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National Toxicology Program. NTP Cancer Hazard Assessment Report on Night Shift Work and Light at Night. Research Triangle Park (NC): National Toxicology Program; 2021 Apr.
The invention of the electric light in the late 1800s resulted in a change in the lighted environment as industrialized and developing societies switched from a sun-based system, supplemented by fire/candle light and gas lamps, to an electricity-based system (Stevens and Rea 2001). Furthermore, technological advances in the 20th and 21st centuries have added other sources of light exposure, including television, computers, cell phones, and other electronic devices. The United Nations proclaimed 2015 the International Year of Light and Light-Based Technologies in recognition of how light “has revolutionized medicine, opened up international communication via the Internet, and continues to be central to linking cultural, economic, and political aspects of the global economy” (UNESCO 2015). In conjunction with these advances, modern electric lighting practices and electronic devices (1) have led to ill-timed, unnatural exposure to light resulting from too little exposure to daylight together with too much exposure to electrical light at night (LAN) and (2) have enabled a dramatic shift in daily activity (including work, play, meal times) and sleep patterns compared to the typical patterns prior to the introduction of electricity. These changes are associated with disruption of the circadian system and potential adverse health effects, including certain cancers (Lunn et al. 2017). In 2016, the American Medical Association Council on Science and Public Health (AMA 2016) noted that the organization supported conversion of community (i.e., primarily street) lighting to light-emitting diodes (LEDs) because of the associated savings in energy, but they recommended that communities consider potential impacts of conversion on human health, including potential melatonin suppression.
The objective of this cancer hazard assessment is to evaluate the relationship between two exposures related to modern electric lighting practices — LAN and night shift work — and cancer. In order to understand the relationship between exposure to ill-timed, unnatural light and adverse biological effects or outcomes, this section presents a brief introduction to circadian regulation and disruption (Section 1.1). It also provides information on the sources and extent of exposure to LAN (Section 1.2), jet lag and social jet lag (Section 1.3), and night shift work (Section 1.4) among U.S. residents. These topics provide a foundation for understanding the relationship between exposures related to modern electric lighting practices (LAN and night shift work) and (1) circadian disruption (Section 2), (2) human cancer (Sections 3 and 4), and (3) cancer in experimental animals (Section 5), as well as potential mechanisms of carcinogenicity of LAN and night shift work, which are thought to be mediated by circadian disruption (Section 6).
1.1. Circadian timing system and its disruption
Virtually all forms of life, from cyanobacteria to humans, exhibit daily oscillations or rhythms of physiological and behavioral processes, and almost all cells in the body contain a molecular circadian clock that regulates the timing of cellular functions, gene expression, and signaling pathways (Arellanes-Licea et al. 2014, Stevens et al. 2014, Turek 2016). Circadian timing systems in all life forms have in common three core characteristics: (1) an endogenous and self-sustaining ~24-hour physiological oscillator, (2) an input mechanism to signal environmental time of day, and (3) an output mechanism to synchronize circadian-controlled behavior, physiology, and metabolism (Lowrey and Takahashi 2004, Stevens et al. 2014, Kiss and Ghosh 2016). These characteristics are illustrated in Figure 1-1. Some of the critical components and factors for maintaining robust circadian rhythms include the daily light-dark cycle, the master circadian clock in the suprachiasmatic nucleus (SCN), clock genes in the SCN and peripheral tissues, neural and neuroendocrine output signals from the SCN, body temperature, feeding-fasting cycles, and sleep-activity patterns (Takahashi et al. 2008, Dibner et al. 2010, Honma 2018). These are briefly discussed below.
Figure 1-1
Regulation of the circadian timing system by internal and external cues. The master circadian clock found in the suprachiasmatic nucleus (SCN) of the brain receives information about the daily light cycle via the retinohypothalamic tract (RHT). The SCN (more...)
As illustrated in Figure 1-1, the circadian timing system is organized in a hierarchical manner consisting of a master oscillator, the bilaterally paired SCN in the anterior hypothalamus (located just above the optic chiasm), and downstream peripheral oscillators in the brain and other tissues (Lunn et al. 2017, Honma 2018). In humans, the SCN maintains a self-sustaining, free-running period, in the absence of any environmental cues, that is slightly longer than 24 hours; however, environmental cues reset and resynchronize the SCN each day to maintain synchrony among behavioral, physiological, and environmental rhythms (Buhr and Takahashi 2013, Figueiro 2017).
The term zeitgeber (German word for time giver) is used in circadian biology to describe any daily environmental cue that synchronizes or entrains the circadian timing system (Lowrey and Takahashi 2004). The light-dark cycle is the primary zeitgeber that synchronizes and resets the SCN to the 24-hour solar day. Input from the light-dark cycle is received by specialized non-visual photoreceptors called intrinsically photosensitive retinal ganglion cells that are anatomically and functionally distinct from the rods and cones used for vision, which play a comparatively minor role in light detection for the circadian system (Berson et al. 2002, Hattar et al. 2002, Schmidt et al. 2011, Figueiro 2017). The non-visual photoreceptors are spread across the retina and transmit photic information to the SCN regarding both time of day (i.e., day versus night) and season (i.e., duration of night) via the retinohypothalamic tract (Takahashi et al. 2008, Lowrey and Takahashi 2011, Stevens et al. 2014). Thus, the natural 24-hour light-dark cycle provides necessary temporal cues to the SCN to achieve and maintain internal synchronization of the period (τ) and phasing (φ) of the circadian time structure to support activity during the day and restoration and repair during sleep at night in humans and other diurnal species (Smolensky et al. 2015).
A fundamental difference between the central clock and peripheral clocks lies in their susceptibility to various synchronization pathways or entrainment signals (Brown and Azzi 2013, Schibler et al. 2015). Whereas the SCN primarily responds to light and is largely insensitive to its own output signals, peripheral clocks respond to a complex network of SCN-driven timing signals. Phase information transmitted from the SCN to the rest of the brain and body allows organisms to control proper timing of diverse behavioral and physiological functions including hormone release, sleep-wake cycles, feeding-fasting schedules, thermoregulation, and metabolism in anticipation of cyclic changes in their environment (Takahashi et al. 2008, Mohawk et al. 2012, Buhr and Takahashi 2013).
Although the mechanisms are not fully understood, the SCN synchronizes cellular oscillators or clocks in the brain and peripheral organs and tissues by directly relaying temporal information via autonomic innervation, and indirectly through neuroendocrine signals (e.g., glucocorticoids from the adrenal gland, melatonin from the pineal gland) and activity-directed signals (Balsalobre et al. 2000, Mohawk et al. 2012, Brown and Azzi 2013, Honma 2018). Activity-directed timing cues for peripheral tissues, including food intake and body temperature, are also important (Buhr et al. 2010, Asher and Sassone-Corsi 2015, Wehrens et al. 2017). In particular, feeding-fasting rhythms are recognized as a dominant zeitgeber for most peripheral clocks (Schibler et al. 2015). There is also evidence that local cellular signaling pathways can affect peripheral clocks and gene expression patterns independently from the SCN (Mohawk et al. 2012, Husse et al. 2015). Although each cell is governed by its own independent clock, these clocks are coupled together to maintain a single rhythm within the tissue, and the hierarchical architecture allows peripheral functions to maintain coordination via cues from the SCN (Dibner et al. 2010, Honma 2018). Thus, peripheral clocks are entrained by multiple and redundant direct and indirect signaling pathways (Brown and Azzi 2013).
The following sections briefly discuss the roles of endocrine signals (melatonin from the pineal gland and glucocorticoids/cortisol from the adrenal gland) and the genetic clock in maintaining circadian rhythms. This is followed by a brief discussion of circadian disruption and exposures that contribute to circadian disruption.
1.1.1. Role of melatonin and glucocorticoids
The SCN conveys timing cues to the pineal gland and adrenal glands via the paraventricular nucleus of the hypothalamus (an important control center of the autonomic nervous system) (Takahashi et al. 2008). The pineal gland produces melatonin while the adrenal gland releases glucocorticoids (cortisol in humans and corticosterone in rodents) (Sollars and Pickard 2015). Both melatonin and glucocorticoids exhibit robust circadian rhythms in humans and laboratory rodents and exert receptor-mediated effects in peripheral tissues. However, some strains of mice (e.g., C57BL/6) produce low levels of melatonin due to a spontaneous mutation in a gene encoding a key enzyme in the melatonin biosynthesis pathway (Pfeffer et al. 2018). Studies using melatonin-deficient strains show that altered light-dark cycles can disrupt the circadian timing system in the absence of a “normal” melatonin secretion pattern and that circadian disruption can affect carcinogenic pathways without causing melatonin suppression or disrupting melatonin rhythms (Filipski et al. 2002, Filipski et al. 2005, Mteyrek et al. 2016). The studies show that melatonin is not the only output signal of the SCN to peripheral tissues and that there are multiple mechanisms and pathways that contribute to internal and external synchronization (Schibler et al. 2015, Pfeffer et al. 2018). Balsalobre et al. (2000) also demonstrated that glucocorticoids were not the only signal involved in resetting the phase of peripheral clocks as mutant mice lacking glucocorticoid receptors in the liver still expressed genes in a circadian manner in this organ.
Melatonin and melatonin-binding receptors. Melatonin (N-acetyl-5-methoxytryptamine) is a tryptophan derivative that is primarily synthesized in the pineal gland, a small endocrine gland located near the center of the brain, that serves as both an output and input factor to the circadian system (Chowdhury et al. 2008, Hardeland 2013). The SCN transfers circadian signals to the pineal gland via a neural pathway, thus driving the rhythmic synthesis of melatonin (i.e., low during the day and high during the night) regardless of whether the animal is diurnal or nocturnal. Melatonin also provides input to the SCN and peripheral clocks and thus functions as an internal synchronizer of circadian rhythms (Figueiro 2017). Although melatonin is primarily produced in the pineal gland, it is also produced in other tissues such as the gastrointestinal tract, skin, retina, and bone marrow (Chowdhury et al. 2008, Slominski et al. 2008, Talib 2018). However, extra-pineal production of melatonin functions locally as an autocrine or paracrine signal and is not released to the blood in significant amounts (Srinivasan et al. 2008).
Three melatonin-binding receptor subtypes have been identified in vertebrates. These include two membrane G protein-coupled receptors (MT1, MT2) that have been identified in all vertebrates so far investigated, and one cytosolic receptor (MT3) that has been found only in non-mammalian species (Reiter et al. 2014, Trivedi and Kumar 2014). Although melatonin does not directly bind to nuclear receptors, it may carry out some of its functions by indirectly stimulating nuclear receptor (e.g., RORα, RORγ) gene transcription, modulating translation/processing, or by interacting with ROR proteins (Slominski et al. 2016). MT1 and MT2 are expressed in most cells in peripheral, immune system, and central nervous system tissues (Giannoulia-Karantana et al. 2006, Hardeland 2013, Reiter et al. 2014). However, as a small lipophilic molecule, melatonin can also enter cells directly (Haus and Smolensky 2013, Reiter et al. 2014). Thus, melatonin has numerous receptor-mediated, as well as receptor-independent, actions and plays an important chronobiological role by directing the temporal organization of almost all organs (without necessarily involving feedback to the SCN), regulating expression of circadian oscillator genes (core clock genes) in central and peripheral tissues, steering expression of melatonin-regulated genes not controlled by self-sustained oscillators, and modulating the secretion of other hormones (e.g., growth hormone, pituitary gonadotropins, adrenocorticotropins, estrogen, glucocorticoids, etc.) (Chowdhury et al. 2008, Slominski et al. 2012, Reiter et al. 2014, Smolensky et al. 2015). Melatonin is also a biomarker of circadian regulation.
Glucocorticoids and glucocorticoid receptors. Glucocorticoids are secreted by the adrenal glands and are regulated by the SCN via the hypothalamic-pituitary-adrenal axis (Faraut et al. 2013, Sollars and Pickard 2015). Glucocorticoid receptors are expressed in most peripheral cell types, but not in the SCN (Brown and Azzi 2013). Thus, glucocorticoid rhythms are potent transcriptional regulators that play an important role in synchronizing peripheral clocks (Sollars and Pickard 2015). A study using the glucocorticoid analog dexamethasone demonstrated that glucocorticoids efficiently synchronized the phase of circadian gene expression in cultured rat fibroblasts and transiently reset the phase of circadian gene expression in peripheral tissues (liver, kidney, and heart) in vivo but not in the SCN (Balsalobre et al. 2000).
1.1.2. Clock genes and circadian rhythms
The clock mechanism in the SCN and the peripheral oscillators are similar at the molecular level and involve a small number of core clock genes (Table 1-1) that generate circadian oscillations in cell-autonomous transcriptional-translational feedback loops (Figure 1-2) (Kettner et al. 2014). The core clock genes are defined as those whose protein products are essential for the generation and regulation of circadian rhythms (Ko and Takahashi 2006). The driving elements of the primary feedback loop include the transcription factors circadian locomotor output cycles kaput (CLOCK) or its homologue — neuronal PAS domain protein 2 (NPAS2) — and brain and muscle aryl hydrocarbon receptor nuclear translocator [ARNT]-like (BMAL1) (Ko and Takahashi 2006, Haus and Smolensky 2013). During the day, the transcription factors CLOCK/NPAS2 and BMAL1 combine to form a heterodimer that binds to E-box regulatory elements in target promoter regions and initiates transcription of Period (Per1, Per2, and Per3), Cryptochrome (Cry1 and Cry2), and other genes. The negative feedback loop component occurs when PER and CRY form heterodimers and translocate back to the nucleus to repress their own transcription by inhibiting CLOCK:BMAL1 heterodimers. During the night, the PER:CRY heterodimer is degraded, thus enabling CLOCK:BMAL1 to initiate a new transcription cycle. The entire cycle is completed in approximately 24 hours (Takahashi et al. 2008). CLOCK:BMAL1 heterodimers also induce another regulatory loop by activating transcription of retinoic acid-related orphan nuclear receptors Rev-erbα and RORα which, respectively, repress and activate transcription of BMAL1. In addition, data indicate that the circadian clock is also regulated by multiple post-translational modifications including phosphorylation, ubiquitination, acetylation, and SUMOylation (Mehra et al. 2009, Hirano et al. 2016, Honma 2018). These modifications of core clock proteins affect most aspects of clock biology and interact with the molecular clock feedback loops to fine-tune the precision of the circadian clock and to enhance its stability and adaptability.
This small number of core clock genes regulates the expression of thousands of genes including cell-cycle regulation, DNA damage response, and energy metabolism cycles (Haus and Smolensky 2013, Stevens et al. 2014, Panda 2016). Estimates for the percentage of transcription regulated by clock genes range from 2% to 10% in given tissues (Haus and Smolensky 2013, Stevens et al. 2014) and up to as much as 40% to 50% in other estimates (Huisman et al. 2016, Mure et al. 2018, Ruben et al. 2018). However, the expression patterns of clock genes in peripheral tissues are tissue specific and optimized to accommodate the particular tissue’s function throughout the circadian cycle (Storch et al. 2002, Buhr and Takahashi 2013, Haus and Smolensky 2013). Further, there is considerable variation among tissues in both the genes involved as well as the timing of their activation in relation to oscillator function, and in some cases, homologous genes have different tissue-specific functions (Brown and Azzi 2013, Buhr and Takahashi 2013).
Table 1-1
Selected mammalian circadian core clock genes, gene products, and primary functions.
Figure 1-2
Core circadian machinery transcription-translation regulatory feedback loops.
1.1.3. Circadian disruption
Circadian disruption occurs when the daily circadian rhythms of some biomarkers are suppressed (Filipski et al. 2005, Filipski and Levi 2009, Filipski et al. 2009) or are no longer coordinated with each other or the 24-hour day and can be defined as internally or externally induced, acute or chronic temporal disorganization including, but not limited to, misalignment of the time structure in living systems potentially leading to adverse health outcomes (Lunn et al. 2017). Several exposure circumstances can cause circadian disruption such as excessive exposure to LAN, certain practices of night shift work (permanent or rotating shifts involving night work), transmeridian travel or a misalignment between social demands and biological time (i.e., social jet lag), and sleep deprivation (Zubidat and Haim 2017).
Exposure to light can affect the circadian system by changing the levels and timing of nighttime melatonin production and by inducing phase shifts (advances or delays) in melatonin or other rhythms. Phase advances (e.g., shortening the period of endogenous rhythms or day) in circadian rhythms occur when people are exposed to light in the latter part of the biological night (when people typically are asleep), travel east across several time zones, or work on a schedule that rotates backwards from night to evening to day shift. Conversely, phase delays in circadian rhythms (e.g., lengthening the period of endogenous rhythms or day) occur when people are exposed to light in the early part of the evening, travel west across several time zones, or work on a schedule that rotates forwards from day to evening to night shift (Stevens et al. 2011). Shift workers are slow to adapt (or may never adapt) to changes in light and sleep schedule. Furthermore, during the process of adapting, and during the adaptation period, endogenous rhythms are not synchronized with the external environment and/or with each other (Arendt 2010).
1.2. Light at night
Modern electric lighting practices involve exposure to ill-timed unnatural light, typically including exposure to electrical dim light during the night or day (e.g., offices and schools) and insufficient exposure to daylight. For most of human history, people were exposed to bright light from natural sources during the daytime and to a very dark environment at night, whereas modern practices have led to exposure to some level of dim light throughout the 24-hour day.
1.2.1. Characteristics and sources of light exposure
Visible light reaching the eye can be either monochromatic (light of a single wavelength or limited range of wavelengths interpreted by the human eye as a single color, such as violet, blue, green, yellow, orange, or red) or polychromatic (light composed of more than one wavelength, including white light, which includes all wavelengths of visible light from 380 to about 780 nm).
Light produced by different sources can be measured in terms of its brightness (generally expressed in units called lumen), but a more useful measurement for exposure to light is the amount of light illuminating a surface, which is measured in units of lux or lumen/m2.
Natural light, which includes all wavelengths of white light, comes directly from the sun, and can be scattered and reflected by the atmosphere, or reflected by the moon. On a clear day, the outdoor light level is about 10,000 lux, but bright sunlight can be as much as 10 times higher at 100,000 lux (NOAO 2015). The daily cycle of exposure to the blue wavelengths in the spectrum of sunlight is most important for synchronizing circadian rhythms (Smolensky et al. 2015). Natural indoor light is generally in the range of 200 lux to 400 lux while the outdoor light level for a full moon is about 0.1 lux (NOAO 2015, Lighting Research Center 2018).
Electric light can be produced by (1) incandescence (light emitted from heating of matter, e.g., a wire filament in an incandescent or halogen light bulb) or (2) luminescence (light emitted when a material absorbs energy from an external stimulus and then releases it as light; e.g., discharge, fluorescent, and light-emitting diode [LED] lamps) (Elert 2018).
Since the patenting of Edison’s incandescent light bulb in the late 19th century, primary light sources for homes and workplaces have evolved through fluorescent lights to light-emitting diodes (LEDs) and more recently to the organic LEDs (OLED) and active-matrix organic LEDs (AMOLED) used in mobile devices, laptops, and televisions (see Figure 1-3). While technological advances have generally increased the energy efficiency of lighting sources for both indoor (e.g., homes and offices) and outdoor (e.g., streets and parking lots) lighting, these light sources emit a larger proportion of total light in wavelengths perceived as blue by the human eye. The spectrum of incandescent light is similar to that of light at sunset, whereas LEDs emit a greater proportion of shorter wavelengths that is more similar to circadian light. These light sources include those used both indoors and outdoors (incandescent, fluorescent, and LED). Newer technologies such as OLEDs and AMOLEDs are not illustrated but these generally use sets of red, green, and blue pixels to produce a mixture of wavelengths that can be perceived by the human eye as white or other colors and thus would be expected to include wavelengths in the blue region of the spectrum.
Circadian light (CLA) is defined as light that impacts the circadian system, which is measured by the light that causes suppression of melatonin synthesis (see Section 2.1), and circadian stimulus (CS) is the relative effectiveness of CLA for producing melatonin suppression under specific conditions. No standardized function (i.e., sanctioned by national or international standard-setting bodies) characterizing the spectral sensitivity of the human circadian system is currently available, but circadian system spectral sensitivity functions (Gall and Bieske 2004, Andersen et al. 2012, Lucas et al. 2014) and one mathematical model have been proposed (Rea et al. 2005).
Figure 1-3
Technology advances in lighting over time have led to lighting with higher levels of short wavelengths. Panel A shows the timeline of key historical events related to the major types of electric lighting and the corresponding spectra. Panel B depicts (more...)
Methods for measuring circadian light are still being developed as this is a relatively new area for research. The traditional instrument for measuring visual light, the photometer, is designed to quantify the response of an average human observer, which is based on a peak effect around 555 nm (Thapan et al. 2001). As a result, measurement of personal circadian light exposure for epidemiological studies of circadian stimulus requires development of new instruments that can reflect the critical role that light within the blue range of the spectrum plays in circadian stimulus. One such instrument is the Daysimeter, which measures personal circadian light exposures as well as rest and activity levels (Bierman et al. 2005, Rea et al. 2005, Rea et al. 2008, Miller et al. 2010). Miller et al. (2010) have proposed use of phasor magnitude as a metric for circadian disruption with a higher value indicating greater synchrony between activity and the light-dark cycle and a lower value indicating less synchrony. Noting that currently there is no standardized model of the spectral sensitivity of the human circadian system, Lucas et al. (2014) recommended that researchers record the spectral power distributions (SPDs) of light exposures in human circadian system response experiments because the SPDs can be used with units of measurement that are currently available or developed in the future.
1.2.2. Human exposure to LAN
A significant number of people in the United States are directly exposed to ill-timed, unnatural electrical light at night from outdoor lighting, indoor lighting at home and at work, lighting from self-luminous electronic devices, and insufficient natural light during the day. Light also can enable other activities that can lead to circadian disruption, including shift work involving night shifts (see Section 1.3) and irregular sleep-wake cycles that can lead to “social jet lag.” Other disruptions of circadian rhythms result from jet lag caused by transmeridian travel across multiple time zones.
Natural light
Median exposure to daylight ≥ 1,000 lux for middle-aged adults (N = 106 study subjects recruited by random telephone dialing) in San Diego, CA was only about 58 min/day (Espiritu et al. 1994, Smolensky et al. 2015). Exposure to outdoor sunlight (5,000 to 100,000 lux) is orders of magnitude higher than exposure to indoor light. Exposure duration is higher in the summer and varies somewhat by geographical location. Median summer exposure to natural daylight ≥ 1,000 lux in different parts of the United States ranged from 2.2 hours/day (San Diego, CA) to 2.4 hours/day (Rochester, MN), and median winter exposure ranged from 0.4 hours/day (Rochester, MN) to 1.3 hours/day (San Diego, CA) (Cole et al. 1995).
Indoor light and electronic use
Indoor electrical lighting exposure is nearly ubiquitous in our society. The light level from indoor electric lights are generally in the range of 20 to 40 lux for residential incandescent/halogen lights and 100 to 200 lux for office fluorescent lights (Figueiro 2018). By comparison, natural indoor light is approximately 200 to 400 lux. The types of lighting used have changed in recent years; traditional incandescent and halogen bulbs have largely been replaced by newer types (DOE 2018, NOAO 2018). The United States Energy Information Administration’s (EIA) Commercial Buildings Energy Consumption Survey data indicated that standard fluorescent lights were used in 78% of all lighted floor space in commercial buildings (e.g., general office space, retirement homes, hospitals) in 2012, while another 13% used compact fluorescent lights (EIA 2017, 2018). Due to their increased efficiency and lower operating costs, use of LED lights for indoor commercial and residential applications (e.g., recessed downlights in offices and kitchens) is rapidly increasing; the Department of Energy (DOE) estimated that from 2014 to 2016, approximately 812 million indoor LED lighting systems have been installed (a market penetration of 12.3%) (DOE 2017, 2018). As mentioned above, these electric light sources generally have different wavelength ranges that include higher amounts of blue light. In addition to LEDs and CFLs, other sources of blue light exposure at night include video displays, which are often based on organic LEDs (OLEDs) or liquid crystal displays (LCDs) (Oh et al. 2015).
Information on normal light levels in the home and from outside light sources are limited. A pilot study by Pacific Northwest National Laboratory collected information on light levels reaching the eye (in lux) for 30 lighting professionals who reported on specific areas within their homes and on outside light visible in the interior (Miller and Kinzey 2018). The results of this study are presented in Table 1-2, with median values as well as minimum and maximum values of illuminance; the light sources associated with those levels are identified in the footnotes. The highest illuminances (347 to 485 lux) were reported for several different light sources, including LEDs, CFLs, and halogen bulbs. The level of exposure to outside light did not exceed 20 lux in this pilot study.
Table 1-2
Summary of illuminances measured at the eye in the homes of 30 lighting professionals.
Many Americans (especially adolescents and teens) use electronic devices with self-luminous displays (e.g., cell phones, computers, e-readers, or tablets) before sleeping. Findings from the 2011 Sleep in America Poll (N = 1,508 participants, ages 13 to 64 years) indicate that an estimated 90% of Americans use some type of electronic device a few nights per week within 1 hour of bedtime with 60% (regardless of age) watching television and a greater percentage of adolescents (72%) and young adults (67%) using cell phones compared to middle-aged (36%) and older adults (16%) (Gradisar et al. 2013, Smolensky et al. 2015).
Parents of newborns (0 to 6 months old) have increased exposure to LAN because they spend approximately 2 hours awake each night performing nocturnal caretaking (McBean and Montgomery-Downs 2015). The same study found that mothers of infants were exposed to estimated light intensity of 90 to 180 lux when using room level light (13.6% of the mothers) or a floor lamp (11.1%) but to less than 20 lux when using a night light (35.4%), leaving a door to another lighted room slightly open (28.3%), using a desk lamp (25.3%), or using light from electronic devices (19.2%); other sources of light were reported by less than 10% of the women. The fathers of the infants were also potentially affected by increased exposure to LAN since the authors noted that fathers provided care 29% of the time; however, no data were collected for the types of light exposure experienced by the fathers in this study.
Outdoor light
Light trespass is light being cast where it is not wanted or needed (Rensselaer Polytechnic Institute 2018), and can be made worse by lighting demands of urban development, e.g., roadways, shopping centers, stadiums, etc. (Pauley 2004, Navara and Nelson 2007). Major sources of light for these applications include halogen lamps (stadium lights), high- and low-pressure sodium lamps (street lights), metal halide lamps (street lights, parking lot lights, and stadium lights) and LED street lamps (NOAO 2018). Further, the use of LED lights outdoors is increasing rapidly; DOE estimated that from 2014 to 2016, approximately 46.1 million outdoor LED lighting systems have been installed (a market penetration of 29.7%) (DOE 2017, NOAO 2018). In 2016, satellite imaging data of the Earth at night indicated that more than 99% of the U.S. population were exposed to sky glow at night (i.e., electric sky brightness was increased at least 8% above the natural background at the zenith, which is the darkest part of the sky hemisphere) (Falchi et al. 2016). Figure 1-4 shows a map of North America’s electric sky brightness as a ratio to the natural sky brightness. The urban areas of the United States with the highest levels of sky glow are the areas in the Northeast megalopolis, including Washington, D.C., Baltimore, Philadelphia, New York, and Boston (Kane 2016). Additionally, the eastern half of the United States from approximately the midline near the eastern edge of Mexico and running north to the Canadian border shows many other intense areas of sky glow. In the Western United States, San Francisco and Los Angeles also have very high levels, but with the exception of a few major cities, the rest of the West has minimal sky glow. Sky glow describes the brightening of the sky caused by outdoor lighting and natural atmospheric and celestial factors (Rensselaer Polytechnic Institute 2018). Light trespass and sky glow are often referred to by the less specific term of “light pollution.”
Figure 1-4
Map of North America’s artificial sky brightness as a ratio to the natural sky brightness.
1.3. Shift work
1.3.1. Types of shift work
“Shift work” can be defined at the organizational or the individual worker level. For example, the International Labour Organization defines shift work as “a method of organization of working time in which workers succeed one another at the workplace so that the establishment can operate longer than the hours of work of individual workers” at different day and night hours (ILO 2004). Table 1-3 summarizes general types of shift work and related shift scheduling criteria.
At the individual level, shift work generally means any arrangement of daily working hours other than standard daylight hours (7:00 AM or 8:00 AM to 5:00 PM or 6:00 PM) such as night or evening (IARC 2010). Night shift work is typically defined as working at least 3 hours between midnight and 5:00 AM (Stevens et al. 2011). Night shift workers work only nights (i.e., permanent night shift workers) or alternate between night, day, and evening shifts (i.e., rotating night shift workers). Forward-rotating schedules are those that go from day to evening to night shifts, whereas backward-rotating schedules go from night to evening to day shifts. (IARC 2010, Stevens et al. 2011, Vermeulen 2016). Schedules can also vary in the number of consecutive days before shift changes. Schedules with increased rotation speeds (e.g., changing daily or every 2 or 3 days) vs. slower-rotating shift schedules can foster higher phase shifts and circadian disruption (Costa et al. 2010, Neil-Sztramko et al. 2014). Many different schedules are possible, but a schedule in common use for more than 20 years is a fast-rotating schedule consisting of 2 day shifts, 2 afternoon or evening shifts, 2 night shifts, and 2 days off over a period of 8 days (Costa et al. 1994, Tucker and Folkard 2012, Business Management Systems 2017). This schedule typically employs 4 teams and three 8-hour shifts with each team rotating through a sequence of 2 day shifts, 2 afternoon or evening shifts, 2 night shifts, and 2 days off over a cycle of 8 days. Intermediate rotating schedules (changing weekly) or slow rotating schedules (changing every 15 to 30 days) are other types of rotating schedules.
Table 1-3
General types of shift work and related shift scheduling criteria.
Other types of shift work schedules include (1) split shifts, in which working time consists of two distinct periods each day (e.g., 4 hours in the morning and 4 hours at night) (McMenamin 2007), and (2) compressed week schedules, in which the standard work week is reduced to fewer than 5 days and the employee makes up the full number of weekly hours by working more hours each day (e.g., four 10-hour days; three 12-hour days; or a week of five 9-hour days followed by a week of four 9-hour days) (WebFinance 2018).
1.3.2. Exposure
Multiple lines of evidence indicate that tens of millions of people in the United States work schedules outside normal daylight hours (i.e., approximately 7:00 AM or 8:00 AM to 5:00 PM or 6:00 PM) either consistently or as part of flexible or rotating work shifts (BLS 2004, 2005, McMenamin 2007, IARC 2010, Presser and Ward 2011, Alterman et al. 2013, CDC 2015). Data from two relatively recent surveys, each of more than 17,000 adults (17,524 adults in a 2010 NHIS-OHS survey [Alterman et al. 2013] and 19,456 adults in the 2015 NHIS–OHS survey [CDC 2015]) indicated that ~27% of employees are estimated to work alternative shifts involving non-day hours (e.g., night, evening, or rotating shifts). The percentages from these data are higher than the prevalence of shift work of 14.8% estimated by the 2004 Bureau of Labor Statistics (BLS) data (based on sampling of 10,189 workers) (BLS 2004, 2005, McMenamin 2007) suggesting a possible increase over time. Definitions of shift work in the 2015 CDC data, the 2010 CDC data (night, evening, or rotating shift), and the 2004 BLS data (evening, night, rotating, or split shift, or employer-arranged irregular schedule) were similar. No comparable data for frequency of night work were reported by BLS.
Approximately 7% of all employed adults (10,834,000 people ≥ 18 years of age) worked frequent nights (i.e., working any amount of time between 1:00 AM and 5:00 AM for 6 to 30 days over the previous 30-day period) according to the 2015 NHIS-OHS survey (based on sampling data for 2,782 adults). Frequent night work was more common in men, African-Americans, and non-Hispanics; was slightly more common in workers having high school education versus having less or more than high school education; and decreased with increasing age. The 3 industries with the highest prevalence of frequent night work were mining (18.08%, an estimated 111,000 people); transportation, warehousing, and utilities (15.48%, an estimated 1,141,000 people); and healthcare and social assistance (11.84%, an estimated 2,021,000 people) (CDC 2015). People engaged in frequent night work in the mining industry tended to be older (≥ 65 years), male, white, and non-Hispanic (NHIS-OHS survey, CDC 2015).
The 5 occupations with the highest prevalence of frequent night work were the following: (1) protective services, (2) transportation and material moving, (3) healthcare practitioners and technical occupations, (4) production, and (5) healthcare support. These five accounted for an estimated 5,288,000 people, or approximately 50% of workers engaged in frequent night work. Figure 1-5 presents prevalence rates and estimated numbers of workers in these occupations with the highest prevalence of night work based on the 2015 NHIS-OHS dataset (CDC 2015). Estimated numbers of workers for these individual occupations ranged from 388,000 people to 1,517,000 people (NHIS-OHS survey, CDC 2015). Data from the American Time Use Survey (using BLS data) found that ~7% to 20% of workers (≥ 15 years old) worked their main job from 11:00 PM to 3:00 AM in similar occupations (protective services, healthcare, production, and transportation), with the highest percentage in protective services (Torpey 2015).
Figure 1-5
Prevalence and estimated numbers of U.S. workers who frequently work night shifts. Frequent night shifts were defined as at least 6 of the past 30 days with any time worked between 1:00 AM and 5:00 AM in 2015. The percentage of U.S. workers for each occupation (more...)
Shift work as a complex exposure scenario
Night shift work includes exposure to electric LAN, sleep disturbances, or changes in meal timing, as well as other potential factors (e.g., social stressors, lifestyle behaviors, decreased exposure to sunlight, and lower vitamin D levels). Shift workers are also affected by social jet lag. One study of 1,829 shift workers estimated average social jet lag of 1.37 hours for day workers and 4.61 hours for night workers (Yong et al. 2016). The direction and speed of shift work rotations does not seem to impact the extent of social jet lag since fast clockwise shift changes were associated with 2.8 hours of social jet lag and slow counterclockwise shift changes with 2.7 hours; social jet lag for day workers was 0.9 hours (Kantermann et al. 2014).
Direct exposure to LAN among shift workers
Typical natural indoor light is in the range of 200 to 400 lux, and an office lit by fluorescent light is in the range of 100 to 200 lux. Only a very limited number of studies have measured personal light exposures at night in shift workers working indoors, and average levels were mostly below 100 lux (see Table 1-4). In all studies, LAN exposures were measured using either (1) light intensity data loggers worn around the neck or at shoulder level to approximate eye-level or (2) a light exposure/activity monitor on the non-dominant wrist. Only Burch et al. (2005), who compared light exposures in workers across three shifts, reported a 24-hour time-weighted light exposure measure which did not account for LAN specifically; however, night shift workers had the lowest light exposure.
Table 1-4
Measurements of personal light exposure in shift workers.
Other exposures enabled by light among shift workers
LAN enables changes in the timing of what would normally be considered “daytime activities” among shift workers, in particular sleep disturbances, meal timing, dietary patterns, and physical activity. However, these changes vary across populations. Meal timing and dietary patterns have been shown to differ between day and night workers and between flight attendants and the general population (Esquirol et al. 2009, Winter et al. 2014, Wirth et al. 2014a, Hemiö et al. 2015) (see Section 6).
Physical activity has been shown generally to be higher among night workers than day workers in a number of studies, although it is not clear if this is due to more activity at night or activity during the day. For example, Wegrzyn et al. (2017) reported that participants in the younger cohort, i.e., the Nurse’s Health Study 2 (NHS2), reported more physical activity than participants in the older cohort, i.e., the Nurse’s Health Study(NHS), and in both cohorts, activity levels in rotating workers were higher than in day workers. Neil-Sztramko et al. (2016) reported that although shift workers had less sedentary time than day workers, they were more likely to have poor body composition, and lower aerobic capacity. In a study of shift workers and metabolic syndrome, Esquirol et al. (2009) reported that shift workers had increased job strain and higher total and at-work physical activity.
1.4. Transmeridian travel and social jet lag
Another category of shift workers is employees working in the airline industry, who in addition to working multiple shifts may travel frequently across multiple time zones. Long distance flights with rapid time zone shifts of more than 3 hours can produce desynchronization between an individual’s circadian rhythms and destination day-night cycles (Rose et al. 1999). Symptoms of this desynchrony, including fatigue, loss of concentration and appetite, indigestion, and irritability, are commonly known as “jet lag.” In 2016, there were over 124,000 airline and commercial pilots and over 116,000 flight attendants in the United States (BLS 2017a, b). The U.S. Department of Transportation reported that approximately 117 million total passengers traveled on transmeridian flights in 2017 (destinations in Europe [65 million], Far East [34 million], Middle East [10 million], Africa [2 million], and Australasia [6 million]) (DOT 2018); further, assuming that the number of flights from these locations to the United States would carry a similar number of passengers, an estimated 234 million passenger flights included transmeridian travel exceeding 3 hours in 2017. One report (Sharma and Shrivastava 2004) estimated that 90% or more of airline crew members experience symptoms of jet lag. Similar data for the general flying public was not identified, but most people crossing more than 3 time zones likely experience it as well.
Social jet lag is misalignment between one’s circadian timing system and sleep-wake cycle based on social clocks, e.g., waking to an alarm clock on weekdays for work or school and then sleeping and waking without an alarm on the weekend (i.e., “sleeping in”) (Roenneberg et al. 2012, Rutters et al. 2014, McMahon et al. 2018, Uzoigwe and Sanchez Franco 2018). Social jet lag symptoms are similar to jet lag symptoms except they are more chronic in nature. For jet lag, upon arrival at a different location, one’s circadian clock can be re-set to local sunrise and sunset times, thereby limiting jet lag symptoms to a transitory experience. For social jet lag, misalignment is chronic as it is continuously experienced on a weekly (or other time unit) basis, usually for long periods of time. Over two-thirds of the general population could be affected by social jet lag (up to 2 hours shift between weekdays and weekends), and adolescents can have even higher social jet lag (≥ 2 hours) (see Table 1-5) (Roenneberg et al. 2012, Rutters et al. 2014, Malone et al. 2016, Koopman et al. 2017, McMahon et al. 2018).
Table 1-5
Social jet lag in various populations.
1.5. Summary
Circadian regulation, i.e., daily oscillations or rhythms of physiological and behavioral processes, occurs in humans and almost all other species. Circadian rhythms in humans are controlled by the master circadian clock in the SCN which communicates with the brain and peripheral organs and tissues directly via neural signals and indirectly via neuroendocrine (e.g., melatonin and glucocorticoids) and activity-related (e.g., feeding-fasting, body temperature) signals. Melatonin, a tryptophan derivative primarily synthesized in the pineal gland, serves as both an output and input factor to the circadian system and is an important biomarker of circadian disruption. Experimental models show that melatonin can modulate expression of circadian clock genes in central and some peripheral tissues. The core clock genes include Clock, Bmal1, Npas2, Per1, 2, and 3, Cry1 and 2, Rev-erbα, and RORs. These and a few other core clock genes regulate expression of thousands of other genes, estimated to make up 50% of the transcriptome with tissue specificities in mammals. The clock genes control cell-cycle regulation, DNA damage response, energy metabolism, and numerous other physiological processes.
The transformation of modern society to an electricity-based sociocultural and work organization system together with technological advances in the 20th and 21st centuries has resulted in widespread exposure to electric light and to light from a multitude of electronic devices. The resulting ill-timed, unnatural light includes light at night (LAN), which enables activities to be performed at any time of the day or night including night shift work. These changes are associated with disruption of the circadian system, which may lead to potential adverse long-term health effects such as cancer. Circadian disruption occurs when the daily circadian rhythms are no longer coordinated or are suppressed and can be defined as internally or externally induced, acute or chronic temporal disorganization including, but not limited to, misalignment of the time structure in living systems. Furthermore, the lack of coordination between sleep-wake, feeding-fasting, and other cycles within the 24-hour day can cause acute or chronic temporal disorganization that potentially leads to many adverse health outcomes.
Since the patenting of Edison’s incandescent light bulb in the late 19th century, primary light sources for homes and workplaces have evolved through fluorescent lights to light-emitting diodes (LEDs) and more recently to the organic LEDs (OLED) and active-matrix organic LEDs (AMOLED) used in mobile devices, laptops, and televisions. While technological advances have generally increased the energy efficiency of lighting sources for both indoor (e.g., homes and offices) and outdoor (e.g., streets and parking lots) lighting, these light sources emit a larger proportion of total light in wavelengths perceived as blue by the human eye. Circadian light (CLA) is defined as light that impacts the circadian system, which is measured by the light that causes suppression of melatonin synthesis, an effect that is more sensitive to blue light.
A significant number of people living in the United States are exposed to LAN because of work schedules outside normal hours (i.e., shift work, including work at night) and from ill-timed, unnatural electric light exposure, which includes “light pollution” at night (a phenomenon that affects more than 99% of the U.S. population), and adolescent and teen use of self-luminous displays from a variety of electronic devices (e.g., cell phones, computer screens, e-readers, or tablets) before sleeping. Mothers caring for infants during the night also are exposed to light at night from various light sources, including the use of electronic devices such as cell phones, lighted tablets, and televisions.
A significant number of US residents – greater than 10.8 million people – have performed frequent night work with various types of permanent or rotating and continuous or discontinuous shift schedules. Industries and occupations with the highest prevalence of night work include protective services, healthcare and social assistance, production and manufacturing, and transportation.
- Circadian Regulation and Disruption, Night Shift, and Light at Night: Characteri...Circadian Regulation and Disruption, Night Shift, and Light at Night: Characterization and Exposure - NTP Cancer Hazard Assessment Report on Night Shift Work and Light at Night
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