The following lecture has been approved for University Undergraduate Students

1. The following lecture has been approved for University Undergraduate Students This lecture may contain information, ideas, concepts and discursive anecdotes that may be thought provoking and challenging It is not intended for the content or delivery to cause offence Any issues raised in the lecture may require the viewer to engage in further thought, insight, reflection or critical evaluation

2. Neurobehavioural testing Welding & Parkinson’s Disease Is there evidence of a link? Prof. Craig Jackson Head of Psychology BCU

3. Parkinson’s Disease Neurological Condition James Parkinson Cell atrophy in substantia nigra Cardinal Symptoms Tremor (initial symptom in 70% cases) Slowness Stiffness of movement (bradykineasia) Postural instability Usual onset in mid-late 50s ( 1 in 20 diagnosed <40 years) Mostly male 1 case per 500 in UK

4. Introduction Parkinson's disease (also known as Parkinson disease or PD) Degenerative disorder of the CNS Impairs the sufferer's motor skills and speech. Belongs to a group of conditions called movement disorders. Primary Symptoms Muscle rigidity Tremor Slowing of physical movement (bradykinesia) Loss of physical movement (akinesia)

5. Dopamine Symptoms result from decreased stimulation of the motor cortex by the basal ganglia caused by insufficient formation and action of dopamine produced in the dopaminergic neurons Secondary symptoms may include: high level cognitive dysfunction subtle language problems. PD is both chronic and progressive.

6. Dopaminergic Pathways

7. Dopamine Symptoms result from the loss of dopamine-secreting (dopaminergic) cells Subsequent loss of melanin (secreted by the same cells) in the substantia nigra These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement Essentially an inhibition of the direct pathway and excitation of the indirect pathway

8. Dopamine Pathways Four major dopamine pathways; nigrostriatal pathway mesocortical volition and emotional responsiveness mesolimbic desire, initiative, and reward Tuberoinfundibular sensory processes and maternal behaviour Disruption of dopamine along the non-striatal pathways explains much of the neuropsychiatric pathology sometimes associated with Parkinson's Disease.

9. Head Injury Previous episodes of head injury are reported more frequently by PD sufferers than by non PD sufferers in the population Those with head injury 4 times more likely to develop PD than those who have never suffered a head injury - Bower et al. 2003 Risk of developing PD increases X 8 head trauma requiring hospitalization Increases X 11severe head injury. However, since head trauma is rare, the contribution to PD incidence in the general population is minimal. T Recall Bias? ? ?

10. Drug Inducement Antipsychotic medication, used to treat / manage psychoses and schizophrenia can induce PD symptoms Lowering dopaminergic activity Due to feedback inhibition, L-dopa can also eventually cause the symptoms of Parkinson's disease that it initially relieves Dopamine agonists can also eventually contribute to Parkinson's disease symptoms by decreasing the sensitivity of dopamine receptors.

11. Pallidotomy Surgery was common Liq Nit 80 Celcius for 6 sec Immediate benefits Limited duration? Declined since LevoDopa Surgery more popular again for drug-resistant PD Deep Brain Stimulation

12. LevoDopa The most widely used form of treatment is L-dopa Various formats. L-dopa is transformed into dopamine in the dopaminergic neurons Done by L-aromatic amino acid decarboxylase (often known by its former name dopa-decarboxylase). Only 1-5% of L-DOPA enters the dopaminergic neurons. The remaining L-DOPA is metabolised to dopamine elsewhere, Causes a wide variety of side effects.

13. LevoDopa Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so eventually becomes counterproductive Carbidopa and Benserazide are dopa decarboxylase inhibitors They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given as combination preparations e.g. Carbidopa / Levodopa (co-careldopa) (e.g. Sinemet, Parcopa) Benserazide / Levodopa (co-beneldopa) (e.g. Madopar). Stalevo

14. New Treatments Gene Therapy Neuroprotective Treatment Neural Transplants Nutrient Therapy Qigong

15. Parkinsonism PD is the most common cause of Parkinsonism A group of similar symptoms. PD is also called "primary parkinsonism" or "idiopathic PD" "idiopathic" - of no known cause Most forms of parkinsonism are idiopathic, there are some cases where the symptoms may result from: genetic mutation drugs other medical complications toxicity head injury

16. Manganism James Couper 1837 Extreme manifestation of PD Excessive manganese poisoning Farmers Miners Steel workers Battery manufacturing Symptoms Parkinsonian Features Dystonia Gait (Cock’s walk) Locuria manganica (manganese madness)

17. Introduction Current Problem in USA Steel Welding Parkinson’s Disease Neurobehavioural Testing Systematic Review Conclusion

18. Litigation October 1st 2004 Larry Elam versus A.O. Smith Elam, former welder, aged 65 Developed PD Lifetime welder Wins £1M from Welding Rod Manufacturers

19. Current Problem in USA March 25th 2005 Fed Judge Kathleen O’Malley “Valid scientific evidence supports the conclusion that manganese exposure is connected to dangerous side effects.” February 27th 2006 Fed Judge Kathleen O’Malley Ruled welding can cause serious neurological damage to welders Out of court settlement for 2 welders, made by welding rod manufacturing company ($ undisclosed )

20. Litigation

21. Welding of Steel Joins pieces of metal that have been made liquid by heat Metal pieces to be joined and a filler metal (rod) coming from a consumable Heat produced as electricity passes from one conductor to another Temperatures >4000 oC in the arc At least 80 different types of welding processes 365,000 welders in USA 1,000,000 full time welders globally 5,000,000 paid welders globally

22. Neurobehavioural Testing Study of specific human functioning Performance across several domains: Cognition Motor Skills Memory Reaction Time Coordination Attention Visuospatial Reasoning General Mostly computerised Portable Relatively cheap

23. The Current Situation 1) Manganese Overload = Parkinson’s Disease 2) Welding Work = High Manganese Exposure Therefore . . . “Neurobehavioural testing is used to identify or screen workers with early symptoms of Parkinson’s disease” Could this be a flawed assumption?

24. Systematic Review of the Literature Three Objectives 1) Is there any evidence of occupational manganese exposure impairing neurobehavioural performance? 2) Which tests (domains) are best at demonstrating such impaired performance? 3) What is the smallest level of Mn exposure associated with test impairment?

25. Systematic Review of the Literature 16 Databases Searched Medline & Pubmed HSE Line CISDOC NIOSHTIC & NIOSHTIC2 PsychoInfo Excerpta Medica Toxfile Embase SciSearch Biosis Previews Web of Science Web of knowledge Science Citation Index Social Science Citation Index

26. Limitations: Human English Language 1970-2006 Systematic Review of the Literature Search Terms Cognition disorder Neurobehavioral / Neurobehavioural (deficit / impairment) Neurological Neuromotor Neuropsychiatric Neuropsychological (test(ing)) Neurotoxicology Neurotoxic Manganese Manganate Manganese alloy / dioxide / dust / ore / oxide Steel Welding Welders

27. Systematic Review of the Literature The Better Quality Studies EU Guidelines for qualitative evaluation of neurobehavioural studies (1997) 1. Population of an adequate size relative to the number of tests used 2. Subject selection method which avoids bias for the exposed group 3. Subject selection method which avoids bias for the control group 4. Pre-stated exclusion/inclusion criteria for study participants 5. High response rate for the exposed group (usually > 60%) 6. High response rate for the control group (usually > 60%) where applicable 7. Control or adjustment for important confounders / modifiers of performance 8. Inclusion of quantitative or semi-quantitative assessment of long-term exposure 9. Control for recent exposure (where applicable) 10. An indication of the standardization of testing conditions After application of Quality Criteria, only 12 studies were of “Better Quality”

28. Expected Neurobehavioural Differences Cognition Motor Skills Memory Reaction Time Coordination Attention Visuospatial Reasoning exposed controls poorer better faster slower better poorer better poorer faster slower better poorer better poorer

29. Locuria Manganica Indeed Very serious implications for litigants and defendants in USA Currently huge numbers of plaintiffs filing cases in USA Share prices dropped globally e.g. BOC Major concern to US Dept of Defense / USAMRC – currently funding research Serious concern to International Manganese Institute Serious concern to International Institute of Welding