Introduction

Carpal tunnel syndrome (CTS) is a common entrapment neuropathy in the general population and in the working population [1], with repercussions on personal and professional life. Several studies have highlighted associations between CTS and personal characteristics (e.g., advanced age, female gender) [2,3], medical conditions (e.g., obesity, diabetes mellitus, arthritis) [4–6] and occupational exposure to biomechanical factors (e.g., repetitive movements, hand-arm transmitted vibration, and forceful manual exertion) [1,7–13]. There is limited epidemiological evidence for an association between psychosocial factors (occupational or not) and CTS [14].

Multi-exposure situations are common in the world of work, whether they involve exposure to multiple biomechanical or chemical factors, or both at the same time. In previous studies, we showed that occupational co-exposure to biomechanical factors and neurotoxic chemicals was observed among 4.8% to 10.9% of men and 0.7% to 3.7% of women [15,16]. Workers under 30 years old, blue-collar workers and those working in small companies are more often co-exposed to biomechanical stressors and chemical agents [16]. Some of the chemical agents encountered in the workplace have neurotoxic properties that can alter the functioning of the central nervous system (CNS) and/or the peripheral nervous system (PNS) [17–25]. To the best of our knowledge, the impact of chemical exposure on the risk of CTS has rarely been studied despite the potential neurotoxicity of some chemicals [15,26–31]. Ophir et al. [29] reported an increased risk of CTS-like symptoms following subclinical sensory polyneuropathy (affecting mainly the median and sural nerves) in workers exposed to prolonged low-level exposure to organophosphate in rural communities in Israel. However, a case-control study of CTS conducted in the general population of Wisconsin failed to report an association between CTS and chemical exposure after adjustment for the known risk factors [26]. The frequent biomechanical and chemical co-exposure raises the question of potential synergistic effects of mechanical stressors and neurotoxic chemicals on the risk of CTS [15]. Systemic peripheral neuropathies (e.g., diabetic polyneuropathy) are known to cause subtle nerve damage, thus rendering the median nerve more vulnerable to compression within the carpal tunnel and against the volar ligament in the case of overexposure to biomechanical stressors [32,33]. Following the same reasoning, exposure to chemicals in the workplace could also cause subclinical changes in the median nerve [29] – producing a form of double crush syndrome that could weaken the median nerve [34]. This could potentiate mechanical stress on the nerve in the event of co-exposure with biomechanical stress factors that increase intra-tunnel pressure. Subclinical changes in the central nervous system (CNS) can also occur in workers exposed to chemicals [35,36] and lead to impaired sensorimotor control of force production and finger dexterity, thus generating greater mechanical stress on the median nerve.

In previous studies, we have shown an association between CTS and co-exposure to biomechanical risk factors and chemicals, after adjustment for confounders in a cohort of French workers [15] and in a cross-sectional study of French Farmers and Agricultural Workers [31]. Lifetime exposure to chemicals has been assessed retrospectively, which may lead to misclassification of exposure. The present study aimed to investigate the association between co-exposure to biomechanical risk factors and potentially neurotoxic chemicals and incident CTS in a large cohort of French workers, using two methods to estimate chemical exposure: job-exposure matrices (JEM) and self-reported exposure.

Methods

Results

At the time of analysis, data were available for 184,055 participants in the CONSTANCES cohort, including 52,555 who met our inclusion criteria (S1 Fig).

Lifetime chemical exposure estimated by JEM

Among the 40,889 participants eligible for analysis with lifetime chemical exposure estimated by JEM (18,940 men and 21,949 women), 1.6% [95% CI 1.4–1.8] of men (n = 304) and 2.6% [95% CI 2.4–2.8] of women (n = 564) reported incident CTS at follow-up (p < 0.001).

The median number of jobs held during the career was 3 (IQR 2–5) for men and 3 (IQR 2–4) for women. The median duration of current job was 8 years (IQR 4–16) for men and 9 years (IQR 4–16) for women. Women were more exposed to biomechanical risk factors than men (32.6% vs. 28.0% respectively, p < 0.001). In detail, women reported more high physical demand (21.1% vs. 19.6% respectively, p < 0.001) repetitive movements (11.3% vs. 8.2%, p < 0.001) and repetitive pinching (4.5% vs. 3.6%, p < 0.001), while men were more exposed to awkward wrist postures (7.4% vs. 6.4%, p < 0.001) and hand-transmitted vibrations (3.4% vs. 0.9%, p < 0.001). Men were more exposed to chemicals during their working life than women (14.9% vs. 13.1% respectively, p < 0.001). In detail, men were more exposed to chlorinated solvents (10.4% vs. 2.7%, p < 0.001) and less exposed to formaldehyde (6.4% and 11.5%, p < 0.001). Co-exposure to biomechanical risk factors and chemicals concerned 7.2% of men and 7.6% of women (p < 0.001, Table 1).

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Table 1. Baseline characteristics of workers (occupational chemical exposure assessed by job-exposure matrices) in men (n = 18,940) and women (n = 21,949).

https://doi.org/10.1371/journal.pone.0329324.t001

More precisely, among men, the most frequent exposures were single exposures: 8.6% were exposed only to high physical perceived exertion, 4.9% only to chlorinated solvents, 3.4% only to repetitive movements and 1.9% only to formaldehyde (S2 Fig). Among women, the most frequent exposures were also single exposures: 10.1% were exposed only to high physical perceived exertion, 5.7% only to formaldehyde, 4.1% only to repetitive movements; 3.8% of women were exposed to high physical perceived exertion and formaldehyde (S3 Fig).

Univariate analysis is shown in S4 Table. In the multivariable analysis, a statistically significant association (p < 0.001) was found for both genders between CTS and exposure to biomechanical risk factors and chemicals. The adjusted OR in the biomechanical exposure group were 2.02 [1.55–2.63] in men and 1.46 [1.20–1.77] in women, and the adjusted OR in the co-exposure group were 2.37 [1.67–3.38] in men and 2.05 [1.58–2.66] in women, compared to non-exposed workers (Fig 1). Age did not show any interaction with co-exposure.

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Fig 1. Multivariate risk models for CTS in a) men (n = 18,940) and b) women (n = 21,949) after adjustment for covariates (age, BMI, diabetes mellitus and/or rheumatoid arthritis, current alcohol consumption and effort-reward imbalance) with lifetime chemical exposure estimated by JEM.

https://doi.org/10.1371/journal.pone.0329324.g001

Self-reported lifetime chemical exposure

Among the 46,809 participants eligible for analysis using self-reported lifetime chemical exposure (22,751 men and 24,058 women), 1.6% [95% CI 1.5–1.8] of men (n = 371) and 2.5% [95% CI 2.3–2.7] of women (n = 611) reported incident CTS at follow-up (p < 0.001).

The median number of jobs and the median duration of current job were identical to the JEM analysis. Women were more exposed to biomechanical risk factors than men (33.2% vs. 29.3% respectively, p < 0.001) and men were more exposed to chemicals during their working life than women (16.4% vs. 7.0%, p < 0.001). Co-exposure to biomechanical risk factors and chemicals concerned 8.2% of men and 3.5% of women (p < 0.001, Table 2) [55]. Among men, the most frequent exposures were single exposures: 8.7% were exposed only to high physical perceived exertion and 3.3% only to repetitive movements (S5 Fig). Among women, the most frequent exposures were: exposed only to high physical perceived exertion (13.0%), exposed only to repetitive movements (5.9%) and exposed to high physical perceived exertion and repetitive movements (2.2%) (S6 Fig).

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Table 2. Baseline characteristics of workers (occupational chemical exposure assessed by self-reported) in men (n = 22,751) and women (n = 24,058).

https://doi.org/10.1371/journal.pone.0329324.t002

Univariate analysis is shown in S4 Table. Similar to the JEM, a statistically significant association (p < 0.001) was found between CTS and exposure to biomechanical risk factors and chemicals for both genders. The adjusted OR in the biomechanical exposure group were 1.92 [1.50–2.46] in men and 1.53 [1.29–1.82] in women (ref: non-exposed workers). The adjusted OR in the co-exposure group were higher than in the analysis with JEM: 2.97 [2.22–3.97] in men and 2.49 [1.80–3.44] in women, compared to non-exposed workers (Fig 2). Age did not show any interaction with co-exposure.

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Fig 2. Multivariate risk models for CTS in a) men (n = 20,877) and b) women (n = 21,291) after adjustment for covariates (age, BMI, diabetes mellitus and/or rheumatoid arthritis, current alcohol consumption and effort-reward imbalance) with self-reported lifetime exposure to chemicals.

https://doi.org/10.1371/journal.pone.0329324.g002

Discussion

Our previous study on a sample of French professionally active adults enrolled in the Constances cohort had showed an higher association between self-reported CTS and co-exposure to biomechanical risk factors and chemicals in both genders after adjustment for personal and medical factors and effort–reward imbalance ratio [15]. The present study, which involved a larger sample, confirmed the associations between co-exposure and incident CTS, by using two different methods to assess chemical exposure (JEMs and self-report).

Little epidemiological data is available on the association between chemical exposures and CTS in spite of their potential neurotoxicity. The association for the co-exposure group may reflect synergic effects of biomechanical stressors and chemicals. Mechanistically, pathophysiological studies show that increased intra-canal pressure (ICP) secondary to wrist movements and external compression at the carpal tunnel represents the main mechanism behind the intraneural vascular disruption and the median nerve damage (peripheral biomechanical component) [56]. Central sensory-motor mechanisms secondary to abnormalities in sensory feedback and motor control of the hand have more recently been highlighted (central sensory-motor component) [57]. Concerning the association for chemical and biomechanical co-exposures, the median nerve at the level of the carpal tunnel is particularly exposed to biomechanical stresses due to wrist mobility. Two putative mechanisms, peripheral and central, may be involved in the combined effects of neurotoxic chemical and biomechanical exposures on the risk of CTS.

First, systemic peripheral nerve damage (peripheral mechanism), secondary to neurotoxic exposure, could induce diffuse nerve microdamage making the median nerve more sensitive to compression in the carpal tunnel secondary to biomechanical stresses (concept of “double crush syndrome” induced by chemicals) [32–34]. Second, central nervous lesions of neurotoxic origin lead to functional and/or structural alterations of the CNS [19,22,25,35,36,50,58] (Central mechanism), in particular in the sensorimotor zones likely to increase the effects of CTS by (i) impairing sensorimotor coordination and disrupting the biomechanical efficiency of professional movements, and (ii) accentuating the decrease in dexterity induced by anomalies in haptic sensory feedback during CTS [59–61]. These mechanisms could lead to an increase in the biomechanical stresses applied to the wrist, and thus create a vicious circle likely to accentuate the risk of CTS in co-exposed workers. However, we cannot rule out that chemical exposure may also be a marker for greater overuse of hand strength at work. Given the rather rudimentary assessment of wrist exposure, it may be that part of the effect of combined exposure is linked to greater biomechanical exposure at the wrist. Indeed, the proportion of blue-collar workers was higher among co-exposed individuals, and it might be expected that blue-collar workers would be more exposed to chemicals and use their hands at higher intensities than employees reporting the same level of hand use. Odds ratios were broadly similar when the study population was restricted to lower-level white-collar and blue-collar workers, but the associations were statistically significant only in women.

The prospective design is one of the major strengths of the study. The Constances cohort includes a large sample of employed men and women of various age groups from different regions in France, covering a variety of occupational groups [37]. Lifetime chemical exposure was evaluated by two methods: JEM and self-report. Both methods found an association between co-exposure to biomechanical risk factors and chemicals and CTS. In addition, the main potential personal and medical risk factors for CTS were taken into account (e.g., age, BMI, diabetes mellitus, arthritis, and alcohol consumption) [4,11]. Analyses were stratified according to gender following the recommendations for the study of musculoskeletal disorders [53,54]. The differences in exposure frequency between men and women could be explained by the fact that women and men do not occupy the same jobs. In addition, even within the same occupation, several studies have shown that exposure differs between men and women due to the gendered distribution of tasks, missions and workspaces [62].

There are several limitations to this study. Despite its size, the study sample does not represent the whole structure of occupations in France, as self-employed workers and farmers are not included in the cohort. There are two cohorts set up by Santé publique France (Coset-MSA and Coset-Indépendants) that would allow to study these specific populations [63].

Epidemiological studies include several definitions of CTS [64]. In our study, CTS was reported by participants using a single question (yes/no). We cannot rule out misclassification, as CTS may have been over-reported by workers who believe they have been exposed to occupational factors causing CTS, whether or not their hand symptoms resemble those of CTS. The cohort design did not allow for the use of a symptom algorithm, physical examination or EMG confirmation, which is an important limitation of the study. The working population studied probably did not include the most severe cases of CTS that may have been excluded from the labor market (i.e., the healthy worker effect), which could lead to an underestimate of the prevalence of CTS.

Measuring self-reported occupational exposure is an important limitation of the study. Direct observation or measurement is costly and difficult to apply to large cohorts. In addition, the assessment of biomechanical risk factors was requested for a typical working day and was based on the recommendations of the European criteria document for the relatedness of MSDs [38], and postures were presented in pictorial form to facilitate workers’ understanding and increase the validity of posture self-assessment. We cannot exclude that biomechanical and chemical exposures were over-reported by workers reporting work-related CTS, which is a potential source of reverse causality. To limit this bias, we have excluded subjects reporting chronic wrist pain and/or CTS at baseline. Nevertheless, there is no evidence to suggest a differential bias depending on whether workers were exposed to biomechanical factors alone or to biomechanical and chemical factors combined. Moreover, the prevalence of self-reported CTS was of the same order of magnitude depending on whether there was biomechanical exposure alone or biomechanical and chemical co-exposure (in analysis with JEM: 2.5% vs 3.1% in men and 3.2% vs 4.5% in women; in analysis with self-report: 2.3% vs 3.6% in men and 3.3% vs 5.2% in women). Although the difference in prevalence was relatively modest, we do not believe that classification bias can explain the results, given the consistency of the results with a subjective assessment and an objective assessment of chemical exposure by JEM.

The list of chemicals was different between the JEM and self-reported analyses, with only trichloroethylene and formaldehyde common to both. Indeed, the self-administered questionnaire does not allow detailed questioning about chemicals (chemical substances, chemical families, complex mixtures and product categories) [17], as workers may be unfamiliar with the chemicals to which they have been exposed during their working careers. Moreover, lifetime self-report was assessed using a single ever/never question and memory bias cannot be ruled out. JEM has the advantage of providing a more accurate estimate of chemical exposure, especially for past exposures. However, by construction, JEM considers that people within the same job code and a given period have the same exposure. Misclassification of exposure is expected to be non-differential with respect to the health outcome, the true association might be stronger than observed. In addition, some known neurotoxic chemicals, such as lead, mercury, n-hexane, were not available in JEM. JEMs developed by Santé publique France for petroleum and oxygenated solvents will soon be updated with the same nomenclatures of jobs as Constances, and analyses taking these solvents into account could be carried out in the future. Given the exposure of workers to a mixture of solvents rather than to a given type of solvent, it cannot be ruled out that workers exposed to chlorinated solvents were also exposed to aliphatic or aromatic solvents [16]. Given the large size of the cohort (over 200,000 adults) and the global nature of the cohort, questions deemed relevant to the study of CTS could not be asked, such as ergonomic measures in the workplace and the wearing of protective equipment. We chose covariates based on the literature [13,6,51,52], and opted to not include tobacco consumption [51]. Physical activity would have also been relevant. However, the physical activity practiced was not indicated in the questionnaire, and some sports, such as tennis or golf have an impact on CTS, while others have no impact. Endocrine disorders such as hyperthyroidism and hypothyroidism were not available in the questionnaires at baseline. In addition, there is no validated algorithm for identifying these disorders in French administrative health care database. Consequently, these disorders could not be used as covariates.

In conclusion, this large prospective study showed an association between self-reported CTS and co-exposure to both occupational biomechanical risk factors and chemicals, using JEM and self-report methods. These results are consistent with those of our previous studies in the same cohort with self-reported chemical exposure [15], and in a cohort of French farmers, although, we lack mechanistic evidence, provide further support for the potential effects of chemical exposure on the risk of CTS in workers exposed to biomechanical risk factors. Access to French administrative health care database will enable us to study associations between surgically treated CTS and occupational co-exposures in a future study. It would also be relevant to study other chemical exposures (petroleum and oxygenated solvents), as well as biomechanical exposures by considering a more objective measure such as JEM.

Supporting information

Acknowledgments

The authors thank the team of the “Population-based cohorts unit” (Cohortes en population) that designed and manages the Constances cohort study. They also thank the French national health insurance (“Caisse nationale d’assurance maladie”, Cnam) and its Health screening centres (“Centres d’examens de santé”), which are collecting a large part of the data, as well as the French national old-age insurance (“Caisse nationale d’assurance vieillesse”, Cnav) for its contribution to the constitution of the cohort, and ClinSearch, Asqualab and Eurocell, which are conducting the data quality control. The authors thank the members of the Matgéné working group from Santé publique France for providing job-exposure matrices.