Address reprint requests to Thomas C. Erren, Institute and Policlinic for Occupational and Social Medicine University of Cologne, Kerpener Strasse 62, 50937 Köln, Lindenthal, Germany.
Abstract: When the International Agency for Research on Cancer (IARC) classified shift-work that involves circadian disruption as probably carcinogenic to humans in 2007, this was the prelude to extensive experimental and epidemiological research in coming years. Indeed, with some 20% of people worldwide being engaged in some type of work at unusual times, including the night, it is a must to investigate, and to clarify as soon as possible, the biologically plausible links via circadian disruption with epidemic cancers such as of the breast or prostate. Surprisingly, neither the IARC information available so far nor the general literature provides a clear definition of what the critical component in the postulated chain of causation, namely circadian disruption, is. Here we offer our definition of chronodisruption (CD), a concept which we proposed in 2003 and which we operationalized recently in research which addressed the putative links between shift-work, time-zone-travel and human cancers independently of the IARC and led to similar causal interpretations. As a basis for further research in this area with possible high relevance for public health, we: (i) elaborate our definition of CD, with melatonin being a key biological intermediary, by putting critical disruptions, and the resulting disorder, of circadian clocks, biological rhythms and circadian organization into thematic and historical context with Colin Pittendrigh’s insights almost half a century ago; (ii) provide material on ‘what are chronodisruptors?’ and (iii) pose a key question which needs to be answered by and for experimental and epidemiological CD research. We hope that defining CD can contribute to studies which may help to find clues to a background incidence of epidemic internal cancers for which – so far in many cases – we lack causal explanations.
In October of 2007, the IARC concluded that ‘shift-work that involves circadian disruption is probably [emphasis added] carcinogenic to humans’ (Group 2A) . This can be viewed as the prelude to a cascade of – experimental and epidemiological – studies that will investigate whether or not shift-work is causally associated with human cancers. It is important to underline, though, that not shift-work per se or all shift-work but ‘shift-work which involves circadian disruption’ was identified as putative cancer hazard by the expert panel of 24 scientists who met in Lyon in October of 2007.
In lieu of the, as yet unpublished, IARC monograph, as a further lead to what type of shift-work the experts considered as probably carcinogenic to humans it was pointed out in Lancet Oncology that ‘among the many different patterns of shift-work, those including nightwork are the most disruptive for the circadian clock’. Taken together, for future studies of possible links between shift-work and internal cancers it will be important to consider disruptions of the circadian clock or so-called ‘circadian disruption’. Intriguingly, though, while ‘circadian disruption’ is increasingly being employed as a scientific term, it is not clearly defined.
Here, we offer our definition of chronodisruption (CD). We do so because we used CD as the key exposure variable when we synthesized abundant experimental and limited observational information both qualitatively and quantitatively in 2008 with regard to the possible nexus between chronodisruption in shift-workers and flight personnel and cancer . Intriguingly, with our operationalization of CD we arrived independently at similar conclusions as the IARC panel with regard to biologically plausible links between shift-work exposures and epidemic breast and prostate cancer in flight and shift personnel.
As a basis for further research in this area with possible high relevance for public health, in the following, we will: (i) elaborate our definition of CD by putting it into thematic and historical context with Pittendrigh’s insights of almost half a century ago; (ii) explain and identify established chronodisruptors; and (iii) identify a key question for experimental and epidemiological research into CD.
Our definition of CD, its thematic and historical context with chronobiological insights over 50 years
More generally, we suggested in 2003 that CD be ‘a relevant disturbance of the circadian organization of physiology, endocrinology, metabolism and behaviour, which links light, biological rhythms and the development of cancers  with melatonin being a key biological intermediary’. Specifically, we proposed:
The increasingly used terms ‘circadian disruption’ or ‘disruption of circadian rhythms’ suggest that rhythms over 24 hr can become desynchronized and that this may have adverse health effects. Since biologically relevant disruptions of rhythms are likely to occur over days and seasons and years, we suggest to use the more general term chronodisturbance for modulations of rhythms over time. It can be expected that the effects of many modulations of rhythms can be physiologically compensated so that they do not necessarily lead to manifest chronic processes. To explicitly describe relevant effects of chronodisturbance beyond some homeostatic threshold to chronicity, we choose to work … with the term chronodisruption.
Recently, we extended the possible links between CD and the development of cancers within a generalized theory . This theory holds that CD can be understood as a critical loss of time order, i.e. a disorder or chaos of an otherwise physiological timing at different organizational levels, including the gene expression levels in individual cells. Historically, while the term CD may be new, the phenomenon is not. Already in the course of the influential Cold Spring Harbor Symposia on Quantitative Biology in 1960 (XXV: Biological Clocks), Pittendrigh suggested , albeit without offering a defining term, that
… circadian rhythms are inherent in and pervade the living system to an extent that they are fundamental features of its organization; and to an extent that if deranged they impair it.
This breakdown [of circadian organization] is in all probability a failure of mutual entrainment among constituent oscillatory subsystems leading to their dissociation and a loss of normal phase relationships. I should be explicit that the statement that damage commonly develops in aperiodic regime is fact (Pittendrigh 1960).
In line with Pittendrigh, we suggest to define CD as being a breakdown of phasing internal biological systems appropriately relative to the external, i.e. environmental changes, which leads to chronobiological disorders. Indeed, biological rhythms constitute a key means to establish physiological order , and to avoid pathological disorder. Importantly, the very entrainment of internal rhythmic subsystems relative to the external, i.e. environmental changes, ultimately allows ‘rhythms of rest and excess’  or regular oscillations of sleep and waking which are critical conditions for human health. Put simply, if there are no ordered sequences of biological rhythms during sleep and wake cycles, this would certainly neither be efficient nor healthy. In this very vein, at a further Cold Spring Harbor Symposium (LXXII: Clocks and Rhythms), Gery and Koeffler left no doubt about the fact that proper circadian regulation is essential for the well-being of organisms . Consider as an analogy the inefficiency and, indeed, the damaging effects if drivers of automobiles were to use the accelerator and brakes simultaneously rather than in appropriate sequences, i.e. in successions of activity and rest cycles.
A necessary condition for the orderly sequences of cyclic events and their coordination is that in organisms there should be one master time rather than billions of independent peripheral times in billions of independent clocks. More generally, this master time is provided by circadian master clocks (CMC) which are connected ‘chemically’ via melatonin as one key messenger and ‘physico-anatomically’ via melanopsin projections with many parts of the brain  and can thus ‘set’ the clocks for innumerous downstream events to be coordinated and in physiological order. More specifically, in the brain of mammals, including man, the central pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus receives light information directly from the eyes via melanopsin-containing retinal ganglion cells which have widespread overall projections to many regions of our brain. In addition, the hypothalamus is the center for autonomic regulation via the sympathetic and parasympathetic nervous systems; certainly these assist the CMC in the coordination of peripheral clocks also and thus have critical influence on peripheral organs and cells and their interplay. To illustrate with a further analogy, similar to Greenwich Mean Time  providing the reference time independent of location for billions of other clocks worldwide, central timing and appropriate coordination of circadian rhythms are achieved by circadian master clocks in the brain which collectively set or govern or ‘tame’  an impressive abundance and variety of peripheral clocks. In doing so via the regulation of a temporal programme in response to ambient light, the CMC coordinates tissue- and organ-specific 24-hr rhythms, which would otherwise act independently of one another.
What are chronodisruptors?
Chronodisruptors are exogenous and endogenous ‘exposures’ or ‘effectors’ which are chronobiolocially active and can thus disrupt the timing and order, i.e. temporal organization of physiologic functions and hierarchies. In principle, whatever allows the establishment of temporal organizational order in organisms should also be capable of disrupting such order or temporal programme when present or applied in excess or deficit and, most importantly, at unusual and inappropriate times, especially if combined with further agonistic or antagonistic chronobiologial effectors.
With these premises, one key exogenous or external chronodisruptor is light at night. Under natural conditions, biological circadian and seasonal rhythms are synchronized to the regular 24-hr and seasonal light–dark cycles and the suprachiasmatic nuclei and melatonin have critical roles in these processes. In fact, light is a key Zeitgeber affecting melatonin rhythms and the circadian rhythms of melatonin can provide clock (24 hr) and calendar (seasonal and yearly) information for many species, including humans . But light, and its antithesis melatonin , when applied at unusual times , can also powerfully disrupt the circadian and seasonal rhythmicity of our biology, thus leading to CD. Importantly, the interactions between light and melatonin may contribute to CD via two phenomena: a light-associated phase-shift of the melatonin rhythm on the one hand and acute suppression of melatonin by light of sufficient intensity on the other. The former phenomenon may yield both secondary influences on the circadian master clocks and on peripheral oscillators, dual effects which may lead to unfavourable, and indeed detrimental, phase positions or oscillator uncoupling. Moreover, the phenomenon of melatonin deficiency after light-induced acute melatonin suppression may in itself, i.e. irrespective of the former inappropriate phase position, cause or contribute to CD because the physiologically rhythmic endogenous regulator melatonin cannot exert its critical role in melatonin-dependent biochemistry at many organizational levels of individual cells, tissues and organs. Further key chronodisruptors include not only food – a long-suspected food-dependent circadian master clock (CMC) has recently been located in the dorsomedial nucleus of the hypothalamus  – but also physical activities and biological stress.
A key question with regard to CD research
In our view, the pressing question is ‘How can we appropriately investigate CD and its effects in experimental and in epidemiological studies?’‘What signs or variables could identify relevant CD which lies on the chain of causation which leads to cancer?’
In the coming years, experimental studies will be required to identify variables for epidemiological research into possible risks of cancer, or other adverse health effects. Preferably, we would identify biomarkers of effect but it is likely that we will have to zero in on biomarkers of exposure. Moreover, rather than focusing on melatonin and its ‘classical anti-cancer properties’ alone, affecting no less than all ‘hallmarks of cancer’ [14–16], parameters which indicate or reflect temporal organization patterns must be identified and empirically tested. Candidates identified via mechanistic studies should then be incorporated into epidemiological research, in particular of cancer developments which may extend over many decades. For the time being, epidemiological studies which investigate cancer development over decades might have to continue to focus on relevant and robust biomarkers of CD such as melatonin or its metabolites in saliva , urine  and blood  and on observational surrogates of CD exposures – be they work at unusual times and/or unusual sleep patterns.
With regard to CD, we hope that defining CD can contribute to studies which may help to find clues to a background incidence of epidemic internal cancers, such as of the breast and prostate, for which – so far in many cases – we lack causal explanations.