Thomas C. Erren

Chronodisruption and cancer

Research into health effects of chronodisruption (CD), a relevant disturbance of the circadian organization of physiology, endocrinology, metabolism and behaviour, is evolving at a rapid pace. With regard to malignancies, our synthesis of key experiments indicates that CD can play a causal role for cancer growth and tumor progression in animals. Moreover, our meta-analyses of 30 epidemiological studies evince that flight personnel and shift workers exposed to chronodisruption may have increased breast and prostate cancer risks: summary relative risks (RRs) for investigations of flight personnel and of shift workers suggested a 70 and 40% increase in the risk of breast cancer, respectively, and excess relative risks of prostate cancer in nine studies in flight personnel (40%) and in two studies in male shift workers. There was a remarkable indication of homogeneity of results from the individual studies that contribute to the average statistics. However, in view of doubts about whether the differing assessments of CD can really be regarded as valid reflections of the same causative phenomenon and the lack of control of covariates in the majority of studies, it is premature to conclude that the risk observations reflect a real, rather than spurious, association with CD. The challenge for future epidemiological investigations of the biologically plausible links between chronodisruption and human cancers is to conduct studies which appreciate details of transmeridian travelling, of shift work and of covariates for the development of the diseases.

Hypotheses for mechanisms linking shiftwork and cancer.

Shift work has been associated with various adverse health outcomes. In particular, there has been a recent flourish in investigating potential cancer risk associated with working night shifts and other shift schedules. Epidemiologic studies have revealed generally weak associations due to several methodological challenges such as lack of standard classifications of shift or night work. The field also has been hindered by a lack of clarity about the possible mechanisms by which shiftwork could have an effect on cancer risk. One possible mechanism is reduced production of melatonin caused by exposure to light at night. Although there is a growing body of evidence that provides some support for this mechanism, several other mechanisms also make sense from a biological point of view. Further, the relatively weak magnitude of the associations between light at night and melatonin level suggests that multiple factors may be operating along the pathway between shift work and adverse health consequences (including cancer risk). Here we propose four additional mechanisms that should be considered for a comprehensive investigation of these potential pathways. These are: phase shift; sleep disruption; lifestyle factors (such as poor quality diets, less physical activity and higher BMI); and lower vitamin D. Consideration of all these mechanisms is necessary in order to design effective preventative workplace strategies. In developed countries, approximately 20% of the population undertake shiftwork and, while we are unlikely to be able to eliminate shiftwork from current work practices, there are aspects of shiftwork that can be modified and there may be facets of individual susceptibility that we may be able to identify and target for prevention.

Synergy between asbestos and smoking on lung cancer risks.

Few studies have investigated the association hetween hody mass index and fecundability, that is, the ability to conceive in a menstrual cycle, among fertile women with normal menstrual cycle pattern. We examined the independent and combined effects of duration and regularity of the menstrual cycle,

Light, timing of biological rhythms, and chronodisruption in man

This paper reviews abundant evidence suggesting that causes and course of aging and cancers can be considered as being both light- and rhythm-related. We define chronodisruption as a relevant disturbance of orderly biological rhythms over days and seasons and years in man. Light is the primary external mediator and melatonin a primary internal intermediary of such disturbances, which can result in earlier deaths via premature aging and cancers. We conclude that experimental and epidemiological research can provide further insights into common denominators of these chronic processes and may offer novel and uniform targets for prevention.

Light-Mediated Perturbations of Circadian Timing and Cancer Risk: A Mechanistic Analysis

In industrialized countries, certain types of cancer, most notably, breast and prostate, are more frequent than in poorly developed nations. This high cancer frequency is not explained by any of the conventional causes. Within the past decade, numerous reports have appeared that link light at night with an elevated cancer risk. The three major consequences of light at night are sleep deprivation, chronodisruption, and melatonin suppression. Each of these individually or in combination may contribute to the reported rise in certain types of cancer. In this article, the potential mechanisms underlying the basis of the elevated cancer risk are briefly discussed. Finally, if cancer is a consequence of excessive nighttime light, it is likely that other diseases/conditions may also be exaggerated by the widespread use of light after darkness onset.

The Association Between Different Night Shiftwork Factors and Breast Cancer: a Case–Control Study

Background:Research on the possible association between shiftwork and breast cancer is complicated because there are many different shiftwork factors, which might be involved including: light at night, phase shift, sleep disruption and changes in lifestyle factors while on shiftwork (diet, physical activity, alcohol intake and low sun exposure).Methods:We conducted a population-based case–control study in Western Australia from 2009 to 2011 with 1205 incident breast cancer cases and 1789 frequency age-matched controls. A self-administered questionnaire was used to collect demographic, reproductive, and lifestyle factors and lifetime occupational history and a telephone interview was used to obtain further details about the shiftwork factors listed above.Results:A small increase in risk was suggested for those ever doing the graveyard shift (work between midnight and 0500 hours) and breast cancer (odds ratio (OR)=1.16, 95% confidence interval (CI)=0.97–1.39). For phase shift, we found a 22% increase in breast cancer risk (OR=1.22, 95% CI=1.01–1.47) with a statistically significant dose–response relationship (P=0.04). For the other shiftwork factors, risks were marginally elevated and not statistically significant.Conclusion:We found some evidence that some of the factors involved in shiftwork may be associated with breast cancer but the ORs were low and there were inconsistencies in duration and dose–response relationships.

Revisiting chronodisruption: when the physiological nexus between internal and external times splits in humans

In this Concepts & Synthesis paper, we expand the definition of chronodisruption in humans by proposing that it can be operationalized as the split nexus of internal and external times. With this premise, we suggest how chronotype may be used as a temporal marker (chronomarker) of exposure to chronodisruption in studies of cancer, and beyond, offer cancer risk predictions for observational research on the basis of a chronotype-related hypothesis and corollary, and point to first empirical data in humans. In an a priori way, we examine possible outcomes and perspectives for preventive measures following from our rationale and the suggested chronobiology-driven studies and close with overall advances of chronodisruption research.

Computing chronodisruption: How to avoid potential chronobiological errors in epidemiological studies of shift work and cancer

We ask if epidemiological studies into shift work and cancer may be prone to chronobiological errors. We illustrate how ignoring internal time (IT), or chronotype, may lead to what we call IT errors. Errors from truncating relevant external time (ET) information (activities start before and do not end with the shift) we call ET errors. We develop how observational research may avoid potential chronobiological biases and how chronodisruption can be computed. We assess how IT and ET errors may have affected studies published so far with a focus on those that considered chronobiological information but were confined to night work.

Shift work and cancer research: can chronotype predict susceptibility in night-shift and rotating-shift workers?

With a recent study in this journal, Hansen and Lassen1 followed a promising path to answer pressing questions with regard to postulated causal links between shift work and cancer.2 By employing diurnal preference to characterise the individuals chronobiological propensity to work and sleep or rest, the authors may have used a marker of susceptibility to stress and strain experienced by individuals who work at chronobiologically unusual times. This novel approach may have captured information relevant to the undefined link, namely ‘circadian disruption’, in the ‘probable’ chain of cancer causation in shift workers which experts of the International Agency for Research on Cancer (IARC) identified in 2007.3 Here is why and how we could diligently follow-up on this thought-provoking case-control study. First, some remarkable observations: In this study of night-shift work among women in the Danish military, diurnal preference was associated with differential breast cancer risks. For those with 884 or more cumulative night shifts, the OR for morning types was 3.9 (95% CI 1.6 to 9.5) and 2.0 (95% CI 0.7 to 5.8) for similarly exposed evening types; in the so-called intermediate types no increased risks were detected. The information on night work was collected before IARCs aforementioned classification, which lends methodological weight to the observations of this case-control study. Second, some necessary information: When Hansen and Lassen refer to ‘morning type’ or ‘evening type’ preference, this corresponds colloquially to ‘larks’ and …

When the Circadian Clock Becomes a Ticking Time Bomb

Virtually every systemic and cellular physiological function varies in a highly periodic and predictable manner over a 24:00-h period. These rhythms, in both the central and peripheral systems, are subservient to the function of the central rhythm generator, the suprachiasmatic nuclei (SCN) located in the anterior diencephalon. In turn, the activity of the SCN is under the synchronizing influence of the prevailing light:dark (LD) cycle as perceived by highly specialized cells in the ganglion cell layer of the retinas (Schmidt et al., 2011). These intrinsically photosensitive retinal ganglion cells (ipRCG) constitute a very small percentage ( < 1%) of the total ganglion cell population and are endowed with a unique photopigment, which is particularly sensitive to short blue light wavelengths (460–480 nm; Chen et al., 2011). A perturbation of the normal environmental LD cycle with the misuse of manufactured light after darkness onset, i.e., at night, provides the central clock with misleading information which alters its activity. Similarly, the disturbed activity of the SCN is communicated to peripheral clocks, which are then likewise corrupted. The perturbations of the internal temporal order of organismal clock processes are manifested by changes described as circadian disruption, circadian deregulation or chronodisruption (CD; Erren & Reiter, 2009a). In our modern 24/7 (24:00 h/d and 7 d/wk) society, CD may result from several conditions such as nocturnal light pollution, jet-lag, shiftwork, frequent nocturnal snacking or nocturnal leisure activities (social jet-lag). The consequences of circadian disruption are by no means trivial. The experimental evidence is now clear that every cell relies on stable and repetitious 24:00-h cycles for its optimal function. Serious and repeated disturbances of these regular recurring, 24:00-h rhythms, which have developed over eons of human evolution and depend on the rising and setting of the sun, are now known to have grave consequences. Among several, the single condition that most frequently undermines the circadian clock is light exposure at an unusual time. Thus, when the night is contaminated with light of proper intensity and wavelength, the clock unwittingly responds to the misinformation as if it is day and the neural and humoral messages it conveys to subservient clocks in cells throughout the body are temporally erroneous. When these slave oscillators go awry and the metabolism of cells becomes abnormal, pathophysiology develops (Dallmann et al., 2012; Hardeland et al., 2012; Zhu et al., 2011). Chronic alteration of the internal temporal order leads directly to pathology, indirectly predisposes to pathology or aggravates pre-existing pathologies. Research, particularly within the last decade, has documented that regular metabolic rhythms are optimal for cellular, organ and organismal health. One of the first examples of this was the observation that light at night suppresses the nocturnal production and secretion of melatonin from the pineal gland; this rhythm represents an easily observable “hand” of the biological clock. Its disruption is a surrogate of a perturbed clock. The melatonin rhythm is capable of being virtually “read” by every cell in the body and low circulating melatonin levels, even though they may occur at night, are unavoidably interpreted as day and adjustments in cellular function are made. Many other messages from the SCN that are conveyed to cells via the central and peripheral nervous systems simultaneously re-enforce the incorrect information being received via the endocrine signal. An elevated cancer risk in humans routinely exposed to light at night has been reported in many studies (Haim & Portnov, 2011; Greene, 2012; Schernhammer & Stone, 2011). If definitively proven to be valid (Stevens, 2011), it is very likely that cancer is only the “tip of the iceberg.”Manyother publications have provided compelling experimental and clinical evidence showing that a very wide spectrum of diseases may be a result of an underlying disturbed circadian rhythm including the melatonin cycle. In addition to cancer, some of these conditions include depression, jet lag, obesity, diabetes, hypertension, metabolic syndrome, sleep disorders, cardiovascular disease, excessive oxidative stress, neurophysiological deterioration, impaired pregnancy success, etc. (Galano et al., 2011; Garaulet &Madrid, 2010; NakanishiMinami et al., 2012; Summa et al., 2012; Tan et al., 2012). This list is very long. Based on these data, which have been contributed by highly reputable scientists in many disciplines throughout the world, it is imperative that more attention should be given to light hygiene (Erren & Reiter, 2009b), on one hand, and to the ubiquitous light pollution that is occurring, especially in the highly developed societies, on the other. It is inevitable, unless appropriate diligence is applied, that light contamination of the night will get much worse. Indeed, under those