Examination of the melatonin hypothesis: Graham et al.'s response. (Correspondence).

We appreciate Frentzel-Beyme's comments about our study (1). Our focus was to determine if melatonin and estradiol concentrations are altered, as suggested by the melatonin hypothesis (2), in women exposed to magnetic fields (EMF) at night or to bright light at night (LAN). Frentzel-Beyme expresses concern that we have reduced the relationship between EMF/LAN and breast cancer to the mechanistic level of estradiol concentrations, and ignored the important roles played by prolactin, depression, insomnia, and LAN in the etiology of the disease. Further, the relevance of our negative results is questioned because hormonal regulation in healthy women, who are supposedly stimulated by being in a laboratory environment, is different from that which occurs in stressed women in real life. Frentzel-Beyme concludes that, for now, this area of environmental health effects does not seem open to experimental approaches such as the one we published.

We take a different point of view. Richard Stevens developed one of the few mechanistic, testable hypotheses in the area of EMF research: namely, that the increased incidence of breast cancer in industrial societies is related to greater exposure to power-frequency EMF and/or the presence of high levels of LAN (2). EMF and LAN are believed to reduce circulating levels of the hormone melatonin which, in turn, allows estrogen levels to rise and stimulate the turnover of breast epithelial stem cells and increase the risk for malignant transformation. This hypothesis has heuristic value precisely because it does describe a mechanistic relationship between environmental exposure and neoplastic disease, one that is subject to experimental observation and manipulation. We believe that testing specific hypotheses under controlled experimental conditions is the foundation of science, and that this process has led to many important advances relevant to human health.

We also disagree with some of the conclusions drawn by Freutzel-Beyme. We did not ignore the hormone prolactin; it simply was not part of the hypothesized chain of events we set out to test. As noted in the recent review on EMF health effects by the National Institute of Environmental Health Sciences (3), studies of EMF exposure in both healthy individuals and electrically hypersensitive people have failed to observe alterations in prolactin concentrations. More generally, the results of multiple human EMF exposure studies provide little evidence for any reliable effect on hypothalamic, pituitary, thyroid, or adrenal hormonal systems.

We see a number of difficulties with Frentzel-Beyme's reasoning. Melatonin levels tend to be stable within an individual, but vary widely from person to person. For example, women in our study showed a 15-fold difference in the total amount of melatonin they secreted overnight (area under the curve range: 86-1,296 pg/mL), and this is not an unusual observation (4). Depression is simply not a function of having low melatonin levels. In fact, endogenous low melatonin levels in humans do not seem to correlate with much of anything. Furthermore, the melatonin rhythm is a function of the light/dark cycle, not the sleep/wake cycle; thus, the quality of night sleep (or the lack of it) does not alter the nightly rhythm of this hormone. As we reported, even when extremely bright LAN is used to cause a marked (> 90 %) reduction in nocturnal blood levels of melatonin, the natural rhythm is rapidly reinstated in humans after the light is discontinued.

As indicated in our paper (1), we certainly agree with Frentzel-Beyme on the need for further research on LAN and its impact on health, particularly as it relates to shift work. Although melatonin may not be responsive to the sleep/wake cycle, prolactin certainly is. We also feel that the issues raised by Frentzel-Beyme involving LAN, depression, and the deregulation of hormones implicated in carcinogenesis are quite amenable to experimental approaches such as we described in our paper (1). For example, it would be quite feasible to assess the hormonal consequences of controlled exposure to EMF or LAN in healthy women compared to women stratified on various measures of depression, insomnia, or other factors. One should bear in mind, however, that if the initiation of breast cancer were limited only to those women who are "stressed, depressed, exhausted, unhappy, and desperate" prior to diagnosis, prevention would be a much easier matter than it is now. Anti-depressant medications are not a currently recommended prophylactic for breast cancer, and sadly, many women who are happy and well-adjusted develop this disease.

Charles Graham
Mary R. Cook
Mary M. Gerkovich
Antonio Sastre
Midwest Research Institute
Kansas City, Missouri
E-mail: [e-mail]

REFERENCES AND NOTES

(1.) Graham C, Cook MR, Gerkovich MM, Sastre A. Examination of the melatonin hypothesis in women exposed at night to EMF or bright light. Environ Health Perspect 109:501-507 (2001).

(2.) Stevens RG. Electric power use and breast cancer: a hypothesis. Am J Epidemiol 125:556-561 (1987).

(3.) Portier C, Wolfe MS, eds. Assessment of Health Effects from Exposure to Power-Line Frequency Electric and Magnetic Fields. NIH Publication no 98-3981. Research Triangle Park, NC:National institute of Environmental Health Sciences,1998.

(4.) Cook MR, Graham C, Kavet R, Stevens RG, Kheifets LI, Davis S. Morning urinary assessment of nocturnal melatonin secretion in older women. J Pineal Res 28:41-47 (2000).