Circadian Phase Shift

       If by circumstances a human organism is forced to work at a time different from that induced by the physiologic light dark regulation of our surrounding, the central and peripheral oscillators follow that new schedule not immediately but over a certain number of transient cycles to adapt to the changed environmental synchronizer phase.  During this time of adaptation, there occurs a desynchronization of the normal rhythmic sequence of events with some genes responding faster than others, which leads to an internal desynchronization within the oscillator mechanism.  In addition, the time adaptation of the central oscillators in the hypothalamus precedes that in the peripheral tissues, which follow at a slower pace and are transiently lost to the hypothalamic control.  This adds to the internal desynchronization within the individual oscillators, a desynchronization between central and peripheral oscillators.  The overall effect of a phase shift of this nature is that the subject involved will through a transitional period, not function, in step with its surrounding.  E.g., the top physical efficiency observed usually in the afternoon, may happen during nighttime.  The propensity to sleep, which is the expression also of a circadian rhythm may be high during the environmental period requiring alertness and efficiency, and may be low leading to insomnia during the time reserved for rest during the new working or living schedule.  During the time of time adaptation, this external and internal desynchronization of the human organism leads to a functional disturbance of its time structure (“dyschronism”) with a loss in performance and the symptomatology best known as the syndrome of jet lag.

Circadian Rhythms of Performance

      The maximum performance in physical tasks, like diverse forms of athletics or manual labor is found during the afternoon in diurnally active human subjects roughly parallel to the circadian rhythm in body temperature.  The circadian rhythms in performance in cognitive functions vary according to the task required in the testing procedure.  In the performance of serial tasks, accuracy and speed may be out of phase.  For example, the speed of performance was found to be high in the afternoon while accuracy is highest in the morning at a time when the speed in performance is low.  These rhythms of physical and cognitive performance are endogenous in nature and persist under “constant conditions” with continuous wakefulness. 

Sleep

      Sleep and the propensity to sleep are circadian rhythmic processes superimposed on which there is an ultradian period manifested among others in the REM sleep episodes.  Sleep deprivation is accompanied by a homeostatic process of linearly increasing tiredness proportioned to the number of waking hours.  Upon this linear process, a circadian rhythm is superimposed leading to a partial improvement of fatigue at the usual time of the circadian peak activity.  Sleep deprivation not only leads to a loss in cognitive and later also physical performance, but leads to serious metabolic consequences, like the suppression of growth hormone and melatonin circadian rhythms, increase in cortisol concentration, and impairment of insulin sensitivity.  Combination of these factors may favor weight gain with obesity, and hypertension with development of the “metabolic syndrome” and type II diabetes mellitus, and suppression of the immune system.  Since sleep deprivation is one of the characteristic features observed in night and shift workers, these metabolic disturbances may explain some of the adverse late effects of prolonged shift work reported recently.

Work Hours and Accidents

      Accidents do not happen at random.  The timing of accidents depends upon the interaction of the patient’s circadian rhythms and environmental factors (periodic or nonperiodic).  The highest number of accidents in many settings is observed at the time of minimum cognitive performance in the late night hours with a peak observed in many series between 02:00 and 03:00 during the night in diurnally active adults.  Often there is a secondary peak occurring during the afternoon.  It is not accidental that the major industrial accidents of the last decades, like the Three-Mile Island Nuclear Plant accident, the Chernobyl nuclear disaster, the deadly chemical release in Bohpal, India, and the Exxon-Veldez oil spill occurred during late night hours.  The relative risk of accidents increases markedly with increasing number of successive night shifts.  The timing of accidents is different in children who mostly are in bed and protected during the night.  In children, the peak accident rate is observed during the afternoon and evening hours, due to internal rhythmicity and environmental exposure. 

Transmeridian Travel over Time Zones and Jet Lag

      Rapid translocation over time zones leads the traveler to a different surrounding with differences in light/dark exposure, together with a change in social surrounding.  The circadian system of the traveler usually adapts over a certain length of time with different speed of adaptation for different variables, and individual differences in time adaptation.  If a change in time zone exceeds 3-5 hours, the traveler may show characteristic symptoms of jet lag in the form of sleep disturbances, loss in performance, gastrointestinal upset, and metabolic changes.  There are differences between the direction of the phase shift (phase advance or phase delay).  The re-entrainment shift rate of most variables and in the majority of subjects is faster for phase advance (east bound flight) as compared to phase delay (west bound flight).  The speed of adaptation and its completeness depend on the exposure to strong or weak environmental time cues, and can be accelerated by exposure to bright light in the mornings, and by outdoor activity and intense social contact at the place of destination.  Repeated phase shifts, like in professional airplane crews together with other factors inherent in this occupation can contribute to cardiovascular problems, hypertension, and increased serum cholesterol with increase in cardiovascular mortality.

Night and Shift Work

      In contrast, to the traveler over time zones, the night and shift work has to be performed out of phase with the astronomic (day and night) and social surrounding.  Apart of the shift, the night and shift worker will be exposed to environmental sunlight before and/or after the work shift, and during time off at the weekend, or after a certain number of shifts, and lives in a social surrounding which is tied to the astronomic day/night schedule.  Although the unusual shifts (early morning, late evening, or night) may lead to a disruption of the worker’s circadian time organization, a time adaptation will seldom be achieved, even in subjects on so-called “permanent” night shift.  In permanent night shift, even after prolonged time spans on this shift, only a minority of night workers will show a phase adaptation of their circadian system to the nocturnal activity pattern.  The majority either does not change at all or may show a rhythm disruption with some intermediate phase alterations.  The least phase adaptation will be observed after rapid rotations (3-4 days) during which the worker will maintain a diurnal activity oriented circadian time organization.  This requires the subject to work at the time of his/her minimum of performance during the night, but leads to the least disruption of the circadian time organization.  Slow rotations (e.g., weekly) may more often lead to a phase alteration without the possibility of a successful completion of phase adaptation during the shift.  From an ergonomic viewpoint of chronobiology, this type of rotation is expected to lead to disruptions in the circadian time organization.  Attempts to accelerate adaptation to the work schedule cannot be successful since the shift time of most variables extends the duration of the shift.  The alteration of the optimal circadian time organization together with the partly through the schedule and partly biologically determined decrease in sleep time by 2-4 hours in the average shift worker, leads to health issues.  Most of these can be traced to circadian rhythm alterations (circadian dyschrony).  Gastrointestinal complaints can be traced to out of phase conditions between food uptake and working requirements.  Gastrointestinal motility, resorption, and liver metabolism are circadian periodic.  Food uptake at a different or irregular timing can disrupt rhythmic functions and lead to a variety of gastrointestinal symptoms and gastric and duodenal ulcers.  In some studies, night and shift-workers showed increased food uptake and preference for carbohydrate rich foods with consequent disturbance of lipid, and especially triglyceride metabolism.

      Very little attention has been focused thus far on differences in shift-workers in the response to therapeutic agents used in clinical medicine.  Changes in the human time organization lead to changes in the chronopharmacokinetics and chronopharmacodynamics of drugs used in clinical medicine.  These changes may raise a question of inappropriate dosage of therapeutic agents due to the altered circadian time organization.

      After prolonged exposure to shift work induced dyschronism, an increase in cardiovascular morbidity and mortality has been reported which increases with the length of exposure of the workers.  Most recently, an increase in incidents in breast cancer and in colorectal cancer, has been reported after prolonged exposure to shift work in women in the Nurses Health Study.  The mechanism postulated was a suppression of the nocturnal melatonin rise since melatonin counteracts tissue proliferation both in breast and in colonic tissues.  However, most recent experimental evidence shows that the internal desynchronization in experimental animals leads to an accelerated take and growth of transplantable tumors in mice.  The same can be achieved by bilateral destruction of the master oscillator in the suprachiasmatic nucleus of the hypothalamus.  In contrast, exposure of the animals to constant light or constant darkness had no significant effect of tumor growth.

      It can be concluded that prolonged exposure to circadian dyschrony together with sleep deprivation poses a health risk for the transmeridian traveler and for the shift worker.  Unfortunately, transmeridian travel over time zones and shift work have become inevitable in our society.  Twenty to 25% of our workforce is exposed to some form of shift work.  It is, therefore, important to find ways to minimize the circadian disruption and/or alleviate its effects. 

Intervention measures to safeguard the health and reduce

performance problems in shift workers

Adaptation of circadian time organization to the night shift:

      Adaptation of circadian time organization to the night shift may be possible in permanent shift workers, but is not feasible in slow and rapidly rotating shifts.  Circadian time adaptation to permanent night shifts require adaptation of the shift worker in his or her general lifestyle, including weekends which is difficult to obtain in our social surrounding.  Interventions with chronobiotic measures, like bright light and melatonin to obtain and solidify a phase shift, have been attempted and under some conditions, like e.g., in work on oil rigs where the shift worker was segregated and removed from his usual social surrounding, were apparently successful.  Time of food uptake, as such shifts some, but not all circadian periodic variables in human subjects and should be adjusted to the changed lifestyle if an adaptation is desired.  All in all, the attempt to phase shift the human time organization to night shift will be successful only in a fraction of workers and only under certain conditions at the work place.

      In rapidly rotating schedules, a circadian time adaptation is neither feasible nor desirable.  In rapidly rotating shifts, the shift worker preferably should stay on the schedule dictated by his/her diurnal living habits.  It has to be understood that the worker under these circumstances is required to work at the minimum of his performance.  In highly trained and motivated workers, the performance achieved can be adequate for the work required.  To avoid partial adaptations with internal desynchronization and dyschronism, the sequence of night shift should not be more than a maximum of 3 or 4 consecutive nights, and they should be followed by an extra day for catching up on sleep deficit.

      Direction of rotation in rapid shifts may be of interest.  Theoretical considerations about the slower adaptation after phase advance in comparison to phase delay have led to the assumption that rapidly forward rotating shift systems would be unfavorable.  Recently, however, it has been shown that rapidly forwarding schedules in contrast to backward rotating schedules had marked positive effects on sleep and well being in young as well as in old shift workers, and had favorable effects on shift work induced changes in serum triglycerides concentrations and raised catecholamine excretion after the rotations.  A change in direction of a rotation to clockwise was reported to have led to a 4% reduction in serum triglycerides in contrast to the change to counterclockwise rotations, which led to a 15% increase in triglycerides.

      Regularity of the shift has been shown to avoid dyschronism and the related health effects.  This is in contrast to the now frequently desired flexibility of shift schedules, which if the selection is irregular, may be unfavorable for the health of the shift worker.  These considerations have to be weighed against the favorable aspects of flexibility for the worker and the social surrounding.  Ergonomic changes in shift schedules should be chosen, which may be preventative and may reduce the incidence of late detrimental health effects.

      Napping, if introduced at the right time of a work shift, may be an effective counter measure against sleepiness at work.  Timing and temporal closeness of the nap to the critical work period is important.  Also, a shift worker has to be aware of the impaired alertness (sleep inertia) 5-20 minutes after awakening from a nap. 

      Chronopharmacologic support may be effective in a proportion of travelers or shift workers in jet lag and/or adaptation to permanent night-, early morning-, or late-evening shifts.  Bright light has been attempted, which if given in the morning leads to a phase advance of the circadian system or if given in the evening to a phase delay.  Bright light exposure at the work place, especially during the first portion of the shift, has been reported as helpful in performance.

      The pineal hormone melatonin works opposite to bright lights and if given in the morning leads to a phase delay, if given in the evening a phase advance.  The combined use of appropriately timed bright light and melatonin is likely to support phase adaptation and may be helpful in the treatment of sleep disorders.  Melatonin is a mild hypnotic, and if given in pharmacologic doses (e.g. 3-10 mg) can, in addition, to a possible phase shifting effect have an effect on sleep with no significant side effects reported and without posthypnotic performance deficits.

      Pharmacologic agents, like benzodiazepines may induce sleep and as such may be helpful in alleviating fatigue during the first nights after arrival in transmeridian travel.  These agents do not act upon the phase of the circadian system, but only induce sleep and with this action may relieve fatigue, although peak and trough of performance will remain unchanged and undergo their usual phase adaptation.

      Exercise and morning exposure to bright light and environmental sunlight are found to be successful in accelerating the adaptation of travelers over several time zones.  Xanthene drugs, like caffeine, may delay sleep onset and may fight sleepiness when sleep onset must be delayed but do not induce a phase shift of the circadian system.

Chronobiologic Criteria Helpful in the Selection of Candidates

for Night and Shift Work

      So-called night persons (“owls”) usually tolerate night and shift work better than morning people (so called “larks”).  Questionnaires for the simple recognition of morning and night people are available.  However, the problem in this separation is that only about 20% of people are pronounced night and another 20% morning people, while the remaining majority is indifferent and cannot be classified by this method.

      People with low circadian rhythm amplitude of variables like body temperature and other reference functions are subject to undergo easily circadian desynchronization and dyschronism.  From this viewpoint, they are unfavorable for rotating shifts where a circadian desynchronization has to be avoided if feasible.  In contrast, subjects with high and stable amplitudes in these rhythmic functions maintain their circadian periodic orientation in rapidly rotating shifts.      Historically, subjects with tolerance of variable sleep schedules and sleep deprivation, good health and a high level of physical fitness are favorable candidates.

      Subjects with any form of depression, other mood disturbances, rigid sleep requirements, diabetes mellitus, heart disease, peptic ulcer, epilepsy, or a pronounced cancer risk, are responding unfavorably to changes in circadian synchronization and should avoid shift work, if feasible.

Conclusion

      An understanding of the human time structure and its physiology and pathology are essential for the design of ergonomically favorable work-schedules which provide effective performance at the job, but at the same time safeguard the health of the worker.

REFERENCES

General Medical Chronobiology

·         Touitou Y., Haus E. (Eds).  1992.  Biologic Rhythms in Clinical and Laboratory Medicine.  Springer‑Verlag Berlin, Heidelberg. pp 1-730.

·         Smolensky M., Lamberg L. (Eds).  2000.  The Body Clock: Guide to Better Health.  Henry Holt and Co., New York.  pp 1-428.

·         Redfern P.H., Lemmer B. (Eds).  1997.  Chronopharmacology: Physiology and Pharmacology of Biological Rhythms.  Springer; Berlin, New York.  pp 1-668.

Molecular Circadian Oscillators

·         Dunlap J. C.  1999.  Molecular bases for circadian clocks.  Cell 96:271-290.

•     Reppert S.M., Weaver D. R.  2002.  Coordination of circadian timing in mammals.  Nature 418: 935-941.

·         Nagano M., Adachi A., et al.  2003.  An abrupt shift in the day/night cycle causes  desynchrony in the mammalian circadian center.  J of Neuroscience  23:6141-6151.

Shiftwork and Chronobiology

·         Reinberg A. et al.  1988.  Alteration of period and amplitude of circadian rhythms in shift workers.  Eur J Appl Physiol  57:15-25.

·         Askenazi I.E., Reinberg A., Motohashi Y.  1997.  Interindividual differences in the flexibility of human temporal organization:  Pertinence to Jet Lag and shift work.  Chronobiology International  14:99-113.

·         Waterhouse J, Redfern P. (Eds).  1997.  Special Issue:  Jet-lag and shift-work: Current perspectives on intervention strategies and treatment.  Chronobiology International 14(2):89-229.

·         Akerstedt T.  2003. Shiftwork and disturbed sleep–wakefulness.  Occupational Medicine  53:89-94.

·         Spiegel K, Leproult R, Van Cauter E.  1999.  Impact of sleep debt on metabolic and endocrine function.  Lancet  356:1435-1439.

·         Folkard S, Akerstedt T.  2004.  Trends in the risk of accidents and injuries and their implications for models of fatigue and performance.  Aviation, Space and Enviroment Med  75:A161-A167.

·         Härmä M.  2001.  Shift work and cardiovascular disease – from etiologic studies to prevention through scheduling.  Scand J Env Health 27:85-86.

·         Lowden A, Akerstedt T, Wibom R.  2004.  Suppression of sleepiness and melatonin by bright light exposure during breaks in night-work.  J Sleep Res  13:37-43.

·         Fischer F. M. Rotenberg L, de Castro Moreno C.R. (Eds).  2003.  Equity and working time: a challenge to be achieved.  Proc XVI International Symposium on Night and Shiftwork.  Shiftwork International Newsletter 20(2) pp 1-215.

·         Reynolds P., et al.  2002.  Cancer incidence in California flight attendants (United States).  Cancer Causes and Control  13:317-324.

·         Davis S., et al.  2001.  Night-Shift Work, light at night and risk of breast cancer.  J Natl Cancer Ins . 93:1557-1562.

·         Schernhammer E. S., et al.  2003.  Night-Shift work and risk of colorectal cancer in the Nurses’ health study.  J Natl Cancer Inst  95:825-828.