Working Time Society consensus statements: Circadian time structure impacts vulnerability to xenobiotics-relevance to industrial toxicology and nonstandard work schedules.

The circadian time structure (CTS) has long been the subject of research in occupational medicine, but not to industrial toxicology, including methods of setting threshold limit values (TLVs) and employee biological monitoring. Numerous animal and human investigations document vulnerability to chemical, contagion, and other xenobiotics varies according to the circadian time of encounter. Permanent and rotating nightshift personnel are exposed to industrial contaminants in the same or higher concentration as dayshift personnel, and because of incomplete CTS adjustment to night work, contact with contaminants occurs during a different biological time than day workers. Thus, the amount of protection afforded by certain TLVs, especially for employees of high-risk settings who work night and other nonstandard shift schedules, might be inadequate. The CTS seems additionally germane to procedures of employee biological monitoring in that high-amplitude 24 h rhythms in biomarkers indicative of xenobiotic exposure may result in misjudgment of health risks when data are not gathered in sufficient frequency over time and properly interpreted. Biological reference values time-qualified for their rhythmic variation, currently of interest to laboratory medicine practice, are seemingly important to industrial medicine as circadian time and work-shift specific biological exposure indices to improve surveillance of personnel, particularly those working nonstandard shift schedules.

Perspectives on the relevance of the circadian time structure to workplace threshold limit values and employee biological monitoring.

The circadian time structure (CTS) and its disruption by rotating and nightshift schedules relative to work performance, accident risk, and health/wellbeing have long been areas of occupational medicine research. Yet, there has been little exploration of the relevance of the CTS to setting short-term, time-weighted, and ceiling threshold limit values (TLVs); conducting employee biological monitoring (BM); and establishing normative reference biological exposure indices (BEIs). Numerous publications during the past six decades document the CTS substantially affects the disposition - absorption, distribution, metabolism, and elimination - and effects of medications. Additionally, laboratory animal and human studies verify the tolerance to chemical, biological (contagious), and physical agents can differ extensively according to the circadian time of exposure. Because of slow and usually incomplete CTS adjustment by rotating and permanent nightshift workers, occupational chemical and other contaminant encounters occur during a different circadian stage than for dayshift workers. Thus, the intended protection of some TLVs when working the nightshift compared to dayshift might be insufficient, especially in high-risk settings. The CTS is germane to employee BM in that large-amplitude predictable-in-time 24h variation can occur in the concentration of urine, blood, and saliva of monitored chemical contaminants and their metabolites plus biomarkers indicative of adverse xenobiotic exposure. The concept of biological time-qualified (for rhythms) reference values, currently of interest to clinical laboratory pathology practice, is seemingly applicable to industrial medicine as circadian time and workshift-specific BEIs to improve surveillance of night workers, in particular. Furthermore, BM as serial assessments performed frequently both during and off work, exemplified by employee self-measurement of lung function using a small portable peak expiratory flow meter, can easily identify intolerance before induction of pathology.

Do night and around-the-clock firefighters' shift schedules induce deviation in tau from 24 hours of systolic and diastolic blood pressure circadian rhythms?

Systolic (S) and diastolic (D) blood pressures (BP) [SBP and DBP] are circadian rhythmic with period (τ) in healthy persons assumed to be maintained at 24.0h. We tested this assumption in a sample of 30 healthy career (mean >12 yrs) 30-to-46 yr-old male Caucasian French firefighters (FFs) categorized into three groups according to work schedule and duties: Group A - 12 FFs working 12h day, 12h night, and occasionally 24h shifts and whose primary duties are firefighting plus paramedical and road rescue services; Group B - 9 FFs working mostly 12h day and 12h night shifts and whose duties are answering incoming emergency calls and coordinating service vehicle dispatch from fire stations with Group A personnel; Group C - 9 day shift (09:00-17:00h) FFs charged with administrative tasks. SBP and DBP, both in winter and in summer studies of the same FFs, were sampled by ambulatory BP monitoring every 1h between 06:00-23:00h and every 2h between 23:01-05:59h, respectively, their approximate off-duty wake and sleep spans, for 7 consecutive days. Activity (wrist actigraphy) was also sampled at 1-min intervals. Prominent τ of each variable was derived by a power spectrum program written for unequal-interval time series data, and between-group differences in incidence of τ≠24h of FFs were assessed by chi square test. Circadian rhythm disruption (τ≠24h) of either the SBP or DBP rhythm occurred almost exclusively in night and 24h shift FFs of Group A and B, but almost never in day shift FFs of Group C, and it was not associated with altered τ from 24.0h of the circadian activity rhythm. In summer, occurrence of τ≠24 for FFs of Group A and B differed from that for FFs of Group C in SBP (p=0.042) and DBP (p=0.015); no such differences were found in winter (p>0.10). Overall, manifestation of prominent τ≠24h of SBP or DBP time series was greater in summer than winter, 27.6% versus 16.7%, when workload of Group B FFs, i.e. number of incoming emergency telephone calls, and of Group A FFs, i.e. number of dispatches for provision of emergency services, was, respectively, two and fourfold greater and number of 12h night shifts worked by Group B FFs and number of 24h shifts worked by Group A FFs was, respectively, 92% and 25% greater. FFs of the three groups exhibited no winter-summer difference in τ≠24h of SBP or SDP; however, τ≠24h of DBP in Group B FFs was more frequent in summer than winter (p=0.046). Sleep/wake cycle disruption, sleep deprivation, emotional and physical stress, artificial light-at-night, and altered nutrient timings are hypothesized causes of τ≠24h for BP rhythms of affected Groups A and B FFs, but with unknown future health effects.

Seven-day human biological rhythms: An expedition in search of their origin, synchronization, functional advantage, adaptive value and clinical relevance.

This fact-finding expedition explores the perspectives and knowledge of the origin and functional relevance of the 7 d domain of the biological time structure, with special reference to human beings. These biological rhythms are displayed at various levels of organization in diverse species - from the unicellular sea algae of Acetabularia and Goniaulax to plants, insects, fish, birds and mammals, including man - under natural as well as artificial, i.e. constant, environmental conditions. Nonetheless, very little is known about their derivation, functional advantage, adaptive value, synchronization and potential clinical relevance. About 7 d cosmic cycles are seemingly too weak, and the 6 d work/1 d rest week commanded from G-d through the Laws of Mosses to the Hebrews is too recent an event to be the origin in humans. Moreover, human and insect studies conducted under controlled constant conditions devoid of environmental, social and other time cues report the persistence of 7 d rhythms, but with a slightly different (free-running) period (τ), indicating their source is endogenous. Yet, a series of human and laboratory rodent studies reveal certain mainly non-cyclic exogenous events can trigger 7 d rhythm-like phenomena. However, it is unknown whether such triggers unmask, amplify and/or synchronize previous non-overtly expressed oscillations. Circadian (~24 h), circa-monthly (~30 d) and circannual (~1 y) rhythms are viewed as genetically based features of life forms that during evolution conferred significant functional advantage to individual organisms and survival value to species. No such advantages are apparent for endogenous 7 d rhythms, raising several questions: What is the significance of the 7 d activity/rest cycle, i.e. week, storied in the Book of Genesis and adopted by the Hebrews and thereafter the residents of nearby Mediterranean countries and ultimately the world? Why do humans require 1 d off per 7 d span? Do 7 d rhythms bestow functional advantage to organisms? Is the magic ascribed to the number 7 of relevance? We hypothesize the 7 d time structure of human beings is endogenous in origin - a hypothesis that is affirmed by a wide array of evidence - and synchronized by sociocultural factors linked to the Saturday (Hebrews) or Sunday (Christian) holy day of rest. We also hypothesize they are representative, at least in part, of the biological requirement for rest and repair 1 d each 7 d, just as the circadian time structure is representative, in part, of the biological need for rest and repair each 24 h.

Chronobiology and chronotherapy of allergic rhinitis and bronchial asthma.

Study of the chronobiology of allergic rhinitis (AR) and bronchial asthma (BA) and the chronopharmacology and chronotherapy of the medications used in their treatment began five decades ago. AR is an inflammatory disease of the upper airway tissue with hypersensitivity to specific environmental antigens, resulting in further local inflammation, vasomotor changes, and mucus hypersecretion. Symptoms include sneezing, nasal congestion, and runny and itchy nose. Approximately 25% of children and 40% of adults in USA are affected by AR during one or more seasons of the year. The manifestation and severity of AR symptoms exhibit prominent 24-h variation; in most persons they are worse overnight or early in the morning and often comprise nighttime sleep, resulting in poor daytime quality of life, compromised school and work performance, and irritability and moodiness. BA is also an inflammatory medical condition of the lower airways characterized by hypersensitivity to specific environmental antigens, resulting in greater local inflammation as well as bronchoconstriction, vasomotor change, and mucus hypersecretion. In USA an estimated 6.5 million children and 15.7 million adults have BA. The onset and worsening of BA are signaled by chest wheeze and/or croupy cough and difficult and labored breathing. Like AR, BA is primarily a nighttime medical condition. AR is treated with H1-antagonist, decongestant, and anti-inflammatory (glucocorticoid and leukotriene receptor antagonist and modifier) medications. Only H1-antagonist AR medications have been studied for their chronopharmacology and potential chronotherapy. BA is treated with some of the same medications and also theophylline and beta2-agonists. The chronopharmacology and chronotherapy of many classes of BA medications have been explored. This article reviews the rather extensive knowledge of the chronobiology of AR and BA and the chronopharmacology and chronotherapy of the various medications used in their treatment.

Euchronism, allochronism, and dyschronism: is internal desynchronization of human circadian rhythms a sign of illness?

The authors define a subject as euchronic when the circadian parameters--tau (tau=period), Ø (acrophse or peak time), A (amplitude), and M (MESOR=24 h rhythm-adjusted mean)--of a set of circadian variables are within the confidence limits of appropriate reference values of healthy subjects (HS). We define internal desynchronization as a state in which the circadian tau of a set of rhythms differs from 24 h and when the tau of a given variable differs from that of other variables. Such a state was first observed in singly isolated HS without access to time cues and clues. Herein, data and analyses are presented demonstrating that internal desynchronization appears to be a rather common phenomenon in HS dwelling in their natural environment (i.e., in the presence of usual zeitgebers). This has been documented by longitudinal studies (n approximately=15 days) of the circadian rhythm in sleep-wakefulness, body temperature, right- and left-hand-grip strength, and reaction time involving a total of 246 HS and 134 shift workers (SW), with 45.5% showing good and 54.5% poor SW tolerance. The presence of internal desynchronization observed in SW was associated SW intolerance, with symptoms being sleep alteration/disturbances, sleeping-pill dependence, persisting fatigue (asthenia), mood alteration, and digestive complaints. Internal desynchronization was also documented in groups of HS and tolerant SW, though it was almost the rule among the intolerant SW. The authors introduce two new terms: allochronism to describe the time organization of those SW who evidence internal desynchronization without detectable clinical symptoms, and dyschronism to describe the time organization of those SW who exhibit internal desynchrobization plus the symptoms of SW intolerance or medical illness. The condition of allochronism is not restricted only to SW tolerance, as it was detected in 112 HS without medical complains when exposed to various experimental conditions, including medications and placebos, sojourn in the high Arctic summer, intensive sport training, and task-loaded cognitive performance testing. Dyschronism in SW who are sleep-deprived is associated with persisting fatigue. An unpublished Gallup survey found that 47% of 2478 respondents experienced a state of asthenia during the previous 12 months, with symptoms mimicking those of SW intolerance. In one-third of the cases, the origin of the asthenia was undetermined. Taking into account the high incidence of internal desynchronization found in past investigations and the clinical observation that sleep deprivation is a consequence of many acute and chronic medical conditions (nocturnal pain, nocturnal asthma, etc.), it is suggested that dyschronism may be responsible for the asthenia of unknown origin, at least for some persons. The interindividual (including sex-related) variability in the propensity to exhibit an altered temporal organization, whether it be transient or persistent (i.e., reversible or non-reversible) suggests the involvement of genetic factors. The Dian-Circadian genetic model previously proposed by the authors seems pertinent to conceptualize and explain the various levels and output of internal desynchronization.