RE: "INVITED COMMENTARY: ELECTROMAGNETIC FIELDS AND CANCER IN RAILWAY WORKERS"

Thomas C. Erren, Peter Bjerregaard, Pierluigi Cocco, Alexander Lerchl and Pia Verkasalo

Institute and Policlinic for Occupational and Social Medicine School of Medicine and Dentistry University of Cologne D-50924 Cologne, Germany
Section for Research in Greenland National Institute of Public Health DK-2100 Copenhagen, Denmark
Occupational Health Section Department of Public Health Faculty of Medicine and Surgery University of Cagliari I-09124 Cagliari, Italy
School of Engineering and Science International University Bremen D-28759 Bremen, Germany
Department of Environmental Health National Public Health Institute FIN-70701 Kuopio, Finland

In a recent interview regarding epidemiologic research on electromagnetic fields (EMFs), Dr. David Savitz stated that he "continue[s] to believe that [black box] epidemiology is capable of addressing health concerns even in the absence of biologic understanding, but what has happened with EMFs is that we've pursued that strategy and gotten the most insight we can" (1Go, p. 3). In the invited commentary (2Go) that stimulated these remarks, Savitz noted that alterations in melatonin levels have been proposed as possible intermediate endpoints between EMF exposures and health outcomes. However, he concluded that "without some unique circumstances offering vast numbers of unambiguously exposed workers, some new integrative indicator of exposure, or a surrogate endpoint allowing new study designs, it seems that 'black box' epidemiology has exhausted its potential..." (2Go, p. 838).

We believe that these difficulties can be overcome. Large populations of individuals differentially exposed to electromagnetic radiation of interest are identifiable. Their melatonin levels can be measured and, if necessary, monitored longitudinally. A plausible biomechanistic hypothesis that links exposure to particular EMFs with well-defined and public-health-relevant endpoints exists, thus providing a basis for coherent "white box" epidemiology.

The melatonin hypothesis provides a biologically plausible link between electromagnetic radiation in the visible range, i.e., light, and cancer (3Go). Extensive research has identified some of the mechanisms by which melatonin may reduce cancer incidence and/or growth (4Go, 5Go). As a corollary, it has also been argued that if light significantly inhibits melatonin secretion, then darkness should increase the levels of this key biologic intermediary—for instance, in Arctic residents who experience extended periods of winter darkness (6Go). We have identified nine studies in the peer-reviewed literature which have examined melatonin levels among healthy individuals living at or north of 60°N latitude (7GoGoGoGoGoGoGoGoGoGo–17Go). Findings of all studies are compatible with the assumption that the lengths of photoperiods significantly affect melatonin homeostasis in the manner predicted. However, to conclude that variations in natural light significantly modulate endocrine systems across populations at different latitudes, researchers would have to collect high-quality empirical data in populations that resided in distinct geographic areas, using identical study designs.

Implicit in the aforementioned corollary to the melatonin hypothesis is the prediction that melatonin levels and rhythms vary between people who are differentially exposed to light by virtue of variations in ambient photoperiods. We suggest that this could be tested in practice by measuring variations in melatonin levels among healthy residents of areas at or near 80, 70, 60, 50, and 40°N latitude—that is, from the Arctic to the Mediterranean. These measurements could then be compared with estimates of the same individuals' exposures to naturally occurring and artificial light during significant seasonal periods. In this way, it would be possible to identify associations and to estimate relations between temporal melatonin rhythms and 1) exposure to natural light, 2) exposure to artificial light, and 3) total exposure (natural light plus artificial light). The light-exposure data that we suggest can be obtained could then be related to melatonin measurements in serum, saliva, and urine.

If the kind of study envisaged—based on EMF dosimetry by geography—showed that light leads to marked contrasts in melatonin levels in large populations, then hypothesis-driven research into the possible link to cancer could proceed. ("Lack of melatonin can reasonably be anticipated to be a human carcinogen" (18Go, p. 313).) This would provide the further insights sought by Dr. Savitz. Since melatonin is also of concern with regard to a variety of other health effects, including sleep disturbances, mood disorders, reproduction, and aging (19Go), elucidation of whether and how light modulates endocrine pathways may also enhance our understanding of other diseases in geographically dispersed populations that can differ in terms of risk.

REFERENCES

  1. Savitz D. EMF epidemiology has reached its limits. (Interview). Microwave News 2001;May/June:3.
  2. Savitz DA. Invited commentary: electromagnetic fields and cancer in railway workers. Am J Epidemiol 2001;153:836–8.[Abstract/Free Full Text]
  3. Stevens RG. Electric power use and breast cancer: a hypothesis. Am J Epidemiol 1987;125:556–61.[ISI][Medline]
  4. Reiter RJ. Historical account of the research related to EMF, melatonin and cancer. In: Erren TC, Piekarski C, eds. Low frequency EMF, visible light, melatonin and cancer: international symposium, May 4–5, 2000, University of Cologne. Zentralbl Arbeitsmed 2000;50:298–314. (http://www.uni-koeln.de/symposium2000).
  5. Karbownik M, Reiter RJ, Burkhardt S, et al. Melatonin attenuates estradiol-induced oxidative damage to DNA: relevance for cancer prevention. Exp Biol Med 2001;226:707–12.[Abstract/Free Full Text]
  6. Erren TC, Piekarski C. Does winter darkness in the Arctic protect against cancer? The melatonin hypothesis revisited. Med Hypotheses 1999;53:1–5.[ISI][Medline]
  7. Beck-Friis J, Von Rosen D, Kjellman BF, et al. Melatonin in relation to body measures, sex, age, season and the use of drugs in patients with major affective disorders and healthy subjects. Psychoneuroendocrinology 1984;9:261–77.[ISI][Medline]
  8. Martikainen H, Tapanainen J, Vakkuri O, et al. Circannual concentrations of melatonin, gonadotrophins, prolactin and gonadal steroids in males in a geographical area with a large annual variation in daylight. Acta Endocrinol (Copenh) 1985;109:446–50.[Medline]
  9. Kauppila A, Kivelä A, Pakarinen A, et al. Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with strong seasonal contrast in luminosity. J Clin Endocrinol Metab 1987;65:823–8.[Abstract]
  10. Kivelä A, Kauppila A, Ylostalo P, et al. Seasonal, menstrual and circadian secretions of melatonin, gonadotropins and prolactin in women. Acta Physiol Scand 1988;132:321–7.[ISI][Medline]
  11. Levine ME, Milliron AN, Duffy LK. Diurnal and seasonal rhythms of melatonin, cortisol and testosterone in interior Alaska. Arctic Med Res 1994;53:25–34.[Medline]
  12. Stokkan K-A, Reiter RJ. Melatonin rhythms in Arctic urban residents. J Pineal Res 1994;16:33–6.[ISI][Medline]
  13. Laakso ML, Porkka-Heiskanen T, Alila A, et al. Twenty-four-hour rhythms in relation to the natural photoperiod: a field study in humans. J Biol Rhythms 1994;9:283–93.[ISI][Medline]
  14. Weydahl A, Sothern RB, Wetterberg L. Seasonal variations in melatonin may modulate glycemic response to exercise. Percept Mot Skills 1998;86:1061–2.[ISI][Medline]
  15. Wetterberg L, Eberhard G, Von Knorring L, et al. The influence of age, sex, height, weight, urine volume and latitude on melatonin concentrations in urine from normal subjects: a multinational study. In: Wetterberg L, ed. Light and biological rhythms in man. Oxford, United Kingdom: Pergamon Press, 1993:275–86.
  16. Wetterberg L, Bratlid T, Von Knorring L, et al. A multinational study of the relationships between nighttime urinary melatonin production, age, gender, body size, and latitude. Eur Arch Psychiatry Clin Neurosci 1999;249:256–62.[ISI][Medline]
  17. Wetterberg L, Bergiannaki JD, Paparrigopoulos T, et al. Normative melatonin excretion: a multinational study. Psychoneuroendocrinology 1999;24:209–26.[ISI][Medline]
  18. Portier C. Decisions about environmental health risks: what are the key questions and how does this apply to melatonin? In: Erren TC, Piekarski C, eds. Low frequency EMF, visible light, melatonin and cancer: international symposium, May 4–5, 2000, University of Cologne. Zentralbl Arbeitsmed 2000;50:298–314. (http://www.uni-koeln.de/symposium2000).
  19. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186–95.[Free Full Text]

 

THE AUTHOR REPLIES

David A. Savitz

Department of Epidemiology School of Public Health University of North Carolina Chapel Hill, NC 27599

I thank Dr. Erren and his coauthors for their observations (1Go). Their comments serve as a useful reminder of how narrowly conclusions about research must be drawn. In preparing my invited commentary (2Go) on the future of research pertaining to occupational electromagnetic field (EMF) exposure and leukemia and brain cancer, I was reminded by colleagues that my conclusion—that we have largely exhausted the contribution of epidemiology without the advent of some conceptual or methodological breakthrough—had to be carefully restricted. This conclusion does not apply to other sources of EMF exposure, e.g., residential fields; to other forms of nonionizing radiation, e.g., those used in cellular telephone communications; or to other health outcomes, e.g., breast cancer or neurologic or cardiovascular disease. In an editorial (3Go) accompanying a large study of magnetic fields and childhood leukemia (4Go), Campion concluded that the new study negated previous evidence for an association between magnetic fields and childhood leukemia. Not only has the certainty that the study's results were unequivocally negative eroded with the passage of time, but the broader assertion that all research on potential adverse health effects from this exposure should draw to a close could not be justified, regardless of how persuasively it addressed residential magnetic fields and childhood leukemia. Analogously, my conclusions should not be interpreted as extending to issues beyond the relation between occupational exposure to extremely low-frequency EMFs and leukemia/brain cancer.

Visible light is, of course, a form of electromagnetic radiation—a reminder that my commentary did not circumscribe the exposure sufficiently. There has been great interest in a potential mediating role of melatonin as a biologic link between EMFs and health effects, but in the hypothesized causal chain (5Go), the weakest link is between environmental levels of EMFs and suppression of nighttime melatonin production. Evidence that EMFs disrupt melatonin pathways is at best inconsistent, with some suggestions of positive effects being observed in field studies of exposed workers (6GoGo–8Go) but largely negative results being obtained from direct human experimentation (9Go, 10Go). Given disruption of melatonin production, which visible light is clearly capable of producing (11Go), a wide range of health consequences ranging from depression (12Go, 13Go) to breast cancer (5Go) becomes quite plausible. Erren et al. (1Go) offer a number of potentially promising directions for epidemiologic research on melatonin-mediated health effects which my commentary should in no way discourage.

REFERENCES

  1. Erren TC, Bjerregaard P, Cocco P, et al. Re: "Invited commentary: electromagnetic fields and cancer in railway workers." (Letter). Am J Epidemiol 2001;154:977–8.[Free Full Text]
  2. Savitz DA. Invited commentary: electromagnetic fields and cancer in railway workers. Am J Epidemiol 2001;153:836–8.[Abstract/Free Full Text]
  3. Campion EW. Power lines, cancer, and fear. (Editorial). N Engl J Med 1997;337:44–6.[Free Full Text]
  4. Linet MS, Hatch EE, Kleinerman RA, et al. Residential exposure to magnetic fields and acute lymphoblastic leukemia in children. N Engl J Med 1997;337:1–7.[Abstract/Free Full Text]
  5. Stevens RG, Davis S. The melatonin hypothesis: electric power and breast cancer. Environ Health Perspect 1996;104(suppl 1):135–40.[ISI][Medline]
  6. Pfluger DH, Minder CE. Effects of exposure to 16.7 Hz magnetic fields on urinary 6-hydroxymelatonin sulfate excretion of Swiss railway workers. J Pineal Res 1996;21:91–100.[ISI][Medline]
  7. Burch JB, Reif JS, Yost MG, et al. Nocturnal excretion of a urinary melatonin metabolite among electric utility workers. Scand J Work Environ Health 1998;24:183–93.[ISI][Medline]
  8. Burch JB, Reif JS, Noonan CW, et al. Melatonin metabolite levels in workers exposed to 60-Hz magnetic fields: work in substations and with 3-phase conductors. J Occup Environ Med 2000;42:136–42.[ISI][Medline]
  9. Graham C, Cook MR, Riffle DW, et al. Nocturnal melatonin levels in human volunteers exposed to 60 Hz magnetic fields. Bioelectromagnetics 1996;17:263–73.[ISI][Medline]
  10. Graham C, Cook MR, Riffle DW. Human melatonin during continuous magnetic field exposure. Bioelectromagnetics 1997;18:166–71.[ISI][Medline]
  11. Cagnacci A. Melatonin in relation to physiology in adult humans. J Pineal Res 1996;21:200–13.[ISI][Medline]
  12. Beck-Friis J, Kjellman BF, Aperia B, et al. Serum melatonin depressive disorder and a hypothesis of a low melatonin syndrome. Acta Psychiatr Scand 1985;71:319–30.[ISI][Medline]
  13. Brown RP, Kocsis JH, Caroff S, et al. Depressed mood and reality disturbance correlate with decreased nocturnal melatonin in depressed patients. Acta Psychiatr Scand 1987;76:272–5.[ISI][Medline]