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American Journal of EpidemiologyCopyright 1999 by The Johns Hopkins University School of Hygiene and Public HealthAll rights reserved

Vol.150, No. 1Printed in U.S.A.

Reduced Excretion of a Melatonin Metabolite in Workers Expo sed to 60 HzMagnetic Fields

James B. Burch,1 John S. Reif,1 Michael G. Yost,2 Thomas J. Keefe,1 and Charles A. Pitrat1

The effects of occupational 60 Hz magnetic field and ambient light exposures on the pineal hormone,melatonin, were studied in 142 male electric utility workers in Colorado, 1995-1996. Melatonin was assessedby radioimmunoassay of its m etabolite, 6-hydroxymelatonin sulfate (6-OHM S), in post-work shift urine samples.Personal magnetic field and light exposures were measured over 3 consecutive days using EMDEX C metersadapted with light sensors. Two independent compo nents of m agnetic field exposure, intensity (geometric timeweighted average) and tem poral stability (standardized rate of change m etric or R CM S), were analyzed for theireffects on creatinine-adjusted 6-OHMS concentrations (6-OHMS/cr) after adjustment for age, month, and lightexposure. Geom etric mean m agnetic field exposures were not associated with 6-OHMS/cr e xcretion. Men in thehighest quartile of temporally stable magnetic field exposure had lower 6-OHMS/cr concentrations on thesecond and third days compared with those in the lowest quartile. Light exposure modified the magnetic fieldeffect. A progressive decrease in mean 6-OHMS/cr concentrations in response to temporally stable magneticfields was observed in subjects with low workplace light exposures (predominantly office workers), whereasthose with high am bient light exposure showed negligible magnetic field effects. Melatonin suppression may beuseful for understanding human biologic responses to magnetic f ield exposures. Am J Epidemiol1999; 150 :27-36electricity; electromagnetic fields; 6-hydroxymelatonin sulfate; pineal body

Research on the biologic effects associated withoccupational exposure to power frequency (50/60 Hz)electric and magnetic fields (EMFs) has intensified inrecent years due to reported associations with leukem iaand brain cancer (1 , 2). Some biologic effects of EMFexposure may be mediated by the hormone, melatonin(3 , 4). Melatonin is produced primarily by the pinealgland and its synthesis is directly inhibited by ambientlight exposure, resulting in a diurnal secretory pattern(high at night, low during the day) (5). Melatonin sup-pression in response to magnetic field exposure hasbeen reported both in experimental animals andhumans (3, 4, 6, 7) and light exposure may be requiredto elicit a magnetic field effect (8-1 0). In addition to itswell-characterized relation with endogenous circadianrhythms (11, 12), melatonin exerts physiologic effectsthat are relevant to carcinogenesis, including suppres-

Received for publication May 19,1 998 , and accepted for publica-tion November 4, 1998.Abbreviations: EMF, electric and magnetic field; 6-OHMS/cr,creatinine-adjusted 6-hydroxymelatonin sulfate; RCMS, standardizedrate of change metric; TWA, time-weighted average.1 Department of Environmental Health, Colorado State University,Fort Collins, CO.2 Department of Environmental Health, University of Washington,Seattle, WA.Reprint requests to Dr. Jame s Burch, Depa rtment ofEnvironmental Health, Colorado State University, Fort Collins, CO80523.

sion of tumor growth in humans and experimental ani-mals (13-15), enhancement of the immune response(15, 16), and scavenging of free radicals (17-19).Disrupted m elatonin secretion following magn etic fieldexposure could therefore influence carcinogenesis viaalteration of these processes. Melatonin also inhibitsthe secretion of estrogen and other tumor-promotinghormones (11, 12, 20, 21). Therefore, suppression ofmelatonin, induced either by EMFs alone or in combi-nation with light-at-night, could enhance estrogensecretion, leading to increased breast cancer risk (4,22). In support of this hypothesis, elevated breast can-cer risks have been reported in male (23-26) andfemale (27-29) EMF-exposed workers although sucheffects have not been observed consistently (30-33).Electric utility workers have occupational magneticfield exposures that are elevated relative to other occu-pations and they work in a complex electromagneticenvironment with respect to the intensity and temporalcharacteristics of their exposure (3438). Althoughmagnetic field intensity (summarized by the time-weighted average [TWA]) is a commonly evaluatedexposure metric, temporal characteristics of magneticfield exposure may be important for eliciting biologiceffects, such as the increased enzymatic activity ofornithine decarboxylase (3 9 ^ 1 ). The temporal auto-correlation between successive EMF measurements

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28 Burch et ai.has been identified as a component of personal EMFexposure in electric utility workers that is independentof magnetic field intensity (38). Further, the temporalautocorrelation of residential magnetic field exposuresmay be important for predicting childhood leukemiarisk when combined with other EMF exposure metrics(42).Reduced excretion of the major urinary melatoninmetabolite, 6-hydroxymelatonin sulfate (6-OHMS),has been shown in two studies of occupational EMFexposure (6, 7). Swiss railway workers were found tohave reduced evening 6-OHMS excretion after 5 daysof exposure to 16.7 Hz fields (7). Recently, we demon-strated decreased nocturnal 6-OHMS excretion associ-ated with exposure to temporally stable 60 Hz magneticfields in male electric utility workers (6). Temporalstability was assessed using an estimate of autocorre-lation, and the effect was most pronounced when bothresidential and occupational exposures were combined(6). The current study reports the effects of occupa-tional exposures to 60 Hz magnetic fields on post-work shift 6-OHMS excretion in the same populationof electric utility workers using measures of fieldintensity and temporal autocorrelation.MATERIALS AND METHODS

The study population was derived from three munic-ipal electric utilities in Colorado. All em ployees, aged20 -60 years, with at least one m onth of electric utilitywork experience were contacted via orientation meet-ings or by telephone. The goal, based on statisticalpowe r calculations, w as to obtain 200 participants; 195subjects were eventually recruited. Of those 195 work-ers, data were available for 173, of which 142 weremen . Workers with electric power g eneration, distribu-tion, or administrative job descriptions were studiedover a one-year period during daytime work hours(approximately 7:00 a.m. to 6:00 p.m.). Data collec-tion was scheduled for the first 3 days of the workweek to permit evaluation of changes in melatoninafter time away from work (6, 7). Non-shift workersparticipated during the daytime after 2 days of non-occupational magnetic field exp osure. In order to gen-erate comparable data for shift workers, they partici-pated while they were working during the day;however, their schedule provided 3 days off prior tocommencing their day shift.A questionnaire was used to collect additional infor-mation concerning factors that might influence mag-netic field or light exp osure and m elatonin production.Potential confounders or modifiers included personal(age, race, body mass index), occupational (job title,years work experience, physical activity, work withspecific chem icals, e.g., creosote, solvents, pesticides),

life-style (tobacco and alcohol consumption, light-at-night, electrical appliance use, exercise), and medicalfactors (medications, disease history). No subjectswere taking exogenous melatonin during participation.Subjects collected one urine sample immediatelyfollowing their work shift on each of 3 consecutivedays (usually Monday, Tuesday, and Wednesday) fordetermination of 6-OHMS. Subjects also collectedfour consecutive overnight urine samples; the M ondaymorning sample was used to evaluate baseline noctur-nal melatonin prior to resuming work. However, thelogistics of having subjects collect a baseline "post-work shift" urine sample while off duty were consid-ered not practical due to concerns about subject com-pliance and quality assurance. The melatoninmetabolite 6-OHMS was measured in urine byradioimmunoassay (43-45) using materials suppliedby CIDtech (Mississauga, Ontario, Canada). Theinterassay coefficient of variation for the slope of thestandard curves obtained during this study was 4 per-cent and the limit of detection for 6-OHMS was 0.1ng/ml. Concentrations of 6-OHMS were normalized tourinary creatinine concentrations (6-OHMS/cr) andare presented as nanograms 6-OHMS per milligramcreatinine (ng/mg cr).Work shift personal magnetic field and ambient lightexposures w ere logged daily for all subjects at a rate ofonce every 15 seconds using EMDEX C meters(Electric Field Measurements, Stockbridge,Massachusetts) worn at the waist. Light exposure wasmeasured with a light sensor (model LX101 , GrasbyOptronics, Orlando, Florida) adapted to the meter'sexternal jack. This photoelectric detector produces alinear output current in proportion to light intensity,from less than 1 lux to approxim ately 100,000 lux.Exposure assessment was performed for 3 work daysdue to battery life and the capacity of digital memoryin the meter. Subjects logged their work activities andhours on duty, permitting the calculation of dailyworkplace exposure metrics. Light exposure was sum -marized by calculating the work shift arithmetic TWA.The geometric TWA was used to assess the intensity ofmagnetic field exposure, and the standardized rate ofchange metric (RCMS), which estimates first-lag auto-correlation, w as used to assess the tempo ral stability ofexposure (6). Low values of RCM S represent relativelysmall differences between successive magnetic fieldmeasurements and are indicative of temporally stableexposures.Analyses were performed with the Statistical AnalysisSoftware (SAS) computer program (SAS Institute Inc.,Cary, North Carolina) using log-transformed values for6-OHMS/cr, geometric mean magnetic field exposures(untransformed values for RCMS), and light data. A

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Magnetic Field Exposure and Human Melatonin 29

univariate procedure (Mest or analysis of variance(ANOVA) for categorical data and linear correlation forcontinuous data) was used to screen 98 questionnaireitems for a potential association with 6-OHMS/cr usinga cutpoint of p < 0.10. Multivariate statistical evalu-ations of the effects of magnetic field exposure on 6-OHMS/cr excretion were conducted using Proc Mixedfor repeated measurements. Analyses were performedwith adjustment for age, month of participation, andTWA light exposure, which were considered potentialconfounders a priori. The results were unchanged whenother potential confounders selected using the univariatescreening process were also included in the analysis(height, tobacco consumption, self-reported stress, exer-cise, shift work, use of electric ovens, use of cellulartelephones, use of acetaminophen). W orkplace m agneticfield exposures were divided into quartiles and dailyleast-squares mean 6-OHMS/cr concentrations wereestimated for each quartile. Mean 6-OHMS/cr levels inthe lowest and highest quartiles were then comparedusing the least significant difference procedure in SAS.Data were also analyzed with Proc Mixed using mag-netic field exposure metrics as continuous v ariables w ithage, month, and light exposure included as covariates.Potential interactions between magnetic field intensityand temporal stability were analyzed by including thesemetrics and their cross-product in the statistical model.Interaction terms for magnetic field metrics with lightexposure were also analyzed.RESULTS

The study population comprised 142 males: 56 (39percent) distribution, 29 (20 percent) generation, and57 (40 percent) administrative and maintenance (com-parison) workers. The mean age (standard error) ofthe population was 41 (0.6) years; approximately 75percent of the study population was between 30 and 50years old. Hispanics and other non-Anglo or nonw hiteracial/ethnic groups accounted for 10.5 percent of thepopulation.As expected, a diurnal variation in mean 6-OHMS/cr concentrations was observed; unadjustedmean 6-OHMS/cr concentrations were 38.3 (1.5)ng/mg cr in the nocturnal (first void) samples and 9.0(0.4) ng/mg cr in the post-work shift samples for allsubjects combined. Mean 6-OHMS/cr concentrationsfor selected personal and occupational factors are pre-sented in table 1. A seasonal pattern in post-wo rk 6-OHM S/cr concentrations was present with a peak dur-ing the winter and a trough during the summ er months.In contrast, there were no statistically significant dif-ferences in mean 6-OHMS/cr levels across quartiles ofworkp lace light exposure (table 1). W hen analyzed asa continuous variable, workplace light exposure was

negatively associated with 6-OHMS/cr excretion (p =0.06). The crude mean 6-OHMS/cr concentrationswere elevated for electric power generation and shiftworkers. These differences were reduced after adjust-ment for month and light exposure. Generation andshift w orkers participated m ainly during the winter andfall (97 percent and 82 percent, respectively), which islikely to explain the differences between crude andadjusted mean 6-OHMS/cr levels. Subjects whosmoked more than one pack of cigarettes per day hadhigher 6-OHMS/cr excretion than those smoking lessthan one pack or nonsmokers. A slight reduction in 6-OHMS/cr concentrations was noted among workerswho consumed alcohol. Among the other variableslisted in table 1, statistically significant (p < 0.05) dif-ferences between crude means for recreational exer-cise and use of acetaminophen disappeared afteradjustment for a priori confounders.

Crude and adjusted means for post-work shift 6-OHMS/cr levels are presented by quartile of work-place geometric mean magnetic field exposure in table2. There were no statistically significant differences in6-OHMS/cr excretion among subjects in the highestand lowest exposure quartiles although a tendencytoward decreasing adjusted mean 6-OHMS/cr excre-tion was apparent on D ay 3 . Table 3 presents mean 6-OHMS/cr concentrations by quartile of temporally sta-ble (RCM S) m agnetic field exposu re at work. Astatistically significant difference in unadjusted mean6-OHMS/cr excretion was observed on each day. Afteradjustment for age, month, and light exposure, therewere no differences in 6-OHMS/cr concentration onDay 1 (table 3). How ever, men with temp orally stablemagnetic field exposures (quartile 4) had lower adjust-ed 6-OHMS/cr concentrations on Day 2 and Day 3,respectively, compared with those with temporallyunstable exposures (quartile 1, table 3).When analyzed as a continuous variable, geometricmean magnetic field exposure was not associated with6-OHMS/cr excretion. A negative association wasobserved between 6-OHMS/cr excretion and temporallystable (RCMS) magnetic field exposure (p = 0.06).More stable magnetic field exposures were associatedwith lower concentrations of the melatonin metabolite.Neither the interaction term for geometric mean withRCM S m agnetic field exposure nor the interaction termfor the geometric mean magnetic field with ambientlight exposure was associated with 6-OHMS/cr.However, there was a statistically significant interactionbetween temporally stable magnetic fields and ambientlight exposures (p = 0.02). In subjects with workplacelight exposures below the median, temporally stablemagnetic field exposures were associated withdecreased 6-OHMS/cr excretion (p < 0.01), whereas no

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30 Burch et al.

TAB LE 1 . Me an * creatinine-adjusted 6-hydroxym elatonin sulfate (6-OHM S/cr) conce ntrations forselected variables in male electric utility workers, Colorado, 1995-1996f

Variable Crude mear4(ng/mg cr) Adjusted meant(ng/mg cr)Age group (years)2 0-3 0 (n= 17)

31^10 {n = 47 )4 1 -50 (n = 59 )51-60 (n= 19)RaceNonwhite or H ispanic (n = 15)White (n= 125)Occupational groupAdministrative/maintenance ( n = 57)Distribution (n = 56)Generation (n = 29)SeasonWinter (n = 45)Spring (n = 21)Summer (n = 32)Fall (n = 44)Mean light exposure1,791 Iux(/7=3O)Cigarette smokingNonsmokers (n = 113)1 pack/day (n = 5)Alcohol consumptionNondrinker (n = 39)12 drinks/month (n = 48)Recreational Exercise>Once per week (n = 92)Seldom or never (n = 50 )Use of acetaminophenYes (n = 36)N o ( n = 1 0 5 )Body ma ss index (kg/m 2) 2 6 ( n = 7 1 )Shift workY e s ( n = 1 7 )N o ( n = 1 2 4 )Use of cell phone at workNever (n = 33 )Seldom 1x/day (n = 26)

4.16.17.07.44.76.46.54.610.9

11.23.92.68.78.75.48.04.66.16.511.88.05.75.65.67.88.35.76.66.0

11.05.86.57.76.04.8

(2.6-6.6)(4.7-7.9)(5.5-8.9)(4.7-11.6)(2.7-8.3)(5.5-7.5)(5.1-8.4)(3.6-5.8)(8.8-13.5)(9.4-13.4)(3.1-4.8)(1.8-3.6)(7.0-10.8)(6.4-11.9)(4.0-7.3)(5.8-10.9)(3.4-6.1)(5.1-7.3)(4.4-9.7)(7.8-17.8)(6.0-10.7)(4.4-7.3)(4.2-7.3)(4.6-6.9)(6.3-9.6)(6.3-10.8)(4.8-6.9)(5.3-8.2)(4.9-7.5)(7.9-15.5)(4.9-6.7)(4.7-8.9)(6.0-9.9)(4.6-8.0)(3.1-7.3)

4.84.15.44.63.74.94.64.56.5

10.33.61.98.05.64.35.24.84.65.58.05.94.05.14.84. 85.34.75.04.76.04. 65.04.75.14.5

(3.5-6.5)(3.4-5.1)(4.6-6.3)(3.5-6.1)(2.7-5.3)(4.4-5.5)(3.8-5.4)(3.8-5.4)(4.8-8.7)(8.5-12.6)(2.7-4.8)(1.5-2.4)(6.5-9.8)(4.8-6.5)(3.6-5.2)(4.3-6.2)(3.9-5.8)(4.1-5.3)(4.2-7.2)(4.5-14.3)(4.8-7.2)(3.3-4.7)(4.2-6.2)(4.2-5.5)(4.0-5.8)(4.2-6.8)(4.2-5.4)(4.2-5.8)(4.1-5.5)(4.2-8.6)(4.1-5.2)(3.9-6.4)(3.9-5.7)(4.1-6.3)(3.6-5.7)

* 9 5% confidence interval in parentheses.t Variations in subject number are due to missing data for selected variables.i Individual results were averaged across 3 days of observation and crude means were then compared by t-test or analysis of variance. Proc Mixed for repeated measurements was used to calculate least-squares m eansadjusted for the effects of age, month of participation, and workplace light exposure.


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1:1.1N011

CO

utility workers , (

Day 1CrudeAdjustedDay 2CrudeAdjustedDay 3CrudeAdjusted

;oiorad(5, 1995-1996T

I(S 0.078)Mean

4.84.25.24.95.85.8

(ng/mg cr)

(3.8-6.0)(3.3-5.4)(4.1-6.6)(3.8-6.4)(4.6-7.5)(4.5-7.6)

Workplace geometric meanII(0.079-0.10)

Mean

7.15.54.64.15.84.8

(ng/mg cr)(5.6-9.1)(4.4-7.1)(3.4-6.2)(3.0-5.5)(4.4-7.6)(3.8-6.2)

magnetic field exposure quartile (nT)tIII(0.10-0.135)

Mean

5.95.06.15.15.54.5

(ng/mg cr)(4.5-7.6)(3.9-6.4)(4.7-7.8)(4.1-6.5)(4.1-7.4)(3.4-5.8)

Mean

5.04.55.74.85.94.4

IV 0.135)(ng/mg cr)

(3.8-6.6)(3.5-6.0)(4.2-7.6)(3.6-6.5)(4.4-7.9)(3.4-5.9)

Relative change (%) in 6-OHMS/crconcentration, quartile I vs. IVMean (95% Cl)

4 (-35 to 33)7 (-34 to 36)10 (-33 to 39)-2 (-48 to 30)

2 ( ~ 4 4 t o 3 1 )-24 (-70 to 7)

p value

0.790.680.630.910.990.14

* 9 5% confidence interval (Cl) in parentheses.t Least-squares means b ased on adjustment for age, season, and mean workplace l ight exposure.j Data arranged from lowest (I) to highest (IV) quartile of workplace ge ome tric mean mag netic field exposu re. jxT, microtesla.

TABLE 3. Mean* creatinine-adjusted 6-hydroxymelatonin sulfate (6-OHMS/cr) concentrations by quartile of temporally stable magnetic field exposure at work in maleelectric utility workers, Colorado, 1995-1996t

Day 1CrudeAdjusted

Day 2CrudeAdjustedDay 3Crude

Adjusted

(;Mean

6.74.97.56.37.36.1

I. 0.90)(ng/mg cr)

(5.2-8.7)(3.8-6.3)(5.8-9.7)(4.8-8.3)(5.4-9.8)(4.6-8.0)

Workplace RCMSII(0.89-0.75)

Mean (ng/mg cr)

5.2 (4.0-6.7)4.2 (3.3-5.3)5.8 (4.4-7.5)4.8 (3.8-6.2)5.8 (4.2-8.0)4.7 (3.5-6.4)

magnetic field exposure quartile (per 15 seconds)^III(0.74-0.58)

Mean (ng/mg cr)

6.0 (4.6-7.9)5.3 (4.1-7.0)5.0 (3.8-6.5)4.5 (3.4-5.9)6.0 (4.7-7.8)5.0 (4.0-6.3)

Mean

4.85.04.44.15.04.2

IV{


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32 Burch et al.association was noted in workers with workplace lightexposures above the median (p = 0.40). This interactionis illustrated in figure 1. Individuals in the lowest quar-tile of workplace light exp osure showed a clear trend ofdecreasing mean 6-OHMS/cr concentrations withincreasing exposure to temporally stable magneticfields, whereas subjects in the highest (or intermediate[results not shown]) quartile of ambient light exposurehad no differences in 6-OHM S/cr excretion across quar-tiles of temporally stable magnetic fields. The propor-tion of subjects who reported office work on their activ-ity logs was greater for subjects in the lowest quartile oflight exposure (71 percent) compared with those in thehighest quartile (49 percent) (p < 0.01 by the chi-squaretest). W hen subjects w ere stratified according to the sea-son in which they participated, subjects with low lightexposures tended to have reduced mean 6-OHMS/crlevels in response to temporally stable magnetic fieldexposures regardless of their season of participation.DISCUSSION

Exposure to temporally stable magnetic fields mayelicit biologic effects in cellular systems (3941). Inour earlier analysis of electric utility workers (6), tem-porally stable 60 Hz magnetic field exposures at homeor at home and work combined were associated with

reductions in total overnight 6-OHMS excretion andnocturnal urinary 6-OHMS/cr concentration. In thecurrent study, we provide evidence that occupationalexposure to temporally stable magnetic fields is alsoassociated with a reduction in post-work shift 6-OHMS/cr excretion. Adjusted mean post-work shift 6-OHMS/cr concentrations were unchanged on the firstday (typically Monday) but were reduced on the sec-ond and third days of occupational exposure to tempo-rally stable magnetic fields. This suggests that sup-pression of post-work shift 6-OHMS/cr excretion byRCMS magnetic fields is dependent on exposure dura-tion and that several days may be required to elicit aneffect.These findings are reasonably consistent with thosein Swiss railway workers (7), where statistically sig-nificant decreases in mean evening (samples collectedat 6:00 p.m.) 6-OHMS concentrations were found inworkers 1 and 5 days after occupational exposure to16.7 Hz magnetic fields. In contrast to the Swiss study(7), we did not observe a reduction in mean 6-OHMS/cr on Day 1, which may have been due to dif-ferences in the intensity of magnetic field exposures,the duration of time off prior to resuming work (2-3days vs. 7-21 days), or differences in the frequency ofthe magnetic field exposures (60 Hz vs. 16.7 Hz).

1 2 3 4Work RCMS Exposure Quartile

FIG UR E 1. Least-sq uares m eans (adjusted for age and season) of daytime urinary creatinine-adjusted 6-hydroxym elatonin sulfate (6-OHMS/cr) concentrations for male electric utility workers in the lowest (black bars) and highest (white bars) quartiles of time-weighted averagelight exposure at work. Data are arranged by increasing quartile of temporally stable magnetic field exposure at work (i.e., 1 = highest quartileof standardized rate of change metric (R CMS ), 4 = lowest quarti le, etc.). *p < 0.05 vs. quarti le 1; **p < 0.01 vs. quarti le 1.Am J Epidemiol Vol. 150, No. 1, 1999

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Magnetic Field Exposure and Human Melatonin 33

Some investigators h ave reported apparent compen-satory increases in nocturnal (46) or evening (7) 6-OHMS excretion following termination of exposure.We did not measure 6-OHM S/cr levels over the week-end and thus were unable to determine whetherincreases occurred at those times. Any compensatoryincreases that may have occurred on Day 1 (Monday)due to cessation of occupational exposure over theweekend may have been negated by magnetic field-induced suppression of 6-OHMS/cr that occurred onDay 1 due to the resumption of w orkplace exposures.The possibility that confounding could be introducedin this study was considered carefully. The effects ofambient light, perhaps the most important factor thatinfluences melatonin synthesis, were carefully moni-tored by assessing personal light exposures concurrentlywith magnetic field exposures and by incorporatingmonth of participation into the analysis. Other factorsthat affect light exposure or circadian rhythmicity, suchas shift work and travel across time zones, were alsoconsidered in the analysis.An effort was made to account for other factors thatinfluence melatonin production (11, 12). Melatoninsynthesis from tryptophan is mediated primarily by thebinding of norepinephrine to its beta-1 receptor onpineal cells (11, 12). This activation can be enhancedby alpha-adrenergic stimulation, increased intracellu-lar calcium, and prostaglandin production (11). Theuse of medications that influence these processes, suchas beta adrenergic and calcium channel blockers, tran-quilizers, antidepressants, and non-steroidal anti-inflammatory agents (aspirin, acetaminophen), wasincluded in the questionnaire (11). Similarly, informa-tion was collected on other factors known to influencemelatonin production, including age, body mass index,cigarette smoking, alcohol consumption, and exercise(11 , 12). Alcohol and tobacco consumption can inducemetabolic enzymes and may therefore increase mela-tonin metabolism and excretion. Evidence for such aneffect was observed with cigarette smoking in thisanalysis but not with alcohol consumption (table 1).Substantial inter-individual differences in melatoninsecretion have led some to suggest that racially dis-tributed genetic polymorphisms may also influencemelatonin production (47), although the differencebetween whites and nonwhites/Hispanics in this studywas negligible (table 1).The well-known negative association between ageand melatonin secretion was not apparent in this study,which may have been due to the relative homogeneityin age among subjects. Decreases in melatonin pro-duction that occur between ages 30 and 50 years aremoderate (48, 49) and results from this study are con-sistent with other studies in which no differences in

circulating melatonin levels were observed amongsubjects within a limited age range (48, 50, 51).Although the possibility of residual confounding bysome unmeasured factor cannot be excluded, screen-ing for all known potential confounders as included inthe questionnaire, and statistical adjustment for factorsassociated with 6-OHMS/cr did not alter the interpre-tation of the results when analyzed either individuallyor collectively.Light exposure that occurred during work was ana-lyzed because it coincided directly with the magneticfield exposure that was being assessed and because itwas considered the most relevant time frame for influ-encing post-work shift 6-OHMS/cr levels. Pinealmelatonin is released directly to the bloodstream fol-lowing synthesis (11 ). The half-life of melatonin in cir-culation has been estimated at 20 to 30 minutes (52,53), and metabolic clearance occurs within 4-8 hours(12). Thus, post-work shift sample collection shouldprovide the best opportunity to evaluate workplacemagnetic field induced changes in melatonin produc-tion. Measured light exposure outside this time framewas not considered relevant for post-work shift 6-OHMS/cr levels.The seasonal variation in mean 6-OHMS/cr excre-tion observed in this study was consistent with previ-ous repo rts (5458). Am bient light expo sure was notstrongly associated with 6-OHMS/cr excretion afterstatistical adjustment for month of participation, indi-cating that seasonal photoperiodic changes were moreimportant than workplace light exposures in determin-ing post-work 6-OHMS/cr levels.Because of its relatively rapid metabolic clearance,the timing of exposure in relation to sample collectionmay explain why workplace RCMS exposures hadmore of an effect on post-work shift rather than noc-turnal 6-OHMS/cr levels. Temporally stable magneticfield exposures at work were associated with 31 per-cent and 35 percent decreases in mean post-work 6-OHMS/cr concentrations, whereas nocturnal 6-OHMS/cr levels from this population were only 7percent lower in response to workplace RCMS mag-netic field exposures (6). For nocturnal 6-OHMS/crdeterminations in our earlier study (6), urine sampleswere collected on the morning after workplace expo-sures occurred, whereas samples were obtained imme-diately following the work shift in the present analysis.This may also explain why reduced concentrations of6-OHMS were observed in post-work shift urine sam-ples but not in first morning voids of railway workersexposed to 16.7 Hz magnetic fields (7).The physiologic significance of nocturnal melatoninsecretion is well established. Less is understood aboutthe effects of melatonin secretion during the afternoon


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34 Burch et al.

or evening, but there are several reasons why reduc-tions in melatonin at these times may be important.Mean daytime melatonin levels in circulation areapproximately 10 pg/ml (12). These levels coincidewith those required for activation of the melatoninreceptor (approximately 5 to 14 pg/ml) (59, 60). Thus,modest (-30 percent) decreases in evening melatoninlevels may reduce melatonin receptor activation,thereby altering functional melatonin responses. Inhumans, ambient light or magnetic field exposures thatinfluence afternoon/evening melatonin levels also sup-press or delay the onset of nocturnal melatonin produc-tion (6, 61-64). The combined reduction of both day-time and nocturnal melatonin secretion would lead toreduced 24-hour melatonin secretion, which could alterimmunologic (15, 16), oncostatic (13-15), or antioxi-dant (17-19) processes influenced by melatonin.

The effects of temporally stable magnetic fields on6-OHMS/cr excretion were modified by workplacelight exposure. Adjusted mean 6-OHMS/cr concentra-tions among subjects within the highest quartile ofambient light exposure were 14 percent lower thanthose in the lowest quartile, whereas those in the high-est quartile of temporally stable magnetic field expo-sures had adjusted mean 6-OHMS/cr levels that were31 to 35 percent lower com pared with those in the low-est quartile. Among individuals in the lowest quartileof ambient light exposure, there was a 36 percent dif-ference in adjusted mean 6-OHMS/cr levels betweenthose in the upper and lower quartiles of temporallystable magnetic field exposures. A dose-response trendof progressively lower 6-OHMS/cr levels withincreasing exposure to temporally stable magneticfields was noted for those with low workplace lightexposure. The basis for the effect modification isuncertain; one possibility is that elevated light expo-sure suppressed post-work 6-OHMS/cr levels to suchan extent that further decreases associated with mag-netic field exposure were not detectable in thosegroups.

Alternatively, light exposure may be linked to thebiologic mechanism of magnetic field effects.Perception of the earth's magnetic field in animals hasbeen associated with photoreceptors located in the retinaand/or the pineal gland (10, 65). In experimental ani-mals, artificial manipulation of the earth's magneticfield suppresses melatonin production (8-10); in somestudies, this effect was dependent on an intact visualsystem (9) or exposure to long wavelength (red) light(8). In our study, low levels of light exposure weremost strongly associated with a magnetic field effectand subjects with low TWA light exposures were pri-marily engaged in office work. Artificial lighting has adifferent spectral composition and in some cases a

greater red component than natural light (66, 67).Thus, spectral or other properties of artificial lightingmay enhance the effects of magnetic fields on mela-tonin production.In conclusion, results presented here provide furtherevidence that occupational exposure to magnetic fieldsis associated with reduced post-work shift 6-OHMS/crexcretion. Low ambient light exposures appear to havean important modifying effect. Additional researchthat incorporates a wide range of ambient light andtemporally stable magnetic field exposure is needed toconfirm these results and to elucidate the differentialresponse to magnetic fields in subjects with high andlow light exposure.

ACKNOWLEDGMENTSThis work was supported by the US Department ofEnergy, Office of Energy Management under contract no.19X-SS755V with Martin Marietta Corporation and byresearch grant no. 1 R01 ES081 17 from the NationalInstitute of Environmental Health Sciences, NationalInstitutes of Health.The authors gratefully acknowledge the cooperation ofthe participating utilities, their employees who participatedin this study, and their representatives: John Fooks, PlatteRiver Power Authority; Dennis Sumner, City of FortCollins; and Larry Graff, Poudre Valley Rural ElectricAuthority. Urinary 6-OHMS assays were performed underthe direction of Dr. Terry Nett, Director of the

Radioimmunoassay Laboratory for the CSU Department ofPhysiology. In particular, the authors thank KatherineSutherland for technical assistance, and D rs. Lee Wilke andMartin Fettman for assistance with creatinine assays. Dr.Gerri Lee of the California Department of Health providedthe EMDEX meters; Platte River Power Authority providedlight meters; Dr. Scott Davis of the Fred Hutchinson CancerResearch Center provided the design for adaptation of thelight meters to the EMDEX monitors and Pablo Lopez ofthe University of Washington provided assistance with thelight meter adaptation. Dr. Lilia Hristova of the CaliforniaDepartment of Health provided programming assistance.

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