Shift work, cancer and "white-box" epidemiology: Association and causation.

This commentary intends to instigate discussions about upcoming epidemiologic research, and its interpretation, into putative links between shift work, involving circadian disruption or chronodisruption [CD], and the development of internal cancers.In 2007, the International Agency for Research on Cancer (IARC) convened an expert group to examine the carcinogenicity of shift work, inter alia characterized by light exposures at unusual times. After a critical review of published data, the following was stated: "There is sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)". However, in view of limited epidemiological evidence, it was overall concluded: "Shiftwork that involves circadian disruption is probably carcinogenic to humans (Group 2A)".Remarkably, the scenario around shift work, CD and internal cancers provides a unique case for "white-box" epidemiology: Research at many levels - from sub-cellular biochemistry, to whole cells, to organs, to organisms, including animals and humans - has suggested a series of quite precise and partly related causal mechanisms. This is in stark contrast to instances of "black box" or "stabs in the dark" epidemiology where causal mechanisms are neither known nor hypothesized or only poorly defined. The overriding theme that an adequate chronobiological organization of physiology can be critical for the protection against cancer builds the cornerstone of biological plausibility in this case.We can now benefit from biological plausibility in two ways: First, epidemiology should use biologically plausible insights into putative chains of causation between shift work and cancer to design future investigations. Second, when significant new data were to become available in coming years, IARC will re-evaluate cancer hazards associated with shift work. Biological plausibility may then be a key viewpoint to consider and, ultimately, to decide whether (or not) to pass from statistical associations, possibly detected in observational studies by then, to a verdict of causation.In the meantime, biological plausibility should not be invoked to facilitate publication of epidemiological research of inappropriate quality. Specific recommendations as to how to design, report and interpret epidemiological research into biologically plausible links between shift work and cancer are provided.Epidemiology is certainly a poor toolfor learning about the mechanismby which a disease is produced,but it has the tremendous advantagethat it focuses on the diseases and the deathsthat actually occur,and experience has shown that it continues to be second to none asa means of discovering linksin the chain of causationthat are capable of being broken.-Sir Richard Doll 1.