Neurobehavioural performances associated with occupational hazards The poor state of

Neurobehavioural performances Neurobehavioural performances associated with associated with

occupational hazardsoccupational hazards

The poor state of The poor state of Neurobehavioural testingNeurobehavioural testing

Prof. Craig JacksonProf. Craig JacksonProfessor of Occupational Health PsychologyProfessor of Occupational Health Psychology

Birmingham City UniversityBirmingham City University

Hon Senior Lecturer in Occupational PsychologyHon Senior Lecturer in Occupational PsychologyInstitute of Occ & Env MedicineInstitute of Occ & Env Medicine

University of BirminghamUniversity of Birmingham

ResearchConsultants.co.ukResearchConsultants.co.uk

Principles of Neurobehavioural TestingPrinciples of Neurobehavioural Testing

Damage to CNS due to exposure toNeurotoxic substancesNeurotoxic medicinesMetabolic disorders

Neurotoxic diseases in top ten work-related diseases in USA

Occupational exposures to toxins such as LeadManganeseSolventsPesticidesHerbicidesInsecticides

Contributors to the development of neurobehavioral dysfunction

Neurobehavioural TestingNeurobehavioural Testing

Standard tests Standard tests

Evaluate different aspects of functioning of the CNS including Evaluate different aspects of functioning of the CNS including CognitionCognition Motor SkillsMotor Skills MemoryMemoryReaction TimeReaction Time CoordinationCoordination AttentionAttentionVisuospatialVisuospatial ReasoningReasoning General General AffectAffect

Non-invasive Non-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.

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:ageagesexsexeducationeducation nn

Numbers recalledNumbers recalled

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 nervous 1983 – WHO wanted battery to screen / identify nervous system effectssystem effects

Neurobehavioural Core Test Battery (NCTB)Neurobehavioural Core Test Battery (NCTB)

19831983

WHO & NIOSHWHO & NIOSH

Seven behavioural tests:Seven behavioural tests:

Digit SpanDigit SpanSanta Ana DexteritySanta Ana Dexterity

Digit SymbolDigit SymbolPursuit Aiming IIPursuit Aiming II

Benton Visual RetentionBenton Visual RetentionProfile of Mood StatesProfile of Mood States

Simple Reaction TimeSimple Reaction Time

Johnson Johnson et al. et al. 1987 1987

Minnesota Manual Dexterity TestMinnesota Manual Dexterity Test

Tower of HanoiTower of Hanoi

Finger TapperFinger Tapper

Testing Must Be Cross-Cultural, Valid, & ReliableTesting Must Be Cross-Cultural, Valid, & Reliable

Higher proportion of:Higher proportion of:MinoritiesMinoritiesForeign born Foreign born > exposures to neurotoxins > exposures to neurotoxinsPoor 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

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

Factors to be Aware of in TestingFactors to be Aware of in Testing

STABLE FACTORSSTABLE FACTORS SITUATIONAL FACTORSSITUATIONAL FACTORSAgeAge 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 acuityComputer experienceComputer experience Restricted movement (injury)Restricted movement (injury)Caffeine (habitual use)Caffeine (habitual use) Cold / fluCold / fluAlcohol (habitual use)Alcohol (habitual use) StressStressNicotine (habitual use)Nicotine (habitual use) Arousal / FatigueArousal / FatigueMedication (habitual use)Medication (habitual use) SleepSleepPaint, glue, pesticide (habitual use)Paint, glue, pesticide (habitual use) Screen luminanceScreen luminanceDiabetesDiabetes Time of dayTime of dayEpilepsyEpilepsy Time of yearTime of yearOther CNS / PNS diseaseOther CNS / PNS disease Alcohol / drug addictionAlcohol / drug addictionHead injury (out >1 hr)Head injury (out >1 hr)Physical activityPhysical activity

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 regulators Difficulties 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 studiese.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

Landmark Occupational Neurobehavioural PapersLandmark Occupational Neurobehavioural Papers

Stollery & Flindt 1988 Memory sequelae of solvent intoxicationStollery & Flindt 1988 Memory sequelae of solvent intoxication

Stephens Stephens et al.et al. 1995 Neuropsychological effects of long-term 1995 Neuropsychological effects of long-term exposure to organophosphates in sheep dipexposure to organophosphates in sheep dip

Lucchini Lucchini et al.et al. 1995 Neurobehavioral effects of manganese in 1995 Neurobehavioral effects of manganese in workers from a ferroalloy plant after temporary cessation of workers from a ferroalloy plant after temporary cessation of exposureexposure

Kishi Kishi et al.et al. 1994 Residual neurobehavioural effects associated with 1994 Residual neurobehavioural effects associated with chronic exposure to mercury vapourchronic exposure to mercury vapour

Sjögren Sjögren et al.et al. 1996 Effects on the nervous system among welders 1996 Effects on the nervous system among welders exposed to aluminium and manganeseexposed to aluminium and manganese

Gamberale 1985 Use of behavioral performance tests in the Gamberale 1985 Use of behavioral performance tests in the assessment of solvent toxicityassessment of solvent toxicity

Landmark Occupational Neurobehavioural PapersLandmark Occupational Neurobehavioural Papers

Rosenstock Rosenstock et al.et al. 1991 Chronic central nervous system effects of 1991 Chronic central nervous system effects of acute organophosphate pesticide intoxication. The Pesticide Health acute organophosphate pesticide intoxication. The Pesticide Health Effects Study GroupEffects Study Group

Verberk Verberk et al.et al. 1990 Health effects of pesticides in the flower-bulb 1990 Health effects of pesticides in the flower-bulb culture in Hollandculture in Holland

Mackay Mackay 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. 

Chia Chia et al.et al. 1994 Impairment of color vision among workers exposed 1994 Impairment of color vision among workers exposed to low concentrations of styreneto low concentrations of styrene

Echeverria Echeverria et al.et al. 1995 A behavioral evaluation of PCE exposure in 1995 A behavioral evaluation of PCE exposure in patients and dry cleaners: a possible relationship between clinical patients and dry cleaners: a possible relationship between clinical and preclinical effectsand preclinical effects

““Careless” Neurobehavioural Testing and Careless” 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

Litigation Litigation

October 1October 1stst 2004 2004

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 Rod Wins £1M from Welding Rod ManufacturersManufacturers

LitigationLitigation

Current Problem in USA Current Problem in USA

March 25March 25thth 2005 2005

Fed Judge Kathleen O’Malley Fed Judge Kathleen O’Malley ““Valid scientific evidence supports the conclusion that Valid scientific evidence supports the conclusion that manganese exposure is connected to dangerous side manganese exposure is connected to dangerous side effects.”effects.”

February 27February 27thth 2006 2006

Fed Judge Kathleen O’Malley Fed Judge Kathleen O’Malley Ruled welding can cause serious neurological damage Ruled welding can cause serious neurological damage to weldersto welders

Out of court settlement for 2 welders, made by welding Out of court settlement for 2 welders, made by welding rod manufacturing company ($ undisclosed )rod manufacturing company ($ undisclosed )

The Current Manganese Situation The 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 testing Neurobehavioural testing is usedis used

to identify or screen workers to identify or screen workers with with

early symptomsearly symptomsofof

Parkinson’s disease”Parkinson’s disease”

Could this be a flawed assumption?Could this be a flawed assumption?

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 a Metal pieces to be joined and a filler metal (rod) coming from a consumable consumable

Heat produced as electricity passes from one conductor to anotherHeat produced as electricity passes from one conductor to another

Temperatures >4000 Temperatures >4000 ooC 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

Welding RodsWelding Rods

Review of the Neurobehavioural Mn LiteratureReview of the Neurobehavioural Mn Literature

Three ObjectivesThree Objectives

1)1)Is there any evidence of occupational manganese exposure Is there any evidence of occupational manganese exposure impairing neurobehavioural performance?impairing neurobehavioural performance?

2)2)Which tests (domains) are best at demonstrating such impaired Which tests (domains) are best at demonstrating such impaired performance?performance?

3)3)What is the smallest level of Mn exposure associated with test What is the smallest level of Mn exposure associated with test impairment?impairment?

Systematic Review of the LiteratureSystematic Review of the Literature

16 Databases Searched16 Databases Searched

Medline & PubmedMedline & PubmedHSE LineHSE LineCISDOCCISDOCNIOSHTIC & NIOSHTIC2NIOSHTIC & NIOSHTIC2PsychoInfoPsychoInfoExcerpta MedicaExcerpta MedicaToxfileToxfileEmbaseEmbaseSciSearchSciSearchBiosis PreviewsBiosis PreviewsWeb of ScienceWeb of ScienceWeb of knowledgeWeb of knowledgeScience Citation IndexScience Citation IndexSocial Science Citation IndexSocial Science Citation Index

Systematic Review of the LiteratureSystematic Review of the Literature

Search TermsSearch Terms

Cognition disorderCognition disorderNeurobehavioral / Neurobehavioural (deficit / impairment)Neurobehavioral / Neurobehavioural (deficit / impairment)NeurologicalNeurologicalNeuromotorNeuromotorNeuropsychiatricNeuropsychiatricNeuropsychological (test(ing))Neuropsychological (test(ing))NeurotoxicologyNeurotoxicologyNeurotoxicNeurotoxicManganeseManganeseManganateManganateManganese alloy / dioxide / dust / ore / oxideManganese alloy / dioxide / dust / ore / oxideSteelSteelWeldingWeldingWeldersWelders

Limitations:Limitations:HumanHuman

English LanguageEnglish Language1970-20061970-2006

Systematic Review of the LiteratureSystematic Review of the Literature

The Better Quality StudiesThe Better Quality StudiesEU 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 used relative to the number of tests used

2. Subject selection method which 2. Subject selection method which avoids bias for the exposedavoids bias for the exposed group group

3. Subject selection method which 3. Subject selection method which avoids bias for the controlavoids bias for the control group group

4. Pre-stated 4. Pre-stated exclusion/inclusion criteriaexclusion/inclusion criteria for study participants for study participants

5. 5. High response rateHigh response rate for the exposed group (usually for the exposed group (usually >> 60%) 60%)

6. 6. High response rateHigh response rate for the control group (usually for the control group (usually >> 60%) where applicable 60%) 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-quantitative 8. 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 the 10. An indication of the standardization of testingstandardization of testing conditions conditions

After applying Quality Criteria, only 12 studies were of “Better Quality”After applying Quality Criteria, only 12 studies were of “Better Quality”

Expected Neurobehavioural DifferencesExpected Neurobehavioural Differences

CognitionCognition

Motor SkillsMotor Skills

MemoryMemory

Reaction TimeReaction Time

CoordinationCoordination

AttentionAttention

VisuospatialVisuospatial

ReasoningReasoning

exposed

exposed

slowerslower

poorerpoorerslowerslowerpoorerpoorer

fasterfaster

betterbetterfasterfasterbetterbetter

poorerpoorer

poorerpoorer betterbetter

betterbetter

poorerpoorer betterbetter

controls

controls

Systematic Review of the LiteratureSystematic Review of the Literature

Initial Search ResultsInitial Search Results153 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 CriteriaInvestigations of non-occupational exposure Investigations of non-occupational exposure Investigations of multiple substancesInvestigations of multiple substancesAnimal studies Animal studies Child studiesChild studiesTest development studies Test development studies Single case studies of living patientsSingle case studies of living patientsPathological reports of deceased individualsPathological reports of deceased individualsInvestigations involving only neurophysiologyInvestigations involving only neurophysiologyInvestigations involving only sensory outcomeInvestigations involving only sensory outcomeStudies of clinical / pharma interventionStudies of clinical / pharma interventionReview papersReview papersMeta-analyses of neurobehavioural studiesMeta-analyses of neurobehavioural studies

37 journal articles 37 journal articles 12 conference abstracts12 conference abstracts

Systematic Review of the LiteratureSystematic Review of the Literature

The Better Quality StudiesThe Better Quality StudiesEU 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 (usually 5. High response rate for the exposed group (usually >> 60%) 60%) 6. High response rate for the control group (usually 6. High response rate for the control group (usually >> 60%) where applicable 60%) 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”

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

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) when Showed 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-exposed Few studies showed differences between exposed and non-exposed workers, all to the detriment of exposed workers, and concerned workers, 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 and Balance of evidence suggests no differences between exposed and non-exposed workers that can be measured by neurobehavioural non-exposed workers that can be measured by neurobehavioural teststests

However . . .However . . .

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 UrineEstimated cumulative exposures to MnEstimated cumulative exposures to Mn

Six studies found workers with higher exposures performed Six 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)

Counter-Intuitive NeurobehaviouralCounter-Intuitive Neurobehavioural ConclusionsConclusions

1.1. Neurobehavioural test literature does not provide convincing Neurobehavioural test literature does not provide convincing evidence of widespread or adverse effects of occupational evidence 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 better Lack of consistently demonstrable adverse effects among better quality studies suggests this conclusion in comparisons between quality 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 higher When better quality studies suggested effects in relation to higher doses and levels of exposures, such effects were consistently doses and levels of exposures, such effects were consistently detected by detected by motor functioning testsmotor functioning tests

4.4. Such dose-related effects are counterintuitive in the absence of Such dose-related effects are counterintuitive in the absence of effects between exposed and non-exposed, and it is proposed that effects between exposed and non-exposed, and it is proposed that such “effects” can be attributed to poor methodological standards in such “effects” can be attributed to poor methodological standards in many neurobehavioural investigations.many neurobehavioural investigations.

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 MRMC Major 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

The Way Forward . . .The Way Forward . . .

““Traditional” Computerised testing lacks context and obvious Traditional” Computerised testing lacks context and obvious situational factorssituational factors

Simulators and simulation equipment may be the way forward Simulators and simulation equipment may be the way forward for increased validityfor increased validity

Video game generation (b. 1970 onwards) have raised the bar of Video 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” ofsolid-state tests . . . .solid-state tests . . . .

Guitar HeroGuitar HeroWii FitnessWii FitnessDirect InterfacesDirect Interfaces

The Way Forward . . .The Way Forward . . .