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REPORT 4 OF THE COUNCIL ON SCIENCE AND PUBLIC HEALTH (A-12) Light Pollution: Adverse Health Effects of Nighttime Lighting Authors: David Blask, PhD, MD (Tulane University School of Medicine); George Brainard, PhD (Jefferson Medical College); Ronald Gibbons, PhD (Virginia Tech); Steven Lockley, PhD (Brigha m and Women's Hospital, Harvard Medical School); Richard Stevens, PhD (University Connecticut Health Center); and Mario Motta, MD (CSAPH, Tufts Medical School). EXECUTIVE SUMMARY Objective. To evaluate the impact of artificial lighting on huma n hea lth, primarily through disruption of circadian biologica l rhythms or sleep, as well as the impact of hea dla mps, nighttime lighting schemes, and glare on driving safety. Concer ns related to energy cost, effects on wildlife and vegetation, and esthetics also are briefly noted. Methods. English-language r eports in humans wer e selected from a PubMed search of the literature from 1995 to March 2012 using the MeSH terms "circadian/biological clocks/rhythm, " "chronobiology/disorders," "photoper iod," "light/lighting" "sleep," "work schedule," or "adaptation," combined with the ter ms "physiology," "melatonin," "adverse effects/toxicity," "pathophysiology," "neoplasm," "epidemiology/etiology," "mental disorders, " "energy metabolism, " and "gene expr ession." Additional articles were identified by manual review of the refer ences cited in these publications; others wer e supplied by experts in the field who contributed to this report (see Acknowledgement). Results. Biological adaptation to the sun has evolved over billions of years. The power to artificially override the natural cycle of light and dark is a recent event and repr esents a man-ma de self-experiment on the effects of exposure to increasingly bright light during the night as human societies acquir e technology and expand industry. In addition to resetting the circadian pacema ker, light also stimulates additional neuroendocrine and neurobeha vioral responses including suppression of melatonin release from t he pineal gland impr oving alertness and perfor mance. Low levels of illuminance in the blue or white fluor escent spectrum disrupt melatonin secr etion. The primary human concer ns with nighttime lighting include disability glare (which affects driving and p edestrian safety) and various hea lth effects. Among the latter are potential carcinogenic effects related to melatonin suppression, especially breast cancer. Other diseases that ma y be exacerbated by circadian disruption include obesity, diabetes, depr es sion and mood disorders, and reproductive problems. Conclusion. The natural 24-hour cycle of light and dark helps maintain precise alignment of circadian biological rhythms, the general activation of the central nervous system and various biological and cellular processes, and entrainment of melatonin release from the pinea l gland. Pervasive use of nighttime lighting disrupts these endogenous processes and creates potentially harmful hea lth effects and/or hazardous situations with varying degr ees of har m. The latter includes the generation of glare from roadway, property, and other artificial lighting sources that can create unsafe driving conditions, especially for older drivers. More direct health effects of nighttime lighting may be attributable to disruption of the sleep-wake cycle and suppression of melatonin release. Even low intensity nighttime light has the capability of suppressing melatonin release. In various laboratory models of cancer, melatonin serves as a circulating anticancer signal and suppresses tumor growth. Limited epidemiological studies support the hypothesis that nighttime lighting and/or repetitive disruption of circadian rhythms incr eases cancer risk; most attention in this arena has been devoted to breast cancer . Further in formation is required to Action of the AMA House of Delegates 2012 Annual Meeting: Council on Science and Public Hea lth Report 4 Recommendations Adopted as Amended, and Remainder of Report filed.


CSAPH Rep. 4-A-12 -- page 2 of 25 evaluate the relative role of sleep versus the period of darkness in certain diseases or on mediators of certain chronic diseases or conditions including obesity. Due to the nearly ubiquitous exposure to light at inappropriate times relative to endogenous circadian rhythms, a need exists for further multidisciplinary research on occupational and environmental exposur e to light -at-night, the risk of cancer, and effects on various chronic diseases


REPORT OF THE COUNCIL ON SCIENCE AND PUBLIC HEALTH CSAPH Report 4-A-12

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INTRODUCTION Current AMA Policy H-135.937 (AMA Policy Database) advocates for light pollution control and reduced glare from (electric) artifical light sources to both protect public safety and conser ve ener gy. Lighting the night has become a necessity in many areas of the world to enhance commerce, promote social activity, and enha nce public safety. However, an emer ging consensus has come to acknowledge the effects of widespr ead nighttime artificial lighting, including the: 1) impact of artificial lighting on human health, primarily through disruption of circadian biological rhythms or sleep; 2) intersection of ocular physiology, vehicle headla mps, nighttime lighting schemes, and harmful glare; 3) energy cost of wasted and unnecessary electric light; and 4) impact of novel light at night on wildlife and vegetation. In addition to these health and environmental effects, an esthetic deficit is apparent with the progr essive loss of the starry night sky and interference with astronomical observations. With the assistance of experts in the field, this report evaluates the effects of pervasive nighttime lighting on huma n hea lth and perfor mance. Concerns related to ener gy cost, effects on wildlife and vegetation, and esthetics are also briefly noted. METHODS English-language r eports in huma ns wer e selected from a PubMed search of the literature from 1995 to March 2012 using the MeSH ter ms "circadian/biological clocks/rhythm, " "chronobiology/disorders," "photoper iod," "light/lighting" "sleep," "work schedule," or "adaptation," combined with the ter ms "physiology," "melatonin," "adverse effects/toxicity," "pathophysiology," "neoplasm," "epidemiology/etiology," "mental disorders," "energy metabolism," and "gene expr ession." Additional articles wer e identified by manual review of the refer ences cited in these publications; others wer e supplied by experts in the field who contributed to this report (see Acknowledgement). LIGHT AND HUMAN PHYSIOLOGY The solar cycle of light and dark provides the essential basis for life on Earth. Adaptation to the solar cycle has resulted in funda mental molecular and genetic endogenous processes in virtually all life for ms that are aligned with an approximately 24-hour period (circadian biological rhythm). The circadia n genetic clock mechanism is intimately involved in many, if not most , facets of cellular and or ganismal function.1 Although the circadian system spontaneously generates near -24hour rhythms, this master clock must be reset daily by the light-dark cycle to maintain proper temporal alignment with the environment. In huma ns and other ma mmals, this daily entrainment is achieved primarily by novel photor eceptors that project dir ectly to the site of the circadian clock (suprachiasmatic nuclei (SCN) of the hypothala mus).2-5 The tandem development of an endogenous rhythm sensitive to light presumably evolved to allow for precise 24-hour regulation of rest and activity, and for adapting to seasonal changes in night -length, while ma intaining the advantages of an under lying physiology that anticipates da y and night. Understanding the molecular and Action of the AMA House of Delegates 2012 Annual Meeting: Council on Science and Public Hea lth Report 4 Recommendations Adopted as Amended, and Remainder of Report filed.


CSAPH Rep. 4-A-12 -- page 2 of 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 physiological basis of endogenous rhythms, how light infor mation is communicated, and the health implications of disruptions to this system are topics of intensive study. ELECTRIC LIGHTING AND HUMAN HEALTH Biological adaptation to the sun has evolved over billions of years. The power to artificially override the natural cycle of light and dark is a recent event and represents a man-ma de selfexperiment on the effects of exposure to incr easingly bright light during the night as human societies acquir e technology and expand industry. At the sa me time, increasing numbers of people work inside buildings under electric lighting both night and day. Artificial lighting is substantially dimmer than sunlight and provides a ver y differ ent spectral irradiance. Sunlight is strong at all visible wavelengths, peaking in the yellow region, whereas electric lighting has either extreme characteristic wavelength peaks (fluor escent) or exhibits a monotonic increase in irradiance as wavelength lengthens (incandescent). In contrast to outdoor lighting conditions, much of the moder n world now lives and works in relatively dim light throughout the day in isolation from the sun, with often poor contrast between night and da y, even for those who live and work in sunny environments.6 Extensive nighttime lighting is requir ed for contemporary society and commerce. Ther efore, it is imperative to evaluate the unintended adverse hea lth consequences of electric lighting practices in the huma n environment, and deter mine their physiological bases so that effective inter ventions can be developed to mitigate harmful effects of suboptima l light exposure. For exa mple, engineers have alr eady developed less disruptive night lighting technologies, and continued progr ess in this area is anticipated. That such technologies exist, however, does not guarantee that they will be purchased, installed and properly implemented. The medical community and public can take the lead on advocating a healthier environment, as illustrated by recent changes in public smoking policies worldwide. As the research on the biology of circadian rhythms has advanced, the range of potential disease connections due to disrupted circadian rhythms and sleep has expanded. Biological Impact of Light on Human Physiology Light is the most powerful stimulus for regulating human circadia n rhythms and is the ma jor environmental time cue for synchronizing the circadian clock. In addition to resetting the circadian pacema ker, light also stimulates additional neuroendocrine and neurobeha vioral responses , including suppression of melatonin release from the pineal gland, dir ectly alerting the brain, and improving alertness and perfor ma nce.7-9 Melatonin is one of the most studied biomarkers of the huma n physiological response to light.10 This substance is the biochemical correlate of darkness and is only produced at night, regardless of whether an organ ism is day-active (diurnal) or nightactive (nocturnal). Conceptually, melatonin provides an internal repr esentation of the environmental photoperiod, specifically night-length. The synthesis and timing of melatonin production requir es an affer ent signal from the SCN. Ablation of this pathway, which occurs in some patients from upper cervica l spinal da mage, completely abolishes melatonin production. Certain other circadian rhythms (e.g., cortisol, body temperature, sleep-wake cycles) do not depend on this pathway and persist if the SCN pathway is damaged. Light is not requir ed to generate circadia n rhythms or pineal melatonin production. In the absence of a light-dark cycle (e. g., totally blind individuals), the circadian pacema ker generates rhythms close to, but not exactly a 24-hour periodicity, reflecting the timing of processes under SCN control.2 However, as previously noted, the timing of SCN rhythms and consequently the rhythms controlled by the circadian clock are affected by light, and requir e daily exposure to the light-dark cycle to be synchronized with the 24-hour day.


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When light infor mation fails to reach the SCN to synchronize the clock and its outputs, the pacema ker reverts to its endogenous non-24-hour period (range 23.7-25.0 h). Consequently, the timing of physiology and behavior that is controlled by the circadian system, for exa mple the sleep wake cycle, alertness and perfor mance patterns, the core body temperature rhythm, and melatonin and cortisol production, becomes desynchronized from the 24-hour day.2 The resultant clinical disor der is ter med "non-24-hour sleep-wake disorder" and is characterized by alter nating episodes of restful sleep, followed by poor night-time sleep and excessive day-time napping, as the non-24hour circadian pacema ker cycles in and out of phase with the 24-hour social da y.11 Another effect of light exposur e at night is the immediate suppression of melatonin production. Under natural conditions, organisms would never be exposed to light during the night i n substantial amounts and would not exper ience melatonin suppression. Electric light, however, efficiently suppresses melatonin at intensities commonly exper ienced in the home at night. 12 Measures of Illumination Luminous flux is the measur e of the per ceived power of light. The lumen is the standard international unit of luminous flux, a measure of the total "amount" of visible light emitted by a source, while illumination is a measure of how much luminous flux is spread over a given area (intensity of illumination). One lux is equal to one lumen/m2. Luminous flux measurements take into account the fact that the huma n eye and visual system is mor e sensitive to some wa velengths than others. The peak luminosity function is in the green spectral region; white light sources produce far fewer lumens. To provide some perspective, the illuminance associated with a full moon is less than 1 lux, versus 50 lux for a typically incandescent lit family room, 80 lux in a narrower hallway, 325-500 lux for office lighting, 1,000 lux for an overcast day, and 32,000130,000 lux for dir ect sunlight. Initially it was thought that bright light of at least 2,500-20,000 lux was needed to suppress nighttime melatonin secr etion or phase shift the melatonin rhythm (as in jet lag) in huma ns.13-15 It is now established that when exposur e of the huma n eye is carefully controlled, illuminance as low as 5-17 lux of monochromatic gr een light or 100 lux of broadband white light can significantly suppress melatonin in nor mal huma n volunteers.12,16-18 Similarly, circadian phase shifts of the melatonin rhythm can be evoked with an illuminance of 5 lux of monochr omatic blue light or <100 lux of white fluorescent light, however, exposure to red light is not disruptive.18,19 Typical lighting in bedrooms in the evening after dusk (but befor e bedtime) can also suppress melatonin and delay its nocturnal surge.12 Acute enhancement of both subjective and objective measures of alertness can be evoked with as little as 5 lux of monochromatic blue light.20 Dose-r esponse curves for melatonin suppression by night-time light exposure to fluorescent light show that ~100 lux of light induces 50% of the maximal response obser ved with 1,000-10,000 lux of light.18,21 Ocular Physiology Mediating Photic Effects Factors that alter the a mount and spectral quality of light reaching the retina include gaze beha vior relative to a light source, age (of the ocular lens), and pupillary dilation. Once a light stimulus reaches the r etina, physiology within the retina and within the ner vous system deter mines the capacity of the stimulus to evoke circadian, neuroendocrine or neurobehavioral responses. This physiology includes: 1) the sensitivity of the operative photopigments and photoreceptors ; 2) location of thes e photoreceptors within the r etina ; 3) the ability of the ner vous system to integrate photic stimuli spatially and temporally; and, 4) the state of photor eceptor adaptation. In particular, both short and long-ter m photor eceptor adaptation can significantly modify the biological and behavioral responses to light and acutely suppress melatonin in huma ns. 22 For


CSAPH Rep. 4-A-12 -- page 4 of 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 exa mple, a full week of daytime exposure to bright light (by daylight and/or indoor light boxes at ~ 5,000 lux) or a three-day period of exposure to moderate indoor lighting (200 lux) reduces an individual's sensitivity to light suppression of nighttime melatonin compared with exposure to dim indoor lighting (0.5 lux); similar dim light conditions also enha nce circadia n phase shifting.23-25 Two hours of exposur e to 18 lux of white incandescent light versus full dark exposure in a single evening modifies the sensitivity of an individual for light-induced melatonin suppression later that same night.26 Hence, photoreceptor adaptation, like the other ocu lar and neural elements noted above, can significantly modify the biological and behavioral responses to light .16 In general, photobiological responses to light are not all -or-none phenomena. In the case of acutely suppressing high nighttime levels of melatonin or phase-shifting the entir e melatonin rhythm, light works in a dose-response fashion. Once thr eshold is exceeded, incr easing irradiances of light elicit incr easing acute plasma melatonin suppression or longer -term phase-shifts of the melatonin rhythm in healthy individuals.16,18,27 All huma ns, however, are not equally sensitive to light ; significant individual differ ences exist in sensitivity to light for both neuroendocrine and circadian regulation.16,18 For a detailed description of the molecular and cellular basis for how photor eceptive input regulates circadian and neur oendocrine system function, see the Addendum. HUMAN CONCERNS-DISABILITY AND DISCOMFORT GLARE Glare from nighttime lighting can cr eate hazards ranging from discomfort to fra nk visual disability. Disability glare has been fairly well-defined based on the physiology of the huma n eye and behavior of light as it enters the ocular media. Discomfort glare is less well-defined and more subjective as it is not based on a physical response per se but rather a psychological response. Accordingly, the respective bases of (and research into) these two responses are funda mentally differ ent. Disability Glare Disability glare is unwanted and poorly dir ected light that temporarily blinds, causes poor vision by decreasing contrast, and creates an unsafe viewing condition, especially at night , by limiting the ability of the person to see. Ther e are natural causes of disability glare, such as solar glare at sunset on a dirty windshield which can be lessened by clea ning the windshield. Unfortunately, nighttime glare while driving is not easily remedied. It is caused by the misapplication of lumina ires that comprise the lighting design which are generally overly bright and unshielded, and/or sources of poorly directed light that enter s the eye and scatters among ocular structures resulting in diminished contrast and impeded vision. Such effects dramatically worsen as the huma n eye ages, contributing to poor night vision and difficulty in driving at night for older drivers. Disability glare is caused by light scatter from ocular media.28 As light enters the eye, it collides with cornea, lens, and vitreous humor , scattering photons and casting a veil of light across the retina29-31 (see Figur e 1). The veil of light reduces the contrast of the object that the driver is trying to see, ha ving the sa me effect as incr easing the background luminance of the object. This veiling light is repr esented by the ter m veiling luminance. Veiling luminance is dir ectly related to the illumina nce of the light source and inversely related to the square of the angle of eccentricity of the light source with an age dependent multiplier across the entir e equation. 28 This means that the disability from a light source is lessened the farther the source is from the line of sight.



As an example, high mast lighting systems where the roadwa y lighting is over 100 feet in the air have significantly less glare than traditional systems, which are typically located 30-50 feet in the air. Because of


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Accordingly, proper design techniques and consideration for the glare caused by lighting systems need to be consider ed. One of the primary difficulties, especia lly for roadways, is that the lighting is not governed by a single jurisdiction. Roadway lighting may be designed properly and provide a low level of glare; however lighting can ema nate from adjacent properties, spilling out into the roadway thus affecting the driver and overall perfor mance and suitability of a lighting system. Control over all environmental sources of nighttime lighting is ther efor e critical for the overall control of disability glare. Discomfort Glare Discomfort glare is less well defined but ema nates from a glare source that causes the observer to feel uncomfortable. The definition of discomfort is not precise, and some r esearch has shown that a person's response to a glare source is based more on his/her emotional state than on the light source itself. Discomfort glare may be based primarily on the observer's light adaptation level, the size, number, luminance and location of the light sources in the scene. 32 Both over hea d roadwa y lighting and opposing hea dla mps are involved with discomfort glare in the driver. A numerica l rating scale based on the dyna mic nature of glare in simulations is available to measur e the discomfort level exper ienced by drivers (Appendix).33 The overall impact of discomfort glare on fatigue and driver safety rema ins an issue. Lighting and Glare. Both discomfort and disability glare have specific impacts on the user in the nighttime environment. Research has shown that both of these glare effects occur simultaneously. Research also shows that the effects of the glare are cumulative, meaning that the glare from two light sources is the sum of the glare from the individual light sources. As a result, every light source within the field of view has an impact on the comfort and visual capability of the driver. Overhead lighting For overhea d roadway lighting, design standards include a metho dology for controlling the disability glare through a ratio of the eye adaptation lumina nce to the veiling luminance caused by the light source. As the veiling lumina nce is related to the illuminance the light source produces at the eye, a roadwa y luminair e that directs light horizontally has a much greater effect on the driver than a light source that cuts off the horizontal light. A trend towards flat glass luminair es, which provide a cut off of light at horizontal angles, provides a lower level of both disability and discomfort glare. Decorative luminair es (e.g., acorn or drop lens) ha ve a high level of are used in areas where pedestrians are the primary roadway users. situation is useful for facial recognition of a pedestrian, but it limits other objects in the roadway. As a result, many cities are designing systems, one for the pedestrian and one for the roadway. horizontal light and typically The horizontal light in this the driver's ability to perceive and installing two lighting

Luminair es employing solid state technologies and light-emitting diodes (LED) provide light from an array of small sources rather than a single large source. These designs either rely on each sma ll source to provide a component of the light distribution, or the components of the lighting array provide individual luminating fields of the light distribution. In the first instance, the arrays are
the inverse squared relationship, a high mast system reduces glare by 75% compared with a traditional system.


CSAPH Rep. 4-A-12 -- page 6 of 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 typically flat and have an optic to provide the light distribution; if a single LED fails, the other s still provide the light distribution. In the second method, the components of the array are aimed to differ ent areas of the bea m distribution. This approach typically results in light aimed at the driver and pedestrians causing a higher glare impact. The other issue with the mu ltiple sources used in LED lumina ires is that each of the sources typically has a very high luminance itself as the source is very small and ver y bright; in the absence of sufficient diffusion, they cause significant glare. Accordingly, solid state lighting systems typically ha ve a higher glare impact than traditional sources. The final issue with glare from overhea d lighting is course along a roadway, they pass from one lumina as they approach the luminaire and then diminishes issue for disability glare, this repetitive process can Opposing vehicle hea dla mps Vehicle headla mps are aimed at the opposing driver eye level resulting in ver y high ocular illumina nce and significant disability glare. The impact of opposing hea dla mps on the ability of the oncoming driver to observe beyond the headla mps is significant. For example, the visibility of a pedestrian standing behind a vehicle ca n be reduced by as much as 50%.35 In order to minimize the glare impact, headla mps are designed with lower left side light intensity than the right side. This reduces the glare to an opposing vehicle but does not eliminate it. New technologies such as turning headla mps and hea dla mps that hide part of the headla mp bea m when a vehicle passes are possible solutions for this issue. With the advent of high intensity discharge Xenon headla mps and LED-based technologies, the gla re issue has become mor e serious. While the intensity towards a driver is limited, the small but brighter source generates a much higher impr ession of glare than traditional technologies. These "blue" headla mp sources have a higher complaint rate for glare tha n for any other light source. Effects of Lighting Design on Traffic Accidents Adult, and especially elderly drivers, experience incr eased glare sensitivity, and elderly drivers ma y not be able to sufficiently fulfill the criteria for night driving ability because of contrast and glare sensitivity.36 Prospective studies indicate that r eduction in the useful field of view, visual field loss, and glare sensitivity incr ease crash risk in older drivers.37,38 Crash risk begins to increase around age 50 years of age and continues to increase with aging.39 No studies have explicitly compared traffic accident rates under different highway lighting conditions. HEALTH EFFECTS OF DISRUPTED CIRCADIAN RHYTHMS Epidemiological studies are a critical component of the evidence base requir ed to assess whether or not light exposure at night affects disease risk, including cancer. These studies, however, are necessarily observational and can rarely provide mechanistic understanding of the associations observed. Carefully designed and controlled basic laboratory studies in experimental anima l models have the potential to provide the empiric support for a causal nexus between light exposure at night and biological/health effects and to help establish plausible mecha nisms. One area of considerable study on the possible effects of nighttime light exposure involves cancer. CANCER th e cyclic nature of the impact. As drivers ire to another. The glare experience increases as they pass beyond. While typically not an cause discomfort and fatigu e. 34


CSAPH Rep. 4-A-12 -- page 7 of 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Light at Night, Melatonin and Circadian Influences on Carcinogenesis Experimental Evidence. The majority of earlier studies in exper imental models of either spontaneous or chemically-induced ma mmary carcinogenesis in mice and rats demonstrated an accelerated onset of ma mmary tumor development accompa nied by incr eased tumor incidence and number in animals exposed to constant br ight fluor escent light during the night as compared with control anima ls maintained on a strict 12 hours light/12 hours dark cycle.40-51 More recent work has focused on the ability of light at night to promote the growth progression and metabolism in huma n breast cancer xenografts. Nocturnal melatonin suppresses the growth of both estrogen receptor negative (ER-) and estrogen r eceptor positive (ER+) huma n breast cancer xenografts; the essential polyunsaturated fatty acid, linoleic acid is necessary for the growth of such (ER-) tumors, and its metabolism can be used as a biomarker of cellular growth.52-55 Exposure of rats with such cancer xenografts to incr easing intensities of white, fluor escent polychr omatic light during the 12 hour dark phase of each daily cycle r esults in a dose-dependent suppression of peak nocturnal serum melatonin levels and a corresponding marked increase in tumor metabolism of linoleic acid and the rate of tumor growth. Exposure to even the very dimmest intensity of light during the night (0.2 lux) suppressed the nocturnal pea k of circulating melatonin by 65% and was associated with marked stimulation in the rates of tumor growth and linoleic acid metabolic activity. In this model, measurable effects on xenograft growth and linoleic acid metabolism wer e apparent with 15% suppression in nocturnal melatonin levels. The ability of light exposur e at night to stimulate tumor growth (including dim exposur es) has been replicated in rat hepatoma models.54,56-58 The reverse also is true; gradually restoring circulating melatonin by reducing initial exposur e to light at night (24.5 lux) is accompanied by a marked reduction in tumor growth and linoleic acid metabolic activity to baseline rates in the breast cancer and hepatoma models.59 The important role of melatonin as a nocturnal antica ncer signa l is further supported by the growth responses of huma n breast cancer xenografts perfused with huma n whole blood collected from young, healthy premenopausal fema le subjects exposed to complete darkness at night (e.g., high melatonin), compared with xenografts that wer e perfused with blood collected from the sa me subjects during the daytime (e. g., low melatonin).54 The growth of xenografts perfused with blood collected during the dark was markedly reduced. Addition of a physiological nocturnal concentration of melatonin to blood collected from light-treated subjects restor ed the tumor inhibitory activity to a level comparable to that observed in the melatonin-rich blood collected at night during total darkness. Moreover, the addition of a melatonin receptor antagonist to the blood collected during darkness (i. e., high melatonin) eliminated the ability of the blood to inhibit the growth and metabolic activity of