of circadian rhythms
Many of the genes concerned with circadian rhythm generation in mammals and other species
have now been identified, e.g. clock, per1, per 2, per 3, tim, cry1, cry2, BMAL1, Rev-Erbα.
The mechanism is similar in all species investigated and substantial homology exists between
for example Drosophila and mammals. Oscillation of clock genes also occurs in peripheral
structures, and in general they are considered to be coordinated through SCN activity.
However, it is possible to shift the timing of some peripheral oscillations (for example in the
liver by timed feeding), independently of the SCN (36). Investigation of polymorphisms in
human clock genes in relation to occupational health and disease is in its infancy. Some
polymorphisms have been identified and associations are emerging with phenotypic
characteristics such as diurnal preference (larks-owls), intrinsic period, vulnerability to
disease and response to sleep deprivation (37-39).
The circadian clock influences hormones, behaviour, cognitive function, metabolism, cell
proliferation, apoptosis and responses to genotoxic stress (22). There is new, strong evidence
concerning the importance of circadian control for health in that disruption of circadian clock
gene expression can lead to increased incidence or progression of cancer (in animals) (22, 40).
Examples of rhythms relevant to human disease
Some examples of human rhythms in disease processes include night time asthma, early
morning increases in blood pressure, death rate from cardiovascular disease and stroke,
disrupted menstrual cycles, abnormal cortisol rhythm in Cushing’s syndrome, sleep disorders
for example delayed sleep phase syndrome, advanced sleep phase syndrome, non-24h sleep
wake cycles (especially in the blind), some psychiatric disorders. Numerous aspects of human
biochemistry show rhythmicity, even urinary creatinine. Thus diagnostic tests should be aware
of these rhythms. Measurement of a given rhythmic variable in someone who has just crossed
several time zones, or worked a series of night shifts, can give false negative or positive
results. Moreover many drugs have a rhythmic variation in both pharmacokinetics and
The melatonin rhythm
A darkness hormone
Melatonin (N-acetyl-5-methoxytryptamine) in an indolic hormone whose principal
physiological function is to provide a humoral time cue for the organisation of seasonal and
circadian rhythms (41). The pineal gland secretes melatonin with a marked circadian rhythm,
peaking at night – it has been called the ‘darkness hormone’ and the duration of its secretion is
directly related to the length of the night. In animals which depend on daylength to time their
seasonal physiology the length of melatonin secretion signals the length of the night. In
humans its circulating concentrations are high from approximately 2100h to 0700h with large
individual variations. This period can be used to define ‘biological night’. The peak secretion
occurs around 0400h, closely associated with the nadir of core body temperature, alertness
and performance (Fig.1). In specific circumstances humans may also show changes in the
duration of secretion (41).
Melatonin as a chronobiotic
Melatonin is not only a so-called ‘hand of the clock’ it has the ability to induce sleepiness or
sleep, change circadian phase and to entrain free-running rhythms when administered in
suitable doses and timing (42). There are several PRCs to melatonin with slight differences,
which can be used to predict the chosen timing in order to hasten a circadian phase shift. This
is important in a shift work context given that a number of attempts have been made to treat
shift workers with melatonin with variable results.
Melatonin suppression by light
Light of sufficient intensity and spectral composition will suppress melatonin production at
night (41, 43). Suppression is detectable at 30-50 lux and maximum from around 1000-2000
lux. Natural daylight can attain more than 100,000 lux. This suppression is associated with
rapidly increased alertness and core body temperature, although causal relationships are not
clear. It is important in a shift work context as light suppression of melatonin has been
hypothesised to be detrimental to health (44). A night shift worker whose circadian clock is in
day mode, or unadapted, will secrete melatonin during work hours. Similarly a worker who
has adapted their clock to night shift will secrete melatonin during the day and on return to
day shift or rest days will secrete melatonin during the hours of natural daylight. Actual
personal light exposure during night shift work has rarely been measured, examples of
personal light exposure on North Sea oil rigs are shown in (57). In general the amount of
suppression reported during field studies on night shift is minor, around 20% (45, 46).
Melatonin indicates the timing of the biological clock
Shifts in the timing of melatonin are considered to represent changes in timing of the central
clock. Measurement of melatonin in plasma, saliva, or its urinary metabolite 6-
sulphatoxymelatonin (43), provides the best peripheral measure of central clock timing
(Fig.3). Other marker rhythms such as core body temperature and cortisol are more subject to
so-called masking, whereby an internal or external influence distorts the rhythm. For example
exercise and food strongly influence core temperature and stress modifies the cortisol rhythm.
The most reliable results regarding circadian status in shift work have been obtained with
melatonin measures and this review will concentrate on melatonin-derived information.
Figure 3. Characteristics of the melatonin rhythm used to define timing of the internal clock.
From (43) by permission.
1500 1700 1900 2100 2300 100
300 500700900 1100 1300 1500 1700
clock time h
plasma melatonin (pg /ml)
acrophase (calculated peak time)
Melatonin (plasma, saliva), 6-sulphatoxymelatonin (urine)
Circadian desynchrony in shift work
Relationship to work hours
There are many varieties of shift work and a legal definition does not appear to exist
except for ‘working outside normal working hours’. For the purposes of this review
let us consider that it is working during ‘average’ biological night, i.e.2100-0700h.
Also for the purposes of this review the assumption is made, based on controlled
laboratory experiments, that when sleep is taken during the period of peak melatonin
secretion (and thus, in theory, the nadir of alertness, performance and core body
temperature) it is optimised. In night shift conditions, if peak melatonin secretion is
shifted to occur during day sleep, it is presumed that adaptation to night shift has
The most numerically important shift work conditions, at least in the UK, are irregular
night shifts (‘sometimes nights and sometimes days’) and rotating schedules
(information from the Office of National Statistics).
UK Annual Labour Force Surveys, Office for National Statistics, 2005
All shiftworkers, 3,551,000
Rotating shifts, 2,722,000
Permanent nightshifts, 343,000
Sometimes nights, sometimes days, 449,000
12.5% of all working population (28,301,000)
Examples of rotations include 3 days early shift (e.g. 06-14h), 3 days late shift (e.g.
14-22h), 3 days night shift (e.g. 22-06h), rest days. These common schedules do not
allow the internal clock to adapt fully to night shift, since there is substantial inertia in
the circadian system. After abrupt large changes in time cues the daily shifts in
circadian timing rarely exceed 1-1.5h on average without interventions. Exposure to
morning light (in the travel home window after night shift) is at a time which opposes
a delay shift of the clock to adapt (Fig.2), and daytime social cues counter circadian
adaptation. Data from field studies indicates that the greater the morning light
exposure the less circadian adaptation is seen (47). Since in temperate latitudes
natural bright light will be more prevalent in summer in the early morning any shift of
the circadian system during night shift will in theory be countered more strongly than
Partial shifts in circadian timing can be seen in short term night shift work, and a
relationship to the timing of light exposure is present, either delays or advances, in
relation to the light phase response curve (29, 48, 49). Natural light exposure, the
most powerful influence, evidently depends on the shift timing. Also important is the
diurnal preference of the subjects (29). Evening preference people are reported, as
might be expected, to have a greater tendency to delay, and morning people to
advance (29, 46)
Most permanent or long term night shift workers (with exceptions, see below) do not
adapt their circadian system to the imposed work schedule. A recent meta-analysis of
6-sulphatoxymelatonin rhythms in permanent night workers indicates that only a
small percentage (<3%) show complete circadian adaptation and less than 25% adjust
to the point that some benefit would be derived from the adaptive shift (50). This may
depend on the ability to maintain night activity and day sleep on days off as well as
other factors such as diurnal preference. However there is a paucity of data and
further research is needed.
Thus the vast majority of shift workers will be working during their circadian nadir,
and trying to sleep during periods of maximum alertness. The curtailment of sleep
when taken during the day in shift workers is well documented, and is a cause of sleep
deprivation. Some examples of short sleep are shown in Table 1.
Sleep deprivation concomitant (inter alia) upon circadian desynchrony has been
attributed a causal role in obesity, metabolic syndrome, glucose intolerance/diabetes,
increased accidents and errors. Sleep restriction has also been associated with
alterations of neuroendocrine control of appetite (51-54).
Table 1. Examples of shorter sleep in night shift workers
4.8h, night shift, fast rotation, Axelsson et al, Int Arch Occup Environ Health
5-6h, morning shift starting before 6 am, Kecklund & Akerstedt, J Sleep Res 1995(56)
6.04h, 7 nights, 7 days, 12h on 12h off, Gibbs et al, HSE Report 318, 2004 (57)
5.83h, 4h on 8h off, permanent night watch, ships crew, Arendt et al, J Biol Rhythms,
7h (approx) healthy adults, Groeger et al, J Sleep Res 2004(59)
8.7h healthy young men, sleep ad lib, Rajaratnam et al, J Physiol, 2004(60)
In relation to sleep deprivation, an important study of interns weekly work hours in
the USA found that they made 36 percent more serious medical errors during a
traditional work schedule than during an intervention schedule that eliminated
extended work shifts. These included 21 percent more serious medication errors and
5.6 times as many serious diagnostic errors (54).
Changing from day to night shift often implies a period of 20-24h without sleep. The
decrements in performance during the latter part of this sleep deprivation may be
equivalent to an illegal level of alcohol in the blood (16). Accidents following a
combination of sleep deprivation and working during the circadian nadir in
performance and the maximum sleep propensity have led to litigation against
individuals and employers (13). It is considered that fatigue may be more important
cause of transport accidents than alcohol.
Top panel: performance levels for the grammatical reasoning task during alcohol
intoxication (left) and sustained wakefulness (right). Bottom panel: performance
levels for the vigilance task during alcohol intoxication (left) and sustained
wakefulness (right). From Dawson and Reid (16) by permission.
The circadian system regulates metabolism (61) and increasing evidence relates
circadian desynchrony to disorders such as metabolic syndrome (insulin resistance,
high blood pressure, central obesity, decreased HDL cholesterol, elevated TAG) and
cardiovascular disease (53). For example eating a standard meal at night (biological
night) leads to high blood lipid (triglyceride, TAG) and evidence for insulin
resistance, compared to the same meal taken during the day (62, 63). Interestingly
there is some evidence that men are more susceptible to these metabolic abnormalities
than women. TAG is an independent risk factor for development of heart disease, and
herein may lie at least a partial explanation for the increased risk of heart disease in
shift workers. In large surveys shift workers have higher TAG levels as well as higher
total cholesterol than the general population (11, 64).
There are associations between polymorphisms in the Clock gene, obesity and the
metabolic syndrome in man, and mice bearing a particular mutation of the gene Clock
develop metabolic syndrome and obesity (65, 66).
Circadian adaptation in unusual environments
Some exceptions to the general rule that shift workers do not fully adapt to night shift
are found in isolated environments. On the British Antarctic Base of Halley, 750S,
each base member does a week of night shift (2000-0800h, fire watch) at a time, in
rotation with other personnel. The vast majority of people shift their circadian system,
assessed by aMT6s rhythms in urine, by up to 10-12h to align with the new work
Mean relative performance
Blood alcohol concentration (%) Hours of wakefulness Blood alcohol concentration (%) Hours of wakefulness
Blood alcohol concentration (%)
.00 .025 .045 .065 .085 .10+ .00 .025 .045 .065 .085 .10+3 7 11 15 19 21 23 3 7 11 15 19 21 23
Mean relative performance
Blood alcohol concentration (%)
Mean relative performance
Blood alcohol concentration (%) Hours of wakefulness Blood alcohol concentration (%) Hours of wakefulnessBlood alcohol concentration (%) Hours of wakefulness
Blood alcohol concentration (%)
.00 .025 .045 .065 .085 .10+.00 .025 .045 .065 .085 .10+ .00 .025 .045 .065 .085 .10+3 7 11 15 19 21 233 7 11 15 19 21 23 3 7 11 15 19 21 23
Mean relative performance
Blood alcohol concentration (%)
Mean relative performance
Blood alcohol concentration (%)Blood alcohol concentration (%)
schedule, within a week (67, 68). Thus the peak of melatonin production occurs
within the daytime sleep period - an important condition for sleep duration, latency
and quality. This is thought to be due to the lack of social and family obligations, no
requirement to return home in natural light, and in winter when the sun does not rise
for three months, a lack of conflicting light exposure. In these circumstances it is
apparent that owls adapt by delay faster than larks (69). Problems occur when
endeavouring to adapt back to day work particularly in winter. Realignment of the
circadian system can take weeks and some people will free run for a time.
These observations in Antarctica prompted studies in somewhat similar circumstances
on North Sea oil rigs. Work schedules vary but tours of duty usually last for 2-3
weeks in a socially isolated environment at high latitudes. Here working 1800-0600h
for one or more weeks also leads to full circadian adaptation in the majority of cases
with the accompanying problems returning to day life (30, 70, 71). Interestingly a
1900-0700h schedule is less conducive to circadian adaptation, possibly due to early
morning light exposure after work especially in summer (72). Sleep is worse during
this shift than the 1800-0600h shift. The so-called ‘swing shifts’ worked in the North
Sea present a confused picture. Seven night shifts (1800-0600h) followed by 7 day
shifts (0600-1800h) leads in most people to adaptation to nights but with a very mixed
response to the following days (30, 73) (Fig.5). Some people delay, some advance and
many show little readaptation to days during the first week. The response is partly
predictable from the initial circadian phase position- delayed, intermediate, or
advanced. Other schedules such as a 7 day, 1200-2400h day shift followed by a 7 day
2400-1200h night shift show partial or no adaptation to night shift which is dependent
on season (71). Again this can be attributed to light exposure countering adaptation.
Figure 5. Progression of the individual timing of the melatonin rhythm (by urinary
aMT6s), during a week of nights (1800-0600h) followed by a week of days (0600-
1800h) in 11 individuals working on a North Sea oil rig. Most shift their timing such
that at the end of nights the peak of melatonin is during the daytime sleep and thus
they are adapted. The subsequent response to a change to day work is highly variable.
From (30) by permission.
Such circumstances, when workers show different circadian timings according to
whether or not they have adapted to nights, have allowed field assessments of the
metabolic consequences of a night shift meal. As with controlled laboratory
experiments, elevated TAG, LDL cholesterol and evidence of insulin resistance were
found when unadapted (57). These sequelae resolved when adaptation had occurred.
Special cases of shift working are seen in marine watchkeeping systems. There are
very few data relating to melatonin rhythms, however a study in submarines has
shown evidence that crew can free-run whilst working an 18h day, submerged for
long periods (58, 74). Crew working 4h on and 8h off on fixed or rotating schedules
on a British Antarctic Survey ship travelling from the UK to 750S showed evidence of
partial circadian adaptation to the 1200-1600h, 2400-0400h fixed watch, but not to
weekly rotating watches (58).
Light at night and the risk of major disease
It is not the purpose of this review to evaluate the epidemiological evidence for
increased risk of disease in shift work, this can be found elsewhere. It is generally
accepted that there is an increased risk of heart disease and some contributory factors
related to the biological clock have been discussed above.
A possible significant association was identified between female breast cancer and
shift work some time ago (75). This is potentially a major problem since estimates
from the Spring 2002 wave of the Labour Force survey suggest that an estimated 1.8
million women in Great Britain usually or sometimes do shift work. Of these, an
estimated 400,000 are involved in night work of various schedules
(http://www.hse.gov.uk/press/2003/e03132.htm). In 2006 the World Health
Organisation (IARC) published a brief report in the Lancet of an expert meeting on
whether or not shift work was associated with an increased risk of cancer, particularly
breast cancer. The conclusion was that shift work was a probable carcinogen (76). A
full monograph is expected from this meeting but has not yet been published. There
are considerable implications arising from this decision and for example, according to
the UK national press in March 2009, the Danish government decided to compensate
shift workers who develop breast cancer. Both the UK and Dutch governments also
issued publications discussing the evidence and in general decided that further
epidemiological evidence and mechanistic data were needed (Parliamentary Office of
Science and Technology, UK, Postnote No.250, 2005, The 24h Society; IEH (2005)
Shift Work and Breast Cancer: Report of an Expert Meeting 12 November
2004 (Web Report W23), Leicester, UK, MRC Institute for Environment and Health,
available at http://www.le.ac.uk/ieh/; Dutch government advisory publication, Night
Work and Breast Cancer: a Causal Relationship? The Hague: Health Council of the
Netherlands, 2006, http://www.gr.nl). Assuming that the risk assessments are correct,
let us consider the possible mechanisms.
The most well known theory concerning cancer and shift work relates to light exposure at
night (LAN). Stevens (44) hypothesised that the increasing incidence of breast cancer in the
developed world was due to light exposure at night. He further proposed that since light
suppresses melatonin and melatonin has some oncostatic activity in animals, that the increase
in breast cancer was due to a decrease in melatonin. Numerous questions arise from this
proposal, some of which can be addressed. The WHO (IARC) expert meeting concluded that
there was definite evidence for anti-cancer effects of melatonin in animals and in vitro, but
little in humans. It should be noted that human in vivo data are sparse. The data which directly
addressed the cause and effect relationship between melatonin and human breast cancer
involved maintaining human breast transplants (xenografts) in rats and assessing short term
markers of cancer with and without circulating endogenous levels of melatonin. Physiological
levels of melatonin were able to reduce or abolish carcinogenic changes in these markers (77).
This latter study does suggest that endogenous melatonin has anti-proliferative effects
working via a membrane receptor. However not all studies have shown anti-proliferative
effects of melatonin in vitro. Is melatonin suppressed in night shift workers? Again the data
are sparse, the existing evidence mentioned previously suggests that an approximately 20%
reduction may be found during the night shift. Is a 20% reduction in melatonin carcinogenic?
There is no answer to this question. However it should be noted that adrenergic beta receptor
blocking drugs such as atenolol and propanolol suppress melatonin and are not known to be
carcinogenic (41). Moreover the individual variability in melatonin production is very large
indeed and in cross sectional studies large numbers of subjects are needed to show this small
overall reduction (41).
More convincing are the effects of general circadian disruption in animals (78).
Exposure of animals to continuous light increases vulnerability to cancer development
(79, 80). Subjecting rodents to forced phase shifts analogous to rotating shift work or
frequent time zone change substantially increases proliferation of implanted cancers
(40). Manipulation of clock gene function likewise has carcinogenic effects (14, 22,
81, 82) and the circadian clock is considered to be a tumour suppressor. So the case is
close to being made for circadian disruption leading to cancer.
The problem is that increasing light at night in short term shift work leads to
improved alertness, performance and possibly metabolism, whilst no doubt increasing
melatonin suppression. At present investigations are proceeding on the use of glasses
which can block the short wavelengths most likely to suppress melatonin whilst
hopefully maintaining alertness and performance.
Approaches to reducing desynchrony
The question arises as to the benefits and disadvantages of aiding, or countering
adaptation in order to secure the maximum duration of good quality sleep and other
health benefits. In the unusual case of full adaptation, it makes sense to hasten this
process and that of readaptation to day work. In short term night shift it may be more
useful to maintain day time circadian phase whilst using strategies such as alerting
stimulants (caffeine, and possibly modafinil), quiet dark sleeping quarters (and
possibly hypnotics) to preserve sleep and performance.
Light of suitable spectral composition and intensity can be used to adjust the timing
and probably amplitude of circadian rhythms. The hormone melatonin can also act as
a zeitgeber (vide supra). Light treatment during the first half of ‘biological night’
prior to the melatonin peak will delay circadian rhythms and during the latter half,
after the melatonin peak, will advance rhythms (Fig.2). Melatonin treatment by
contrast advances rhythms in the first half of ‘biological night’ and delays them in the
There is no doubt that in controlled laboratory situations, and with good compliance
at home, both light and melatonin, separately or in combination, can be used with
correct timing to hasten phase shift of the circadian system to align it with the new
work rest schedule (32, 43, 49, 83). Moreover with suitable timing the sleep inducing
effects of melatonin during ‘biological day’ can be exploited: There are clear benefits
for sleep, alertness and performance. In field situations the results are inconsistent.
Very probably this is due to the large individual differences in response to phase shift,
and in consequence mistiming of the treatment. However in studies offshore and in
Antarctica useful results have been reported with timed light treatment (67, 84). The
author is only aware of one combined treatment study which was offshore and with
beneficial effects (85). Possibly the most useful application of melatonin to shift
workers would be to facilitate sleep or a nap, prior to night shift. It is particularly
difficult to sleep in the early evening, and the combination of low dose melatonin, a
dark room and recumbency is very effective at enabling sleep at this time of day (60).
An alternative approach has been described recently. This is to shift the circadian
system, using timed light and melatonin, just to the point where the melatonin peak
falls within the sleep period, avoiding large shifts which lead to readaptation
problems (34, 86). This strategy appears to provide benefit for sleep, alertness and
performance. However if the timing is wrong the opposite of the desired result will be
produced. For example instead of adapting to an 8h advance in work time by
advancing the clock, the system may delay. Avoidance of light at the wrong time is
possibly more important than the light treatment itself.
A genetic variant predicting intolerance to sleep deprivation
Morningness has been related to intolerance to shift work in some studies although
not all are consistent. Recently a length polymorphism (variable number tandem
repeat polymorphism) in the clock gene PER3 (PER3 5/5, 4/5, 4/4) was found to
relate to diurnal preference, the longer repeat 5/5 being associated with extreme
morningness and the 4/4 with extreme eveningness (38). Subsequently it was found
that the 5/5 genotype suffered more from sleep deprivation than the 4/4 genotype and
these differences could be explained by an effect of the polymorphism on sleep
homeostasis (37): it was associated with greater sleep propensity and a higher
proportion of slow wave sleep than the 4/4 genotypes. Most importantly the subjects
with the 5/5 variant suffered far greater consequences of sleep deprivation in terms of
performance (notably during the circadian nadir) than the 4/4 genotypes. Mongrain
and Dumont have also shown that morning types have a higher homeostatic response
to sleep disruption than evening types (87). This observation suggests that workers
who are extreme morning types should choose their schedules carefully with regard to
preserving sleep. One further study addressing a similar question, but different
methodology, found an association with sleep homeostasis but did not confirm the
effect on neurobehavioural responses (88).
It is of interest to note there are also preliminary reports of greater susceptibility to
breast cancer in women with the 5/5 variant and prostate cancer in men with the
CRY2-variant C allele (39, 89). No doubt more information will be available shortly
given the importance of predicting the possible health consequences of shift work.
I would like to thank all colleagues, students, volunteers and funding bodies who have
provided input, samples and support for our work on biological rhythms over the
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