Chul Gab Lee

doi:10.35371/aoem.2026.38.e20

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Review Reframing welders’ parkinsonism: from the “idiopathic” label to biological causation and legal recognition: Chul Gab Lee^1,2^,*; Annals of Occupational and Environmental Medicine 2026;38:e20.
DOI: https://doi.org/10.35371/aoem.2026.38.e20
Published online: June 17, 2026

¹Department of Occupational and Environmental Medicine, Chosun University Hospital, Gwangju, Korea

²Gwangju Branch of Korea Occupational Disease Surveillance Center, Gwangju, Korea

*Corresponding author: Chul Gab Lee Department of Occupational and Environmental Medicine, Chosun University Hospital, 365, Pilmun-daero, Dong-gu, Gwangju 61453, Korea E-mail: cglee@chosun.ac.kr, eecg@daum.net

• Received: March 13, 2026 • Revised: May 31, 2026 • Accepted: June 8, 2026

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
BACKGROUND
METHODS
RESULTS
DISCUSSION
CONCLUSIONS
Abbreviations
NOTES
SUPPLEMENTARY MATERIAL
REFERENCES

Abstract

In Korea, welders diagnosed with “idiopathic Parkinson's disease (iPD)” often face denial of workers’ compensation, as “idiopathic” is interpreted as excluding occupational contribution. This narrative review examines whether a categorical distinction between iPD and “toxic parkinsonism” is defensible on diagnostic, pathological, neuroimaging, epidemiological, causal-inference, and legal grounds. The 2024 NSD-ISS (Neuronal α-synuclein disease Integrated Staging System) and SynNeurGe (Synuclein-Neurodegeneration-Gene) frameworks challenge categorical use of the “idiopathic” label by defining Parkinson's disease (PD)–related disease biologically, irrespective of etiology. Nonhuman primate studies show that chronic low-dose manganese exposure can produce nigrostriatal deficits and α-synuclein aggregation overlapping with PD biology. Dichotomous use of FP-CIT dopamine transporter imaging or levodopa responsiveness to separate manganese poisoning from iPD is therefore scientifically unsound, as chronic welding exposure can induce presynaptic dysfunction and treatment responses indistinguishable from PD. Epidemiological findings diverge methodologically: direct clinical examination has reported elevated parkinsonism prevalence among welders, whereas administrative cohorts have generally found no increased PD risk. This divergence is plausibly explained by differences in case ascertainment, exposure assessment, healthy-worker-survivor selection, and disease latency. Bradford Hill and Rothman frameworks support a causal interpretation, although validated biomarkers and dose-response thresholds remain undefined. Under Korea’s Industrial Accident Compensation Insurance Act, causation is evaluated as a “proximate causal relationship” rather than strict scientific proof. A multi-hit model integrating genetic predisposition, aging, and cumulative environmental exposure supports recognition under this standard, and compensation eligibility should not depend on whether the diagnosis label is ‘PD’ or ‘parkinsonism.’ When parkinsonian symptoms occur in welders with at least approximately 20,000 exposure-weighted welding hours, or with substantial high-intensity exposure such as confined-space welding, inadequate ventilation, or flux-cored arc welding, occupational contribution should be considered under a weight-of-evidence approach. This criterion is sufficient for recognition but is not a necessary condition.
Keywords: Parkinson’s disease; Parkinsonism; Welding; Manganese poisoning; Causality; Workers' compensation

BACKGROUND

Parkinson's disease (PD), recognized as the second most prevalent neurodegenerative disorder with a global prevalence of approximately 8.5 million cases,¹^-³ has historically been categorized as “idiopathic,” indicating the absence of an identifiable external cause.⁴^-⁶ In Korea, this label can contribute to denial of workers' compensation for welders who develop parkinsonian symptoms after prolonged exposure to manganese-containing fumes. However, the 2024 NSD-ISS (Neuronal α-synuclein disease Integrated Staging System) and SynNeurGe (Synuclein-Neurodegeneration-Gene) frameworks challenge categorical use of the “idiopathic” label and are compatible with environmental neurotoxins acting as component causes or accelerants.⁷^-⁹

This shift in understanding creates a significant disconnect between contemporary neuroscience and the outdated diagnostic terminology still employed in occupational compensation adjudication. Welding fumes, which comprise a complex mixture of manganese, iron, chromium, nickel, and ultrafine metallic particles, have been classified as group 1 carcinogenic to humans by the International Agency for Research on Cancer (IARC).¹⁰ Although carcinogenic classification does not prove neurodegenerative causation, it underscores the toxic-mixture nature of welding fumes. The neurodegenerative potential of chronic welding-fume exposure remains contentious primarily because medicolegal reasoning often retains a traditional distinction between "manganese parkinsonism" and idiopathic Parkinson's disease (iPD). A Korean translation of this article is available in Supplementary Data 1.

Objectives

This narrative review examines the evolution of diagnostic concepts for PD by integrating neuropathological and neuroimaging evidence, epidemiological findings, causal-inference frameworks, and legal standards. Its objective is to determine whether a categorical distinction between iPD and “toxic parkinsonism” remains scientifically defensible and legally decisive in cases involving welding-fume exposure.

METHODS

Ethics statement

This is a literature-based study; therefore, neither institutional review board approval nor informed consent was required.

Study design

This narrative review was based on a broad, purposive search of academic databases and relevant legal and regulatory sources.

Information sources and search strategy

PubMed and Google Scholar were searched using combinations of the following terms: “Parkinson's disease,” “parkinsonism,” “welding,” “welding fumes,” “manganese,” “occupational exposure,” “dopamine transporter imaging,” “alpha-synuclein,” “causal inference,” and “workers’ compensation.” Reference lists of retrieved articles were manually reviewed. No date restrictions were applied; the last search was conducted in February 2026. The initial search yielded approximately 1,200 records. After relevance screening, 180 full-text articles were assessed, of which 90 met the inclusion criteria. Because this was a narrative rather than a systematic review, no formal risk-of-bias assessment was performed, and the inherent limitation of selective citation is acknowledged.¹¹

Selection process

Studies were included if they addressed the diagnostic classification of PD, neuropathological or neuroimaging findings associated with manganese or welding-fume exposure, epidemiological associations between welding and parkinsonism, causal-inference methods, or legal frameworks for the recognition of occupational diseases. Editorials, conference abstracts, and non-peer-reviewed sources were excluded, except for official legal instruments and government regulations.

RESULTS

The evolution of diagnostic concepts: from “idiopathic” to biological classification

The first issue concerns the evolution of diagnostic criteria. The 1988 United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) criteria used a three-step algorithm: (1) confirmation of parkinsonism; (2) application of exclusion criteria that disqualified any cases with a history of toxic exposure, including manganese; and (3) assessment of supportive criteria.¹²^,¹³ This structure risked circular reasoning: occupational exposure could preclude a PD diagnosis, while a PD diagnosis could be interpreted as implying the absence of relevant exposure. The 2015 Movement Disorder Society (MDS) criteria partly mitigated this problem by moving away from the “idiopathic” qualifier and by requiring exclusion criteria and red flags to be interpreted within a broader clinical context rather than as a simplistic occupational/non-occupational dichotomy.¹⁴ Table 1 summarizes this evolution.

The most significant shift occurred with the biological redefinition of PD in 2024. Two research frameworks—the NSD-ISS and SynNeurGe—were published,⁷^,⁸ and the Movement Disorder Society concurrently stated that PD is fundamentally biological.⁹ Both frameworks conceptualize PD-related disease around biological anchors, including α-synuclein pathology, nigrostriatal neurodegeneration, and genetic status, irrespective of whether the initiating factors are genetic, environmental, or mixed. Under this definition, a welder who has an S+N+G−profile would be classified within the same biological framework as a patient traditionally labeled as having iPD (Table 1), making categorical exclusion of occupational contribution increasingly difficult to sustain.

Both 2024 frameworks were designed as research tools and have not been validated for clinical diagnosis or medicolegal adjudication.¹⁵^,¹⁶ Approximately 7%–10% of clinically diagnosed PD patients are seed amplification assays (SAA)–negative, particularly those without REM-sleep behavior disorder (RBD), with younger age at onset, or with dominant tremor—phenotypes that overlap with welding-associated presentations.¹⁷^-¹⁹ Current SAA assays are derived chiefly from Parkinson's Progression Markers Initiative and population-based cohorts and have not been standardized in welder populations; although α-synuclein aggregation has been demonstrated in nonhuman primate (NHP) models that parallel some welder exposure patterns, direct human pathological confirmation in welders remains absent.²⁰^,²¹ At present, SAA status should be regarded as an emerging auxiliary biomarker rather than a definitive test for occupational causation. Future research may clarify whether SAA can contribute more directly to occupational causal assessment.

Traditional differentiation criteria and the exposure-pathology continuum

A central challenge in occupational causal assessment is the traditional pathological distinction between manganism and PD. This distinction is based on several axes, including lesion site, α-synuclein pathology, neuroimaging patterns, pharmacological response, clinical phenotype, and disease progression, all of which were largely derived from the classical high-dose manganism model. Table 2 compares these axes across iPD, classical manganism, and chronic low-dose welding-fume exposure and evaluates each criterion's discriminatory power.⁷^,⁸^,¹²^,¹⁴^,²⁰^-⁴⁰

Classical manganism, resulting from high-concentration exposure (airborne Mn >1–5 mg/m³) in mining or ferromanganese smelting, predominantly causes postsynaptic pallidal destruction (globus pallidus neurons), while presynaptic nigrostriatal terminals remain relatively intact.²²^,²³^,³⁸^,⁴¹ In contrast, PD is characterized by degeneration of the substantia nigra pars compacta (SNc) with Lewy body (α-synuclein) pathology. This anatomical distinction—postsynaptic pallidal damage versus presynaptic nigrostriatal degeneration—forms the theoretical basis for nearly all other differentiation criteria.²⁶ The traditional differentiation model was developed from observations of high-dose acute or subacute manganese exposure in miners and battery workers during the mid-20th century, when ambient concentrations often exceeded 1–5 mg/m³.⁴² Modern welding environments, particularly electric arc welding with manganese-containing electrodes, generally involve substantially lower but chronic exposures (0.01–0.2 mg/m³) sustained over one to three decades.⁴³^,⁴⁴ The critical question for occupational medicine is whether differentiation criteria validated for classical high-dose manganism remain applicable to this fundamentally different exposure scenario. As detailed below and summarized in Table 2, the evidence suggests that they often do not.

This dichotomy is challenged by the chronic low-dose Mn exposure typical of modern electric arc welding. NHP studies have demonstrated that chronic low-dose Mn can produce nigrostriatal dopaminergic deficits alongside pallidal changes.²⁴^,⁴⁵ Magnetic resonance imaging (MRI) diffusion abnormalities have been reported in both the substantia nigra and globus pallidus of Mn-exposed welders.²⁵ Critically, Mn promotes α-synuclein aggregation and prion-like cell-to-cell exosomal transmission,²¹ and chronic Mn exposure induces α-synuclein-positive inclusions resembling Lewy bodies in the NHP frontal cortex.²⁰ These inclusions have not been conclusively shown to be identical to classical Lewy bodies, and no postmortem study of human welders has confirmed Lewy body pathology—a critical evidence gap. These findings support an exposure-pathology continuum reflecting dose and duration rather than categorically distinct diseases.⁴⁶

Conceptually, manganese-related neurodegeneration can be understood along a continuum. This spectrum extends from classical manganism at the high-dose end to PD-like nigrostriatal degeneration at the chronic low-dose end, with intermediate phenotypes showing mixed pallidal and nigral involvement.⁴⁶^-⁴⁸ This exposure-pathology continuum challenges the categorical classification often used in compensation adjudication, where a binary distinction is made between “manganese poisoning” and “idiopathic PD.” Biologically, the process may represent a graded transition rather than a discrete boundary.

Limitations of neuroimaging as a differential diagnostic tool

Dopamine transporter (DAT) imaging and brain MRI serve complementary diagnostic roles.²²^,²³ DAT imaging (FP-CIT [¹⁸F-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane] or FDOPA [6-[¹⁸F]fluoro-L-DOPA] PET [positron emission tomography]) quantifies presynaptic dopaminergic terminal density in the striatum. In iPD, uptake is typically reduced asymmetrically, with greater loss in the putamen contralateral to the predominantly affected limb. Although historically treated as highly characteristic of PD, this pattern is not etiologically specific: recent welder cohorts have reported similar asymmetric presynaptic deficits after cessation of exposure, indicating that DAT imaging cannot reliably distinguish nigrostriatal injury of occupational origin from idiopathic PD.²⁹^,³⁰^,⁴⁰ Korean compensation adjudication often follows a binary logic: normal DAT indicates manganese parkinsonism (compensable), whereas abnormal DAT suggests iPD (non-compensable). However, DAT imaging measures presynaptic dopamine transporter density—a topographic assessment of neuronal loss, not a causal explanation. It is essential to differentiate between topographic information in DAT imaging and the issue of causal inference, as these concepts are frequently conflated in workers' compensation practices.

This binary framework is based on the premise that manganism causes postsynaptic pallidal lesions while preserving presynaptic terminals.²²^,²³ That premise is inadequate for chronic low-dose exposure in both directions. On one hand, FP-CIT PET studies in welders have demonstrated asymmetric posterior putaminal depletion similar to PD,²⁹ and an independent Penn State-Hershey program has reported microstructural diffusion-tensor changes in the substantia nigra and globus pallidus of welders that scale nonlinearly with cumulative lifetime welding exposure.²⁵^,⁴⁹^,⁵⁰ NHP studies have confirmed nigrostriatal DAT deficits at lower dose ranges.²⁴^,⁴⁵ On the other hand, welders with predominantly pallidal damage may exhibit preserved DAT uptake at the time of evaluation, yet this does not preclude subsequent nigrostriatal degeneration, as the longitudinal case discussed below illustrates.³²^,⁴⁰ A normal DAT imaging result therefore provides a snapshot of current presynaptic integrity, not a guarantee against future dopaminergic decline.

Structural MRI provides complementary but temporally limited information. T1-weighted hyperintensity in the globus pallidus reflects current paramagnetic Mn accumulation and is characteristic of active exposure.³¹^,³³^,⁵¹ However, the brain half-life of Mn spans months to years; in retired welders, the T1 signal may have completely normalized despite significant cumulative past exposure.³³ Therefore, the absence of globus pallidus T1 hyperintensity at clinical evaluation cannot be interpreted as evidence that prior Mn exposure was insufficient to cause neurological damage. This temporal limitation has direct implications for compensation adjudication. Many welders present for evaluation years after retirement, when the MRI T1 signal may have normalized. Using the absence of globus pallidus hyperintensity as evidence against manganese-related disease in these cases conflates the current Mn body burden with the cumulative historical exposure that may have already initiated irreversible neurodegeneration. The MRI T1 signal is a marker of recent exposure, not a measure of past neurotoxic injury.⁵¹^,⁵²

A longitudinal case illustrates these temporal complexities. A welder initially presented with symmetric parkinsonism and T1 globus pallidus hyperintensity consistent with active Mn retention; several years after cessation of exposure, the T1 signal normalized while DAT (single-photon emission computed tomography) imaging uptake progressively declined in an asymmetric pattern indistinguishable from iPD.³²^,⁴⁰ Resolution of the Mn-retention marker coupled with an emerging presynaptic deficit indicates that neuroimaging findings in welders are dynamic and that an iPD-like late presentation does not exclude a prior welding-fume-related contribution.

In summary, a normal DAT imaging result does not preclude future nigrostriatal degeneration, and an abnormal result cannot determine whether deficits are attributable to endogenous neurodegeneration, occupational exposure, or both. A single time point DAT imaging study does not provide etiological determination.

Pharmacological and clinical differentiation: erosion of traditional criteria

The clinical literature in welders is heterogeneous (Table 3). Workplace and clinic series have reported preserved or initial levodopa responses in up to half of affected welders, whereas a double-blind crossover trial in welders diagnosed with manganese-induced parkinsonism showed no benefit.³⁴^-³⁷ A common clinical argument against occupational causation is that a positive levodopa response indicates iPD. Classical manganism is generally characterized by a poor response to levodopa, attributed to postsynaptic pallidal lesions: when postsynaptic circuitry is impaired, exogenous levodopa may be ineffective despite intact or partially intact presynaptic dopamine supply.²²^,²³ Conversely, chronic low-dose exposure that injures SNc neurons provides a plausible neurochemical basis for levodopa responsiveness.²⁴^,³¹ Levodopa unresponsiveness may help distinguish severe manganism from PD, but a positive response in a welder is compatible with preserved nigrostriatal function and does not itself exclude welding-fume-related nigrostriatal injury.²²^,²³^,²⁹

Beyond pharmacological response, clinical motor phenotype has traditionally been used to distinguish classical manganism from PD. The two conditions differ in symmetry of onset, tremor type, gait pattern, dystonia, and psychiatric manifestations.¹²^,¹⁴^,²²^,²³ However, these clinical distinctions become less reliable in chronic low-dose welding-fume exposure. Clinical studies have demonstrated that welders present features indistinguishable from iPD, including unilateral onset, resting tremor, and bradykinesia. In a blinded workplace study, the motor phenotype of parkinsonism in welders with the highest exposure significantly overlapped with that of newly diagnosed, untreated PD, although welders exhibited somewhat less pronounced resting tremor and more symmetric distribution.³⁷ Gait provides an example: PD is characterized by a stooped, shuffling gait with festination and freezing episodes, whereas classical manganism produces the distinctive “cock-walk” pattern of toe-walking with trunk retroflection.³⁸ In cases of chronic low-dose exposure, gait patterns are variable and may closely resemble those observed in PD rather than the classical manganism pattern. Dystonia, which is prominent and appears early in classical manganism but typically manifests only in the later stages of PD as off-period dystonia, presents intermediate patterns in cases of chronic low-dose exposure.³⁸^,⁴⁶ Psychiatric manifestations, including emotional lability, impulse dyscontrol, and psychotic symptoms, are indicative of classical manganism and typically manifest only in the advanced stages of PD; however, they have not been systematically studied in chronically exposed welders.²²^,²³^,³⁸

Age at onset is an important epidemiological clue. A mean age at onset of approximately 46 years among welders, compared with the typical 60–65-year range in PD, suggests that occupational exposure may accelerate neurodegenerative manifestation by approximately 15–17 years in some cohorts.²⁹ An independent Canadian clinic-based cohort of 290 PD patients from three Quebec movement-disorder centers showed a similar direction of effect: welding-exposed patients had an age at onset of 54.3 years versus 59.3 years in unexposed controls, an approximately 5-year earlier onset in a separate population and design.³⁹ This observation aligns with the multi-hit hypothesis, which suggests that environmental exposure can accelerate disease manifestation.⁵³ Early onset should therefore increase the index of suspicion for occupational factors when evaluating parkinsonian symptoms in individuals with extensive welding histories, particularly when symptoms occur before age 55.

Clinical course after exposure cessation provides an additional dimension for differentiation. Classical manganism may partially stabilize or improve after exposure ceases, whereas PD is characterized by continued progression. In a recent longitudinal case,³²^,⁴⁰ reversible Mn-induced parkinsonism in a welder was followed, after apparent clinical and radiological recovery, by delayed-onset asymmetric, DAT-deficient, levodopa-responsive PD. As illustrated in the case noted above, chronic low-dose exposure can be followed by delayed emergence of progressive PD that fulfills diagnostic criteria even after exposure cessation. Thus, initial improvement after exposure cessation does not preclude later occupationally contributed neurodegeneration. As shown in Table 2, nearly all traditional distinguishing features lose discriminatory power when applied to chronic low-dose welding-fume exposure.

Beyond manganese: the complex neurotoxic exposure of welding fumes

Welding fumes, classified by IARC as group 1 carcinogenic to humans,¹⁰ are a complex mixture whose composition depends on welding method, base metal, and electrode type.⁴³^,⁵⁴ Although manganese has received the greatest attention, other potentially neurotoxic constituents—iron, aluminum, chromium, nickel, copper, cobalt, and ultrafine particulates—are of growing concern.⁵⁴^,⁵⁵ These components may act through overlapping mechanisms: iron and copper participate in Fenton-type reactive oxygen species generation, aluminum can accelerate α-synuclein aggregation, and ultrafine particulates have the potential to directly damage dopaminergic neurons. Shared transporters (DMT1, ZIP8/14) lead to additive toxicity at the cellular level.⁵⁶^-⁵⁸ A welder is therefore exposed to a neurotoxic mixture rather than to Mn alone, so an American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value for Mn alone may be insufficient to characterize total nigrostriatal burden.⁵⁹

Epidemiological evidence: two research streams and meta-analysis

Where both positive and negative reports exist, compensation adjudication often treats inconsistency as evidence of no association, without fully evaluating the methodological strengths and limitations of each evidence stream. Table 4 compares cohort studies from Denmark and Sweden, which are frequently cited to argue against an association between welding and PD, with a representative U.S. research program from 2001 to 2017 that used increasingly refined clinical and exposure-assessment methods to evaluate associations and dose-response relationships.²⁹^,³⁷^,⁶⁰^-⁶⁴

The negative association stream: administrative cohort studies

Population-based cohort studies using administrative records have not demonstrated an elevated risk of PD among welders. A Swedish cohort of 49,488 welders reported an adjusted relative risk of 0.89 (95% confidence interval [CI]: 0.79–0.99),⁶² and successive Danish registry analyses yielded null or modestly protective estimates.⁶³^,⁶⁴ These studies share four structural limitations that systematically bias risk estimates toward the null. First, case ascertainment through International Classification of Diseases (ICD)–coded hospital records is insensitive to early or unreferred parkinsonism, so affected workers who have not been hospitalized are not captured. Second, occupational exposure is inferred from job-title proxies without fume-level quantification or process-specific stratification. Third, the decade-long prodromal phase of PD is not accommodated within typical administrative follow-up windows. Fourth, healthy-worker-survivor selection may preferentially retain resistant workers while susceptible workers leave exposed employment before outcome ascertainment. Together, these features render administrative cohorts structurally biased toward the null.⁶²^-⁶⁵

A 2012 industry-associated meta-analysis of welders reported a pooled relative risk of 0.86, interpreted by the authors as a possible protective effect of manganese.⁶⁶ Such a hormesis interpretation is not biologically plausible given the established neurotoxicity of manganese.²²^,²³^,⁶⁷ Four of the 13 included papers (including the above two cohort studies) were sponsored by welding-related entities, and the first author disclosed expert-witness engagements for corporate defendants; therefore, the pooled estimate should be interpreted in light of funding source and study design, not as definitive evidence of protection.⁶⁸

The positive association stream: direct clinical examination studies

In contrast, studies by movement-disorder specialists using blinded in-person UPDRS-3 (Unified Parkinson's Disease Rating Scale part 3) examination and quantitative exposure reconstruction have consistently demonstrated elevated parkinsonism prevalence among welders. The methodological lineage progressed from initial symptom-based case series (2001), to blinded cross-sectional examination of active welders (2005), to exposure–response modeling with job-exposure matrices (2012), and to longitudinal imaging with follow-up cohorts integrating T1/R1 MRI and diffusion tensor imaging with UPDRS-3 trajectories (2017).²⁹^,³⁷^,⁶⁰^,⁶¹ Prevalence ratios of 7.6–10.0 and an earlier age of onset (approximately 46 years) were observed, with reproducible dose–response relationships. Additional evidence from a confined-space bridge-welder cohort, European ferroalloy programs, a Canadian movement-disorder clinic, longitudinal imaging series, and NHP studies converges on biological plausibility and supports the same association (Table 5).²⁰^,²⁴^,³⁵^,³⁷^,³⁹^,⁴⁵^,⁴⁶^,⁴⁹^,⁵¹^,⁶⁰^,⁶¹^,⁶⁸^-⁷¹

Methodological critique: why the two streams diverge

The divergence between the negative administrative stream in Europe and the positive clinical-examination stream in the United States can be attributed to four methodological differences that are summarized in Table 4: (1) case ascertainment via ICD-coded hospital records (administrative) versus blinded in-person UPDRS-3 examination (clinical); (2) exposure characterization based on job-title proxies versus quantitative workplace monitoring and job-exposure matrices; (3) outcome timing shaped by PD's decade-long prodromal phase; and (4) differential susceptibility to healthy-worker-survivor selection.

The primary reason for the conflicting reports concerning the association between welding and PD is rooted in the differing research methodologies and broader socioeconomic contexts in which the two investigative streams have developed. The two research streams have evolved under distinct methodological traditions: the direct-examination stream has progressively refined clinical phenotyping and exposure-metric resolution in high-exposure cohorts, whereas the administrative-cohort stream has applied population-scale registry analyses of heterogeneously coded outcomes. Consequently, the observed “two-stream divergence” is indicative not only of methodological asymmetry, characterized by the contrast between systematic clinical examination and ICD-coded registry ascertainment, but also of a structural asymmetry in terms of investigator expertise, programmatic independence, and subject-matter focus. Moreover, some evidence in this field has been generated directly or indirectly in the context of medical-malpractice litigation involving welding-rod manufacturers and patients with PD. Therefore, these factors must be considered when interpreting discordant effect estimates. The absence of replication of a specific design does not equal absence of any independent supporting evidence.⁶⁸^,⁷²

DISCUSSION

Interpretation: causal inference frameworks

Causal inference frameworks offer a structured approach for assessing the relationship between welding-fume exposure and parkinsonism. Table 6 summarizes the application of major frameworks.⁷³^-⁸¹ Hill's nine viewpoints—explicitly framed as considerations rather than rigid criteria—support a causal interpretation across multiple dimensions:⁷³ the association is strong in high-sensitivity clinical studies (age-adjusted prevalence ratio: 7.6–10.0);³⁷^,⁶⁰ a dose-response gradient is supported by longitudinal follow-up;⁶¹ biological plausibility is supported across multiple mechanistic pathways;⁴⁷^,⁴⁸^,⁵⁵^,⁵⁶ and the analogy with pesticide-associated PD is instructive, although imperfect. The pesticide literature demonstrates greater consistency across both clinical and administrative cohort designs, a consistency that has yet to be demonstrated for welding, partly due to the methodological limitations detailed above.⁸² Critically, the apparent lack of consistency for welding is not evidence against causation but is itself explained by the methodological asymmetry between the two research streams; once differences in case ascertainment, exposure precision, and healthy-worker-survivor selection are accounted for, the direct-examination evidence is internally consistent and dose-dependent.

Rothman's sufficient-component cause model⁷⁴ suggests that diseases arise from combinations of component causes. For instance, a welder carrying a glucocerebrosidase gene (GBA) or leucine-rich repeat kinase 2 gene (LRRK2) variant and chronically exposed to welding fumes (including Mn, Fe, and ultrafine particles) may experience a convergence of component causes sufficient to produce disease. Null findings at the population level in studies with crude exposure assessment do not preclude individual causation in workers with high cumulative exposure.

Within the Neyman-Rubin counterfactual framework,⁷⁵^,⁷⁶ causation is conceptualized as the difference between potential outcomes under exposure Y(1) and non-exposure Y(0). The 2012 blinded workplace study approximates this comparison, with a 15.6% versus 0% prevalence difference serving as an estimate of the average causal effect.³⁷ However, full exchangeability cannot be assumed: the approximately 50% participation rate introduces potential selection bias, and a cross-sectional design cannot rule out reverse causation. These limitations constrain population-level estimates but do not eliminate individual-level inference when considered alongside longitudinal dose-response evidence.⁶¹ In Korean social-insurance adjudication, the more relevant question is whether occupational exposure materially contributed to disease onset or acceleration under the proximate-causation standard, rather than whether deterministic “but-for” causation can be proven; given dose-dependent progression and established biological plausibility, the counterfactual probability that a welder with over 20,000 exposure-weighted welding hours would have remained disease-free is substantially lower than for an unexposed individual.

Pearl's structural causal model can formalize the biological pathway—welding-fume exposure → Mn/Fe accumulation → α-synuclein aggregation and nigrostriatal injury → parkinsonism—with genetic susceptibility and age acting as effect modifiers.⁷⁷^,⁷⁸ Within this framework, the healthy worker survivor effect (HWSE) can be understood as collider-stratification bias: conditioning on continued employment may open a spurious non-causal path that attenuates or inverts the observed exposure-outcome association.

Robins' g-methods address the same phenomenon at the level of estimation: by explicitly modeling the time-varying relationship between employment status, exposure, and outcome, they can correct for the confounding that conventional regression cannot.⁷⁹^,⁸³ These methods have not yet been applied to welding-PD cohort studies; they constitute the appropriate analytic remedy for HWSE-type time-varying confounding. Until they are applied, the null findings in administrative cohorts cannot be interpreted as definitive evidence of no association. Controlled human exposure is ethically infeasible; the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)–induced NHP chronic-exposure model provides the cardinal clinical and neuropathological features of PD and is widely regarded as a paradigmatic model of environmental neurotoxin-induced parkinsonism.²⁰^,⁴⁵^,⁸⁴^,⁸⁵

In summary, the diverse causal frameworks utilized in this analysis converge on a unified interpretation: the epidemiological discrepancies documented in the literature can be attributed to well-documented methodological biases, and do not substantiate the assertion that a biological causal relationship is absent.

Medico-legal framework for proximate cause in Korean social insurance

Under the Industrial Accident Compensation Insurance Act (IACI Act), occupational origin is evaluated through a “proximate causal relationship” standard.⁸⁶ This standard is explicitly lower than medical or scientific certainty, distinct from the “but-for”⁸⁷ or “balance of probabilities”⁸⁸ tests familiar to common-law practitioners. Instead of requiring proof from a medical or natural-scientific perspective, or proof of a biological mechanism, it allows for inference of causality by comprehensively considering all circumstances, including the worker's pre-employment health status, the presence of known hazardous substances in the workplace, the specific work environment and duration of exposure, and the clinical course.⁸⁹^-⁹¹ The Supreme Court of Korea (SCOK) has refined this standard in cases involving limited, novel, or conflicting epidemiological evidence. The SCOK has held that scientific uncertainty cannot be equated with evidence of no association and that conflicting findings alone cannot justify denial of occupational attribution. It has also emphasized that compliance with a single-factor exposure limit does not necessarily prevent disease when hazards interact cumulatively.⁸⁹^,⁹⁰ This approach reflects the philosophical, social, and legal principles that the purpose of social insurance should be not only compensation but also disease prevention.⁹¹ Recognition under this standard, therefore, does not presume scientific certainty; it requires that the occupational contribution be reasonably probable on the totality of the evidence. The biological reconceptualization of PD as a synucleinopathy, the convergence of independent lines of evidence (Table 5), and the methodological asymmetry between investigative streams together support recognition in welders meeting the exposure threshold outlined above.

Welding fumes are a complex, multifactorial neurotoxic mixture for which no integrated occupational exposure limit exists. The “multiple hit” hypothesis posits that PD is caused by the combined effects of genetic predisposition, aging, and environmental exposures.⁵³ Even movement disorder specialists achieve an accurate diagnosis in only 76%–90% of cases, with a misclassification rate of 10%–24%.¹³^,⁹² Therefore, clinical diagnostic labels alone are not sufficient for making compensation decisions. Genetic factors such as apolipoprotein E gene (APOE) or GBA/LRRK2 variants are not mutually exclusive with environmental causes. According to the sufficient-component causation model, genetic susceptibility is a component that, when combined with occupational exposure, can complete the sufficient cause of a disease. This represents vulnerability, not exclusion. The welder with the GBA mutation who developed PD after decades of fume exposure is a classic example of a multi-hit complex phenomenon, where neither genetic predisposition nor environmental exposure alone could have caused the disease within the observation period.

This review proposes that, when a welder with a documented history of occupational welding exposure files a workers’ compensation claim for parkinsonian motor symptoms, such as bradykinesia, resting tremor, and rigidity, a work-related contribution to the onset of symptoms should be presumed if the cumulative duration of welding exposure is approximately 20,000 hours or more. This exposure threshold should be understood as a sufficient, but not necessary, criterion for recognition. The proposed cumulative exposure threshold is not arbitrary. Rather, it is based on reasonable inferences drawn from multiple lines of evidence. For example, each 1 mg/m³·year increase in cumulative manganese exposure has been associated with an annual increase of 0.24 points in the UPDRS Part III motor score;³⁷^,⁶¹ reduced nigrostriatal FDOPA uptake has been observed in active or asymptomatic welders;²⁵^,³⁰ longitudinal data interpreted within the 2024 NSD-ISS framework suggest that the median interval from biologically defined stage 2B to a clinically meaningful milestone is 8.3 years (95% CI: 6.2–10.1);⁷^,¹⁹ in isolated RBD cohorts 73.5% of individuals photoconvert to overt parkinsonism within 12 years;⁹³ and France recognizes PD as an occupational disease among agricultural workers with at least 10 years of pesticide exposure.⁸² These inferences are further supported by additional studies.⁴⁹^,⁵¹

The primary purpose of this proposal is to enable prompt administrative recognition of a ‘proximate causal relationship,’ so that welders with parkinsonian symptoms can receive appropriate treatment under psychologically and economically stable conditions. However, when exposure intensity was particularly high—for example, during flux-cored arc welding in poorly ventilated confined spaces—the exposure-duration threshold should be adjusted downward through appropriate exposure weighting. Although some may oppose this proposal or raise concerns about its implications, it should also be acknowledged that insufficient research has been conducted to produce objective evidence on occupational health problems among welders in Korea’s major industrial sectors, including shipbuilding, automobile manufacturing, and construction. Beyond academic debate, this proposal may also serve as a practical measure to reduce social conflict, including unnecessary litigation that is inconsistent with the purpose of workers’ compensation as a social insurance system.

Limitations

Several notable limitations warrant acknowledgment. First, although independent lines of evidence from multiple research programs across different countries—a U.S. case–control study,⁷¹ Bay Bridge confined-space cohort,⁶⁹ Italian ferroalloy cohorts,⁴⁶^,⁷⁰ Canadian movement-disorder clinic cohort,³⁹ the Penn State–Hershey longitudinal imaging program,⁴⁹^-⁵¹ a US double-blind pharmacological trial,³⁴ a Taiwanese longitudinal cohort,³⁵ and a NHP program—converge on the welding–parkinsonism association,²⁰^,²⁴^,⁴⁵ the largest blinded workplace prevalence cohorts—with standardized UPDRS-3 examination and quantitative exposure reconstruction in active workers—remain concentrated within a single investigative program.³⁷^,⁶⁰^,⁶¹ Independent replication of this specific high-sensitivity design is therefore limited. This scarcity reflects structural constraints on the conduct of such studies, as detailed in the Epidemiology section, rather than biological inconsistency. Second, positive-stream cohorts are susceptible to recruitment-stage selection bias when participants are identified through legal-screening or clinical referral pathways,⁶⁰ whereas administrative cohorts likely underestimate risk through insensitive case ascertainment and healthy-worker-survivor depletion.⁶²^-⁶⁵ Methodological biases therefore operate in both directions, and neither stream provides an unbiased population-level effect estimate.

Third, SAA for α-synuclein has not been validated in manganese-exposed workers,¹⁷^,¹⁸^,⁹⁴^,⁹⁵ and it remains unknown whether chronic welding exposure increases the probability of an S+ biological phenotype under the current NSD-ISS/SynNeurGe criteria.⁷^,⁸^,¹⁹ Fourth, no postmortem neuropathological study of human welders has yet confirmed—or refuted—the presence of Lewy-body pathology, leaving a critical gap between the classical manganism neuropathology,²⁶ the experimental α-synuclein aggregation evidence in nonhuman primates,²⁰^,⁴⁵ and direct human pathological confirmation.

Fifth, and as a corollary to the bidirectional bias noted above, contemporary analytic methods for time-varying confounding—notably Robins' g-methods (marginal structural models, inverse-probability weighting)—have not yet been applied to welding–PD cohort data.⁷⁹^-⁸¹^,⁸³ Until they are, the null estimates derived from administrative records cannot be interpreted as definitive evidence of no association. Sixth, smoking—inversely associated with PD—is a potential confounder for which adjustments have been inconsistently applied across the literature, and cumulative occupational nicotine exposure in some welder subgroups is poorly characterized.⁹⁶ Seventh, few studies integrate individual-level cumulative exposure measurements with longitudinal clinical phenotyping.³⁰^,⁵⁰^,⁶¹ Without such data, dose–response thresholds cannot be precisely estimated, and the approximately 20,000-hour cumulative-exposure benchmark advanced in this review remains a pragmatic reference point rather than a rigorously derived threshold.

Lastly, these gaps justify substantial investment in prospective occupational cohort studies that integrate standardized neurological assessment, individual-level exposure monitoring, and emerging biological markers.³⁰^,³⁷ They do not, however, warrant the categorical denial of compensation claims. In the context of social insurance, when the totality of evidence indicates a probable occupational contribution, fairness dictates recognition.⁵⁹^,⁹⁷ As a narrative review, this analysis is inherently prone to selective citation,¹¹ and it is important to consider the author's perspective in occupational medicine when evaluating the interpretations presented.

Implications

This review advocates for a departure from traditional perspectives when assessing the work-relatedness of parkinsonism in patients with a history of welding in Korea. The process of compensation adjudication should transcend the reliance on the “idiopathic” PD label as a basis for claim denial. DAT imaging and levodopa responsiveness ought to be contextualized within the exposure-pathology continuum, rather than being treated as binary etiological markers. There is an urgent need for prospective occupational cohort studies that incorporate standardized neurological assessments, individual exposure monitoring, and emerging biomarkers. Until such data are available, compensation adjudication should adopt a weight-of-evidence approach that integrates individual exposure history (including duration, intensity, welding method, and ventilation conditions), neuroimaging findings (contextualized within the exposure-pathology continuum rather than used as binary classifiers), clinical presentation, pharmacological response, and the known biological mechanisms by which welding-fume constituents can initiate and accelerate parkinsonian neurodegeneration.

CONCLUSIONS

The medico-legal analysis of welders' parkinsonism must incorporate the contemporary understanding of PD biology. The 2024 NSD-ISS and SynNeurGe frameworks illustrate that PD exists on a biological continuum initiated by various factors, including environmental neurotoxins. This exposure-pathology continuum renders the categorical dichotomy between “idiopathic PD” and “secondary parkinsonism” increasingly difficult to sustain in adjudication, with definitive diagnosis still requiring postmortem examination. Recognition under Korea's proximate causation standard does not presume scientific certainty; it asks whether occupational contribution is reasonably probable on the totality of the evidence — a question to which current science answers affirmatively for appropriate exposure profiles.⁹¹ Ignoring claims based on outdated terminology fails to account for α-synuclein pathophysiology, the exposure-pathology continuum, the synergistic effects of mixed welding fumes, and pertinent epidemiological evidence.

Abbreviations

Clinical/disease entities

iPD

idiopathic Parkinson's disease

MDS

Movement Disorder Society

NSD-ISS

Neuronal α-synuclein disease Integrated Staging System

Parkinson's disease

RBD

REM-sleep behavior disorder

SynNeurGe

Synuclein–Neurodegeneration–Gene (2024 biological classification framework)

SAA

seed amplification assay

UKPDSBB

United Kingdom Parkinson's Disease Society Brain Bank

Neuroanatomy/pathology

α-syn

α-synuclein

globus pallidus

substantia nigra

SNc

substantia nigra pars compacta

S+N+G−

synucleinopathy-positive/neurodegeneration-positive/genetic-negative (NSD-ISS or SynNeurGe biological profile)

Genetics/molecular

APOE

apolipoprotein E gene

DMT1

divalent metal transporter 1

GBA

glucocerebrosidase gene

LRRK2

leucine-rich repeat kinase 2 gene

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

ZIP8/ZIP14

Zrt/Irt-like protein 8 and 14 metal transporters

Neuroimaging

DAT

dopamine transporter

DAT imaging

dopamine transporter imaging (used collectively for the FP-CIT PET, FDOPA PET, and ¹²³I-ioflupane SPECT modalities)

DaTscan

¹²³I-ioflupane SPECT

DTI

diffusion tensor imaging

FDOPA

6-[¹⁸F]fluoro-L-DOPA

FP-CIT

¹⁸F-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane

MRI

magnetic resonance imaging

PET-CT

positron emission tomography–computed tomography

longitudinal T1 relaxation rate (MRI marker of brain Mn accumulation)

SPECT

single-photon emission computed tomography

Clinical assessment

UPDRS-III (UPDRS-3)

Unified Parkinson's Disease Rating Scale, Part III (motor examination)

Epidemiology/biostatistics

aRR

adjusted relative risk

confidence interval

DAG

directed acyclic graph

HRR

hazard rate ratio

HWSE

healthy worker survivor effect

ICC

intraclass correlation coefficient

IPW

inverse-probability weighting

MSM

marginal structural model

NHP

nonhuman primate

odds ratio

prevalence ratio

SHR

sub-hazard ratio (and, in Table 4, standardized hospitalization ratio)

Occupational hygiene/welding

ACGIH

American Conference of Governmental Industrial Hygienists

JEM

job-exposure matrix

Regulatory/legal/institutional

IACI Act

Industrial Accident Compensation Insurance Act (Republic of Korea)

IARC

International Agency for Research on Cancer

ICD

International Classification of Diseases

IEI

International Epidemiology Institute (private epidemiologic consulting firm, Rockville, MD)

MJFF

Michael J. Fox Foundation for Parkinson’s Research

NIH

National Institutes of Health (USA)

SCOK

Supreme Court of Korea

NOTES

Competing interests

The authors declare that they have no competing interest.

SUPPLEMENTARY MATERIAL

Supplementary Data 1.

Korean translation of "Reframing welders’ parkinsonism: from the “idiopathic” label to biological causation and legal recognition."

aoem-2026-38-e20_Supplementary-Data-1.pdf

Table 1.

Evolution of PD diagnostic criteria and implications for occupational medicine

Feature	UKPDSBB (1988)¹²^,¹³	MDS Clinical (2015)¹⁴	NSD-ISS/SynNeurGe (2024)⁷^-⁹
Terminology	Idiopathic PD	Clinically established/probable PD; "Idiopathic" removed	Neuronal α-synuclein disease; etiology no longer treated as inherently unknown
Toxin exposure	Absolute exclusion criterion	Red flag (requires careful evaluation, not automatic exclusion)	Not applicable; PD defined biologically by S/N/G anchors regardless of etiology
Diagnostic basis	Clinical syndrome (motor signs + exclusion criteria)	Clinical syndrome with ancillary testing (DAT imaging as exclusion criterion)	Biological markers: synucleinopathy (S), neurodegeneration (N), genetics (G)
Implication for welders	Mn exposure excludes PD diagnosis, creating circular logic	Mn exposure is a red flag but does not automatically exclude PD	Mn-induced S+N+G− profile is biologically indistinguishable from sporadic PD

PD: Parkinson's disease; UKPDSBB: United Kingdom Parkinson's Disease Society Brain Bank; MDS: Movement Disorder Society; NSD-ISS/SynNeurGe: Neuronal α-synuclein disease Integrated Staging System/Synuclein-Neurodegeneration-Gene; DAT: dopamine transporter (DaTscan).

Table 2.

Comparison of differentiation criteria: idiopathic PD, classical manganism, and chronic low-dose welding-fume exposure

Feature	Idiopathic PD	Classical manganism	Chronic low-dose welding-fume exposure	Discriminatory power
Primary lesion site	SNc (presynaptic)¹²^,¹⁴	GP (postsynaptic)²²^,²³	SNc + GP (dual targeting)²⁴^,²⁵	Lost in chronic low-dose
α-Synuclein/Lewy body	Present (Braak staging; SAA+)⁷	Absent²⁶	NHP: α-syn inclusions present; human autopsy unconfirmed²⁰^,²¹	Potentially lost; human evidence gap
DAT imaging (FP-CIT/FDOPA PET; DaTscan)	Abnormal: asymmetric posterior putaminal loss²⁷^,²⁸	Normal or near-normal²²^,²³	Can show iPD-identical pattern²⁹^,³⁰	Lost in chronic low-dose
Structural MRI (T1)	Normal¹⁴	GP bilateral hyperintensity³¹	Active exposure: hyperintensity possible; retired: normalizes³²^,³³	Lost in retired welders
Levodopa response	Good (≥30% UPDRS-3 improvement)¹⁴	Poor (postsynaptic lesion)²²^,³⁴	Heterogeneous (preserved in chronic low-dose presynaptic phenotype; poor in pallidal phenotype)³⁴^-³⁷	Lost in chronic low-dose
Onset laterality	Unilateral, asymmetric¹²^,¹⁴	Bilateral, symmetric²²^,²³	Asymmetric possible (iPD-like)²⁹	Reduced
Tremor character	Rest tremor (pill-rolling)¹²	Postural/action tremor; rest tremor rare²²	Rest tremor reported²⁹	Reduced
Distinctive motor features	Shuffling gait, freezing¹⁴	Cock-walk gait, early dystonia, psychiatric features²²^,²³^,³⁸	Variable; iPD-like or mixed²⁹^,³⁷	Partially retained for classical only
Age of onset	Mean 60–65 years¹²	Exposure-dependent	Mean 46 years (15–17 years earlier)²⁹^,³⁹	Early onset suggests occupational acceleration
Course after exposure cessation	Progressive (no plateau)¹⁴	May stabilize or improve²²^,³⁵	May continue progressing; delayed iPD emergence possible³²^,⁴⁰	Lost (Han/Shin case)
SynNeurGe biological profile	S+N+G− or S+N+Gp⁷^,⁸	S−N−G− (traditionally)⁷^,⁸^,²⁶	If Mn induces S+ and N+: S+N+G− = iPD-identical⁷^,⁸^,²¹	Boundary collapses under biological definition

All features listed as “typical” admit exceptions. No single criterion is pathognomonic.

The “Discriminatory power” column indicates reliability for distinguishing chronic low-dose welding-fume exposure from idiopathic PD.

PD: Parkinson's disease; SNc: substantia nigra pars compacta; GP: globus pallidus; SAA: seed amplification assay; NHP: nonhuman primate; DAT: dopamine transporter; FP-CIT: ¹⁸F-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane; FDOPA: 6-[¹⁸F]fluoro-L-DOPA; DaTscan: ¹²³I-ioflupane SPECT; iPD: idiopathic Parkinson's disease; MRI: magnetic resonance imaging; UPDRS-3: Unified Parkinson's Disease Rating Scale part 3; SynNeurGe: Synuclein–Neurodegeneration–Gene; Mn: manganese; S+N+G−: synucleinopathy-positive/neurodegeneration-positive/genetic-negative.

Table 3.

Representative reports about heterogeneity of levodopa response in welders and in manganese-induced parkinsonism

Population/design	Sample	Reported response to levodopa
Taiwanese longitudinal cohort of chronic Mn exposure³⁵	6 Subjects	Initial response in half; declining response over time
U.S. academic-medical-center cohort; welders diagnosed with parkinsonism³⁷	15 Welders	Preserved response comparable to idiopathic PD
Case report, single welder with bilateral pallidal T1 hyperintensity³⁶	1 Welder	Absent response
Double-blind placebo-controlled crossover trial in welders diagnosed with manganese-induced parkinsonism³⁴	13 Welders	No clinically meaningful response
Review of high-dose industrial Mn toxicity²²^,²³	n/a (review)	Poor or absent response (postsynaptic pallidal phenotype)

Response pattern spans a spectrum—from preserved (workers with predominantly presynaptic nigrostriatal injury) to absent (classical or severe postsynaptic manganism).

A positive response is therefore compatible with preserved nigrostriatal function and does not by itself exclude a welding-fume–related contribution.PD: Parkinson's disease; n/a: not applicable.

Table 4.

Comparative summary of the two epidemiological research streams

Feature	Negative stream (European administrative cohorts)	Positive stream (U.S. clinical studies)²⁹^,³⁷^,⁶⁰^,⁶¹
Representative studies	Fryzek et al. (2005), Fored et al. (2006), Kenborg et al. (2012)⁶²^-⁶⁴	Racette et al. (2001, 2005, 2012, 2017)²⁹^,³⁷^,⁶⁰^,⁶¹
Case ascertainment	ICD-coded hospital discharge records	Systematic UPDRS-3 by movement disorder specialist (blinded)
Exposure assessment	Census occupational codes; single questionnaire (JEM)	Quantitative: cumulative welding hours, weighted exposure-years
Key finding	aRR 0.89 (Sweden); SHR 0.9–1.05, HRR 0.83 per decade (Denmark)	PR 7.6–10.0 (age-adjusted); 15.6% overall parkinsonism prevalence; dose-dependent UPDRS-3 progression
Healthy worker effect	Pronounced survival bias; inverse dose–response in Danish data	Addressed; worksite-based recruitment
Disease latency	Cross-sectional or insufficient follow-up	Longitudinal follow-up included
Strengths	- Large population-based samples (Sweden 49,488; Denmark 27,839 welders)	- High sensitivity for subclinical parkinsonism via standardized UPDRS-3
	- Long follow-up periods (up to 40 years)	- Blinded movement disorder specialist examiners
	- Complete outcome ascertainment via national registries	- Quantitative dose–response analysis with weighted exposure-years
	- Minimal selection bias (census-based, independent of litigation)	- Longitudinal follow-up (2017) confirming temporal relationship
	- Smoking directly adjusted in Kenborg 2012 (Cox model)	- Video-based inter-rater verification (ICC 0.85–0.88)
	- Diagnostic verification by movement disorder specialists in subsamples	- Convergence across multiple study sites
		- Independent funding for worksite studies (NIH, MJFF)
Weaknesses	- ICD-coded hospital records structurally incapable of detecting subclinical parkinsonism (15.6% detection gap)	- Predominantly cross-sectional designs limiting causal inference
	- Census occupational codes (1–2 time points): non-differential misclassification biasing toward null	- All positive studies from single research group (Racette); no independent replication
	- Healthy worker survivor effect unaddressed; Danish inverse dose–response (HRR 0.83/decade) consistent with survival bias	- Alabama study recruited via legal screening referrals (Welder Health Fund): selection/funding bias
	- Insufficient disease latency coverage for 10–20 year PD preclinical phase	- ~50% participation rate in shipyard study (volunteer bias)
	- Swedish cohort funded by welding consumable manufacturers via IEI	- Limited unexposed control group (n = 59)
		- Young mean age (~46 years) complicating comparison with degenerative PD
		- Self-reported occupational history without individual exposure measurements
Assessment	- Convergence of four methodological factors produces systematic null-ward bias predictable from epidemiological theory	- Despite single-group origin, convergence across multiple sites and confirmed dose–response on longitudinal follow-up collectively provide robust evidence base
	- Large sample sizes cannot compensate for fundamentally insensitive case detection	- High case-ascertainment sensitivity captures subclinical parkinsonism spectrum that administrative approaches systematically miss
	- Paradoxical inverse dose–response (Danish HRR 0.83) more parsimoniously explained by survival bias than by protective hormetic effect	- 2017 Longitudinal data (exposure precedes progression) substantially strengthen causal inference beyond cross-sectional prevalence
	- Industry funding of Swedish cohort necessitates consideration of potential funding bias	- Blinded examination design minimizes observer bias
Funding	Welding industry defense group (Swedish cohort)	NIH, MJFF (positive studies); Welder Health Fund (Alabama screening study)

ICD: International Classification of Diseases; UPDRS-3: Unified Parkinson's Disease Rating Scale Motor Examination; JEM: job-exposure matrix; aRR: adjusted relative risk; SHR: standardized hospitalization ratio; HRR: hazard rate ratio; PR: prevalence ratio; ICC: intraclass correlation coefficient; NIH: National Institutes of Health; MJFF: Michael J. Fox Foundation; PD: Parkinson's disease; IEI: International Epidemiology Institute.

Table 5.

Positive association studies for welding-fume and parkinsonism relationship

Program/country	Design	Key finding
Washington University, USA³⁷^,⁶⁰^,⁶¹	Blinded workplace prevalence with standardized UPDRS-3	Prevalence ratio 7.6–10.0 for clinical parkinsonism; earlier onset (~46 years)
Bay Bridge confined-space cohort, USA⁶⁹	Confined-space worksite cohort	Prevalence of 15.6%; dose-response with fume exposure
U.S. academic medical center⁷¹	Case-control	Adjusted OR 10.61 (95% CI: 1.06–105.83) for Mn exposure >20 years
Italian ferroalloy program⁴⁶^,⁷⁰	Community exposure and adolescent cohort	Tremor, olfactory changes in exposed adolescents; manganism-to-PD continuum
Canadian movement-disorder clinic³⁹	Clinic-based independent cohort (290 PD patients)	Welding-exposed onset 54.3 years vs. 59.3 years (~5 years advancement)
Penn State–Hershey, USA⁴⁹^,⁵¹	Longitudinal imaging program (T1/R1 MRI, DTI)	Nonlinear Mn accumulation in GP/SN; nigral microstructural changes in asymptomatic welders
Taiwanese cohort³⁵	Longitudinal follow-up of Mn-exposed workers	Progression continued after exposure cessation
NHP chronic-exposure model²⁰^,²⁴^,⁴⁵	Experimental chronic low-dose Mn in nonhuman primates	Nigrostriatal DAT deficits; microglial activation; α-synuclein aggregation in frontal cortex

UPDRS-3: Unified Parkinson's Disease Rating Scale part 3; OR: odds ratio; CI: confidence interval; PD: Parkinson's disease; MRI: magnetic resonance imaging; DTI: diffusion tensor imaging; Mn: manganese; GP: globus pallidus; SN: substantia nigra; NHP: nonhuman primate; DAT: dopamine transporter.

Table 6.

Causal inference frameworks applied to the welding-parkinsonism association

Framework	Application to welding-PD	Key limitation
Bradford Hill viewpoints⁷³	Strength (PR 7.6–10.0), biological gradient (dose-dependent UPDRS-3), plausibility (α-synuclein aggregation, neuroinflammation), coherence (NHP models) satisfied; specificity weakest (multi-causal disease)	Viewpoints, not criteria; no threshold for number that must be met
Rothman's sufficient-component cause⁷⁴	Mn/welding fumes as component cause interaction with genetic susceptibility (GBA, LRRK2) and aging; absence of population effect does not exclude individual causation	Component causes cannot be empirically isolated without gene-environment interaction data
Neyman-Rubin counterfactual⁷⁵^,⁷⁶	15.6% vs. 0% in blinded study approximates average causal effect; but-for causation supported by dose-response and biological plausibility	The exchangeability assumption may not be fully satisfied in cross-sectional design
Pearl's structural causal model (DAG)⁷⁷^,⁷⁸	Welding fumes → Mn/Fe accumulation → α-synuclein aggregation + nigrostriatal degeneration → parkinsonism; identifies HWSE as collider-stratification bias	Causal structure assumed, not empirically verified in welding context
Robins' g-methods (MSM, IPW)⁷⁹^-⁸¹	Address time-varying confounding from HWSE; would create pseudo-population where employment is independent of past health status	Not yet applied to welding-PD cohorts; analytical gap limits causal interpretation of null results

PD: Parkinson's disease; PR: prevalence ratio; UPDRS-3: Unified Parkinson's Disease Rating Scale part 3; NHP: nonhuman primate; DAG: directed acyclic graph; HWSE: healthy worker survivor effect; MSM: marginal structural model; IPW: inverse-probability weighting.

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Reframing welders’ parkinsonism: from the “idiopathic” label to biological causation and legal recognition

Ann Occup Environ Med. 2026;38:e20 Published online June 17, 2026

DOI: https://doi.org/10.35371/aoem.2026.38.e20

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Reframing welders’ parkinsonism: from the “idiopathic” label to biological causation and legal recognition

Feature	UKPDSBB (1988)12,13	MDS Clinical (2015)14	NSD-ISS/SynNeurGe (2024)7-9
Terminology	Idiopathic PD	Clinically established/probable PD; "Idiopathic" removed	Neuronal α-synuclein disease; etiology no longer treated as inherently unknown
Toxin exposure	Absolute exclusion criterion	Red flag (requires careful evaluation, not automatic exclusion)	Not applicable; PD defined biologically by S/N/G anchors regardless of etiology
Diagnostic basis	Clinical syndrome (motor signs + exclusion criteria)	Clinical syndrome with ancillary testing (DAT imaging as exclusion criterion)	Biological markers: synucleinopathy (S), neurodegeneration (N), genetics (G)
Implication for welders	Mn exposure excludes PD diagnosis, creating circular logic	Mn exposure is a red flag but does not automatically exclude PD	Mn-induced S+N+G− profile is biologically indistinguishable from sporadic PD

Feature	Idiopathic PD	Classical manganism	Chronic low-dose welding-fume exposure	Discriminatory power
Primary lesion site	SNc (presynaptic)12,14	GP (postsynaptic)22,23	SNc + GP (dual targeting)24,25	Lost in chronic low-dose
α-Synuclein/Lewy body	Present (Braak staging; SAA+)7	Absent26	NHP: α-syn inclusions present; human autopsy unconfirmed20,21	Potentially lost; human evidence gap
DAT imaging (FP-CIT/FDOPA PET; DaTscan)	Abnormal: asymmetric posterior putaminal loss27,28	Normal or near-normal22,23	Can show iPD-identical pattern29,30	Lost in chronic low-dose
Structural MRI (T1)	Normal14	GP bilateral hyperintensity31	Active exposure: hyperintensity possible; retired: normalizes32,33	Lost in retired welders
Levodopa response	Good (≥30% UPDRS-3 improvement)14	Poor (postsynaptic lesion)22,34	Heterogeneous (preserved in chronic low-dose presynaptic phenotype; poor in pallidal phenotype)34-37	Lost in chronic low-dose
Onset laterality	Unilateral, asymmetric12,14	Bilateral, symmetric22,23	Asymmetric possible (iPD-like)29	Reduced
Tremor character	Rest tremor (pill-rolling)12	Postural/action tremor; rest tremor rare22	Rest tremor reported29	Reduced
Distinctive motor features	Shuffling gait, freezing14	Cock-walk gait, early dystonia, psychiatric features22,23,38	Variable; iPD-like or mixed29,37	Partially retained for classical only
Age of onset	Mean 60–65 years12	Exposure-dependent	Mean 46 years (15–17 years earlier)29,39	Early onset suggests occupational acceleration
Course after exposure cessation	Progressive (no plateau)14	May stabilize or improve22,35	May continue progressing; delayed iPD emergence possible32,40	Lost (Han/Shin case)
SynNeurGe biological profile	S+N+G− or S+N+Gp7,8	S−N−G− (traditionally)7,8,26	If Mn induces S+ and N+: S+N+G− = iPD-identical7,8,21	Boundary collapses under biological definition

Population/design	Sample	Reported response to levodopa
Taiwanese longitudinal cohort of chronic Mn exposure35	6 Subjects	Initial response in half; declining response over time
U.S. academic-medical-center cohort; welders diagnosed with parkinsonism37	15 Welders	Preserved response comparable to idiopathic PD
Case report, single welder with bilateral pallidal T1 hyperintensity36	1 Welder	Absent response
Double-blind placebo-controlled crossover trial in welders diagnosed with manganese-induced parkinsonism34	13 Welders	No clinically meaningful response
Review of high-dose industrial Mn toxicity22,23	n/a (review)	Poor or absent response (postsynaptic pallidal phenotype)

Feature	Negative stream (European administrative cohorts)	Positive stream (U.S. clinical studies)29,37,60,61
Representative studies	Fryzek et al. (2005), Fored et al. (2006), Kenborg et al. (2012)62-64	Racette et al. (2001, 2005, 2012, 2017)29,37,60,61
Case ascertainment	ICD-coded hospital discharge records	Systematic UPDRS-3 by movement disorder specialist (blinded)
Exposure assessment	Census occupational codes; single questionnaire (JEM)	Quantitative: cumulative welding hours, weighted exposure-years
Key finding	aRR 0.89 (Sweden); SHR 0.9–1.05, HRR 0.83 per decade (Denmark)	PR 7.6–10.0 (age-adjusted); 15.6% overall parkinsonism prevalence; dose-dependent UPDRS-3 progression
Healthy worker effect	Pronounced survival bias; inverse dose–response in Danish data	Addressed; worksite-based recruitment
Disease latency	Cross-sectional or insufficient follow-up	Longitudinal follow-up included
Strengths	- Large population-based samples (Sweden 49,488; Denmark 27,839 welders)	- High sensitivity for subclinical parkinsonism via standardized UPDRS-3
	- Long follow-up periods (up to 40 years)	- Blinded movement disorder specialist examiners
	- Complete outcome ascertainment via national registries	- Quantitative dose–response analysis with weighted exposure-years
	- Minimal selection bias (census-based, independent of litigation)	- Longitudinal follow-up (2017) confirming temporal relationship
	- Smoking directly adjusted in Kenborg 2012 (Cox model)	- Video-based inter-rater verification (ICC 0.85–0.88)
	- Diagnostic verification by movement disorder specialists in subsamples	- Convergence across multiple study sites
		- Independent funding for worksite studies (NIH, MJFF)
Weaknesses	- ICD-coded hospital records structurally incapable of detecting subclinical parkinsonism (15.6% detection gap)	- Predominantly cross-sectional designs limiting causal inference
	- Census occupational codes (1–2 time points): non-differential misclassification biasing toward null	- All positive studies from single research group (Racette); no independent replication
	- Healthy worker survivor effect unaddressed; Danish inverse dose–response (HRR 0.83/decade) consistent with survival bias	- Alabama study recruited via legal screening referrals (Welder Health Fund): selection/funding bias
	- Insufficient disease latency coverage for 10–20 year PD preclinical phase	- ~50% participation rate in shipyard study (volunteer bias)
	- Swedish cohort funded by welding consumable manufacturers via IEI	- Limited unexposed control group (n = 59)
		- Young mean age (~46 years) complicating comparison with degenerative PD
		- Self-reported occupational history without individual exposure measurements
Assessment	- Convergence of four methodological factors produces systematic null-ward bias predictable from epidemiological theory	- Despite single-group origin, convergence across multiple sites and confirmed dose–response on longitudinal follow-up collectively provide robust evidence base
	- Large sample sizes cannot compensate for fundamentally insensitive case detection	- High case-ascertainment sensitivity captures subclinical parkinsonism spectrum that administrative approaches systematically miss
	- Paradoxical inverse dose–response (Danish HRR 0.83) more parsimoniously explained by survival bias than by protective hormetic effect	- 2017 Longitudinal data (exposure precedes progression) substantially strengthen causal inference beyond cross-sectional prevalence
	- Industry funding of Swedish cohort necessitates consideration of potential funding bias	- Blinded examination design minimizes observer bias
Funding	Welding industry defense group (Swedish cohort)	NIH, MJFF (positive studies); Welder Health Fund (Alabama screening study)

Program/country	Design	Key finding
Washington University, USA37,60,61	Blinded workplace prevalence with standardized UPDRS-3	Prevalence ratio 7.6–10.0 for clinical parkinsonism; earlier onset (~46 years)
Bay Bridge confined-space cohort, USA69	Confined-space worksite cohort	Prevalence of 15.6%; dose-response with fume exposure
U.S. academic medical center71	Case-control	Adjusted OR 10.61 (95% CI: 1.06–105.83) for Mn exposure >20 years
Italian ferroalloy program46,70	Community exposure and adolescent cohort	Tremor, olfactory changes in exposed adolescents; manganism-to-PD continuum
Canadian movement-disorder clinic39	Clinic-based independent cohort (290 PD patients)	Welding-exposed onset 54.3 years vs. 59.3 years (~5 years advancement)
Penn State–Hershey, USA49,51	Longitudinal imaging program (T1/R1 MRI, DTI)	Nonlinear Mn accumulation in GP/SN; nigral microstructural changes in asymptomatic welders
Taiwanese cohort35	Longitudinal follow-up of Mn-exposed workers	Progression continued after exposure cessation
NHP chronic-exposure model20,24,45	Experimental chronic low-dose Mn in nonhuman primates	Nigrostriatal DAT deficits; microglial activation; α-synuclein aggregation in frontal cortex

Framework	Application to welding-PD	Key limitation
Bradford Hill viewpoints73	Strength (PR 7.6–10.0), biological gradient (dose-dependent UPDRS-3), plausibility (α-synuclein aggregation, neuroinflammation), coherence (NHP models) satisfied; specificity weakest (multi-causal disease)	Viewpoints, not criteria; no threshold for number that must be met
Rothman's sufficient-component cause74	Mn/welding fumes as component cause interaction with genetic susceptibility (GBA, LRRK2) and aging; absence of population effect does not exclude individual causation	Component causes cannot be empirically isolated without gene-environment interaction data
Neyman-Rubin counterfactual75,76	15.6% vs. 0% in blinded study approximates average causal effect; but-for causation supported by dose-response and biological plausibility	The exchangeability assumption may not be fully satisfied in cross-sectional design
Pearl's structural causal model (DAG)77,78	Welding fumes → Mn/Fe accumulation → α-synuclein aggregation + nigrostriatal degeneration → parkinsonism; identifies HWSE as collider-stratification bias	Causal structure assumed, not empirically verified in welding context
Robins' g-methods (MSM, IPW)79-81	Address time-varying confounding from HWSE; would create pseudo-population where employment is independent of past health status	Not yet applied to welding-PD cohorts; analytical gap limits causal interpretation of null results

Table 1. Evolution of PD diagnostic criteria and implications for occupational medicine

Table 2. Comparison of differentiation criteria: idiopathic PD, classical manganism, and chronic low-dose welding-fume exposure

All features listed as “typical” admit exceptions. No single criterion is pathognomonic.

The “Discriminatory power” column indicates reliability for distinguishing chronic low-dose welding-fume exposure from idiopathic PD.

Table 3. Representative reports about heterogeneity of levodopa response in welders and in manganese-induced parkinsonism

Response pattern spans a spectrum—from preserved (workers with predominantly presynaptic nigrostriatal injury) to absent (classical or severe postsynaptic manganism).

A positive response is therefore compatible with preserved nigrostriatal function and does not by itself exclude a welding-fume–related contribution.PD: Parkinson's disease; n/a: not applicable.

Table 4. Comparative summary of the two epidemiological research streams

Table 5. Positive association studies for welding-fume and parkinsonism relationship

Table 6. Causal inference frameworks applied to the welding-parkinsonism association