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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 PsychologyInstitute of
Occ Env Medicine University of Birmingham
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Brain Training
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Brain Training
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The Exposed Brain Structural Changes Functional
Changes Behavioural Changes Susceptibility to
other neurotoxins Possibly largest contributor
to Learning disability Attentional
Disorders Development Disabilities
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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
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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
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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 Sol
vents Pesticides Herbicides Insecticides
Contributors to the development of
neurobehavioral dysfunction
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Neurobehavioural Testing Standard tests
Evaluate different aspects of functioning of
the CNS including Cognition Motor
Skills Memory Reaction Time Coordination Attent
ion Visuospatial Reasoning General
Affect Non-invasive Portable Cheap Range
of behavioural functions affected is extremely
wide Investigators typically use sets
(batteries) of tests.
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Speed / Accuracy Trade-off
slow and accurate
Accuracy
optimum
fast but sloppy
Reaction Time (sec)
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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
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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
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Pencil and Paper Tests - Line Tracing
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Digit Span Subject presented with
numbers Subject must recall numbers Number
string gets longer each time Outcome Length
of longest correct recall
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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
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Benton Visual Retention Subject presented with
stimulus Subject must find target Outcome Ti
me taken to react Correct responses Errors
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Pattern Memory Test Subject presented with
stimulus Subject must decide which is target
after rotation Outcome Time taken to
react Correct responses Errors
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Continuous Performance Test Focused
attention Divided attention Sustained
attention Sustained Focused
attention Efficiency Accuracy / Speed
F F F F E F F F F F F E F F E F F F F F F F E
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
X X

X
X
X
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
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Colour Word Vigilance RED GREEN YELLOW
BLUE BLACK RED YELLOW BLUE GREEN Subj
ect presented with stimulus Subject must find
target word which matches colour Outcome Time
taken to react Correct responses Errors
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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
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Speed / Accuracy Trade-off
slow and accurate
Accuracy
optimum
fast but sloppy
Reaction Time (sec)
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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
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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
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Neurobehavioural Core Test Battery
(NCTB) 1983 WHO NIOSH Seven behavioural
tests Digit Span Santa Ana
Dexterity Digit Symbol Pursuit Aiming
II Benton Visual Retention Profile of Mood
States Simple Reaction Time
Johnson et al. 1987
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Minnesota Manual Dexterity Test
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Tower of Hanoi
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Finger Tapper
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Testing Must Be Cross-Cultural, Valid,
Reliable Higher proportion of Minorities Fo
reign born gt exposures to
neurotoxins Poor status
pathogens May not speak English May be
developmentally delayed Test batteries must be
suitable for people of all abilities backgrounds
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Testing Conditions All subjects tested under
same conditions Standardized testing Not always
possible in the field Furniture Lighting Vi
sual distraction Ambient sound Temperature
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Factors to be Aware of in Testing STABLE
FACTORS SITUATIONAL FACTORS Age Alcohol
(recent use) Education Caffeine (recent
use) Sex Nicotine (recent use) Socioeconomics
Medication (recent use) Language Paints,
glues, pesticides (recent) Handedness Near
visual acuity Computer experience Restricted
movement (injury) Caffeine (habitual use) Cold
/ flu Alcohol (habitual use) Stress Nicotine
(habitual use) Arousal / Fatigue Medication
(habitual use) Sleep Paint, glue, pesticide
(habitual use) Screen luminance Diabetes Time
of day Epilepsy Time of year Other CNS / PNS
disease Alcohol / drug addiction Head injury
(out gt1 hr) Physical activity
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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
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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
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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
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Neurobehavioural testing Welding Parkinsons
Disease Is there evidence of a link? Prof.
Craig Jackson Head of Psychology BCU
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Careless Neurobehavioural Testing and the
Manganese Problem Current Problem in USA Steel
Welding Parkinsons Disease Neurobehavioural
Testing Systematic Review Conclusion
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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
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Parkinsons Disease Neurological
Condition James Parkinson Cell atrophy in
substantia nigra Cardinal Symptoms Tremor
(initial symptom in 70 cases) Slowness Stiffnes
s of movement (bradykineasia) Postural
instability Usual onset in mid-late 50s ( 1 in
20 diagnosed lt40 years) Mostly male 1 case per
500 in UK
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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)
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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.
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Dopaminergic Pathways
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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
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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.
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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? ? ?
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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.
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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
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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.
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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
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New Treatments Gene Therapy Neuroprotective
Treatment Neural Transplants Nutrient
Therapy Qigong
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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
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Manganism James Couper 1837 Extreme
manifestation of PD Excessive manganese
poisoning Farmers Miners Steel
workers Battery manufacturing Symptoms Parki
nsonian Features Dystonia Gait (Cocks
walk) Locuria manganica (manganese madness)
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Litigation
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Current Problem in USA March 25th 2005 Fed
Judge Kathleen OMalley Valid scientific
evidence supports the conclusion that manganese
exposure is connected to dangerous side
effects. February 27th 2006 Fed Judge
Kathleen OMalley Ruled welding can cause
serious neurological damage to welders Out of
court settlement for 2 welders, made by welding
rod manufacturing company ( undisclosed )
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The Current Manganese Situation 1) Manganese
Overload Parkinsons Disease 2) Welding Work
High Manganese Exposure Therefore . .
. Neurobehavioural testing is used to identify
or screen workers with early symptoms of Parkins
ons disease Could this be a flawed assumption?
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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 gt4000
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
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Welding Rods
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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?
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Systematic Review of the Literature 16 Databases
Searched Medline Pubmed HSE Line CISDOC NIOSHTI
C NIOSHTIC2 PsychoInfo Excerpta
Medica Toxfile Embase SciSearch Biosis
Previews Web of Science Web of knowledge Science
Citation Index Social Science Citation Index
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Limitations Human English Language 1970-2006
Systematic Review of the Literature Search
Terms Cognition disorder Neurobehavioral /
Neurobehavioural (deficit / impairment) Neurologic
al Neuromotor Neuropsychiatric Neuropsychological
(test(ing)) Neurotoxicology Neurotoxic Manganese M
anganate Manganese alloy / dioxide / dust / ore /
oxide Steel Welding Welders
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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 gt 60) 6. High response
rate for the control group (usually gt 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
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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
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Systematic Review of the Literature Initial
Search Results
153 articles
42 symptoms alone not NB
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
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
49 articles
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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 gt 60) 6. High response
rate for the control group (usually gt 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
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Systematic Review of the Literature The 12
Better Quality Studies Functional domains where
differences were found
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Systematic Review of the Literature The 12
Better Quality Studies 1. Showed mostly negative
results (absence of effects) when comparing
exposed versus non-exposed workers 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 . . .
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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-H
and Coordination, Aiming, Finger tap, Tremor,
Reaction time) Only one of these tests was
cognitive (Digit Symbol)
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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.
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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
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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
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The Way Forward . . . Thanks for
Listening