Transcript Part - time MSc course Epidemiology & Statistics Module
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Neurobehavioural performances associated with occupational hazards The poor state of Neurobehavioural testing
Dr. Craig Jackson Professor of Occupational Health Psychology Birmingham City University Hon Senior Lecturer in Occupational Psychology Institute of Occ & Env Medicine University of Birmingham
Brain Training
Brain Training
The Exposed Brain
Structural Changes Functional Changes Behavioural Changes Susceptibility to other neurotoxins Possibly largest contributor to: Learning disability Attentional Disorders Development Disabilities
Head Injuries
Severity depends on amount of Primary and Secondary brain injury Main cause of Secondary injury = hypoxia Categories: Open or Closed Forces: Shearing and Compression
Multiple Toxic Substances
Industrial Chemicals Pesticides Therapeutic Drugs Drugs of Abuse Food Additives Brain is highly vulnerable to toxic effects In utero Post-natal Ingestion Inhalation Absorption Multiple toxic exposures: Alter cell migration, synaptic connections, cell death
Principles of Neurobehavioural Testing
Damage to CNS due to exposure to Neurotoxic substances Neurotoxic medicines Metabolic disorders Neurotoxic diseases in top ten work-related diseases in USA Occupational exposures to toxins such as Lead Manganese Solvents Pesticides Herbicides Insecticides Contributors to the development of neurobehavioral dysfunction
Neurobehavioural Testing
Standard tests Evaluate different aspects of functioning of the CNS including Cognition Motor Skills Memory Reaction Time Visuospatial Coordination Reasoning Attention General Affect Non-invasive Portable Cheap Range of behavioural functions affected is extremely wide Investigators typically use sets (batteries) of tests.
Speed / Accuracy Trade-off
optimum fast but sloppy Reaction Time (sec) slow and accurate
Example of Neurobehavioural Tests
Trail-making 1) Worker presented diagram 2) Worker must join dots 1 – A – 2 – B etc Outcomes: a) Time to complete b) No. of errors made error
Example of Neurobehavioural Tests
Complex Reaction Time Worker presented with 4 stimuli Worker must click button on cue (4 possible responses) Outcomes: a) Time taken to react (milliseconds) b) No. correct responses c) No. errors
Pencil and Paper Tests - Line Tracing
Digit Span
Subject presented with numbers Subject must recall numbers Number string gets longer each time Outcome: Length of longest correct recall
Digit Symbol
Subject presented with number and symbol code Subject must fill in blanks, working left to right Outcome: Number of correct cells completed Time taken to get to bottom of list
Benton Visual Retention
Subject presented with stimulus Subject must find target Outcome: Time taken to react Correct responses Errors
Pattern Memory Test
Subject presented with stimulus Subject must decide which is target after rotation Outcome: Time taken to react Correct responses Errors
Continuous Performance Test
Focused attention F F F F E F F F F F F E F F E F F F F F F F E Divided attention V V V V W W W V W W W W W V W W V W F F F F E F F F F F F E F F E F F F F F F F E Sustained attention X X X X X Sustained & Focused attention Y Y Y Y Y Y X Y Y Y Y Y Y Y Y Y Y Y Y Y X Y Y Y Y Y Y Y Y Y Y Y X Y Y Y Y X Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y X Y Y Y Y Y Y Y Y Y Y X Y Y Y Y Y Efficiency = Accuracy / Speed
Colour Word Vigilance
RED GREEN BLUE BLACK YELLOW BLUE
Subject presented with stimulus Subject must find target word which matches colour Outcome: Time taken to react Correct responses Errors
YELLOW RED GREEN
Pre-Test Procedures
Pre-test questionnaire Determine subjects’ general state at time of test Exclude subjects with: Seizures Functional visual impairment Language problems Drug effects Temporary physical impairment Mental impairment Illiteracy
Speed / Accuracy Trade-off
optimum fast but sloppy Reaction Time (sec) slow and accurate
Rationale of Neurobehavioural Testing
Evaluate functioning in individuals exposed to pathogens Normal population exhibits a range of performance function Exposure places individuals outside of that normal range Some factors affect performance: age sex education n Numbers recalled
History
Behavioural testing began in 1960s Hanninen (1979) developed first behavioural test battery Assess effects of chemicals and neurotoxins 1980 - 60 unique tests 1990 - 250 unique tests 1983 – WHO wanted battery to screen / identify nervous system effects
Neurobehavioural Core Test Battery (NCTB)
1983 WHO & NIOSH Seven behavioural tests: Digit Span Digit Symbol Benton Visual Retention Simple Reaction Time Santa Ana Dexterity Pursuit Aiming II Profile of Mood States Johnson et al. 1987
Minnesota Manual Dexterity Test
Tower of Hanoi
Finger Tapper
Testing Must Be Cross-Cultural, Valid, & Reliable
Higher proportion of: Minorities Foreign born Poor status > exposures to neurotoxins & pathogens May not speak English May be “developmentally delayed” Test batteries must be suitable for people of all abilities & backgrounds
Testing Conditions
All subjects tested under same conditions Standardized testing Not always possible in the field Furniture Lighting Visual distraction Ambient sound Temperature
Factors to be Aware of in Testing
STABLE FACTORS Age Education Sex Socioeconomics Language Handedness Computer experience Caffeine (habitual use) Alcohol (habitual use) Nicotine (habitual use) Medication (habitual use) Paint, glue, pesticide (habitual use) Diabetes Epilepsy Other CNS / PNS disease Head injury (out >1 hr) Physical activity SITUATIONAL FACTORS Alcohol (recent use) Caffeine (recent use) Nicotine (recent use) Medication (recent use) Paints, glues, pesticides (recent) Near visual acuity Restricted movement (injury) Cold / flu Stress Arousal / Fatigue Sleep Screen luminance Time of day Time of year Alcohol / drug addiction
Problems of Neurobehavioural Testing
Used since the 1960s in occ and env health toxicology Interpretation of different test scores is not straightforward Less straightforward role in the regulation of chemicals Difficulties neurobehavioural studies encountered by regulators (1) Studies lack scientific rigor (2) Interpretation of results of scientific studies e.g.
clinically meaningful?
which domains effected?
smallest level of exposure associated with impairment?
Stephens & Barker 1998
Landmark Occupational Neurobehavioural Papers
Stollery & Flindt 1988 Memory sequelae of solvent intoxication Stephens
et al.
1995 Neuropsychological effects of long-term exposure to organophosphates in sheep dip Lucchini
et al.
1995 Neurobehavioral effects of manganese in workers from a ferroalloy plant after temporary cessation of exposure Kishi
et al.
1994 Residual neurobehavioural effects associated with chronic exposure to mercury vapour Sjögren
et al.
1996 Effects on the nervous system among welders exposed to aluminium and manganese Gamberale 1985 Use of behavioral performance tests in the assessment of solvent toxicity
Landmark Occupational Neurobehavioural Papers
Rosenstock
et al.
1991 Chronic central nervous system effects of acute organophosphate pesticide intoxication. The Pesticide Health Effects Study Group Verberk
et al.
1990 Health effects of pesticides in the flower-bulb culture in Holland Mackay
et al.
1987 Behavioral changes during exposure to 1,1,1 trichloroethane: time-course and relationship to blood solvent levels.
Chia
et al.
1994 Impairment of color vision among workers exposed to low concentrations of styrene Echeverria
et al.
1995 A behavioral evaluation of PCE exposure in patients and dry cleaners: a possible relationship between clinical and preclinical effects
Neurobehavioural testing Welding & Parkinson’s Disease Is there evidence of a link?
Prof. Craig Jackson Head of Psychology BCU
“Careless” Neurobehavioural Testing and the Manganese Problem
Current Problem in USA Steel Welding Parkinson’s Disease Neurobehavioural Testing Systematic Review Conclusion
Litigation
October 1 st 2004
Larry Elam versus A.O. Smith Elam, former welder, aged 65 Developed PD Lifetime welder
Wins £1M from Welding Rod Manufacturers
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
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)
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.
Dopaminergic Pathways
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
Dopamine Pathways
Four major dopamine pathways; nigrostriatal pathway mesocortical volition and emotional responsiveness mesolimbic desire, Tuberoinfundibular initiative, and reward 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.
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? ? ?
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.
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
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.
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
New Treatments
Gene Therapy Neuroprotective Treatment Neural Transplants Nutrient Therapy Qigong
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
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)
Litigation
Current Problem in USA
March 25 th 2005
Fed Judge Kathleen O’Malley “Valid scientific evidence supports the conclusion that manganese exposure is connected to dangerous side effects.”
February 27 th 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 )
The Current Manganese 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?
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 o C 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
Welding Rods
Review of the Neurobehavioural Mn 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?
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
Systematic Review of the Literature
Limitations:
Human English Language 1970-2006
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
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 applying Quality Criteria, only 12 studies were of “Better Quality”
Expected Neurobehavioural Differences
poorer slower poorer poorer slower poorer poorer Cognition Motor Skills Memory Reaction Time Coordination Attention Visuospatial Reasoning better faster better better faster better better
Systematic Review of the Literature
Initial Search Results
153 articles
Exclusion Criteria Investigations of non-occupational exposure Investigations of multiple substances Animal studies Child studies Test development studies Single case studies of living patients Pathological reports of deceased individuals Investigations involving only neurophysiology Investigations involving only sensory outcome Studies of clinical / pharma intervention Review papers Meta-analyses of neurobehavioural studies
49 articles
42 symptoms alone – not NB 25 editorials 15 not occupational 14 technical / theoretical 5 multiple chemical exposures e.g. Pb Al 1 single-case follow up 1 intervention study 1 meta-analysis
37 journal articles 12 conference abstracts
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”
Systematic Review of the Literature
The 12 Better Quality Studies
Functional domains where differences were found
Systematic Review of the Literature
The 12 Better Quality Studies 1.
Showed mostly negative results (absence comparing exposed versus non-exposed workers of effects) when
2.
Few studies showed differences between exposed and non-exposed workers, all to the detriment of exposed workers, and concerned Eye-Hand Coordination and Tremor (e.g. motor tasks)
3.
Balance of evidence suggests no differences between exposed and non-exposed workers that can be measured by neurobehavioural tests
However . . .
Counter-Intuitive Neurobehavioural Findings
The 12 Better Quality Studies
Many studies measured Mn Bloods & Mn Urine Estimated cumulative exposures to Mn Six studies found workers with higher exposures performed significantly worse than workers with low or medium exposures All but one of these tests were motor-function: (Eye-Hand Coordination, Aiming, Finger tap, Tremor, Reaction time) Only one of these tests was cognitive: (Digit Symbol)
Counter-Intuitive Neurobehavioural Conclusions
1.
Neurobehavioural test literature does not provide convincing evidence of widespread or adverse effects of occupational manganese exposure upon neurobehavioural functions
2.
Lack of consistently demonstrable adverse effects among better quality studies suggests this conclusion in comparisons between exposed and non-exposed workers
3.
When better quality studies suggested effects in relation to higher doses and levels of exposures, such effects were consistently detected by motor functioning tests
4.
Such dose-related effects are counterintuitive in the absence of effects between exposed and non-exposed, and it is proposed that such “effects” can be attributed to poor methodological standards in many neurobehavioural investigations.
Locuria Manganica Indeed!
Perilous Neurobehavioural Interpretations
Very serious implications for litigants and defendants in USA Currently large numbers of plaintiffs filing cases in USA Share prices dropped globally e.g. BOC Major concern to US Dept of Defence / USA MRMC currently funding research Serious concern to International Manganese Institute Serious concern to International Institute of Welding
The Way Forward . . .
“Traditional” Computerised testing lacks context and obvious situational factors Simulators and simulation equipment may be the way forward for increased validity Video game generation (b. 1970 onwards) have raised the bar of human performance A return to the “Novelty value” of solid-state tests . . . .
Guitar Hero Wii Fitness Direct Interfaces