Lifetime report of perceived stress at work and cancer among men: A case-control study in Montreal, Canada

Accepted Manuscript Lifetime report of perceived stress at work and cancer among men: A case-control study in Montreal, Canada

Audrey Blanc-Lapierre, Marie-Claude Rousseau, Deborah Weiss, Mariam El-Zein, Jack Siemiatycki, Marie-Élise Parent PII: DOI: Reference:

S0091-7435(16)30399-1 doi: 10.1016/j.ypmed.2016.12.004 YPMED 4858

To appear in:

Preventive Medicine

Received date: Revised date: Accepted date:

20 April 2016 30 November 2016 1 December 2016

Please cite this article as: Audrey Blanc-Lapierre, Marie-Claude Rousseau, Deborah Weiss, Mariam El-Zein, Jack Siemiatycki, Marie-Élise Parent , Lifetime report of perceived stress at work and cancer among men: A case-control study in Montreal, Canada. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ypmed(2016), doi: 10.1016/j.ypmed.2016.12.004

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ACCEPTED MANUSCRIPT Lifetime report of perceived stress at work and cancer among men: a case-control study in Montreal, Canada Audrey Blanc-Lapierre1, PhD, Marie-Claude Rousseau1,2,3, PhD, Deborah Weiss1, PhD, Mariam El-Zein1,

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PhD, Jack Siemiatycki2,3, PhD, *Marie-Élise Parent1,2,3, PhD

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*Corresponding author 1

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Epidemiology and Biostatistics Unit, INRS-Institut Armand-Frappier, Institut national de la recherche scientifique (INRS), University of Quebec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada. [email protected] 2

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School of Public Health, Department of Social and Preventive Medicine, University of Montreal, 7101 Avenue du Parc, Montreal, QC H3N 1X9, Canada. 3

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University of Montreal Hospital Research Center (CRCHUM), Tour Saint-Antoine, 850 St. Denis Street, Montreal, QC H2X 0A9, Canada.

Highlights

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Perceived workplace stress associated with 5 out of 11 cancer sites First study assessing perceived stress at work over the entire career among men Subjects identified changes in stress level across jobs Stress ascribed to several reasons other than high demand

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   

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Running head: Perceived work-related stress and cancer

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Word counts: Abstract – 250; Text – 3,495

November 30, 2016

ACCEPTED MANUSCRIPT Abstract Background. The association between perceived workplace psychological stress, over the entire work career, and cancer among men has never been assessed. This was explored in the context of a population-based case-control study conducted in Montreal, Canada.

Methods. 3103 incident cancer cases (11 types) diagnosed in 1979-1985 and 512 population controls

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were interviewed. Subjects described in detail each job held during their lifetime, including the

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occurrence of stress, and its reason. Logistic regression estimated odds ratios (OR) and 95% confidence

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intervals (CI) for the association between perceived workplace stress and its duration, and each cancer site, adjusting for lifestyle and occupational factors.

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Results. Employment in at least one stressful job was associated with increased odds of cancers of the lung (OR=1.33, 95% CI: 1.01-1.75), colon (OR=1.51, 95% CI: 1.15-1.98), bladder (OR=1.37, 95% CI: 1.031.81), rectal (OR=1.52, 95% CI: 1.10-2.10), and stomach (OR=1.53, 95% CI: 1.08-2.15). A duration-

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response trend was found for cancers of the lung, colon, rectum, stomach, and for NHL. Subjects reported changes in stress level over their career. Perceived stress was ascribed to several sources,

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including high demand and time pressure, financial issues, job insecurity, and hazardous conditions.

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Conclusion. Prolonged exposure to perceived stress at work was associated with greater odds of cancer at 5 out of 11 sites. While over reporting of stress by cases cannot be fully ruled out, these

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associations, if substantiated, would bear important public health significance. Prospective studies building on detailed stress assessment protocols considering all sources and changes over the career are

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necessary.

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Key terms: Workplace stress; Self-report; Cancer; Men; Case-Control; Lifetime

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Introduction Chronic psychological stress has been found to have a deleterious impact on health. While there is mounting evidence for an implication in the development of cardiovascular disease [1-3], hypertension [4], and type 2 diabetes [5], its role in cancer etiology has yet to be established. Stress was set as a high-

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priority exposure for upcoming reviews by the Monograph Program of the International Agency for

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Research on Cancer [6].

Psychological stress is a broadly applied concept. It can result from trauma, abuse and major life

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events, and can occur in the home, workplace, or community [7, 8]. The perception of threat from stressors by the sympathetic nervous system (SNS) interacts with an individual’s attitudes and coping,

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which then results in perceived stress [9]. Therefore, the objective occurrence of a stressor is not the only relevant aspect. The perception of a stressor and an individual’s reaction to it are also important.

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Most of the literature to date on this issue has been devoted to breast cancer [10-17]. Other studies have looked at childhood stresses and lung [18] or other cancers [19, 20]; socioeconomic disadvantage

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and prostate cancer [21]; stress and coping, and prostate cancer [22]; general stress level and endometrial cancer [23]; as well as stressful life events and cancer [24, 25]. The emerging picture

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indicates at most a weak association between stress and cancer.

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The workplace is reported to be the main source of psychological stress in Canadian workers [26]. Few studies have addressed the role of work-related stress in cancer development, with conflicting

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findings [27-33, 14, 34]. The most extensive report on this issue is a meta-analysis of several European cohort studies using a common detailed assessment protocol [35], suggesting no association between job strain and cancers of the breast, lung, colon and prostate. However, the single baseline assessment

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of stress and the limited number of stress-exposed cases may have hampered the ability to detect associations.

We report here on the association between perceived work-related stress over the lifetime and cancer at 11 sites among men, in the context of a population-based study.

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ACCEPTED MANUSCRIPT Methods Study population The design and data collection methods of the Montreal Multisite Case-Control Cancer Study have been described previously [36-38]. Cases were men aged 35-70 years diagnosed with a histologicallyconfirmed cancer in 1979-1985 at one of 19 hospitals in the Montreal area. This ensured virtually

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complete (97%) population-based ascertainment of cases. In all, 4,576 eligible cases were ascertained,

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3,726 (81%) of which were recruited. For all sites combined or for a given site, response rates did not

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vary substantially according to socio-economic characteristics available from medical records. Most cases (86%) were ascertained within 3 months of diagnosis. The 11 largest case series retained for analysis included lung (n=761), colon (n=439), bladder (n=439), prostate (n=400), rectum (n=236),

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stomach (n=228), kidney (n=158), pancreas (n=94), esophagus (n=91) and melanoma (n=94), as well as Non-Hodgkin lymphoma (NHL) (n=197). Concomitantly (from 1981 to 1985), 740 population controls

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were randomly selected from electoral lists of Montreal residents and age-stratified to the age distribution (±5-years) of our cancer cases (all sites combined); 533 (72%) of them participated. Eighty-

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one percent of subjects responded for themselves; proxies, mostly spouses, provided information for

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the rest.

The study was approved by the ethics committees of all participating institutions and subjects

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provided informed consent. Data collection

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In-person interviews were conducted in two parts. The first used a structured questionnaire to collect information on socio-demographic and lifestyle factors, and a medical history. One question enquired

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whether the participant had ever had frequent anxiety, depression or trouble sleeping, at least once a week, for at least six months, during adulthood. This variable is subsequently referred to as “psychological symptoms”. In the second part of the interview, a semi-structured questionnaire was used to elicit a detailed description of each job held for at least 6 months over the lifetime. This included the company name, location, specific tasks, equipment used, and activities carried out by co-workers. Job descriptions were translated into chemical exposures by chemists-hygienists [36]. For each job held, participants were asked “How stressful was the job? Did this job make you feel tense or anxious most of the time?” This 4

ACCEPTED MANUSCRIPT question was used to define perceived work-related stress for a given job, based on a dichotomous variable (yes/no). For affirmative answers, the sources of stress (stressors) were sought in an openended format. Statistical analysis Analyses were restricted to participants who had complete occupational histories, i.e., 3,103 cases (84%)

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and 512 controls (96%). Unconditional logistic regression was used to estimate the odds ratio (OR) and

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95% confidence interval (CI) for the association between each cancer type and perceived work-related stress. Use of unconditional logistic regression while controlling for the matching factors is indicated in

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frequency-matched case-control studies to yield better statistical precision [39].

Perceived work-related stress was expressed in two different ways. In the first, it was dichotomized

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(ever/never) based on any occurrence. The second considered the cumulative number of years in jobs reported as stressful over the lifetime, categorized as follows: 0, 1 to ˂15 years, 15 to 30 years, >30

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years. Tests for trend assessing duration-response patterns were carried out by assigning values from 1 to 4 to the four categories, then treated as continuous. Sensitivity analyses testing the robustness of

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associations for different cutpoints (1 to 20 years, >20 years of perceived work stress) were conducted.

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Analyses were carried out using age-adjusted and fully-adjusted regression models. The latter included age, ancestry, education, family income and respondent status, along with several covariates specific to each cancer site and potentially associated with perceived stress at work, including smoking,

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physical activity, alcohol and coffee intakes, frequency of use of beta-carotene containing foods, body

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mass index and occupational carcinogens (Table 1) [40-46]. We assessed whether perceived workplace stress was related to the occurrence of psychological

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symptoms, reported in the medical history. Since the reason for reporting psychological symptoms was not collected, it could have been attributable to any life circumstance, occupational or personal. Perceived workplace stress and psychological symptoms might have been related, leading to one another in either direction, or they might have been unrelated. We estimated odds ratios for the association between perceived work-related stress and cancer adjusting for psychological symptoms, as well as according to the presence/absence of psychological symptoms. Other sensitivity analyses were carried out excluding proxy respondents, and stratifying subjects according to a history of night work, or to age at diagnosis or interview (
ACCEPTED MANUSCRIPT Results Cases tended to have had a lower income and educational level, to have been heavier smokers, and to have reported psychological symptoms more often than controls (Table 2). No clear pattern emerged among controls between the cumulative number of years of perceived

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stress at work and most of the socio-demographic and lifestyle characteristics (Appendix 1). However,

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men in the upper category of perceived stress duration (>30 years) had the highest mean family income,

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were the heaviest coffee and alcohol drinkers, and reported psychological symptoms the most often. The highest prevalence of reported work stress within a professional category (Appendix 2) was observed among firemen (40% of firefighting jobs), followed by industrial and aerospace engineers

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(31%), and motor vehicle and rail transport mechanics and repairmen (28%). The prevalence of jobs perceived as stressful was higher among white-collar (17%) than blue-collar (11%) jobs. Most frequently

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mentioned reasons associated with perceived work-related stress included high demand (e.g., sales, productivity), time pressure, responsibilities, subject’s anxious temperament, financial insecurity,

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danger, employee supervision, personal conflicts, difficult working conditions, and traffic issues (Appendix 3). Among subjects having reported stress at work, the proportion of those having reported

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all jobs to be stressful was similar among cases (20%) and controls (21%, Appendix 4). Among subjects who reported changes in perceived work-related stress over their career, reporting at least one

among cases and controls.

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transition from a stressful job to a non-stressful one (39%), or the opposite (91%), was observed as often

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Overall, 38% of controls reported ever experiencing work-related stress, compared with 44% of cases. In cases, the lifetime prevalence of perceived work-related stress ranged from 39% for prostate

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cancer, to 49% for melanoma (Table 3). There were little differences in odds ratios for the association between cancer and perceived workplace stress derived from age-adjusted or full models. Men who had experienced work-related stress had an increased odds of lung (OR=1.33, 95% CI: 1.01, 1.75), colon (OR=1.51, 95% CI: 1.15, 2.98), bladder (OR=1.37, 95% CI: 1.03, 1.81), rectal (OR=1.52, 95% CI: 1.10, 2.10), and stomach (OR=1.53, 95% CI: 1.08, 2.15) cancers (full models). Results were unchanged when proxy respondents were excluded (data not shown). Reporting less than 15 years of work-related stress over the work history was not associated with cancer (Table 3). By contrast, significant (lung, colon, bladder, rectum, stomach, NHL) or borderline 6

ACCEPTED MANUSCRIPT significant (prostate) associations were observed for a greater cumulative duration of exposure to perceived stress at work, either for 15-30 years, or >30 years . A duration-response trend was found for cancers of the lung, colon, rectum, stomach, and for NHL. When changing the cutpoints for perceived work stress duration to 1-20 and ˃20 years, higher odds of lung, colon, bladder, rectum, stomach cancers and NHL were also observed in the upper exposure category (data not shown).

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The prevalence of psychological symptoms reported in the medical section of the interview was 15%

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and 10% among cases and controls, respectively. In cases who reported psychological symptoms, 60% also reported work-related stress; the corresponding value for controls was 50%. Adjusting models for

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psychological symptoms or stratifying analyses according to its occurrence had little influence on odds ratios for the association between perceived workplace stress and cancer types (data not shown). Odds

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ratios were similar between men with and without a history of night work; no significant interaction was observed between age at diagnosis or interview (< 60 or ≥60 years) and perceived work-related stress

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duration for any of the cancer sites (data not shown).

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Discussion

The aim of this study was to evaluate the association between perceived stress at work and cancer.

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Perceived stress at work referred here to a lifetime experience, and associations were tested among men from various occupational groups. Reporting prolonged exposure to stress at work was associated

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with greater odds of cancers of the lung, colon, rectum and stomach, and NHL, with evidence of

Previous studies

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duration-response patterns.

The association between work-related stress and breast cancer has been assessed in six studies, with

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conflicting findings [32, 33, 14, 30, 31, 35]. Hormone-sensitive cancers may be influenced by stress in a different way than other types [47]. Moreover, the family and home environments may have a stronger impact on the level of stress perceived by women than men [48, 49]. Unlike many others, our study focused on cancer occurrence in men. Work-related stress determinants [50, 49] and the hormonal response to stress [51, 48] reportedly differ among men and women. Few studies have assessed the work stress-cancer relationship for other sites. Positive associations have been reported between job strain 20 years earlier, and esophageal and cardia cancers [29]. An excess colon cancer risk has been linked with jobs with high demand/low control [34] and with low 7

ACCEPTED MANUSCRIPT control jobs held 5 years earlier [27], suggesting a role for work stress in gastrointestinal cancers, in line with our findings. A recent analysis of 12 European cohorts reported no association between job strain and the occurrence of breast, lung, colorectal, or prostate cancer [35]. It involved a meta-analysis based on results from the individual cohorts, along with a pooled analysis of subjects from a subset of

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participating countries. While this has been the largest study to date, and it benefited from a detailed

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assessment of job strain, methodological issues may have obscured possible associations. First, job strain was assessed at baseline only, and stress prevalence was relatively low (9-18% across cancer

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sites), as compared to our estimate of 39-47% over the lifetime. We observed that the presence of stress varied across jobs during adulthood, suggesting that baseline levels may not accurately represent

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later ones. Second, cohort participants were aged 17 to 70 years when the single job strain assessment was performed; this wide age range translates into very different work circumstances and it is unclear

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that job strain assessed in late adolescence and in more advanced age would relate to cancer risk several decades later in the same way. Contrastingly, our study assessed cumulative exposure from early adulthood to middle or older age (age at diagnosis or interview). Third, although based on several large

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European cohorts, the number of exposed cases in the pooled analyses remained limited, i.e., 64, 78 and

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79 cases of lung, colorectal, and prostate cancer, respectively. In our study, the corresponding number of cases ever exposed over the lifetime for these sites were 330, 313 and 164.

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Work-related stress assessment

A commonly-used metric for assessing work-related stress is the demand-control model developed

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by Karasek whereby the most stressful jobs are those with high demands and low control, a situation referred to as ‘job strain’ [52]. The predictive validity of the Karasek ‘s model has been evaluated in

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terms of cardio-vascular [3, 53, 54] and mental health effects [55]. However, it is not necessarily a good predictor of the potential carcinogenic effects of stress, which might explain the heterogeneity of the results regarding the job strain – cancer relationship [31, 33, 32, 27, 29, 35, 28, 34]. Job strain was assessed using a questionnaire, except in two studies using a job-exposure matrix [28, 27]. The conflicting results from two studies using the same sample but different job strain assessment protocols, a questionnaire [29] and a job-exposure matrix [28], demonstrates the influence of assessment approaches. Results from a study on breast cancer suggested a specific role for job authority, with increased risks observed among higher-status occupations [14]. 8

ACCEPTED MANUSCRIPT A major caveat of previous studies on cancer is that none has assessed work-related stress over the entire work history. Previous investigations have relied on stress information at only one, and sometimes two time points, focusing on the time of diagnosis [30], 20 years before diagnosis [29], the longest job [28], 5 and 30 years prior to interview [27], at follow-up [30], or most often at baseline [31, 33, 35, 14]. This precluded evaluating the role of the duration of exposure to stress at work, which may be relevant to cancer development. In our study, subjects had held about 4 jobs, on average, during

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their career with some men reporting over a dozen. Men who reported work-related stress were able to

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distinguish stressful and non-stressful jobs sequentially. They would report some jobs as stressful, and

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others not, both within and across occupational titles. This highlights the need to cover the full work career and bears implications on the type of assessment tool to be used, in terms of feasibility.

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Our study was based on a limited set of relatively crude questions, and the degree of perceived stress, within a given job, could not be quantified beyond its presence or absence. However, unlike most

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previous studies, our perceived stress assessment was not based on a pre-selected set of dimensions, such as those contributing to job strain. Rather, our open-ended question elicited information on the underlying reasons perceived to contribute to stress in each job. Subjects identified factors which are

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not assessed as part of the job strain questionnaire, such as personal conflicts, insecurity, financial and

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health hazard issues, demonstrating the value of a comprehensive coverage of the assessment. Recall issues

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Measurement error certainly occurred in our study, some of which may have been related to the retrospective nature of the study. An over-reporting of past stressful episodes by cases could explain

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some, or all, of the elevated odds ratios observed across several sites. Breast cancer patients often point to stress as a cause of their illness [56, 57]. Men may be at least as likely as women to identify stress as a

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possible risk factor for cancer [58, 59]. Unlike case-control studies, cohort studies circumvent the potential recall bias issue. Among the 12 cohort-based studies having investigated the stress-cancer relationship, 5 observed a positive association [33, 14, 18, 23, 60] and 7 no association [35, 31, 32, 21, 24, 12, 17]. In comparison, four [28, 27, 61, 16] and three [29, 30, 22] case-control studies respectively found positive and no associations. While recall issues cannot be ruled out, the study was not set in a context that would necessarily favor over-reporting by cases. It was conducted in the early 1980s, among men, and in an era when there were no widespread public beliefs about a role of stress in cancer development. Also, stress was 9

ACCEPTED MANUSCRIPT not a primary focus of the study. The few questions on stress in the workplace were part of a 2-hour in person interview eliciting information on a very large number of lifestyle and occupational factors. We observed that controls reported an entire history of stressful jobs as often as cases did. In addition, when reporting on subsequent jobs over their entire career, cases and controls identified in similar proportions jobs that were stressful followed by others that were not. Cases thus appeared to be

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more discriminatory in their reports than could have been expected under strong reporting bias.

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Controls in our study, although chosen on the basis of being cancer-free, were not exempt from having other significant health problems. The subjects’ medical history, including the presence of

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cardiovascular disease and hypertension, was covered in the first part of the interview, prior to the occupational history section. This may have contributed to situating the subject in a broader health

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context.

A unique characteristic of the present study is that its main focus was to assess the association

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between chemical exposures and cancer based on a detailed description of each job and its specific tasks. This recollection likely helped the subject situating themselves within the overall work

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Other methodological considerations

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circumstances which could have entailed stress.

Response rates were relatively high overall, albeit somewhat lower among controls. Should men, and

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particularly controls, experiencing high levels of stress at work have been less inclined to participate in the study, this would have led to a spurious overestimation of estimated odds ratios. However, in the

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absence of information on reasons for non-participation, we have no means to confirm or refute this. Strengths of this study include the ability to assess, for the first time, perceived workplace stress over

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the entire employment history. Further, we were able to document changes in perceived work-related stress. This supports the importance of measuring stress at multiple time points throughout the career. As well, we were able to identify the occupations most often entailing stress at the population level and we described the sources of stress identified by study participants. We were also able to adjust for a wide range of potential confounders, including occupational exposures to known carcinogens. Finally, when assessing perceived workplace stress-cancer associations, we were able to consider, at least to some extent, confounding and effect modification by psychological symptoms that may result from other circumstances. 10

ACCEPTED MANUSCRIPT Possible mechanistic pathways Lifestyle behaviors, including resorting to smoking and drinking alcohol, might mediate the association between stress and cancer [18, 62]. A formal assessment of the potential mediation by lifestyle factors was outside the scope of the current study. However, to the extent that our data enabled its assessment, there was little evidence that the perceived stress-cancer associations were

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subject to confounding by lifestyle factors, although individuals cumulating over 30 years of perceived

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stress at work tended to be heavier coffee and alcohol consumers. Personality traits do not appear to play an important role in the stress-cancer relationship, if at all [63, 64]. It would have been of interest

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to consider other parameters, such as coping strategies, social support or job satisfaction, but information on these was not collected in the study.

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Stress, when experienced chronically, leads to the activation of neuroendocrine pathways including the SNS and the hypothalamic-pituitary-adrenal (HPA) axis. Biological mechanisms identified as potential

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direct carcinogenic effects of SNS are DNA repair, oncogene activation, inflammation and immune response, hematopoiesis, angiogenesis, survival and apoptosis [65]. Activation of the HPA axis by

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chronic stress induces the secretion of cortisol and glucocorticoids. Cortisol has been shown to have direct effects on growth and development of some cancers [9], and glucocorticoids are suspected to

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decrease the immune surveillance of tumors by inhibiting the cellular immune response [9, 66].

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Conclusions

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Positive association were observed between perceived stress at work over a prolonged period and cancer at five sites (lung, colon, rectum, stomach cancers and NHL), out of the 11 sites studied. Subjects

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reported changes in stress occurrence over their career. Stress was ascribed to different sources, related and unrelated to factors assessed as part of the frequently-used job strain questionnaire. While over reporting of stress by cases cannot be fully dismissed, the associations observed, if substantiated, would bear important public health significance. Prospective studies building on detailed stress assessment protocols considering all sources and changes over the career are necessary.

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ACCEPTED MANUSCRIPT Funding This study was supported by research and personnel support grants from Health Canada, the National Cancer Institute of Canada, the Institut de recherche en santé et sécurité au travail du Québec, and the Fonds de la recherche du Québec - Santé (FRQS). M.E.P. and M.C.R. held career awards from the FRQS. M.C.R. held a New Investigator Award from the Canadian Institutes of Health Research. J.S. holds the

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Guzzo-CRS Research Chair in Environment and Cancer.

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Acknowledgements

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The authors would like to acknowledge the entire fieldwork team at INRS-Institut Armand-Frappier who

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were involved in the data collection of the study. The fieldwork was coordinated by Lesley Richardson. Ethics statement

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Ethics committees from the following hospitals approved the conduct of the study: Hôpital Notre-Dame, Hôpital St-Luc, Hôtel-Dieu de Montréal, Hôpital Maisonneuve-Rosemont, Hôpital Jean-Talon, Hôpital

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Charles-Lemoyne, Hôpital de Fleury, Hôpital du Sacré-Coeur de Montréal, Hôpital Lachine, Hôpital Santa Cabrini, Jewish General Hospital, Royal-Victoria Hospital, Montreal General Hospital, St-Mary’s Hospital,

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Lakeshore General Hospital, Hôpital de Lasalle, Montreal Chest Hospital, Hôpital de Verdun, Hôpital

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Pierre-Boucher. Conflict of interest

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The authors declare no conflict of interest.

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Authors’ contributions

A.B-L: Data analysis, interpretation of the data and critical revision of the manuscript. M-C.R: Interpretation of the data and critical revision of the manuscript. D.W: Interpretation of the data and critical revision of the manuscript M.E-Z: Data analysis, interpretation of the data and critical revision of the manuscript. J.S: Conception and design of the original study and critical revision of the manuscript. M-E.P: Conception and design of the analytical strategy, interpretation of the data and writing of the manuscript. All authors read and approved the final manuscript. 12

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50. Ardito C, d'Errico A, Leombruni R. Exposure to psychosocial factors at work and mental well-being in Europe. La Medicina del lavoro. 2014;105(2):85-99. 51. Goel N, Workman JL, Lee TT, Innala L, Viau V. Sex differences in the HPA axis. Comprehensive Physiology. 2014;4(3):1121-55. doi:10.1002/cphy.c130054. 52. Karasek R, Theorell T. Healthy work: Stress, Productivity and the Reconstruction of Working Life. New York: Basic Books; 1990. 53. Belkic KL, Landsbergis PA, Schnall PL, Baker D. Is job strain a major source of cardiovascular disease risk? Scand J Work Environ Health. 2004;30(2):85-128. 54. Kivimaki M, Virtanen M, Elovainio M, Kouvonen A, Vaananen A, Vahtera J. Work stress in the etiology of coronary heart disease--a meta-analysis. Scand J Work Environ Health. 2006;32(6):431-42. 55. Stansfeld S, Candy B. Psychosocial work environment and mental health--a meta-analytic review. Scand J Work Environ Health. 2006;32(6):443-62. 56. Thomson AK, Heyworth JS, Girschik J, Slevin T, Saunders C, Fritschi L. Beliefs and perceptions about the causes of breast cancer: a case-control study. BMC research notes. 2014;7:558. doi:10.1186/17560500-7-558. 57. Dumalaon-Canaria JA, Hutchinson AD, Prichard I, Wilson C. What causes breast cancer? A systematic review of causal attributions among breast cancer survivors and how these compare to expert-endorsed risk factors. Cancer Causes Control. 2014;25(7):771-85. doi:10.1007/s10552-014-0377-3. 58. Wardle J, Waller J, Brunswick N, Jarvis MJ. Awareness of risk factors for cancer among British adults. Public health. 2001;115(3):173-4. doi:10.1038/sj/ph/1900752. 59. Sach TH, Whynes DK. Men and women: beliefs about cancer and about screening. BMC Public Health. 2009;9:431. doi:10.1186/1471-2458-9-431. 60. Hamer M, Chida Y, Molloy GJ. Psychological distress and cancer mortality. J Psychosom Res. 2009;66(3):255-8. doi:S0022-3999(08)00527-8 [pii] 10.1016/j.jpsychores.2008.11.002. 61. Jahn I, Becker U, Jockel KH, Pohlabeln H. Occupational life course and lung cancer risk in men. Findings from a socio-epidemiological analysis of job-changing histories in a case-control study. Soc Sci Med. 1995;40(7):961-75. doi:027795369400151I [pii]. 62. Belkic K, Nedic O. Workplace stressors and lifestyle-related cancer risk factors among female physicians: assessment using the Occupational Stress Index. J Occup Health. 2007;49(1):61-71. doi:JST.JSTAGE/joh/49.61 [pii]. 63. Nakaya N, Bidstrup PE, Saito-Nakaya K, Frederiksen K, Koskenvuo M, Pukkala E et al. Personality traits and cancer risk and survival based on Finnish and Swedish registry data. Am J Epidemiol. 2010;172(4):377-85. doi:10.1093/aje/kwq046. 64. Ranchor AV, Sanderman R, Coyne JC. Invited commentary: personality as a causal factor in cancer risk and mortality--time to retire a hypothesis? Am J Epidemiol. 2010;172(4):386-8. doi:10.1093/aje/kwq210. 65. Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK. Sympathetic nervous system regulation of the tumour microenvironment. Nature reviews Cancer. 2015;15(9):563-72. doi:10.1038/nrc3978. 66. Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and cancer. Lancet Oncol. 2004;5(10):617-25. doi:S1470204504015979 [pii] 10.1016/S1470-2045(04)01597-9.

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Table 1. Covariates included in regression models assessing the relation between perceived work-related stress and each cancer site, Montreal Multisite Case-Control Cancer Study Number of cases 761 439 439 400 236 228 197 158 94 94 91

Cancer type Lung Colon Bladder Prostate Rectum Stomach Non-Hodgkin lymphoma Kidney Melanoma Pancreas Esophagus

Additional potential confounders included in regression modelsa

T P

Smoking, β-carotene, occupational exposure to asbestos and silica Smoking, alcohol, β-carotene, body mass index, occupational physical activity Smoking, coffee, β-carotene, occupational exposure to aromatic amines Smoking, alcohol, body mass index, occupational physical activity, farming Smoking, beer, body mass index Smoking, alcohol, β-carotene, birthplace None Smoking, alcohol, coffee, body mass index β-carotene, sports and/or outdoor activities Smoking, alcohol, coffee, β-carotene, body mass index Smoking, alcohol, coffee, tea, β-carotene

I R

C S

U N

a

A

D E

M

All models included age (years; continuous), ancestry (French, English, Italian, Jewish, Other European, Other), education (elementary, secondary, post-secondary), family income (Canadian dollars; continuous), and respondent status (self, proxy). Site-specific covariates: smoking (ever smoking, cigarette-years, number of years since quitting), beer or alcohol consumption (drink-years of beer, wine and spirits; continuous), β-carotene index (derived from the frequency of consumption of 10 β-carotene-rich foods; tertiles), tea or coffee consumption (cup-years; continuous), body mass index (weight (kg)/height(m)2 < 25, 25 to <30, ≥30; tertiles), birthplace (Montreal, Quebec excluding Montreal, Canada excluding Quebec, United States, Northern Europe, Asia/Africa, other), occupational exposure to crystalline silica, asbestos, or aromatic amines (ever, never), farming (ever, never), occupational physical activity (low, intermediate, high), sports and/or outdoor activities (not often/never, often).

T P

E C

C A

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Table 2. Selected characteristics of cases and controls by cancer site, Montreal Multisite Case-Control Cancer Study Participant group

Mean Age, years (SD)

% Proxy

% French ancestry

Controls

59.6 (7.9)

12.9

64.1

Cancer site Lung Colon Bladder Prostate Rectum Stomach NHL Kidney Melanoma Pancreas Esophagus

59.2 (7.0) 59.4 (7.6) 59.2 (7.6) 63.0 (5.0) 58.7 (8.0) 58.3 (8.2) 55.0 (9.7) 58.2 (7.6) 52.9 (10.0) 58.9 (7.5) 59.7 (7.6)

23.9 14.4 12.5 11.0 15.7 16.7 18.8 10.8 12.8 43.6 27.5

69.0 54.9 57.9 65.3 58.5 58.3 63.5 53.8 36.2 57.4 64.8

Mean years of schooling (SD)

Mean annual family incomea (SD)

Mean coffee, cup-years (SD)

10.0 (4.6)

26.5 (8.7)

92.3 (88.6)

8.5 (3.8) 9.9 (4.2) 10.0 (4.7) 9.3 (4.4) 9.3 (4.5) 8.8 (4.0) 10.6 (4.2) 9.4 (4.3) 12.3 (4.5) 8.5 (4.1) 8.9 (3.7)

22.4 (8.0) 26.0 (8.9) 25.8 (10.0) 24.7 (9.0) 26.3 (9.1) 24.2 (8.3) 26.2 (8.3) 26.3 (9.0) 29.6 (8.9) 25.8 (9.7) 24.4 (8.0)

117.0 (129.2) 93.3 (96.1) 116.2 (118.3) 106.7 (122.9) 85.0 (77.8) 97.8 (107.2) 82.4 (81.6) 94.7 (94.6) 88.9 (76.2) 106.3 (103.1) 119.1 (126.8)

T P

D E

Mean cigarette-years (SD)

Mean alcohol, beverageyears (SD)

810.4 (706.7)

61.7 (127.7)

1,493.7 (829.7) 802.1 (731.1) 1,034.8 (704.3) 968.7 (809.8) 790.8 (762.2) 966.8 (849.3) 757.3 (665.1) 803.8 (691.5) 483.7 (592.6) 991.7 (769.8) 1,255.3 (843.1)

172.4 (334.8) 103.2 (235.9) 115.1 (286.3) 129.0 (315.6) 78.9 (134.0) 99.1 (194.3) 83.2 (254.8) 97.2 (188.7) 49.8 (80.6) 157.1 (353.9) 234.7 (360.8)

E C

T IP

6,155.6 (3384.9)

R C

S U

N A M

Mean βcarotene indexb (SD)

5,478.2 (3401.8) 5,952.5 (3514.8) 6,166.5 (3355.6) 6,426.7 (3456.6) 5,959.8 (3259.1) 5,635.0 (3300.8) 5,882.0 (3404.5) 6,168.6 (3412.8) 5,803.9 (3211.9) 5,253.5 (3120.0) 5,805.2 (3386.5)

Mean BMIc, kg/m2 (SD)

% Psychological symptomsd

25.6 (3.5)

9.8

24.7 (3.8) 25.4 (3.3) 25.1 (3.4) 25.8 (3.4) 25.5 (3.7) 24.8 (3.6) 25.6 (3.6) 26.4 (4.3) 25.7 (3.2) 25.5 (3.6) 24.8 (3.9)

13.9 18.3 15.3 17.9 12.3 12.4 14.3 12.0 12.8 16.1 15.7

BMI, Body mass index; SD, Standard deviation, NHL, Non-Hodgkin lymphoma. a Expressed as Canadian dollars, in thousands. b Data were missing for 56 controls and 27 lung, 95 colon, 123 bladder, 152 prostate, 21 rectal, 56 stomach, 50 NHL, 37 kidney, 21 melanoma, 18 pancreatic, and 27 esophageal cancer cases. c Data were missing for 3 controls and 1 lung, 3 colon, 1 bladder, 4 prostate, 2 rectal, 2 stomach, 2 NHL, 2 pancreatic, and 1 esophageal cancer cases. d Defined as frequent anxiety, depression or trouble sleeping. Data were missing for 1 control and 8 lung, 2 colon, 1 bladder, 3 prostate, 2 stomach, 1 NHL, 1 pancreatic, and 2 esophageal cancer cases.

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Table 3. Association between ever exposure and cumulative duration of exposure to perceived work-related stress and each cancer site, Montreal Multisite Case-Control Cancer Study Ever exposure Participant group

Cumulative duration of perceived work-related stress, in years

Age-adjusted model N

n

%

OR

OR

512

192

37.5

Ref.

Lung

761

330

43.4

1.27

1.01, 1.60

1.33

Colon

439

204

46.5

1.44

1.11, 1.87

Bladder

439

199

45.3

1.37

1.05, 1.78

Prostate

400

164

41.0

1.26

Rectum

236

109

46.2

Stomach

228

103

NHL

197

89

Kidney

158

Melanoma

95% CI

1 - < 15 years 95% CI

OR

56

10.9

Ref.

n

%

OR

67

13.1

Ref.

1.01, 1.75

90

11.8

0.99

0.65, 1.52

123

1.51

1.15, 1.98

49

11.2

1.32

0.85, 2.05

75

1.37

1.03, 1.81

60

13.7

1.43

0.93, 2.19

78

C S

0.96, 1.67

1.26

0.95, 1.68

30

7.5

0.93

0.56, 1.53

1.40

1.02, 1.91

1.52

1.10, 2.10

24

10.2

1.18

45.2

1.34

0.98, 1.84

1.53

1.08, 2.15

22

9.6

0.95

45.2

1.26

0.89, 1.78

1.36

0.96, 1.94

21

10.7

0.91

66

41.8

1.15

0.79, 1.65

1.17

0.80, 1.71

94

46

48.9

1.31

0.82, 2.08

1.19

0.71, 2.00

Pancreas

94

37

39.4

1.06

0.68, 1.67

1.27

0.76, 2.10

Esophagus

91

40

44.0

1.31

0.83, 2.06

1.44

0.86, 2.42

Cancer site

T P

D E

a

I R

%

Ref.

T P

15 - 30 years

a

n

Controls

95% CI

Fully-adjusted modela

95% CI

> 30 years n

a

%

OR

69

13.5

Ref.

95% CI

16.2

1.47

0.99, 2.20

117

15.4

1.51

1.02, 2.25

0.01

17.1

1.52

1.03, 2.24

80

18.2

1.64

1.11, 2.42

<0.01

17.8

1.59

1.07, 2.37

61

13.9

1.11

0.74, 1.69

0.12

63

15.8

1.48

0.98, 2.23

71

17.8

1.31

0.88, 1.94

0.07

0.69, 2.03

19.9

1.84

1.18, 2.87

38

16.1

1.48

0.93, 2.35

0.01

M

A

47

0.53, 1.69

47

20.6

2.15

1.35, 3.44

34

14.9

1.48

0.89, 2.45

0.01

0.51, 1.64

38

19.3

1.47

0.90, 2.39

30

15.2

1.69

1.01, 2.82

0.02

U N

17

10.8

1.00

0.54, 1.86

24

15.2

1.14

0.66, 1.98

25

15.8

1.34

0.78, 2.30

0.30

16

17.0

1.08

0.50, 2.31

18

19.1

1.29

0.64, 2.62

12

12.8

1.20

0.55, 2.64

0.48

9

9.6

1.12

0.49, 2.57

16

17.0

1.70

0.85, 3.39

12

12.8

1.01

0.47, 2.18

0.47

9

9.9

1.29

0.55, 2.99

11

12.1

1.19

0.54, 2.64

20

22.0

1.75

0.89, 3.45

0.12

E C

CI, Confidence interval; OR, Odds ratio, NHL, Non-Hodgkin lymphoma. a

P for trend

C A

Adjusted for age, ethnicity, education level, family income, respondent status and site-specific non-occupational and occupational covariates described in Table 1. A missing indicator was used for missing data for body mass index and β-carotene.

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Appendix 1. Selected characteristics of the 512 population controls by cumulative duration of perceived work-related stress, Montreal Multisite Case-Control Cancer Study Characteristics Age, years, mean (SD) Proxy respondent, n (%) French ancestry, n (%) Years of schooling, mean (SD) Annual family income, CAN$, mean (SD) Coffee, cup-years, mean (SD) Cigarette-years, mean (SD) Alcohol, beverage-years, mean (SD) β-carotene index, mean (SD)a Body mass index, kg/m2, mean (SD)b Psychological symptoms, n (%)c

0 (n = 320) 60.2 (7.4) 44 (13.8) 212 (66.3) 9.8 (4.6) 25,920 .0 (8,321) 91.2 (91.1) 795.1 (688.6) 62.8 (111.8) 6,085.9 (3,376.4) 25.5 (3.6) 25 (7.8)

Cumulative duration of work-related stress, years 1- < 15 15 – 30 > 30 (n = 56) (n = 67) (n = 69) 56.2 (9.5) 57.3 (8.8) 62.1 (6.3) 6 (10.7) 8 (11.9) 8 (11.6) 31 (55.4) 40 (59.7) 45 (65.2) 10.7 (4.6) 11.2 (4.8) 9.5 (3.7) 27,832.0 (9,730) 26,338.0 (7,875) 28,383.0 (9,819) 80.0 (78.8) 99.4 (89.7) 101.0 (83.1) 993.2 (865.9) 656.0 (652.6) 883.2 (672.1) 42.2 (93.0) 57.1 (108.3) 77.4 (211.9) 6,357.2 (3,453.7) 6,284.6 (3,614.8) 6,186.3 (3,187.0) 25.8 (3.0) 26.3 (3.5) 25.7 (2.9) 9 (16.1) 4 (6.1) 12 (17.4)

D E

T P

I R

C S

U N

A

M

CAN$, Canadian dollars; SD, Standard deviation. a Data were missing for 33 controls (no exposure category), 4 controls (1-< 15 years duration category), 7 controls (15-30 years duration category), and for 12 controls (> 30 years duration category). b Data were missing for 2 controls (no exposure category) and for 1 control (1-< 15 years duration category). c Defined as frequent anxiety, depression or trouble sleeping. Data were missing for 1 control (15-30 years duration category).

T P

E C

C A

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Appendix 2. Proportion of jobs reported as stressful for the occupationsa most often entailing perceived stressb, Montreal Multisite Case-Control Cancer Study Occupation group Firemen Industrial and aerospace engineers Motor vehicle and rail transport mechanics and repairmen Sewing machine operators, textile and similar materials Social sciences workers Sales occupations Writers and editors Railway and subway transport operators Patternmaking, marking and cutting occupations: textile, fur and leather products Plasterers and related occupations Printing operators Health care workers Bus drivers Commercial travelers Supervisors (regardless of specialty) Teachers Managers and administrative workers Miners

D E

a b

T P

E C

Corresponding to more than 30 jobs in the study population. At least 20% of jobs in the occupation group reported as stressful.

C A

21

% of jobs reported as stressful 40.4 31.2 28.3 27.0 26.8 24.5 23.8 23.1 22.9 22.6 22.6 22.4 22.1 21.0 20.5 20.3 20.2 20.0

T P

I R

C S

U N

A

M

Total number of jobs 47 48 46 37 82 184 42 117 70 31 115 125 86 267 796 187 961 35

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M

AN

US

CE 22

IP

CR

% of jobs 17.7 10.7 7.9 6.1 5.7 5.6 5.0 4.7 3.7 2.6 2.2 1.8 1.5 1.1 1.0 0.9 0.8 0.7 0.5 0.4 20.4 11.2

The subject could have indicated several reasons for the same job.

AC

a

N jobs 485 293 217 167 157 153 137 128 100 70 60 48 42 29 28 25 21 20 14 12 560 306

PT

ED

Sourcesa High demand and time pressure Sales commissions / customer service Responsibility Subject’s anxious temperament Production Financial insecurity Hazardous work conditions Employees supervision Conflictive relationship / bad atmosphere Environment / working conditions Driving Own business Precision and concentration required Public Shift work or night work Teaching Lack of interest Physical demand Unpredictability Health concerns Other reason Not specified

T

Appendix 3. Reported sources of perceived work-related stress, Montreal Multisite Case-Control Cancer Study

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Appendix 4. Transitions in perceived work-related stress across jobs over the lifetime among cases and controls, Montreal Multisite Case-Control Cancer Study Cases (N=1375)

Work-related stress over the lifetime*

N

%

276

20.1

41

21.4

1099

80.0

151

1

370

1

23

0.76

61.6

90

59.6

33.7

55

36.4

4.7

6

4.0

US

AC

CE

PT

ED

*Among subjects ever reporting stress.

M

>1

52

0.22

96

8.7

12

8.0

899

81.8

131

86.7

104

9.5

8

5.3

AN

>1 Number of transitions from a non-stressful job to a stressful one No

CR

677

P value 0.68

78.6

IP

Stress reported for all jobs held Changes in stress level reported across jobs during career Number of transitions from a stressful job to a non-stressful one No

%

T

N

Controls (N=192)

ACCEPTED MANUSCRIPT

Highlights

CE

PT

ED

M

AN

US

CR

IP

T

Perceived workplace stress associated with 5 out of 11 cancer sites First study assessing perceived stress at work over the entire career among men Subjects identified changes in stress level across jobs Stress ascribed to several reasons other than high demand

AC

   

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