Claus Piekarski

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.

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.

Lung Cancer Mortality and Carbon Black Exposure: Cox Regression Analysis of a Cohort From a German Carbon Black Production Plant

Objective: We undertook a lung cancer mortality analysis of 1528 German carbon black workers, followed between the years of 1976–1998, who produced furnace black, lamp black, and gas black. Methods: We used Cox modeling across age with time-dependent covariates, ie, cumulative and mean carbon black exposure, duration of work in departments, adjusting for calendar time, a smoking indicator, and age at hire. Exposures were lagged up to 20 years. Analyses were performed with the full cohort and after restriction to an inception cohort. Results: A total of 50 lung cancer deaths occurred. No positive association was found with carbon black exposure indices. Some models indicated an increasing risk across duration of work in the lamp black producing department. Conclusions: Our results do not suggest that carbon black exposure is a human lung carcinogen. The lamp black results, if no artifact, may point at historical exposures to gaseous polycyclic aromatic hydrocarbons.

Lung cancer mortality and carbon black exposure: uncertainties of SMR analyses in a cohort study at a German carbon black production plant.

Objective: We undertook a sensitivity analysis of the lung cancer standardized mortality ratios (SMRs) in a study of 1522 German carbon black workers from 1976 to 1998. Methods: We applied results from a case–control study to adjust the SMR for smoking habits and exposures experienced before the carbon black job. In addition, sensitivity to reference rates was explored. Results: On the basis of 47 lung cancer deaths, the SMRs were 1.62, 1.72, and 2.08 (local, state, and national rates, respectively). Adjustment for previous exposures and smoking yielded additional correction factors of 0.64 or 0.74, varying with the chosen reference. Conclusions: Lung cancer SMRs (95% confidence intervals) for the full cohort ranged from 1.20 (0.88–1.59) to 2.08 (1.53–2.77) in this sensitivity analysis. Thus, overall SMRs are only weak measures of causal associations and should be complemented by internal modeling of exposure effects whenever possible.

Lung cancer mortality and carbon black exposure: a nested case-control study at a German carbon black production plant.

Objective: The objective of this study was to conduct a case–control study of lung cancer nested within a cohort of 1528 German carbon black workers, 1976–1998. Methods: The authors conducted risk-set sampling of two controls matched on year of birth and conditional logistic regression modeling of cumulative carbon black exposure, duration of work in different departments, feedstock contact, asbestos exposure, smoking, age at hire, exposures before the carbon black job, and serving as a soldier in World War II or being a prisoner of war. Analyses were performed with both the full cohort and members of an inception cohort subset. Exposures were lagged by 10 years. Results: Analysis of 50 lung cancer deaths showed no association to carbon black exposure. Conclusions: Carbon black exposure was not linked to lung cancer risk. Suggestions of positive associations with asbestos exposure, feedstock contact, and work in specific departments are inconclusive due to small numbers.

Maximal manual stretcher carriage: performance and recovery of male and female ambulance workers

The effects of a maximal duration stretcher carriage on heart rate (HR), lactate concentration, hand steadiness and hand-grip strength were studied up to 72 h post-exercise in 17 male and 15 female military ambulance personnel. Using both hands for transport, the participants walked on a treadmill ergometer at a speed of 4.5 km/h. Force measurements at the handlebars yielded mean loads of 245 N (25 kg) on each side. Each step on the treadmill induced additional force oscillations with peak forces up to 470 N corresponding to 130% (women) and 98% (men) of maximal voluntary contraction (MVC). In the males the maximal transport time was about twice the time in women (mean ± SD: 184 ± 51 s vs. 98 ± 34 s). These differences had no significant effect on HR and lactate values. The same applies to hand steadiness, which showed only a transient deterioration immediately after exercise. In contrast to these parameters, substantial differences were seen in hand-grip strength recovery. Immediately after exercise, maximal hand-grip strength decreased by 150 N (25% MVC) in the males vs. 50 N (14%) in the females. Irrespective of gender, individuals with larger hand-grip strength and longer carriage durations (range 120 s–280 s) showed the slowest strength recoveries (up to 72 h) as compared to 1 h of recovery in participants with short transport durations (range 27 s–120 s). These findings suggest that the increasing number of eccentric strains during uninterrupted stretcher carriage induces cumulative muscle damages that may require some days for complete recovery.

Estimation of metabolic rate from cardiac frequency for field studies: correcting for “thermal pulses”

Abstract (1) Metabolic rate in field studies is usually estimated during short measurements, but may be estimated for complete shifts by linking these measurements to cardiac frequency. (2) An increase of body temperature leads to a rise of cardiac frequency; this increase of cardiac frequency from thermal origin (“ thermal pulses ”) should be taken into account when metabolic rate is to be calculated out of cardiac frequency. (3) By improving a heuristic methodology proposed by Vogt et al. (Le Travail Humaine 33 (1970) 125), it is possible to determine the contribution of thermal pulses to cardiac frequency for complete shifts in field studies, if body core temperature is measured continuously. (4) This methodology was applied in a study where strain of coal miners at hot working places underground was determined during 112 shifts; the thermal pulses constitute 31% of the increase of cardiac frequency above resting values in the mean of all shifts—if the rise of metabolic rates above resting values is determined from cardiac frequency, then the consideration of thermal pulses reduces the overestimation of metabolic rates by 25%.

Chronodisruption and melatonin: the need for sensible exposure metrics in epidemiological studies

Chronodisruption (CD), a relevant disturbance of the circadian organization of physiology, endocrinology, metabolism and behaviour, links light, biological rhythms and the development of cancers [1, 2] with melatonin being a key biological intermediary. In numerous experiments, the pineal indolamine has been shown to have anti-cancer properties via many different mechanisms [3]; indeed, it can offer some protection against all six hallmarks of cancer [4], namely against self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis [5]. With circadian or CD added to the hypothesized causal chains of melatonin-associated carcinogenesis, experimental and epidemiological studies into possible relationships between light, shift-work, melatonin, circadian rhythms and cancer developments were reviewed by an authoritative panel of 24 scientists in October of 2007 [6]. The overall evaluation was that shift-work that involves circadian disruption is probably carcinogenic to humans (Group 2A; emphasis added). Intriguingly, IARC scientists commented that the available sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night) [6] could have justified a Group I classification of shift-work that involves circadian disruption , namely that it is carcinogenic to humans. And yet, for such judgement we would need sufficient evidence that what experimental data and biological plausibility suggest is really valid for human beings. At this stage, though, the Working Group saw limited evidence in humans for the carcinogenicity of shift-work that involves nightwork [6]. With specific regard to observational studies in man, one of the foremost epidemiologists of the 20th century, Sir Richard Doll, pointed out that epidemiology is certainly a poor tool for learning about the mechanism by which a disease is produced, but it has the tremendous advantage that it focuses on the diseases and the deaths that actually occur, and experience has shown that it continues to be second to none as a means of discovering links in the chain of causation that are capable of being broken [7]. In this vein, epidemiological studies are necessary when researching CD, and its effects on humans, for two reasons: first, to complement the experimental information with observational data which, at present, are too limited to further classify shift-work that involves circadian disruption – be it that future study results strengthen or, indeed, weaken the overall evidence of carcinogenicity in humans. Second, if associations between CD and cancer may be interpreted as causal, real life observational studies would be needed as a basis for assessing what level of CD may be tolerable and what not. Importantly, IARCs call for epidemiological studies investigating further cancer endpoints beyond breast cancer on which the panel focussed has been addressed subsequently in two ways. In November of 2007, Cancer Research published a first study into shift-work and endometrial cancer, with a twofold risk increase in obese women working rotating hours [8]. In January of 2008, meta-analyses of investigations in individuals exposed to CD evinced increased prostate cancer risks (40%) in nine studies in flight personnel and in two studies of shift-workers [1]. These results will provide further incentives for epidemiologists to look diligently into the disconcerting possibility that breast, prostate, endometrial or other cancers may be causally associated with CD which can be widespread in our 24-hour-7-day societies, at work and at homes. But rather than having tens of studies in the near future employing incomparable exposure assessments, it seems advisable to see the 2007 IARC meeting in Lyon, France, as a starting point for concerted efforts by experimental and epidemiological scientists. Clearly, some aspects of relevant exposure variables will become overt only in the course of further research but, equally clearly, some candidate information can and should be considered a priori. To exemplify, both occupational (length, type, regularity, direction and tolerance of shift-work) and non-occupational (individual s age, exercise, medication, light exposure history , etc.) facets may critically determine the severity of CD, and its effects on the continuum from health to disease. An additional challenge which experimental and epidemiologicial researchers should try to meet stems from further melatonin considerations which may have to be taken into account and possibly integrated into comprehensive exposure metrics, namely that there are individuals who have genetically weak machinery and produce low melatonin levels nightly, i.e. they suffer from hypomelatoninaemia [9]. Moreover, circadian changes in melatonin receptor density or sensitivity [10], or the lack of, may be extremely relevant but this is usually not appreciated. In fact, while some of melatonin s oncostatic actions may not involve receptors, some actions on cancer growth surely do require them. This issue is often ignored because it is more difficult to get to the receptors in humans. Also, besides the membrane receptors for melatonin, nuclear-binding sites for the indoleamine may also be important for its ability to restrain cancer cell proliferation [11]. But until we define the definitive mechanisms (there may be many different J. Pineal Res. 2008; 45:335–336

Reducing heat stress under thermal insulation in protective clothing: microclimate cooling by a ‘physiological’ method

Heat stress caused by protective clothing limits work time. Performance improvement of a microclimate cooling method that enhances evaporative and to a minor extent convective heat loss was tested. Ten male volunteers in protective overalls completed a work-rest schedule (130 min; treadmill: 3 × 30 min, 3 km/h, 5% incline) with or without an additional air-diffusing garment (climatic chamber: 25°C, 50% RH, 0.2 m/s wind). Heat loss was supported by ventilating the garment with dry air (600 l/min, ≪5% RH, 25°C). Ventilation leads (M ± SD, n = 10, ventilated vs. non-ventilated) to substantial strain reduction (max. HR: 123 ± 12 b/min vs. 149 ± 24 b/min) by thermal relief (max. core temperature: 37.8 ± 0.3°C vs. 38.4 ± 0.4°C, max. mean skin temperature: 34.7 ± 0.8°C vs. 37.1 ± 0.3°C) and offers essential extensions in performance and work time under thermal insulation. Practitioner Summary: Heat stress caused by protective clothing limits work time. Performance can be improved by a microclimate cooling method that supports evaporative and to a minor extent convective heat loss. Sweat evaporation is the most effective thermoregulatory mechanism for heat dissipation and can be enhanced by insufflating dry air into clothing.