A high rate of breast cancer is present among Finnish female flight attendants after a mean of 13·9 years at work (standard incidence ratio 1·87 [95% CI 1·15-2·23]). The risk is most prominent 15 years after recruitment.1 This increase may be due to melatonin deficiency, resulting from work-associated interruptions in sleep-waking cycles (jetlag). Chronic disturbances in circadian rhythm are thought to lead to many of the health problems reported by shift workers, and because flight attendants commonly work at night and travel across many time zones, they are exposed to chronic interruptions in circadian rhythms.2
Jetlag is characterised by fatigue, headache, weakness, irritability, memory difficulties, loss of concentration, and gastrointestinal disturbances. Eastward travel is associated with worse disturbances than westward, perhaps because getting to sleep at bedtime at the destination is more difficult than premature wakening. Several days may be needed for full recovery.3 Severity of symptoms is related to the menstrual cycle, disruptions of which are also common in flight attendants.2 Jetlag disrupts the function of the pineal gland, which secretes melatonin in response to darkness and inhibits secretion during daylight. Melatonin is the chief hormone secreted by the pineal gland, and has a robust secretion cycle, starting at about 2100 h and ending at about 0800 h. Disruption of pineal-gland activity as a result of being awake during normal sleep time and attempting to sleep during normal waking time would, therefore, be expected to decrease secretion. Melatonin production is decreased by exposure to bright light during normal sleep time, whereas supplementary melatonin prevents the symptoms and is thought to be the best available pharmacological treatment for jetlag.3,4
Breast cancer is associated with decreased melatonin production, and supplementary melatonin has a protective effect against breast cancer in animals. A tumour size-dependent decline in the circadian amplitude of serum melatonin occurs in unoperated patients with primary breast cancer. Melatonin inhibits the growth of human breast-cancer cells, seemingly by down-regulating oestrogen receptor expression; at physiological concentrations (about 1 nmol/L) melatonin also augments the inhibitory actions of tamoxifen on human breast-cancer-cell growth. A significant difference in the luteal heat cycle has been reported between normal and precancerous breasts; the latter were persistently hotter, had an earlier rise in temperature, and showed a smaller increase during the luteal phase. Circadian rhythms in tissue proliferation and drug handling are also well documented. Melatonin is antiproliferative in oestrogen-responsive breast cancer (which accounts for about two-thirds of all breast cancers) and shows menstrual-cycle variation, with the highest values near menstruation and the lowest at ovulation.4,5
These data suggest that work-associated disturbances in biological rhythms in general and melatonin production in particular are involved in breast cancer, and may contribute to the increase of about two-fold in risk of breast cancer among female flight attendants. If this hypothesis is correct, female flight attendants as a group, and especially those with more disturbed sleep patterns, would be expected to have lower circulating melatonin than controls; duration of employment as a flight attendant should correlate positively with breast cancer risk and inversely with serum melatonin; and flight attendants with breast cancer should have more work-associated exposure to jetlag, and lower melatonin than those without breast cancer.
1 Pukkala E, Auvinen H, Wahlberg G. Incidence of cancer among Finnish airline cabin attendants, 1967-1992. BMJ 1995; 311: 649-52.
2 Suvanto S, Harma M, Ilmarinen J, Partinen M. Effects of 10 h time zone changes on female flight attendants' circadian rhythms of body temperature, alertness and visual search. Ergonomics 1993; 36: 613-25.
3 Waterhouse J, Reilly T, Atkinson G. Jet-lag. Lancet 1997; 350: 1611-16.
4 Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336: 186-95.
5 Bartsch C, Bartsch H, Karenovics A, et al. Nocturnal urinary 6-sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age-matched controls and shows negative correlation with tumor-size. J Pineal Res 1997; 23: 53-81.
Research Planning and Evaluation, Carolinas Health Care System, Charlotte, NC 28232, USA ,(A R Mawson; e-mail amawson@carolinas.org)
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