Occupational Exposure to Manganese, Copper, Lead ...

NeuroToxicol ogy® 20(2-3): 239-248, 1999 Copyright © 1999 by lntox Press, Inc.

Occupational Exposure to Manganese, Copper, Lead, Iron, Mercury and Zinc and the Risk of Parkinson's Disease J .M. G ORELL1•5,

C.C. J oHNSON2.s, B.A. R YBICKI2, E.L. P ETERSON2 ,

G.X. K oRTSHA, G.G. BRowN3 AND

R.J. RICHARDSON"

Departments of' Neurology and 28iostatistics and Research Epidemiology, Henry Ford Health System, Detroit, Michigan; 3Psyclzology Seroice, Veterans Administration Medical Center and Department of Psychiatry, University ofCalifomia San Diego, San Diego, California; •Toxicology Program, Department of Environmental a11d Industrial Health, School of Public Health, University of Michigan, Ann Arbor, Michigan; 5NIEHS Center i11 Molecular and Cellular Toxicology with Human Applications, Wayne State University, Detroit, Michigan Abstract: J.M. GoRELL, C.C. JOHNSON, B.A. R YBICKI, E.L. PETERSON, G.X. K oRTSHA, G.G. BROWN AND R.J. RICHARDSON. Occupational Exposure to Manganese, Copper, Lead, Iron, Mercury and Zinc and the Risk of Parkinson's Disease. Neurotoxicology 20(2-3):239-248, 1999. A population-based case-control study was conducted in the Henry Ford H ealth System (HFHS) in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron, mercury and zinc as risk factors for Parkinson's disease (PO). N on-demented men and w omen 50 years of age who were receiving primary medical care at HFHS were recruited, and concurrently enrolled cases (n = 744) and controls (n = 464) were frequency-matched for sex, race and age (± 5 years). A risk factor questionnaire, administered by trained interviewers, inquired about every job held by each subject for 6 months from age 18 onward, including a detailed assessment of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to subjects' case-control status, used these data to rate every job as exposed or not exposed to one or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of occupational exposure to any metal was not associated with PO. However, more than 20 years exposure to manganese (Odds Ratio /OR] = 70.6 7, 95% Confidence Interval /Cl] = 7.06, 105.83) or copper (OR = 2.49, 95% Cl = 1.06,5.89) was associated with PO. Occupational exposure for> 20 years to combinations of lead-copper (OR = 5.24, 95% Cl= 7.59, 17.2 7), lead-iron (OR= 2.83, 95% Cl= 1.07,7.50), and iron-copper (OR= 3.69, 95% Cl = 1.40,9.77) was also associated with the disease. No association of occup ational exposure to iron, mercury or zinc with PD was found. A lack of statistical power precluded analyses of metal combinations for those with a low prevalence of exposure (i.e., manganese, mercury and zinc). Our findings suggest that chronic occupational exposure to manganese or copper, individually, or to dual combinations of lead, iron and copper, is associated with PD. © 7999 lntox Press, Inc.

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Key Words:

Manganese, Copper, Iron, l ead, Mercury, Zinc, Parkinson's Disease

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INTRODUCTION

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ta

Parkinson's disease (PD) has been linked with several me tals in var ying contexts. For example, occupational manganese exposure has long been known to produce, in some individuals, clinical signs similar to

those displayed by subjects with PD (Cotzias et al., 1968; Mena et al., 1980). Mercury exposure has been associated with PD in Singapore (Ngirn and Devathasan, 1989). There is increased iron deposition in the PD substantia nigra [SN] (Dexter et al., 1989; Riederer et al., 1989; Sofie et al., 1991), and intranigral iron injection has produced progressive

Please send request for reprints to Jay M. Gorell, M .D., Department of Neurology, Henry Ford Hospital and Health Sciences Center, 2799 W. Grand Blvd. Detroit, Ml 48202. e·mail: gorell @neuro.hfh.edu.

Submitted:

September 16, 1998. Accepted: February 5, 1999.

For pennission to photocopy Neurotoxicology (0161-813X) contact the Copyright Clearance Center: 978-750-8400, Fax 978-750-4470.

240 - NeuroToxicology 20(2-3): 1999

neuronal death (Sengstock et nl., 1992,1993), likely by oxidative stress (Gerlach et nl., 1994). Copper has been measured in PD brain regions postmortem and has been found to be either decreased (Dexter et nl., 1989) o r unchanged (Riederer et al., 1989). Zinc is reported to be e levated in the SN, ca udate and putamen of PD brain postmortem (Dexter el al., 1989). Fina lly, both iron and aluminum have been found in SN Lewy bodies in PD brain postmortem (Hirsch et al., 1991 ). Des p ite these neu rochemi ca l observations suggestin g a role for meta ls in PD, the relationship between occupatio na l exposure to specifie meta ls and the disease has been examined infrequently, e.g., to manganese (Zayed et al., 1990; Semchuk et nl., 1993; Seidler cl al., 1996), mercury (Ohlso n and H ogs tedt, 1981; Ngim a nd Dcvathasan, 1989; Seidler et nl., 1996 ), lead (Seid ler et al, 1996), copper (SeidJer ct al, 1996), zinc (Seidler et nl., 1996) o r iron (Zayed et nl., 1990). Moreover, findin gs of ea rlie r PD epidemiological studies have varied, in large part due to differences in the methods used to assess occupational exposure to these metals. We conducted a population-based case-control study foc using o n the systema ti c historical assessment of occupational exposure to manganese, copper, iron, lead, mercury and zinc and PD (Gorc11 et nl., 1997). A p rccis of that work and of rela ted methodological studies are presented below.

METHODS Our general methods have been detailed e lsewhere (Gorell et nl., 1997). Briefly, cases and controls were drawn from a population base consisting of a ll individuals ~ 50 yea rs of age residing in the tri-county metropolitan Detroit area who were receiving medical care from the Henry Ford llea lth System (HFHS) [n = 239,7221. This popu lation matches, w ithin 1%, the sex and race demographics of individuals in each five year epoch fro m age 50 to more than 85 when compa red with 1990 U.S. census d a ta for this region (Gorell el nl., 1997). Only individua ls receiving p rimary medical care at HFHS were recruited in an effort to minimize selection bias (Rybicki et al., 1995). Case ascertainment began w ith rev iew of medical records from 1,243 potential cases coded with the JCD-9 designation for PD. These were frequency-ma tched for sex, race and age (± 5 years) with potential control subjects, approximately three controls per case. Excl usions fro m the s tudy population were made for: 1) lack of primary med ical care a t HFHS; 2) death; 3) residence outside of the tri-county Detroit metropolitan area; 4) fai lure of sta ff neurologists to confirm and fully document the diagnosis of PD in

GORELL ETAL

putative cases; 5) presence of PD for more than 10 years, in order to minimize survival bias; 6) a history of dementia; 7) other medical conditions that would preclude a reliable interv iew; and 8) an inability to contact potential subjects. All cases fu lfi ll ed dia g nostic criteria for PD by staff neu rologist examination, includ ing two or more of its four cardinal signs (i.e., bradykinesia, muscular rigidity, resting lim b tremor, a nd loss o f postu ral reflexes), excl uding individuals w ith either signs of other moto r disorders (i.e., cerebellopathy, unexplained corticospinal tract deficit, significant d ysa utonomia, or supranuclear gaze palsy) or evid ence o f second ary pa rki nsonism. Controls who reported a n y of e igh t sy mptoms of poten tially undiagnosed PD (Mutch et nl., 1991) were excluded. Potential subjects who fai led a face to face Mini-Mental State examination (Fobtein et nl., 1975) [score 20 years

5.24

(1.59, 17.21)

0.006

Lead and iron

both exposures >20 years

2.83

(1.07, 7.50)

0.036

Iron and copper

both exposures >20 years

3.69

(1.40, 9.71)

0.008

• Adjusted for age, race, sex, and pack-years of smoking. + 95% confidence inte rval. From Gorell et al.. 1997 (with permission).

NeuroToxicology 20(2-3): 1999 - 243

METALS AND PARKINSON'S DISEASE

TABLE 5. Years Worked by Subjects in Occupations in Which more than 20 Years of Exposure to Selected Individual Metals or Combinations of Metals Occurred. Controls Occupation

Manganese

Copper

Lead-Copper

Lead-Iron

Iron-Copper

Auto body repairman

0

0

0

38

0

Die maker (leader)

9

0

0

28

0

Electrical designer

0

32

32

0

0

Electrician

0

41

39

39

39

Electrician

0

24

24

24

24

Jig-bone operator

0

35

0

0

35

Lineman

0

43

0

0

43

Lithographer

0

43

0

0

0

Machine operator

0

34

34

34

34

' Machinist/Supervisor

29

29

29

29

29

Mold maker

0

3

3

25

3

Postal clerk

0

30

0

0

0

Supervising engineer

0

35

0

0

0

1

1

Maintenance supervisor

0

35

0

0

35

• Tool and die maker

0

0

0

26

0

Vehicle mechanic

0

0

0

41

0

Welder

0

0

0

21

0

40

40

Cases

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Chemist

40

40

Consulting engineer

0

39

0

0

39

Electrician

0

24

24

0

0

1J Electrician

0

35

35

35

35

Firefighter

31

31

31

31

31

Machinist

0

0

0

30

0

I

40

1

Machinist

0

23

0

0

23

Pipe fitter

0

35

35

35

35

Process technician

41

0

0

0

0

:Product engineer

0

0

0

36

0

Steam fitter

0

22

22

22

22

Supervisor electrician

0

47

b

0

47

Toolmaker

0

22

22

22

22

(> 20 years) exposure variable yielded significant ORs for manganese (OR= 10.61; 95% CI = 1.06, 105.83; p = 0.044) and copper (OR = 2.49; 95% CI = 1.06,5.89; p = 0.037), whereas the OR for lead, 2.05, (95% CI= 0.97, 4.31), was elevated though not significant ( p-value = 0.059). Occupational exposure for > 20 years to iron (OR= 1.27; 95% CI= 0.69, 2.34), zinc (OR= 1.19; 95% CI= 0.24, 6.02) and mercury (OR = 0.65; 95% CI = 0.07, 5.79) did not indicate an association with PD.

The backwards stepwise routine identified a single significant variable in each of the interaction models considered. In all three models, if an individual was exposed to a combination of two metals for more than 20 years, the OR of having PD was greater than that to each of these metals alone (Table 4), i.e., the OR for dual exposure to lead and copper was 5.25 (95% Cl=l.59,17.21), that for iron and lead was 2.84 (95% CI=l.07,7.50), and that for iron and copper was 3.69 (95% CI=l.40, 9.71). All


three ORs were statistically significant, i.e., lead-copper p == 0.006; lead-iron p == 0.036; iron-copper p == 0.008. The low prevalence of occupational exposure to manganese, mercury and zinc precluded testing interaction models with these metals. Since the greatest risk for PD was occupational metal exposures for more than 20 years to copper and manganese, individually, or to dual combinations of copper, iron and lead, we examined the occupations in our subjects with such a history (Table 5). It is of interest that a total of 13 of the 144 cases (9.0%) had long-term exposure to one or more of the study metals. The jobs held by these individuals, for a variable period of time, included pipe fitter, electrical worker (electrician, contractor, design engineer), engineer (consulting, plant, product), chemist, machinist, process technician, firefighter, steam fitter and toolmaker.

DISCUSSION We found a significant association with PD of occupational exposure to manganese for more than 20 years. Though there were only four individuals in our study exposed to manganese for this length of time, the association with PD was striking. This finding is of interest in light of the long-known ability of the metal to produce signs resembling PD in some miners of the ore and in some individuals working with manganese dioxide (Cotzias et al., 1968; Mena, 1980; Huang et al.; 1989; Huang et al., 1993). Zayed et al. (1990) found a significant association between PD and self-reported occupational exposure to a combination of manganese, iron and aluminum, particularly for more than 30 years (O.R. 13.64; p :S: 0.05), but the contribution made by each of these metals to the association with the disease could not be determined. Semchuk et al. (1993), in a population based case-control study in Calgary, Alberta, found no increase of PD risk for occupational manganese exposure, as assessed by selfreport. Seidler et al. (1996), in a case-control study recruiting subjects from clinics throughout Germany, reported no significant association of PD with occupational exposure to manganese, but exposure was assessed (to manganese, copper, lead, zinc and mercury) by both self-report of ever exposure, as well as by a job exposure matrix they created. Actual worksite conditions were not evaluated. Occupational exposure to copper, individually, for more than 20 years was significantly associated with PD in our study, and the OR for lead exposure for that period of time was also increased, though not statistically significant. Seidler et al. (1996) found no association with

GORELL ET AL.

PD of ever exposure to copper, though they did associate PD with ever lead exposure by comparison with one of two of their control groups. Occupational exposure to iron, individually, was not related to PD in our study, though we had the statistical power to detect such a relationship if one existed (i.e., an 80% power to detect an OR of :'.".1.8 using a two-sided 0.05 alpha level test). We are unaware of other case-control studies with sizeable populations that examined a potential association of iron with PD. Our study was unable to find an association of PD with occupational exposure to mercury, as Ngim and Devathasan (1989) had shown among subjects in Singapore, perhaps because of population or other exposure-related differences. Zinc was not associated with PD in our study or in that of Seidler et al. (1996). Because of its low prevalence of exposure, a much larger population will be required to definitively test whether zinc is a risk factor for PD if case-control methodology is used. Our finding that dual occupational exposures to specific metals, i.e., to lead and copper, to iron and copper, and to lead and iron, was associated with PD is of particular interest. It may be that a combination of metals acts together to increase the risk of the disease, though confirmation of these results will be needed. If confirmed, it would be of interest to know whether such exposures have to be simultaneous or sequential for such a process to occur. Though the mechanism(s) of neurotoxicity has not been established, manganese (Kawanishi, 1995), copper (Goldstein and Czapski, 1986), lead (Kawanishi, 1995) and iron (Gerlach et al., 1994) have been shown to promote oxidative stress by free radical generation, a process that is ongoing in the PD SN (Gerlach et al., 1994). Iron (as Fe 3+ and as total levels) has been reported to be elevated in the PD SN (Sofie et al., 1991), but copper has either been reported to be increased (Riederer et al., 1989) or decreased (Dexter et al., 1989) there, and no change in manganese or lead in this region has been reported thus far in PD brain (Dexter et al., 1989). Manganese may, however, have a role in catecholamine autoxidation (Archibald and Tyree, 1987), in the formation of neuromelanin (Graham, 1978), and, perhaps, in the production of Lewy bodies (Mon tine et al., 1995). Copper(II) can react with ascorbate (Stich et al., 1979) or levodopa (Spencer et al., 1994) to produce genotoxic free radicals. Lead(II) may be directly genotoxic, as it inhibits DNA polymerase (Popenoe and Schmaeler, 1979), possibly hampering DNA repair. This potential action of lead (Rao, 1993) may be particularly important in a neurodegenerative disorder associated with aging. The strengths and limitations of our study have been discussed at length (Gorell et al., 1997). Briefly, the fact that PD cases and control subjects were drawn from a

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j defined and representative population is a strong asset of f this work, increasing confidence in the suitability of the

i control group and limiting referral and other selection . biases that may be found in the recruitment of patients i and control subjects from a specialty clinic or hospital setting (Rybicki et al., 1995). Though it is possible that we may have missed a few cases in our population due to I ICD-9 miscoding, such potential errors are not systematically related to the risk factors under study. We 1 tried to minimize the possibility of differential reporting 1 of information relating to potential exposures among cases and controls by permitting the industrial hygienist to pose I other, specific questions to subjects via the interviewer, ·. maintaining blindness to the case-control status of these I individuals, when job information did not allow a clear judgment to be made about exposures to one or more I metals (e.g., if there was any question about whether a l :particular metal of interest was used in a certain job, or if I the means of its use or potential protection from exposure ;was unclear). If our method of exposure assessment was i I subject to misclassification, it would likely have been non1 !differential, biasing any positive results toward the null. 1J We sought to further critically examine our method [of occupational metal exposure by an industrial hygienist. I; In a parallel study of the same population reported here Ii (Rybicki et al., 1997), we compared methods of assessment l.·•.·.such as self-report, job titles linked to a job exposure matrix ,(JEM), and assignment by an industrial hygienist. ·Exposure assessment based on the JEM compared with the industrial hygienist (taken as the gold standard in these ctomparisons) resulted in greater misclassification relative ':to self-report. For three study metals (i.e., copper, iron ;and lead), combining the information from both direct ··self-report and the JEM did not improve upon the results jfor self-report alone. This study showed that the method of exposure assessment can potentially have a large ;influence on the measure of association between a disease ·outcome and exposure. In a second, parallel methodological study using data from this study (Rybicki :1et al., 1998), we reported the intra- and inter-rater reliability 'involving two industrial hygienists in the assessment of .occupational exposure to the three most prevalent metals .Ji.e., copper, iron and lead). The percent agreements for ~he intra-hygienist comparisons were 89.6 for copper, 87.9 for iron and 94.6 for lead, whereas the inter-hygienist percent agreements were 86.4 for copper, 81.1 for iron and 76.2 for lead. Based on the assumption that reliability is related to validity, we calculated an estimate of misclassification of metal exposure by one hygienist, and showed a sizable attenuation of the odds ratio, with the expected bias similar for copper and iron when using

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NeuroToxico/ogy 20(2-3): 1999 -245

either intra-rater or inter-rater reliability results to estimate misclassification. Our results suggest that variation in the expert assessment of metal exposure is due mainly to the difficulties involved in transforming an occupational history into an estimate of exposure. These results further suggest the need for a more objective measure of metal exposure. With the last point in mind, a clear limitation of our current study is the absence of a direct measurement of metals of interest in the workplaces or bodies of subjects. Despite the limitations discussed, this is the first casecontrol study to find an increased association with PD of more than 20 years of occcupational exposure to manganese and copper, individually, as well as an increased association with the disease with more than 20 years of occupational exposure to dual combinations of iron-copper, lead-copper and lead-iron. In the case of manganese, in which few subjects had long term occupational exposure, we regard conclusions about its possible association with PD as tentative. Our findings should be replicated in other populations, perhaps most practically by the study of the incidence of PD in occupational cohorts with a high prevalence of exposure to these metals. If studies of occupational cohorts are undertaken, we suggest that close collaboration between occupational toxicologists, industrial hygienists or occupational physicians, neurologists, epidemiologists and statisticians occur on a larger scale than has been done so far. If this can be accomplished, the professional skills of all involved will most likely provide state-of-the-art assessments of diagnosis, occupational exposures, study design and analysis. In so far as it is technically possible, future studies that employ measurements of body metal burden in subjects that can be related to the time during which risk was acquired will be particularly welcome, as will further postmortem studies of regional brain metal levels.

ACKNOWLEDGMENTS J.M. Gorell wishes to acknowledge the support of a grant from the National Institute of Environmental Health Sciences (ES 06418), as well as support from the William T. Gossett Parkinson's Disease Center and the Louis Hayman Parkinson's Disease Research Fund, both of Henry Ford Health System. G.G. Brown wishes to acknowledge the support of a grant from the National Institute of Neurological Disorders and Stroke (NS 30618). Finally, the authors gratefully acknowledge the excellent professional and t.echnical work of the dedicated nurses and other interviewers, data managers, medical chart abstractors, data entry and secretarial personnel on this project.


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