GUEST EDITORIALS – SUMMARY EVALUATIONS

The Darkness at the End of the Tunnel:
Summary and Evaluation of an International Symposium on Light, Endocrine Systems and Cancer
Charles Poole
University of North Carolina School of Public Health,
Chapel Hill, NC, USA.

Submitted June 4, 2002,
Neuroendocrinology Letters 2002; 23(suppl 2):71–78

Key words: light; endocrine systems; cancer; latitude; consensus and controversy; attributable fraction; attributable risk; exposure surrogate; confounding; graphical methods

Abstract
Research on light at night and cancer is evolving at an accelerating pace, fueled largely by exciting results in rodent toxicology and basic human biology. Epidemiologic research is at a relatively early stage of development in which the exposure surrogates such as shift work and blindness predominate. Causal graphs for shift work, light at night and breast cancer illustrate some of the subtleties that can arise in the use of exposure surrogates of different kinds. Baseline data on circadian rhythms and melatonin cycles among human populations living at different latitudes are needed. Epidemiologic study of this topic is expected to mature soon as studies begin to incorporate quantitative and semiquantitative measurements and personal histories of exposure to light at night. The current emphasis on breast cancer should widen to include other cancers and intermediate outcomes. An advance in epidemiologic studies of blind persons would be to compare cancer rates between the "cortically blind" and the "retinally blind" within levels of visual impairment. Without a proposed intervention to reduce exposure to light at night, attributable fraction and attributable caseload estimates are meaningless. In the near future, both epidemiologic and laboratory research in this area are expected to grow appreciably in scope and scale.

Introduction
It was a pleasure and an honor for an epidemiologist who has conducted no research on light, endocrine systems and cancer, and whose most recent laboratory work was concluded during the Nixon administration, to be asked to summarize and provide evaluative commentary on the International Symposium on Light, Endocrine Systems and Cancer at the University of Cologne, Germany, May 2–3, 2002. The organizers' desire for a fresh, unbiased perspective unavoidably brought them a perspective of naïveté and ignorance as well. Prudence thus dictates breadth in this closing commentary, with an occasional foray into the author's familiar terrain of general epidemiologic methods.
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Comments on the International Symposium on
Light, Endocrine Systems and Cancer
Christopher J. Portier
Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 USA.

Submitted May 17, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):79–81

Key words: light-dark cycle; molecular clocks; clock genes; physics of light; endocrine pathways; cancer mechanisms; animal evidence; epidemiology; tumor burden

Abstract
A conference was held at the University of Cologne on May 2–3, 2002, to discuss the strength-of-the-evidence supporting a linkage between light, endocrine systems and cancer. This overview of the conference is intended to summarize some of the key elements of the conference and to indicate both conclusions and research gaps identified by this reviewer.

Introduction
If I had to pick a theme song for this conference it would be "I Got Rhythm"1 which asks the rhetorical question, "Who could ask for anything more?" From the keynote address by Russ Reiter to the closing comments by Charles Poole, this conference focused on the "rhythm" that evolution has provided to most organisms on this planet through regular light-dark cycles. The recognition that these cycles may play an important role in cancer incidence through changes in levels of critical endocrine hormones is beginning to gain considerable scientific support and is the key focus of this conference. In my summary, I will discuss some of the research presented at the workshop and provide opinion on where critical data gaps exist and new research opportunities are emerging. In the final summary, I will discuss the general question of whether changes in the light-dark cycle should be considered a human carcinogen.
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Light, Endocrine Systems, and Cancer -
A View from Circadian Biologists
Till Roenneberg, Robert J. Lucas
1. Centre for Chronobiology, Institute for Medical Psychology,
Munich, GERMANY.
2. Centre for Chronobiology, Division of Neuroscience and Psychological Medicine, Faculty of Medicine,
Imperial College London W6 8RF, UNITED KINGDOM.

Submitted May 16, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):82-83

Key words: circadian biology; light; endocrine systems; cancer; melatonin; Light-at-night (LAN); shift work; pineal; entrainment; epidemiology

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Light, Endocrine Systems and Cancer -
A Meeting Report
Vladimir N. Anisimov, Johnni Hansen
1. Department of Carcinogenesis and Oncogerontology,
N.N. Petrov Research Institute of Oncology, St. Petersburg, RUSSIA
2. Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, DENMARK.

Submitted May 20, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):84-87

Key words: Light-at-night (LAN); melatonin; endocrine systems; cancer; animal studies; epidemiological studies; shift work; blind people; latitude; Arctic

The International Symposium "Light, Endocrine Systems and Cancer" was held on May 2–3 at Cologne University, Germany. The symposium was organized by Professor Claus Piekarski and Dr. Thomas C. Erren, Institute and Polyclinic for Occupational and Social Medicine. The main goal of the symposium was to evaluate the epidemiological and experimental data on the effect of the exposure to light-at-night on cancer risk and to indicate the main directions of future research in the field. The symposium covered also the mechanisms and epidemiology of skin cancer which, however, are not included in the present summary.
The alternation of the day and night circadian cycle is a very important regulator of a wide variety of physiological rhythms in living organisms, including humans. Due to the introduction of electricity and artificial light about hundred years ago the pattern and duration of human exposure to light has changed dramatically, and thus light-at-night has become an increasing and essential part of modern lifestyle. Light exposure at night seems associated with a number of serious behavioral as well as health problems, including cancer. The meeting gave unique possibilities to discuss the available data on this issue and to evaluate the strength of evidence for carcinogenic risks arising from epidemiological studies, experimental animal data, etc..
In the opening lecture of Professor Russel J. Reiter (University of Texas Health Science Center, San Antonio, U.S.A.) "Excessive light exposure: Endocrine influences particularly as they relate to cancer initiation and progression" it was stressed that oxygen ... ... ...

REVIEW ARTICLES

Potential Biological Consequences of Excessive Light Exposure: Melatonin Suppression, DNA Damage, Cancer and Neurodegenerative Diseases
Russel J. Reiter
Department of Cellular and Structural Biology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, USA.

Submitted: May 2, 2002
Accepted: May 5, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):9–13

Key words: light exposure; melatonin suppression; DNA damage;
free radical scavenging; neurodegeneration; diseases of aging

Abstract:
This brief review summarizes some of the biological effects of light exposure at an inappropriate time (during the normal dark period) and the potential negative physiological consequences of this light exposure. Two major systems are significantly influenced by light at night. Thus, the circadian system and melatonin synthesis are altered when light is extended into the normal dark period or when the dark period is interrupted by light. This summary reviews the potential sequelae of chronic inappropriate light exposure and the suppression of endogenous melatonin levels. Given that melatonin is a free radical scavenger and antioxidant, conditions that involve free radical damage may be aggravated by light suppression of melatonin levels. The conditions of particular interest for this review are excessive DNA damage (which potentially leads to cancer), cellular destruction in neurodegenerative diseases and aging itself. Further research should be conducted to more accurately define the potential negative impact of light at abnormal times on animal and human pathophysiology.

Introduction
It has typically been assumed that the use of usual artificial light sources during the normal dark period is essentially inconsequential in terms of the physiology of mammals including man. With the discovery of an organ, the pineal gland, whose biochemical and secretory activity is inextricably linked to the prevailing light:dark environment, however, the implications of the possible "misuse" of light during the normal dark period have become of major interest. Throughout evolution, our predecessors were exposed to a photoperiodic environment where the duration of light (and darkness) was exclusively related to the interval that the sun was above the horizon. This allowed for highly regulated daily and seasonal changes in the light:dark cycle which control endogenous circadian [1] and circannual [2] rhythms. Not surprisingly, because of these predictable cycles of light and darkness, organisms evolved a complex of structures which translated this information into benefits for the species. ... ... ...

The physics of light and sunlight
Sidney Perkowitz
Department of Physics; Emory University, Atlanta, GA, USA.

Submitted: April 20, 2002
Accepted: May 22, 2002
Key words: light; sunlight; ultraviolet; UV; ozone; cancer; melatonin
Neuroendocrinology Letters 2002; 23(suppl 2):14–16

Abstract
The physical properties of light, both natural and artificial, play a significant role in its interaction with humans. Although there is a yet-to-be-explained duality between light as waves and light as photons, we do understand many of the characteristics of light that affect living things. Here I review the general history of light and its properties, especially those that affect human health.

1. A brief history of light and sunlight
Light began when the universe did. The Big Bang that started the cosmos some 15 billion years ago was an intense explosion of light emitted at a temperature of billions of degrees. Some of that light energy was converted into matter according to the equation E = mc2, and so light is responsible for matter as well. Table I shows other steps in the evolution of light and its effect on life, including the formation of our own sun [1, 2]. Today, we live in a world dominated by sunlight.

2. Understanding light
Since the earliest times humanity has recognized the importance of light, but there has been only a slow clarification of its nature, with the key question being whether light is wave-like or particle-like. The particle picture dominated after Isaac Newton sent white light through a glass prism and split the light into colors, ... ... ...

The light-dark regimen and cancer development
Vladimir N. Anisimov
Department of Carcinogenesis and Oncogerontology, N.N. Petrov Research Institute of Oncology, St.Petersburg, RUSSIA.

Submitted: April 30, 2002
Accepted: May 16, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):28–36
Key words: cancer; pineal gland; light-at-night; light deprivation; melatonin; cancer prevention

Abstract
The role of the modulation of the pineal gland function in development of cancer is discussed in the review. An inhibition of the pineal function with pinealectomy or with the exposure to the constant light regimen stimulates mammary carcinogenesis, whereas the light deprivation inhibits the carcinogenesis. Epidemiological observations on increased risk of breast cancer in night shift workers, flight attendants, radio and telegraph operators and on decreased risk in blind women are in accordance with the results of experiments in rodents. Treatment with pineal indole hormone melatonin inhibits carcinogenesis in pinealectomized rats or animals kept at the standard light/dark regimen (LD) or at the constant illumination (LL) regimen.

Introduction
According to the International Agency for Research on Cancer report [1], breast cancer constituted a huge disease burden in developed countries in the year 2000. It is the most common cancer in women with an estimated 999,000 new cases of breast cancer each year (about 22% of cancers in women) resulting in some 375,000 deaths. More than half of all cases are registered in industrialized countries: about 335,000 in Europe and 195,000 in North America. The disease is not yet as common among women in developing countries although proliferation is increasing. Risk of breast cancer incidence had been associated with higher socio-economic status such as income, education, housing, etc. as they were related to such health factors as age at menstruation and menopause, obesity, height, alcohol consumption, late age at first birth, low parity, estrogen replacement therapy, some diet habits, etc. Two conditions unique to developed countries are an increasing exposure to light-at-night and power frequency (50–60 Hz) magnetic fields.
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Endocrine modulation and the fragile balance of homeostasis - an overview
Günter Vollmer, Susanne Starcke, Jannette Wober & Oliver Zierau
Molecular Cell Physiology & Endocrinology, Faculty for Mathematics and Science, Institute for Zoology, GERMANY.

Submitted: May 2, 2002
Accepted: May 5, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):37–42
Key words: phytoestrogens; estrogen receptor-a and b; development; menopause; tissue specificity; endocrine disruption

Abstract
Endocrine modulation by natural and synthetic chemicals and the eventually resulting beneficial or adverse effects for human and animal health are controversially debated not only among scientists but particularly in the public. Most information is available on so-called environmental estrogens, however the amount of information on substances interfering with other hormonal axes steadily increases, particularly on those exhibiting (anti)androgenic activities. The aim of this paper is to summarize existing data and to give an overview on the potential pathways leading to interferences of environmental hormones with homeostasis and eventually resulting health effects. Experimental evidence suggests the hypothesis that fetal and neonatal organisms may be at risk if exposed to environmental estrogens. In contrary, it appears as if phytoestrogens, particularly those with selective estrogen receptor modulator- (SERM-)like activities have the potential to be useful in medical application, both as dietary means and as pharmaceuticals. Lacking valid information about the detailed analysis of the molecular mode of action for environmental estrogens, the possibility for an ultimate classification of environmental estrogens in "dangerous endocrine disruptors" and phytoestrogens in "useful pharmaceuticals" cannot be supported conclusively. Nevertheless both activities are likely.

Exposure to environmental hormones
Most information is available on so-called environmental estrogens, however, the amount of information on substances interfering with other hormonal axes steadily increases, particularly on those exhibiting (anti)androgenic activities. Xenobiotic substances capable to interfere with estrogen function add up to >230 individual compounds [1, 2]. They comprise naturally occurring compounds e.g. endogenous estrogens, phyto-and mycoestrogens, as well as man-made chemicals e.g. oral contraceptives or industrial products with hormone-like activities (for review see [3]). However, it has to be kept in mind that some of these synthetic xenobiotics accused to cause effects in the male reproductive tract or affect its function e.g. sperm quality and quantity, occur in the environment in concentrations orders of magnitude lower than those estrogens which are used for oral contraception and hormonal replacement therapies [4] or contained in meat of the daily diet [5]. Further, the exposure to hormonally active xenobiotics can be neglected to the amount of phytoestrogens ingested with the diet or through herbal potions use in so-called "life style medicine" [4]. The latter are at least able to induce hormonal changes in females and may exhibit toxicity in males. Despite numerous effects described in many different experimental systems there is no conclusive evidence about the capability of environmental hormones to induce impacts on human health [6]. Potential risks and benefits of exposure or use of environmental estrogens, particularly of phytoestrogens, which occur in high concentrations, will be discussed below.

Molecular mechanisms triggered by hormones from the environment ... ...

Endocrine Dismodulation and Cancer
Christopher J. Portier
Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 USA

Submitted: May 13, 2002
Accepted: May 16, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):43–47
Key words: mathematical model; cancer mechanisms; endocrine disruption; receptor biology; xenobiotic ligand; feedback; crosstalk

Abstract

OBJECTIVE: Carcinogenesis has generally been viewed as a genomic disease resulting from genetic mutations occurring at critical locations in the genome in a particular sequence. In the last 10 years, scientists have increasingly identified changes in the levels, frequency and types of endocrine hormones as important contributors to the major cancers faced by western populations such as breast cancer (estrogen, progesterone, prolactin), prostate cancer (estrogen, testosterone), endometrial cancer (estrogen) and thyroid cancer (TSH, T3, T4). This manuscript summarizes cancer mechanisms linked to changes in endocrine function and discusses tools for analyzing and understanding the associated data.

DISCUSSION: A number of chemicals in the environment mimic the role of hormones to bind to receptors (e.g. phytoestrogens as estrogen mimics), alter signaling pathways (e.g. retinoids), inhibit steroid hormone synthesis (such as some fungicides) or alter steroid hormone metabolism (such as TCDD altering the metabolism of both estrogen and thyroid hormones). Genomic and non-genomic endocrine signaling pathways are extensively present in the body and function in a complicated fashion. In order to fully understand the basis for endocrine-induced cancers, one must simultaneously study the various receptors, ligands, enzymes, other proteins within different organs which all contribute to endocrine system function. Also, cross-talk between endocrine systems is common and is key to understanding a potential role of light-dark cycles on human cancer risks.

CONCLUSION: Mechanism-based mathematical models are the only analysis tool available to address all aspects of these complicated networks.

Introduction
According to the Cambridge International Dictionary of English [1], modulate is defined as "to change (something such as an action or a process) to make it more suitable for its situation". Dismodulation refers to the opposite; to change something and make it less suitable for its situation. Endocrine dismodulators (also known as endocrine disruptors, environmental hormones, endocrine active compounds, etc.) are compounds in the environment that are able to change the carefully balanced (over daily, monthly, yearly and life-stage) levels of endogenous hormones in tissues in a living system. Endocrine hormones are produced by certain glands in the body and provide communication between various tissues in the body to regulate a number of critical body functions such as growth, development, reproduction and metabolic homeostasis. The entire family of protein-based hormones consists of approximately 100 small proteins ranging in size from three amino acids (thyrotropin-releasing hormone) to almost 200 amino acids (growth hormones). In addition, a variety of smaller chemical signals, like melatonin, act in the same manner as protein-based hormones. Hormones express their biological action in four different ways; endocrine signaling for communication across different organs, paracrine signaling for communication among adjacent cells, neuroendocrine signaling for synthesis and release of hormones from peptidergic neurons and as neurotransmitters in concert with classic aminergic transmitters. In many cases, a single hormone will have all of these functions. Dismodulation of any of the endocrine systems in the body can result from a growing number of natural and anthropogenic compounds and/or agents with diverse chemical structures and diverse activities.
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Disruptions in Hormone Synthesis and Release ... ...
Disruptions in Hormone Metabolism ... ...
Disruptions in Hormone Response ... ...

Epidemiology of Skin Cancer
Roland Böni, Christian Schuster, Britta Nehrhoff, Günther Burg
Department of Dermatology; University Hospital of Zürich, SWITZERLAND.

Submitted: May 1, 2002
Accepted: May 23, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):48–51
Key words: epidemiology; skin cancer; cutaneous tumors; melanoma; squamous cell carcinoma; basal cell carcinoma; bowen's disease; actinic keratoses

Abstract
The skin is the most common site of malignancy. Due to several mostly unknown factors, the frequency of skin tumors is increasing. Except for malignant melanoma, reliable statistical data on the frequency of skin tumors are scarce.
Discussion on the epidemiology of skin tumors may take different aspects and factors into consideration: (1) histogenetic type; (2) race, (3) sex; (4) age, (5) localization; (6) environment. Moreover, precancerous conditions also may play an important role in this context.
Epithelial tumors, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most frequent tumors of the skin. Figures show a wide range between 40 and over 700 or 5 and 250 respectively per 100 000 inhabitants per year depending on the country or area of report.
Malignant melanoma is more frequently seen in Caucasians living in sunny regions (40) than in northern countries or in dark skinned races (4–12 per 100 000 per year), representing 4% of all skin tumors, but being responsible for 79% of skin cancer deaths.
Other types of skin tumors like cutaneous lymphoma, Kaposi sarcoma, lipomas, adnexal tumors etc. are either not reported regularly and reliable epidemiologic data is not available, or are rare cutaneous tumors (taken all together < 1%).

ORIGINAL ARTICLES

Ocular Input for Human Melatonin Regulation: Relevance to Breast Cancer
Gena Glickman, Robert Levin, George C. Brainard
1. Department of Neurology, Jefferson Medical College, Philadelphia PA
2. Lighting Research Center, Rensselaer Polytechnic Institute,
Troy, NY, USA

Submitted: May 21, 2002
Accepted: May 24, 2002
Key words: light; melatonin; cancer; photoreceptor; circadian; action spectrum
Neuroendocrinology Letters 2002; 23(suppl 2):17–22

Abstract
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.

Ocular Input for Human Melatonin Regulation:
Relevance to Breast Cancer Risk
Breast cancer is the most common form of malignancy found in women and the second leading cause of cancer mortality. Based on epidemiological evidence collected from 1995 to 1997, the National Cancer Institute estimates that approximately 1 in 8 women in the United States will develop breast cancer during her lifetime. Identified risk factors for female breast cancer include: early age at onset of menarche, late age at onset of menopause, first full-term pregnancy after age 30, history of pre-menopausal breast cancer for mother and/or a sister, and a personal history of breast cancer or benign proliferative breast disease. Environmental conditions associated with technological advancements also appear to be indicative of an increased risk, with a much higher prevalence of breast cancer in industrialized regions as compared to that of developing nations. Consequently, theories about the potential role of exposure to light at night have been proposed [1, 2]. The theory that nighttime light exposure may be a risk factor for cancer is suggested by the suppressive effects of nocturnal light on pineal melatonin [3,4] and the decrease in melatonin production that has been associated with increased risk of breast cancer [5]. A wide range of human, animal and in vitro studies further support this theory [6].
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Biological rhythms in the context of light at night (LAN)
Alexander Lerchl
International University Bremen, School of Engineering and Science, Bremen, GERMANY.

Submitted: May 21, 2002
Accepted: May 22, 2002
Key words: chronobiology; biological clocks; melatonin; entrainment; light at night
Neuroendocrinology Letters 2002; 23(suppl 2):23–27

Historical and experimental evidence indicates that human responses
to seasonal changes in the natural photoperiod may have been
more robust prior to the Industrial Revolution and that
subsequently they have been increasingly suppressed
by alterations of the physical environment.
– Thomas A. Wehr, J Biol. Rhythms 16: 348-364 (2001)

Abstract
In mammals including man, the most important zeitgeber for endogenous rhythms is the environmental light/dark cycle. Mammals perceive light through the eyes and that perception is relayed to the suprachiasmatic nucleus (SCN) by means of neuronal signals. The SCN, in turn, innervates the pineal gland, resulting in the production and release of melatonin almost exclusively during night-time hours. Thus, besides object recognition, eyes serve as the sensory organ for detecting the presence or absence of light. The way that light entrains the SCN is still a matter of intense research. It has been shown, for example, that the light intensities required for affecting melatonin rhythms are much higher than the intensities needed for object identification. On the other hand, even in rodents who completely lack the "classical" photoreceptors of the retina, their endogenous rhythms still can be synchronized by normal light/dark cycles. These two observations led to the hypothesis that there must be photoreceptors, apart from the known (object-identifying) retinal photoreceptors, which are responsible for the entrainment of internal rhythms. Very recently, a number of reports showed that in fact a completely new type of retinal photoreceptor, located in ganglion cells, may be responsible for entraining the SCN. It contains a photopigment, melanopsin, which shares homologies with rhodopsin, but also is evolutionarily older. Compared to rods or cones, the melanopsin-containing neurons are rare, but evenly distributed within the retina, indicating that they serve as a global, integrating light sensor. These ganglion cells apparently project directly into the SCN. Taken together, these new developments in photo-chronobiology open new areas of research. It will be of special interest, for example, to determine how the photosensitive ganglion cells and their dendrites integrate the environmental light stimuli.

Features of biological clocks
The physical and biological constraints of the environment of every organism set limits for its spatial and temporal orientation. Those constraints include, for example, climatic variables, presence of predators, and availability of food. As a consequence, most physiological, morphological, and behavioural processes have become adapted so that the organism fits in its ecological niche. If, for any reason, these adaptations considerably change, less optimal fitness or even death will be the consequence.
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Effects of light at night ... ... ...
The components of biological clocks in mammals ... ... ...
Photoreceptors for photoperiod ... ... ...
Seasonal rhythms and secular trends ... ... ...

Light during darkness, melatonin suppression and cancer progression
David E. Blask, Robert T. Dauchy, Leonard A. Sauer, Jean A. Krause
& George C. Brainard
Laboratory of Experimental Neuroendocrinology/Oncology, Bassett Research Institute, Cooperstown, NY, USA.
Department of Neurology, Thomas Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.

Submitted: May 2, 2002
Accepted: May 10, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):52–56
Key words: melatonin suppression; cancer; light during darkness;
pineal gland; fatty acids

Over the past few years, we have shown that the surge of melatonin in the circulation during darkness represents a potent oncostatic signal to tissue-isolated rat hepatoma 7288CTC, which is an ER+ adenocarcinoma of the liver. This oncostatic effect occurs via a melatonin receptor-mediated suppression of tumor cAMP production that leads to a suppression of the tumor uptake of linoleic acid (LA), an essential fatty acid with substantial oncogenic properties. The ability of LA to promote cancer progression is accomplished by its intracellular metabolism to 13-hydroxyoctadecadienoic acid (13-HODE) which amplifies the activity of the epidermal growth factor receptor/mitogen-activated protein kinase pathway leading to cell proliferation. By blocking tumor LA uptake, melatonin effectively blocks the production of 13-HODE and thus, markedly attenuates tumor growth. A similar effect of melatonin is observed in tissue-isolated, ER+ MCF-7 human breast cancer xenografts and nitrosomethylurea (NMU)-induced rat mammary cancers. When male rats bearing tissue-isolated hepatomas are exposed either to constant bright light (300 lux) or dim light (0.25 lux) during the dark phase of a 12L:12D photoperiod, the latency to onset was significantly reduced while the growth of tumors was markedly increased over a 4 wk period as compared with control tumors in 12L:12D-exposed rats. In constant light- and dim light during darkness-exposed rats, melatonin levels were completely suppressed while tumor growth, LA uptake and 13-HODE production were markedly increased. Similar results were obtained in constant bright light-exposed female rats bearing tissue-isolated NMU-induced mammary cancers or MCF-7 human breast cancer xenografts. To date, these studies provide the most definitive experimental evidence that light exposure during darkness increases the risk of cancer progression via elimination of the nocturnal melatonin signal and its suppression of tumor LA uptake and metabolism to 13-HODE.

Lighting During the Day and Night: Possible Impact on Risk of Breast Cancer
Richard G. Stevens
UConn Health Center, Farmington, CT

Submitted: May 15, 2002
Accepted: May 22, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):57–60
Key words: circadian disruption; electric light; breast cancer

Abstract

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.

Does light cause internal cancers?
- The problem and challenge of an ubiquitous exposure
Thomas C. Erren
Institute and Policlinic for Occupational and Social Medicine, School of Medicine and Dentistry, University of Cologne, GERMANY.

Submitted: May 2, 2002
Accepted: May 21, 2002
Neuroendocrinology Letters 2002; 23(suppl 2):61–70
Key words: light; melatonin; endocrine systems; hormone-dependent cancer; epidemiological studies; ubiquitous exposure

Abstract
Visible light of sufficient intensity and duration inhibits melatonin biosynthesis, and experimental studies suggest that melatonin may protect against cancer. From a public health point of view it is important to verify or falsify the hypothesis that artificial light – or even sunlight itself – suppresses melatonin production sufficiently to increase the risk of developing cancers of internal organs in man. Epidemiology is a discipline that can contribute to in-vivo verification of experimental findings. But when attempting to study the effects of light on man, epidemiologists are faced with a major problem: the ubiquitous nature of natural and anthropogenic light, which renders everyone, everywhere exposed. The challenge is to identify populations with demonstrable varying exposures to light.
This paper summarizes how recent epidemiological investigations have sought to tackle the problem by studying shift-workers, blind people and Arctic residents. It is suggested that future studies should test the underlying assumptions regarding endocrine responses to light, i.e., that melatonin levels are reduced among shift-workers, and that they are increased among the blind and those who live in the Arctic. A systematic investigation of exposure-response relationships could be based on "light dosimetry by geography". Such a study is envisaged by European researchers who aim to study melatonin and other hormones in samples from healthy general populations that are differentially exposed to light by virtue of varying ambient photoperiods. Further methodologic options for prospective and retrospective epidemiologic studies are suggested.
It is concluded that the biologically plausible link between ubiquitous light, hormones and the development of very frequent malignancies such as breast cancer and prostate cancer should be investigated rigorously by additional well-designed epidemiological research.

Introduction
Man is exposed to the sun's light everywhere, and anthropogenic light sources constitute further universal exposures to visible electromagnetic radiation. Breast cancer is the leading cause of cancer morbidity and mortality among women in many countries, and prostate cancer is the most common non-cutaneous cancer in men [1]. Large differences in rates of hormone-related cancers internationally suggest that environmental factors play an etiologic role, and since the development of both malignancies involve hormones it seems likely that modulation of endocrine systems is relevant [2, 3]. Light is an ubiquitous environmental factor which does just that. An abundance of experimental and clinical evidence indicates a very robust relationship between visible light, at intensities that we experience regularly, and endocrine systems. Light entering the eyes powerfully controls and modifies circadian and neuroendocrine systems. Melatonin is the key biologic intermediary. Light inhibits [4] and darkness stimulates synthesis of melatonin [5] in the pineal gland in the center of the brain as a product of the tryptophan-serotonin metabolism. A dose-response relationship between light and melatonin suppression has been confirmed in human studies [6–8], and there is some evidence which suggests that the blue-green spectrum (~500 nm) is most effective in reducing melatonin production [6]. It is important to note that considerably more light is needed for melatonin suppression than for vision [9]. Research is under way to clarify how the phototransduction of non-visually mediated phenomena on endocrine systems operates [10].
The experimental, and limited epidemiological evidence available in 1987 was used to formulate the so-called melatonin hypothesis. This posited a link between light-at-night (LAN), and extremely low frequency electric and/or magnetic fields (ELF-EMF), to increased breast cancer risks via impaired pineal secretion of melatonin [11]. The idea was that low melatonin levels were expected to result in increased levels of gonadal steroids (e.g., testosterone in males, and estrogens in females, respectively) by specific actions on the pituitary, and would thus eventually promote cancer growth. Empirically, these relations between melatonin secretion and gonadotropins levels have been suggested in men [12], but ELF-EMF have not been shown convincingly to inhibit melatonin secretion [13]. Exposure to light, however, has been linked consistently with impaired melatonin secretion in humans, and experimental evidence suggests that melatonin can suppress mammary tumorigenesis in animals [14] and possibly in humans [15]. Furthermore, a number of clinical studies indicate that low melatonin levels are associated with certain types of hormone-dependent cancers, including breast [3], endometrial [16], and prostate cancer [17]. To date, extensive research over many years has identified some of the mechanisms by which melatonin can reduce cancer incidence and/or growth [3,18].
The melatonin hypothesis is biologically plausible and is testable in principle. It remains then to transform the "biological plausibility" into a convincing mapping of a biological pathway that occurs in real life. Laboratory studies are being pursued intensively in an effort to provide direct evidence that supports or refutes the hypothesized causal link between light, melatonin and cancer. But epidemiological studies of light and hormone-dependent cancers are difficult and still very rare. This paper discusses current strategies and viable additional options for epidemiological studies of the issue. Such research may provide in vivo verification of the suggestion that the intriguing experimental and clinical findings summarised above impact importantly on public health. ... ...
Predictions ...
– P1|H ...
– P2|C ...
– P3|C ...
– P4|C ...
Study options ... Prospective studies ... Retrospective studies ... Light ... Biomarkers ... An alternative indirect measure of "exposure" ...
Perspectives ...

PRESENTATION ABSTRACTS

Excessive light exposure: Endocrine influences particularly as they relate to cancer initiation and progression
Russel J. Reiter
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.

The Physics of Light and Sunlight
Sidney Perkowitz
Department of Physics, Emory University, Atlanta, GA, USA.

Heritable daylength-thresholds and the evolution of temporal orientation
Klaus Peter Sauer
Institute for Evolutionary Biology and Ecology, University of Bonn, GERMANY.

Ocular input for human melatonin regulation
George C. Brainard & Robert Levin
1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
2. OSRAM SYLVANIA, Salem, MA, USA.

Light and biological rhythms
Alexander Lerchl
School of Engineering and Science, International University Bremen, GERMANY.

Light, melatonin and aging
Russel J. Reiter
Department of Cellular and Structural Biology; University of Texas Health Science Center, San Antonio, TX, USA.

Endocrine modulation and the fragile balance of homeostasis
Günter Vollmer
Molecular Cell Physiology and Endocrinology, Institute of Zoology; Technical University Dresden, GERMANY.

Endocrine Dismodulation and Cancer
Christopher J. Portier
Environmental Toxicology Program, NIEHS, NIH;
Research Triangle Park, NC, USA.

Mechanisms of skin cancer
Karin Scharffetter-Kochanek
Clinic for Dermatology and Allergology, University of Ulm, GERMANY.

Epidemiology of skin cancer
Gunter Burg
Department of Dermatology, University Hospital of Zurich, SWITZERLAND.

Light during darkness, melatonin suppression and cancer progression
David E. Blask, Robert T. Dauchy, Leonard A. Sauer, Jean A. Krause & George C. Brainard
1. Laboratory of Experimental Neuroendocrinology/Oncology,
Bassett Research Institute, Cooperstown, NY, USA.
2. Department of Neurology, Thomas Jefferson University,
Philadelphia, PA, USA.

Epidemiological Studies of Light and Breast Cancer
Richard G. Stevens
UConn Health Center, University of Connecticut, Farmington, CT, USA.

Novel Mechanistic Research
Richard G. Stevens
UConn Health Center, University of Connecticut, Farmington, CT, USA.

Does light cause internal cancers? - The challenge to study an ubiquitous exposure epidemiologically
Thomas C. Erren, Peter Bjerregaard, Pierluigi Cocco, Maria Feychting, Alexander Lerchl, Andreas Pinger, Richard G. Stevens,
Pia Verkasalo & Claus Piekarski
1. Institute and Policlinic for Occupational and Social medicine, University of Cologne, GERMANY.
2. National Institute of Public Health, Kopenhagen, DENMARK.
3. Department of Public Health, Occupational Health Section, University of Cagliari, ITALY.
4. Institute of Environmental Medicine, Karolinska Institute, Stockholm, SWEDEN.
5. School of Engineering and Science, International University Bremen, GERMANY.
6. UConn Health Center, University of Connecticut, Farmington, CT, USA.
7. National Public Health Institute, Helsinki, FINLAND.

POSTER ABSTRACTS

The Growth of DMBA-Induced Mammary Tumours Is Affected by Melatonin and Constant Light Only at Early Stages of Differentiation
Hella Bartsch, Christian Bartsch & Dieter Mecke
1. Center for Research in Medical and Natural Sciences, University of Tübingen, Tübingen, GERMANY.
2. Institute of Physiological Chemistry, University of Tübingen, Tübingen, GERMANY.

The Stimulatory Effect of Constant Light on Spontaneous Endometrial Carcinomas in BDII/Han Rats Depends on Initiation of Treatment at an Early Time in Life
Christian Bartsch, Hella Bartsch, Friedrich Deerberg & Dieter Mecke
1. Center for Research in Medical and Natural Sciences, University of Tübingen, Tübingen, GERMANY.
2. Institute of Physiological Chemistry, University of Tübingen, Tübingen, Germany.
3. Seebachhof 4, Hannover, GERMANY.

The Effect of Constant Light Regimen on Estrus Function and Mammary Tumorigenesis in Female Transgenic HER-2/neu Mice and CBA Mice
D.A. Baturin, I.N. Alimova, V.N. Anisimov, E.K. Ailamazyan,
I.G. Popovich, Zabezhinski & K. Manton
1. Department of Carcinogenesis and Oncogerontology, N.N. Petrov Research Institute of Oncology, St. Petersburg, RUSSIA.
2. Department of Obstetrics and Gynecology, I.P. Pavlov State Medical University, St. Petersburg, RUSSIA.
3. Center for Demographic Sciences, Duke University, Durham, N.C., U.S.A.

Modification of N-nitrosoethylurea (NEU)-induced Transplacental Carcinogenesis by Light/dark Regimen in Rats
D.Sh. Beniashvili, Sh. Benjamin, 1 DA. Baturin & V.N. Anisimov
1. Department of Pathology, G. Wolfson Medical Center, Holon, ISRAEL.
2. Department of Carcinogenesis and Oncogerontology, N.N. Petrov Research Institute of Oncology, Pesochny-2, St.Petersburg 197758, RUSSIA.

Non-Linear Negative Correlation Between Sex Hormone Receptors in Breast Cancer Tissues in Spring and Fall
Mikhail F. Borisenkov
Institute of Physiology, 50, Pervomaiskaya St., Syktyvkar 167982, RUSSIA.

The Hydroxyl-Radical Derived Destruction of the Pancreatic ß-cells is Noticeably Decreased by Melatonin
Hans-Jürgen Brömme, Henning Ebelt, Dorothee Peschke
& Elmar Peschke
1. Institute of Pathophysiology, Martin Luther University, Halle-Wittenberg, Halle/Saale, GERMANY.
2. Institute of Anatomy and Cell Biology, Martin Luther University, Halle-Wittenberg, Halle/Saale, GERMANY.

Suppression of Melatonin Secretion by Bright Light and Possible Consequences for Shiftwork
Hermann C. Roemer & Barbara Griefahn
Institute for Occupational Physiology at the University of Dortmund, Ardeystraße 67, D-44139 Dortmund, GERMANY.

Sensitive Assay for the Interaction of Melatonin and Estradiol in MCF-7 Cells
R. Girgert, W. Schuller, W. Körner & V. Hanf
1. Department of Obstetrics and Gynecology, University of Ulm; Ulm, GERMANY.
2. Bayerisches Landesamt für Umweltschutz, Augsburg, GERMANY.
E-mail: rainer.girgert@medizin.uni-ulm.de

Neuroendocrine Alterations in Lung Cancer Patients
Gianluigi Mazzoccoli, Stefano Carughi, Angelo De Cata, Marco La Viola, Antonio Giuliani, Roberto Tarquini & Federico Perfetto
1. Department of Internal Medicine, Regional General Hospital "Casa Sollievo della Sofferenza", Cappuccini Av, S.Giovanni Rotondo (FG), ITALY.
2. Center of Chronobiology, Department of Internal Medicine,
University of Florence, Pieraccini Av.,Florence (FI), ITALY.

Is there a link of sunshine and suicidal behaviour? Analyses in 20 OECD countries of the Northern and Southern hemispheres
Eleni Petridou, Fotios C. Papadopoulos, Constantine E. Frangakis, Alkistis Skalkidou, & Dimitrios Trichopoulos
1. Department of Hygiene and Epidemiology, Athens University Medical School, 75 Mikras Asias St, Athens 11745, GREECE.
2. Department of Epidemiology, Harvard School of Public Health, 677 Huntigton Ave, Boston, MA 02115, USA.
3. Department of Biostatistics, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.

NEW! Risk factors for non-melanoma skin cancer in the district of Prievidza, Slovakia
B. Pesch, K. Unfried, P. Jakubis, M. Jakubis, T. Keegan, P. Miskovic, M.J. Nieuwenhuijsen, A. Hergemöller, S. Rabstein &
U. Ranft
1. Environmental Health Research Institute, Düsseldorf, GERMANY.
2. BGFA, Bochum, GERMANY.
3. State Health Institute, Prievidza, SLOVAKIA.
4. Imperial College of Science, Technology and Medicine, London, U. K.
5. State Health Institute, Banska Bystrica, SLOVAKIA.

NEW! Receptor (MT1) Mediated Influence of Melatonin on cAMP Concentration and Insulin Secretion of Pancreatic Islets and Glucose Responsive Insulinoma Cell Line INS-1 of Rats
Elmar Peschke, Eckhard Mühlbauer, Erik Chankiewitz &
Dorothee Peschke
1. Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, D-06097 Halle/Saale, GERMANY.
2. Saxon Academy of Sciences, Karl-Tauchnitz-Strasse 1, D-04107 Leipzig, GERMANY.

NEW! The Insulin Release from Perifused Rat Pancreatic Islets is Generated by an Intrainsular Circadian Pacemaker Influenced by Melatonin
Elmar Peschke & Dorothee Peschke
1. Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, D-06097 Halle/Saale, GERMANY.
2. Saxon Academy of Sciences, Karl-Tauchnitz-Strasse 1, D-04107 Leipzig, GERMANY.