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Neurobehavioural Testing

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  • 1. Neurobehavioural performancesNeurobehavioural performances associated withassociated with occupational hazardsoccupational hazards The poor state ofThe poor state of Neurobehavioural testingNeurobehavioural testing Dr. Craig JacksonDr. Craig Jackson Professor of Occupational Health PsychologyProfessor of Occupational Health Psychology Birmingham City UniversityBirmingham City University Hon Senior Lecturer in Occupational PsychologyHon Senior Lecturer in Occupational Psychology Institute of Occ & Env MedicineInstitute of Occ & Env Medicine University of BirminghamUniversity of Birmingham ResearchConsultants.co.ukResearchConsultants.co.uk
  • 2. Brain TrainingBrain Training
  • 3. The Exposed BrainThe Exposed Brain Structural ChangesStructural Changes Functional ChangesFunctional Changes Behavioural ChangesBehavioural Changes Susceptibility to other neurotoxinsSusceptibility to other neurotoxins Possibly largest contributor to:Possibly largest contributor to: Learning disabilityLearning disability Attentional DisordersAttentional Disorders Development DisabilitiesDevelopment Disabilities
  • 4. Head InjuriesHead Injuries Severity depends on amount of Primary and Secondary brain injurySeverity depends on amount of Primary and Secondary brain injury Main cause of Secondary injury = hypoxiaMain cause of Secondary injury = hypoxia Categories: Open or ClosedCategories: Open or Closed Forces: Shearing and CompressionForces: Shearing and Compression
  • 5. Multiple Toxic SubstancesMultiple Toxic Substances Industrial ChemicalsIndustrial Chemicals PesticidesPesticides Therapeutic DrugsTherapeutic Drugs Drugs of AbuseDrugs of Abuse Food AdditivesFood Additives Brain is highly vulnerable to toxic effectsBrain is highly vulnerable to toxic effects In uteroIn utero Post-natalPost-natal IngestionIngestion InhalationInhalation AbsorptionAbsorption Multiple toxic exposures:Multiple toxic exposures: Alter cell migration, synaptic connections, cell deathAlter cell migration, synaptic connections, cell death
  • 6. Principles of Neurobehavioural TestingPrinciples 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
  • 7. Neurobehavioural TestingNeurobehavioural Testing Standard testsStandard tests Evaluate different aspects of functioning of the CNS includingEvaluate different aspects of functioning of the CNS including CognitionCognition Motor SkillsMotor Skills MemoryMemory Reaction TimeReaction Time CoordinationCoordination AttentionAttention VisuospatialVisuospatial ReasoningReasoning GeneralGeneral AffectAffect Non-invasiveNon-invasive PortablePortable CheapCheap Range of behavioural functions affected is extremely wideRange of behavioural functions affected is extremely wide Investigators typically use sets (batteries) of tests.Investigators typically use sets (batteries) of tests.
  • 8. Speed / Accuracy Trade-off fast but sloppyfast but sloppy optimumoptimum slow and accurateslow and accurate Reaction Time (sec)Reaction Time (sec) AccuracyAccuracy
  • 9. Rationale of Neurobehavioural TestingRationale of Neurobehavioural Testing Evaluate functioning in individuals exposed to pathogensEvaluate functioning in individuals exposed to pathogens Normal population exhibits a range of performance functionNormal population exhibits a range of performance function Exposure places individuals outside of that normal rangeExposure places individuals outside of that normal range Some factors affect performance:Some factors affect performance: ageage sexsex educationeducation nn Numbers recalledNumbers recalled
  • 10. HistoryHistory Behavioural testing began in 1960sBehavioural testing began in 1960s Hanninen (1979) developed first behavioural test batteryHanninen (1979) developed first behavioural test battery Assess effects of chemicals and neurotoxinsAssess effects of chemicals and neurotoxins 1980 - 60 unique tests1980 - 60 unique tests 1990 - 250 unique tests1990 - 250 unique tests 1983 – WHO wanted battery to screen / identify nervous1983 – WHO wanted battery to screen / identify nervous system effectssystem effects
  • 11. Neurobehavioural Core Test Battery (NCTB)Neurobehavioural Core Test Battery (NCTB) 19831983 WHO & NIOSHWHO & NIOSH Seven behavioural tests:Seven behavioural tests: Digit SpanDigit Span Santa Ana DexteritySanta Ana Dexterity Digit SymbolDigit Symbol Pursuit Aiming IIPursuit Aiming II Benton Visual RetentionBenton Visual Retention Profile of Mood StatesProfile of Mood States Simple Reaction TimeSimple Reaction Time JohnsonJohnson et al.et al. 19871987
  • 12. Minnesota Manual Dexterity TestMinnesota Manual Dexterity Test
  • 13. Tower of HanoiTower of Hanoi
  • 14. Finger TapperFinger Tapper
  • 15. Testing Must Be Cross-Cultural, Valid, & ReliableTesting Must Be Cross-Cultural, Valid, & Reliable Higher proportion of:Higher proportion of: MinoritiesMinorities Foreign bornForeign born > exposures to neurotoxins> exposures to neurotoxins Poor statusPoor status & pathogens& pathogens May not speak EnglishMay not speak English May be “developmentally delayed”May be “developmentally delayed” Test batteries must be suitable for people of all abilities &Test batteries must be suitable for people of all abilities & backgroundsbackgrounds
  • 16. Testing ConditionsTesting Conditions All subjects tested under same conditionsAll subjects tested under same conditions Standardized testingStandardized testing Not always possible in the fieldNot always possible in the field FurnitureFurniture LightingLighting Visual distractionVisual distraction Ambient soundAmbient sound TemperatureTemperature
  • 17. Factors to be Aware of in TestingFactors to be Aware of in Testing STABLE FACTORSSTABLE FACTORS SITUATIONAL FACTORSSITUATIONAL FACTORS AgeAge Alcohol (recent use)Alcohol (recent use) EducationEducation Caffeine (recent use)Caffeine (recent use) SexSex Nicotine (recent use)Nicotine (recent use) SocioeconomicsSocioeconomics Medication (recent use)Medication (recent use) LanguageLanguage Paints, glues, pesticides (recent)Paints, glues, pesticides (recent) HandednessHandedness Near visual acuityNear visual acuity Computer experienceComputer experience Restricted movement (injury)Restricted movement (injury) Caffeine (habitual use)Caffeine (habitual use) Cold / fluCold / flu Alcohol (habitual use)Alcohol (habitual use) StressStress Nicotine (habitual use)Nicotine (habitual use) Arousal / FatigueArousal / Fatigue Medication (habitual use)Medication (habitual use) SleepSleep Paint, glue, pesticide (habitual use)Paint, glue, pesticide (habitual use) Screen luminanceScreen luminance DiabetesDiabetes Time of dayTime of day EpilepsyEpilepsy Time of yearTime of year Other CNS / PNS diseaseOther CNS / PNS disease Alcohol / drug addictionAlcohol / drug addiction Head injury (out >1 hr)Head injury (out >1 hr) Physical activityPhysical activity
  • 18. Problems of Neurobehavioural TestingProblems of Neurobehavioural Testing Used since the 1960s in occ and env health toxicologyUsed since the 1960s in occ and env health toxicology Interpretation of different test scores is not straightforwardInterpretation of different test scores is not straightforward Less straightforward role in the regulation of chemicalsLess straightforward role in the regulation of chemicals Difficulties neurobehavioural studies encountered by regulatorsDifficulties neurobehavioural studies encountered by regulators (1) Studies lack scientific rigor(1) Studies lack scientific rigor (2) Interpretation of results of scientific studies(2) Interpretation of results of scientific studies e.g.e.g. clinically meaningful?clinically meaningful? which domains effected?which domains effected? smallest level of exposure associated with impairment?smallest level of exposure associated with impairment? Stephens & Barker 1998Stephens & Barker 1998
  • 19. Landmark Occupational Neurobehavioural PapersLandmark Occupational Neurobehavioural Papers Stollery & Flindt 1988 Memory sequelae of solvent intoxicationStollery & Flindt 1988 Memory sequelae of solvent intoxication StephensStephens et al.et al. 1995 Neuropsychological effects of long-term1995 Neuropsychological effects of long-term exposure to organophosphates in sheep dipexposure to organophosphates in sheep dip LucchiniLucchini et al.et al. 1995 Neurobehavioral effects of manganese in1995 Neurobehavioral effects of manganese in workers from a ferroalloy plant after temporary cessation ofworkers from a ferroalloy plant after temporary cessation of exposureexposure KishiKishi et al.et al. 1994 Residual neurobehavioural effects associated with1994 Residual neurobehavioural effects associated with chronic exposure to mercury vapourchronic exposure to mercury vapour SjögrenSjögren et al.et al. 1996 Effects on the nervous system among welders1996 Effects on the nervous system among welders exposed to aluminium and manganeseexposed to aluminium and manganese Gamberale 1985 Use of behavioral performance tests in theGamberale 1985 Use of behavioral performance tests in the assessment of solvent toxicityassessment of solvent toxicity
  • 20. Landmark Occupational Neurobehavioural PapersLandmark Occupational Neurobehavioural Papers RosenstockRosenstock et al.et al. 1991 Chronic central nervous system effects of1991 Chronic central nervous system effects of acute organophosphate pesticide intoxication. The Pesticide Healthacute organophosphate pesticide intoxication. The Pesticide Health Effects Study GroupEffects Study Group VerberkVerberk et al.et al. 1990 Health effects of pesticides in the flower-bulb1990 Health effects of pesticides in the flower-bulb culture in Hollandculture in Holland MackayMackay et al.et al. 1987 Behavioral changes during exposure to 1,1,1-1987 Behavioral changes during exposure to 1,1,1- trichloroethane: time-course and relationship to blood solvent levels.trichloroethane: time-course and relationship to blood solvent levels. ChiaChia et al.et al. 1994 Impairment of color vision among workers exposed1994 Impairment of color vision among workers exposed to low concentrations of styreneto low concentrations of styrene EcheverriaEcheverria et al.et al. 1995 A behavioral evaluation of PCE exposure in1995 A behavioral evaluation of PCE exposure in patients and dry cleaners: a possible relationship between clinicalpatients and dry cleaners: a possible relationship between clinical and preclinical effectsand preclinical effects
  • 21. ““Careless” Neurobehavioural Testing andCareless” Neurobehavioural Testing and the Manganese Problemthe Manganese Problem Current Problem in USACurrent Problem in USA Steel WeldingSteel Welding Parkinson’s DiseaseParkinson’s Disease Neurobehavioural TestingNeurobehavioural Testing Systematic ReviewSystematic Review ConclusionConclusion
  • 22. LitigationLitigation October 1October 1stst 20042004 Larry Elam versus A.O. SmithLarry Elam versus A.O. Smith Elam, former welder, aged 65Elam, former welder, aged 65 Developed PDDeveloped PD Lifetime welderLifetime welder Wins £1M from Welding RodWins £1M from Welding Rod ManufacturersManufacturers
  • 23. LitigationLitigation
  • 24. Current Problem in USACurrent Problem in USA March 25March 25thth 20052005 Fed Judge Kathleen O’MalleyFed Judge Kathleen O’Malley ““Valid scientific evidence supports the conclusion thatValid scientific evidence supports the conclusion that manganese exposure is connected to dangerous sidemanganese exposure is connected to dangerous side effects.”effects.” February 27February 27thth 20062006 Fed Judge Kathleen O’MalleyFed Judge Kathleen O’Malley Ruled welding can cause serious neurological damageRuled welding can cause serious neurological damage to weldersto welders Out of court settlement for 2 welders, made by weldingOut of court settlement for 2 welders, made by welding rod manufacturing company ($ undisclosed )rod manufacturing company ($ undisclosed )
  • 25. The Current Manganese SituationThe Current Manganese Situation 1) Manganese Overload = Parkinson’s Disease1) Manganese Overload = Parkinson’s Disease 2) Welding Work = High Manganese Exposure2) Welding Work = High Manganese Exposure Therefore . . .Therefore . . . ““Neurobehavioural testingNeurobehavioural testing is usedis used to identify or screen workersto identify or screen workers withwith early symptomsearly symptoms ofof Parkinson’s disease”Parkinson’s disease” Could this be a flawed assumption?Could this be a flawed assumption?
  • 26. Welding of SteelWelding of Steel Joins pieces of metal that have been made liquid by heatJoins pieces of metal that have been made liquid by heat Metal pieces to be joined and a filler metal (rod) coming from aMetal pieces to be joined and a filler metal (rod) coming from a consumableconsumable Heat produced as electricity passes from one conductor to anotherHeat produced as electricity passes from one conductor to another Temperatures >4000Temperatures >4000 oo C in the arcC in the arc At least 80 different types of welding processesAt least 80 different types of welding processes 365,000 welders in USA365,000 welders in USA 1,000,000 full time welders globally1,000,000 full time welders globally 5,000,000 paid welders globally5,000,000 paid welders globally
  • 27. Welding RodsWelding Rods
  • 28. Review of the Neurobehavioural Mn LiteratureReview of the Neurobehavioural Mn Literature Three ObjectivesThree Objectives 1)1) Is there any evidence of occupational manganese exposureIs there any evidence of occupational manganese exposure impairing neurobehavioural performance?impairing neurobehavioural performance? 2)2) Which tests (domains) are best at demonstrating such impairedWhich tests (domains) are best at demonstrating such impaired performance?performance? 3)3) What is the smallest level of Mn exposure associated with testWhat is the smallest level of Mn exposure associated with test impairment?impairment?
  • 29. Systematic Review of the LiteratureSystematic Review of the Literature 16 Databases Searched16 Databases Searched Medline & PubmedMedline & Pubmed HSE LineHSE Line CISDOCCISDOC NIOSHTIC & NIOSHTIC2NIOSHTIC & NIOSHTIC2 PsychoInfoPsychoInfo Excerpta MedicaExcerpta Medica ToxfileToxfile EmbaseEmbase SciSearchSciSearch Biosis PreviewsBiosis Previews Web of ScienceWeb of Science Web of knowledgeWeb of knowledge Science Citation IndexScience Citation Index Social Science Citation IndexSocial Science Citation Index
  • 30. Systematic Review of the LiteratureSystematic Review of the Literature Search TermsSearch Terms Cognition disorderCognition disorder Neurobehavioral / Neurobehavioural (deficit / impairment)Neurobehavioral / Neurobehavioural (deficit / impairment) NeurologicalNeurological NeuromotorNeuromotor NeuropsychiatricNeuropsychiatric Neuropsychological (test(ing))Neuropsychological (test(ing)) NeurotoxicologyNeurotoxicology NeurotoxicNeurotoxic ManganeseManganese ManganateManganate Manganese alloy / dioxide / dust / ore / oxideManganese alloy / dioxide / dust / ore / oxide SteelSteel WeldingWelding WeldersWelders Limitations:Limitations: HumanHuman English LanguageEnglish Language 1970-20061970-2006
  • 31. Systematic Review of the LiteratureSystematic Review of the Literature The Better Quality StudiesThe Better Quality Studies EU Guidelines for qualitative evaluation of neurobehavioural studies (1997)EU Guidelines for qualitative evaluation of neurobehavioural studies (1997) 1.1. Population of an adequate sizePopulation of an adequate size relative to the number of tests usedrelative to the number of tests used 2. Subject selection method which2. Subject selection method which avoids bias for the exposedavoids bias for the exposed groupgroup 3. Subject selection method which3. Subject selection method which avoids bias for the controlavoids bias for the control groupgroup 4. Pre-stated4. Pre-stated exclusion/inclusion criteriaexclusion/inclusion criteria for study participantsfor study participants 5.5. High response rateHigh response rate for the exposed group (usuallyfor the exposed group (usually >> 60%)60%) 6.6. High response rateHigh response rate for the control group (usuallyfor the control group (usually >> 60%) where applicable60%) where applicable 7.7. Control or adjustment for important confoundersControl or adjustment for important confounders / modifiers of performance/ modifiers of performance 8. Inclusion of quantitative or semi-quantitative8. Inclusion of quantitative or semi-quantitative assessment of long-term exposureassessment of long-term exposure 9.9. Control for recent exposureControl for recent exposure (where applicable)(where applicable) 10. An indication of the10. An indication of the standardization of testingstandardization of testing conditionsconditions After applying Quality Criteria, only 12 studies were of “Better Quality”After applying Quality Criteria, only 12 studies were of “Better Quality”
  • 32. Expected Neurobehavioural DifferencesExpected Neurobehavioural Differences CognitionCognition Motor SkillsMotor Skills MemoryMemory Reaction TimeReaction Time CoordinationCoordination AttentionAttention VisuospatialVisuospatial ReasoningReasoning exposed exposed slowerslower poorerpoorer slowerslower poorerpoorer fasterfaster betterbetter fasterfaster betterbetter poorerpoorer poorerpoorer betterbetter betterbetter poorerpoorer betterbetter controls controls
  • 33. Systematic Review of the LiteratureSystematic Review of the Literature Initial Search ResultsInitial Search Results 153 articles153 articles 42 symptoms alone – not NB42 symptoms alone – not NB 25 editorials25 editorials 15 not occupational15 not occupational 14 technical / theoretical14 technical / theoretical 5 multiple chemical exposures e.g. Pb Al5 multiple chemical exposures e.g. Pb Al 1 single-case follow up1 single-case follow up 1 intervention study1 intervention study 1 meta-analysis1 meta-analysis 49 articles49 articles Exclusion CriteriaExclusion Criteria Investigations of non-occupational exposureInvestigations of non-occupational exposure Investigations of multiple substancesInvestigations of multiple substances Animal studiesAnimal studies Child studiesChild studies Test development studiesTest development studies Single case studies of living patientsSingle case studies of living patients Pathological reports of deceased individualsPathological reports of deceased individuals Investigations involving only neurophysiologyInvestigations involving only neurophysiology Investigations involving only sensory outcomeInvestigations involving only sensory outcome Studies of clinical / pharma interventionStudies of clinical / pharma intervention Review papersReview papers Meta-analyses of neurobehavioural studiesMeta-analyses of neurobehavioural studies 37 journal articles37 journal articles 12 conference abstracts12 conference abstracts
  • 34. Systematic Review of the LiteratureSystematic Review of the Literature The Better Quality StudiesThe Better Quality Studies EU Guidelines for qualitative evaluation of neurobehavioural studies (1997)EU Guidelines for qualitative evaluation of neurobehavioural studies (1997) 1. Population of an adequate size relative to the number of tests used1. Population of an adequate size relative to the number of tests used 2. Subject selection method which avoids bias for the exposed group2. Subject selection method which avoids bias for the exposed group 3. Subject selection method which avoids bias for the control group3. Subject selection method which avoids bias for the control group 4. Pre-stated exclusion/inclusion criteria for study participants4. Pre-stated exclusion/inclusion criteria for study participants 5. High response rate for the exposed group (usually5. High response rate for the exposed group (usually >> 60%)60%) 6. High response rate for the control group (usually6. High response rate for the control group (usually >> 60%) where applicable60%) where applicable 7. Control or adjustment for important confounders / modifiers of performance7. Control or adjustment for important confounders / modifiers of performance 8. Inclusion of quantitative or semi-quantitative assessment of long-term exposure8. Inclusion of quantitative or semi-quantitative assessment of long-term exposure 9. Control for recent exposure (where applicable)9. Control for recent exposure (where applicable) 10. An indication of the standardization of testing conditions10. An indication of the standardization of testing conditions After application of Quality Criteria, only 12 studies were of “Better Quality”After application of Quality Criteria, only 12 studies were of “Better Quality”
  • 35. Systematic Review of the LiteratureSystematic Review of the Literature The 12 Better Quality StudiesThe 12 Better Quality Studies Functional domains where differences were foundFunctional domains where differences were found
  • 36. Systematic Review of the LiteratureSystematic Review of the Literature The 12 Better Quality StudiesThe 12 Better Quality Studies 1.1. Showed mostly negative results (absence of effects) whenShowed mostly negative results (absence of effects) when comparing exposed versus non-exposed workerscomparing exposed versus non-exposed workers 2.2. Few studies showed differences between exposed and non-exposedFew studies showed differences between exposed and non-exposed workers, all to the detriment of exposed workers, and concernedworkers, all to the detriment of exposed workers, and concerned Eye-Hand Coordination and Tremor (e.g. motor tasks)Eye-Hand Coordination and Tremor (e.g. motor tasks) 3.3. Balance of evidence suggests no differences between exposed andBalance of evidence suggests no differences between exposed and non-exposed workers that can be measured by neurobehaviouralnon-exposed workers that can be measured by neurobehavioural teststests However . . .However . . .
  • 37. Counter-Intuitive Neurobehavioural FindingsCounter-Intuitive Neurobehavioural Findings The 12 Better Quality StudiesThe 12 Better Quality Studies Many studies measured Mn Bloods & Mn UrineMany studies measured Mn Bloods & Mn Urine Estimated cumulative exposures to MnEstimated cumulative exposures to Mn Six studies found workers with higher exposures performedSix studies found workers with higher exposures performed significantly worse than workers with low or medium exposuressignificantly worse than workers with low or medium exposures All but one of these tests were motor-function:All but one of these tests were motor-function: (Eye-Hand Coordination, Aiming, Finger tap, Tremor, Reaction time)(Eye-Hand Coordination, Aiming, Finger tap, Tremor, Reaction time) Only one of these tests was cognitive:Only one of these tests was cognitive: (Digit Symbol)(Digit Symbol)
  • 38. Counter-Intuitive NeurobehaviouralCounter-Intuitive Neurobehavioural ConclusionsConclusions 1.1. Neurobehavioural test literature does not provide convincingNeurobehavioural test literature does not provide convincing evidence of widespread or adverse effects of occupationalevidence of widespread or adverse effects of occupational manganese exposure upon neurobehavioural functionsmanganese exposure upon neurobehavioural functions 2.2. Lack of consistently demonstrable adverse effects among betterLack of consistently demonstrable adverse effects among better quality studies suggests this conclusion in comparisons betweenquality studies suggests this conclusion in comparisons between exposed and non-exposed workersexposed and non-exposed workers 3.3. When better quality studies suggested effects in relation to higherWhen better quality studies suggested effects in relation to higher doses and levels of exposures, such effects were consistentlydoses and levels of exposures, such effects were consistently detected bydetected by motor functioning testsmotor functioning tests 4.4. Such dose-related effects are counterintuitive in the absence ofSuch dose-related effects are counterintuitive in the absence of effects between exposed and non-exposed, and it is proposed thateffects between exposed and non-exposed, and it is proposed that such “effects” can be attributed to poor methodological standards insuch “effects” can be attributed to poor methodological standards in many neurobehavioural investigations.many neurobehavioural investigations.
  • 39. Locuria Manganica Indeed!Locuria Manganica Indeed! Perilous Neurobehavioural InterpretationsPerilous Neurobehavioural Interpretations Very serious implications for litigants and defendants in USAVery serious implications for litigants and defendants in USA Currently large numbers of plaintiffs filing cases in USACurrently large numbers of plaintiffs filing cases in USA Share prices dropped globally e.g. BOCShare prices dropped globally e.g. BOC Major concern to US Dept of Defence / USA MRMCMajor concern to US Dept of Defence / USA MRMC currently funding researchcurrently funding research Serious concern to International Manganese InstituteSerious concern to International Manganese Institute Serious concern to International Institute of WeldingSerious concern to International Institute of Welding
  • 40. The Way Forward . . .The Way Forward . . . ““Traditional” Computerised testing lacks context and obviousTraditional” Computerised testing lacks context and obvious situational factorssituational factors Simulators and simulation equipment may be the way forwardSimulators and simulation equipment may be the way forward for increased validityfor increased validity Video game generation (b. 1970 onwards) have raised the bar ofVideo game generation (b. 1970 onwards) have raised the bar of human performancehuman performance A return to the “Novelty value” ofA return to the “Novelty value” of solid-state tests . . . .solid-state tests . . . . Guitar HeroGuitar Hero Wii FitnessWii Fitness Direct InterfacesDirect Interfaces
  • 41. The Way Forward . . .The Way Forward . . . Thanks for ListeningThanks for Listening

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