This article was downloaded by: [Virginia Tech Libraries]On: 01 September 2014, At: 04:07Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number:1072954 Registered office: Mortimer House, 37-41 Mortimer Street,London W1T 3JH, UK

ErgonomicsPublication details, including instructions forauthors and subscription information:http://www.tandfonline.com/loi/terg20

Pathomechanisms of work-related musculoskeletaldisorders: conceptual issuesMartin S. Forde a , Laura Punnett b & David H.Wegman ba University of Massachusetts Lowell, 1University Avenue, Lowell, MA 01854;Department of Public Health, St. George'sUniversity, PO Box 7, St. George's, Grenada,West Indiesb University of Massachusetts Lowell, 1University Avenue, Lowell, MA 01854, USAPublished online: 10 Nov 2010.

To cite this article: Martin S. Forde , Laura Punnett & David H. Wegman (2002)Pathomechanisms of work-related musculoskeletal disorders: conceptual issues,Ergonomics, 45:9, 619-630, DOI: 10.1080/00140130210153487

To link to this article: http://dx.doi.org/10.1080/00140130210153487

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of allthe information (the “Content”) contained in the publications on ourplatform. However, Taylor & Francis, our agents, and our licensorsmake no representations or warranties whatsoever as to the accuracy,completeness, or suitability for any purpose of the Content. Any opinionsand views expressed in this publication are the opinions and views ofthe authors, and are not the views of or endorsed by Taylor & Francis.The accuracy of the Content should not be relied upon and should beindependently verified with primary sources of information. Taylor andFrancis shall not be liable for any losses, actions, claims, proceedings,demands, costs, expenses, damages, and other liabilities whatsoever

or howsoever caused arising directly or indirectly in connection with, inrelation to or arising out of the use of the Content.

This article may be used for research, teaching, and private studypurposes. Any substantial or systematic reproduction, redistribution,reselling, loan, sub-licensing, systematic supply, or distribution in anyform to anyone is expressly forbidden. Terms & Conditions of accessand use can be found at http://www.tandfonline.com/page/terms-and-conditions

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

Pathomechanisms of work-related musculoskeletal disorders:conceptual issues

MARTIN S. FORDE{{*, LAURA PUNNETT{ and DAVID H. WEGMAN{

{University of Massachusetts Lowell, 1 University Avenue, Lowell, MA 01854,USA

{Department of Public Health, St. George’s University, PO Box 7, St. George’s,Grenada, West Indies

Keywords: Work-related musculoskeletal disorders; Pathomechanisms; Exposureassessment; Epidemiological study design.

Work-related musculoskeletal disorders (WRMSDs) by de®nition are a subset ofmusculoskeletal disorders (MSDs) that arise out of occupational exposures.While traditional exposure assessment techniques have proved to be successful inidentifying ergonomic exposures that are epidemiologically linked to thesedisorders, some are troubled by the lack of one-to-one correspondence betweenspeci®c occupational exposure pro®les and speci®c MSDs. In the absence of moresophisticated hypotheses that might explain the occurrence of WRMSDs in avariety of exposure patterns, the aetiologic relationships may (again) be calledinto question. Another unanswered question is whether speci®c types ofWRMSDs have qualitatively diVerent exposure-response relationships. A clearerunderstanding of the underlying pathomechanisms associated with speci®cWRMSDs could help future researchers better determine how and when variousoccupational exposure pro®les become pathogenic. Such knowledge could also beused to design exposure assessment tools to capture exposure information morerelevant to the risk of WRMSDs. The main goals of this paper are to summarizeseveral recently described pathomechanisms, most of which have been discussedprimarily in clinical and experimental literature that might not be widely read byoccupational health scientists. Suggestions are made as to how future researchcould evaluate whether these phenomena are relevant to the eVects of physicalexposures and the underlying disease processes of common WRMSDs.

1. IntroductionTo date, a large and increasing body of occupational epidemiologic ®ndings hasshown strong and consistent links between musculoskeletal disorders (MSDs) andseveral occupational ergonomic exposures such as forceful exertions, highlyrepetitive motions, sustained static muscle loading, lack of su� cient rest, awkwardbody postures, localized mechanical stress, whole body and segmental vibration, lowtemperatures, and features of the organizational structure of the work environmentsuch as restrictive, high demand-low control jobs. Comprehensive reviews of the

*Author for correspondence at the Department of Public Health, St. George’s University,

PO Box 7, St. George’s, Grenada, West Indies. e-mail: mforde@sgu.edu

ERGONOMICS, 2002, VOL. 45, NO. 9, 619 ± 630

Ergonomics ISSN 0014-0139 print/ISSN 1366-584 7 online # 2002 Taylor & Francis Ltdhttp://www.tandf.co.uk/journals

DOI: 10.1080 /0014013021015348 7

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

epidemiology on ergonomic factors and MSD morbidity can be found in Armstronget al. (1993), Bongers et al. (1993), Sommerich et al. (1993), Kuorinka and Forcier(1995), Viikari-Juntura (1995), Bernard (1997), Grieco et al. (1998), NationalResearch Council (1998, 1999, 2001), Sluiter et al. (2000), and Malchaire et al.(2001), to name a few.

However, there is less consensus regarding the nature of common epidemiologicendpoints such as symptoms and physical examination ®ndings, and whether or notthey represent pathogenic processes at the tissue or cellular levels. Several generaldescriptions of the typical course of work-related musculoskeletal disorders(WRMSDs) have been formulated based on self-reported symptoms and clinicallyobservable events. One approach is to describe several stages based on symptomreversibility and outcome (Browne et al. 1984, Kroemer 1989). Such modelsacknowledge a progression in symptomatology from symptoms that are mild andintermittent to symptoms that are severe and chronic. Variation in progression hasbeen observed clinically, with onset of symptoms after the ®rst exposure rangingfrom gradual (weeks or months) to sudden (days or hours). Unknown, however, isthe extent to which time from symptom onset to physiological or pathologic changesis related to the type and intensity of exposures, the type of WRMSD (tendon, nerve,neurovascular) , and/or speci®c mechanisms.

A major goal of pathology is to document the sequence of events in the responseof the tissues or cells to an aetiologic agent, from the initial stimulus to the ultimateexpression of the disease. For example, to properly understand a tendinitis such as deQuervain’s disease would be to know not only that this disorder can be caused by®brosis of the sheath of the tendon of the thumb but also to be able to describe thebiochemical, immunologic and morphologic events leading to pain on the side of thewrist and at the base of the thumb.

A clearer understanding of the underlying pathogenesis of WRMSDs would bevaluable for several reasons. First, it would provide a basis for explaining the signsand symptoms manifested by patients and a sound foundation for rational clinicalcare and therapy. WRMSDs of interest in today’s modern work environment areoften di� cult to diagnose precisely (Deyo et al. 1992, Viikari-Juntura and RiihimaÈ ki1999). Self-reported symptoms without objective con®rmation of pathology aresometimes suspect, even though available diagnostic and imaging techniques havetheir own limitations.

In addition, as others have pointed out (Viikari-Juntura 1997, Gordon andWeinstein 1998, Marras 2000, Kumar 2001), a clear understanding of the underlyingpathology and pathomechanisms involved can assist ergonomists and epidemiolo-gists to determine which exposure factors (force, repetition, sustained static postures,etc.) and which dimensions of each factor (intensity, duration, dose rate, exposuretemporal pro®le, etc.) are relevant to each disease outcome. This is still a challengingtask, as changes in the nature and organization of work in both manufacturing andservices have led to increasingly varied, dynamic, and complex occupationalexposure pro®les. MSDs are generally acknowledged to be multifactorial, i.e. theremay by several aetiological factors that contribute to the production of a disorder;however, the interactions among the diVerent types of exposures have been unevenlydescribed. Two related questions are whether there are common pathways for thesevaried exposures that ultimately lead to the same type of MSD (Armstrong et al.1993), and whether diVerent types of MSD have speci®c and diVerent relationshipswith ergonomic exposures.

620 M. S. Forde et al.

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

Thus, the main goals of this paper are: (1) to review current conceptual thinkingabout progression from initial occupational exposure to the clinical expression of amusculoskeletal disorder; and (2) to examine several pathogenic processes that mighthave relevance to the underlying mechanisms of common WRMSDs and suggesthow these might be studied further in epidemiologic settings.

2. Current generic WRMSD conceptual constructsEVorts have been made to develop generic conceptual constructs to explain theexposure-related pathogenesis of WRMSDs. Implicit in these is the concept thatrepeated and cumulative exposure to occupational ergonomic factors leads todisease (Radin 1976, Pugh 1982, Armstrong et al. 1993). In general, cumulative orrepetitive modelling constructs are based on the concept that each exposure(stressor) gives rise to tissue micro-trauma. Although disorders do not result froma single exposure event, over a period of time it is postulated that multiple micro-lesions occur in muscles, tendons, ligaments, or cartilage, resulting in symptomsand/or impairment. Although such constructs appear to have biologicalplausibility, their continued use presents biological and study design issues thatdeserve careful consideration.

First, given the postulation that musculoskeletal disorders result from`cumulative’ micro-damage over an extended period of time, it is a challenge tode®ne the `critical’ thresholds of exposure. Second, cumulative constructs do notexplicitly account for the bene®cial eVects of activity and physical conditioning(Hakkinene et al. 1985, Hadler 1993) nor for biological regenerative and reparativeprocesses. Provided that su� cient rest periods are allowed and the damage-repairmachinery of the exposed cells have not in some way been compromised, at leastsome micro-damageÐif it has occurredÐcan be repaired and the aVected tissue ororgan system restored to good condition in due time. Third, there may be a shift inthe nature of the prevailing pathomechanisms as the intensity or dose rate goes fromlow to high (Smith 1992). The temporal features of exposure, such as duration anddose rates, may be more relevant and predictive of disease risk than aggregateaccumulated dose (exposure6duration) in situations where the aetiologic mechan-isms are more complex (Checkoway 1986). All these factors are further complicatedby individual diVerences in genetics, anatomy and physiology.

Separate from these characteristics of any given exposure, workers are oftenexposed to multiple WRMSD aetiologic risk factors that interact, leading to one ormore pathomechanisms being triggered with multiple possible MSD outcomes.

3. Pathomechanisms possibly relevant to WRMSDs pathologyHistorically, the study of WRMSD pathology has been based on observed grossmorphological changes of muscles (Lieber and Fride n 1995, Sjogaard and Jensen1997), tendons (Vogel and Koob 1989, Fu et al. 1991, Fulcher et al. 1998), ligaments,cartilage, bones (Doran et al. 1990, Judex et al. 1999), nerves (Gelberman et al. 1983,Novak and Mackinnon 1998, Rempel 1999) and joints (Radin et al. 1995). Over thepast decade, these have been added to due to advances in the areas of biochemistry,molecular biology and genetics (Gordon et al. 1995, National Research Council1998, 1999, 2001, Johansson 2000). It now appears feasible to broaden and deepenour understanding of WRMSD causality, particularly how micro-ergonomicexposures and their various dimensions are linked to pathogenic biochemical,immunologic and morphologic processes.

621Pathomechanisms of WRMSDs

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

A few speci®c pathomechanisms that may be of relevance to WRMSD pathologyhave been selected for review. These do not provide an exhaustive and complete listof all potential pathomechanisms but rather an illustrative sample of mechanismsthat highlight the range of disease processes that might underlie the occurrence ofWRMSDs. Also, as a fairly extensive body of basic science studies exists on thesemechanisms, this summary provides a ready starting point for researchers looking todevelop more biophysiological exposure assessment tools.

Consistent with the conceptual model proposed by Armstrong et al. (1993) , someof these pathomechanisms act at the organ and tissue levels; others at the cellularlevel. Along with a description of each phenomenon, its possible relevance toWRMSD aetiology and progression is discussed.

3.1. Posturally induced muscular imbalanceMackinnon and colleagues (Mackinnon and Novak 1994, Higgs and Mackinnon1995) have proposed that the maintenance of static postures leads to muscularimbalances, with some muscles being overused and others underused. The overusedgroup undergoes hypertrophy whereas the underused group becomes weakened dueto lack of use. This combination produces a self-perpetuating condition thatmaintains the abnormal posture and muscle imbalance. This in turn leads to furtherstrengthening and hypertrophy of the overused muscles and further weakening of theunderused muscles. Static loading on the overused muscles produces reducedperipheral circulation and myalgia, as has been described by others (Lieber andFride n 1995). Relief is obtained if muscle balance is restored and the worker istrained to recruit and strengthen speci®cally the underused muscles. To evaluate thishypothesis, information on the duration of uninterrupted (static) postural strain ofindividual muscle groups, as distinguished from the aggregated cumulative exposureto many short periods of postural strain, would be required.

In addition, maintaining abnormal or prolonged static postures can also increasethe pressure around peripheral nerves or stretch them, causing increased tensionwithin the nerve, which results in chronic nerve compression. This is discussed in thenext section.

3.2. Neural pathomechanismsCertain highly repetitive jobs may invoke primary neural pathomechanisms. Forexample, in a study examining the eVects of hand movement strategy (a highlyarticulated, repetitive hand-squeezing strategy versus a more variable repetitive arm-pulling strategy) on the primary somatosensory cortex of two owl monkeys, Byl et al.(1997) found that the highly articulated hand-squeezing strategy caused motordeterioration and dediVerentiation of the normally sharply segregated areas of thehand representation in the monkey’s brain. Conversely, there was only milddegradation of the hand representation and no motor dysfunction in the monkeythat used the more variable repetitive proximal arm-pulling strategy.

This study demonstrates that certain characteristics of the exposure pro®leÐinthis case, the nature of the task as well as the movement strategy employed (hand-versus arm-centric movement strategies)Ðcan have very diVerent eVects on thesomatosensory cortex. The implications of these ®ndings are that certain exposurepro®les in which the movement strategy of the limb is highly constrained orstereotyped can trigger permanent changes in the somatosensory cortex. Addition-ally, it may be that only certain temporal exposure pro®les cause somatosensory

622 M. S. Forde et al.

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

cortex changes to take place whereas other do not. Monitoring changes in workers’motor recruitment patterns, in parallel with symptom surveillance, might provideinsights into high-risk occupational situations.

Neural mechanisms may also appear as secondary sequelae triggered bycompressive force while maintaining abnormal or prolonged static postures (Novakand Mackinnon 1998). Such postures can either directly increase the pressure aroundperipheral nerves or stretch them, causing increased tension within the nerve, whichresults in chronic nerve compression. The peripheral nerve trunk is well vascularizedand therefore compression, irritation, or stretching may trigger an in¯ammatoryresponse in and around the nerve trunk with subsequent swelling and impairment ofthe vascular supply. Given that nerve trunks are mobile, gliding structures(Lundborg and Dahlin 1995), swelling or formation of an in¯ammatory reactionmay impair or inhibit such gliding. A cycle is thus induced in which swelling,in¯ammation, and impaired micro-circulation combined with restricted gliding leadto further events and ultimately, to nerve ®bre dysfunction (Lundborg and Dahlin1995). Additionally, the decreased blood ¯ow to the nerve due to chronic tensionand/or direct mechanical compression encourages ®broblast invasion (®brosis) inand around the nerve. This in turn tethers the nerve, preventing its necessaryexcursion during normal extremity movement.

Research is needed to determine whether the intensity of the compressive force orits duration or some interaction of these two exposure factors are the prime triggersfor these secondary pathologic neural events. Certain exposure pro®les (e.g. highcompressive force/short duration) may be innocuous or insu� cient to trigger anin¯ammatory response around the nerve; others (e.g. low compressive force/longduration) may exceed neural physiologic limits or compromise protective mechan-isms.

3.3. The `Cinderella hypothesis’ of motor unit recruitmentA perplexing problem that has been observed in several studies is the occurrence ofMSDs in jobs with static workloads well below suggested threshold limits of forceexertion (e.g. 15% of maximum voluntary contraction). This apparent discrepancyhas been addressed by the `Cinderella hypothesis’ of preferential motor unit (MU)recruitment proposed by HaÈ gg (1991).

According to this hypothesis, sustained low-level isometric contractions set up astereotyped recruitment pattern of MUs according to the size principle. As a result,the same low threshold MUs (mostly Type I MUs)Ðthe `Cinderella’ unitsÐareconstantly active even in situations where the total muscle load is very low. It shouldbe noted that each time a MU is activated, it generates approximately 30% of MVCeven if a speci®c job demands a mean load of only 10% of MVC (Sjogaard andJensen 1997). Therefore, the relatively few active MUs will be working at least at30% of their strength. Provided that the contractions are sustained for a long periodof time, the expected end result would be a number of metabolically overloaded`Cinderella’ muscle ®bres highly susceptible to loss of calcium homeostasis andsubsequent activation of autogenic destructive processes causing work-relatedmyalgia and other musculoskeletal disorders.

The main challenge to this hypothesis is `the apparent lack of ``muscularwisdom’’ in assuming that a recruitment pattern that allows the systematic overloadand destruction of single muscle ®bers is permitted’ (Fallentin 2000: page 8). In theproduction of submaximal sustained moments about a joint, reduced activity in one

623Pathomechanisms of WRMSDs

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

or several MUs can be dealt with by MU rotation or substitution (Westgaard and DeLuca 1999). Therefore, the Cinderella phenomenon, if it occurs, may berepresentative of a pathologic process that has replaced or overwhelmed the normal,protective MU recruitment patterns.

A related theory is that of Johansson and Sojka (1991) who postulated thatmetabolic changes resulting from stereotypical recruitment patterns trigger twopositive feedback loops that ultimately cause increased re¯ex-mediated muscletension or stiVness in the primary and secondary muscles. These feedback systemsmay induce a self-perpetuating vicious cycle as more and more secondary ®bres arere¯exly activated, fatigued, and overloaded. This may explain why pain due to staticor monotonous contractions often becomes chronic and spreads even when exposureis eliminated.

The Cinderella response has been explained as a `systems failure’ related toinadequate activation of the elements in the Johansson-Sojka model (Fallentin 2000).Low-level static contractions with non-postural muscles might create an environmentwhere the risk for initiating such a `systems failure’ is increased by exposure to otherfactors such as psychosocial or mental stress in susceptible individuals (Fallentin 2000).

This highlights how an understanding of the underlying pathology of work-related myalgia could aid in determining which dimension(s) of exposure arepathogenic. If the Cinderella hypothesis is true, then the duration of exposure to lowintensity MVC levels, rather than the force level alone, would be the critical exposuredeterminant of work-related myalgia. Additionally, some levels of static loadingmight only be a problem in the presence of adverse psychosocial exposures, as mayoccur with monotonous work.

3.4. Reperfusion injury mechanismIt is well known that tissue damage and necrosis typically follows any ischaemiccondition that persists for more than a few minutes (Cotran et al. 1999). However, therestoration of blood ¯ow to a previously oxygen-deprived area, i.e. reperfusion, canalso cause tissue damage. This is because a complex biochemical process, closelyresembling an in¯ammatory response, takes place once blood ¯ow is restored. Themost prominent cell contributing to tissue damage is the neutrophil, which producestoxic oxygen products such as hypochlorite ordinarily to kill invading micro-organisms and to ®ght infections. When a blocked blood vessel re-opens, it appearsthat the body’s response mechanism is triggered even though no microbes are present.

Reperfusion could be relevant to WRMSDs such as neurovascular disorders (e.g.Raynaud’s phenomenon). It is also possible that reperfusion injury plays a mediatingrole in many WRMSDs. For example, tasks that cause intermittent blood ¯owblockage, which is subsequently reperfused, may be partly responsible for anin¯ammatory response in the soft tissues. Several types of research would be neededto determine which exposure pro®les are likely to trigger such a mechanism: animalexperiments to ®nd the lowest extent of blockage at which reperfusion occurs,followed by observation of exposure pro®les likely to cause such ischaemia andmeasurement of appropriate, speci®c biomarkers in such exposed persons.

3.5. Impaired heat shock responseHeat shock proteins, also called chaperone proteins, are produced by cells inresponse to stress caused by heat, poisons or signals from nerves or hormones(Saladin 1998, Cotran et al. 1999). Even under non-stressed conditions, cells

624 M. S. Forde et al.

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

maintain a low level of chaperone production. These chaperones are essential inensuring that newly-made protein folds properly once the amino-acid sequence hasbeen completed.

Exposing cells to stressÐwhether it be heat stress, oxygen stress as occurs inin¯ammatory responses, or ischaemic conditionsÐleads to an increased productionof chaperones as the cell strives to protect its vital proteins (Cotran et al. 1999). Thisprocess is controlled by another master protein called heat shock factor (HSF),which spurs the genes that encode chaperone proteins to make more of them duringstress. However, at a certain critical level, chaperones in and of themselves becomeharmful to the cell. This occurs because even as they protect other proteins,chaperones straitjacket them and prevent them from carrying out their appropriatefunctions. Thus, healthy cells produce high levels of chaperones only brie¯y, even ifstressful conditions persist.

It is now known that certain chaperone proteins can bind to and regulate HSF,thus providing a molecular, self-limiting, feedback loop in which chaperones causethe shut down of their own production. Another `oV-switch’ regulator of chaperoneproduction that has been recently discovered is Heat Shock Binding Protein 1(HSBP-1) (Satyal et al. 1998). HSBP-1 binds both to the chaperones and to HSFand prevents HSF from activating genes to produce more chaperones (®gure 1).However, as cells ageÐeither naturally or prematurely due to adverse externalexposuresÐthe heat shock response does not function properly, which ironicallyoccurs at a time just when it needs to be most e� cient.

It seems reasonable to postulate that sustained exposure to ergonomic stressorscould disrupt the heat shock response and lead to sustained pathogenic levels ofchaperone production, which in turn ultimately results in focal cell death. Whethertypical occupational situations (ergonomic exposures) produce such levels of cellularstress is presently unknown. If so, an impaired heat shock response may provide anearly indicator or biomarker that a particular exposure pro®le is likely to result incellular and tissue damage in the musculoskeletal system.

Figure 1. Heat shock response. HSBP-1, Heat Shock Binding Protein 1; Hsps, Heat ShockProteins

625Pathomechanisms of WRMSDs

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

3.6. Stress-induced mitochondrial damageMitochondria, organelles found in each cell, are the only organelles known to havetheir own DNA (mtDNA), distinct from nuclear DNA (nDNA). One key function ofmitochondria is to convert unusable forms of energy into a usable chemical form,adenosine triphosphate (ATP), so that other vital cellular chemical reactionsthroughout the body can occur. Mitochondria also carry out a number of other non-ATP-related functions that are intimately involved with most of the metabolicpathways used by a cell to build, break down, and recycle its molecular building blocks.

In the production of ATP, the mitochondrial electron transport is not perfect.Even under ideal conditions, some electrons `leak’ from the electron transport chain.These leaking electrons interact with oxygen to produce superoxide radicals.Mitochondria are the chief source of endogenous oxidants, including hydrogenperoxide, superoxide, and hydroxyl radicals. With mitochondrial dysfunction,leakage of electrons increases signi®cantly (Dean and Fowkes 1998) thereby creatinga vicious circle in which the electron transport chain becomes progressively more`leaky’.

The close proximity of mtDNA to the ¯ux of superoxide and hydroxyl radicals, aswell as its lack of protection and repair mechanisms, leads to opportunities for freeradical-mediated mutations and deletions. Furthermore, recent studies of individualcells (Yoneda et al. 1992) have shown that mitochondria whose mtDNA has beendamaged actually proliferate at the expense of healthy ones. Thus, mitochondrialdamage accumulates in cells (particularly non-dividing cells, such as nerves andmuscles) during life.

Factors and conditions that cause mitochondrial dysfunction can severely aVectoverall cellular metabolism and, ultimately, the organism’s energy levels andsurvival. Even de®cits as low as 1% in mtDNA function can cause severe weakness,fatigue and cognitive di� culties (de Gray 1997). Sports physiologists have foundthat long-term exertionÐsuch as maintained by long-distance runners and athletesengaging in endurance-type sportsÐin¯ict severe damage to the mitochondria in themuscle cells involved, likely caused by highly reactive by-products of oxygenmetabolism (Miquel 1991, 1992, Ames et al. 1993, Shigenaga et al. 1994). St. Clair etal. (1998) found that prolonged exercise may arti®cially age muscle mitochondria tothe point that they stop working properly.

Many occupational settings require workers to exert continuous or near-continuous exertions albeit not at the levels required of a long-distance runner ormountain climber. It is possible, however, that long-term, low-level exertions usingthe same muscle groups over an extended period of time may lead to mitochondrialdamage that exceeds what one would expect due to the natural ageing process.Appropriate assays to assess mitochondrial function would be needed in order toassess whether chronic, low-dose exposures to ergonomic stressors could trigger (oraccelerate) mitochondrial dysfunction in such exposed workers.

4. DiscussionIn order to meet the greater demands being placed on today’s researchers to evaluateincreasingly varied, dynamic, and complex occupational exposure pro®les, a growingnumber of epidemiologists and ergonomists (Viikari-Juntura 1997, Gordon andWeinstein 1998, Marras 2000, Kumar 2001) have pointed out the need for a clearunderstanding of the pathology underlying WRMSDs. This paper reviews severalpathomechanisms that may be relevant.

626 M. S. Forde et al.

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

A common problem faced by many ergonomists and policy-makers is trying todetermine where the cut-oV point lies between safe and hazard exposures. The focushas been on determining critical threshold levels at which tissue damage causessymptoms and/or observable clinical ®ndings. Symptom reporting is not universallyaccepted as valid and is probably aVected by factors external to the severity ofcellular or tissue damage; clinical examination manoeuvres are speci®c to only sometypes of disease and may have low sensitivity and reproducibility. In this context,biomarkers for pathologic processes such as reperfusion injury, impaired heat shockresponse, or mitochondrial dysfunction might provide more useful indicators ofwhen tissue damage occurs, especially in relation to symptom occurrence.

Developments within the last few decades in the medical measurement techniquesavailable for researchers (e.g. radioimmunologic, enzymatic, mass-spectrometric,gas-chromatographic , and ¯uorimetric techniques) have opened up an array of newresearch possibilities. For example, advances in biomedical techniques have made itpossible to monitor how various hormones and biomarkers of cellular activity andfunction change in response to various exposures over time. Miniaturization ofambulatory recording devices has enabled monitoring of nearly all organs in thebody, including the brain, in such a way that they are minimally intrusive and do nothinder the subject from moving freely while exposed to stressors of diVerent kinds.

The practical implications of these ®ndings, however, still remains to beaddressed. There is a need for basic science researchers to determine how exposure toergonomic stressors (e.g. awkward postures, forceful motions, vibration, localizedmechanical stressor, etc.) might disrupt cellular processes such as the heat shockresponse and mitochondrial function and, if so, which exposure domains and at whatlevels. If the relations are biologically plausible at exposure levels foundoccupationally, biomarkers are needed for monitoring cellular processes. Giventhat there may be multiple physiological responses to a speci®c exposure (i.e. severalpathogenic as well as restorative processes may be triggered), it is important thatassessment strategies allow for the assessment of the complete spectrum of chemical,immunologic, and neuroactive responses.

5. Recommendations for further researchFirst, develop more conceptually sound bio-physiological models. There is a currentneed for conceptual models that are more biologically speci®c and give a clearerpicture of the disease process typical of diVerent types of MSDs preferably at thetissue and cellular level. New conceptual models should explicitly take into accountthe dynamic nature of the muscle, tendon, ligament, and neurovascular organsystems of the body and their cellular regenerative and reparative processes.

Second, develop appropriate biomarkers. Some physiologic processes have beenused extensively to describe the body’s response to physical loading. Most of theseinvolve functional assessment of organ systems (e.g. electromyography, bloodpressure, heart rate, oxygen consumption, and minute ventilation). None of thesetechniques, however, provide a clear picture of what occurs at the cellular andmolecular levels. If speci®c biologic markers could be identi®ed that track muscularand neurovascular responses to physical (and psychosocial) stressors in the workenvironments, these would be signi®cantly more informative about the eVects ofexposure. In time, well-designed ®eld laboratory studies that closely monitor cellularevents via appropriately chosen biomarkers might prove to be logistically andeconomically viable. The use of appropriate biologic markers could thus help to

627Pathomechanisms of WRMSDs

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

reduce misclassi®cation and lead to epidemiologic studies that give better estimatesof the eVects of various ergonomic exposure pro®les.

Third, examine the co-occurrence of relevant pathomechanisms. Research needsto be done to determine whether and how any of these pathomechanisms occursimultaneously or interact with each other. It is even possible that diVerentcombinations of pathomechanisms result in diVerent WRMSDs. Once these`pathomechanistic systems’ can be fully mapped, how diVerent features of exposure(type, duration, interaction, time course, etc.) are related to these systems can then beexplored.

Finally, promote dialogue with basic science researchers. There is an obviousneed for settings that promote interchanges between epidemiologists and basicscience researchers. For example, epidemiologists and ergonomists need to pay moreattention to the clinical and experimental literature. Pathologists in turn need beknow which exposure types and patterns are typically encountered in the workplacein order to conduct experiments that have relevance to common occupationalsettings.

AcknowledgementsThe authors gratefully acknowledge the thought-provokin g discussions with DrsThomas Smith, David Kriebel and Bryan Buchholz and the comments of severalmembers of the Department of Work Environment musculoskeletal disordersjournal club.

ReferencesAMES, B. N., SHIGENAGA, M. K. and HAGAN, T. M. 1993, Oxidants, antioxidants, and the

degenerative diseases of aging, Proceedings of the National Academy of Science of theUnited States of America, 90, 7915 ± 7922.

ARMSTRONG, T. J., BUCKLE, P., FINE, L. J., HAGBERG, M., JONSSON, B., KILBOM, A., KUORINKA, I.A. A., SILVERSTEIN, B. A., SJOGAARD, G. and VIIKARI-JUNTURA, E. R. A. 1993, Aconceptual model for work related neck and upper-limb musculoskeletal disorders,Scandinavian Journal of Work, Environment & Health, 19, 73 ± 84.

BERNARD, B. P. 1997, Musculoskeletal disorders and workplace factors: a critical review ofepidemiologic evidence for work-related musculoskeletal disorders of the neck, upperextremity, and low back. US Department of Health and Human Services (DHHS)Publication No. 97-141, Center for Disease Control and Prevention, National Instituteof Occupational Safety and Health, Cincinnati, OH.

BONGERS, P. M., DE WINTER, C. R., KOMPIER, M. A. and HILDEBRANDT, V. H. 1993, Psychosocialfactors at work and musculoskeletal disease, Scandinavian Journal of Work, Environ-ment & Health, 19, 297 ± 312.

BROWNE, C. D., NOLAN, B. M. and FAITHFULL, D. K. 1984, Occupational repetition straininjuries: guidelines for diagnosis and management, The Medical Journal of Australia, 17,329 ± 332.

BYL, N. N., MERZENICH, M. M., CHEUNG, S., BEDENBAUGH, P., NAGARAJAN, S. S. and JENKINS, W.M. 1997, A primate model for studying focal dystonia and repetitive strain injury:eVects on the primary somatosensory cortex, Physical Therapy, 77, 269 ± 284.

CHECKOWAY, H. 1986, Methods of treatment of exposure data in occupational epidemiology,Medicina del Lavoro, 77, 48 ± 73.

COTRAN, R. S., KUMAR, V. and COLLINS, T. 1999, Robbins Pathologic Basis of Disease, 6th ed.(Philadelphia, PA: W. B. Saunders).

DEAN, W. D. and FOWKES, S. W. 1998, Mitochondrial nutrition, aging and cognition, http://www.ceri.com/mito.htm, Cognitive Enhancement Research Institute (CERI), PO Box4029, Menlo Park, CA 94026, USA.

DE GRAY, A. D. N. J. 1997, A proposed re®nement of the mitochondrial free radical theory ofaging, BioEssays, 19, 161 ± 166.

628 M. S. Forde et al.

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

DEYO, R. A., RAINVILLE, J. and KENT, D. L. 1992, What can the history and physical examinationtell us about low back pain?, Journal of the American Medical Association, 268, 760 ± 765.

DORAN, A., GRESHAM, G. A., RUSHTON, N. and WATSON, C. 1990, Tennis elbow: aclinicopathologic study of 22 cases followed for 2 years, Acta Orthopaedic Scandinavica,61, 535 ± 538.

FALLENTIN, N. 2000, Motor unit recruitment in relation to genesis of muscle pain (Cinderellahypothesis). Workshop on Neuromuscular Mechanisms behind Work-Related Myalgia,held at the Swedish Trades Unions, Brussels, 7 ± 9 February.

FU, F. H., HARNER, C. D. and KLEIN, A. H. 1991, Shoulder impingement syndrome: a criticalreview, in M. R. Urist, Clinical Orthopaedics and Related Research, No. 269(Philadelphia, PA: J. B. Lippincott).

FULCHER, S. M., KIEFHABER, T. R. and STERN, P. J. 1998, Upper-extremity tendinitis andoveruse syndromes in the athlete, Clinic in Sports Medicine, 17, 433 ± 448.

GELBERMAN, R. H., SZABO, R. M., WILLIAMSON, R. V., HARGENS, A. R., YARU, N. C. andMINTEER-CONVERY, M. A. 1983, in M. R. Urist, Clinical Orthopaedics and RelatedResearch, No. 178 (Philadelphia, PA: J. B. Lippincott).

GORDON, S. L. and WEINSTEIN, J. N. 1998, A review of basis science issues in low back pain,Physical Medicine and Rehabilitation Clinics of North America, 9, 323 ± 342.

GORDON, S. L., BLAIR, S. J. and FINE, L. J. 1995, Repetitive Motion Disorders of the UpperExtremity (Rosemont, IL: American Academy of Orthopaedic Surgeons).

GRIECO, A., MOLTENI, G., DE VITO, G. and SIAS, N. 1998, Epidemiology of musculoskeletaldisorders due to biomechanical overload, Ergonomics, 41, 1253 ± 1260.

HADLER, N. M. 1993, Occupational Musculoskeletal Disorders (New York: Raven Press).HAÈ GG, G. 1991, Static work loads and occupational myalgia: a new explanation model, in P.

A. Anderson, D. J. Hobart and J. V. DanoV (eds), Electromyographical Kinesiology(Amsterdam: Elsevier), 141 ± 144.

HAKKINENE, K., ALLEN, M. and KIMI, P. V. 1985, Changes in isometric force and relaxation-time, electromyography and muscle ®ber characteristics of human skeletal muscleduring strength training and detraining, Acta Physiologica Scandinavica, 125, 573 ± 585.

HIGGS, P. E. and MACKINNON, S. E. 1995, Repetitive motion injuries, Annual Reviews Medicine,46, 1 ± 16.

JOHANSSON, H. 2000, Neuromuscular mechanisms behind work-related myalgia, Workshop onNeuromuscular Mechanisms behind Work-Related Myalgia, held at the Swedish TradesUnions, Brussels, 7 ± 9 February.

JOHANSSON, H. and SOJKA, P. 1991, Pathophysiological mechanisms involved in genesis andspread of muscular tension in occupational muscle pain and in chronic musculoskeletalpain syndromes: a hypothesis, Medical Hypotheses, 35, 196 ± 203.

JUDEX, S., WHITING, W. C. and ZERNICKE, R. F. 1999, Exercise-induced bone adaptation:considerations for designing an osteogenically eVective exercise program, InternationalJournal of Industrial Ergonomics, 24, 235 ± 238.

KROEMER, K. H. E. 1989, Cumulative trauma disorders: their recognition and ergonomicsmeasures to avoid them, Applied Ergonomics, 20, 274 ± 280.

KUMAR, S. 2001, Theories of musculoskeletal injury causation, Ergonomics, 44, 17 ± 47.KUORINKA, I. and FORCIER, L. 1995, Work Related Musculoskeletal Disorders (WRMSDs): A

Reference Book for Prevention (London: Taylor & Francis).LIEBER, R. L. and FRIDEÂ N, J. 1995, Skeletal muscle metabolism, fatigue, and injury, in S.

Gordon, S. Blair and L. Fine (eds), Repetitive Motion Disorders of the Upper Extremity(Rosemont, IL: American Academy of Orthopaedic Surgeons), 287 ± 300.

LUNDBORG, G. and DAHLIN, L. B. 1995, Pathophysiology of nerve compression, in S. Gordon,S. Blair and L. Fine (eds), Repetitive Motion Disorders of the Upper Extremity(Rosemont, IL: American Academy of Orthopaedic Surgeons), 381 ± 397.

MACKINNON, S. E. and NOVAK, C. B. 1994, Clinical commentary: pathogenesis of cumulativetrauma disorder, Journal of Hand Surgery, 19A, 873 ± 883.

MALCHAIRE, J., COCK, N. and VERGRACHT, S. 2001, Review of the factors associated withmusculoskeletal problems in epidemiological studies, International Archives of Occupa-tional and Environmental Health, 74, 79 ± 90.

MARRAS, W. S. 2000, Occupational low back disorder causation and control, Ergonomics, 43,880 ± 902.

629Pathomechanisms of WRMSDs

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14

MIQUEL, J. 1991, An integrated theory of aging as the result of mitochondrial DNA mutationin diVerentiated cells, Archives of Gerontology and Geriatrics, 12, 99 ± 117.

MIQUEL, J. 1992, An update on the mitochondrial-DNA mutation hypothesis of cell aging,Mutation Research, 275, 209 ± 216.

NATIONAL RESEARCH COUNCIL 1998, Work-related Musculoskeletal Disorders: A Review of theEvidence (Washington, DC: National Academy Press).

NATIONAL RESEARCH COUNCIL 1999, Work-related Musculoskeletal Disorders: The ResearchBase (Washington, DC: National Academy Press).

NATIONAL RESEARCH COUNCIL 2001, Musculoskeletal Disorders and the Workplace: Low Backand Upper Extremities (Washington, DC: National Academy Press).

NOVAK, C. B. and MACKINNON, S. E. 1998, Nerve injury in repetitive motion disorders, ClinicalOrthopaedics and Related Research, 351, 10 ± 20.

PUGH, J. 1982, Biomechanical aspects of osetoarthritic joints, mechanisms and noninvasivedetection, in D. N. Ghista (ed.), Osteoarthromechanics (New York: McGraw-Hill), 162.

RADIN, E. L. 1976, Mechanical aspects of osteoarthrosis, Bulletin on the Rheumatoid Diseases,26, 862 ± 865.

RADIN, E. L., SCHAFFLER, M., GIBSON, G. and TASHMAN, S. 1995, Osteoarthrosis as the result ofrepetitive trauma, in K. E. Kuettner and V. M. Goldberg (eds), Osteoarthritic Disorders(Rosemont, IL: American Academy of Orthopaedic Surgeons).

REMPEL, D. 1999, Work-related Musculoskeletal Disorders: The Research Base (Washington,DC: National Academy Press).

SALADIN, K. S. 1998, Anatomy and Physiology: The Unity of Form and Function (New York:McGraw-Hill).

SATYAL, S. H., CHEN, D., FOX, S. G., KRAMER, J. M. and MORIMOTO, R. I. 1998, Negativeregulation of the heat shock transcriptional response by HSBP1, Genes andDevelopment, 12, 1962 ± 1974.

SHIGENAGA, M. K., HAGEN, T. M. and AMES, B. N. 1994, Oxidative damage and mitochondrialdecay in aging, Proceedings of the National Academy of Sciences of the United States ofAmerica, 91, 10771 ± 10778.

SJOGAARD, G. and JENSEN, B. R. 1997, Muscle pathology with overuse, in D. Ranney (ed.),Chronic Musculoskeletal Injuries in the Workplace (Philadelphia, PA: W. B. Saunders).

SLUITER, J. K., REST, K. M. and FRINGS-DRESEN, M. H. W. 2000, Criteria document forevaluation of the work-relatedness of upper extremity musculoskeletal disorders.SALTSA Joint Programme for Working Life Research in Europe and AcademicMedical Center, University of Amsterdam, Amsterdam.

SMITH, T. J. 1992, Occupational exposure and dose over time: limitations of cumulativeexposure, American Journal of Industrial Medicine, 21, 35 ± 51.

SOMMERICH, C. M., MCGLOTHLIN, J. D. and MARRAS, W. S. 1993, Occupational risk factorsassociated with soft tissue disorders of the shoulders: a review of recent investigations inthe literature, Ergonomics, 36, 697 ± 717.

ST. CLAIR, G. A., LAMBERT, M. I., WESTON, A. R., MYBURGH, K. H., EMMS, M., KIRBY, P.,MARINAKI, A. M., OWEN, E. P., DERMAN, E. W. and NOAKES, T. D. 1998, Exercise-inducedmitochondrial dysfunction in an elite athlete, Clinical Journal of Sports Medicine, 8, 52 ± 55.

VIIKARI-JUNTURA, E. 1995, The role of physical stressors in the development of hand/wrist andelbow disorders, in S. Gordon, S. Blair and L. Fine (eds), Repetitive Motion Disorders ofthe Upper Extremity (Rosemont, IL: American Academy of Orthopaedic Surgeons), 7 ± 30.

VIIKARI-JUNTURA, E. 1997, The scienti®c basis for making guidelines and standards to preventwork-related musculoskeletal disorders, Ergonomics, 40, 1097 ± 1117.

VIIKARI-JUNTURA, E. and RIIHIMAKI, H. 1999, New avenues in research on musculoskeletaldisorders, Scandinavian Journal of Work, Environment & Health, 25, 564 ± 568.

VOGEL, K. G. and KOOB, T. J. 1989, Structural specialization in tendons under compression,International Reviews of Cytology, 115, 267 ± 293.

WESTGAARD, R. H. and DE LUCA, C. J. 1999, Motor unit substitution in long-duration contractionof the human trapezius muscle, The Journal of Neurophysiology, 82, 501 ± 504.

YONEDA, M., CHOMYN, A, MARTINUZZI, A., HURKO, O. and ATTARDI, G. 1992, Markedreplicative advantage of human mtDNA carrying a point mutation that causes theMELAS encephalomyopathy, Proceedings of the National Academy of Science, 89,11164 ± 11168.

630 M. S. Forde et al.

Dow

nloa

ded

by [

Vir

gini

a T

ech

Lib

rari

es]

at 0

4:07

01

Sept

embe

r 20

14