Electric power,

pineal

fufiction,

RICHARD G.. STEVENS’2, BARY W. WILSON*,2 *Padflc Northwest Laboratory,

scorr

Center, Seattle,

98104,

DAVISt.!,

Richiand,

Washington

and the risk of breast cancer

DAVID

Washington

99352,

Breast cancer is the leading cause of cancer death in women in the industrialized world, and the rates of breast cancer incidence are rising. Although risk is high in industrialized societies, it is low in nonindustrialized areas. The search for the causes of breast cancer has not yet yielded a convincing explanation for the geographic and temporal patterns in the occurrence of breast cancer. Generation of electric power is a hallmark of industrialization, and two products of electric power, light-at-night (LAN) and electromagnetic fields (EMF), may affect breast cancer risk. Exposure to either LAN or EMF can decrease production of melatonin by the pineal gland. Melatonin, in turn, has been shown to suppress mammary tumorigenesis in experimental animals. Moreover, recent epidemiological findings indicate an increased risk of breast cancer in workers occupationally exposed to EMF. On the basis of these considerations, it is proposed that the use of electrical power accounts, in part, for the higher risks of breast cancer in industrialized societies.-Stevens, R. G.; Davis, S.; Thomas, D. B.; Anderson, L E.; Wilson, B. W. Electric power, pineal function, and the risk of breast cancer. FASEBJ. 6: 853-860; 1992 breast

cancer’

electric

powerS

pineal

gland

melatonin

or PINEAL FuNmON us been implicated in the etiology of several types of cancer, including breast, prostate, ovarian, and melanoma (1). Two products of electric SUPPRESSION

power, (EMF),

light-at-night can suppress

hypothesis

part,

that

use

(LAN)4

and

electromagnetic fields This suggests the

pineal function. of electric power

for the international

variations

cer, as well as the increases in countries as they have industrialized

account,

in

in risk of breast

may

can-

breast cancer within (2-4). This paper

describes the current understanding of the causes breast cancer and how suppression of pineal function LAN

and

EMF

might

influence

breast

USA; and

AND

cancer

of by

risk.

TIME

1Fred Hutchinson

AND

Cancer

Research

younger age groups represent women who their adult lives at greater lifetime risk.

Class cer

in Japanese living in Hawaii, living in California (9, 10). Since

and

Hoover

incidence

(17)

analyzed

trends

have

started

in breast

can-

from 1960 to 1985 in a large populationregistry (Kaiser Permanente) in Portland,

based tumor Oregon. They reported a 131% increase in estrogen receptor positive (ER +) breast cancer between the mid1970s and the mid-1980s. In contrast, there was only a 22-27% increase in ER negative (ER-) tumor incidence. These increases in reported breast cancer incidence were unlikely to arise solely from improved screening and diagnosis. These authors concluded that hormonal factors may account for the large increases in incidence of breast cancer in the U.S. over recent years. Although

age-adjusted

breast

cancer

mortality

rates

in

the U.S. and England and Wales have remained relatively stable since the 1930s, death rates have been increasing in each successive birth cohort of women born since 1900 (13, 18-20). As the low-risk cohorts of the early 1900s have been depleted over the past decade, the overall age-adjusted mortality has increased (5). Industrialization

may

be an

important

factor

in deter-

mining the incidence of breast cancer. However, it is difficult to identifi which aspects of industrialization are important because of the many changes that occur as industrialize.

TRENDS

Breast cancer is the leading cause of cancer death among women in the industrialized world (5). There are, however, large international differences in breast cancer incidence and mortality (6, 7). Rates are low in Africa and Asia, intermediate in southern Europe and South America, and high in northern Europe and North America (8). Race does not appear to account for the geographic variation in rates. Rates are low in Japan, intermediate Japanese

ANDERSON*2,

Iceland have risen from a low level, as in Asia, to a level approaching that of the United States (11). Incidence in Sweden is rising rapidly as well (12). Japanese women have about one-fifth the rate of American women (13, 14), although their rates are rising (13, 15). Examination of the incidence and mortality of breast cancer by age in Japan for particular time periods (e.g., 1971-1975) shows that rates are highest between ages 40 and 55, and then decline in old age. This apparent decrease in risk in older Japanese women, however, has been shown to result from a higher risk in successively born birth cohorts of women (16) as the country has industrialized. (A birth cohort is defined as all women born during a particular 5-year period in history.) Older age groups represent women who have been at lower risk for most of their lives, whereas

societies INTERNATIONAL VARIATION IN BREAST CANCER

LARRY E.

USA

ABSTRACT

Key Words:

B. ThOMAS,

and 1911,

high rates

in in

‘To whom reprint requests should be addressed. 2Pacific Northwest Laboratory, Richland WA, 99352, USA. Supported by the U. S. Department of Energy under contract DE-ACO6-76RLO-1830. 3Fred Hutchinson Cancer Research Center, 1124 Columbia, Seattle, WA 98104, USA 4Abbreviations: LAN, light-at-night; EMF, electromagnetic fields; NK, natural killer; SIR, Standardized Incidence Ratios; DMBA, dimethylbenzanthracene.

853 0892-6638/92/0006-853/Si .50. c FASEB ww.fasebj.org by Univ of So Dakota Lommen Hlth Sci Library (192.236.36.29) on September 23, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNum

RISK FACTORS

FOR BREAST

CANCER

The work of MacMahon and colleagues (6), beginning in the 1950s, contributed greatly to the identification of several important risk factors for female breast cancer. These include a family history of breast cancer and the fertility factors of early age at menarche, late age at menopause, and late age of a woman at the birth of her first child (“age at first birth”). In addition, dietary fat consumption has also been investigated as a potential factor that might account for the international variations

The known major risk factors for breast cancer (age at menarche, age at menopause, age at first birth) have shown time trends in Japan. Hoel et al. (14) estimated that some, but not all, of the difference between Japan and the U.S. might be explained by these factors. However, Japanese men have breast cancer rates that are about one-fourth those of American men (24). This fact argues against reproductive factors per se accounting for the differences in risk between the two countries, and argues for environmental factors common to both sexes being implicated.

in risk.

fat

Dietary

Fertility

factors

Analyses using population data on fertility have not convincingly demonstrated that trends in incidence and mortality correspond to changes in these factors. MacMahon (18) used graphical techniques to examine the relationship of time trends in number of live births per 1000 women and breast cancer mortality in England and Wales and in the state of Connecticut. He concluded

that “it is evident were experiencing rates [in England

therefore that most of the cohorts that increasing breast cancer mortality and Wales] were at the same time ex-

periencing increasing fertility. This, of course, is contrary to the usual relationship between breast cancer and fertility, and it suggests not only that fertility changes were

not responsible for the mortality were in the direction of tending increase

in

risk.”

He

but that

they

to minimize the made a similar observation in Connecticut. Armstrong

real for (20)

breast cancer incidence also used graphical techniques mortality

in

the

U.S.

and

increase,

to analyze

England

and

1950 and 1973. He concluded that period could only partly be explained in childbearing.

Blot

(21)

compared

incidence Wales

and

between

increases over this by cohort changes age-specific

breast

cancer mortality in the U.S. with percentages of the female population aged 20 to 24 who were nulliparous. In contrast to MacMahon, he concluded that changes in the percentage of nulliparous women corresponded well with changes in mortality during the period from 1950 to 1975. Hahn and Moolgavkar (22) analyzed incidence in Connecticut over the period from 1935 to 1982. Their quantitative

approach

estimated

expected

incidence

as

each cohort aged, based on population data on each cohort’s fertility (i.e., nulliparity and age at first birth). They used relative risks based on known associations of fertility factors with risk of breast cancer derived from case control studies. They compared the predicted incidence with the actual incidence and concluded, as MacMahon had, that “Secular trends and international differences in this common disease remain largely unexplained. The present study provides further evidence that prominent childbearing events in cohorts predict changes in cohort breast cancer contrary to those that have occurred.” Thus, there is disagreement in the published work as to whether, and to what extent, population changes in fertility factors over time account for time trends in breast cancer incidence and/or mortality within countries. In Iceland there has been a well-documented dramatic increase in breast cancer incidence since 1911, yet based on fertility factor data obtained from each individual woman in the population, changes in these factors would have predicted decreasing rates (23).

854

Vol. 6

February

1992

Dietary practices change with industrialization. Tannenbaum (25) first showed that dietary fat consumption increases mammary cancer risk in experimental animals. Many laboratories have replicated the finding that, in animals, dietary fat intake increases the risk of spontaneous and chemically induced tumors, and increases the

growth of transplanted tumors (26). There is evidence that high fat intake decreases survival in human breast cancer (27), and that breast cancer rates are highly correlated with per capita fat consumption on a population level (15, 28, 29). However, epidemiologic studies of dietary fat and breast cancer are inconclusive. Howe et al. (30) conducted a combined analysis of 12 case-control studies of diet and breast cancer and concluded that, taken together, they support an association of high fat intake and risk in postmenopausal women but not in premenopausal women. The authors estimated that if all women in North America reduce their fat intake to account

for

9%

of calories,

postmenopausal

breast

cancer

would be reduced by only 10%. They concluded that dietary factors other than fat intake may influence risk of breast cancer. Prospective studies done in the U.S. do not support an association of postmenopausal

dietary fat and breast cancer in pre- or women (31, 32). Prentice et al. (29) arthat lack of variability in fat consumption may in low power to detect true effects of fat intake on cancer risk in studies done within countries. Wil-

gued result breast lett (33), however, reviewed the epidemiologic studies and concluded that dietary fat probably does not account for the differences among countries in breast cancer risk. Willett also contends that the apparently compelling animal model is not so convincing because fat consumption cannot be disentangled from total energy intake. The effect, if any, of dietary fat intake on risk of breast cancer in humans is unclear at this time.

PINEAL

FUNCTION

AND

BREAST

CANCER

In its role as a neuroendocrine transducer, the pineal gland provides a hormonal signal that is synchronized to the daily light-dark cycle (34). Melatonin, the principal pineal hormone, exerts a generally suppressive action on other endocrine glands. Reduced circulating concentrations of melatonin may result in increased prolactin release by the pituitary and increased estrogen and testosterone release by the gonads (35, 36). Production of

melatonin is suppressed by light as perceived by the retina. Hence, circulating melatonin concentrations are low in daylight and higher at night (37). Cohen et al. (38) suggested that reduced pineal melatonin production might increase human breast can-

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cer risk because lower melatonin output would lead to an increase in circulating estrogen levels, and would stimulate the proliferation of breast tissue. Progesterone

in the

prolactin. A suggested that reduced melatonin

mechanism for these results is resulted in increased circulating

may

estrogen

and

turnover malignant

of the breast transformation

and, consequently, epithelial stem cells

also

play

an important

role

in proliferation

tissue (39). Indeed, early menarche, and nulliparity are each associated with of breast cancer (6), and all result in a proliferation of the breast epithelial (40). Cohen et al. (38) postulated ing as a possible factor that might

late

of breast

menopause,

an increased

risk

longer period for stem cells at risk

environmental lead to reduced

lightmela-

tonin

production. of three key experiments, (41) showed that pinealectomy increased

Tamarkin

cer

(dimethylben-

In a series in

rats

treated

with

DMBA

et al.

mammary

can-

zanthracene), whereas melatonin injection inhibited it. In their first experiment, 60 female Sprague-Dawley rats received 15 mg of DMBA in peanut oil by intragastric intubation at age 50 days. After the tion, 30 rats received daily injections

30 received

vehicle

ministration,

veloped group

DMBA administraof melatonin and injection. At 90 days after DMBA adof the vehicle-treated rats had de-

50%

tumors whereas none of the melatonin-treated had tumors. Melatonin was discontinued in the group at this time, and tumors later began to ap-

latter pear. In their second 36 sham-operated ministered

experiment, 36 pinealectomized and rats received 7 mg of DMBA ad-

as before.

Two

months

after

DMBA,

48%

of

the pinealectomized rats had mammary tumors, whereas none of the sham group had tumors. By the 240th day (termination of the experiment), 88% of the pinealectomized rats had tumors, whereas only 22% of the sham group had tumors. A third experiment demonstrated that melatonin administration to pinealectomized rats reduced the number of tumors. Histological examination of palpated nodules in this experiment showed that 84 of 86 were malignant epithelial tumors. These experimental observations suggest that melatonin suppresses mammary tumorigenesis, and lack of melatonin increases tumor formation. Tamarkin et al. (41) concluded that “These studies suggest that a possible role of pineal function and the daily melatonin rhythm should be examined as an etiological factor in human breast cancer.” There are at least three possible mechanisms by which reduced circulating melatonin concentrations may enhance

mammary

carcinogenesis

in

rats.

Reduced

mela-

tonin may 1) increase proliferation of the stem cells at risk, 2) stimulate proliferation of cancer cells, and 3) impair immune function. Implications for reducing breast cancer risk in humans would differ depending on which, if any, of these mechanisms operated. Effects on stems cells

suggest

that

exposures

resulting

in

suppressed

melatonin occurring many years before diagnosis could be important, whereas direct effects on cancer cells suggest that recent exposures could be important. Effects Constant

on stem

cells

has been tumorigenesis

light

mammary fectively suppresses gland. At 55 days

used to increase DMBA-induced in rats (42). Constant light ef-

melatonin of age, rats

production by the exposed to constant

pineal light

from birth showed a greater concentration of terminal end buds and alveolar buds in mammary tissue than did rats raised on a 10-h light:14-h dark regimen. Constant light animals also showed greater DNA synthesis activity ELECTRIC POWER AND

BREAST CANCER

mammary

Effects

tissue,

and

prolactin,

on growth

higher

levels

of circulating

increased at risk of

(42, 43).

of cancer

cells

Hill and Blask (44) examined the effects of melatonin on breast cancer cells in vitro. Using the ER + human breast cancer cell line MCF-7, they showed that medium containing 109_10h1 molar melatonin stopped the growth and induced marked structural alterations in the cells

consistent

Melatonin

with

sublethal,

concentrations

but

reversible,

of 10-10”

to the levels found in blood during nal surge in humans. Concentrations and above 10910h1 molar did not fects on MCF-7 in culture. In related

al. (45) reported but also cytotoxic cell lines. These

sible

results

cell

molar

injury.

correspond

the normal nocturof melatonin below have observable efstudies, Shellard et

that melatonin was not only oncostatic to breast, ovarian, and bladder cancer suggest

mechanism

a second,

whereby

and

very

different,

the suppression

pos-

of melatonin

might result in an increased incidence of breast cancer (46). Suppression of the normal rise in melatonin might result in proliferation of previously quiescent estrogenresponsive breast cancer cells.

Effects

of immune

function

Evidence indicates that circadian synthesis and release of melatonin have a modulatory effect on the immune system. Pharmacological inhibition of pineal gland function in mice

significantly

depressed

antibody

response

to in-

jected sheep red blood cells (47). Appropriately timed injections of melatonin restored normal immune function, as determined by this assay. Melatonin was also shown, in these same studies, to antagonize the immunosuppressive effects of corticosterone injections. Natural killer (NK) cell cytotoxicity was augmented by melatonin, suggesting that it may enhance immune surveillance (48). NK cell activity is an important aspect of

immune function in protecting against tumor growth. There appears to be a reciprocal interaction between pineal melatonin and the opioid peptides (49). Both melatonin

steroid

and

opioid

levels, which

peptides

in turn

can

influence

affect

circulating

immune

function

(50). Opioid peptides also interact directly with the immune system, as exemplified by the presence of opioid peptide receptors on lymphocytes, and enhancement of the lymphocyte proliferative response to T cell mitogens by 3-endorphins (51). An intact opioid system is required for observation of many of the neuromodulatory

functions melatonin

of melatonin, and there is direct evidence that interacts with opioid peptides at their recep-

tor

(52).

sites

This

melatonin

with

important

mechanism

ces immune Melatonin

the

recently

opioid

recognized

system

by which

the

interaction

may prove pineal

gland

of

to be an influen-

function. and breast

cancer

in humans

Tamarkin et al. (53) determined plasma melatonin levels in women with ER+ breast cancer, ER - breast cancer, and in healthy control women during a 24-h period. Measured at 2si, they found that women with ER + 855

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breast

cancer

had

significantly

lower

nocturnal

mela-

tonin levels (46 pg/mI) than ER - cases (78 pg/mI) or controls (65 pg/mI). They also found a significant nega-

tive correlation between tumor estrogen receptor concentration and nighttime melatonin concentration: the lower the melatonin, the higher the estrogen receptor concentration. They speculated that “Thus, the absence of nocturnal peak melatonin may serve as a biochemical marker for increased risk of developing ER + breast cancer.” Bartsch et al. (54) made similar observations. Lissoni et al. (55), however, reported that serum melatonin, when measured between 8 and 9AM, was higher in breast cancer cases (27 pg/mI) than controls (15 pg/mI). Although

these

concentrations

are

typical

of

Light

AND PINEAL

POWER

at Night

FUNCTION

and 16%, respectively. Some sensitive to LAN. McIntyre

depressive

melatonin

intensity light (1500 These experiments

level

female was

individuals et al. (61)

patient

are exquisitely reported on

whose

precipitously

Electromagnetic et al. (62)

fields

a

nighttime

reduced

exposure at night to light of substantially (200 lux) than that used by Lewy (59).

electric

in the

residential

magnetic

field

accounted

it remains to be determined EMF exposures can affect

production

in humans,

a preliminary may affect

blanket

some individuals (68). Wilson et al. (69) speculate

enzyme

that

for

the

effects. typical pineal melatonin study indicates that

whether

pineal

effects

function

of EMF

on

in the

pineal gland may mediate a variety of health outcomes, including depression and reproductive anomalies as well as cancer. Comtemplation of the effect of melatonin on

Light

lish whether dim light has a small effect. McIntyre et al. (60) investigated a dose-response in humans and found that 1 h exposure at midnight to 3000, 1000, 500, 350, and 200 lux reduced serum melatonin by 71, 67, 44, 38,

a 60-Hz

change Although

EPIDEMIOLOGICAL

demonstrated that the human pineal response to light is qualitatively similar to that in other mammals, and that there may be a dose-response effect: the lower the light intensity, the less melatonin production is suppressed. The number of subjects was too small to estab-

Wilson

rate-limiting

(LAN)

(500 lux) did not, and intermediate lux) partially reduced melatonin.

blood

the

in the production of melatonin from serotonin, and reduction of melatonin synthesis and release. They concluded that induced currents from the rapid time rate of

mammary cancer in rats (41), and of the effect of EMF on melatonin (62), suggests an experiment as described by Stevens (2):EMF exposure effects on mammary cancer in rats.

Very low intensity light (as low as 0.222 j.tW/cm2) can reduce melatonin production by the pineal in LongEvans rats (56). The effect of light is wavelength-specific, with blue-green light having maximum effect and red light having little or no effect (57, 58). Lewy et al. (59) used volunteers to determine whether LAN affects serum melatonin levels in humans. Subjects were exposed to light at 2AM, and blood was sampled from an indwelling catheter. Bright light (2500 lux; -150 j.tW/cm2) quickly reduced the melatonin level, dim light

seasonally

serotonin-N-acetyltransferase,

use of an electric

daytime

levels, and hence their studies are not directly comparable to those of Tamarkin et al. (53) and Bartsch et al. (54) who measured nighttime melatonin, Lissoni et al. (55) noted that the higher melatonin levels were associated with improved prognosis.

ELECTRIC

terations of the local geomagnetic field. Lerchl et al. (66, 67) examined effects of periodic activation and deactivation of static magnetic fields on pineal function in rats and found rapid (within 1 h) increases in serotonin content of the gland, suppression of the activity of

lower

upon

intensity

demonstrated

at Night

Based on the hypothesis that sighted women who are exposed to LAN may be at increased risk of breast cancer, Hahn (70) reasoned that blind women would be at reduced risk of breast cancer compared with sighted women because they do not perceive LAN. He analyzed more than 100,000 hospital discharge records published by the National Hospital Discharge Survey to determine how frequently there was a diagnosis of profound bilateral blindness in women also diagnosed with breast cancer, compared with control women with diagnoses of

stroke women,

or cardiovascular 0.26%

that

disease. also

blind,

Among which

the

control

is approximately

that expected on the basis of national surveys of nonhospitalized women. Among the women with breast cancer, however, only 0.15% were also blind, which is consistent with confounded

Hahn’s prediction. by diabetes or marital

This status.

result was The effect

not did,

however, diminish with age. Urban breast cancer mortality rates are higher than rural rates (71). Several factors have been suggested to account ces in

for this exposure

Electromagnetic 3 wk of exposure

in suppression

were

observation; however, possible to LAN and EMF have not

differen-

been

ex-

amined.

(EMF)

field resulted

EVIDENCE

to

of the nor-

mal nocturnal rise in pineal melatonin production in adult rats. Field intensities as low as 1.7 kV/m were effective in their system. Normal pineal melatonin production returned within 3 days of cessation of exposure

(63). Reiter et al. (64) followed this work and showed that exposure to 60-Hz electric fields beginning in utero resulted in a 50% reduction in pineal melatonin content at 2 in 23-day-old rats, and a phase delay in the peak production at night. Welker et al. (65) found a similar effect on pineal melatonin production as a result of al-

fields

on exposure to EMF are limited and often indirect. Schipper et al. (72) studied international variations in residential electric power consumption and reported that the average consumption per household in Japan was 1.9 megawatt hours in 1973 and rose to 2.9 in 1983. Data

In the U.S. the average and 9.0 in 1983. Thus, industry for some time,

home

has been

much

consumption was 8.2 in 1973 although Japan has had heavy electricity consumption in the

lower

than

in the U.S. In a study

of 48 residences in western Washington state, Kaune et al. (73) found that electricity consumption over a 24-h period was not related to 60-Hz magnetic fields meas-

856 Vol. 6 February 1992 The FASEB Journal STEVENS EF AL. ww.fasebj.org by Univ of So Dakota Lommen Hlth Sci Library (192.236.36.29) on September 23, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNum

ured over the same period. Whether long-term household electricity consumption is related to long-term exposure to LAN and EMF is not known. The

exposure

level

of

1.7

kV/m

used

to

suppress

pineal melatonin production in rats (62) corresponds to an approximate range of 100-300 V/m in humans, after accounting for differences in body shape (74). Although this level is still well above ambient field strengths typically present in residential settings (73), it is comparable to levels found in some occupational settings (75, 76) and under an electric blanket (77, 78). Epidemiologic studies of electric power and breast cancer are few. Studies of residential exposure include one by Wertheimer and Leeper (79), who noted an association between pre- but not postmenopausal breast cancer and residential wiring configurations in a study of adult cancers in Colorado. It is unknown how well their exposure metric reflected chronic exposure to LAN or EMP. Morton (80) studied women in Oregon and hypothesized that housewives in homes with electrical heating had higher cancer risk (including breast cancer). McDowall (81) examined cancer mortality in the vicinity of electrical transmission facilities in Britain and found no increase in breast cancer, although very few breast cancer cases were identified in this study. Vena et al. (82) examined electric blanket use and risk of female breast cancer in a case-control study and found nonsignificant elevations of risk associated with continuous use throughout the night, although no dose-response with exposure duration was seen. The study had low power due to a small number of heavy users, limited information of blanket use restricted to only the previous 10 years, and unknown reliability of reported use. An occupational cohort study reported by Matanoski et al. (83) found an excess of breast cancer in male New York Telephone workers who had probable high magnetic field exposure. Two cases were reported where none was expected. To test the observation of Matanoski et al. (83), Demers et al. (84) examined occupational EMF exposure in a case control study of breast cancer in men. Each subject in the study reported the two longest held occupations during his life. These occupations were grouped into five categories, each with at least some putative EMF exposure. Those men with no expected exposure assigning

formed each

occupation, compared

the unexposed referent category. After subject to an exposure category based on

the number of cases in each category was with the number of controls. There was an es-

timated

1.8-fold

combined exposed exposure

five exposed categories compared with the uncategory. One of the expected frequent EMF categories included electricians, power plant

operators,

increased

power

workers. This breast cancer.

line

group

risk

of

workers,

had

breast

and

a sixfold

cancer

in

telephone

increased

of

and Andersen (85) of the Cancer Registry of reported on an occupational study that encompassed the entire nation. The Norwegian Central Bureau of Statistics provided data, including occupation, to

Tynes Norway

these

authors

on

all

living

persons

20 years

and

older

and alive in the 1960 census. There were 37,952 men who held occupations that the authors considered to have potential EMF exposure. Standardized Incidence Ratios (SIR) for breast cancer based on all working men in the 1960 census were calculated over the years 1961 to 1985. There were 12 cases observed and 5.81 ex-

ELECTRIC POWER AND

BREAST CANCER

The

SIR was 2.07

(95%

confidence

interval

=

1.07 to 3.61). Although breast cancer in men is histologically similar to breast cancer in women, and most areER+, it is unclear whether these results have implications for breast

cancer

in women.

OTHER

FACTORS

AFFECTING

PINEAL

FUNCTION

Alcohol administration reduces the nocturnal melatonin peak in rats (86), and human alcoholics studied by Wetterberg (87) showed a depressed nocturnal peak in melatonin. Borg et al. (88) found lower urinary melatonin in alcoholics studies support the

increases and

breast

Hiatt

than in nonalcoholic controls. Some hypothesis that alcohol consumption

cancer

(92)

nocturnal

melatonin

mechanism

for

In a study

risk in humans

suggested these

that

that

level

may serum

54 patients with a major depressive disorder, and in 33 healthy subjects,

Adult

height

has

been

Stevens

suppression

provide

of

a biological

observations.

examined

found a significant nocturnal melatonin

(89-91).

alcohol

melatonin

negative association peak and height reported

rhythms

episode Beck-Friis

to be

in

or affective et al. (93)

of maximum of the subject. a risk

factor

for

breast cancer (94-96). Beck-Friis et al. (93) also found seasonal variation in inelatonin peaks; subjects examined during the winter had greater nocturnal melatonin production than subjects examined in the spring. Others (97) have proposed that the apparent reduction in melatonin in spring and summer arises from seasonal shifts in the time of occurrence of the nighttime peak. A seasonal variation in the pattern of breast cancer detection has been reported in which first symptoms occur more often in spring and summer than in winter (98100). Shift work may be expected to affect pineal function, and may therefore be associated with risk of breast can-

cer. Positive associations of risk of cancer EMF exposure in occupational studies may

with putative have resulted

in part from shift work requirements in these occupations. This possibility has not been examined. The Nurse’s Health Study conducted by Speizer and colleagues (31, 89) has recently incorporated research on possible effects of shift work on the long-term health of a large cohort of nurses that is being followed prospectively.

the

line

risk

pected.

OTHER

CANCERS

In addition to breast cancer, pineal dysfunction may also be associated with cancer development in other tissues that are known, or suspected, to be influenced by pineal hormones. Prostate cancer shows marked international variation in mortality rates, and rates are rising in the West (5). Philo and Berkowitz (101) examined the effects of melatonin injection of the growth of prostatic adenocarcinoma cells inoculated into male Fisher rats. The authors showed that melatonin reduced serum testosterone concentration, reduced the size of the prostate gland, and slowed the growth of the inoculated prostate cancer

cells.

Bartsch

et al.

(102)

measured

serum

tonin level every 4 h over a 24-h period in elderly and found that men with prostate carcinoma had

mela-

men, a sig-

857

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nificantly lower out cancer.

McGivern

average

et al. (103)

nighttime

exposed

peak

male

than

men

rats in utero

with-

to a

pulsed 15-Hz magnetic field of peak intensity of 8 gauss. The animals were killed at 120 days of age, and organ weights were determined. The average prostate weight of 11 exposed rats was 0.216 g per 100 g body weight; the average in 6 sham-exposed rats was 0.109. Increasing proliferation of tissue in this manner may render the tissue more susceptible to malignant transformation (104), although this has not yet been tested directly in the prostate gland. The same cohort follow-up study of New York Telephone workers that yielded several breast cancers in men with occupations with putative EMF exposure also yielded elevated risks of prostate cancer (83). The exposed groups of cable splicers and central office workers had about fourand about threefold, respectively, the number of cases expected based on the experience of the nonexposed workers in the same study. Reduced pineal melatonin production may also increase risk of both ovarian cancer (105) and melanoma

6.

7. 8.

9.

10. 11.

12.

13.

14.

(106). 15. CONCLUDING

REMARKS

16.

There are striking international differences in breast cancer incidence and mortality. The search for the causes of these differences has not yet yielded a convincing explanation. Meanwhile, risk of breast cancer continues to increase, even in those societies with historically high rates. The idea that some aspect of industrialization is responsible is appealing, but only slightly narrows the search because industrialization affects the human environment in so many ways. We have proposed in this

paper

that

the introduction

and

increasing

17.

18. 19. 20.

use of elec-

tric power may increase breast cancer risk, and that more data should be gathered to determine if this salient feature of industrialization is implicated in breast cancer etiology. The benefits of electric power to the quality of life can scarcely be overstated. However, certain products of electric power, such as IAN and EMF, represent changes in the human environment that may not be entirely benign.

21.

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