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Manganese cumulative exposure and symptoms: A follow-up study of alloy workers
NeuroToxicology 29 (2008) 577–583
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NeuroToxicology
Manganese cumulative exposure and symptoms: A follow-up study of alloy workers Maryse Bouchard a,*, Donna Mergler a, Mary E. Baldwin a, Michel Panisset b a b
CINBIOSE (Centre de recherche interdisciplinaire sur la biologie, la sante´, la socie´te´ et l’environnement), Universite´ du Que´bec a` Montre´al, Montre´al, Canada Unite´ des troubles du mouvement Andre´-Barbeau, Centre Hospitalier de l’Universite´ de Montre´al, Montre´al, Canada
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 January 2008 Received in revised form 15 April 2008 Accepted 21 April 2008 Available online 2 May 2008
Long-term exposure to manganese (Mn) particulates through inhalation can be neurotoxic, with deficits in neuromotor and cognitive domains. Mn-exposed individuals also report symptoms, including fatigue, mood changes, irritability, concentration difficulties, and sweating in the absence of physical effort. The long-term course of Mn-related symptoms after cessation of exposure has never been examined. Male workers from a Mn-alloy production plant participated in a study on nervous system functions (initial examination), and were followed-up 14 years after plant closure. The relation between self-reported symptoms and Mn cumulative exposure index (CEI) was examined among 71 Mn-alloy workers and 71 referents. Symptoms from the questionnaire were grouped into categories, and the reported frequency was compared between referents and Mn-alloy workers in each Mn CEI tertile using General Linear Models, controlling for age, education, and alcohol consumption. A gradual increase in symptoms frequency was observed for complaints related to hearing and movement control both at initial and follow-up examination, and fatigue and autonomic nervous system only at initial examination. In addition, an exposure–effect relation was apparent for symptoms related to memory, concentration and balance reported at both examinations, with Mn-workers in the highest CEI tertile reporting the highest level of symptomatology. Sleeping complaints were not associated with exposure to Mn, while musculoskeletal pain and muscular weakness were reported more often by Mn-workers than referents but were not clearly related to CEI. The findings suggest that former Mn-alloy workers continue to perceive symptoms many years after cessation of exposure. Despite the limitations of self-reported symptoms, subjective complaints are an important part of a health assessment since they relate directly to perceived health status and day-to-day functioning. ß 2008 Elsevier Inc. All rights reserved.
Keywords: Manganese alloy-workers Cumulated exposure indices Symptoms Neurotoxicity Cohort study Motor Cognitive Mood
1. Introduction Manganese (Mn) is an essential nutrient which, in case of overexposure via inhalation or ingestion, can turn into a potent neurotoxicant. Upon high exposure, Mn accumulates in the globus pallidus, but also in other basal ganglia including caudate and putamen (Pal et al., 1999). In long-term exposed workers, the accumulation of Mn, as indicated by pallidal T1-weighted magnetic resonance signal hyperintensity has been shown to correlate with several Mn-exposure metrics, such as airborne Mn, blood Mn, and cumulative exposure (Shin et al., 2007). In addition, accumulation of Mn in the frontal white matter and a concurrent decrease in
* Corresponding author at: CINBIOSE, UQAM (SB-1983), C.P. 8888, Succ. CentreVille, Montre´al (Que´bec) H3C 3P8, Canada. Tel.: +1 514 987 3000/4759; fax: +1 514 987 6183. E-mail address: [email protected] (M. Bouchard). 0161-813X/$ – see front matter ß 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.neuro.2008.04.013
N-acetylaspartate (NAA)/creatine (Cr) ratio, indicative of neuronal degeneration, has been reported in non-human primates injected with Mn sulfate (Guilarte et al., 2006). Mn neurotoxicity disrupts neurotransmitter equilibrium, including dopaminergic and glutamate systems (Fitsanakis et al., 2006; Guilarte and Chen, 2007). The mechanisms of toxicity are not fully elucidated but it has been suggested that excitotoxicity may occur due to Mn-induced altered glutamate metabolism (Erikson and Aschner, 2003). Over exposure through inhalation of Mn particulates can result in a severe intoxication syndrome, manganism, resembling Parkinson’s disease (Calne et al., 1994; Rodier, 1955). The symptomatology of manganism includes adverse mood states (irritability, depressive feelings), decreased memory and concentration, fatigue, headache, vertigo, equilibrium loss, insomnia, tinnitus, trembling of fingers, muscle cramp, rigidity, alteration of libido and sweating (Tanaka, 1988). This debilitating condition persists or can even aggravate after cessation of exposure (Huang et al., 1998). Long-term exposure to Mn at lower levels than those
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implicated in the development of manganism has been associated with deficits in neuromotor and some cognitive functions, including poor hand–eye coordination, difficulty performing alternating movements, hand tremor, postural instability, prolonged reaction time, decreased memory and cognitive flexibility (for a review, see Zoni et al. (2007)), although not all studies have observed effects (Myers et al., 2003a,b). Several studies of active workers have surveyed symptoms using a great variety of questionnaires. While some noted important differences between exposed workers and referent groups (Bowler et al., 2007; Chia et al., 1993; Ferraz et al., 1988; Jonderko, 1979; Sinczuk-Walczak et al., 2001), others found an increase only for non-specific symptoms (Bast-Pettersen et al., 2004; Deschamps et al., 2001; Myers et al., 2003b; Roels et al., 1987) or a small number of symptoms (Lucchini et al., 1999; Sjo¨gren et al., 1996). A number of issues have been raised regarding the use of symptom questionnaires in neurotoxicity studies (Williamson, 2007). Among the concerns expressed are that, compared to objective evaluations, these measures are more vulnerable to misrepresentation for numerous reasons including malingering, social desirability, problems of language, question style, unreliable recall and unintentional biases (Williamson, 2007). On the other hand, there are several reasons to include symptom surveys. Increased symptom prevalence reflects decreased well being (Gregersen et al., 1987; Mergler, 1999) and has been interpreted as evidence of neurological dysfunction (Hanninen et al., 1979; Hawkins, 1990). Neurotoxicants have been associated with emotional disturbances and mood lability, which are intrinsically subjective experiences that can only be assessed and reported by the person him- or her-self. In the case of transient problems (e.g., increased saliva), or when the functional limitation is only apparent in certain circumstances (e.g., insomnia), self-reporting provides important information difficult to obtain objectively (Williamson, 2007). Finally, the profile of symptom reporting can be valuable in assisting physician practitioners confronted with possible cases of overexposed individuals. The long-term course of the effects of Mn exposure after cessation of exposure, in the absence of a diagnostic of manganism, has seldom been reported. In 1990, we conducted a matched-pair, cross-sectional study on nervous system functions of male workers from a Mn-alloy production plant. The Mn-exposed workers reported significantly more symptoms compared to the reference group (Mergler et al., 1994). The plant closed shortly after completion of the study, and in 2004, we conducted a follow-up study of the former Mn-alloy workers and referents. The results for neurobehavioral functions (Bouchard et al., 2007a) and neuropsychiatric findings (Bouchard et al., 2007b) are reported elsewhere. The present investigation aimed at exploring the relation between different symptoms and cumulative Mn exposure, both during exposure and 14 years following its cessation. 2. Participants and methods 2.1. Recruitment and study participants The initial 1990 study was carried out with workers employed in a ferro- and silico-Mn production plant located in South-West Quebec. The strategy adopted for this study was a matched-pair design where workers from the plant were matched to blue-collar non-exposed workers from the same region on the variables age, education, smoking habits and number of children (Mergler et al., 1994). A total of 115 Mn-alloy workers and 145 referents were tested at initial investigation. These men constituted the target population for the follow-up study, carried out in 2004. Informed consent was obtained from each participant and the Institutional
Table 1 Characteristics of the study population at the 2004 follow-up examination Characteristics Age (years) Range
a
Referents (n = 71)
Mn-workers (n = 71)
56.9 (7.2) 43.5–74.1
58.0 (5.4) 48.6–71.4
Education (years) a Range
11.1 (2.4) 6.0–17.5
11.0 (1.7) 6.0–15.5
Alcohol consumption (g/week)a Range
129 (145) 0–594
Tobaccob Current Former Never
17 (24) 36 (51) 18 (25)
Cumulative exposure indexa (mg Mn/m3 years) Lowest tertile n/a Middle tertile Highest tertile
149 (131) 0–1152
17 (24) 41 (58) 13 (18)
6.0 (4.3) 19.5 (5.0) 58.2 (21.7)
n/a: not applicable. a Mean (S.D.). b Frequency (%).
Ethics Board (Universite´ du Que´bec a` Montre´al) approved the study protocol. The details on recruitment of participants and exclusion of those with central nervous system (CNS) problems unlikely to be related to Mn exposure are presented elsewhere (Bouchard et al., 2007a). Seventy-one individuals remained in each exposure group after exclusions; their characteristics are presented in Table 1. Age, education, alcohol and tobacco consumption were similarly distributed in the two groups. 2.2. Mn exposure For the Mn-alloy workers included in the present analyses, the mean number of years of exposure to Mn was 15.7 (range: 7.4–17.3 years) and only 1 worker had less than 10 years of exposure. A description of the process of Mn-alloy production and exposure to Mn in the plant is reported in Bouchard et al. (2007a). The Mn exposure history of each worker was reconstructed using several sources of information: historical dust sampling data over the Mn alloy production period, company records relating to payroll and production which located every worker for every working day, and personal and environmental sampling data performed in 1991 (Baldwin et al., 2008). Exposure to Mn in total dust was estimated for each year of employment, and the sum resulted in the cumulative exposure index (CEI). The median CEI was 19.0 mg Mn/ m3 years, ranging from 0.3 to 100.2 mg Mn/m3 years. CEI were further grouped into tertiles for use in the statistical analyses. 2.3. Symptoms questionnaire A 38-item symptoms frequency questionnaire was administered both at initial examination and follow-up; the exact same questionnaire was used on the two occasions. This questionnaire was designed to be sensitive to the effects of Mn exposure and other conditions in the plant. It was derived from previous questionnaires used in studies of neurotoxicity (Johnson and World Health Organization, 1987) supplemented by symptoms associated with manganism (Tanaka, 1988), and pre-tested with a group of Mn-exposed workers to ensure comprehensibility of the items. The respondents were asked to rate symptom frequency on a four-point scale: 0: ‘‘Never’’, 1: ‘‘Rarely’’, 2: ‘‘Sometimes’’, and 3: ‘‘Often’’. Symptoms were grouped into nine categories: (1) memory and concentration; (2) fatigue; (3) sleeping; (4) autonomic nervous system; (5) movement control; (6) musculoskeletal
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Table 2 List of items included in each symptom category Memory and concentration (n = 6)
Memory loss noted by others, memory loss, forget what wanted to say or do, forget where put things, take note of everything, difficulty concentrating
Fatigue (n = 3)
Tired with no inclination to do anything, abnormal fatigue, tired after sleeping
Sleeping (n = 3)
Difficulty falling asleep, nightmares, insomnia
Autonomic nervous system (n = 2)
Saliva increased, sweating without physical efforts
Movement control (n = 5)
Difficulty articulating, difficulty button and unbutton, uncontrolled movement, difficulty going towards a fixed point, changes in writing
Musculoskeletal pain (n = 3)
Lower back pain, joint pain, stiff neck
Muscular weakness (n = 3)
Tiredness in legs, difficulty lifting a weight, muscular weakness when squeezing
Balance (n = 2)
Loss of balance when turning, loss of balance
Hearing (n = 2)
Buzzing in ears, difficulty hearing
pain; (7) muscular weakness; (8) balance; and (9) hearing. Table 2 displays the items included in each category. For the present analyses, seven items related to mood disturbances were excluded because mood and neuropsychiatric symptoms were addressed with better designed questionnaires (Bouchard et al., 2007a,b). In addition, two items were excluded from the analysis. The item ‘‘Difficulty walking’’ is too vague and a positive answer could be attributed either to musculoskeletal pain, movement control, fatigue, or balance. The other item, ‘‘Itching’’, did not fit in any of the above mentioned category and we did not find it appropriate to create a category for it, or to modify the present categories to accommodate its inclusion. 2.4. Statistical analysis Statistical analyses were performed with SPSS 14.0 (SPSS Inc., Chicago, IL). For each symptom category of Table 2, the mean reported frequency was computed and analyzed with regard to exposure using General Linear Model (GLM), with age (years), education (years), and alcohol consumption (grouped into quintiles) included as covariates. For the exposure variable, the CEI values were grouped in tertiles (see Table 1) and a dummy variable was entered in the model as an ordinal variable (0 = referents, 1 = lowest tertile, 2 = middle tertile, 3 = highest tertile). In order to better ascertain a possible exposure–effect relationship, the mean frequency of reported symptoms in each category was compared between referents and Mn-workers in each CEI tertile. These comparisons were performed using the method of planned contrasts, which breaks down the variance accounted for by the model into component parts to avoid inflating Type I error (Field, 2000). All analyses were performed separately for the initial 1990 and 2004 follow-up examinations, but the exact same methods were used for the statistical analyses. This approach was chosen over analyses for repeated measures because we were interested in the effect of exposure to Mn on symptoms reporting at each point in time (initial examination while currently exposed and follow-up after cessation of exposure), rather than the effect of exposure on the intra-individual change in symptoms reporting. The limit for statistical significance was set at p < 0.05, and p values between 0.05 and 0.1 are reported as tendencies. 3. Results Table 3 presents the results of the GLM analysis on mean frequency of symptom reporting in each of the nine categories by tertile of CEI, controlling for age, education and alcohol intake. At initial examination, increasing tertile of Mn CEI was significantly associated with frequency of reported symptom for all categories
but sleeping, e.g., memory and concentration, fatigue, autonomic nervous system, movement control, musculoskeletal pain, muscular weakness, balance, and hearing. At follow-up, increasing tertiles of Mn CEI was significantly associated with frequency of reported symptoms relative to memory and concentration, fatigue, movement control, balance and hearing. The relationships for the categories relative to autonomic nervous system, musculoskeletal pain and muscular weakness were marginally significant. The mean frequency of symptoms reported in 1990 and 2004 by category, adjusted for the same covariates as above, was plotted with respect to tertiles of Mn CEI (Fig. 1), and Mn-workers in each CEI tertile were compared with referents. For memory and concentration, post hoc tests showed that Mn-workers in all three tertiles of CEI reported symptoms significantly more frequently than referents in 1990, but in 2004, it was only the case for those in the highest CEI tertile. For fatigue, increasing CEI was also significantly associated with increased complaints in 1990; in 2004 there was no apparent increase with CEI, although former Mn-workers in general reported a higher level of complaint than referents. Sleeping complaints showed no significant relation with tertile of Mn CEI in 1990 or 2004. The frequency of autonomic nervous system symptoms reported increased significantly with CEI in 1990 but not in 2004. For movement control, increasing CEI was significantly associated with the frequency of symptoms in 1990; in 2004 Mn-workers in the highest tertile reported the highest frequency of symptoms, but those in the middle CEI tertile reported less symptoms than in the lowest tertile. Complaints relative to musculoskeletal pain were more frequently reported by Mn-workers than referents, but there was no relation with CEI. For
Table 3 Effect of cumulative exposure index to manganese on the mean frequency of symptoms reported in the 1990 initial examination and the 2004 follow-up 1990 initial examination
Memory and concentration Fatigue Sleeping Autonomic nervous system Movement control Musculoskeletal pain Muscular weakness Balance Hearing
2004 follow-up
F
p
F
p
11.2 13.4 3.5 21.0 12.3 13.5 14.2 14.9 17.1
.001 .000 .064 .000 .001 .000 .000 .000 .000
6.0 10.8 1.0 3.1 12.5 3.7 3.8 4.1 13.5
.016 .001 .320 .080 .001 .056 .054 .045 .000
F- and p-values for exposure are reported (exposure used as an ordinal variable), controlling for age, education and alcohol consumption. Post hoc tests compared the referent group with Mn-workers in each tertile of CEI.
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Fig. 1. Adjusted mean frequency of symptoms with respect to tertiles of Mn cumulative exposure indices (CEI) for initial examination (1, solid line) and follow-up (2, dotted line). p-Values of post hoc comparisons for Mn-alloy workers in each CEI tertile with referents are displayed as n.s.: not significant (p .1); tp < 0.1; *p < 05; **p < 0.01; ***p < 0.001. Referents: n = 71; lowest tertile: n = 23; middle tertile: n = 24; highest tertile: n = 24.
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Fig. 1. (Continued ).
muscular weakness, frequency of symptoms reported in 1990 increased with CEI, but not in 2004. Balance problems were reported significantly more frequently by Mn-workers in the highest CEI tertile, both in 1990 and 2004, but Mn-workers with less exposure did not report these problems more than referents. Finally, the frequency of reported hearing complaints increased significantly with CEI, both in 1990 and 2004, although in 1990 only workers in the highest tertile of CEI reported them significantly more often than referents. 4. Discussion The findings of the present study show that both while exposed and 14 years after cessation of exposure, Mn-alloy workers reported several symptoms significantly more frequently in comparison to a group of referents comprised of non-exposed blue-collar workers of similar age, education, region of residence, and alcohol consumption. Not all reported symptoms were necessarily related to Mn exposure, some probably reflected the effects of other working conditions in the plant, e.g., musculoskeletal strain, which we could not take into account in the analyses. However, several groups of symptoms increased with Mn CEI, suggesting that Mn exposure contributed to these problems, during exposure or after cessation of exposure. A gradual increase
in symptoms frequency was observed for complaints related to hearing and movement control both at initial and follow-up examination, and fatigue and autonomic nervous system only at initial examination. In addition, an exposure–effect relation was apparent for symptoms of memory, concentration and balance reported at both examinations, since Mn-workers in the highest tertile of Mn CEI reported the highest level of symptomatology. Sleeping complaints were not associated with exposure to Mn, while musculoskeletal pain and muscular weakness were reported more often by Mn-workers than referents but were not clearly related to CEI. In the present study, the investigated symptoms were mainly related to motor and cognitive functions, with few items addressing complaints to the autonomic nervous system and sensory functions. Since this was part of a follow-up study and because of time constraints, we decided to limit the questionnaire to the same items as the initial study, although since that time much more is known about the effects of Mn. For example, a more detailed investigation of autonomic complaints would be important since previous reports suggest autonomic dysfunction in exposed workers (Barrington et al., 1998). In the present study, a marked increase in reporting of two such symptoms (salivation and sweating) with CEI was observed for data collected at initial examination when workers were still exposed to Mn. In addition, it
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is noteworthy that the two hearing complaints during ongoing exposure were reported significantly more frequently with higher CEI. Ototoxic chemicals and noise have been shown to have a synergic action causing hearing loss (Hoet and Lison, 2008), but further research involving objective assessment of hearing would be necessary to find out whether it is also the case for Mn. Increased symptom reporting with respect to estimates of cumulative exposure to Mn has been reported by Bowler et al. (2007) for confined space welders. Myers et al. did not find a relation between CEI and symptoms frequency, assessed using the Q16, a questionnaire designed for symptoms of exposure to organic solvents (Axelson and Hogstedt, 1988) in South African mine (2003a) or smelter workers (2003b). In the present study, the former Mn-alloy production workers were aware that they were the exposed group, which may have introduced a bias. Furthermore, follow-up symptom reporting differences between the former Mn-alloy workers and the referents may reflect their experiences since plant closure. However, the Mn-alloy workers were unaware of their CEI, which was unrelated to seniority and age. The CEIs were the result of comprehensive retrospective analyses of company records, including each worker’s work history in the plant, written reports of historical airborne Mn sampling, as well as individual sampling and area measurements made prior to plant closure (Baldwin et al., 2008). It is interesting to note that most of the symptoms reported can be ascribed to dysfunction of the basal ganglia. Indeed, the mild cognitive/concentration deficit, without dementia, fatigue, the dysarthria, difficulty walking or with tasks that require dexterity are similar to complaints from patients with Parkinsonism (Pal et al., 2002). This is compatible with the site of predilection for Mninduced damage in the CNS. We did not detect cases of Parkinsonism in this cohort, it is possible that the relatively young age and previous good health (people who perform daily hard physical work in a hostile environment for years) could compensate for mild basal ganglia dysfunction. If this hypothesis is true, more obvious neurological syndrome of Mn-induced Parkinsonism could appear with further follow-up. Among the strengths of the present study is its follow-up design many years after cessation of exposure. The Mn-alloy workers recruited in 1990 were pair-matched to referents on several characteristics, and found similar in many others (e.g., height, weight, alcohol and tobacco consumption) (Mergler et al., 1994). The socio-demographic similarity was reflected in the sub-group that was located and agreed to participate in the follow-up study (see Table 1). Workers were not involved in any form of litigation, either at the time of the initial investigation or at follow-up, and thus, no gain could be expected from the study results. Collaboration with the workers union and the company provided comprehensive records and information, necessary to construct the CEIs. The major weakness of the present investigation is the small sample size. As Thompson and Myers (2006) have pointed out, this is a common problem of many workplace studies and may influence statistical modeling of the data. In the present study, the sample size reflects the size of the plant, which employed 115 men, of whom 10 had died in the intervening years. The participation rate was 78% for the Mn alloy-workers and 67% for the referents, which further reduced the numbers. It is noteworthy that comparison of the follow-up participants and non-participants showed that there were no differences on socio-demographic variables, but the Mn-alloy workers who participated had significantly higher CEI compared to the non-participants (Bouchard et al., 2007a). The assessment of subjective symptoms is very often used in studies of neurotoxic effects among exposed groups and has been
found useful to describe the pattern of disturbances (Hanninen et al., 1979; Mergler, 1999). Although useful, the meaning and validity of subjective symptom assessments are debated. Williamson (2007) has provided a well-founded review of the issues surrounding the use of symptom questionnaires in studies of neurotoxic substances, including reliability and validity problems often occurring with this type of instrument. The present questionnaire, which was initially applied in 1990, suffers from some of the limitations described by Williamson, for example, the fact that different responses can have different meaning depending on the individuals and situations. To the question ‘‘Do you have to take note of everything?’’ responding ‘‘Often’’ could translate in a different frequency for one person than for another. However, the bias in response is likely to be randomly distributed across levels of CEI, causing an inflated error term which would produce results more likely to underestimate the effect of Mn (Jurek et al., 2005). Unlike personality and mood inventories that produce validated scales meant to represent underlying psychological constructs, the present symptom questionnaire rather broadly explore complaints experienced by the subjects (Johnson and World Health Organization, 1987). Thus, there is no gold-standard validation procedure pertaining to the present context (neither for content, concurrent, nor convergent validity). However, pre-tests with a group of Mnalloy workers ensured comprehensibility of the items. Another major concern about self-report measures is the potential influence of demand characteristics and respondent expectations. In the present study, there was no possible gain from the study results on the part of the former Mn-exposed workers or the referents. As for recall bias, one can argue that the Mn-exposed workers would be more aware of symptoms because of their past exposure to Mn. While this may explain at least partially the differences between the exposed and referents, it would not explain the relations with CEI. 5. Conclusion The present study suggests that several nervous system symptoms were present long after cessation of exposure to Mn, and that CEI was a determinant for symptom reporting both during and after cessation of exposure. The findings of the present study support the need for assessing symptoms as part of the overall pattern of neurotoxic effects. However, further research needs to be done to refine questionnaire design for workers exposed to Mn. Acknowledgements The authors would like to express their gratitude to the participants who kindly participated in the study. The authors would like to acknowledge Catherine Desjardins, David Fontaine, Nathalie Socard, Patrick Doiron-Cadet for their work. The funding of the study was provided by the Canadian Institutes of Health Research (CIHR, grant #117076). CIHR also provided a scholarship (Maryse Bouchard). The Institut de recherche Robert Sauve´ en sante´ et se´curite´ au travail funded the baseline study and also provided a scholarship (Maryse Bouchard). References Axelson O, Hogstedt C. On the health effects of solvents. In: Zenz C, editor. Occupational medicine: principles and practical applications. Chicago: Year Book Medical Publishers; 1988. p. 775–84. Baldwin M, Bouchard M, Larribe F, Mergler D. Past occupational exposure to airborne manganese in a manganese alloy plant. J Occup Environ Hyg 2008;5:426–37. Barrington W, Angle CR, Willcockson NK, Padula MA, Korn T. Autonomic function in manganese alloy workers. Environ Res 1998;78:50–8.
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NeuroToxicology
Manganese cumulative exposure and symptoms: A follow-up study of alloy workers Maryse Bouchard a,*, Donna Mergler a, Mary E. Baldwin a, Michel Panisset b a b
CINBIOSE (Centre de recherche interdisciplinaire sur la biologie, la sante´, la socie´te´ et l’environnement), Universite´ du Que´bec a` Montre´al, Montre´al, Canada Unite´ des troubles du mouvement Andre´-Barbeau, Centre Hospitalier de l’Universite´ de Montre´al, Montre´al, Canada
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 January 2008 Received in revised form 15 April 2008 Accepted 21 April 2008 Available online 2 May 2008
Long-term exposure to manganese (Mn) particulates through inhalation can be neurotoxic, with deficits in neuromotor and cognitive domains. Mn-exposed individuals also report symptoms, including fatigue, mood changes, irritability, concentration difficulties, and sweating in the absence of physical effort. The long-term course of Mn-related symptoms after cessation of exposure has never been examined. Male workers from a Mn-alloy production plant participated in a study on nervous system functions (initial examination), and were followed-up 14 years after plant closure. The relation between self-reported symptoms and Mn cumulative exposure index (CEI) was examined among 71 Mn-alloy workers and 71 referents. Symptoms from the questionnaire were grouped into categories, and the reported frequency was compared between referents and Mn-alloy workers in each Mn CEI tertile using General Linear Models, controlling for age, education, and alcohol consumption. A gradual increase in symptoms frequency was observed for complaints related to hearing and movement control both at initial and follow-up examination, and fatigue and autonomic nervous system only at initial examination. In addition, an exposure–effect relation was apparent for symptoms related to memory, concentration and balance reported at both examinations, with Mn-workers in the highest CEI tertile reporting the highest level of symptomatology. Sleeping complaints were not associated with exposure to Mn, while musculoskeletal pain and muscular weakness were reported more often by Mn-workers than referents but were not clearly related to CEI. The findings suggest that former Mn-alloy workers continue to perceive symptoms many years after cessation of exposure. Despite the limitations of self-reported symptoms, subjective complaints are an important part of a health assessment since they relate directly to perceived health status and day-to-day functioning. ß 2008 Elsevier Inc. All rights reserved.
Keywords: Manganese alloy-workers Cumulated exposure indices Symptoms Neurotoxicity Cohort study Motor Cognitive Mood
1. Introduction Manganese (Mn) is an essential nutrient which, in case of overexposure via inhalation or ingestion, can turn into a potent neurotoxicant. Upon high exposure, Mn accumulates in the globus pallidus, but also in other basal ganglia including caudate and putamen (Pal et al., 1999). In long-term exposed workers, the accumulation of Mn, as indicated by pallidal T1-weighted magnetic resonance signal hyperintensity has been shown to correlate with several Mn-exposure metrics, such as airborne Mn, blood Mn, and cumulative exposure (Shin et al., 2007). In addition, accumulation of Mn in the frontal white matter and a concurrent decrease in
* Corresponding author at: CINBIOSE, UQAM (SB-1983), C.P. 8888, Succ. CentreVille, Montre´al (Que´bec) H3C 3P8, Canada. Tel.: +1 514 987 3000/4759; fax: +1 514 987 6183. E-mail address: [email protected] (M. Bouchard). 0161-813X/$ – see front matter ß 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.neuro.2008.04.013
N-acetylaspartate (NAA)/creatine (Cr) ratio, indicative of neuronal degeneration, has been reported in non-human primates injected with Mn sulfate (Guilarte et al., 2006). Mn neurotoxicity disrupts neurotransmitter equilibrium, including dopaminergic and glutamate systems (Fitsanakis et al., 2006; Guilarte and Chen, 2007). The mechanisms of toxicity are not fully elucidated but it has been suggested that excitotoxicity may occur due to Mn-induced altered glutamate metabolism (Erikson and Aschner, 2003). Over exposure through inhalation of Mn particulates can result in a severe intoxication syndrome, manganism, resembling Parkinson’s disease (Calne et al., 1994; Rodier, 1955). The symptomatology of manganism includes adverse mood states (irritability, depressive feelings), decreased memory and concentration, fatigue, headache, vertigo, equilibrium loss, insomnia, tinnitus, trembling of fingers, muscle cramp, rigidity, alteration of libido and sweating (Tanaka, 1988). This debilitating condition persists or can even aggravate after cessation of exposure (Huang et al., 1998). Long-term exposure to Mn at lower levels than those
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implicated in the development of manganism has been associated with deficits in neuromotor and some cognitive functions, including poor hand–eye coordination, difficulty performing alternating movements, hand tremor, postural instability, prolonged reaction time, decreased memory and cognitive flexibility (for a review, see Zoni et al. (2007)), although not all studies have observed effects (Myers et al., 2003a,b). Several studies of active workers have surveyed symptoms using a great variety of questionnaires. While some noted important differences between exposed workers and referent groups (Bowler et al., 2007; Chia et al., 1993; Ferraz et al., 1988; Jonderko, 1979; Sinczuk-Walczak et al., 2001), others found an increase only for non-specific symptoms (Bast-Pettersen et al., 2004; Deschamps et al., 2001; Myers et al., 2003b; Roels et al., 1987) or a small number of symptoms (Lucchini et al., 1999; Sjo¨gren et al., 1996). A number of issues have been raised regarding the use of symptom questionnaires in neurotoxicity studies (Williamson, 2007). Among the concerns expressed are that, compared to objective evaluations, these measures are more vulnerable to misrepresentation for numerous reasons including malingering, social desirability, problems of language, question style, unreliable recall and unintentional biases (Williamson, 2007). On the other hand, there are several reasons to include symptom surveys. Increased symptom prevalence reflects decreased well being (Gregersen et al., 1987; Mergler, 1999) and has been interpreted as evidence of neurological dysfunction (Hanninen et al., 1979; Hawkins, 1990). Neurotoxicants have been associated with emotional disturbances and mood lability, which are intrinsically subjective experiences that can only be assessed and reported by the person him- or her-self. In the case of transient problems (e.g., increased saliva), or when the functional limitation is only apparent in certain circumstances (e.g., insomnia), self-reporting provides important information difficult to obtain objectively (Williamson, 2007). Finally, the profile of symptom reporting can be valuable in assisting physician practitioners confronted with possible cases of overexposed individuals. The long-term course of the effects of Mn exposure after cessation of exposure, in the absence of a diagnostic of manganism, has seldom been reported. In 1990, we conducted a matched-pair, cross-sectional study on nervous system functions of male workers from a Mn-alloy production plant. The Mn-exposed workers reported significantly more symptoms compared to the reference group (Mergler et al., 1994). The plant closed shortly after completion of the study, and in 2004, we conducted a follow-up study of the former Mn-alloy workers and referents. The results for neurobehavioral functions (Bouchard et al., 2007a) and neuropsychiatric findings (Bouchard et al., 2007b) are reported elsewhere. The present investigation aimed at exploring the relation between different symptoms and cumulative Mn exposure, both during exposure and 14 years following its cessation. 2. Participants and methods 2.1. Recruitment and study participants The initial 1990 study was carried out with workers employed in a ferro- and silico-Mn production plant located in South-West Quebec. The strategy adopted for this study was a matched-pair design where workers from the plant were matched to blue-collar non-exposed workers from the same region on the variables age, education, smoking habits and number of children (Mergler et al., 1994). A total of 115 Mn-alloy workers and 145 referents were tested at initial investigation. These men constituted the target population for the follow-up study, carried out in 2004. Informed consent was obtained from each participant and the Institutional
Table 1 Characteristics of the study population at the 2004 follow-up examination Characteristics Age (years) Range
a
Referents (n = 71)
Mn-workers (n = 71)
56.9 (7.2) 43.5–74.1
58.0 (5.4) 48.6–71.4
Education (years) a Range
11.1 (2.4) 6.0–17.5
11.0 (1.7) 6.0–15.5
Alcohol consumption (g/week)a Range
129 (145) 0–594
Tobaccob Current Former Never
17 (24) 36 (51) 18 (25)
Cumulative exposure indexa (mg Mn/m3 years) Lowest tertile n/a Middle tertile Highest tertile
149 (131) 0–1152
17 (24) 41 (58) 13 (18)
6.0 (4.3) 19.5 (5.0) 58.2 (21.7)
n/a: not applicable. a Mean (S.D.). b Frequency (%).
Ethics Board (Universite´ du Que´bec a` Montre´al) approved the study protocol. The details on recruitment of participants and exclusion of those with central nervous system (CNS) problems unlikely to be related to Mn exposure are presented elsewhere (Bouchard et al., 2007a). Seventy-one individuals remained in each exposure group after exclusions; their characteristics are presented in Table 1. Age, education, alcohol and tobacco consumption were similarly distributed in the two groups. 2.2. Mn exposure For the Mn-alloy workers included in the present analyses, the mean number of years of exposure to Mn was 15.7 (range: 7.4–17.3 years) and only 1 worker had less than 10 years of exposure. A description of the process of Mn-alloy production and exposure to Mn in the plant is reported in Bouchard et al. (2007a). The Mn exposure history of each worker was reconstructed using several sources of information: historical dust sampling data over the Mn alloy production period, company records relating to payroll and production which located every worker for every working day, and personal and environmental sampling data performed in 1991 (Baldwin et al., 2008). Exposure to Mn in total dust was estimated for each year of employment, and the sum resulted in the cumulative exposure index (CEI). The median CEI was 19.0 mg Mn/ m3 years, ranging from 0.3 to 100.2 mg Mn/m3 years. CEI were further grouped into tertiles for use in the statistical analyses. 2.3. Symptoms questionnaire A 38-item symptoms frequency questionnaire was administered both at initial examination and follow-up; the exact same questionnaire was used on the two occasions. This questionnaire was designed to be sensitive to the effects of Mn exposure and other conditions in the plant. It was derived from previous questionnaires used in studies of neurotoxicity (Johnson and World Health Organization, 1987) supplemented by symptoms associated with manganism (Tanaka, 1988), and pre-tested with a group of Mn-exposed workers to ensure comprehensibility of the items. The respondents were asked to rate symptom frequency on a four-point scale: 0: ‘‘Never’’, 1: ‘‘Rarely’’, 2: ‘‘Sometimes’’, and 3: ‘‘Often’’. Symptoms were grouped into nine categories: (1) memory and concentration; (2) fatigue; (3) sleeping; (4) autonomic nervous system; (5) movement control; (6) musculoskeletal
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Table 2 List of items included in each symptom category Memory and concentration (n = 6)
Memory loss noted by others, memory loss, forget what wanted to say or do, forget where put things, take note of everything, difficulty concentrating
Fatigue (n = 3)
Tired with no inclination to do anything, abnormal fatigue, tired after sleeping
Sleeping (n = 3)
Difficulty falling asleep, nightmares, insomnia
Autonomic nervous system (n = 2)
Saliva increased, sweating without physical efforts
Movement control (n = 5)
Difficulty articulating, difficulty button and unbutton, uncontrolled movement, difficulty going towards a fixed point, changes in writing
Musculoskeletal pain (n = 3)
Lower back pain, joint pain, stiff neck
Muscular weakness (n = 3)
Tiredness in legs, difficulty lifting a weight, muscular weakness when squeezing
Balance (n = 2)
Loss of balance when turning, loss of balance
Hearing (n = 2)
Buzzing in ears, difficulty hearing
pain; (7) muscular weakness; (8) balance; and (9) hearing. Table 2 displays the items included in each category. For the present analyses, seven items related to mood disturbances were excluded because mood and neuropsychiatric symptoms were addressed with better designed questionnaires (Bouchard et al., 2007a,b). In addition, two items were excluded from the analysis. The item ‘‘Difficulty walking’’ is too vague and a positive answer could be attributed either to musculoskeletal pain, movement control, fatigue, or balance. The other item, ‘‘Itching’’, did not fit in any of the above mentioned category and we did not find it appropriate to create a category for it, or to modify the present categories to accommodate its inclusion. 2.4. Statistical analysis Statistical analyses were performed with SPSS 14.0 (SPSS Inc., Chicago, IL). For each symptom category of Table 2, the mean reported frequency was computed and analyzed with regard to exposure using General Linear Model (GLM), with age (years), education (years), and alcohol consumption (grouped into quintiles) included as covariates. For the exposure variable, the CEI values were grouped in tertiles (see Table 1) and a dummy variable was entered in the model as an ordinal variable (0 = referents, 1 = lowest tertile, 2 = middle tertile, 3 = highest tertile). In order to better ascertain a possible exposure–effect relationship, the mean frequency of reported symptoms in each category was compared between referents and Mn-workers in each CEI tertile. These comparisons were performed using the method of planned contrasts, which breaks down the variance accounted for by the model into component parts to avoid inflating Type I error (Field, 2000). All analyses were performed separately for the initial 1990 and 2004 follow-up examinations, but the exact same methods were used for the statistical analyses. This approach was chosen over analyses for repeated measures because we were interested in the effect of exposure to Mn on symptoms reporting at each point in time (initial examination while currently exposed and follow-up after cessation of exposure), rather than the effect of exposure on the intra-individual change in symptoms reporting. The limit for statistical significance was set at p < 0.05, and p values between 0.05 and 0.1 are reported as tendencies. 3. Results Table 3 presents the results of the GLM analysis on mean frequency of symptom reporting in each of the nine categories by tertile of CEI, controlling for age, education and alcohol intake. At initial examination, increasing tertile of Mn CEI was significantly associated with frequency of reported symptom for all categories
but sleeping, e.g., memory and concentration, fatigue, autonomic nervous system, movement control, musculoskeletal pain, muscular weakness, balance, and hearing. At follow-up, increasing tertiles of Mn CEI was significantly associated with frequency of reported symptoms relative to memory and concentration, fatigue, movement control, balance and hearing. The relationships for the categories relative to autonomic nervous system, musculoskeletal pain and muscular weakness were marginally significant. The mean frequency of symptoms reported in 1990 and 2004 by category, adjusted for the same covariates as above, was plotted with respect to tertiles of Mn CEI (Fig. 1), and Mn-workers in each CEI tertile were compared with referents. For memory and concentration, post hoc tests showed that Mn-workers in all three tertiles of CEI reported symptoms significantly more frequently than referents in 1990, but in 2004, it was only the case for those in the highest CEI tertile. For fatigue, increasing CEI was also significantly associated with increased complaints in 1990; in 2004 there was no apparent increase with CEI, although former Mn-workers in general reported a higher level of complaint than referents. Sleeping complaints showed no significant relation with tertile of Mn CEI in 1990 or 2004. The frequency of autonomic nervous system symptoms reported increased significantly with CEI in 1990 but not in 2004. For movement control, increasing CEI was significantly associated with the frequency of symptoms in 1990; in 2004 Mn-workers in the highest tertile reported the highest frequency of symptoms, but those in the middle CEI tertile reported less symptoms than in the lowest tertile. Complaints relative to musculoskeletal pain were more frequently reported by Mn-workers than referents, but there was no relation with CEI. For
Table 3 Effect of cumulative exposure index to manganese on the mean frequency of symptoms reported in the 1990 initial examination and the 2004 follow-up 1990 initial examination
Memory and concentration Fatigue Sleeping Autonomic nervous system Movement control Musculoskeletal pain Muscular weakness Balance Hearing
2004 follow-up
F
p
F
p
11.2 13.4 3.5 21.0 12.3 13.5 14.2 14.9 17.1
.001 .000 .064 .000 .001 .000 .000 .000 .000
6.0 10.8 1.0 3.1 12.5 3.7 3.8 4.1 13.5
.016 .001 .320 .080 .001 .056 .054 .045 .000
F- and p-values for exposure are reported (exposure used as an ordinal variable), controlling for age, education and alcohol consumption. Post hoc tests compared the referent group with Mn-workers in each tertile of CEI.
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Fig. 1. Adjusted mean frequency of symptoms with respect to tertiles of Mn cumulative exposure indices (CEI) for initial examination (1, solid line) and follow-up (2, dotted line). p-Values of post hoc comparisons for Mn-alloy workers in each CEI tertile with referents are displayed as n.s.: not significant (p .1); tp < 0.1; *p < 05; **p < 0.01; ***p < 0.001. Referents: n = 71; lowest tertile: n = 23; middle tertile: n = 24; highest tertile: n = 24.
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Fig. 1. (Continued ).
muscular weakness, frequency of symptoms reported in 1990 increased with CEI, but not in 2004. Balance problems were reported significantly more frequently by Mn-workers in the highest CEI tertile, both in 1990 and 2004, but Mn-workers with less exposure did not report these problems more than referents. Finally, the frequency of reported hearing complaints increased significantly with CEI, both in 1990 and 2004, although in 1990 only workers in the highest tertile of CEI reported them significantly more often than referents. 4. Discussion The findings of the present study show that both while exposed and 14 years after cessation of exposure, Mn-alloy workers reported several symptoms significantly more frequently in comparison to a group of referents comprised of non-exposed blue-collar workers of similar age, education, region of residence, and alcohol consumption. Not all reported symptoms were necessarily related to Mn exposure, some probably reflected the effects of other working conditions in the plant, e.g., musculoskeletal strain, which we could not take into account in the analyses. However, several groups of symptoms increased with Mn CEI, suggesting that Mn exposure contributed to these problems, during exposure or after cessation of exposure. A gradual increase
in symptoms frequency was observed for complaints related to hearing and movement control both at initial and follow-up examination, and fatigue and autonomic nervous system only at initial examination. In addition, an exposure–effect relation was apparent for symptoms of memory, concentration and balance reported at both examinations, since Mn-workers in the highest tertile of Mn CEI reported the highest level of symptomatology. Sleeping complaints were not associated with exposure to Mn, while musculoskeletal pain and muscular weakness were reported more often by Mn-workers than referents but were not clearly related to CEI. In the present study, the investigated symptoms were mainly related to motor and cognitive functions, with few items addressing complaints to the autonomic nervous system and sensory functions. Since this was part of a follow-up study and because of time constraints, we decided to limit the questionnaire to the same items as the initial study, although since that time much more is known about the effects of Mn. For example, a more detailed investigation of autonomic complaints would be important since previous reports suggest autonomic dysfunction in exposed workers (Barrington et al., 1998). In the present study, a marked increase in reporting of two such symptoms (salivation and sweating) with CEI was observed for data collected at initial examination when workers were still exposed to Mn. In addition, it
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is noteworthy that the two hearing complaints during ongoing exposure were reported significantly more frequently with higher CEI. Ototoxic chemicals and noise have been shown to have a synergic action causing hearing loss (Hoet and Lison, 2008), but further research involving objective assessment of hearing would be necessary to find out whether it is also the case for Mn. Increased symptom reporting with respect to estimates of cumulative exposure to Mn has been reported by Bowler et al. (2007) for confined space welders. Myers et al. did not find a relation between CEI and symptoms frequency, assessed using the Q16, a questionnaire designed for symptoms of exposure to organic solvents (Axelson and Hogstedt, 1988) in South African mine (2003a) or smelter workers (2003b). In the present study, the former Mn-alloy production workers were aware that they were the exposed group, which may have introduced a bias. Furthermore, follow-up symptom reporting differences between the former Mn-alloy workers and the referents may reflect their experiences since plant closure. However, the Mn-alloy workers were unaware of their CEI, which was unrelated to seniority and age. The CEIs were the result of comprehensive retrospective analyses of company records, including each worker’s work history in the plant, written reports of historical airborne Mn sampling, as well as individual sampling and area measurements made prior to plant closure (Baldwin et al., 2008). It is interesting to note that most of the symptoms reported can be ascribed to dysfunction of the basal ganglia. Indeed, the mild cognitive/concentration deficit, without dementia, fatigue, the dysarthria, difficulty walking or with tasks that require dexterity are similar to complaints from patients with Parkinsonism (Pal et al., 2002). This is compatible with the site of predilection for Mninduced damage in the CNS. We did not detect cases of Parkinsonism in this cohort, it is possible that the relatively young age and previous good health (people who perform daily hard physical work in a hostile environment for years) could compensate for mild basal ganglia dysfunction. If this hypothesis is true, more obvious neurological syndrome of Mn-induced Parkinsonism could appear with further follow-up. Among the strengths of the present study is its follow-up design many years after cessation of exposure. The Mn-alloy workers recruited in 1990 were pair-matched to referents on several characteristics, and found similar in many others (e.g., height, weight, alcohol and tobacco consumption) (Mergler et al., 1994). The socio-demographic similarity was reflected in the sub-group that was located and agreed to participate in the follow-up study (see Table 1). Workers were not involved in any form of litigation, either at the time of the initial investigation or at follow-up, and thus, no gain could be expected from the study results. Collaboration with the workers union and the company provided comprehensive records and information, necessary to construct the CEIs. The major weakness of the present investigation is the small sample size. As Thompson and Myers (2006) have pointed out, this is a common problem of many workplace studies and may influence statistical modeling of the data. In the present study, the sample size reflects the size of the plant, which employed 115 men, of whom 10 had died in the intervening years. The participation rate was 78% for the Mn alloy-workers and 67% for the referents, which further reduced the numbers. It is noteworthy that comparison of the follow-up participants and non-participants showed that there were no differences on socio-demographic variables, but the Mn-alloy workers who participated had significantly higher CEI compared to the non-participants (Bouchard et al., 2007a). The assessment of subjective symptoms is very often used in studies of neurotoxic effects among exposed groups and has been
found useful to describe the pattern of disturbances (Hanninen et al., 1979; Mergler, 1999). Although useful, the meaning and validity of subjective symptom assessments are debated. Williamson (2007) has provided a well-founded review of the issues surrounding the use of symptom questionnaires in studies of neurotoxic substances, including reliability and validity problems often occurring with this type of instrument. The present questionnaire, which was initially applied in 1990, suffers from some of the limitations described by Williamson, for example, the fact that different responses can have different meaning depending on the individuals and situations. To the question ‘‘Do you have to take note of everything?’’ responding ‘‘Often’’ could translate in a different frequency for one person than for another. However, the bias in response is likely to be randomly distributed across levels of CEI, causing an inflated error term which would produce results more likely to underestimate the effect of Mn (Jurek et al., 2005). Unlike personality and mood inventories that produce validated scales meant to represent underlying psychological constructs, the present symptom questionnaire rather broadly explore complaints experienced by the subjects (Johnson and World Health Organization, 1987). Thus, there is no gold-standard validation procedure pertaining to the present context (neither for content, concurrent, nor convergent validity). However, pre-tests with a group of Mnalloy workers ensured comprehensibility of the items. Another major concern about self-report measures is the potential influence of demand characteristics and respondent expectations. In the present study, there was no possible gain from the study results on the part of the former Mn-exposed workers or the referents. As for recall bias, one can argue that the Mn-exposed workers would be more aware of symptoms because of their past exposure to Mn. While this may explain at least partially the differences between the exposed and referents, it would not explain the relations with CEI. 5. Conclusion The present study suggests that several nervous system symptoms were present long after cessation of exposure to Mn, and that CEI was a determinant for symptom reporting both during and after cessation of exposure. The findings of the present study support the need for assessing symptoms as part of the overall pattern of neurotoxic effects. However, further research needs to be done to refine questionnaire design for workers exposed to Mn. Acknowledgements The authors would like to express their gratitude to the participants who kindly participated in the study. The authors would like to acknowledge Catherine Desjardins, David Fontaine, Nathalie Socard, Patrick Doiron-Cadet for their work. The funding of the study was provided by the Canadian Institutes of Health Research (CIHR, grant #117076). CIHR also provided a scholarship (Maryse Bouchard). The Institut de recherche Robert Sauve´ en sante´ et se´curite´ au travail funded the baseline study and also provided a scholarship (Maryse Bouchard). References Axelson O, Hogstedt C. On the health effects of solvents. In: Zenz C, editor. Occupational medicine: principles and practical applications. Chicago: Year Book Medical Publishers; 1988. p. 775–84. Baldwin M, Bouchard M, Larribe F, Mergler D. Past occupational exposure to airborne manganese in a manganese alloy plant. J Occup Environ Hyg 2008;5:426–37. Barrington W, Angle CR, Willcockson NK, Padula MA, Korn T. Autonomic function in manganese alloy workers. Environ Res 1998;78:50–8.
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