Altered coordination between sleep timing and cortisol profiles in night working female hospital employees.

BACKGROUND: Cortisol typically peaks in the morning after waking up and declines throughout the day, reaching its lowest levels during nighttime sleep. Shift work can cause misalignment between cortisol levels and sleep-wake timing. We analyzed this misalignment in female shift workers focusing on the timing and extent of these changes. METHODS: We conducted a cross-sectional study involving 68 shift workers (aged 37 ± 10 years) and 21 non-shift workers (aged 45 ± 10 years) from a hospital. Shift workers were monitored through two day shifts and three night shifts, whereas non-shift workers were monitored during two day shifts. Each participant collected six to eight saliva samples (depending on their shift type) and provided sleep timing information, which was recorded via polysomnography and sleep diaries. Generalized additive mixed models were used to estimate shift-specific differences in cortisol smooth curves. Summary measures calculated for the cortisol smooth curves included cortisol awakening response, peak-to-bed slope, and total output. RESULTS: Between shift workers and non-shift workers, we observed similar diurnal cortisol profiles with a steep negative diurnal slope during day shifts. In shift workers on night shifts, a flattened U-shaped cortisol profile after the post-awakening maximum was observed, with a peak-to-bed slope close to zero. When comparing night to day shifts in the group of shift workers, mean cortisol levels were lower between 42 and 56 minutes and 1.8-11.9 hours after waking up, and higher between 14.9 and 22 hours after waking up. CONCLUSION: Our findings indicate altered cortisol profiles in female hospital employees on night shifts. Specifically, cortisol levels were lower at night when higher levels would typically be necessary for work activities, and higher at bedtime after a night shift, when levels should normally be low.

Club cell protein (CC16) in serum as an effect marker for small airway epithelial damage caused by diesel exhaust and blasting fumes in potash mining.

OBJECTIVE: The effect marker club cell protein (CC16) is secreted by the epithelium of the small respiratory tract into its lumen and passes into the blood. Increased amounts of CC16 in serum are observed during acute epithelial lung injury due to air pollutants. CC16 in serum was determined as part of this cross-sectional study in underground potash miners on acute and chronic health effects from exposures to diesel exhaust and blasting fumes. METHODS: Nitrogen oxides, carbon monoxide, and diesel particulate matter were measured in 672 workers at a German potash mining site on a person-by-person basis over an early shift or midday shift, together with CC16 serum concentrations before and after the respective shift. CC16 concentrations and CC16 shift-differences were evaluated with respect to personal exposure measurements and other quantitative variables by Spearman rank correlation coefficients. CC16 shift-differences were modeled using multiple linear regression. Above-ground workers as reference group were compared to the exposed underground workers. RESULTS: Serum concentrations of CC16 were influenced by personal characteristics such as age, smoking status, and renal function. Moreover, they showed a circadian rhythm. While no statistically significant effects of work-related exposure on CC16 concentrations were seen in never smokers, such effects were evident in current smokers. CONCLUSION: The small airways of current smokers appeared to be vulnerable to the combination of measured work-related exposures and individual exposure to smoking. Therefore, as health protection of smokers exposed to diesel exhaust and blasting fumes, smoking cessation is strongly recommended.

Systemic inflammatory effects of zinc oxide particles: is a re-evaluation of exposure limits needed?

Exposure to airborne substances such as gases, vapours, and particles remains a relevant health risk in many workplaces. A current topic and cause for discussion is the investigation of the health effects of particles containing zinc oxide (ZnO). Among other data, those collected from our study on human exposure data of ZnO in 2018 prompted the National Research Centre for the Working Environment 2021 to formulate a new, sharply lowered proposed occupational exposure limit (OEL) for zinc in workplaces. Since the publication of the Danish report, further studies have been conducted with ZnO. In the following text, all arguments for deriving this new limit value for zinc from the report are discussed, extended with the more recent data since 2018. It should be noted that especially the application of time extrapolation factors needs further discussion and harmonization between regulatory authorities. From our point of view, the data situation can justify a higher OEL for zinc than that proposed by the Danish National Research Centre for the Working Environment.

Impact of diesel exhaust exposure on urinary 1-hydroxypyrene in underground salt and potash workers.

BACKGROUND: Diesel engine exhaust (DEE) and some of the polycyclic aromatic hydrocarbons (PAH) it contains are carcinogenic to humans (for example benzo(a)pyrene) and can cause lung cancer in workers. The objective of this study was to assess exposures to DEE and its component PAH and the potential associations between these two health hazards in a salt and potash mining population. METHODS: Between 2017 and 2019, 1003 underground workers (mining n = 801, maintenance n = 202) and 243 above-ground facility workers from two German mines participated. Personal exposure to DEE was assessed in air as elemental carbon for diesel particulate matter (EC-DPM), whereas exposure to PAH was assessed in pre- and post-shift urine samples in terms of 1-hydroxypyrene (1-OHP). Associations between EC-DPM and 1-OHP were studied using linear regression models. RESULTS: The highest EC-DPM exposures were measured in mining workers (median 0.06 mg/m³) followed by workers in the maintenance (0.03 mg/m3) and facility areas (<0.02 mg/m3). Exposures above the current German occupational threshold level of 0.05 mg/m3 were observed in 56%, 17%, and 5% of mining, maintenance and facility workers, respectively. 1-OHP increased statistically significantly across a work shift in underground workers but not in facility workers. Regression analyses revealed an increase of post-shift 1-OHP by almost 80% in mining and 40% in maintenance compared with facility workers. 1-OHP increased with increasing EC-DPM among underground workers. However, internal exposure of 1-OHP mainly remained at levels similar to those of the German general population in more than 90% of the urine samples. CONCLUSIONS: While exposures to DEE above the current German OEL for EC-DPM are quite common in the studied population of underground salt and potash miners (39.5% overall), urinary concentrations of 1-OHP did not reflect these findings.

Underground salt and potash workers exposed to nitrogen oxides and diesel exhaust: assessment of specific effect biomarkers.

PURPOSE: Occupational exposure limits (OEL) for nitrogen oxides (NO, NO2) and diesel exhaust (EC-DPM) were reassessed by the German authorities in 2016/2017. We performed a clinical cross-sectional study among salt and potash underground workers exposed to these substances at relatively high levels to examine possible indicators of acute effects on workers' health. METHODS: We measured post- versus pre-shift differences in cardiovascular, inflammatory, immune, and respiratory effect biomarkers and assessed their associations with personal exposures measured during the same shift. We also compared post- versus pre-shift differences in biomarker levels between exposure groups defined based on work site and job type. RESULTS: None of the above-ground workers exceeded the OEL for NO2 and only 5% exceeded the OEL for EC-DPM exposure. Among underground workers, 33% of miners and 7% underground maintenance workers exceeded the OEL for NO2; the OEL for EC-DPM was exceeded by 56% of miners and 17% of maintenance workers. Some effect biomarkers (thrombocytes, neutrophils, MPO, TNF-α, IgE, FeNO) showed statistically significant differences between pre- versus post-shift measurements; however, there were no consistent associations between pre- and post-shift differences and exposure group or personal exposure measurements during the shift. CONCLUSIONS: We did not find evidence of associations between workplace exposure to NO, NO2 or EC-DPM and clinically relevant indicators of acute cardiovascular, inflammatory and immune, or respiratory effects among salt and potash underground workers in Germany.

Night work, chronotype and cortisol at awakening in female hospital employees.

To examine the effect of night shift on salivary cortisol at awakening (C1), 30 min later (C2), and on the cortisol awakening response (CAR, the difference between C2 and C1). We compared shift and non-shift workers with a focus on the impact of worker chronotype. Our study included 66 shift-working females (mean age = 37.3 years, SD = 10.2) and 21 non-shift working females (mean age = 47.0 years, SD = 8.9). The shift workers collected their saliva samples at C1 and C2 on each two consecutive day shifts and night shifts. Non-shift workers collected their samples on two consecutive day shifts. We applied linear mixed-effects models (LMM) to determine the effect of night shift on CAR and log-transformed C1 and C2 levels. LMMs were stratified by chronotype group. Compared to non-shift workers, shift workers before day shifts (i.e. after night sleep) showed lower cortisol at C1 (exp [Formula: see text]=0.58, 95% CI 0.42, 0.81) but not at C2. In shift workers, the CARs after night shifts (i.e. after day sleep) were lower compared to CARs before day shifts ([Formula: see text]= - 11.07, 95% CI - 15.64, - 6.50). This effect was most pronounced in early chronotypes (early: [Formula: see text]= - 16.61, 95% CI - 27.87, - 5.35; intermediate: [Formula: see text]= - 11.82, 95% CI - 18.35, - 5.29; late: [Formula: see text]= - 6.27, 95% CI - 14.28, 1.74). Chronotype did not modify the association between night shift and CAR. In our population of shift workers, there was a mismatch between time of waking up and their natural cortisol peak at waking up (CAR) both during day and night shift duties.

Lost in the woods: Finding our way back to the scientific method in systematic review.

Systematic review has become the preferred approach to addressing causality and informing regulatory and other decision-making processes, including chemical risk assessments. While advocates of systematic reviews acknowledge that they hold great potential for increasing objectivity and transparency in assessments of chemicals and human health risks, standardizing and harmonizing systematic review methods have been challenging. This review provides a brief summary of the development of systematic review methods and some of the frameworks currently in use in the US and Europe. We also provide an in-depth evaluation and comparison of two "competing" US EPA systematic review frameworks, informed by the constructively critical recommendations from the US National Academies of Science, Engineering and Medicine. We conclude with suggestions for moving forward to harmonize systematic review methods, as we believe that further criticism of individual available frameworks likely will be unproductive. Specifically, we issue a call to action for an international collaboration to work toward a blueprint that embraces the most scientifically critical elements common to most systematic review frameworks, while necessarily accommodating adaptations for specific purposes. Despite the array of available systematic review methods, it is clear that there is a shared goal and desire to promote objective assessment and synthesis of scientific evidence informing globally important issues regarding disease causality and human health risk evaluation.

Naphthalene: irritative and inflammatory effects on the airways.

OBJECTIVE: This cross-sectional study determined whether acute sensory irritative or (sub)chronic inflammatory effects of the eyes, nose or respiratory tract are observed in employees who are exposed to naphthalene at the workplace. METHODS: Thirtynine healthy and non-smoking male employees with either moderate (n = 22) or high (n = 17) exposure to naphthalene were compared to 22 male employees from the same plants with no or only rare exposure to naphthalene. (Sub)clinical endpoint measures included nasal endoscopy, smell sensitivity, self-reported work-related complaints and the intensity of naphthalene odor and irritation. In addition, cellular and soluble mediators in blood, nasal lavage fluid (NALF) and induced sputum (IS) were analysed. All measurements were carried out pre-shift on Monday and post-shift on Thursday. Personal air monitoring revealed naphthalene shift concentrations up to 11.6 mg/m3 with short-term peak concentrations up to 145.8 mg/m3 and 1- and 2-naphthol levels (sum) in post-shift urine up to 10.1 mg/L. RESULTS: Acute sensory irritating effects at the eyes and upper airways were reported to occur when directly handling naphthalene (e.g., sieving pure naphthalene). Generally, naphthalene odor was described as intense and unpleasant. Habituation effects or olfactory fatigue were not observed. Endoscopic examination revealed mild inflammatory effects at the nasal mucosa of exposed employees in terms of reddening and swelling and abnormal mucus production. No consistent pattern of cellular and soluble mediators in blood, NALF or IS was observed which would indicate a chronic or acute inflammatory effect of naphthalene in exposed workers. CONCLUSIONS: The results suggest that exposure to naphthalene induces acute sensory irritative effects in exposed workers. No (sub)chronic inflammatory effects on the nasal epithelium or the respiratory tract could be observed under the study conditions described here.

(Mono-) Exposure to Naphthalene in the Abrasives Industry: Air Monitoring and Biological Monitoring.

Exposure to the bicyclic aromatic hydrocarbon naphthalene occurs in most cases along with other polycyclic aromatic hydrocarbons. Here we report from an investigation of 63 healthy, non-smoking male employees in the abrasives industry where naphthalene is the only relevant chemical exposure. Exposure assessment was performed using a combination of Air and Biological Monitoring over nearly a whole working week (Mo.-Th.). Air measurements were carried out during the shift on Thursday with the GGP mini-sampling system, combining particle and vapour sampling at low flow rates. In urine spot samples, the metabolites 1- and 2-naphthol were measured Mo.-Th. pre- and post-shift (for the reference group only Mo. pre- and Th. post-shift). With regard to naphthalene concentrations measured in air and concentrations of its metabolites (1- and 2-naphthol) in urine, study participants could be divided into a high and a low exposure group, and a reference group. The naphthalene concentration in air was in the range of 0.1-11.6 mg m-3, and naphthol concentrations (sum of 1- and 2-naphthol) in post-shift urine were in the range of <1 to 10 127 µg l-1. Naphthalene concentrations in air and naphthol concentrations in urine were closely correlated, indicating mainly airborne exposure at the investigated workplaces. As expected from toxicokinetic data, internal body burden increased slightly during a working week and did not completely decline over a work-free weekend to background concentrations observed in occupationally not exposed persons. Taking into account the observed increase in pre- and post-shift values during the working week, urine sampling for Biological Monitoring at workplaces should be carried out after several preceding shifts. Our data allow the derivation of biological limit values for the sum of 1- and 2-naphthol in urine corresponding to occupational exposure limits for naphthalene in air.

Decreased psychomotor vigilance of female shift workers after working night shifts.

BACKGROUND: We compared psychomotor vigilance in female shift workers of the Bergmannsheil University Hospital in Bochum, Germany (N = 74, 94% nurses) after day and night shifts. METHODS: Participants performed a 3-minute Psychomotor Vigilance Task (PVT) test bout at the end of two consecutive day and three consecutive night shifts, respectively. Psychomotor vigilance was analyzed with respect to mean reaction time, percentage of lapses and false starts, and throughput as an overall performance score, combining reaction time and error frequencies. We also determined the reaction time coefficient of variation (RTCV) to assess relative reaction time variability after day and night shifts. Further, we examined the influence of shift type (night vs. day) by mixed linear models with associated 95% confidence intervals (CI), adjusted for age, chronotype, study day, season, and the presence of obstructive sleep apnea (OSA). RESULTS: At the end of a night shift, reaction times were increased (ß = 7.64; 95% CI 0.94; 14.35) and the number of lapses higher compared to day shifts (exp(ß) = 1.55; 95% CI 1.16-2.08). By contrast, we did not observe differences in the number of false starts between day and night shifts. Throughput was reduced after night shifts (ß = -15.52; 95% CI -27.49; -3.46). Reaction times improved across consecutive day and night shifts, whereas the frequency of lapses decreased after the third night. RTCV remained unaffected by both, night shifts and consecutive shift blocks. DISCUSSION: Our results add to the growing body of literature demonstrating that night-shift work is associated with decreased psychomotor vigilance. As the analysis of RTCV suggests, performance deficits may selectively be driven by few slow reactions at the lower end of the reaction time distribution function. Comparing intra-individual PVT-performances over three consecutive night and two consecutive day shifts, we observed performance improvements after the third night shift. Although a training effect cannot be ruled out, this finding may suggest better adaptation to the night schedule if avoiding fast-changing shift schedules.

Differences in twenty-four-hour profiles of blue-light exposure between day and night shifts in female medical staff.

Light is the strongest zeitgeber currently known for the synchronization of the human circadian timing system. Especially shift workers are exposed to altered daily light profiles. Our objective is the characterization of differences in blue-light exposures between day and night shift taking into consideration modifying factors such as chronotype. We describe 24-hour blue-light profiles as measured with ambient light data loggers (LightWatcher) during up to three consecutive days with either day or night shifts in 100 female hospital staff including 511 observations. Linear mixed models were applied to analyze light profiles and to select time-windows for the analysis of associations between shift work, individual factors, and log mean light exposures as well as the duration of darkness per day. Blue-light profiles reflected different daily activities and were mainly influenced by work time. Except for evening (7-9 p.m.), all time windows showed large differences in blue-light exposures between day and night shifts. Night work reduced the duration of darkness per day by almost 4 h (ß^ = -3:48 hh:mm, 95% CI (-4:27; -3.09)). Late chronotypes had higher light exposures in the morning and evening compared to women with intermediate chronotype (e.g. morning ß^ = 0.50 log(mW/m2/nm), 95% CI (0.08; 0.93)). Women with children had slightly higher light exposures in the afternoon than women without children (ß^ = 0.48, 95% CI (-0.10; 1,06)). Time windows for the description of light should be chosen carefully with regard to timing of shifts. Our results are helpful for future studies to capture relevant light exposure differences and potential collinearities with individual factors. Improvement of well-being of shift workers with altered light profiles may therefore require consideration of both - light at the workplace and outside working hours.

Night Shift Work Affects Urine Metabolite Profiles of Nurses with Early Chronotype.

Night shift work can have a serious impact on health. Here, we assess whether and how night shift work influences the metabolite profiles, specifically with respect to different chronotype classes. We have recruited 100 women including 68 nurses working both, day shift and night shifts for up to 5 consecutive days and collected 3640 spontaneous urine samples. About 424 waking-up urine samples were measured using a targeted metabolomics approach. To account for urine dilution, we applied three methods to normalize the metabolite values: creatinine-, osmolality- and regression-based normalization. Based on linear mixed effect models, we found 31 metabolites significantly (false discovery rate <0.05) affected in nurses working in night shifts. One metabolite, acylcarnitine C10:2, was consistently identified with all three normalization methods. We further observed 11 and 4 metabolites significantly associated with night shift in early and late chronotype classes, respectively. Increased levels of medium- and long chain acylcarnitines indicate a strong impairment of the fatty acid oxidation. Our results show that night shift work influences acylcarnitines and BCAAs, particularly in nurses in the early chronotype class. Women with intermediate and late chronotypes appear to be less affected by night shift work.

Dilution correction for dynamically influenced urinary analyte data.

Urinary analyte data has to be corrected for the sample specific dilution as the dilution varies intra- and interpersonally dramatically, leading to non-comparable concentration measures. Most methods of dilution correction utilized nowadays like probabilistic quotient normalization or total spectra normalization result in a division of the raw data by a dilution correction factor. Here, however, we show that the implicit assumption behind the application of division, log-linearity between the urinary flow rate and the raw urinary concentration, does not hold for analytes which are not in steady state in blood. We explicate the physiological reason for this short-coming in mathematical terms and demonstrate the empirical consequences via simulations and on multiple time-point metabolomic data, showing the insufficiency of division-based normalization procedures to account for the complex non-linear analyte specific dependencies on the urinary flow rate. By reformulating normalization as a regression problem, we propose an analyte specific way to remove the dilution variance via a flexible non-linear regression methodology which then was shown to be more effective in comparison to division-based normalization procedures. In the progress, we developed several, easily applicable methods of normalization diagnostics to decide on the method of dilution correction in a given sample. On the way, we identified furthermore the time-span since last urination as an important variance factor in urinary metabolome data which is until now completely neglected. In conclusion, we present strong theoretical and empirical evidence that normalization has to be analyte specific in dynamically influenced data. Accordingly, we developed a normalization methodology for removing the dilution variance in urinary data respecting the single analyte kinetics.

Associations between blood lead, olfaction and fine-motor skills in elderly men: Results from the Heinz Nixdorf Recall Study.

Lead (Pb) is a recognized neurotoxin. Pb2+ can interfere with divalent metal transporters and ion channels and may thus affect other brain metals and cation signaling in neurons. Thereby, cognitive and sensory functions can be impaired. Whereas cognitive effects are well described less is known about olfaction and motor functions in the general population at currently lower exposure levels. The objective of this study was to evaluate the influence of Pb in blood (PbB) on odor identification and fine motor skills within the framework of the Heinz Nixdorf Recall Study (HNRS), a prospective cohort study among an elderly German population. Data on odor identification assessed with Sniffin' sticks and fine motor test results were collected during the second follow-up of HNRS (2011-2014) in 1188 elderly men aged 55 to 86 years. PbB was determined in 1140 blood samples archived at baseline (2000-2003) and in 796 samples from the second follow-up. The association between PbB and impaired odor identification (normosmia as reference) was estimated with proportional odds ratios (PORs) with 95% confidence intervals (CI). The odds ratios (OR) of substantially impaired dexterity (tapping hits <10th percentile, errors in aiming, line tracing, or steadiness>90th percentile) were estimated with mixed logistic regression models for test results with both hands, where PbB was adjusted for covariates. PbB at baseline (median 32.9 µg/L; 2.27% ≥90 µg/L) was higher than at follow-up (25.9 µg/L; 0.84% ≥90 µg/L). The individual concentrations were correlated (Spearman rs 0.59, 95% CI 0.54 - 0.63). PORs of an impaired odor identification in men with baseline PbB ≥90 µg/L were 1.96 (95% CI 0.94-4.11) and 1.57 (95% CI 0.47-5.19) with follow-up PbB. Fine-motor tests were not affected by elevated PbB with the exception of tapping in men with follow-up PbB ≥50 µg/L (OR 2.14, 95% CI 1.09-4.23). Increasing age had strong effects on all outcomes. Low education was associated with impaired odor identification, tapping, and aiming. Also, alcohol consumption and current smoking affected the test results, particularly steadiness. In this community-based cohort of elderly men, we could confirm indication of an influence of elevated PbB on odor identification. Small numbers of men with elevated PbB due to an on-going trend of decreasing PbB in the general population, strong covariates and multiple comparisons hamper the evaluation of adversity of these effects of PbB on olfaction and dexterity.

Vitamin D supply in shift working nurses.

We studied determinants of Vitamin D in serum of 67 female health care workers (aged 25-60 years), including age, body mass index, physical activity, and shift work. Overall, vitamin D levels were low, ranging from 6 to 51 ng/mL (median: 20 ng/mL). Lower serum levels were found in samples drawn in winter and spring and in obese subjects. Shift work had only small effects on vitamin D levels. The high prevalence of vitamin D undersupply is in line with observations from the German general population. Vitamin D supply particularly in winter and spring should be ensured to avoid health problems.

Sensory irritation as a basis for setting occupational exposure limits.

There is a need of guidance on how local irritancy data should be incorporated into risk assessment procedures, particularly with respect to the derivation of occupational exposure limits (OELs). Therefore, a board of experts from German committees in charge of the derivation of OELs discussed the major challenges of this particular end point for regulatory toxicology. As a result, this overview deals with the question of integrating results of local toxicity at the eyes and the upper respiratory tract (URT). Part 1 describes the morphology and physiology of the relevant target sites, i.e., the outer eye, nasal cavity, and larynx/pharynx in humans. Special emphasis is placed on sensory innervation, species differences between humans and rodents, and possible effects of obnoxious odor in humans. Based on this physiological basis, Part 2 describes a conceptual model for the causation of adverse health effects at these targets that is composed of two pathways. The first, "sensory irritation" pathway is initiated by the interaction of local irritants with receptors of the nervous system (e.g., trigeminal nerve endings) and a downstream cascade of reflexes and defense mechanisms (e.g., eyeblinks, coughing). While the first stages of this pathway are thought to be completely reversible, high or prolonged exposure can lead to neurogenic inflammation and subsequently tissue damage. The second, "tissue irritation" pathway starts with the interaction of the local irritant with the epithelial cell layers of the eyes and the URT. Adaptive changes are the first response on that pathway followed by inflammation and irreversible damages. Regardless of these initial steps, at high concentrations and prolonged exposures, the two pathways converge to the adverse effect of morphologically and biochemically ascertainable changes. Experimental exposure studies with human volunteers provide the empirical basis for effects along the sensory irritation pathway and thus, "sensory NOAEChuman" can be derived. In contrast, inhalation studies with rodents investigate the second pathway that yields an "irritative NOAECanimal." Usually the data for both pathways is not available and extrapolation across species is necessary. Part 3 comprises an empirical approach for the derivation of a default factor for interspecies differences. Therefore, from those substances under discussion in German scientific and regulatory bodies, 19 substances were identified known to be human irritants with available human and animal data. The evaluation started with three substances: ethyl acrylate, formaldehyde, and methyl methacrylate. For these substances, appropriate chronic animal and a controlled human exposure studies were available. The comparison of the sensory NOAEChuman with the irritative NOAECanimal (chronic) resulted in an interspecies extrapolation factor (iEF) of 3 for extrapolating animal data concerning local sensory irritating effects. The adequacy of this iEF was confirmed by its application to additional substances with lower data density (acetaldehyde, ammonia, n-butyl acetate, hydrogen sulfide, and 2-ethylhexanol). Thus, extrapolating from animal studies, an iEF of 3 should be applied for local sensory irritants without reliable human data, unless individual data argue for a substance-specific approach.

Night work and breast cancer estrogen receptor status--results from the German GENICA study.

OBJECTIVES: The potential mechanisms that link night-shift work with breast cancer have been extensively discussed. Exposure to light at night (LAN) depletes melatonin that has oncostatic and anti-estrogenic properties and may lead to a modified expression of estrogen receptor (ER) α. Here, we explored the association between shift work and breast cancer in subgroups of patients with ER-positive and -negative tumors. METHODS: GENICA (Gene-ENvironment Interaction and breast CAncer) is a population-based case-control study on breast cancer with detailed information on shift work from 857 breast cancer cases and 892 controls. ER status was assessed by immunohistochemical staining. Associations between night-shift work and ER-positive and -negative breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders. RESULTS: ER status was assessed for 827 cases and was positive in 653 and negative in 174 breast tumors. Overall, 49 cases and 54 controls were "ever employed" in shift work including night shifts for ≥ 1 year. In total, "ever shift work" and "ever night work" were not associated with an elevated risk of ER-positive or -negative breast tumors. Night work for ≥ 20 years was associated with a significantly elevated risk of ER-negative breast cancer [odds ratio (OR) 4.73, 95% confidence interval (95% CI) 1.22-18.36]. CONCLUSIONS: Our case-control study suggests that long-term night-shift work is associated with an increased risk of ER-negative breast cancers. Further studies on histological subtypes and the analysis of other potentially relevant factors are crucial for discovering putative mechanisms.