Lighting during the day and night: possible impact on risk of breast cancer

Risk of breast cancer varies by about 5-fold among societies, and incidence and mortality have been increasing worldwide for many decades. Migrants from low-risk Asian societies to the U.S. suffer elevated risk of breast cancer in their own lifetimes, and the second or third generation Asian-Americans attain the high risk of the multi-generational European immigrants [1,2]. Something about a modern Western lifestyle apparently increases risk dramatically. Madigan et al. [3] estimate that 41% of the new U.S. cases of breast cancer are explained by "known risk factors"; these include the reproductive factors of age at first birth, menarche, menopause. They ascribe about 30% to reproductive factors when they are analyzed alone. "High income" is estimated to account for about 19% when analyzed by itself. The 41% is an analysis taking all the factors together, and since they are related, the total is less than the sum of estimates for the individual items. By itself, "High income" has no biological interpretation and must reflect attributes of lifestyle and/or environment that increase risk. So, the proportion of breast cancer cases in the U.S. that can be accounted for by known biological risk factors is about one third. Therefore, at least half of breast cancer risk in the U.S., and other Westernized/industrialized societies, is in excess of that found in non-industrialized societies and is without any agreed-upon explanation. Many candidate factors exist, each with a cadre of proponents. The sum of these may turn out to explain the bulk of the excess risk in modern societies. On the other hand, they may not, and worse, may fall woefully short.     

Working against our endogenous circadian clock: Breast cancer and electric lighting in the modern world

Breast cancer incidence increases rapidly as societies industrialize. Many changes occur during the industrialization process, one of which is a dramatic alteration in the lighted environment from a sun-based system to an electricity-based system. Increasingly, the natural dark period at night is being seriously eroded for the bulk of humanity. Based on the fact that light during the night can suppress melatonin, and also disrupt the circadian rhythm, it was proposed in 1987 that increasing use of electricity to light the night accounts in part for the rising risk of breast cancer globally. Predictions from the theory include: non-day shift work increases risk, blindness lowers risk, long sleep duration lowers risk, and population level community nighttime light level co-distributes with breast cancer incidence. Thus far, studies of these predictions are consistent in support of the theory. A new avenue of research has been on function of circadian genes and whether these are related to breast cancer risk. In particular, a length variant of Per3 (5-VNTR) has been associated with increased risk in young women, and this same 5-VNTR variant has also been found to predict morning diurnal type and shorter sleep duration compared to the 4-VNTR variant. An important question is how an effect of light-at-night (LAN) exposure on breast cancer risk might be modified by polymorphisms and/or epigenetic alterations in the circadian genes, and conversely whether light-at-night exposure (e.g., shift work) can induce deleterious epigenetic changes in these genes.     

EMF and current cancer concepts

Exposure to power frequency electric and magnetic fields (EMF) is ubiquitous, and a body of epidemiologic studies has produced evidence suggestive of a possible link between EMF exposure and cancer of several types. This paper provides a perspective that holds key findings in the EMF literature against the background of important models and established principles in cancer biology. It is intended primarily for scientists whose expertise lies outside of cancer biology and animal bioassays. Current thinking holds that carcinogenesis is a multistep process that requires at least two genotoxic events in its critical path but that is facilitated by nongenotoxic proliferative effects on target cells. EMF, which itself is not believed to be genotoxic, could influence carcinogenesis if it exerted either direct or indirect effects on target cell turnover. Such effects could operate through receptor-mediated or nonreceptor-mediated pathways. However, effects relevant to carcinogenesis have not been confirmed, and a mode of action for EMF has not been determined. Chronic bioassays in rodents are in progress to examine the potential carcinogenicity of EMFs. EMF research has the opportunity to capitalize on the recent major advances in our understanding of carcinogenic processes. © 1996 Wiley-Liss, Inc.     

Light at night co-distributes with incident breast but not lung cancer in the female population of Israel

Recent studies of shift-working women have reported that excessive exposure to light at night (LAN) may be a risk factor for breast cancer. However, no studies have yet attempted to examine the co-distribution of LAN and breast cancer incidence on a population level with the goal to assess the coherence of these earlier findings with population trends. Coherence is one of Hill's "criteria" (actually, viewpoints) for an inference of causality. Nighttime satellite images were used to estimate LAN levels in 147 communities in Israel. Multiple regression analysis was performed to investigate the association between LAN and breast cancer incidence rates and, as a test of the specificity of our method, lung cancer incidence rates in women across localities under the prediction of a link with breast cancer but not lung cancer. After adjusting for several variables available on a population level, such as ethnic makeup, birth rate, population density, and local income level, a strong positive association between LAN intensity and breast cancer rate was revealed (p<0.05), and this association strengthened (p<0.01) when only statistically significant factors were filtered out by stepwise regression analysis. Concurrently, no association was found between LAN intensity and lung cancer rate. These results provide coherence of the previously reported case-control and cohort studies with the co-distribution of LAN and breast cancer on a population basis. The analysis yielded an estimated 73% higher breast cancer incidence in the highest LAN exposed communities compared to the lowest LAN exposed communities.     

Can EMF exposure during development leave an imprint later in life?

People in industrialized nations live in an environment of ubiquitous electromagnetic field (EMF) exposure, both natural and anthropogenic. The intensity, variety, and geographic distribution of anthropogenic EMF exposures have grown dramatically since the mid 20th century, with many uses serving, and in close proximity to, human populations, such as electric power distribution, radio and television transmission, and more recently, personal cell phone communication units and transmitting towers. Thus, it is reasonable to ask if this EMF exposure could cause alterations in the physiology of developing organisms, since they are generally assumed to be the most sensitive to chemical stressors. In this report, we review work published beginning in the late 1980s. Initial reports indicated that exposure of chicken eggs during embryonic development to power-line electric fields of 50 and 60 Hz, at 10 V/m in air (which is frequently in locations inhabited by humans), could cause the brain tissues of the hatched chickens to respond differently in a particular test. More recently, an anecdotal report of human sensitivity to EMF has appeared that shows a health-related influence of prior exposure history to particular power-line frequencies in chemically sensitized individuals. These reports open the question of whether the ambient electromagnetic environment can leave an imprint on developing organisms and if such imprint changes have the potential for health consequences.     

Light at Night Co‐distributes with Incident Breast but not Lung Cancer in the Female Population of Israel

Recent studies of shift‐working women have reported that excessive exposure to light at night (LAN) may be a risk factor for breast cancer. However, no studies have yet attempted to examine the co‐distribution of LAN and breast cancer incidence on a population level with the goal to assess the coherence of these earlier findings with population trends. Coherence is one of Hill's “criteria” (actually, viewpoints) for an inference of causality. Nighttime satellite images were used to estimate LAN levels in 147 communities in Israel. Multiple regression analysis was performed to investigate the association between LAN and breast cancer incidence rates and, as a test of the specificity of our method, lung cancer incidence rates in women across localities under the prediction of a link with breast cancer but not lung cancer. After adjusting for several variables available on a population level, such as ethnic makeup, birth rate, population density, and local income level, a strong positive association between LAN intensity and breast cancer rate was revealed (p<0.05), and this association strengthened (p<0.01) when only statistically significant factors were filtered out by stepwise regression analysis. Concurrently, no association was found between LAN intensity and lung cancer rate. These results provide coherence of the previously reported case‐control and cohort studies with the co‐distribution of LAN and breast cancer on a population basis. The analysis yielded an estimated 73% higher breast cancer incidence in the highest LAN exposed communities compared to the lowest LAN exposed communities.     

Induction of cell activation processes by low frequency electromagnetic fields

Electromagnetic fields (EMF) such as those from electric power transmission and distribution lines (50/60 Hz) have been associated with increased risk of childhood leukemia, cancer of the nervous system, and lymphomas. Several in vitro studies on EMF effects were performed to clarify the existing controversies, define the risks, and determine the possible mechanisms of adverse effects. In some of these reports, the effects were related to other mechanisms of carcinogenesis. Modification in cell proliferation was observed after EMF exposure and a few reports on cytotoxic effects have also been published. This limited review gives an overview of the current results of scientific research regarding in vitro studies on the effects of power line frequency EMF, but also cell biological mechanisms and their potential involvement in genotoxicity and cytotoxicity are discussed. Cell cycle control and signal transduction processes are included to elucidate the biochemical background of possible interactions. Exposure to EMF has been also linked to the incidence of leukemia and other tumors in some epidemiological studies and is considered as "possibly carcinogenic to humans", but there is no well-established biological mechanism that explains such a relation. Furthermore, EMF is also shown as a stimulus for immune relevant cells (e.g., macrophages) to release free radicals. It is known that chronic activation of macrophages is associated with the onset of phagocytosis and leads to increased formation of reactive oxygen species, which themselves may cause DNA damage and are suggested to lead to carcinogenesis. To demonstrate a possible interaction between EMF and cellular systems, we present a mechanistic model describing cell activation as a major importance for cellular response.     

Hormonal aspects in the causation of human breast cancer: epidemiological hypotheses reviewed, with special reference to nutritional status and first pregnancy

Epidemiology of breast cancer has identified early age at menarche, late first pregnancy, low parity and late menopause as risk factors, but in addition genetic factors, height, weight and living in western countries play a significant role. The international variation in incidence is almost exclusively due to non-genetic factors. Hypotheses in prevention-oriented research are reviewed: 1. obesity-related oestrogen production as a stimulus of the tumour in postmenopausal women; 2. nutritional status and energy expenditure during puberty and adolescence, developed for fertility and fecundity and extended later to breast cancer; 3. reproductive life during early adulthood, age at first pregnancy and its specific effects on breast tissues. The message of preventability of breast cancer is that mammary epithelial differentiation should come early. Our insight concerning events in puberty and early adulthood can be consolidated in one concept on the risk of extended proliferation of breast epithelium during early adulthood in the absence of full differentiation induced by pregnancy. The combined effects of Western-type nutrition, lack of exercise and Western-type women's emancipation sets the stage for breast cancer already at a young age. Since it is unlikely that emancipated women in affluent societies will return to the original life-style of getting pregnant as soon as it is biologically possible, a novel daring way of protection has to be considered. Could a "Breast Differentiation Pill" be developed to offer protection?     

Signal transduction of the melatonin receptor MT1 is disrupted in breast cancer cells by electromagnetic fields

The growth of estrogen‐receptor positive breast cancer cells is inhibited by the pineal gland hormone, melatonin. Concern has been raised that power‐line frequency and microwave electromagnetic fields (EMFs) could reduce the efficiency of melatonin on breast cancer cells. In this study we investigated the impact of EMFs on the signal transduction of the high‐affinity receptor MT1 in parental MCF‐7 cells and MCF‐7 cells transfected with the MT1 gene. The binding of the cAMP‐responsive element binding (CREB) protein to a promoter sequence of BRCA‐1 after stimulation with melatonin was analyzed by a gel‐shift assay and the expression of four estrogen‐responsive genes was measured in sham‐exposed breast cancer cells and cells exposed to a sinusoidal 50 Hz EMF of 1.2 µT for 48 h. In sham‐exposed cells, binding of CREB to the promoter of BRCA‐1 was increased by estradiol and subsequently diminished by treatment with melatonin. In cells exposed to 1.2 µT, 50 Hz EMF, binding of CREB was almost completely omitted. Expression of BRCA‐1, p53, p21^WAF, and c‐myc was increased by estradiol stimulation and subsequently decreased by melatonin treatment in both cell lines, except for p53 expression in the transfected cell line, thereby proving the antiestrogenic effect of melatonin at molecular level. In contrast, in breast cancer cells transfected with MT1 exposed to 1.2 µT of the 50 Hz EMF, the expression of p53 and c‐myc increased significantly after melatonin treatment but for p21^WAF the increase was not significant. These results convincingly prove the negative effect of EMF on the antiestrogenic effect of melatonin in breast cancer cells. Bioelectromagnetics 31:237–245, 2010. © 2009 Wiley‐Liss, Inc.     

Risk factors and risk reduction of breast cancer

Because of its increasing incidence, breast cancer is a significant burden for women worldwide. In industrialized countries, breast cancer is the second-leading cause of cancer-related deaths among women, and it is estimated that 1 in every 8 women will develop the disease during her lifetime. Sufficient evidence indicates that a number of genetic, environmental and lifestyle risk exposures during life may play important roles in the etiology of this disease. The purpose of this paper is to review some etiologic factors and underlying mechanisms in relation to breast cancer risk. Based on the published literature, there is sufficient evidence that some established factors are associated with breast cancer risk. Age, early age at menarche, late menopause, height, post-menopausal obesity, family history of breast cancer, ionizing radiation, oral contraceptives, hormonal replacement therapy, mammographic density, some gene mutations and clinical conditions, such as benign breast disease, are associated with an increased risk of breast cancer. The risk decreases with early childbearing, high parity and physical activity, and breastfeeding. Alcohol increases the risk, while caloric restriction may confer protection from breast cancer. Epidemiological evidence for other nutritional factors is insufficient. These results suggest that breast cancer is a multifactorial disease where genetic susceptibility, environment, nutrition and other lifestyle risk factors interact. Better identification of modifiable risk factors and risk reduction of breast cancer may allow implementation of useful strategies for prevention.     

Light at night and melatonin have opposite effects on breast cancer tumors in mice assessed by growth rates and global DNA methylation

Light-at-night (LAN) is a worldwide problem co-distributed with breast cancer prevalence. We hypothesized that exposure to LAN is coincided with a decreased melatonin (MLT) secretion level, followed by epigenetic modifications and resulted in higher breast cancer tumors growth-rate. Accordingly, we studied the effect of LAN exposure and exogenous MLT on breast cancer tumors growth-rate. 4T1 cells were inoculated into BALB/c short day-acclimated mice, resulting in tumors growth. Growth rates were followed under various light exposures and global DNA methylations were measured. Results demonstrated the positive effect of LAN on tumors growth-rate, reversed by MLT through global DNA methylation.     

Does the modern urbanized sleeping habitat pose a breast cancer risk?

Due to its disruptive effects on circadian rhythms and sleep deprivation at night, shiftworking is currently recognized as a risk factor for breast cancer (BC). As revealed by the present analysis based on a comparative case-control study of 1679 women, exposure to light-at-night (LAN) in the "sleeping habitat" is significantly associated with BC risk (odds ratio [OR]?=?1.220, 95% confidence interval [CI]?=?1.118-1.311; p?相似文献   

Global Co‐Distribution of Light at Night (LAN) and Cancers of Prostate,Colon, and Lung in Men

The incidence rates of cancers in men differ by countries of the world. We compared the incidence rates of three of the most common cancers (prostate, lung, and colon) in men residing in 164 different countries with the population‐weighted light at night (LAN) exposure and with several developmental and environmental indicators, including per capita income, percent urban population, and electricity consumption. The estimate of per capita LAN exposure was a novel aspect of this study. Both ordinary least squares (OLS) and spatial error (SE) regression models were used in the analysis. We found a significant positive association between population exposure to LAN and incidence rates of prostate cancer, but no such association with lung cancer or colon cancer. The prostate cancer result is consistent with a biological theory and a limited number of previous studies of circadian disruption and risk. The LAN‐prostate cancer connection is postulated to be due to suppression of melatonin and/or disruption of clock gene function. An analysis holding other variables at average values across the 164 countries yielded a risk of prostate cancer in the highest LAN‐exposed countries 110% higher than in the lowest LAN exposed countries. This observed association is a necessary condition for a potentially large effect of LAN on risk of prostate cancer. However, it is not sufficient due to potential confounding by factors that increase the risk of prostate cancer and are also associated with LAN among the studied countries.     

Suppression of natural killer cell activity on Candida stellatoidea by a 50 Hz magnetic field

Exposure to electromagnetic fields (EMF) is ubiquitous for almost all individuals living in industrialized countries. Epidemiological and laboratory studies suggest that exposure to Extremely Low Frequency (ELF) EMF increase cancer risk. The immune system functions as one of the body's main protective mechanisms, and Natural Killer (NK) cells are a subset of lymphocytes that can destroy several types of tumor cells. In this study, we investigated, NK cell activity after exposure to a 50 Hertz (Hz), 2 mT magnetic field generated by a Helmholtz Coil. Nineteen male, 10-12 week old guinea pigs were used, and NK cytotoxic activity of splenocytes was measured in vitro by natural anticandidial colorimetric index. The Mann-Whitney U test was applied for statistical analysis. NK cell cytotoxic activity was decreased in exposed compared to controls. Our data suggests that part of the immune system, the NK cell, can be suppressed by a 50 Hz magnetic field.     

Ocular input for human melatonin regulation: relevance to breast cancer

The impact of breast cancer on women across the world has been extensive and severe. As prevalence of breast cancer is greatest in industrialized regions, exposure to light at night has been proposed as a potential risk factor. This theory is supported by the epidemiological observations of decreased breast cancer in blind women and increased breast cancer in women who do shift-work. In addition, human, animal and in vitro studies which have investigated the melatonin-cancer dynamic indicate an apparent relationship between light, melatonin and cancer, albeit complex. Recent developments in understanding melatonin regulation by light in humans are examined, with particular attention to factors that contribute to the sensitivity of the light-induced melatonin suppression response. Specifically, the role of spectral characteristics of light is addressed, and recent relevant action spectrum studies in humans and other mammalian species are discussed. Across five action spectra for circadian and other non-visual responses, a peak sensitivity between 446-484 nm was identified. Under highly controlled exposure circumstances, less than 1 lux of monochromatic light elicited a significant suppression of nocturnal melatonin. In view of the possible link between light exposure, melatonin suppression and cancer risk, it is important to continue to identify the basic related ocular physiology. Visual performance, rather than circadian function, has been the primary focus of architectural lighting systems. It is now necessary to reevaluate lighting strategies, with consideration of circadian influences, in an effort to maximize physiological homeostasis and health.     

Is there a real risk of radiation-induced breast cancer for postmenopausal women?

The risk of radiation-induced breast cancer decreases with increasing age at exposure. Thus, for calculating the individual risk for a patient undergoing mammography, age-related risk coefficients need to be used. In this report, the results of epidemiological studies on risks of radiation-induced breast cancer are reviewed indicating that the available data do not show the risk to be enhanced for women exposed at the age of 55 years or older. This lack of evidence is reflected by the fact that the risk coefficients recommended by national and international advisory bodies differ by a factor of 10 or more for age at exposure of 50–60 years or older. A hypothesis is proposed indicating that the risk of radiation-induced breast cancer might decrease considerably at the time of menopause. The hypothesis is based on the following line of arguments: (1) evidence has accumulated from molecular genetic studies indicating that the development of colorectal cancer requires a cascade of subsequent mutations consisting of at least seven genetic events. (2) For colorectal cancer, the annual rates of incidence and mortality increase with age to the power of 5–6. Thus, the number of mutation steps (minus 1) is approximately reflected by the power of age dependence. (3) For western populations, the incidence and mortality of breast cancer up to the age of about 50 years increase with age to the power of about 6, indicating that a similar number of genetic events might be involved in development of breast cancer as has been identified for colorectal cancer. (4) For women aged 50 years or older, breast cancer occurs at an annual rate that is about proportional to age or age squared. This may mean that after menopause, the processes in the multistep mutation cascade leading to breast cancer are slowed down by a factor of about 4 or more. (5) The constant relative risk model of radiation carcinogenesis implies for solid cancers that radiation acts by inducing additional mutations in the earlier steps of the multistep cascade. It is suggested that the break-point in the age-specific annual rate of breast cancer incidence at menopause is associated with a corresponding drop in radiation sensitivity with respect to induction of breast cancer. Received: 8 January 2001 / Accepted: 20 March 2001     

Breast implants and cancer: causation, delayed detection, and survival

Concern for many women with breast implants has been focused on three topics: cancer (both breast and other cancers), delayed detection of breast cancer, and increased breast cancer recurrence or decreased length of survival. In this study, a qualitative review of the literature on these subjects was conducted, coupled with a meta-analysis of the risk for breast cancer or other cancers (excluding that of the breast). Researchers have consistently found no persuasive evidence of a causal association between breast implants and any type of cancer. The meta-analysis results obtained by combining the epidemiology studies support the overall conclusion that breast implants do not pose any additional risk for breast cancer (relative risk, 0.72; 95% confidence interval, 0.61 to 0.85) or for other cancers (relative risk, 1.03; 95% confidence interval, 0.87 to 1.24). This analysis suggests that breast implants may confer a protective effect against breast cancer. Women with implants should be reassured by the consistency of scientific studies which have uniformly determined that, compared with women without implants, they are not at increased risk for cancer, are not diagnosed with later-stage breast malignancies, are not at increased risk for breast cancer recurrence, and do not have a decreased length of survival.     

WHO health risk assessment process for static fields

The World Health Organization (WHO) has a commitment to helping Member States achieve safe, sustainable and health-enhancing human environments, protected from biological, chemical and physical agents. The latter includes advising on the health impact of electromagnetic fields (EMFs) and radiation.

The results of the WHO/ICNIRP/NRPB workshop on static magnetic fields, published in this volume, provide a valuable and much needed contribution to the health risk assessment of exposure to static electric and magnetic fields, which is currently being coordinated by the WHO's International EMF Project. This WHO health risk assessment will be published as an environmental health criteria (EHC) monograph in early 2005.

This paper briefly gives an overview of the process of developing the WHO static fields EHC monograph, the criteria applied to studies that could contribute to the EHC, along with the ‘weight-of-evidence’ approach to health risk assessment. In addition, there is an increasing awareness of the need to account for uncertainty in the science database. This is traditionally addressed by further research, and the EMF project addresses these needs through the development of a ‘research agenda’. However, research programmes may take several years to complete, and the long latency associated with diseases such as cancer in people may also preclude a rapid outcome in some studies. The issue of current uncertainty is being addressed by the WHO EMF project through the development of a ‘precautionary framework’ in which precautionary measures will be applied to policy recommendations.     

Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin in postmenopausal women

Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint β = -0.126; joint P = 2.09 × 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10(-5)), several were located at the CYP19A1 gene locus. Overall results were similar in secondary meta-analyses that included ~900 NHS current postmenopausal hormone users. No variant associated with estradiol, testosterone, or SHBG at P<10(-5) was associated with postmenopausal breast cancer risk among CGEMS participants. Our results suggest that the small magnitude of difference in hormone levels associated with common genetic variants is likely insufficient to detectably contribute to breast cancer risk.